Determination of the absolute configuration and solution conformation of a novel disubstituted pyrrolidine acid A by vibrational circular dichroism

Abstract

Compound A, a novel disubstituted pyrrolidine acid, is a member of a new class of agents that are potentially useful for the treatment of diabetes and dyslipidemia. The absolute configuration of this compound was determined by using vibrational circular dichroism (VCD). The results are in agreement with the assignments based on both X-ray analysis and the stereo-selective chemical synthesis. During VCD analysis, the solution conformation for a portion of compound A in CDCl(3) was also established. The compound is found to associate as an H-bonded carboxylic acid "dimer" in CDCl(3) solution, and VCD calculations on a model dimer fragment were required to establish the absolute configuration.

Doubly resonant three-wave-mixing spectroscopy of a chiral coupled-chromophore system in solution: Coherent two-dimensional optical activity spectroscopy

“…Consequently, the VCD has been known to be a better and sometimes an incisive tool for determining absolute configuration of chiral molecules in condensed phases. [61][62][63][64] However, the present 2D IR-IR SFG spectrum can provide even more information on the two-exciton state energies, which cannot be extracted from any other 1D vibrational spectroscopic techniques because the latter can only explore the one-exciton states. For instance, even at 1 = + , the 2D IR-IR SFG spectrum is additionally dependent on yet another frequency, 2 , which is associated with vibrational transitions from ͉ϩ͘ state to one of the three two-exciton states, i.e., ͉a͘, ͉2+͘, and ͉2−͘.…”

Enantiomeric separation and determination of absolute stereochemistry of asymmetric molecules in drug discovery—Building chiral technology toolboxes

“…Besides determining absolute stereochemistry of molecules containing one or more asymmetric centers, or planes or axes of asymmetry, i.e., atropisomerism, [319][320][321][322][323][324] additional information about solution conformation can be obtained. 304,[325][326][327] Also, VCD can be used for real-time reaction monitoring. [328][329][330] VCD has been used to determine the absolute stereochemistry of natural products, 320,331 compounds derived via asymmetric enzymatic catalysis, 332 as well as carboxylic acids 333,334 and alcohols 204 in derivatized form in order to improve calculations by obviating the presence of dimers or rigidifying the molecule of interest, respectively.…”

Progress in the Chemistry of Organic Natural Products 100

“…Such studies were performed on crambin (255), myoglobin (256), lysozyme (257), human transthyretin (258), gamma-chymotrypsin (259), type-III antifreeze protein (260), the trypsin-BPTI complex (261), hemoglobin (262)(263)(264)(265), carbonic anhydrase II (266), insulin (267), ribonuclease A (268), elastase (269), HIV protease (270,271), diisopropyl fluorophosphatase (272), photoactive yellow protein (PYP) (273), dihydrofolate reductase (274), d-xylose isomerase (275), human aldose reductase (276), concanavalin A (277,278), rubredoxin (279), and endothiapepsin (280). Preliminary reports describing the collection of neutron diffraction data concern endoxylanase II from Trichoderma longibrachiatum (281), human ABO(H) blood group A glycosyltransferase (282), porcine pancreatic elastase (270),…”

“…The Δ 2,4 -compound sorbic acid methyl ester yields the pyrylium ion m/z 111. The EI mass spectra of the double bond isomeric hexenoic acid methyl esters ( 280 ), notwithstanding the characteristic ion m/z 113 for the Δ 2 -isomer, differ in relative abundances of their ions, but with increasing chain length the mass spectra of double-bond isomers assimilate more and more until they become practically indistinguishable ( 283 ).…”