151671-03-3Relevant academic research and scientific papers
Trading N and O. Part 4: Asymmetric synthesis of syn-β-substituted-α-amino acids
Davies, Stephen G.,Fletcher, Ai M.,Greenaway, Catherine J.,Kennedy, Matthew S.,Mayer, Christoph,Roberts, Paul M.,Thomson, James E.
, p. 5049 - 5061 (2018/05/08)
A total of nine enantiopure syn-β-substituted-α-amino acids have been synthesised, comprising both syn-β-hydroxy-α-amino acids and syn-β-fluoro-α-amino acids. The key step in the synthetic strategy towards these syn-β-substituted-α-amino acids involves a stereospecific rearrangement, which proceeds via the intermediacy of the corresponding aziridinium ions. The requisite enantiopure syn-α-hydroxy-β-amino esters were prepared via asymmetric aminohydroxylation of the corresponding α,β-unsaturated esters followed by epimerisation of the resultant anti-α-hydroxy-β-amino esters at the C(2)-position. Subsequent activation of the α-hydroxy moiety as a leaving group followed by displacement by the β-amino substituent gave the corresponding aziridinium species. Regioselective in situ ring-opening of the aziridinium intermediates with either water or fluoride gave the corresponding syn-β-hydroxy-α-amino ester or syn-β-fluoro-α-amino ester, respectively, and N-deprotection and ester hydrolysis afforded the target syn-β-substituted-α-amino acids as single diastereoisomers in good overall yield.
Trading N and O. Part 2: Exploiting aziridinium intermediates for the synthesis of β-hydroxy-α-amino acids
Davies, Stephen G.,Fletcher, Ai M.,Frost, Aileen B.,Roberts, Paul M.,Thomson, James E.
, p. 5849 - 5862 (2015/03/30)
The β-hydroxy-α-amino acids (S,S)-allo-threonine, (S,S)-β-hydroxyleucine and a range of aryl substituted (S,S)-β-hydroxyphenylalanines were prepared from the corresponding enantiopure anti-α-hydroxy-β-amino esters via a rearrangement protocol, which proceeds via the intermediacy of the corresponding aziridinium ions. The starting anti-α-hydroxy-β-amino esters were prepared in >99:1 dr using our diastereoselective aminohydroxylation procedure, whereby conjugate addition of lithium (R)-N-benzyl-N-(α-methylbenzyl)amide to an α,β-unsaturated ester is followed by oxidation of the resultant enolate with (-)-camphorsulfonyloxaziridine. Subsequent activation of the hydroxyl group within the anti-α-hydroxy-β-amino esters promoted aziridinium ion formation [which proceeds with inversion of configuration at C(2)], and regioselective ring-opening of the intermediate aziridinium ions with H2O [which proceeds with inversion of configuration at C(3)] gave the corresponding anti-β-hydroxy-α-amino esters as single diastereoisomers (>99:1 dr). Deprotection of these substrates via sequential hydrogenolysis and ester hydrolysis gave the corresponding β-hydroxy-α-amino acids in good yield and high diastereoisomeric and enantiomeric purity.
Trading N and O: Asymmetric syntheses of β-hydroxy-α-amino acids via α-hydroxy-β-amino esters
Davies, Stephen G.,Fletcher, Ai M.,Frost, Aileen B.,Lee, James A.,Roberts, Paul M.,Thomson, James E.
, p. 8885 - 8898 (2013/09/23)
Both diastereoisomers of 2-amino-3-hydroxybutanoic acid and 2-amino-3-hydroxy-3-phenylpropanoic acid have been prepared from enantiopure α-hydroxy-β-amino esters via the intermediacy of the corresponding cis- and trans-aziridines. Aminohydroxylation of two α,β-unsaturated esters produced enantiopure 2,3-anti-α-hydroxy-β-amino esters in >99:1 dr. Subsequent epimerisation at the C(2)-position via a sequential oxidation/diastereoselective reduction protocol gave the corresponding enantiopure 2,3-syn-α-hydroxy-β-amino esters in >99:1 dr. These syn- and anti-substrates were then converted into the corresponding N-Boc protected cis- and trans-aziridines, respectively, via a three step reaction sequence: (i) hydrogenolysis and in situ N-Boc protection; (ii) OH-activation; and (iii) aziridine formation. Subsequent regioselective ring-opening of the C(3)-methyl-aziridines with Cl3CCO2H proceeded with inversion of configuration to give the corresponding 2-amino-3-trichloroacetate esters, whereas the analogous reaction with the C(3)-phenyl-aziridines resulted in rearrangement to the corresponding oxazolidin-2-ones with retention of configuration. In each case, hydrolysis of the products from these ring-opening reactions produced the corresponding enantiopure β-hydroxy-α-amino acids as single diastereoisomers.
Asymmetric synthesis of α-amino carbonyl derivatives using lithium (R)-N-benzyl-N-α-methylbenzylamide
Davies, Stephen G.,Epstein, Simon W.,Garner,Ichihara, Osamu,Smith, Andrew D.
, p. 1555 - 1565 (2007/10/03)
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.
Asymmetric synthesis of α-amino carbonyls (aldehydes, ketones and acids) using lithium (R)-N-benzyl-N-α-methylbenzylamide
Davies,Epstein,Ichihara,Smith
, p. 1599 - 1601 (2007/10/03)
The diastereoselective conjugate addition of lithium (R)-N-benzyl-N-α-methylbenzylamide to α,β-unsaturated esters and subsequent enolate hydroxylation, followed by reduction and oxidative cleavage provides a facile route to N,N-protected α-amino aldehydes and ketones. Further manipulation furnishes α-amino acids in high enantiomeric excess.
Asymmetric Synthesis of β-Amino-α-Hydroxy Acids via Diastereoselective Hydroxylation of Homochiral β-Amino Enolates
Bunnage, Mark E.,Chernega, Alexander N.,Davies, Stephen G.,Goodwin, Christopher J.
, p. 2373 - 2384 (2007/10/02)
The highly diastereoselective conjugate addition of lithium N-benzyl-N-α-methylbenzylamide with enoate acceptors, and the electrophilic hydroxylation of the resultant β-amino enolates with (camphorsulfonyl)oxaziridine, is identified as a direct and general strategy for the asymmetric synthesis of homochiral β-amino-α-hydroxy acids and their derivatives.A structurally diverse array of β-amino enolate substrates can be hydroxylated with generally excellent anti diastereoselectivity (>90percent d.e.) using this protocol; an alternative stepwise hydroxylation procedure, where the β-amino enolate is prepared by enolisation of the preformed conjugate adduct is also found to lead to formation of the anti diastereomer.The diastereofacial selectivity of enolate hydroxylation appears to be under predominantly substrate-controlled asymmetric induction, although a measurable degree of chirality predominantly substrate-controlled asymmetric induction, although a measurable degree of chirality recognition with the oxaziridine reagent can be observed.Homochiral β-amino-α-keto esters are also prepared and their stereoselective reductions examined.
Asymmetric Synthesis of Homochiral syn- and anti-3-Phenylisoserine Derivatives: A Practical Strategy for the Synthesis of the Taxol C-13 Side Chain
Bunnage, Mark E.,Davies, Stephen G.,Goodwin, Christopher J.
, p. 1375 - 1376 (2007/10/02)
A tandem lithium amide conjugate addition-electrophilic hydroxylation approach to the synthesis of N-benzoyl-3-phenylisoserine methyl esters affords a strategy for the practical synthesis of the taxol side chain.
