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.     

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’).     

Integrated Discussion on Stereogenicity and Chirality for Restructuring Stereochemistry

To discuss the difference between stereogenicity and chirality, we propose the concept of RS-stereoisomeric groups. Beginning with this concept, we have further proposed the concepts of holantimers, stereoisograms, and RS-stereogenicity. Thereby, we have clarified that the concept of RS-stereogenicity, but not conventional stereogenicity, is closely related to chirality. Thus, five RS-stereogenicity types are defined and examined to discuss the difference between stereogenicity and chirality. Combinatorial enumerations have also been studied by considering the RS-stereogenicity.     

‘O-Acyl isopeptide method’ for the efficient synthesis of difficult sequence-containing peptides: use of ‘O-acyl isodipeptide unit’

A novel ‘O-acyl isodipeptide unit’, Boc-Thr(Fmoc-Val)-OH 5 has been successfully used for the efficient synthesis of a difficult sequence-containing pentapeptide based on the ‘O-acyl isopeptide method’, in which racemization-inducible esterification could be omitted, suggesting that the use of O-acyl isodipeptide units allows the application of this method to fully automated protocols for the synthesis of long peptides or proteins.     

A highly selective and femto-molar sensitive fluorescence ‘turn-on’ chemodosimeter for Hg

A selective fluorescence ‘turn-on’ chemodosimeter N,N′-bis-(4-cyanobenzylidene)-2,4,6-trimethylbenzene-1,3-diamine (3) based on a Schiff base for femto-molar detection of the Hg²⁺ has been described. It presents the highest level of detection limit for Hg²⁺ through Schiff base hydrolysis.     

Synthesis and ‘double click’ density functionalization of 8-aza-7-deazaguanine DNA bearing branched side chains with terminal triple bonds

The 7-[di(prop-2-ynl)amino]prop-1-ynyl derivative of 8-aza-7-deaza-2′-deoxyguanosine (1) was synthesized from 7-iodo-8-aza-7-deaza-2′-deoxyguanosine (7) by Sonogashira cross-coupling and converted into the phosphoramidite building block 10. Oligonucleotides bearing branched side chains with terminal triple bonds were prepared by solid-phase synthesis containing single or multiple residues of 1 as 2′-deoxyguanosine surrogates. T_m measurements demonstrate that compound 1 has a positive effect on duplex stability, which is comparable to the stabilizing effect of the octa-1,7-diynylated non-branched nucleoside 2. Nucleoside 1 and corresponding oligonucleotides were functionalized by the Cu(I)-mediated 1,3-dipolar cycloaddition ‘double click’ reaction with diverse ligands (AZT 3, benzyl azide 4, 11-azidoundecanol 5 and m-dPEG™₄-azide 6). The conjugation reactions were carried out in solution and on solid support. Nucleoside 1 allowed ‘double’ functionalization of a single residue with two reporter groups. The ‘double click’ reaction proceeded smoothly even when two residues of nucleoside 1 were arranged in proximal positions. Hybridization with complementary strands led to a stable oligonucleotide duplex. Molecular modeling indicates that inspite of the crowded steric situation with four AZT ligands within closest proximal positions, all ligands are well accommodated in the major groove not disturbing the DNA helix.     

Anthracene coupled trans-pyridylcinnamide: a new fluororeceptor for selective sensing of dicarboxylates

trans-Pyridylcinnamide has been established as an alternative hydrogen bonding synthon, in place of urea for carboxylate binding. This alternative motif has been used in the design and synthesis of new fluorescent ‘On-Off’ signalling chemical sensor 1, which is found to bind aliphatic dicarboxylates with moderate binding constants. The recognition ability has been established by fluorescence, UV-vis and ¹H NMR spectroscopic methods. The receptor is found to be selective for long chain pimelate.     

Conduramine F-1 epoxides: synthesis and their glycosidase inhibitory activities

Starting from (±)-7-oxanorbornenone ((±)-14), (±)-(1RS,2RS,3SR,6SR)-6-azidocyclohex-4-en-1,2,3-triol ((±)-24) and (±)-(1RS,2RS,3SR,6RS)-6-azidocyclohex-4-en-1,2,3-triol ((±)-26) were obtained. Epoxidation of the latter cyclohexene derivative gave two epoxides (±)-30 and (±)-31 that were converted into (±)-conduramine F-1 epoxides (±)-10 and (±)-11 and N-substituted derivatives (±)-12 and (±)-13. Compound (±)-(1RS,2SR,3RS,4SR,5RS,6SR)-5-({[4-(trifluoromethyl)phenyl]methyl}amino)-7-oxabicyclo[4.1.0]heptane-2,3,4-triol ((±)-12c) is a good, non-competitive inhibitor of β-xylosidase from Aspergillus niger (K_i=2.2 μM), and (±)-(1RS,2RS,3SR,4RS,5SR,6SR)-5-{[(biphenyl-4-yl)methyl]amino}-7-oxabicyclo[4.1.0]heptane-2,3,4-triol ((±)-13d) is a good inhibitor of α-glucosidase from brewer's yeast (K_i=2.8 μM, non-competitive).     

Asymmetric aziridine synthesis by aza-Darzens reaction of N-diphenylphosphinylimines with chiral enolates. Part 1: Formation of cis-aziridines

The aza-Darzens (‘ADZ’) reactions of N-diphenylphosphinyl (‘N-Dpp’) imines with chiral enolates derived from oxazolidinones and camphorsultam have been studied. Whilst oxazolidinone enolates reacted poorly in terms of aziridination, the use of the chiral enolate derived from both antipodes of N-bromoacetyl 2,10-camphorsultam, 2R-(5) and 2S-(5), with N-diphenylphosphinyl aryl and tert-butylimines proceeded in generally good yield to give, respectively, (2′R,3′R)- or (2′S,3′S)-cis-N-diphenylphosphinyl aziridinoyl sultams of high de.     

Conceptual defects of modern stereochemistry. Comprehensive remedy by stereoisograms based on RS-stereoisomerism for mediating between enantiomerism and stereoisomerism

The recognition of chirality as a single kind of handedness is a conceptual defect of modern stereochemistry, which has caused serious confusion in its theoretical foundations and stereochemical nomenclature. To remedy this defect, RS-stereogenicity is developed as another kind of handedness. These two kinds of handedness are integrated to give RS-stereoisomerism, which is formulated diagrammatically by stereoisograms. During the process of the remedy, the lack of the concept of ligand reflections has been revealed as another conceptual defect. The lack of the concept of orbits (equivalence classes) has been found to be one more defect, which has caused a misleading classification of isomers. By adopting the concept of orbits, the revised hierarchy of isomerism is developed, i.e., isomers $?$ isoskeletomers $?$ stereoisomers $?$ RS-stereoisomers $?$ enantiomers $?$ 3D-structures. Thereby, the theoretical foundations of modern stereochemistry are restructured rationally.     

Racemic [1SR,2RS,(RS)]-N-cyano(phenyl)methyl-1-aminoindan-2-ol: crystal structure and reactivity towards thermal epimerization in the solid state

A diastereomeric mixture of racemic α-amino nitriles [1SR,2RS,(SR)]- (1) and [1SR,2RS,(RS)]-N-cyano(phenyl)methyl-1-aminoindan-2-ol (2) was thermally epimerized in the solid state to give diastereopure [1SR,2RS,(SR)]-1. The reaction was about 26 times slower than the same reaction of a mixture of their enantiopure counterparts, showing that different mechanisms operated between the two transformations. X-ray crystallographic analysis revealed that in the former transformation, racemic-compound crystals of 2 were converted into conglomerate crystals of 1, while in the latter, enantiomeric crystals of 2 were converted into enantiomeric crystals of 1. The difference in the reactivity toward the epimerization between the racemic and the enantiopure mixture could be rationalized by the difference in the stability of compound 2 in the two crystal forms.     

Synthesis of ‘inside-outside’ medium-sized rings via ring-closing metathesis

Functionalized and unfunctionalized dienes were synthesized from lactones 7 and 6, respectively, which were subjected to ring-closing metathesis (RCM) using Grubbs’ catalysts. These dienes provide a systematic study of the stereochemical requirements for efficient cyclization. Moreover, it has been established that, within a uniquely defined oxabicyclo[3.3.0]octane template, medium sized rings bearing an ‘in-out’ intrabridgehead stereochemical relationship can been synthesized in good yield.     

Stereo-conserved synthesis of syn-diarylheptanoids, active principles of Zingiber, starting from d-glucose

A highly efficient and stereo-controlled synthetic strategy has been developed to access syn-diarylheptanoids, for example, 2,3, 4, and 5b starting from d-glucose as a chiral pool. The 3-(R), 5-(S)-syn-diol stereochemistry present in these heptanoids was obtained after conserving C2 and C4 stereochemistry of d-glucose during the course of synthetic transformation. The key features of this synthetic strategy include: (i) conversion of d-glucose to a known chiral template 6 armored with the required 1,3-syn-diol stereochemistry as well as two terminal aldehyde functionalities for building up customized ‘diaryl wings’; (ii) conversion of 6 to 7 via an initial Wittig olefination at the C5-aldehyde; (iii) use of the hemiacetal 7 as a common intermediate to obtain the individual heptanoids via a second Wittig reaction at its anomeric center using appropriately chosen ylides.     

Unsymmetrical double Wittig olefination on the syntheses of insect pheromones. Part 1: Synthesis of 5,9-dimethylpentadecane, the sexual pheromone of Leucoptera coffeella

An expeditious three-step synthesis of a mixture of stereoisomers of 5,9-dimethylpentadecane 1, the sexual pheromone of the coffee leaf miner Leucoptera coffeella, is described. The route employs an unsymmetrical double Wittig olefination to build the carbon skeleton of the molecule, as the key reaction. The bis-phosphonium salt 3, derived from 1,3-dibromopropane 2, reacted ‘one-pot’ with the ketones 2-octanone and 2-hexanone, affording the asymmetric diene 4. This was readily hydrogenated over Pd/C, furnishing pheromone 1 in 54% overall yield. Synthetic 1 showed high biological activity when tested in field experiments.