An efficient approach to enantiomerically pure fluorhydrins

optically pure α′-monofluoro-α-sulphinyl ketones have been reduced with high diastereoselection to give α′-fluoro-α-sulphinyl alcohols which upon removal of the sulphinyl residue produced enantiomerically pure fluorhydrins.     

An efficient access to novel enantiomerically pure steroidal delta-amino acids

A highly chemoselective sequence of Stille and Heck couplings on the heterocyclic bromoenol triflates 2 a-c with the bicycloalkenylstannanes cis-3 and trans-3 furnished the intermediate bromobutadienes 4 a-c in good yields ranging from 73-94 %. A modified Heck coupling protocol employing the palladacycle 8 and an additional bidentate ligand such as 1,4-bis(diphenylphosphinyl)butane allowed a significant reduction in catalyst loading while still obtaining the heterocyclic 1,3,5-hexatrienes 5 a-c in good yields (71-94 %). The unsymmetrically substituted 1,3,5-hexatrienes 5 a-c in solution underwent 6pi-electrocyclizations following an optimized microwave-heating protocol to yield the steroidal tetracycles cis-7 a-c and trans-7 b (59-69 %). Tetracycles cis-7 a-c are the products of a subsequent 1,5-hydrogen shift to the thermodynamically more stable, more highly substituted diene units. Removal of the tert-butyl groups provided the novel steroidal delta-amino acid 9 a and the delta-amino acid derivatives 9 b, c in good yields (76-86 %).     

A tandem asymmetric synthesis approach for the efficient preparation of enantiomerically pure 9-(hydroxyethyl) anthracene

A tandem approach for the preparation of gram quantities of enantiomerically pure 9-(hydroxyethyl)-anthracene is presented using an asymmetric reduction followed by kinetic resolution that has potential applicability to other chiral alcohols.     

An efficient chemoenzymatic approach to enantiomerically pure 4-[2-(difluoromethoxy)phenyl] substituted 1,4-dihydropyridine-3,5-dicarboxylates

An efficient chemoenzymatic synthesis of (−)-3-methyl 5-(2-propoxyethyl) (4R)-4-[2-(difluoromethoxy)phenyl]-2,6-dimethyl-1,4-dihydro-3,5-pyridinedicarboxylate has been achieved. The key step is a highly stereoselective Candida rugosa lipase (CRL)-mediated asymmetrisation of the prochiral bis[(isobutyryloxy)methyl]-4-[2-(difluoromethoxy)phenyl]-1,4-dihydro-2,6-dimethyl-3,5-pyridinedicarboxylate.     

Stereoselective synthesis of enantiomerically pure 1-(E)-alkenylsulfoximines

Optically active (E)-N-tosyl-S-(1-alkenyl)-S-phenylsulfoximines 4 are synthesized stereoselectively in a one pot sequence from readily available 1 via C-silylation, metallation and reaction of the corresponding lithiosulfoximine 3 with various carbonyl compounds. The El-MS spectra of the so prepared alkenylsulfoximines 4 show unexpected fragmentations, pointing to a new, unusual S-O-migration of the 1-alkenyl moiety.     

Asymmetric synthesis using enantiomerically pure 2-(p-anisylsulfinyl)-2-cycloalkenones

Conjugate additions of many organometallic reagents to 2-(p-anisylsulfinyl)-2-cycloalkenones, 2 proceed with much greater diastereoselectivity than additions to the corresponding 2-(p-tolylsulfinyl)-2-cycloalkenones, 7. Complexation of 2 with zinc dibromide followed by addition of various Grignard reagents lead, after reductive removal of the sulfoxide, to 3-substituted cycloalkanones of higher optical purity than those obtained from 7. Addition of methyltitanium triisopropoxide to 2-(p-anisylsulfnyl)-2-cyclohexenone, 2b, in the absence of zinc dibromide, proceeds with virtually complete asymmetric induction.     

A practical preparation of enantiomerically pure (R)- and (S)-2-bromohexadecanoic acids

The efficient preparation of enantiomerically pure (R)- and (S)-2-bromohexadecanoic acids with e.e.>95% through resolution with the use of a recoverable chiral auxiliary is described. The procedure involves three reactions: Steglich esterification, DIBAL reduction, and Sharpless oxidation. The assessment of the enantiomeric purity is based on NMR analysis by using (1R,2R)-(+)-diphenylethane-1,2-diamine as a chiral solvating agent.     

Enantioselective synthesis of 2-hydroxy-1-indanone,a key precursor of enantiomerically pure 1-amino-2-indanol

Enantiomerically pure (R)- or (S)-2-hydroxy-1-indanone was synthesized by enzymatic kinetic resolution of racemic 2-acetoxy-1-indanone through hydrolysis or transesterification.     

An efficient asymmetric synthesis of (3S)-3-amino-1-(4-cyanophenyl)-2-oxopyrrolidine hydrochloride salt

Reaction of 4-aminobenzonitrile with 2-bromo-4-chlorobutyryl bromide in the presence of sodium phosphate followed by treatment of the coupled product with sodium hydroxide followed by ammonium hydroxide in acetonitrile yielded the title compound as the racemic (R)-(−)-mandelic acid salt in an overall yield of 64%. The title compound was then obtained with an ee >96% and in 78% yield after a dynamic resolution of the racemic salt in IPA using a catalytic amount of salicylaldehyde followed by salt exchange.     

An efficient synthesis of enantiomerically pure unnatural aryl glycinols and aryl glycines

A quick route to enantiomerically pure unnatural aryl glycinols and aryl glycines has been established based on an asymmetric azidation reaction using a chiral benzosultam auxiliary. The synthesis of aryl glycinols involves three steps starting from arylacetic acids, and the chiral auxiliary can be readily recovered.     

An efficient procedure for the preparation of (1S,3R)- and (1S,3S)-1-amino-3-(hydroxymethyl)cyclopentanes

Enantiomerically pure (1S,3S)- and (1S,3R)-1-amino-3-(hydroxymethyl)cyclopentanes have been efficiently synthesized from L-aspartic acid. The title compounds are isosteres of ribose and may be used to construct nucleoside analogs with important antiviral and antineoplastic activities as demonstrated by a concise total synthesis of (+)-4'-deoxycarbapentostatin nucleoside.     

An efficient synthesis of enantiomerically pure 2-[(2R)-arylmorpholin-2-yl]ethanols,key intermediates of tachykinin receptor antagonist

We report herein an efficient and practical synthetic method for the preparation of enantiomerically pure 2-[(2R)-arylmorpholin-2-yl]ethanols 1a–d, key intermediates of tachykinin receptor antagonist. Sharpless catalytic asymmetric dihydroxylation of 4a–d was employed to introduce the required absolute stereochemistry, and cyclization of 7a–d was accomplished by the Mitsunobu reaction.     

Biotransformation-mediated synthesis of (1S)-1-(2,6-dichloro-3-fluorophenyl)ethanol in enantiomerically pure form

An efficient four-step biotransformation-mediated synthesis of (1S)-1-(2,6-dichloro-3-fluorophenyl)ethanol in enantiomerically pure form is described. This compound is a key intermediate required for the preparation of PF-2341066, a potent inhibitor of c-Met/ALK that is currently in clinical development. The described synthesis was used to manufacture 6 kg of the title compound and can also be employed to produce the corresponding (1R)-enantiomer.     

New synthesis of enantiomerically pure (S)-3-amino-2-phenyl propanoic acid via the asymmetric transformation of its racemic N-phthaloyl derivative

The synthesis of racemic N-phthalyl 3-amino-2-phenyl propanoic acid and its asymmetric transformation via the corresponding prochiral ketene have been investigated, allowing the preparation of enantiomerically pure (S)-3-amino-2-phenyl propanoic acid.     

An efficient and selective enzymatic oxidation system for the synthesis of enantiomerically pure D-tert-leucine

[reaction: see text] d-tert-Leucine was prepared with an enantiomeric excess of >99% by an enzyme-catalyzed oxidative resolution of the racemic mixture of dl-tert-leucine with use of leucine dehydrogenase. The l-amino acid was oxidized completely due to coupling of the primary reaction with a highly efficient irreversible NAD(+)-regenerating step by NADH oxidase.     

Facile and efficient synthesis of 6-(hydroxymethyl)purines

[reaction: see text] A facile and efficient methodology of the synthesis of 6-(hydroxymethyl)purine derivatives (bases and nucleosides) was developed based on Pd-catalyzed cross-coupling reactions of 6-halopurines with acyloxymethylzinc iodides followed by deprotection. Several title compounds are inhibitors of adenosine deaminase and exert cytostatic activity.     

An efficient synthesis of chiral terminal 1,2-diamines using an enantiomerically pure [1-(1′R)-methylbenzyl]aziridine-2-yl]methanol

Enantiomerically pure terminal 1,2-diamines, which can serve as precursors for the synthesis of many biologically important compounds, were synthesized efficiently from a commercially available chiral [1-(1′R)-methylbenzyl]aziridine-2-yl]methanol. Various enantiomerically pure 2-vinylaziridines were prepared by Wittig reactions from aziridine-2-carboxaldehyde and the corresponding phosphonium salts. The C(2)-N bond of the vinyl substituted aziridine ring was regioselectively cleaved by azidotrimethylsilane (TMSN₃). The azido group and the double bond were reduced successively to give the target compounds in high yields.     

Efficient synthesis of enantiomerically pure beta2-amino acids via chiral isoxazolidinones

We report a practical and scalable synthetic route for the preparation of alpha-substituted beta-amino acids (beta(2)-amino acids). Michael addition of a chiral hydroxylamine, derived from alpha-methylbenzylamine, to an alpha-alkylacrylate followed by cyclization gives a diastereomeric mixture of alpha-substituted isoxazolidinones. These diastereomers are separable by column chromatography. Subsequent hydrogenation of the purified isoxazolidinones followed by Fmoc protection affords enantiomerically pure Fmoc-beta(2)-amino acids, which are useful for beta-peptide synthesis. This route provides access to both enantiomers of a protected beta(2)-amino acid.     

The synthesis of diastereo- and enantiomerically pure beta-aminocyclopropanecarboxylic acids

The synthesis of diastereo- and enantiomerically pure beta-aminocyclopropanecarboxylic acids (beta-ACCs) is described. Starting from pyrrole, (rac)-4 is readily obtained, which was kinetically resolved by enzymatic hydrolysis. Subsequent oxidation of (-)-4 and deformylation gives rise to the cis-beta-ACC derivative (ent)-9, while (+)-10 was converted to the trans-beta-ACC derivative 8. Both 8 and (ent)-9 and their benzyl esters 13 and 16, being conformationally restricted beta-alanine or gamma-aminobutyric acid (GABA) derivatives, represent useful building blocks for peptides containing unnatural amino acids.     

An efficient synthesis of enantiomerically pure (R)-pipecolic acid, (S)-proline, and their N-alkylated derivatives

Enantiomerically pure (R)-(+)-pipecolic acid was synthesized in four steps and 42% overall yield starting from dihydropyran and (R)-alpha-methylbenzylamine. A general short strategy is also described for preparing (S)-proline (47.5% overall yield) and derivatives.