Entry to New Conformationally Constrained Amino Acids. First Synthesis of 3-Unsubstituted 4-Alkyl-4-carboxy-2-azetidinone Derivatives via an Intramolecular N^α-C^α-Cyclization Strategy

Abstract

A systematic study on the base-assisted intramolecular alkylation of N-benzyl-N-chloroacetyl amino acid derivatives is described. This study resulted in the first concise and versatile route to the preparation of 3-unsubstituted 4-alkyl-4-carboxy-2-azetidinones, to be included into the scarce family of beta-lactams with quaternary centers at the C(4) position. Particularly noteworthy is that the intramolecular N(alpha)-C(alpha)-cyclization of Phe and Leu derivatives afforded the corresponding beta-lactam derivatives with moderate enantioselectivity (up to 56%). It is suggested that, in these particular cases, the cyclization reaction proceeds by way of planar enolate intermediates, which possess dynamic chirality. The described sequence of reactions, that is compatible with commonly used protecting moieties for the alpha-carboxy group, cannot be applied to dipeptides, since the cyclization to the six-membered 2,5-diketopiperazine ring occurs preferentially.

Protonation‐Assisted Conjugate Addition of Axially Chiral Enolates: Asymmetric Synthesis of Multisubstituted β‐Lactams from α‐Amino Acids

“…[4] We sought to apply this method to the synthesis of b-lactams with contiguous tetra-and trisubstituted stereocenters starting from commercially available a-amino acids (Scheme 2). [5,6] b-Lactams are expected to be produced through 4-exo-trig cyclization of axially chiral enolates such as B. However, we had expected that this process might be unfavorable because the conjugate addition of enolate B should give highly strained b-lactam enolate C with a labile CÀC bond (1.63 by DFT calculations when M = Cs, R 1 = R 2 = R 3 = R 4 = Me, see the Supporting Information).…”

Synthesis of β‐Lactams by 4‐exo‐tet Cyclization Process Induced by Electrogenerated Cyanomethyl Anion, Part 2:[1] Stereochemical Implications

“…A similar reaction was carried out by Gonzµlez-MuÇiz and co-workers [18] starting from a halogenated amide 1 (Scheme 3, in which R = H, X = p-methoxybenzyl, Y = OCH 3 and Cl instead of Br) in MeCN as solvent and using Cs 2 CO 3 as base; in this case the reaction took 10 days to obtain the corresponding blactam 2 in 54 % yield. This fact confirms the validity of our electrogenerated cyanomethyl anion as a highly reactive base.…”

Diimine Reduction of C=C Double Bonds: Scope and Limitations of the Application to Solid‐Phase Peptide Synthesis

“…It is known that reductive amination is of special interest in the synthesis of ψ[CH 2 ‐NH] pseudo‐peptides15 and that it is a practical procedure to access N ‐alkyl‐amino acids 16. In our particular case, this application has the additional interest of affording key intermediates in the above‐mentioned synthesis of 4‐alkyl‐4‐carboxy‐2‐azetidinones from amino acids 13,14. Thus, after removal of the Fmoc group from compound 1 , the resulting amine was treated with isobutyraldehyde to generate the corresponding imine intermediate under the conditions previously optimized in our group 17.…”

“…In addition, the N ‐chloroacetyl derivative 32 was prepared by N ‐Fmoc deprotection of 29 and subsequent reaction with 2‐chloroacetyl chloride13 (Scheme ). These derivatives have special interest for us as they are key intermediates in the synthesis of 4‐alkyl‐4‐carboxy‐2‐azetidinones from amino acids 13,14. On this occasion Rink Amide resin was used as solid support to avoid early cleavage due to the sensitivity of the 2‐ClTrt resin to the acidic media.…”