Stereospecific synthesis of chiral caprolactone monomers from D-glucose

The synthesis and characterisation of a novel chiral bicyclic oxacaprolactone is reported. The choice of diisopropylidene-D-glucose as a starting material allowed selective introduction of the synthetic equivalent necessary for the formation of the seven-membered ring of the lactone, i.e., one carbon atom and the carbonyl of the ester which was to become the carbonyl group of the lactone. In order to complete the formation of the seven-membered ring, via intramolecular lactonisation, it was necessary to excise carbon six and to establish a primary alcohol group at C-5. The lactone was fully characterised and available for ring-opening polymerisation.     

Natural-product-like chiral derivatives by solid-phase synthesis

In this genomics and proteomics age, highly functionalized natural products or natural-product-like compounds are likely to play important roles in understanding the functions of emerging biological targets because they serve as small-molecule chemical probes in modulating a target's specific actions (i.e. activation or deactivation). Development of stereoselective reaction-derived methods on solid phase provides a means of obtaining functionalized chiral core structures that may be used for high-throughout syntheses.     

Stereospecific synthesis of (+)-oxybiotin from D-xylose

A new 14-step synthesis of (+)-oxybiotin, an oxygen analogue of (+)-biotin, was achieved starting from D-xylose by use of selected 2,5-anhydro sugar derivatives as key intermediates.     

One-pot synthesis and chiral analysis of cyclopropane derivatives

A user-friendly, one-pot procedure was developed to access racemic as well as enantiomerically enriched cyclopropanes. Thus, the cyclopropanation of olefin (3) was performed using Meldrum's acid (4) or dimethyl malonate (5) and diacetoxyiodobenzene PhI(OAc)2 (6) or iodosyl benzene PhI=O (7) for in situ generation and decomposition of the phenyliodonium ylide 1 and 2, respectively. The reaction proceeds well with 5 mol% of achiral rhodium (II)-catalyst [Rh2(OAc)4] and a 10-fold excess of olefin affording the cyclopropane derivates 10 and 11, respectively, with high yield. The system is compatible with chiral Rh(II)-catalysts 8 and 9 and an enantiomeric excess up to 66% was achieved. An effective baseline separation of the enantiomers of the resulting cyclopropane derivatives was achieved using gas chromatography on the chiral stationary phase Chirasil-beta-dex.     

Stereospecific effects of benzo[d]isothiazolyloxypropanolamine derivatives at beta-adrenoceptors: synthesis, chiral resolution, and biological activity in vitro

We performed the asymmetric synthesis of four enantiopure benzo[d] isothiazo-3-or 5-yloxypropanolamine derivatives, previously described as competitive antagonists at beta-adrenoceptors. The chemical characterization of each enantiomer was accomplished by (1)H NMR and HPLC/DAD/CD. The direct chromatographic separation of the enantiomers via chiral HPLC was investigated. The best resolutions were achieved using cellulose tris (3,5-dimethylphenyl carbamate) (Chiralcel OD-H) and amylose tris (3,5-dimethylphenyl carbamate) (Chiralpak AD). The enantiomers obtained had enantiomeric purities suitable for biological assays. Tested in isolated rat cardiac and intestinal tissues to evaluate their effects at beta(1)- and beta(3)-adrenoceptors, the (S)-enantiomers revealed a higher degree of antagonism than (R)-enantiomers at both subtypes, even though their activity was greater at the cardiac beta(1)-subtype. The potent and cardiospecific antagonistic effect exerted by the compounds tested suggests that the benzisothiazole moiety could be an interesting scaffold for discovering new chiral beta-blocking drugs.     

Application of microorganisms towards synthesis of chiral terpenoid derivatives

Biotransformations are a standard tool of green chemistry and thus are following the rules of sustainable development. In this article, we describe the most common types of reactions conducted by microorganisms applied towards synthesis of chiral terpenoid derivatives. Potential applications of obtained products in various areas of industry and agriculture are shown. We also describe biological activity of presented compounds. Stereoselective hydroxylation, epoxidation, Baeyer-Villiger oxidation, stereo- and enantioselective reduction of ketones, and various kinetic resolutions carried out by bacteria and fungi have been reviewed. Mechanistic considerations regarding chemical and enzymatic reactions are presented. We also briefly describe modern approaches towards enhancing desired enzymatic activity in order to apply modified biocatalysts as an efficient tool and green alternative to chemical catalysts used in industry.     

Alkylating agents from sugars: synthesis of chlorambucil derivatives carried by chiral glycosyl glycerols derived from D-glucosamine

Chlorambucilamide derivatives involving chiral glycosyl glycerols derived from D-glucosamine were synthesized in good yield by coupling the chlorambucil moiety to the amino group of omega-amino-(omega-1)-hydroxyalkyl 2-acylamino-4,6-O-benzylidene-2-deoxy-beta-D-glucopyranosides, and subsequent hydrolysis of the benzylidene group. The starting material was easily available from 2-acetamido-2-deoxy-D-glucose. The bonding of 2,3,4,6-tetra-O-pivaloyl-beta-D-galactopyranosylamine to chlorambucil by formation of an amide function is also described.     

Stereospecific synthesis of trans-arachidonic acids.

An effective synthesis is described for the preparation of all four mono trans isomers of arachidonic acid via deoxidation of epoxide precursors with lithium diphenylphosphide and quaternization with methyl iodide.     

Bicyclic nucleoside analogues from D-glucose: synthesis of chiral as well as racemic 1,4-dioxepane ring-fused derivatives

The dioxepanofuranose derivatives 4 and 12, obtained through the cyclization of the 3-(2-hydroxyethyl) ether of a D-xylo-pentodialdose derivative, were appropriately functionalized and elaborated to the first examples of the new class of 3'-O and 5'-O-bicyclic nucleoside analogues 9, 10, and 14 with a fused seven-membered ring. Reactions carried out through the intermediacy of the D-xylo-pentodialdose derivative 5 yielded racemic products, while prior protection of the 4-formyl group (as in 7) before deprotection of the 1,2-hydroxyl groups led to optically active analogues.     

Stereospecific synthesis of alpha-anomeric pyrimidine nucleoside.

A facile stereospecific synthetic method for alpha-anomeric 2'-deoxypyrimidine nucleoside unit utilizing aminooxazoline derivative of ribofuranose was investigated. Thus, easily accessible riboaminooxazoline derivative prepared by ribose and cyanamid was allowed to react with ethyl alpha-bromoethylacrylate to give corresponding adduct. The adduct was cyclized by strong base such as potassium t-butokiside. The resulted 2,2'-cyclonucleoside was then treated with acetyl bromide followed by n-butyltin hydride to give alpha-anomeric 3',5'-di-O-acetylthymidine. 3',5'-Di-O-acety groups of the nucleoside were easily removed by the action of excess of triethyl amine in methanol. Essentially same procedure afforded corresponding 2'-deoxyuridine, which was further, converted to alpha-anomeric 2'-deoxycytidine.     

Stereospecific synthesis and absolute configuration of mexiletine

Data on the absolute configuration of mexiletine (MEX) do not appear to have been published, although in several published reports the configuration is referred to as (?)-(R) and (+)-(S), based on information from manufactures providing the drug stereoisomers. We demonstrate that (?)-MEX has the (R)-configuration by mean of a new stereospecific synthesis. X-Ray analysis of an optical active sample of (+)-MEX as its hydrobromide salt, obtained from chemical resolution of the racemic mixture, was carried out in order to obtain precise information on bond lengths and angles, useful for studies on structure–activity relationships. We also report the NMR analysis in presence of Eu(hfc)₃ as shift reagent, which represents a simple method for the determination of enantiomeric excess (ee) in addition to the well-known chiral HPLC methods. © 1994 Wiley-Liss, Inc.     

Stereospecific synthesis of 3 beta-hydroxylated bile alcohols

This paper describes the synthesis of 5 beta-cholestane-3 beta, 7 alpha,25-triol and 5 beta-cholestane-3 beta, 7 alpha, 12 alpha, 25-tetrol from their corresponding 3 alpha-analogs. The method consists of refluxing a mixture of a steroid alcohol, triphenylphosphine, and diethyl azodicarboxylate in benzene solution with an acid such as formic acid. The sterically pure ester (3 beta-formate) so formed after saponification then allows an easy access to the epimer of the starting alcohol. Differentiation of these 3 beta-hydroxy bile alcohols from their corresponding 3 alpha-epimeric analogs was made possible on the basis of proton, 13C-NMR, and mass spectra as well as chromatographic mobility. Steric requirements of sterols and nucleophilicity of attacking acidic components played an important role for the success of this synthesis. Only equatorial hydroxyl groups in these bile alcohols reacted under mild conditions and epimerization, as well as protection of the alcoholic group, was achieved in one step. Formic acid was the acid of choice since the axial formate ester formed is sufficiently reactive to be hydrolyzed (KHCO3/aq X MeOH) under mild conditions.     

Stereospecific synthesis and enzyme studies of CDP-diacylglycerols

The fatty acid specificity of two enzymes that metabolize CDPdiacylglycerol, CDPdiacylglycerol hydrolase (EC 3.6.1.26) and CDPdiacylglycerol: inositol phosphatidyltransferase (EC 2.7.8.11), has been examined in guinea pig brain. Mixed CDPdiacylglycerols were stereospecifically synthesized by the following sequence: (i) hydrolysis of a homodiacyl lecithin to 1-acyl lysoPC by action of snake venom phospholipase A2, (ii) reacylation with the anhydride of the desired second fatty acid and dimethylaminopyridine, (iii) hydrolysis of the resultant heterodiacyl lecithin to phosphatidate with cabbage phospholipase D, and (iv) reaction of phosphatidate with CMPmorpholidate to give CDPdiacylglycerol. CDPdiacylglycerol: inositol phosphatidyltransferase showed the following rates of conversion of 40-microM suspensions of CDPdiacylglycerol in 0.15% Triton X-100 to phosphatidylinositol relative to the 1-stearoyl-2-oleoyl derivative (100%): dipalmitoyl, 70%; distearoyl, 38%; diarachidonoyl, 9%; 1-arachidonoyl-2-stearoyl, 6%; 1-stearoyl-2-arachidonoyl, 4%. These results indicate that the composition of isolated phosphatidylinositol and related lipids is not explained by the fatty acid specificity of the biosynthetic enzymes and supports the intervention of a deacylation-reacylation sequence. The rates of hydrolysis of the synthetic CDPdiacylglycerols at 76 microM, in 0.3% Triton X-100, by the CDPdiacylglycerol hydrolase relative to the 1-stearoyl-2-oleoyl derivative (100%) were: dipalmitoyl, 70%; distearoyl, 32%; 1-arachidonoyl-2-stearoyl, 30%; 1-stearoyl-2-arachidonoyl, 28%; diarachidonoyl, 22%. Inhibition of this enzyme by AMP was shown to be non-competitive, with a Ki of 40 microM. The lysosomal localization of the mammalian hydrolase was confirmed.     

Stereospecific synthesis and antiviral activities of beta-L-2',3'-dideoxy-5-chloropyrimidine nucleoside derivatives.

Several 5-chlorouracil and 5-chlorocytosine beta-L-dideoxynucleosides were stereospecifically synthesized and their activities against human immunodeficiency virus (HIV) and hepatitis B virus (HBV) were examined in cell culture.     

Matrix synthesis of chiral carboxy derivatives: Aldehyde chiral discrimination due to a two-point coordination of Mg2+

To control stereoselectivity in aldol-like reactions with chiral carbohydrate templates, we studied the interaction between completely protected dialdo compounds and magnesium enediolates of arylacetic acids. Diastereomeric mixtures of the highly functionalized acids obtained were esterified to isolate individual methyl uronates. It was found that all the diastereomeric esters exhibit Cotton effects of the same positive sign in the 220–230 nm region and so possess the same S configuration of the aryl chiral center C(6). Chiral center C(5) configurational assignments were performed using IR and ORD spectroscopy. We separated and specified four pairs of diastereomeric methyl uronates. It follows that the precursory acids have the same 5R*, 6S (major isomers) and 5S*, 6S (minor isomers) configurations. A tentative mechanism for complexation and possible models of Mg²⁺ -protected dialdose intermediate complexes has been proposed. We have concluded that a kind of orbital steering is realized, accompanied by some “tuning” of molecular assembly conditioned by two-point coordination between Mg²⁺ and potential cation-binding sites in the substrate molecules. Thus it has been demonstrated that reasonable diastereo-selectivity can be achieved even through the use of small matrix molecules using rather small functional groups, which do not impose any stringent steric requirements. © 1993 Wiley-Liss, Inc.     

Privileged structure based ligands for melanocortin receptors--substituted benzylic piperazine derivatives

Replacement of the aryl piperazine moiety in compound 1 with a variety of substituted benzylic piperazines (6) yields compounds that afford melanocortin receptor 4 (MCR4) activity. Analogs with ortho substitution on the aromatic ring afforded the highest affinity. Resolution of the stereocenter of the benzylic piperazine based privileged structure revealed that the R-enantiomer was more active.     

Stereospecific synthesis of (-)-neplanocin F

The stereospecific synthesis of (-)-neplanocin F was achieved in 15 steps from 2,3-O-isopropylidene-D-1,4-ribonolactone. The synthetic methodology can give an access through appropriate modifications to new series of carbanucleosides.