title: Stereoselective Synthesis of 1-Tuberculosinyl Adenosine; a Virulence Factor of Mycobacterium tuberculosis.
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.
authors.affiliation: Stratingh Institute for Chemistry, University of Groningen , Nijenborgh 7, 9747 AG Groningen, The Netherlands.
authors.forename: Jeffrey
authors.initials: J
authors.lastname: Buter
authors.affiliation: Stratingh Institute for Chemistry, University of Groningen , Nijenborgh 7, 9747 AG Groningen, The Netherlands.
authors.forename: Dorus
authors.initials: D
authors.lastname: Heijnen
authors.affiliation: Stratingh Institute for Chemistry, University of Groningen , Nijenborgh 7, 9747 AG Groningen, The Netherlands.
authors.forename: Ieng Chim
authors.initials: IC
authors.lastname: Wan
authors.affiliation: Department of Theoretical Chemistry and Amsterdam Center for Multiscale Modeling (ACMM), Vrije Universiteit Amsterdam , De Boelelaan 1083, 1081 HV Amsterdam, The Netherlands.
authors.forename: F Matthias
authors.initials: FM
authors.lastname: Bickelhaupt
authors.affiliation: 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.
authors.forename: David C
authors.initials: DC
authors.lastname: Young
authors.affiliation: Stratingh Institute for Chemistry, University of Groningen , Nijenborgh 7, 9747 AG Groningen, The Netherlands.
authors.forename: Edwin
authors.initials: E
authors.lastname: Otten
authors.affiliation: 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.
authors.forename: D Branch
authors.initials: DB
authors.lastname: Moody
authors.affiliation: Stratingh Institute for Chemistry, University of Groningen , Nijenborgh 7, 9747 AG Groningen, The Netherlands.
authors.forename: Adriaan J
authors.initials: AJ
authors.lastname: Minnaard
mesh_terms: D000241:Adenosine; D003198:Computer Simulation; D061565:Cycloaddition Reaction; D004224:Diterpenes / Q000737:chemistry; D008055:Lipids / Q000138:chemical synthesis* / Q000737:chemistry; D009169:Mycobacterium tuberculosis / Q000737:chemistry*; D012984:Software; D013237:Stereoisomerism; D013816:Thermodynamics; D037521:Virulence Factors / Q000737:chemistry*
chemical_list: C587948:1-tuberculosinyladenosine; D004224:Diterpenes; D008055:Lipids; D037521:Virulence Factors; C551415:tuberculosinol; D000241:Adenosine