Stereoselective allylboration using ( B )- γ - alkoxyallyldiisopinocampheylboranes: highly selective reactions for organic synthesis

This review describes the synthesis of novel alkoxyallylborane reagents derived from α -pinene and their applications in stereoselective total synthesis of natural products. These reagents can be conveniently prepared and react readily with a wide variety of aldehydes and imines to provide the corresponding α -alkoxy substituted homoallylic alcohols/amines respectively. The ( Z )- γ -alkoxyallylborane reagents provide 1,2-syn α -alkoxy homoallylic alcohols/amines while the corresponding ( E )- γ -alkoxyallylborane reagents furnish 1,2-anti products exclusively in very high enantioselectivities.


Introduction
Allylboration is an important C-C bond forming reaction in organic chemistry. 1Reaction of "allyl"boranes 1 with aldehydes 2 is advantageous over many "allyl"metalations in terms of stereoselectivity because allylboration proceeds via a rigid six-membered boracyclic transition state 3 (Figure 1).Unlike several other metals that produce toxic metal byproducts, boron eventually gets converted to boric acid salts that are non-toxic and less cumbersome to dispose.There are theoretically five different points of substitution on the "allyl" borane 2 thereby making this reaction highly versatile in terms of obtaining a wide variety of complex products.
Several chiral auxiliaries have been examined for the asymmetric allylboration of aldehydes/imines to prepare the optically pure homoallylic alcohols/amines in high ee and de. 2 Hoffmann, Brown, Yamamoto, Roush, and others have made significant contributions in this area.Hoffmann pioneered the first asymmetric allyl and crotylborations utilizing a camphorderived auxiliary 3 for both single and double diastereoselective asymmetric synthesis. 4amamoto and coworkers introduced tartrate esters as chiral auxiliaries for propargylboration and allenylboration of aldehydes to produce homoallenyl and homopropargylic alcohols respectively in very high ee. 5They demonstrated that the ee's of the alcohols depend on the sterics of the alkyl group in the tartrate ester.Ethyl and isopropyl tartrates lead to lower ee's, while sterically bulky groups such as cyclododecyl and 2,4-dimethylpentyl tartrates lead to higher ee's. 6Roush extended the use of isopropyl tartrate as a chiral auxiliary for allyl and crotylborations. 7Several other "allyl"boranes derived from chiral 1,2-diols 5-8, 8 oxazaborolane 9, 9 and diazaborolane 10, 10 etc. have also been developed for the asymmetric allylboration of aldehydes/imines (Figure 2).
ARKAT USA, Inc.However, till date, the chiral allylborane derived from α-pinene (Ballyldiisopinocampheylborane 11), 11 has proven to be the most effective in terms of high optical purity observed for a wide range of achiral and chiral aldehydes (Scheme 1).2a,b Several higher order "allyl"boranes derived from α-pinene have been readily prepared either in situ or as isolable reagents.2a,b All these reagents provide very good yields of the corresponding homoallylic alcohols/amines upon reaction with aldehydes/imines in excellent enantio-and diastereoselectivities.

Preparation of (B)-(Z)-γ-[alkoxyallyl]diisopinocampheylborane
One of the several higher order allylboranes developed by Brown et.al. is (B)-(Z)-γalkoxyallyldiisopinocampheylborane 20.This reagent is typically prepared and used in situ.Thus, the treatment of allylic ether 17 with a strong base such as sec-BuLi results in the formation of a (Z)-allylic anion 18.The exclusive Z-stereochemistry of the double bond is explained based on the coordination of lithium and oxygen resulting in a five membered cyclic transition state. 12Reaction of this anion 18 with Ipc 2 BOMe provides an "ate" complex 19, with a (Z) geometric conformation of the olefin.Addition of a strong Lewis acid to the "ate" complex 19, releases the allylborane reagent (B)-(Z)-(γ)-alkoxyallyldiisopinocampheylborane 20.Reaction of aldehyde with 20 followed by oxidative workup using alkaline hydroperoxide yields the 1,2-syn α-alkoxy homoallylic alcohol 22 in very high de and ee (Scheme 2).The reaction is highly reagent controlled and the enantiomer of the homoallylic alcohol is strictly governed by the antipode of Ipc 2 BOMe used.e.g. the reagent obtained from (+)-Ipc 2 BOMe always furnishes homoallylic alcohols with α-configuration while the analogous reagent obtained from (-)-Ipc 2 BOMe provides alcohols with β-configuration (Scheme 3). 13Thus the reaction of allylmethyl ether 17 with sec-butyl lithium followed by (+)-Ipc 2 BOMe, BF 3 .Et 2 O, and acetaldehyde provided (S,S)-22a in 92% ee.Similarly, acetaldehyde provided 90% ee of (R,R)-22a upon reaction with the alkoxyallylborane derived from (-)-Ipc 2 BOMe.A variety of aldehydes such as propionaldehyde, isobutyraldehyde, benzaldehyde, and acrolein afforded the corresponding (R,R)-or (S,S)-alcohols in 89-92% ee depending on the antipode of the reagent used (Scheme 3). 13e R Although the alkoxyallylboration using allyl methyl ether is highly useful, the methoxy group in the product homoallylic alcohols requires strong reaction conditions and reagents for deprotection.This sometimes limits the application of the reagent especially in a molecule with sensitive functional/protecting groups.Accordingly, following the initial reports by Brown, several groups have modified the protecting groups on the reagent to obtain a variety of alkoxyallylborane reagents 20a-f (Figure 3).For example, the allylborane obtained by replacing the methoxy group (20a) with methoxymethyl (MOM) group (20b) results in the formation of α-MOM substituted homoallylic alcohols, which could be further deprotected under mild reaction conditions to afford the 1,2-syn diols.The utility of several of these substituted reagents will be discussed in detail in the following sections.

Applications of (B)-(Z)-γ-[methoxyallyl]diisopinocampheylborane, 20a
A formal synthesis of Carbomycin, a macrolide antibiotic, was achieved by Wuts and coworkers by utilizing the stereoselective alkoxyallylboration with 20a (Scheme 4). 14Thus the reaction of 3-benzyloxypropionaldehyde 23 with 20a afforded the homoallylic alcohol 24 in >99% diastereoselectivity and 90% ee.Further transformations on 24 provided the subunit 25, which was earlier synthesized by Nicolaou during the synthesis of Carbomycin.Several research groups have employed alkoxyallylboration as a key step in the synthesis of Herbimycin A, a potent antibiotic belonging to the class benzoquinoid ansamycin. 16Tatsuta reported the alkoxyallylboration of an α-β-unsaturated aldehyde 26 with allylborane 20a providing the homoallylic alcohol 27, which was further converted to Herbimycin A 28 in several steps.16a Very recently, a similar type of aldehyde was also utilized by Cossy towards the synthesis of Herbimycin.Ganesh and Nicholas demonstrated that the cobalt carbonyl complexes of the acetylenic aldehydes 31 react with γ-methoxyallyldiisopinocampheylborane 20a to provide the homoallylic alcohols 32 in high yield and stereoselectivity (Scheme 6). 17It is important to note that the corresponding uncomplexed acetylenic aldehydes react under the same conditions and provide a very low yield of the product alcohols.It is relatively straight forward to carry out the deprotection of the cobalt carbonyl complexes using ceric ammonium nitrate to obtain the free homoallylic alcohols.Scheme 6. Alkoxyallylboration of CO 2 (CO) 6 complexes of acetylenic aldehydes.
Jung and coworkers developed a novel regio-and diastereoselective amination of allylic ethers using chlorosulfonyl isocyanate CSI. 18A wide variety of allylic ethers (e.g.34) undergo this amination providing the corresponding acetamides 35.They were further able to extend this protocol for the synthesis of novel cytokine modulators namely cytoxazone and epi-cytoxazone 36 starting from the alkoxyallylboration of p-anisaldehyde 33 (Scheme 7).ARKAT USA, Inc.

Applications of (B)-(Z)-γ-[(methoxymethoxy)allyl]diisopinocampheyl borane, 20b
Burgess and Henderson developed a novel approach for the synthesis of polyhydroxylated indolizidines 43 utilizing the homoallylic alcohols obtained from the alkoxyallylboration of aldehydes in four steps.They observed that the allylboranes obtained from both (+)-and (-)-Ipc 2 BOMe react with the aldehyde 44 to provide the same enantiomer of the homoallylic alcohol 45 (Scheme 10). 22This is an interesting observation, as in most cases, α-pinene based allyl reagents undergo reagent controlled additions to aldehydes, and incipient chirality of the substrate has no enantiocontrol over the product formation.Smith and Duan developed an IBr mediated diastereoselective electrophilic cyclization of carbonates derived from homoallylic alcohols 50 to afford α-iodocarbonate 51 (Scheme 12). 24he product iodocarbonates are highly versatile intermediates in organic synthesis and can be utilized for the synthesis of epoxy alcohols, iodohydrins, diols, triols, cyclic carbonates etc. 25 ARKAT USA, Inc. Alkoxyallylboration of an aldehyde 52 derived from arabinose, with γmethoxymethoxyallyldiisopinocampheylborane 20b provided the homoallylic alcohol 53 in 80% yield and >99% diastereoselectivity (Scheme 13). 26 Coleman and coworkers demonstrated the synthesis of a potent anti-tumor agent Azinomycin A starting with alkoxyallylboration of acrolein with allylborane reagent 20b (Scheme 16). 30The homoallylic alcohol 61, thus obtained was conveniently transformed into the fully functionalized aziridine core 62, of Azinomycin A. Barrett and coworkers synthesized restrictinol, the hydrolysis product of the anti-fungal natural product restricticin, utilizing the alkoxyallylboration of the α-chiral aldehyde 63 derived from Roche's ester (Scheme 17). 31The homoallylic alcohol 64 thus obtained was further transformed into restrictinol.Barrett's group also developed an efficient method for the formation of 1,2-oxasilines 68 starting from the homoallylic alcohols 67.Protection of alcohols 67 as vinylsilyl ethers, ARKAT USA, Inc.
Ramachandran et al. have demonstrated the utility of alkoxyallylboration with B-γalkoxyallyldiisopinocampheylborane as the key step for the synthesis of several anti-tumor styryllactones such as goniodiol, epigoniodiol, and deoxygoniopypyrone. 41he alkoxyallylboration of benzaldehyde with 20c, provided (S, S)-α-alkoxyhomoallylic alcohol 96.The target lactones 97-100 were prepared in 6-7 steps starting from the homoallylic alcohol 96 via tandem allylboration and ring closing metathesis protocol (Scheme 27).
ARKAT USA, Inc.The same group also achieved the stereoselective synthesis of C 7 -C 21 subunit of potent anticancer agent Epothilone A, 103 starting from the (S,S) α-alkoxyhomoallylic alcohol 102 derived from the alkoxyallylboration of acetaldehyde (Scheme 28).They were further able to demonstrate the applicability of the α-alkoxy homoallylic alcohols for the synthesis of β-hydroxy-δ-lactones. 43 The reaction of homoallylic alcohols 105 with acryloyl chloride followed by ring closing metathesis with Grubbs's II Generation catalyst 107 afforded α-pyrones 108.Diastereoselective dihydroxylation of the double bond in 108 provided the 1,2-cis diol 109 that upon reaction with phenyl chlorothionoformate and Bu 3 SnH and AIBN yielded the α-hydroxy-δ-lactone 110 regioselectively (Scheme 29).This protocol was applied for the synthesis of C 1 -C 8 and C 15 -C 21 subunits of a potent anti-cancer agent Discodermolide. 43RKAT USA, Inc. Extension of alkoxyallylboration to perfluoroaldehydes, provided the fluoro-homoallylic alcohols 116 which were eventually converted to the fluorinated γ-lactones 117 and δ-lactones 118 in 2-3 steps (Scheme 31). 45A trifluoromethyl analog of blastmycinolactol 121 was also synthesized starting the homoallylic alcohol 120 derived from alkoxyallylboration of trifluoroacetaldehyde 119 (Scheme 32).Recently, Curran and coworkers utilized the alkoxyallylboration of n-tridecanal with both antipodes of B-γ-alkoxyallyldiisopinocampheylborane for the synthesis of (S, S) and (R, R) 1,2syn α-alkoxy homoallylic alcohols syn-126. 49Mitsunobu inversion of the corresponding alcohols afforded two anti alcohols anti-126.All these four diastereomers were later tagged to a fluorous PMB-bromide 50

Applications of (B)-(Z)-γ-[(2-trimethylsilylethoxymethoxy)allyl] diisopinocampheylborane, 20d
Barrett and coworkers demonstrated for the first time that silyl protecting groups could also be utilized for the alkoxyallylboration of aldehydes (Scheme 35). 51As is apparent, the SEM ether is sensitive to the Lewis acid (BF 3 .Et 2 O), and hence they carried out the allylboration without the use of BF 3 .Et 2 O.The "ate" complex of the reagent 20d was equally reactive like the free "allyl"borane to provide the alcohol 129 that upon further transformations provided the C 1 -C 25 subunit 130 of Calyculin A (Scheme 35).Similarly, Roush (hydroxylamino sugar of Calicheamycin, Scheme 36), 52 and Overman (Laurencin, Scheme 37) 53 also utilized the alkoxyallylboration of the corresponding aldehydes 131 and 134 with B-γ-trimethylsilylethoxymethoxyallyldiisopinocampheyl-borane 20d as the main steps in their respective syntheses.
The initial alkoxyallylboration of benzaldehyde with allylborane 20e led to the formation of the homoallylic alcohol 138.The judicious choice of PMP protecting group in the allylborane 20e was made, so as to utilize p-methoxyphenol as a nucleophile in the next step (Mitsunobu inversion) of alcohol 138 to bis aryl ether 140 (Scheme 38).ARKAT USA, Inc.

Preparation and Applications of (B)-(E)-γ-Methoxyallyldiisopino campheylborane (149)
Ganesh and Nicholas were successful in the synthesis of anti-β-alkoxyhomoallylic alcohols 150 via the alkoxyallylboration of cobalt complexed acetylenic aldehydes with the Emethoxyallyldiisopinocampheylborane (Scheme 41). 56The (E)-alkoxyallylborane 149 was prepared utilizing a procedure by Hoffmann and coworkers involving the reduction of methoxy-

Scheme 4 .
Scheme 4. Synthesis of a subunit of Carbomycin.
Synthesis of C 1 -C 15 side chain of Mycolactone A.
and were converted to (+)-Murisolin and fifteen other diastereomers in several steps (Scheme 34).