Chiral Base-Catalyzed Enantioselective Synthesis of 4-Aryloxyazetidinones and 3,4-Benzo-5-oxacephams

Abstract

Readily available 4-formyloxyazetidinone was enantioselectively transformed into 3,4-benzo-2-hydroxy-5-oxacephams and 4-phenyloxyazetidinones upon treatment with 0.1 equiv of the cinchona alkaloid in toluene via intermolecular nucleophilic trapping of N-acyliminium intermediate by the hydroxyl moiety of phenols or o-hydroxybenzaldehydes. Additionally, the absolute configuration of title compounds was established by CD spectroscopy.

Quinidine catalyzed reaction between 4-formyloxy-azetidin-2-one and some thiophenols, thiols and alcohols

“…The selectivity in the formation of 13 was similar to that found for reaction of 2 with salicylaldehyde. 7 The experiments on cinchonine catalyzed substitutions testify that the switch from the oxygen nucleophile to the sulfur analog does not affect the enantioselectivity of the process. This might suggest that the elimination-addition mechanism of the first step is the same for both nucleophiles.…”

“…As has been demonstrated recently, the reaction between phenols and 4-formyloxyazetidin-2-one 1 in the presence of a catalytic amount of quinidine proceeds in good yield and moderate enantioselectivity to afford the corresponding 4-aryloxyazetidin-2-ones. 7 Different results were noticed when aliphatic alcohols or mercaptans were applied in the same reaction ( Table 2, 3). In the case of aliphatic alcohols 14 an equimolar amount of quinidine was required to obtain full conversion of 1.…”

“…In particular, quinidine effectively catalysed the reaction between 1 and salicyl aldehydes 2 providing the corresponding 3,4-benzo-2-hydroxy-5-oxacephams 5 (Scheme 1). 7 The key step of this cascade reaction is based on the chiral Lewis base (quinidine) mediated, enantioselective intermolecular alkylation of the phenol hydroxy group with neutral 1,4-dehydroazetidin-2-one 3 which is followed by formation of the cyclic hemiacetal 5. 8 Other phenols react with 1 with similar enantioselectivity providing the corresponding 4-aryloxyazetidinones.…”

“…The absolute configuration of 5 was assigned on the basis of the CD spectra and depends on the cinchona alkaloid used. 7 We have also described a chiral Lewis acid mediated intramolecular alkylation of the phenol hydroxy group by the acyliminium ion 8 generated from the corresponding 4-formyloxy-Nsubstituted-azetidinones 6. 9 This reaction, however, always requires an equimolar amount of the acid promoter 7 and proceeds in a low yield but high asymmetric induction as a kinetic resolution of the primary formed racemic 3,4-benzo-5-oxacepham 9-rac.…”

The use of carbonyl group anisotropy effect in determination of the relative configuration of carbapenams

“…Therefore, it would be advantageous to have a fast and unequivocal method to verify the configuration at newly formed stereogenic centers. The absolute configuration of the bridgehead carbon atom, C-5 at bicyclic β-lactams, can be established by CD spectroscopy [9][10][11][12][13][14][15][16] whereas the same assignment by NMR spectroscopy is not always as simple since it may be interlinked to the known configuration of the other stereogenic center. The …”