Synthesis of 3-Amino-4-substituted Monocyclic ß-Lactams-Important Structural Motifs in Medicinal Chemistry

Abstract

Monocyclic ß-lactams (azetidin-2-ones) exhibit a wide range of biological activities, the most important of which are antibacterial, anticancer, and cholesterol absorption inhibitory activities. The synthesis of decorated monocyclic ß-lactams is challenging because their ring is highly constrained and consequently reactive, which is also an important determinant of their biological activity. We present the optimized synthesis of orthogonally protected 3-amino-4-substituted monocyclic ß-lactams. Among several possible synthetic approaches, Staudinger cycloaddition proved to be the most promising method for initial ring formation, yielding monocyclic ß-lactams with different substituents at the C-4 position, a phthalimido-protected 3-amino group, and a (dimethoxy)benzyl protected ring nitrogen. Challenging deprotection methods were then investigated. Oxidative cleavage with cerium ammonium nitrate and ammonia-free Birch reduction was found to be most effective for selective removal of ring nitrogen protection. Hydrazine hydrate was used for deprotection of the phthalimido group, and the procedure had to be modified by the addition of HCl in the case of aromatic substituents at the C-4 position. The presented methods and the synthesized 3-amino-4-substituted monocyclic ß-lactam derivatives are an important step toward new ß-lactams with potential pharmacological activities.

Keywords: 3-amino-4-substituted azetidin-2-one; Staudinger [2+2] cyclocondensation; cerium ammonium nitrate; hydrazine hydrate; monocyclic ß-lactam.

Figure 1

Typical synthetic routes to known C-4-substituted 3-amino-ß-lactams with antibacterial activity ((A) Staudinger [2+2] cyclocoaddition, (B) Mitsunobu-mediated cyclization, (C) bromine-induced cyclization).

Scheme 1

Reaction conditions for synthesis of imines and structures of products (1–17). Reagents and reaction conditions: Na₂SO₄ (4EQ), DCM/MeOH, 2–16 h or DCM, 0 °C, 2–4 h.

Scheme 2

General reaction scheme for Staudinger [2+2] cycloaddition, starting from ketene, generated from acyl chloride, and a Schiff base. Bn: benzyl, DMB: 2,4-dimethoxybenzyl. Reagents and reaction conditions: 1. (COCl)₂, cat.DMF, DCM; 2. Et₃N, toluene.

Scheme 3

General reaction scheme for Staudinger [2+2] cyclocondensation starting from ketene, generated from diazoketone, and Schiff base under microwave radiation. Reagents and reaction conditions: 1. ClCOOEt, Et₃N, THF; 2. TMSCHN₂ (2 M in hex.), MeCN; 3. MW, 180 °C, 1,2-dimethoxyethane.

Scheme 4

General reaction scheme for Staudinger [2+2] cyclocondensation starting from ketene, generated from mixed anhydride, and Schiff base. Reagents and reaction conditions: 1. ClCOOEt, Et₃N, THF; 2. Et₃N, DCM.

Scheme 5

Deprotection of phthalimide protecting group with hydrazine hydrate. Reagents and reaction conditions: 1.NH₂NH₂ × H₂O, MeOH, rt, 1–2 h; 2. HCl, MeOH, 5 min; 3. MeOH, rt, 16 h.

Scheme 6

Deprotection of lactam nitrogen with ammonia-free Birch reduction. Reagents and reaction conditions: Na, 15-Crown-5, iPrOH, THF, 0 °C.

Scheme 7

Deprotection of lactam nitrogen with cerium ammonium nitrate. Reagents and reaction conditions: Ce(NH₄)₂(NO₃)₆, H₂O/CH₃CN (1:1), −10 °C.

Scheme 8

Synthesis of fully deprotected 3-amino-4-substituted azetidin-2-one 55. Reagents and reaction conditions: 1. a. NH₂NH₂×H₂O, MeOH, rt, 1 h; b. HCl, MeOH, 5 min; c. MeOH, rt, 16 h; 2. (Boc)₂O, Et₃N, DCM; 3. Ce(NH₄)₂(NO₃)₆, H₂O/CH₃CN (1:1), −10 °C or Na, 15-Crown-5, iPrOH, THF, 0 °C; 4 CF₃COOH, anisole, DCM.