Synthesis of novel fused β-lactams by intramolecular 1,3-dipolar cycloadditions. Part 9. Preparation of the 7-oxo-1,3-diazabicyclo[3.2.0]- heptane-2-carboxylate and 8-oxo-1,3-diazabicyclo[4.2.0]octane-2-carboxylate ring systems

Abstract

4-Vinylazetidin-2-one (24) has been converted into 1-[1-azido-1-benzyloxycarbonylmethyl]-4-vinylazetidin-2-one (27) and 1-[1-azido-1-benzyloxycarbonylmethyl]-4-(2-methoxycarbonylvinyl)- azetidin-2-one (43) which on thermolysis in toluene gave (2RS,5RS)-benzyl 4-methyl-7-oxo-1,3-diazabicyclo[3.2.0]hept-3-ene-2-carboxylate (12) and (2RS,5RS)-benzyl 4-methoxycarbonyl- methylene-7-oxo-1,3-diazabicyclo[3.2.0]heptane-2-carboxylate (39) respectively. The double bond geometry in (39) was confirmed by X-ray crystallography. Ozonolysis of (39) gave (2RS,5RS)-benzyl 4,7-dioxo-1,3-diazabicyclo[3.2.0]heptane-2-carboxylate (44). An identical sequence on 4-allylazetidin-2-one (30) gave the corresponding homologous bicyclic derivatives (16), (51), and (54). A similar strategy has been utilised to synthesize the analogous bicyclic C(6)-acylamino-derivatives (103), (65), and (62), and bicyclic C(7)-acylamino-derivatives (106), (76), and (78) from the appropriate monocyclic azetidinones.

(3RS,4RS)-3-Azido-1-[4-methoxymethoxyphenyl]-4-styrylazetidin-2-one (68) was transformed into (3RS,4RS)-4-(2-methoxycarbonylethenyl)-1-[4-methoxymethoxyphenyl]-3-phenoxyacet-amidoazetidin-2-one (71). Ceric ammonium nitrate-mediated removal of the N-protecting group from (71) then afforded the corresponding azetidinone (72). The conversion of the azide (68) into (3RS,4RS)-1-(4-methoxymethoxyphenyl)-4-(2-nitroethyl)-3-phenoxyacetamidoazetidin-2-one (98) is described. Elaboration of the 4-nitroethyl moiety in (98) to a 4-(3-methoxycarbonylprop-2-enyl) funtionality was accomplished via an ozonolysis procedure. Subsequent N-deblocking gave the azetidione (81). (3RS,4SR)-3-Phenoxyacetamido-4-vinylazetidin-2-one (118) was obtained by sequential catalytic semi-hydrogenation and N-deprotection of (3RS,4SR)-4-ethynyl-1-(4-methoxymethoxyphenyl)-3-phenoxyacetamidoazetidin-2-one (108).

The total synthesis of (3RS,4SR)-4-(3-hydroxypropyl)-1-(4-methoxymethoxyphenyl)-3-phenoxyacetamidoazetidin-2-one (113) starting from azidoacetic acid, prop-3-yno1, and 4-methoxymethoxyaniline is described. A mesylation–selenenylation sequence on (113) afforded the corresponding 4-allylazetidinone (111) which was N-deprotected to give (3RS,4SR)-4-allyl-3-phenoxyacetamidoazetidin-2-one (121). The conversion of (51) to the Δ² derivative (58) was accomplished using electrophilic bromination-dehydrobromination but hydrogenolysis of (58)caused rapid β-lactam cleavage. The acids, derived by hydrogenolysis of the corresponding benzyl esters, were devoid of antibacterial activity except for (75), (77), and (80) which possessed weak Gram-positive activity.