An Investigation of the Pederin Family: Total Synthesis of Theopederin D; Synthesis and Determination of the Relative and Absolute Configuration of Psymberic Acid
An investigation of the pederin family of natural products has led to the total synthesis of theopederin D, a synthesis of the C1-C6 portion of psymberin (psymberic acid), and the determination of the absolute configuration of C4 and C5 of this fragment.
Highlights of our theopederin D synthesis include the use of an asymmetric ketene-aldehyde cycloaddition to synthesize the A ring (or pederic acid subunit), a 1,5-anti-boron mediated aldol to construct the C16-C17 bond with high a high level of diastereocontrol, formation of the C and D rings in a one-pot, six reaction sequence, selective differentiation of a tetrahydrofuranol in the presence of a tetrahydropyranol, and elaboration of the C ring using vinylation chemistry developed by Yamamoto and Rainier.
The stereochemically labile B ring of theopederin D was constructed during the late stages of this synthesis using carbon-carbon bond activation via an Electron Transfer Initiated Cyclization (ETIC) method previously developed in the Floreancig research laboratories. This transformation proceeded under essentially neutral conditions and furnished the desired amidotrioxadecalin in high yield. The total synthesis of theopederin D was completed through coupling of pederic acid and an aminotrioxadecalin fragment using a modified diastereoselective strategy initially developed by Rawal.
Our efforts toward the total synthesis of psymberin involved the synthesis of psymberic acid, as its absolute and relative stereochemistry was previously undefined. The use of readily available starting materials (D- or L-serine) and subsequent elaboration using syn or anti selective methallylation allowed for the efficient construction of all possible stereoisomers of psymberic acid. The absolute configuration of psymberic acid was determined through natural product and model system degradative studies, and analysis of the reaction products using a gas-chromatography/ mass spectrometry apparatus (GC-MS) outfitted with a chiral stationary phase.
Advisor:Peter Wipf; Jeff Hildebrand; Craig Wilcox; Paul Floreancig
School:University of Pittsburgh
School Location:USA - Pennsylvania
Source Type:Master's Thesis
Date of Publication:01/28/2009