Synthesis of Fused Oxepane HIV Integrase Inhibitor MK-1376
Received: 22 January 2020
Accepted after revision: 20 February 2020
16 March 2020 (online)
Published as part of the Special Topic Synthesis in Industry
Controlling the absolute and relative stereochemistry of a seven-membered oxepane in the formation of HIV integrase inhibitor MK-1376 was accomplished through a strategy involving the use of asymmetric allylation and stereoconvergent, substrate-directed installation of an amine fragment. Surprising reactivity was demonstrated during the asymmetric allylation in which the allyl-pyrimidone product was formed reversibly. The stereoconvergent amine addition was accomplished through an elimination/addition sequence involving a quinone methide reactive intermediate, and nucleophilic trapping of the reactive quinone methide intermediate with methylamine. This novel approach delivered MK-1376, offering 100-fold greater productivity and 50-fold less waste than the initial synthetic chemistry route.
- 1 New address: Arrowhead Biopharmaceuticals, 502 South Rosa Road, Madison, WI 53719, USA
- 2 New address: Colgate Palmolive Company, 909 River Rd, Piscataway, NJ 08854, USA
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- 12 No hydrogenation reaction was observed in dichloromethane.
- 13 During this oxidation screen an interesting unprecedented oxidation was discovered using Tl(NO3)3 in HOAc, which oxidized the oxepane to the olefin (Scheme 11). This olefin could then be converted into the dibromide, which gave the vinyl bromide regioselectively upon base-mediated elimination. Further pursuit of this method was not attempted due to the toxicity of thallium; but, it was encouraging to note traces of the desired C-10 halogenated compound were observed after halogenations in the presence of Tl(NO3)3 using NBS, NCS and t-BuOCl. At this point, evidence from the thallium(III) catalyzed and Pyr2INO3 halogenations indicated an auxiliary oxidant may be beneficial in driving the halogenation to completion.
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Impact of L/M ratio and effect of Bu4NBr in Trost allylation has been previously reported, see: