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Triene precursors (1a − e, 2a − k) were constructed for substrate-controlled asymmetric Diels−Alder reactions. Boc-l-phenylalanal and Boc-l-valinal were condensed with triethyl phosphonoacetate or 2-phosphonopropionate to generate the α,β-unsaturated esters as dienophiles. Removal of the Boc group to give free amines 4a−d, which after, or without N-benzylation, were treated with 3,5-hexadienoyl chloride to give 1a − e, or with 2,4-hexadienoyl chloride to afford 2a − f. The trienes 2g−i were prepared via reductive alkylation of amines 4a−i with 2,4-hexadienal. The secondary amide triene 1a failed to yield any Diels−Alder product when heated at 170 °C. The tertiary amide trienes 1b − e produced in refluxing toluene the major cycloaddition products that were cis-fused and derived from the exo transition states. Trienes 2a − k underwent surprisingly facile Diels−Alder reactions to produce the major trans-fused isomers that were derived from the endo transition states. For trienes 2b − h and 2j,k, Diels−Alder reactions proceeded at room temperature. For the primary amide 2a, the Diels−Alder reaction proceeded smoothly in refluxing toluene. The tertiary amide triene 22 was constructed to have two electron-withdrawing ester substituents at the termini of the triene. The Diels−Alder reaction of 22 took place spontaneously at room temperature upon benzoylation of the secondary amine 21 and produced a single isomer derived from the endo transition state. 1,3-Allylic strain is discussed as an important factor in control of the diastereoselectivity.

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The abundance of α-fetoprotein (AFP), a natural protein produced by the fetal yolk sac during pregnancy, correlates with lower incidence of estrogen receptor positive (ER+) breast cancer. The pharmacophore region of AFP has been narrowed down to a four amino acid (AA) region in the third domain of the 591 AA peptide. Our computational study focuses on a 4-mer segment consisting of the amino acids threonine-proline-valine-asparagine (TPVN). We have run replica exchange molecular dynamics (REMD) simulations and used 120 configurational snapshots from the total trajectory as starting configurations for quantum chemical calculations. We optimized structures using semiempirical (PM3, PM6, PM6-D2, PM6-H2, PM6-DH+, PM6-DH2) and density functional methods (TPSS, PBE0, M06-2X). By comparing the accuracy of these methods against RI-MP2 benchmarks, we devised a protocol for calculating the lowest energy conformers of these peptides accurately and efficiently. This protocol screens out high-energy conformers using lower levels of theory and outlines a general method for predicting small peptide structures.

The 'H (400 MHz) and carbon 13C (100 MHz) NMR peak assignments of two oxymorpbone alkaloids including the free base and the hydrochloride (HCI) salt and four oxycodone alkaloids including the free base, the HCi salt, the N-oxide and the methyl iodide quaternary salt were assigned using a variety of two-dimensional NMR techniques. Proton coupling constants provide evidence that the cyclohexanone (D) and the piperidine (E) rings adopt slightly distorted chair conformations. Nuclear Overhauser enhancement difference experiments indicate that the conformation of the N-methyl group is equatorial and the O-methyl group prefers a cis orientation relative to C-2. The minor component observed in aqueous 'H and 13C NMR spectra of eacb HCI salt and the N-oxide is produced by the reaction of the alkaloid with water a t the C-6 carbonyl, forming a gem-diol, and is not due to the presence of the axial isomer. The first complete soiution and solid conformational analyses of oxycodone N-oxide by NMR and x-ray crystallography have been investigated. The data indicate that the C-14-OH proton is intramolecularly hydrogen bonded to the NO oxygen.

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