Dynamic kinetic resolution of racemic gamma-aryl-delta-oxoesters. Enantioselective synthesis of 3-arylpiperidines

Cyclodehydration of racemic gamma-aryl-delta-oxoesters with (R)- or (S)-phenylglycinol stereoselectively affords bicyclic delta-lactams, in a process that involves a dynamic kinetic resolution. Subsequent reduction of these lactams leads to enantiopure 3-arylpiperidines. Starting from racemic aldehyde esters, this short sequence has been applied to the synthesis of (R)-3-phenylpiperidine and the antipsychotic drug (-)-3-PPP (an (S)-3-arylpiperidine), whereas starting from racemic ketone esters enantiopure cis-2-alkyl-3-arylpiperidines are prepared.     

Asymmetric chemoenzymatic synthesis of ramatroban using lipases and oxidoreductases

A chemoenzymatic asymmetric route for the preparation of enantiopure (R)-ramatroban has been developed for the first time. The action of lipases and oxidoreductases has been independently studied, and both were found as excellent biocatalysts for the production of adequate chiral intermediates under very mild reaction conditions. CAL-B efficiently catalyzed the resolution of (±)-2,3,4,9-tetrahydro-1H-carbazol-3-ol that was acylated with high stereocontrol. On the other hand, ADH-A mediated bioreduction of 4,9-dihydro-1H-carbazol-3(2H)-one provided an alternative access to the same enantiopure alcohol previously obtained through lipase-catalyzed resolution, a useful synthetic building block in the synthesis of ramatroban. Inversion of the absolute configuration of (S)-2,3,4,9-tetrahydro-1H-carbazol-3-ol has been identified as a key point in the synthetic route, optimizing this process to avoid racemization of the azide intermediate, finally yielding (R)-ramatroban in enantiopure form by the formation of the corresponding amine and the convenient functionalization of both exocyclic and indole nitrogen atoms.     

Practical asymmetric synthesis of the herbicide (S)-indanofan via lipase-catalyzed kinetic resolution of a diol and stereoselective acid-catalyzed hydrolysis of a chiral epoxide

Racemic indanofan [(+/-)-1] was efficiently converted to enantiopure (S)-indanofan [(S)-1] by a combination of enzymatic resolution and chemical inversion techniques. An additional important technique is the use of an o-xylene complex of a hemiketal (S)-3c as a precursor, which can be quantitatively converted to (S)-indanofan and easily purified by recrystallization from o-xylene.     

Resolution of racemic 1-benzyl-5-oxo-3-pyrrolidinecarboxylic acid with enantiopure (S)-phenylalanine N-benzylamide via diastereomeric salt formation

The resolution of racemic 1-benzyl-5-oxo-3-pyrrolidinecarboxylic acid 1, a potent chiral synthon with high pharmacological activity, was investigated with a variety of basic chiral resolving agents via diastereomeric salt formation. The findings in the optimization of resolution conditions aiming at an industrial-scale production revealed that (S)-phenylalanine benzylamide (S)-10 and 2-propanol containing ca. 4 mol % of water to (RS)-1 were the best conditions for obtaining enantiopure less-soluble diastereomeric salt, (S)-1/(S)-10/0.5H₂O (81%, 98% de, E 79%). X-ray crystallographic analysis of the salt clearly revealed that water molecules play a key role in crystallizing the enantiopure salt crystals, while stabilizing the crystal structure via three types of hydrogen-bond network associated with water molecules in addition to usual acid–base hydrogen bond.     

(S)-2-[(R)-fluoro(phenyl)methyl]oxirane: a general reagent for determining the ee of alpha-chiral amines

(S)-2-[(R)-Fluoro(phenyl)methyl]oxirane is a new, synthetic, yet enantiopure, chiral resolution reagent, readily obtained from enantiopure (2S,3S)-phenylglycidol, that reacts with a variety of alpha-chiral primary and secondary amines in a straightforward manner through a regioselective ring-opening. Diastereomeric products are easily identified and quantified by (19)F, (1)H, and (13)C NMR and by HPLC, which makes this fluorinated compound a most versatile reagent for the analysis of scalemic mixtures of amines. [reaction: see text]     

Straightforward synthesis of (R)-(-)-kjellmanianone

A direct route to enantiomerically pure (-)-kjellmanianone is reported. The synthesis involves a cerium-catalyzed alpha-hydroxylation and an enzyme-catalyzed procedure to resolve tertiary alcohols at key stages. The intermediate beta-oxo ester was alpha-hydroxylated to give good yields of racemic kjellmanianone. The resolution of the racemic material was achieved by enzymatic saponification, followed by a chemical decarboxylation sequence to give enantiopure (-)-kjellmanianone with 99 % ee. Bromination then afforded the (-)-bromo derivative, whose X-ray structure provided evidence for the R configuration of (-)-kjellmanianone.     

New enzymatic and chemical approaches to enantiopure etodolac

(+)- and (−)-etodolac enantiomers were prepared both by classical resolution via crystallisation of diastereoisomeric salts with (+) and (−)--methylbenzylamine, and by suitable manipulation of derivatives (−)-3- and (+)-4, obtained by lipase-catalysed kinetic resolution of racemic 3 X-ray diffraction analysis of the 4-bromobenzoate derivative of (+)-3, obtained from enantiopure acetate (+)-4, allowed us to determine the absolute (R) configuration of (−)-etodolac.     

Successive optical resolution of two compounds by one enantiopure compound

By using (1R,2R)-1,2-diphenylethylenediamine as a single enantiopure compound, we achieved a novel successive optical resolution of more than one kind of racemic compound through supramolecular crystallization.     

A simple resolution procedure using the Staudinger reaction for the preparation of P-stereogenic phosphine oxides.

The resolution of a variety of (+/-)-P-stereogenic phosphines is achieved by exploiting the Staudinger reaction of a (+/-)-phosphine with enantiopure (1S,2R)-O-(tert-butyldimethylsilyl)isobornyl-10-sulfonyl azide. The resulting mixtures of diastereomeric phosphinimines are generally separable by fractional crystallization or flash chromatography. Subsequent acid-catalyzed hydrolysis provides the corresponding optically pure phosphine oxides in high yields.     

Trifluoromethyl- and difluoromethyl-β-lactams as useful building blocks for the synthesis of fluorinated amino acids, dipeptides, and fluoro-taxoids

Enantiopure 1-acyl-3-hydroxyl-4-CF₂H-azetidin-2-ones and 1-acyl-3-hydroxy-4-CF₃-azetidin-2-ones serve as versatile intermediates for the syntheses of CF₂- and CF₃-containing α-hydroxy-β-amino acids, dipeptides, and taxoid anticancer agents. Both enantiomers of 3-hydroxy-4-CF₂H-β-lactams can be obtained in high yields through the diethylaminosulfur trifluoride (DAST) reaction of the corresponding enantiopure 4-formyl-β-lactam that is prepared through [2+2] cycloaddition of acetoxyketene to a 3-methyl-2-butenaldimine, followed by enzymatic optical resolution and ozonolysis. (+)-3-Hydroxy-4-CF₃-β-lactams and (−)-3-hydroxy-4-CF₃-β-lactams can also be readily obtained in enantiopure form through [2+2] cycloaddition of a CF₃-imine with a ketene, followed by enzymatic optical resolution. Practical processes for the preparations of these enantiopure 3-hydroxy-4-R_f-β-lactams as well as their synthetic applications are described.     

Renewable camphor-derived hydroperoxide: synthesis and use in the asymmetric epoxidation of allylic alcohols

Renewable enantiopure tertiary furyl hydroperoxide has been easily synthesized in two steps starting from low cost (+)-(1R)-camphor and it has been used in the asymmetric epoxidation and kinetic resolution of allylic alcohols (enantioselectivities up to 46%).     

An enantiopure galactose oxidase model: synthesis of chiral amino alcohols through oxidative kinetic resolution catalyzed by a chiral copper complex

An enantiopure galactose oxidase (GO) enzyme model has been synthesized from readily available (R)-BINAM and Cu(OTf)₂, and the enantiopure GO model has been effectively used in situ as an efficient chiral catalyst for the synthesis of chiral amino alcohols through oxidative kinetic resolution (OKR), where molecular oxygen is used as the sole oxidant. Under the proposed catalytic conditions, both ortho- and para-substituted amino alcohols were resolved with good to excellent enantiomeric excesses through oxidative kinetic resolution.     

Bacterial preparation of enantiopure unactivated aziridine-2-carboxamides and their transformation into enantiopure nonnatural amino acids and vic-diamines

[reaction: see text] Enantiopure (1R,2S)-1-benzyl- and 1-arylaziridine-2-carboxamides were obtained by kinetic resolution of their racemates by Rhodococcus rhodochrous IFO 15564 catalyzed hydrolysis. Several regio- and enantioselective nucleophilic ring openings of (1R,2S)-1-benzylaziridine-2-carboxamide or its LAH-reduced product led to a series of enantiopure products, such as O-methyl-l-serine and some vicinal diamines.     

Inherently chiral phosphonatocavitands as artificial chemo- and enantio-selective receptors of natural ammoniums

Inherently chiral phosphonatocavitands with various bridging moieties at their wide rim were synthesized. Optical resolution by chiral HPLC was performed with cavitand 8 to afford enantiopure compounds (+)-8 and (-)-8. The molecular structures of hosts 8 and 12 were determined by X-ray diffraction. The host properties were investigated by (1)H and (31)P NMR spectroscopy. The phosphonatocavitands form inclusion complexes with chiral ammonium neurotransmitters, some presenting enantioselectivity towards the right or left-handed host enantiomers.     

Cover Picture

The cover picture shows a further example of the power of transition metal complexes in organic synthesis: the enantiopure imidozirconium complex, top left, reacts with 1,3- disubstituted racemic allenes (right) in a highly enantioselective, stepwise cycloaddition. Both the enantiomers of an allene react to give the same diastereopure azazirconacyclobutane complex, the structure of which is shown in the center of the picture as a space filling model with the molecular framework superimposed. The reaction with 1,2-propadiene (bottom center) releases the enantiopure allene from the metallacycle. The overall process couples kinetic resolution with the complete inversion of the absolute configuration of a 1,3-disubstituted allene. More about this unusual new method for enantiomer separation and enrichment is reported by R. G. Bergman et al. on page 2339 pp.     

Synthesis and chiroptical properties of ferrocene-[4]-helicenequinones: kinetic resolution of a planar-chiral diene

Both enantiomers of ferrocene [4]-helicenequinone 6, showing planar and helical chiralities, have been synthesized with very high optical purities using, as the key step, a kinetic resolution process between planar-chiral racemic ferrocene diene 2 and enantiopure sulfinyl benzoquinone (S)-3.     

Global and local expression of chirality in serine on the Cu{110} surface

Establishing a molecular-level understanding of enantioselectivity and chiral resolution at the organic-inorganic interfaces is a key challenge in the field of heterogeneous catalysis. As a model system, we investigate the adsorption geometry of serine on Cu{110} using a combination of low-energy electron diffraction (LEED), scanning tunneling microscopy (STM), X-ray photoelectron spectroscopy (XPS), and near-edge X-ray absorption fine structure (NEXAFS) spectroscopy. The chirality of enantiopure chemisorbed layers, where serine is in its deprotonated (anionic) state, is expressed at three levels: (i) the molecules form dimers whose orientation with respect to the substrate depends on the molecular chirality, (ii) dimers of L- and D-enantiomers aggregate into superstructures with chiral (-1 ?2; 4 0) lattices, respectively, which are mirror images of each other, and (iii) small islands have elongated shapes with the dominant direction depending on the chirality of the molecules. Dimer and superlattice formation can be explained in terms of intra- and interdimer bonds involving carboxylate, amino, and β-OH groups. The stability of the layers increases with the size of ordered islands. In racemic mixtures, we observe chiral resolution into small ordered enantiopure islands, which appears to be driven by the formation of homochiral dimer subunits and the directionality of interdimer hydrogen bonds. These islands show the same enantiospecific elongated shapes those as in low-coverage enantiopure layers.     

Rhodium-Catalyzed Asymmetric Conjugate Additions of Boronic Acids to enones using DIPHONANE: a novel chiral bisphosphine ligand

[reaction: see text] The synthesis of a novel enantiopure C2-symmetric bisphosphine, DIPHONANE, was accomplished starting from 2,5-norbornadione, utilizing (R,R)- and/or (S,S)-(2,3-O-di[(phenylamino)carbonyl]tartaric acid for the resolution of an intermediate phosphineoxide. The application of this ligand in the rhodium-catalyzed asymmetric conjugate addition of boronic acids to cyclic enones provides the 1,4-addition products in good yields (69-98%) and high ee's (78-95% ee). A byproduct arising from a consecutive 1,4-addition and 1,2-addition was also observed.     

Enzymatic transformations. Part 55: Highly productive epoxide hydrolase catalysed resolution of an azole antifungal key synthon

A highly productive bioprocess for the preparation of enantiopure azole antifungal chirons is described. These are key building blocks for the synthesis of new triazole drug derivatives known to display valuable activity against such infections as for instance fluconazole-resistant oro-oesophageal candidiasis. Using commercially available recombinant Aspergillus niger epoxide hydrolase under optimised experimental conditions, the hydrolytic kinetic resolution of 1-chloro-2-(2,4-difluorophenyl)-2,3-epoxypropane was performed in plain water, at room temperature, using a two-phase reactor. This methodology allowed the process to be run at a substrate concentration as high as 500 g/L (i.e., 2.5 M) and afforded the (unreacted) epoxide and the corresponding vicinal diol, both in nearly enantiopure form and quantitative yield.     

Chemoenzymatic synthesis and synthetic application of enantiopure aminocyclopentenols: total synthesis of carbocyclic (+)-uracil polyoxin C and its alpha-epimer

Carbocyclic uracil polyoxin C (+)-2 and its alpha-epimer (-)-3 were synthesized in an efficient fashion from cis-4-(N-tert-butylcarbamoyl)cyclopent-2-en-1-ol (+/-)-7. The synthesis incorporates a concise, inexpensive chemoenzymatic synthesis of enantiopure aminocyclopentenols, a Pd(0)-catalyzed substitution reaction, and a mild reduction of an alpha-nitro ester by TiCl(3)/sodium borohydride. Significantly, this process demonstrates the synthetic utility of the versatile enantiopure aminocyclopentenol building block (-)-4.