Stereoselectivity in the Salt–Cocrystal Products formed by Phenylglycinol or Phenylglycine with their Respective Sodium or Hydrochloride Salts

The salt and stereoselective cocrystal phenomena associated with 2‐phenylglycinol and 2‐phenylglycine have been studied using X‐ray powder diffraction and differential scanning calorimetry. The chiral identities of the free acids and their sodium salts, or the free bases and their chloride salts, were found to play a determining role as to whether a salt–cocrystal product could or could not be formed. In particular, when cocrystallization of an enantiomerically pure basic or zwitterionic substance with its enantiomerically pure acid addition salt was attempted, a salt–cocrystal was only obtained when the absolute configuration of the two reactants is opposite. On the other hand, it has been found that no stereoselectivity in salt–cocrystal formation existed in the cocrystallization of an enantiomerically pure acidic or zwitterionic substance with its enantiomerically pure base addition salt. Chirality 25:8–15, 2013. © 2012 Wiley Periodicals, Inc.     

Synthesis of Diastereomeric Bicyclo[3.3.1]nonane Dibenzoyl Esters and Study of Their Chiroptical Properties

A synthesis of diastereomeric bicyclic dibenzoyl esters derived from enantiomerically pure (1S,5S)‐bicyclo[3.3.1]nonane‐2,6‐dione was accomplished. Molecules containing two benzoyl chromophores with different configuration in the bicyclic framework were obtained. Chiroptical properties of the synthesized enantiomerically pure molecules were studied. Diastereomeric esters exhibited exciton couplets in the circular dichroism (CD) spectra because of transannular interaction between non‐conjugated benzoate chromophores. The conformational effects and solvent impact on the exciton coupling were examined by CD spectroscopy. Theoretical computation of the CD spectra of diastereomers correctly reproduced the sign of the exciton couplets in the studied molecules, however, no major solvent dielectric constant influence and conformational effects per se on the exciton coupling was observed. Chirality 24:810–816, 2012. © 2012 Wiley Periodicals, Inc.     

Desymmetrization of cyclic anhydrides mediated by cinchona alkaloids: Synthesis and olfactory properties of new fragrances based on (R)‐ and (S)‐2‐ethylhexanol

A series of enantiomerically pure new fragrances, derived from 2‐ethylhexanol, have been prepared and their olfactory properties evaluated. The key step of the synthesis is cinchona‐alkaloid‐catalyzed desymmetrization of cyclic meso‐anhydrides with (R)‐ and (S)‐2‐ethylhexanol and proceeded in good to excellent diastereoselectivities (92:8–98:2 dr). Enantiomerically pure alcohols were prepared by lipase‐catalyzed kinetic resolution of 2‐ethylhexanol using vinyl laurate as acyl donor. Chirality 2009. © 2009 Wiley‐Liss, Inc.     

Parallel kinetic resolution of D‐labelled 2‐aryl‐propionic and butanoic acids using quasi‐enantiomeric combinations of oxazolidin‐2‐ones

The parallel kinetic resolution of racemic 2‐aryl‐2‐deuterio‐propionic and butanoic acids using an equimolar combination of quasi‐enantiomeric oxazolidin‐2‐ones is discussed. The levels of diastereoselectivity were high leading to enantiomerically pure D ‐labeled products in good yield. Chirality, 2010. © 2009 Wiley‐Liss, Inc.     

Highly Enantioselective Production of Chiral Secondary Alcohols with Candida zeylanoides as a New Whole Cell Biocatalyst

The increasing demand for biocatalysts in synthesizing enantiomerically pure chiral alcohols results from the outstanding characteristics of biocatalysts in reaction, economic, and ecological issues. Herein, fifteen yeast strains belonging to three food originated yeast species Candida zeylanoides, Pichia fermentans, and Saccharomyces uvarum were tested for their capability for asymmetric reduction of acetophenone to 1‐phenylethanol as biocatalysts. Of these strains, C. zeylanoides P1 showed an effective asymmetric reduction ability. Under optimized conditions, substituted acetophenones were converted to corresponding optically active secondary alcohols in up to 99% enantiomeric excess and at high yields. The preparative scale asymmetric bioreduction of 4‐nitroacetophenone ( 1m ) by C. zeylanoides P1 gave (S)‐1‐(4‐nitrophenyl)ethanol ( 2m ) with 89% yield and > 99% enantiomeric excess. Compound 2m has been obtained in an enantiomerically pure and inexpensive form. Additionally, these results indicate that C. zeylanoides P1 is a promising biocatalyst for the synthesis of chiral alcohols in industry.     

Asymmetric ring opening of terminal epoxides via kinetic resolution catalyzed by new bimetallic chiral (salen)Co complexes

The highly enantioselective hydrolytic kinetic resolution (HKR) of racemic terminal epoxides by new bimetallic chiral (salen)Co provides a operationally very simple protocol for the synthesis of enantiomerically enriched terminal epoxides (>99% ee) and diols. Optically pure chlorohydrins have been synthesized in one step by ring‐opening reactions of terminal epoxides with HCl using kinetic resolution. © 2005 Wiley‐Liss, Inc. Chirality     

Highly stereoselective hydrogenations—As key‐steps in the total synthesis of statins

Statins are inhibitors of 3‐hydroxy‐3‐methyl‐glutaryl coenzyme A reductase (HMG‐CoA reductase) and became the standard of care for treatment of hypercholesterolemia because of their efficacy, safety, and long‐term benefits. They are administered as diastereo‐ and enantiomerically pure compounds. We summarize here two new approaches for the total synthesis of the most important representatives, atorvastatin, and rosuvastatin, based on highly stereoselective hydrogenations as key‐steps. Chirality 2010. © 2009 Wiley‐Liss, Inc.     

Synthesis and Utilization of Trialkylammonium‐Substituted Cyclodextrins as Water‐Soluble Chiral NMR Solvating Agents for Anionic Compounds

Cationic trialkylammonium‐substituted α‐, β‐, and γ‐cyclodextrins containing trimethyl‐, triethyl‐, and tri‐n‐propylammonium substituent groups were synthesized and analyzed for utility as water‐soluble chiral nuclear magnetic resonance (NMR) solvating agents. Racemic and enantiomerically pure (3‐chloro‐2‐hydroxypropyl)trimethyl‐, triethyl‐, and tri‐n‐propyl ammonium chloride were synthesized from the corresponding trialkyl amine hydrochloride and either racemic or enantiomerically pure epichlorohydrin. The ammonium salts were then reacted with α‐, β‐, and γ‐cyclodextrins at basic pH to provide the corresponding randomly substituted cationic cyclodextrins. The ¹H NMR spectra of a range of anionic, aromatic compounds was recorded with the cationic cyclodextrins. Cyclodextrins with a single stereochemistry at the hydroxy group on the (2‐hydroxypropyl)trialkylammonium chloride substituent were often but not always more effective than the corresponding cyclodextrin in which the C‐2 position was racemic. In several cases, the larger triethyl or tri‐n‐propyl derivatives were more effective than the corresponding trimethyl derivative at causing enantiomeric differentiation. None of the cyclodextrin derivatives were consistently the most effective for all of the anionic compounds studied. Chirality 28:299–305, 2016. © 2016 Wiley Periodicals, Inc.     

Studies Towards the Synthesis of Medermycin via Dötz Benzannulation

The C‐arylglycosides are available in enantiomerically pure form via the Dötz benzannulation reaction between Fischer alkenyl chromium carbene complexes and alkynes; it also could be converted to a precursor of medermycin by O‐carbamate directed ipso bromination and nitrile substitution in good overall yields. Chirality 27:18–22, 2015. © 2014 Wiley Periodicals, Inc.     

Optical Purifications via Self‐Disproportionation of Enantiomers by Achiral Chromatography: Case Study of a Series of α‐CF3‐containing Secondary Alcohols

This work demonstrates that self‐disproportionation of enantiomers via achiral chromatography can be recommended as inexpensive and general method for optical purification of enantiomerically enriched compounds. In particular, the advantage of this approach over conventional recrystallization is that it can be used for both crystalline as well as liquid compounds. Chirality, 25:365‐368, 2013. © 2013 Wiley Periodicals, Inc.     

Absolute Configuration Determination and Convenient Asymmetric Synthesis of cis-3-(9-Anthryl)cyclohexanol with Proline as a Catalyst

cis‐(3R)‐(9‐anthryl) derivative of cyclohexanol was conveniently obtained in enantiomerically pure form from 2‐cyclohexenone using asymmetric Michael addition of anthrone catalyzed by l ‐proline in a key step. The absolute configuration of the addition product was unequivocally determined by means of electronic circular dichroism measurements combined with calculation of the circular dichroism spectrum by using a density functional theory method. Chirality 24:833–839, 2012. © 2012 Wiley Periodicals, Inc.     

Synthesis and Anti‐HIV Activity of Guanine Modified Fluorinated Acyclic Nucleoside Phosphonate Derivatives

The preparation of an unprecedented series of nucleobase modified 3‐fluoro‐2‐(phosphonomethoxy)propyl (FPMP) acyclic nucleosides in both their (R) and (S) enantiomerically pure forms is described. The synthesis focuses on a Mitsunobu alkylation reaction to construct the C?N(9) bond between a chiral fluorinated side‐chain residue and 6‐ or 7‐modified guanine analogs. Prodrugs of FPMP‐7‐deazaguanine were also synthesized by derivatization of the corresponding phosphonic acid functionality with (bis)diamyl aspartate amidate groups, leading to moderate activity against human immunodeficiency virus type 1 (HIV‐1).     

Stereoselective synthesis and characterization of new enantiomerically pure phosphoric acids

Starting from (R)‐6,6′‐dimethyldiphenyl‐2,2′‐dicarboxylic acid, a novel class of enantiomerically pure cyclic dialkyl phosphates was synthesized and properly characterized. The absolute configuration was determined by 2D NOESY experiments. The catalytic behavior of the new chiral Bronsted acids was investigated in the stereoselective addition of a silyl keteneacetal to aldimines. The Mannich‐type reaction was promoted in up to 94% yields and enantioselectivities up to 55%. On the basis of preliminary molecular mechanic calculations, a model of stereoselection was also proposed to explain the sense of the enantioselectivity observed in the reaction. Chirality 2010. © 2009 Wiley‐Liss, Inc.     

Development of Chiral Building Blocks Having a Bicyclo[3.3.0]Octane Framework Using a Diastereomeric Resolution‐Selective Deprotection

A protocol is presented for an efficient and practical approach to the synthesis of enantiomerically pure bicyclo[3.3.0]octane derivatives from achiral C_s‐symmetric bicyclo[3.3.0]octane‐2,8‐dione using a diastereomeric resolution‐selective deprotection method. This method affords chiral building blocks having bicyclo[3.3.0]octane framework with the same site of diastereotopic carbonyl functional group. Chirality 27:364–369, 2015. © 2015 Wiley Periodicals, Inc.     

High‐performance liquid chromatography separation of enantiomers of mandelic acid and its analogs on a chiral stationary phase

The enantiomers of mandelic acid and its analogs have been chromatographically separated on a chiral stationary phase (CSP) derived from 4‐(3,5‐dinitrobenzamido) tetrahydrophenanthrene. The rationale of separations of these compounds is discussed with respect to the method development for determining enantiomeric purity and possibility of obtaining enantiomerically pure materials by high‐pressure liquid chromatography. The relationship of analyte structure to the extent of enantiomeric separation has been examined and separation factors (α) are presented for various groups of structurally related compounds. Chiral recognition models have been suggested to account for the observed separations. These models provide mechanistic insights into the chiral recognition process. Chirality 2010. © 2009 Wiley‐Liss, Inc.     

A Novel Convergent Synthesis of the Antiglaucoma PGF2α Analogue Bimatoprost

The 17‐phenyl PGF_2α analogue bimatoprost ( 10a ) is the most efficacious ocular hypotensive agent currently available for the treatment of glaucoma or ocular hypertension. A novel convergent synthesis of 13,14‐en‐15‐ol prostamideF_2α analogues was developed employing Julia–Lythgoe olefination of the structurally advanced phenylsulfone (+)‐(5Z)‐ 15 with an enantiomerically pure aldehyde ω‐chain synthon (–)‐(S)‐ 16a . Subsequent hydrolysis of protecting groups and final amidation of the diol 26a yielded bimatoprost ( 10a ). The main advantage of the current strategy is the preparation of high‐purity bimatoprost ( 10a ). The novel convergent strategy allows the synthesis of a whole series of 13,14‐en‐15‐ol prostamideF_2α analogues with the desired C‐15 asymmetric center configuration from a common and structurally advanced prostaglandin intermediate (+)‐(5Z)‐ 15 . The preparation and identification of two synthetic impurities, 15‐epi isomer ( 10b ) of bimatoprost and a new prostaglandin related amide (+)‐(5Z)‐ 18 , are also described. Chirality 25:170–179, 2013. © 2013 Wiley Periodicals, Inc.     

Biocatalysis for industrial production of fine chemicals

Chiral intermediates constitute a significant part of the fine chemicals market, which is strongly influenced by trends in the pharmaceutical industries, where approximately 70% of pharmaceuticals are expected to be enantiomerically pure in the next century as compared to 25% today. The main technologies by which enantiomerically pure ingredients are obtained today are (dynamic) resolutions of racemic mixtures. Asymmetric syntheses are being developed, but their applications in industry are still under represented. Biotechnological methods, resolutions as well as asymmetric syntheses, are becoming increasingly important in the industrial production of fine chemicals.     

Candida tenuis Xylose Reductase Catalyzed Reduction of Aryl Ketones for Enantioselective Synthesis of Active Oxetine Derivatives

Candida tenuis xylose reductase shows high catalytic efficiencies in carbonyl reduction of acetophenone and 1‐phenyl‐1‐propanone derivatives. The quite low substrate solubility in aqueous buffer systems is circumvented by addition of methanol or by two‐phase solvent systems. In the latter, methanol improves the substrate phase transfer as solvent mediator and leads to reasonable space/time yields. Resulting enantiomerically pure chiral alcohols are key intermediates for synthesis of active pharmaceutical ingredients. (R)‐Atomoxetine is exemplarily synthesized in four steps, and the further use for generation of other oxetine derivatives and a polo‐like kinase 1 inhibitor are discussed. Chirality 00:000–000, 2012. © 2012 Wiley Periodicals, Inc.     

Note

This work demonstrates that self‐disproportionation of enantiomers via achiral chromatography can be recommended as inexpensive and general method for optical purifica‐ tion of enantiomerically enriched compounds. In particular, the advantage of this approach over conventional recrystallization is that it can be used for both crystalline as well as liquid com‐ pounds. Chirality, 25:365–368, 2013. © 2013 Wiley Periodicals, Inc.     

Asymmetric synthesis of carbocyclic pyrimidine nucleosides via pi-allylpalladium complex

Racemic and enantiomerically pure carbocyclic pyrimidine nucleosides were synthesized efficiently by a convergent approach using Trost nucleophilic addition of pi-allylpalladium complexes.