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

Jeffrey Buter, Dorus Heijnen, Iem Ching Wang, Matthias Bickelhaupt, David Young, Edwin Otten, Branch Moody, Adriaan Minnaard

Research output: Contribution to journalArticleAcademicpeer-review


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 N6-tuberculosinyl adenosine (N6-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 N6-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
JournalThe Journal of Organic Chemistry
Issue number15
Publication statusPublished - 11 Jul 2016
Externally publishedYes


  • organic chemistry
  • total synthesis
  • natural product
  • tuberculosis


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