Amino-zinc-ene-enolate cyclization: a short access to cis-3-substituted prolino-homotryptophane derivatives

Proline chimeras are useful tools for medicinal chemistry and/or biological applications. The asymmetric synthesis of cis-3-substituted prolines can be easily achieved via amino-zinc-ene-enolate cyclization followed by transmetalation of the cyclic zinc intermediate for further functionalization. Syntheses of prolino-homotryptophane derivatives were achieved through Negishi cross-coupling of the zinc intermediate with indole rings. The use of Pd catalyst derived from Fu's [(t-Bu3)PH]-BF4 was required to avoid the undesired beta-hydride elimination. Optically pure and orthogonally protected compounds were obtained readily usable for peptide synthesis.     

Facile construction of the benzofuran and chromene ring systems via PdII-catalyzed oxidative cyclization

[reaction: see text]. We herein report the development of one-pot procedures for the conversion of allyl aryl ethers to 2-methylbenzofurans (via sequential Claisen rearrangement and oxidative cyclization) and for the conversion of aryl homoallyl ethers to chromenes (via direct oxidative cyclization). It is likely that both reactions proceed via a common Pd-catalyzed pathway involving olefin activation, nucleophilic attack, and beta-hydride elimination.     

Enantio- and diastereoselective total synthesis of EI-1941-1, -2, and -3, inhibitors of interleukin-1beta converting enzyme, and biological properties of their derivatives

[reaction: see text] The first asymmetric total synthesis of EI-1941-1, -2, and -3, inhibitors of the interleukin-1beta converting enzyme (ICE), has been accomplished, starting from a chiral epoxy iodoquinone 11, a key intermediate in our total synthesis of epoxyquinols A and B. Despite a failure to synthesize the inhibitors by our postulated biosynthetic route, we were able to diastereoselectively synthesize them via an intramolecular carboxypalladation with the key steps being a 6-endo cyclization mode followed by beta-hydride elimination. The investigation of the biological properties of EI-1941-1, -2, and -3 and their derivatives disclosed them to be potent and effective ICE inhibitors with less cytotoxicity than EI-1941-1 and -2 in a cultured cell system.     

Stereoselective total synthesis of ent-EI-1941-2 and Epi-ent-EI-1941-2

The first asymmetric total syntheses of ent-EI-1941-2 and epi-ent-EI-1941-2 have been accomplished, starting from a chiral epoxy iodoquinone 6, a key intermediate in our total syntheses of epoxyquinols A and B. A key step in the preparation of ent-EI-1941-2 is an intramolecular carboxypalladation via a 6-endo cyclization mode, followed by beta-hydride elimination, while carboxymercuration is a key step in the synthesis of epi-ent-EI-1941-2. [reaction: see text]     

Palladium-catalyzed cyclization of 1,omega-dienols: multiple ways to intramolecularly trap a carbocation

The tandem catalytic cyclization-rearrangement of 1,omega-dien-3-ols by palladium(II) produces different types of products, depending on the structure of starting material. The pinacol rearrangement, benzannulation, and oxy-Cope rearrangement are major pathways of transforming the putative sigma-alkylpalladium carbocation. Turnover of the cyclization is achieved by beta-hydride elimination and reoxidation of palladium with benzoquinone. The overall course of the reaction is very sensitive to small changes in the substrate structure.     

Transition state for beta-hydride elimination in alkyl groups on Pt(111)

The transition state for beta-hydride elimination in alkyl groups on the Pt(111) surface has been probed by studying the effects of fluorine substitution on the barriers to beta-hydride elimination, DeltaE++(betaH). Four different fluoroalkyl groups have been formed on the Pt(111) surface by dissociative adsorption of four fluoroalkyl iodides: RCH(2)CH(2)-I (R = CF(3), CF(3)CH(2), and CF(3)CF(2)) and (CF(3))(2)CHCH(2)-I. In the absence of preadsorbed hydrogen, fluoroalkyl groups on the Pt(111) surface dehydrogenate via beta-hydride elimination to form unsaturated fluorocarbons and deposit hydrogen atoms onto the surface. Those hydrogen atoms then hydrogenate the remaining fluoroalkyl groups to produce fluoroalkanes that desorb rapidly from the surface. The kinetics of hydrogenation and fluoroalkane desorption are rate limited by the beta-hydride elimination step and thus serve as measures of the kinetics of beta-hydride elimination. The field effects of the fluorinated substituents increase the barriers to beta-hydride elimination with a reaction constant of rho(F) = 19 +/- 2 kJ/mol. The interpretation of this effect is that the beta-carbon atom in the transition state is cationic, [RC(delta+...)H]++, with respect to the reactant. The field effect of the fluorinated substituent energetically destabilizes the electron deficient beta-carbon atom in the transition state. This is consistent with observations made on the Cu(111) surface; however, the substituent effect is significantly smaller on the Pt(111) surface. On the Pt(111) surface, the transition state for beta-hydride elimination is less polarized with respect to the initial state alkyl group than on the Cu(111) surface.     

Elucidating the significance of beta-hydride elimination and the dynamic role of acid/base chemistry in a palladium-catalyzed aerobic oxidation of alcohols

The mechanistic details of aerobic alcohol oxidation with catalytic Pd(IiPr)(OAc)(2)(H(2)O) (IiPr = 1,3-bis(2,6-diisopropylphenyl)imidazol-2-ylidene) are disclosed. Under optimal conditions, beta-hydride elimination is rate-limiting supported by kinetic studies including a high primary kinetic isotope effect (KIE) value of 5.5 +/- 0.1 and a Hammett rho value of -0.48 +/- 0.04. On the basis of these studies, a late transition state is proposed for beta-hydride elimination, which is further corroborated by theoretical calculations using density functional theory. Additive acetic acid modulates the rates of both the alcohol oxidation sequence and regeneration of the Pd catalyst. With no additive [HOAc], turnover-limiting reprotonation of intermediate palladium peroxo is kinetically competitive with beta-hydride elimination, allowing for reversible oxygenation and decomposition of Pd(0). With additive [HOAc] (>2 mol %), reprotonation of the palladium peroxo is fast and beta-hydride elimination is the single rate-controlling step. This proposal is supported by an apparent decomposition pathway modulated by [HOAc], a change in alcohol concentration dependence, a lack of [O(2)] dependence at high [HOAc], and significant changes in the KIE values at different HOAc concentrations.     

Palladium(II)-catalyzed asymmetric cyclization of (Z)-4'-acetoxy-2'-butenyl 2-alkynoates. Role of nitrogen-containing ligands in palladium(II)-mediated reactions.

Pd(OAc)(2) combined with nitrogen-containing ligands (e.g., 2,2'-bipyridine) catalyzed the cyclization of (Z)-4'-acetoxy-2'-butenyl 2-alkynoates (1) in acetic acid to afford the alpha-(Z)-acetoxyalkylidene-beta-vinyl-gamma-butyrolactones (2) with high efficiency and high stereoselectivity. The nitrogen-containing ligands, like halides, served to favor beta-heteroatom elimination over beta-hydride elimination in Pd(II)-mediated reactions. The generality of this ligand effect was probed in both stoichiometric and catalytic reactions. With these results in hand, the catalytic asymmetric protocol was achieved with high enantioselectivity (up to 92% ee) when pymox (pyridyl monooxazoline) or bisoxazoline was used. The absolute configuration of the products and the synthetic utility of this asymmetric transformation were established through the convenient synthesis of (3S)-(+)-A-factor.     

End-group-confined chain walking within a group 4 living polyolefin and well-defined cationic zirconium alkyl complexes for modeling this behavior

Living polymers derived from the polymerization of 1-butene using the cationic zirconium initiator, {Cp*ZrMe[N(Et)C(Me)-N(tBu)]}[B(C6F5)4] (Cp* = eta5-C5Me5) (1), have been shown to undergo end-group-confined chain walking that is competitive with direct beta-hydride elimination and chain release at -10 degrees C. The well-defined complexes, {Cp*Zr(iBu)[N(Et)C(Me)N(tBu)]}[B(C6F5)4] (2) and {Cp*Zr(2-ethylbutyl)[N(Et)C(Me)N(tBu)]}[B(C6F5)4] (3), were prepared, and each was found to possess a strong beta-hydrogen agostic interaction that is absent in the living polymer. The isotopically single- and double-labeled derivatives, {Cp*Zr(2-d-2-methylpropyl)[N(Et)C(Me)N(tBu)]}[B(C6F5)4] (2') and {Cp*Zr(1-13C-2-d-2-methylpropyl)[N(Et)C(Me)N(tBu)]}[B(C6F5)4] (2' '), were also prepared and found to undergo isotopic label scrambling at 0 degrees C. For 2' ', the observation that after scrambling each deuterium label is located on a 13C-labeled carbon atom is consistent with the Busico mechanism for chain-end epimerization rather than the Resconi mechanism. Decomposition of 3 yielded olefinic products also consistent with chain walking prior to beta-hydride elimination and chain release. Finally, the unexpected decrease in stability of the living polymer relative to that of the model complexes reveals the importance of subtle differences in steric and electronic factors in controlling beta-hydride elimination and chain release.     

Rh-catalyzed intermolecular cyclopropanation with alpha-alkyl-alpha-diazoesters: catalyst-dependent chemo- and diastereoselectivity

A Rh-catalyzed procedure for the cyclopropanation of alkenes with alpha-alkyl-alpha-diazoesters is described. With dirhodium tetraoctanoate, the predominant pathway is beta-hydride elimination. While a number of sterically demanding carboxylate ligands serve to avoid beta-hydride elimination, it was found that triphenylacetate (TPA) also imparts high diastereoselectivity.     

Palladium-catalyzed carbonylative cyclization of unsaturated aryl iodides and dienyl triflates,iodides, and bromides to indanones and 2-cyclopentenones

Indanones and 2-cyclopentenones have been successfully prepared in good to excellent yields by the palladium-catalyzed carbonylative cyclization of unsaturated aryl iodides and dienyl triflates, iodides, and bromides, respectively. The best results are obtained by employing 10 mol % of Pd(OAc)(2), 2 equiv of pyridine, 1 equiv of n-Bu(4)NCl, 1 atm of CO, a reaction temperature of 100 degrees C, and DMF as the solvent. This carbonylative cyclization is particularly effective on substrates that contain a terminal olefin. The proposed mechanism for this annulation includes (1) Pd(OAc)(2) reduction to the active palladium(0) catalyst, (2) oxidative addition of the organic halide or triflate to Pd(0), (3) coordination and insertion of carbon monoxide to produce an acylpalladium intermediate, (4) acylpalladation of the neighboring carbon-carbon double bond, (5) reversible palladium beta-hydride elimination and re-addition to form a palladium enolate, and (6) protonation by H(2)O to produce the indanone or 2-cyclopentenone.     

Mechanism of the aerobic oxidation of alcohols by palladium complexes of N-heterocyclic carbenes

Quantum mechanics (B3LYP density functional theory) combined with solvation (Poisson-Boltzmann polarizable continuum solvent model) was used to investigate six mechanisms for the aerobic oxidation of alcohols catalyzed by (NHC)Pd(carboxylate)(2)(H(2)O) complexes (NHC = 1,3-bis(2,6-diisopropylphenyl)imidazol-2-ylidene). Of these, we find that "reductive beta-hydride elimination", in which the beta-hydrogen of a palladium-bound alkoxide is transferred directly to the free oxygen of the bound carboxylate, provides the lowest-energy route and explains the published kinetic isotope effect, activation enthalpy, reaction orders, and dependence of rate on carboxylate pK(a). The traditional beta-hydride elimination mechanism cannot be responsible for the experimentally observed kinetic parameters, which we find could result from the subsequent reductive elimination of acetic acid, which yields a slightly higher calculated activation barrier. Reversible beta-hydride elimination may provide a mechanism for the racemization of chiral alcohols, which would undermine attempts at an enantioselective oxidation. Competition among these pathways can be influenced by changing the electronic properties of the carboxylate and substrate.     

Ruthenium catalyzed addition reaction of carboxylic acid across olefins without beta-hydride elimination

The cationic ruthenium catalyst (Cp*RuCl2)2/AgOTf/Ligand promotes the addition reaction of carboxylic acids across olefins without beta-hydride elimination.     

Cobalt-catalyzed regioselective dehydrohalogenation of alkyl halides with dimethylphenylsilylmethylmagnesium chloride

Cobalt-catalyzed reactions of haloalkanes with dimethylphenylsilylmethylmagnesium chloride result in highly regioselective dehydrohalogenation. The reaction does not follow the conventional E2 elimination mechanism but includes beta-hydride elimination from the corresponding alkylcobalt intermediate. The interesting reaction mechanism of the cobalt-catalyzed dehydrohalogenation offered unique transformations that are otherwise difficult to attain.     

Diastereoselective yang photocyclization reactions in solution. synthesis of enantiopure azetidin-3-ol derivatives

[reaction: see text] Chiral 2-acyl-3-allyl- or 2-acyl-3-benzyl-substituted perhydro-1,3-benzoxazines readily cyclized under irradiation to azetidin-3-ol derivatives. The diastereoselectivity of the cyclization is dependent on the nature of the substituents at the nitrogen atom. N-allyl-substituted derivatives yielded only two of the four possible diastereomers in moderate to good diastereomeric excess. The cyclization of N-benzyl derivatives was totally diastereoselective leading to a single diastereomer. The elimination of the menthol appendage lead to enantiopure 2,3-disubstituted azetidin-3-ol derivatives.     

Investigations of the scope and mechanism of the tandem hydroesterification/lactonization reaction

Heating allylic and homoallylic alcohols and 2-pyridylmethyl formate in the presence of Ru(3)(CO)(12) initiates a tandem sequence of hydroesterification and lactonization. Mechanistic studies suggest that regioselectivity and overall reaction efficiency are governed by the relative rates of reductive elimination and beta-hydride elimination for the alkylruthenium intermediates.     

Stereoselective synthesis of polysubstituted 2,5-dihydrofurans from reaction of 1,4-dilithio-1,3-dienes with aldehydes

[reaction: see text] Reaction of 1,4-dilithio-1,3-diene derivatives with 2 equiv of aldehydes affords polysubstituted 2,5-dihydrofurans in good to high yields with perfect regio- and stereoselectivities. Hexa-2,4-diene-1,6-dialcoholates are proposed as the first intermediates, which undergo a cyclization and subsequent elimination of Li(2)O to generate the 2,5-dihydrofuran derivatives.     

Cross-coupling of sp(3) C-H bonds and alkenes: catalytic cyclization of alkene-amide substrates

We herein present a new oxidative cyclization of alkene-amide substrates under neutral and catalytic conditions. This overall transformation requires tandem sp3 C-H activation (at the position adjacent to the amide nitrogen) and C-C bond formation. Specifically, pyrrolidine 1 was converted to pyrrolizidinone 3 and indolizidinone 4 in 66% and 17% yield, respectively, in the presence of [Ir(coe)2Cl]2, the carbene ligand IPr (1:1 metal/ligand ratio, 5-10 mol % of Ir), and the hydrogen acceptor (NBE or TBE, 3-10 equiv). The results presented in this study suggest that complex 10 [IPr-Ir(Cl)(substrate)] is the key intermediate in the catalytic cycle. On the mechanistic front, the key advance was the ability to facilitate C-H activation and alkene insertion in tandem, and in preference to beta-hydride elimination, in the context of amide substrates. With respect to complex synthesis, catalytic and neutral conditions of this method unlock new exciting opportunities as illustrated by regioselective cyclization of the proline-derived substrate 16.     

Switching of alcohol oxidation mechanism on nickel surfaces by fluorine substitution

A partial switch in mechanism for the partial oxidation of alcohols on nickel surfaces can be induced by substitution of gamma-hydrogens with more electronegative fluorine atoms. While exclusive dehydrogenation to acetone via beta-hydride elimination from 2-propoxide surface species is seen with 2-propanol, some dehydration to 3,3,3-trfluoropropene is observed with 1,1,1-trifluoro-2-propanol. The latter reaction involves a gamma-hydride elimination rate-limiting step.     

Using mechanistic and computational studies to explain ligand effects in the palladium-catalyzed aerobic oxidation of alcohols

The experimental and computational mechanistic details of the Pd(OAc)(2)/TEA-catalyzed aerobic alcohol oxidation system are disclosed. Measurement of various kinetic isotope effects and the activation parameters as well as rate law derivation support rate-limiting deprotonation of the palladium-coordinated alcohol. Rate-limiting deprotonation of the alcohol is contrary to the majority of related kinetic studies for Pd-catalyzed aerobic oxidation of alcohols, which propose rate-limiting beta-hydride elimination. This difference in the rate-limiting step is supported by the computational model, which predicts the activation energy for deprotonation is 3 kcal/mol higher than the activation energy for beta-hydride elimination. The computational features of the similar Pd(OAc)(2)/pyridine system were also elucidated. Details of the study illustrate that the use of TEA results in an active catalyst that has only one ligand bound to the Pd, resulting in a significant lowering of the activation energy for beta-hydride elimination and, therefore, a catalyst that is active at room temperature.