Rhodium-catalyzed asymmetric hydroformylation of vinylarenes with novel chiral P,N-ligands derived from 1,2:5,6-di-O-cyclohexylidene-d-mannitol

Several new chiral P,N-ligands were prepared from 1,2:5,6-di-O-cyclohexylidene-d-mannitol, 1,1′-binaphthol, and phenyl isocyanate derivatives. Their Rh(I) complexes were applied as catalyst precursors in the asymmetric hydroformylation of vinylarenes. The steric and electronic properties of the phenylcarbamate substituents and the chiral binaphthyl moiety showed remarkable effects on the enantioselectivity and regioselectivity of the reaction. The matching combination of phenylcarbamate and the binaphthyl moiety of the ligand 1,2:5,6-di-O-cyclohexylidene-3-phenylcarbamate-4-[(S)-1,1′-binaphthyl-2,2′-diyl]phosphite-d-mannitol gave 50% ee and an 89/11 b/n ratio (branch-to-normal ratio). A synergic effect between the chiralities of mannitol and the binaphthol moieties was observed. Hydroformylation of the styrene gave the product in 75% ee when 1,2:5,6-di-O-cyclohexylidene-3,4-bis[(R)-1,1′-binaphthyl-2,2′-diyl]phosphite-d-mannitol was used as the chiral ligand.     

Synthesis of novel diphosphite ligands derived from d-mannitol and their application in Cu-catalyzed enantioselective conjugate addition of organozinc to enones

A series of novel chiral diphosphite ligands have been synthesized from d-mannitol derivatives and chlorophosphoric acid diary ester, and were successfully employed in the copper catalyzed enantioselective conjugate addition of organozinc reagents diethylzinc and dimethylzinc to cyclic and acyclic enones. The stereochemically matched combination of d-mannitol and (R)-H₈-binaphthyl in ligand 1,2:5,6-di-O-isopropylidene-3,4-bis[(R)-1,1′-H₈-binaphthyl-2,2′-diyl] phosphite-d-mannitol was essential to afford 93% ee for 3-ethylcyclohexanone, 92% ee for 3-ethylcyclopentanone, and 90% ee for 3-ethylcycloheptanone in toluene, using Cu(OTf)₂ as a catalytic precursor. The results clearly indicated that the chiral organocopper reagent exhibited high enantioselectivies for cyclic enones bearing different ring sizes. As for the backbone of this type of ligand, it has been demonstrated that 1,2:5,6-di-O-isopropylidene-d-mannitol was more efficient than 1,2:5,6-di-O-cyclohexylidene-d-mannitol. The sense of the enantiodiscrimination was mainly determined by the configuration of the diaryl phosphite moieties in the 1,4-addition of cyclic enones.     

Screening of a modular sugar-based phosphoroamidite ligand library in the asymmetric nickel-catalyzed trialkylaluminium addition to aldehydes

A modular sugar-based phosphoroamidite ligand library for the Ni-catalyzed trialkylaluminium addition to aldehydes has been synthesized and screened. After systematic variation of the sugar backbone, the substituents at the phosphoroamidite moieties and the flexibility of the ligand backbone, the monophosphoroamidite ligand 3-amine-3-deoxy-1,2:5,6-di-O-isopropylidene-((3,3′-di-trimethylsilyl-1,1′-biphenyl-2,2′-diyl)phosphite)-α-d-glucofuranose 1d were found to be optimal. Activities were high and enantioselectivities were good (ees up to 78%) for several aryl aldehydes.     

Efficient novel 1,2-diphosphite ligands derived from d-mannitol in the Pd-catalyzed asymmetric allylic alkylation

A novel Pd/1,2-diphosphite catalyzed asymmetric allylic alkylation of 1,3-diarylpropenyl acetate with malonates was developed. Catalyst optimization via a variation in the protecting groups at the 1,2- and/or 5,6-positions of d-mannitol skeleton and in biaryl moieties of the ligands led to a ‘lead’ catalyst, which efficiently mediated the allylic alkylations. The activities and enantioselectivities of the reaction clearly showed that the stereogenic centers of the skeleton and the axially chiral diaryl moieties of the ligands had a synergic effect. The ligand 1,2:5,6-di-O-isopropylidene-3,4-bis[(S)-1,1′-binaphthyl-2,2′-diyl]phosphite-d-mannitol afforded excellent yields (up to 99%) and high levels of enantioselectivies (ee up to 98%) in 1,4-dioxane/CH₂Cl₂ mixture (v/v, 1:1) using [Pd(π-allyl)Cl]₂ as catalytic precursor and LiOAc as base. Dramatic changes in the sense and in the degree of the enantioselectivity depending on the configuration of the diaryl moieties of the ligands and reaction conditions were observed.     

Asymmetric Baylis–Hillman reaction using sugar acrylates—synthesis of optically active α-methylene-β-hydroxy alkanoates

A study on the asymmetric Baylis–Hillman reaction of three chiral acrylates; 1,2:5,6-di-O-iso-propylidine-α-d-glucofuranose-3-acrylate 1, 2,3:5,6-di-O-iso-propylidine-α-d-mannofuranose-1-acrylate 2 and 1,2-O-iso-propylidine-5-O-tert-butyldimethylsilyl-α-d-xylofuranose-3-acrylate 3, with various aldehydes was conducted, resulting in adducts with moderate diastereoselectivity (5–40% e.e.).     

A chiral phosphepine–olefin rhodium complex as an efficient catalyst for the asymmetric conjugate addition

A monophosphine–olefin was synthesised from a 2,2′-bridged 1,1′-binaphthyl precursor, which served as a chiral bidentate ligand in the Rh catalysed 1,4-additions of arylboronic acids to cycloalkenones and 5,6-dihydro-2H-pyran-2-one. Fair yields (64–88%) and high asymmetric inductions (88–98% ee) have been obtained. The crystal structure of a corresponding cationic Rh(I) complex was determined.     

Asymmetric synthesis of monohydroxy tetradecanoic acids and their methyl esters

Methyl 3-, 6- and 13-oxo tetradecanoates were reduced by NaBH₄ in the presence of 1,2:5,6-di-O-isopropylidene-d-glucofuranose (DIPGH) and (−)-menthol together with isovaleric and pivalic acids in THF solution. The highest enantiomeric purity was found for the 13-hydroxy ester isomer of 96% ee. Enantiomeric excess (ee, %) was determined by chiral HPLC and ¹H NMR with shift reagent, Eu(tfc)₃.     

Direct vinylation of glucose derivatives with acetylene

Vinyl ethers, promising chiral carbohydrate synthons, have been synthesized by the addition of glucose acetals (1,2:5,6-di-O-isopropylidene-α-d-glucofuranose, methyl 4,6-O-benzylidene-α-d-glucopyranoside, 1,2-O-cyclohexylidene-α-d-glucofuranose, methyl α-d-glucopyranoside) to acetylene under atmospheric and elevated pressures in an autoclave in the presence of superbase catalytic systems (KOH-DMSO, t-BuOK-DMSO). The complete vinylation of 1,2:5,6-di-O-isopropylidene-α-d-glucofuranose and methyl α-d-glucopyranoside has been realized under elevated pressure of acetylene in the system KOH-THF as well.     

Chemical studies of carbohydrates. Part I. Conversion of derivatives of glucose and allose into pyrazoles and pyridazines

On reaction of 1,2:5,6-di-O-isopropylidenc-3-O-(p-tolylsulfonyl)-α-D-glueofuranose ( 1 ) with hydrazine hydrate at 140° besides formation of 3-deoxy-3-hydrazino-1,2:5,6-di-O-isopropylidene-α-D-allofuranose ( 2 ) and 3-dcoxy-1,2:5,6-di-O-isopropylidene-α-D-erythro-hex-3-enofuranose ( 3 ), ring transformation into 3-[4′-(2′,2′-dimethyl-1′,3′-dioxolanyl)]pyridazine ( 4 ) takes place. At 170°, however, only 2 and 4 are formed, indicating that 3 is the precursor of 4. Treatment of 3 with hydrazine hydrate at 170° indeed gives a nearly quantitative ring expansion into 4. Treatment of 3-dcoxy-3-hydrazino-1,2:5,6-di-O-isopropylidenc-α-D-glucofuranose ( 8 ) as well as the stereoisomeric allofuranose 2 with concentrated hydrochloric acid gives a nearly quantitative ring interconversion into 3-(D-erythro-trihydroxypropyl)pyrazole ( 9 ).     

Introduction of a New Class of Ligands for the Metal-Catalyzed Enantioselective Synthesis

Protected thiosugars were prepared as ligands for the metal-catalyzed enantioselective synthesis. The protecting groups in these ligands were varied to test a proposed new concept for the metal-catalyzed enantioselective synthesis. This new concept centres on the use of a stair-like ligand with a large substituent on one side and a small substitutent on the other rather than the commonly employed ligands which have C₂ symmetry (see Fig.3). In such a ligand, both substituents should have a major influence on the coordination of a prochiral substrate. To test this proposal, 3-thio-α-D -glucofuranose derivatives with the following substituents were synthesized: 1,2-O-isopropylidene-5,6-O-methylidene (see 24 ), 1,2:5,6-di-O-isopropylidene (see 2 ), 5,6-O-cyclohexylidene-1,2-O-isopropylidene (see 23 ), 1,2-O-cyclohexylidene-5,6-O-isopropylidene (see 14 ), 1,2:5,6-di-O-cyclohexylidene (see 13 ), 5,6-O-(adamantan-2-ylidene)-1,2-O-isopropylidene (see 21 ), and 1,2:5,6-di-O-(adamantan-2-ylidene) (see 25 , Table 2). As a representative of the allofuranoses, 1,2:5,6-di-O-isopropylidene-3-thio-α-D -allofuranose ( 6 ) was chosen. The following derivatives of 1,2-O-isopropylidene-α-D -xylofuranose were also synthesized: 1,2-O-isopropylidene-5-deoxy-3-thio-α-D -xylofuranose ( 29 ), 1,2-O-isopropylidene-3-thio-α-D -xylofuranose ( 28 ) and 5-O-[(tert-butyl)-diphenylsilyl]-1,2-O-isopropylidene-3-thio-α-D -xylofuranose ( 15 , see Table 2). The proposed concept was tested using the copper-catalyzed 1,4-addition of BuMgCl to cyclohex-2-en-1-one. The enantioselectivity was very dependent on the ligand used and was up to 58%.     

Highly sterically hindered binaphthalene-based monophosphane ligands: synthesis and application in stereoselective Suzuki–Miyaura reactions

A series of new sterically hindered (R)-(2′-aryl-1,1′-binaphthalene-2-yl)phosphanes with ortho-substituted phenyls as aryl groups were prepared via Negishi monoarylation of enantiopure 2,2′-dibromo-1,1′-binaphthalene followed by lithiation and quenching with diphenylphosphanyl or dicyclohexylphosphanyl chloride. These ligands were applied to the stereoselective Suzuki–Miyaura coupling for the preparation of substituted biaryls. The enantioselectivity correlated positively when increasing the hindrance of the 2′-aryl group of the ligand. Using the best performing diphenylphosphane ligand with a 2,6-dimethoxyphenyl aryl group, various arylnaphthalenes were prepared in high to excellent yields (68–99%) with low to good ee (12–75% ee), the latter being comparable to the best values reported when using other chiral monophosphane ligands.     

Catalytic enantioselective reactions. Part 18: Preparation of 3-deoxy-3-N,N-dialkylamino-1,2;5,6-di-O-isopropylidene-d-altritol derivatives from d-mannitol and their applications for catalytic enantioselective addition of dialkylzinc to aldehydes

A series of new chiral β-aminoalcohols, 3-deoxy-3-N,N-dialkylamino-1,2;5,6-di-O-isopropylidene-d-altritol derivatives 2–4 possessing a variety of amine substituents at the 3-position and thiol or acetylthio group at the 4-position was prepared from d-mannitol and enantioselective additions of diethylzinc to aldehydes using them as chiral catalysts were examined.     

Improved Preparation of Cyclohexylidene Derivatives of MYO-Imositol

Condensation of myo-inositol with 1,1-dimethoxy-cyclohexane in the presence of Nafion-H affords directly 1,2-O-cyclohexylidene-myo-inositol in 45 - 50% yield, along with 1,2:3,4-, 1,2:4,5- and 1, 2 : 5,6-di-O-cyclohexylidene-myo-inositols in lesser amounts.     

Chemical studies of carbohydrates (II) On the mechanism of the conversion of a glucose derivative into a pyridazine compound

The formation of 3-(2′,2′-dimethyl-1′,3′-dioxolan-4′-yl)pyridazine ( 4 ) by reacting 1,2:5,6-di-O-isopropylidene-3-O-(p-tolylsulfonyl)-α-D-glucofuranose ( 1 ) with hydrazine hydrate via the intermediate 3-deoxy-1,2:5,6-di-O-isopropylidene-α-D-erythro-hex-3-enofuranose ( 3 ) is explained by a mechanism, involving an initial attack of the hydrazine molecule at position 4 in compound 3 , a subsequent ring opening by fission of the C₄? O bond and a ring closure by formation of a N? C₁ bond.     

A convenient chromatography-free access to enantiopure 6,6′-di-tert-butyl-1,1′-binaphthalene-2,2′-diol and its 3,3′-dibromo,di-tert-butyl and phosphorus derivatives: utility in asymmetric synthesis

A simple chromatography-free high-yielding synthesis of the hexane-soluble enantiopure 6,6′-di-tert-butyl-1,1′-binaphthalene-2,2′-diol 3 (6,6′-di-tert-butyl BINOL) using Friedel–Crafts reaction on 1,1′-binaphthalene-2,2′-diol 1 (BINOL) is described. The enantiomeric purity was fully maintained in the reaction. Compound 3 has been used as an entry point for the convenient chromatography-free synthesis of 3,3′,6,6′-tetra-tert-butyl BINOL 4 and 3,3′-dibromo-6,6′-di-tert-butyl BINOL 5. A straightforward route to enantiopure bisphosphites [(6,6′-R₂C₂₀H₁₀O₂)P]₂[O₂C₂₀H₁₀-6,6′-R₂] [R = H 15, t-Bu 16] by simply reacting phosphorochloridite (6,6′-R₂C₂₀H₁₀O₂)PCl [R = H 20, t-Bu 6] with metallic sodium is highlighted. The identity of 15 and 16 as their selenium-oxidized products 17 and 18 (at phosphorus center) is confirmed by X-ray crystallography (17 in the enantiopure form and 18 as racemate). Various enantiopure phosphoramidites of the modified BINOL have been synthesized. It is established that even when the phosphoramidites derived from the unsusbstituted BINOL 1 fail to give an appreciable optical induction in the asymmetric reduction of acetophenone/phenacyl chloride, those derived from 3 do induce moderate chiral induction (up to 30% ee in the case for acetophenone and 43% ee in the case of phenacyl chloride), thus leaving scope for further improvement in ee for related reactions.     

A divergent synthesis of d- and l-carbocyclic 4′-fluoro-2′,3′-dideoxynucleosides as potential antiviral agents

d- and l-Carbocyclic 4′-fluoro-2′,3′-dideoxynucleosides have been synthesized from 2, which can be conveniently prepared from 1,2:5,6-di-O-isopropylidene-d-mannitol 1 in eight steps. Ruthenium-catalyzed ring-closing metathesis has been employed in the synthesis of d-nucleosides, whereas the l-series have been obtained through an intramolecular nucleophilic substitution reaction. The Mitsunobu condensation was used as a general tool for the synthesis of both purine and pyrimidine nucleosides.     

Asymmetric cyclization of meso-diepoxides using chiral (salen)Co(III)OAc catalyst forming optically active 1,4-anhydropentitols and 2,5-anhydrohexitols

The asymmetric hydrations of meso-diepoxides, 1,2:4,5-dianhydro-3-O-methylxylitol 2, 1,2:5,6-dianhydro-3,4-di-O-methylallitol 3 and 1,2:5,6-dianhydro-3,4-di-O-methylgalactitol 4, were carried out using (R,R)-1 and (S,S)-1. An optically active five-membered cyclic compound was selectively produced in good yield from 2, but a mixture of the five- and six-membered cyclic compounds was obtained in the cases of 3 and 4. The ees of all cyclic products exceeded 90%.     

Synthesis of (S,S)-1,2-Bis(3,5-DI-Tert-Butylphenyl)Ethane-1,2-Diol

The synthesis of (S,S)-1,2-bis(3,5-di-tert-butylphenyl)ethane-1,2-diol (98.6% ee), which should be useful as a chiral ligand of catalysts in asymmetric inductions, is described.     

Thermal analysis of new glycopolymers derived from monosaccharides

A novel monomer carrying carbohydrate moiety was prepared by simple reaction of methacrylic acid with 3-O-(2′,3′-epoxy-propyl)-1,2:5,6-di-O-isopropylidene-α-d-glucofuranose. Another d-glucose oligomer was synthesized by the polycondensation of a dicarboxylic acid including the carbohydrate residue into the main polymeric chain, 3-O-benzyl-5,6-(bis-O-(acryloyloxy))-1,2-di-O-isopropylidene-α-d-glucofuranose, with propane-1,3-diol using p-toluenesulfonic acid as catalyst. These products were copolymerized with styrene and 2-hydroxypropyl methacrylate, respectively, at different mass ratios, using benzoyl peroxide as initiator. Differential scanning calorimetry was performed in order to study the copolymerization process of the monomer and oligomer into the chosen co-monomers, respectively, and the activation energy of this process was evaluated using Kissinger–Akahira–Sunose (KAS) method. The storage and loss modulus of the obtained glycopolymers were evaluated using dynamic mechanical analysis. The thermal stability of the obtained products was studied via thermogravimetry.     

Towards the total synthesis of clavosolide A

The synthesis of the monomeric unit of clavosolide A from 1,2:5,6-di-O-isopropylidene-α-d-glucose is presented.