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
Key words
MK-1376 - HIV integrase inhibitor - π-allyl alkylation - palladium catalysis - quinone methide
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.
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.
