Total Synthesis of (−)-Bafilomycin A1: Application of Diastereoselective Crotylboration and Methyl Ketone Aldol Reactions

Abstract

A careful orchestration of protecting groups is an essential requirement for the total synthesis of the macrolide antibiotic bafilomycin A (1). Key steps were the Suzuki cross-coupling reaction of two advanced, suitably protected intermediates prior to closure of the macrocycle, as well as a highly stereoselective methyl ketone aldol reaction.

1,4‐Pentenyne as a Five‐Carbon Synthon for Efficient and Selective Syntheses of Natural Products Containing 2,4‐Dimethyl‐1‐penten‐1,5‐ylidene and Related Moieties by Means of Zr‐Catalyzed Carboalumination of Alkynes and Alkenes

“…A similar route to the TES‐protected analogue of 25 and (−)‐bafilomycin A 1 was also reported by Hanessian 6i. Our conversion of 35 to 25 followed closely the route employed by Roush6e, f and Marshall,6g, h as shown in Scheme . Thus, 25 with 98 % isomeric purity was prepared in 11 steps from TIPSCCH in 16 % overall yield.…”

“…In some cases, however, it is desirable to reverse the order of their execution (protocol II). Synthesis of the variously protected preferred intermediate 25 6e–j for the synthesis of (−)‐bafilomycin A 1 is a case in point. Conversion of 12 into 26 proceeded in 72 % yield.…”

“…After protection of the hydroxyl group with TBSOTf (98 % yield), oxidation first with N ‐methylmorpholine‐ N ‐oxide (NMO) in the presence of 1.0 mol % of OsO 4 and then with NaIO 4 produced 35 in 71 % yield. The same compound was also used by the Roush6e, f and Marshall6g, h groups in the synthesis of 25 and eventually of (−)‐bafilomycin A 1 6. A similar route to the TES‐protected analogue of 25 and (−)‐bafilomycin A 1 was also reported by Hanessian 6i.…”

“…Thus, 25 with 98 % isomeric purity was prepared in 11 steps from TIPSCCH in 16 % overall yield. Besides being efficient, in part by virtue of the use of 1,4‐pentenyne and its derivatives permitting the combined use of the ZMA and ZACA reactions, this appears to be the only catalytic and fully enantioselective synthesis of 25 or its analogues with different protective groups 6e–j…”

Metal‐Catalyzed Cross‐Coupling Reactions of Organoboron Compounds with Organic Halides

“…The boronic acids thus obtained couple with iodoalkenes at room temperature when a thallium base is used in the presence of [Pd(PPh 3 ) 4 ]. The protocol has been suc- cessfully used for a number of syntheses of natural products, including (-)-bafilomycin A (197) [308,309]. The (Z,Z,E)-triene structure in (þ)-fostriecin [310] is synthesized by the cross-coupling reaction of (Z,E)-alkadienylboronic ester 199, which is obtained via rhodium-catalyzed Z-selective hydroboration of terminal alkynes [18].…”