The cytotoxic, cyclic heptadepsipeptide, natural product callipeltin B was synthesized on a solid-phase support in 15% overall yield. Comparison of the 1H NMR spectra of three synthetic isomers with those of callipeltin B confirmed the configurational reassignment of its threonine residues as d-allothreonine and the assignment of the configuration of its beta-methoxytyrosine residue as (2R,3R).
Resonant two-photon ionization (R2PI), resonant ion-dip infrared (RIDIR), and UV-UV hole-burning spectroscopies have been employed to obtain conformation-specific infrared and ultraviolet spectra under supersonic expansion conditions for O-(2-acetamidoethyl)-N-acetyltyramine (OANAT), a doubly substituted aromatic in which amide-containing alkyl and alkoxy side chains are located in para positions on a phenyl ring. For comparison, three single-chain analogs were also studied: (i) N-phenethyl-acetamide (NPEA), (ii) N-(p-methoxyphenethyl-acetamide) (NMPEA), and (iii) N-(2-phenoxyethyl)-acetamide (NPOEA). Six conformations of OANAT have been resolved, with S(0)-S(1) origins ranging from 34,536 to 35,711 cm(-1), denoted A-F, respectively. RIDIR spectra show that conformers A-C each possess an intense, broadened amide NH stretch fundamental shifted below 3400 cm(-1), indicative of the presence of an interchain H bond, while conformers D-F have both amide NH stretch fundamentals in the 3480-3495 cm(-1) region, consistent with independent-chain structures with two free NH groups. NPEA has a single conformer with S(0)-S(1) origin at 37,618 cm(-1). NMPEA has three conformers, two that dominate the R2P1 spectrum, with origin transitions between 35,580 and 35,632 cm(-1). Four conformations, one dominate and three minor, of NPOEA have been resolved with origins between 35,654 and 36,423 cm(-1). To aid the making of conformational assignments, the geometries of low-lying structures of all four molecules have been optimized and the associated harmonic vibrational frequencies calculated using density functional theory (DFT) and RIMP2 methods. The S(0)-S(1) adiabatic excitation energies have been calculated using the RICC2 method and vertical excitation energies using single-point time-dependent DFT. The sensitivity of the S(0)-S(1) energy separation in OANAT and NPOEA primarily arises from different orientations of the chain attached to the phenoxy group. Using the results of the single-chain analogs, tentative assignments have been made for the observed conformers of OANAT. The RIMP2 calculations predict that interchain H-bonded conformers of OANAT are 25-30 kJ/mol more stable than the extended-chain structures. However, the free energies of the interchain H-bonded and extended structures calculated at the preexpansion temperature (450 K) differ by less than 10 kJ/mol, and the number of extended structures far outweighs the number of H-bonded conformers. This entropy-driven effect explains the presence of the independent-chain conformers in the expansion, and cautions future studies that rely solely on relative energies of conformers in considering possible assignments.
Four unique diastereomers of 3-hydroxy-2,4,6-trimethylheptanoic acid--(2R,3R,4R), (2S,3R,4R), (2S,3R,4S), and (2R,3R,4S)--the fatty acid component of callipeltin A and D, have been synthesized from commercially available (+)- and (-)-pseudoephedrine propionamide in 6 steps and 59% average overall yield. Comparison of the 1H and 13C NMR and optical rotation data of the resulting isomers with the natural fragment unambiguously verifies the configurational assignment of the natural isomer as (2R,3R,4R).
A series of mimetic cores composed of a synthetic scaffold and amino acids have been constructed and their properties investigated in chloroform. A relative measure of H-bond strength was obtained by comparing temperature coefficients derived from variable-temperature (1)H NMR experiments. Although most templates had a strong H-bond, only a single template composed of D- and L-phenylalanines was able to form two strong H-bonds. Templates containing D- and L-leucines formed only a single H-bond. The results of these studies suggest that aromatic edge-to-face interactions provide greater stabilization energy than aliphatic-aromatic interactions in the tightly packed hydrophobic cores of proteins. Partial structures of the templates were derived by analyzing a series of two-dimensional (1)H NMR spectra and performing molecular mechanics calculations using AMBER and MMFF94 force fields.
Medicinal chemistry, a field typically left to the graduate and commercial realm, can be an effective pedagogical tool at an undergraduate institution. The drug-discovery process can be used as a tool to provide a broad range of research experiences that includes the design, synthesis, and testing of novel small molecules as potentially new therapeutic agents. Herein we discuss our scientific and pedagogical efforts and detail some of the available resources that faculty working at primarily undergraduate colleges may find useful in their exploration of a medicinal chemistry-related research program.
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