A. Roderick MacKenzie

Additive Pummerer reactions of vinylic sulfoxides. Synthesis of γ-hydroxy-α,β-unsaturated esters, α-hydroxyketones, and 2-phenylsulfenyl aldehydes and primary alcohols☆

Treatment of β-monosubstituted vinylic sulfoxides 1 with trifluoroacetic anhydride in dichloromethane gave excellent yields of 1,2-bis(trifluoroacetoxy)thioethers 6. Mildly basic methanolysis of 2-alkyl-substituted 6 gave α-hydroxyaldehydes 11 as monomer-dimer mixtures; similar treatment of the 2-aryl analogues afforded aryl (hydroxymethyl) ketones 12. Compounds 11 underwent Wittig reactions with methoxycarbonylmethylenetriphenylphosphorane to give high yields of γ-hydroxy-α,β-unsaturated esters 13, predominantly as the E-isomers. β-Monosubstituted vinylic sulfoxides 1 possessing a β-aryl group, and β-disubstituted vinylic sulfoxides 3 reacted with trifluoromethanesulfonic anhydride-sodium acetate in acetic anhydride to give 2-(phenylsulfenyl)acylals 14. These gave 2-phenylsulfenyl aldehydes 15 upon basic methanolysis, and the corresponding primary alcohols 16 on reduction with sodium borohydride. Reaction of both geometric isomers of enantiomerically pure vinylic sulfoxide 1o with TFAA gave racemic 6o as a mixture of diastereomers. Reaction of optically pure (E)- and (Z)-1p with trifluoromethanesulfonic anhydride-sodium acetate in acetic anhydride gave acylal 19 in 10.5 and 23% e.e., respectively.

Additive pummerer reactions of vinylic sulphoxides. Synthesis of γ-hydroxy-α,β-unsaturated esters and α-hydroxyketones

Abstract Reaction of α,β-unsaturated sulphoxides with trifluoroacetic anhydride gives α,β-bis(trifluoroacetoxy)thioethers in near-quantitative yields. Subsequent basic methanolysis gives monomeric and dimeric α-hydroxyaldehydes or αhydroxyketones, depending on the nature of the β-R group. The former undergo Wittig olefination with methoxycarbonylmethylenetriphenylphosphorane to give γ-hydroxy-α,β-unsaturated esters in high overall yields.

Synthesis of tetrahydroisoquinolines via intramolecular electrophilic aromatic substitution reactions of Pummerer-derived substituted N-benzyl-N-tosyl-α-aminothionium ions

Abstract Conjugate addition to (phenylsulfinyl)ethene 1 of substituted benzylic amines 2 followed by N -tosylation gives substituted N -benzyl- N -tosyl-2-amino-1-(phenylsulfinyl)ethanes 3 . Treatment of 3 with trimethylsilyl trifluoromethanesulfonate-Hunigs base gives 4-(phenylsulfenyl)- N -tosyl-1,2,3,4-tetrahydroisoquinolines 4 via presumed intramolecular trapping of Pummerer-derived substituted N -benzyl- N -tosyl-α-aminothionium ions 5 .

4-Amino-2-(aryl)-butylbenzamides and Their conformationally constrained analogues. Potent antagonists of the human neurokinin-2 (NK2) receptor

A library, evaluating a range of piperazines, piperidines and acyclic amines, as replacements for the 4-hydroxy-4-phenylpiperidine moiety in lead (1b) was prepared. These efforts identified the 4-((N)-benzimidazolone)piperidine analogue (2a) which was further optimised using classical single-compound synthesis to yield the 3-((N)-morpholino)azetidine (2j). Conformationally constrained analogues of (2j), generally offered no potency advantage in this particular series.

Additive Pummerer reactions of vinylic sulphoxides. Synthesis of 2-(phenylsulphenyl) aldehydes and primary alcohols

Abstract Reaction in acetic anhydride solution of α,β-unsaturated sulphoxides 1 with sodium acetate and triflic anhydride gives 2-(phenylsulphenyl) acylals 4 . Basic methanolysis of 4 gives 2-(phenylsulphenyl) aldehydes 8 , whilst reduction gives directly 2-(phenylsulphenyl) primary alcohols 9 .

Synthesis of the bacterial coenzyme methoxatin

A short synthesis of the bacterial coenzyme methoxatin, based on the thermolysis of the azide (3) to give the indole (4) and the regioselective formation of the pyrroloquinoline (5), is described.

Vinyl azides in heterocyclic synthesis. Part 7. Synthetic studies on the cytotoxic marine alkaloid amphimedine

In an approach to the synthesis of the pentacyclic alkaloid amphimedine (1), a key tetracyclic structure (6) is readily constructed from 2-methoxyacridine-9-carbaldehyde in three steps. Condensation of the aldehyde (2) with methyl azidoacetate gives the vinyl azide (3) which on thermolysis in xylene gives the pyridoacridines (4) and (5) in high yield (78% and 19% respectively); this represents the first cyclisation of a vinyl nitrene to a peri-position. Oxidation of the major pyridoacridine (4), or of the mixed pyridoacridines (4) and (5), with manganese dioxide gives the pyridoacridone (6), but neither (6) nor the analogous isopropyl ester (9) undergoes Diels–Alder reaction with the azadiene (7).

Vinyl azides in heterocyclic synthesis. Part 6. Synthesis of isoquinolines by intramolecular aza-Wittig reaction

Azidocinnamates containing ortho-carbonyl substituents are versatile intermediates for heterocyclic synthesis. Isoquinolines (8) and (9) are formed under mild neutral conditions by intramolecular aza-Wittig reactions of iminophosphoranes, readily derived from azides (1) and (2), respectively, with triethyl phosphite. The azafluoranthene (10) can also be prepared from the azide (3)via the isolable iminophosphoranes (11) and (12). Thermolysis of the azides (1) in toluene or xylene gives the 4-substituted indoles (13) in varying yield (Table 2). Similarly the indoles (14) and (19) are formed from the azides (3) and (6a and b) respectively.

Paclitaxel synthetic studies. A Diels–Alder approach to the A-ring

Highly substituted cyclohexenes corresponding to the A-ring of the anti-cancer diterpene natural product paclitaxel are synthesised using a Diels–Alder reaction and decarboxylative elimination as the key steps.