A chemo-enzymatic route to diastereoisomers of 2-methyl-1-phenyl-1,3-butanediol: the dual role of microorganisms

Diastereoisomers (1S,2R,3S)-, (1R,2R,3S)-, (1R,2S,3S)- and (1S,2S,3S)-2-methyl-1-phenyl-1,3-butanediols were prepared by simple and convenient strategies using two different chemo-enzymatic approaches for the reduction of racemic 2-methyl-1-phenyl-1,3-butanedione, both involving in situ racemization. The first method comprised a one-pot microbial reduction coupled with a chemical reduction, while in the second method, stepwise chemo-enzymatic reductions were performed.     

An improved method for synthesizing antennary β-d-mannopyranosyl disaccharide units

The merits of an indirect protecting method for hydroxyl groups using allyl groups via allyloxycarbonyl groups in the synthesis of antennary β-d-mannopyranosyl disaccharides from β-d-galactopyranosyl disaccharides were studied. Regioselective allyloxycarbonylation and conversion reactions involving simultaneous double S_N2 nucleophilic substitution at C-2′ and C-4′ of benzyl O-[β-d-galactopyranosyl]-(1-4)-3,6-di-O-benzyl-2-deoxy-2-N-phthalimido-β-d-glucopyranoside were examined for comparison with the direct allylation method. The required β-d-mannopyranosyl disaccharide having proper protecting groups was obtained using this indirect method in 52% yield. In contrast, the reported direct allylation method using methyl O-(β-d-galactopyranosyl) disaccharide gave the corresponding β-d-mannopyranosyl disaccharide in only 7.5% yield.     

Imino 1,2-Wittig rearrangement of hydroximates and its application to synthesis of cytoxazone

The imino 1,2-Wittig rearrangement of hydroximates provides a novel method for the construction of 2-hydroxyoxime ethers. Upon treatment with LDA, Z-hydroximates smoothly underwent stereoselective rearrangement to give Z-2-hydroxyoxime ethers in good yield, which were converted into amino alcohols. On the other hand, the rearrangement of E-hydroximates gave a mixture of E- and Z-2-hydroxyoxime ethers. This method was successfully applied to a practical synthesis of cytoxazone.     

Regio- and stereoselective methods for the conversion of (2S,3R)-β-phenylglycidic acid esters to taxoids and other enantiopure (2R,3S)-phenylisoserine esters

A novel efficient method was proposed for the synthesis of enantiopure precursors of taxane-containing cytostatics, i.e., methyl esters of (2R,3S)- and (2S,3R)-N-benzoylphenylisoserine and similar taxoid esters. The method is based on the regio- and stereoselective hydrobromolysis of the corresponding trans-β-phenyl glycidate enatiomers, consecutive reactions of O-acylcarbamoylation of the obtained 3-bromohydrins, intramolecular cyclization to 4-phenyloxazolidin-2-one-5-carboxylic acid derivatives, and oxazolidinone ring opening.     

Stereoselective synthesis of azasugars by electrochemical oxidation

A new method using electrochemical oxidation has been exploited for the stereoselective synthesis of 2,3,6-trihydroxylated 5S-piperidine derivatives. The electrochemical method was successively used for the conversion of N-protected piperidines to N-protected 1-methoxypiperidines and for the conversion of 1-methoxy-2,3-didehydropiperidine derivatives to 1,2,3-triacetoxypiperidine derivatives. The method provided a new synthetic route to 2S,3S,6-triacetoxy-5S-methylpiperidine and 2R,3R,6-triacetoxy-5S-methylpiperidine.     

Pd-Cu-catalyzed synthesis of N-(2E,4)- and N-(2Z,4)-enyne cyclic amines

By Pd-Cu-catalyzed coupling of (2E)- and (2Z)-3-chloroprop-2-en-1-ylamines and alkynes a stereoselective method of the synthesis was developed for a series of (2E,4)- and (2Z,4)-enyne cyclic amines.     

A palladium-catalyzed facile and general method for the stereoselective synthesis of (E)-3-arylidene-3,4-dihydro-2H-1,4-benzoxazines and their naphthoxazine analogues

Palladium-catalyzed cyclocondensation of an aryl iodide with N-tosyl-2-(prop-2′-ynyloxy)aniline at room temperature is shown to constitute a convenient general method for the synthesis of (E)-3-arylidene-3,4-dihydro-2H-1,4-benzoxazines in moderate to very good yields. The method could also be extended to the synthesis of (E)-3-arylidene-2H-naphth[1,2-b][1,4]oxazines. The regio- and stereo-selectivity of the process, short reaction time, operational simplicity, and use of inexpensive starting materials represent its attractive features.     

An enantioselective synthesis of nitrogen protected 3-arylserine esters

A method for the preparation of (2R,3S) nitrogen protected arylserine esters is described. The method consists of rhodium mediated insertion of tert-butylcarbamate into the corresponding 3-keto-2-diazoester, affording the N-protected α-amino-β-ketoester, followed by asymmetric reduction/dynamic resolution to afford the corresponding N-protected 3-arylserine esters in good chemical yield, and in most cases high enantiomeric excess.     

Novel iodine catalyzed diastereoselective synthesis of trans-2,6-disubstituted tetrahydro-2H-pyrans: synthesis of C1–C13 fragment of bistramide-A

A new method for the stereoselective synthesis of trans 2.6-disubstituted tetrahydro-2H-pyrans has been developed involving iodine catalyzed allylation of tetrahydro-2H-pyranol with excellent trans selectivity. The method was also applied toward the construction of C1–C13 fragment of bistramide-A in 11 steps with 21.4% overall yield.     

Solution of difficult steady state separation problems by use of the functional transformation method

An extension of the range of convergence of the classical Newton-Raphson method and modified forms of it by use of the functional transformation method is demonstrated herein by use of numerical examples of difficult- to-solve distillation problems. Variations of the Newton-Raphson method considered are as follows: (1) the 2N Newton-Raphson method with the Broyden modification; (2) the 2N Newton-Raphson method with the Broyden-Bennett modification; (3) the almost-band algorithm with the Broyden-Householder modification; (4) the almost-band algorithm with Schubert's modification; and (5) parametric continuation with step size selection by Gear's method.     

Application of p-TSA in the one pot synthesis of N-methyl-3-nitro-aryl-benzo[4,5]imidazo[1,2-a]pyrimidin-2-amine

A simple, efficient, eco-friendly, and cost-effective method has been developed for the synthesis of N-methyl-3-nitro-aryl-benzo[4,5]imidazo[1,2-a]pyrimidin-2-amine derivatives using 2-aminobenzimidazole, aldehydes and (E)-N-methyl-1-(methylthio)-2-nitroethenamine, in the presence of catalytic amount of p-toluenesulfonic acid (p-TSA) in ethanol at 80?°C conditions. The advantages of this method are the use of an inexpensive and readily available catalyst, shorter reaction times, a wide range of functional group tolerance, and high yield of products via a simple experimental and work-up procedure.     

One step synthesis of 1,5-diaryl pyridin-2(1H)-ones from 2-aryl vinamidinium salts and N-aryl cyanoacetamides

A one step, direct method for the synthesis of 1,5-diaryl pyridin-2(1H)-one derivatives by condensation of 2-aryl vinamidinium salts with N-aryl cyanoacetamides has been developed. This method can conveniently provide the corresponding 1,5-diaryl pyridin-2(1H)-one derivatives with various substituents in good yields and overcome the drawbacks of existing methods such as poor substrate scope, heavy metal pollution, and low yields. The formation mechanism of the products was illustrated.     

VSCF in internal coordinates and the calculation of anharmonic torsional mode transitions

The vibrational self-consistent field (VSCF) method assumes separability in normal modes in its usual version. However, the method fails in cases such as soft torsional modes which are better treated by angular variables. We develop VSCF equations based on the assumption of wave function separability in internal coordinates. To test the method, simple illustrative applications to small systems are provided: trans-HONO, cis-HONO, H₂S₂, and H₂O₂. The code directly uses points from ab initio calculations, and the method proves to be accurate for all types of transitions. For typical torsional transitions, the error in the computed frequency is smaller than that of VSCF in normal coordinates. The wave functions for the torsional mode are compared with the corresponding normal mode wave functions. The differences are substantial. The results are encouraging for extension of the model for large polyatomic systems. Work along these lines is in progress.     

N,N-Dichlorobis(2,4,6-trichlorophenyl)urea (CC-2) as a new reagent for the synthesis of pyrimidone and pyrimidine derivatives via Biginelli reaction

A simple and efficient method for the synthesis of 3,4-dihydropyrimidin-2-(1H)one and benzo[4,5]imidazo/thioazo[1,2-a]pyrimidine derivatives has been described using N,N′-dichlorobis(2,4,6-trichlorophenyl)urea (CC-2) as a new reagent. This method is found to be efficient and convenient for the synthesis of pyrimidone and pyrimidine derivatives.     

syn-2,3-Disubstituted-2,3-dihydro-1,4-benzoxathiin rings: preparation from quinone ketals and 2-mercaptoethanols

A general method for the preparation of syn-2,3-disubstituted-2,3-dihydro-1,4-benzoxathiin rings from 2-mercaptoethanols and quinone ketals is presented. This ring system is produced by Michael addition of a 2-mercaptoethanol to a quinone ketal, followed by cyclization of the initial Michael adduct, and subsequent aromatization to afford a syn-2,3-disubstituted-1,4-benzoxathiin in fair to good chemical yield. Several chiral syn-2,3-disubstituted-2,3-dihydro-1,4-benzoxathiin rings were prepared with this method from enantioenriched 2-mercaptoethanols. No loss of enantiopurity was observed.     

Stereoselective synthesis of cyclohexa-2,4-dien-1-ones and cyclohex-2-en-1-ones from phenols

A convenient synthetic method for the synthesis of substituted cyclohex-2-en-1-ones by the direct alkylation of phenols has been developed. Furthermore, enantiomerically enriched 2,6-dimethyl-6-(3-methylbut-2-enyl)-cyclohexa-2,4-dienone was prepared by the deprotonation of 2,6-dimethylphenol with a sparteine–lithium complex followed by alkylation with 1-chloro-3-methylbut-2-ene. 2,6-Dimethyl-6-(3-methyl-but-2-enyl)-cyclohex-2-enone was prepared from the corresponding cyclohexa-2,4-dien-1-one by selective hydrogenation of the 4,5-double bond. The method was extended to 2-methyl-naphthalen-1-ol and 1-methyl-naphthalen-2-ol resulting in 2-(R)-methyl-2-(3-methylbut-2-enyl)-2H-naphthalen-1-one and 1-(S)-methyl-1-(3-methylbut-2-enyl)-1H-naphthalen-2-one, respectively.     

Intramolecular arylation reactions: first efficient synthesis of novel fused pyridoimidazoquinolinones or pyridoimidazoazepinones libraries

An efficient method for the synthesis of new polycyclic skeletons: pyrido[2′,1′:2,3]imidazo[5,4-c]quinolin-6(5H)-ones and pyrido[2′,1′:2,3]imidazo[5,4-c]azepin-7(6H)-ones libraries is described via Pd-catalyzed intramolecular arylation involving C(sp2)-H activation. This method permits the synthesis of polycyclic derivatives in good yield. The process tolerates a variety of aryl substituents as well as alkyl imidazo[1,2-a]pyridine-2-carboxamide structures. The resultant compounds, 10(11)-chloro-pyrido[2′,1′:2,3]imidazo[5,4-c]quinolinones or azepinones are functionalized under Suzuki cross-coupling conditions to give polyfunctional compounds.     

Sequential enzymatic procedure for the preparation of enantiomerically pure 2-heteroaryl-2-hydroxyacetic acids

Starting from the racemic 2-benzofuranyl- and 2-benzo[b]thiophenyl-2-hydroxyacetic acid ethyl esters as substrates, a general method was developed for the efficient synthesis of the corresponding highly enantiomerically enriched (ee up to 99%) (R)- and (S)-2-heteroaryl-2-hydroxyacetic acids.     

Copper-catalyzed synthesis of 2-sulfenylindoles from indoline-2-thiones and aryl iodides

A novel and efficient method for synthesis of 2-sulfenylindole via copper-catalyzed coupling reaction of indoline-2-thiones with aryl iodides has been developed. A series of N-substituted and N-free 2-sulfenylindole were obtained in high yields. Furthermore, the method was employed to synthesis of benzothieno[2,3-b]indoles from indoline-2-thiones with 1,2-diiodobenzene in the presence of CuI and Pd(OAc)₂ as catalysts.     

Novel organomagnesium reagents in synthesis. Catalytic cyclomagnesiation of allenes in the synthesis of N-, O-, and Si-substituted 1Z,5Z-dienes

An efficient method for the synthesis of valuable N-, O-, and Si-containing 1Z,5Z-diene compounds was developed. The method comprises Cp₂TiCl₂-catalyzed homo- and cross-cyclomagnesiation of 1,2-dienes by Grignard reagents (RMgR′) to give 2,5-dialkylidenemagnesacyclopentanes in up to 96% yield. This approach was successfully used in the synthesis of 5Z,9Z-dienoic acids, precursors of acetogenins and insect pheromones.