title: Total Synthesis of K777: Successful Application of Transition-Metal-Catalyzed Alkyne Hydrothiolation toward the Modular Synthesis of a Potent Cysteine Protease Inhibitor.
abstract: We report the total synthesis of K777 and a series of analogues via alkyne hydrothiolation catalyzed by Wilkinson's complex (ClRh(PPh3)3). The alkyne hydrothiolation reactions proceeded with excellent regio- and diastereoselectivity to generate the desired E-linear vinyl sulfides in high yield. The use of Ellman's auxiliary generates the requisite propargyl amines in excellent enantiomeric excess (ee) and obviates the use of L-homophenylalanine, an expensive unnatural amino acid. The vinyl sulfone derivatives exhibit a large difference in rate toward Michael addition. Kinetic data are consistent with rate-limiting nucleophilic attack to generate the carbanion intermediate.
authors.affiliation: Department of Chemistry, 2036 Main Mall, The University of British Columbia , Vancouver, BC, Canada , V6T 1Z1.
authors.forename: Erica R
authors.initials: ER
authors.lastname: Kiemele
authors.affiliation: Department of Chemistry, 2036 Main Mall, The University of British Columbia , Vancouver, BC, Canada , V6T 1Z1.
authors.forename: Matthew
authors.initials: M
authors.lastname: Wathier
authors.affiliation: Department of Chemistry, 2036 Main Mall, The University of British Columbia , Vancouver, BC, Canada , V6T 1Z1.
authors.forename: Paul
authors.initials: P
authors.lastname: Bichler
authors.affiliation: Department of Chemistry, 2036 Main Mall, The University of British Columbia , Vancouver, BC, Canada , V6T 1Z1.
authors.forename: Jennifer A
authors.initials: JA
authors.lastname: Love
mesh_terms: D000480:Alkynes / Q000737:chemistry*; D000588:Amines / Q000737:chemistry; D000596:Amino Acids / Q000737:chemistry; D000613:Aminobutyrates / Q000737:chemistry; D002384:Catalysis; D015853:Cysteine Proteinase Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D004151:Dipeptides / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D015394:Molecular Structure; D010649:Phenylalanine / Q000031:analogs & derivatives; D010879:Piperazines; D013237:Stereoisomerism; D013438:Sulfhydryl Compounds / Q000737:chemistry*; D013440:Sulfides / Q000138:chemical synthesis / Q000737:chemistry; D014105:Tosyl Compounds; D028561:Transition Elements / Q000737:chemistry; D014753:Vinyl Compounds / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*
chemical_list: D000480:Alkynes; D000588:Amines; D000596:Amino Acids; D000613:Aminobutyrates; D015853:Cysteine Proteinase Inhibitors; D004151:Dipeptides; D010879:Piperazines; D013438:Sulfhydryl Compounds; D013440:Sulfides; D014105:Tosyl Compounds; D028561:Transition Elements; D014753:Vinyl Compounds; C487484:N-pip-phenylalanine-homophenylalanine-vinyl sulfone phenyl; D010649:Phenylalanine; C014328:2-amino-4-phenylbutyric acid