- A systematic study of the solid state and solution phase conformational preferences of β-peptides derived from C(3)-alkyl substituted transpentacin derivatives
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The solid state and solution phase conformational preferences of a homologous series of β-peptides derived from a range of 2-amino-3-alkylcyclopentanecarboxylic acid residues have been investigated using a variety of spectroscopic and crystallographic techniques. These studies indicate that C(3)-alkyl substitution trans to the amino group on the cyclopentane backbone is tolerated by the established 12-helix secondary structural preference of the parent pentamer and hexamer derived from 2-aminocyclopentanecarboxylic acid (transpentacin) residues in both the solid state and solution phase. Evidence for the alternative turn type conformation identified for the C(3)-unsubstituted tetramer was not observed in the C(3)-alkyl substituted derivatives, consistent with the alkyl substituent anti to the amino functionality destabilising this motif. These results suggest that oligomers based around the transpentacin scaffold may be amenable to further elaboration at C(3) anti to the amino group with retention of the secondary structure.
- Abraham, Elin,Claridge, Timothy D.W.,Davies, Stephen G.,Odell, Barbara,Roberts, Paul M.,Russell, Angela J.,Smith, Andrew D.,Smith, Lorna J.,Storr, Helen R.,Sweet, Miles J.,Thompson, Amber L.,Thomson, James E.,Tranter, George E.,Watkin, David J.
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- Kinetic resolution of tert-butyl (RS)-3-alkylcyclopentene-1-carboxylates for the synthesis of homochiral 3-alkyl-cispentacin and 3-alkyl-transpentacin derivatives
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High levels of stereocontrol are observed in the conjugate addition of lithium dibenzylamide to tert-butyl (RS)-3-alkylcyclopentene-l-carboxylates (alkyl = Et, Bn), with addition occurring exclusively anti- to the 3-alkyl substituent. Treatment of a range of tert-butyl (RS)-3-alkylcyclopentene-l-carboxylates (alkyl = Et, Bn, 'Pr, 'Bu) with lithium (RS)-N-benzyl-N-α-methylbenzylamide indicates that good enantiorecognition is observed (E > 80) in their mutual kinetic resolution. In these reactions, conjugate addition of the lithium amide occurs exclusively anti- to the 3-alkyl substituent, with subsequent C(1)-protonation occurring preferably anti- to the 2-amino group in the 3-Et, 3-Bn and 3-'Pr cases, giving predominantly the corresponding 1,2-syn-2,3-anti-diastereoisomers. Conjugate addition to (RS)-3-tert-butyl cyclopentene-l-carboxylate results in exclusive 2,3-anti-addition and a reversal in C(1)-protonation selectivity, giving predominantly the 1,2-anti-2,3-anti-diastereoisomer. Furthermore, the kinetic resolution of the tert-butyl (RS)-3-alkylcyclopentene-l-carboxylates (alkyl = Et, Bn, 'Pr, 'Bu) with lithium (S)-N-benzyl-N-αmethylbenzylamide proceeds efficiently, giving, at between 47 and 51% conversion, the resolved 3-alkylcyclopentene-l-carboxylates in >85 to >98% ee and the β-amino ester products of conjugate addition in high de, consistent with E > 80 in each case. Subsequent deprotection of the 1,2-syn-2,3-anti-3-alkyl-β-amino esters (alkyl = Et, Bn, 'Pr) by hydrogenolysis and ester hydrolysis gives the corresponding 1,2-syn-2,3-anti-3-alkylcispentacins in >98% de and 98 ±1% ee. Selective epimerisation of the 1,2-syn-2,3-anti-3-alkyl-β-amino esters (alkyl = Et, Bn, 'Pr, 'Bu) by treatment with KO'Bu in 'BuOH gives the corresponding 1,2-anti-2,3-anti-3-alkyl-β-amino esters in quantitative yield and in >98% de, with subsequent deprotection by hydrogenolysis and ester hydrolysis giving the corresponding 1,2-anti-2,3-anti-3-alkylcispentacin hydrochlorides in >98% de.
- Bunnage, Mark E.,Davies, Stephen G.,Parkin, Richard M.,Roberts, Paul M.,Smith, Andrew D.,Withey, Jonathan M.
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p. 3337 - 3354
(2007/10/03)
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