Asymmetric cyclization-carbonylation of 2-alkyl-2-propargylcyclohexane-1,3-diones: facile access to optically active hydrindanes

Oxidative cyclization-carbonylation of 2-alkyl-2-propargylcyclohexane-1,3-diones mediated by Pd(TFA)₂/2,2′-isopropylidenebis[(4R)-4-(3,4-dimethoxyphenyl)-2-oxazoline] 28 afforded bicyclic-β-alkoxyacrylates in 51-74% yields with 72-82% ee. The products containing quaternary carbon were converted to optically active hydrindanes 33.     

Non-C2-symmetrical antimony-phosphorus ligand, (R/S)-2-diphenylphosphano-2′-di(p-tolyl)stibano-1,1′-binaphthyl (BINAPSb): preparation and its use for asymmetric reactions as a chiral auxiliary

A new non-C₂-symmetrical antimony-phosphorous ligand, (±)-2-diphenyl-phosphano-2′-di(p-tolyl)stibano-1,1′-binaphthyl (BINAPSb) 3, has been prepared from 2-bromo-2′-diphenylphosphano-1,1′-naphthyl 4 via its borane complex 6, and could be resolved by the separation of a mixture of the diastereomeric palladium complexes 8A and 8B derived from the reaction of (±)-3 with optically active palladium reagent (S)-7. The enantiomerically pure BINAPSb 3 has proved to be highly effective in the palladium-catalyzed asymmetric hydrosilylation of styrene as a chiral auxiliary.     

Catalytic asymmetric synthesis of ethyl (1R,2S)-dehydrocoronamate

A synthesis of (1R,2S)-dehydrocoronamic acid ethyl ester was developed employing a regio- and enantioselective palladium-catalysed nucleophilic ring-opening of 3,4-epoxy-1-butene with a glycine anion equivalent as the key enantiodifferentiating step. The desired selectivity was achieved using Trost’s naphthyl ligand. The subsequent activation of the free hydroxyl group and ring-closure by intramolecular S_N2 reaction gave the desired amino acid ethyl ester.     

Synthesis of (±)-2R,4R,5S-2-methoxy-4-nitro-5-(2,3,4-trimethoxyphenyl)cyclohexanone and (±)-2R,4S,5R-2-methoxy-5-nitro-4-(2,3,4-trimethoxyphenyl)cyclohexanone as colchicine mimetics

Colchicine mimetic (±)-4S,5R-4-nitro-5-(2,3,4-trimethoxyphenyl)cyclohexene (1) was epoxidized to afford a mixture of epoxides. The epoxides were separately converted in two steps, with high stereoselectivity, to two regioisomeric α-methoxyketones. One regioisomer, (±)-2R,4S,5R-2-methoxy-5-nitro-4-(2,3,4-trimethoxyphenyl)cyclohexanone (17), proved to be about 12-fold more potent than synthetic precursor 1 against HCT-116 tumor cells while the other regioisomer, (±)-2R,4R,5S-2-methoxy-4-nitro-5-(2,3,4-trimethoxyphenyl)cyclohexanone (16), and the synthetic intermediates tested showed no improvement in potency.     

An efficient stereoselective synthesis of (2S,4S,5R)-(−)- and (2R,4R,5S)-(+)-bulgecinine

A short synthetic route to (−)-and (+)-bulgecinine, the amino acid moiety of the bulgecins was achieved from the readily available nonchiral pool starting material cis-2-butene-1,4-diol in which a Claisen orthoester rearrangement and a Sharpless asymmetric dihydroxylation were used as the key steps.     

Lewis acid-catalyzed asymmetric radical additions of trialkylboranes to (1R,2S,5R)-2-(1-methyl-1-phenylethyl)-5-methylcyclohexyl-2H-azirine-3-carboxylate

The asymmetric addition of alkyl radicals to (1R,2S,5R)-2-(1-methyl-1-phenylethyl)-5-methylcyclohexyl-2H-azirine-3-carboxylate (1) yielding the corresponding 2-alkylaziridine-2-carboxylates has been investigated. High diastereoselectivities and good yields were obtained in the addition of primary alkyl radicals to azirine 1, while secondary radicals gave a lower dr. The influence of Lewis acids was also investigated; 10 mol% of CuCl were found to increase the dr.     

Pd-catalyzed asymmetric allylic alkylation with nitromethane using a chiral diaminophosphine oxide: (S,RP)-Ph-DIAPHOX. Enantioselective synthesis of (R)-preclamol and (R)-baclofen

A Pd-catalyzed asymmetric allylic alkylation with nitromethane using an aspartic acid-derived P-chirogenic diaminophosphine oxide [(S,R_P)-Ph-DIAPHOX] is described. This method was successfully applied to enantioselective synthesis of (R)-preclamol and (R)-baclofen.     

The synthesis and reactions of a monocyclic β-lactam tripeptide, 1-[(1R)-carboxy-2-methylpropyl]- (3R -[(5S-5-amino- 5-carboxypentanamido]-(4R)-mercaptoazetidin-2-one,a putative intermediate in penicillin biosynthesis

The disulphide corresponding to the above thiol has been synthesised, but all attempts to reduce this substance to the thiol were unsuccessful, although an alternative procedure via a thiomercury intermediate, enabled the thiol to be generated in situ, the properties of this thiol, however, are not in accord with those previously described for a putative free intermediate in penicillin biosynthesis.¹     

Straightforward synthesis of (R,R/S,S)-2-[2-(2-aryl)-1-phenyl-ethyl]-morpholines: a new class of inhibitors of the norepinephrine transporter

Diastereoselective synthesis of (R,R/S,S)-2-[2-(2-aryl)-1-phenyl-ethyl]-morpholines 6 has been achieved through the preparation of key E-enol-triflate 4 and its further coupling with benzylzinc reagents and final hydrogenation.     

Enantioselective synthesis of (2S,3′R,7′Z)-N-(3′-hydroxy-7′-tetradecenoyl)-homoserine lactone

A concise enantioselective total synthesis of (2S,3′R,7′Z)-N-(3′-hydroxy-7′-tetradecenoyl)-homoserine lactone is described. Key feature of this protocol is a catalytic asymmetric hydrogenation and a prophenol-zinc-catalyzed diazo addition to imine reaction as genesis of chirality. Moreover, flexibility is built in the synthesis to generate enantioenriched analogs using catalytic amount of enantioenriched C₂-symmetric ligands.     

Asymmetric synthesis of (R)- and (S)-2-trifluoromethylepinephrine

An asymmetric synthesis of (R)- and (S)-2-trifluoromethylepinephrine (1R and 1S) is presented. Trifluoromethylation involves nucleophilic aromatic substitution of halobenzene 4 most likely via a copper mediated CF₃ anion equivalent generated in situ. The asymmetric step involves conversion of 3,4-dimethoxy-2-trifluoromethylbenzaldehyde (5) to silyl cyanohydrin (6R and 6S) using a chiral salen catalyst in the presence of titanium. 1R and 1S are potential alternatives to currently used vasoconstrictors in local anesthetic formulations.     

Concise and practical synthesis of (2S,3R,4R,5R) and (2S,3R,4R,5S)-1,6-dideoxy-1,6-iminosugars

The syntheses of (2S,3R,4R,5R) and (2S,3R,4R,5S)-1,6-dideoxy-1,6 iminosugars 1a and 1b, respectively, from d-glucose are described. The key transformations in this reaction sequence include regio-selective epoxide ring opening with N-benzylamine followed by intramolecular reductive amination of amino-aldehyde.     

Formal syntheses of (−)- and (+)-aphanorphine from (2S,4R)-4-hydroxyproline

We describe the efficient formal syntheses of both natural (−)-aphanorphine and unnatural (+)-aphanorphine from the same commercially available amino acid, (2S,4R)-4-hydroxyproline. The tricyclic framework was constructed by intramolecular Friedel-Crafts reaction. (1R,4S)-1-Methyl-8-methoxy-3-(4-toluenesulfonyl)-2,3,4,5-tetrahydro-1,4-methano-3-benzazepine (8) was synthesized in six steps from sulfonamide 3; (−)-aphanorphine methyl ether 24 was obtained in seven steps from lactone 10. Intramolecular etherification of 18 proceeded with excellent stereoselectivity in the presence of BF₃·OEt₂, which has paved an efficient synthetic route to a series of medicinally attractive heterocycles.     

Stereoselective synthesis of (1R,2S)- and (1S,2R)-1-amino-cis-3-azabicyclo[4.4.0]decan-2,4-dione hydrochlorides: bicyclic glutamic acid derivatives

Asymmetric synthesis of (1R,2S)- and (1S,2R)-1-amino-cis-3-azabicyclo[4.4.0]decan-2,4-diones has been achieved. The underlying second generation asymmetric synthesis proceeds via a Strecker reaction with commercially available (R)-1-phenylethylamine (1-PEA) as chiral auxiliary, TMSCN as cyanide source and racemic ethyl 2-(2-oxocyclohex-1-yl)ethanoate. A ring closure addition-elimination reaction between an amide nitrogen and the ester functionality leads to the 1-amino-3-azabicyclo[4.4.0]decan-2,4-diones. The absolute configurations of the title compounds have been assigned based on detailed NMR-spectroscopic analysis and X-ray data.     

Studies on the aza-Claisen rearrangement of 4,5-dihydroxylated allylic trichloroacetimidates: the stereoselective synthesis of (2R,3S)- and (2S,3S)-2-amino-3,4-dihydroxybutyric acids

Two new synthetic approaches, involving substrate directed aza-Claisen rearrangements and aza-Claisen rearrangements mediated by chiral Pd(II) catalysts, have been developed for the stereoselective synthesis of (2R,3S)-2-amino-3,4-dihydroxybutyric acid, a dihydroxylated α-amino acid from the edible mushroom, Lyophyllum ulmarium and its (2S,3S)-unnatural diastereomer.     

Total synthesis of (3S,4S,2′S)- and (3R,4R,2′S)-viridiofungin A triester

The total synthesis of an alkylcitrate secondary metabolite from the fungi Trichoderma viride is described. An ester dienolate [2,3]-Wittig rearrangement and a S. Julia-Kocienski olefination served as key C/C-connecting transformations. The highly convergent synthesis consists of a longest linear sequence of 17 steps.     

Synthesis and structure of chiral-at-metal complexes with the ligand (S)-2-[(Sp)-2-(diphenylphosphino)ferrocenyl]-4-isopropyloxazoline

Half-sandwich complexes of formula [(ηⁿ-ring)MClL]PF₆ [L = (S)-2-[(S_p)-2-(diphenylphosphino)ferrocenyl]-4-isopropyloxazoline; (ηⁿ-ring)M = (η⁵-C₅Me₅)Rh; (η⁵-C₅Me₅)Ir; (η⁶-p-MeC₆H₄iPr)Ru; (η⁶-p-MeC₆H₄iPr)Os] have been prepared and spectroscopically characterised. The molecular structures of the rhodium and iridium compounds have been determined by X-ray crystallography. The related solvate complexes [(η⁵-C₅Me₅)ML(Me₂CO)]²⁺ (M = Rh, Ir) are active catalysts for the Diels-Alder reaction between methacrolein and cyclopentadiene.     

Synthesis of 3,3′-disubstituted-2,2′-biindolyls through sequential palladium-catalysed reactions of 2,2,2-trifluoro-N-(2-(4-[2,2,2-trifluoro-acetylamino)-phenyl]-buta-1,3-diynyl)-phenyl)-acetamide with organic halides/triflates

Palladium-catalysed reactions of aryl iodides/vinyl triflates with 2,2,2-trifluoro-N-(2-(4-[2,2,2-trifluoro-acetylamino)-phenyl]-buta-1,3-diynyl)-phenyl)-acetamide provide a straightforward entry into 3,3′-disubstituted-2,2′-biindolyls. Subsequent application of the procedure to homochiral aryl iodides affords the corresponding chiral 3,3′-disubstituted-2,2′-biindolyls. The methodology can also be applied to the synthesis of benzo[c]indolo[2,3-a]carbazoles.     

Operationally convenient asymmetric synthesis of (S)- and (R)-3-amino-4,4,4-trifluorobutanoic acid: Part II. Enantioselective biomimetic transamination of 4,4,4-trifluoro-3-oxo-N-[(R)-1-phenylethyl]butanamide

An asymmetric synthesis of (S)- and (R)-3-amino-4,4,4-trifluorobutanoic acid via DBU-catalyzed asymmetric 1,3-proton shift transfer reaction of (Z)-3-[(R)-1-phenylethylamino]-4,4,4-trifluoro-N-[(R)-1-phenylethyl]but-2-enamide has been developed. The intermediate Schiff base (S,R′)-9 was found to be relatively configurationally stable under the highly basic reaction conditions allowing preparation of the target amino acid in high chemical yield and enantioselectivity. This method was demonstrated to be practical for large (>25 g) scale synthesis of the target β-amino acid.     

(R)-6,6′-Bis(trifluoromethanesulfonyl)-2,2′-dihydroxy-1,1′-binaphthyl: a new ligand for asymmetric synthesis

The new (R)-6,6′-bis(trifluoromethanesulfonyl)-2,2′-dihydroxy-1,1′-binaphthyl (1) has been synthesized and proved to generate highly active zirconium-based catalysts for asymmetric Mannich-type reactions.