Raymond McCague

Development of the biocatalytic resolution of 2-azabicyclo[2.2.1]hept-5-en-3-one as an entry to single-enantiomer carbocyclic nucleosides

Abstract For the resolution of the bicyclic lactam 2-azabicyclo[2.2.1]hept-5-en-3-one, efficient whole cell biocatalysts have been identified and from these, enzymes (lactamases) have been isolated. While the two enzymes obtained act on different enantiomers of the lactam, either can be used in scaleable processes to obtain synthons for carbocyclic nucleosides having the natural configuration.

The synthesis of (R)-(+)-lipoic acid using a monooxygenase-catalysed biotransformation as the key step

2-(2-Acetoxyethyl)cyclohexanone (4) was converted into the lactone (-)-(5) regio- and enantioselectively using 2-oxo-delta 3-4,5,5-trimethylcyclopentenyl acetyl-CoA monooxygenase, an NADPH-dependent Baeyer-Villiger monooxygenase from camphor grown Pseudomonas putida NCIMB 10007. The lactone (-)-(5) was converted into (R)-(+)-lipoic acid in six steps. In contrast cyclopentanone monooxygenase, an NADPH-dependent Baeyer-Villiger monooxygenase from cyclopentanol-grown Pseudomonas sp. NCIMB 9872 selectively oxidized the (S)-enantiomer of the ketone (4) giving better access to optically enriched, naturally occurring lipoic acid.

Synthesis of enantiomerically pure α-hydroxyaldehydes from the corresponding α-hydroxycarboxylic acids: novel substrates for Escherichia coli transketolase

Enantiomerically pure (R)-α-hydroxyaldehydes (>95% ee) are prepared from the corresponding α-hydroxyesters by silyl protection, reduction with diisobutylaluminium hydride, and finally deprotection under acidic conditions; subsequent coupling of these aldehydes with lithium hydroxypyruvate, catalysed by Escherichia coli transketolase, leads to novel optically pure triols.

A route to conformationally restricted antioestrogens by coupling of a vinyl triflate with an aryl zinc chloride

Abstract Palladium complex catalysed coupling of a benzocycloheptenyl triflate with aryl zinc chlorides gives an efficient approach to the synthesis of conformationally restricted antioestrogens.

Enzymatic resolution of oxalate esters of a tertiary alcohol using porcine pancreatic lipase

The tertiary alcohol 5 has been resolved to 90% ee (42% yield) by hydrolysis of its oxalate 6b with porcine pancreatic lipase in pH 7 buffer containing 13%tert-butyl alcohol.

Stereoselective olefin formation from the dehydration of 1-(p-alkoxyphenyl)-1,2-diphenylbutan-1-ols: application to the synthesis of tamoxifen

Acid-catalysed dehydration of either diastereoisomer of a 1-(p-alkoxyphenyl)-1,2-diphenylbutan-1-ol gives mainly the Z isomer of the but-1-ene via a common carbenium ion intermediate that can be regenerated by protonation of the (Z)- or (E)-butene with fluorosulphonic acid. Highly stereoselective syn eliminations were achieved by treatment of the butan-1-ols with base and carbon disulphide but dehydrations using N,N,N-triethylammonio-N′-methoxycarbonylsulphamidate proceeded mainly via a carbenium ion. Aspects of the stereoselectivity of the reactions are discussed. The methods can be applied to give simple stereoselective syntheses of the anti-cancer drug tamoxifen.

An analogue of the antioestrogen tamoxifen of sufficient rigidity to exist as distinct enantiomers: synthesis and conformational dynamics studies

Abstract The conformationally constrained tamoxifen analogue 1-methyl-8-phenyl-4-[4-[2-(dimethylamino)ethoxy]phenyl-6,7-dihydro-5- H -benzocycloheptane has been synthesised. A key synthetic step is a novel method for introduction of a methyl group into the aromatic ring of bnenzosuberone by enolate oxygen directed lithiation. Conformational studies were carried out on the methoxy of the above compound. Dynamic 1 H NMR revealed a free energy barrier to racemisation of enantiomeric atropisomers, ΔG ‡ - 20 (±1) kcal mol −1 . It could be separated by chromatography at −5°C on (+)-poly(triphenylmethylmethacryate) into enantiomers which racemised with t 1 2 1.8 h at −5.2°C corresponding to ΔG ‡ -20.9 20.9 kcal mol −1 . The difficulties in designing analogues having a greater degree of conformational constraint are discussed.

Tricyclic [10]annulenes. Part 5. Phenol–keto tautomerism in the 2- and 5-hydroxy derivatives of 7b-methyl-7bH-cyclopent[cd]indene

The 2- and 5-hydroxy derivatives of the 10π aromatic system 7b-methyl-7bH-cyclopent[cd]indene have been synthesised and their properties compared. The 2-hydroxy isomer (7) exists entirely in the non-aromatic keto form (8)(+1.41) but its lithium enolate (13; M = Li)(–1.45), like its methyl(–1.51) and trimethylsilyl (–1.51) ethers, (14) and (12), sustains a substantial diamagnetic ring current. The ketone (8) is methylated on oxygen and on carbon, at the C-2a position only, the ratio varying with conditions in the expected manner. In contrast, the 5-hydroxy isomer (9) exists entirely in the annulenol form (–1.49), as does the 5-hydroxy-diester (25)(–1.15) and the 5-hydroxy-dialdehyde (32)(–1.00). These three compounds are thus the first [10]annulenols to be isolated.

Tricyclic [10]annulenes. Part 4. The effect of benzo-fusion: synthesis, properties, and X-ray structure of 9c-methyl-9cH-cyclopenta[jk]fluorene

The effect of benzo-fusion on the tricyclic [10]annulene (1) has been investigated. The benzo-fused annulene (7) was synthesised from the dialdehyde (6) by a bis-Wittig reaction, and has been shown to retain about two-thirds of the ring current of (1). Accurate bond lengths in (7) have been determined by X-ray crystallography. Synthesis of the annulenequinone (5) and the annulenopyridazine (8), and the X-ray structure determination of the dialdehyde (6) are also described.

3aH-Indenes. Part 2. Cycloaddition reactions of 3-methoxy- and 3-trimethylsiloxy-3a-methyl-3aH-indene

The title 3a-methyl-3aH-indenes (1a) and (1b) have been prepared from indan-1-one via the dienone (5) and the trienone (6), and the preparation of the key intermediates (5) and (6) has been improved. The 3aH-indene (1b) behaves similarly to the methoxy derivative (1a), and rearranges on heating to the 1H-isomer. Cycloaddition reactions of (1a) to N-phenylmaleimide and maleic anhydride give isolable [4 + 2]-adducts (12), which rearrange on heating to give the exo- and endo-[8 + 2]-adducts (13) and (14). In contrast, both 2-chloroacrylonitrile and 2-chloroacryloyl chloride give [8 + 2]-adducts with (1a). The 2-chloroacryloyl chloride adducts are readily converted into the tricyclic ketone (23). The trimethylsiloxy 3aH-indene (1b) undergoes cycloaddition reactions with dimethyl acetylenedicarboxylate, 2-chloroacryloyl chloride, and dichloroketene. The trimethylsilyl derivative (1b) offers some advantages over the methoxyindene (1a) in synthetic work.