Toward Ideality: The Synthesis of (+)-Kalkitoxin and (+)-Hydroxyphthioceranic Acid by Assembly-Line Synthesis

Sebastien Balieu, Gayle E. Hallett, Matthew Burns, Teerawut Bootwicha, John Studley, Varinder K. Aggarwal*

*Corresponding author for this work

Research output: Contribution to journalArticle (Academic Journal)peer-review

88 Citations (Scopus)

Abstract

The iterative homologation of boronic esters using chiral lithiated benzoate esters and chloromethyllithium has been applied to the highly efficient syntheses of two natural products, (+)-kalkitoxin and (+)-hydroxyphthioceranic acid. The chiral lithiated benzoate esters (>99% ee) were generated from the corresponding stannanes, which themselves were prepared by Hoppe-Beak deprotonation of ethyl 2,4,6-triisopropyl-benzoate with s-BuLi in the presence of (+)- or (-)-sparteine and trapping with Me<inf>3</inf>SnCl followed by recrystallization. In addition, it was found that purification between several homologations could be avoided, substantially increasing both chemical and manpower efficiency. In the case of (+)-kalkitoxin, six iterative homologations were conducted on commercially available p-MeOC<inf>6</inf>H<inf>4</inf>CH<inf>2</inf>Bpin to build up the core of the molecule before the C-B bond was converted into the desired C-N bond, without purification of intermediates. In the case of (+)-hydroxyphthioceranic acid, 16 iterative homologations were conducted on p-MeOC<inf>6</inf>H<inf>4</inf>Bpin with only four intermediate purifications before oxidation of the C-B bond to the desired alcohol. The stereocontrolled and efficient syntheses of these complex molecules highlight the power of iterative chemical synthesis using boronic esters. (Chemical Equation Presented).

Original languageEnglish
Pages (from-to)4398-4403
Number of pages6
JournalJournal of the American Chemical Society
Volume137
Issue number13
DOIs
Publication statusPublished - 8 Apr 2015

Structured keywords

  • BCS and TECS CDTs

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