Synthesis of chiral epoxyalkynes

The synthesis of novel chiral propargylic epoxides ((R)-1-t-butyldimethylsilyl-3,4-epoxy-1-butyne, (3S,4S)-3,4-epoxy-1-octyne, (3R,4S)-1-t-butyldimethylsilyl-3,4-epoxy-1-pentyne) has been developed starting from the readily available tartaric acid derivative, (S,S)-(+)-2,3-O-isopropylidene-L-threitol.     

Beta-hydroxy-gamma-lactones as chiral building blocks for the enantioselective synthesis of marine natural products

The enantioselective synthesis of trans-(+)-laurediol, (2S,3S,5R)-5-[(1R)-1-hydroxy-9-decenyl]-2-pentyltetrahydro-3-furanol, and (2S,3S,5S)-5-[(1S)-1-hydroxy-9-decenyl]-2-pentyltetrahydro-3-furanol are described. In addition, a formal synthesis of trans-(-)-kumausyne is also developed. All the synthetic procedures have in common the use of enantiomerically enriched beta-hydroxy-gamma-lactones, easily available by Sharpless asymmetric dihydroxylation (AD) from the suitable beta,gamma-unsaturated ester. The use of Katsuki-Sharpless asymmetric epoxidation (AE) as an additional enantioselective reaction provides cyclic compounds of high enantiomeric purity.     

Asymmetric synthesis of (+)-lentiginosine using a chiral aziridine based approach

The synthesis of the indolizidine alkaloid, (+)-lentiginosine, is described. A key feature of the preparative route is the efficient and stereoselective construction of a dihydroxylated pyrrolidine via Sharpless asymmetric dihydroxylation of an aziridine-enoate, which was prepared from commercially available 1-(S)-α-methylbenzylaziridine-2-methanol. In addition, a regioselective aziridine-to-pyrrolidinone ring expansion process followed by a Wittig olefination was employed to construct a late stage pyrrolidine intermediate that was transformed into (+)-lentiginosine.     

Synthesis of chiral chromans by the Pd-catalyzed asymmetric allylic alkylation (AAA): scope, mechanism, and applications

The Pd-catalyzed asymmetric allylic alkylation (AAA) of phenol allyl carbonates serves as an efficient strategy to construct the allylic C-O bond allowing access to chiral chromans in up to 98% ee. The effect of pH and the influence of olefin geometry, as well as substitution pattern on the ee and the absolute configuration of the chiral chromans were explored in detail. These observations suggest a mechanism involving the cyclization of the more reactive pi-allyl palladium diastereomeric intermediate as the enantiodiscriminating step (Curtin-Hammett conditions). This methodology led to the enantioselective synthesis of the vitamin E core, the first enantioselective total synthesis of (+)-clusifoliol and (-)-siccanin, and the synthesis of an advanced intermediate toward (+)-rhododaurichromanic acid A.     

Congeners of Troeger's base as chiral ligands

(S)-(+)-Troeger's base can be deprotonated and alkylated without loss of stereochemical integrity. An examination of the ability of Troeger's base and several derivatives prepared in this fashion to effect asymmetric induction in the addition of diethylzinc to aromatic aldehydes was conducted. Enantiomeric excesses as high as 86% were achieved, providing evidence that Troeger's base represents a chiral framework which can be modified to produce ligands for catalytic asymmetric synthesis.     

Prototropic acetylene-allene isomerization in planarly chiral ferrocenes. Intramolecular acymmetric induction in the course of the formation of chiral axis

Racemic 2-trimethylsilyl- and 2-trimethylstannyl-1-(3-phenyl-2-propynyl)ferrocene (rac-1a,b) as well as the dextrorotatory specimen of the latter, (+)-1b, were synthesized in two steps from racemic 1-formyl-2-trimethylsilyl- and 1-formyl-2-trimethylstannylferrocenes (2a,b) or from the levorotatory specimen of the latter, (–)-2b, respectively. On the contact with strongly alkaline alumina compounds1a,b and (+)-1b undergo diastereoselective prototropic acetylene-allene rearrangement to give predominantly one of the two possible stereoisomers of 2-trimethylsilyl- or 2-trimethylstannyl-1-(3-phenyl-1,2-propadienyl)ferrocenes,rac-4a,b or (+)-4b, depending on the starting material (d. e. 30–40 %). The extent of intramolecular asymmetric induction in the formation of the axially chiral fragment during the transformation of (+)-1b to (+)-4b is estimated at 38 %.Translated fromIzvestiya Akademii Nauk. Seriya Khimicheskaya, No. 6, pp. 1111– 1115, June, 1994.The work was carried out with financial support from the Russian Fundamental for Basic Research (Project No.93-03-5827).     

Achiral auxiliary-assisted chiral transfer via microwave-accelerated aza-Claisen rearrangement: a short synthesis of (+)-1-hydroxyquinolizidinone

A short and efficient synthesis of (+)-1-hydroxyquinolizidinone as an advanced core intermediate for the syntheses of (+)-epiquinamide, (+)-homopumiliotoxin, and (+)-lupinine is described. The key feature of our strategy includes a sequential chiral transfer using an achiral phenylsulfide auxiliary via microwave-accelerated aza-Claisen rearrangement of the unexplored N-thiophenoxyacetyl-α-vinyl piperidine substrate and the oxone-induced transannulation.     

Ligand self-recognition in the stereoselective assembly of [2 + 2] metallomacrocycles from racemic chiral bisbipyridyl molecular clefts and zinc(II)

The synthesis of racemic and optically pure ligand L, in which two 6,6'-disubstituted bipyridines are connected by methyleneoxy linkers to the molecular cleft dibenzobicyclo[b,f][3.3.1]nona-5a,6a-diene-6,12-dione, is reported. In the presence of 2 equivalents of zinc(ii) trifluoromethansulfonate (+/-)- undergoes slow reversible coordination over 24 h to form a pair of enantiomeric [2 + 2] metallomacrocycles, [Zn2(+)L2](OTf)(4) and [Zn2(-)L2](OTf)(4) respectively, that contain either two (+)-L ligands or two (-)-L ligands. This assignment was confirmed by independent studies with either (+)-L or (-)-L which formed the same complexes but at a significantly faster rate (3 h), and circular dichroism spectra of [Zn2(+)L2](OTf)(4) and [Zn2(-)L2](OTf)(4) which gave signals of the same intensity with the opposite sign. Treatment of (+/-)-L or optically pure L with copper(I) showed rapid formation of a mixture of oligomers as well as the [2 + 2] metallomacrocycle. The complex Zn2L2(OTf)(4) exhibits slow exchange between two species on the NMR time scale at room temperature. The results are consistent with the formation of a library of metal complexes in which the zinc(ii) binds initially to the most accessible bipyridyl binding sites in (+/-)-. Equilibration over several hours results in self-recognition of enantiomeric ligands to form a pair of enantiomeric metallomacrocycles, which have been tentatively assigned as having the helical configuration. Slow exchange is attributed to the preference for both metal centres to adopt 6-coordinate geometries involving the linker oxygens, but are limited to exchanging 5-coordinate complexes due to the shape of the cleft and the short linker.     

Catalytic, asymmetric trans-selective hetero Diels-Alder reactions using a chiral zirconium complex

[reaction: see text] The first catalytic, asymmetric 2,3-trans-selective hetero Diels-Alder reaction has been developed. The reactions of aldehydes with Danishefsky's dienes proceeded smoothly to afford the pyranone derivatives in high yields with high trans-selectivities and enantioselectivities in the presence of a chiral zirconium complex, which was prepared from zirconium tert-butoxide and (R)-3,3'-diiodobinaphthol or its derivatives, primary alcohol, and a small amount of water. This reaction was applied to the concise synthesis of (+)-prelactone C.     

Synthesis of planar chiral ferrocene dicarboxylic acids using a sugar derivative as a resolution tool

The synthesis of planar chiral ferrocene dicarboxylic acids has been accomplished via diastereoselective esterification at the 2- and 3-positions with (+)-(4,6-O-benzylidene)methyl-α-d-glucopyranoside.     

N-isopropylsulfinylimines as useful intermediates in the synthesis of chiral amines: expeditive asymmetric synthesis of the calcimimetic (+)-NPS R-568

An efficient and high-yielding approach for the asymmetric synthesis of calcimimetic (+)-NPS R-568 (1) has been developed. The key step of the synthesis is the highly diastereoselective addition of methyl Grignard to the (SS,E)-N-(3-methoxybenzylidene)-2-propanesulfinamide [5(S)], which afforded a single diastereoisomer in high yield in short reaction time.     

A practical new chiral controller for asymmetric Diels-Alder and alkylation reactions

[formula: see text] The enantiomerically pure hydroxy sulfones (+)- and (-)-2 have been prepared from 1,2-epoxycyclohexane by a simple and practical procedure. The acrylate esters of these alcohols undergo BCl3-catalyzed Diels-Alder reactions with a variety of dienes at -78 to -55 degrees C in CH2Cl2 or C7H8 with high dienophile face selectivity (Table 1). The chiral esters so formed are readily cleaved with recovery of the controllers (+)- or (-)-2. Esters of (+)- and (-)-2 can be converted to Z-potassium enolates and alkylated with high face selectivity.     

Synthesis and characterization of new chiral liquid crystalline polyacrylates from L-isoleucine

The synthesis of chiral side chain liquid crystalline polyacrylates with a two-stereogenic centre from L-alpha-aminoacid is described. The chiral tail is 2-chloroalcohol obtained from L-isoleucine and the spacer group has either four or eleven methylene units. The mesogenic moiety is derived from phenyl benzoate. The stereochemistry of the key intermediate (2 S ,3 S )-(+)-4- [1-(2-chloro-3-methyl)pentyloxy]phenyl benzoate ( 6 ) obtained by a Mitsunobu reaction was established by single crystal X-ray analysis. This result indicates that the nucleophilic displacement of chiral diazonium salts proceeds with overall retention of configuration. The liquid crystalline behaviour of polyacrylates P 13 and P 14 was investigated by DSC, optical microscopy, small angle X-ray scattering and depolarized light scattering. The polyacrylate P 13 , with eleven methylene units in the spacer, exhibits a chiral smectic A phase whereas the polyacrylate P 14 , with a spacer containing four methylene units, displays a chiral nematic phase.     

Synthesis and characterization of new chiral liquid crystalline polyacrylates from L-isoleucine

The synthesis of chiral side chain liquid crystalline polyacrylates with a two-stereogenic centre from L-α-aminoacid is described. The chiral tail is 2-chloroalcohol obtained from L-isoleucine and the spacer group has either four or eleven methylene units. The mesogenic moiety is derived from phenyl benzoate. The stereochemistry of the key intermediate (2S,3S)-(+)-4- [1-(2-chloro-3-methyl)pentyloxy]phenyl benzoate (6) obtained by a Mitsunobu reaction was established by single crystal X-ray analysis. This result indicates that the nucleophilic displacement of chiral diazonium salts proceeds with overall retention of configuration. The liquid crystalline behaviour of polyacrylates P13 and P14 was investigated by DSC, optical microscopy, small angle X-ray scattering and depolarized light scattering. The polyacrylate P13, with eleven methylene units in the spacer, exhibits a chiral smectic A phase whereas the polyacrylate P14, with a spacer containing four methylene units, displays a chiral nematic phase.     

Enzymatic synthesis of a chiral chalcogran intermediate

Two lipases, Novozyme 435 (lipase B from Candida Antarctica) and Lipozyme TL IM (Thermomyces lanuginosus) were used successfully for the kinetic resolution of racemic 1-(2-furyl)-3-pentanol, the key intermediate in synthesis of the bark beetle pheromone, chalcogran. The desired S-(+)-enantiomer was prepared in enantiomeric excesses higher than 98 % and with yields of 26.3 % and 32.5 %, respectively. Methyl tert-butyl ether and vinyl acetate were found to be the best reaction media and the acetyl donor to achieve fast and effective resolution.     

Practical synthesis of chiral ligands for catalytic enantioselective cyanosilylation of ketones and ketoimines

A practical synthesis of chiral ligands that are useful for catalytic enantioselective cyanosilylation of ketones and ketoimines is described. Compared with the previous synthetic route, the number of total steps is decreased and the total yield is greatly improved. Furthermore, both (+)- and (-)-ligands are readily available by this new synthetic route.     

PuPHOS: a synthetically useful chiral bidentate ligand for the intermolecular Pauson-Khand reaction

Here we describe the synthesis and use of the Pulegone-derived bidentate P,S ligands PuPHOS and CyPuPHOS in the intermolecular Pauson-Khand reaction. Ligand exchange reaction of hexacarbonyldicobalt-alkyne complexes with PuPHOS provides a diasteromeric mixture of complexes (up to 4.5:1) from which the major isomers can be conveniently separated by simple crystallization. An isomerization-crystallization sequence of the original mixture results in a dynamic resolution that allows the preparation of the pure major Co(2)(mu-TMSC(2)H)(CO)(4)-PuPHOS (15a) in a multigram scale. Pauson-Khand reaction of 15a with norbornadiene provided, for the first time, the corresponding enone 18 with up to 93% yield and 97% ee. The use of (+)-18 as a surrogate of chiral cyclopentadienone is also demonstrated. Copper-catalyzed Michael addition of a Grignard reagent followed by removal of the TMS group with TBAF were the most reliable methods to transform (+)-18 into valuable starting materials 20a-e for the enantioselective synthesis of cyclopentenoid systems.     

Synthetic studies on nogalamycin congeners [2]1,2 chiral synthesis of the cdef-ring system of nogalamycin

The chiral synthesis of the (+)-naphthoquinone (4), the CDEF-ring system of nogalamycin congeners, has been accomplished following the synthetic scheme developed for the model (-)-DEF-ring system (3) in the preceding paper. This synthesis features (1) stereoselective construction of the C5'-asymmetric center by introducing the naphthalene moiety into the (-)-methyl ketone (5), the glycoside part, (2) regio-selective oxidation of the 1,4,5,8-tetramethoxynaphthalene moiety with cerium(III) ammonium nitrate , and (3) efficient formation of bicyclic acetal system.     

Synthesis and characterization of some new C2 symmetric chiral bisamide ligands derived from chiral Feist's acid

The hemilabile chiral C2 symmetrical bidentate substituted amide ligands (1R,2R)-5(a-d) and (1S,2S)-6(a-d) were synthesized in quantitative yield from (1R,2R)-(+)-3-methylenecyclo-propane-1,2-dicarboxylic acid (1R,2R)-3 and (1S,2S)-(-)-3-methylene-cyclopropane-1,2-dicarboxylic acid (1S,2S)-3, in two steps, respectively. The chiral Feist's acids (1R,2R)-3 and (1S,2S)-3 were obtained in good isomeric purity by resolution of trans-(±)-3-methylene-cyclopropane-1,2-dicarboxylic acid from an 8:2 mixture of tert-butanol and water, using (R)-(+)-α-methylbenzyl amine as a chiral reagent. This process is reproducible on a large scale. All these new synthesized chiral ligands were characterized by 1H-NMR, 13C-NMR, IR, and mass spectrometry, as well as elemental analysis and their specific rotations were measured. These new classes of C2 symmetric chiral bisamide ligands could be of special interest in asymmetric transformations.     

Chiral amines as reagents for HPLC-MS enantioseparation of chiral carboxylic acids

Mass spectrometry (MS) has become a popular analytical technique because of its high sensitivity and specificity. Therefore, the use of a chiral derivatization reagent for the MS detection seems to be efficient for the enantiomeric separation of racemates. However, the number of chiral reagents for the liquid chromatography (LC)-tandem mass spectrometry (MS/MS) analysis is very limited. The applicability of commercially available chiral amines as the derivatization reagents for the enantiomeric separation of chiral carboxylic acids is reported in this paper by using non-steroidal anti-inflammatory drugs (NSAIDs), i.e. ibuprofen, flurbiprofen, and loxoprofen. The efficiency of the chiral reagents was evaluated in terms of tagging easiness, separation by reversed-phase chromatography, and detection sensitivity by electrospray ionization (ESI)-MS/MS. Among the tested eight chiral amines, i.e. (R)-(+)-4-(3-aminopyrrolidin-1-yl)-7-(N,N-dimethylaminosulfonyl)-2,1,3-benzoxadiazole (DBD-APy), (S)-(+)-1-(2-pyrrolidinylmethyl)-pyrrolidine (PMP), L-prolinamide, (3R)-(-)-1-benzyl-3-aminopyrrolidine, (S)-(+)-1-cyclohexyl-ethylamine, (3R)-(+)-3-(trifluoroacetamido)-pyrrolidine (TFAP), (R)-(-)-1-aminoindan (AI), and (S)-(+)-tetrahydrofurfuryl-amine, DBD-APy, PMP, AI, and TFAP could be used as the chiral reagents for the enantiomeric separation of the NSAIDs. The Rs values and the detection limits of the derivatives were in the range of 1.29-3.85 and 0.57-0.96 fmol, respectively. These four reagents were applied for the determination of the NSAIDs in rat plasma.