Anthony Schofield

Memory of chirality effects in aldol cyclisations of 1-(3-oxobutyryl) derivatives of l-4-oxaproline and l-proline isopropyl esters

Abstract Stereoretentive CC bond formations are features of the aldol cyclisations of the 1-(3-oxobutyryl) derivatives of l -4-oxaproline and l -proline isopropyl esters, consistent with the involvement of axially chiral enolate intermediates.

Regio- and stereo-selective bromoalkoxylations of (E)-α-(2′,3′,4′,6′,-tetra-O-acetyl-β-d-glucopyranosyloxymethylene) carbonyl compounds: a route to stereopure α-bromo-α-dioxymethyl carbonyl compounds

Abstract Compounds 3a-d and 6a react with N -bromosuccinimide and propan-1-ol to give mainly the bromopropoxy adducts 8g,h,c,i and 14 ; the adducts 8c,h are converted into the ethylene acetals 16a,b in the presence of ethane-1,2-diol and trifluoroacetic acid.

Diastereoselective hydrogenations of α-(2′,3′,4′,6′-tetra-O-acetyl-β-d-glucopyranosyloxymethylene) carboxylic esters: A route to stereopure aldol derivatives

Abstract New methodology for the stereoselective α-oxymethylation of esters/lactones is described.

‘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.

Diastereoselective hydrogenations of α-alkyl α-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyloxy)methylene carbonyl compounds. New route to stereopure α-alkyl α-oxymethyl carbonyl compounds

Wittig condensation of the stabilised phosphoranes 9, 10 and 26 with 1-formyl-2,3,4,6-tetra-O-acetyl-β-D-glucopyranose 11 leads to the vinylogous carbonates 12, 13 and 22. The salts 27–30 and 44, prepared from the corresponding carbonyl compounds, ethyl formate and sodium methoxide, react with acetobromoglucose 21 to give compounds 22–25 and 43.The vinylogous esters/carbonates 12, 13, 22–25 and 43 undergo stereoselective catalytic hydrogenations under mild conditions to give mainly the dihydro derivatives 14, 15, 31–34 and 16. Although the selectivity for re-face addition is modest (ranging from 85:15 to 67:33), it is possible to isolate the dihydro derivatives 15 and 31–33 in acceptable yields (ranging from 71 to 49%) simply by fractional crystallisation. Acidic hydrolysis of compound 31 provides (αS)-α-hydroxymethyl-γ-butyrolactone 39 in high yield with an ee of ∼96%.A model to account for the role of the 2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyl unit in the stereoinduction process is presented.

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.

Regio- and stereo-selective bromo(alkoxylation)s of (E)-α-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyloxymethylene) carbonyl compounds. A route to near-stereopure α-bromo α-dioxymethyl carbonyl compounds

(E)-4-Methoxymethoxy-3-methylbut-3-en-2-one 17b reacts with NBS in propan-1-ol in a highly regio- and anti-stereo-selective manner to give (3R*,4R*)-3-bromo-4-methoxymethoxy-3-methyl-4-propoxybutan-2-one 18. Compound 10, a relative of the butenone 17b in which the methoxymethyl group is replaced by the 2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyl unit, undergoes an analogous bromo(propoxylation) reaction with reasonable facial selectivity to give an 86∶14 mixture of (3R,4R)-3-bromo-3-methyl-4-propoxy-4-(2′,3′,4′,6′-tetra-O-acetyl-β-D-glucopyranosyloxy)butan-2-one 11c and its (3S,4S)-diastereomer 12c. The major bromo(propoxy) derivative, isolable in 57% yield by fractional crystallisation, is assigned the stereostructure 11c by single-crystal X-ray crystallographic analysis. Other primary alcohols and methanol participate in the reaction of compound 10 with NBS, leading predominantly (with selectivities ranging from 75∶25 to 89∶11) to bromo(alkoxy) products of type 11 which are usually separable from their diastereomers of type 12 by fractional crystallisation (in yields ranging from 41 to 64%). A model to account for the role of the 2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyl unit in the stereoinduction process is proposed. Related bromo(propoxylation)s are observed with the vinylogous esters 24, 25a and 25b, leading to the isolation of the major products, 28, 30a and 30b (in yields ranging from 39 to 55%), and with the vinylogous carbonates 32a, 32c, 37a and 37b, providing access to the major products 33a, 33c, 38a and 38b (in yields ranging from 52 to 73%). In the presence of trifluoroacetic acid and ethane-1,2-diol, the bromo(propoxy) derivatives 11c, 28, 30b and 33c undergo transacetalisation to give the ethylene glycol acetals 40a, 40b, 41 and 40c with ees of 94–98%, in yields ranging from 56 to 67%. p

Studies related to penicillins. Part 28. β-Elimination reactions of sulphones derived from penicillins leading to cis-3-acylamino-4-oxoazetidine-2-sulphinic acids

The reactions of the 3-acetyl and 3-formyl derivatives of (3S,5R,6R)-2,2-dimethyl-6-phenoxyacetamidopenam 1,1-dioxide, i.e. compounds (5e,f), and of p-nitrophenyl (3S,5R,6R)benzylpenicillinate 1,1-dioxide (1f) with 1,5-diazabicyclo[5.3.0]non-5-ene (DBN) followed by iodomethane have been studied. In the case of penam dioxide (5e), epimerisation at position 6 competes with the β-elimination at position 3 and a mixture of the trans- and cis-azetidinones (11a) and (12a) is isolated. No epimerisation is observed with compounds (5f) and (1f), which react to give the corresponding cis-azetidinones (12b,c). It is possible to avoid the epimerisation of the penam dioxide (5e), and to isolate the cis-azetidinesulphinate salt (13), by using potassium t-butoxide in place of DBN. The cis-azetidinesulphinic acid (8c) is also isolable from the reaction of the penicillinate dioxide (1f) with DBN followed by acidic work-up. It undergoes O-methylation of the sulphinic acid group in the presence of diazomethane to give the methyl sulphinate (19), as a mixture of diastereoisomers. Saponification of the p-nitrophenyl ester of the cis-azetidinesulphinic acid (8c) is effected by sodium hydroxide to give the disodium salt (18b), which undergoes methylation in the presence of iodomethane to afford the dimethyl derivative (12d).