Pseudoasymmetry, stereogenicity, and the RS-nomenclature comprehended by the concepts of holantimers and stereoisograms

The concepts of holantimer and stereoisogram are applied to comprehensive discussions on the term ‘pseudoasymmetry’, where the concept of RS-stereogenicity is used as a more definite concept than usual stereogenicity. Thereby, three relationships contained in each stereoisogram can be definitely specified: an enantiomeric relationship is related to chiral/achiral, an RS-diastereomeric relationship is related to RS-stereogenic/RS-astereogenic, and a holantimeric relationship is related to scleral/ascleral, which is coined to keep the terminology in a balanced fashion. Such stereoisograms are classified into five types (Types I-V) by virtue of the three relationships. Among them, Type I, III, and V are selected as a set of RS-stereogenic units: chiral/ascleral RS-stereogenic unit (or Type I unit), chiral/scleral RS-stereogenic unit (or Type III unit), and achiral/scleral RS-stereogenic unit (or Type V unit). Thereby, the term ‘pseudoasymmetric stereogenic units’ should be replaced by the term ‘achiral/scleral RS-stereogenic units’ (or ‘Type V units’).     

Stereoisograms for reorganizing the theoretical foundations of stereochemistry and stereoisomerism. Part 3: rational avoidance of misleading standpoints for pro-R/pro-S-descriptors

The stereoisogram approach is introduced to settle the misleading terminology due to ‘prochirality’ in modern stereochemistry. After the term prochirality is redefined as having a purely geometric meaning, a method based on probe stereoisograms and another method based on equivalence classes (orbits) are introduced to determine prochirality and/or pro-RS-stereogenicity. Enantiotopic and RS-diastereotopic relationships appearing in probe stereoisograms are respectively used to determine prochirality and pro-RS-stereogenicity, where ‘stereoheterotopic’ relationships used in modern stereochemistry are abandoned. Alternatively, an enantiospheric orbit for specifying prochirality and an RS-enantiotropic orbit for specifying pro-RS-stereogenicity are emphasized by using coset representations and Young tableaux. The pro-R/pro-S-system is clarified to be based on pro-RS-stereogenicity and not on prochirality.     

Enantioselective cyclization of chiral butane-1,4-diols to chiral tetrahydrofurans: synthesis of chiral trans-2-(3-methoxy-5-methylsulfonyl-4-propoxyphenyl)-5-(3,4,5-trimethoxyphenyl)tetrahydrofuran (L-659,989), a potent PAF-receptor antagonist

Acid catalyzed cyclization of (1R,4RS)- and (1S,4RS)-1-(3-methoxy-5-methylsulfonyl-4-propoxyphenyl)-4-(3,4,5-trimethoxyphenyl)butane-1,4-diols to the corresponding chiral cis- and trans-tetrahydrofurans proceeds with retention of configuration at C-1. Using this stereo- and regioselective reaction, the two optically active enantiomers of L-659,989, a potent PAF-receptor antagonist, were prepared.     

Stereoselective synthesis of kurzilactone and determination of its absolute configuration

Both (5S,7S)- and (5R,7S)-isomers of kurzilactone were synthesized from a ‘chiral epoxy-aldehyde synthon’ through the coupling of an acyl anion equivalent and the dianion of acetoacetate, followed by formation of the Kawa-type lactone by cyclization and elimination. Comparing the spectral data of the synthesized and naturally occurring kurzilactone, the C(5)- and C(7)-stereogenic centers of the natural kurzilactone was assigned a corrected anti-relationship with (5R,7S)-absolute configuration.     

Symmetry-itemized enumeration of quadruplets of RS-stereoisomers. II. The partial-cycle-index method of the USCI approach combined with the stereoisogram approach

The symmetry-itemized enumeration of quadruplets of stereoisograms is discussed by starting from a tetrahedral skeleton, where the partial-cycle-index (PCI) method of the unit-subduced-cycle-index approach (Fujita in Symmetry and combinatorial enumeration of chemistry. Springer, Berlin, 1991) is combined with the stereoisogram approach (Fujita in J Org Chem 69:3158–3165, 2004, Tetrahedron 60:11629–11638, 2004). Such a tetrahedral skeleton as contained in the quadruplet of a stereoisogram belongs to an RS-stereoisomeric group denoted by $\mathbf{T}_{d\widetilde{\sigma }\widehat{I}}$ , where the four positions of the tetrahedral skeleton accommodate achiral and chiral proligands to give quadruplets belonging to subgroups of $\mathbf{T}_{d\widetilde{\sigma }\widehat{I}}$ according to the stereoisogram approach. The numbers of quadruplets are calculated as generating functions by applying the PCI method. They are itemized in terms of subgroups of $\mathbf{T}_{d\widetilde{\sigma }\widehat{I}}$ , which are further categorized into five types. Quadruples for stereoisograms of types I–V are ascribed to subgroups of $\mathbf{T}_{d\widetilde{\sigma }\widehat{I}}$ , where their features are discussed in comparison between RS-stereoisomeric groups and point groups.     

Enantiomer separation and absolute configuration of densely functionalized 2-oxatricyclo[4.3.1.03,8]decanes by CD spectroscopy and chemical correlation

Enantiomer separation by HPLC on a swollen microcrystalline triacetylcellulose column of highly substituted 2-oxatricyclo[4.3.1.0^3,8]decane (2-oxaprotoadamantane) structures afforded enantiomers of this molecule. Application of the octant rule to the carbonyl chromophore to establish the absolute configuration of the enantiomers did not lead to an unequivocal conclusion. The enantioselective synthesis of 4-bromo-3-methoxy-oxaprotoadamantanone was performed from homochiral (+)-(1S,5S)-bicyclo[3.3.1]nonane-2,6-dione thus permitting the assignment of the (1R,3S,4S,6R,8R)-configuration to the title structures.     

Stereochemical effects in mass spectrometry. 7. Determination of absolute configuration of some organic molecules by reaction mass spectrometry

It was found that in the chemical ionization (isobutane) mass spectra of some asymmetric secondary alcohols and α-amino acids, when a pair of enantiomers (such as R- and S-2-phenyIbutyric anhydride, R- and S-mandelic acid, R- and S-2-methylbutanoic acid or R- and S-α-phenyl ethyl amine) were used as reaction reagents, the relative abundances of characteristic ions formed by the stereoselective reaction between sample and reagent of the same configuration were much higher than those ions formed by the sample and a reagent of a different configuration. The absolute configuration of the sample molecule may be predicted by examination of mass spectra of the sample measured with R- and S-reagent respectively. This approach proved to be a convenient way for determination of the absolute configurations of organic molecules on a micromole level by mass Spectrometry.     

Enantioselective transesterification of (±)-1-phenylundecan-3-ol catalyzed by the lipase from Burkholderia cepacia

Enantiomerically enriched (R)- and (S)-1-phenylundecan-3-ols were obtained by kinetic resolution of the racemate with vinyl acetate in ButOMe at 20 °C using the lipase from Burkholderia cepacia. The absolute configuration of the enantiomers was confirmed by a direct stereochemical correlation with the known (R)- and (S)-dodecanolides.     

Absolute configuration of the four stereoisomers of valnoctamide (2-ethyl-3-methyl valeramide), a potentially new stereospecific antiepileptic and CNS drug

Valnoctamide (2-ethyl-3-methyl valeramide, Nirvanil^®, VCD), a mild tranquilizer endowed with anticonvulsant properties, exhibits diastereoselective and enantioselective pharmacokinetics in healthy subjects and epileptic patients. The purpose of this paper is to assign the absolute configuration of the four VCD stereoisomers and to describe the stereoselective synthesis used to prepare two-key VCD stereoisomers. We have synthesized two out of the four stereoisomers, with high diastereomeric excess, by two different synthetic methods. In both methods the (S) configuration at C-3 of VCD was fixed by synthesizing (S)-3-methyl valeric acid from l-isoleucine. In the first method the diastereomeric mixture (2RS,3S)-VCD was prepared. This mixture gave one of the diastereomers via repeated crystallizations, and its absolute configuration (2R,3S)-VCD, was established by X-ray crystallography using a single crystal. The absolute configuration of all four VCD stereoisomers, separated by chiral gas chromatography, was established on the basis of diastereomeric and enantiomeric correlations. In order to assess stereoselective pharmacodynamic properties of VCD, the single stereoisomers have to be synthesized. Stereoselective synthesis of (2R,3S)-VCD and (2S,3S)-VCD was accomplished by using chiral oxazolidinone auxiliaries. These diastereomers were obtained in 99.6% diastereomeric excess.     

Enantioselective syntheses of both enantiomers of cis-pyrrolidine 225H

The efficient and expeditious syntheses of both enantiomers of the amphibian alkaloid cis-225H have been achieved. Utilizing a common cis-2,5-disubstituted pyrrolidine building block derived from (+)-2-tropinone, the enantioselective syntheses have established the absolute configuration of these alkaloids as (+)-(2R,5S) and (−)-(5S,2R).