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

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Stratingh Institute for Chemistry, University of Groningen, Nijenborgh 7, 9747 AG Groningen, The Netherlands
Department of Theoretical Chemistry and Amsterdam Center for Multiscale Modeling (ACMM), Vrije Universiteit Amsterdam, De Boelelaan 1083, 1081 HV Amsterdam, The Netherlands
§ Division of Rheumatology, Immunology, and Allergy, Brigham and Women’s Hospital, Harvard Medical School Smith Building, Room 538,1 Jimmy Fund Way, Boston, Massachusetts 02115, United States
Cite this: J. Org. Chem. 2016, 81, 15, 6686–6696
Publication Date (Web):July 11, 2016
Copyright © 2016 American Chemical Society

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    Abstract Image

    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.

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    The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.joc.6b01332.

    • Associated analytical data (1H NMR, 13C NMR, and APT spectra for all compounds, CID-MS of 2′-deoxy 1-TbAd, and computational data (PDF)

    • Crystallographic data (CIF)

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