Crotylboronates

HOFFMAN - YAMAMOTO Stereoselective adylations Synthesis of syn or anti homoallylic alcohols from Z or E crotylboronate and aldehydes (Hoffman) or of syn homoallylic alcohols from crotylstannanes, BF3 and aldehydes (Yamamoto)... 

Some special features arise from pericyclic reactions. In the reaction of an a-methyl-branched aldehyde with ( )-crotylboronates, Cram selectivity is enhanced, whereas the Z-isomers show moderate anti-Cram selectivity23 - 25 (see Section D.1.3.3.3.3.1.3.). These findings can most likely be applied generally. 

The addition of (E)- and (Z)-crotylboronates 7 to aldoximes 6 has been realized in good yield by performing the reaction under 3-6 x 10° Torr pressure10. The resulting hydroxylamines 8 can easily be reduced to yield the primary amines. The addition of E-l leads preferentially to the anh-diastereomcr 8, while (Z)-crotylboronate 7 shows a modest selectivity towards formation of the vyy -diastereomer 8 (same sense as in the reaction with aldehydes). Some effort has been made to elucidate the mechanism, but this is not yet well understood. 

The corresponding crotylboronates, (R,R)- and (S,S)-5 also undergo highly diastereoselective reactions with the same chiral aldehydes, and again the diaster-... 

Solutions to problems (i) and (ii) were already available as a result of studies by Hoffmann and Wuts on the reactions of 7-alkoxyaIlyl-boronates with achiral aldehydes (Figure 6). 3 Relatively little information was available, however, regarding the stereochemistry of such reactions with chiral aldehydes. Hoffman had published several examples of reactions of (E)- and (Z)-crotylboronates (methyl replacing OMe in Figure 6) with chiral aldehydes such as 2-methylbutanal, but the best diastereofacial selectivity that had been reported was only 83 17.14 Thus, it was by no means certain that the chemistry summarized in Figure 7 would be successful.3a... 

Stereoselectivity diminished or disappeared altogether as the C(3) substituent was removed (allyl reagent 25) or inverted ((E)-crotylboronate 26 see Figure 10).3 ... 

Figure 10. Reactions of allyl- and crotylboronates with D-glyceraldehyde acetonide (23).

The presence of a stereogenic center on the aldehyde can strongly inlinence the diastereoselectivity in allylboration reactions, especially if this center is in the a-position. Predictive rules for nucleophilic addition on snch a-snbstitnted carbonyl substrates such as the Felkin model are not always snitable for closed transition structures.For a-substituted aldehydes devoid of a polar substituent, Roush has established that the minimization of ganche-ganche ( syn-pentane ) interactions can overrule the influence of stereoelectronic effects. This model is valid for any 3-monosubstituted allylic boron reagent. For example, althongh crotylboronate (E)-7 adds to aldehyde 39 to afford as the major prodnct the diastereomer predicted by the Felkin model (Scheme 2), " it is proposed that the dominant factor is rather the minimization of syn-pentane interactions between the Y-snbstitnents of the allyl unit and the a-carbon of the aldehyde. With this... 

The E-crotylboronate derivatives 28 and 75 behave similarly. As shown in Eqs. 61 and 62, these reagents were successfully tested with simple ahphatic aldehydes and benzaldehyde and provide very high levels of stereoselectivity in the formation of anti-propionate products. Although the a-methoxy derivative 75 is more diastereoselective, it provides lower enantioselectivity because it can be obtained only in 90% ee from enantiopure 28 via an Sn2 displacement that canses some erosion of the enantiomeric purity. 

Scheme 9. Stereoinduction model for the additions of chiral a-methyl crotylboronate 21.

In earher work, the Hall group found that catalytic amounts of triflic acid promoted the addition of aUylboronates to aldehydes [132], While aUylboration reactions catalyzed by chiral Lewis acids in general led to only low levels of enan-tioselection [133], Hall found that chiral LBA 1 catalyzes the asymmetric addition of allyl- and crotylboronates to various aldehydes to provide products in excellent yields and moderate to high ee s (Scheme 5.71) [134]. Further, double diastereose-lective crotylboration could also be achieved with high selectivities using the... 

Z)-Crotylboration of Boc-prolinal with Chiral (Z)-Crotylboronate 47 Synthesis of fcrf-Butyl 2-(l-Hydroxy-2-methylbut-3-enyl)pyrroKdine-l-carboxylate (48) 81 ... 

P-Methylhomoallylic alcohols.2 These crotylboronates (1) react with aldehydes to give /3-methylhomoallylic alcohols with a diastereoselectivity of > 95% (equations I and II). This condensation has certain advantages over the aldol condensation, since the products 2 can be converted to / -hydroxy aldehydes or carboxylic acids by... 

Reaction of crotylboronates (18) with aldehydes in the presence of In(OTf)3 has been found to be temperature dependent. At low temperatures, the expected 2-substituted homoallylic alcohols (19) were formed. At room temperature, by contrast,... 

Diisopropyl crotylboronates, 1. These chiral crotylboranates are prepared in 98-99% ee from diisopropyl tartrate. 

In a related study, Hoffmann and Kemper also synthesized the y-methoxyallylboronates 3E and 3Z and performed addition reactions into a variety of aldehydes to explore the possibility of a stereoselective synthesis of vicinal diols5 (Scheme 3.III). Once again, the reaction is highly diastereoselective, affording an anti -isomer from the E -boronate and a syn -isomer from the Z-boronate. The nearly perfect diastereoselectivity observed in the reaction of crotylboronates... 

The tartrate-based E-crotylboronate (S,S)-43E, which can readily be prepared... 

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. 

Liu and Zhou applied Roush s crotylboration to the stereoselective synthesis of the orostanal 70, a novel sterol that induces apoptosis in human acute promyelotic leukemia cells28 (Scheme 3.ly). The aldehyde 72, prepared from hyodeoxycholic acid methyl ester, underwent asymmetric reaction with crotylboronate (R,R)-43E to furnish 73. Hydrogenation of the terminal alkene followed by Swem oxidation gave the ketone 74. Methylenation of the ketone and removal of the protective groups afforded orostanal in 50% yield. 

Another synthetic application of Roush s crotylboration methodology using a (Z)-crotylboronate can be found in the formal synthesis of (+)-discodermolide (75)29 (Scheme 3.1z). The aldehyde (S)-67, which was prepared from the Roche ester, reacted with (Z)-crotylboronate (S,S)-43Z to give the syn-homoallylic alcohol 76. Silylation of alcohol and oxidative cleavage of the alkene 77 provided the aldehyde 78, from which the final product (75) can be synthesized according to a known procedure.30... 

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