David C. Billington

Total synthesis of (–)-ovalicin and analogues from L-quebrachitol

We describe here the first chiral total synthesis of (–)-ovalicin and the synthesis of several related analogues, from the naturally occurring cyclitol L-quebrachitol.

Synthesis of myo-inositol 1-phosphate and 4-phosphate, and of their individual enantiomers

New methodology is described which allows the synthesis of myo-inositol 1-phosphate completely free of contamination by the 2-isomer, and novel resolution procedures have been developed for the preparation of the enantiomers of myo-inositol 1- and 4-phosphates.

Synthesis of myo-inositol 1,3,4,5-tetraphosphate and myo-inositol 1,3-bisphosphate

myo-Inositol 1,3,4,5-tetraphosphate, myo-inositol 3,4-bisphosphate, and myo-inositol 4-phosphate have been prepared via routes in which a key step is a novel, highly regioselective monoalkylation of myo-inositol orthoformate.

Stereoselective total synthesis of racemic (3S,4R/3R,4S)- and a diastereoisomeric mixture of (6E, 10Z)-3,4,7,11-tetramethyl-trideca-6,10-dienal (faranal); the trail pheromone of the Pharaoh's ant

Racemic (3S,4R/3R,4S)-faranal [(1a)+(1b)] has been synthesised by a convergent, stereospecific route which employed the addition of alkylcopper complexes to terminal acetylenes, to generate two trisubstituted double bonds, and a Diels–Alder reaction to establish the relative stereochemistry of the C-3, C-4 methyl groups. A diastereoisomeric mixture of faranals, enriched in the (3S,4S/3R,4R)-enantiomeric pair [(1c)+(1d)], has been synthesised by a somewhat shorter route via an intermediate diester, obtained from electrochemical dimerisation of ethyl crotonate.

Stereoselective synthesis of (3R,4S/3S,4R)-(6E, 10Z)-3,4,7,11-tetramethyltrideca-6,10-dienal (faranal); the trail pheromone of the Pharaoh's ant

Recemic (3R, 4S/3S, 4R)-faranal, has been synthesised by a convergent, stereospecific route from (1E, 5Z)-1-iodo-2, 6-dimethylocta-1,5-diene in good overall yield; this synthesis employed the addition of alkylcopper complexes to terminal acetylenes to generate the two trisubstituted double bonds, and a Diels–Alder reaction to establish the relative configuration of the C-3, C-4 methyl groups.

Synthesis of 2- and 6-deoxyinositol 1-phosphate and the role of the adjacent hydroxy groups in the mechanism of inositol monophosphatase

The 2- and 6-hydroxy groups of myo-inositol 1-phosphate have been shown to be independently associated with the mechanisms of hydrolysis and binding in the dephosphorylation of the substrate by inositol monophosphatase.

Aspects of the chemistry of dehydromethionine

Dehydromethionine [(1R,3S)-S-methylisothiazolidine-3-carboxylate] is shown to be a useful intermediate for the preparation of methyl-labelled methionines via its base-catalysed exchange in [2H4]methanol or methan[2H]ol. However, it is not possible to effect stereoselective exchange of protons at C-5 of dehydromethionine using sodium[2H3]methoxide–[2H4]methanol. A complete analysis of the 1H n.m.r. spectrum of dehydromethionine has been achieved by computer-assisted simulation and by comparison with the spectra of 2H-labelled dehydromethionines. Dehydromethionine is converted, by treatment with aqueous sodium hydroxide, mainly into the (S,S)-sulphoxide of methionine. This result can be rationalised by postulating a trigonal bipyramidal intermediate having in-line OH and NH attached to sulphur. Syntheses of stereochemically distinct [3,4-2H2]methionines are described.

Proton exchange in dehydromethionine; Synthesis of [C2H3]-L-methionine

Abstract Methyl-labelled methionines can be easily prepared via dehydromethionine (1), which undergoes clean exchange at its methyl group with cat. MeONa/MeO 2 H.

The biosynthesis of spermidine. Part 1: biosynthesis of spermidine from L-[3,4-13C2]methionine and L-[2,3,3-2H3]methionine

Three mechanisms are discussed for the biosynthesis of spermidine from butane-1,4-diamine and decarboxylated adenosylmethionine catalysed by spermidine synthase: (i) enzyme-mediated SN2 attack of butane-1,4-diamine at the aminopropyl group of decarboxylated adenosylmethionine; (ii)SN2 attack at the aminopropyl group by a nucleophilic group of the synthase, to give an aminopropylated enzyme, which reacts with butane-1,4-diamine to give spermidine (double SN2 displacement); and (iii) enzyme-induced intramolecular closure of decarboxylated adenosylmethionine to give protonated azetidine, which reacts with butane-1,4-diamine to give spermidine (alternative double SN2 displacement).Using n.m.r. spectroscopy to determine isotope distributions in spermidines derived from Escherichia coli fed on [3,4-13C2]methionine and [2,3,3-2H3]methionine, mechanisms (i) and (ii) are shown to be tenable, but mechanism (iii) is eliminated from consideration.

The conversion of 2-(methylthio)ethanol into 1-chloro-2-(methylthio)-ethane: a 13C-labelling study with the aid of 13C nuclear magnetic resonance spectroscopy

The synthesis of 2-(methylthio)[1-13C]ethanol from [1-13C]acetic acid is described. This labelled alcohol and 13C n.m.r. spectroscopy were used to evaluate the propensity for rearrangement of four methods for effecting the conversion ROH → RCl[R3P(R = Ph, Pri or n-C8H17)–CCl4; CCl3CN–HCl; MsCl–collidine–LiCl; TsCl–py,-Cl–]. In every case the product observed at all stages of the reaction was a 1:1 mixture of 1-chloro-2-(methylthio)[1-13C]ethane and 1-chloro-2-(methylthio)[2-13C]ethane. It is proposed that activation of the hydroxy-group of 2-(methylthio)[1-13C]ethanol is followed by internal displacement by the methylthio-group giving the 1-methylthiiranium ion, which is captured by chloride.