ABSTRACT
[reaction: see text] An efficient and practical N-methylation of amino acid derivatives with dimethyl sulfate in the presence of sodium hydride and a catalytic amount of water is described. Reaction of water with sodium hydride generated highly reactive dry sodium hydroxide, which led to much faster reaction rates than powdered sodium hydroxide itself.
Subject(s)
Amino Acids/chemical synthesis , Methylation , Sodium Hydroxide/chemistry , Sulfuric Acid Esters/chemistry , Water/chemistryABSTRACT
An efficient and large-scale enantioselective synthesis of PNP405 (1), a purine nucleoside phosphorylase inhibitor, is described. This synthesis of 1 involved eight steps starting from o-fluorophenylacetic acid with a 21.6% overall yield and >99.5% enantiopurity. The key stereogenic center with (R)-configuration was created using Evans' asymmetric alkylation methodology. This synthesis also features the racemization-free reductive removal of the chiral auxiliary in 5 using sodium borohydride, protection of the gamma-cyano alcohol 6 as the trityl ether by a new water-assisted tritylation with trityl chloride and triethylamine or with trityl alcohol and catalytic trifluoroacetic acid, and an efficient one-pot cyclo-guanidinylation of 10 using cyanamide as the guanidinylating agent.
