First Asymmetric Total Synthesis of Penarolide Sulfate A₁

Abstract

Penarolide sulfate A1, with three contiguous stereogenic centers on a macrocyclic skeleton, affords promise as an α‐glucosidase inhibitor. Herein, we describe the first asymmetric total synthesis of this natural product. A stereoselective strategy for rapid assembly of the complete framework of the 30‐membered macrocyclic core is delineated herein. Sequential amidation and intramolecular Sonogashira cross‐coupling reactions were pivotal to the success of our efforts. (© Wiley‐VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2008)

Total Syntheses of Cochliomycin B and Zeaenol

“…of Cs 2 CO 3 , affording compound 18 readily in a yield of 68 % 20c. The esterification of compound 18 and fragment 11 was initially explored in two conventional steps, that is, hydrolysis of compound 18 with 2 M aqueous LiOH followed by ester formation with alcohol 11 in the presence of condensation agents such as N ′‐(3‐dimethylaminopropyl)‐ N ‐ethylcarbodiimide (EDCI) 28. However, purification of the free acid from the hydrolysis products of compound 18 encountered difficulties with respect to purity and recovery due to its good hydrophilicity.…”

“…[20c] The esterification of compound 18 and fragment 11 was initially explored in two conventional steps, that is, hydrolysis of compound 18 with 2 m aqueous LiOH followed by ester formation with alcohol 11 in the presence of condensation agents such as NЈ-(3-dimethylaminopropyl)-N-ethylcarbodiimide (EDCI). [28] However, purification of the free acid from the hydrolysis products of compound 18 encountered difficulties with respect to purity and recovery due to its good hydrophilicity. Fortunately, transesterification [29] of 18 with the alkoxide anion derived from the treatment of fragment 11 with NaH in dry THF was carried out successfully presenting compound 19 in 75 % yield.…”

Sonogashira coupling in natural product synthesis

“…Sonogashira coupling also proved useful for synthesizing the highly complex maduropeptin chromophore (21), which contains a bicyclo[7.3.0]enediyne and a 15-membered ansamacrolactam with atropisomerism. This compound exhibits potent antitumor and antibacterial activity through a mechanism that differs from that of other enediyne natural products.…”

“…Scheme 6 Sonogashira coupling of fragments to synthesize the aglycon of maduropeptin chromophore (21). Coupling terminal alkyne 29 with vinyl iodide 30 in the presence of (PPh 3 ) 2 PdCl 2 and CuI gave the coupling product in 94% yield, which was then esterified with fragment 32 to achieve vinyl iodide 33.…”

Synthesis and biological activity of naturally occurring α-glucosidase inhibitors

“…To date, a single total synthesis of the penarolides has been reported, by Mohapatra and co-workers, who employed an intramolecular Sonogoshira coupling reaction to establish the 30-atom macrolide ring of penarolide A 1 (330) (Schemes 50-53). 170 In this highly convergent approach, synthesis of the C1-C18 carboxylic acid subunit 342 commenced from dodecane-1,12-diol (337), which was converted via a three-step sequence to 338 (Scheme 50). Sharpless asymmetric dihydroxylation of this E,E-dienoate proceeded with complete regiocontrol to provide 339, which was then converted to 340 through a succession of diol protection, reduction and Sharpless asymmetric epoxidation.…”