Gold-catalyzed synthesis of bicyclo[4.3.0]nonadiene derivatives via tandem 6-endo-dig/Nazarov cyclization of 1,6-allenynes

Catalytic cyclization of 1,6-allenynes was achieved by AuPPh(3)SbF(6) (5 mol %) in cold CH(2)Cl(2) (0 degrees C, 0.5-4 h) to form bicyclo[4.3.0]nonadiene products; this cyclization proceeded more efficiently for a substrate bearing R = alkyl (yields >70%). We propose a reaction mechanism involving a 6-endo-dig cyclization of Au(I)-pi-alkyne, followed by Nazarov cyclization.     

Cyclic tetra- and hexaynes containing 1,4-donor-substituted butadiyne units: synthesis and supramolecular organization

Cyclic bis(1,3-butadiynes) with sulfur centers placed in the alpha-position to the 1,3-butadiyne units (2(n)) were synthesized by Glaser coupling of the corresponding open chain dithia-alpha,omega-diynes 1(n). In a second protocol we applied a four-component cyclization by reacting alpha,omega-dithiocyanatoalkanes 6(n) or alpha,omega-diselenocyanatoalkanes 7(n) with dilithium-1,3-butadiynide. This concept afforded either the cyclic dimers (S, 2(n); Se, 9(n)) or the cyclic trimers (S, 8(n); Se, 10(n)). Most of the molecular structures of 2(n) and 9(n) adopt chairlike conformations in the solid state. Tubular structures in the solid state with short distances between the chalcogen centers of neighboring stacks were encountered for 2(5), 9(5), 8(4), 10(4), and 10(5). Recrystallization of 10(5) from various polar and nonpolar solvents yielded inclusion of the solvent guest molecules. The solvent-accessible volume was calculated to vary from 19% (n-hexane) to 25% (mesitylene). The elastic properties of our cycles are due to the flexible methylene chains and the easily variable torsional angles between the rigid 1,3-butadiyne rods.     

Asymmetric cyclization of omega-formyl-1,3-dienes catalyzed by a zerovalent nickel complex in the presence of silanes

A nickel(0)-catalyzed asymmetric cyclization of omega-formyl-1,3-diene in the presence of silanes in which five- or six-membered carbocycles or pyrrolidine derivatives were afforded up to 86% ee by the use of (2R,5R)-2,5-dimethyl-1-phenylphospholane as a monodentate chiral ligand was investigated. The reaction course of this asymmetric cyclization can be explained for by two possible mechanisms: one in which the cyclization proceeds via a pi-allylnickel intermediate to produce a cyclized product having an internal olefin in the side chain, and one in which the cyclization proceeds via a sigma bond metathesis of silane and the nickel-oxygen bond of oxanickelacycle to produce a cyclized compound having a terminal olefin and/or an internal olefin in the side chain. It was speculated that both of these mechanisms operate in this asymmetric cyclization depending upon the nature of silanes and the reaction conditions.     

Nickel(0)-catalyzed disilylative and silastannylative cyclizations of 1,3-diene and tethered aldehyde

Nickel(0)-catalyzed bismetallative cyclization of 1,3-diene and a tethered aldehyde in the presence of PhF₂SiSiMe₃ or Me₃SiSnBu₃ gave the corresponding cyclized product having an allylsilyl or an allylstannyl unit in the side chain in good yields. The cyclized product obtained from the reaction in the presence of Me₃SiSnBu₃ had reactivity as an allylstannane derivative, and the coupling reaction with benzaldehyde proceeded in a diastereoselective manner. When the silastannylative cyclization was carried out in the presence of a chiral monodentate phosphine ligand, the cyclized product was produced as an optically active form with modest enantiomeric excess.     

Total synthesis of a cytotoxic acetogenin,pyranicin

[structure: see text] The first total synthesis of a new cytotoxic acetogenin, pyranicin (1), is described. SmI(2)-induced reductive cyclization of beta-alkoxy acrylate 4 proceeded stereoselectively to give 16,20-syn-19,20-trans-THP derivative 14, which was efficiently transformed into the 19,20-cis-THP derivative 18 through Mitsunobu lactonization. Wittig reaction of the phosphonium salt 2 obtained therefrom with butenolide 3 at -78 degrees C followed by reduction and deprotection afforded 1 in good overall yield.     

Regioselective Heck couplings of alpha,beta-unsaturated tosylates and mesylates with electron-rich olefins

[chemical reaction: see text]. Highly regioselective Heck couplings of alpha,beta-unsaturated tosylate and mesylate derivatives with N-acyl N-vinylamines and vinyl ethers were achieved. Several 2-alkoxy-1,3-dienes and 2-acylamino-1,3-butadienes were synthesized in good yields using 1.5 mol % of Pd2(dba)3, 3 mol % of DPPF, and diisopropylethylamine in dioxane. When working with alpha,beta-unsaturated ketones and esters, this method provides a less costly alternative to similar couplings using a triflate electrophile.     

Super acid-induced Pummerer-type cyclization reaction: improvement in the synthesis of chiral 1,3-dimethyl-1,2,3,4-tetrahydroisoquinolines

Improved synthesis of four stereoisomeric chiral 1,3-dimethyl-1,2,3,4-tetrahydroisoquinolines (1a, b, ent-1a, b) was achieved via the super acid-induced cyclization of chiral N-[1-methyl-2-(phenylsulfinyl)ethyl]-N-(1-phenylethyl)formamides (4a, b, ent-4a, b) using the Pummerer-type cyclization reaction as a key step. The cyclization leading to the isoquinoline ring proceeded in a quantitative manner when trifluoromethane sulfonic acid (TFSA) was used as the super acid, although Friedel-Crafts-type alkylation of 4-phenylsulfanyl TIQ derivatives (5) with benzene used as the solvent accompanied cyclization to yield the 4-phenyl-TIQs (7). The byproduct (7) was exclusively formed when a large excess amount of TFSA was used.     

Diastereoselective synthesis of spiro derivatives of 3-substituted 2,3,4,4a,5,6-hexahydro-1<Emphasis Type="Italic">H</Emphasis>-benzo[<Emphasis Type="Italic">c</Emphasis>]quinolizines

The cyclization via the mechanism of “tert-amino effect” of 2-(4-R-piperidino)benzaldehydes with cyclic active methylene components (Meldrum’s acid, 1,3-cyclohexanedione, and N,N-disubstituted barbituric acids) proceeded stereoselectively giving spiro-joined 2,3,4,4a,5,6-hexahydro-1H-benzo[c]quinolizines with axially oriented hydrogen atoms in the positions 3 and 4a of the benzo[c]quinolizine ring.     

Formation of a quaternary carbon center through the Pd(0)/PhCOOH-catalyzed allylation of cyclic beta-keto esters and 1,3-diketones with alkynes

Formation of a quaternary carbon center through the allylation of beta-keto esters and 1,3-diketones with alkynes is accomplished by the use of Pd(0)/benzoic acid catalyst. Reactions of various cyclic beta-keto esters and 1,3-diketones with alkynes in the presence of Pd(2)dba(3).CHCl(3) (5 mol %), PPh(3) (40 mol %), and PhCOOH (10 mol %) proceeded at 100 degrees C in toluene (5 M) to give the corresponding allylation products in high yields in a regio- and stereoselective manner. The possibility of asymmetric allylation is also discussed.     

Ruthenium-catalyzed cyclization of 2-alkyl-1-ethynylbenzenes via a 1,5-hydrogen shift of ruthenium-vinylidene intermediates

Catalytic cyclization of 2-alkyl-1-ethynylbenzene derivatives was implemented by TpRuPPh3(CH3CN)2PF6 (10 mol %) in hot toluene (105 degrees C, 36-100 h) to form 1-substituted-1H-indene and 1-indanone products; such cyclizations proceeded more efficiently for substrates bearing electron-rich benzenes. We propose that the cyclization mechanism involves a 1,5-hydrogen shift of initial metal-vinylidene intermediate.     

Stereoselective synthesis of 1-nitrobicyclo[3.1.0]hexanes and fused isoxazoline-N-oxides from primary nitro compounds

The one-step preparation of 1-nitrobicyclo[3.1.0]hexane and bicycloisoxazoline-N-oxide was readily achieved from conjugate adducts of nitro alkenes and allylmalonates by treatment with Ag(2)O and iodine under basic conditions. We observed that when a primary alkyl group was present at the β-position of the nitro group, bicyclo[3.1.0]hexane was preferentially formed, whereas if a secondary alkyl group occupied that position, isoxazoline-N-oxide was predominantly produced. High cis-selectivity was observed for the formation of cyclopentane units for both reactions. An iodomethyl adduct, considered an intermediate of the cyclization, was isolated, and its conversion to isoxazoline-N-oxide was successfully achieved. The isoxazoline-N-oxide underwent 1,3-dipolar cycloaddition with alkenes to yield tricycloheterocyclic compounds, which were readily converted to spirolactam in good yield by reductive cleavage of N-O bonds using Raney-Ni. On the other hand, 1,3-dipolar cycloaddition of the isoxazoline-N-oxide to terminal alkynes yielded tricyclic aziridines stereoselectively.     

Formation and characterization of a multicomponent equilibrium system derived from cis- and trans-1-aminomethylcyclohexane-1,2-diol

Both cis and trans isomers of amino diols 3-6 were prepared stereoselectively. In the reactions between 3-6 and phenyl isothiocyanate, the ring closure proceeded regioselectively and resulted only in spiro derivatives of 2-phenyliminooxazolidines 9, 10, 13, and 14. The reaction of cis- (or trans-)1-aminomethylcyclohexane-1,2-diol 4 (or 6) with 1 equiv of an aromatic aldehyde 15a-g in EtOH at room temperature resulted in a complex, multicomponent equilibrium mixture of 16a-g and 18a-g (or 17a-g and 19a-g), in each case consisting of a five-component, ring-chain tautomeric system 16A-E (or 17A-E), involving the Schiff base, two epimeric spirooxazolidines, two epimeric condensed 1,3-oxazines, and some of the four tricyclic compounds 18A-D (or 19A-D). The five-component, ring-chain equilibria were found to be adequately described by the Hammett-Brown linear free energy equation.     

Diastereoselective dl-hydrocoupling of benzalacetones by electroreduction

Electroreduction of benzalacetones with an undivided cell in Et(4)NOTs/acetonitrile gave cyclized dl-hydrodimers as mixtures of two diastereomers. The hydrodimerization proceeded stereoselectively to afford linear dl-hydrodimers, and the following cyclization led to two thermodynamically stable diasteromers of cyclopentanols.     

Studies on the intramolecular oxa-Pictet-Spengler rearrangement of 5-aryl-1,3-dioxolanes to 4-hydroxy-isochromans

The success and stereochemical outcome of the TiCl₄-promoted oxa-Pictet-Spengler cyclization of 5-aryl-1,3-dioxolanes to produce 1,3-disubstituted-4-hydroxy-isochromans, is influenced by the length and nature of the side chains bound to C-2 and C-4 of the dioxolane. Methyl groups yield a mixture of 4-hydroxy-isochromans in which the 1,3-trans diastereomer predominates, while bulkier substituents give 1,3-cis diastereomers. Functional groups in the C-2 side chain of the dioxolane ring may hinder cyclization by complexation with the promoter.     

Gold(I)-catalyzed regioselective inter-/intramolecular addition cascade of di- and triynes for direct construction of substituted naphthalenes

The gold-catalyzed cascade intermolecular addition-intramolecular carbocyclization reaction of dialkynylbenzenes was developed. In this reaction, regioselective addition of an external nucleophile toward the terminal alkyne and subsequent 6-endo-dig cyclization proceeded to give the 1,3-disubstituted naphthalenes in good yields. The direct synthesis of disubstituted chrysenes via a gold-catalyzed addition and double cyclization cascade using a triyne-type substrate was also achieved.     

Chelation-control in the formal [3+3] cyclization of 1,3-bis-(silyloxy)-1,3-butadienes with 1-hydroxy-5-silyloxy-hex-4-en-3-ones. One-pot synthesis of 3-aryl-3,4-dihydroisocoumarins

The [3+3] cyclization of 1,3-bis(silyloxy)-1,3-butadienes with 1-hydroxy-5-silyloxy-hex-4-en-3-ones resulted in the one-pot formation of 3-aryl-3,4-dihydroisocoumarins. The reactions proceeded by regioselective cyclization to give 6-(2-aryl-2-chloroethyl)salicylates, which underwent a silica gel-mediated lactonization. The cyclizations of protected 1-amino-5-silyloxy-hex-4-en-3-ones proved to be not regioselective.     

New insight into anionic cyclizations of alkynyl- and ortho-dialkynylarenes: a specific reactivity of 3-alkynyl-2-chloro- and 2,3-dialkynylquinoxalines and related compounds toward CH-acids’ carbanions

The reactivity of 3-alkynyl-2-chloroquinoxalines, 2,3-dialkynylquinoxalines, and some related pyrazine derivatives toward carbanions of the CH-acids (malononitrile, ethyl cyanoacetate, diethyl malonate, 1,3-dimethylbarbituric acid) has been studied. Most of the observed reactions proceeded as tandem or cascade cyclizations yielding polynuclear heterocyclic compounds. The process starts with the addition of a nucleophile to an alkyne triple bond. Depending on the nature of the used C-nucleophile, the thus formed anionic adduct underwent further cyclization via (i) intramolecular nucleophilic substitution of the chlorine atom, (ii) intramolecular acylation of the ring nitrogen atom by the ester side chain or (iii) intramolecular nucleophilic attack on the second CC bond. Reactions of 3-alkynyl-2-chloro- and 2,3-dialkynylpyrazines with 1,3-dimethylbarbituric acid in the presence of t-BuOK were accompanied by recyclization of the 1,3-dimethylbarbituric acid moiety.     

Enantioselective synthesis of 2-alkylidenetetrahydrofurans based on a ‘cyclization/enzymatic resolution’ strategy

Enantiomerically pure 2-alkylidenetetrahydrofurans have been prepared by TiCl₄ mediated enantiospecific reactions of 1,3-bis-silyl enol ethers with enantiomerically pure epichlorohydrin. In addition, the enzymatic kinetic resolution of 2-alkylidenetetrahydrofurans, using Candida antarctica lipase B (CAL-B), was studied. Enzymatic kinetic resolution of monocyclic 5-vinyl-2-alkylidenetetrahydrofuran with CAL-B afforded the enantiomerically pure ester with 97% ee. For a bicyclic 2-alkylidenetetrahydrofuran, this proceeded with excellent enantioselectivity (E >100) affording the enantiomerically pure acid with 98% ee. 2-Alkylidenetetrahydrofurans were prepared by [3+2] cyclization reactions of 1,3-dicarbonyl dianions (‘free dianions’) or 1,3-bis-silyl enol ethers (‘masked dianions’).     

Synthesis of spiro[4.5]decane and bicyclo[4.3.0]nonane ring systems by self-cyclization of (Z)- and (E)-2-(trimethylsilylmethyl)pentadienal derivative

The two title carbon frameworks were synthesized utilizing a new type of iron-induced cyclization reaction of 2-(trimethylsilylmethyl)pentadienal. 2-Methylspiro[4.5]dec-2-en-1-one was obtained from (Z)- and (E)-4-cyclohexylidene-2-(trimethylsilylmethyl)but-2-enal. It was found that the (Z)-substrate isomerized to (E)-intermediate followed by cyclization to afford the initial product, 2-methylenespiro[4.5]dec-3-en-1-ol, which was isomerized to the above product. The cyclization of 4-(4-alkyl)cyclohexylidene-2-(trimethylsilylmethyl)but-2-enal proceeded stereoselectively. While, (E)-3-(cyclohex-1-en-1-yl)-2-(trimethylsilylmethyl)prop-2-en-1-al cyclized immediately affording 8-methylenebicyclo[4.3.0]non-9-en-7-ol. The corresponding (Z)-isomer gave several cyclization products as a complex mixture.     

A stereoselective enyne cross metathesis

[reaction: see text] Intermolecular enyne metathesis reaction of alkynes with olefins catalyzed by second-generation Grubbs catalyst (1) proceeded stereoselectively under ethylene atmosphere to produce 1,3-disubstituted butadienes with E stereochemistry.