Synthesis and stereochemistry of some new derivatives of cis-dihydropinol

The synthesis of four new derivatives of cis-hydroxy-cis-dihydropinol with allyl-, epoxyalkyl-, hydroxyalkyl- and ketoalkyl-groups substituted on the cyclohexane ring is presented. The cis-orientation of hydroxyl group at C-2 and the configuration of all stereogenic centers is confirmed by X-ray crystallography.     

Etude RMN1H et radiocristallographique de la stéreochimie de 3-aryl-9b-hydroxy-1,3,3a,9b-tétrahydro-4H-thiéno[3,4-c] benzo[e]pyrane-1-carboxylates d'éthyle. Configuration et conformation

The reaction of ethyl mercaptoacetate with some 3-aryliden-4-chromanones yields the corresponding ethyl 3-aryl-9b-hydroxy-1,3,3a,9b-tetrahydro-4H-thieno[3,4-c]benzo[e]pyrane-1-carboxylates. In spite of the presence of four chirality centers, the reaction is diastereospecific and gives a single diastereoisomer whose configuration and conformation were specified by its PMR data.The cis-fused tetrahydrothiophenic and dihydropyranic cycles lie in half-chair conformation. The 9b-hydroxyl and the 3-aryl groups are in a cis equatorial and pseudoequatorial disposition. The ester group, also cis with the hydroxyl group, presents a hydrogen bond with the hydroxyl. In the presence of an ortho-substituent at the phenyl group (particularly a chlorine atom), this phenyl group undergoes a notable rotation as is pointed out by a radiocristallographic study. A comparative study between the NMR and radiocristallographic data allows the confirmation of the maintenance of the same conformation in solid and dissolved states.     

Cyclopentanones—VIII : Stereochemistry of the lithium-liquid ammonia reduction of 2,3-dialkyl-4-hydroxy-2-cyclopentenones

2,3-Dialkyl-1,4-cyclopentanediols are obtained by lithium-liquidammonia-alcohol reduction of 2,3-dialkyl-4-hydroxy-2-cyclopentenones. The configuration of the diastereoisomers formed was proved by ¹H-NMR spectroscopy and by chemical evidence. In the most abundant isomer the alkyl groups are trans and each is in trans position to the vicinal hydroxyl function. In another diastereoisomer formed in substantial amount the alkyl groups have a cis orientation and are trans to the vicinal hydroxyl function. The ¹H-NMR parameters found are more useful generally for configurational assignments to synthetic and modified prostaglandins.     

Addition of lithium ethyl fluoroacetate to cis and trans α,β-epoxyaldehydes. Access to C2 fluorinated butyrolactones

The aldolisation reaction of lithium ethyl fluoroacetate with cis and trans α,β-epoxyaldehydes in their racemic forms proceeds with good C₃-OH diastereoselectivity and much less at the C₂-F carbon atom. A two-step reaction on the major aldol compounds (iodination, lactonisation) led to racemic functionalised C₂ fluorinated lactones, possessing a C₂/C₃cis relationship between the fluorine and hydroxyl groups.     

A new route into hexahydro-cyclopenta[b]pyrrole-cis-3a,6-diols. Synthesis of constrained bicyclic analogues of pyrrolidine azasugars

Compounds that simultaneously combine charge and conformational features of glycosyltransfer transition states are of interest as transition state analog inhibitors. The synthesis of a central intermediate, cis-3a,6-dihydroxy-hexahydro-cyclopenta[b]pyrrol-2-one, which yielded a family of substituted cis-3a,6-dihydroxy-hexahydro-cyclopenta[b]pyrroles that combine conformational biasing and transition state charge mimicry, is described. The key steps in this synthesis involve synthesis of (2-azido-1,3-dihydroxy-cyclopentyl)-acetic acid ethyl ester in four steps from cyclopentenone, followed by an efficient reductive cyclization of the azide to the bicyclic lactam. The lactam was subsequently converted into the corresponding bicyclic pyrrolidine, and analogs having phenyl, hydroxyl, and phosphate substituents.     

Carbon-13 pulse Fourier transform NMR : Conformational preference of the hydroxyl and the acetoxyl group in 2-cyclohexenol and its acetate

¹³C Fourier transform NMR spectra of cis and trans 5-t-butyl-2-cyclohexenols, 2-cyclohexenol and their acetates have been examined indicating that the pseudo-axial orientation of the hydroxyl and the acetoxyl group at the allylic position is favoured in 2-cyclohexenol and its acetate.     

A concise and stereospecific synthesis of some cyclitols containing eight-membered rings: cyclooctane-1,2,3,4-tetraoles

A concise and efficient synthesis of cyclooctane-1,2,3,4-tetraoles, new polyhydroxylated eight-membered carbocycles, is described starting from cis,cis-1,3-cyclooctadiene. Cyclooctene endoperoxide obtained by photooxygenation of cis,cis-1,3-cyclooctadiene was the key compound in the synthesis. Reduction of the endoperoxide with zinc or thiourea followed by acetylation of the hydroxyl group and OsO₄/NMO oxidation of the double bond gave (1R(S),2S(R),3R(S),4S(R))-cyclooctane-1,2,3,4-tetraol. Interestingly, epoxidation of cyclooctene-1,4-diol with m-CPBA also afforded trans-epoxy-diol 17. (1R(S),2R(S),3R(S),4S(R))-cyclooctane-1,2,3,4-tetraol was easily obtained by hydrolysis of epoxy-diol 17.     

Synthesis and structure characterization of ladder-like polymethylsilsesquioxane (PMSQ) by isolation of stereoisomer

The stereo cyclic siloxane compounds having tetra hydroxyl and tetra methyl group were synthesized by hydrolysis of tetrahydrido tetramethyl cyclosiloxane consisting of four stereoisomers. Among the stereo cyclic isomers, cis-trans-cis tetrahydroxyl tetramethyl cyclosiloxane (2) was separated by recrystallization and was used as a monomer species for preparation of ladder-like polymethylsilsesquioxane (PMSQ). The isolated isomer was directly polymerized in THF with potassium carbonate (K₂CO₃) by systematic ring condensation. The hydrolyzed stereoisomers were characterized by ¹H and ²⁹Si NMR, and HPLC. The structure of the synthesized PMSQs were characterized by size exclusion chromatography (SEC), MALDI-TOF mass, ²⁹Si NMR, and small angle X-ray scattering (SAXS).     

Synthesis of enantiopure cis-decahydroquinolines from homotyramines by Birch reduction and aminocyclization

Birch reduction of homotyramines with a syn-β-amino alcohol unit followed by acid treatment of formed dihydroanisole derivatives gives polysubstituted enantiopure cis-decahydroquinolines. The stereoselectivity of the process differs if the hydroxyl group is free or protected. The procedure allows the synthesis of 7-oxodecahydroquinolines embodying four stereogenic centres with the same relative configuration as that of lepadins F and G.     

Stereoselective synthesis of (2S,7S)-7-(4-phenoxymethyl)-2-(1-N-hydroxyureidyl-3-butyn-4-yl)oxepane: a potential anti-asthmatic drug candidate

We have achieved a short, efficient stereoselective synthesis of 7-membered oxepane derivatives with potential against asthma. Highlights of our synthetic strategy are regioselective oxidation of a hydroxyl group and efficient ring closure of an open chain aldehyde to a 2-benzenesulfonyl oxepane derivative with PhSO₂H. Surprisingly the cis-isomer showed better activity than the trans-isomer.     

Analyse conformationnelle de derives bicyclo (4.1.0) heptaniques cis—I

¹H NMR conformational studies of cis-3(4) epoxy bicyclo (4.1.0) heptanes endo and exo, and of related alcohols (3-norcaranols) has been carried out using Eu(dpm)₃ as shift reagent. Comparatively the conformational analysis of cis and trans-1(2), -4(5) diepoxy cyclohexanes has been performed. The experimental data agree with a predominant planar conformation of the two -3(4) epoxy bicyclo (4.1.0) heptanes and of the cis diépoxy cyclohexane, but do not distinguish between the planar conformation and the $\text{1}\text{1}$ equilibrium of the two equivalent boat conformations of the trans diepoxyde. For the two alcohols, they adopt the same semi chair form in which the hydroxyl group is axial for the exo isomer and equatorial for the endo.     

Synthesis of novel thiol taxoids based on the 7,10-di-(2,2,2-trichloroethyloxycarbonyl)-10-deacetylbaccatin III: both the syn and anti 10-deacetyl-2′-deoxy-2′-mercaptopaclitaxels

Two new kinds of docetaxel compound, with a mercapto group instead of the hydroxyl on the C13 side chain (both syn and anti), via the 7,10-di-(2,2,2-trichloroethyloxycarbonyl)-10-deacetylbaccatin III route, were synthesized. The uses of trans and cis oxazoline compounds, and their stereoselective ring-opening reactions with thiolacetic acid, were proved to be key steps.     

Facile construction of 1,2-cis glucosidic linkage using sequential oxidation-reduction route for synthesis of an ER processing α-glucosidase I substrate

The fluorescence-labeled hexasaccharide (Glcα1-2Glcα1-3Glcα1-3Manα1-2Manα1-2Manα) was synthesized as a substrate for the processing enzyme α-glucosidase I. To construct the 1,2-cis glucosidic linkages, we employed an α stereoselective coupling using the mannosyl donor by assisted neighboring-group participation, followed by conversion of the stereochemistry of the C-2 hydroxyl group in the mannose residue using sequential oxidation of C-2 hydroxyl group to a 2-keto group and stereoselective reduction of the hydroxyl group to the gluco-configuration to provide the corresponding α-glucoside derivative. Using this strategy, the three consecutive α-glucosidic linkages were easily obtained in a stereoselective manner. Finally, the Dansyl labeled hexasaccharide derivative was used to measure the activity of processing α-glucosidase I.     

Carbon-13 pulse fourier transform NMR : Conformational preference of the hydroxyl and the acetoxyl group in 2-methyl-2-cyclohexenol and its acetate

¹³C Fourier transform NMR of cis and trans 5 - t - butyl - 2 - methyl - 2 - cyclohexenol, 2 -methyl - 2 - cyclohexenol and their acetates has been examined indicating that the pseudo-axial orientation of the hydroxyl and the acetoxyl group at the allylic position is favoured in 2 - methyl - 2 -cyclohexenol and its acetate.     

Reactivity study of 1,1,2,4,4,5,7,7,8,8,9,9,9-tridecafluoro-5-trifluoromethyl-3,6-dioxanon-1-ene in nucleophilic reactions: fluorination properties of secondary amine adducts

A series of nucleophiles was reacted with 1,1,2,4,4,5,7,7,8,8,9,9,9-tridecafluoro-5-trifluoromethyl-3,6-dioxanon-1-ene (1) as a representative of perfluoro(alkyl vinyl ethers). All reactions were completely regioselective with the nucleophilic attack at the terminal carbon atom. Reactions of hydroxy compounds, thiols and sec-amines afforded addition products, but butyllithium, tributylphosphane or complex hydrides caused displacement of vinylic fluorine: butyllithium afforded cis-derivative, while reactions with hydrides and the phosphane led to mixtures of cis- and trans-derivatives. Diethylamine and piperidine adducts displayed the property to substitute hydroxyl for fluorine in hexadecan-1-ol. Molecular properties of hexafluoropropene and perfluoro(methyl vinyl ether) were calculated by ab initio method at the MP2/6-311G(d,p) level of theory and their impact on relative reactivity was estimated.     

Efficient regioselective protection of myo-inositol via facile protecting group migration

A cis-1,2-cyclohexanediol, 1,4,5,6-tetra-O-benzyl-myo-inositol, was selectively protected at the axial C2-hydroxyl via acid-mediated rearrangement of the corresponding 1,2-orthoacetate, or via the base-induced migration of a protecting group that had previously been easily installed with complete regioselectivity at the adjacent equatorial hydroxyl. Esters 4a-6a were synthesized in high yields (75-82%) while sulfonate 7a and silyl ether 8a were obtained in 85 and 31% yields, respectively. The migration of the esters induced by DBU results in equilibrium between regioisomers favouring the C2 protected isomer, but NaH induced migration of sulfonyl and silyl groups results in complete migration from equatorial to axial hydroxyl groups.     

Surprising stereoselectivity in the Payne epoxidation of terpinen-4-ol with acetonitrile/hydrogen peroxide

A surprisingly high level of cis-stereoselectivity in the Payne epoxidation has been identified with the homoallylic alcohol, terpinen-4-ol. Very high efficiencies for hydrogen peroxide are realized under mild conditions. The necessity for peroxyimidic acid stabilization by solvent is replaced by coordination to the directing hydroxyl function, resulting in dramatically improved space yields at up to the one kilogram scale.     

Antioxidant activity and redox properties of cis-2,4,5-tris(hydroxyaryl)imidazolines

New effective antioxidants of cis-2,4,5-tris(hydroxyaryl)imidazoline type were assembled from aromatic aldehydes and ammonia. Their antioxidant activity was measured against hydroxyl radical and superoxide radical anion in physiological media, and oxidation potentials were measured by cyclic voltammetry. The lead compound bearing 3,4,5-hydroxyphenyl moieties showed activity 3.5 times higher compared to Trolox.     

Synthesis of eight-membered aminocyclitol analogues

The first syntheses of four stereoisomeric diaminocyclooctane diols, as well as a chlorocyclooctane aminodiol, are reported. In the first part, photooxygenation of cis,cis-1,3-cyclooctadiene gave a bicyclic endoperoxide, which was reduced with zinc followed by mesylation of the hydroxyl groups. Treatment with sodium azide afforded 1,4- and 1,2-cyclooctene diazides. Oxidation of the double bonds in the isomeric diazides with OsO₄, followed by hydrogenation of the azide groups, led to 3,8-diaminocyclooctane-1,2-diol and 3,4-diaminocyclooctane-1,2-diols. In the second part, cis-3,8-diazidocyclooctene was converted into the corresponding epoxide. Stereospecific hydrolysis of the epoxide ring with HCl_(g) in methanol, and hydrogenation of the azide groups gave 3,8-diamino-2-chloro-cyclooctan-1-ol. Bromination of the double bond in cyclooctene diacetate, followed by acetate deprotection, azidolysis of the bromides, and hydrogenation of the azide groups resulted in the formation of 2,3-diaminocyclooctane-1,4-diol.     

Recherches dans la série des cyclitols XLII. Synthèses de cyclitols tout-cis dérivés du cyclopentane; préparation des cyclopentane-tétrol et - pentol tout-cis

All-cis cyclitols derived from cyclopentane have been prepared in two ways: (i) by LiAlH₄ reduction of all-cis epoxypolyos; (ii) by dimethyl sulfoxide treatment, in the presence of sodium hydrogencarbonate, of brominated derivatives containing a neighbouring benzoyloxy group; under these conditions, the halogen is replaced by a cis-oriented hydroxyl group. Thus all-cis cyclopentane-tetrol and -pentol have been prepared; their configuration has been confirmed by NMR. spectroscopy.