title: Toward ideality: the synthesis of (+)-kalkitoxin and (+)-hydroxyphthioceranic acid by assembly-line synthesis.
abstract: The iterative homologation of boronic esters using chiral lithiated benzoate esters and chloromethyllithium has been applied to the highly efficient syntheses of two natural products, (+)-kalkitoxin and (+)-hydroxyphthioceranic acid. The chiral lithiated benzoate esters (>99% ee) were generated from the corresponding stannanes, which themselves were prepared by Hoppe-Beak deprotonation of ethyl 2,4,6-triisopropyl-benzoate with s-BuLi in the presence of (+)- or (-)-sparteine and trapping with Me3SnCl followed by recrystallization. In addition, it was found that purification between several homologations could be avoided, substantially increasing both chemical and manpower efficiency. In the case of (+)-kalkitoxin, six iterative homologations were conducted on commercially available p-MeOC6H4CH2Bpin to build up the core of the molecule before the C-B bond was converted into the desired C-N bond, without purification of intermediates. In the case of (+)-hydroxyphthioceranic acid, 16 iterative homologations were conducted on p-MeOC6H4Bpin with only four intermediate purifications before oxidation of the C-B bond to the desired alcohol. The stereocontrolled and efficient syntheses of these complex molecules highlight the power of iterative chemical synthesis using boronic esters.
authors.affiliation: †School of Chemistry, University of Bristol, Cantock's Close, Bristol BS8 1TS, United Kingdom.
authors.forename: Sebastien
authors.initials: S
authors.lastname: Balieu
authors.affiliation: †School of Chemistry, University of Bristol, Cantock's Close, Bristol BS8 1TS, United Kingdom.
authors.forename: Gayle E
authors.initials: GE
authors.lastname: Hallett
authors.affiliation: †School of Chemistry, University of Bristol, Cantock's Close, Bristol BS8 1TS, United Kingdom.
authors.forename: Matthew
authors.initials: M
authors.lastname: Burns
authors.affiliation: †School of Chemistry, University of Bristol, Cantock's Close, Bristol BS8 1TS, United Kingdom.
authors.forename: Teerawut
authors.initials: T
authors.lastname: Bootwicha
authors.affiliation: ‡Vertex Pharmaceuticals Limited, Milton Park, Abingdon OX14 4RW, United Kingdom.
authors.forename: John
authors.initials: J
authors.lastname: Studley
authors.affiliation: †School of Chemistry, University of Bristol, Cantock's Close, Bristol BS8 1TS, United Kingdom.
authors.forename: Varinder K
authors.initials: VK
authors.lastname: Aggarwal
mesh_terms: D001897:Boronic Acids / Q000138:chemical synthesis* / Q000737:chemistry*; D060326:Chemistry Techniques, Synthetic; D005227:Fatty Acids / Q000138:chemical synthesis* / Q000737:chemistry*; D008055:Lipids / Q000138:chemical synthesis* / Q000737:chemistry*; D013237:Stereoisomerism; D013844:Thiazoles / Q000138:chemical synthesis* / Q000737:chemistry*
chemical_list: D001897:Boronic Acids; D005227:Fatty Acids; D008055:Lipids; D013844:Thiazoles; C522296:phthioceranic acid; C121885:kalkitoxin