title: Diastereoselective aldol reaction of zincated 3-chloro-3-methyl-1-azaallylic anions as key step in the synthesis of 1,2,3,4-tetrasubstituted 3-chloroazetidines.
abstract: Zincated 3-chloro-3-methyl-1-azaallylic anions undergo a stereoselective aldol addition across aromatic aldehydes and subsequent mesylation to produce syn α-chloro-β-mesyloxyketimines, which were isolated in 80-84% yield and high diastereomeric excess (dr > 97/3) after purification via flash chromatography. The syn α-chloro-β-mesyloxyketimines were further stereoselectively reduced to give stereochemically defined 3-aminopropyl mesylates, which were cyclized to 1,2,3,4-tetrasubstituted 3-chloroazetidines containing three contiguous stereogenic centers. DFT calculations on the key aldol addition revealed the presence of a highly ordered bimetallic six-membered twist-boat-like transition state structure with a tetra-coordinated metal cyclic structure. DFT calculations revealed that chelation of both zinc and lithium cations in the transition state structure leads to the experimentally observed high syn diastereoselectivity of aldol reactions.
authors.affiliation: Department of Sustainable Organic Chemistry and Technology, Faculty of Bioscience Engineering, Ghent University, Coupure Links 653, B-9000 Ghent, Belgium.
authors.forename: Sven
authors.initials: S
authors.lastname: Mangelinckx
authors.forename: Bart
authors.initials: B
authors.lastname: De Sterck
authors.forename: Filip
authors.initials: F
authors.lastname: Colpaert
authors.forename: Saron
authors.initials: S
authors.lastname: Catak
authors.forename: Jan
authors.initials: J
authors.lastname: Jacobs
authors.forename: Stijn
authors.initials: S
authors.lastname: Rooryck
authors.forename: Michel
authors.initials: M
authors.lastname: Waroquier
authors.forename: Veronique
authors.initials: V
authors.lastname: Van Speybroeck
authors.forename: Norbert
authors.initials: N
authors.lastname: De Kimpe
mesh_terms: D000838:Anions / Q000737:chemistry*; D001384:Azetidines / Q000138:chemical synthesis* / Q000737:chemistry*; D015394:Molecular Structure; D009942:Organometallic Compounds / Q000737:chemistry*; D013237:Stereoisomerism; D015032:Zinc / Q000737:chemistry*
chemical_list: D000838:Anions; D001384:Azetidines; D009942:Organometallic Compounds; D015032:Zinc