Stereoselective synthesis and absolute configuration of the C33-C42 fragment of symbiodinolide

Cross-metathesis of methyl ester which was prepared from symbiodinolide with ethylene was performed to give the C33-C42 degraded fragment. This fragment was estimated to be (36S,40S)-diol by the modified Mosher method. Stereoselective synthesis of the (36S,40S)-diol and its diastereomer (36R,40S)-diol was achieved from l-aspartic acid. Synthetic bis-(S)- and (R)-MTPA esters which were derivatized from the (36S,40S)-diol exhibited spectroscopic data identical with those of bis-(S)- and (R)-MTPA esters derived from the degraded product. Thus, the absolute stereochemistry of the C33-C42 fragment was elucidated to be (36S,40S).     

Determination of the absolute configuration of marine oxylipin topsentolide A1 by the synthesis of the enantiomer of the natural product

Two possible stereoisomers of topsentolide A₁, a cytotoxic oxylipin against human solid tumor cell lines, were prepared in order to determine the stereochemistry of natural product. That is, the enantiomer of topsentolide A₁, (8S,11S,12R)-isomer, and its diastereomer was efficiently synthesized in a stereoselective manner. The stereochemistry of topsentolide A₁ was determined to be 8R,11R,12S by comparing NMR spectra and specific rotations of the synthetic isomers and the natural product.     

Isolation,structural assignment and insecticidal activity of (−)-(1S,2R,3R,4S)-1,2-epoxy-1-methyl-4-(1-methylethyl)-cyclohex-3-yl acetate,a natural product from Minthostachys tomentosa

(−)-(1S,2R,3R,4S)-1,2-Epoxy-1-methyl-4-(1-methylethyl)-cyclohex-3-yl acetate has previously been identified as the active compound of Minthostachys tomentosa responsible for the insecticidal activity against Oncopeltus fasciatus. Its structure was initially assigned on the basis of spectral data. In order to confirm the structure and to define the stereochemistry, stereoselective synthesis of its enantiomer, (+)-(1R,2S,3S,4R)-1,2-epoxy-1-methyl-4-(1-methylethyl)-cyclohex-3-yl acetate, starting from (R)-(−)-piperitone, was carried out using a Sharpless reaction as the key step. The natural product is dextro-rotatory while the synthetic product is levo-rotatory. Measurements of insecticidal activities of the different steroisomers revealed that only the natural product is active.     

Stabilization of zeylenone in rat plasma by the presence of esterase inhibitors and its LC‐MS/MS assay for pharmacokinetic study

Six esterase inhibitors, namely EDTA·2Na⁺, NaF, phenylmethanesulfonyl fluoride, dichlorvos, bis‐nitrophenyl phosphate (BNPP) and thenoyltrifluoroacetone, and the mixture of NaF and BNPP, were evaluated for the stabilization of labile benzoate containing zeylenone in rat plasma. The mixture appeared to exhibit the most effectively stabilizing effect with the degraded content of zeylenone decreasing from >60% (in the absence of inhibitors) to <6%. Following the stabilization by the addition of NaF (5 mm ) and BNPP (5 mm ), the analytes in rat plasma were acidified by formic acid and extracted into ethyl acetate at 0°C. After chromatographic separation, the detection of zeylenone was performed on a 3200 Q‐Trap with positive ion electrospray mode, monitoring the ion transition m/z 383.2 → 105.0. The method was validated over the range from 2.68 to 1340 ng/mL with inter‐ and intra‐run precision for the quality control samples being less than 6.8%. The assay accuracy was within 100 ± 7.0%. The validated method was successfully applied to a pharmacokinetic study in rats after the intratracheal administration of zeylenone in free drug or polymeric micellar solutions. The results showed that the pulmonary absorption of zeylenone loaded in micelles was significantly retarded compared with that of free drug solutions. Copyright © 2012 John Wiley & Sons, Ltd.     

Synthesis of optically active dihydrocarveol via a stepwise or one-pot enzymatic reduction of (R)- and (S)-carvone

A recombinant enoate reductase LacER from Lactobacillus casei catalyzed the reduction of (R)-carvone and (S)-carvone to give (2R,5R)-dihydrocarvone and (2R,5S)-dihydrocarvone with 99% and 86% de, respectively, which were further reduced to dihydrocarveols by a carbonyl reductase from Sporobolomyces salmonicolor SSCR or Candida magnolia CMCR. For (R)-carvone, (1S,2R,5R)-dihydrocarveol was produced as the sole product with >99% conversion, while (1S,2R,5S)-dihydrocarveol was obtained as the major product, but with a lower de when (S)-carvone was used as the substrate. The one-pot reduction was performed at a 0.1 M substrate concentration, indicating that it might provide an effective synthetic route to this type of chiral compound.     

Enantioselective Total Synthesis of the （＋） Antipode of Zeylenone

Starting from shikimic acid, the total synthesis of zeylenone was studied. The product was proved to be the ( )antipode of zeylenone through analysis and comparison of their respective spectra (including NMR, MS, IR and CD) and optical data. The absolute configuration of the natural product was thus determined to be (1 S,2S,3R).     

Synthesis of 2,6-disubstituted piperidine alkaloids from ladybird beetles Calvia 10-guttata and Calvia 14-guttata

Optically pure (+)-calvine, (+)-2-epicalvine, (2S,6S)-(6-pentylpiperidin-2-yl)acetic acid methyl ester and (2R,6S)-(6-pentylpiperidin-2-yl)acetic acid methyl ester, four piperidine alkaloids isolated from ladybird beetles of the genus Calvia (Coccinellidae), were synthesised from a common precursor using cyclisative Pd(II)/Cu(II)-catalysed carboamination-(methoxy)carbonylation tandem reaction of alkenylamines as a key step. The first single-crystal X-ray analysis of (+)-calvine confirmed its proposed absolute configuration to be (2S,6S) corresponding to that of natural product.     

Chiral terpene auxiliaries II. Spiroborate esters derived from α-pinene—new catalysts for asymmetric borane reduction of prochiral ketones

New spiroborate esters derived from (1R,2R,3S,5R)-3-aminopinan-2-ol and ethylene glycol, propane-1,3-diol, pinacol, catechol, (1S,2S,3R,5S)-pinane-2,3-diol, and (1R,2R,3S,5R)-pinane-2,3-diol were used as catalysts in the borane reduction of acetophenone and other prochiral aryl alkyl ketones producing the corresponding alcohols in high yields. The influence of the spiroborate structure on the enantioselectivity and configuration of the product alcohols was examined.     

Stereoselective alkylation of C2-symmetric chiral N-phthaloylglycinamides in the preparation of enantiopure α-amino acids

The novel, chiral glycinamides (S,S)-3 and (S,S)-4 were prepared in good yields from C₂-symmetric chiral amines (S,S)-1 and (S,S)-2, respectively. Enolate formation and addition to methyl iodide and benzyl bromide proceeded in good yield and high diastereoselectivity, especially in the presence of LiCl or DMPU. Removal of the phthaloyl protecting group with hydrazine, followed by hydrolysis with 6N HCl, converted the benzylated product (S,S,S)-7 to enantiopure (S)-phenylalanine.     

First enantioselective synthesis of isagarin,a natural product isolated from Pentas longiflora Oliv.

For the first time, an enantioselective synthesis of both 1R,4S-isagarin 1a and 1S,4R-isagarin 1b was achieved starting from 1,4-dimethoxy-2-vinylnaphthalene 2. The key steps involve a Sharpless asymmetric dihydroxylation and reaction with an acetonylating pyridinium ylid. The different optical rotations and melting points of the enantiopure 1R,4S-isagarin 1a and 1S,4R-isagarin 1b with respect to the isolated natural product will be addressed.     

Vibrational circular dichroism study for natural bioactive schizandrin and reassignment of its absolute configuration

Bioactive natural product (+)-schizandrin was assigned as (7S,8S) using NMR. Recently, we obtained (+)-schizandrin from TCM Schisandra sphenanthera Rehd. et Wils. Its planar structure was well established using NMR and HR-MS including the reported references. Its absolute configuration is assigned using vibrational circular dichroism (VCD). By careful VCD investigation of (7S,8S) and (7S,8R) using B3LYP/6-311+G(d) methods, absolute configuration of (+)-schizandrin is assigned as (7S,8R). Electronic circular dichroism (ECD) was used for the discussion too and it gave the same conclusion.     

Stereospecific synthesis and absolute configuration of the (2S,3S,4S)-isomer of 2-methyl-2-(carboxycyclopropyl)glycine (MCCG)

The conformationally restricted metabotropic glutamate receptor antagonist (2S,3S,4S)-2-methyl-2-(carboxycyclopropyl)glycine 1 (MCCG) has been synthesized in a stereoselective manner (>99% ee) with the (2S,3S,4S) absolute configuration of this molecule being confirmed by X-ray crystallographic analysis. Subsequent physico–chemical studies were undertaken and the data are at odds with those of the commercially available product.     

Synthesis of (2S,7S)-dibutyroxynonane, the sex pheromone of the orange wheat blossom midge, Sitodiplosis mosellana (Géhin) (Diptera: Cecidomyiidae), by diastereoselective silicon-tethered ring-closing metathesis

The sex pheromone of Sitodiplosis mosellana, (2S,7S)-dibutyroxynonane, has been synthesised using a mixed di-t-butylsilaketal prepared from (S)-5-hexen-2-ol and prochiral 1,4-pentadiene-3-ol. Ring-closing metathesis occurs diastereoselectively and after the removal of the silyl group and the reduction of the double bonds, generates (2S,7S)-nonanediol with a diastereoisomeric excess of 94% as measured by gas chromatographic analysis of the diacetylated product.     

Efficient synthesis of an optically pure β-bromo-β,β-difluoroalanine derivative,a general precursor for β,β-difluoroamino acids

A highly efficient enantioselective preparation of a β-bromo-β,β-difluoroalanine derivative, a promising general precursor for optically active β,β-difluoroamino acids, is described. Alkylation of the hydroxypinanone glycinate Schiff base 2a with CF₂Br₂ resulted in the production of undesired dehydrobrominated product 4a promoted by the lithium alkoxide moiety on the hydroxypinanone chiral auxiliary. Dehydrobromination was prevented by protection of the hydroxyl group on the chiral auxiliary. Utilization of TMSOTf resulted in production of (S,S,S,S)-3b as the sole diastereomer without dehydrobromination. Further transformations of (S,S,S,S)-3b to other optically active β,β-difluoroamino acids were demonstrated.     

Structure elucidation and stereoselective total synthesis of pavettamine, the causal agent of gousiekte

The structure elucidation of a novel natural product pavettamine (1), the causal agent of the plant toxicosis gousiekte, is reported. The structure was defined by analysis of NMR and MS data and the relative configuration followed from the ¹³C NMR data of the acetonide derivative. The absolute stereochemistry was established by total synthesis from (2S)-malic acid using chiral sulfoxide methodology as (2S,4R,8R,10S)-1,11-diamino-6-aza-undecane-2,4,8,10-tetraol.     

Synthesis of (−)-okundoperoxide and determination of the absolute configuration of natural (+)-okundoperoxide

The first enantioselective synthesis of (3S,4aR,8aR)-1 (the enantiomer of natural okundoperoxide) has been accomplished. The synthesis features: 1) stereoselective installation of the peroxy functionality (16 → 17); 2) ring opening of peroxyacetal and subsequent intramolecular reaction between the hydroperoxide and the vinyl epoxide to form the peroxy six-membered ring (5 → 1). The absolute configuration of okundoperoxide was determined to be 3R,4aS,8aS by comparing specific rotations of the synthetic sample and the natural product.     

Challenges in the assignment of relative and absolute configurations of complex molecules: computation can resolve conflicts between theory and experiment

The configuration of (−)-brevianamides was assigned as (2S,13S) based on X-ray structure analysis and hydrolysis experiments. However, our theoretical investigation of its chiroptical properties strongly implied that the correct configuration should be (2R,13R). The reasons for the incorrect earlier assignment are analyzed by calculations of conversion energy barriers among different intermediates, starting materials and final products. This study demonstrates that conflicting theoretical and, experimental results suggest that it is premature to assign the configuration of a natural product.     

An efficient synthesis of chiral isoquinuclidines by Diels-Alder reaction using Lewis acid catalyst

The Diels-Alder reaction of 1,2-dihydropyridine derivatives (1-phenoxycarbonyl-1,2-dihydropyridine 1 or 1-methoxycarbonyl-1,2-dihydropyridine 4) with N-acryloyl (1S)-2,10-camphorsultam (1S)-2 {or N-acryloyl (1R)-2,10-camphorsultam (1R)-2} in the presence of Lewis acid, such as titanium tetrachloride, zirconium tetrachloride, and hafnium tetrachloride afforded the endo-cycloaddition product, 2-azabicyclo[2.2.2]octane derivatives in good yields with excellent diastereoselectivity. The absolute stereochemistry assignment of the endo-cycloaddition product (1S)-5a starting from N-acryloyl (1S)-2,10-camphorsultam (1S)-2 has been established to be (1S,4R,7S) and the reaction mechanism was proposed.     

PEG-400-H2O as a green and recyclable medium for asymmetric hydrogenations of aromatic ketones catalyzed by RuCl2(TPPTS)2-(S,S)-DPENDS

PEG-400-H₂O was found to be a green and recyclable reaction medium for asymmetric hydrogenations of aromatic ketones catalyzed by a ruthenium achiral monophosphine complex RuCl₂(TPPTS)₂ [TPPTS: P(m-C₆H₄SO₃Na)₃] modified by (S,S)-DPENDS [disodium salt of sulfonated (S,S)-1,2-diphenyl-1,2-ethylene-diamine]. The acetophenone product was obtained with 86.3% ee under the optimized conditions. The resulting products can be easily separated from the catalyst by extraction with n-hexane. The catalyst immobilized in PEG-400-H₂O not only exhibits excellent activity and enantioselectivity, but also can be recycled and reused several times without a loss of activity or enantioselectivity.     

Asymmetric conjugate addition of thiols to (E)-3-crotonoyloxazolidin-2-one by iron or cobalt/pybox catalyst

The enantioselective conjugate addition of thiols to (E)-3-crotonoyloxazolidin-2-one was effectively catalyzed by the Fe(BF₄)₂·6H₂O/(S,S)-ip-pybox catalyst, and the addition product was obtained with up to a 95% ee. Furthermore, the Co(ClO₄)₂·6H₂O/(S,S)-ip-pybox catalyst also catalyzed the same reaction with a high enantioselectivity.