Diastereoselective synthesis homoallylic alcohols

Allylboron compounds have proven to be an exceedingly useful class of allylmetal reagents for the stereoselective synthesis of homoallylic alcohols via reactions with carbonyl compounds, especially aldehydes1. The reactions of allylboron compounds and aldehydes proceed by way of cyclic transition states with predictable transmission of olefinic stereochemistry to anti (from L-alkene precursors) or syn (from Z-alkene precursors) relationships about the newly formed carbon-carbon bond. This stereochemical feature, classified as simple diastereoselection, is general for Type I allylorganometallicslb. 

B. Potassium allyl- and crotyltrifluoroborates undergo addition to aldehydes in biphasic media as well as water to provide homoallylic alcohol in high yields (>94%) and excellent diastereoselectivity (dr >98 2). The presence of a phase-transfer catalyst (e.g., B114NI) significantly accelerates the rate of reaction, whereas adding fluoride ion retards the reaction (Eq. 8.70).165 The method was applied to the asymmetric total synthesis of the antiobesity agent tetrahydrolipstatin (orlistat).166... 

Aldehyde 13, readily prepared by a four step synthesis from L-threonine,3a-i5 was treated with the known (Z)-7-methoxyallylboronate 1412a,c. This reaction, as with other reactions of pinacol allylboronates, was relatively slow and required 24-48 h at room temperature to reach completion. It was, however, extremely selective ana provided homoallyl alcohol 15 in 70% yield with greater than 95% diastereoselectivity. The stereochemistiy of this compound was quickly verified by conversion to 3 as shown in Figure 7.3a We now believe that this reaction proceeds by way of the Conforth-like transition state depicted in Figure 7, and not by way of a Felkin transition state as suggested in our original ublication, since a serious nonbonded interaction exists between the (Z)-methoxyl group and the C(3) substituents of 13 in the Felkin transition state. A... 

The tandem silylformylation/allylsilylation reaction is particularly well suited to the synthesis of skipped polyol motifs such as are found in the oxopolyene macroHdes. The synthesis of protected triol 43 (an intermediate in the mycoticin A formal synthesis described above see Scheme 5.18) relied on an application of this methodology. Thus, homoallylic alcohol 76 was transformed into triol 77 in 55% overall yield and >10 1 diastereoselectivity (Scheme 5.27) [23]. Selective protection of the triol to give 43... 

Starting from Boc-prolinal, double stereodifferentiation, where both substrate and reagent match, allows diastereoselective access to the homoallylic alcohol 3,4-syn-4,5-anti-48 in the synthesis of dolaproine (8) (Scheme 18) J81l... 

W. Adam, C. R. Saha-Moller, and K. S. Schmid, Synthesis of 4,6-dideoxyfuranoses through the regioselective and diastereoselective oxyfunctionalization of a dimethylphenylsilyl-substituted chiral homoallylic alcohol, J. Org. Chem., 66 (2001) 7365-7371. 

Furthermore, the authors explored the epoxidation of more complex homoallylic alcohols, in view of their application as precursors for the synthesis of the polypropionate chains of Streptovaricins D and U (Scheme 45) [ 187— 189]. These complex alcohols were found to undergo the VO(acac)2-catalyzed epoxidations smoothly under microwave-assisted conditions and the products were isolated in very high yields in only 10 min, after being protected as the corresponding acetonides (Scheme 45). Moreover, in this specific case, the authors were successful in obtaining exclusive diastereoselectivity, as only the sjn-isomers were isolated as the products of epoxidation. 

Asymmetric allylboration has also been applied to y-methoxyallyl derivatives. Isomerically pure (Z)-y-methoxyallyldiisopinocampheylborane (rf31), prepared from Ipc2lSOMe and the lithium anion of allyl methyl ether, reacts with various aldehydes to afford the yyn - j-m e (boxy homoallylic alcohol (32a) in a highly regio- and stereoselective manner17 (Scheme 3.In). This one-pot synthesis of enantiomerically pure 1,2-diol derivatives went as smoothly as the asymmetric Brown crotylation, affording products with uniformly high diastereoselectivity. 

In order to apply tartrate ester-modified allyl- and crotylboronates to synthetic problems,23 Roush and Palkowitz undertook the stereoselective synthesis of the C19-C29 fragment 48 of rifamycin S, a well-known member of the ansamycin antibiotic group24 (Scheme 3.1u). The synthesis started with the reaction of (S,S)-43E and the chiral aldehyde (S)-49. This crotylboration provided the homoallylic alcohol 50 as the major component of an 88 11 1 mixture. Compound 50 was transformed smoothly into the aldehyde 51, which served as the substrate for the second crotylboration reaction. The alcohol 52 was obtained in 71% yield and with 98% diastereoselectivity. After a series of standard functional group manipulations, the alcohol 53 was oxidized to the corresponding aldehyde and underwent the third crotylboronate addition, which resulted in a 95 5 mixture... 

Roush et al. applied the diastereoselective crotylboration methodology in the total synthesis of bafilomycin Ai (66), a potent vacuolar ATPase inhibitor that displays broad antibiotic activity27 (Scheme 3.lx). In the synthesis, the known aldehyde (R)-67 was treated with ( )-crotylboronate (R,R)-43E to provide an 85 15 mixture of the homoallylic alcohol 68 and the undesired 3,4-anti-4,5-syn diastereomer with an isolated 78% yield of 68. Alcohol protection as a TBS ether followed by hydroboration mediated by Wilkinson s catalyst efficiently provided the primary alcohol 69. 

Corey s asymmetric allylation methodology was utilized in the total synthesis of amphidinolide T3 (95), a marine natural product that exhibits significant antitumor properties37 (Scheme 3.1gg). The asymmetric allylation of the aldehyde 96 was carried out successfully with chiral allylborane reagent generated in situ from allyltributylstannane and (R,R)-82 to furnish the homoallylic alcohol desired (97) in 85% yield with excellent diastereoselectivity. Subsequent conversion of the alcohol to the tosylate ester followed by treatment with potassium hydroxide resulted in formation of the trisubstituted tetrahydrofuran 98. 

Thus ailylboration of carbonyl compounds with B-allylic derivatives of 9-BBN, followed by transesterification with ethanolamine, provides a simple, convenient method for the synthesis of homoallylic alcohols It has been reported that enantiomerically enriched allylic boranes provide homoallylic alcohols with high degree of enantio- and diastereoselectivity. The scheme is illustrated in Eqs. 48 and 49... 

With the cationic rhodium complex (15) diastereoselectivity is high (>91%) at 44 atm of hydrogen, but it falls off at atmospheric pressure. Hydrogenation with the cationic iridium complex (20) in dichloromethane (25 C, 1 atm H2) exhibits a low level of diastereoselection. ° The rhodium complex (15) is also superior to iridium complex (20) in the hydrogenation of homoallyl alcohols,as in the stereoselective synthesis of (18) from (17),... 

The generation of allylic indium reagents by transmetallation of allylic stannanes with InCl3 and subsequent reaction of these with aldehydes represents an important advance for diastereoselective synthesis of homoallylic alcohols [203]. In these reactions, the stannane is added to a premixed solution of the aldehyde and InCl3 in acetone. In this way, the reaetion of cyclohexanecarboxaldehyde with the 2-butenylindium reagent affords a 98/2 antilsyn mixture of homoallylic alcohols (Scheme 10-104). 

Panek and co-workers have demonstrated that crotylsilanes 217 and 343 react with a variety of electrophiles including aldehydes, a, ff-unsaturated ketones, acetals and imines under appropriate activation conditions (usually Lewis acidic) to form homoallylic ethers [149, 261], homoallylic alcohols [58, 150, 151], tetrahy-drofurans [262, 263], cyclopentanes [264], pyrrolidines and homoallylic amines [265] with high levels of enantio- and diastereoselectivity [12]. This review will focus on the reactions of crotylsilanes 217 with Lewis acid-activated acetals and aldehydes, and the application of these reactions to the synthesis of polypropionate natural products [266-271]. 

Of the BINOL/BINAP-metal catalyst complexes, only the allylation procedure described by Keck using the BINOL-Ti(IV) catalyst 451 has been applied in the synthesis of natural products, presumably because it has the most substrate generality and the field is so new. In a preliminary report, Evans disclosed the synthesis of the 4-hydroxy buteneolide terminus 470 of mucocin, where he uses Keck s original catalytic asymmetric allylation procedure to effect conversion of aldehyde 469 to the homoallylic alcohol 470 in good yield and high diastereoselectivity (Scheme 11-36) [312]. 

In addition, recent studies towards the synthesis of bryostatin 1 have described high diastereoselectivity for the chelation-controlled condensation of the substituted stannane 68 with ent-33 leading to the desired i yn-product 69 via 70 (Scheme 5.2.17).While ketones have rarely been explored as reactive electrophiles for stereoselective allylations, proximate coordination of a Lewis acid through a-chelation can produce favorable results, as illustrated in the exclusive formation of the tertiary homoallylic alcohol 72 from 71 (Scheme 5.2.17).28... 

Intramolecular bis-silylation of homoallylic alcohols, which proceeds with high diastereoselectivity, is applied to the stereoselective synthesis of 1,2,4-triols 109 (Eq.59) [67-71]. 

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