David P. G. Hamon

The asymmetric synthesis of α-amino acids via the addition of grignard reagents to imine derivatives.

Abstract The ester-8-phenylmenthyl N-Boc-glycinate 5a, undergoes free radical bromination by N-bromosuccinimide to give 8-phenylmenthyl N-Boc-bromoglycinate 8. Treatment of the bromide 8 with a variety of Grignard reagents at low temperature gave 8-phenylmenthyl (S-N-Boc-2-alkylglycinates with high diastereoselectivity. Conditions were found for the hydrolysis of these derivatives with no racemization of the resultant amino acid.

Asymmetric induction in acyclic radical reactions: Enantioselective syntheses of α-amino acids via carbon-carbon bond forming radical reactions

Abstract The derivative of glycine, 8-phenylmenthyl N-Boc-2-bromoglycinate 1 reacted with allyltri-n-butylstannanes via the corresponding radical 2 by the SH2′ mechanism to give (2S) allyl amino acid drrivatives with high diastereoselectivity. The reaction of 1 with triphenyl(1,2-propadienyl)stannane and triphenyl(2-propynyl)stannane gave the (2S) allenyl and (2S) propargyl amino acid derivatives respectively also with high diastereoselectivity but by a different mechanism.

Enantioselective syntheses of α-amino acids via carbon–carbon bond forming radical reactions

The derivative of glycine, 8-phenylmenthyl N-Boc-2-bromoglycinate 2 reacts with unsaturated stannanes to give unsaturated amino acid derivatives with high diastereoselectivity.

Asymmetric induction in acyclic radical reactions: enantioselective syntheses of (s)-2-deuterioglycine and (r)-2-deuterioglycine.

Abstract The (-)-8-phenylmenthol esters of N-Boc-glycine and N-Boc-2,2-dideuterioglycine were brominated with N-bromosuccinimide and the bromo compounds were reduced with tri-n-butyldeuteriostannane and tri-n-butylstannane respectively, to give the chiral glycine derivatives in 90% optical yield. Hydrolysis yielded the amino acid without racemisation.

Enantioselective syntheses of 2-arylpropanoic acids: (S)-2-phenylpropanoic acid

Abstract (S)-2-Phenylpropanoic acid, an intermediate for the preparation of optically active Ibuprofen, has been synthesized using, as the key steps, Sharpless epoxidation and benzylic hydrogenlysis.

The synthesis of (R)-(−) and (S)-(+)-hydroxysaclofen

Abstract 2-(4-Chlorophenyl)-3-hydroxypropene has been separately converted to both enantiomers of its epoxide. The epoxides were converted to (R)-(−) and (S)-(+)-hydroxysaclofen. Only the latter showed activity as a specific GABA B antagonist.

ASYMMETRIC DIHYDROXYLATION IN AN APPROACH TO THE ENANTIOSELECTIVE SYNTHESIS OF 2-ARYLPROPANOIC ACID NON-STEROIDAL ANTI-INFLAMMATORY DRUGS

Abstract Naproxen (( S )-2-(6-methoxy-2-naphthyl)propanoic acid) and flurbiprofen (( S )-2-(3-fluoro-4-phenylphenyl)propanoic acid) have been synthesised in high enantiomeric excess. The synthetic strategy employed was to introduce asymmetry into the molecules by Sharpless asymmetric dihydroxylation of the appropriate methyl styrenes. The resultant diols were then converted into optically active epoxides and the required stereogenic centre was assembled by catalytic hydrogenolysis of the introduced benzylic epoxide oxygen bond, followed by oxidation of the derived optically active primary alcohol.

Enantioselective syntheses of 2-arylpropanoic acid non-steroidal antiinflammatory drugs and related compounds.

Abstract (S)-2-[4′-(2″-Methylpropyl)phenylpropanoic acid (ibuprofen) and (S)-2-(3′-benzoylphenyl)propanoic acid (ketoprofen) have been synthesised in high enantiomeric excess. Control of stereochemistry was achieved by a combination of Sharpless epoxidalion followed by catalytic hydrogenolysis of the introduced benzylic epoxide oxygen bond. Also, the coupling of organic compounds in the presence of palladium with enantiopure 2-(3-iodophenyl)propanoic and 2-(4-iodophenyl)propanoic acids, prepared by the methodology above, is a general method for the synthesis of optically active arylpropanoic acids.

Asymmetric Synthesis of (S)-1-Methyl-2-cyclohexen-1-ol, a Constituent of the Aggregation Pheromone of Dendroctonus pseudotsugae

Abstract 1-Methyl-2-cyclohexen-1-ol has been prepared by a three step synthesis from 1-methylcyclohexene, in greater than 94% e.e., via a ‘merged substitution–elimination reaction’ between NaSePh and 2-methyl-2-hydroxycyclohexyl p-toluenesulphonate.

Asymmetric synthesis of ibuprofen and ketoprofen

Abstract ( S )-2-[4′-(2″-Methylpropyl)phenyl]propanoic acid (ibuprofen) and ( S )-2-(3′-benzoylphenyl)propanoic acid (ketoprofen) have been synthesised in high enantiomeric excess. Control of the stereochemistry was achieved by a combination of Sharpless epoxidation followed by catalytic hydrogenolysis of the introduced benzylic epoxide oxygen bond.