Regioselective synthesis of the 1-bromo-4-phenyl-tetrahydro-7-amino-benzocyclohepten-6-one,a subnanomolar aminopeptidase-N/CD13 inhibitor

A regioselective synthesis of the title 1-bromo-4-phenyl-tetrahydro-7-amino-benzocyclohepten-6-one 2 has been pursued and develop in order to allow a large scale synthesis of this highly potent and selective APN inhibitor (K_i 60 pM). The pivotal step in this approach was the desymmetrization of the ketones 6a,b through regioselective generation of the silyl enol ethers 5a,b. After obtention of the corresponding enones 13a,b and the ene-amides 4a,b–4′a,b, it was possible to separate the regioisomers at this step. Conversion to the desired phenylbromo-amide 17 was achieved from the both isolated major and minor regioisomers through chemical manipulations including Suzuki coupling and Sandmeyer reaction. The title compound 2·HCl was finally synthesized after a series of deprotections/protection.     

Synthesis of azepane and nojirimycin iminosugars: the Sharpless asymmetric epoxidation of d-glucose-derived allyl alcohol and highly regioselective epoxide ring opening using sodium azide

The Sharpless asymmetric epoxidation of d-glucose-derived allyl alcohol 4 afforded α- and β-epoxides 5a and 5b in high stereoselectivity. The epoxide ring opening in 5a/5b was studied with different nucleophilic azido reagents, under various reaction conditions, and was found to be highly regioselective to give the preferential formation of 6-azido diol 6a/6b over 5-azido-diol 7a/7b. The 6-azido diol 6a/6b and 5-azido diol 7a/7b thus obtained were converted to the corresponding seven- and six-membered iminosugar, namely, azepane 1a/1b and 1-deoxy-nojirimycin 2a/2b.     

Stereospecific enzymatic hydrolysis of racemic epoxide: a process for making chiral epoxide

Among various microbial cultures evaluated, Rhodotorula glutinis SC 16293 and Aspergillus niger SC 16311 catalyzed the stereospecific hydrolysis of the racemic epoxide, RS-1-{2′,3′-dihydrobenzo[b]furan-4′-yl}-1,2-oxirane, 1 to the corresponding R-diol, R-1-{2′,3′-dihydrobenzo[b]furan-4′-yl}-ethane-1,2-diol, 3. The S-epoxide, S-1-{2′,3′-dihydrobenzo[b]furan-4′-yl}-1,2-oxirane, 2 remained unreacted in the reaction mixture. A reaction yield of 45–50% (theoretical maximum yield is 50%) and an enantiomeric excess (ee) of >95% were obtained for unreacted S-epoxide 2 using each culture. Addition of 10% methyl tert-butyl ether to an aqueous reaction mixture during hydrolysis by R. glutinis improved the ee of the unreacted S-epoxide 2 to >99% (yield 48%) and that of the R-diol 3 to 79%. Unlike R. glutinis, hydrolysis of racemic epoxide 1 in the presence of 10% methyl tert-butyl ether by A. niger showed an adverse effect and gave S-epoxide 2 in 54% yield and 49% ee.     

Total synthesis of lycopene-5,6-diol and γ-carotene-5′,6′-diol stereoisomers and their HPLC separation

Lycopene-5,6-diol stereoisomers (1a,b) and (2a,b) and γ-carotene-5′,6′-diol stereoisomers (3a,b) and (4a,b) were synthesized by a stepwise C₁₅ + C₁₀ + C₁₅ double Wittig reaction strategy. The key compounds erythro(anti)-C₁₅-dihydroxy aldehydes 17a,b and their threo(syn)-stereoisomers 23a,b were prepared via Sharpless asymmetric epoxidation of geraniol and nerol followed by acidic hydrolysis of the epoxides in a stereospecific manner. The enantiomerically enriched anti-isomers were obtained by way of recrystallization of 2,3-epoxygeranyl 3,5-dinitrobenzoates 9a,b, whereas syn-isomers were obtained as enantiomerically pure forms via recrystallization of dihydroxyneryl 3,5-dinitrobenzoates 21a,b. In order to determine the absolute stereochemistry of natural products, HPLC separation methods for each enantiomers 1a,b–4a,b were established by using a column carrying a chiral stationary phase.     

A substituent directed regioselective synthesis of aryl/pyronyl pendant unusual adipate and tetrahydronaphthalene

An efficient regioselective synthesis of pyronyl pendant ethyl methylthiocarbonylalkanoates 5 has been delineated from the base catalyzed reaction of suitably functionalized 2-pyranone 1 and 2-carbethoxycycloalkanones 2, 6 through successive substitution and regioselective ring opening by in situ generated mercaptide ion. To assess the effect of C-4 substituent on regioselectivity, reactions of 6-aryl-3-cyano-4-(piperidin-1-yl)-2-oxopyran 8 with 2-carbethoxycyclohexanone 6a and 2-carbethoxy-2-methylcyclohexanone 6b were carried out separately under analogous reaction conditions but the compounds isolated were identical and characterized as 4-aryl-8-methyl-2-piperidin-1-yl-5,6,7,8-tetrahydronaphthalene-1-carbonitriles 9. Ethyl 2-(5-amino-4′-bromo-4,6-dicyanobiphenyl-3-yl)-5-methylsulfanylcarbonylpentanoate 10 has also been prepared through base catalyzed ring transformation of ethyl 2-[6-(4-bromophenyl)-3-cyano-2-oxo-2H-pyran-4-yl]-5-methylsulfanylcarbonylpentanoate 5d by malononitrile in DMF.     

Short synthesis of phenylpropanoid glycosides calceolarioside-B and eutigoside-A

A convenient 4-step synthesis of calceolarioside-B 1 and eutigoside-A 2 in high overall yield is described. The key step involved the regioselective, Me₂SnCl₂-catalyzed O-6 acylation of unprotected 2-phenylethyl-β-d-glucosides 5a–b with cinnamoyl chlorides 6a–b in excellent yields. Acylation at O-6 is selective with the acid chlorides used. This work serves as a model for the convenient synthesis of phenylpropanoid glycosides acylated at O-6.     

Total synthesis of myxol and deoxymyxol stereoisomers and their application to determining the absolute configurations of the natural products

The total synthesis of myxol stereoisomers 1a,b and deoxymyxol (plectaniaxanthin) stereoisomers 2a,b was accomplished by Wittig reaction of (S)- and (R)-C₁₀-phosphonium salts 8a,b bearing a silyl-protected 1,2-dihydroxy-ψ end group with C₃₀-apocarotenals 6 and 7. The phosphonium salts 8a,b were derived from aldehydes 11a,b possessing a cyclopentylidene ketal moiety, prepared via Sharpless asymmetric epoxidation of allylic alcohol 12 followed by regioselective cleavage of the oxirane ring. We established an analytical HPLC method using a chiral column to separate stereoisomers 1a,b and 2a,b and thus determined the absolute configurations of the natural products. The HPLC analyses established that both myxol and deoxymyxol isolated from bacteria have the 2′S-configuration.     

Synthesis of endoperoxides derived from cyclooctatetraenes via singlet oxygenation

Cyclooctatetraene (1) reacted with photo-generated singlet oxygen to give the endoperoxide 7,8-dioxabicyclo[4.2.2]deca-2,4,9-triene (1a), which was further transformed to the cis-diepoxide 1b by catalytic rearrangement with Co-TTP to the unsaturated cis-diol 1c and the saturated cis-diol 1d by catalytic hydrogenation, to the saturated endoperoxide 1e by reaction with diimide, and to the epoxycyclooclatetraene If by deoxygenation with dimethylphosphine. Similarly, the methoxy-, phenyl- and methyl-substituted cyclooctatetraenes 3-5, respectively, gave the corresponding endoperoxides with the substituents located at the 1-position (3a, 5a), the 2-position (5b) and the 9-position (3b, 4a). Their structures were determined on the basis of their ¹H- and ¹³C-NMR data and by means of chemical transformation to the corresponding syn-diepoxides, i.e. 5,10-dioxatricyclo[7.1.0.0^4,6]deca-2,7-dienes. The formation of the endoperoxides is postulated to involve an electron transfer mechanism to give the radical cation of cyclooctatetraene and the superoxide ion. The latter couples into the homotropylium-type zwitterionic intermediate and subsequent cyclization leads to the endoperoxides.     

SnCl4-mediated oxidative biaryl coupling reaction of 1-naphthol and subsequent ring closure of 2,2′-binaphthol to the dinaphthofuran framework

A simple method for the direct synthesis of 2,2′-binaphthols 2 and dinaphtho[1,2-b;2′,1′-d]furans 3 under mild conditions was developed, utilizing a biaryl coupling reaction via electron donor-acceptor complexes of 1-naphthols with SnCl₄. Heating of the complex in a sealed tube for (18-24 h) afforded the corresponding o-o coupled product 2 in excellent yield. Prolonged reaction (56-65 h) under the same conditions afforded 3 in high yield in one step. We also found that in the case of α-naphthol without substituents other than a hydroxyl group at the C-1 position, regioselective o-o coupling reaction proceeded. The products 2a, 2b and 2g should be useful as synthetic intermediates for naturally occurring 3,3′-bijuglone, 3,3′-biplumbagin and elliptinone.     

Synthesis of 2S-(2-hydroxyethyl)-3R-hydroxy-4S-(thymin-1-yl or adenin-9-yl)-tetrahydrofuran

Two synthetic strategies were developed to obtain isonucleosides 2a and 2b. Starting from the known compound 4, an extension of one carbon unit at sugar 6-terminal was achieved by Wittig reaction and Stannyl-desulfonylation reaction. After oxidation of the double bond, the isonucleosides with elongated side chain 2a and 2b were synthesized. For the synthesis of isonucleosides containing different bases, an epoxide intermediate approach was developed. Isonucleosides 2a and 2b were synthesized by regioselective epoxide opening reaction of 18 in good yield.     

A concise synthesis of (+)-cassiol

A synthesis of the anti-ulcerogenic compound (+)-cassiol 1b with 43% overall yield has been achieved. This short and efficient synthesis features the one-pot Julia olefination reaction of lactol (S)-2 with sulfone 3b through the key intermediate (−)-4b.     

Selective oxidation of acetylenic 1,4-diols with dioxiranes in comparison with the methyltrioxorhenium-hydrogen peroxide oxidant

Dimethyldioxirane (1a) and its trifluoro analog (1b) were employed to achieve selectively the direct transformation of hex-3-yne-2,5-diol 3a and 1,4-diphenyl-but-2yne-1,4-diol 3b (two representative acetylenic 1,4-diols) into the corresponding carbonyls, leaving the carbon-carbon triple bond moiety untouched. The results are compared with those recorded in the analogous oxidation using the methyltrioxorhenium (MTO)/85% H₂O₂ homogeneous system. The powerful methyl(trifluoromethyl)dioxirane (1b) is the reagent of choice to achieve optimum yields of the target alkyne-1,4-diones, which are extremely versatile synthons.     

Convenient synthesis of 10H-indolo[3,2-b]quinolines and 6H-indolo[2,3-b]quinolines by sequential chemoselective Suzuki reaction followed by double C-N coupling

A convenient and regioselective synthesis of two series of indolo[2,3-b]quinolines, namely 10H-indolo[3,2-b]quinolines and 6H-indolo[2,3-b]quinolines, has been developed. The synthesis, proceeds in moderate to high yields, involving chemoselective palladium catalyzed Suzuki reaction of 2,3-dihaloquinolines with 2-bromophenylboronic acid, followed by a double Buchwald-Hartwig C-N coupling.     

A new sesquiterpene from Caragana intermediia

A new alloaromadendrane-type sesquiterpene,(-)-alloaromadendrane-3β,9β-diol(1),has been isolated from the aerial part of Caragana intermediia.The structure of (-)-alloaromadendrane-3β,9β-diol(1)was established by spectroscopic methods, including X-ray analysis that provided its relative stereochemistry.Bioassay showed that (-)-alloaromadendrane-3β,9β-diol (1)possesses anti-pyricularia oryzae P-2b activity with MIC value of 10μg/mL.     

A mild and efficient CAN mediated oxidation of Morita-Baylis-Hillman adducts of 5-methyl-N-alkylisatin to 5-formyl-N-alkylisatin

A simple, mild and efficient CAN mediated oxidation of Morita-Baylis-Hillman adducts of 5-methyl-N-alkylisatins 1a-13a to 5-formyl-N-alkylisatins 1b-13b under ambient reaction conditions is reported. Simple and isomerized 5-methyl-N-alkylisatin derivatives 1-4 have also been tested and failed to provide the corresponding formylated products. A plausible reaction mechanism has been proposed.     

First total synthesis of （±）-malaysianone A and （±）-tanariflavanones B

A concise approach for the frst total synthesis of two naturally occurring flavanoids,（）-malaysianone A（1）and（）-tanariflavanones B（2）,has been accomplished with total yields of 12.9%and 10.4%,respectively.The key steps were regioselective deprotection and regioselective synthesis of 5-formaldehyde-8-hydroxy-2-[40-methyl-30-penteneyl]-dihydro-1-benzopyran（8）.     

Autoxidation of terpenic aldehydes—I

The autoxidation reaction of diterpenic 4-axial-aldehyde torulosal (1b) has been studied. Naturally occurring 4-hydroxy-nor-diterpenes have been proved to be artefacts arising in the autoxidation of the corresponding 4-aldehyde. Hydroperoxides (1d) and (2d), the main autoxidation products of 1b, have also been postulated as intermediates in the formation of 4-hydroxy-nor-diterpenes (1a and 2a).     

Resolution of C2-symmetric 2,3-diphenylbutane-1,4-diol and purification of diastereomeric 1,4-diphenylbutane-1,4-diol using (S)-proline and boric acid

Racemic 2,3-diphenylbutane-1,4-diol (±)-1 is resolved to obtain the corresponding (R,R)-isomer in 98% e.e. through reaction with (S)-proline and boric acid. Partially resolved (R,R)-(−)-1 and (S,S)-(+)-1 have been enriched to obtain samples of 95 and 97% e.e. through reaction with (S)-proline and boric acid. Diastereomeric 1,4-diphenylbutane-1,4-diol 2 has been purified to obtain the (R,R)-isomer in 98% e.e. using (S)-proline and boric acid.     

Regioselective synthesis of 6-benzylthiazolo[3,2-b]1,2,4-triazoles during Sonogashira coupling

The reaction of 3-mercaptopropargyl-1,2,4-triazoles with various iodobenzenes catalyzed by Pd-Cu leads to the regioselective formation of 6-benzylthiazolo[3,2-b]1,2,4-triazoles 4. The structure of 4d was confirmed by X-ray analysis.     

Construction of polyheterocyclic spirotetrahydrothiophene derivatives via sulfa-Michael/aldol cascade reaction

A series of polyheterocyclic spirotetrahydrothiophene derivatives were obtained in moderate to excellent yields via a catalyst-free sulfa-Michael/aldol cascade reaction of chalcones 1 and commercially available 1,4-dithiane-2,5-diol 2 under mild conditions. We also present the first asymmetric sulfa-Michael/aldol cascade reaction of chalcones 1 and commercially available 1,4-dithiane-2,5-diol 2 with moderate to good enantioselectivities catalyzed by readily available chiral phase-transfer catalysts (PTCs).