20 Total Synthesis of (+)-Macquarimicin A
Ryosuke Munakata, Hironori Katakai, Tatsuo Ueki, Jun Kurosaka, Ken-ichi Takao, Kin-ichi Tadano
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(+)-Macquarimicin A (1) was isolated from Micromonospora chalcea in 1995. Later, it was found that 1 is a selective inhibitor of membrane-bound neutral sphingomyelinase (N-SMase) and exhibits an anti-inflammatory activity. The structure of 1 is characterized by a novel tetracyclic framework, which comprises a cis-tetrahydroindanone ring, a β-keto-δ-lactone ring, and a 10-membered carbocycle. In addition, 1 would be biosynthesized via an intramolecular Diels-Alder reaction (IMDA) of a polyketide intermediate. This formidable molecular architecture, combined with the remarkable biological profiles, makes 1 an attracting synthetic target. Herein, we describe the first total synthesis of natural (+)-macquarmicin A (1) and determination of its absolute configuration. (Z)-Stannylalkene 10 and (E)-iodoalkene 11, each synthesized from known 12 and 17 respectively, were converted into 8 via a CuCl promoted Stille coupling reaction. The macroallylation of 8 was successfully carried out to form a 17-membered ring using Pd(PPh_3)_4/dppe (1:1) as a catalyst. Formation of the β-keto-δ-lactone ring under thermal conditions followed by the introduction of the double bond afforded 7 as a mixture of geometrical isomers. Under thermal conditions(130℃), the transannular Diels-Alder reaction of 7 furnished the desired diastereomer 6 as a sole cycloadduct. In this reaction, the geometry of (Z,E)-diene is the origin of endo selectivity, while the lactone ring restricts the conformation of transition state to control the diastereofacial selectivity. Silylation of 6 and deprotection of the MPM group provided 28. Dess-Martin oxidation of 28 and subsequent PPTS catalyzed cleavage of the TES group afforded (+)-1. Spectral properties (^1H and ^<13>C NMR and IR) of synthetic (+)-1 were completely identical with those of a natural sample. Furthermore, optical rotation of synthetic (+)-1 ([α]^<23>_D +285°(c 0.780, MeOH)) established the absolute configuration of natural (+)-1 ([α]^<25>_D +285.6°(c 0.2, MeOH)).
