Stereoselective synthesis of thiaerythrinanes based on an α-amidoalkylation/RCM approach

Parham cyclisation-intermolecular α-amidoalkylation and nucleophilic addition-intramolecular α-amidoalkylation sequences constitute diastereocomplementary routes to 1,10b-cis and trans thiazolo[4,3-a]isoquinolinones. These thiazolidinediones, that incorporate allyl groups at C-1 and C-10b, are efficient precursors of thiaerythrinanes by ring-closing metathesis reactions.     

New stereoselective syntheses of cis- and trans-2-methyl-4-arylpiperidines

A stereoselective approach has been developed for the synthesis of cis- and trans-2-methyl-4-arylpiperidines from a common intermediate. The Ni-catalyzed hydrogenolysis of N-Boc-2-methyl-4-aryl-4-piperidinols, obtained by addition of organometallic reagents on N-Boc-2-methyl-4-piperidone, afforded the trans derivatives with up to 95% selectivity whereas the corresponding cis isomers were obtained in the presence of palladium catalysts.     

Synthesis of trans-vaccenic acid and cis-9-trans-11-conjugated linoleic acid

The preparation of the monounsaturated fatty acid, trans-vaccenic acid 4 (TVA), using both Wittig and one-pot Julia-Kocieński olefination protocol, was achieved in good yield. Similarly a Wittig approach was employed for the stereoselective synthesis of cis-9-trans-11-conjugated linoleic acid 2 from trans-2-nonenal and (8-carboxyoctyl)triphenylphosphonium bromide 12.     

Syntheses of chiral 1,3-disubstituted tetrahydro-β-carbolines via CIAT process: highly stereoselective Pictet–Spengler reaction of d-tryptophan ester hydrochlorides with various aldehydes

A highly stereoselective Pictet–Spengler reaction of d-tryptophan methyl ester hydrochloride 1-HCl with various aldehydes via a CIAT (crystallization-induced asymmetric transformation) process is described. It was revealed that the CIAT process should be performed in a mixed solvent of nitromethane and toluene, and a fine tuning of the ratio of nitromethane and toluene for each epimer mixture of 2-HCl was necessary in order to get as high yields and stereoselectivities as possible. Enantiomerically pure cis (or trans) 1,3-disubstituted tetrahydro-β-carbolines 2a–2v were obtained by recrystallization or flash chromatography after neutralization of the corresponding hydrochloride salts cis-2-HCl or trans-2-HCl.     

A Highly Stereoselective Synthesis of C(11)-Functionalized Aromatic Steroids by an Intramolecular Benzocyclobutene-Olefin -Cycloaddition. Preliminary Communication

The racemic cis-anti-trans-steroids 9 to 11 have been synthesized in a highly stereoselective manner starting from 4-methoxybenzocyclobutene carboxylic acid via the key step 8 → 9 . (cf. Scheme 2).     

Highly stereoselective transformation of (1S,3S)-cis-1,3-disubstituted tetrahydro-β-carbolines into (1S,3R)-trans-1,3-disubstituted tetrahydro-β-carbolines: an improved asymmetric synthesis of tadalafil from l-tryptophan

An efficient and general method for the highly stereoselective transformation of (1S,3S)-cis-1,3-disubstituted 1,2,3,4-tetrahydro-β-carbolines (THBCs) into (1S,3R)-trans-1,3-disubstituted THBCs is described. The method contains the following three steps: the enantiomerically pure (1S,3S)-cis-1,3-disubstituted THBCs 1 were first converted into (1S,3S)-cis-1,2,3-trisubstituted THBCs 2 by N-1-naphthylmethylation/benzylation; (1S,3S)-cis-1,2,3-trisubstituted THBCs2 were then converted into (1S,3R)-trans-1,2,3-trisubstituted THBCs 3 in high yields and with high stereoselectivities via a base-catalyzed epimerization at C-3; (1S,3R)-trans-1,2,3-trisubstituted THBCs 3 were subsequently converted into (1S,3R)-trans-1,3-disubstituted THBCs 4 after reductive removal of the 1-naphthylmethyl/benzyl group. In addition, as an application of this method, an improved and highly stereoselective synthesis of the PDE5 inhibitor tadalafil (Cialis®) starting from natural and less expensive l-tryptophan was developed.     

Experimental and theoretical investigations for the regio and stereoselective transformation of trans 1,2,3-trisubstituted aziridines into trans oxazolidin-2-ones

The regio and stereoselective transformation of trans 1,2,3-trisubstituted aziridines into trans oxazolidin-2-ones takes place in good yield. However, the cis configuration at C2 and C3 in monocyclic aziridines is a limiting factor for this transformation. Ab initio calculations show that while the ring-opening process assisted by iodide is regioselective, the subsequent ring-closure is responsible for the retention of the configuration at the trans oxazolidin-2-one. The larger energy found for the ring-closure process for the cis aziridines accounts for the non-formation of the cis oxazolidin-2-ones.     

The synthesis of potential Neramexane metabolites: cis- and trans-3-amino-1,3,5,5-tetramethylcyclohexanecarboxylic acids

A seven step synthetic route toward potential Neramexane metabolites cis- and trans-3-amino-1,3,5,5-tetramethylcyclohexanecarboxylic acids, cis-1 and trans-1, has been developed from isophorone. The synthetic procedure represents a useful method for the preparation of γ-amino acids with both amino and carboxyl groups situated at tertiary carbon atoms.     

Trans-cis octahedral interconversion pathway in diorganotin compounds

Using structural data from bis(bidentate)diorganotin compounds in the Cambridge Structural Database a potential pathway for trans-cis interconversion is envisaged with nondissociative Sn-donor bonds and retaining metal coordination number 6. C-Sn-C bond angles in the range 180-145° correspond to skewed trapezoid bipyramidal geometry for 6- and 5-membered O,O′ chelates; geometries that resemble the transition state of the trans-cis pathway starts forming at about C-Sn-C 134°. cis-Diorganotins explored in this work have C-Sn-C bond angles in the range 102-110°; it is the statistically favored configuration for diphenyltins. The proposed trans-cis conversion pathway is deduced from a series of geometries associated with decreasing the C-Sn-C bond angle and shows 2 weakly (secondary) bound chelating atoms lengthening their bonds until near the transition state and later strengthening; they end up cis to each other and opposite to the organic groups. Conversely, the other 2 (primary) donors shorten their bonds until the transition state is reached and later lengthen; they end up trans to each other. The entire transformation from trans to cis configuration occurs with relative rotation of 3 bonds.     

Stereoselective intramolecular 1,3-dipolar nitrile oxide cycloaddition reaction of N-formyl-β-nitroamides

The stereoselective intramolecular nitrile oxide cycloaddition (INOC) reaction was achieved from N-formyl-β-nitroamides, which were prepared through the Michael addition of allylic formamides to nitroalkenes, and cis-pyrroroisoxazoles and trans-piperidinoisoxazoles were obtained in a stereoselective manner.     

A facile domino protocol for the stereoselective synthesis of trans-2,3-dihydrobenzofurans and cis-5,6-dihydrofuro[2,3-d]pyrimidines

A facile protocol for the stereoselective construction of trans-2,3-dihydrobenzofurans and cis-5,6-dihydrofuro[2,3-d]pyrimidines from the reactions of 2,2′-sulfonylbis(1,3-diarylprop-2-en-1-ones) with cyclic 1,3-diketones, viz. cyclohexane-1,3-diones, barbituric acid, and 2-thioxodihydropyrimidine-4,6(1H,5H)-dione in the presence of DBU in ethanol is described. This transformation presumably occurs via domino Michael addition-proton exchange-annulation via intramolecular displacement sequence.     

Stereoselective synthesis of cis- and trans-2′,5′-disubstituted N-arylpyrrolo[3′,4′:1,9](C60-I h )[5,6]fullerenes by the 1,3-dipolar cycloaddition of azomethine ylides from dialkyl aziridinedicarboxylates to fullerene C60

A stereoselective method for the synthesis of 2′,5′-disubstituted N-arylpyrrolofullerenes from anilines, alkyl glyoxylates, alkyl diazoacetates, and fullerene C₆₀ was proposed. The key step of the synthesis is the 1,3-dipolar cycloaddition reaction of fullerene with azomethine ylides generated by heating of dialkyl aziridinedicarboxylates. The thermal opening of the aziridine ring to azomethine ylide and the cycloaddition of the latter to C₆₀ at 100 °C are nearly completely stereoselective: only trans-adducts are formed from cis-aziridines, whereas trans-aziridines give exclusively cis-adducts.     

Enantioselective synthesis of 2-[(3-ethyl-4-piperidyl)methyl]indoles from a phenylglycinol-derived lactam: formal synthesis of Strychnos alkaloids

A diastereodivergent synthesis of enantiopure cis- and trans-2-[(3-ethyl-4-piperidyl)methyl]indole (cis-1b and trans-1b) from a common phenylglycinol-derived oxazolopiperidone lactam 3 is reported. The key step is a stereocontrolled conjugate addition, either under kinetic or thermodynamic control, of the dilithium salt of 2-(2-indolyl)-1,3-dithiane to unsaturated lactam 3.     

1,2-Disubstituted cyclohexane nucleosides: comparative study for the synthesis of cis and trans adenosine analogues

A new class of adenosine analogues with 1,2-disubstituted carbocycles (with cis and trans stereochemistry) have been synthesized. Construction of the base on the amino group of (±)-cis-(2-aminocyclohexyl)methanol was more efficient than the Mitsunobu condensation between the purine base and protected (±)-trans-(2-hydroxymethyl)cyclohexanol. The latter strategy gave the final compound with cis stereochemistry in a short number of steps with the overall yield depending on the nature of the protecting group on the hydroxymethyl group of the diol. However, Mitsunobu condensation between a purine base and the protected (±)-cis-(2-hydroxymethyl)cyclohexanol is not an ideal method to obtain trans purine derivatives because the elimination reaction is faster than the substitution reaction.     

RuO4-catalyzed oxidative polycyclization of squalene. Determination of the configuration of the penta-tetrahydrofuranyl diol product

The configuration of the penta-tetrahydrofuranyl diol (penta-THF) product obtained by a single-step, RuO₄-catalyzed oxidative polycyclization of squalene, has been determined as cis-threo-cis-threo-trans-threo-trans-threo-trans. The cis-cis-trans-trans-trans sequence for the five contiguous THF rings has been established through extensive 2D-NMR spectroscopic studies carried out both on the intact molecule and on some of its derivatives, including the oxidative cleavage products obtained by degradation of the penta-THF with PCC/AcOH. Four different chemical approaches were devised to determine each of the four threo relationships within each carbon pair connecting adjacent THF rings in the molecule. To this aim, studies have been carried out either on some intermediates of the process leading to penta-THF, obtained by stopping the oxidation of squalene prior to completion, or on a degradation product of the penta-THF, obtained from the latter through a bidirectional double oxidative degradation with PCC.     

Intermolecular stacking of a tetranuclear cyclic Pt(II) complex: NMR characterization and X-ray crystal structure of cis-trans-cis-trans tetra[μ-2,6-diethynyl-4-nitroaniline-bis(tri(p-tolyl)phosphine)platinum(II)]

The synthesis and characterization of a tetranuclear Pt complex, cis-trans-cis-trans tetra[μ-2,6-diethynyl-4-nitroaniline-bis(tri(p-tolyl)phosphine) platinum(II)], namely [L₂Pt-DENA]₄ with L = tri-p-tolylphosphine, is reported. The complex was obtained by the dehydrohalogenative condensation of 2,6-diethynyl-4-nitroaniline (DENA) with cis-[dichlorobis(tri(p-tolyl)phosphine)platinum(II)]. The single crystal structure determination of [L₂Pt-DENA]₄ indicated the formation of a neutral molecular cycle with four alternating platinum units in cis and trans configurations, all bridged with DENA spacers with the presence of solvent (toluene) crystallization molecules. A twisted tetranuclear cyclic feature was identified. The formation of intermolecular stacks of the tetranuclear complex in solution was assessed by means of nuclear Overhauser enhancement spectroscopy (NOESY) and rotating frame Overhauser effect spectroscopy (ROESY) characterizations.     

SmI2-induced cyclization of optically active (E)- and (Z)-β-alkoxyvinyl sulfoxides with aldehydes

SmI₂-induced reaction of (E)-β-alkoxyvinyl (R)- and (S)-sulfoxides with aldehydes effected a highly stereoselective intramolecular cyclization to give 2,6-anti-2,3-cis- and 2,6-syn-2,3-trans-tetrahydropyran-3-ols, respectively. The reaction of (Z)-(R)-isomer gave 2,6-syn-2,3-cis-tetrahydropyran-3-ol and a ring-opened product, and that of (Z)-(S)-isomer yielded many products.     

RuO4-catalyzed oxidative polycyclization of the Cs-symmetric isoprenoid polyene digeranyl. An unexpected stereochemical outcome

The RuO₄-catalyzed oxidative polycyclization of digeranyl, a C_s-symmetric tetraene possessing a repetitive 1,5-diene structural motif, has been studied. The required substrate has been synthesized by Ti(III)-mediated tail-to-tail homocoupling of geranyl bromide. The process afforded two hitherto unknown isomeric tris-tetrahydrofuran products possessing unexpected all-threo cis-trans-cis and cis-trans-trans relative configuration. The new stereochemical outcome is explained based on previously formulated chelation or steric control models on the basis of structural differences between digeranyl and previously studied isoprenoid polyenes farnesyl acetate, geranylgeranyl acetate and squalene.     

PhP-PPh group bound to 1,8-positions of naphthalene: Preparation of cis isomer and synthesis of binuclear complex

A thermodynamically less stable cis isomer of 1,2-diphosphacycle was prepared from the corresponding trans isomer. Diphosphine, in which a PhP-PPh bond bridges the 1,8-positions of naphthalene, 1,2-diphenyl-1,2-dihydronaphtho[1,8-cd][1,2]diphosphole (1), was first prepared according to a previously reported method, and the trans isomer of 1 was irradiated in tetrahydrofuran with UV-vis light to reach equilibrium with cis-1 in a trans:cis ratio of 1:2. When a similar photochemical conversion was carried out using a saturated hexane solution of trans-1, cis-1 was precipitated in a good yield of 94%. The configuration of cis-1 was confirmed by X-ray analysis. Both cis- and trans-1 diphosphine ligands were used for the preparation of binuclear gold complexes. The crystal structure of (μ-cis-1)-[AuCl]₂ demonstrated that the two lone pairs of cis-1 are suitably directed for arrangement of the two gold centers in close proximity to each other. The two independent (μ-cis-1)-[AuCl]₂ molecules in the crystal were found to form a dimer through the multiple intermolecular interaction among the gold centers.     

Conversion of a trans-syn-trans to a cis-syn-trans perhydrobenz[e]indenone triggered by intramolecular 1,5-hydrogen transfer

The conversion of a trans-syn-trans perhydroiodomethyltrimethylbenz[e]indenone to the corresponding cis-syn-trans perhydrobenz[e]indenone occurred during the reduction of the iodomethyl to a methyl group under radical conditions.