Synthesis of the possible carcinogenic dihydrodiol and diol epoxide of phthalazine

Inverse-Diels-Alder reaction of dimethyl 1,2,4,5-tetrazine-3,6-dicarboxylate with benzene cis-diol gave dihydrodiol containing the 1,4-dihydropyridazine ring. Attempts at oxidation of the dihydropyridazine ring with PIFA and MnO₂ resulted in the formation of 5- and 5,6-dihydroxy-phthalazine derivatives. The oxidation of the dihydropyridazine ring was achieved by way of photooxygenation. The phthalazine type dihydrodiol is unstable and easily undergoes aromatization. The Diels-Alder reaction of tetrazine with cyclohexadiene acetonide and epoxy-ketal cyclohexene as a dienophile was investigated. These reactions led to the possible carcinogenic phthalazine type of dihydrodiol and diol epoxide where the hydroxyl groups are protected.     

Aerobic oxidative desymmetrization of meso-diols with bifunctional amidoiridium catalysts bearing chiral N-sulfonyldiamine ligands

Asymmetric aerobic oxidation of a range of meso- and prochiral diols with chiral bifunctional Ir catalysts is described. A high level of chiral discrimination ability of Cp^∗Ir complexes derived from (S,S)-1,2-diphenylethylenediamine was successfully demonstrated by desymmetrization of secondary benzylic diols such as cis-indan-1,3-diol and cis-1,4-diphenylbutane-1,4-diol, providing the corresponding (R)-hydroxyl ketones with excellent chemo- and enantioselectivities. Enantiotopic group discrimination in oxidation of symmetrical primary 1,4- and 1,5-diols gave rise to chiral lactones with moderate ees under similar aerobic conditions.     

Stereochemistry and mechanism of the hydrogenation of substituted cyclopentenes

1,2- and 2,3-disubstituted cyclopentenes were hydrogenated with several transition metal catalysts. The hydrogenation of 1,2-disubstituted cyclopentenes gave preferably the cis products with Raney Ni, whereas 2,3-disubstituted cyclopentenes gave preferably the trans isomers. The trans products were favoured in the hydrogenation of 1,2- and 2,3-dialkylcyclopentenes with Pt or Pd catalysts. A detailed product analysis of the hydrogenation of 1,2-dialkylcyclopentenes indicates that the double bond migration occurred to form 2,3-dialkylcyclopentenes in advance of the hydrogenation. In contrast, 1-methyl-2-phenylcyclopentene gave predominantly the cis product irrespective of the kind of catalyst. These results suggest the formation of a π-benzylic species during the course of the reaction. The mechanism is discussed in terms of the modified Horiuti-Polanyi mechanism.     

A concise enantioselective synthesis of 1,4-dideoxy-1,4-imino-d-arabinitol using Co(III)(salen)-catalyzed hydrolytic kinetic resolution of a two-stereocentered anti-azido epoxide

A concise enantioselective synthesis of 1,4-dideoxy-1,4-imino-d-arabinitol, (+)-DAB-1, has been described in good overall yield (18.1%) and with high enantiomeric purity (up to 98% ee) starting from a simple raw material, cis-2-butene-1,4-diol. The Co-catalyzed hydrolytic kinetic resolution of a two-stereocentered racemic azido epoxide followed by asymmetric dihydroxylation of the alkene and ‘one pot’ reductive cyclisation of the azido diol are key reactions in the synthetic sequence.     

Stereocontrolled synthesis of the aminocyclitol moiety of (+)-trehazolin via C-H insertion reaction of alkylidenecarbene

The aminocyclitol moiety of (+)-trehazolin, a powerful trehalase inhibitor, was synthesized in a stereocontrolled manner from cis-2-butene-1,4-diol via C-H insertion reaction of the alkylidenecarbene, followed by regioselective opening of the epoxide ring. It was obtained in an enantiomerically pure form by twice using Sharpless asymmetric epoxidation.     

cis,cis,cis,cis-1,2,3,4,5-Pentakis(hydroxymethyl)cyclopentane

All-cis pentamethanolcyclopentane has been obtained in six steps by Diels–Alder condensation of maleic anhydride with (benzyloxymethyl)cyclopenta-2,4-diene, reduction of the anhydride to a diol that was protected as the acetonide. Then, ozonolysis of the double bond, followed by reduction led to a cis-diol. Then successive deprotections of the three other methanol groups gave the cis,cis,cis,cis-1,2,3,4,5-pentakis(hydroxymethyl)cyclopentane.     

Studies towards the total synthesis of cruentaren A and B: Stereoselective synthesis of fragments C1-C11, C12-C22 and C23-C28

A convergent and stereoselective approach for the synthesis of C1-C11, C12-C22, and C23-C28 fragments of cytotoxic natural products cruentaren A and B are accomplished. Highlights of the strategy include a Sharpless epoxidation followed by a regioselective opening of epoxide to generate anti and syn-stereochemistry at C9-C10 and C15-C16, an Alder-Rickert reaction between a 1,5-dimethoxy-1,4-cyclohexadiene and dienophile to construct the aromatic ring, and a lithium-mediated aldol reaction to install the C17-C18 anti-stereochemistry. The synthesis of C1-C11 and C12-C22 fragments proceed with a longest linear sequence of 10 and 17 steps from commercially available 2-butyne-1,4-diol and cis-2-butene-1,4-diol respectively.     

Microwave-assisted copper-catalyzed stereoselective ring expansion of three-membered heterocycles with α-diazo-β-dicarbonyl compounds

Microwave-assisted copper-catalyzed ring expansions of three-membered heterocycles with α-diazo-β-dicarbonyl compounds were investigated. Thiiranes generated 3-acyl-5,6-dihydro-1,4-oxathiines in the presence of copper sulfate and trans-3-acyl-5,6-dihydro-1,4-oxathiines as stereospecific products for 1,2-disubstituted cis-thiiranes through an intramolecular S_N2 process. Oxiranes gave rise to 2-acyl-5,6-dihydro-1,4-dioxines under the catalysis of copper hexafluoroacetylacetonate and cis-3-acyl-5,6-dihydro-1,4-dioxines as stereospecific products for 1,2-disubstituted cis-oxiranes via an intimate ion-pair mechanism. The current method provides a direct and simple strategy in efficient preparation of 3-acyl-5,6-dihydro-1,4-oxathiines and 2-acyl-5,6-dihydro-1,4-dioxines, important agents in medicinal and agricultural chemistry, from readily available thiiranes and oxiranes, respectively.     

Stereoselective ring-opening reactions with AcBr and AcCl. A new method for preparation of some haloconduritols

The actions of AcX (X=Br, Cl) on 7-oxa-bicyclo[2.2.1]hept-5-ene-2,3-diol diacetates and a transoid-epoxide prepared from the acetonide of cyclohexa-3,5-diene-cis-1,2-diol were studied. H₂SO₄-catalyzed cleavage of exo-cis-7-oxa-bicyclo[2.2.1]hept-5-ene-2,3-diol diacetate with AcCl gave (1α,2α,3α,6β)-6-chloro-4-cyclohexene-1,2,3-triol triacetate, from which the corresponding chloroconduritol was obtained by trans-esterification (MeOH/HCl). A similar reaction of the exo-diacetate with AcBr in the presence of H₂SO₄ resulted in bromine addition. The formation of bromine from the reaction of AcBr and H₂SO₄ was observed by independent experiments. H₂SO₄-catalyzed reaction of endo-cis-7-oxa-bicyclo[2.2.1]hept-5-ene-2,3-diol diacetate with AcX (X=Br, Cl) gave (1α,2α,3β,6β)-6-halo-4-cyclohexene-1,2,3-triol triacetates. The reaction of the transoid-epoxide with AcX (X=Br, Cl) with no catalyst gave also (1α,2α,3β,6β)-6-halo-4-cyclohexene-1,2,3-triol triacetates.     

(-)-Menthol as a source of new N,N-diamine ligands for asymmetric transfer hydrogenation

The synthesis of new chiral N-monotosylated-1,2-diamines based on the (-)-menthol skeleton is presented. The elimination of HCl from neomenthyl chloride obtained from an Appel reaction led to p-menth-3-ene in excellent yield. Further functionalization of the double bond in p-menth-3-ene with chloramine-T gave the corresponding N-tosylaziridines, which upon reaction with sodium azide and subsequent reduction of the azide functional group, formed the 1,2-diamine system. The synthesized chiral ligands proved effective in the asymmetric transfer hydrogenation of aromatic ketones and an endocyclic imine.     

Synthesis of 2,5-diethynyl substituted oxepins from trans-1,4-diethynylcyclohexa-2,5-diene-1,4-diols

Reaction of trans-1,4-bis(trimethylsilylethynyl)cyclohexa-2,5-diene-1,4-diol with n-BuLi followed by methanesulfonyl chloride resulted in the formation of a dark red solid, which was identified as 2,5-bis(trimethylsilylethynyl)oxepin. Deprotection of the silyl groups resulted in the formation of 2,5-diethynyloxepin, a red, shock sensitive solid. Reaction of a differentially substituted cyclohexa-2,5-diene-1,4-diol gave a mixture of 2,5-diethynyl substituted oxepins.     

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.     

Cyclodehydration of cis-2-butene-1,4-diol with active methylene compounds catalyzed by a diphosphinidenecyclobutene-coordinated palladium complex

(π-Allyl)palladium triflate coordinated with 1,2-bis(4-methoxyphenyl)-3,4-bis(2,4,6-tri-t-butylphenylphosphinidene)cyclobutene (DPCB-OMe), [Pd(η³-C₃H₅)(DPCB-OMe)]OTf, efficiently catalyzes cyclodehydration of cis-2-butene-1,4-diol with active methylene compounds such as acetylacetone and ethyl acetoacetate in toluene in the presence of pyridine. The reactions can be performed in air, giving 2-vinyl-2,3-dihydrofurans in good to high yields.     

Two-directional synthesis of the non-adjacent bis(tetrahydrofuran) core of cis-sylvaticin

Synthesis of the C₂-symmetric, non-adjacent bis(tetrahydrofuran) core of cis-sylvaticin in seven steps and 24% overall yield from (2R,3S)-1,2-epoxy-4-penten-3-ol is reported. A strategy involving assembly of the central 1,4-diol unit by silicon-tethered ring-closing metathesis and subsequent two-directional functionalization, including establishment of the cis/threo stereochemical relationships of the tetrahydrofuran rings by Sharpless asymmetric dihydroxylation/S_N2 cyclization, is employed.     

Darstellung von PdCl2-komplexen substituierter cis,cis-cycloocta-1,5-diene aussachtringen und den entsprechenden substituierten cis-1,2-divinylcyclobutanen. cis,trans-zuordnung 3,4-,3,7- und 3,8-disubstituierter cis,cis-cycloocta-1,5-diene

cis-1,2-Divinylcyclobutanes are transformed with dibenzonitrilepalladium(II) chloride into the corresponding cis,cis-cycloocta-1,5-diene-PdCl₂ complexes. When e.g. the 3-methyl-cis,cis-cycloocta-1,5-diene-PdCl₂ complex is prepared using trans- or cis-3-methyl-cis-1,2-divinylcyclobutane or the corresponding eight-membered ring. two PdCl₂ complexes with the methyl group in the equatorial or axial position are formed in different percentages. With the aid of ¹H NMR spectroscopy the cis- or trans-configurations of 3,4-, 3,7- or 3,8-disubstituted cis,cis-cycloocta-1,5-dienes can be determined unambiguously in PdCl₂ complexes.     

C-Galactosylceramide diastereomers via Sharpless asymmetric epoxidation chemistry

C-Glycoside analogs of α-galactosylceramide (KRN7000) were synthesized in 19 linear steps with Sharpless asymmetric epoxidation as a key reaction. Opening of a hydroxy epoxide with sodium azide provided an anti vicinal azido diol with inversion of configuration at the azide-bearing carbon while opening with Ti(O-i-Pr)₂(N₃)₂ gave syn vicinal azido diol with retention. The latter, unusual outcome could be rationalized either by invoking Ti-catalyzed intramolecular double S_N2 inversion or by epoxide opening/intramolecular delivery of azide from the Ti complex.     

Novel and enantioselective syntheses of (R)- and (S)-3-hydroxy-4-(2,4,5-trifluorophenyl)butanoic acid: a synthon for sitagliptin and its derivatives

A new synthetic strategy for (R)- and (S)-3-hydroxy-4-(2,4,5-trifluorophenyl)butanoic acid, a building block in the preparation of sitagliptin and its derivatives, was developed. Pd(OAc)₂ catalyzed coupling of 2,4,5-trifluoro-1-iodobenzene with allyl alcohol gave 3-(2,4,5-trifluorophenyl)propanal in a yield of 95%. l-Proline catalyzed reaction of the 3-phenylpropanal (in only 1.2 molar equiv) with nitrosobenzene followed by reduction with NaBH₄ and Pd/C catalyzed hydrogenation gave (R)-3-(2,4,5-trifluorophenyl)propane-1,2-diol with >99% ee and 65% yield. Selective tosylation of primary hydroxyl group of the 1,2-propandiol unit followed by cyanide displacement afforded (R)-3-hydroxy-4-(2,4,5-trifluorophenyl)butanenitrile (80%). The nitrile was converted to the title β-hydroxy acid under basic hydrolysis in a yield of 90%. Thus, (R)-3-hydroxy-4-(2,4,5-trifluorophenyl)butanoic acid was prepared enantioselectively from the starting material in four steps and 45% overall yield. The reaction sequence was repeated with d-proline as the catalyst to give (S)-3-hydroxy-4-(2,4,5-trifluorophenyl)butanoic acid in 45% overall yield and >99% enantiomeric excess.     

Etude structurale du poly (pentadiene-1,3) par RMN du proton a 100 ET 220 MHz

High-resolution proton NMR spectra of C₆D₆ solutions of samples of poly(1,3-pentadiene) having different structures and different stereoregularities are presented and interpreted. Methylene resonances of isotactic and syndiotactic cis-1,4-polypentadienes measured at 220 MHz exhibit three-peak and eight-peak patterns, respectively, indicating that the methylene protons are non-equivalent in the syndiotactic polymer. Methyl groups of cis-1,4 units are about 0.02 ppm more shielded than those of trans-1,4 units. Spectra of trans-1,2-polypentadiene and spectra of polypentadiene prepared with lithiumnaphthalene in tetrahydrofuran are also interpreted.     

Silicon-carbon unsaturated compounds. 73. Photolysis of cis- and trans-1,2-dimethyl-1,2-diphenyl-1,2-disilacyclohexane in the presence of tert-butyl alcohol and acetone

Irradiation of cis-1,2-dimethyl-1,2-diphenyl-1,2-disilacyclohexane (1a) in the presence of tert-butyl alcohol in hexane with a low-pressure mercury lamp bearing a Vycor filter proceeded with high stereospecificity to give cis-2,3-benzo-1-tert-butoxy-1,4-dimethyl-4-phenyl-1,4-disilacyclooct-2-ene (2a), in 33% isolated yield, together with a 15% yield of 1-[(tert-butoxy)methylphenylsilyl]-4-(methylphenylsilyl)butane (3). The photolysis of trans-1,2-dimethyl-1,2-diphenyl-1,2-disilacyclohexane (1b) with tert-butyl alcohol under the same conditions gave stereospecifically trans-2,3-benzo-1-tert-butoxy-1,4-dimethyl-4-phenyl-1,4-disilacyclooct-2-ene (2b) in 41% isolated yield, along with a 12% yield of 3. Similar photolysis of 1a and 1b with tert-butyl alcohol-d₁ produced 2a and 2b, respectively, in addition to 1-[(tert-butoxy)(monodeuteriomethyl)(phenyl)silyl]-4-(methylphenylsilyl)butane. When 1a and 1b were photolyzed with acetone in a hexane solution, cis- and trans-2,3-benzo-1-isopropoxy-1,4-dimethyl-4-phenyl-1,4-disilacyclooct-2-ene (4a and 4b) were obtained in 25% and 23% isolated yield. In both photolyses, 1-(hydroxymethylphenylsilyl)-4-(methylphenylsilyl)butane (5) was also isolated in 4% and 5% yield, respectively. The photolysis of 1a with acetone-d₆ under the same conditions gave 4a-d₆ and 5-d₁ in 18% and 4% yields.     

A novel synthesis of (2S)-3-(2,4,5-trifluorophenyl)propane-1,2-diol by sharpless asymmetric epoxidation method

Synthesis of (2S)-3-(2,4,5-trifluorophenyl)propane-1,2-diol by the Sharpless asymmetric epoxidation reaction has been achieved. 2,4,5-Trifluorobenzaldehyde with methyl 2-(triphenyl-λ⁵-phosphanylidene)acetate gave methyl (E)-3-(2,4,5-trifluorophenyl)acrylate in 83% yield. The reduction of ester group with DibalH followed by Sharpless asymmetric epoxidation gave ((2R,3R)-3-(2,4,5-trifluorophenyl)oxiran-2-yl)methanol. Pd/C-catalyzed hydrogenation of epoxy alcohol furnished (2S)-3-(2,4,5-trifluorophenyl)propane-1,2-diol with >90% ee and 71% yield.