The Development of an Electron Transfer Initiated Cyclization Approach Toward the Total Synthesis of Mycalamide B. The Synthesis of the N7-C25 Fragment of Psymberin
The electron transfer initiated cyclization (ETIC) has been shown to be an efficient method for the generation of cyclic amido acetals. The tetrahydrofuranyloxy methyl ether was shown to be a stable nucleophilic hemiacetal surrogate allowing for the incorporation of a formaldehyde equivalent in the ETIC reaction.
The ETIC reaction was employed in the stereoselective synthesis of amido trioxadecalin systems relevant to the synthesis of the mycalamides, onnamides and theopederins. The stereoselectivity resulting from these cyclizations was controlled by the substituents of the tetrahydropyran ring and the conformational bias of the developing trioxadecalin system. The epimerization of the N-acylaminal center of the amido trioxadecalin system was possible under mildly acidic conditions.
An efficient and stereoselective synthetic route has been developed that intends to employ the ETIC reaction to selectively generate the N-acylaminal of mycalamide B. A linear approach to the generation of the right half of mycalamide B has been applied allowing for expedient access to the dimethyl tetrahydropyran core. The synthetic sequence employs an asymmetric Leighton allylation, selective boron mediated aldol, 1,3-syn-reduction, and selective epoxidation and syn-vinylation to establish the stereochemistry of the right hand fragment of mycalamide B.
The stereoselective synthesis of the N7-C24 fragment of psymberin was developed. The synthesis is highlighted by the de novo generation of the C25-C17 pentasubstituted arene that allows for the expedient generation of multigram quantities of this intermediate. The stereochemistry of this fragment was established by an asymmetric Brown crotylation and Leighton allylation, selective Mukaiyama aldol addition, 1,3-syn-reduction, and a selective Lewis acid catalyzed TMSCN displacement of an acyl lactol.
Advisor:Prof. Kazinori Koide; Prof. Peter Wipf; Prof. Jeff Hildebrand; Prof. Paul E. Floreancig
School:University of Pittsburgh
School Location:USA - Pennsylvania
Source Type:Master's Thesis
Date of Publication:03/20/2006