Michael J. Betts

Synthesis of 3-methyleneazetidin-2-one derivatives from α-keto-amides

Several α-methyleneazetidin-2-one derivatives (CH2[graphic omitted]HR2, R1= cyclohexyl, PhCH2; R2= H, Me, Et, Prn, etc.) were prepared from the 2-(2,4,6-tri-isopropylbenzenesulphonylhydrazones) of primary α-ketoamides (CH3COCONHR1) using the Shapiro reaction. Thus, trimetallation of these hydrazone derivatives at –78 °C and warming to between –10 and +25° C gave the allenic dianions [CH2CC(O–)N–R]. Reaction of these with the aldehydes (R2CHO), followed by toluene-4-sulphonyl chloride or -sulphonic anhydride, gave the title β-lactams.

‘Hidden’ axial chirality as a stereodirecting element in reactions involving enol(ate) intermediates. Part 1. Cyclisation reactions of methyl (4R)-3-(2-diazo-3-oxobutanoyl)thiazolidine-4-carboxylate and related compounds

Methyl (4R)-3-(2-diazo-3-oxobutanoyl)thiazolidine-4-carboxylate 1b underwent cyclisation, under a variety of basic conditions, to give methyl (6S)-2-oxo-8-thia-1.4,5-triazabicyclo[4.3.0]non-3-ene-6-carboxylate 2a in an enantiopure state. The absolute configuration of compound 2a was deduced by X-ray crystallography. Similar stereoselective cyclisations, proceeding with retention of configuration, were observed with methyl (4R)-3-[diazo(methoxycarbonyl)acetyl]thiazolidine-4-carboxylate 1g(to give compound 5a). methyl (4R)-3-(2-diazo-3-oxobutanoyl)-2,2-dimethylthiazolidine-4-carboxylate 20a(to give compound 21a) and methyl (2R,4R)-3-(2-diazo-3-oxobutanoyl)-2-methylthiazolidine-4-carboxylate 22a(to give compound 24). An X-ray crystallographic analysis of compound 22a revealed that the amide and diazo ketone units, although individually near planar, were twisted from each other by 35°; it was notable that the amide linkage adopted the (Z)-geometry required for the cyclisation reaction whereas the diazo moiety was incorrectly aligned. It is suggested that the cyclisation reactions proceed by way of planar enol(ate) intermediates, e.g. 6a, which possess axial chirality.

‘Hidden’ axial chirality as a stereodirecting element in reactions involving enol(ate) intermediates. Part 2.† Cyclisation reactions of methyl (4R)-3-(2-diazo-3-oxobutanoyl)-1,1-dioxo-1λ6,3- (and 1-oxo-1λ4,3-) thiazolidine-4-carboxylates

Methyl (4R)-3-(2-diazo-3-oxobutanoyl)-1,1-dioxo-1λ6,3-thiazolidine-4-carboxylate 14 undergoes a base-induced cyclisation to give methyl (8aS)-3-acetyl-4,7,7-trioxo-1,4,6,7,8,8a-hexahydro-7λ6-[1,3]thiazolo[4,3-c][1,2,4]triazine-8a-carboxylate 15 in a state of high enantiomeric purity. Similar stereoselective cyclisations, proceeding with retention of configuration, are observed with methyl (1R,4R)- and (1S,4R)-3-(2-diazo-3-oxobutanoyl)-1-oxo-1λ4,3-thiazolidine-4-carboxylates 25 and 27 to give compounds 33 and 34. It is suggested that the cyclisation reactions proceed by way of planar ester enol(ate) intermediates which possess axial chirality, e.g. 35.The bicyclic sulfone 15 and the bicyclic sulfoxides 33 and 34 are also produced by oxidation of methyl (8aS)-3-acetyl-4-oxo-1,4,8,8a-tetrahydro[1,3]thiazolo[4,3-c][1,2,4]triazine-8a-carboxylate 5 with m-chloroperoxybenzoic acid (in DMF in the case of the sulfone 15 and in CHCl3 in the case of the sulfoxides 33 and 34). The use of the oxidant in methanol or of hydrogen peroxide in formic acid leads to an oxidative deacetylation to give methyl (8aS)-3,4,7,7-tetraoxoperhydro-7λ6-[1,3]thiazolo[4,3-c][1,2,4]triazine-8a-carboxylate 17, the structure of which is established by an X-ray crystallographic analysis. The analysis reveals an interesting packing arrangement of the molecules in the crystal, attributable to an intermolecular H-bonding network. In particular, intermolecular H-bonding between the ester carbonyl oxygen atom and the amino hydrogen atom at position 1 provides a possible explanation for the shift of the ester carbonyl absorption to 1680 cm–1 in the solid-state IR spectrum of compound 17.

2,2,2-Trichloroethylsulphonyl, 2,2,2-trichloroethoxysulphonyl, and trifluoroacetyl isocyanates in β-lactam synthesis

Condensation of the title isocyanates with olefins and subsequent dissolving-metal reduction (sulphonyl derivatives) or chromatography on Florisil (trifluoroacetyl derivatives) gave several N-unsubstituted β-lactams including two 8-aza-2-oxabicyclo[4.2.0]octan-7-one derivatives.

A cyclisation reaction of methyl (4R)-3-(2-diazo-3-oxobutanoyl)thiazolidine-4-carboxylate which proceeds with retention of configuration, probably via a planar ester enolate intermediate possessing axial chirality

Under basic conditions, the title compound 1b is converted into methyl (6S)-3-acetyl-2-oxo-8-thia-1,4,5-triazabicyclo[4.3.0]non-3-ene-6-carboxylate 4a, the absolute configuration of which is established by X-ray crystallography.

Novel syntheses of 3-methylene-azetidin-2-one derivatives and related systems

Syntheses of the title compounds via 1-lithiooxy-1-lithio-amino-allene derivatives or lithium phenyl-ethynolate are described.