Synthesis of conformationally constrained 5-fluoro- and 5-hydroxymethanopyrrolidines. Ring-puckered mimics of gauche- and anti-3-fluoro- and 3-hydroxypyrrolidines.

N-acetylmethanopyrrolidine methyl ester and its four 5-syn/anti-fluoro and hydroxy derivatives have been synthesized from 2-azabicyclo[2.2.0]hex-5-ene, a 1,2-dihydropyridine photoproduct. These conformationally constrained mimics of idealized C(ß)-gauche and C(ß)-anti conformers of pyrrolidines were prepared in order to determine the inherent bridge bias and subsequent heteroatom substituent effects upon trans/cis amide preferences. The bridgehead position and also the presence of gauche(syn)/anti-5-fluoro or 5-hydroxy substituents have minimal influence upon the K(T/C) values of N-acetylamide conformers in both CDCl(3) (43-54% trans) and D(2)O (53-58% trans). O-Benzoylation enhances the trans amide preferences in CDCl(3) (65% for a syn-OBz, 61% for an anti-OBz) but has minimal effect in D(2)O. The synthetic methods developed for N-BOC-methanopyrrolidines should prove useful in the synthesis of more complex derivatives containing α-ester substituents. The K(T/C) results obtained in this study establish baseline amide preferences that will enable determination of contributions of α-ester substituents to trans-amide preferences in methanoprolines.

Asymmetric total synthesis of (S)-(+)-cocaine and the first synthesis of cocaine C-1 analogs from N-sulfinyl ß-amino ester ketals.

Sulfinimine-derived α,ß-unsaturated pyrrolidine nitrones, on heating with Al(O-t-Bu)(3), undergo a highly stereoselective intramolecular [3 + 2] cycloaddition to give tricyclic isoxazolidines, which are transformed in three-steps to give C-1 substituted cocaine analogs.

Asymmetric synthesis of substituted homotropinones from N-sulfinyl beta-amino ketone ketals. (-)-Euphococcinine and (-)-adaline.

Sulfinimine-derived N-sulfinyl beta-amino ketone ketals on heating with NH(4)OAc:HOAc undergo a four-step intramolecular Mannich cyclization cascade reaction to give homotropinones, such as (-)-euphococcinine, in excellent yields as single isomers.

5(6)-anti-Substituted-2-azabicyclo[2.1.1]hexanes: a nucleophilic displacement route.

Nucleophilic displacements of 5(6)-anti-bromo substituents in 2-azabicyclo[2.1.1]hexanes (methanopyrrolidines) have been accomplished. These displacements have produced 5-anti-X-6-anti-Y-difunctionalized-2-azabicyclo[2.1.1]hexanes containing bromo, fluoro, acetoxy, hydroxy, azido, imidazole, thiophenyl, and iodo substituents. Such displacements of anti-bromide ions require an amine nitrogen and are a function of the solvent and the choice of metal salt. Reaction rates were faster and product yields were higher in DMSO when compared to DMF and with CsOAc compared to NaOAc. Sodium or lithium salts gave products, except with NaF, where silver fluoride in nitromethane was best for substitution by fluoride. The presence of electron-withdrawing F, OAc, N(3), Br, or SPh substituents in the 6-anti-position slows bromide displacements at the 5-anti-position.

Conformational preferences of substrates for human prolyl 4-hydroxylase.

Prolyl 4-hydroxylase (P4H) catalyzes the posttranslational hydroxylation of (2 S)-proline (Pro) residues in procollagen strands. The resulting (2 S,4 R)-4-hydroxyproline (Hyp) residues are essential for the folding, secretion, and stability of the collagen triple helix. Even though its product (Hyp) differs from its substrate (Pro) by only a single oxygen atom, no product inhibition has been observed for P4H. Here, we examine the basis for the binding and turnover of substrates by human P4H. Synthetic peptides containing (2 S,4 R)-4-fluoroproline (Flp), (2 S,4 S)-4-fluoroproline (flp), (2 S)-4-ketoproline (Kep), (2 S)-4-thiaproline (Thp), and 3,5-methanoproline (Mtp) were evaluated as substrates for P4H. Peptides containing Pro, flp, and Thp were found to be excellent substrates for P4H, forming Hyp, Kep, and (2 S,4 R)-thiaoxoproline, respectively. Thus, P4H is tolerant to some substitutions on C-4 of the pyrrolidine ring. In contrast, peptides containing Flp, Kep, or Mtp did not even bind to the active site of P4H. Each proline analogue that does bind to P4H is also a substrate, indicating that discrimination occurs at the level of binding rather than turnover. As the iron(IV)-oxo species that forms in the active site of P4H is highly reactive, P4H has an imperative for forming a snug complex with its substrate and appears to do so. Most notably, those proline analogues with a greater preference for a C (gamma)- endo pucker and cis peptide bond were the ones recognized by P4H. As Hyp has a strong preference for C (gamma)- exo pucker and trans peptide bond, P4H appears to discriminate against the conformation of proline residues in a manner that diminishes product inhibition during collagen biosynthesis.