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ABSTRACT: A new cycloadduct: The title reaction of methylene-trimethylenemethane (TMM) with α,β-unsaturated N-acyl pyrroles is an efficient method for the construction of vinylidenecyclopentanes. A asymmetric protocol using this unique donor forms cycloadducts in excellent yield and enantioselectivity, making use of a bisdiamidophosphite ligand derived from trans-1,2-stilbenediamine.
Angewandte Chemie International Edition 04/2013; · 13.45 Impact Factor
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ABSTRACT: The mechanism, solvent effects, and origins of selectivities in Ru(II)-catalyzed intramolecular (5+2) cycloaddition and ene reaction of vinylcyclopropanes (VCPs) and alkynes have been studied using density functional theory. B3LYP/6-31G(d)/LANL2DZ optimized structures were further evaluated with the M06 functional, 6-311+G(2d,p) and LANL2DZ basis sets, and the SMD solvent model. The favored mechanism involves an initial ene-yne oxidative cyclization to form a ruthenacyclopentene intermediate. This mechanism is different from that found earlier with rhodium catalysts. The subsequent β-hydride elimination and cyclopropane cleavage are competitive, determining the experimental selectivity. In trans-VCP, the cyclopropane cleavage is intrinsically favored and leads to the (5+2) cycloaddition product. Although the same intrinsic preferences occur with the cis-VCP, an unfavorable rotation is required in order to generate the cis-double bond in seven-membered ring product, which reverses the selectivity. Acetone solvent is found to facilitate the acetonitrile dissociation from the precatalyst, destabilizing the resting state of the catalyst and leading to a lower overall reaction barrier. In addition, the origins of diastereoselectivities when the allylic hydroxyl group is trans to the bridgehead hydrogen are found to be the electrostatic interactions. In the pathway that generates the favored diastereomer, the oxygen lone pairs from the substituent are closer to the cationic catalyst center and provide stabilizing electrostatic interactions. Similar pathways also determine the regioselectivities, that is, whether the more or less substituted C-C bond of cyclopropane is cleaved. In the trans-1,2-disubstitued cyclopropane substrate, the substituent from the cyclopropane is away from the reaction center in both pathways, and low regioselectivity is found. In contrast, the cleavage of the more substituted C-C bond of the cis-1,2-disubstituted cyclopropane has steric repulsions from the substituent, and thus higher regioselectivity is found.
Journal of the American Chemical Society 04/2013; · 9.91 Impact Factor
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ABSTRACT: O rings: An approach to the title compounds has been developed utilizing a cycloaddition of trimethylenemethane with aryl ketones. The products are formed in up to a 96 % yield with 95 % ee. The reaction is catalyzed by palladium in the presence of L1, which possesses a stereogenic phosphorus atom, and only a single epimer at the phosphorus atom yields the active catalyst. Cp=cyclopentadiene, TMS=trimethylsilyl.
Angewandte Chemie International Edition 03/2013; · 13.45 Impact Factor
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ABSTRACT: Triple A: The catalytic asymmetric allylic alkylation (AAA) of 3-aryloxindoles with allylidene dipivalate is described. This reaction affords stable, synthetically useful enol pivalates in high yield and with excellent regio- and enantioselectivity. A broad range of substrates is tolerated, including unprotected and 3-heteroaryl nucleophiles.
Angewandte Chemie International Edition 01/2013; · 13.45 Impact Factor
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ABSTRACT: The development of a highly stereospecific process for the C-O to C-N exchange with retention of configuration is described. This transformation enables access to optically enriched β-amido-α-diazoesters. These products are transformed to β-amino acids not readily accessible using known methods.
Organic Letters 01/2013; · 5.86 Impact Factor
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ABSTRACT: A new ligand class: The title reaction was made possible by the discovery of a new class of phosphoramidite ligands. A variety of sterically and electronically diverse allylarenes undergo reaction with 2-acetyl-1-tetralones to form quaternary carbon stereocenters. This is a conceptually and mechanistically distinct strategy from traditional methods for the synthesis of enantioenriched allylic substitution products. 2,6-DMBQ=2,6-dimethylbenzoquinone.
Angewandte Chemie International Edition 12/2012; · 13.45 Impact Factor
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ABSTRACT: The first total synthesis of aeruginosin 98B (1) was accomplished. The key step includes a highly diastereoselective Pd-catalyzed intramolecular asymmetric allylic alkylation (AAA) reaction of a diastereomeric mixture of allylic carbonates, which is enabled by the use of racemic phosphine ligand L1.
Journal of the American Chemical Society 11/2012; · 9.91 Impact Factor
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ABSTRACT: The development of a general and practical zinc-catalyzed enantioselective alkyne addition methodology is reported. The commercially available ProPhenol ligand (1) has facilitated the addition of a wide range of zinc alkynylides to aryl, aliphatic, and α,β-unsaturated aldehydes in high yield and enantioselectivity. New insights into the mechanism of this reaction have resulted in a significant reduction in reagent stoichiometry, enabling the use of precious alkynes and avoiding the use of excess dimethylzinc. The enantioenriched propargylic alcohols from this reaction serve as versatile synthetic intermediates and have enabled efficient syntheses of several complex natural products.
Chemistry 10/2012; · 5.93 Impact Factor
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ABSTRACT: Here it goes again: A tandem catalytic process that effects sequential Pd(0) -catalyzed allylic alkylations through leaving group ionization and Pd(II) -catalyzed allylic alkylations by CH activation is reported. By employing an oxidative trigger to convert the catalytic species from Pd(0) to Pd(II) , both transformations can be conducted in a single reaction vessel using the same precatalyst. This allows for the selective introduction of otherwise indistinguishable allyl groups.
Angewandte Chemie International Edition 10/2012; · 13.45 Impact Factor
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ABSTRACT: We describe a palladium-catalyzed diastereo- and enantioselective formal [3 + 2]-cycloaddition between substituted vinylcyclopropanes and electron-deficient olefins in the form of azlactone- and Meldrum's acid alkylidenes to give highly substituted cyclopentane products. By modulation of the electronic properties of the vinylcyclopropane and the electron-deficient olefin, high levels of stereoselectivity were obtained. The remote stereoinduction afforded by the catalyst, distal from the chiral pocket generated by the ligand, is proposed to be the result of a new mechanism invoking the Curtin-Hammett principle.
Journal of the American Chemical Society 10/2012; 134(42):17823-31. · 9.91 Impact Factor
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ABSTRACT: This protocol describes a new approach for the preparation of α-allylated α,β-unsaturated carbonyl compound by chemoselective cross-coupling of propargyl alcohols with allyl carbonates using an unprecedented vanadium/palladium contemporaneous dual catalysis. This process involves 1,3-transposition of propargyl alcohols by an oxyvanadium catalyst to generate vanadium allenoates and the activation of allyl carbonates by a palladium catalyst to generate π-allylpalladium species. These two active intermediates trap each other more rapidly to afford the observed product, rather than being intercepted by the large excess of starting propargyl alcohol. One example for the preparation of this type of α-allylated α,β-unsaturated carbonyl compound is included in the text. It takes ~20 h to complete the protocol: 1.0 h to set up the reaction, 16 h for the reaction and 2.0 h for isolation and purification. This chemistry has been applied to obtain a wide range of α-allylated α,β-unsaturated ketones, esters and amides, which are highly valuable building blocks in organic synthesis.
Nature Protocol 08/2012; 7(8):1497-501. · 8.36 Impact Factor
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ABSTRACT: Aiming high: The title reaction for the synthesis of tertiary α-hydroxyketones is reported. Protected 1,2-enediol carbonates, the starting materials, were accessed from simple and readily available enol carbonates. Highly functionalized tertiary α-hydroxyketones can be obtained in high yield with excellent enantioselectivity using this method.
Angewandte Chemie International Edition 07/2012; 51(33):8290-3. · 13.45 Impact Factor
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ABSTRACT: Pyrroles can serve as competent nucleophiles with meso electrophiles in the Pd-catalyzed asymmetric allylic alkylation. The products from this transformation were obtained as a single regio- and diastereomer in high yield and enantiopurity. A nitropyrrole-containing nucleoside analogue was synthesized in seven steps to demonstrate the synthetic utility of this transformation.
Organic Letters 04/2012; 14(9):2254-7. · 5.86 Impact Factor
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ABSTRACT: Activated: the title reaction proceeds with a broad range of nucleophiles and variously substituted 1,4-dienes under mild conditions, and provides direct access to the corresponding 1,3-diene-containing products with high regio- and stereocontrol (see scheme; 2,6-DMBQ=2,6-dimethylbenzoquinone, EWG=electron-withdrawing group). This is the first catalytic allylic C-H alkylation that proceeds in the absence of sulfoxide ligands.
Angewandte Chemie International Edition 04/2012; 51(20):4950-3. · 13.45 Impact Factor
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ABSTRACT: Palladium-catalyzed asymmetric benzylation has been demonstrated with azlactones as prochiral nucleophiles in the presence of chiral bisphosphine ligands. Benzylic electrophiles are utilized under two sets of reaction conditions to construct a new tetrasubstituted stereocenter. Electron density of the phenyl ring dictates the reaction conditions, including the leaving group. The reported methodology represents a novel asymmetric carbon-carbon bond formation in an amino acid precursor.
Journal of the American Chemical Society 03/2012; 134(13):5778-81. · 9.91 Impact Factor
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ABSTRACT: An atom-economical procedure for the direct synthesis of cycloalkanes from propargyl alcohols is reported. This high-yielding one-pot process involves a sequence consisting of a Ru-catalyzed redox isomerization of ynols into enones or an enal followed by an intramolecular Michael addition of a variety of carbon nucleophiles. Furthermore, an asymmetric variant of this protocol realized by the aid of a chiral nonracemic diamine catalyst, which provides the cyclization products in up to 97% ee, is presented.
Organic Letters 03/2012; 14(7):1708-11. · 5.86 Impact Factor
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ABSTRACT: The first stage in the development of a synthetic route for the total synthesis of laulimalide (1) is described. Our retrosynthetic analysis envisioned a novel macrocyclization route to the natural product by using a Ru-catalyzed alkene-alkyne coupling. This would be preceded by an esterification of the C19 hydroxyl group, joining together two equally sized synthons, the northern fragment 7 and the southern fragment 8. Our first generation approach to the northern fragment entailed a key sequential Ru/Pd coupling sequence to assemble the dihydropyran. The key reactions proceeded smoothly, but the inability to achieve a key olefin migration led to the development of an alternative route based on an asymmetric dinuclear Zn-catalyzed aldol reaction of a hydroxyl acylpyrrole. This key reaction led to the desired diol adduct 66 with excellent syn/anti selectivity (10:1), and allowed for the successful completion of the northern fragment 7. The key step for the synthesis of the southern fragment was a chemoselective Rh-catalyzed cycloisomerization reaction to form the dihydropyran ring from a diyne precursor. This reaction proved to be selective for the formation of a six-membered ring, over a seven. The use of an electron-deficient bidentate phosphine allowed for the reaction to proceed with a reduced catalyst loading.
Chemistry 03/2012; 18(10):2948-60. · 5.93 Impact Factor
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ABSTRACT: Herein, we present a full account of our efforts to couple the northern and the southern building blocks, the synthesis of which were described in the preceding paper, along with the modifications required to ultimately lead to a successful synthesis of laulimalide. Key highlights include an exceptionally efficient and atom-economical intramolecular ruthenium-catalyzed alkene-alkyne coupling to build the macrocycle, followed by a highly stereoselective 1,3-allylic isomerization promoted by a rhenium complex. Interestingly, the designed synthetic route also allowed us to prepare an analogue of the natural product that possesses significant cytotoxic activity. We also report a second generation route that provides a more concise synthesis of the natural product.
Chemistry 03/2012; 18(10):2961-71. · 5.93 Impact Factor
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ABSTRACT: A protocol for the enantioselective [3 + 2] cycloaddition of trimethylenemethane (TMM) with imines has been developed. Central to this effort were the novel phosphoramidite ligands developed in our laboratories. The conditions developed to effect an asymmetric TMM reaction using 2-trimethylsilylmethyl allyl acetate were shown to be tolerant of a wide variety of imine acceptors to provide the corresponding pyrrolidine cycloadducts with excellent yields and selectivities. Use of a bis-2-naphthyl phosphoramidite allowed the successful cycloaddition of the parent TMM with N-Boc imines, and has further permitted the reaction of substituted donors with N-tosyl aldimines and ketimines in high regio-, diastereo-, and enantioselectivity. Use of a diphenylazetidine ligand allows the complementary synthesis of the exocyclic nitrile product shown, and we demonstrate control of the regioselectivity of the product based on manipulation of the reaction parameters.
Journal of the American Chemical Society 03/2012; 134(10):4941-54. · 9.91 Impact Factor
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ABSTRACT: The first synthesis of the biologically active humulene natural product asteriscunolide D has been accomplished in nine steps without the use of protecting groups. The challenging 11-membered ring was forged via a diastereoselective thionium ion initiated cyclization, which constitutes a formal aldol disconnection to form a strained macrocycle. A stereospecific thioether activation-elimination protocol was developed for selective E-olefin formation, thus providing access to the most biologically active asteriscunolide. The absolute stereochemical configuration was established by the Zn-ProPhenol catalyzed enantioselective addition of methyl propiolate to an aliphatic aldehyde to afford a γ-hydroxy propiolate as a handle for butenolide formation via Ru-catalyzed alkene-alkyne coupling.
Journal of the American Chemical Society 01/2012; 134(3):1474-7. · 9.91 Impact Factor
