Timothy J. Ritchie

Stereoselective free radical reactions in the preparation of 2-deoxy-β-D-glucosides

Decarboxylation of the O-methyl, O-p-cresyl and O-3β-cholestanyl glycosides of 3-deoxy-4,5,7-tri-O-benzyl-D-arabino-heptulosonic acid by means of the derived O-acyl thiohydroxamates leads stereoselectively to the corresponding 2-deoxy-β-D-glucosides.

Physicochemical descriptors of aromatic character and their use in drug discovery.

Published physicochemical descriptors of molecules that convey aromaticity-related character are reviewed in the context of drug design and discovery. Studies that have employed aromatic descriptors are discussed, and several descriptors are compared and contrasted.

Diastereoselective free-radical reactions. Part 1. Preparation of 2-deoxy-β-glycosides by synthesis and reductive decarboxylation of 3-deoxyulosonic acid glycosides

A general procedure for the synthesis of 2-deoxy-β-D-glycosides involving the preparation of 3-deoxyulosonic acid glycosides from glycals and their reductive decarboxylation is described.

Preparation and reactions of some cyclic orthoester derivatives

Abstract Deprotonation of the alkoxysulphone ( 5 ) followed by quenching with diphenyl disulphide yields the dithioorthoester ( 6 ) and not the expected ketene monothioacetal (7). Attempts at orthoester exchange of ( 6 ) with decanol with a variety of reagents lead to ring opened products. Quenching of the anion derived from ( 5 ) with sulphuryl chloride or bromine leads respectively to the chloride ( 19 ) and bromide ( 20 ). Solvolysis of these halides leads to formation of sulphinate esters.

Heterocyclic replacements for benzene: Maximising ADME benefits by considering individual ring isomers

The impact of replacing a mono-substituted benzene (phenyl) ring with thirty three aromatic and nine aliphatic heterocycles on nine ADME-related screens (solubility, lipophilicity, permeability, protein binding CYP450 inhibition and metabolic clearance) was assessed using matched molecular pair analysis. The results indicate that the influence on the ADME profile can differ significantly depending on the ring identity and importantly on the individual regioisomers that are possible for some rings. This information enables the medicinal chemist to make an informed choice about which rings and regioisomers to employ as mono-substituted benzene replacements, based upon the knowledge of how such replacements are likely to influence ADME-related parameters, for example to target higher solubility whilst avoiding CYP450 liabilities.

Synthesis of 2,9,10-trioxatricyclo[4.3.1.0]decane analogues of resiniferatoxin

Structurally simplified analogues of the daphnane diterpene resiniferatoxin (RTX)1, possessing the unusual 2,9,10-trioxatricyclo[4.3.1.0]decane system have been synthesised stereoselectively from cyclohexa-1,3-diene: functionalisation of the diene afforded the anti-epoxide, 1,4-di-O-benzyl-t-2,t-3-epoxycyclohexane-r-1,c-4-diol 4, the ring-opening of which was examined using various organo-metallic reagents; organoaluminium species were found to be the most efficient to effect this reaction. When trimethylsilyl (in place of benzyl) ethers were used to protect the diol, selective deprotection of 1,4-di-O-trimethylsilyl-2-O-(p-tolylsulfonyl)-c-3-[3-(tert-butyldiphenylsilyloxy)-prop-1-ynyl]cyclohexane-r-1,t-2,c-4-triol 16 was achieved using citric acid in methanol—the equatorially disposed trimethylsilyl ether was found to be more easily cleaved than the axially orientated one. Formation of the tricyclic orthoester was achieved by the generation of a dioxolenium ion from 1-O-phenylacetyl-2-O-(p-tolylsulfpnyl)-c-3-[3-(tert-butyldiphenylsilyloxy)-prop-1-ynyl]cyclohexane-r-1,t-2,c-4-triol 19, by heating in 2,4,6-trimethylpyridine, with in situ intramolecular trapping by the suitably orientated hydroxy group to give 1-benzyl-7-(3-tert-butyldiphenylsilyloxyprop-1-ynyl)-2,9,10-trioxatricyclo[4.3.1.0] decane 20.

Some Studies on Carbonyl Radical Cyclizations and on the Synthesis of 2-Deoxy-β-D-Glycosides by Stereoselective Radical Reactions

The effect of substituents on the mode (exo- or endo-) and efficiency of 6, 7-olefinic carbonyl radical cyclizations has been studied. A new method for the synthesis of 2-deoxy-β-D-glycosides, in which the key step is a stereoselective radical decarboxylation, has been developed.

A concise synthesis of 3-deoxy-2-O-methyl-4,5,7-tri-O-benzyl-D-arabino-heptulosonic acid and related compounds from 3,4,6-tri-O-benzyl-D-glucal

A concise, de novo synthesis of the 3-deoxyulosonic acid glycosyl donors (14) and (15) from trio-O-benzyl-D-glucal and their transformation into the corresponding O-methyl glycosides is described.

The stereoselective synthesis of 2,9,10-trioxatricyclo[4.3.1.0]decane analogues of resiniferatoxin

Structurally simplified analogues of the diterpene resiniferatoxin possessing a 2,9,10-trioxatricyclo[4.3.1.0]decane system are synthesised stereoselectively from cyclohexa-1,3-diene.