Conformational analysis by NMR spectroscopy and restrained molecular dynamics (MD) of the 0-glycosylated cyclic hexapeptide cyclo(~-Prol-Phe~-Ala'-Ser~[ 0-2-deoxy-~-lactopyranosyl-a-( 1-3)]-Phe5-Phe6) (I) and the cyclic hexapeptide precursor cyclo(~-Pro'-Phe~-Ala~-Ser~-Phe~-Phe~) (11) is described. For II, an X-ray structure was obtained and compared with the structure in solution. For both compounds, the distance constraints derived from 2D NMR measurements could not be completely satisfied by a single conformation, but distance violations occurred only in the PheS region of the peptide. The specific pattern of NOE-derived distances in this part of the molecule suggested an equilibrium between two conformers containing 01-and BII-type turns, respectively, with PheS at i + 2. MD simulations with time-dependent distance constraints support the assumption of a bI/BII flip in I and 11. The conformations were refined using restrained MD simulations in vacuo, in water, and in DMSO. To study the exoanomeric effect of b(1-4)-and a-glycosidic linkages on conformation, new force field parameters derived from literature data were incorporated, leading to greater flexibility and significantly populated alternate conformers around the b( 1-4)-glycosidic bond, in agreement with literature data. The a-glycosidic linkage connecting the disaccharide moiety to the peptide prefers only one conformation. Both I and I1 have similar backbone conformations and hydrogen-bonding patterns. Therefore, the 0-glycosylation does not affect the conformation or the overall shape of the peptide backbone or side chains.
Keywords: Medium rings / Ring contractions / Ring expansion / Sigmatropic rearrangements / ZwitterionsThe bicyclic core of the pumiliotoxins was synthesized in nine to eleven steps starting from L-(−)-proline. This chiral pool starting material was initially converted into an optically active 2-vinylpyrrolidine by standard operations. The first key step allowed the generation of a nine-membered ring lactam by means of a zwitterionic aza-Claisen rearrangement. The 1,4 chirality transfer was found to be low, but the double bond of the azoninone was generated with an exclusive trans configuration in a planar-S arrangement. The mixture of diastereomers thus obtained was immediately epoxid-
Ca(C8H404). H20, monoclinic, P2~/c, Z = 4, a = 11.213(8), b = 6.680(5), c = 11.988 (8) A, fl = 98.91 (5) °, V = 887 A 3, D~ = 1.68 g cm-3; singlecrystal diffractometer data up to sin 8/2 = 0.70 A-I;Mo Ka radiation, Nb-filtered. The structure was refined to R = 0.029 for 2451 reflections. All H atoms were located. The water molecule is linked by two hydrogen bonds to the carboxyl groups. The results are compared with those of earlier work. The hydrogen-bond system reported previously was found to be in error.
Keywords: Aldol reactions / Alkaloids / Lactams / Olefinations / Total synthesisThe convergent total synthesis of pumiliotoxins by attachment of the side chain to a suitably functionalized core indolizidinone derivative has been achieved. The use of an aldoltype addition condensation strategy, intended to provide for the stereoselective generation of the exocyclic double bond, gave no satisfactory results. The method of choice was a Horner olefination. Initially, the reactant core indolizidinone was converted into an α phosphono amide by amide enolate formation, enol phosphate generation, and a final phosphatephosphonate migration. The amido phosponates smoothly
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.