Palladium-catalyzed Cycloadditions of Substituted Trimethylenemethane Complexes and Application to the Synthesis of 11-hydroxyjasionone and 7-EPI-11-hydroxyjasionone PDF Download
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Author: Jonathan Robert Parquette
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ISBN:
Category :
Languages : en
Pages : 672
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Author: Jonathan Robert Parquette
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ISBN:
Category :
Languages : en
Pages : 672
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Author: Steven Mark Silverman
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Category :
Languages : en
Pages :
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The development of new methods for chemical synthesis is motivated by the desire to add efficient chemo-, regio-, diastereo-, and enantioselective reactions to the repository of transformations available to researchers. In addition to reaction development, a primary goal of methodology research is to fundamentally understand chemical reactivity. This understanding provides the impetus for further discovery, inevitably allowing for the rapid synthesis of complex molecules as well as the development of industrially feasible processes. The research described herein discusses method development and seeks to place it within this context. Cycloaddition reactions have been widely used in organic synthesis since initial accounts of the Diels-Alder reaction were reported over 80 years ago. These reactions can proceed by either stepwise or concerted processes, can be thermally or photochemically initiated, metal catalyzed or non-metal catalyzed, but one unifying feature of this reaction class is the ability to quickly assemble a complex molecular architecture. A method for the synthesis of cyclopentane rings was disclosed by the Trost group in 1979 through the controlled generation of trimethylenemethane (TMM), a three-carbon dipole capable of participating in a palladium-catalyzed stepwise cycloaddition. Over the ensuing 20 years, this procedure was expanded to other five-membered rings, including pyrrolidines and tetrahydrofurans. It was generalized to include [4+3] and [6+3] cycloadditions in addition to the initial [3+2] reaction. However, only minimal advances were made in the establishment of a catalytic, asymmetric variant of the reaction, which would have enormous value in that chiral variants of the above molecules could be prepared. A protocol for the enantioselective TMM reaction was developed and is described herein. The synthesis of novel phosphoramidite ligands was critical in this effort, and the preparation and reactivity of these ligands is detailed. The evolution of the ligand design, commencing with acyclic amine-derived phosphoramidites and leading to cyclic azetidine and pyrrolidine structures is discussed. The initial conditions used to effect an asymmetric TMM reaction using 2-trimethylsilylmethyl allyl acetate were shown to be tolerant of a wide variety of alkene acceptors, providing the desired cyclopentanes with high levels of enantioselectivity. The donor scope was also explored and various substituted systems were tolerated, including one bearing a nitrile moiety and a one bearing a propiolate function. These were reactive with unsaturated acylpyrroles, giving the product cyclopentane rings bearing three stereocenters in high enantioselectivity and complete diastereoselectivity. The nitrile donor was reactive with methyleneoxindoles, providing products containing up to three adjacent stereocenters, two being all-carbon quaternary. Furthermore, ligand controlled diastereoselection was seen. The methodology was further applied to the synthesis of heterocycles. The parent donor successfully reacted with N-aryl and N-Boc imines. A nitrile donor was found to react with a series of N-Tosyl imines, giving the pyrrolidines in high yield. Multiple regioisomers were formed and reaction conditions were developed to favor each product. In the case of N-Tosyl ketimines, the desired cycloadducts containing tetrasubstituted centers were prepared with nearly complete enantio- and diastereoselectivity. The protecting group could be removed to afford a synthetically versatile compound with several handles for further elaboration. Conditions were also developed to perform an enantioselective TMM reaction with aldehydes, giving the desired tetrahydrofurans in moderate to good enantioselectivity. Finally, an asymmetric [4+3] cycloaddition utilizing ortho-quinone methides was successfully performed in an effort to prepare oxepanes. Taken collectively, these results demonstrate that the palladium-phosphoramidite catalyst system represents a versatile method for the rapid assembly of complex molecular architectures from simple starting materials via cycloaddition.
Author:
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Category : Dissertation abstracts
Languages : en
Pages : 800
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Author: Dustin Anthony Bringley
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Category :
Languages : en
Pages :
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Cycloadditions are among the most powerful reactions in organic chemistry due to their ability to rapidly build molecular complexity from simple, readily available precursors. In 1979, the Trost group described a novel method for the synthesis of cyclopentane rings by the in situ generation and subsequent [3+2] dipolar cycloaddition of palladium-bound trimethylenemethane (TMM). The method has proven to be a powerful approach for the synthesis of five-membered rings, including tetrahydrofurans and pyrrolidines, as well as larger rings sizes via [4+3] and [6+3] cycloaddition. In 2006, the Trost group demonstrated for the first time a general asymmetric protocol by employing phosphoramidites bearing cyclic amines as the chiral ligands. Using these ligands, highly enantioselective cycloadditions with electron-deficient olefins and imines were described. Herein, we describe the successful extension of the asymmetric methodology to include reactions with carbonyl groups and nitroalkenes, allowing for the synthesis of tetrahydrofurans and nitrocyclopentanes, respectively, with good to excellent enantioselectivity. For reactions with carbonyl groups, the development of novel C1-symmetric phosphoramidites was critical, and the optimized ligand was derived from a BINOL bearing a fused furan. The evolution of the ligand design will be discussed, beginning with the initial discovery that phosphoramidites with mono-substituted BINOL derivatives gave improved selectivity. In addition, since these phosphoramidites are chiral at phosphorus, the impact of this chirality on the TMM reaction is explored. The use of the optimized ligand allowed for reactions with both aromatic aldehydes and ketones. In addition, the asymmetric conditions did not require a Lewis acid co-catalyst, in contrast to the achiral ligands that had been previously investigated. For reactions with nitroalkenes, both [beta]-substituted and [beta], [beta]-disubstituted nitroalkenes could be employed as acceptors, where the use of the latter allowed for the synthesis of nitrocyclopentanes bearing a quaternary stereocenter. The nitrocyclopentane products were demonstrated to be versatile synthetic precursors, capable of undergoing further alkylation with excellent diastereoselectivity or converted to cyclopentylamines and cyclopentenones with little to no racemization. In one example, the asymmetric cycloaddition constitutes a formal synthesis of (+)-cephalotaxine. Finally, substituted TMM donors were explored and the use of a cyano donor was found to proceed with nearly perfect levels of selectivity and yield. Finally, the asymmetric TMM cycloaddition using a cyano-substituted donor was applied to the synthesis of ( - )-marcfortine C. Notably, the reaction proceeds in nearly quantitative yield with high diastereo- and enantioselectivity, and the resulting chiral center was used to establish all remaining stereocenters in the natural product. Additional highlights include a direct allylic oxidation of the exocyclic olefin, a diastereoselective intramolecular Michael addition, and an oxidative radical cyclization. Using this route, ( - )-marcfortine C was prepared in 16 steps and 2.4% overall yield.
Author:
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ISBN:
Category : Dissertations, Academic
Languages : en
Pages : 638
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Author: Stanford University
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Category :
Languages : en
Pages : 476
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Author: Ronald Michael Painter
Publisher: Stanford University
ISBN:
Category :
Languages : en
Pages : 110
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The chemoselective oxidation of vicinal diols to α-hydroxyketones is a challenge in organic syntheses because not only does the diol need to be oxidized selectively to a monocarbonyl compound, but diols are also prone to overoxidation and oxidative cleavage. Employing a cationic palladium complex, [(neocuproine)Pd(OAc)]2(OTf)2, we were able to demonstrate the selective oxidation of glycerol to dihydroxyacetone mediated by either benzoquinone or O2 as the terminal oxidant, an accomplishment that has little precedent in homogeneous catalysis. Mechanistic studies were undertaken to uncover the nature of this remarkable chemoselectivity. Kinetic and deuterium-labeling studies implicate reversible β-hydride elimination from isomeric Pd alkoxides and turnover-limiting displacement of the dihydroxyacetone product by benzoquinone. We successfully extended this methodology to other terminal 1,2-diols and symmetric vicinal 1,2-diols and have carried out aerobic oxidation of these substrates catalyzed by 1. Examination of the reactivity of 1 with conformationally-restricted 1,2-cyclohexanediols suggests that the diol must chelate to the Pd center for effective oxidation to the hydroxyketone product. In a separate project, we have also investigated the electrocatalytic reduction of dioxygen by several dinuclear copper complexes, an important reaction for fuel cell applications.
Author: Angela Lynn Marquart
Publisher:
ISBN:
Category :
Languages : en
Pages : 128
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![Palladium-catalyzed Asymmetric Formal [3+2]-cycloadditions with Donor-acceptor Cyclopropanes PDF](https://books.google.com/books/content/images/frontcover/jpmOAQAACAAJ?fife=w80-h100)
Author: Patrick Joseph Morris
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Languages : en
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Abstract: The development of new methods for the synthesis of densely-functionalized enantioenriched five-membered hetero- and carbocycles is of importance in organic chemistry. Such functionalized five-membered ring are one of the motifs found in a wide array of biological targets. One atom- and step-economical method for the synthesis of these these five-membered ring systems is via a formal [3+2]-cycloaddition between a 1,3-dipole and a dipolarophile. Vicinally-substituted donor-acceptor cyclopropanes contain an electron-withdrawing group at the 1-position and an electron-donating group at the 2-position. This allows for their heterolytic cleavage to form a 1,3-dipoles under appropriate reaction conditions. Typically, Lewis acid-catalysis has been utilized to affect formal [3+2]-cycloadditions with donor-acceptor cyclopropanes. However, the use of palladium-catalysis to affect formal [3+2]-cycloadditions with donor-acceptor cyclopropanes has been relatively unexplored, and prior to this work had never been examined in an asymmetric fashion. The asymmetric allylic alkylation ligands developed by Trost and coworkers have been extensively used over the last 15 years in a variety of enantioselective reactions. However, the ability of these ligands to induce enantioselectivity in a bond-forming event two-bonds away from the [pi]-allyl-palladium center had never been demonstrated. The development of an asymmetric formal [3+2]-cycloaddition with donor-acceptor cyclopropanes and Meldrum's acid alkylidenes demonstrated the ability of this class of ligands to direct stereochemistry quite far away from the [pi]-allyl-palladium complex. A range of substituted cyclopentane derivatives were synthesized in this manner. An analysis of the relative stability of the donor-acceptor cyclopropanes in conjunction with the the palladium-ligand complex led to the development of a new class of donor-acceptor cyclopropane, the bis(2,2,2-trifluoroethyl)malonate-substituted vinyl cyclopropane. This new class of donor-acceptor cyclopropane was then utilized successfully in a formal [3+2]-cycloaddition with a variety of dipolarophiles, including the nitroolefins, isocyanates, and N-tosylimines. The azlactone alkylidenes, which represent protected amino acids, were further explored as dipolarophiles for this reaction, and a range of spirocyclic products were synthesized in high yield, enantiomeric excess and diastereomeric excess. Notably, three contiguous stereocenters were set in this reaction. In addition to this project, two approaches towards the synthesis of biyouyanagin A were explored. The initial approach, involving a proposed 11-endo-dig cyclization of an alcohol onto an alkyne ultimately proved to be unsuccessful. A secondary approach involved the use of a palladium-catalyzed dynamic kinetic asymmetric reaction between a hydroxyfuran and isoprene monoepoxide. Use of this strategy successfully synthesized hyperolactone C, which represented a formal synthesis of biyouyanagin A.
Author: Ei-ichi Negishi
Publisher: John Wiley & Sons
ISBN: 0471473812
Category : Science
Languages : en
Pages : 1657
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Organized to provide maximum utility to the bench synthetic chemist. The editor is well-known for his work in exploring, developing, and applying organopalladium chemistry. Contributors include over 24 world authorities in the field.
