Stereoselective synthesis and tautomeric conversions of pyridyl-substituted 3,4-trans-1,2,3,4-tetrahydropyridines

Condensation of pyridinium ylides with pyridylmethylenecyanoacetic ester or pyridylmethylenecyanothioacetamide proceeds stereoselectively to form substituted 4-pyridyl-3-(1-pyridinio)-3,4-trans-1,2,3,4-tetrahydropyridine-6-(olates)thiolates. Substituted 2-(oxo)thio-4-(4-pyridyl)-3-(1-pyridinio)-3,4-trans-1,2,3,4-tetrahydropyridine-6-(olates)thiolates in DMSO-d₆ solution exist in tautomeric equilibrium with 4-(4-pyridinio)-3-(1-pyridinio)-1,4-dihydropyridine-2,6-(diolates)-dithiolates.Translated from Izvestiya Akademii Nauk SSSR, Seriya Khimicheskaya, No. 7, pp. 1630–1637, July, 1991.     

The Asymmetric Syntheses of Methyl <small>D</small>-Digitoxoside, <small>L</small>-Oleandrose and <small>L</small>-Cymarose from Methyl Sorbate, an Achiral Precursor

The addition of 4?eq of chloral to osmundalactone (4S,5R)-4 gave quantitative formation of the hemiacetal derivative (4S,5R)-8, which was treated with methane sulfonic acid to afford the intramolecular Micheal addition product (+)-(3S,4S,5R)-9 possessing a 3,4-cis-dihydroxy-δ-lactone in 78% overall yield from (4S,5R)-4. The obtained (+)-(3S,4S,5R)-9 was subsequently converted to methyl D-digitoxoside (pyranoside) (12) in 13% overall yield and methyl D-digitoxoside (furanoside) (12) in 20% overall yield. The reaction of benzyl-osmundalactone (4R,5S)-3 and MeOH in the presence of Amberlyst A-26 as a basic catalyst gave 3,4-trans-δ-lactone (－)-(3S,4R,5S)-20 in 28% yield and 3,4-cis-δ-lactone (－)-(3R,4R,5S)-21 in 45% yield. Dibal-H reduction of (－)-(3S,4R,5S)-20 followed by catalytic hydrogenation gave L-oleandrose (6) in 86% overall yield, while Dibal-H reduction of (－)-(3R,4R,5S)-21 followed by catalytic hydrogenation provided L-cymarose (7) in 85% overall yield.     

Three Novel Rhusouyangins A～Ｃ from the Roots of Rhus semialata

The root of Rhus semialata (Anacardiaceae) was a folk herb for treating diarrhea, spermatorrhea and malaria.[1,2]Recently, it was found to have other activity of inhibitors of Iκ Bα kinase.[3] inhibited human cell proliferation activated by IL-1β and IL-6, antifungal activity and antithrombin activity. The roots of it, collected from the island of Taiwan, was extracted with MeOH. The n-BuOH-soluble materials of the extract were subjected to Sephadex LH-20 (H2O/MeOH)column chromatography and then separated by RP-18 and Silica gel to yield rhusouyangins A (1), B (2), and C (3) as colorless amorphous solids, together with 2,3-cis-3,4-trans-4',7-dihydroxyflavan-3,4-diol, 2,3-trans-3,4-cis-4',7-dihydroxyflavan-3,4-diol, 3',5,5',7-tetrahydroxyflavanone.     

羟甲芬太尼对映异构体的^1H NMR及立体化学

本文对强效镇痛剂羟甲芬太尼(OMF)八个对映异构体中的其中四个, 即(-)-cis-(3R,4S,2'R)-OMF (1), (+)-cis-(3-R,4S,2'S)-OMF (2),(+)-trans-(3S,4S,2'R)-OMF (3), 和(+)-trans-(3S,4S,2'S)-OMF (4)进行了^1HNMR研究, 归属了所有的共振谱线。对哌啶环质子间偶合常数的分析表明, 所有顺式和反式异构体中的哌啶环都呈现相同的椅式构象。在顺式异构体中3-甲基位于直立键, 而4-N-苯基丙酰胺基位于平伏键, 反式异构体中它们均位于平伏键。讨论了3-甲基和4-N-苯基丙酰胺基的立体取代对NMR的影响, 在顺式异构体中4-N-苯基丙酰胺基的构象相对固定, 而在反式异构体中则较为自由。     

Diastereoselective protocols for the synthesis of 2,3-trans- and 2,3-cis-6-methoxy-morpholine-2-carboxylic acid derivatives

Two diastereoselective and straightforward protocols for the high-yielding synthesis of 2,3-trans- and 2,3-cis-6-methoxy-3-substituted morpholine-2-carboxylic esters were realized in few steps, through the condensation between 5,6-diethoxy-5,6-dimethyl-1,4-dioxan-2-one and an appropriate imine, which is the key reaction to control the C2-C3 relative stereochemistry, followed by a methanolysis/ring-closure tandem reaction sequence. In particular, 2,3-trans-morpholines derive from the R*,S*-product of the acid condensation of N-functionalized alkylimines with the silylketene acetal of the above lactone, whereas 2,3-cis-morpholines derive from the R*,R*-product of basic condensation of an N-tosylimines with the lactone.     

Toward a general strategy for the synthesis of 3,4-dihydroxyprolines from pentose sugars

A general strategy is proposed, wherein a pentose sugar gamma-lactone can be converted, via a series of nine reactions, to a 3,4-dihydroxyproline, suitably protected for use in peptide synthesis. Thus, D-ribonolactone (6) has been converted to N-fluorenylmethoxycarbonyl-3,4-di-O-tert-butyldimethylsilyloxy-D-2,3-cis-3,4-cis-proline (7) in 18.9% overall yield. Likewise, L-arabinonolactone (11) has been converted to N-fluorenylmethoxycarbonyl-3,4-di-O-tert-butyldimethylsilyloxy-L-2,3-cis-3,4-trans-proline (36) in 13.7% overall yield and L-lyxonolactone (12) to N-fluorenylmethoxycarbonyl-3,4-di-O-tert-butyldimethylsilyloxy-L-2,3-trans-3,4-cis-proline (37) in 11.2% overall yield. These building blocks have also been fully deprotected to give the free amino acids. We believe that this series of reactions ought to be applicable to the synthesis of any of the eight stereoisomers of 3,4-dihydroxyproline, by judicious selection of the pentose starting material.     

Regio- and stereoselective synthesis of tetrahydroindolysines,tetrahydropyridin-6-olates,and cyclopropanes from pyridinium ylides and unsaturated nitriles

The regio- and stereoselectivity of the reactions of pyridinium ylides with unsaturated nitriles are dependent on the electronic nature of the substituent in position 3 of the pyridine ring. The reaction of 1-carbamoylmethylide-3-cyanopyridinium with arylmethylenemalononitriles or arylmethylcyanoacetic esters proceeds regio- and stereoselectively with the formation of substituted 2-aryl-3-carbamoyl-6-cyano-2,3-trans- or 2,3-cis-1,2,3,8a-tetrahydroindolysines. The condensation of pyridinium 1-carbamoylmethylide with arylmethylenecyanoacetic ether leads to 4-aryl-2-oxo-3-(1-pyridinio)-5-cyano-3,4-trans-1,2,3,4-tetrahydropyridin-6-olates. The reaction of pyridinium (3-methylpyridinium) 1-carbamoylmethylide with arylmethylenemalononitriles results in the formation of 2-aryl-1,1-dicyano-3-carbamoyl-3-(1-pyridinio)- or (3-methyl-1-pyridinio)-1-propanides, which undergo stereoselective 1,3-transelimination with the formation of 3-aryl-1,1-dicyano-2-carbamoylcyclopropanes.Translated from Izvestiya Akademii Nauk SSSR, Seriya Khimicheskaya, No. 1, pp. 146–155. January, 1991.     

Determination of the absolute configuration of flexible molecules by ab initio ORD calculations: a case study with cytoxazones and isocytoxazones

Ab initio calculations of the optical rotatory power of the natural cytokine modulator cytoxazone 1 and its trans-diastereomer 2, as well as the structural isomers cis-3 and trans-4 isocytoxazones, have been performed at four different wavelengths (589, 546, 435, and 405 nm) by Density Functional Theory. The calculation of ORD curves provides a reliable method for the assignment of absolute configuration of these conformationally flexible molecules. The absolute configurations of isocytoxazones has been established as (+)-(4R,5S)-cis-3 and (+)-(4S,5S)-trans-4.     

Zur Synthese sulfonierter Derivate von 2,3-Dimethylanilin und 3,4-Dimethylanilin

On the Synthesis of Sulfonated Derivatives of 2,3-Dimethylaniline and 3,4-Dimethylaniline Baking the hydrogensulfate salt of 2,3-dimethylaniline ( 1 ) or of 3,4-dimethylaniline ( 2 ) led to 4-amino-2,3-dimethylbenzenesulfonic acid ( 4 ) and 2-amino-4,5-dimethylbenzenesulfonic acid ( 5 ), respectively (Scheme 1). The sulfonic acid 5 was also obtained by treatment of 2 with sulfuric acid or by reaction of 2 with amidosulfuric acid. 3-Amino-4,5-dimethylbenzenesulfonic acid ( 3 ) and 5-Amino-2,3-dimethylbenzenesulfonic acid ( 6 ) were prepared by sulfonation of 1,2-dimethyl-3-nitrobenzene ( 9 ) to 3,4-dimethyl-5-nitrobenzenesulfonic acid ( 11 ) and of 1,2-dimethyl-4-nitrobenzene ( 10 ) to 2,3-dimethyl-5-nitrobenzenesulfonic acid ( 12 ), respectively, with subsequent Béchamp reduction (Scheme 1). Preparations of 2-amino-3,4-dimethylbenzenesulfonic acid ( 7 ) and of 6-amino-2,3-dimethylbenzenesulfonic acid ( 8 ) were achieved by the sulfur dioxide treatment of the diazonium chlorides derived from 3,4-dimethyl-2-nitroaniline ( 24 ) and from 2,3-dimethyl-6-nitroaniline ( 31 ) to 3,4-dimethyl-2-nitrobenzenesulfonyl chloride ( 29 ) and 2,3-dimethyl-6-nitrobenzenesulfonyl chloride ( 32 ), respectively, followed by hydrolysis to 3,4-dimethyl-2-nitrobenzenesulfonic acid ( 30 ) and 2,3-dimethyl-6-nitrobenzenesulfonic acid ( 33 ), and final reduction (Scheme 3). Compound 7 was also synthesized by reaction of 4-chloro-2,3-dimethylaniline ( 23 ) with amidosulfuric acid to 2-amino-5-chloro-3,4-dimethylbenzenesulfonic acid ( 20 ) and subsequent hydrogenolysis (Scheme 2). 4′-Bromo-2′, 3′-dimethyl-acetanilide ( 13 ) and 4′-chloro-2′, 3′-dimethyl-acetanilide ( 14 ) on treatment with oleum yielded 5-acetylamino-2-bromo-3,4-dimethylbenzenesulfonic acid ( 17 ) and 5-acetylamino-2-chloro-3,4-dimethylbenzenesulfonic acid ( 18 ), respectively. Their structures were proven by hydrolysis to 5-amino-2-bromo-3,4-dimethylbenzenesulfonic acid ( 21 ) and 5-amino-2-chloro-3,4-dimethylbenzenesulfonic acid ( 22 ), followed by reductive dehalogenation to 3 .     

Stereoselective synthesis of and atropisomerism in 4-pyridyl-3-(1-pyridinio)-3,4-trans-1,2,3,4-tetrahydropyridines and their transformation products

A series of 2-oxo-4-pyridyl-3-(1-pyridinio)-5-cyano-3,4-trans-1,2,3,4-tetrahydropyridine-6-6-olates were prepared by condensation of pyridinium ylides with α,β-unsaturated carbonyl compounds or more conveniently by a three-component condensation of pyridinium ylides, pyridine aldehydes, and ethyl cyanoacetate 3 and/or 6 . This analogues of the above tetrahydropyridines were prepared in a similar way starting from suitable substrates. Spectroscopic data revealed that the reaction leads to trans-isomers around the C³-C⁴ bond and is atroposelective. The conformation of and tautomerism in the tetrahydropyridines are discussed in the light of ¹H NMR data. The reaction of 5-cyano-3-(3-methyl-1-pyridinio)-2-oxo-4-(3-pyridyl)-1,2,3,4-tetrahydropyridine-6-thiolate 10c with phenacyl bromide was found to give 3-hydroxy-5-oxo-7-(3-pyridyl)-6-(3-methyl-1-pyridinio)-3-phenyl-8-cyano-6,7-trans-2,3,6,7-tetrahydrothiazol[3,2a]pyridine bromide, the crystal and molecular structure of which has been determined by X-ray crystallographic analysis.     

1,5-Benzoxathiepin derivatives. III. Optical resolution of methyl (+/-)-cis-3-hydroxy-4-[3-(4-phenyl-1-piperazinyl)propyl]-3,4-dihydro- 2H-1,5-benzoxathiepin-4-carboxylate hydrochloride ((+/-)-CV-5197) with selective 5-hydroxytryptamine2(5-HT2)-antagonistic activity

The selective 5-HT2-receptor antagonist, methyl (+/-)-cis-3-hydroxy-4-[3-(4-phenyl-1-piperazinyl)propyl]-3,4-dihydro-2H- 1,5-benzoxathiepin-4-carboxylate hydrochloride ((+/-)-CV-5197) was resolved in high optical purity using (R)-(-)- and (S)-(+)-1,1'-binaphthyl-2,2'-diyl hydrogen phosphates ((R)-(-)- and (S)-(+)-BNP). The absolute configuration of (+)-CV-5197 was determined to be 3S,4R by X-ray crystallographic analysis. In the binding assay, it was demonstrated that (+)-CV-5197 was a more active isomer (IC50 = 23 nM +/- 6.3) for 5-HT2 receptor binding than the (-)-enantiomer (IC50 = 1600 nM +/- 82). (+)-CV-5197 completely inhibited the 5-HT-induced contraction of the isolated pig coronary artery at a concentration of 3 x 10(-7) M, whereas (-)-CV-5197 showed little antagonistic activity, even at 3 x 10(-4) M. Thus, the agreement between the results of the binding assays and the biological activities for the 3S,4R enantiomer of CV-5197 suggests that its physiological activity is probably exerted through 5-HT2-receptor antagonism.     

A general enantioselective approach to jasmonoid fragrances: synthesis of (+)-(1R,2S)-methyl dihydrojasmonate and (+)-(1R,2S)-magnolione

Methyl dihydrojasmonate 1 and magnolione 3 are of both academic and industrial interest. In this paper, we describe a flexible, high-yielding route to diastereomerically pure (+)-cis-(1R,2S)-methyl dihydrojasmonate 1 and the first synthesis of (+)-cis-(1R,2S)-magnolione 3, both with enantiomeric excesses up to 93%. The two syntheses diverged from the same advanced intermediate 5, readily available from the enantioenriched hydroxymethyl delta-lactone (-)-(3aS,4S,6aR)-6. The olfactory properties of (1R,2S)-1 and (1R,2S)-3 are reported.     

The impact of pyrrolidine hydroxylation on the conformation of proline-containing peptides

[structure: see text] A series of eight dipeptides of the general formula Ac-Phe-Pro-NHMe was synthesized and the thermodynamics of the cis --> trans isomerization about the central amide bond were studied by NMR. Pro* represents the following prolines: l-proline (Pro), l-trans-4-hydroxyproline (Hyp), l-cis-4-hydroxyproline (hyp), l-cis-4-methoxyproline (hyp[OMe]), l-trans-3-hydroxyproline (3-Hyp), l-cis-3-hydroxyproline (3-hyp), l-2,3-trans-3,4-cis-3,4-dihydroxyproline (DHP), and l-2,3-cis-3,4-trans-3,4-dihydroxyproline (dhp). The conformation of the pyrrolidine ring in each case is discussed in light of previous structural studies, analysis of potential stereoelectronic effects, and NMR data. Hydroxy substituents at C-4 have a greater impact on cis --> trans isomerization than analogous substituents at C-3 as a result of the intervening bond distances and bridging groups. The position of the equilibrium and its dependence on temperature are a reflection of both enthalpic and entropic factors, the latter being complicated in this study by an Ar-Pro interaction in the cis conformation. The substituents on the pyrrolidine ring determine the conformation of the five-membered ring, which in turn influences the strength of the Ar-Pro interaction, backbone dihedral angles, and the relative energy of the cis and trans species. The ultimate position of the equilibrium depends on a complex blend of steric, electronic, and conformational factors.     

Synthesis,Crystal Structure and Insecticidal Activities of(4aR,7aS)-6-Benzyl-1-((R)-2-(2-chlorophenyl)-4,5-dihydrothiazole-4-carbonyl)hexahydro-5H-pyrrolo[3,4-b]pyridine-5,7(6H)-dione

The title compound(4aR,7aS)-6-benzyl-1-((R)-2-(2-chlorophenyl)-4,5-dihydrothiazole-4-carbonyl)-hexahydro-5H-pyrrolo[3,4-b]pyridine-5,7(6H)-dione(C24H22ClN3O3S)w...     

Fate of diradicals in the caldera: stereochemistry of thermal stereomutation and ring enlargement in cis- and trans-1-cyano-2(E)-propenylcyclopropanes

This study of thermally induced stereomutation and ring enlargement in both (-)-trans-1-cyano-2(E)-propenylcyclopropane [(-)-trans-1] and (+)-cis-1-cyano-2(E)-propenylcyclopropane [(+)-cis-1] to cyclopentenes definitively contraindicates the usefulness of Woodward-Hoffmann rules of orbital symmetry as a theoretical basis for predicting the stereochemistry of the products. From both diastereomers, the same (+)-trans-4-cyano-3-methylcyclopentene [(+)-trans-2] is the major product among the four diastereomeric products, "allowed" and formally the result of a single internal rotation of the cyano-bearing carbon atom from (-)-trans-1, "forbidden" and the result of zero internal rotations from (+)-cis-1. Stereomutation and ring enlargement are discussed in detail in terms of rotational propensity, thermodynamic preference, and the possible role of diradicals in transit and diradicals as intermediates in a caldera.     

Synthesis of enantiomerically pure 1,2-diamine derivatives of 7-azabicyclo[2.2.1]heptane. New leads as glycosidase inhibitors and rigid scaffolds for the preparation of peptide analogues

Enantiomerically pure alcohols (-)- and (+)-7-tert-butoxycarbonyl-6-endo-p-toluenesulfonyl-7-azabicyclo[2.2.1]hept-2-en-5-endo-ol ((-)-11 and (+)-11) have been obtained from the Diels-Alder adduct of N-(tert-butoxycarbonyl)pyrroel and 2-bromo-1-p-toluenesulfonylacetylene, including a resolution method. These two alcohols were converted into (+)- and (-)-5-exo-amino-7-(tert-butoxycarbonyl)-2,3-exo-isopropylidenedioxy-7-azabicyclo[2.2.1]heptane ((+)-18 and (-)-18) and (+)- and (-)-5-endo-amino-7-(tert-butoxycarbonyl)-2,3-exo-isopropylidenedioxy-7-azabicyclo[2.2.1]heptane ((+)-19 and (-)-19) after adequate functionalization and desulfonylation steps. The corresponding conformationally constrained bicyclic 1,2-diamines (+)-4, (-)-4, (+/-)-5, (+/-)-6, (+)-7, and (-)-7 were obtained from the protected precursors 18 and 19 and evaluated as glycosidase inhibitors. Diamines (+)-4, (-)-4, (+)-6, and (-)-6 can be seen as new nonpeptide molecular scaffolds for the design of peptide analogues.     

Diastereoselective hydroxylation of 6-substituted piperidin-2-ones. An efficient synthesis of (2S,5R)-5-hydroxylysine and related alpha-amino acids

The synthesis of (2S,5R)-5-hydroxy-6-oxo-1,2-piperidinedicarboxylates (5) and related (3S,6R)-3-hydroxy-6-alkyl-2-oxo-1-piperidinecarboxylates has been developed. The approach is based on the asymmetric hydroxylation of enolates generated from the corresponding N-protected-6-substituted piperidin-2-ones. The utility of 5a as a precursor in the synthesis of (2S,5R)-5-hydroxylysine (1), an amino acid unique to collagen and collagen-like proteins, has also been demonstrated. (2S)-6-oxo-1,2-piperidinedicarboxylates (6) required for hydroxylation studies were prepared in 38-74% yield, starting from conveniently protected aspartic acid as inexpensive chiral adduct. Hydroxylation of 6 to 5 proceeds in high yield and excellent diastereoselectivity by treatment of their Li-enolate with (+)-camphorsulfonyloxaziridine at -78 degrees C. Ring opening of di-tert-butyl (2S,5R)-6-oxo-1,2-piperidinedicarboxylate ((5R)-5a) under reductive conditions afforded the corresponding 1,2-diol (17) in 91%, which was further transformed to (2S,5R)-5-hydroxylysine in four steps (84%). 17 is also a versatile intermediate in the preparation of tert-butyl (2S,5R)-2-[(tert-butoxycarbonyl)amino]-5-hydroxy-6-iodohexanoate (3) and tert-butyl (2S)-2-[(tert-butoxycarbonyl)amino]-4-[(2R)-oxiranyl]butanoate (4), two amino acid derivatives used in the total synthesis of the bone collagen cross-link (+)-pyridinoline (2a).     

Kinetics of thermal rearrangements in the Delta2-Thujene system: a full quadrisection of a perturbed bicyclo[3.1.0]hex-2-ene

Further insight into the behavior of suppositional diradicals in a caldera is sought in the thermal rearrangements among the four "Delta2-thujenes", two 1-isopropyl-4-methylbicyclo[3.1.0]hex-2-enes [(-)-cis-1 and (+)-trans-2] and two isomers, exo- and endo-3-isopropyl-6-methylbicyclo[3.1.0]hex-2-ene [(+)-exo-3 and (-)-endo-4]. Optically pure trans-3-isopropyl-5-vinylcyclopentene (5) is the final, strongly thermochemically favored product, the result of an intramolecular homodienyl shift of a methyl hydrogen atom in (-)-endo-4. The set of twelve specific rate constants, four sets of three each, that define the interrelations among the four isomers has been extracted from data acquired starting from each isomer. An attractive mechanistic hypothesis involving an intermediate diradical of iso conformation, common, for example, to both (-)-cis-1 and (+)-exo-3 (as educts), that proceeds to an anticonformer common to both (+)-trans-2 and (-)-endo-4 does not lead to a satisfactory rationalization of the product distribution. Addition of a second mechanistic conceptual scheme, that of a diradical-in-transit behaving as if there were a measure of continuous bonding (for example, (+)-trans-2 proceeding directly to (-)-cis-1), improves agreement with experiment. Over a 30 degrees C range of temperature, there is no credible change in product distribution.     

Synthesis of novel 4(5)-(5-aminotetrahydropyran-2-yl)imidazole derivatives and their in vivo release of neuronal histamine measured by brain microdialysis

The (2R,5S)-trans- and (2S,5S)-cis-stereoisomers 1a and 1b of 4(5)-(5-aminotetrahydropyran-2-yl)imidazole, which have two chiral centers and adopt a stable chair conformation, were synthesized via cyclization of diol intermediates 7 using L-glutamine as the starting material. Their enantiomers, (2S,5R)-trans-1c and (2R,5R)-cis-1d, were synthesized by the same methodology from D-glutamine. Stereo isomers 1a-d were converted into cyanoguanidines 11a-d, and into N-isopropyl and N-3,3-dimethylbutyl derivatives 12a-d and 13a-d, respectively. The results of in vivo brain microdialysis of the derivatives apparently indicated that only (2S,5R)-isomers increased the release of neuronal histamine. Among the many (2S,5R)-N-alkyl derivatives, 13c (OUP-133) and 18 (OUP-153) increased histamine release to 180-190% and 180-200% of basal levels, respectively, and were found to be novel histamine H(3) antagonists.     

Stereoselective transformation of 1,3-dithia-4-cyclohexene enaminonitriles into substituted 3,4-trans-1,2,3,4-tetrahydropyridine-6-thiolates with pyridinium ylides

4-Amino-6-aryl-2,2-dialkyl-5-cyano-1,3-dithia-4-cyclohexenes react with pyridinium ylides in thermodynamically controlled conditions with the formation of 4-aryl-2-oxo-thioxo)-3-(1-pyridino)-5-cyano-3,4-trans-1,2,3,4-tetrahydropyridine-6-thiolates. Arylidenecyanothioacetamides act as intermediates of this recyclization, and the corresponding pyridine-6-thiolates were obtained from them by an independent method. The synthesized hydrogenated pyridine-6-thiolates are in the half-chair conformation with a trans-diaxial position of the 3-H and 4-H hydrogen atoms.Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 8, pp. 1082–1086, August, 1991.