Convenient diastereospecific synthesis of a rociverine precursor and its resolution by lipase-catalyzed transesterification

(±)-1-Cyclohexyl-c-2-hydroxymethyl-r-1-cyclohexanol 3, a precursor of the antimuscarinic drug Rociverine 1, was obtained diastereospecifically in very high yield, from the Grignard reaction between C₆H₁₁MgCl and an appropriately protected 2-(hydroxymethyl)cyclohexanone. The preparation of enantiomerically enriched cis diol (+)-(1R,2S)-3 and the corresponding 2-acetoxymethyl derivative (+)-(1S,2R)-12 was achieved by lipase PPL-catalyzed transesterification of racemic diol (±)-3.     

Synthesis of four stereoisomers of the higher dipteran juvenile hormone III bisepoxide

The 6S,7S,10R-, 6S,7S,10S-, 6R,7R,10S-, and 6R,7R,10R-stereoisomers of the juvenile hormone III bisepoxide from higher Dipteran insects have been synthesised in high stereoisomeric purity. The route involves Sharpless epoxidation of geraniol to enantiomeric epoxyalcohols, which are each elaborated via separable diastereomeric bromohydrins.     

Synthesis of new chiral amino ether derivatives: synthetic application of meso aziridinium ions prepared from β-amino alcohols

Methods of synthesis of new chiral amino ether derivatives through the opening of aziridinium ions, prepared in situ using trans-(±)-2-(1-N,N-dialkylamino)cyclohexyl mesylate with (R)-(+)-1,1′-bi-2-naphthol, are described. The (R,R,R)-diastereomer was obtained as the major product and isolated as an enantiopure salt, and characterized by single crystal X-ray analysis. The C₂-chiral (R,R,R,R,R)-diamino ether was obtained as the major product by opening of the aziridinium ion, prepared using trans-(±)-2-(1-pyrrolidino)cyclohexyl mesylate and (R)-(+)-1,1′-bi-2-naphthol in the presence of aq NaOH. This was also characterized by single crystal X-ray analysis.     

Chiral C2-symmetric 2,3-disubstituted aziridine and 2,6-disubstituted piperidine as chiral ligands in the addition reaction of diethylzinc with arylaldehydes

Chiral C₂-symmetric 2,3-disubstituted aziridines and 2,6-disubstituted piperidines having a β-amino alcohol moiety have been successfully synthesized and their catalytic chiral induction properties have been examined in the asymmetric addition reactions of diethylzinc with arylaldehydes in hexane. When N-(2,2-diphenyl-2-hydroxyethyl)-(S,S)-2,3-bis(methoxymethyl)aziridine 11 was used as a catalytic chiral ligand, sec-alcohols having (S)-configuration formed in high yields of 86–92% but low enantiomeric excesses (ee's) of 11–13%. However, when N-(2,2-diphenyl-2-hydroxyethyl)-(R,R)-2,6-disubstituted piperidine derivatives 16 and 20 were used as the chiral ligands under the same reaction conditions, the ee's of the corresponding sec-alcohols were 20–30 and 5–6%, respectively, along with the inversion of absolute configuration. A plausible mechanism for this inversion is proposed.     

Enzymatic desymmetrization of meso cis,cis-2,4,6-substituted tetrahydropyrans

The stereoselective acylation of meso-tetrahydropyrans 6 and 7 by enol esters (vinyl acetate or isopropenyl acetate) in the presence of Candida antarctica lipase in organic media gave the corresponding (2R,4S,6S)-monoesters 10 and 11 in high enantiomeric purity. The hydrolysis of the corresponding diacetate derivatives 8 and 9 in the presence of the same enzyme provided the opposite enantiomers, (2S,4R,6R)-monoesters 10 and 11.     

Chemoenzymatic synthesis of enantiomerically pure terminal 1,2-diols

A new practical method for the enzymatic synthesis of 1,2-diols has been developed by employing a lipase catalyzed one-pot transesterification protocol. A series of substituted -acetoxyphenylethanones 3a–g have been reduced to the corresponding alcohols under mild conditions employing sodium borohydride and moist neutral alumina, and further subjected for lipase catalyzed irreversible transesterification in the same pot to give mono- and diacetate diols (R)-4 and (S)-5, which on hydrolysis afforded terminal 1,2-diols, (R)- and (S)-6 in high enantiomeric excess.     

Stereoselective synthesis of (1R,2S)-2-amino-1,3-diols from (R)-cyanohydrins

Vinyl substituted (1R,2S)-amino alcohols 5 were obtained by addition of vinyl magnesium bromide to the corresponding cyanohydrin O-trimethylsilyl ethers (R)-2. The O- and N-protected vinyl amino alcohols 6 were ozonized at −78°C in methanol yielding (1R,2S)-2-amino-1,3-diols7 in high enantiomeric and diastereomeric excesses. For purification, compounds 7 in some cases were acetylated to give the derivatives (1R,2S)-8. Racemic 6a was converted by oxidative ozonolysis at −78°C in methanolic NaOH solution to the corresponding methyl N-acetyl-β-hydroxy propanoate 9a. The configuration of (1R,2S)-8a was confirmed by x-ray crystallographic analysis.     

Enzymatic production of (3S,4R)-(−)-4-(4′-fluorophenyl)-6-oxo-piperidin-3-carboxylic acid using a commercial preparation from Candida antarctica A: the role of a contaminant esterase

The enantioselective hydrolysis of (3RS,4RS)-trans-4-(4′-fluorophenyl)-6-oxo-piperidin-3-ethyl carboxylate (±)-2 was effected using a commercial preparation of lipase from C. antarctica A (CAL-A). We found that the hydrolytic activity of the lipase (immobilized on a number of very different supports) with this substrate was negligible. However, a contaminant esterase with Mw of 52 KDa from this commercial preparation exhibited much higher activity with (±)-2. This enzyme was purified and immobilized on PEI-coated support and the resulting enzyme preparation was highly enantioselective in the hydrolysis of (±)-2 (E >100), hydrolyzing only the (3S,4R)-(−)-3, which is a useful intermediate for the synthesis of pharmaceutically important (−)-paroxetine. Optimization of the reaction system was performed using a racemic mixture with a substrate concentration of 50 mM. This enzyme preparation was used in three reaction cycles and maintained its catalytic properties.     

Synthesis of (2R,3S,4S)-4-aryl-3-hydroxyprolinols

Synthesis of (2R,3S,4S)-4-aryl-3-hydroxyprolinols has been established starting from 2-benzyloxymethylpyrrolidin-2-one framework, which is derived from commercially available trans-(2S,4R)-4-hydroxyproline. The single diastereomer having a trans–cis relative configuration with C₂ and C₃ and C₃ and C₄ is constructed in two one-pot functional group transformations of Grignard addition/dehydration and epoxidation/isomerization as the key steps in moderate yield.     

通过增强电荷转移激发态构建激发态下稳定的基于氰基二苯乙烯的E/Z构型

The E/Z isomerization reaction is found extensively in most organic molecules containing double bond unit. This limits their practical application as luminescent materials partly, especially under photoirradiation. Therefore, it is important to obtain E/Z isomers with stable configuration in the excited state after photoirradiation. It is well known that cyanostilbene and its analogues play an important role in the development of organic opto/electronic materials. The substituted cyano group on C＝C double bonds has strong electron-withdrawing ability and large steric hindrance, which benefits the formation of donor-acceptor (D-A) structures and formation of intramolecular charge transfer. In our previous work, we reported a triphenylamine-cyanostilbene molecule (TPNCF) formed by modifying the cyanostilbene structure with triphenylamine, which maintained a stable E/Z configuration as a film and in high polar solvents. According to solvatochromism mechanisms and the results of theoretical calculations, we proposed that the charge transfer (CT) excited state between the triphenylamine donor and cyanostilbene acceptor groups induced the stable configuration of the E- and Z- isomers under photoirradiation. Under irradiation, the E/Z isomerization process occurring at a higher energy locally excited (LE) state was suppressed by a rapid internal conversion process from the LE to CT state. This work inspired us to provide a universal and effective molecular design strategy by modifying D-A substituents on double bonds that can successfully stabilize E/Z isomers. To further confirm that the CT excited state induced stable E- and Z- isomers in the cyanostilbene structure under photoirradiation, we designed and synthesized a donor-acceptor phenoxazine-cyanostilbene molecule (PZNCF) and successfully characterized its two E/Z isomers. In comparison with the reported TPNCF molecule, the in-situ NMR and UV spectra of E- and Z- isomers of PZNCF demonstrated that the E/Z isomerization rate became slower under photoirradiation, which indicated that the stronger electron-donating group of phenoxazine substituted in the cyanostilbene structure induced a more stable E/Z isomer configuration in its excited state. DFT calculations and photophysical results indicated that a stronger CT state was generated in both E- and Z- isomers of PZNCF. This further confirmed our hypothesized mechanism where the stable E/Z configuration can be obtained under photoirradiation by forming a suitable donor-acceptor structure to suppress the E/Z isomerization reaction in the LE state by a rapid internal crossing process from the LE to CT state. This molecular design strategy is of great significance to organic photochemistry and photoelectronics for molecules with double bond units.     

Syntheses and absolute configurations of the cytokinins 1′-methylzeatin and its 9-riboside

On the basis of the chiral syntheses of (1′R)-I and (1′S)-I and of their 9-ribosides (1″R)-III and (1″S)-III from D- and L-alanines, the structures of the cytokinins 1′-methylzeatin and its 9-riboside have been established to be (1′R)-I and (1″R)-III.     

Enantioselective inclusion of (R)-phenylglycyl-(R)-phenylglycine with benzyl methyl sulfoxides

A crystalline dipeptide, (R)-phenylglycyl-(R)-phenylglycine (RR-1), recognized p-halobenzyl methyl sulfoxides with high R-enantioselectivity (86–99% ee) to form inclusion compounds. The single-crystal X-ray analyses showed that RR-1 molecules are arranged in parallel and zigzags via hydrogen bonding to construct a pleated sheet. The guest molecules that form hydrogen bond with ⁺NH₃ of RR-1 are accommodated in the channel cavity between the layers. In contrast to the inclusion crystals of parent benzyl methyl sulfoxide, in which a rectangular cavity is formed, the cavity including p-halobenzyl methyl sulfoxides becomes rhomboidal. We also examine the guest exchange in these inclusion compounds and it was found that the guest exchanges occur when the host structure changes.     

Two new acetylated ginsenosides from the roots of Panax quinquefolium

Two new acetylated ginsenosides, 20（S）-protopanaxatriol-6-O-α-L-rhamnopyranosyl （1 → 2）-β-D-6＇-O-acetylglucopyranoside （1） and 20（R）-protopanaxatrol-6-O-α-L-rhamnopyranosyl （1 → 2）-β-o-6＇-O-acetylglucopyranoside （2）, were isolated from the roots of Panax quinquefolium. The structures were elucidated on the basis of spectroscopic techniques and chemical means.     

3-exo,3′-exo-(1R,1′R)-Bithiocamphor — a versatile source for functionally different 3,3′-bibornane derivatives, II. 1 An access to 3-exo,3′-exo-(1r,1′r)-bicamphor and related compounds

3-exo,3′-exo-(1R,1′R)-bicamphor (12) is obtained from 3-exo,3′-exo-(1R,1′R)-bithtiocamphor (3) by condensation with hydrazine hydrate followed by hydrolysis of the resulting dihydropyridazine 11. Deprotonation of 12 with NaH and subsequent treatment with potassium hexacyanoferrate (III) furnishes the 2,2′-dioxo-3,3′-bibornanylidene 13, whilst reduction of 12 with L1AlH₄ affords the 3,3′-biisoborneol 16. Further related transformations to various 2,2′-difunctional 3,3′-bibornane derivatives are described, which are could be of interest as chiral ligands     

多孔有机笼毛细管电色谱手性柱的制备及应用

多孔有机笼(POCs)是一种新型的具有稳定有序三维空腔结构的多孔材料。通过2-羟基-1,3,5-均苯三甲醛与1R,2R-1,2-二苯基乙二胺发生席夫碱的缩合反应,合成了一种具有羟基功能基团的单一手性POCs材料;将其均匀涂敷在毛细管壁上制成色谱柱,利用电色谱柱成功拆分了二氢黄酮、吡喹酮、萘普生和3,5-二硝基-N-(1-苯乙基)苯甲酰胺4种手性化合物。探究了分离电压、缓冲溶液浓度及其pH值等因素对手性拆分的影响,获得了4种手性物质在POCs色谱柱上的最佳拆分条件。实验研究表明,二氢黄酮、吡喹酮、萘普生和3,5-二硝基-N-(1-苯乙基)苯甲酰胺获得优化分离效果所需的工作电压分别为13、14、14和12 kV;二氢黄酮适宜Tris-H₃PO₄缓冲溶液浓度为0.075 mol/L,吡喹酮、萘普生和3,5-二硝基-N-(1-苯乙基)苯甲酰胺适宜Tris-H₃PO₄缓冲溶液浓度为0.100 mol/L; 4种手性物质得到最佳分离效果时的pH值均为3.51。二氢黄酮、吡喹酮、萘普生和3,5-二硝基-N-(1-苯乙基)苯甲酰胺均达到基线分离,分离度分别为2.99、2.10、2.58和3.59。该POCs色谱柱还成功拆分了o,m,p-碘苯胺、o,m,p-硝基苯胺两种位置异构体。该研究表明POCs手性电色谱柱具有良好的手性识别能力,是一种优秀的手性分离材料,具有很大的电色谱手性分离应用前景。     

Total asymmetric syntheses of d-lividosamine and 2-acetamido-2,3-dideoxy-d-arabino-hexose derivatives.

The “naked sugar” (+)-(1R, 4R)-7-oxabicyclo[2.2.1]hept-5-en-one((+)-2) has been converted to D-lividosamine ((+)-1: 3-deoxy-D-glucosamine) and derivatives via (+)-2-chloro-2,3-dideoxy-5,6-O-isopropylidene-D-arabino-hexono-1,4-lactone ((+)-33) and (+)-2-azido-2,3-dideoxy-5,6-O-isopropylidene-D-ribo-hexono-1,4-lactone ((+)-34) in a highly stereoselective fashion. Similarly, 2-acetamido-2,3-dideoxy-D-arabino-hexose and derivatives were derived from the “naked sugar” (−)-(1S,4S-7-oxabicyclo[2.2.1]-hept-5-en-2-one ((−)-2) via the double hydroxylation of the C=C double bond in (−)-N-benzyl-N-[(1R,2S,4S)-6-bromo-7-oxabicyclo[2.2.1]hept-5-en-2-endo-yl] amine ((−)-40).     

Biocatalytic procedure for obtaining all four diastereoisomers of 1-(1-hydroxyethyl)-3-ethylferrocene: synthons for chiral 1,3-disubstituted ferrocenes

Lipase from Candida antarctica has been successfully used to realise the selective esterification of the four 1-(1-hydroxyethyl)-3-ethylferrocene isomers, possessing central/planar chirality. In this reaction, the lipase recognises only the two isomers possessing an (R)-configuration, independently from planar chirality. This allows us to split the mixture into two couples of diastereoisomers, namely the (S_p,R_c)-/(R_p,R_c)- and (R_p,S_c)-/(S_p,S_c)-isomers, conveniently separated in the single constituents by crystallisation from hexane.     

A short, practical synthesis of the ant venom alkaloid, three (3R,5S,8aS)-3-alkyl-5-methylindolizidines

A short, practical and diastereoselective method for preparing the ant venom alkaloid, three (3R,5S,8aS)-3-alkyl-5-methylindolizidines (1–3), has been developed. The stereoselective intramolecular amidomercuration of the N-alkenylurethane 4 followed by oxidative demercuration provides the piperidine alcohol cis-6 as a major product. Thereafter, oxidation of cis-6 followed by the Horner-Emmons elongation of the ring appendages affords the enones 8, 10, and 11, which are stereoselectively converted into 1, 2, and 3, respectively, by catalytic hydrogenation.     

Enzymatic resolution of (RS)-β-hydroxy selenides in organic media

Kinetic resolutions of a number of β-hydroxy selenides promoted by enzymes were performed using PPL (free Porcine pancreatic lipase), PSL (Amano PS—free Pseudomonas sp. lipase) and CALB (NOVOZYM 435^®—immobilized Candida Antarctica lipase type B) with (RS)-1-phenylselanyl-propan-2-ol. CALB gave the best results and provided both (R)- and (S)-enantiomers in high enantiomeric purity. A comparative study of the effect of temperature, solvent, enzyme immobilization and the structure of the substrates on the resolution is presented.     

Lipase TL®-mediated kinetic resolution of benzoin: facile synthesis of (1R,2S)-erythro-2-amino-1,2-diphenylethanol

The lipase TL®-mediated kinetic resolution of (±)-benzoin (1) proceeded to give the corresponding optically pure benzoin (R)-1. On the other hand, (S)-benzoin-O-acetate (5) could be hydrolyzed without epimerization to give (S)-benzoin (S)-1, under alkaline conditions. Further, (R)-1 was converted to (1R,2S)-2-amino-1,2-diphenylethanol (99:1 er) according to the procedure reported previously.