Studies on the Synthesis of Bafilomycin A₁:  Stereochemical Aspects of the Fragment Assembly Aldol Reaction for Construction of the C(13)−C(25) Segment

Abstract

Highly stereoselective syntheses of aldols 8a-c corresponding to the C(13)-C(25) segment of bafilomycin A(1) were developed by routes involving fragment assembly aldol reactions of chiral aldehyde 6a and the chiral methyl ketones 7. A remote chelation effect plays a critical role in determining the stereoselectivity of the key aldol coupling of 6a and the lithium enolate of 7b. The protecting group for C(23)-OH of the chiral aldehyde fragment also influences the selectivity of the lithium enolate aldol reaction. In contrast, the aldol reaction of 6a and the chlorotitanium enolates of 7a,c were much less sensitive to the nature of the C(15)-hydroxyl protecting group. Studies of the reactions of chiral aldehydes with Takai's (gamma-methoxyallyl)chromium reagent 40 are also described. The stereoselectivity of these reactions is also highly dependent on the protecting groups and stereochemistry of the chiral aldehyde substrates.

Stereoselective Acetate Aldol Reactions from Metal Enolates

“…For instance, a thorough analysis reported by Roush et al on the addition of the syn b-tert-butyldimethylsilyloxy-a-methyl ketone 78 to the chiral aldehyde 79a established the dependence of the aldol stereoselectivity on the metal enolate (Scheme 25, equation 1). 89 Furthermore, the moderate and low diastereoselectivities observed for related ketones 82 and 83 (Scheme 25, equations 2 and 3) suggest that the presence of a chelating group at the d-position is crucial for attaining high stereocontrol and prove that these aldol reactions are governed by several subtle structural details. 89 Parallel studies on the titanium-mediated aldol reactions of ketone 84 unveiled a close diastereoselectivity dependence on the protecting group of the aldehyde 79 (Scheme 25, equation 4), thus providing new proof of the sensitivity of these substrate-controlled transformations.…”

Current Progress in the Acetate/Methyl Ketone Aldol Reaction

“…A recent example is given by Roush and coworkers [11][12][13][14] who used a methyl ketone aldol reaction in the synthesis of a fragment of bafilomycin A 1 (5). By varying the enolization conditions as well as the stereochemistry and protecting groups of the donor (6) and acceptor (7), the resulting selectivity in the aldol products (8:9) varied from Excellent diastereoselectivities were obtained by Dias et al when reacting protected dihydroxy methyl ketone 10 with aldehydes, using (c-Hex) 2 BCl/Et 3 N enolization conditions (Scheme 2) [15].…”

Synthesis of the C1-C17 Macrolactone of Tedanolide

“…Subsequent PMB-protection gave the protected olefin in 60% yield over two steps (Scheme 7). 32 This protocol was followed by ozonolysis and in situ Wittig reaction to the a,b-unsaturated ester 29 in only one step and 76% yield. It was also possible to perform an in situ dihydroxylation/diol cleavage sequence to furnish aldehyde 28.…”