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. 2011 Nov 4;76(21):8588-98.
doi: 10.1021/jo201450s. Epub 2011 Oct 4.

Total synthesis of α-1C-galactosylceramide, an immunostimulatory C-glycosphingolipid, and confirmation of the stereochemistry in the first-generation synthesis

Zheng Liu  1 , Hoe-Sup Byun, Robert Bittman
Affiliations

Total synthesis of α-1C-galactosylceramide, an immunostimulatory C-glycosphingolipid, and confirmation of the stereochemistry in the first-generation synthesis

Zheng Liu et al. J Org Chem. .

Abstract

A nonisosteric α-C-glycoside analogue of KRN7000 (α-1C-GalCer, 1) was reported to induce a selective type of cytokine release in human invariant natural killer cells in vitro. We report here a very concise synthetic route to 1 and its analogue 1'. The key steps include olefin cross-metathesis, Sharpless asymmetric epoxidation, and epoxide opening by NaN(3)/NH(4)Cl. Inversion of configuration at the amide-bearing carbon in the phytosphingosine backbone constructed by epoxide opening in our previous synthesis of 1 was verified, indicating that remote group participation is not involved during the epoxide-opening reaction.

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Figures

Scheme 1
Scheme 1
Opening of Epoxide 4 and Formation of Bicyclic Triazole 6
Scheme 2
Scheme 2
Possible Mechanism of Retention in the Opening of Epoxide 4
Scheme 3
Scheme 3
Retrosynthetic Plan to 1
Scheme 4
Scheme 4
Synthesis of 1 and 1′
Scheme 5
Scheme 5
Synthesis of 21 from 6
Chart 1
Chart 1
Structures of KRN7000 (2) and C-Glycoside Analogues 1 and 3
See this image and copyright information in PMC

References

    1. Lu X, Song L, Metelitsa LS, Bittman R. Chem Bio Chem. 2006;7:1750. - PubMed

    1. For very recent reviews of KRN7000 (compound 2) and its analogues, see: Banchet-Cadeddu A, Hénon E, Dauchez M, Renault JH, Monneaux F, Haudrechy A. Org Biomol Chem. 2011;9:3080.Mori K, Tashiro T. Heterocycles. 2011;83:951.

    1. For a review of α-C-GalCer (compound 3), see: Franck RW, Tsuji M. Acc Chem Res. 2006;39:692.

    1. For reviews of glycomimetics, see: Sears P, Wong CH. Angew Chem, Int Ed. 1999;38:2300.Wong CH. Acc Chem Res. 1999;32:376.Koester DC, Holkenbrink A, Werz DB. Synthesis. 2010;19:3217.

    1. Nolen EG, Kurish AJ, Potter JM, Donahue LA, Orlando MD. Org Lett. 2005;7:3383. - PubMed

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