Reversed diastereoselectivity in the ring-opening reaction of (S)-TFPO with a chiral aminoacetonitrile Schiff base

Diastereoselective ring opening of (S)-2,3-epoxy-1,1,1-trifluoropropane [(S)-TFPO: 75% ee] with an aminoacetonitrile Schiff base bearing the (R,R,R)-hydroxypinanone chiral auxiliary [(R)-Schiff base] are described. The reaction of (S)-TFPO with the (R)-Schiff base selectively gave one diastereomer out of the four possible, while that with the (S)-Schiff base gave a complex mixture of all four possible diastereomers. The stereochemistry of the reaction products was greatly dependent on the base used for abstracting a proton from the (R)-Schiff base; utilization of LDA and KO^tBu resulted in production of (R,R,R,S,S)- and (R,R,R,R,S)-isomers as the major diastereomers, respectively.     

Iridodials: enantiospecific synthesis and stereochemical assignment of the pheromone for the golden-eyed lacewing, Chrysopa oculata

1R,2S,5R,8R; 1R,2S,5R,8S; 1S,2S,5R,8R; and 1S,2S,5R,8S-Iridodials have been prepared in five steps from 4aS,7S,7aR and 4aS,7S,7aS-nepetalactones, major components of catnip oil. 1R,2S,5R,8R-Iridodial has been identified as a male-produced male-aggregation pheromone for Chrysopa oculata, the first pheromone of any kind identified for lacewings.     

Ring-expanded chiral rhombamine macrocycles for efficient NMR enantiodiscrimination of carboxylic acid derivatives

Novel 46-membered chiral rhombamine macrocycles (R,R,R,R)-8a and 8b were synthesized by [2+2] cyclocondensation reactions of (R,R)-1,2-diaminocyclohexane with the corresponding dialdehydes and subsequent reduction with NaBH₄. The X-ray crystal structure of 1:4 dioxane complex with (R,R,R,R)-8a indicated a rhombus conformation of the chiral macrocycle. Compounds (R,R,R,R)-8a and 8b were tested as chiral shift reagents for a wide range of α-substituted carboxylic acids and amino acid derivatives. Enantiodiscrimination of ¹H NMR signals was observed with ΔΔδ values of up to 0.214 ppm.     

Determination of the absolute stereochemistry of lupane triterpenoids by fucofuranoside method and ORD spectrum

The absolute configurations of the secondary alcohols at C-3 position in betulinic acid and 3-epibetulinic acid have been unambiguously determined as S- and R-configurations, respectively, based on the fucofuranoside method. The absolute stereochemistry of 3α, 27-dihydroxylupen-20(29)-en-28-oic acid methyl ester, a potent topoisomerase II inhibitor, was determined to be 3R, 5R, 8R, 9R, 10R, 13R, 14S, 17S, 18R, and 19R by NMR and ORD spectroscopic studies.     

Synthesis and biological activity of diastereoisomeric octahydro-1H-indole-5,6,7-triols,analogues of castanospermine

A straightforward stereoselective route towards (3aR,5R,6S,7R,7aR)- and (3aR,5R,6S,7R,7aR)-octahydro-1H-indole-5,6,7-triol, analogues of castanospermine, starting from the corresponding shikimic acid derivatives is described. The key transformations of this approach are the Overman rearrangement and ring-closing metathesis to form the diastereoisomeric cis-fused (5R,6S,7R)-octahydro-1H-indole-5,6,7-triols in good overall yields. Evaluation for in vitro cytotoxicity revealed for some prepared compounds significant antiproliferative activity and weak glycosidase inhibition.     

Chemoenzymatic synthesis and HPLC analysis of the stereoisomers of miyakosyne A [(4E,24E)-14-methyloctacosa-4,24-diene-1,27-diyne-3,26-diol], a cytotoxic metabolite of a marine sponge Petrosia sp., to determine the absolute configuration of its major component as 3R,14R,26R

Six samples [(3R,14R,26R)-, (3R,14S,26R)-, (3S,14R,26S)-, and (3S,14S,26S)-1, a mixture of (3R,14R,26S)- and (3S,14R,26R)-1, and a mixture of (3R,14S,26S)- and (3S,14S,26R)-1] of miyakosyne A [1, (4E,24E)-14-methyloctacosa-4,24-diene-1,27-diyne-3,26-diol] were synthesized starting from the enantiomers of citronellal (2), employing olefin cross metathesis and R-selective asymmetric acetylation of a stereoisomeric mixture of acetylenic alcohols with vinyl acetate and lipase PS as key reactions. Separation of the eight stereoisomer of 1 by reversed phase HPLC at −56 °C was achieved after their esterification with (1R,2R)-2-(anthracene-2,3-dicarboximido)cyclohexanecarboxylic acid (16), and the natural miyakosyne A was found to be a mixture of 95.7% of (3R,14R,26R)-1 and 4.3% of (3R,14S,26R)-1. This is different from the (3R,14S,26R)-configuration of 1 as tentatively assigned by X-ray analysis.     

Enantioselective cyanosilylation of aldehydes catalysed by a diastereomeric mixture of atropisomeric thioureas

New bifunctional atropisomeric thioureas 1 were synthesised and tested as both a mixture of diastereomers (aR/aS)-(R,R)-1 and as single diastereomers (aR)-(R,R)-1 and (aR)-(S,S)-1, in the organocatalysed, enantioselective, cyanosilylation of a range of aldehydes (aromatic and aliphatic). Moderate enantiomeric excesses (up to 69% ee) and quantitative yields were obtained. The best results were achieved using a mixture of thiourea diastereomers (aR/aS)-(R,R)-1 instead of the single diastereomers alone.     

Synthetic studies on homophymine A: stereoselective synthesis of (2R,3R,4R,6R)-3-hydroxy-2,4,6-trimethyloctanoic acid

An efficient and highly stereocontrolled synthesis of (2R,3R,4R,6R)-3-hydroxy-2,4,6-trimethyloctanoic acid, the β-hydroxy acid unit that acylates the N-terminus of homophymine A, has been devised starting from iodoethane and (S,S)-pseudoephedrine propionamide in 9 steps and 36% average overall yield. Comparison of the ¹H and ¹³C NMR and optical rotation data of the resulting β-hydroxy acid with the natural fragment unambiguously verifies the configurational assignment as (2R,3R,4R,6R).     

Two chiral mononuclear and one-dimensional cadmium(II) complexes constructed by (1R,2R)-N1,N2-bis(pyridinylmethyl)cyclohexane-1,2-diamine derivatives: Effect of positional isomerism

Reactions of (1R,2R)-N¹,N²-bis(pyridinylmethyl)cyclohexane-1,2-diamine derivatives, (1R,2R)-2-bpcd and (1R,2R)-3-bpcd [(1R,2R)-2-bpcd = (1R,2R)-N¹,N²-bis(pyridin-2-ylmethyl)cyclohexane-1,2-diamine, (1R,2R)-3-bpcd = (1R,2R)-N¹,N²-bis(pyridin-3-ylmethyl)cyclohexane-1,2-diamine], with CdI₂ in an analogous way led to the formation of a chiral discrete mononuclear complex and a chiral one-dimensional polymeric chain, respectively, which may be attributed to the positional isomerism of the ligands. The chiral organic ligands and complexes display luminescent properties indicating that they may have a potential application as optical materials. Powder second-harmonic generation (SHG) efficiency measurement shows that the SHG efficiency of the complexes is approximately 0.3 and 0.45 times that of KDP, respectively.     

Novel chiral hexaazamacrocycles for the enantiodiscrimination of carboxylic acids

New enantiopure amines (R,R)-1 and (S,S)-1 were obtained from (R)- or (S)-2,2′-diamino-1,1′-binaphthyl and 2,6-diformylpyridine in a synthesis templated by lead(II) or lanthanide(III) ions, reduction with NaBH₄ and subsequent demetallation. Similarly new amines (R,R,R,R)-2 and (S,S,S,S)-2 were obtained from (1R, 2R)- or (1S, 2S)-1,2-diphenylethylenediamine. The X-ray crystal structure of the Pb(II) complex with macrocyclic Schiff base precursor of (R,R)-1 indicates helical twisted conformation of this macrocycle, while the ROESY spectrum of R,R-1 suggests less twisted conformation. (R,R)-1 and (R,R,R,R)-2 were tested as chiral shift reagents (chiral solvating agents) for various α-substituted carboxylic acids, including non steroidal anti-inflammatory drugs. Enantiodiscrimination of carboxylate ¹H NMR signals was observed with ΔΔδ values up to 0.1 ppm.     

Studies on the transformation of nitrosugars into iminosugars III: synthesis of (2R,3R,4R,5R,6R)-2-(hydroxymethyl)azepane-3,4,5,6-tetraol and (2R,3R,4R,5R,6S)-2-(hydroxymethyl)azepane-3,4,5,6-tetraol

A divergent synthesis of the two novel polyhydroxylated azepanes (2R,3R,4R,5R,6R)-2-(hydroxymethyl)azepane-3,4,5,6-tetraol and (2R,3R,4R,5R,6S)-2-(hydroxymethyl)azepane-3,4,5,6-tetraol from d-mannose is described. The method involves a Henry reaction between dimethyl-tert-butylsilyl 2,3-O-isopropylidene-α-d-lyxo-pentodialdo-1,4-furanoside and 2-nitroethanol followed by a reductive ring closure of the resulting epimeric nitro aldols. Glycosidase inhibition tests showed that (2R,3R,4R,5R,6S)-2-(hydroxymethyl)azepane-3,4,5,6-tetraol exhibits a weak but selective inhibition against α-l-fucosides.     

Stereocontrolled synthesis and structural confirmation of the C14-C24 degraded fragment of symbiodinolide

The C14-C24 fragment of symbiodinolide possessing the 17R/18R/21R absolute configuration, which was obtained as one of the degraded products of symbiodinolide, and its diastereomer possessing the 17R/18S/21R absolute stereochemistry were synthesized stereoselectively from cis-2-butene-1,4-diol, respectively. The detailed comparison of the synthetic products with the degraded product in the spectroscopic data confirmed unambiguously that the stereostructure of the C14-C24 fragment was 17R, 18R, and 21R.     

Synthesis and properties of S,R-alternating octinaphthalenes

(S,R,S,R,S,R,S)- and (S,R,S,S,S,R,S)-octinaphthalenes were synthesized by oxidative coupling of (S,R,S)-quaternaphthalene, and differences due to axis chirality of (S,R,S,R,S,R,S)-, (S,R,S,S,S,R,S)-, (S,S,S,R,S,S,S)-, and (S,S,S,S,S,S,S)-octinaphthalenes were compared using the R_f values on TLC, specific optical rotations, ¹H NMR chemical shifts of the hydroxy groups, and CD spectra. A clear CD additivity was found in the Δ? values of the ¹L_a transition around 290 nm, which are proportional to the difference between the numbers of S and R binaphthalene units.     

Preparation of a new 1,2,3-trithiolane, trans-9,10,11-trithiabicyclo[6.3.0]undecane, and its oxidation reactions

The reaction of trans-cyclooctene with S₈O yielded a novel bicyclic 1,2,3-trithiolane and trans-9,10,11-trithiabicyclo[6.3.0]undecane (7). Oxidation of the trithiolane with dimethyldioxirane yielded three monoxides, which are assigned to two isomeric 9-oxides, rel-(1R,8R,9S)-9-oxide (15) and rel-(1R,8R,9R)-9-oxide (16), and 10-oxide (17). Further oxidation of rel-(1R,8R,9S)-9-oxide (15) provided rel-(1R,8R,9S,11S)-9,11-dioxide (18) and rel-(1R,8R,9R,11S)-9,11-dioxide (19), while that of rel-(1R,8R,9R)-9-oxide (16) gave rel-(1R,8R,9R,11S)-9,11-dioxide (19) and rel-(1R,8R,9R,11R)-9,11-dioxide (20). The structures of 18 and 19 were determined by X-ray crystallography. The structures of other oxides were elucidated by the spectroscopic data and results of further chemical transformations. Two isomers, 15 and 16, isomerized to one another. A 9,11-dioxide 20 isomerized to 19, which is in equilibrium with 18, where 18 is thermodynamically the most stable isomer.     

Synthesis of four enantiomers of 2,3-di(N-Boc-amino)-1-hydroxypropylphosphonates

Enantiomerically pure diethyl (1S,2R)-, (1S,2S)-, (1R,2R)- and (1R,2S)-2,3-di(tert-butoxycarbonyl)amino-1-hydroxypropylphosphonates were synthesised from diethyl (1S,2R,1′S)-, (1S,2S,1′R)-, (1R,2R,1′S)- and (1R,2S,1′R)-[N-(1-phenylethyl)]-2,3-epimino-1-hydroxypropylphosphonates, respectively, via aziridine ring opening with neat TMSN₃ followed by hydrogenolysis in the presence of Boc₂O. A plausible mechanism for the aziridine ring opening in 2,3-epimino-1-hydroxypropylphosphonates involving the intermediate aziridinium ions was proposed. Significant differences in the rates of the aziridine ring opening between diastereoisomeric phosphonates (1S,2R,1′S) and (1S,2S,1′R) were rationalised taking into account different conformations of the 1-phenylethyl group in both diastereoisomers.     

Stereoselective synthesis of 3,4,5,6-tetrahydroxycyclohexyl β-amino acid derivatives

Stereoselective syntheses of racemic (1S,2R,3R,4R,5S,6R)- and (1S,2R,3R,4S,5S,6R)-3,4,5,6-tetrahydroxy derivatives of 2-aminocyclohexanecarboxylic acid have been achieved by a stereospecific Diels-Alder reaction between furan and maleic anhydride, a Curtius rearrangement and hydroxylation reactions.     

Palladium-catalyzed asymmetric Diels–Alder reactions with novel chiral imino-phosphine ligands

Palladium-catalyzed asymmetric Diels–Alder reactions have been achieved with considerably high enantioselectivity by using chiral imino-phosphine ligands derived from (1S,4R)-(+)-fenchone, (1R,2R,5R)-(+)-2-hydroxy-3-pinanone derivatives, (1S,5R)-(−)-menthone, (1R,4R)-(+)-camphor, and (1S)-(+)-ketopinic acid. A mechanism for the asymmetric induction is proposed on the basis of the stereochemical outcome of the reactions.     

Synthesis of the trichloroacetamide derivative of enantio-iso-ADDA methyl ester

The divergent syntheses of the trichloroacetamide derivatives of (2S,3R,8R,9R,4E,6E)-3-amino-9-methoxy-2,6,8-trimethyl-10-phenyl-decadenoic acid (enantio-iso-ADDA), and (2R,3R,8R,9R,4E,6E)-3-amino-9-methoxy-2,6,8-trimethyl-10-phenyl-decadenoic acid (enantio-ADDA), have been achieved. Our approach takes advantage of highly efficient non-aldol aldol, palladium catalysed aza-Claisen and cross-metathesis methodologies.     

Stereoselective synthesis of 3-mono- and 1,3-disubstituted 4-phenyl-1,2,3,4-tetrahydroisoquinolines

(1S,2S)-(+)-Thiomicamine was transformed in high yield and with high diastereoselectivity into (3R,4R)-4-phenyl-1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid and enantiomerically pure (3R,4R)-3-hydroxymethyl-4-phenyl- and (1R,3R,4R)-3-hydroxymethyl-1-methyl-4-phenyl-1,2,3,4-tetrahydroisoquinoline derivatives.