The asymmetric synthesis of enantiopure C(5)-substituted transpentacins via diastereoselective conjugate additions to a β′-amino-α,β-unsaturated ester

The asymmetric synthesis of a range of 1,2-anti-1,5-syn-transpentacins, bearing either alkyl, phenyl or hydroxymethyl substituents at the C(5)-position, has been achieved using the diastereoselective conjugate additions of Grignard reagents to an enantiopure β′-amino-α,β-unsaturated ester as the key step. In addition, the doubly diastereoselective conjugate addition of an enantiopure lithium amide reagent to the β′-amino-α,β-unsaturated ester provided access to the corresponding β,β′-diamino ester, which was subsequently converted to both (S,S)-(2,5-diaminocyclopent-1-yl)methanol and (S,S)-2,5-diaminocyclopentane-1-carboxylic acid. In each case, the final enantiopure products were obtained as single diastereoisomers (>99:1 dr) in good yields over five steps or fewer from commercially available starting materials.

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(5R,αS)-5-[N-Benzyl-N-(α-methylbenzyl)amino]cyclopent-1-ene-1-carboxylateC22H25NO2[α]D20 = −119.0 (c 1.0, CHCl3)Absolute configuration: (5R,αS)Source of chirality: asymmetric synthesis

Methyl (S,S)-5-[N-benzyl-N-(α-methylbenzyl)amino]cyclopent-1-ene-1-carboxylateC22H25NO2[α]D20 = +23.3 (c 1.0, CHCl3)Absolute configuration: (S,S)Source of chirality: asymmetric synthesis

Methyl (S,S,S,S)-2-[N-benzyl-N-(α-methylbenzyl)amino]-5-[N′-benzyl-N′-(α′-methylbenzyl)amino]cyclopentane-1-carboxylateC37H42N2O2[α]D20 = −67.3 (c 1.0, CHCl3)Absolute configuration: (S,S,S,S)Source of chirality: asymmetric synthesis

Methyl (2R,5R,αS,α′S)-2-[N-benzyl-N-(α-methylbenzyl)amino]-5-[N′-benzyl-N′-(α′-methylbenzyl)amino]cyclopentane-1-carboxylateC37H42N2O7[α]D20 = −35.6 (c 1.0, CHCl3)Absolute configuration: (2R,5R,αS,α′S)Source of chirality: asymmetric synthesis

Methyl (S,S,S,S)-2-[N-benzyl-N-(α-methylbenzyl)amino]-5-phenylcyclopentane-1-carboxylateC28H31NO2[α]D20 = −43.0 (c 0.5, CHCl3)Absolute configuration: (S,S,S,S)Source of chirality: asymmetric synthesis

Methyl (S,S,S,S)-2-[N-benzyl-N-(α-methylbenzyl)amino]-5-ethylcyclopentane-1-carboxylateC24H31NO2[α]D20 = +39.4 (c 1.0, CHCl3)Absolute configuration: (S,S,S,S)Source of chirality: asymmetric synthesis

Methyl (1S,2S,5R,αS)-2-[N-benzyl-N-(α-methylbenzyl)amino]-5-vinylcyclopentane-1-carboxylateC24H29NO2[α]D20 = +18.6 (c 1.3, CHCl3)Absolute configuration: (1S,2S,5R,αS)Source of chirality: asymmetric synthesis

Methyl (1S,2S,5R,αS)-2-[N-benzyl-N-(α-methylbenzyl)amino]-5-isopropylcyclopentane-1-carboxylateC25H33NO2[α]D20 = +2.6 (c 1.0, CHCl3)Absolute configuration: (1S,2S,5R,αS)Source of chirality: asymmetric synthesis

Methyl (S,S,S)-2-amino-5-phenylcyclopentane-1-carboxylateC13H17NO2[α]D20 = −14.7 (c 1.0, CHCl3)Absolute configuration: (S,S,S)Source of chirality: asymmetric synthesis

Methyl (S,S,S)-2-amino-5-ethylcyclopentane-1-carboxylateC9H17NO2[α]D20 = +45.4 (c 1.0, CHCl3)[α]D20 = +47.5 (c 1.0, CHCl3)Absolute configuration: (S,S,S)Source of chirality: asymmetric synthesis

Methyl (1S,2S,5R)-2-amino-5-isopropylcyclopentane-1-carboxylateC10H19NO2[α]D20 = +6.3 (c 0.2, CHCl3)Absolute configuration: (1S,2S,5R)Source of chirality: asymmetric synthesis

(S,S,S)-2-Amino-5-phenylcyclopentane-1-carboxylic acidC12H15NO2[α]D20 = +17.5 (c 0.5, H2O)Absolute configuration: (S,S,S)Source of chirality: asymmetric synthesis

(S,S,S)-2-Amino-5-ethylcyclopentane-1-carboxylic acidC8H15NO2[α]D20 = +73.3 (c 1.0, H2O)Absolute configuration: (S,S,S)Source of chirality: asymmetric synthesis

(1S,2S,5R)-2-Amino-5-isopropylcyclopentane-1-carboxylic acidC9H17NO2[α]D20 = +6.0 (c 0.2, H2O)Absolute configuration: (1S,2S,5R)Source of chirality: asymmetric synthesis

(S,S,S)-2-Amino-5-(hydroxymethyl)cyclopentane-1-carboxylic acidC7H13NO3[α]D20 = +91.3 (c 0.2, H2O)Absolute configuration: (S,S,S)Source of chirality: asymmetric synthesis

(S,S,S,S)-{2-[N-Benzyl-N-(α-methylbenzyl)amino]-5-[N′-benzyl-N′-(α′-methylbenzyl)amino]cyclopent-1-yl}methanolC26H42N2O[α]D20 = −9.4 (c 1.0, CHCl3)Absolute configuration: (S,S,S,S)Source of chirality: asymmetric synthesis

(S,S)-(2,5-Diaminocyclopent-1-yl)methanolC6H14N2O[α]D20 = +64.0 (c 0.3, MeOH)Absolute configuration: (S,S)Source of chirality: asymmetric synthesis

(S,S)-5-[N-Benzyl-N-(α-methylbenzyl)amino]cyclopent-1-ene-1-carboxylic acidC21H23NO2[α]D20 = +16.3 (c 0.5, CHCl3)Absolute configuration: (S,S)Source of chirality: asymmetric synthesis

(S,S)-2,5-Diaminocyclopentane-1-carboxylic acidC6H12N2O2[α]D20 = +70.4 (c 0.5, H2O)Absolute configuration: (S,S)Source of chirality: asymmetric synthesis