Octanone Derivatives Research Articles

Asymmetric One‐Pot Mukaiyama Michael/Michael Reaction Catalyzed by Diphenylprolinol Silyl Ether

The asymmetric catalytic Mukaiyama Michael reaction between α,β‐unsaturated aldehydes and silyl enol ether derived from a cyclic ketone was catalyzed by diphenylprolinol silyl ether to afford Michael products with excellent diastereo‐ and enantioselectivities. Bicyclo[2.2.2]octanone derivatives can be synthesized as a single isomer in a nearly optically pure form via a two‐step, one‐pot reaction, comprising the sequential Mukaiyama Michael reaction and intramolecular Michael reaction starting from dienol silyl ether and α,β‐unsaturated aldehydes, catalyzed by diphenylprolinol silyl ether. In the second Michael reaction, positive kinetic resolution occurred to increase the enantioselectivity.

Reversal of Regioselectivity in Zinc-Dependent Medium-Chain Alcohol Dehydrogenase from Rhodococcus erythropolis toward Octanone Derivatives.

The zinc‐dependent medium‐chain alcohol dehydrogenase from Rhodococcus erythropolis (ReADH) is one of the most versatile biocatalysts for the stereoselective reduction of ketones to chiral alcohols. Despite its known broad substrate scope, ReADH only accepts carbonyl substrates with either a methyl or an ethyl group adjacent to the carbonyl moiety; this limits its use in the synthesis of the chiral alcohols that serve as a building blocks for pharmaceuticals. Protein engineering to expand the substrate scope of ReADH toward bulky substitutions next to carbonyl group (ethyl 2‐oxo‐4‐phenylbutyrate) opens up new routes in the synthesis of ethyl‐2‐hydroxy‐4‐phenylbutanoate, an important intermediate for anti‐hypertension drugs like enalaprilat and lisinopril. We have performed computer‐aided engineering of ReADH toward ethyl 2‐oxo‐4‐phenylbutyrate and octanone derivatives. W296, which is located in the small binding pocket of ReADH, sterically restricts the access of ethyl 2‐oxo‐4‐phenylbutyrate, octan‐3‐one or octan‐4‐one toward the catalytic zinc ion and thereby limits ReADH activity. Computational analysis was used to identify position W296 and site‐saturation mutagenesis (SSM) yielded an improved variant W296A with a 3.6‐fold improved activity toward ethyl 2‐oxo‐4‐phenylbutyrate when compared to WT ReADH (ReADH W296A: 17.10 U/mg and ReADH WT: 4.7 U/mg). In addition, the regioselectivity of ReADH W296A is shifted toward octanone substrates. ReADH W296A has a more than 16‐fold increased activity toward octan‐4‐one (ReADH W296A: 0.97 U/mg and ReADH WT: 0.06 U/mg) and a more than 30‐fold decreased activity toward octan‐2‐one (ReADH W296A: 0.23 U/mg and ReADH WT: 7.69 U/mg). Computational and experimental results revealed the role of position W296 in controlling the substrate scope and regiopreference of ReADH for a variety of carbonyl substrates.

ChemInform Abstract: Gold‐Catalyzed Cyclizations of Alkynyl Silyl Enol Ethers: An Easy Access to Bicyclo[3.2.1]octanone Derivatives.

The efficient gold-catalyzed cyclization reactions of alkynyl silyl enol ethers were successfully applied to the preparation of bicyclo[3.2.1]octanone derivatives. Accordingly, after optimization of the gold catalytic system, several bicyclic α,β-unsaturated keto adducts were synthesized in good to excellent yields. The process followed a major 5-exo cyclization via an anti addition of the silyl enol ether to the π-activated intermediate, which was demonstrated by a deuterium incorporation experiment. A 6-endo cyclization process was observed for a silyl enol ether bearing an electron-donating aromatic group.

Gold‐Catalyzed Cyclizations of Alkynyl Silyl Enol Ethers: An Easy Access to Bicyclo[3.2.1]octanone Derivatives

AbstractThe efficient gold‐catalyzed cyclization reactions of alkynyl silyl enol ethers were successfully applied to the preparation of bicyclo[3.2.1]octanone derivatives. Accordingly, after optimization of the gold catalytic system, several bicyclic α,β‐unsaturated keto adducts were synthesized in good to excellent yields. The process followed a major 5‐exo cyclization via an anti addition of the silyl enol ether to the π‐activated intermediate, which was demonstrated by a deuterium incorporation experiment. A 6‐endo cyclization process was observed for a silyl enol ether bearing an electron‐donating aromatic group.magnified image

Highly diastereoselective synthesis of bicyclo[4.2.0]octanone derivatives by the [2+2] photocycloaddition of chiral cyclohexenonecarboxylates to ethylene

The diastereoselective [2+2] photocycloaddition of a cyclohexenonecarboxylate containing (−)-8-(4-nitrophenyl)menthyl as a chiral auxiliary to ethylene gave the photocycloadduct, a bicyclo[4.2.0]octanone derivative, with a high degree of diastereoselectivity. A photoreaction, conducted in CH 2Cl 2 at −78 °C gave the corresponding photocycloadduct in 88% de. In the presence of Ti(OR) 4 or Me 3SnCl, the diastereoselectivity was increased up to 92% de.

4‐Aminobicyclo[2.2.2]octanone Derivatives with Antiplasmodial and Antitrypanosomal Activities.

AbstractFor Abstract see ChemInform Abstract in Full Text.

4‐Aminobicyclo[2.2.2]octanone Derivatives with Antiprotozoal Activities.

AbstractFor Abstract see ChemInform Abstract in Full Text.

4-Aminobicyclo[2.2.2]octanone Derivatives with Antiplasmodial and Antitrypanosomal Activities

4-Aminobicyclo[2.2.2]octanones were converted to their N-oxides and to 4-aminobicyclo[2.2.2]octanes. Furthermore, the 6,7-bis-(4-methoxyphenyl) analogues were synthesized. All products were screened for their activities against Trypanosoma b. rhodesiense and Plasmodium falciparum. The pharmacological results were compared with those of formerly tested bicyclo[2.2.2]octanones and bicyclo[2.2.2]octanols. Structure-activity relationships are discussed.

4-Aminobicyclo[2.2.2]octanone Derivatives with Antiprotozoal Activities

4-Aminobicyclo[2.2.2]octanones which were prepared in one-pot-reactions from benzylidene acetone and dialkylammonium rhodanides were reduced stereoselectively to their corresponding alcohols. The activities of the bicyclic compounds against causative organisms of tropical deseases were examined. The 4-aminobicyclo[2.2.2]octan-2-ols were in general more active against Trypanosoma b. rhodesiense and Plasmodium falciparum than the corresponding keto compounds.

Synthesis of Bicyclo[3.2.1]-octanone Derivatives by Metal Catalyzed Decomposition of α-Diazomethylketones

Highly functionalized bicyclo[3.2.1]-octanone derivatives have been prepared by metal catalyzed decompostion of diazoketones through a net retention of configuration at the benzylic center. Present Address: University of Texas, M.D. Anderson Cancer Center, Department of Molecular Pathology-89, 1515 Holcolmbe Blvd., Houston, TX 77030, USA

Synthesis and Odour of Bicyclo[2.2.2]octanone Derivatives: β‐Hydroxy Ketones and Enones

AbstractFrom bicyclo[2.2.2]octan‐2‐one (1) the β‐hydroxy ketones 2‐13 were prepared by aldol reaction with various aldehydes. Dehydration of the ketols furnished the corresponding enones 14‐22. The odour properties of these bicyclic, rigid hydroxy ketones as well as of the enones are described.

CNS-agents: synthesis and properties of 3-anilino-8-oxatropanes

Reaction of the 8-oxabicyclooctenone and -octanone derivatives 3 and 4 with aniline and metal hydrides yields the 3 alpha-isomers of the aniline derivatives 7 and 8, preferably. The configuration can be determined by NMR-spectroscopy and by cyclization to the scopoline analogue 9b. Depending on the N-substitution the pyran rings of the alpha-isomers are flattened (7,8) or deformed to give a boat conformation (10,11,13). The conformationally restricted aniline derivative 18 can be obtained from 4 with 2-aminobenzaldehyde and diborane, trans-configuration is preferred in 18. Some substrates reveal CNS-effects in mice.

Optical resolution of bicyclo[2.2.1]heptanone, bicyclo[2.2.2]octanone, and bicyclo[3.2.1]octanone derivatives by inclusion complexation with optically active host compounds

Optical resolution of bicyclo[2.2.1]heptanone, bicyclo[2.2.2]octanone, and bicyclo[3.2.1]octanone derivatives by inclusion complexation with optically active host compounds

Synthesis of 4,4-disubstituted cyclohexenones. Part 2. Cycloaddition of 2-chloroacrylonitrile to 5-substituted 1,3-dimethoxycyclohexa-1,4-dienes

The cycloaddition of 2-chloroacrylonitrile to 1,3-dimethoxycyclohexadienes (3; R1= OMe, R2= H), derived by in situ conjugation of the Birch reduction products (12) produced from aromatic precursors (11) gave after acid work-up mainly bicyclo[2.2.2]octanone derivatives (5) and rearranged products(13). There is a strong preference for addition to the less hindered face of (3; R1= OMe, R2= H)[to give product (5) in which R3 is ‘syn’ to the carbonyl group], especially when the R3 substituent is large, and there is also a preference for the CN group in (5) to be ‘endo’. This is illustrated most favourably in the formation of the cyclic acetals (24) produced by fluoride desilylation of the adducts (5ix) and (5iy) followed by acid cyclisation. Although the chloronitrile function in (5) could not be solvolysed (aqueous Na2S) to the corresponding ketone, this conversion could be effected after the carbonyl group in (5) had been reduced to alcohol. Lithium t-butoxyaluminium hydride reduction of ketones (5ax) and (5ay) gave diols (6ax) and (6ay) respectively whereas borohydride reduction of ketone (5bx) gave the alcohols (19a) and (19b). Alcohols (19a), (19b), (6ax), and (6ay) were then converted respectively into ketones (20a) and (20b)[for (19)] and (7a)[for (6)]. Novel by-products in the sodium sulphide solvolysis of (6ax), (6ay) were the diols (21aa) and (21ab) which were shown to arise by reduction of (7a) in the presence of sodium sulphide. Jones oxidation of keto alcohol (7a) gave (18a) and oxidation of either keto alcohol (20a) or (20b) gave the same diketone (18b). Beckmann fragmentation of the corresponding oxime gave the cyclohexenone (22) thus establishing a formal route to cyclohexenones.

ChemInform Abstract: Resolution of Bicyclo(2.2.1)heptanone, Bicyclo(2.2.2)octanone, and Bicyclo(3.2.1)octanone Derivatives by Complexation with Optically Active Host Compounds.

ChemInform Abstract: Resolution of Bicyclo(2.2.1)heptanone, Bicyclo(2.2.2)octanone, and Bicyclo(3.2.1)octanone Derivatives by Complexation with Optically Active Host Compounds.

ChemInform Abstract: Regiocontrolled Cyclization of Acetylenic Ketones. First Example of Selective Desilylation of a Triple Bond in the Presence of a Silyl Enol Ether.

AbstractCyclization of the 1‐(3‐butyryl)bicyclo(3.3.0)octanone derivatives (I), (Vb), or (VIII) yields the propellanes (II) or (IX) and/or the tricyclic ketones (III) or (VI).

Cyclopentenone Derivatives, XI. Stereoselective Routes to Bicyclo[3.3.0]octanones

AbstractAnnulation of double donating molecules like dimethyl glutaconate as well as dimethyl 3‐oxoglutarate to 4‐acetoxy‐2‐cyclopenten‐1‐one opens stereoselective routes to various bicyclo[3.3.0]octanone derivatives.

Cycloaddition of dichloroketene with functionalized cycloalkenes, synthesis of bicyclo[4.2.0]octanone-3-yl derivatives and of 3,4- dicarbomethoxy-1-methylbicyclo [4,2,0] octan-7-one

Dichloroketene reacts with some cycloalkenes in which an ester function is in homoallylic or in an even more remote position with respect to sp 2 carbon atoms. In fact acetate and benzoate of 3,5,5-trimethylcyclohex-3-en-1-ol and 1,2-dicarbo-methoxy-4-methyl-cyclohex-4-ene undergo 2+2 cycloaddition of dichloroketene to produce the corresponding bicyclo[4.2.0]octanone derivatives in 60–65% yield. In the latter case the process occurs regiospecifically to give 3,4-dicarbomethoxy-1-methylbi-cyclo[4,2.0]octan-7-one as product after dechlorination. The Hassner zinc dehalogenation method of generating dichloroketene is the best procedure.

Photoelectron spectroscopic studies of some 2-azabicyclo[2.2.2]octan-5-one and bicyclo[2.2.2]octanone derivatives

The HeI photoelectron spectra of several 2-ethoxycarbonyl-2-azabicyclo[2.2.2]octane and bicyclo[2.2.2]octanone derivatives have been measured. The low ionization potentials of these compounds are well characterised by comparison with the results of HAM/3 molecular orbital calculations. In particular, a significant interaction is observed between the nitrogen lone-pair and the carbonyl oxygen at C-5 of 2-ethoxycarbonyl-2-azabicyclo[2.2.2]octan-5-one