Oxiranyl anion-mediated synthesis of highly enantiomerically enriched styrene oxide derivatives

[reaction: see text] The stereospecific alpha-lithiation of optically active styrene oxides and the trapping reaction of the corresponding highly reactive intermediates with electrophiles to produce optically active styrene oxide derivatives are described. This methodology has been applied to the synthesis of an optically active oral antifungal agent of industrial interest.     

Intramolecular alkene carboamination reactions for the synthesis of enantiomerically enriched tropane derivatives

The synthesis of tropane derivatives via intramolecular Pd-catalyzed alkene difunctionalization reactions is described. Enantiopure N-aryl-γ-aminoalkenes bearing an aryl or alkenyl halide adjacent to the amino group were converted to benzo- or cycloalkenyl-fused tropane products in good yield and with no loss of enantiopurity.     

Chemoenzymatic synthesis of enantiomerically enriched kavalactones

Lipase-mediated kinetic resolution of methyl-3-hydroxy-5-phenylpentanoate and (6E)-ethyl 5-hydroxy-3-oxo-7-phenylhept-6-enoate is described in high enantiomeric excess and good yields. The effect of different lipases in different solvents has been screened using different acylating agents. This protocol has been extended for the preparation of enantiomerically pure biologically important kavalactones.     

Highly enantiomerically enriched alpha-haloalkyl Grignard reagents

alpha-Chloro- and alpha-bromoalkyl Grignard reagents 11 and 30 with > 97% ee (enantiomeric excess) were generated by a sulfoxide/magnesium exchange reaction from the enantiomerically and diastereomerically pure sulfoxides 25 and 27. The resulting alpha-haloalkyl Grignard reagents are configurationally stable at -78 degrees C. Racemization sets in at or above -60 degrees C, especially when the solution contains bromide ions. In the absence of halide ions, the configurational stability extends up to -20 degrees C, when chemical decomposition commences.     

Direct access to enantiomerically enriched alpha-amino phosphonic acid derivatives by organocatalytic asymmetric hydrophosphonylation of imines

A simple and efficient organocatalytic enantioselective hydrophosphonylation of imines to enantiomerically enriched alpha-amino phosphonates is reported. By using 10 mol % of quinine as the catalyst in the enantioselective addition of diethyl phosphite to N-Boc protected imines, alpha-amino phosphonates are obtained in moderate to good yields and with up to 94% ee.     

Synthesis of a highly enantiomerically enriched silyllithium compound

The highly enantiomerically enriched silyllithium compound lithiomethylphenyl(1-piperidinylmethyl)silane (4) reacts stereospecifically with chlorosilanes, but over a period of several hours slow racemization in solution at room temperature occurs, which can be suppressed by a transmetalation reaction with MgBr2(thf)4.     

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.     

Chemoenzymatic synthesis of enantiomerically enriched aminoalkenols and glycosides thereof

1-t-Butoxycarbonylamido-3-pentene-1-ol 3 and 2-azido-4-phenyl-3-butene-1-ol 4 were enantiomerically enriched by enzymatic acetylation using various lipases and esterases (CHIRAZYM) to give acetylated compounds 5 and 7, respectively. Compound 3 gave the best results (E=94) with Candida antarctica A lipase (CHIRAZYM L-5), whereas 4 could not be separated into the enantiomers with satisfactory E values. The absolute configurations were proven for both compounds via independently prepared derivatives. Both enantiomers of 5, as well as racemic 7, were N-deblocked and condensed with octonic acid derivatives 14 to give the corresponding C-glycosides 17 and 22 after deprotection of the intermediates in good overall yield. Compound 4 was similarly condensed with glucose imidate 11 to give the diastereomeric O-glycosides 13 after deprotection. The latter glycosides were prepared as precursors for the generation of the corresponding aldehydes as substrates for aldolase catalyzed reactions.     

Synthesis of enantiomerically enriched oxazolinyl[1,2]oxazetidines

The first stereoselective synthesis of oxazolinyl[1,2]oxazetidines based on the reaction of lithiated 2-(1-chloroethyl)-2-oxazolines with nitrones is described. Highly enantioenriched oxazolinyl[1,2]oxazetidines have also been prepared starting from a 1:1 diastereomeric mixture of optically active 2-(1-chloroethyl)-2-oxazolines.     

Catalytic asymmetric approaches towards enantiomerically enriched diarylmethanols and diarylmethylamines

Enantiopure diarylmethanols and diarylmethylamines are important intermediates for the synthesis of pharmaceutically relevant products with antihistaminic, antiarrhythmic, diuretic, antidepressive, laxative, local-anesthetic and anticholinergic properties. Furthermore, they have been used as precursors for 1,1-diarylalkyl moieties, which occur in other antidepressants as well as in antimuscarinics and endothelin antagonists. In this critical review catalytic strategies towards enantioenriched diarylmethanols and diarylmethylamines are discussed, including methods for asymmetric carbon-carbon bond formations by aryl transfer reactions to aldehydes and arylimines, respectively, and enantioselective reductions of diarylketones.     

Nitrile biotransformations for the synthesis of enantiomerically enriched Baylis-Hillman adducts

Catalysed by the nitrile hydratase/amidase-containing Rhodococcus sp. AJ270 cells, a number of beta-aryl- and beta-alkyl- beta-hydroxy-alpha-methylenepropiononitriles (the Baylis-Hillman nitriles) 1 underwent hydrolysis under mild conditions to produce the corresponding enantiomerically enriched Baylis-Hillman amides 2 and acids 3. The enantioselectivity of the biotransformations was strongly determined by the steric effect of the substituents at the beta-position of the substrates. The protection of the free hydroxy of beta-phenyl-beta-hydroxy-alpha-methylenepropiononitrile 1a by methylation led to the enhancement of enantiocontrol of the biohydrolysis.     

Synthesis of enantiomerically enriched secondary and tertiary phenylthio- and phenoxy-aldols

α-Phenoxy- and phenylthio-ketones have been explored as donors and acceptors in organocatalytic aldol reactions. Our studies have revealed effective methodologies for accessing structurally varied and enantiomerically enriched secondary and tertiary phenylthio- and phenoxy-aldols, expanding the scope and potential synthetic utility of organocatalytic direct aldol reactions.     

Synthesis of enantiomerically pure 3-aminochroman derivatives

Enantiomerically pure (3R)-amino-5-methoxy-3,4-dihydro-2H-1-benzopyran was successfully synthesised in nine steps starting from l-serine. The same synthetic pathway was used to prepare the (3S)-aminochroman derivative starting from d-serine. The enantiomeric purity of the final aminochroman derivatives was determined by capillary electrophoresis using β-cyclodextrin as the chiral selector.     

Organocerium additions to proline-derived hydrazones: synthesis of enantiomerically enriched amines

The addition of organocerium reagents (from both organolithium and organomagnesium precursors) to chiral aldehyde hydrazones prepared from 1-aminoproline derivatives has been studied. The additions proceed in good yield and high diastereoselectivity and with good nucleophile (Me, n-Bu, i-Pr, t-Bu, Ph, etc.) and substrate scope (alkyl, alkenyl and aryl). The resulting hydrazines can be converted to amines by N–N bond cleavage through hydrogenolysis (Raney nickel) or by acylation and cleavage with Li/NH₃. The influence of the side chain on the diastereoselectivity was investigated through variation of the substituents to include more coordinating atoms (oxygen and nitrogen) as well as the removal of coordinating atoms. The SAMEMP auxiliary bearing a 2-methoxyethoxymethyl group gave the highest diastereoselectivities. Remarkably, auxiliaries bearing simple methyl and isobutyl substituents gave high selectivities as well. Hypotheses for the origin of the selectivity are presented.     

Highly efficient synthesis of enantiomerically enriched 2-hydroxymethylaziridines by enzymatic desymmetrization

Both enantiomers of protected and unprotected 2-hydroxymethylaziridines are efficiently and enantiospecifically synthesized by using a combination of enzymatic and synthetic methods. PPL was used for lipase-catalyzed desymmetrization of N-protected serinol. [reaction: see text].     

A convenient method for synthesis of enantiomerically enriched methylphenidate from N-methoxycarbonylpiperidine

[formula: see text] This report describes a new method to prepare optically active methylphenidate starting from piperidine. The method consists of a transformation of N-methoxycarbonylpiperidine to the corresponding alpha-methoxylated carbamate I by utilizing electrochemical oxidation followed by the coupling reaction with optically active Evans imides II to produce optically active methylphenidate derivatives III with high stereoselectivities, threo-(2R,2'R)-Methylphenidate (IV; Ar = Ph; Ritalin) was easily prepared from III in three steps.     

Synthesis of enantiomerically enriched atrolactic acid and other α-hydroxy acids

The α-anions of 2-substituted 1,3-dioxolan-4-ones derived from chiral mandelic and lactic acid ($\text{2a}$, $\text{2b}$; $\text{3a}$; $\text{10a}$, $\text{10b}$) were alkylated with high stereoselectivity. The products formed were hydrolysed to α-hydroxy acids with 65–85% e.e. ((S)(+)-$\text{5}$,$\text{7}$,$\text{9}$, (R)(–)-$\text{13}$).