Total syntheses of (+)-acutiphycin and (+)-trans-20,21-didehydroacutiphycin

Shuyong Chen, University of Pennsylvania

Abstract

Chapter 1 describes an asymmetric synthesis of a C(1)-C(11) fragment of (+)-acutiphycin (1). Starting from (S)-malic acid (8), alcohol (+)-7$\alpha$ was assembled in seven steps. A five step sequence involving oxidation, addition of propynyl lithium to the resultant aldehyde, oxidation of the derived alcohol, chelation controlled introduction of the methyl unit, and semi-reduction of the acetylene provided the tertiary allylic alcohol (+)-14. The highlight of the synthesis involved a stereocontrolled (2,3) -sigmatropic rearrangement to furnish alcohol (+)-15a with diastereoselective introduction of the remote methyl group at C(10). Aldehyde (+)-25 was then obtained in good yield via standard transformations. Chapter 2 describes the first total synthesis of (+)-acutiphycin (1). Advanced aldehyde (+)-32 was prepared from (+)-25 in four steps involving a chemoselective reduction of a thioester. The acutiphycin southern hemisphere (e.g. vinyl bromide (+)-33) was synthesized from 1-heptene (34) in 8 steps employing Sharpless asymmetric dihydroxylation methodology. With both aldehyde 32 and vinyl bromide 33 in hand, union of the two fragments was achieved via coupling of the vinyl Grignard reagent derived from 33 with aldehyde 32. After significant investigation, seco acid (+)-31 was identified as the suitable precursor for the crucial Yamaguchi macrolactonization reaction to construct the highly congested 16-membered macrolactone (+)-58. Selective silylation, Dess-Martin oxidation and removal of all protecting groups afforded (+)-acutiphycin (1). Chapter 3 describes the first total synthesis of (+)-trans-20,21-didehydroacutiphycin (2). The requisite vinyl bromide 64 was constructed from aldehyde (+)-10 by two different routes. With both coupling partners available, (+)-trans-20,21-didehydroacutiphycin (2) was synthesized by the same strategy used in the preparation of acutiphycin. A comparison of the NMR spectra of natural and synthetic (+)-trans-20,21-didehydroacutiphycin is also included.$\sp*$ ftn$\sp*$Please refer to the dissertation for diagrams.

Subject Area

Organic chemistry

Recommended Citation

Chen, Shuyong, "Total syntheses of (+)-acutiphycin and (+)-trans-20,21-didehydroacutiphycin" (1996). Dissertations available from ProQuest. AAI9627900.
https://repository.upenn.edu/dissertations/AAI9627900

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