Asymmetric Palladium-Catalysed Intramolecular Wacker-Type Cyclisations of Unsaturated Alcohols and Amino Alcohols

The palladium (II)-catalysed reactions of alkenols and aminoalkenols such as oxycarbonylations or bicyclisations are powerful methods for the construction of oxygen and nitrogen-containing heterocyclic compounds. This review highlights recent progress in the development of the asymmetric palladium(II)-catalysed Wacker-type cyclisations of unsaturated polyols and aminoalcohols. The scope, limitations, and applications of these reactions are presented.


Introduction
Palladium-catalysed functionalisations of alkenes have become a powerful tool in organic synthesis [1][2][3][4]. Today, there are numerous applications of these transformations in the preparation of a large array of the useful products. Among them, an intramolecular oxidative cyclisation, referred to as the Wacker-type cyclisation, is one of the most versatile methods for the preparation of heterocycles [5][6][7]. Particularly, palladium(II)-catalysed reactions of unsaturated alcohols and amino alcohols such as oxy-/aminocarbonylations [8][9][10][11][12][13][14][15], bicyclisations [16][17][18] and domino cyclisation-cross couplings [19][20][21][22][23] serve as a potent stereoselective methods for the construction of oxa-/azaheterocyclic structures found in many natural or biologically relevant compounds [19][20][21]24,25]. The key intermediate of these domino transformations is an alkyl-σ-Pd(II) complex A, which is trapped by carbon monoxide OPEN ACCESS and/or by cyclisation with a second hydroxyl function specifically placed in the substrate to give bicyclic products B, C (Scheme 1). Trapping of the intermediate A by other nucleophilic species provides oxa/azaheterocyclic compounds D linked with various substituents. Although a number of reviews on palladium-catalysed oxidative cyclisation and issues of stereochemical control already exist [3][4][5][6][7][22][23][24][26][27][28][29][30][31][32][33][34], no general summary on the asymmetric versions of the Pd(II)-catalysed Wacker-type cyclisation of unsaturated alcohols and aminoalcohols has been published. Considering the great potential for application of these methods to the synthesis of biologically active targets and for the extension to the synthesis of optically pure saturated heterocycles, we report here a summary of the main achievements in this area.

Asymmetric Wacker-Type Oxidative Heterocyclisations
The intramolecular Wacker-type cyclisation using oxygen or nitrogen nucleophiles is one of the most important processes for the preparation of O-and N-heterocycles [4][5][6]. The palladium(II) coordinates to the alkene C−C double bond and activates it towards nucleophilic attack. Subsequent β-hydride elimination leads to the cyclised product in its thermodynamically stable form (Scheme 2).

Scheme 3.
Asymmetric Pd(II)-catalysed Wacker-type cyclisation of allylphenol 1a using (S,S)-boxax ligands. Another significant feature of this transformation is the strong dependence of catalytic activity on the nature of the anionic ligands attached to the palladium. The reaction of 1a was much faster with the palladium catalyst generated from palladium bis(trifluoroacetate) than that from palladium diacetate or dichlorobis(acetonitrile)palladium. Furthermore, this reaction was not catalysed by chloride complex PdCl 2 {(S,S)-i Pr-boxax} at all. Thus, it was expected that a cationic palladium/boxax complex was generated as the active species by dissociation of palladium bis(trifluoroacetate) to the relatively stable trifluoroacetate anion in polar solvent. Indeed, a cationic palladium(II)/boxax species generated by addition of 2 equiv. of (S,S)-i Pr-boxax to Pd(CH 3 CN) 4 (BF 4 ) 2 was found to be catalytically much more active than the Pd(OCOCF 3 ) 2 {(S,S)-i Pr-boxax} complex. The reaction of 1a in the presence of mentioned cationic species was complete in 50 min, giving 91% yield of (S)-2a with 97% ee. Generation of cationic species by abstraction of chloride from PdCl 2 {(S,S)-i Pr-boxax} through treatment with 2 equiv. of a silver(I) salt (AgBF 4 , AgPF 6 or AgSbF 6 ) was also successful (full conversions of 1a were achieved in 1 hour to give the product in 86%-91% yield with 95%-98% ee).
The Stoltz laboratory has developed an enantioselective Pd(II)-catalysed oxidative phenol cyclisation in nonpolar organic solvents with molecular oxygen using (−)-sparteine as the chiral ligand [40,41] (Scheme 4).   [42][43][44][45][46], the one worthy of emphasis, published by Zhang [44,45], reports a new family of tetraoxazoline ligands 5 for the construction of chelation-induced axially chiral catalytic systems ( Figure 1). The axially achiral tetraoxazoline ligands 5, in which four identical chiral oxazoline groups are induced into the four ortho positions of a biphenyl axis, may produce only one of two possible diastereomeric metal complexes during the coordinating process. As it can be seen in Figure 1, the metal complexes (S,aS) are sterically more favorable compared with their diastereomers (S,aR). Hence, it is expected that only one diastereomeric metal complex with (S)-axial configuration is formed during the chelation-induced process.  The generality of the chelation-induced axially chiral Pd-catalyst, 5c-Pd(OCOCF 3 ) 2 , has been successfully demonstrated through the Wacker-type cyclisation of a series of o-allylphenols 1a-h and o-allylnaphtol 1i. As shown in Scheme 5, a wide array of chiral 2,3-dihydrobenzofurans 2a-h and dihydronaphto [1,2-b]furan 2i was obtained with excellent enantioselectivities (up to 99% ee), regardless of the steric or electronic properties of the aromatic moiety on the substrate 2. Scheme 5. Asymmetric intramolecular Wacker-type cyclisation of 1 using tetraoxazoline 5c-Pd(OCOCF 3  The first Pd-catalysed asymmetric aza-Wacker-type cyclisation of the olefinic tosylamides was published by the same group in 2010 [46]. By using a chiral quinolineoxazoline ligand 6 in the presence of Pd(II)-trifluoroacetate and oxygen at 0 °C, o-allylanilines 7 were cyclised to enantiomerically enriched dihydroindoles 8 in good yields with up to 74% ee (Scheme 6).

Coupling with Alkenes via Heck Vinylation
In 1993, Semmelhack showed that an organo-Pd(II) intermediate, formed by intramolecular oxypalladation of hydroxyalkenes, can be trapped by alkenes in the process of Heck vinylation reaction using stoichiometric amount of Pd(OAc) 2 [53]. From the screening of reoxidation systems for the catalytic version of this transformation, the use of CuCl (1 equiv.)/O 2 system turned out to be most effective (Wacker conditions). However, this method is limited to substrates that cannot undergo β-hydride elimination from organo-Pd(II) intermediate.
One of the possible mechanisms involves the coordination of the alkene to the Pd(Ar)(X) species [generated upon oxidative addition of the aryl halide to Pd(0)], which activates the double bond toward nucleophilic attack (Scheme 12, Path A). The alkyl-σ-Pd(II) complex formed in the process of anti-heteropalladation is subsequently converted to the product through the well-known carbon-carbon bond forming reductive elimination. anti-Heteropalladation reactions are well-established with relatively electrophilic PdX 2 complexes, however, these processes are not as common with less-electrophilic Pd(Ar)(X) intermediates [58,59]. Another plausible mechanism could proceed through oxidative addition of the aryl halide to Pd(0) followed by substrate deprotonation and substitution to provide alkene-bound palladium(aryl)(alkoxide/amide) complexes (Scheme 12, Path B). The alkyl-σ-Pd(II) complex is then formed in the process of syn-1,2-migratory insertion into the Pd-O/N bond and converted to the product by reductive elimination [22,23,57].   The first asymmetric variant of this methodology was developed by Wolfe and Mai for the synthesis of enantioenriched pyrrolidines [60]. The substrates 24a-c were coupled with several different aryl or alkenyl bromides and iodides using (R)-Siphos-PE as ligand to give the desired products in moderate to good yields with 72%-94% ee (Scheme 13). Interestingly, little or no stereocontrol was observed with chiral bidentate ligands. Scheme 13. Asymmetric palladium-catalysed carboamination reaction for the synthesis of enantiomerically enriched pyrrolidines using (R)-Siphos-PE ligand. The asymmetric carboamination method was applied towards a concise enantioselective synthesis of (-)-tylophorine [60]. Aryl bromide 25 was coupled with N-boc-pent-4-enylamine (24a) using the Pd/(R)-Siphos-PE catalyst (Scheme 14). The desired pyrrolidine 26 was formed in 69% yield and 88% ee, and converted to (-)-tylophorine in two steps and nearly quantitative yield.

Scheme 14.
Synthesis of (-)-tylophorine. The utility of asymmetric carboamination method was also illustrated in an enantioconvergent synthesis of the benzomorphan alkaloid (+)-aphanorphine [61].  Most recently, Wolfe and Hopkins described the first asymmetric alkene carboamination reaction between N-allyl urea derivatives and aryl halides [62]. The authors initially examined the effect of nitrogen nucleophilicity on asymmetric induction using (S)-Siphos-PE ligand (Scheme 16). The level of asymmetric induction increased with increasing electron-withdrawing ability of the p-substituent on N-aryl moiety, however, the chemical yield decreased due to the diminished reactivity of these substrates. The enhancement of the reaction temperature (120 °C in xylenes) solved the problem with reactivity and the desired products were generated in 81%-87% yield with 86%-92% ee. Afterwards, the substrates 31a,b were coupled with a range of different aryl halide derivatives (Scheme 17). It was found that addition of 2 equiv of water (or 40 mol % of TFA) to the reaction mixtures in some cases significantly improved the enantioselectivities. Efforts to employ alkenyl halides as coupling partners were mostly unsuccessful.

Intramolecular Alkoxylation/Lactonisation
In 2008, Gracza and co-workers [70,71] disclosed an enantioselective variant of another Wackertype Pd(II)-catalysed cyclisation. The oxycarbonylative annulations of unsaturated polyols and amino alcohols, either diastereoselective or enantioselective, proceeded to bicyclic lactones using chiral palladium(II) complexes. In the initial report [70], a method for the kinetic resolution of alkene-α,γ-1,3-diols 49 via asymmetric oxycarbonylative bicyclisation has been investigated.  [71]. Similarly, the syn-diols (±)-49b and (±)-49c afforded the corresponding natural Hagen's glands exo-lactones (R,R,R)-50b and (R,R,R)-50c, with high diastereoselectivity and good yields, however with low enantioselectivities. It should be noted that, contrary to CuCl 2 , the regeneration of the active Pd(II) species with p-benzoquinone is carried out in the absence of AcONa. Efforts from Vo-Thanh's and Gracza's group improved the efficiency of the process [71]. By application of ionic liquids and/or microwave activation, noticeable propitious enhancements in both reaction rate and enantiomeric excess (up to 80% ee) were observed (Scheme 23).

Scheme 23.
Kinetic resolution of pent-4-ene-1,3-diol (±)-49a by Pd(II)-catalysed oxycarbonylation in ionic liquids. In a later study of the transformation of symmetric substrates [72], the same authors reported Pd-catalysed oxycarbonylation of the meso-diols xylo-55, ribo-57 and pseudo-C 2 -symmetric D-arabino-derivative 56. The Pd(II)-initiated oxycarbonylative bicyclisation of meso-diols 55, 57 in the presence of chiral Pd-catalysts using ligands with opposite asymmetric induction [(R,S)-indabox 52, (S,S)-bis(4-isopropyloxazolin-2-yl)methane (62)] afforded bicylic lactones 58 and 61 in good yields and with excellent 2,3-threo-diastereoselectivity (Scheme 24). In the reaction of the of the pseudo-C 2 -symmetric enitol 56, the diastereomer D-gluco-59 was isolated as a major product (65% yield, resulting from the intramolecular Si-attack of nucleophilic hydroxyl group to the Pd(II)-activated double bond) along with its minor diastereomer D-galacto-60 (9%). Such product distribution is most probably due to the endo-positions of two attached substituents on fused rings of lactone D-galacto-60, which in consequence increased the steric hindrance, and therefore its formation is slowed down. In fact, simply raising of temperature to 60 °C led to the complete consumption of enitol 56 in only 30 min to form energetically favorable diastereomer D-gluco-59 as the sole product in 78% yield.

Conclusions
The palladium(II)-catalysed Wacker-type cyclisations of alkenes have evolved into a highly useful methodology in synthetic organic chemistry. The domino and/or multicatalytic processes involving intramolecular oxidative cyclisation reactions, employing oxygen/nitrogen-containing nucleophiles, can provide various heterocyclic compounds. In many cases, the chemo-, regio-and diastereoselective Pd(II)-mediated cyclisations have succeeded in building of complex structures. This overview summarised the asymmetric versions of these palladium(II)-catalysed processes. The main issues include: (1) asymmetric Wacker-type oxidative cyclisations of substrates having both a carbon-carbon double bond and an amino/hydroxylated tether; (2) asymmetric domino Pd-catalysed N/O-cyclisation/ coupling reactions; (3) asymmetric intramolecular alkoxylation/ methoxycarbonylation; (4) asymmetric intramolecular alkoxylation/lactonisation. Although considerable progress has been made in this area, some future trends are easy to predict: new catalytic systems will be developed to make Pd(0)-reoxidation more efficient, and a larger variety of chiral ligands will be available for enantioselective transformations. There are also many opportunities for the development of further domino processes and new modifications of the reaction system, omitting carbon monoxide atmosphere for extended use in medicinal chemistry exploiting automated workflows for liquid-phase parallel synthesis. In addition, there is a great potential for the application of these methods for the synthesis of natural products and biologically active heterocycles.