1.Rigid dipeptide mimics: synthesis of enantiopure C6-functionalized pyrrolizidinone amino acids.
Rao MH1, Pinyol E, Lubell WD. J Org Chem. 2007 Feb 2;72(3):736-43.
Enantiopure (3S,5S,6R,8S)- and (3S,5S,6S,8S)-6-hydroxypyrrolizidinone 3-N-(Boc)amino 8-methyl carboxylates (6R)- and (6S)-1 were synthesized in seven steps starting from (2S)-alpha-tert-butyl N-(PhF) aspartate beta-aldehyde (10). Carbene-catalyzed acyloin condensation of beta-aldehyde 10 followed by acetylation provided a separable mixture of diastereomeric (2S,5RS,7S)-diamino-4-oxo-5-acetoxysuberates (13). Reductive amination and lactam annulation of the respective alpha-acetoxy ketones 13 provided hydroxypyrrolizidinones (6R)- and (6S)-1 with retention of the C6-position stereochemistry. The X-ray crystallographic study of (6R)-1 indicated dihedral angles constrained within the heterocycle that were consistent with the ideal values for the i + 1 and i + 2 residues of a type II' beta-turn. Hydrogen-bonding studies on N'-methyl-N-(Boc)aminopyrrolizidin-2-one carboxamides (6R)- and (6S)-21 in DMSO-d6, demonstrated different NH chemical shift displacements and temperature coefficients for the amide and carbamate protons, indicative of solvent shielded and exposed hydrogens in a turn conformation.
2.Asymmetric synthesis of anti-(2S,3S)- and syn-(2R,3S)-diaminobutanoic acid.
Bunnage ME1, Burke AJ, Davies SG, Millican NL, Nicholson RL, Roberts PM, Smith AD. Org Biomol Chem. 2003 Nov 7;1(21):3708-15.
Conjugate addition of homochiral lithium N-benzyl-N-alpha-methylbenzylamide to tert-butyl (E)-cinnamate or tert-butyl (E)-crotonate and in situ amination with trisyl azide results in the exclusive formation of the corresponding 2-diazo-3-amino esters in > 95% de. Amination of the lithium (E)-enolates of tert-butyl (3S,alphaR)-3-N-benzyl-N-alpha-methylbenzylamino-3-phenylpropanoate or tert-butyl (3S,alphaS)-3-N-benzyl-N-alpha-methylbenzylaminobutanoate with trisyl azide gives the (2R,3R,alphaR)- and (2S,3S,alphaS )-anti-2-azido-3-amino esters in good yields and in 85% de and > 95% de respectively. Alternatively, tert-butyl anti-(2S,3S,alphaS)-2-hydroxy-3-N-benzyl-N-alpha-methylbenzylaminobutanoate may be converted selectively to tert-butyl anti-(2S,3S,alphaS)-2-azido-3-N-benzyl-N-alpha-methylbenzylaminobutanoate by aziridinium ion formation and regioselective opening with azide. Deprotection of tert-butyl (2S,3S,alphaS)-2-azido-3-aminobutanoate via Staudinger reduction, hydrogenolysis and ester hydrolysis furnishes anti-(2S,3S)-diaminobutanoic acid in 98%, de and 98% ee.
3.3-Aminopyrrolidine-4-carboxylic acid as versatile handle for internal labeling of pyrrolidinyl PNA.
Reenabthue N1, Boonlua C, Vilaivan C, Vilaivan T, Suparpprom C. Bioorg Med Chem Lett. 2011 Nov 1;21(21):6465-9. doi: 10.1016/j.bmcl.2011.08.079. Epub 2011 Aug 23.
Conformationally restricted pyrrolidinyl PNAs with an α/β-dipeptide backbone consisting of a nucleobase-modified proline and a cyclic five-membered amino acid spacer such as (1S,2S)-2-aminocyclopentanecarboxylic acid (ACPC) (acpcPNA) can form very stable hybrids with DNA with high Watson-Crick base pairing specificity. This work aims to explore the effect of incorporating 3-aminopyrrolidine-4-carboxylic acid (APC), which is isosteric to the ACPC spacer, into the acpcPNA. It is expected that the modification should not negatively affect the DNA binding properties, and that the additional nitrogen atom in the APC should provide a handle for internal modification. Orthogonally-protected (N(3)-Fmoc/N(1)-Boc and N(3)-Fmoc/N(1)-Tfa) APC monomers have been successfully synthesized and incorporated into the acpcPNA by Fmoc-solid-phase peptide synthesis. T(m), UV and CD spectroscopy confirmed that the (3R,4S)-APC could substitute the (1S,2S)-ACPC spacer in the acpcPNA with only slightly decreasing the stability of the hybrids formed between the modified acpc/apcPNA and DNA.
4.Diastereomeric differentiation of norbornene amino acid peptides by electrospray ionization tandem mass spectrometry.
Raju B1, Ramesh V, Sudhakar A, Ramesh M, Sarma VU, Chandrasekhar S, Srinivas R. Rapid Commun Mass Spectrom. 2009 Sep;23(18):2965-74. doi: 10.1002/rcm.4211.
A new class of diastereomeric pairs of non-natural amino acid peptides derived from butyloxycarbonyl (Boc-)protected cis-(2S,3R)- and trans-(2S,3S)-beta-norbornene amino acids including a monomeric pair have been investigated by electrospray ionization (ESI) tandem mass spectrometry using quadrupole time-of-flight (Q-TOF) and ion-trap mass spectrometers. The protonated cis-BocN-beta-nbaa (2S,3R) (1) (betanbaa = beta-norbornene amino acid) eliminates the Boc group to form [M+H-Boc+H](+), whereas an additional ion [M+H-C(4)H(8)](+) is formed from trans-BocN-beta-nbaa (2S,3S) (2). Similarly, it is observed that the peptide diastereomers (di-, tri- and tetra-), with cis-BocN-beta-nbaa (2S,3R)- at the N-terminus, initially eliminate the Boc group to form [M+H-Boc+H](+) which undergo further fragmentation to give a set of product ions that are different for the peptides with trans-BocN-beta-nbaa (2S,3S)- at the N-terminus. Thus the Boc group fragments differently depending on the configuration of the amino acid present at the N-terminus.