Clive Leslie Branch

SYNTHESIS OF 6-HYDROXY-2-METHYL-3-THIOXO-2H-1,2,4-TRIAZIN-5-ONE

Abstract The title compound has been prepared in three steps from 2-methylthiosemicarbazide following acylation, cyclisation and cation exchange chromatography. It was fully characterised by the usual spectroscopic means as well as by 15N nmr spectroscopy and X-ray crystallographic analysis.

An Expedient Synthesis of Allylic Polyprenyl Phosphates

Abstract Allylic polyprenyl phosphates 6c-d have been prepared in high yield from polyprenyl alcohols via an operationally straightforward oxidation and deprotection sequence utilising phosphite triesters 4.

Preparation and properties of 7α-formamido cephalosporins

The preparation of novel antibacterially active 7α-formamido cephalosporins from the corresponding 7α-(methylthio) analogues by mercury (II)-mediated displacement with ammonia and subsequent formylation is described. The amine (2), a versatile intermediate, was prepared and acylated to give a wider range of 7α-formamido cephalosporins. Modifications at C-3 are discussed, in particular the preparation of the 3-(heterocyclylthiomethyl) cephalosporin (44) and the 3-(pyridylmethyl) derivative (49).

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

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.

Direct incorporation of a 6α(7α)-formamido group into penicillin and cephalosporin sulphides and sulphoxides

6β(7β)-[N-(2,2,2-Trichloroethoxycarbonyl)-N-trifluoromethylsulphonyl)amino]-penicillins and-cephalosporins have been converted into the corresponding 6α(7α)-formamido-6β(7β)-(2,2,2-trichloroethoxycarbonylamino) derivatives by treatment with N,N-bis(trimethylsilyl)formamide and triethylamine. The trifluoromethyl group could be replaced (in approximately decreasing order of effectiveness) by nonafluorobutyl, pentafluorophenyl, 2,4,5-trichlorophenyl, 2,4-dinitrophenyl, 4-nitrophenyl, p-tolyl, and methyl. The 6α(7α)-formamido-(2,2,2-trichloroethoxy)carbonylamino derivatives were oxidised and the structure of the derived α- and β-sulphoxides confirmed by unambiguous synthesis. The antibacterial activity of the α- and β-sulphoxide isomers of the penicillin (45) is presented.

Synthesis of novel 3-formamido-3-acylamino-monobactams

Abstract The syntheses and biological activities of potassium (3RS)-3- [(2R)-2-(4-ethyl-2,3-dioxopiperazin-1-ylcarboxamido)-2-phenylacetamido]-3- formamido-2-oxoazetidine-1-sulphonate and potassium (3RS)-3-[(Z)-2-(2- aminothiazol-4-yl)-2-methoxyiminoacetamido]-3-formamido-2-oxoazetidine-1- sulphonate are described.

Synthesis of novel fused β-lactams by intramolecular 1,3-dipolar cycloadditions. Part 10. The 9-oxo-6-thia-1,3-diazabicyclo[5.2.0]nonene, 8-oxo-5-thia-1,3-diazabicyclo[4.2.0]octene, and 8-oxo-5-oxa-1,3-diazabicyclo[4.2.0]octene ring systems

4-Acetoxyazetidin-2-one (6) has been converted into (E)- and (Z)-1-[azido(t-butoxycarbonyl)methyl]-[2-(ethoxycarbonyl)vinylthio]azetidin-2-one (10) and (13). Thermolysis of either geometrical isomer in refluxing xylene afforded t-butyl (2RS,6RS)-4-ethoxycarbonylmethyl-8-oxo-5-thia-1,3-diaza-bicyclo[4.2.0]oct-3-ene-2-carboxylate (17) and both C-2 epimers of 5-ethoxycarbonyl-9-oxo-6-thia-1,3-diazabicyclo[5.2.0]non-4-ene-2-carboxylate (14) and (15).The penicillin-derived (3S,4S)-4-acetoxy-3-phenoxyacetamidoazetidin-2-one (22) has been used to prepare (1 RS,3S,4R)-1-[azido(benzyloxycarbonyl)methyl]-4-prop-1-enyloxy-3-phenoxyacetamido-azetidin-2-one (27), which when heated in refluxing toluene gave benzyl (2S,6R,7S)-4-ethyl-8-oxo-7-phenoxy-acetamido-5-oxa-1,3-diazabicyclo[4.2.0]oct-3-ene-2-carboxylate (29). The corresponding free acid (30) was antibacterially inactive.