A highly diastereoselective vinylogous Mannich condensation and 1,4-conjugate addition of (Z)-propenyl cuprate in the synthesis of an influenza neuraminidase inhibitor
✍ Scribed by David M. Barnes; Lakshmi Bhagavatula; John DeMattei; Ashok Gupta; David R. Hill; Sukumar Manna; Maureen A. McLaughlin; Paul Nichols; Ramiya Premchandran; Michael W. Rasmussen; Zhenping Tian; Steven J. Wittenberger
- Publisher
- Elsevier Science
- Year
- 2003
- Tongue
- English
- Weight
- 346 KB
- Volume
- 14
- Category
- Article
- ISSN
- 0957-4166
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✦ Synopsis
A practical synthesis of neuraminidase influenza inhibitor, A-322278, has been developed. Asymmetry is introduced into the synthesis by an enzyme mediated ester hydrolysis. A highly diastereoselective vinylogous Mannich condensation reaction of N-Boc-2-tert-butyldimethylsilyloxypyrrole (TBSOP) and an N-(triphenylmethylsulfenyl)imine proceeds under thermodynamic control to assemble the framework. A significant temperature dependent rate difference for the transfer of (Z)-and (E)-propenyl moieties from a cuprate reagent during a 1,4-conjugate addition was observed. A very selective addition of cyanide to an N-acyliminium intermediate was employed to control the final stereocenter.