Synthesis of new mono-N-tosylated diamine ligands based on (R)-(+)-limonene and their application in asymmetric transfer hydrogenation of ketones and imines

A synthetic procedure leading to the preparation of a new family of enantiopure mono-N-tosylated-1,2-diamines derived from (R)-(+)-limonene is described. (+)-Limonene was transformed into the appropriate N-tosyl derivative using N-tosylaziridination based on chloramine-T trihydrate. Subsequent ring opening by sodium azide afforded the corresponding isomeric azides. Finally, reduction of the azide function gave enantiomerically pure mono-N-tosylated-1,2-diamines. The ligands obtained proved to be effective in the asymmetric transfer hydrogenation protocol on aromatic ketones and imines.     

Bacillus subtilis epoxide hydrolase-catalyzed preparation of enantiopure 2-methylpropane-1,2,3-triol monobenzyl ether and its application to expeditious synthesis of (R)-bicalutamide

Expeditious synthesis of (R)-bicalutamide (1), a synthetic antiandrogen, from enantiopure 2-methylpropane-1,2,3-triol monobenzyl ether (4) was achieved. An engineered Bacillus subtilis epoxide hydrolase worked enantioselectively on the racemic epoxide (7) to provide the above starting material in highly enantiomerically enriched state.     

Highly diastereoselective synthesis of α-trifluoromethylated α-propargylamines by acetylide addition to chiral CF3-substituted N-tert-butanesulfinyl ketimines

A convenient and practical method for the preparation of enantiomerically pure α-trifluoromethylated α-propargylamines is described. A range of enantiopure α-trifluoromethylated α-propargyl sulfinamides were obtained by the addition of lithium acetylides generated in situ with n-BuLi and terminal alkynes to diverse chiral CF₃-substituted (S)-N-tert-butanesulfinyl ketimines in moderate to excellent yields (56–97%) and with uniformly excellent diastereoselectivities (>99:1) by using Ti(OⁱPr)₄ as the catalyst and THF as the polar solvent. Enantiomerically pure α-trifluoromethylated α,α-dibranched propargyl amines were then readily obtained in excellent yields (87–97%) by acidic cleavage of the tert-butanesulfinyl group.     

A one-step synthesis of enantiopure 2-substituted 4,5-dihydro-1,4-benzodiazepine-3-ones via intramolecular azide cycloaddition

Starting from the appropriate azides bearing the (S)-1-phenylethylamine and the l-alanine benzylester as chiral pendants, a facile and effective synthetic route to the title compounds in their enantiopure form was developed with excellent product yields obtained. Basic hydrolysis of the ester group of title compounds 3a–c gave the corresponding, readily functionalisable carboxylic acids. Catalytic reduction of 2-benzyl derivatives 3c and 3f gave 4-functionalised 1,2,4,5-tetrahydro-1,4-benzodiazepin-3-ones in enantiopure forms.     

Metal-catalyzed asymmetric oxidations mediated by optically pure furyl hydroperoxides

Metal-catalyzed asymmetric oxidations which rely on the use of commercially available t-butyl (TBHP) or cumyl hydroperoxides (CHP) and enantiopure ligands represent the majority of protocols reported to obtain enantiomerically enriched valuable compounds such as epoxides, sulfoxides, diols, etc. Herein, we review our recent results on the complementary and less studied oxidative approach based on the use of optically pure alkyl hydroperoxides as oxygen and chirality source. The synthetic sequence to enantiopure furyl hydroperoxides, easily accessible from ketones of the chiral pool is firstly described. Examples of metal-catalyzed asymmetric oxidations using these compounds for the production of enantiomerically enriched sulfoxides and epoxy alcohols are shown. The entire protocol is made more advantageous by recovering the optically pure alcohols during the purification procedure and recycling them for the one-step synthesis of the hydroperoxides.     

Chemoenzymatic synthesis of highly enantiomerically enriched secondary alcohols with a thiazolic core

Stereoselective preparative enzymatic acylation and hydrolysis/methanolysis of various C-substituted rac-thiazol-2-yl-methanols were achieved for the preparation of enantiopure or enantiomerically enriched, naturally occurring 2-hydroxymethylthiazoles. The absolute configurations of the resulting secondary alcohols were determined by a detailed ¹H NMR study of Mosher’s derivatives.     

Novel one pot synthesis of substituted quinazolin-4(3H)-ones and pyrazolo[4,3-d]pyrimidin-7(6H)-ones using copper iodide,azides and terminal alkynes

A simple and highly efficient copper iodide catalyzed one-pot synthesis of 2-substituted quinazolin-4(3H)-ones have been developed from anthranilamide, terminal alkynes and azides. A wide variety of alkynes were screened to understand the scope of this methodology. This method has been extended for the synthesis of 5-substituted pyrazolo[4,3-d]pyrimidin-7(6H)-ones which are having potential applications in medicinal chemistry.     

Lipase-promoted kinetic resolution of racemic,P-chiral hydroxymethylphosphonates and phosphinates

Lipase-mediated acetylation of racemic P-chiral hydroxymethylphosphonates and phosphinates, and hydrolysis of their O-acetyl derivatives have been conducted under kinetic resolution conditions to give the enantiomerically enriched title products with up to 92% ee. Their absolute configuration has been determined by means of chemical correlation and CD measurements.     

Rhodium-catalyzed conjugate addition-enantioselective protonation: the synthesis of alpha,alpha'-dibenzyl esters

Alpha-benzyl acrylates, which are conveniently prepared from the corresponding aldehydes, can be employed as substrates in a tandem rhodium-catalyzed conjugate addition-enantioselective protonation protocol to afford enantiomerically enriched alpha,alpha'-dibenzyl esters. The synergistic effect of enantiopure ligand and proton source was rapidly optimized with use of a microwave reactor.     

Design and Synthesis of New Chacones Substituted with Azide/Triazole Groups and Analysis of Their Cytotoxicity Towards HeLa Cells

A series of new chalcones substituted with azide/triazole groups were designed and synthesized, and their cytotoxic activity was evaluated in vitro against the HeLa cell line. O-Alkylation, Claisen-Schmidt condensation and Cu(I)-catalyzed cycloaddition of azides with terminal alkynes were applied in key steps. Fifteen compounds were tested against HeLa cells. Compound 8c was the most active molecule, with an IC₅₀ value of 13.03 μM, similar to the value of cisplatin (7.37 μM).     

Stereoselective synthesis of γ-lactone fused cyclopentanoids

The stereoselective synthesis of γ-lactone fused cyclopentanoids applying chemoenzymatic methods is described. rac-2-Hydroxymethyl-1,4,5,6-tetrachloro-7,7-dimethoxybicyclo[2.2.1]hept-5-ene and rac-2-hydroxymethyl-1,4,5,6,7,7-hexachlorobicyclo[2.2.1]hept-5-ene were successfully resolved by Candida rugosa lipase (CRL), to afford enantiomerically enriched products with an ee of 94 and 97%, respectively. The enantiomerically enriched acetates were then subjected to ruthenium and/or cerium catalyzed oxidation to afford α-diketones and subsequent alkaline H₂O₂ mediated oxidative cleavage reaction of α-diketones, followed by CH₂N₂ esterification, gave enantiomerically enriched γ-lactone fused cyclopentanoids with known absolute configurations.     

Andersen chemistry with an α,β-unsaturated sulfinyl chloride: synthesis and Grignard reactions of homochiral cholesteryl (R)S-(E)-t-butylethenesulfinate

(−)-Cholesteryl (R)_S-(E)-t-butylethenesulfinate 2 was prepared in enantiopure form through the reaction of (E)-t-butylethenesulfinyl chloride and (−)-cholesterol in the presence of quinine (ca. 36% yield). Diastereomerically enriched versions of (S)-2 were prepared with d.e.s up to 75%. Grignard substitution reactions of 2 proceed with high stereospecificity to provide a new access to enantiomerically enriched (E)-2-t-butylethenylaralkyl sulfoxides in good yield and excellent e.e.     

Formation of N-sulfonylamidines by copper-catalyzed coupling of sulfonyl azides, terminal alkynes, and trialkylamines

A copper-catalyzed synthesis of N-sulfonylamidines via three-component coupling of sulfonyl azides, terminal alkynes, and trialkylamines is reported.     

Stereoselective synthesis of optically active cyclitol precursors via a chemoenzymatic method

Racemic α′-acetoxy α,β-unsaturated cyclohexanone has been converted to the corresponding enantiomerically enriched α′-hydroxylated and acetoxylated compounds with 97% ee via enzymatic resolution with PLE. OsO₄-Catalyzed dihydroxylation of enantiomerically enriched α′-acetoxylated compound afforded a single diastereomer in 85% chemical yield. The absolute configuration of 2,3,6-triacetoxycylohexanone was determined by X-ray diffraction analysis. Subsequent Luche reduction allowed us to obtain corresponding syn-type cyclitol precursors in a highly stereoselective manner as expected.     

Convenient route to enantiopure substituted butyrolactones: application in a formal synthesis of both enantiomers of enterolactone

A simple route for the synthesis of enantiopure substituted γ-butyrolactones involving a highly diastereoselective alkylation of an enantiomerically pure substituted latent succinate ester is described. This route provides entry into both enantiomers of 3,4-disubstituted butyrolactones from a single enantiomer, 2,3-di-O-cyclohexylidine-R-(+)-glyceraldehyde. The synthetic potential of this methodology has been demonstrated by a formal synthesis of both enantiomers of enterolactone.     

Chemoenzymatic synthesis of enantiomerically enriched 2-oxobicyclo[m.1.0]alkan-3-yl acetate derivatives

Racemic α′-acetoxy α,β-unsaturated cyclopentanone and cyclohexanone have been resolved into the corresponding enantiomerically enriched α′-hydroxylated and acetoxylated compounds with 96–97% ee via PLE hydrolysis. Stereoselectivity in the palladium(II)-catalyzed reaction between the enantiomerically enriched α′-acetoxylated compounds and diazomethane has been investigated. In the α′-acetoxylated cyclopentenone, preferential cyclopropanation occurs in the anti-form, whereas α′-acetoxylated cyclohexenone affords both syn- and anti-products (syn:anti, 61:36%). The relative configuration of the products was determined by NOE experiments.     

A practical asymmetric synthesis of 2,6-cis-disubstituted piperidines

A highly diastereoselective intramolecular Mannich reaction involving enantiopure α-methylamine 7 and achiral aldehydes is employed to prepare enantiomerically pure 2,6-cis-disubstituted piperidines. This methodology provides an efficient and selective route to 2,6-cis-disubstituted piperidines, 2,6-cis-disubstituted 4-piperidones and 2,6-cis-disubstituted 4-piperidinols.     

Regio- and stereoselective synthesis of Z-vinylic tellurides from propargylic alcohols: a route to chiral Z-enynes

tert-Butyldimethylsilyl ethers of propargylic alcohols are hydrotellurated regioselectively to give 1,2-Z-vinylic tellurides. Enantiomerically pure propargylic alcohols give enantiomerically pure vinylic tellurides, which are coupled with alkynes under Pd catalysis to give enantiomerically pure allylic enynols.     

Conversion of tertiary alcohols to tert-alkyl azides by way of quinone-mediated oxidation-reduction condensation using alkyl diphenylphosphinites

A novel method for the preparation of alkyl azides from alcohols by way of oxidation-reduction condensation is described. In this reaction, the sterically-hindered tert-alkyl phosphinites that are prepared from the corresponding alcohols are converted into tert-alkyl azides with almost complete inversion of their stereochemistry: the obtained alkyl azides are then successfully reduced to afford the corresponding amines on treatment with LiAlH₄, thus, a versatile method for the preparation of chiral amines from the corresponding chiral alcohols is established.     

First stereoselective synthesis of (4aS,5R)-4,4a,5,6,7,8-hexahydro-4a,5-dimethyl-2(3H)-naphthalenone

The synthesis of enantiomerically pure (4aS,5R)-hexahydro-4a,5-dimethyl-2(3H)-naphthalenone (−)-1 is described for the first time. The synthesis starts from (R)-3-methylcyclohexanone and involves the preparation of Piers enol lactone 6 in its enantiopure form as the key intermediate. Treatment of (+)-6 with methyl lithium followed by an intramolecular aldol reaction gives the bicyclic enone (−)-1.