Enantioselective Total Synthesis of (+)-Jasplakinolide

Abstract

An enantioselective total synthesis of (+)-jasplakinolide is described. The synthesis of the polyketide template utilized a diastereoselective syn-aldol, ortho-ester Claisen rearrangement followed by efficient conversion to a cyanide. The beta-amino acid unit was constructed in a highly diastereoselective manner utilizing nucleophilic addition to a chiral sulfinimine. Yamaguchi macrocyclization and removal of the protecting group provided a convenient access to (+)-jasplakinolide.

Capturing the Essence of Organic Synthesis: From Bioactive Natural Products to Designed Molecules in Today’s Medicine

“…Chemical and biological investigations of jasplakinolide, and its analogs, remain an extremely active area of research. We have devised a practical synthesis of jasplakinolide that has enabled us to prepare a number of structural variants 28. As shown in Figure 15, the polyketide segment of 21 was first constructed by a diastereoselective aldol reaction that provided 83 , followed by an ortho-ester-promoted Claisen rearrangement to form the γ,δ-unsaturated ester 85 in a 7:1 mixture of diastereomers.…”

“…The β-amino acid segment 87 was synthesized using an asymmetric enolate addition to a chiral sulfinimine derivative developed by David and co-workers 62. Strategic assembly of the various segments led to the synthesis of jasplakinolide ( 21 ) 28. This synthesis enabled us to probe the importance of various substituents, improve potency, and reduce complexity.…”

Synthesis of Bioactive Natural Products by Asymmetric syn- and anti-Aldol Reactions

“…The polypropionic acid segment was synthesized by using an aldol reaction followed by a Claisen rearrangement as the key steps. 35 …”

Harnessing Nature’s Insight: Design of Aspartyl Protease Inhibitors from Treatment of Drug-Resistant HIV to Alzheimer’s Disease

“…This endeavor resulted in the total synthesis of numerous targets, covering over two dozen or so different structural families. Some notable examples of our accomplished bioactive targets include novel and exceedingly potent microtubule stabilizing agents, laulimalide ( 1 )4 and peloruside A ( 2 )5 a potent microtubule destabilizing agent cryptophycin 52 ( 3 )6; anticancer agents amphidinolide T ( 4 )7, amphidinolide W ( 5 )8, and lasonolide A ( 6 )9; antibiotic agent, madumycin II ( 7 )10; pancreatic lipase inhibitor, tetrahydrolipstatin ( 8 )11; novel actin inhibitory agents doliculide ( 9 )12 and jasplakinolide ( 10 )13; novel antibacterial agent platensimycin ( 11 )14; and the histone deacytelase inhibitor, largazole ( 12 )15 (see Figure 1). The unique structural features of these natural products required the development of new synthetic tools and methodologies for their synthesis.…”