A novel enantiopure tricyclic β-lactam via stereoselective intramolecular nitrilimine cycloaddition

Starting from the Staudinger [2+2] cycloaddition between the 1-azadiene 1 and acetoxyacetylketene, generated in situ from acetoxyacetyl chloride, we developed a seven-step synthesis of the novel azeto[3′,4′:2,3]pyrano[4,5-c]pyrazole skeleton 9 in both racemic and enantiopure forms. Silver carbonate treatment of the functionalised hydrazonoyl chloride 7 promoted in situ generation of the corresponding nitrilimine 8, which underwent a clean, stereoselective cycloaddition to the target tricyclic β-lactam 9. The key step of the synthetic pathway leading to enantiopure 9 was the production of the enantiopure azetidinone (3R,4S)-3 by enzymatic resolution with Amano Lypase PS of the racemic precursor (3S∗,4R∗)-2.

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(3S,4R)-1-(4-Methoxyphenyl)-3-hydroxy-4-[2-(E)-phenyl]ethylidene-azetidin-2-oneC18H17NO3[α]D25=-293.0 (c 1.25, CHCl3)Source of chirality: (3S∗,4R∗)-1-(4-methoxyphenyl)-3-acetoxy-4-[2-(E)-phenyl]ethylidene-azetidin-2-oneAbsolute configuration: (3S,4R)

(3R,4S)-1-(4-Methoxyphenyl)-3-(1-metoxycarbonyl)hydroxymethylene-4-[2-(E)-phenyl]ethylidene-azetidin-2-oneC22H23NO5[α]D25=+140.5 (c 1.04, CHCl3)Source of chirality: (3R,4S)-1-(4-methoxyphenyl)-3-hydroxy-4-[2-(E)phenyl] ethylidene-azetidin-2-oneAbsolute configuration: (3R,4S)

(6R,9S,10S,11S)-1,11-Diphenyl-7-oxo-8-(4-metoxyphenyl)-azeto[3′,4′:2,3]pyrano[4,5-c]pyrazoleC26H23N3O4[α]D25=-292.0 (c 0.11, CHCl3)Source of chirality: (3R,4S)-1-(4-methoxyphenyl)-3-(2-chloro-2-phenylhydrazino imino)hydroxyethylene-4-[2-(E)-phenyl]ethylidene-azetidin-2-oneAbsolute configuration: (6R,9S,10S,11S)