Stereoselective total synthesis of racemic BCX-1812 (RWJ-270201) for the development of neuraminidase inhibitors as anti-influenza agents.
A convergent and versatile racemic total synthesis of the anti-influenza agent BCX-1812 (RWJ-270201) was accomplished on the basis of a sequence of stereoselective reactions. Despite intensive research to develop neuraminidase inhibitors to treat infections due to influenza, currently available agents are still in the need of optimization with respect to selectivity and potency, as well as to minimize adverse effects. Our synthetic approach, introduced in this report, is highly exploitable for further derivatization due to flexibility that will eventually accommodate diversified substituents. In addition, the size of the core ring can be varied depending on the size of the diene used for the preparation of the key cycloadduct 10 using an acylnitroso-based hetero-Diels-Alder reaction. Elaboration of 10 to methyl ester 14 followed by a precedented [3+2] dipolar cycloaddition gave bicyclic isoxazoline 17 in a regio- and stereoselective fashion. Incorporation of the peripheral guanidino group and subsequent deprotection provided the target molecule. The details of the synthesis are described herein.
Mineno
Tomoko
T
Department of Chemistry & Biochemistry, University of Notre Dame, 251 Nieuwland Science Hall, Notre Dame, Indiana 46556-5670, USA.
Miller
Marvin J
MJ
D000146:Acids, Carbocyclic; D000998:Antiviral Agents / Q000138:chemical synthesis*; D002384:Catalysis; D003517:Cyclopentanes / Q000138:chemical synthesis*; D004791:Enzyme Inhibitors / Q000138:chemical synthesis; D006146:Guanidines; D006801:Humans; D007202:Indicators and Reagents; D007251:Influenza, Human / Q000188:drug therapy; D009439:Neuraminidase / Q000037:antagonists & inhibitors*; D013237:Stereoisomerism; D014227:Triazines
D000146:Acids, Carbocyclic; D000998:Antiviral Agents; D003517:Cyclopentanes; D004791:Enzyme Inhibitors; D006146:Guanidines; D007202:Indicators and Reagents; D014227:Triazines; D009439:Neuraminidase; C004632:cyanuric acid; C414210:peramivir