Stereoselective total synthesis and absolute configuration of the natural decanolides (-)-microcarpalide and (+)-lethaloxin. Identity of (+)-lethaloxin and (+)-pinolidoxin

[reaction: see text] Convergent, stereoselective syntheses of the pharmacologically active, naturally occurring lactones (-)-microcarpalide and (+)-lethaloxin have been achieved from the commercially available, chiral reagents (R)-glycidol, (S,S)-tartaric acid, and d-ribose as the starting materials. These syntheses have further served to establish the hitherto unknown absolute configuration of (+)-lethaloxin and to show its identity with (+)-pinolidoxin.     

Synthesis of (-)-fortamine and (+)-2-deoxyfortamine from resolved 3S,4S-N-carbomethoxy-3-aminocyclohexen-4-ol

A three step sequence (Scheme I) starting with racemic 3,4-epoxycyclohexene (5) and (S)-α-methylbenzylamine gave 3S,4S-N-carbomethoxy-3-aminocydohexen-4-ol (10) with chromatographic removal of the undesired 3R,4R byproduct. The absolute configuration of 10 was established by x-ray crystallographic analysis of its precursor, 6 (as the HCl salt). Resolved 10 was converted to the aminocyditols (-)-fortamine (1) and (+)-2-deoxyfortamine (2) by efficient routes which parallel those previously developed in the racemic series.     

First enantioselective syntheses of (+)- and (-)-wilforonide by using chiral auxiliaries derived from the same chiral source

[see structure]. The first enantioselective syntheses of both (+)-wilforonide (>98% ee) and (-)-wilforonide (>98% ee) have been accomplished by employing chiral auxiliaries derived from the same chiral source, (R)-pulegone. The bicyclic skeleton of wilforonide was constructed by using Mn(III)-based oxidative radical cyclization reactions of chiral beta-keto esters. The absolute configuration of natural wilforonide has been established to be (5aR,9aR).     

Total Synthesis of (+)-(8S,13R)-Cyclocelabenzine

An asymmetric synthesis of the spermidine alkaloid (+)-cyclocelabenzine ( 1a ) and its (?)-(13S)-epimer 1b is described using optically active (+)-(3S)-3-amino-3-phenylpropionic acid as the chiral building block. The isoquinolin-1-one fragment 15 was synthesized by a modified Bischler-Napieralski reaction. The relative configuration of the (?)-isomer was determined by an X-ray crystal-structure analysis, which enabled us to determine the absolute configuration of natural (+)- 1a as (8S,13R).     

Synthesis of the Juvenoid (S)-(+)-Hydroprene from L-(-)-Menthol

The versatile chiral synthon methyl (R)-5,5-dimethoxy-3-methylpentanoate has been prepared for the first time via ozonolytic decyclization of (R)-4-menthenone, which is available from L-(-)-menthol. The optically pure juvenoid (S)-(+)-hydroprene can be prepared from the synthon     

The absolute configuration of (+)-(E)-4-phenylbut-3-ene-2-ol

A derivative of (+)-(E)-4-phenylbut-3-ene-2-ol is shown by X-ray crystallography to be of (R) configuration, confirming the assumption in the literature that the absolute configuration of (+)-(E)-4-phenylbut-3-ene-2-ol is (R).     

Simultaneous assay of four stereoisomers of diltiazem hydrochloride. Application to in vitro chiral inversion studies

Summary The simultaneous stereospecific assay of four stereoisomers of diltiazem hydrochloride in bulk drug and aqueous solution was developed using HPLC on a Chiralcel OF column. The four isomers were quantitated with good precision by the internal standard method. The chiral inversion of (+)-cis-diltiazem hydrochloride in vitro, stability of its (2S, 3S) configuration in the solid and aqueous states was examined by HPLC. Chiral inversion of (+)-cis-diltiazem hydrochloride was not observed in the solid state, and its (2S, 3S) configuration was stable to heat, humidity and light. Chiral inversion of (+)-cis-diltiazem hydrochloride (2S, 3S) was observed in aqueous solution under UV, but not in aqueous solution stored at 80°C for 5 h nor under visible light for 10 h. The (+)-cis-diltiazem hydrochloride (2S, 3S) epimerized to (+)-trans-diltiazem hydrochloride (2R, 3S) with a half-life of 5 h in aqueous solution under UV but the reverse chiral inversion of (+)-trans-diltiazem hydrochloride (2R, 3S) to (+)-cis-diltiazem hydrochloride (2S, 3S) was not observed.     

Simultaneous assay of four stereoisomers of diltiazem hydrochloride. Application to in vitro chiral inversion studies

Summary The simultaneous stereospecific assay of four stereoisomers of diltiazem hydrochloride in bulk drug and aqueous solution was developed using HPLC on a Chiralcel OF column. The four isomers were quantitated with good precision by the internal standard method. The chiral inversion of (+)-cis-diltiazem hydrochloride in vitro, stability of its (2S, 3S) configuration in the solid and aqueous states was examined by HPLC. Chiral inversion of (+)-cis-diltiazem hydrochloride was not observed in the solid state, and its (2S, 3S) configuration was stable to heat, humidity and light. Chiral inversion of (+)-cis-diltiazem hydrochloride (2S, 3S) was observed in aqueous solution under UV, but not in aqueous solution stored at 80°C for 5h nor under visible light for 10 h. The (+)-cis-diltiazem hydrochloride (2S, 3S) epimerized to (+)-trans-diltiazem hydrochloride (2R, 3S) with a half-life of 5h in aqueous solution under UV but the reverse chiral inversion of (+)-trans-diltiazem hydrochloride (2R, 3S) to (+)-cis-diltiazem hydrochloride (2S, 3S) was not observed.     

1,5-Benzoxathiepin derivatives. III. Optical resolution of methyl (+/-)-cis-3-hydroxy-4-[3-(4-phenyl-1-piperazinyl)propyl]-3,4-dihydro- 2H-1,5-benzoxathiepin-4-carboxylate hydrochloride ((+/-)-CV-5197) with selective 5-hydroxytryptamine2(5-HT2)-antagonistic activity

The selective 5-HT2-receptor antagonist, methyl (+/-)-cis-3-hydroxy-4-[3-(4-phenyl-1-piperazinyl)propyl]-3,4-dihydro-2H- 1,5-benzoxathiepin-4-carboxylate hydrochloride ((+/-)-CV-5197) was resolved in high optical purity using (R)-(-)- and (S)-(+)-1,1'-binaphthyl-2,2'-diyl hydrogen phosphates ((R)-(-)- and (S)-(+)-BNP). The absolute configuration of (+)-CV-5197 was determined to be 3S,4R by X-ray crystallographic analysis. In the binding assay, it was demonstrated that (+)-CV-5197 was a more active isomer (IC50 = 23 nM +/- 6.3) for 5-HT2 receptor binding than the (-)-enantiomer (IC50 = 1600 nM +/- 82). (+)-CV-5197 completely inhibited the 5-HT-induced contraction of the isolated pig coronary artery at a concentration of 3 x 10(-7) M, whereas (-)-CV-5197 showed little antagonistic activity, even at 3 x 10(-4) M. Thus, the agreement between the results of the binding assays and the biological activities for the 3S,4R enantiomer of CV-5197 suggests that its physiological activity is probably exerted through 5-HT2-receptor antagonism.     

Terpenes in organic synthesis. 8. Synthesis of optically active (2R/S, 3S, 7R/S)-(-)-diprionyl acetate from (S)-(+)-3,7-dimethyl-1,6-octadiene

Conclusions A seven-stage synthesis has given optically active (2R/S, 3S, 7R/S)-2-acetoxy-3,7-dimethylpentadecane from the readily available (S)-(+)-3,7-dimethyl-1,6-octadiene, in an overall yield of 36%. The synthetic route utilizes all ten carbon atoms of the starting chiral diene.For previous communication, see [1].Translated from Izvestiya Akademii Nauk SSSR, Seriya Khimicheskaya, No. 5, pp. 1142–1146, May, 1988.     

erythro-1-Naphthyl-1-(2-piperidyl)methanol: synthesis,resolution, NMR relative configuration,and VCD absolute configuration

The erythro isomer of 1-naphthyl-1-(2-piperidyl)methanol 4, an efficient chiral modifier for asymmetric heterogeneous hydrogenation, was obtained as the major isomer (95%) in two steps while the threo isomer can be obtained as the major isomer (67%) in three steps. erythro-4 and threo-4 were resolved on a CHIRALCEL OD-RH column. It has been shown by VCD that the diastereomer determined as the erythro by NMR was indeed the erythro and that the first eluted (-)-enantiomer on CHIRALCEL OD-R or -RH columns has the (1R,2S) configuration. The VCD studies identify the presence of at least five conformers in CDCl(3) solution. Moreover, this (-)-(1R,2S) absolute configuration found by VCD is consistent with the expected stereo-outcome of catalytic hydrogenation of pyruvate into lactate, which supported the (+)-(1S,2R) assignment.     

Asymmetric synthesis,stereochemistry, and absolute configuration of 1,2-5-trimethyl-5-(2-cyanoethyl)- and 1,2,5-trimethyl-4-piperidinones

The asymmetric Michael alkylation of (–)-1,2,5-trimethyl-4-(1S-phenylethylimino)piperidine by electrondeficient alkenes proceeds with the formation of(+)-cis-(2S,5S)- and (–)-trans-(2R,5S) diastereomers of 1,2,5-trimethyl-5-(2-cyanoethyl)- and 1,2,5-trimethyl-5-(2-methoxycarbonylethyl)-4-piperidinones containing a chiral quaternary center C(₅). The spatial structure of these new chiral 4-piperidinones has been established on the basis of ¹H and ¹³C NMR spectroscopic data. The absolute configuration of the C(₂) and c(₅) chiral centers in the diastereomers has been determined by stereochemical correlation on the basis of circular dichroism data.Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 10, pp. 1369–1378, October, 1992.     

Stereoselective Synthesis and Complexation of a New Chiral Hybrid Phosphine-Phosphine Oxide Ligand from (S)-(+)-Prolinol

Abstract

The synthesis and the complex formation of chiral heterotopic ligands with two different binding sites each capable of bonding a different type of metal are described. The action of bis(dimethylamino) aryl phosphine on (S)-(+)-prolinol gives rise to the kinetic stereoisomer (2S,4S)-2-phenyl-1,3,2-oxazaphospholidine 1 and the thermodynamic stereoisomer (2R,4S)-2-phenyl-1,3,2-oxazaphospholidine 2. 1 is then totally converted into 2 at the end of the reaction. The Michaelis Arbuzov reaction of 2 with benzylbromide affords (R_p)-benzylaryl-(2-(S)-bromomethyl pyrrolidine-1-yl) phosphine oxide 3 in 80% yield. Compound 3 is an ideal chiral precursor for the synthesis of chiral hybrid phosphine-phosphine oxide ligands. The bromide atom is smoothly displaced by lithium diphenylphosphide to afford in 80% yield (R_p)-benzylaryl-(2-(S)-diphenylphosphinomethylpyrrolidine-1-yl) phosphine oxide 5. These reaction are proved to be totally stereoselective : the Michaelis Arbuzov reaction does not change the configuration at C2 in the proline ring. The relative configuration (R_p) of 5 (aryl = phenyl) was determinated by X-ray diffraction, from the known configuration of (S)-(+)-prolinol.     

Efficient syntheses of four stable-isotope labeled (1R)-menthyl (1S,2S)-(+)-2-phenylcyclopropanecarboxylates

Many carbenoid cyclopropanation reactions promoted by chiral catalysts give product mixtures reflecting impressive diastereo- and enantioselectivities. Few provide a single chiral product efficiently. This limitation has been overcome in cyclopropanations of styrene and isotopically labeled styrenes with alpha-diazoacetates. Convenient syntheses on a 20 g scale of each of four chiral isotopically labeled (1R)-menthyl (1S,2S)-2-phenylcyclopropanecarboxylates (the 1-d-3-(13)C, 1,(3S)-d2, 1,2,(3S)-d3, and 1,3,3-d3 isotopomers) of better than 99% ee have been realized.     

Total synthesis of (S)-(+)-curcudiol, and (S)-(+)- and (R)-(-)-curcuphenol.

A highly enantioselective synthesis of the versatile chiral synthons possessing one stereogenic center, (S)- and (R)-4-aryl-5-hydroxy-(2E)-pentenoate (3) was achieved based on the enzymatic reaction of (+/-)-3 with commercially available lipases MY-30 or OF-360 from Candida rugosa. Application of (S)-3 and (R)-3 to the total syntheses of(S)-curcuphenol (1), (S)-curcudiol (2), and (R)-curcuphenol (1), respectively, is described.     

Gamma-radiolysis of chiral molecules: R(+)-limonene, S(-)-limonene and R(-)-a-phellandrene

Three isomeric chiral terpenes, R(+)-limonene, S(-)-limonene and R(-)-a-phellandrene were γ-radiolyzed in sealed vials at room temperature with a total radiation dose of 317 kGy. The radiolyzed samples were analyzed by FT-IR, electronic absorption spectroscopy, liquid chromatography using a diode-array detector (HPLC-DAD) and by polarimetry. Despite a relatively high radiation dose used, all the chiral molecules selected have shown a low radioracemization rate. This fact and the role played by the impurities in the selective radio-degradation of one of the two enantiomers has been discussed in the context of the origin of chirality in prebiotic molecules and the chirality enhancement in a prebiotic world. The results were also discussed in the frame of the radiosterilization technique of chiral drugs, perfumes and food components. This revised version was published online in July 2006 with corrections to the Cover Date.     

Synthese et configuration absolue de terpenes naturels: (+) uroterpenol, (+) et (−) α-bisabolols, (−) α-bisabololone

Stereoisomers of 8,9-epoxy p-menthene-1 have been synthetised and after separation their absolute configurations have been determined. From the (+)-epoxides we obtained isomers of (+)-uroterpenol and (+)-α-bisabolol. From the (?)-epoxides we obtained isomers of (?)-α-bisabololone. Natural (+)-and (?)-α-bisabolols are of configuration (4R, 8S) and (4S, 8R) respectively. Natural (?)-a-bisabololone has the (4S, 8R) configuration.     

Enantioselective synthesis of (S)-(+)-pantolactone

[reaction: see text] The Prins reaction of a chiral alkylidene morpholinone derived from (1R,2S)-ephedrine and 3-methyl-2-oxobutanoic acid proceeds with good diastereoselectivity to generate a spiro bis-acetal. Lewis acid mediated diastereoselective reductive cleavage of the spiro acetal and subsequent removal of the ephedrine portion generates a alpha-hydroxy-gamma-methoxy carboxamide which is readily converted to (S)-(+)-pantolactone with high enantiomeric excess.     

Studies on the constituents of Gentiana species. II. A new triterpenoid,and (S)-(+)- and (R)-(-)-gentiolactones from Gentiana lutea

A new triterpenoid, 12-ursene-3beta, 11alpha-diol 3-O-palmitate (1), has been isolated from the rhizomes and roots of Gentiana lutea, together with the artificial diene derivative, 9 (11), 12-ursadien-3beta-ol 3-O-palmitate (1a) and five known compounds (3-7). Their structures were established on the basis of spectral analysis. In addition, (+/-)-gentiolactone [(+/-)-2], isolated from this plant, was successfully separated into its enantiomers [(+)-2, (-)-2] for the first time, and the absolute configurations at C-9 of (+)-2, (-)-2 were assigned as S and R, respectively, from the optical rotations and the circular dichroism (CD) spectral data.     

Synthesis of chiral glycolurils from (<Emphasis Type="Italic">S</Emphasis>)-(+)- and (<Emphasis Type="Italic">R</Emphasis>)-(-)-1-<Emphasis Type="Italic">sec</Emphasis>-butyl-3-methylurea

Chiral dialkyl- and tetraalkylglycolurils have been obtained using chiral (S)-(+)- and (R)-(-)-1-sec-butyl-3-methylurea as starting materials. The diastereomer (S)-(+)-2,6-di-sec-butyl-4,8-dimethyl-2,4,6,8-tetraazabicyclo[3.3.0]-octane-3,7-dione was separated into stereoisomers, for the higher melting of which the absolute configuration was determined as (S,S,S,S) by X-ray structural analysis.