Synfacts 2021; 17(01): 0001
DOI: 10.1055/s-0040-1719523
Synthesis of Natural Products and Potential Drugs

Synthesis of HIV Integrase Inhibitor MK-1376

Contributor(s):
Philip Kocienski
Maligres PE, *, Song ZJ, *, Strotman NA, Yin J, Pei T, Strotman HR, Itoh T, Sherer EC, Humphrey GR. Merck & Co., Inc., Kenilworth, USA
Synthesis of Fused Oxepane HIV integrase Inhibitor MK-1376.

Synthesis 2020;
52: 3378-3388
DOI: 10.1055/s-0040-1707994.
 

Significance

MK-1376 is an HIV integrase inhibitor that is of interest for the treatment of AIDS. The key step in the synthesis of MK-1376 is the Trost palladium-catalyzed asymmetric π-allylation reaction that installed the stereogenic center at C-6 in the 1,4-oxazepane ring of C. Prolonged reaction times led to erosion of ee from reversible ring closure. This is the first example of reversibility in a π-allylation reaction. The epimerization processes were suppressed by addition of 1.5 mol% palladium acetate prior to workup.


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Comment

Introduction of the stereogenic center at C-10 was accomplished by reaction of methylamine with the amides Ha,b (syn/anti = 1:1) that gave the syn-isomer J (syn/anti = 97:3), independent of the original stereochemistry at C-10, consistent with the diastereoselective addition of ­methylamine to quinone methide intermediate I.


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Publication History

Publication Date:
16 December 2020 (online)

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