Syntheses of (S)-(+)-trihexyphenidyl hydrochloride and (S)-(+)-procyclidine hydrochloride, two anticholinergics, using (S)-(-)-3-cyclohexyl-3-hydroxy-3-phenylpropanoic acid as chiral synthon

The absolute configuration of the more active (-)-enantiomer of the anticholinergic trihexyphenidyl hydrochloride has been established as (R) by syntheses of (S)-(+)-procyclidine hydrochloride, whose absolute configuration has been established previously, and (S)-(+)-trihexyphenidyl hydrochloride from the same chiral building block, viz. (S)-(-)-cyclohexyl-3-hydroxy-3-phenylpropanoic acid. Both enantiomers of this chiral synthon were prepared by optical resolution of the corresponding racemate, employing (R)- and (S)-1-phenylethylamine, respectively, as resolving agents.     

Diastereomers of N-alpha-phenylethyl-t-butylsulfinamide: absolute configurations and predominant conformations

N-alpha-Phenylethyl-t-butylsulfinamide is a complicated system for determining molecular stereochemistry because of numerous possibilities for assigning the absolute configuration and a predominant conformation. Two diastereomers of N-alpha-phenylethyl-t-butylsulfinamide derived from (-)-(S)-alpha-phenylethyl amine, a (+)-diastereomer and a (-)-diastereomer, have been synthesized and their experimental chiroptical spectroscopic properties have been measured. These properties include vibrational circular dichroism, electronic circular dichroism and optical rotatory dispersion. Using these experimental data, in conjunction with corresponding density functional theoretical predictions, the absolute configuration and predominant conformations of these two diastereomers have been determined. Also, the absolute configuration of (-)-diastereomer has been independently confirmed by determining its structure from X-ray diffraction data.     

Enantioselective organocatalytic oxyamination of unprotected 3-substituted oxindoles

An enantioselective α-oxyamination of unprotected 3-substituted oxindoles with nitrosobenzene catalyzed by tertiary amine-thiourea bifunctional organocatalysts has been developed and affords the corresponding 3-amino-2-oxindole derivatives in good yields and with moderate to excellent enantioselectivities (up to > 99.9?:?0.1 er when the product is isolated by direct filtration from the reaction mixture). The absolute configuration of the major enantiomers of the products has been established both by chemical correlation and by comparison between the theoretically calculated and the experimental ECD.     

Enantioselective synthesis of 4-substituted 4,5-dihydro-1H-[1,5]benzodiazepin-2(3H)-ones by the Lewis base-catalyzed hydrosilylation

Enantioselective synthesis of 4-substituted 4,5-dihydro-1H-[1,5]benzodiazepin-2(3H)-ones has been accomplished through chiral Lewis base-catalyzed hydrosilylation. The corresponding products were obtained in excellent yields (up to 99%) and enantioselectivities (up to 98%). The absolute configuration of product 3n has been determined as S by X-ray crystallographic analysis.     

Chiral cyclohexane based fluorescent chemosensors for enantiomeric discrimination of aspartate

Some new chiral cyclohexyl based fluorescent anion receptors have been synthesized and their absolute configuration has been determined by using circular dichroism (CD). Complexation experiments have been carried out with several dicarboxylates, and stoichiometries and complexation constants for the corresponding complexes have been determined. The chiral discrimination ability of these ligands for chiral dicarboxylates has been studied and the best results have been obtained with TMA aspartate.     

Stereoselective synthesis of optically active cyclitol precursors via a chemoenzymatic method

Racemic α′-acetoxy α,β-unsaturated cyclohexanone has been converted to the corresponding enantiomerically enriched α′-hydroxylated and acetoxylated compounds with 97% ee via enzymatic resolution with PLE. OsO₄-Catalyzed dihydroxylation of enantiomerically enriched α′-acetoxylated compound afforded a single diastereomer in 85% chemical yield. The absolute configuration of 2,3,6-triacetoxycylohexanone was determined by X-ray diffraction analysis. Subsequent Luche reduction allowed us to obtain corresponding syn-type cyclitol precursors in a highly stereoselective manner as expected.     

Absolute Configuration Assignment from Optical Rotation Data by Means of Biphenyl Chiroptical Probes

A non-empirical approach for the assignment of the absolute configuration of chiral 2-alkyl-substituted carboxylic acids and primary amines by [α]_D measurements has been developed. The method requires the conversion of the chiral acids or amines into the corresponding 4,4′-disubstituted biphenylamides or biphenylazepines, respectively. In these derivatives a central-to-axial chirality transfer induces a preferred torsion in the biphenyl moiety revealed by the sign of the biphenyl A band in the ECD spectrum. By 4,4′-substitution on the biphenyl moiety a redshift of the A band is obtained, leading to an increase of its relative contribution to optical rotation. This allows to reliably establish a direct correlation between the [α]_D sign, the biphenyl twist and, then, the substrate absolute configuration. This approach thus constitutes a really practical and reliable method to assign the absolute configuration of chiral carboxylic acids and primary amines by simple and straightforward [α]_D measurement, readily obtainable by a routine instrumentation like the polarimeter.     

5-Methyl-4H-1,3-dioxins,new chiral building blocks: transformation into (R)- and (S)-4-hydroxymethyl-4-methyl-1,3-dioxolanes via oxidation and rearrangement and determination of the absolute configuration

5-Methyl-4H-1,3-dioxins obtained by asymmetric double-bond isomerization have been transformed into 4-hydroxymethyl-4-methyl-1,3-dioxolanes by m-chloroperbenzoic acid oxidation, ring contraction and reduction. The stereochemical course of this transformation has been studied, while the relative configuration of the intermediate oxidation product and the absolute configuration of the resulting camphanyl ester of 2-tert-butyl-4-hydroxymethyl-4-methyl-1,3-dioxolane was established by X-ray crystallography. From these results, the absolute configuration of the dioxins has been deduced.     

New macrocyclic sesterterpenoids from a scale insect (ceroplastes ceriferus)

Six new macrocyclic sesterterpenoids 1–6 were isolated from the secretion of a scale insect, Ceroplastes ceriferus Anderson, and their structures determined. Chemical correlation has also been accomplished. Stereochemistry was elucidated by comparison of the CD spectra of the ozonolysis product of 1-acetate and a corresponding synthetic substance of known absolute configuration.     

Determination of the absolute configurations using electronic and vibrational circular dichroism measurements and quantum chemical calculations

The stereochemistry of products obtained via a chemical reaction may not always be obvious from the reaction scheme utilized. The identification of convenient methods to determine the stereochemistry in such cases is highly desirable. To identify these methods, we considered a substituted 4-vinyl-1-azabicyclo[3.2.0]hept-3-en-7-one that undergoes spontaneous oxidation in the atmosphere at room temperature, yielding an epoxide with unknown absolute configuration. To determine the absolute configuration of the resulting epoxide, three different approaches have been utilized: (a) experimental NOE measurements; (b) experimental electronic circular dichroism (ECD) spectroscopic measurements and their analysis using corresponding quantum chemical predictions at the B3LYP/aug-cc-pVDZ level; (c) experimental vibrational circular dichroism (VCD) spectroscopic measurements and their analysis using corresponding quantum chemical predictions at the B3LYP/aug-cc-pVDZ level. It was found that the NOE data could not provide enough proof for assigning the absolute configuration, while ECD data could not provide enough discrimination to distinguish between the two possible stereoisomers. On the other hand, VCD spectroscopic analysis provided enough discrimination to distinguish between the two possible stereoisomers, and the absolute configuration could be assigned with confidence.     

Coulomb Explosion Imaged Cryptochiral (R,R)‐2,3‐Dideuterooxirane: Unambiguous Access to the Absolute Configuration of (+)‐Glyceraldehyde

The absolute configuration of (R,R)‐2,3‐dideuterooxirane, which has been independently determined using Coulomb explosion imaging, has been unambiguously chemically correlated with the stereochemical key reference (+)‐glyceraldehyde. This puts the absolute configuration of D (+)‐glyceraldehyde on firm experimental grounds.     

Stoffwechselprodukte von Mikroorganismen. 50. Mitteilung. Die Konfiguration der Arcanose

The L -xylo configuration of arcanose, a sugar from the antibiotic lankamycin, has been proven by its transformation into cladinose. The determination of the absolute configuration at C-3 of arcanose and cladinose has been accomplished utilizing a new procedure.     

Experimental and Computational Study of the Catalytic Asymmetric 4π‐Electrocyclization of N‐Heterocycles

The first asymmetric metal‐catalyzed Nazarov cyclization of N‐heterocycles has been developed. The use of a chiral catalyst allows the enantioselective electrocyclization of N‐heterocycles under mild conditions and the corresponding products are obtained in good yields with excellent enantio‐ and diastereoselectivity. The reaction mechanism and the absolute configuration of the obtained products are explained by means of computational studies.     

Die absolute konfiguration des (+)-corynolins

From Corydalis incisa (+)-corynoline (2) was isolated together with (±)-corynoline (2'), which has been reported to be the major alkaloid. Optical resolution of 2' was achieved by resolving the corresponding diastereomeric esters with (-)-menthoxyacetic acid. The quaternary hydroxide of (+)-corynoline-O-acetate (3) was subjected to Emde degradation to afford the hydromethine base (5), the methiodide of which was converted by further Emde degradation into the optically active nitrogenfree product (6). This product was identical with the nitrogen-free product resulting from Emde degradation of (+)-14-epicorynoline (1), whose absolute configuration has been determined by means of an X-ray analysis. This result shows the absolute configuration of (+)-corynoline (2) to be 11S, 13R and 14R.     

On the absolute stereochemistry of the photochemical rearrangement of 2,5-cyclohexadienones to lumiketones

Specification of the absolute configurations of starting material and product in the photochemical rearrangement of a 2,5-cyclohexadienone to a bicyclo[3.1.0]hexen-2-one (lumiketone) permits unambiguous determination of the stereochemistry at two crucial stages in the generally accepted reaction mechanism, namely the electrocyclic ring closure to give a 3,5-bonded intermediate, and the subsequent [1,4]-sigmatropic shift. The stereochemical course of the latter process in turn allows specification of whether the rearrangement is occurring directly from an electronically excited intermediate or a ground state zwitterion. An unconstrained monocyclic chiral cyclohexadienone has been studied in which steric constraints are minimal, and in which the system should have free choice of available pathways. The absolute configuration of the resolved dienone was determined by X-ray crystallographic analysis of a derivative containing a chiral center of known configuration. The absolute configuration of the resultant optically active diastereomeric lumiketones has been assigned from the Cotton effects observed on the corresponding dihydrolumiketones, assuming these chiroptical effects are governed by a normal Octant Rule instead of the Inverse Octant Rule which empirically correlates such data for cyclopropyl ketones lacking polarizable substituents. The limitations on these assignments are discussed, as well as alternative efforts to obtain completely unambiguous stereochemical assignments for the lumiketones. On the basis of these assignments, it is concluded that the sigmatropic shift proceeds with inversion of configuration at the migrating carbon, consistent with reaction via a ground state zwitterion.     

Diastereoselective addition of enantiopure lithium tert-butylsulfinylferrocene to imines

(S)-tert-Butylsulfinylferrocene was submitted to ortho-metalation, and the corresponding lithium derivative was trapped by alkyl or aryl imines bearing various electron-withdrawing groups on the nitrogen atom (Ts, Dpp, Boc). New aminosulfoxides were obtained with complete diastereocontrol when Dpp or Boc groups were used. The absolute configuration (SS,SFc,S) has been determined by single-crystal X-ray analysis and chemical correlation. An unusual pseudocyclic boatlike transition state has been proposed to explain the stereochemical course of this reaction.     

Determination of the absolute stereochemistry of Etzionin

The absolute configuration of Etzionin, a marine peptide-like compound isolated in 1989 from a red tunicate collected from the Red Sea has been determined by a combination of synthetic and spectroscopic procedures. Finally, its absolute stereochemistry has been established as 3S,3′R.     

Application of a modified Mosher’s method for the determination of enantiomeric ratio and absolute configuration at C-3 of chiral 1,3-dihydroxy ketones

The enantiomeric ratio and absolute configuration of products of the transketolase reaction are typically determined by comparison of the specific rotation or derivatisation and HPLC or GC. A Mosher’s ester method has been developed via ester formation at the primary alcohol C-1 which can be used to determine the stereoselectivity of the reaction, as well as the absolute configuration of the product at C-3.     

Stereoselective synthesis of (1R,2R)-1-amino-2-hydroxycyclobutanecarboxylic acid—serine derivative—, from racemic or optically active 2-benzyloxycyclobutanone

An easy and efficient one-pot reaction from readily available 2-benzyloxycyclobutanone gave, by means of an asymmetric Strecker synthesis, a kinetic or thermodynamic nitrile with good selectivity. After separation, the major trans-amino nitrile underwent basic hydrolysis and hydrogenolysis, followed by acidic hydrolysis, to give optically active (1R,2R)-1-amino-2-hydroxycyclobutanecarboxylic acid, serine derivative. The absolute configuration has been established by X-ray analysis of the corresponding cis-amino nitrile.     

Highly diastereoselective indium-mediated synthesis of β-lactam carbohydrates from imines

A simple and very effective approach to versatile carbohydrate β-lactam synthons of predictable absolute configuration has been developed. The procedure, which is based on the indium-mediated reaction of imines and bromoesters, was applied to the enantioselective synthesis of 3-monosubstituted and 3-disubstituted β-lactams from readily available carbohydrates. The opening of the β-lactamic ring gave rise to the corresponding sugar-derived β-amino acids. Transformation of the β-lactams into the corresponding azetidines was also achieved.