Total Synthesis of the Originally Proposed and Revised Structures of Palmerolide A and Isomers Thereof

Abstract

Palmerolide A is a recently disclosed marine natural product possessing striking biological properties, including potent and selective activity against the melanoma cancer cell line UACC-62. The total syntheses of five palmerolide A stereoisomers, including the originally proposed (1) and the revised [ent-(19-epi-20-epi-1)] structures, have been accomplished. The highly convergent and flexible strategy developed for these syntheses involved the construction of key building blocks 2, 19-epi-2, 20-epi-2, ent-2, 3, ent-3, 4, and ent-4, and their assembly and elaboration to the target compounds. For the union of the building blocks, the Stille coupling reaction, Yamaguchi esterification, Horner-Wadsworth-Emmons olefination, and ring-closing metathesis reaction were employed, the latter being crucial for the stereoselective formation of the macrocycle of the palmerolide structure. The Horner-Wadsworth-Emmons olefination and the Yamaguchi lactonization were also investigated and found successful as a means to construct the palmerolide macrocycle. The syntheses were completed by attachment of the enamide moiety through a copper-catalyzed coupling process.

Rapid synthesis of cyclic oligomeric depsipeptides with positional, stereochemical, and macrocycle size distribution control

“…Additionally, KBF 4 increased the overall isolated yield of macrocycles from 64 to 81% along with evidence that less material was converted into linear DIAD substrate acylation by-products. This type of by-product is common (52)(53)(54) in Mitsunobu reactions, especially in the presence of excess coupling reagents, which are generally required for a macrolactonization to occur. However, an ion template would allow the linear chain to reside in a conformation that increases the rate of cyclization relative to acylation, and the latter would be inherently slower as the linear chain increases in size.…”

Asymmetric trapping of zwitterionic intermediates by sulphur ylides in a palladium-catalysed decarboxylation-cycloaddition sequence

“…For example, in the well-known JohnsonCorey-Chaykovsky reaction 6 , which was first discovered in the 1960s (refs 7,8), sulphur ylides can react with polar substrates (for example, aldehydes, ketones, imines and electron-deficient alkenes) to produce a wide range of significant small-ring molecules such as epoxides, aziridines and cyclopropanes. More importantly, their synthetic potential has been well demonstrated in the synthesis of numerous bioactive natural products and pharmaceuticals 6,9,10 . In the past decade, the cycloaddition chemistry of sulphur ylides has evolved dramatically beyond three-membered rings, largely as a consequence of the valuable contributions made by Aggarwal and co-workers [11][12][13][14][15][16][17][18][19][20][21][22] , among others.…”

The Vinylogous Mukaiyama Aldol Reaction in Natural Product Synthesis

“…The polyketide subunit 61 of kulokekahilide-2 (62) was established via VMAR maneuver of silyloxy diene (59) and aldehyde (60) in moderate yield but excellent diastereoselection as single diastereomer (Scheme 2.15, (5)) [34]. In a second generation synthesis of aurilide (22) (chemical structure, see Scheme 2.6), the VMAR between 18 and silyl ketene acetal (59) afforded methyl ester (63) in 87% yield as a single diastereomer (Scheme 2.15, (6)) [35]. The excellent Felkin-Anh and 1,3-anti-diastereoselectivity of these two examples can be explained by the transition state model proposed by Evans and coworkers (cf.…”