Synthetic Approaches toward Monocyclic 3-Amino-β-lactams

Abstract

Due to the emerging resistance against classical β-lactam-based antibiotics, a growing number of bacterial infections has become harder to treat. This alarming tendency necessitates continued research on novel antibacterial agents. Many classes of β-lactam antibiotics are characterized by the presence of the 3-aminoazetidin-2-one core, which resembles the natural substrate of the target penicillin-binding proteins. In that respect, this Review summarizes the different synthetic pathways toward this key structure for the development of new antibacterial agents. The most extensively applied methods for 3-amino-β-lactam ring formation are discussed, in addition to a few less common strategies. Moreover, approaches to introduce the 3-amino substituent after ring formation are also covered.

Keywords: 3-amino-β-lactams; Staudinger synthesis; cyclization; cycloaddition; reactivity.

Figure 1

Different classes of β‐lactam antibiotics.

Figure 2

Synthetic applications of 3‐amino‐β‐lactams to produce a broad variety of β‐lactam and non‐β‐lactam products.

Scheme 1

Staudinger [2+2] cyclocondensation between ketenes 5 and imines 6.

Scheme 2

Ketene generation by photolysis of chromium–carbene complexes 11 and münchnones 14.

Scheme 3

Synthesis of 3‐amino‐β‐lactam 19 starting from acetyl chloride 16 and imine 17.

Figure 3

Dane salt 20.

Figure 4

Reagents for activating carboxylic acids in β‐lactam synthesis.

Scheme 4

Asymmetric Staudinger synthesis using (4S)‐2‐oxo‐4‐phenyloxazolidin‐3‐ylacetyl chloride (23) and imines 24.

Scheme 5

Asymmetric synthesis using N‐[bis(trimethylsilyl)methylidene]amines 28.

Scheme 6

Asymmetric synthesis using camphorsultam‐derived ketenes.

Scheme 7

Asymmetric induction by imines 36 derived from (1R)‐1‐phenyl‐ and (1R)‐1‐(1‐naphtyl)ethylamine.

Figure 5

Imines 39–41 derived from chiral amines d‐glucosamine, 2‐amino‐1‐phenylpropane‐1,3‐diol and d‐threonine.

Scheme 8

Asymmetric induction by imines 43 derived from d‐glyceraldehyde acetonide.

Scheme 9

Asymmetric induction by imines 45 derived from O‐silyl‐protected α‐hydroxy aldehydes.

Figure 6

Imines derived from chiral aldehydes: nitrogen analogue 48 of d‐glyceraldehyde acetonide, α‐amino imines 49 and α,β‐epoxyimines 50.

Scheme 10

Double asymmetric induction approach using chiral ketenes derived from 51 and chiral N‐substituted imines 52.

Scheme 11

Double asymmetric induction approach using “matched” or “mismatched” chiral templates.

Scheme 12

The catalytic, asymmetric, “umpolung” Staudinger reaction. Ts, p‐toluenesulfonyl; BQ, benzoylquinine (63).

Scheme 13

Conversion of hexahydro‐s‐hydrazines 66 to monomeric formaldimines 67 by treatment with a Lewis acid.

Scheme 14

Staudinger synthesis with dialkylhydrazones 69.

Scheme 15

The cyclocondensation between α‐amino esters 71 and imines 73 or N‐(cyanomethyl)amines 74.

Scheme 16

The Kinugasa cycloaddition between 3‐ethynyloxazolidin‐2‐ones 77 and nitrones 78.

Scheme 17

The copper‐catalyzed conversion of phthalimido acetylene (83) and cyclic nitrones 84 to monocyclic β‐lactam 88.

Scheme 18

N1−C4 cyclization of α‐amino‐β‐hydroxy hydroxamates 89.

Scheme 19

Conversion of C‐fused β‐lactam 92 to monocyclic 3‐aminoazetidin‐2‐one 95.

Figure 7

Elimination products 97 and pyrrolidinone side products 98 of the cyclization of dipeptides 96, and aziridine side products 100 of the cyclization of N‐arylamides 99.

Scheme 20

A Pummerer‐type rearrangement of tripeptide 101.

Scheme 21

The ring‐closure‐induced ring opening of cyclic sulfamidate 105.

Scheme 22

The Pd‐catalyzed amidation of amide 109.

Scheme 23

N1−C2 cyclization of α,β‐diamino carboxylic acids and esters 112.

Scheme 24

C3−C4 bond formation by oxidative coupling of amide 114.

Scheme 25

Conversion of 3‐carboxy‐β‐lactam 117 to 3‐amino‐β‐lactam 118.

Scheme 26

Conversion of 3‐hydroxy‐β‐lactams 119 to 3‐azido derivatives 121.

Scheme 27

Different approaches to introduce the 3‐amino group starting from 3‐oxo‐β‐lactams 122.

Scheme 28

Treatment of 3‐oxo‐β‐lactams 128 with secondary amines.

Scheme 29

Bismuth‐nitrate‐catalyzed conversion of 3‐oxo‐β‐lactams 130 toward 3‐pyrrolyl‐β‐lactams 131.

Scheme 30

Introduction of a 3‐amino group after lithium–halogen exchange.

Scheme 31

Addition of N‐nucleophiles onto 3‐alkylidene‐β‐lactams 134.

Scheme 32

Conversion of 3‐unsubstituted β‐lactams 136 to 3‐amino‐β‐lactams 138.

Scheme 33

Simultaneous azide transfer and N−O bond cleavage during diazotization of β‐keto ester 139.

Scheme 34

Addition of N‐nucleophiles to 3‐unsubstituted N‐tosyloxy‐β‐lactams 141.

Scheme 35

Ugi reaction of α‐azido‐β‐amino acid 144, formaldehyde (145) and isocyanides 146.