Assignment of the absolute configuration of (+)-5,5′,6,6′-tetrahydro-7,7′-spiro[7H-cyclopenta[b]pyridine], a new inherently chiral spiropyridine,by a nonempirical analysis of its circular dichroism spectrum

The absolute configuration of (+)-spiropyridine 1, obtained in its enantiopure form by chromatographic resolution of the racemate upon the CSP Chiralcel AD, has been assigned as (aS) by simulating the ECD spectrum in the range 320–235 nm both by coupled oscillator (DeVoe) and TD DFT/B3LYP/6-31G¹ calculations.     

Synthesis of rigid and C2-symmetric 18-crown-6 type macrocycles bearing diamide–diester groups: enantiomeric recognition for α-(1-naphthyl)ethylammonium perchlorate salts

A series of rigid and chiral C₂-symmetric 18-crown-6 type macrocycles (S,S)-4, (S,S)-5, (S,S)-6 and (R,R)-2 bearing diamide–ester groups were synthesized. The binding properties of these macrocycles were examined for α-(1-naphthyl)ethylammonium perchlorates salts by an ¹H NMR titration method. Taking into account the host employed, important differences were observed in the K_a values of (R)- and (S)-enantiomers of guests for macrocycles (S,S)-4 and (S,S)-6, K_S/K_R = 3.6, and K_S/K_R = 0.1 (K_R/K_S = 10.3) ΔΔG = 3.19 and ΔΔG = ?5.77 kJ mol^?1, respectively. The results indicated excellent enantioselectivity of macrocyclic (S,S)-6 towards the enantiomers of α-(1-naphthyl)ethylammonium perchlorate salts.     

(Vapour + liquid) equilibria and excess molar enthalpies for mixtures with strong complex formation. Trichloromethane or 1-bromo-1-chloro-2,2,2-trifluoroethane (halothane) with tetrahydropyran or piperidine

Isothermal (vapour  +  liquid) equilibria were measured for (trichloromethane  +  tetrahydropyran or piperidine) at T =  333.15 K and {1-bromo-1-chloro-2,2,2-trifluoroethane (halothane)  +  tetrahydropyran or piperidine} atT =  323.15 K with a circulation still. The results were verified by effective statistical procedures and used to calculate activity coefficients and excess molar Gibbs free energiesG_m^E . Excess molar enthalpiesH_m^E for these mixtures were determined at T =  298.15 K by means of an isothermal CSC microcalorimeter equipped with recently reconstructed flow mixing cells. Reliable performance of the calorimetric setup was proved by the good agreement of H_m^Efor (hexane  +  cyclohexane), (2-propanone  +  water), and (methanol  +  water), with the best literature results. The trichloromethane- or halothane-containing mixtures exhibit strong negative deviations from Raoult’s law and are highly exothermic, thus indicating that complex formation via hydrogen bonding is a governing nonideality effect. A close similarity in the behaviour of corresponding mixtures with trichloromethane and halothane is observed, but for halothane-containing mixtures,G_m^E and H_m^Eare consistently more negative, confirming that halothane is a more powerful proton donor than chloroform.     

Transformation of (+)-thiomicamine into the p-methylthio analogue of (+)-5-epi-cytoxazone

(2S,3S)-(+)-Thiomicamine 3, a commercially available aminodiol, was transformed into (4R,5S)-5-hydroxymethyl-4-(p-methylthiophenyl)-2-oxazolidinone 10, a compound related to cytoxazone-type biologically active natural products. The synthetic strategy of the highly regio- and stereoselective synthesis was based upon the reversal of the position of the hydroxyl and amine functionalities in 3, accomplished via azidolysis of the key intermediate, epoxide 6.     

Synthesis of the (1S,2S)- and (1R,2S)-stereoisomers of the respective E- and Z-isomers of ethyl 4-[(2-hydroxycyclohexyl)methyl]phenoxy-3-methyl-2-butenoate using yeast whole cell bioreduction of the parent ketones

Saccharomyces cerevisiae, strain DBM 2115, was successfully employed in the reduction of the separated Z- and E-isomers of ethyl 4-[(2-oxocyclohexyl)methyl]phenoxy-3-methyl-2-butenoates 1 and 2, in order to prepare the (1S,2S)- and (1R,2S)-enantiomers of the corresponding ethyl 4-[(2-hydroxycyclohexyl)methyl]phenoxy-3-methyl-2-butenoates 3–6. The products were obtained with the required absolute configuration: (1S,2S)-3 (ee = 98%; yield 48%), (1R,2S)-4 (ee = >99%; yield 45%), (1S,2S)-5 (ee = 98.5%; yield 47%), and (1R,2S)-6 (ee = >99%; chemical yield 44%).     

Synthesis of (+)-1,3,5,7 -tetrakis[2-(1S,3S,5R,6S,8R,10R)-D3-trishomocubanylbuta-1,3-diynyl]adamantane : The first optically active organic molecule with t symmetry and of known absolute configuration

(-)-(1S,3S,5R,6S,8R,10R)-Trishomocubanethanoic acid (5) of known absolute configuration and absolute rotation was converted into (+)-(1S,3S,5S,6S,8R,10R)-2-bromoethynyl-D₃-trishomocubane (27) of C₃ symmetry. 1,3,5,7-Tetraethynyladamantane (22), with Td symmetry, was prepared from 1,3,5,7-tetrakis(hydroxymethyl)adamantane(13). Coupling of the C₃-component 27 with the Td component 22 was successfully accomplished by Chodkiewicz and Cadiot's procedure providing (+)-1,3,5,7-tetrakis[2-(1S,3S,5R,6S,8R,10R)-D₃-trishomocubanylbuta-1,3-diynyl]adamantane(4) whose highest attainable static and time-averaged dynamic symmetry are T and (C₃)⁴ XXX T,respectively.     

Synthesis of novel C2-symmetric chiral crown ethers and investigation of their enantiomeric recognition properties

A series of new C₂-symmetric chiral aza crown ether macrocycles 1–4 have been synthesized from (S)-3-aryloxy-1,2-propanediol and (S)-1,2-propanediol for the enantiomeric recognition of amino acid ester derivatives. These new macrocycles have been shown to be strong complexing agents for primary organic ammonium salts (with K up to 176.93 M^?1 and ΔG° up to 12.81 kJ mol^?1) by ¹H NMR titration. These macrocyclic host exhibited enantioselective bonding toward the d-enantiomer of phenylalanine methyl ester hydrochloride with K_D/K_L up to 6.87 in CDCl₃ with 0.25% CD₃OD.     

Absolute configuration of 2-hydroxy-2-(1-naphthyl)propionic acid as determined by the 1H NMR anisotropy method

Enantiopure 2-hydroxy-2-(1-naphthyl)propionic acid (+)-2 was prepared by the stereoselective Grignard reaction of 1-naphthylmagnesium bromide with (1R,3R,4S)-menthyl pyruvate 3 or (1R,3R,4S)-8-phenylmenthyl pyruvate 4, and the absolute configuration of acid (+)-2 was unambiguously determined to be S by the ¹H NMR anisotropy method.     

Reactions of β-substituted amines-IV: Kinetics and stereochemistry of the thermal to (r) 3-chloro-1-ethylpiperidine,and the stereo-chemical course of their reactions with nucleophiles

The rate of the thermal rearrangement of (S) 2 chloromethyl-1-ethylpyrrolidine [(S)-1a] to (R)-3-chloro-1-ethylpiperidine [(R) 2a] has been examined at three temperatures in benzene by PMR and polarimetry. The rearrangement was shown to be completely stereospecific and to obey a simple first order rate law. The calculated E_a ΔH3 and ΔS3 were 22 ± 2 $\text{kcal}\text{mole}$ (25°), 21 ± 2.5 $\text{kcal}\text{mole}$ (25°) and - 10 ± 2 e.u. (0°K) respectively. The effect of solvents having differing dielectric constants was also studied. A transition state 9'a and an ion pair intermediate 3a are suggested for the rearrangement. The stereochemical course of the reactions of (S)-1a, (R)-2a and (S)-2a with hydroxide and methoxide ions have been shown to be 100% stereospecific with an uncertainty of about 1%. The absolute configurations of all optically active reactants and products [(S)- and (R)-4a, (S)-4b (R)- and (S)-5a, (R)-5b, (S,S')-6a, (S,R')-7a and (R,R')-8a] were established by chemical correlations with known compounds or by ORD and chemical inference. The ring opening of both the primary and secondary aziridinium ion positions of 1-azonia-1-ethylbicyclo [3.1.0]hexane [(S)-3a] by nucleophiles proceeds entirely by S_N2 processes. The conversion of (R)-1-ethyl-3-hydroxypiperidine [(R)-5a] to (S)-2a. HCl with thionyl chloride in chloroform proceeds by inversion with 4.8% racemization, whereas the thermal rearrangement of (S)-1a to (R)-2a occurs with complete retention of absolute configuration.     

Unusual reactivity of 3-chloro-1-pentafluorosulfanylpropene in nucleophilic substitution reactions

Treatment of 3-chloro-1-pentafluorosulfanylprop-1-ene 1 with KCN yielded the product of prototropic rearrangement ClCHCHCH₂SF₅, whereas reactions with NaN₃ and KSCN gave the S_N2 products. Ab initio calculations at MP2/6-311++G** level are used to explain the unusual behaviour of cyanide. It was found that proton transfers from both 1 to CN⁻ and from HCN to the anion of 1 are exothermic. In contrast, azide and thiocyanate ions are too weakly basic to deprotonate 1.     

Synthesis and absolute configuration of (S)-(+)-chichimol ketone: the defensive secretion of walking stick Agathemera elegans

The first enantioselective synthesis of chichimol ketone (4-methyl-1-hepten-3-one) is described and the absolute configuration of the main semiochemical compound is determined as having an (S)-configuration. The synthesis features the use of a ruthenium catalytic asymmetric hydrogenation reaction to introduce chirality into acid 2. The synthetic chichimol ketone (S)-1 displayed a specific rotation that was in accordance with that of the natural product, thereby supporting the (S) configuration for natural chichimol ketone. To assure the correct stereochemical assignment, (S)-1 was converted in the known ketone (S)-5: the main alarm pheromone of the ant Atta texana that is 400 times more active than its (R)-enantiomers.     

An efficient synthesis of (7S,10R)-2-bromo-5,6,7,8,9,10-hexahydro-7,10-epiminocyclohepta[b]indole: application in the preparation and structural confirmation of a potent 5-HT6 antagonist

(7S,10R)-5-Methyl-2-((3-(trifluoromethyl)phenyl)sulfonyl)-5,6,7,8,9,10-hexahydro-7,10-epiminocyclohepta[b]indole 1a is a potent 5-HT₆ antagonist (h5-HT₆ K_i = 1.5 nM) which is derived from an epiminocyclohept[b]indole scaffold. In order to synthesize 1a on a multi-gram scale to support advanced biological testing, an efficient chiral resolution of the intermediate tert-butyl 2-bromo-5,6,7,8,9,10-hexahydro-7,10-epiminocyclohepta[b]indole-11-carboxylate 2 was developed. After derivatizing 2 with (1R)-(?)-menthyl chloroformate it was found that a single diastereomer 7a could be isolated by selective precipitation from n-hexane. The absolute stereochemistry of 7a was determined by X-ray crystallography and the structure was confirmed as (7S,10R)-tert-butyl 2-bromo-5,6,7,8,9,10-hexahydro-7,10-epiminocyclohepta[b]indole-11-carboxylate. Removal of the chiral auxiliary under basic conditions afforded intermediate 2a in >99% enantiomeric purity and with 80% yield based on recovery from the racemic compound 2. Intermediate 2a was used successfully to synthesize 5-HT₆ antagonist 1a on a multi-gram scale.     

Structure and atropisomerisation of new diastereomeric gossypol Schiff bases with (R)-(+)-2-amino-3-benzyloxy-1-propanol studied by NMR,ECD and DFT methods

Gossypol Schiff base with (R)-(+)-2-amino-3-benzyloxy-1-propanol 1 was synthesised and resolved by HPLC method into diastereomers to study their atropisomerisation process. The spectroscopic analysis performed by one- and two-dimensional NMR, UV–vis and FT-IR methods indicated that the compound exists in solution as an enamine-oxo tautomer. The ECD measurements and TD-DFT calculations allowed us to unambiguously determine the configuration about the axially chiral biaryl moiety of 1. The conditions of the atropisomerisation processes of diastereopure gossypol Schiff bases (S_AX,R)-1 and (R_AX,R)-1 were determined on the basis of ECD and NMR measurements. Exposure of the diastereomers of 1 to sunlight and to the light at λ = 254 nm significantly accelerated the atropisomerisation when compared to its rate in the dark.     

Sterically hindered and completely arrested nitrogen inversion in pyrazolidines

Syntheses of trans-1,2-di-tert-butylpyrazolidine 1, d,l- and semi-meso-1,2-diisopropyl-3,5-dimethylpyrazolidines, 2a and 2b, respectively, have been developed. Activation parameters of the nitrogen inversion in 1 (ΔG^≠ = 123 kJ mol⁻¹ at 110 °C, ΔH^≠ = 114 kJ mol⁻¹, ΔS^≠ = −15 J K⁻¹ mol⁻¹) have been determined. The steric veto of the nitrogen inversion in 2a has been confirmed. Chemical transformations of 1 have been studied, and the crystal structures of 2a·picrate and 2b·HCl determined.     

Formal enantioselective synthesis of (+)-vincamine. The first enantioselective route to (+)-3,14-epivincamine and its enantiomer

A formal synthesis of (+)-vincamine (1) from (S)-(+)-2-ethyl-2-(2-methoxycarbonylethyl) cyclopentanone (6a) is described. This intermediate had previously been obtained by our research group in 90% ee through d'Angelo's deracemizing alkylation of the chiral imine 7, easily prepared from (R)-(+)-α-methylbenzylamine and 2-ethyl cyclopentanone with methyl acrylate. A potencial advanced intermediate for the synthesis of (+)-4, an epimer of (+)-1 at positions C-3 and C-14, has also been prepared from 6a.     

Two diasteoisomers of 5-hydroxy-6-methylpipecolic acid from seeds of Fagus silvatica L.

Two diastereoisomers of 5-hydroxy-6-methylpipecolic acid have been isolated from beechnuts. The configurations of the two amino acids have been assigned as (2S, 5S, 6S) (1) and (2S, 5R, 6S) (2). The determination of structure and configuration for the two new amino acids is mainly based on spectroscopic and rotatory evidence. The ¹³C-NMR and ¹H-NMR spectra of the three ionic forms of the two amino acids and of S-pipecolic acid and (2S, 5R)-5-hydroxypipecolic acid and the CD-curves of the cations and amfoions of 1, 2, and (2S, 5R)-5-hydroxypipecolic acid have been recorded.     

The synthesis of S-(+)-2,2-dimethylcyclopropane carboxylic acid: a precursor for cilastatin

S-(+)-2,2-Dimethylcyclopropane carboxylic acid, a precursor for cilastatin, was prepared from 2-methylpropene and chiral iron carbene in three steps. Asymmetric cyclopropanation reaction of 2-methylpropene with iron carbene complex having chirality at the carbene ligand, followed by exhaustive ozonolysis, produced S-(+)-2,2-dimethylcyclopropanecarboxylic acid of up to 92% ee. The absolute configuration of complexed chiral cyclopropane (−)-8 was determined by X-ray crystallographic analysis.     

Sharpless asymmetric dihydroxylation as the key step in the enantioselective synthesis of spirocyclic σ1 receptor ligands

The enantioselective synthesis of fluorinated spirocyclic σ₁ ligands involved three key steps: (1) the Sharpless asymmetric dihydroxylation of 2-bromostyrene 5 provided enantiomerically pure diols (R)-6 and (S)-6 establishing the stereogenic center; (2) the intramolecular opening of the oxirane ring of (R)-11 and (S)-11, which occurred with excellent regioselectivity and complete inversion of configuration giving access to enantiomerically pure alcohols (S)-7a and (R)-7a; (3) the treatment of alcohols (S)-7b and (R)-7b with DAST, which led to the fluoromethyl derivatives (S)-1 and (R)-1 without racemization. X-ray crystal structure analysis of the tosylate (R)-13 confirmed the absolute configuration of the spirocyclic compounds as well as the enantioselectivity during the Sharpless asymmetric dihydroxylation of 5. The (S)-configured fluoromethyl derivative (S)-1 revealed a high σ₁ affinity (K_i = 1.8 nM), high eudismic ratio (factor 8) and high selectivity over the σ₂ subtype (667-fold).     

Enantioselective transesterification of (RS)-1-chloro-3-(3,4-difluorophenoxy)-2-propanol using Pseudomonas aeruginosa lipases

Lipases from the bacterial strain, Pseudomonas aeruginosa, isolated from the soil by enrichment techniques, are assessed for the enantioselective transesterification of (RS)-1-chloro-3-(3,4-difluorophenoxy)-2-propanol (rac-CDPP) to (R)-1-chloro-3-(3,4-difluorophenoxy)-2-propanol, a key intermediate in the synthesis of the chiral drug (S)-Lubeluzole. The lipases produced by the organism yielded the (S)-ester and the (R)-alcohol as the remaining substrate with an excellent yield (>49.9%) and almost complete enantioselectivity (ee >99.9%) in the presence of vinyl butyrate as an acyl donor in an organic medium. In contrast, purified and expensive commercially available lipases of Candida rugosa and porcine pancreas achieved much lower conversion with enantioselectivities of 15% and 5%, respectively. A well-mixed (∼1000 rev min⁻¹) batch reactor having the aqueous phase finally dispersed in hexane was used in these studies. The parameters of the transesterification reaction were optimized and the optimal concentrations of rac-CDPP and vinyl butyrate were found to be 5 and 150 mM at 30 °C. A preparative-scale reaction yielded the (S)-ester at 42% conversion and ee >99%.     

Heterocycles 35. CaL-B mediated synthesis of enantiomerically pure (R)- and (S)-ethyl 3-(2-arylthiazol-4-yl)-3-hydroxypropanoates

Herein we present the lipase catalyzed synthesis of four new enantiomerically pure (R)- and (S)-ethyl 3-(2-arylthiazol-4-yl)-3-hydroxypropanoates and their butanoates by enzymatic enantioselective acylation of the racemic alcohols rac-1a–d and by ethanolysis of the corresponding racemic esters rac-2a–d mediated by lipase B from Candida antarctica (CaL-B) in organic solvents. In terms of stereoselectivity and activity, both procedures, the acylation and alcoholysis, are successful (50% conversion, E ≫ 200). The absolute configuration of the resolution products was determined by a detailed ¹H NMR study of the Mosher’s derivatives of (S)-1a.