Stereoselective multigram-scale synthesis of cis- and trans-β-phenylproline derivatives

Efficient routes for the gram-scale preparation of the proline analogues that bear a phenyl substituent attached to the pyrrolidine β carbon (cis- and trans-β-phenylproline) have been developed. The cis derivative was synthesized from N-Boc-β-alanine in six steps and 78% overall yield. The generation of a vinyl triflate with full regiochemical control together with a high-yielding cross-coupling reaction and a completely stereoselective hydrogenation are at the basis of the high efficiency of the procedure. Epimerization of the cis β-phenylproline derivative with lithium bis(trimethylsilyl)amide provided access to the trans isomer.     

Facile stereoselective synthesis of cis- and trans-3-alkoxyazetidin-2-ones

A highly stereoselective synthesis of cis- and trans-3-alkoxy-3-phenyl/benzylthioazetidin-2-ones is described. The reaction of α-chlorosulfide-β-lactams with various alcohols catalyzed by a Lewis acid such as ZnCl₂ in the presence of molecular sieves (3-4 Å) leads to cis-3-alkoxy-3-phenyl/benzylthio-β-lactams whereas treatment of potassium 2-alkoxy-2-phenylthioethanoate with appropriate Schiff's base using POCl₃ in the presence of triethylamine leads to the formation of trans-3-alkoxy-3-phenylthioazetidin-2-ones as major products.     

Kinetically distinct triplets in the photorearrangement of 2-phenylcyclohexanone to cis- and trans-6-phenyl-5-hexenals

A reinvestigation of the photochemistry of 2-phenylcyclohexanone reveals that the two aldehyde products, cis- and trans-6-phenyl-5-hexanal, come from triplets of different lifetimes. That the two distinct triplets are not simply the two conformers with phenyl axial and equatorial is demonstrated by the similar behavior of cis-4-t-butyl-2-phenylcyclohexanone. The trans isomer of this ketone is photostable. It is concluded that trans-enal arises by an almost concerted out-of-plane cleavage which forms a 1,6-biradical in the perfect geometry for disproportionation to trans-enal.The precursor to cis-enal may be a minor rotamer of 1 which is forced by nonbonded interactions into a cleavage mode which twists the biradical into a geometry suitable for at least partial formation of cis-enal. In both cases biradicals must be very short-lived and not rotationally equilibrated.     

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.     

Concise synthesis of trans- and cis-3,4-disubstituted piperidines based on regio- and stereoselective allylation of cyclopentenyl esters

3,4-Disubstituted piperidines were synthesized through anti S_N2′ allylation of 4-substituted 2-cyclopentenyl esters with reagents based on RMgX and CuX, thus allowing equal access to both trans- and cis-isomers. As an application, the paroxetine intermediate was synthesized efficiently. During the investigation, the MeOCH₂CO₂ group was found to show high reactivity in the pivotal anti S_N2′ type reaction using the reagent derived from (i-PrO)Me₂SiCH₂MgCl and CuCN.     

Stereochemistry of organophosphorus cyclic compounds—II : Stereospecific synthesis of cis- and trans 2-halogeno-2-oxo-4-methyl-1,3,2-dioxaphosphorinans and their chemical transformations

cis- and trans-2-Chloro-2-oxo-4-methyl-1,3,2-dioxaphosphorinans have been obtained by stereospecific reactions of diastereomerically pure 2-methoxy-4-methyl-1,3,2-dioxaphosphorinans or 2-hydrogen-2-oxo-4-methyl-1,3,2-dioxaphosphorinans with chlorine and sulphuryl chloride, respectively. Similarly, the action of the corresponding brominating agents on isomeric phosphites and phosphonates afforded pure cis- and trans-2-bromo-2-oxo-4-methyl-1,3,2-dioxaphosphorinans. It has been shown that halogenolysis proceeds with retention of configuration at the P atom. On the basis of the ¹H- and ³¹P-NMR spectra conformation of the halogenoanhydrides obtained has been discussed briefly.It has been also found that model nucleophilic substitution reactions occur with inversion of configuration at the P atom in the cyclic halogenoanhydrides.     

The first asymmetric synthesis of all four isomers of cis- and trans-3,4-dihydroxy-3,4-dihydromollugin

Asymmetric synthesis of all the four stereoisomers of cis-3,4-dihydroxy-3,4-dihydromollugins 4 and 6 and trans-3,4-dihydroxy-3,4-dihydromollugins 5 and 7 was achieved. The O-methoxymethyl mollugin derivatives were dihydroxylated to (−)- and (+)-cis-3,4-dihydroxy-3,4-dihydromollugin derivatives using both AD-mix-α and AD-mix-β. Deprotection of the MOM-ethers of cis-dihydroxy compounds resulted in the targeted stereoisomers (−)-(3R,4R)-cis-3,4-dihydroxy-3,4-dihydromollugin 4, (−)-(3R,4S)-trans-3,4-dihydroxy-3,4-dihydromollugin 5, (+)-(3S,4S)-cis-3,4-dihydroxy-3,4-dihydromollugin 6 and (+)-(3S,4R)-trans-3,4-dihydroxy-3,4-dihydromollugin 7. These routes were paved with difficulties, for example, incompatibility of the substrates with AD-mixes, the unexpected formation of trans-dihydroxy compounds and failures in deprotection protocols.     

Heterobimetallic [Ru(II)/Fe(II)] complexes: On the formation of trans- and cis-[RuCl2(dppf)(diimines)]

The synthesis and characterization of trans/cis-[RuCl₂(dppf)(diimines)], dppf = 1,1′-bis(diphenylphosphino)ferrocene; diimines = 2,2′-bipyridine (trans/cis-(1)), the new complexes with 4,4′-dimethyl-2,2′-bipyridine (trans/cis-(2)) and 1,10-phenanthroline (cis-(3)) are presented. The complexes were synthesized using two routes and the trans/cis-isomer formation is dependent upon conditions and the precursor applied. The trans-isomer (kinetic) readily isomerizes to the cis-isomer (thermodynamic) when exposed to light (fluorescent) and this process was followed by cyclic voltammetry and UV-vis. The electrochemical studies on these complexes reveal that Fe^(III)/Fe^(II) couples are insensitive to the isomer (trans/cis) formed, but the Ru^(III)/Ru^(II) couples are dependent on the isomer. Transfer-hydrogenation reactions for reduction of acetophenone were conducted using complexes cis-(1) and cis-(2) and the results are compared with that obtained for similar complexes. X-ray structure for cis-(3) are presented and discussed.     

Improved synthesis of trans-4-alkylcyclohexane carboxylic acids

Several stereomerically pure amino acid derivatives containing the N-terminal trans-4-alkylcyclohexanoyl fragment were obtained. Hydrogenation of 4-alkylbenzoic acids in the presence of a special Ru-Ni/C catalytic system and isomerization of the resulting mixture of trans- and cis-isomers of 4-alkylcyclohexanecarboxylic acids were used as the key steps. The stereomeric configuration of all compounds was confirmed by ¹H NMR spectroscopy. The compounds obtained possess a broad biological activity potential and are useful intermediates in the synthesis of stereomerically pure modified peptides.     

The conversion of 3,4-cis- to 3,4-trans-cannabinoids

An investigation of the conversion of Δ¹-3,4-cis-THC 1a to Δ⁶-3,4-trans-THC 2a with BBr₃ is described. By use of 1a of known optical purity it was determined that the main epimerization occurs at C-4. The small loss of optical purity observed during formation of 2a results from either competitive epimerization at C-3 or a racemization process. The conversion of 3,4-cis- to 3,4-trans-HHCs proceeds with exclusive C-4 inversion.     

Synthesis, stereochemical and conformational properties of trans-2,3-dihydro-2-methyl-3-(1,2,4-triazolyl)-4H-1-benzopyran-4-one oxime ethers

A convenient synthesis and structural characterization of (Z)- and (E)-trans-2,3-dihydro-2-methyl-3-(1,2,4-triazolyl)-4H-1-benzopyran-4-one oxime ethers has been achieved. By analysis of vicinal interproton coupling constants, it is believed that trans-2,3-dihydro-2-methyl-3-(1,2,4-triazolyl)-4H-1-benzopyran-4-ones which exist predominantly in the diequatorial half-chair or sofa conformation was found to exist predominantly in the diaxial orientation upon conversion to the corresponding oxime ether derivatives.     

The vibrational analysis and torsional study of trans-1,2-dimethylcyclopropane and cis-1,2-dimethylcyclopropane

The infrared spectra of cis-1,2-dimethylcyclopropane and trans-1,2-dimethylcyclopropane have been recorded between 4000 and 200 cm^?1 in the polycrystalline solid phase, and 4000 to 80 cm^?1 in the gas phase. The Raman spectra of these two compounds in the gaseous and liquid phases were also recorded between 3100 and 10 cm^?1. An assignment of the thirty-nine fundamental vibrations for both cis- and trans-1,2-dimethylcyclopropane is proposed, and comparisons are made with the vibrations of other similar molecules. Additionally, ten torsional transitions were observed in the far infrared and Raman spectra of cis-1,2-dimethylcyclopropane, and four transitions were observed in the spectra of the trans compound. From these spectral data, torsional barriers were determined. The effective barriers to methyl torsion are 2.92 kcal mol^?1 (12.20 kJ mol^?1) for cis-1,2-dimethylcyclopropane and 2.61 kcal mol^?1 (11.14 kJ mol^?1) for trans-1,2-dimethylcyclopronane.     

Synthesis and conformational analysis of N-aryl-N-(3-thienyl)acetamides

The cis-trans conformational equilibrium of amides is of interest because it can be used to control functional activity. Here, we designed and synthesized a series of N-(3-thienyl)amides in order to study the factors affecting their conformational equilibrium. NMR studies showed that the major conformer of N-methyl-N-(3-thienyl)amide in solution is the E-form (cis form), as is the case for N-methylacetamide. For N-aryl-N-(3-thienyl)amides bearing an N-phenyl moiety, the major conformers differ depending on not only the relative π-electron density of the N-aryl moiety, but also its size. X-ray analysis showed that their solid-state conformational preferences were similar to those in solution.     

Stereoselective synthesis of cis- and trans-3-fluoro-1-phenylcyclobutyl amine

A stereoselective approach to the synthesis of cis- and trans-3-fluoro-1-phenylcyclobutylamine has been developed. Excellent stereoselectivity was obtained by the reduction of the appropriately substituted cyclobutanone to give either cis- or trans-isomers of 3-hydroxyl-1-phenylcyclobutylamine, which was stereoselectively converted to the 3-fluoro derivative.     

Complete investigation on the synthesis of [Ru(bpydip)Cl2]: the nonformation of cis isomer

Complexation between the Schiff base N₄-tetradentate N,N′-bis(7-methyl-2-pyridylmethylene)-1,3-diiminopropane (bpydip) and ion Ru(II) occurs only in trans geometry. However, it is known that the most complex of these ligands with ruthenium present predominantly cis geometry. In order to clarify the effects that drive the formation of the complex [Ru(bpydip)Cl₂], we performed a new experimental study of the reaction and a complete theoretical investigation of their transition states. The results showed that nonformation of the cis isomer could be explained by the difference in relative stability of the reaction products and the transition states proposed.     

Influence de la nature du solvant sur le comportement photochimique de complexes trans- ET cis-[PtCl2(éthylène)(amine)]

Nature of the solvent plays a major role in the photochemical behaviour of cis- and trans-[PtCl₂(ethylene)(amine)] complexes. Dimeric compounds [Pt₂Cl₄-(amine)₂] are obtained on irradiation of these complexes in chloroform or diethyl ether. A non-stereospecific reaction of photosubstitution is observed in nitrile solvents. When methanol, dimethoxyethane or dimethylformamide are used as solvents, cis and trans complexes have a quite different photochemical behaviour, but in all of the cases, a photodegradation leading to ionic species [PtCl₃(ethylene)]^? H⁺ amine and [PtCl₃(amine)]^? H⁺ amine is the main reaction.     

Stereoselective synthesis of anti-2-oxazolidinones by Ph3P-CCl4-Et3N mediated SN2 cyclization of N-Boc-β-amino alcohols

Ethyl anti-4-substituted phenyl-2-oxo-1,3-oxazolidine-5-carboxylates were synthesized stereoselectively in excellent yields using the Ph₃P-CCl₄-Et₃N system by S_N2 cyclization of N-Boc-β-amino alcohols. syn to anti conversion of ethyl 4-substituted phenyl-2-oxo-1,3-oxazolidine-5-carboxylates using DBU as base is also described.     

Palladium-catalyzed reduction of alkynes employing HSiEt3: stereoselective synthesis of trans- and cis-alkenes

The palladium-catalyzed semi-hydrogenation of alkynes to trans- or cis-alkenes employing HSiEt₃ as the reductant is developed. The CuSO₄ played a significant role for the trans/cis stereoselectivity. The labeling study revealed that the two olefinic hydrogen atoms came from HSiEt₃ and H₂O, respectively.     

Baylis-Hillman chemistry: synthesis of cis- and trans-α-methylene-γ-lactones

syn-Homoallylic alcohols prepared from Baylis-Hillman adducts react with CBr₄/PPh₃ to give trans-α-methylene-γ-lactones. Notably, the same alcohols yield the cis-α-methylene-γ-lactones in the presence of traces of p-toluenesulfonic acid.     

Short diastereoselective synthesis of cis- and trans-hexahydropyrido[2,1-a]isoindole derivatives

A new and highly stereoselective access to 4,10b-trans or 4,10b-cis hexahydropyrido[2,1-a]isoindole derivatives is reported, both requiring an intramolecular Mannich-type reaction as key step. The cis diastereoisomer is obtained in three steps from a 2-alkyl benzaldehyde through the stereoselective formation of a 2,6-cis-disubstituted piperidine, while the trans stereomer is efficiently obtained, in a single step, if a 2-formyl benzoic acid is involved in the Mannich cyclization process.