Total Syntheses of (−)-Macrolactin A, (+)-Macrolactin E, and (−)-Macrolactinic Acid:  An Exercise in Stille Cross-Coupling Chemistry

Abstract

The total syntheses of the potent antiviral agent (−)-macrolactin A (1) and two related family members, (+)-macrolactin E (5) and (−)-macrolactinic acid (7), have been achieved, exploiting a unified, convergent, and highly stereocontrolled strategy. Extensive use of the palladium-catalyzed Stille cross-coupling reaction for the stereospecific construction of the three isolated dienes including macrocyclization formed the cornerstone of the successful strategy. The total syntheses of these natural products, no longer available via fermentation, confirm their relative and absolute stereochemistries and provide access to possible analogues for further biological study.

7- O -Malonyl Macrolactin A, a New Macrolactin Antibiotic from Bacillus subtilis Active against Methicillin-Resistant Staphylococcus aureus , Vancomycin-Resistant Enterococci, and a Small-Colony Variant of Burkholderia cepacia

“…(10,16,18,23). Six macrolactins were first described in 1989 by Gustafson (22,33,34). Macrolactins are considered to be potent antiviral and cytotoxic agents that also have antibacterial activity (10,16).…”

One‐Flask Tethered Ring Closing Metathesis–Electrocyclic Ring Opening for the Highly Stereoselective Synthesis of Conjugated Z/E‐Dienes

“…Where signal assignments in 1 H or 13 C NMR spectra are given, these are based on H,H-and H,C-correlation spectroscopy, and on NOE NMR spectroscopy if necessary. 19 F NMR spectra were recorded at 282 MHz in CDCl 3 with C 6 F 6 (δ = -163 ppm) as internal standard. IR spectra were recorded neat, and peak positions are given in wavenumbers (ν) in cm -1 .…”

“…The methods commonly used for the stereoselective synthesis of Z,E-configured conjugated dienes can be roughly classified as follows: (a) Z-selective olefination reactions [10] have been applied for the synthesis of macrolactin A, [11] dictyostatin, [12] stagonolide E, [13] and dienoic acids 1a, [14] 1c [15] and 1e; [15] (b) the Stille coupling [16] of Z-vinyl stannanes and E-vinyl iodides (or vice versa) [17] was used, inter alia, for the synthesis of macrolactins; [11,18,19] (c) the E-selective ring closing metathesis (RCM) of terminal Z-dienes, a process that normally suffers from insufficient regio-and stereocontrol when applied to the synthesis of macrocyclic tion of the method to the synthesis of the natural product fusanolide A suggests that the originally published structure was erroneously assigned and should be revised. polyenes, was recently successfully applied in the synthesis of iejimalides [3,20] and lactimidomycin; [21] (d) the electrocyclic base-induced ring opening of α,β-unsaturated δ-lactones 2, which gives, under kinetic conditions, the (2Z,4E)-dienoic acids (1).…”

Marine Drugs – Macrolactins

“…This led to the total synthesis of macrolactin A [8 -17] based on its estimated three-dimensional architecture [18]. In the meanwhile, macrolactin E was also chemically synthesized [16].…”