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Total synthesis of the ristocetin aglycon

Academic Article
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Overview

related to degree

  • Crowley, Brendan Michael, Ph.D. in Chemistry, Scripps Research 2000 - 2005

authors

  • Crowley, Brendan Michael
  • Mori, Y.
  • McComas, C. C.
  • Tang, D. T.
  • Boger, Dale

publication date

  • 2004

journal

  • Journal of the American Chemical Society  Journal

abstract

  • The first total synthesis of the ristocetin aglycon is described employing a modular and highly convergent strategy. An effective 12-step (12% overall) synthesis of the ABCD ring system 3 from its amino acid subunits sequentially features an intramolecular aromatic nucleophilic substitution reaction for formation of the diaryl ether and closure of the 16-membered CD ring system (65%), a respectively diastereoselective (3:1, 86%) Suzuki coupling for installation of the AB biaryl linkage on which the atropisomer stereochemistry can be further thermally adjusted, and an effective macrolactamization (51%) for closure of the 12-membered AB ring system. A similarly effective 13-step (14% overall) synthesis of the 14-membered EFG ring system 4 was implemented employing a room-temperature intermolecular S(N)Ar reaction of an o-fluoronitroaromatic for formation of the FG diaryl ether (69%) and a key macrolactamization (92%) with formation of the amide linking residues 1 and 2. The two key fragments 3 and 4 were coupled, and the remaining 16-membered DE ring system was closed via diaryl ether formation to provide the ristocetin tetracyclic ring system (15 steps, 8% overall) enlisting an unusually facile (25 degrees C, 8 h, DMF, >/=95%) and diastereoselective (>/=15:1) aromatic nucleophilic substitution reaction that benefits from substrate preorganization.

subject areas

  • Anti-Bacterial Agents
  • Doxorubicin
  • Ristocetin
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Identity

International Standard Serial Number (ISSN)

  • 0002-7863

Digital Object Identifier (DOI)

  • 10.1021/ja039795a

PubMed ID

  • 15053621
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Additional Document Info

start page

  • 4310

end page

  • 4317

volume

  • 126

issue

  • 13

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