Contribution to the development of new substitution patterns of optically active .beta.-lactams: synthesis of homochiral 4-(1-aminoalkyl)azetidin-2-ones from N-(tert-butyloxycarbonyl) .alpha.-amino aldehyde-derived imines via asymmetric Staudinger reaction

Abstract

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Highly Stereoselective Synthesis of β‐Lactams Utilizing α‐Chloroimines as New and Powerful Chiral Inductors

“…[5,6] On the other hand, high stereoselectivities are attained when chiral imines derived from chiral aldehydes (usually a-oxy-or a-aminoaldehyde derived imines) are used. [7,8] Chiral a-alkylimines, derived from chiral a-alkylaldehydes, are known to be unreactive in terms of both chemical reactivity and diastereoselectivity in the Staudinger reaction towards b-lactams. [2a] The origin of the asymmetric induction in the Staudinger synthesis of b-lactams has been rationalized on the basis of the magnitude of the stereoelectronic effect exerted by the s*A C H T U N G T R E N N U N G (CÀX) orbital (X being an electronegative atom and C a stereogenic carbon atom) over the HOMO in the transition states.…”

“…[2a] The origin of the asymmetric induction in the Staudinger synthesis of b-lactams has been rationalized on the basis of the magnitude of the stereoelectronic effect exerted by the s*A C H T U N G T R E N N U N G (CÀX) orbital (X being an electronegative atom and C a stereogenic carbon atom) over the HOMO in the transition states. [8] The angular disposition between C 3 and the C À X bond in transition state 5 minimizes the steric interaction between R 3 and the forming b-lactam ring, but at the cost of loss of efficiency of the stabilizing interaction between the HOMO and the s*A C H T U N G T R E N N U N G (CÀX) orbital. In the case of transition state 3, the aforementioned steric interaction does not occur, and therefore the HOMO-s*A C H T U N G T R E N N U N G (CÀX) stabilization takes place more efficiently, favored by the linear arrangement between C 3 and the exocyclic C À X bond.…”

“…Consequently, the latter transition state 3 has a lower energy and is preferred (Scheme 1). [8] According to a theoretical study on the hyperconjugative acceptor ability of s bonds, the s*A C H T U N G T R E N N U N G (CÀX) acceptor abilities increase by at least 30 % when X is a halogen atom in comparison with X being an oxygen or a nitrogen atom. [9] In other words, the use of chiral a-chloroimines might lead to higher stereoselectivities compared with those obtained with a-oxy-or a-aminoaldehyde derived imines.…”

“…[10] Herein, a-chloroimines are used for the first time as powerful inductors for the stereoselective synthesis of azetidin-2-ones. This approach is inspired by the mechanistic rationale of the [2 + 2]-cycloaddition of ketenes and imines derived from a-oxy and a-amino substituted aldehydes, [8] and a predicted higher hyperconjugative acceptor ability of halogens in comparison with both oxygen and nitrogen as the aheteroatom. [9] Furthermore, a new approach towards (S)-a-chloroald-A C H T U N G T R E N N U N G imines starting from (2S)-chloro-1-propanol is disclosed as an improved alternative over known enantioselective achlorination procedures for short-chain aldehydes.…”

Theoretical Studies on the Addition Reactions of Ketene with NH3in the Gas Phase and in Non-Aqueous Solutions

“…In solution, however, such species can be stabilized by solvation and studies should be therefore expanded to take these species into account. Zwitterions, formed from the reaction of ketene with tertiary amines, 13 have in fact been identified experimentally by UV and IR by use of time-resolved laser flash photolyses 14 and theoretically in AM1 15 or BLYP calculations. 16 The addition of NH 3 or a primary amine to ketene can proceed by two different pathways, stepwise via a ketenenucleophile zwitterion, (I), or concerted via a neutral fourcenter cyclic transition state as shown in Scheme 1.…”