1.pH Dependent Chiroptical Properties of (1R,2R)- and (1S,2S)-trans-Cyclohexane Diesters and Diamides from VCD, ECD, and CPL Spectroscopy.
Mazzeo G1, Abbate S1,2, Longhi G1,2, Castiglioni E1,3, Boiadjiev SE4, Lightner DA5. J Phys Chem B. 2016 Mar 10;120(9):2380-7. doi: 10.1021/acs.jpcb.5b11223. Epub 2016 Feb 22.
Diesters of (1R,2R)- and (1S,2S)-cyclohexanediols and diamides of (1R,2R)- and (1S,2S)-diaminocyclohexane with p-hydroxycinnamic acid have been known for some time to exhibit intense bisignate electronic circular dichroism (ECD) spectra in CH3OH. It was also known that added NaOH causes a bathochromic shift of ∼50 nm in CH3OH, and an even higher one in DMSO. We have measured vibrational circular dichroism (VCD) spectra both for neutral compounds and in the presence of NaOH and other bases. The VCD and IR spectra in the mid-IR region for CD3OD and DMSO-d6 solution exhibit high sensitivity to the charged state for the diesters. They possess two strong bisignate features in the presence of bases in the mid-IR, which are interpreted in terms of vibrational exciton couplets, while this phenomenon is less evident in diamides. VCD allied to density functional theory (DFT) calculations allows one to shed some light on the spectral differences of diesters and diamides by studying their conformational properties.
2.Iminolactones as tools for inversion of the absolute configuration of α-amino acids and as inhibitors of cancer cell proliferation.
Jensen CM1, Chow HQ1, Chen M2, Zhai L1, Frydenvang K1, Liu H1, Franzyk H1, Christensen SB3. Eur J Med Chem. 2016 May 23;114:118-33. doi: 10.1016/j.ejmech.2016.02.037. Epub 2016 Feb 23.
A library of iminolactones was prepared by esterification of several 2-hydroxyketones with a number of N-protected d- and l-α-amino acids. Some of the hydroxyketones were of terpenoid origin while others were obtained via synthesis. After N-deprotection of the intermediate esters, the free amines spontaneously underwent condensation with the ketone to form iminolactones. Esters of (1S,2S,5S)-2-hydroxypinan-3-one with both d- and l-α-amino acids were partially epimerized at the α-carbon atom to give a diastereomeric ester mixture. Only iminolactones of l-amino acids were formed after cyclization of (1S,2S,5S)-2-hydroxypinan-3-one, and correspondingly only d-amino acid iminolactones were formed after reaction with (1R,2R,5R)-2-hydroxypinan-3-one. The protocol thus enables inversion of the absolute configuration of amino acids. Some members of the prepared library of iminolactones displayed significant anti-proliferative effects toward three cancer cell lines (EL4, MCF7, PC3) with insignificant effect on non-malign cell lines (McCoy, MCF10A, NIH3T3).
3.Advanced asymmetric synthesis of (1R,2S)-1-amino-2-vinylcyclopropanecarboxylic acid by alkylation/cyclization of newly designed axially chiral Ni(II) complex of glycine Schiff base.
Kawashima A1, Shu S2, Takeda R1, Kawamura A1, Sato T1, Moriwaki H1, Wang J2, Izawa K1, Aceña JL3, Soloshonok VA4,5, Liu H2. Amino Acids. 2016 Apr;48(4):973-86. doi: 10.1007/s00726-015-2138-3. Epub 2015 Dec 11.
Asymmetric synthesis of (1R,2S)-1-amino-2-vinylcyclopropanecarboxylic acid (vinyl-ACCA) is in extremely high demand due to the pharmaceutical importance of this tailor-made, sterically constrained α-amino acid. Here we report the development of an advanced procedure for preparation of the target amino acid via two-step SN2 and SN2' alkylation of novel axially chiral nucleophilic glycine equivalent. Excellent yields and diastereoselectivity coupled with reliable and easy scalability render this method of immediate use for practical synthesis of (1R,2S)-vinyl-ACCA.
