Deciphering the Chameleonic Chemistry of Allenols: Breaking the Taboo of a Onetime Esoteric Functionality

The allene functionality has participated in one of the most exciting voyages in organic chemistry, from chemical curiosities to a recurring building block in modern organic chemistry. In the last decades, a special kind of allene, namely, allenol, has emerged. Allenols, formed by an allene moiety and a hydroxyl functional group with diverse connectivity, have become common building blocks for the synthesis of a wide range of structures and frequent motif in naturally occurring systems. The synergistic effect of the allene and hydroxyl functional groups enables allenols to be considered as a unique and sole functionality exhibiting a special reactivity. This Review summarizes the most significant contributions to the chemistry of allenols that appeared during the past decade, with emphasis on their synthesis, reactivity, and occurrence in natural products.


INTRODUCTION
Allenes are far considered the most useful and widely employed of the cumullenes. Since Van't Hoff's early predictions about structure and composition, 1 chemists have produced a continuous stream of research in the allene field, facilitated by the perfect balance of reactivity and stability in the allene unit. 2−13 Opposite to alkynes or alkenes, allenes show three reaction sites coupled to potential axial chirality. They can behave both as electrophiles and nucleophiles, 14−17 and they can undergo cycloaddition reactions, 18−21 thermal or radical rearrangements. 22,23 Besides their synthetic utility, they are also recurring subjects in catalysis and theoretical studies.
In the last decades, a special kind of allene, namely, allenol, has emerged in both organic and physical organic chemistry, becoming a common building block for the synthesis of a wide range of structures.. 24−36 Allenols are formed by an allene and a hydroxyl functional group showing diverse connectivity. The synergistic effect of one functional group over the other when sharing the same skeleton makes the allenol unit a unique and sole functional group exhibiting a special reactivity. In one hand, allenols can be viewed as π-activated alcohols showing an extra reactivity toward eliminations, substitutions, or rearrangements. On the other hand, they can be viewed as allenes bearing extra electron pairs, which promote intramolecular cyclizations or provide an alternative metal-coordination site. This overview is focused in the most recent examples dealing with the enhanced chemical behavior of allenols, leaving aside the more particular situations where the allene and alcohol motifs react separately within the allenol molecules.
Herein we will discuss the most significant contributions to the allenol chemistry appeared during the past decade. Nevertheless, selected early works will be also mentioned to keep a critic and accurate review about the history of allenols. First of all, we will describe the most representative advances for the synthesis of allenols, specially focusing in the more challenging highly substituted structures and chiral allenes. Also, the different connectivity between the allene and hydroxyl moieties leading to α-, β-, γ-, or δ-allenols will be detailed. In a second chapter, synthetic utility of the allenol functional group will be discussed. This chapter will be organized according to the diverse reactivity of the allenol skeleton. Thus, in a first section, allenols as special π-activated alcohols will be considered, mainly showing hydroxyl units as leaving groups through elimination, substitution, aromatization, or rearrangement processes. A second section will describe the bidentate nature of the allenol, acting both as nucleophile and electrophile in annulation reactions. A third section is dedicated to all the examples where the OH group is not leaving or attacking the cumullene bonds. Instead, the alcohol unit is acting as a coordination site facilitating diverse transformations as additions, bond migrations, or isomerizations. A final section will contemplate the most recent achievements in chirality transfer using allenols through any kind of transformation. In addition, and to proof the extensive use of allenols in every field related to organic chemistry, a last chapter will be considered discussing the last contributions in natural product chemistry. Both allenols as key reaction intermediates and as motifs in the final structure will be presented.

SYNTHESIS OF ALLENOLS
The extensive use of allenols in organic chemistry has also facilitated a considerable number of methodologies for their preparation. In addition to the most conventional routines, such as the allenation of terminal alkynes or the metal catalyzed addition of propargyl derivatives to aldehydes, different strategies have emerged during the past decade to provide more complex structures through more creative procedures. Among the diverse family of allenols, those bearing the hydroxyl unit at the α position, namely α-allenols, represent the widest number and focus the main part of investigations regarding both synthesis and applications. On the other hand, the synthesis of allenols exhibiting different connectivities such as β-, γ-, or δallenols have been frequently described following adapted methodologies from α-allenol synthesis. Thus, to get a concise discussion with a more homogeneous distribution, a classi-fication according to the synthethic strategy is herein presented. Moreover, differently substituted allenols in both racemic and enantioenriched versions will be discussed.

Racemic Allenols
The most classical methodologies for the synthesis of racemic allenols start from alkynes, mainly including homologation of propargylic alcohols and addition of propargyl bromides to aldehydes (Scheme 1, reactions a and b). Also, activated allenes have been often used as starting materials in the aldol-type addition to carbonyl compounds (Scheme 1, reaction c).
Among the homologation procedures, allenation of terminal alkynes from propargylic alcohols is still one of the most common methodologies for the construction of the allenol skeleton. In the late 70s, Crabbéand co-workers reported the first synthesis of allenes from terminal alkynes, isopropylamine, paraformaldehyde, and CuBr as metal catalyst. 37−39 The presence of a hydroxyl group in the alkyne unit seemed to activate the transformation providing α-allenols with excellent yields. Nevertheless, this transformation was limited to paraformaldehyde leading only to monosubstituted allenols as reaction products. In recent years, Ma research group has extensively investigated the scope of the allenation of terminal alkynes toward the synthesis of di-and trisubstituted allenes, by extending the methodology to diverse aldehydes and ketones. 40 Thus, yields and scope were first improved by changing the original CuBr/propylamine pair for CuI/cyclohexylamine toward the optimized synthesis of terminal allenes 2. This methodology was successfully applied for the preparation of different allenols, such as βor γ-allenols, normally showing low yields under original Crabbe's reaction conditions (Scheme 2, reaction a). 41−46 To extend the reaction to normal aldehydes, the same research group assumed that finding the proper metal salt/secondary amine combination should be the key for the direct allenylation. Fortunately, diverse matching combination such as ZnI 2 /morpholine or CuI/Bu 2 NH gave successful results from different starting materials (Scheme 2, reaction b); 1,3disubstituted allenols 3 were therefore accessible. 47,48 Further extension to trisubstituted allenols 4 was achieved by reaction with ketones using CdI 2 /pyrrolidine or the less toxic CuBr-ZnBr 2 /pyrrolidine reagent combination in a sequential addition procedure, or CuBr-ZnBr 2 −Ti(OEt) 4 /pyrrolidine in the one pot version (Scheme 2, reaction c). 49−51 An alternative approach for the homologation of terminal alkynes under copper catalysis employs differently substituted diazo compounds instead of aldehydes. First described by Wang and collaborators, 52 this methodology has also been applied for the synthesis of substituted allenols by diverse research groups (Scheme 3). 53−56 Alkyl and aryl-substituted allenes, allenoates, and TMS-disubstituted allenes are described in the recent literature following this strategy. In addition, both αand βallenols are accessed with no considerable decrease of yield.
Allenylation of aldehydes with propargyl derivatives bearing an appropriate leaving group (normally bromides) represent another classical approach for the allenol synthesis. Many reports have appeared dealing with the regioselective control between propargylation and allenylation, including a wide variety of metal catalysts, such as Sn complexes, 57−59 Zn, 60−62 Bi, or Cd salts. 63 Among all these well-known procedures, Inpromoted allenylation in aqueous media has possibly provided the best results. 64−67 In this field, Cr-catalyzed allenylation of aldehydes is probably the only contribution appeared during the past decade, allenols are prepared in a complete regioselective manner allowing both racemic and enantioselective synthesis, with the late being further discussed in the next section. 84 In a similar approach, propargyl boronic esters have recently shown a good control in the regioselectivity toward the addition to aldehydes. Copper catalysis allowed the synthesis of both alkynol 9 and α-allenol structures 10 by switching the phosphine-based ligand (Scheme 4, reaction a). 68,69 This study has been analyzed from both experimental and theoretical perspectives. Alternatively, the MOF (metal−organic framework)-supported mineral acid catalyst MIL-101 yielded similar α-allenols 10 as sole reaction products through a related transformation (Scheme 4, reaction b). 70 Kobayashi and co-workers have also reported an example of regiocontrol toward the allenylation versus propargylation of both aldehydes and ketones from boronic esters. In this case, Znpropargyl or Zn-allenyl species are generated in situ from allenylboronic derivatives 11. The regioselectivity of the process was found to be temperature-dependent, yielding α-allenol species 12 as major reaction products at lower temperatures (Scheme 4, reaction c). 71 Direct allene addition onto carbonyl compounds have also provided several examples of α-allenol synthesis through allenealdol or Baylis-Hillman-type reactions, including both αand γselective additions. 72 −74 In the recent literature, γ-addition has been reported from substituted allenoates 14 and 16 and diverse aldehydes through Morita-Baylis-Hillman additions using different catalysts (Scheme 5, reactions a and b). 75,76 Direct addition of allenes to carbonyls frequently shows scope limitation as activated substrates are needed, normally allenoates. One rare example of this kind of transformation using a different activated allene employs tosyl derivatives 18. Treatment with nBuLi at low temperature yields the corresponding organolithium compound, which is reported to be trapped in the presence of different aldehydes generating α-allenols 19 (Scheme 5, reaction c). 77 A wide variety of aldehydes or ketones and arylsulfones are tolerated, although the challenging trisubstitution pattern around the allene skeleton should be already present in the starting material.
Besides the above-mentioned general strategies for the racemic allenol synthesis, the past decade has witnessed an increasing number of more specific transformation leading to more challenging α-allenol structures. Backvall research group has employed protected alkyndiols 20 and 22 through an ironcatalyzed cross-coupling reaction with Grignard reagents for the synthesis of di-, tri-and tetra-substituted allenols 21 and 23 (Scheme 6, reactions a and b). 78 Acetate-protected hydroxyls act as the leaving group facilitating the cumullene generation, while TBS-protected OH remains unaltered in the final allenol skeleton. The two alcohol units could be placed in either opposite (20) or same (22) side of the alkyne moiety, providing a wider scope and versatility. Also, the mild reaction conditions allowed an extensive functional group compatibility in both the alkyndiol system and the Grignard reagent. Related work from Sherburn's and Dou's research groups have independently shown alkyndiol efficiency in the allenol synthesis (Scheme 6, reactions c and d). Pd-catalyzed Suzuki-Miyaura cross-coupling reaction from symmetrically substituted alkynes 24 allowed the synthesis of allenes 25. Nevertheless, only sterically hindered boronic acids were tolerated to avoid 2-fold addition processes (Scheme 6, reaction c). 79 The use of rhodium catalysis in a similar transformation from diols 26 provided higher control toward the single addition reaction. Less hindered boronic acids were allowed, and unsymmetrically substituted alkyndiols 26 were also tolerated under Rh conditions (Scheme 6, reaction d). 80 Propargyl epoxides 28 have also been employed for the synthesis of substituted α-allenols through S N 2′-type reactions in the presence of nucleophiles. 81−86 While C-based nucleophiles such as Grignard reagents have been previously reported in classic methodologies, heteronucleophiles are much more scarcely described. 87−90 Nevertheless, recent publications have started to focus in this transformation for the synthesis of allenes showing carbon-heteroatom bonds, not easily accessible through any other approach. Thus, B-, 91 P-, 92 and Sn-decorated allenols 29−31, 93−95 have been synthesized using different transition metals as catalysts and mild reaction conditions (Scheme 7).
Multicomponent reactions allow the synthesis of highly substituted and complex structures in one single step. This approach has been recently applied to the synthesis of βand αallenols from allenyl or propargyl boronic compounds, respectively. Petasis and co-workers have reported the synthesis of allenyl aminoalcohols 35, exhibiting a β-allenol motif, by a metal-free three-component process using allenyl boronic acids 32, amines 33, and hydroxyaldehydes 34. 96 Regioselectivity (allenylation vs propargylation) was found to be dependent on the amine. Thus, secondary aliphatic amines selectively furnished the corresponding allenols (Scheme 8, reaction a), while primary and aromatic amines yielded the propargylation products. Alternatively, Thomson research group described a multicomponent reaction from alkynyl trifluoroborate salts 36, hydroxyaldehydes 34, and sulfonylhydrazines 37. 97 The strategy was based in the in situ decomposition of the intermediate propargyl diazine 38 to yield the allenol compound 39 as sole reaction product through a so-called traceless Petasis-type process (Scheme 8, reaction b).

Enantioenriched Allenols
Asymmetric synthesis and chirality transfer processes have attracted much attention during the last years. Enantioenriched starting materials as chirality transfer agents represents one of the most common approaches. Thus, great interest has been shown in the design and synthesis of enantioenriched allenols, useful building blocks in asymmetric synthesis through diverse transformations as it will be later detailed. Because of the orthogonal distribution of cumullene molecular orbitals, allenes exhibit axial chirality when differently substituted. In addition, the presence of the extra alcohol unit in the allenol skeleton provides a potential stereogenic center. Synthesis of enantioenriched allenols may therefore contemplate axial chirality generation, central chiral generation, or both in the most complex cases. The principal methodologies for the synthesis of enantioenriched allenols that will be discussed in this section may be divided in three general groups; chirality transfer from enantioenriched starting materials, asymmetric synthesis using enantiopure catalysts, and dynamic resolution of racemic allenols.
2 Showing Axial Chirality and Axial-Central Chirality. Allenation of terminal alkynes of terminal alkynols has also been investigated in the asymmetric version to yield optically pure allenols. Ma and co-workers have employed differently substituted prolinols 42 and 45 as chirality transfer agents providing practical yields and good to excellent enantioselectivities. TBS-protected alkynols 40 were first explored in combination with both (R)-and (S)-diphenylprolinol (42). Axial enantioselectivity is perfectly controlled from the absolute configuration of the amines 42 (Scheme 9, reactions a and b), while the stereochemistry of the hydroxyl carbon in the starting alkynol 40 is retained throughout the reaction when enantioenriched substrates were tested (Scheme 9, reaction c). The authors also point that the bulky TBS group in the alkynol 40 may have double role by avoiding the allene racemization and enhancing the enantioselectivity. 106,107 In a later work, dimethylprolinol (45) was found to exhibit higher enantiodirection, allowing the use of unprotected alkynols 44 as starting materials and extending the scope to the obtention of β-, γ-, and δ-allenols (Scheme 9, reaction d). 108 Yu's research group has envisioned an aldol allenoate addition to aldehydes 47 promoted by chiral bromoboranes 48 in the presence of tertiary amines. Both regiochemical and stereochemical outcomes of the reaction are explained through a Curtin-Hammet-type transition state 49, selectively favoring γaddition products 50 and providing excellent chiral and central enantioselectivities (Scheme 10). The methodology was also applied for the kinetic resolution of racemic aldehydes, and further generation of the butenolide core of the natural product (+)-xilogiblactone A. 109−112 Enantioenriched oxiranes have also been employed for the synthesis of di-and trisubstituted allenols with good diastereoselectivites. 113−115 Two related approaches based in metal catalysis and organoboron reagents have been described. Propargyl epoxides 51 undergo a ring-opening through a synhydride borane addition using MeOH as proton shuttle, followed by selective syn-elimination catalyzed by copper salts. The proper phosphine-base combination seemed to be crucial for the axial selectivity toward allenols 52 (Scheme 11, reaction a). 116 On the other hand, enynyl oxiranes 53 have been reported to react through a formal S N 2′ mechanism in the presence of aryl boronic esters and palladium catalysts to provide enantioenriched allenols 54 (Scheme 11, reaction b). 117 Another example of a central-to-axial chirality transfer uses optically pure ethynyl β-lactams 55 and different aldehydes for the asymmetric synthesis of structurally complex allene diols 56. The process includes initial in situ generation of the propargyl indium reagent, and further addition onto aldehydes. Although complete selectivity in the generation of the new α-hydroxy chiral center was not achieved, a reasonable dr = 11:89 could be attained (Scheme 12). 118 Ma and colleagues have accomplished the synthesis of enantioenriched βand γ-allenols 58 taking advantage of the reduction of optically pure allenoic acids 57 with LiAlH 4 (Scheme 13, reaction a). 119−121 The preparation of enantioenriched α-allenol 60 from allenoic acid 59 required an esterification followed by reduction with DIBAL-H (Scheme 13, reaction b). 122 The above processes occur with efficient chirality transfer, which shows the high synthetic potential of this methodology in asymmetry synthesis. The DIBAL-Hpromoted reduction of racemic α-allenoates into α-allenols can be conveniently achieved, 123 while the LiAlH 4 -assisted reduction of enantioenriched α-allenoates 61 (Scheme 13, reaction c 124 and the double 1,2-addition of allyl magnesium chloride to axially chiral α-allenoate 63 (Scheme 13, reaction d) 125 generated with retained chirality the corresponding optically active α-allenols 62 and 64, respectively.
2.2.1.2. Allenols Showing Central Chirality. [2,3]-Wittig rearrangement of propargylic ethers provides the α-allenol skeleton in one single synthetic step. A first approach to the asymmetric version of the Wittig rearrangement was applied to the synthesis of a pharmacologically attractive α-hydroxy γamino acid 66 bearing an allene unit, despite in poor yield (Scheme 14, reaction a). 126 More recently, a Wittig-based methodology was also employed for the synthesis of a family of substituted asymmetric α-allenols 68. In this case, a remote Scheme 10. Aldol Allenoate Addition to Aldehydes Promoted by Chiral Bromoboranes Scheme 11. Chiral Oxiranes as αand γ-Allenol Precursors Scheme 12. Central-to-Axial Chirality Transfer from Ethynyl β-Lactams Scheme 13. Chiral Allenoic Acids and Allenoates as α-, β-, and γ-Allenol Precursors chiral sulfoxide in the starting propargylic ether 67 was responsible of the stereochemistry, behaving as a chiral inductor rather than a chirality transfer agent (Scheme 14, reaction b). 127 In both cases, good diastereoselectivities were achieved, although no axial chirality is described, and the lack of a wider scope in the methodology leaves much work yet to be explored in this field.
Other examples dealing only with central chirality in the newly formed hydroxyl carbon use the asymmetric version of the allenyl boronate addition onto aldehydes. Zn catalysis provides complete regioselectivity toward the allenylation versus propargylation processes, while chiral α-amino aldehydes 69 are responsible of the stereoselectivity observed as chiral inductors. Diastereoselectivity can be tuned by simply modifying the aldehyde substitution. NHBoc-substituted aldehydes led to syn amino allenols 71 though a Cram-chelation model 71′, while NBnBoc-substituted aldehydes yielded anti isomers 72 through a Felkin-Ahn addition model 72′ (Scheme 15). 128 More specific transformations include the asymmetric propargylboration of aldehydes using 10-trimethylsilyl-9borabicyclo[3.3.2]decanes, 129 or Barluenga's multicomponent reaction of chromium carbenes 73, oxazolidine-2-ones lithium enolates 74, and Grignard reagents 75 to yield highly substituted cyclohexenones 76 bearing allenolic units. 130 Central-to-central chirality transfer is reported, using optically pure oxazolidines as chiral inductors, and yielding allenols 76 showing up to 99% ee (Scheme 16).

Kinetic
Resolution of Racemic Allenols. Because of the more effective and economic chirality transfer approaches based in enantiopure catalysts, the past decade has experienced a decay in the number of contributions dealing with kinetic resolution strategies. Nevertheless, pioneer research groups in this field such as Backvall's, 131−134 have continued their interest in kinetic resolution strategies proposing new alternatives and more efficient procedures.
Dynamic kinetic resolution (DKR) by means of thermal or chemical induced isomerization has been extensively used to overcome the limited yield disadvantage inherent to KR. Axially chiral trisubstituted α-allenols 78 were obtained through esterification of 77 in the presence of lipase from porcine pancreas and vinyl butyrate. DKR was achieved by using palladium catalysis, inducing the allene 77 isomerization through the corresponding π-allyl palladium complex. The reported hybrid chemo-enzymatic methodology led to improved yields up to 83%, and good enantioselectivities (Scheme 17). 135 One different conceptual approach to get access to chiral allenols with high yields employs prochiral starting materials in desymmetrization processes. Thus, allene diols 79 react selectively with vinyl butyrate in the presence of Lipase from porcine pancreas as sole catalyst to yield optically pure monoesters 80. Yields were good to excellent for allenes bearing aromatic susbtituents, and expectedly lower for aliphatic systems, though practical high enantioselectivities up to 99% were reported (Scheme 18). 136 The group of Ma reported in 2002 the use of Novozym-435 as a convenient biocatalyst for the kinetic resolution of racemic αallenols, giving rise to enantioenriched (S)-(−)-α-allenols and (R)-(+)-α-allenyl acetates in an efficient way. 137 Hong and coworkers have contributed to the asymmetric synthesis of allenols with central chirality by developing different KR methodologies. In this regard, both enzymatic and chemical alternatives have been studied. Acetylation of α-allenols 81 in the presence of the appropriate lipase allowed the preparation of optically pure compounds (R)-81 and (S)-82 with yields up to 50% and enantiomeric excesses above 99%. After an enzyme screening, lipase AK (Pseudomonas f luorescens) was identified as the best candidate to achieve this transformation. The methodology was expanded to many differently substituted terminal allenols, including alkyl-, alkenyl-, and aryl-decorated structures (Scheme 19). 138 Taking advantage of the transition metals ability to catalyze allenol cycloisomerizations, which will be further discussed in the next chapter, a chemical KR of allenols was envisioned. The chiral silver phosphate 84 allowed the selective oxycyclization of the (S)-enantiomers from the racemic mixture of allenols 83. Thus, enantioenriched dihydrofurans 85 were obtained, while unreacted (R)-allenols 83 were recovered. Both species were easily separable after column chromatography, providing arylsubstituted terminal allenols with yields up to 50% and up to 99% ee (Scheme 20). 139,140 2.2.3. Asymmetric Synthesis Using Enantiopure Catalysts. The use of enantiopure catalysts represents a strategy of increasing interest in asymmetric synthesis. The possibility to avoid the preparation of optically pure starting materials in large scale, along with the catalyst recycling facilitates more economic synthetic routes. Regarding the synthesis of enantioenriched allenols, both enantiopure ligands in metal catalysis and enantiopure organocatalysts are described.
2.2.3.1. Enantiopure Ligands in Metal Catalysis: Axial and Axial-Central Chirality. Ma and co-workers have studied the asymmetric allenation of terminal alkynes using enantiopure ligands as chirality transfer agents in the synthesis of enantioenriched α-allenols. Readily available propargylic alcohols 86 were first submitted to Cu catalysis using pyrrolidine (88) as amine and (R,R a )-PINAP as ligand. To achieve practical reaction conversions, cocatalysts ZnBr 2 or CdI 2 were needed, describing a one pot/two steps and a one pot/one step procedures respectively (Scheme 21, reaction a). 141,142 Further investigations on this transformation revealed that increasing the amine ring size (90) led to high enantioselectivities under CuI as sole catalytic species in a more efficient and economic manner (Scheme 21, reaction b). Also, reversal enantioselectivity was easily achieved by using enantiomer (R,S a )-PINAP as chiral ligand. 143 Good axial enantioselectivities were reported through a versatile and practical methodology.
Aldol-type additions of both propargylic and allenyl substrates onto carbonyls also find a stereoselective variant based on the use of chiral ligands in transition metal catalysis for the synthesis of α-allenols. Alkynylogous aldol reaction from propargylic carboxylates 91 catalyzed by copper salts and (R)-DTBM-SEGPHOS (94) as chiral ligand was found to be very effective for the synthesis of 2,3-allenols 93 from aromatic aldehydes (Scheme 22, reaction a). On the other hand, aliphatic aldehydes showed better stereoselectivities in the presence of (R,R)-Ph-BPE (95) as chiral ligand, which provided opposite central enantioselectivity. In both cases, high diastereo-and enantioselectivities were obtained (Scheme 22, reaction a). 144,145 Au (III) salts have been reported to promote the aldol-type addition of allenic esters 96 onto isatin 97. In this case, a chiral N,N-dioxide 99 was used as chirality transfer agent, providing tri-and tetrasubstituted allenols 98 in good to excellent yields and good enantioselectivities (Scheme 22, reaction b). 146 In a different approach, condensation of boronic acids with α-hydroxycarbonyls 100 formed 1,3-dioxaboroles 102, which can be used as electrophiles in asymmetric allenylation reactions for the synthesis of β-allenols. Thus, racemic allenes 101 were transformed into enantioenriched allenols 103 using palladium catalysis and enantiopure phosphine ligands (Scheme 22, reaction c). 147 1,3-Enynes have also been employed as common starting materials for the asymmetric synthesis of allenols exhibiting diverse allene-hydroxyl connectivity. Challenging tri-and tetra-substituted allenols 107 showing axial chirality are accessible through a cooperative Cu−Pd arylboration of enynes 105. Treatment of boron intermediates 106 with NaBO 3 eventually yielded the expected α-allenols 107. The appropriate use of both metal catalyst and the noncommercial chiral sulfoxide 112 as ligand is reported to be responsible of the high enantioselectivity observed, avoiding racemization of allenyl copper intermediates (Scheme 23, reaction a). 148 In a different contribution, related 2trifluoromethyl enynes 108 decorated with a hydroxyl group, provided the allenol skeleton through a similar Cu-catalyzed 1,4protoborylation or 1,4-protosylilation. In this case, new designed chiral bisoxazoline ligands 113 showed the best results yielding up to 97% ee (Scheme 23, reaction b). 149 Alternatively, copper hydride semireduction of enynes 110 provided axially chiral disubstituted allenols 111. Mild reaction conditions and the use of water as proton source allowed a wide functional group compatibility. Commercially available 1,2-bis((2S,5S)-2,5-diphenyl-phospholano)ethane [(S,S)-Ph-BPE] (114) showed enantiomeric excesses above 99% (Scheme 23, reaction c). 150

Enantiopure Ligands in Metal Catalysis: Central
Chirality. Besides the above-mentioned coupling reaction with enynes, organoboron reagents have shown great versatility toward allenol preparation, both starting from diverse substrates and through different transition metal-catalyzed reaction mechanisms. Cross-coupling reaction between propargylic carbonates 115 and boronate complexes 116 under Pd catalysis afforded β-boryl allenes 117 as reaction intermediates. Again, boron functionalization was effectively used as hydroxyl precursors by treatment with NaBO 3 . (S,S)-MandyPhos ligand (119) was employed to induce central chirality, providing βallenols 118 with good yields and enantioselectivities up to 98% (Scheme 24, reaction a). 151 A related approach reacted vinyl arenes 121 and bis(pinacolato)diboron B 2 (pin) 2 with propargylic phosphates 120 under Cu catalysis and (R,S)-Josiphos (124) as chirality transfer agent. Following a similar strategy, the hydroxyl group was obtained after treatment of the corresponding β-boryl allenes 122 with NaBO 3 (Scheme 24, reaction b). 152 More particular transformations based on enantiopure ligands include reaction between diazoesters 125 and propargylic compounds 126 through a tandem ylide formation/[2,3]sigmatropic rearrangement (Scheme 25, reaction a), 153 [2,3]-Wittig rearrangement of propargylic isatins 128 (Scheme 25, reaction b), 154 Wacker-type oxyallenylation of cyclic alkenes 131 (Scheme 25, reaction c), 155 or a Cr-catalyzed addition of propargyl bromides 136 onto aldehydes (Scheme 25, reaction d). 156 2.2.3.3. Enantiopure Organocatalysts. Enantiopure organocatalysts have been scarcely reported for the synthesis of allenols. Nevertheless, during the last years, different research groups have started to apply this methodology to the asymmetric addition of propargyl and allenyl compounds to carbonyls. This transformation unravelling intriguing catalytic strategies allows the synthesis of both axially and centrally chiral allenols with good yields. Hoveyda's research group has described a general methodology for the asymmetric nucleophilic addition to carbonyls controlled by fluorine−ammonium electrostatic interactions. The organocatalyzed procedure was applied to the addition of allenyl boronic complexes 140 to trifluoromethyl ketones 139, yielding α-allenols 142. An enantiopure organocatalyst 141 showing the appropriate electronic features delivered allenols 142 in excellent yields and enantioselectivities above 99% (Scheme 26, reaction a). 157 Chen and co-workers have also studied a related organoboron addition onto carbonyls for the asymmetric approach to the allenol skeleton. In this case, propargylic boronates 144 were added to aldehydes in the presence of a chiral phosphoric acid 145, providing α-allenols 146 with good to excellent yields and showing central chirality with up to 99% ee (Scheme 26, reaction b). 158 Following with the extensive use of unsaturated organoboron compounds, and continuing with the applications of Petasistype reactions, Thomson and co-workers have developed a chiral organocatalyzed version of the multicomponent reaction between propargyl boronates 147, protected aldehyde 148, and sulfonyl hydrazine 149. Enantiopure biphenol 150 gave access to enantioenriched allenols 151 displaying axial chirality, with moderate to good yields and up to 99% ee (Scheme 27). 159 Organocatalyzed alkynylogous Mukaiyama aldol reaction also constitutes a feasible methodology for the asymmetric allenol preparation. List and collaborators have recently reported an enyne addition onto aldehydes catalyzed by a newly designed chiral disulfonimide 154. Challenging tetrasubstituted allenols 155 were prepared, exhibiting both axial and central chirality. The scope of the transformation includes aromatic aldehydes 152 and differently substituted alkyl enynes 153. Mild reaction conditions are reported, leading to moderate or excellent yields, diasteroselectivities up to 27:1, and enantiomeric excesses up to 98.5% (Scheme 28). 160

SYNTHETIC UTILITY
3.1. Allenols as π-Activated Alcohols Hydroxyl units are traditionally considered bad leaving groups in organic chemistry, unless previous OH-activation has been made. π-Activated alcohols are a special class of hydroxylic compounds in which the positive charge at the α-carbon is stabilized by the presence of conjugated π-orbitals. Taking advantage of this particular reactivity, π-activated α-allenols have been reported to undergo a wide number of transformations where the C−O bond cleaves at one certain point of the reaction mechanism. In this context, reactivity of allenols may be divided in two main groups: (i) those where the OH leaves the molecule at the first steps of the mechanism, leading normally to the diene, enone or enyne skeletons, and (ii) those where the OH loss occurs at the final stages of the process, which are normally found in tandem reactions for the synthesis of aromatic rings and alkaloids. Thus, either when a 1,3-migration reaction takes place or an external nucleophile attacks the central allenic carbon promoting the extrusion of the previously activated alcohol in a S N 2′-type reaction, diene/enone skeletons may be formed (Scheme 29, path a). On the other hand, if a base abstracts a terminal allenic proton, rearrangement and activated alcohol elimination can take place to yield the enyne motif (Scheme 29, path b). In addition, when the allenic carbocation resulting from C−O bond dissociation is stable enough, an allene transfer process may happen by nucleophilic trapping, retaining the allene moiety (Scheme 29, path c). Finally, C−OH cleavage can take place through a further dehydratation step after carbo-or heterocyclization processes, leading normally to aromatic or heteroaromatic compounds (Scheme 29, path d).
3.1.1. OH as a Leaving Group in the First Stage of the Reaction. 3.1.1.1. Synthesis of Dienes and Enones. Dienes are easily generated from allenols and protected allenols trough 1,3rearrangement processes. Several methodologies including acid or base promoted isomerizations and metal promoted reactions have been recently reported. 161−184 Starting from allenols 156 and the appropriate sulfonyl chloride, the Alcaide and Almendros research group described a novel [3,3]-sigmatropic rearrangement of nonisolable α-allenic methanesulfonates and arylsulfonates 157. The formal OH migration to yield dienes 159 is proposed to proceed through a six membered ring transition state 158 (Scheme 30). 185,186 DFT calculations supported an aromatic transition state in accordance to a pericyclic reaction mechanism, in view of a negative nucleus independent chemical shift obtained at the ring critical point of the electron density (NICS = −6.5 ppm). Also, a low calculated activation barrier of only 17.7 kcal/mol shows coincidence with the mild experimental reaction conditions needed for the transformation.
The methodology was extended to a wide number of substituted allenols 156 and applied to the preparation of different fused polycyclic structures. In one hand, a tandem [3,3]-sigmatropic rearrangement/Diels−Alder reaction provided optically pure tricyclic β-lactams such as 160 (Scheme 30, reaction a). 185 On the other hand, related [3,3]-sigmatropic transposition of arylsulfonyl allenes produced dienes 159b or 159c, which are employed to the synthesis of enantiopure polycyclic sultones such as 162b or 162c trough a two-step sequence (Scheme 30, reactions b and c). 186 Wang's research group has presented an alternative procedure for the [3,3]-sigmatropic allenol rearrangement using sulfonic acids 164 instead of sulfonyl chlorides. The methodology was applied to di-and trisubstituted allenols 163 (Scheme 31, reaction a). 187 Related work from Lee and collaborators provided E-dienes 167 with good yields and good to excellent stereoselectivities using trimethylsilyl triflate or trimethylsilyl chlorides 166. In this case, triflate-and chlorine-decorated dienes 167 were respectively prepared, expanding the scope of diene functionalization. DFT calculations also pointed to a similar six membered aromatic transition state, based on hydrogen bonding. Nevertheless, the change of 1,3-migration reagent from sulfur-to TMS-derivatives seemed to induce a slight loss of stereoselectivity, leading to E/Z mixtures in rates depending on the allenol substitution (Scheme 31, reaction b). 188 Different 1,3-migration strategies involving a previous reaction of the OH unit in α-allenols with coupling or protecting reagents have appeared. Thus, reaction of allenols 163 with TsNCO yielded the corresponding allenic N-tosylcarbamates 168. Taking advantage of the thermal instability of these Ntosylcarbamates, a decarboxylative aza-Michael addition/ elimination sequence generating dienes 169 has been induced by heating at 125°C in the presence of a basic catalyst (Scheme 32, reaction a). The 4-ethoxycarbonyl substitution on the allene moiety seems to be crucial for the transformation, although both alkyl and aryl substituents at the carbinolic core are well tolerated, and excellent steroselectivities achieved. 189 Protection of the hydroxyl group as acetate led to acetoxyallenes 170, which were described to undergo an Ireland-Claisen-type rearrangements in the presence of a base. A [3,3]-sigmatropic reaction mechanism was therefore proposed, proceeding via a six membered chair-type transition state 172 (Scheme 32, reaction b). It was also described the use of N,N-dimethylacetamide dimethylacetal as protective reagent instead of acetic acid, promoting an Eschenmoser-Claisen rearrangement leading to similar results. 190 Reaction of the alcohol unit in allenols 174 under Mitsunobu conditions using N-isopropylidine-N′-2-nitrobenzenesulfonyl hydrazine (175) as nucleophile, led to allenyl diazenes 176. Those substrates were envisioned as precursors of 1,3-dienes through a reductive transposition, via a retro-ene-type transition state 177. The above methodology generated unsubstituted dienes 178 in moderate to good yields. Opposite to previously mentioned [3,3]-sigmatropic rearrangements, the reaction course proceeded with a notable lack of stereoselectivity, yielding cis/trans dienes in rates from 3:1 to 1:1 (Scheme 32, reaction c). 191 Preprepared HCl or HBr solutions in ether or ethyl acetate are reported to promote the isomerization of (1-hydroxybuta-2,3dien-2-yl)diphenylphosphine oxides 179 into chlorinated or brominated phosphinoyl 1,3-butadienes 180. The methodology is applied to primary alcohols, and no stereocontrol is stated at the C3−C4 double bond. Added value to this acid-promoted metal-free methodology is given by further applicability of halogenated dienes 180 on epoxidation or Suzuki-type reactions, providing tetrasubstituted epoxides 181 and arylsubstituted dienes 182, respectively (Scheme 33). 192,193 A conceptually different approach for the synthesis of dienes was based on a S N 2′ reaction in 1-acetoxy-2-allenoates 183.  194,195 Metal species are also reported to promote isomerization of allenols to dienes in both equimolecular and catalytic manner. The cobalt-catalyzed regioselective C8 dienylation of quinoline N-oxides with allenylcarbinol carbonates has been reported by Volla and co-workers, while the use of unprotected allenylcarbinols as the dienylating agents resulted in diminished yields. 196 Alcaide and Almendros research group has described the use of FeBr 3 or FeCl 3 for the halogenation/rearrangement of 2indolinone-tethered allenols 187 yielding 2-halo-1,3-dienes 188 (Scheme 35, reaction a). The transformation tolerated different substitution on the aromatic ring and exhibited complete Zselectivity in every case. The high stereoselectivity observed could be explained considering a pseudopericyclic transition state 189, rather than a stepwise reaction mechanism. Thus, reaction course could be initiated by coordination of the OH group to the metal salt acting as a Lewis acid. Then, a sixmembered chair-type transition state 189 facilitates the cleavage of the hydroxyl with concomitant halogen delivery. Extra coordination of the metal ion with the C=O group displayed in axial position could also support the high stereoselectivity found for this transformation. Further Suzuki-Miyaura coupling reaction from 2-halo-1,3-dienes 188 and aryl boronic acids 190 provided the corresponding aryl-substituted dienes 191, showing the synthetic applicability of the methodology. 197 Following a similar idea, Lin and co-workers developed a FeBr 3 -mediated bromination/rearrangement reaction to yield related 2,5-dibromo-4-aryl-1,3-pentadienes 193. Further onepot N-alkylation/Diels-Alder reaction with tosyl-amines 194 provided products 195 bearing the hexahydro-1-H-isoindole skeleton with good yields and high diastereoselectivities (Scheme 35, reaction b). 198 The ability of α-allenols to easily isomerize to dienes through 1,3-migration reactions was also illustrated during the attempts to oxidize allenyl vinyl alcohols to the corresponding allenyl vinyl ketones. Harmata and collaborators envisioned the synthesis of ketones 198 as starting materials for Nazarov cycloadditions using PCC as mild oxidant. Surprisingly, Crmediated 1,3-migration took place leading to unexpected α′hydroxydienones 197 (Scheme 36). According to the authors, a mechanistic explanation for this result could start from formation of the chromate ester 199, followed by 1,3transposition through the habitual six-membered chair-type transition state 200 to give the chromium enolate 201. Spontaneous (2,3)-sigmatropic rearrangement could produce the new chromate ester 202, which could yield the observed dienyl ketones 197 after hydrolysis. The methodology was extended to a wide number of structures with different substituents, exhibiting moderate to excellent yields and excellent stereoselectivity. 77 Metal species in catalytic amounts have also been reported to promote allenol transformations into dienes showing several advantages. As previously mentioned, phosphinoyl allenols were described to react in the presence of acid solutions yielding phosphinoyl dienes despite of low efficiency and lack of stereoselectivity (179 to yield 180 in Scheme 33). Nevertheless, related 4-phosphoryl-2,3-allenols 203 have been recently found to provide the corresponding 1-phosphoryl 1,3-butadienes 205 in excellent diastereoselectivities using palladium catalysis through a Suzuki-Miyaura cross-coupling reaction with aryl boronic acids 204 (Scheme 37). A plausible reaction mechanism could start with coordination of the metal species to the terminal C−C double bond, and simultaneous activation of the OH groups with the boronic acid in complex 206. C−O bond cleavage would then take place generating the corresponding πallyl palladium complex 207. The high diasteroselectivity resulting from this transformation could be explained by the extra coordination of the metal unit with the P(O) group, leading to the stabilized vinyl palladium complex 208. Transmetalation and reductive elimination in species 209 would provide observed phosphinoyl dienes 205 and regenerate Pd(0) to the catalytic cycle (Scheme 37). 199 Palladium and platinum catalysis has also been employed in the transformation of simple allenols and boronic acids. Exploring the addition of arylboronic acids onto a wide variety of allenes, one example of 1,3-diene synthesis is reported when allenol 210 is submitted to Pd or Pt conditions in the presence of boronic acid 211. Nevertheless, chemoselectivity is not complete, and addition of boronic acids without dehydratation is observed (Scheme 38, reaction a). 200 A rhodium-catalyzed alternative for this transformation was described using 4-arylbuta-2,3-dien-1-ols (214) as starting material and different aryl boronic acids 215. In this case, carbometalation across the phenyl-substituted allenic bond, followed by δ-elimination of Rh(I)−OH was proposed as mechanistic rationale. Again, metal catalysis provided higher selectivity toward the Z-dienes 216 compared with the metalfree analogous transformation. Nevertheless, the lack of an extra coordination site such as the phosphoryl group in allenols 203 resulted in a slight decrease in the Z/E ratio, observing mixtures of diastereomers (from 89:11 to 95:5) in dienes 216 (Scheme 38, reaction b). 201 The palladium-catalyzed preparation of (1Z)-1,2-dihalo-3vinyl-1,3-dienes 220 has been accomplished in a stereoselective manner through the coupling between allenol esters, namely 2,3butadienyl acetates 218, and haloalkynes 219 in the presence of lithium bromide (Scheme 39, top). Particularly interesting is the finding that haloalkynes show increase reactivity in comparison with allenes or acetylenes under the halopalladation reaction conditions. A plausible reaction path is depicted in Scheme 39 (bottom). The initial formation of alkenyl-palladium intermediates I should occur by trans-addition of the halide toward haloalkynes 219. Next, the carbopalladation reaction with allenol acetates 218 should form allyl-palladium intermediates II. β-Heteroatom elimination releases trienes 220 with concomitant regeneration of the catalytic species. 202 A different mechanistic pathway was proposed to explain the results observed from the reaction of different α-allenols 221 in the presence of catalytic amounts of iron triflate or iron Scheme 37. Palladium-Catalyzed Synthesis of 1-Phosphoryl 1,3-butadienes trichloride. Opposite to the above-mentioned halogenation/ rearrangement reaction of allenols promoted by iron halides in equimolecular manner (compounds 191 and 193 in Scheme 35), catalytic addition of similar metal species yielded the enone skeleton 222 through a Meyer-Schuster-type rearrangement (Scheme 40). The methodology showed best results for aryland heteroaryl-substituted allenols, and Fe(OTf) 3 as metal catalyst, avoiding halogenated byproducts as observed in the presence of FeCl 3 , or decomposition products when acid catalysis was employed. The high E-selectivity observed in final enones 222 was found to be independent of the geometry in the starting materials, pointing to a stepwise reaction mechanism. Thus, first coordination of the metal species to the hydroxyl group in intermediate 223 could led to carbocation 224 by C−O bond cleavage. Addition of one molecule of water could then generate the metalated complex 225, evolving to the experimentally observed enones 222 through sequential demetalation/isomerization processes (Scheme 40). A related mechanistic pathway has been recently proposed by Gao and Xu et al., for the acid-catalyzed synthesis of ketophosphine oxides, although in both cases an alternative mechanistic pathway describing the inverse addition/elimination sequence may not be discarded. 203,204 Trost's research groups have extensively investigated the metal-catalyzed Meyer-Schuster rearrangement of allenols 227 from a different perspective. Instead of delivering the corresponding enones from demetalation/isomerization of species 228, intermediates 228 were envisioned as coupling reagents with both electrophiles and nucleophiles, providing a wide and diverse family of functionalized ketones. Thus, reaction of vanadium enolate 228 with vinyl epoxides 229 as masked aldehydes in the presence of a Lewis acid, provided aldol products 230 (Scheme 41, right). 205 Vanadium enolates in the presence of diazocompounds 231 as electrophiles provided ketones 232 from a direct sigmatropic amination reaction (Scheme 41, bottom). 206 Noteworthy, reaction of allenes with diazocompounds are well-known to yield vinyl diazines through Alder-ene mechanisms. 207,208 On the other hand, reaction of vanadium enolates 228 with different nucleophile halogen sources such as NCS or NFSI provided the corresponding αhaloketones 233 with moderate to excellent yields (Scheme 41, left). 209 The allenol-enone metal-catalyzed isomerization has been recently proposed as an intermediate step toward the synthesis of spirocyclic scaffolds in compounds 237. First, treatment of sulfonyl allenols 234 with a Pd catalyst yielded the corresponding enones 235, through a 1,3-migration rearrangement via the corresponding metal-enolate 238. Enones 235 evolved in the presence of a base and p-quinone methides 236 to the observed adducts 237 through a cascade Michael-type addition/ring closing reaction (Scheme 42). 210 Bis ( Loss of water would then lead to the diene skeleton 251, which may undergo intramolecular oxycyclization to build the dihydrobenzofuran system in oxonium ion 252. TfOH extrusion and demetalation would then provide the observed oxindole-functionalized dihydrobenzofurans 248 (Scheme 44). 212 3.1.1.2. Synthesis of Enynes. During the attempts to oxidize the alcohol group in different allenols employing the Swern protocol, Ma and co-workers developed a straightforward methodology for the transformation of α-allenols 254 into conjugated enynes 255 and chlorinated dienes 256. It was found that the presence of triethylamine as a base notably favored the enyne 255 synthesis, while the presence of DMSO promoted the halogenation/isomerization process toward the diene 256 generation (Scheme 45, reaction a). 213 Nevertheless, complete selectivity was only achieved in certain cases. Besides, this divergent protocol was restricted to a particular type of 2,3allenols, namely, allenols having a 2-ethoxycarbonyl substituent. This example clearly illustrates the divergent behavior of allenols under subtle modifications on the experimental reaction conditions.
Alcaide and Almendros research group has presented an alternative procedure for the same transformation avoiding competitive halogenation/isomerization processes. Related OH-activation/elimination strategy was described, employing different reagents and bases. Thus, reaction of differently substituted α-allenols 259 with acetyl chloride and NaOH in aqueous media yielded conjugated E-1,3-enynes 260 in good yields and complete regio-and stereoselectivity. In addition, the methodology was compatible with a wide range of functional groups, and extended to hindered tertiary alcohols, which are  214−216 Sawama and collaborators have developed a phosphatemediated synthesis of related conjugated E-enynes 263 from allenols 262. Trimethyl phosphate was used as activator of the hydroxyl group, while NaH acted as the basic reagent favoring the enyne synthesis by H 2 release. Terminal substitution at the allene moiety 262 was tolerated, providing the synthesis of challenging inner alkynes and allowing therefore the extension of the methodology, despite of a slight decrease in the E/Z selectivity (Scheme 45, reaction c). 217 Lee has described an efficient protocol for the direct and stereoselective conversion of allenyl acetates into (E)-α-ethynyl-α,β-unsaturated esters 255 using DABCO in catalytic amounts (10 mol %). 218 Metal catalysis has been scarcely reported for the allenolenyne transformation. One rare contribution described the use of Cu(OTf) 2 acting both as hydroxyl activator and proton catcher. Thus, α-allenols 265 reacted in the presence of catalytic amounts of copper triflate providing enynes 266 in good to excellent yields and complete E-selectivity (Scheme 46, reaction a). The methodology was reported to be useful starting from secondary aryl-substituted allenols and was also extended to the synthesis of dienynes and enedyines. The reaction is proposed to require an initial C−O bond cleavage promoted by the Lewis acidic nature of the metal salt, yielding allenic carbocation species 269 and metal complex Cu(OTf)(OH) 268. Loss of water would then generate observed enynes 266 and regenerate the metal catalyst Cu(OTf) 2 (Scheme 46, bottom). Further Z-E isomerization experiments on Z-enyne 266a′ under similar reaction conditions showed that formation of the observed Eenynes 266 should be thermodynamically controlled (Scheme 46, reaction b). Zwitterionic allenyl copper species Cu-270 and Cu-270′ are proposed as intermediates in the observed alkene isomerization. 219 Enynes have been also proposed as reaction intermediates in the transformation of allenols into the 2H-pyran-2-one skeleton, or into substituted benzene rings. 3-Hydroxy-4,5-dienoates 271 can be converted into differently substituted pyranones 272 under protic acid catalysis. Protonation of the hydroxyl group followed by elimination of water is proposed to generate 1,4enynes 273 as reaction intermediates. Addition of water to the terminal propargylic carbon atom on 273 and further intramolecular transesterification could explain the obtained 2Hpyran-2-ones 272 (Scheme 47, reaction a). 220 Iodine is well-known to efficiently promote the dehydratation of tertiary alcohols. When propargylic allenols 274 were treated with I 2 in refluxing acetonitrile, iodobenzaldehydes or iodoarylketones 275 were synthesized, depending on the alkynyl substitution in 274. In this case, allenyl enynes 276 are described as plausible intermediates for this transformation. Further iodine activation of the triple bond followed by allene−alkyne cyclization would furnish the aromatic core in 275, while the observed carbonyl functional groups may proceed from oxidation of the iodine substituent by atmospheric oxygen (Scheme 47, reaction b). 221 In a related approach, allenols 274 reacted with thiophenols 277 under transition metal catalysis generating 1,3,5-trisubstituted benzene rings 278. Ring closing and aromatization reaction is triggered by the nucleophilic addition of thiophenols 277 to the central allenic carbon in intermediates 279. InI 3 exhibited a dual behavior as σand π-acid because it was used as metal source, activating both the hydroxyl group in 279 and the alkyne functional group in enyne intermediate 280 (Scheme 47, reaction c). 222 3.1.1.3. Allene Transfer Reactions. The cleavage of the C−O bond in the allenol skeleton after the appropriate hydroxyl activation may result in the generation of an allenic carbocation. When this kind of carbocation is trapped by a nucleophile without isomerization or rearrangement, the overall process results in a formal allene transfer reaction. Because of the high reactivity of the allene functional group, transfer reactions where the allene moiety remains unaltered are still rare. Nevertheless, recent reports have appeared dealing with this transformation and its synthetic applications.
Ma and collaborators have used diverse α-arylallenols 281 as precursors of stabilized allenic carbocations 284 under acid catalysis. Thus, treatment of 281 with p-toluenesulfonic acid in the presence of indoles 281 as nucleophiles, yielded 3-allenyl indoles 283 with moderate to excellent yields through an allene transfer process. 3-Allenyl indoles 283 were employed as precursors for the synthesis of a family of heteroaromatic compounds 285 showing the carbazole scaffold. 223,224 The synthetic strategy included a carbocyclization process catalyzed by gold, followed by oxidation of the resulting dihydrocarbazoles with DDQ to yield the fully aromatic structure in compounds 285 (Scheme 48).
Tsukamoto's research group has developed a metal-catalyzed variant of the allene transfer reaction, employing primary alcohols 286 and diverse pronucleophiles (287,290). The reaction is reported to possible proceed through a π-allyl palladium complex intermediate 289, generated by the oxidative addition of Pd(0) species to allenols 286. Nucleophilic addition toward the unsubstituted carbon on the π-allyl complex would furnish the new allene structure 288 (Scheme 49, reaction a).
When the reaction takes place with ketones 290 bearing electron-withdrawing groups as pronucleophiles allenones 291 are obtained, which in situ undergo a palladium-catalyzed oxycyclization providing vinyl dihydrofurans 292 (Scheme 49, reaction b). 225 Oshima and collaborators have reported a different strategy to achieve the allene transfer process. Copper carbene complexes 295 have shown great activity promoting a challenging C(sp 3 )-C(sp 3 ) bond cleavage (Scheme 50, top, path b) in allenol structures 293, instead of the more frequent C−OH dissociation (Scheme 50, top, path a). Coordination of the metal species with both the OH group and the cumullene is reported to generate metal intermediate 297, which may evolve through PhCOMe elimination providing copper propargyl complex 298. This strategy induced an umpolung on the normal electronic charges in allene transfer processes, allowing the reaction of allenols with electrophiles such as imines 294. As a result, allenyl amines 296 were synthesized and in situ submitted for aza-cyclization reaction yielding the pyrrole scaffold in compounds 299 with good to excellent yields (Scheme 50). 226,227 3.1.2. OH as a Leaving Group in the Last Stages of the Reaction. Although less frequent, the C−OH bond dissociation Scheme 47. Enynes as Reaction Intermediates in the Synthesis of 2H-Pyran-2-ones and Substituted Benzenes from α-Allenols can happen at the last stages of the reaction pathway, opposite to what has been so far reported in diene, enone, enyne or allene transfer procedures. Late OH release takes normally place in the form of dehydration leading to aromatic or conjugated systems, and it usually constitutes the driving force of the transformation. This methodology has been extensively used for the synthesis of different structures exhibiting the carbazole motif, a natural occurring alkaloid showing a wide range of biological and pharmacological activities. Both platinum and gold catalysis have been found to catalyze the carbocyclization/dehydration of indole-tethered allenols to yield the carbazole skeleton in a highly efficient manner. 228−230 Ma and collaborators have invested much effort in developing synthetic routes to carbazolebased natural products through this approach, later discussed in the natural products section. 231,232 The Alcaide and Almendros research group has focused its research in this field on the mechanistic insights of this transformation under gold and palladium catalysis. Indoletethered allenols 300 may exhibit three possible reaction sites, leading therefore to the corresponding carbo-, oxy-, or azacyclization products 301, 302, and 303, respectively. Despite the ability of gold salts to promote oxy-cyclization reactions, complete selectivity toward the carbo-cyclization process (compounds 301) was found in the presence of AuCl as metal catalyst (Scheme 51, top). The transformation succeeded for both methyl-and sterically hindered phenyl-substituted allenols 300, leading to the carbazole core 301 with good yields. The reaction mechanism was proposed to start with coordination of the metal to the terminal allenic bond, followed by a 6-endo carboauration process generating the zwitterionic vinyl gold specie 305. Loss of HCl would then lead to the neutral complex 302. A final dehydration and protodemetalation step should furnish the experimentally observed carbazoles 301 and return AuCl to the catalytic cycle (Scheme 51, bottom). 233 Taking advantage of the more π-coordinating nature of palladium ions, a tandem reaction including a similar carbocyclization process followed by cross-coupling reactions of allenols 300 with allyl bromides 307 was envisioned (Scheme 52, reaction a). Different allyl-substituted carbazoles 308 were synthesized in good yields and complete regioselectivity. 233 Noteworthy, when related cross-coupling reaction was performed in the presence of a second allenic unit 309, pharmacologically attractive 3-(buta-1,3-dienyl) carbazoles 310 were obtained (Scheme 52, reaction b). Yields were moderate to good and a wide number of allenols bearing a different pattern of substitution were reactive under those conditions. In addition, the transformation took place in a complete chemo-regio-and stereoselective manner, showing a previously unreported cross-  234 DFT calculations revealed a computed carbocyclization reaction profile notably lower in energy compared to the oxycyclization process from indole-tethered allenols 300, supporting the chemoselectivity observed in the first step of the tandem reaction. Also, the complete stereoselectivity observed in the diene generation can be explained considering the computed results for the depalladation step (Scheme 53).
Free rotation along the C−C single bond in intermediate 314 could lead to both cis-315 or the more stabilized trans-315 complex. Demetalation step is calculated to proceed through a lower energy barrier from trans-315 adduct, yielding the also more favored trans-316 coordination complex. Thus, the more plausible reaction pathway is the kinetically and thermodynamically controlled trans-deacetoxypalladation process via transition state TS1-trans.
3-Halo-(indol-2-yl)-α-allenols 317 revealed an intriguing reactivity pattern, showing divergent behavior depending on the halide substitution. 3-Chloro-and 3-bromo-indoles reacted with gold salts to yield dienes 318 via a 1,3-hydroxyl migration in complex reaction mixtures (Scheme 54, top left). Also, traces of oxycyclization products were observed. Interestingly, palladium catalysis only provided dihydrofuran systems 319 in low yields when 3-bromo-(indol-2-yl)-α-allenols 317 were employed (Scheme 54, bottom left). Noteworthy, when iodine-substituted indoles 317 were submitted to gold-catalyzed conditions a different reactivity was observed, obtaining mixtures of the previously reported carbazole structures 301 along with novel iodocarbazole compounds 320 (Scheme 54, top right). Complete selectivity toward the iodocarbazole skeleton was achieved under palladium conditions, yielding structures 320 with moderate to good yields (Scheme 54, bottom right). Opposite to normal metal catalyzed reactions from aryl halides where the halogen atom is lost during the reaction course, the observed iodine reincorporation into the final skeleton means an atom-economic improvement and unravels an unreported reaction mechanism. 235 DFT calculations supported a 1,3-intramolecular iodine migration from dihydrocarbazole intermediate 321 to generate the corresponding iododihydrocarbazole 322. Iodonium cation 322 is proposed as the most favorable intermediate to achieve this transformation (Scheme 55, top). Also, computed reaction profile comparison of the migratory ability of chlorine, bromine, and iodine derivatives 321 supported the observed results. Activation barriers for the intramolecular 1,3-migration process are much higher for Br and Cl-substituted indoles (TS2-Br and TS2-Cl, respectively), leading therefore to diene adducts 318 or dihydrofurans 319. On the other hand, a lower energy barrier for the 1,3-iodine migration through transition state TS2-I facilitates the halogen recycling toward iodocarbazoles 320 (Scheme 55, bottom).
In a different approach, a wide family of naphthopyrans exhibiting large π-conjugation have been prepared. Naphthol (325) and related polyaromatic compounds reacted with conveniently substituted alkoxyallenes 324 in the presence of acid catalysts through a cascade process, providing naphthopyrans 326 in moderate to excellent yields. The reaction sequence includes a first allylation step to generate allyl naphthols 327, followed by oxycyclization, loss of one molecule of HOBn to build intermediate 315, and final dehydration to give the observed polyaromatic structures 326. Late C−OH cleavage inducing the extended conjugation in systems 326 is assumed as the driving force of the overall transformation (Scheme 56). 236,237

Allenols as Bidentate Nucleophiles−Electrophiles
The inherent reactivity of hydroxyl groups and activated allene moieties as nucleophiles and electrophiles respectively, has prompted the oxycyclization reaction as one of the most

Scheme 54. Divergent Reactivity on 3-Halo-(indol-2-yl)-αallenols under Metal Catalysis
Chemical Reviews pubs.acs.org/CR Review extensively and traditionally reported transformation. The 5-Endo-trig cyclization leading to the dihydrofuran skeleton, 6endo-trig processes providing dihydropyran motifs and cocyclization processes such as cyclocarbonilations leading to lactones have been widely employed in organic synthesis, exhibiting diverse applications in catalysis or natural products preparation. 238−249 During the past decade the investigations in this field have been focused on developing new and more selective strategies for the oxycyclization reaction, greener and more economic procedures, and more sophisticated transformations for the synthesis of challenging molecular targets through tandem processes. Opposite to the π-activated alcohol reactivity discussed in the previous section, bidentate reactivity is not limited to α-allenol systems. Although less frequently reported, reactivity from β-, γ-, and δ-allenols will be also discussed. In addition, the oxycyclization of allenols has been largely employed as model reaction for the design of new catalysts with improved reactivity. Alcaide and Almendros research group has devised a dual selectivity strategy for the oxycylization of α-allenols based both on the metal catalyst and on the allene substitution. To achieve a rare 4-exo-dig vs the most common 5-endo-trig cyclization, arylsubstituted allenes 330 were synthesized to induce an extra stabilization on the η 2 gold intermediate complexes and to promote the nucleophlic attack toward the central allenic carbon. Interestingly, the selectivity toward the oxetene adducts 331 was improved by raising the temperature, indicating thermodynamic control over the 4-exo-trig products 331 (Scheme 57, top right). DFT calculations also supported this result, pointing to a reaction mechanism proceeding through a zwitterionic oxetene gold complex 335, which after loss of HCl and 1,3-gold migration could provide the rearranged neutral oxetane 337. A rare β-hydride elimination in gold catalysis could explain the observed oxetene adducts 331 (Scheme 57, bottom right). 250 The use of platinum salts in substrates 330 revealed a divergent behavior toward the cycloetherification process. While PtCl 2 cleanly provided the expected dihydrofuran systems 332, the addition of AgOTf promoted a dramatic change in the reactivity yielding exclusively substituted enones 333 (Scheme 57, top left). Supported on the precedents reported by the same group, the authors proposed a reaction mechanism passing by similar oxetene intermediates 335. A ring opening process instead of metal-migration to yield complex 338, followed by deprotopalladation would furnish the observed enones 333 (Scheme 57, bottom left). In addition, control experiments indicated the active role of silver ions in the reaction mechanism, through a yet not fully understood bimetallic catalytic species. 251 Cycloetherification versus carbocyclization/dehydration has also been recently studied as a substrate-dependent methodology in metal-catalyzed experiments. α-Aryl-α′-hydroxyallenic esters 339 undergo 5-endo oxycyclization to yield arylsubstituted dihydrofurans 340 when the aryl moiety is decorated with electron withdrawing or mild electron donating groups (Scheme 58, reaction a, right). 252 Nevertheless, and under similar reaction conditions, allenoates 339 were previously . In this case, the enhanced nucleophilicity of the aromatic ring seems to be responsible for the reactivity switch of hydroxyallenic esters 339 toward a sequential carbocyclization/dehydratation, which is also favored by the extra stability of final aromatic compounds 341. 253 A related approach from novel (indol-3-yl)-α-allenols 342 on the selective oxycyclization versus carbocyclization/aromatization process which can be easily modulated by changing the substitution on the pyrrolic nitrogen in 342 has been described. Thus, deactivated indoles yielded dihydrofuran derivatives 343 by gold-catalyzed cycloetherification processes with moderate to excellent yields, also allowing a wide functional group compatibility (Scheme 58, reaction b, right). On the other hand, NH-indoles 342 provided the carbazole skeleton 344 through a previously described tandem carbocyclization/ dehydratation reaction. Moreover, cross-coupling reaction in the presence of allyl bromides and palladium catalysts generated the corresponding allyl-carbazoles 345 in good yields and in a regio-and chemo-selective fashion (Scheme 58, reaction b, left). 254 Allenyl acetates have also been used as competent substrates in cyclization reactions. Thus, Zhang reported a gold-catalyzed formal [3 + 3] benzannulation strategy for the preparation of polysubstituted benzyloxy arenes from 4-(benzyloxy)hexa-1,4,5-trien-3-yl acetates, 255 while Mukai described a protocol for the formation of indole-2,3-quinodimethanes utilizing a potassium carbonate-promoted aminocyclization of 2-(2-((tertbutoxycarbonyl)amino)aryl)buta-2,3-dien-1-yl acetates with concomitant acetic acid release 256 In an earlier report 257 Cha prepared ethynyl-substituted ciclopropanes through the reaction of β-allenyl tosylates by basic treatment with LDA, in a cyclization which is supposed to proceed by sequential deprotonation of the internal allene hydrogen and cyclization with concurrent 4-methylbenzenesulfonic acid loss.
Different reports on the oxycyclization reactions selectivity including a competitive ring expansion versus cycloetherification in 3-allenyl-3-hydroxyindolones, 258 counterion-controlled double bond isomerization in the oxycyclization of δ-allenols, 259 or substrate-dependent 5-endo-versus 6-endo-in phosphorus-based allenols have appeared. 260 Much effort has also been invested in developing different procedures to achieve the cycloetherification reaction from more economic or greener perspectives. In this regard, mercury salts were found to catalyze the oxycyclization of α-allenols 346 in a cheaper approach, compared to the most frequent precious metal-based methodologies. Thus, inexpensive and watertolerant Hg(ClO 4 ) 2 ·3H 2 O provided the dihydrofuran skeleton 347 in good yields and wide scope, as it happens in sterically hindered tertiary allenols (Scheme 59, reaction a). In addition, complete selectivity toward the oxycyclization was observed even when electron rich aryl allenols 346a were employed, which normally led to mixtures 348a/347a under gold catalysis (Scheme 59, reaction b). 261 Recent metal-based alternatives to the classic cycloetherification reaction include the use of stoichiometric amounts of copper carboxylates 350 for the dioxygenation of allenols 349. Dihydrofuran systems 351 decorated with the vinyl carboxylate ester functionality were obtained through a 5-exo-trig cyclization of γ-allenols (Scheme 60, reaction a). 262 Exocyclic γ-allenol 352 has been also described to react through a 5-exo-trig cyclization path in a Pd(0) catalyzed reaction (Scheme 60, reaction b). 263 On the other hand, silver fluoride has been effectively used for Chemical Reviews pubs.acs.org/CR Review the 5-endo-trig oxycyclization of highly substituted and sterically encumbered α-allenols 354, leading to dihydrofurans 355 exhibiting excellent yields and wide group compatibility (Scheme 60, reaction c). 264 Palladium nanoparticles (PdNPs) have shown high efficiency catalyzing the oxycyclization of differently substituted α-allenols 356a and 356b. Preformed nanoparticles using PdCl 2 as metal source, K 2 CO 3 as reducing agent and TBAB as stabilizer led to a wide family of dihydrofuran systems 357a and 357b in similar yields as the ones reported through the classic precious-metal approaches in homogeneous conditions (Scheme 61). Interestingly, phenols were needed as additives to achieve higher yields and conversions. TEM analysis showed an average particle size of 2.2 nm, and recycling experiments indicated a slight loss of the catalytic activity of solely 8% after four cycles, pointing to a low grade of bleaching in the catalytic system. Although higher temperatures are required compared to analogous homogeneous strategies, the lower catalyst loading of 1 mol %, the higher recycling performance, and the use of water as solvent establish the PdNP methodology as an effective greener procedure. 265 An alternative strategy for the catalyst recycling has been recently reported by Krause and collaborators, based on the use of gold catalysis in ionic liquids. Different trifluoromethylated allenols 358 were selected as model substrates for the 5-endo-trig cyclization reaction using both cationic and neutral gold species (Scheme 62).  6 ], creating a heterogeneous system and allowing the gold catalyst recovering. A low decline of the yield in just 8% after 5 runs shows the practicality of the procedure. Also, mechanistic studies revealed a remarkable kinetic change when allenols bearing a R 4 = CF 3 substituent were submitted to Au-cycloeteherification conditions. In this case, formation of the π-complex was identified as the rate-determining step, opposite to the most habitual protodeauration reaction as the regulating step in gold-catalyzed oxycyclizations. This change is probably due to the stronger deactivating effect of the CF 3 group when located at the terminus of the allenic moiety. 266 Gold catalyzed-cycloetherification has also been involved in the preparation of different compounds exhibiting an added value as molecular materials or naturally occurring alkaloid fragments. The 5-endo-dig cyclization of α-allenols 363 has been employed as one of the key steps en route to cyclophanes 365. Thus, double oxycyclization of allenols 363 led to bis-(dihydrofurans) 364. Ruthenium-mediated ring closing metathesis yielded the expected aromatic, sugar-or beta lactam-based cyclophanes 365 (Scheme 63, reaction a). 267 In a different approach, the tetracyclic indoline skeleton 368 was synthesized by a gold catalyzed cascade reaction, including a propargyl migration in aniline based compounds 366 to yield allenic indole intermediates 367. Further cyclization and rearrangement provided the observed bridged indolines 368. Challenging three-dimensional polycyclic skeletons are furnished, building three rings and four C−C bonds in one sole operational step (Scheme 63, reaction b). 268 A metal-free oxycyclization of allenic hydroxyketones 369 in aqueous media has been reported. Inexpensive NaOH promotes the nucleophilic attack of the OH group toward the central  272 Enallenols, multifunctional molecular targets bearing an alkene and allene moieties along with a hydroxyl group, have Density functional theory calculations showed coincident results according to the experimental observations. Thus, in both gold-based alkenol (reaction profile from 393) and allenol (reaction profile from 394) cyclizations, protodemetalation was identified as the bottleneck step of the whole process, finding a much lower energy barrier for the allenol cyclization resulting in the formation of dihydrofuran 396 (Scheme 68, left). Nevertheless, activation of the hydroxyl unit in substrates 397 should be the starting point of the catalytic cycle when iron salts are present, triggered by their strong Lewis acidity. In this case, alkenol cyclization pass by a notably lower energy barrier to yield the tetrahydrofuran skeleton 395 under kinetic control (Scheme 68, right). 273 Different reports on enallenol chemistry have stated the importance of designing the appropriate enallenol skeleton to modulate its reactivity. Backvall and co-workers have explored enallenol cyclization reactions under palladium catalysis in the presence of different cocyclization partners. In both substrates 398 and 403, where the previously mentioned allenol versus alkenol competitive cyclization is not feasible, palladium catalyzed cocyclization reaction should start by dual coordination of the metal ion with both allene and alkene moieties (coordination intermediates 400 and 406). Thus, when enallenols 398 were submitted to Pd(OAc) 2 tretament under CO atmosphere, spirolactones 399 were obtained as sole reaction products in moderate to good yields. The process includes a cascade oxidative carbonylation-olefin insertion to form intermediates 402, followed by a second CO insertionlactonization sequence providing spirocycles 399 (Scheme 69a). 274 Noteworthy, three C−C single bonds, one C−O bond, and an all-carbon quaternary center are generated in one single operational step. On the other hand, when enallenols 403 were treated with palladium catalysts in the presence of terminal alkynes 405 as cocyclization partners, substituted furans 404 were obtained with good to excellent yields. In this case, a heterogeneous palladium catalyst was employed, based on an aminopropyl-decorated siliceous mesocellular foam which hosts palladium nanoparticles, exhibiting great performance and high recyclability. Again, palladium insertion into the central allenic carbon would yield intermediate 407, which may evolve through alkyne insertion to adduct 408. Nucleophilic attack of the

Scheme 69. Palladium-Catalyzed Cascade Processes of Enallenols
Chemical Reviews pubs.acs.org/CR Review hydroxyl unit to the Pd-activated alkyne and further isomerization would furnish the observed furans 404 (Scheme 69b). 275 Co-cyclization of allenols with aldehydes through Prins-type processes have also been reported, providing the synthesis of oxacycles with different ring sizes. β-Allenols 409 react with aromatic aldehydes in the presence of Bi(OTf) 3 as Lewis acid catalyst to yield the dihydropyran skeleton 410 in moderate yields (Scheme 70, reaction a). 276 When allenols 409 were treated with In(OTf) 3 as Lewis acid catalyst, major efficiency in terms of catalyst loading toward the cocyclization adducts 410 was found (Scheme 70, reaction b). 277 Interestingly, reaction of 5,5-dimethyl substituted β-allenol 409a and aldehydes under In(OTf) 3 catalysis exhibited a special behavior. After the expected Prins-type cocyclization of 409a and the corresponding aldehydes, indium-mediated ring opening and further rearrangement took place, generating the alternative dihydropyran structures 411 in practical yields (Scheme 70, reaction c). 277 In addition, tetrahydrofuran-based compounds 413a were achieved by reaction of α-hydroxy allenylsilane 412a with α,βunsaturated aldehydes under acid catalysis. Also, larger ring sizes were accessible through this methodology in excellent yields, such as 3,4-dimethylidene oxepanes 413b obtained from the reaction of γ-allenol 412b using both aromatic and aliphatic aldehydes (Scheme 70, reaction d). 278 One recurrent strategy to achieve the synthesis of poly substituted furans or dihydrofurans lays on the metal-catalyzed oxycyclization of α-allenols, followed by a cross-coupling process using diverse reagents such as aryl halides. Taking advantage of the low redox potential of palladium, many reports have appeared describing cascade processes of allenols promoted by palladium salts. 279−287 Thus, a multicomponent reaction of α-allenols 414 with aryl iodides 415, aliphatic alcohols 416 and carbon monoxide led to tetrasubstituted furans 417 through an oxidative addition/carbonylation reaction sequence (Scheme 71, reaction a). 288 In a similar approach, the presence of tertiary amines 418 instead alcohols 416 in the reaction media provided the corresponding methylene acetamide-decorated furans 419 (Scheme 71, reaction b). 289 Gong and collaborators have reported a related methodology using allenol 414a, aryl iodides 415 and imines 420 as reaction partners also under palladium catalysis to provide an extense family of oxazolidine derivatives 421. In this case, the proposed reaction mechanism includes carbopalladation onto the central carbon atom of the allene moiety, nucleophilic attack of the oxygen onto the C−C double bond of the imine, and latter ring closing step through nucleophilic addition of the nitrogen onto the inner π-allylic carbon atom (Scheme 71, reaction c). 290 Palladium species have also been found to be useful catalyzing homodimerization and heterodimerization processes of allenols. PdCl 2 in the presence of NaI as additive has shown great activity promoting the tandem oxycyclization−cross-coupling reaction of 2-substituted allenols 422a, yielding 4-(1′,3′-dien-2′-yl)-2,5dihydrofurans 423 (Scheme 72, reaction a). 291 Interestingly, the reaction of two different allenic species under similar reaction conditions allowed the synthesis of substituted dihydrofurans 424, as a result of the chemoselective oxycyclization of 2substituted allenols 422b, followed by cross-coupling reaction with 2-unsubstituted allenols 422c (Scheme 72, reaction b). 292 Besides the classical palladium-cross-coupling strategies, the past decade has started to witness the use of different metals to improve the efficiency and expand the scope of the methodology. Rhodium catalysis has been used to promote an oxycyclization−cross-coupling reaction of allenols with diverse benzamides including a challenging arene C−H bond insertion. Reaction of α-allenols 425 293 A mechanistically different arene functionalization dealing with the intermolecular cyclization reaction of β-allenols in the presence of indoles catalyzed by a platinum salt, has been reported to afford C3-substituted indole derivatives with a tetrahydro-2H-pyran ring. 294 Opposite to palladium or rhodium species, the high redox potential of gold makes the oxidative addition/reductive elimination steps hard to perform on gold-mediated transformations, and consequently inadequate for cross-coupling reactions. On the other hand, the well-known ability of gold salts to catalyze allenol oxycyclizations, frequently the first step in cross-coupling processes, has prompted different research groups to find solutions to circumvent this problem. Thus, photoredox catalysis has been successfully applied to achieve a gold-mediated cross-coupling reaction of allenols and diazonium salts. Allenols 430 reacted with aryldiazonium salts 431 in the presence of AuClPPh 3 and [Ru(bpy) 3 ][PF 6 ] 2 as photoactive catalyst under visible light. The reaction provided a wide family of 2,3,4-trisubstituted dihydrofurans 432 in a regioselective manner (Scheme 74). Yields were moderate to excellent, finding the best results when deactivated aryldiazonium salts 431 were employed. In addition, diverse functionalities were well tolerated, such as CF 3 , Br or OMe. A mechanistic proposal may start from oxidative arylation of the gold species promoted by single electron transfer from photoactivated ruthenium complex, generating Au(III) species 434. Coordination of 434 onto the allenic moiety of 430 resulted in complex 435, which would induce the oxycyclization step, generating intermediate 436. Reductive elimination would then recover the Au(I) species to the catalytic cycle and explain the formation of the observed 4-aryl-dihydrofurans 432 after deprotonation. 295,296 The reactivity of allenols has also been used in catalysis as a platform for testing the versatility of recently developed metal complexes. The allenol oxycyclization process has been applied as a model reaction to investigate new catalytic pathways along with the design and tuning of novel catalysts. In this context, Rueping and collaborators have informed of a rare metal−ligand dual catalysis for the cycloisomerization of β-allenols. Allenes 437 bearing a β-hydroxyl unit reacted with catalytic amounts of iron cyclopentadienone complex 438, yielding 3,4-dihydro-2Hpyrans 439, through a selective 6-endo-trig oxycyclization/ double bond isomerization process (Scheme 75, reaction a). The methodology was extended to both aromatic and aliphatic substituted allenols, providing the pyran skeleton in good yields. In addition, benzoxepine structure 441 was also accessible under similar reaction conditions through a more challenging 7-endotrig heterocyclization (Scheme 75, reaction b). 297 The cooperative metal−ligand catalysis strategy was further applied to the synthesis of dihydrofuran systems 443 through a 5-endotrig cycloetherification of α-allenols 442 (Scheme 75, reaction Chemical Reviews pubs.acs.org/CR Review adducts 452 would need a disfavored proton release from the POM skeleton, explaining the low reaction rates (up to 5 days to completion) compared to regular homogeneous gold-catalyzed hydroalkoxylations. Finally, special solubility of POM systems provides catalyst recycling, constituting this approach as a greener and more economic strategy. 300 During the past decade, different contributions on gold catalysis have appeared describing both a rationale design as well as synthesis and applications of novel catalysts that could be able to provide higher efficiency and greener procedures. Noteworthy, the hydroalkoxylation of allenols has been frequently chosen as model reaction. Hilvert's research group has described the synthesis of thiazolium gold(I) carbenes 457, as a greener alternative to the well-known imidazolium analogous. The higher hydrophilicity of thiamine units, together with the presence of a pyrophosphate group, improves the catalyst stability, and allows the use of aqueous media in hydroalkoxylation reactions. Thus, γ-allenol 458 could be successfully transformed (up to 98% conversion) into tetrahydrofuran 459 under mild reaction conditions and open-air experiments (Scheme 78). 301 In the pursuit of more economic and environmentally friendly strategies including precious metal catalysis, Lipshutz and coworkers have recently reported the use of gold(I) salts in micellar systems. Surfactant Nok (SPGS-550-M) was employed in combination with the newly synthesized gold(I) salt 460, showing an improved lipophilicity (Scheme 79). The micellar cavities based on aggregation of Nok molecules in aqueous media behaved as organic-based nanoreactors, encapsulating the hydrophobic reagents and therefore increasing their effective concentration. Thus, both uses of solvent and catalyst could be minimized, resulting in high conversions with catalyst loadings of 0.1 mol %. Also, an E factor of 7.6 for the oxycyclization of allenols 462 into spirocyclic systems 463 indicates the promising greener advantages of the micellar-based strategy. 302 Bergman, Raymond, Toste, and collaborators have introduced supramolecular chemistry in gold catalysis from a different perspective. Gallium-based tetrahedral macromolecule 464 has been used as a supramolecular host for cationic gold species, acting as an enzyme-mimic catalyst. Again, hydroalkoxylation of allenol 458 has been selected as model transformation, to study the catalytic activity of Au-464 species (Scheme 80). Noteworthy, encapsulation of the gold salt induces ionic bond dissociation, resulting in more active "naked" cationic gold species. Thus, the catalytic activity is 8-fold increased compared to regular homogeneous cationic gold procedures, and up to 67 catalytic turnovers were observed. 303 Following a similar concept, Reek et al. have envisioned a gold(I) system bearing supramolecular ligands, as inductor of selectivity in the oxycyclization reaction of allenols. Pyridyldecorated phosphoramidite ligands 465 were used to both bonding to the active gold ion and to link Zn template 466 through the pyridyl nitrogen atom, generating the supramolecular structure 467. Although lower conversions were achieved compared to AuCl(L) complexes under similar reaction conditions, complete selectivity toward 5-exo-trig cyclization of allenol 468 was observed, yielding vinyl tetrahydrofuran 469 as sole reaction product (Scheme 81). 304

Allenols as Allenes Showing an Extra Coordination Site
Besides the allenol transformations where the hydroxyl group behaves as a leaving group or as a nucleophile, seen in previous sections 3.1 and 3.2 respectively, the recent literature has also provided several examples of alternative hydroxyl-assisted reactions. This third class of allenol reactivity includes both metal-catalyzed processes where the M−O coordination is crucial for a specific transformation as well as bond migration reactions promoted by the hydroxyl lone electron pairs. In those cases, the hydroxyl unit is retained unaltered in the final products or oxidized into a carbonyl group.
Araki and co-workers reported one early example of OHassisted allylindation of allenols. Hydroxyl-chelated bicyclic species are reported as the most plausible transition states for this transformation.  311 The cyclopentenone skeleton is a recurring target in organic synthesis, exhibiting an extense range of biological activities and synthetic applications. Besides the well-known Pauson-Khand and Nazarov cyclizations, metal-catalyzed cycloisomerizations have recently appeared as synthetic strategies to achieve the cyclopentenone motif. 312−315 In this context, Cha and coworkers have described an allenol-based ring expansion process involving a ruthenium−oxygen coordination to provide the cyclopentenone system. Thus, allenyl cyclopropanols 495 were treated with ruthenium complex 496 and In(OTf) 3 as additive, generating cyclopentenones 497 in moderate to good yields (Scheme 85, reaction a, left). The mechanistic pathway may start from dual coordination of the metal in alcoholate 498. Ring  and CuI as bimetallic pair, yielding differently substituted fused cyclopentenones 504 and 506 in good yields (Scheme 85, reaction b), through a proposed intramolecular Heck-type coupling reaction mechanism. 318 Hydroxyl-assisted bond migrations in allenol systems have been frequently reported by different research groups. Ma and collaborators have pioneered halogen-promoted 1,2-aryl shift, and 1,2-H shift in allenol skeletons. 319,320 Thus, secondary and tertiary allenols were reported to smoothly generate 3-halo-3alkenals and 2-halo-2-alkenyl ketones respectively, under halogenating reagents such as Br 2 , I 2 , NIS, or NBS. During the past decade, related halogen-promoted 1,2-bond migrations in allenol systems have been employed in ring expansion processes. Moreover, selenating reagents were found to induce an intriguing selectivity on this transformation. Thus, 2-azetidinone-tethered allenols 507 were reported to undergo a selective 1,2 C−C bond migration in the presence of NBS, providing tetramic acids 510 (Scheme 86, reaction a). In contratst, the use of N-phenylselenophthalimide as electrophile promoted the oxycyclization process yielding spirocyclic seleno-β-lactams 511, under otherwise similar reaction conditions. 321 Species 508 and 509, formed by coordination of the electrophile to the proximal and distal allene double bond respectively, are proposed as raisonable intermediates for the divergent transformation (Scheme 86, reaction a). In addition, 2-indolinone-

Scheme 84. Allenol Transformations Promoted by Previous Metal-Hydroxyl Previous Coordination
tethered allenols 512 under NBS conditions provided the corresponding quinolone skeletons 513 and 514 through a related ring expansion process (Scheme 86, reaction b, right). 322 Noteworthy, mixtures of two regioisomers were frequently found, quinolone-2,3-diones 513 as major products from a C3− C4 bond cleavage, together with quinoline-2,4-diones 514 from a less favorable C2−C3 bond breakage. Interestingly, selenating reagents improved the divergency of the process, finding selenoquinoline-2,3-diones 515 as major or sole reaction products in the presence of N-phenylselenophthalimide (NPSP) (Scheme 86, reaction b, top left). Spirocyclic selenolactams 516 where achieved when phenylselenyl bromide was used. Also, AuCl 3 −NPSP cocatalyzed reaction of allenols 512 favored the formation of the spirocyclic products 516, probably due to the gold ability in promoting oxycyclization transformations in allenols (Scheme 86, reaction b, bottom left). 323 Toste's research group has presented a photoredox-catalyzed ring expansion methodology in ciclopropane-linked allenol systems. Compounds 517 undergo ring expansion and oxidative arylation processes in the presence of electrophilic gold(III)-aryl complex 520 which is generated in situ from benzenediazonium salt 518. Coordination of the gold complex to the proximal allenic double bond in allenols 517 to give intermdediates 521 would promote the oxidative ring expansion process toward intermediates 522. The observed four-membered cyclic ketones 519 are obtained in practical yields from reductive elimination of intermediates 522 (Scheme 87). 324 325 Liu and co-workers have reported a methoxy-assisted allene migration to explain the synthesis of pyrroles 530 and pyrrolo[1,2-a]quinoline derivatives 531 from 4-methoxy-1,2dienyl-5-ynes 526 with anthranil (527). Anthranil is proposed to attack the π-activated alkyne moiety in complex 528 (formed in the presence of gold salts), generating α-imino gold carbene intermediate 529. 1,2-Allene migration and further goldmediated aza-cyclization would furnish pyrroles 530. When allene ester systems are employed, subsequent aldol reaction would explain evolution toward the polycyclic structures 531 (Scheme 88, top). 326 On the other hand, reaction of 4-methoxy-1,2-dienyl-5-ynes 526 with isoxazole (532) as nucleophile provided the indolizine skeleton 536 and 537 under identical reaction conditions, unravelling a different mechanistic pathway. In this case, alkyne attack to the π-activated allene moiety in gold complex 533 would produce cyclic intermediate 534, which afer methoxy-assisted ring-opening and isomerization could lead to vinyl gold carbene 535. Nucleophilic attack of the isoxazole unit to the gold carbene carbon followed by a cascade azacyclization/ rearrangement and aromatization would explain the observed indolizine compounds 536 and 537 (Scheme 88, bottom). 327 Selenium-based π-acid-type catalysis has been used for the preparation of α,β-unsaturated α′-alkoxy ketones from alkoxyallenes through alkoxy migration. 328

Allenols in Chirality Transfer Processes
The development of new strategies to provide enantioenriched molecules constitutes one of the principal interests of the chemistry community. During the past decade, allenol-based reactions have also provided a notorious and increasing number of chirality transfer methodologies to get access to a wide family of enantioenriched structures. Chirality transfer from both central and axially chiral allenols has been reported. Also, it has been described the use of racemic allenols as precursors for the obtention of enantioenriched final compounds employing enzymatic catalysis, optically pure ligands in metal catalysis, and hybrid methodologies.
3.4.1. Central-to-Central Chirality Transfer. The Alcaide and Almendros research group has described the synthesis of optically pure dihydropyran, tetrahydrofuran, and tetrahydrooxepine skeletons from enantiopure β,γand γ,δ-allendiols. Also, furan systems were synthesized. The methodology revealed an intriguing selectivity toward the oxycyclization reaction of secondary hydroxyls versus primary hydroxyls in both β,γand γ,δ-allendiols. The choice of the metal catalyst and the Chemical Reviews pubs.acs.org/CR Review appropriate substituent was found to be crucial to achieve the optimal regioselectivity. Thus, β,γ-allendiols 538 reacted with gold(III) salts to produce the dihydropyran skeleton 539 through a 6-endo cycloisomerization process involving the secondary hydroxyl group and the terminal allenic carbon (Scheme 89, reaction a, top right). Interestingly, allendiol 538 provided carbaldehyde 540 in the presence of platinum salts, from a similar 6-endo cycloetherification reaction followed by a subsequent oxidation (Scheme 89, reaction a, bottom right). In contrast, furan 541 was obtained when β,γ-allendiol 538 was exposed to a lanthanide complex under catalytic conditions, through a 5-exo cyclization toward the central allenic carbon (Scheme 89, reaction a, top left). Although palladium salts failed in promoting an effective cycloetherification to yield dihydropyrans 539 from allendiols 538, the use of a Pd(II) catalysts and allyl bromide as coupling counterpart smoothly led to substituted dihydropyrans 542 (Scheme 89, reaction a, bottom left). This transformation revealed a selective 6-endo cyclization/ cross-coupling cascade reaction toward the terminal allenic carbon. On the other hand, benzyloxy homologous γ,δallendiols 543a provided dihydrofurans 544a under gold(III) catalytic conditions (Scheme 89, reaction b, top right). Noteworthy, diastereomer 543b provided the corresponding 5-membered oxacycle 544b through a related 5-exo-trig cyclization, but exhibiting a decrease in the diastereoselectivity (Scheme 89, reaction b, top left). Although platinum catalysts did not show efficiency in the conversion of γ,δ-allendiols into oxacycle systems, lanthanide complexes provided dihydrofuran 544a in similar yields as gold salts (Scheme 89, reaction b, right). More interestingly, palladium-catalyzed cross-coupling reaction conditions unravelled a dramatic change in the regiochemistry of the oxycyclization reaction depending on the absolute configuration of the starting material. Thus, γ,δ-allendiols 543b provided the substituted tetrahydrooxepine 545 through a rare 7-endo-trig cyclization, while diastereomer 543a yielded tetrahydrofuran 545 through a 5-exo-trig cyclization toward the inner allenic carbon (Scheme 89, reaction b, bottom). 329 More recently, the same research group has reported the metal-based chemoselective azaversus oxy-cyclization reaction of enantiopure α-amino-β-hydroxyallenes. Gold salts were reported to selectively promote the 5-endo azacyclization toward the synthesis of optically pure 2,5-dihydro-1H-pyrroles, while the palladium cyclization/cross-coupling cascade strategy yielded 6-dihydro-2H-pyrans through a 6-endo cycloetherification reaction. 330 Also, optically pure β-lactam-tethered allenols were employed as chirality transfer reagents for the preparation of a wide variety of enantiopure polycyclic structures, such as morpholines, oxocines, dioxonines, 331 and the already mentioned tetramic acids 510 and spirolactams 511 (see Scheme 86), 321 through halogen or selenium-promoted reactions, respectively.
Ma and collaborators have described the synthesis of enantiopure oxacycles from optically pure allenols presenting a tetrahedral chiral carbon through metal-catalyzed cascade processes involving oxycyclization steps. Highly substituted 2(5H)-furanones 548a/548b were obtained by treatment of allenols 547a/547b with Grignard reagents and CO 2 atmosphere (Scheme 90, reaction a). The proposed reaction mechanism starts with the insertion of the organometallic reagent into the terminal allenic double bond, generating the cyclic intermediate 549 by Mg−O interaction. Reaction with CO 2 would produce the corresponding γ-hydroxy-Z-alkenoic carboxylic acid 550, which could undergo lactonization to yield the observed butenolides 548 without racemization. 332 In a different approach, oxa-bridged benzocycloheptanes 551a/551b were synthesized by reaction between optically pure allenols 547 and iodobenzaldehyde in the presence of palladium salts and a base (Scheme 90, reaction b). In this case, initial oxidative addition of Pd(0) species into the aryl halide would provide intermediate 552. Then, carbopalladation of the corresponding allenol 547 (547b in Scheme 90, reaction b, bottom) would produce both π-allyl intermediates anti-553 and syn-553, being the latter the most sterically favored. Intramolecular attack of the alkoxide to the carbaldehyde group in syn-553 would lead to diastereomers 554 and 555. The observed diasteroselectivity of the overall process could be explained by selective oxycyclization toward the allylic position in 554, providing the less sterically hindered oxa-bridged benzocycloheptanes 551b from allenes 547b. 333 Taking advantage of the versatile chemical behavior of the enallenol skeleton, Backvall research group has reported the preparation of a wide variety of molecules exhibiting high structural diversity and up to two sterogenic centers in optically pure form. Enantioenriched enallenol 556 reacted with Pd(TFA) 2 under CO atmosphere to yield bicyclic lactone 557 with complete enantioretention (Scheme 91, reaction a). 334 The reaction mechanism to explain this transformation would include a palladium-mediated allene-alkene carbocyclization reaction, followed by a sequential carbonylation/lactonization . Homogeneous Pd(OAc) 2 catalysis was employed to achieve this transformation, which should imply a related allene-alkene carbocyclization followed by ligand exchange with the borane reagent and reductive elimination. 335 Noteworthy, coordination of the hydroxyl unit with the metal ion at the first stages of the reaction mechanism is proposed to be crucial to explain formation of compounds 557 and 559.
In contrast, enallenols 560 were transformed into oxaboroles 561 by reaction with B 2 pin 2 under heterogeneous palladium catalysis (Scheme 91, reaction c, right). Enantioenriched allenols 560 were prepared through kinetic resolution of the racemic mixture using Candida Antarctica Lipase B, showing >99% ee. Interestingly, despite of the palladium ability to induce racemization in allylic alcohols, no loss of optical purity was detected. 209 The same catalytic system provided γ-lactones 562 in optically pure manner from reaction of allenols 560 under CO atmosphere. Moderate to good yields were achieved with full retention of the enantiopurity in final compounds 562 (Scheme 91, reaction c, left). 336 Amino-supported heterogeneous palladium has also been recently used by Backvall et al. in a domino reaction from related enallenols with alkynes. The chelating activity of the hydroxyl group is responsible of the observed diastereoselectivity. 337 More particular methodologies for the synthesis of stereodefined oxacycles have been recently reported. Anderson et al. have described the reaction of enantiopure cyclic alkynyl carbonates with palladium catalysts to yield alkynyl tetrahydrofuran systems through in situ generated allenol-palladium intermediates. 338 Guinchard and collaborators have employed gold-catalyzed cyclizations of tetrahydro β-carboline structures decorated with enallenol motifs for the synthesis of optically pure decahydrofuro[2,3-f ]indolo-[2,3-a]quinolizines. Gold(I) salts have been reported to exhibit optimal reaction conversions providing full enantioretention and good control on the enantioselectivity of the newly formed sterogenic centers. 339 Opposite to the most commonly reported cyclization reactions, intermolecular processes involving enantioenriched allenols in asymmetric synthesis are scarce. Taking advantage of the chelating effect of the hydroxyl group, as explored in section 3.3, palladium-catalyzed multicomponent reactions of different allenols 563, aryl iodides 564 and benzylamine proceeded with no loss of enantiopurity, even in the absence of enantiopure phosphine ligands. Interestingly, a change on the allenol substitution provided a dramatic change on the regioselectivity. Thus, phenyl-substituted allenols yielded homoalylic alcohols 565, while alkyl-substituted substrates provided allylic alcohols 566, through the attack of the amine to the terminal allenic carbon (Scheme 92). 340 3.4.2. Axial-to-Central Chirality Transfer. Opposite to central-to-central chirality transfer methodologies from enantioenriched allenols, reports on axial-to-central chirality transfer using axially chiral enantioenriched allenols are rare. One of the principal challenges to circumvent is the ease of racemization of the allene moiety under metal catalyzed conditions. Normally, metal activation of the allene unit starts with π-coordination of one of the double allenic bonds with the metal ion in a η 2 complex 567 (Scheme 93). When such intermediates are in equilibrium with the corresponding π-allyl cations 568, free bond rotation falls into loss of the optical purity of the allene moiety. Avoiding the above-mentioned equilibrium by stabilizing the η 2 complex constitutes one of the most recurrent strategies to achieve axial chirality transfer reactions in allenes. The choice of the metal catalyst and the appropriate substituents on the allene core are the principal tools to achieve a successful chirality transfer transformation. In the context of allenol-based reactions, Lalic and co-workers have reported the first synthesis of teytrahydrofuran and tetrahydropyran systems bearing a tetrasubstituted stereogenic center. Substituted βand γ-allenols 570 were submitted to gold catalysis providing the expected oxycyclization products 571 with good to excellent yields and a chirality transfer of up to 99% (Scheme 94). Gold(I)-based salts bearing a tosylate group together with electron-rich sterically hindered phosphine ligands were found to provide the best results, also promoting complete E-selectivity in the double bond formation in compounds 571. A plausible reaction mechanism would start from coordination of the metal species to the proximal double bond in intermediate 572, followed by carbometalation to furnish vinyl gold intermediate 573 without the occurrence of allene racemization. Opposite to Widenhoefer's statement about digold alkenyl intermediates as catalyst resting states, 299 monogold(I) intermediate 573 is herein presented as the most likely resting state due to the weakly electrophilicity of the gold complex, and the highly coordinating character of the counterion. 341 Similarly, Yin's research group has reported the synthesis of substituted dihydrofurans 575 showing up to 20:1 dr through a gold-catalyzed oxycyclization process. Allenols 574, exhibiting both axial and central chirality, have been prepared according to the previously mentioned asymmetric Cu-catalyzed alkynylogous aldol reaction (Scheme 22, reaction a), and successfully converted into cyclic structures 575, current motifs in anti-Alzheimer and Down's Syndrome drugs (Scheme 95). 144 A different approach based on gold catalysis has been reported by Krause and Lipshutz et al., following their interest in discovering new micellar systems to provide greener methodologies, high catalyst efficiency and recyclability. 280 It has been reported that micellar catalysis in aqueous media was also effective for the synthesis of enantioenriched structures from αallenols, employing poly(oxyethyl)-α-tocopheryl sebacate (PTS, 578) as amphiphile and AuBr 3 as metal source. Dihydrofuran structures 577 bearing two stereogenic centers were achieved, exhibiting good to excellent yields and complete chirality transfer (Scheme 96). 342 Carbometalation of the allenic double bond from the less sterically hindered adduct 583 could explain the E-selectivity observed, furnishing vinyl rhodium compound 585, which may suffer protonolysis to give 586. Eventual lactonization would explain the experimentally observed cyclic structures 581. 343 Metal-free strategies regarding axial-to-central chirality transfer are scarce. Zhang and Bao and collaborators have recently reported the NIS-promoted allenol oxycyclization to yield dihydropyran systems showing central chirality. 344 Sakaguchi and Ohfune and co-workers have described the enantiomeric version of the Prins-type reaction of allenols with carbonyls. β-Allenols 587 bearing a terminal silyl group were selected as chirality transfer agents, reacting through an uncommon 5-endotrig cyclization in the presence of TMSOTf as Lewis acid catalyst and both aldehydes and ketones as reaction counterparts. Silylalkynyl-decorated tetrahydrofurans 589 were obtained as single diastereomers, exhibiting two stereogenic centers (Scheme 98, reaction a). To test the axial-to-central chirality transfer efficiency, enantioenriched allenol 587a was synthesized with a 92% ee. Reaction of 587a with benzaldehyde (588a) and TMSOTf as acid catalyst provided the expected oxycyclization product 589a showing an enantiomeric excess of 78%. Increasing the Lewis acid load up to 1.1 equiv allowed an 85% ee in final tetrahydrofuran 589a, showing solely slight racemization during the reaction (Scheme 98, reaction b). 345

Metal-Based Catalysts as Chirality Transfer
Agents. Metal catalysis offers a wide variety of alternatives to achieve an efficient chirality transfer with associated formation of enantioenriched molecules. The most traditional and extended strategy is based in the joined use of the metal along with a chiral phosphine ligand which induces enantioselectivity during the reaction. Michelet and Scalone and collaborators have synthesized an unprecedented bromine-decorated diphosphine ligand (S)-591 showing chiral atropisomerism. The catalytic system Ag/591 was applied for the synthesis of vinyl tetrahydrofurans 592 through a 5-exo-trig cyclization of γallenols 590. Yields were moderate to excellent, and enantiomeric ratios up to 91.5:8.5 were stated (Scheme 99, reaction a). 346 Ma's research group has devised an enantioselective palladium-catalyzed cross-coupling reaction of γ-allenols 590 with aryl iodides 594 yielding styryl tetrahydrofuran systems 577 through a similar 5-exo-trig cyclization. Optically pure diphophine (R,R)-591 was employed, finding enantioinversion in vinyl-substituted tetrahydrofuran structures 595 with respect to systems 592. Good yields and up to 92% ee were stated (Scheme 99, reaction b). 347 Zhang's research group has envisioned an accelerative gold catalysis by ligand−metal coordination to γ-allenols 590 providing vinyl tetrahydrofuran skeletons 595 (Scheme 100, reaction a). Opposite to classic enantiopure ligand approaches, tetrahydrofurans 595 with good to excellent yields and enantioselectivities up to >99% ee. Also, catalyst loadings as low as 200 ppm were allowed. 348 A similar strategy was applied to the synthesis of enantioenriched dihydrofuran structures from in situ generated α-allenol systems. 349 The 5-exo-trig oxycyclization of γ-allenol 598 has also been in the focus of an intriguing case of enantioinversion in final vinyl tetrahydrofuran molecules (S)-592a and (R)-592a (Scheme 98, reaction b). Furstner et al. have found that even under the same optically pure gold catalyst 599, formed from AuCl and phosphoramidite (S,S,S,S)-599, enantioselection could be achieved by changing the solvent, temperature, and counterion. Moreover, a synergistic effect between the three parameters could be perform, achiving enantiomeric excesses from 97% ee in (R)-595a (Scheme 100, reaction b, right) to 68% ee in (S)-592a (Scheme 100, reaction b, left). Experimental and computational studies revealed that a change in the rate determining step lays on the base of the change in the sterochemical outcome. Protic solvents and coordinating counterions supported an additiveassisted reaction mechanism favoring the (R)-595a isomer. Also, temperature has a dramatic entropic effect, promoting the additive-assisted mechanism on cryogenic conditions providing (R)-579a isomer as major compound. 350,351 Related enantiopure oxaphosphorous ligands 602 and 603 have been used in the context on an unprecedented enantioselective silver-catalyzed oxycyclization of allenols. Reaction of Ag 2 CO 3 salts with the corresponding phosphoric acid yielded catalyst complexes Ag-602 and Ag-603. Treatment of different allenols 600 with the preprepared catalytic species allowed the synthesis of vinyl tetrahydrofuran and tetrahydropyran compounds 601 (Scheme 101). Also, furanones were obtained starting from the corresponding allenic carboxilyc acids. DFT calculations on this transformation pointed to ionic interactions between ligand and substrate as the major forces contributing to the enantioselectivity of the process. 352 Chemical desymmetrization of prochiral allendiols has been accomplished using palladium catalysts and enantiopure phosphoric acids as ligands. α,α′-Allendiols 604 were submitted to Pd(OAc) 2  Chemical Reviews pubs.acs.org/CR Review the catalytic system and the allenol unit through both metalcoordination to the central allenic carbon and hydrogen bonding with the hydroxyl group. 353 In a similar but conceptually different approach, γ,γ′-allendiols 609 were converted into enantioenriched tetrahydrofuran derivatives 611 through a goldcatalyzed oxycyclization (Scheme 102, reaction b). In this case, enantiopure phosphoric silver salts (R)-609 were introduced in the reaction system as chiral counterions, while achiral phosphine ligands such as 610 are linked to the reactive gold ion and are used as enantioselectivity modulators. This methodology allowed the generation of two stereogenic centers in one single operational step, furnishing oxacycles 611 with good to excellent yields and up to 93% ee. 354 Different authors have investigated the synergistic effect of both enantiopure chiral ligands and enantiopure counterions to achieve higher enantioselectivities without loss of catalytic activity. Regarding allenol oxycyclizations, Mikami et al. have described the use of neutral dinuclear gold complexes 613 as catalytic species with improved activity for the 5-exo-trig cyclization of substituted γ-allenols (Scheme 103, reaction a).
The optimal reaction conditions were found when same catalytic amount of 613 and the silver salt Ag-614 bearing an enantiopure chiral phosphoric acid counterion were added. Vinyl tetrahydrofurans 615 were obtained with good to excellent yields and up to 95% ee. According to experimental studies, it has been proposed species (R)-616 from ligand exchange with one equivalent of silver complex Ag-614 as the catalytically active system. Complex (R)-613 in the absence of silver salts was ineffective for the indicated transformation, while complex (R)-617 from the addition of two equivalents of Ag-614 showed lower yields and enantioselectivity (Scheme 103, reaction a). 355 Toste and co-workers described the enantioselective azacyclization/halogenation tandem reaction of allenamides 618 with brominating reagent 619 to yield bromovivnyl pyrrolidine structures 621 under gold catalysis in the presence of BINAPtype ligands (Scheme 103, reaction b). The methodology also included one example of 5-exo-trig oxycyclization of γ-allenol 622 to produce bromovinyl tetrahydrofuran 625 (Scheme 103, reaction c). This transformation promoted by gold catalyst 623 provided a poor enantioselectivity (25% ee) of the indicated structure 625. Interestingly, the combined use of 623 and silver salt Ag-624 bearing a chiral counterion provoked a remarkable impact, both increasing the selectivity up to 86% ee and reverting the enantioselectivity compared to adducts 621. 356 Despite the widespread presence of carbocations in organic synthesis, its utilization as reaction intermediates in asymmetric synthesis is still scarcely described. The challenging facial discrimination in planar carbocation species has been mainly limited to diastereoselective-substrate control, or to the addition of an enantiopure chiral anion forming ion pairs with the carbocationic molecule. Carreira research group has envisioned an alternative approach for developing asymmetric S N 1-type reactions in α-allenols and related systems, based in η 2 coordination complex 633 (Scheme 104, bottom). Species 633 formed from interaction of iridium salts bearing an enantiopure chiral phosphine and the distal double bond of the allene moiety can be considered as mimics of diastereoselective-control substrates and constitutes one rare example of enantioselectivity in allenol transformations apart from oxycyclization processes. Thus, racemic Boc-protected αallenols 626 reacted with organozinc nucleophiles 628 in the presence of iridium catalysts Ir-(R)-627 to provide compounds 629 in practical yields and excellent enantioselectivities, through an asymmetric allene-transfer reaction (Scheme 104, reaction a). 357 In addition, related methodology has been applied to describe the first example of an enantioselective reductive deoxygenation of tertiary alcohols. Thus, racemic α-allenols 630 were submitted to catalytic system Ir-(S)-627 in the presence of Hantzsch ester analogues 631 as hydride source, providing  358 Different approaches to achieve asymmetric synthesis from racemic allenols and enantiopure catalysts also includes denitrogenative annulation of 1,2,3-benzotriazin-4(3H)-ones with allenes under nickel catalysis, 359 synthesis of 1Hisochromene structures through copper catalyzed oxycupration/allylation reaction using optically pure phosphine ligands, 360 the enantioselective synthesis of spiropentanes from hydroxymethylallenes catalyzed by Zn, 361 the asymmetric palladium-catalyzed homoallenilation of amines, 362 or the synthesis of cyclodextrin-tethered gold(I) carbene complexes as water-soluble and recyclable catalysts for several transformations including oxycyclizations of αand γ-allenols. 363 Racemic 2-(2′,3′-alkadienyl)malonates were obtained through the Pd(PPh 3 ) 4 -catalyzed alkylation reaction of allenyl acetates with malonates 364 while racemic allenes bearing a quaternary carbon center α to the cumullene were prepared by [Ir(cod)Cl] 2 /dppe-catalyzed allylic alkylation of 1,1-disubstituted-2,3-butadienyl acetates with malonates. 365 A smart approach for obtaining optically active allenes is the direct preparation from achiral allenyl acetates, allenyl phosphonates, and allenyl carbamates via π-allylmetal intermediates, taking advantage of the great leaving aptitude of the acetate, phosphonate, and carbamate moieties. Imada, Murahashi, and Naota achieved the metal-catalyzed synthesis of enantioneriched α-allenamines 635 by asymmetric amination of allenyl phosphonates 634 using Pd2(dba)3CHCl3 as the palladium source and (R)-SEGPHOS as the ligand (Scheme 105, reaction a). 366 Starting from precursors 1, the same research group did also reported the asymmetric alkylation with 2-acetamidomalonate. 367 Trost and co-workers accomplished the asymmetric synthesis of allenes (S)-635 and (S)-637 from allenyl acetates 636 by palladium-catalyzed dynamic kinetic reactions with both malonates and amines involving α-methylidene π-allylpalladium species (Scheme 105, reaction b). 368 The optimized reaction conditions require the use of Pd2dba3 (2.5 mol %), phosphine 104 (7.5 mol %), THACl (tetrahexylammonium chloride) (5 mol %), and a base in THF. Hamada performed the same palladium-catalyzed reaction between allenyl acetates 636 and malonates but replacing Trost ligand with (S,R P )-DIAPHOXs, a chiral nonracemic diaminophosphine oxide, which results in the formation of axially chiral allenes (R)-637 in good yields with up to 99% ee. 369 The above-mentioned palladium-catalyzed amination of allenyl phosphonates, 370 and the addition of malonates to allenyl acetates, 371,372 have also been explored by Ma and collaborators in the context of achieving central as much as axial chirality from racemic allenes. The same research group has deeply investigated different allenyl esters in the presence of various nucleophiles yielding substituted allenes exhibiting both types of chirality. Thus, racemic allenyl acetates 638 have been reported to undergo a S N 2′-type oxidative addition in the presence of palladium complexes and enantiopure (R)-DTBM-SEGPHOS as ligand. Echoing effect between the central and axial chirality is stated, providing enantioenriched allenes 640 showing both axial and central chirality (Scheme 105, recation c). 373 Asymmetric allenylation of malonates have also been achieved using racemic allenyl carbonates. Selectivity between mono-and bis-allenylation is reported using Pd2(dba)3/(R)-DTBM-SEGPHOS as catalytic pair. 374 In a related work, a smart approach to allenylamines exhibiting axial chirality has been accomplished through the palladium-catalyzed decarboxylative amination of allenyl carbamates 641. Pd2(dba)3/(S)-DTBM-SEGPHOS catalytic pair promotes the loss of CO2 providing the corresponding π-allylpalladium intermediates. Further nucleophilic attack of the in situ generated amide ion yields the observed allenylamines 635a exhibiting up to 99% ee and good to excellent yields (Scheme 105, reaction d). 375 3.4.4. Chirality Transfer in Enzymatic Catalysis. Although enzymatic systems have been largely employed as biocatalysts for KR and DKR in allenol synthesis, strategies for the preparation of enantiopure compounds from racemic allenols including enzymatic resolution are almost unexplored. Backvall research group has contributed to develop this methodology with the synthesis of dihydrofuran and cyclobutanol skeletons with excellent enantiomeric excesses. During attempts to achieve an efficient DKR of allenols, Shvo catalyst (645) was used in combination with Candida Antarctica lipase B (CAlB) to promote the expected consecutive recemization and selective acetylation of α-allenols 642. Despite the well-known activity of ruthenium catalyst 645 for the racemization of secondary alcohols, oxycyclization products 643 were found instead, along with the corresponding acetylated allenols 644 (Scheme 106, reaction a). Noteworthy, enantioselectivities in dihydrofuran skeletons 643 were remarkably higher in comparaison with any other standard oxycyclization procedure.

Scheme 105. Palladium-Catalyzed Enantioselective Synthesis of Functionalized Allenes from Allenyl Esters
Chemical Reviews pubs.acs.org/CR Review In addition, mechanistic insights pointed to ruthenium carbene species 647 as reaction intermediates, explaining the eventual double bond isomerization found in final adducts 643 through a 1,2-H shift. 376 Alternatively, a cheaper and less toxic approach based on iron catalyst 646 and same enzymatic system allowed the preparation of dydrofurans 643 through milder reaction conditions (Scheme 106, reaction b). 377 The same research group has also taken advantage of the fruitful reactivity of enallenol skeletons under palladium catalysis, previously mentioned in section 3.2, to perform the synthesis of cyclobutenol structures. Reaction of racemic enalenols 648 and boronic esters 649 in the presence of palladium nanoparticles yielded the four-membered ring systems 650 trough a tandem carbocyclization/borylation reaction. Moderate to good yields and high diastereoselectivities were observed. In addition, palladium nanoparticles were suspended on amino-decorated mesocellular foam (Pd-Amp-MCF), providing high recyclability and efficiency (Scheme 101, reaction a). In combination with biocatalyst CAlB, cyclobutenol structure (1S,4S)-650a was obtained with a good 83% yield from enantioenriched enallenol (S)-648a, and a high 95% ee (Scheme 107, reaction b). From the mechanistic point of view, hydroxyl group is proposed to perform a multiple role, promoting the carbocyclization process by coordination with the metal unit, and directing the stereoselectivity on final adducts 630 through intermediates 651. 378 Following their interest in supramolecular host−guest catalyzed reactions (see Scheme 80,ref 281, Bergman, Raymond, and Toste and collaborators have extended the applications of Ga 4 L 6 -encapsulated gold ions 464 in tandem reactions with biocatalysts. Nonencapsulated metal catalyst, especially gold species, can partially poison biocatalysts by binding amino-acid groups from the protein skeleton. This fact may incur in a loss of catalytic activity, unless great excess of enzyme is used. In addition, the use of supramolecular hosts exhibited many other advantages such as catalyst stabilization or aqueous media allowance. Thus, racemic acetylated γ-allenols 652 were reported to undergo KR in the presence of different enzymes such as Amano lipase PS providing enantioenriched allenols 653, which after oxycyclization in the presence of supramolecular catalyst 464 yielded dihydrofurans 654 showing up to 96% ee. Notably, the supramolecular host−guest catalytic system 464 allowed a decrease in the enzymatic loading to six units, compared with the 25 units needed when naked Me 3 PAuCl complex was used as catalyst. Kinetic experiments supported the hypothesis of the enzyme poisoning from free metal salts, revealing no interference between encapsulated gold systems 464 and lipase enzymes (Scheme 108). 379

ALLENOLS IN NATURAL PRODUCTS
The diverse reactivity of allenols under different reaction conditions has been applied to the synthesis of a wide family of natural and pharmaceutically attractive products. During the past decade, several reports have appeared describing the total synthesis of naturally occurring structures incorporating allenol chemistry, normally as a key step in the whole reaction sequence. Also, natural products have been characterized and synthesized exhibiting the allenol motif in the final structure. In the first part of this section, the most significant and recent uses of allenols as key intermediates in total synthesis will be described. In a second part, allenol synthesis strategies applied to the preparation of natural product bearing an allenol unit will be detailed.

Allenols as Key Intermediates in Natural Product Synthesis
The great ability of allenes to undergo carbo-and heterocyclization reactions has been largely employed for the synthesis of the cyclic core of different naturally occurring compounds. Concretely, oxycyclization of allenols has been one the most recurring tools to get access to natural products containing 5and 6-membered oxacycles. Silver catalysis has been frequently described to provide tetrahydrofuran systems from ennartioenriched allenols without racemization. In this context, Ballereau and co-workers have reported one short synthetic route to the natural product Jaspine B (655), a cytotoxic marine compound consisting in a trisubstituted tetrahydrofuran skeleton. The heterocyclic core was obtained through a silver-catalyzed 5-endotrig cyclization of α-allenol 657, obtained from the enantioselective Crabbe-type reaction of propargylic alcohol (655) with aldehyde 656 using optically pure (R)-α,α-diphenylprolinol as secondary amine (Scheme 109, reaction a). Axial-to-central chirality transfer from enantioenriched allenol 657 allowed the full retention of the enantiopurity in dihydrofuran 658. Further transformations included epoxidation, ring opening reaction in the presence of sodium azide and reduction to yield Jaspine B (659) in 12% overall yield through a six-step sequence. 380 Deska et al. reported the desymmetrization of prochiral allendiol 660 using enzymatic catalysis providing enantioenriched allenol 661 exhibiting 99% ee (Scheme 109, reaction b). Silver-catalyzed 5-endo-trig cyclization followed by enzymatic ester hydrolysis generated the corresponding dihydrofuran skeleton in product 662, with no racemization observed. Compound 662 was used as precursor for the synthesis of diastereomers Hyperione A (663) and Hyperione B (664), secondary metabolites found in the leaves of Hypericum Chinese, showing pharmaceutical activity. 381 (+)-Sylvone A (669) is a highly functionalized tetrahydrofuran metabolite principally extracted from the seeds and fruits of piper sylvaticum and piper logum plants. Yu's research group has envisioned a synthetic sequence to yield (+)-Sylvone A, based also on a silver-catalyzed 5-endo-trig cyclization of enantioenriched α-allenols. In this case, optically pure borane 666 was used as chiral inductor in the enantioselective aldol-type reaction of allenoate 665 with 3,4-dimethoxybenzaldehyde to yielded enantioenriched allenol 667 exhibiting 93% ee (Scheme 109, reaction c). Silver nitrate was then employed as the most convenient metal catalyst to promote the dihydrofuran generation from 667 to compound 668 avoiding racemization processes. Further transformations including a Michael addition provided the expected natural product (+)-Sylvone A (669) through a short 5-step reaction sequence. 382 Metal-catalyzed oxycyclization of α-allenols have also been involved in longer synthethic pathways toward the synthesis of natural products exhibiting higher structural complexity. Chemical Reviews pubs.acs.org/CR Review rearranges to produce α-allenol 672 as nonisolable reaction intermediate. In situ oxycyclization of 672 generates dihydrofuran 673 in 85% yield and dr >20:1. The complete synthesis of macrolide 670 comprises 34 steps in the longest linear sequence, and its synthesis has helped to elucidate the absolute configuration of the whole structure, unresolved since its first isolation more than two decades ago. 383 Leiodolide B metabolite (674) is a natural product isolated from marine sponges, showing a challenging tetrahydrofuran unit bearing four stereogenic centers on its northern fragment (Scheme 110, reaction b). Furstner and collaborators have envisioned a total synthesis of compound 674 through a 26-step reaction sequence. To achieve the tetrahydrofuran structure with the appropriate stereochemistry, a silver-promoted 5-endotrig oxycyclization of enantioenriched α-allenol 675 was proposed. In this manner, dihydrofuran 676 was therefore achieved in high 91% yield and further converted into tetrahydrofuran 677. Further transformations allowed the preparation of macrolide 674, although full charecterization and interpretation of the naturally isolated analogous remains unresolved, leaving the quest for the Leiodolide B absolute configuration still open. 384 The γ-butyrolactone scaffold is ubiquitous in nature and present in different biologically active alkaloids. Stenine (578) and Stemoamide (579), two naturally occurring heterocycles from the stemona alkaloid family, exhibit a γ-butyrolactone unit which has been achieved trough a ruthenium-catalyzed carbonylation of allenols. In both cases, related exocyclic allenols 580 and 583 were synthesized and submitted to ruthenium catalysis under CO atmosphere to yield butenolide systems 581 and 584 (Scheme 111). In the final steps of the synthesis of the stenine and stemoamide cores, double bond reduction by treatment with Mg/MeOH and nickel boride, respectively, led to the desired compounds 682 and 679. 385,386 In a recent total synthesis of (+)-Xilogyblactone A (685), an alternative gold-based methodology has been introduced to access the butanolide motif. t Butyl allenoate 686 reacted through an asymmetric aldol-type transformation with aldehyde 687 in the presence of enantiopure organoboron reagent 666. Enantioenriched α-allenol 688 was therefore synthesized exhibiting >99% ee. Interestingly, gold treatment of allenol 688 yielded the butenolide skeleton from selective nucleophilic attack of the carboxylic oxygen to the allene moiety. (+)-Xilogyblactone (685) was obtained after acidic hydrolysis of the TBSO group through a short three-step sequence and a 41% overall yield (Scheme 112). 387 A related gold-catalyzed cycloisomerization of allenyl carboxylates has also provided the γ-butyrolactone unit in the total synthesis of Xestospongienes E, F, G, and H. 388 Dihydropyran and tetrahydropyran fragments found in natural products have been accessed from oxycyclization of βallenols through diverse strategies. The dihydropyran C1−C15 subunit 689 of Sorangicin A, a potent antibiotic isolated from Sorangium Cellulosumi bacteria, has been synthesized through the gold-catalyzed 6-endo-trig cyclization of enantioenriched βallenol 692a, prepared from oxidation and further asymmetric reduction of the diastereomeric mixture 692a/692b (Scheme 113, reaction a). 389 Prins-type cyclization of β-allenol 695 with dimethyl acetals 696 and 697 followed by Tsuji reduction led to the C14−C35 fragment of Eribulin (693) and the C14−C38 fragment of Halichondrin (694), respectively, two macrolides of marine origin exhibiting potent antitumor activity. Chirality transfer from enantioenriched allenols and acetals led to the stereocontrolled generation of the C27 sterocenter, and further Tsuji reduction under palladium conditions provided the stereodefined C25 center in both fragments 693 and 694 (Scheme 113, reaction b). 390 A more intrincate reaction mechanism was envisioned for the synthesis of (−)-Gilbertine natural product (680), a member of the uleine alkaloid family. Allenyl azide 678 undergoes photoinduced azacyclization to yield indolidene intermediate 679, which after 6-exo-trig oxycyclization reaction from the hydroxyl group yields the fused tetrahydropyran skeleton, favored by the formation of the more stable indol aromatic ring in compound 680 (Scheme 114). 391 In the context of allenol oxycyclization reactions toward the synthesis of naturally occurring products, related allenyl hydroxylamines have been described to undergo in situ Scheme 111. Ruthenium-Catalyzed Carbonylation of α-Allenols toward the Synthesis of the γ-Butyrolactone Scaffold in Natural Products Scheme 112. Synthesis of (+)-Xylogiblactone A through Gold-Catalyzed Cycloisomerization of Enantioenriched Allenols Chemical Reviews pubs.acs.org/CR Review cycloisomerization to yield polycyclic oxazines en route to the total synthesis of Casuarine, Australine, and diverse non-natural derivatives. 392 Breit and co-workers have recently reported a diasteroselective synthesis of dihydropyrans through the rhodiumcatalyzed oxycyclization of both terminal and internal allenols, using dppf as ligand. The methodology has been successfully applied to the synthesis of (−)-centrolobine (683) through a six-steps reaction sequence and 20% overall yield (Scheme 115). 393 The β-allenol scaffold has been also presented as precursor of acyclic fragments. Syn-1,3-diol is a common motif in every compound of the statin family. Breit and collaborators have developed the diasteroselective synthesis of syn-dioxanes 690 from in situ generated allenyl hemiacetals 689 as syn-1,3-diol precursors (Scheme 116). The asymmetric version of this transformation was achieved using acetylsultam borylenolate 686 as chiral inductor. Coupling reaction of compound 686 with allenyl carbaldehyde 687 followed by amide hydrolysis led to enantiopure β-allenol 688. Further coupling reaction of syndioxanes 690 with the appropriate phosphoryl compound 691 and acetal hydrolysis allowed the total synthesis of Rosuvastatin (684) and Pitavastatin (685). 394 As previously mentioned in section 3.1.2, tandem carbocyclization/dehydratation reactions of allenols constitute straightforward procedures for the preparation of aromatic and heteroaromatic polycyclic structures. Ma and co-workers have employed this strategy for the synthesis of a wide variety of alkaloids from the carbazole family, starting from readily available methoxypropadiene (693) 231 Cycloaddition reactions involving allenol molecules en route to natural products and fragments have also been described. Early examples deal with the Diels-Alder of allenols and methyl propiolate in the total synthesis of Quassin. 395 More recent advances include the intramolecular (5 + 2) cycloaddition of allenol 705 for the synthesis of the tetracyclic core of Bufogargarizin C (707) (Scheme 118, reaction a), 396 or the tandem Diels-Alder/carbonyl-ene reaction from allenol 708 to provide the Chloropupukeananin D analogous 710 (Scheme 118, reaction b). 397 The first and asymmetric total synthesis of the bioactive bufospirostenin A, an unusual spirostanol natural product, has been accomplished taking advantage of the intramolecular allenic Pauson−Khand reaction of an alkynetethered allenol for the construction of a tetracyclic skeleton. 398 Jogyamicin (712) is an aminocyclopentitol-based natural product recently isolated from Streptomyces culture broth. Its potent antiprotozoal activity along with its challenging structure has attracted the interest of diverse research groups. One recent approach to the five-membered core of Jogyamicin starts from enantioenriched β-allenol 713, which after protection as allenic sulfamate 714, followed by oxidative allene amination under rhodium catalysis led to cyclic sulfamate 716 through aziridineintermediate 715 (Scheme 119). A 15-step reaction sequence from sulfamate 716 provided the pentacyclic structure 717 in a 6% overall yield, a known key intermediate in the total synthesis of Jogyamicin. 399 Palladium-catalyzed additions and hydroborations of allenes has been applied to the preparation of different natural products. Yoshida's research group has described the synthesis of sesquiterpenes (−)-HM-3 and (−)-HM-4 based on the palladium-catalyzed addition of boronic acids to α-allenols, 400 and the synthesis of enokipodins A and B, two sesquiterpenoids from the α-cuparenone family exhibiting antimicrobial activity through a similar strategy. 401 Roulland and co-workers have reported the total synthesis of the antibiotic Tiacumicin B incorporating a palladium-mediated cross-coupling reaction of alkynes and allenols. 402 Hong and collaborators have envisioned a total synthesis of Lasonolide A (718), a natural product from marine origin and promising activity in pancreatic cancer therapies. The proposed retrosynthesis disconnects the macrolide product in fragments 719 and 720, prepared from the hydroboration of both allenes (+)-721-Ac and (−)-721, after a 12-and 11-step sequence, respectively. Enantiopure allenes (+)-721-Ac and (−)-721 have been prepared taking advantage of the enzymatic resolution of racemic allenol 721. Julia-type olefination of fragments 719 and 720 followed by Yamaguchi macrolactonization and total desilylation provided the expected structure of the Lasonolide A polyketide (Scheme 120). 403 Recently, the ability of allenyl carbamates, readily available from the corresponding allenols, to generate dienes as reaction intermediates has been employed in the total synthesis of trachelanthamidine and supinidine through a (4 + 1) ring closing process. Thus, allenyl carbamates 725 reacted under phosphine-promoted conditions to yield pyrrolines 727, key

Natural Products Bearing the Allenol Motif
Once considered chemical curiosities and extremely reactive compounds, allenes are currently found in more than 150 thermally and photochemically stable natural products. 405 Despite the allenol system is infrequent in naturally occurring systems, and linear allenes commonly show chemical instability, some simple linear molecules bearing the allenol motif have exhibited important antibiotic activity, such as the diyonic compounds marasin (730), 406 and 07F275 molecule (731), 407 both described in the late 80s (Scheme 122). During the past decade, some examples describing naturally occurring linear allenes have been reported. Ma's research group has applied their chiral amine enantioselective allenation of terminal alkynes for the one-step synthesis of (R)-8-hydrox-yocta-5,6-dienoate (735), a potent antifungal and antibiotic molecule extracted from the Japanese tallow tree Sapium japonicum. Reaction of propargylic alcohol (732) and methyl-5-oxopentanoate 733 in the presence of (S)-diphenyl-(pyrrolidin-2-yl)methanol 734 and CuBr 2 as metal catalyst led to the expected 1,3-disubstituted allene moiety in compound 735 (Scheme 123). Efficient chirality transfer from optically pure secondary amine 734 allowed the obtention of allenol 735 in 94% ee. 388 Thomas and collaborators have reported the total synthesis of the allenol-based natural product Puna'auic acid (736), a fatty acid isolated from marine cyanobacterium. The allenol motif is generated in one of the latter steps of the reaction sequence, through a copper-catalyzed conjugated hydride addition to enantioenriched epoxy alkyne 737, following Krause's procedure. 408 Although the allene biosynthethic origins are not yet fully understood, the discovery of minor alkyne metabolites related to structure 736 from the same natural sources point to a similar conjugated hydride addition as the most plausible biosynthethic route (Scheme 124). 409 (+)-Iso-A82775C natural product (739) has been isolated from the fermentation culture of fungus Pestalotiopsis fici, and it has been proposed as a biosynthethic intermediate of the previously mentioned chloropupukeananin family. Compound 739 is a polysubstituted cyclohexane ring bearing an exocyclic allene. Its structure and complex stereochemistry have attracted the interest of different research groups, reporting alternative synthethic strategies. Suzuki and Tanino and co-workers have proposed a Seyferth−Gilbert homologation of carbaldehyde 740 to generate ethynyl cyclohexane structure 742 (Scheme 125, reaction a). Epoxidation of the endocyclic olefin followed by Cu-mediated anti-S N 2′ reaction of the chloroalkyne with Total synthesis of 739 was completed with further carbonyl reduction and desylylation steps. 411 Carotenoids represent the largest group of natural products exhibiting the allenol motif, being the Grasshopper ketone (749) one of the most commonly reported. First synthesis and isolation date to the late 60s, 412 pointing to a dietary metabolism of larger carotenoids as the most plausible biological origin of compound 749. Eugster et al. described a total synthesis of allenol 749 based on a S N 2′ hydride addition onto propargylic oxirane precursor 750, followed by selective oxidation under MnO 2 conditions (Scheme 126). 413 A related exocyclic allene unit is present in the wide family of xanthophyll norcarotenoids, naturally occurring compounds isolated from marine microalgae. Great effort has been made during the last years to provide an efficient synthethic route to some of these carotenoid molecules such as the most abundant Peridinin (752a), Fucoxanthin (752c), the biosynthetic intermediate Paracentrone (752d), and diverse natural and non-natural derivatives (Scheme 127).
Álvarez and de Lera et al. have proposed a retrosynthethic analysis for the total synthesis of Peridinin based on Julia-Kocienski olefinations, and a Stille coupling reaction to incorporate the allenic moiety from fragment 753 (Scheme 128, path a). Also, in depth investigations on the stereoselective oxidative addition or S N 2′ substitution of palladium reagents to iodoallene derivatives 753 were reported. Iodoallene 753 was prepared from the corresponding alkyne 755. 414−416 Burke's research group has devised a Suzuki coupling of iodoallene 753 and the corresponding boronic acids 756 to incorporate the allenic fragment utilizing the same disconnection strategy (Scheme 128, path b). 417,418 A different retrosynthetic approach for the total synthesis of analogous deoxy-Peridinin (752b) has been proposed by Sakaguchi and Katsumara and collaborators. Despite this strategy being Suzuki-based, the novelty lays on a Chemical Reviews pubs.acs.org/CR Review different disconnection, which results in allenic fragment 757 and boronic acids 758 (Scheme 128, path c). 419 Wittig olefination from previously known enallenal 759 provided the dienallenyl iodide 757. 420 Katsumara's research group has proposed a total synthesis for both Fucoxanthin (752c) and Paracentrone (752d) natural products following similar strategies. Sonogashira coupling of ethynyl epoxide 760 and iodo triene 761 yielded trienynyl carboxylate 762 (Scheme 129). Next, treatment with DIBAL-H as hydride source smoothly rearranged the ethynyl epoxide moiety to generate the allenol motif and also reduced the carboxylate unit to the corresponding terminal alcohol building compound 763. Further Dess-Martin oxidation followed by Wittig olefination in the presence of phosphonium salt 765 provided the Paracentrone skeleton (752d) (Scheme 129, left). 421 A Suzuki alternative for the Wittig olefination in the last steps of the synthesis has also been stated, 422 also allowing the synthesis of related 19-hexanoyloxyparacentrone 3-acetate. 423 Likewise, Fucoxanthin (752c) total synthesis has been achieved through a Julia-type olefination of the allenic fragment 764 with hydroxysulfone 766 (Scheme 129, right). 424 Besides the above-mentioned synthethic approaches to naturally occurring targets, the determination of both structure and absolute configuration of allenol-containing natural products have been reported. Thus, Maoka et al. have stated the absolute configuration of minor carotenoid 4-Ketodeepoxyneoxanthin (767) in basis of NMR investigations. 425 Che's and Souto's research groups have respectively proposed the full structure and stereochemistry of Chloropestolide metabolite 768, 426 and Marilzabicycloallene A (769), exhibiting an unusual bromoallene motif (Scheme 130). 427 The diverse and intriguing biological properties of naturally occurring allenols described so far, have paved the way to the synthesis of non-natural analogous and the examination of their pharmaceutical activities. Zemlicka has recently reported a critical comparison of the antiviral properties of a wide family of lipophilic nucleoside analogous and their phosphoramidates, including several examples of allenol-containing systems. 428 For instance, adenosine-and cytosine-based compounds 770 and 771 have been prepared through basic equilibration from the corresponding alkynol precursors. Both molecules exhibit potent cytotoxic and antiviral activities. Interestingly, anti-HIV properties of 770 and 771 were found to be in close dependency of the absolute configuration of the allene moiety, being the (R)isomer obtained through enzymatic resolution the active species (Scheme 131). 429,430 More non-natural pharmacologically attractive allenols were described and reviewed during the 80s and 90s decades such as allenol-based prostaglandin and carbacyclin systems, 431 allenic amino acids bearing hydroxyl groups, 432 and allenic steroids. 433

CONCLUSIONS
Allenol chemistry remains to be a hot research topic, which includes two main areas, namely the development of new methods for their synthesis and the discovery of novel and fascinating reactivity, which converts the allenol moiety in a powerful building block in the modern synthetic arsenal. Allenes decorated with hydroxyl units, namely allenols, exhibit unique and particular reactivity compared to the nonsubstituted analogous. The allenol reactivity could be classified in three main categories: (i) Allenols reacting as π-activated alcohols, where the hydroxyl group leaves the molecule or undergoes 1,3migration rearrangement processes, leading to open-chained systems such as dienes or enynes, or to aromatic cyclic structures. (ii) Those reacting as bidentate nucleophileselectrophiles, taking advantage of both the hydroxyl nucleophilicity as well as the allene electrophilicity when π-metal activation takes place. Oxacyclic structures such as furans or pyrans are accessed. (iii) Those where the hydroxyl group assists any kind of allene transformation, frequently by metal intermediate coordination. Also, the frequent use of allenols as key intermediates for the total synthesis of natural product deserves to be mentioned. The extensive use of allenols as synthetic intermediates is associated with the implementation of an increasing number of methodologies for their preparation, both in racemic and enantiopure manner. Particularly attractive is the use of modern catalytic methods for the synthesis of enantioenriched allenols, which can display astonishing axial and central chirality. Last but not least, despite that the allenol scaffold is not commonly encountered in Nature, several allenol-based natural products have been isolated, characterized and synthesized. All contributions together support the widespread use and importance of the allenol functionality in current organic chemistry.
The intriguing reactivity so far exhibited by the allenol functional group, and the wide range of structures accessible from allenol starting materials will certainly inspire organic chemist to pursuit new advances and results that will be shortly coming in this area. In one hand, allenol-containing molecules constitute an ideal playground to continue the development of modern synthetic methodologies, as it has been recently illustrated by the recent micellar catalysis or the gold-based supramolecular catalysis, both of them based on allenol oxycyclization reactions. The field is dominated by the use of catalysts derived from expensive transition metals such as gold and palladium, with punctual incorporation of other metals. It should be desirable the widespread use of inexpensive and more environmentally friendly metals such as iron, copper, etc. Besides, despite the appearance of several catalytic protocols in heterogeneous phase through the use of metal nanoparticles, the more of the reactions are performed in homogeneous conditions. On the other hand, covalent−organic frameworks (COFs) and metal−organic frameworks (MOFs) have attracted considerable interest in recent years, but its application in allenol chemistry remains elusive. Consequently, more sustainable processes are desirable. In this context, the incorporation of recent progresses in photochemical methods and modern electrochemistry persist as a challenge. The application of photochemistry in allenol chemistry is restricted to a couple of isolated reports dealing with photoredox catalysis while there is absence of information concerning electrochemical methods. The use of enzymes in allenol chemistry is limited to the classical use for the resolution of racemic mixtures, but an efficient use of bioengineering advances should be taken into account. Besides, ongoing endeavors to discover competent asymmetric routes are largely based on designing and building new and exotic chiral nonracemic ligands or catalysts; however, the recognition of conveniently activated allenol precursors to enlarge catalytic effectiveness is critical too. On the other hand, the potential axial chirality of the allene motif is still unexploited, being the axial-tocentral chirality transfer processes from axially enantioenriched 1,2-dienes one of the most notable challenges regarding the chemistry of allenes. Also, the inexhaustible search of new and more potent drugs, and the synthesis and characterization of yet unreported natural products often bearing oxacyclic moieties, will be certainly supported by the rich and efficient chemistry of the allenol system.