Onchidin B (4) is a cyclic depsipeptide isolated from the pulmonate mollusc Onchidium sp. Its structure was determined by extensive 2D-NMR, FABMS, tandem FAB MS/MS, selective hydrolysis, and synthesis. It contains four R-amino acids [two units of N-methyl valine (MeVal), two units of proline (Pro)], four R-hydroxy acids [two 2-hydroxyisovaleric acids (Hiv), two 2-hydroxy-3-methylpentanoic acid moieties (Hmp)] and two units of the new -hydroxy acid: 3-hydroxy-2-methyloct-7-ynoic acid (Hymo)]. Selective hydrolysis and direct comparison by chiral GC-MS with authentic samples of the R-amino and R-hydroxy acids allowed us the assignment of the entire absolute stereochemistry of onchidin B. In this way, the R-hydroxy acids were found to be (S)-Hiv and (S,S)-Hmp, and the R-amino acids (R)-proline, (S)-proline, and (R)-MeVal. In order to establish the absolute configuration of the new -hydroxy acid, Hymo, its four possible stereoisomers were stereoselectively synthesized using chiral N-propionyl oxazolidinones and hex-5
The synthesis of a series of cycloadduct products carried out in a glass microchip under pressure driven flow is presented. Initially, four different compounds were synthesized individually with conversions similar to those obtained in the corresponding batch macroscale reactions. Using identical experimental conditions for all four compounds, the results were highly predictable and reproducible, without the need for individual optimization. A multi-reaction experiment was then carried out in a single chip achieving the synthesis of a three-member array in a single run.
The total synthesis of the 3S,2S and 3R,2S diastereomers (1a and 1b) of minalemine A and the identification of the natural compound as the 3R,2S isomer is described. The key step in the synthesis is the preparation of the two enantiomers of the beta-amino diacid 3-(N-carboxymethyl)-aminodecanoic acid (Ncma), which were obtained by stereoselective alkylation with allyl bromide of two nonanoic acid imides bearing chiral oxazolidinones as chiral auxiliaries. Natural minalemine A shows identical 1H NMR and very similar 13C NMR spectra compared to the two synthetic diastereomers. Sufficient differences in their chromatographic behavior to allow conclusive identification were not found. However, the corresponding N-2-naphthoyl amides presented quite distinct circular dichroism spectra (CD), and these confirmed the 3R,2S configuration for the natural minalemines and the R configuration for the constituent beta-amino diacid, Ncma.
Treatment of amines under a carbon dioxide atmosphere with tetramethylphenylguanidine (PhTMG) and diphenylphosphoryl azide (DPPA) in acetonitrile below 0 degrees C provides carbamoyl azides in high to excellent yields. In addition, epimerization is not observed when optically pure alpha-amino esters are used as substrates.
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