A. Christopher Garner

Kinetic resolution and parallel kinetic resolution of methyl (+/-)-5-alkyl-cyclopentene-1-carboxylates for the asymmetric synthesis of 5-alkyl-cispentacin derivatives.

Conjugate addition of lithium dibenzylamide to methyl 5-isopropyl, 5-phenyl- and 5-tert-butyl-cyclopentene-1-carboxylates occurs with high levels of substrate control (>88% de), with preferential addition to the face of the cyclic alpha,beta-unsaturated acceptor anti- to the stereodirecting 5-alkyl substituent. Treatment of a range of methyl (+/-)-5-alkyl-cyclopentene-1-carboxylates with both lithium (+/-)-N-benzyl-N-alpha-methylbenzylamide and lithium (+/-)-N-3,4-dimethoxybenzyl-N-alpha-methylbenzylamide indicates significant enantiorecognition in their mutual kinetic resolutions, with preferential addition anti- to the 5-alkyl substituent, giving the 1,2-syn-1,5-anti-arrangement (E >16) after enolate protonation anti- to the amino functionality. The kinetic resolution of a range of methyl (+/-)-5-alkyl-cyclopentene-1-carboxylates with lithium (S)-N-benzyl-N-alpha-methylbenzylamide, and their efficient parallel kinetic resolution with a pseudoenantiomeric mixture of lithium (S)-N-benzyl-N-alpha-methylbenzylamide and lithium (R)-N-3,4-dimethoxybenzyl-N-alpha-methylbenzylamide are also demonstrated, giving a range of 5-alkyl-cispentacin derivatives in >98% de and high ee after N-deprotection.

Asymmetric synthesis and applications of β-amino Weinreb amides: asymmetric synthesis of (S)-coniine

Conjugate addition of lithium (S)-N-benzyl-N-alpha-methylbenzylamide to a range of alpha, beta-unsaturated Weinreb amides proceeds with high levels of diastereoselectivity (>95% de). The beta-amino Weinreb amide products may be transformed into beta-amino ketones via reactions with Grignard reagents, while treatment with DIBAL-H furnishes beta-amino aldehydes. Trapping of the aldehyde via Wadsworth-Emmons reaction and subsequent manipulation offers an efficient route to homochiral delta-amino acid derivatives and 2-substituted piperidines. The application of this methodology for the synthesis of (S)-coniine is demonstrated.

Convenient synthetic routes to bidentate and monodentate 2-, 3- and 4-pyridyl phosphines: potentially useful ligands for water-soluble complex catalysts

The monodentate and bidentate pyridyl phosphines, PR3 and R2P(CH2)2PR2, where R=3- or 4-pyridyl can be prepared in high yields by treatment of butyllithium/TMEDA/3- or 4-bromopyridine with PCl3 or Cl2P(CH2)2PCl2 at low temperature. 1,2-Bis(di-2-pyridylphosphino)ethane is conveniently synthesised by an alternative route involving reaction of 1,2-dibromoethane with lithium di-2-pyridylphosphide.

Parallel kinetic resolution of tert-butyl (RS)-3-oxy-substituted cyclopent-1-ene-carboxylates for the asymmetric synthesis of 3-oxy-substituted cispentacin and transpentacin derivatives

tert-Butyl (RS)-3-methoxy- and (RS)-3-tert-butyldiphenylsilyloxy-cyclopent-1-ene-carboxylates display excellent levels of enantiorecognition in mutual kinetic resolutions with both lithium (RS)-N-benzyl-N-(alpha-methylbenzyl)amide and lithium (RS)-N-3,4-dimethoxybenzyl-N-(alpha-methylbenzyl)amide. A 50 : 50 pseudoenantiomeric mixture of lithium (S)-N-benzyl-N-(alpha-methylbenzyl)amide and lithium (R)-N-3,4-dimethoxybenzyl-N-(alpha-methylbenzyl)amide allows for the efficient parallel kinetic resolution of the tert-butyl (RS)-3-oxy-substituted cyclopent-1-ene-carboxylates, affording differentially protected 3-oxy-substituted cispentacin derivatives in high yield and >98% de. Subsequent N-deprotection and hydrolysis provides access to 3-oxy-substituted cispentacin derivatives in good yield, and in >98% de and >98% ee, while stereoselective epimerisation and subsequent deprotection affords the corresponding transpentacin analogues in good yield, and in >98% de and >98% ee.

Parallel kinetic resolution of tert-butyl (RS)-3-alkyl-cyclopentene-1-carboxylates for the asymmetric synthesis of 3-alkyl-cispentacin derivatives

The double mutual kinetic resolution of tert-butyl (RS)-3-benzyl-cyclopentene-1-carboxylate with a 50 : 50 mixture of lithium (RS)-N-benzyl-N-alpha-methylbenzylamide and lithium (RS)-N-3,4-dimethoxybenzyl-N-alpha-methylbenzylamide gives, after protonation with 2,6-di-tert-butylphenol, a 50 : 50 mixture of the readily separable N-benzyl-(1SR,2RS,3RS,alphaRS)- and N-3,4-dimethoxybenzyl-(1SR,2RS,3RS,alphaRS)-beta-amino esters in >98% de in each case. This product distribution indicates that these amides react at very similar rates and with no mutual interference to furnish readily separable products, and are thus ideal for parallel kinetic resolution. The efficient parallel kinetic resolution (E > 65) of a range of tert-butyl (RS)-3-alkyl-cyclopentene-1-carboxylates with a pseudoenantiomeric mixture of homochiral lithium (S)-N-benzyl-N-alpha-methylbenzylamide and lithium (R)-N-3,4-dimethoxybenzyl-N-alpha-methylbenzylamide gives, after separation and N-deprotection, a range of carboxylate protected 3-alkyl-cispentacin derivatives in >98% de and >95% ee.

Preparation of methyl (1R,2S,5S)- and (1S,2R,5R)-2-amino-5-tert-butyl-cyclopentane-1-carboxylates by parallel kinetic resolution of methyl (RS)-5-tert-butyl-cyclopentene-1-carboxylate.

Comparison of the kinetic and parallel kinetic resolutions of methyl (RS)-5-tert-butyl-cyclopentene-1-carboxylate allows for the efficient synthesis of both (1R,2S,5S)- and (1S,2R,5R)-enantiomers of methyl 2-amino-5-tert-butyl-cyclopentane-1-carboxylate.

Asymmetric conjugate reductions with samarium diiodide: asymmetric synthesis of (2S,3R)- and (2S,3S)-[2-2H,3-2H]-leucine-(S)-phenylalanine dipeptides and (2S,3R)-[2-2H,3-2H]-phenylalanine methyl ester

The highly diastereoselective samarium diiodide and D(2)O-promoted conjugate reduction of homochiral (E)- and (Z)-benzylidene and isobutylidene diketopiperazines (E)-5,7 and (Z)-6,8 has been demonstrated. This methodology allows the asymmetric synthesis of methyl (2S,3R)-dideuteriophenylalanine 27 in > or = 95% de and >98% ee, and (2S,3R)- or (2S,3S)-dideuterioleucine-(S)-phenylalanine dipeptides 37 and 38 in moderate de, 66% and 74% respectively. A mechanism is proposed to account for this process.

On the origins of diastereoselectivity in the alkylation of diketopiperazine enolates

High levels of diastereoselectivity are observed for benzylation of the lithium enolates of (S)-N,N′-bis-para-methoxybenzyl-3-iso-propyl-piperazine-2,5-dione, (S)-N(1)-para-methoxybenzyl-N(4)-methyl-3-iso-propyl-piperazine-2,5-dione and (S)-N(1)-methyl-N(4)-para-methoxybenzyl-3-iso-propyl-piperazine-2,5-dione. These data suggest that the high diastereofacial selectivity observed for alkylation of these diketopiperazine templates is mainly a consequence of the relay of stereochemical information from C(3) to C(6) via the influence of 1,2-torsional strain introduced by the N-alkyl substituents, rather than through minimisation of steric interactions alone.

Asymmetric synthesis of α-amino carbonyl derivatives using lithium (R)-N-benzyl-N-α-methylbenzylamide

An efficient protocol for the transformation of homochiral α-hydroxy-β-amino esters to their α-amino carbonyl components is presented. Diastereoselective conjugate addition of lithium (R)-N-benzyl-N-α-methylbenzylamide to a range of α,β-unsaturated esters and subsequent enolate hydroxylation with (1R)-(-)-(camphorsulfonyl)oxaziridine, followed by LiAlH4 reduction produces homochiral 3-amino 1,2-diols. Subsequent oxidative cleavage with H5IO6 provides N-benzyl-N-α-methylbenzyl protected α-amino aldehydes (96-98% d.e.) and ketones (88% d.e.). Further oxidation of the α-amino aldehydes with sodium chlorite and Pd-catalysed hydrogenation provides α-amino acids in 94-98% e.e.

Diastereoselective conjugate reduction with samarium diiodide: asymmetric synthesis of methyl (2S,3R)-N-acetyl-2-amino-2,3-dideuterio-3-phenylpropionate

A highly diastereoselective conjugate reduction using SmI2 and D2O has been demonstrated on a homochiral benzylidene diketopiperazine template, giving methyl (2S,3R)-N-acetyl-2-amino-2,3-dideuterio-3-phenylpropionate in 93% de and 90% ee after deprotection, hydrolysis and N-acetylation.