Total Synthesis of Archazolid F

Abstract

A partial bioinspired as well as the total synthesis of archazolid F, a highly potent V-ATPase inhibitory, antiproliferative polyketide macrolide, is described. Key features of the synthetic routes include a highly stereoselective aldol condensation of two elaborate fragments and macrocyclizations either by a Shiina macrolactonization or by a challenging RCM reaction of an octaene substrate. The syntheses unequivocally confirm the full architecture of this very scarce archazolid.

Design, Synthesis and Biological Evaluation of Highly Potent Simplified Archazolids

“…The synthesis of these derivatives uses a methodology developed during the total synthesis of archazolid F. [17] As shown in Figure 3, the implementation of the analogues 5-8 was achieved by the combination of two fragments, that is, a main northern subunit of type 10 and various southern segments of type 9. Following our own precedence, [17] an aldolcondensation sequence was planned to forge the 18,19-double bond, while a novel macrolactonization approach was considered to close the ring. Schemes 1, 2 and 3 show the synthesis of the main fragments 27, 28, 39 and 40 by robust and reliable routes involving aldol and olefination reactions that have previously been established on related systems.…”

“…This hypothesis was further supported by docking calculations and molecular dynamics experiments. [23] Accordingly, a novel synthetic route towards such macrolides was developed and applied for the total synthesis of archazolid F. [17] This strategy relied on disconnections of the C18-C19 bond, by an aldol condensation and a ring closing metathesis along the C3-C4 bond. The synthetic methodology route was subsequently used for the total synthesis of a first series of unnatural analogues.…”

“…Conditions Yield [a] E/Z the starting ketones 27, 28, 39 and 40 in the initial aldol coupling were obtained with lithium tetramethylpiperidine (LiTMP). Indeed, it was found that LiTMP offers the double benefit of full conversion and facile work-up in contrast to Ph 2 NLi used in the total synthesis of archazolid F. [17] . Acetate esterification of the aldol products and a 1,8-Diazabicyclo[5.4.…”

“…As shown in Scheme 5, for completion of the synthesis, ketones 43 a/b and 44 a/b were selectively reduced by means of NaBH 4 . This procedure was originally described by the Trauner group [15] in their total synthesis of archazolid B and had subsequently also been used by us in the preparations of archazolid F [17] and related analogues. [13] Gratifyingly, this protocol again proceeded with good selectivity (dr 10 : 1) and yields to give, after methylation with Meerwein salt, the corresponding ethers 47 a/b and 48 a/b.…”

“…So far, one total synthesis of archazolid A was published by us in 2007, [14] and two total syntheses of archazolid B have been reported by the Trauner group [15] and our group in 2007 and 2009. [16] In 2018, we accomplished the total synthesis of archazolid F. [17] Furthermore, elaborate fragment synthesis of 2,3-dihydroarchazolid was published by O'Neil et al [18][19][20]…”