Kinetic resolution of racemic lactones by conjugate additions of allylic organolithium species: direct formation of three contiguous centers with high diastereo- and enantioselectivities

[reaction: see text] Kinetic resolution of racemic alpha,beta-unsaturated lactones by the organolithium species produced from asymmetric lithiation of N-Boc-N-(p-methoxyphenyl)cinnamylamine provides conjugate addition products with three contiguous stereogenic centers in yields of 62-77% with diastereomeric ratios from 75:25 to >99:1 and enantiomeric ratios for the major diastereomers from 94:6 to 98:2.     

Mn(III)acetate-mediated additions of active methylene compounds to bicyclic olefins: Synthesis of bicyclic olefin-fused dihydrofurans

Bicyclic alkenes such as benzonorbornadiene, oxabenzonorbornadiene, norbornene, and norbornadiene were reacted with 1,3-cyclohexanedione and ethyl acetoacetate in the presence of Mn(OAc)₃ and Cu(OAc)₂. Except for the reaction of benzonorbornadiene and ethyl acetoacetate, dihydrofuran derivatives were the only products obtained. The formation of naphthalene derivatives was observed together with dihydrofuran in the aforementioned benzonorbornadiene/ethyl acetoacetate reaction. Additionally, the dihydrofuran product from the addition of ethyl acetoacetate to norbornadiene was slowly converted into epoxide derivative with air. The mechanism for the formation of the products is discussed.     

Asymmetric carbon-carbon bond formations by conjugate additions of lithiated N-boc allylic amines to nitroalkenes: enantioselective synthesis of functionalized cyclopentanoids

[reaction: see text] Allylic organolithiums generated by enantioselective deprotonation of N-Boc-N-(p-methoxyphenyl) allylic amines undergo conjugate additions with nitroalkenes to provide enecarbamates containing two contiguous stereogenic centers in good yields with high diastereoselectivities and enantioselectivities. Further elaboration of these adducts to enantioenriched substituted cyclopentanones and aminocyclopentanes is reported.     

Synthesis of highly enantioenriched all-carbon quaternary centers: conjugate additions of chiral organolithium nucleophiles to alpha,alpha-dinitrile beta,beta-disubstituted olefins

[reaction: see text]. Highly enantioenriched quaternary centers are obtained by the reaction of chiral lithiated intermediates complexed to (-)-sparteine with tetrasubstituted, alpha,alpha-dinitrile activated olefins. Lithiated N-Boc-N-Aryl benzylamine furnishes products with drs from 78:22 to 95:5, with ers exceeding 94:6. Lithiated N-Boc-N-Aryl allylamine reactants provide enecarbamate products with drs from 55:45 to 99:1, with ers ranging from 87:13 to 97:3.     

Asymmetric reductive ring-opening of bicyclic olefins catalyzed by palladium and nickel complexes

[reaction: see text] Asymmetric reductive ring opening of oxa- and azabenzonorbornadienes with organic acids and zinc powder under mild conditions catalyzed by Ni(binap)Cl(2) or Pd(binap)I(2) produces the corresponding 1,2-dihydronaphth-1-ols in good to excellent yields with high enantioselectivity.     

Palladium-catalyzed aminoallylation of activated olefins with allylic halides and phthalimide

The three-component aminoallylation reaction of the activated olefins 2 with the phthalimide 1a and allyl chloride proceeded very smoothly in the presence of Pd(2)dba(3).CHCl(3) (5 mol %)/P(4-FC(6)H(4))(3) (40 mol %) and Cs(2)CO(3) (3 equiv against 2) in dichloromethane at room temperature to give the corresponding aminoallylated products, N-pent-4-enylphthalimides 3, in 58-99% yields. The reaction of oxazolidinone 1b also proceeded very smoothly to give N-(2,2-dicyano-1-phenylpent-4-enyl)oxazolidinone in a quantitative yield; however, the Tsuji-Trost-type allylation products 4 were obtained in the case of dibenzylamine, N-tosylaniline, and pyrrolidin-2-one. Further, 2 underwent cycloaddition with N-tosylvinylaziridine 9a in the presence of Pd(2)dba(3).CHCl(3) (5 mol %)/P(4-FC(6)H(4))(3) (40 mol %) in THF at room temperature, giving the corresponding pyrrolidines 11 in 69-99% yields.     

Dimethylzinc-mediated additions of alkenylzirconocenes to aldimines. New methodologies for allylic amine and C-cyclopropylalkylamine syntheses

Hydrozirconation of alkynes with zirconocene hydrochloride followed by in situ transmetalation to dimethylzinc provides access to reactive alkenyl organometallic reagents from readily available precursors. Upon addition of imines, 1,2-attack leads to synthetically useful allylic amine building blocks. In the presence of CH(2)I(2) or CH(2)Cl(2), the N-metalated allylic amide intermediate is cyclopropanated and C-cyclopropylalkylamines are formed in high yield and excellent diastereoselectivities favoring the anti products. The use of enynes as starting materials for this domino reaction provides conjugated biscyclopropanes and thus allows the stereoselective formation of five new carbon-carbon bonds. A transition state that explains the need for both zirconocene complex and alkyl zinc in the cyclopropanation reaction is proposed.     

Highly efficient [2 + 2] intramolecular cyclizations of allenynes under microwave irradiation: construction of fused bicyclic compounds

A palladium [2 + 2] cycloaddition of 1,6- and 1,7-allenyne carboxylates and microwave-mediated [2 + 2] cycloaddition of various 1,n-allenynes were developed and, particularly, the microwave irradiated [2 + 2] cycloaddition of allenynes can provide a simple, general and eco-friendly synthetic method to fused bicyclo[m,2,0]alkadienes.     

Stereoselective synthesis of heterocyclic cage compounds by domino conjugate additions

Heterocyclic cage compounds have been stereoselectively synthesized from enantiopure [(S)R]-[(p-tolylsulfinyl)methyl]-p-quinols or their amine analogues and 2-(trimethylsilyloxy)furan in the presence of Bu4NF. The method is particularly valuable not only because of the stereochemical control but also because the reactions occur in an experimentally simple one-pot procedure through a domino sequence of three consecutive conjugate additions. The intermediate 1,4-adducts could be isolated when the reaction was carried out in the presence of BF3 x OEt2.     

Asymmetric synthesis of β-substituted alcanoic acids via highly stereoselective conjugate additions of organocopper compounds to chiral enoates

Conjugate additions of organocopper compounds RCu·.BF₃ to encates of sulfonamide-shielded alcohols 1x and 1n quite generally proceed with > 99% ee and > 90% yield.     

Convenient approaches to heterocycles via copper-catalysed additions of organic polyhalides to activated olefins

An efficient method for the synthesis of 2,3-dichloro-5-substituted (Cl, CF₃, alkyl) pyridines $\text{29}$ starting from the 1:1 adducts of the copper-catalysed addition of chloral or the corresponding 2,2-dichloroaldehydes to acrylonitrile is presented. Proper choice of experimental conditions allows the preparation of $\text{29}$ in a one-pot process. Similarly, the CuCl-catalysed reaction of methyl itaconate with several trichloromethyl compounds R-CCl₃ gives 6-R-substituted 2-pyrone derivatives $\text{40}$ via dehalogenation and subsequent thermal ring closure of the primary 1:1-adducts. The new electrophilic 2-pyrone $\text{40b}$ undergoes [4+2]-cycloaddition reactions with inverse electron demand with a number olefins and acetylenes, allowing thereby regioselective transfer of a trifluoromethyl group from a simple Freon derivative (1,1,1-trichloro-2,2,2-trifluoroethane) into more complex organic molecules. Finally, the 1:1-adduct of trichloroacetylchloride with methyl acrylate allows a very convenient synthesis of novel N-substituted derivatives $\text{66}$ of pyroglutamic acid as well as of proline.     

Asymmetric conjugate additions of α-substituted-α-cyanoacetates to acetylenic ketones by chiral phase transfer catalysis

Asymmetric conjugate addition of α-substituted-α-cyanoacetates to acetylenic ketones has been achieved with high enantioselectivity and moderate E/Z selectivity under the influence of our recently designed, binaphthyl-modified 3,5-bis[3,5-bis(trifluoromethyl)phenyl]phenyl substituted phase transfer catalyst.     

Synthesis of new bicyclic compounds containing fused sulfolane and pyrazolidine rings

3-Aryl-6а-methyl-6-nitro-1-carbamoylhexahydrothieno[2,3-d]pyrazole-4,4-dioxides, novel original bicyclic species consisting of fused pyrazolidine and sulfolane rings, and 1,4-adducts were obtained by reacting 2-benzylidene-3-methyl-4-nitro-3-thiolene-1,1-dioxide and its derivatives with semicarbazide.     

C-nitroso compounds—XXXI: The addition of α-chloronitroso compounds to olefins containing allylic hydrogen

α Chloronitrosoadamantane 1a gives upon reaction with 2-phenylpropene at room temperature virtually quantitatively a stable ketonitrone salt, the α,α-adamantylidene-N-(2-phenyl)prop-1-en-3-yl nitrone hydrochloride 2a. Evidence for the structure of the crystalline product is based on microanalytical data and spectroscopic properties, together with degradation studies. Similar aliphatic ketonitrone hydrochlorides have been obtained from reaction of 2-phenylpropene with other α-chloronitroso compounds 1b-1e (73–91%), and from α-chloroni-trosoadamantane . and a series of allylic olefins (76–95%). Rearrangement of an intermediary N-α-chloroalkyl-N-alkenylhydroxylamine, which has been initially formed by an ene-type process between the reactants, can explain formation of the product.     

Asymmetric conjugate addition of carbonyl compounds to nitroalkenes catalyzed by chiral bifunctional thioureas

Readily available chiral thioureas derived from cyclohexane-1,2-diamine were prepared and found to be highly effective organocatalysts for the conjugate addition of aldehydes and ketones to nitroalkenes. Excellent enantioselectivities and yields were obtained for a variety of aryl and heteroaryl nitroalkenes. The base additives are essential for good yields and excellent enantioselectivities in this transformation. Based on new experimental evidence, a modified catalytic mechanism was proposed to rationalize the important role of the base additives.     

Organopalladium approaches to prostaglandins. 2. Synthesis of prostaglandin endoperoxide analogs via π-allylpalladium additions to bicyclic olefins

A variety of prostaglandin endoperoxide analogos are readily available by addition of π-allylpalladium compounds to bicyclic olefins and subsequent treatment with alkenyl and alkynyl organometallics. Pronounced biological activity is evident in these compounds.     

Asymmetric conjugate additions of chiral phosphonamide anions to alpha,beta-unsaturated carbonyl compounds. A versatile method for vicinally substituted chirons

Reactions of anions derived from chiral nonracemic allyl, crotyl, and cinnamyl bicyclic C(2)-symmetrical phosphonamides with alpha, beta-unsaturated cyclic ketones, esters, lactones, and lactams take place at the gamma-position of the reagents. The products are diastereomerically pure or enriched beta-substituted carbonyl compounds. The method also provides easy access to vicinal substitution of as many as three stereogenic centers including in some cases quaternary carbon atoms, in a one-pot sequence.     

Asymmetric carbon-carbon bond formations in conjugate additions of lithiated N-Boc allylic and benzylic amines to nitroalkenes: enantioselective synthesis of substituted piperidines,pyrrolidines, and pyrimidinones

(-)-Sparteine mediated lithiations of N-Boc-allylic and benzylic amines provide configurationally stable intermediates which on conjugate additions to nitroalkenes provide highly enantioenriched enecarbamate products in good yields, and with high diastereoselectivities. Straightforward transformations of these adducts offer general routes to substituted 3,4-substituted piperidines, 3,4-substituted pyrrolidines, and 4,5-substituted pyrimidinones. Diastereoselective substitutions of intermediate lactams followed by reduction provide 3,4,5-substituted piperidines and 3,4-trisubstituted pyrrolidines. Lithiation adjacent to nitrogen of 3,4-substituted piperidines and pyrrolidines followed by diastereoselective substitution opens a route to 2,4,5- and 2,4,5,6-substituted piperidines as well as 2,3,4- and 2,3,4,5-substituted pyrrolidines. The enantiomers of the enecarbamate and 3,4-substituted piperidine products may be accessed by stannylation/transmetalation sequences as well as by further manipulation of 4-substituted piperidones. The methodology is used to synthesize both enantiomers of an aspartic peptidase inhibitor intermediate, 3-hydroxy-4-phenylpiperidine, as well as the antidepressant (+)-femoxetine.