Stereoselective Synthesis of 1-Tuberculosinyl Adenosine; a Virulence Factor of Mycobacterium tuberculosis

Jeffrey Buter, Dorus Heijnen, Ieng Chim Wan, F Matthias Bickelhaupt, David C Young, Edwin Otten, D Branch Moody, Adriaan J Minnaard

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13 Citations (Scopus)

Abstract

Despite its status as one of the world's most prevalent and deadly bacterial pathogens, Mycobacterium tuberculosis (Mtb) infection is not routinely diagnosed by rapid and highly reliable tests. A program to discover Mtb-specific biomarkers recently identified two natural compounds, 1-tuberculosinyl adenosine (1-TbAd) and N-6-tuberculosinyl adenosine (N-6-TbAd). Based on their association with virulence, the lack of similar compounds in nature, the presence of multiple stereocenters, and the need for abundant products to develop diagnostic tests, synthesis of these compounds was considered to be of high value but challenging. Here, a multigram-scale stereoselective synthesis of 1-TbAd and N-6-TbAd is described. As a key-step, a chiral auxiliary-mediated Diels-Alder cycloaddition was developed, introducing the three stereocenters with a high exo endo ratio (10:1) and excellent enantioselectivity (>98% ee). This constitutes the first entry into the stereoselective synthesis of diterpenes with the halimane skeleton. Computational studies explain the observed stereochemical outcome.

Original languageEnglish
Pages (from-to)6686-6696
Number of pages11
JournalJournal of Organic Chemistry
Volume81
Issue number15
DOIs
Publication statusPublished - 5-Aug-2016

Keywords

  • MOLECULAR-ORBITAL THEORY
  • DIMROTH-REARRANGEMENT
  • DITERPENE CYCLASE
  • LEWIS-ACID
  • BIOMARKERS
  • APPROXIMATION
  • PHENYLALANINE
  • NUCLEOSIDES
  • DYSIDIOLIDE
  • METABOLITES

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