Browsing by Subject "Transfer hydrogenation"
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Item Carbon-carbon bond formation via catalytic hydrogenation and transfer hydrogenation : application in the total synthesis of bryostatin 7(2012-08) Lu, Yu, active 2012; Krische, Michael J.Under the conditions of transfer hydrogenation employing ortho-cyclometallated iridium C,O-benzoate catalysts, two protocols of iterative chain elongation of 1,3-diols to furnish 1,3-polyols were developed. First, one-directional chain elongation employing mono-protected 1,3-diols as starting materials was achieved. In all cases, high levels of catalyst-directed enantioselectivity and diastereoselectivity were observed. Then, double asymmetric allylation of 1,n-glycols to deliver C₂-symmetric adducts with exceptional level of enantioselectivity was devised. Iterative two-directional elongation of 1,3-diols to furnish 1,3-polyols with high level of catalyst-directed diastereoselectivity was then achieved. Implementation of this methodology and other hydrogenative C-C bond formations proved to be effective means for the preparation of a known bryostatin A-ring fragment and the total synthesis of bryostatin 7.Item Carbon-carbon bond formation via transition metal-catalyzed transfer hydrogenative carbonyl addition(2022-11-28) Spinello, Brian Joseph; Krische, Michael J.; Liu, Hung-Wen; Hull, Kami; Whitman, Christian PCarbonyl addition persists as one of the most broadly utilized methods for the construction of carbon-carbon bonds. However, classical methods for carbonyl addition require preformed organometallic reagents, which are often highly basic, moisture sensitive, and hazardous. To circumvent these issues, novel synthetic methods have been developed for the construction of carbon-carbon bonds via metal-catalyzed transfer hydrogenative carbonyl reductive coupling, which avoid the use of stoichiometric organometallic reagents. Three methods for ketone formation are described that involve rhodium-catalyzed carbonyl reductive coupling to deliver allylic or homoallylic alcohols, which undergo immediate redox-isomerization to generate saturated ketones products. Additionally, the use of a novel iodide-bound ruthenium-JOSIPHOS catalyst system catalyzes anti-diastereo- and enantioselective carbonyl crotylations of primary alcohols mediated by methylallene and butadiene. Finally, π-allyliridium C,O-benzoate complexes catalyze enantioselective electrophilic allylation of α,α-disubstituted nitronates providing entry to β-stereogenic α-quaternary primary amines after zinc-mediated nitroalkane reduction.Item Development of neutral redox carbon-carbon bond forming reactions via transition metal-catalyzed transfer hydrogenation(2018-01-24) Nguyen, Khoa Dang, Ph. D.; Krische, Michael J.; Que, Emily; Humphrey, Simon; Keatinge-Clay, Adrian T; Liu, Hung-WenSince C–C bonds form the backbone of every organic molecule and reside at the heart of chemical science, the development of new efficient methods for promoting C–C bond formation is of great significance. Inspired and expanded from traditional Grignard reactions, the work presented in this dissertation focuses on metal catalyzed neutral redox-triggered carbonyl addition via transfer hydrogenation. Advancing the native reducing capability of alcohols, employment of catalytic transition metals enables the formation of nucleophile-electrophile pairs in situ, en route to the products of formal alcohol C–H functionalization. These redox-triggered reactions circumvent the stoichiometric metallated byproduct waste and streamline the construction of complex molecules from simple and/or readily available feedstocks. The research reported herein discloses new developed methodologies of ruthenium and iridium catalyzed coupling reactions of primary and secondary alcohols with various pi-unsaturates. These studies contribute to the growing body of redox-triggered alcohol C–C couplings – new carbonyl addition chemistry that extends beyond the use of premetalated reagents.Item Development of transition metal catalyzed carbon-carbon bond forming reactions with abundant or scarce chemicals(2017-08) Luong, Tom Tuan; Krische, Michael J.; Martin, Stephen F; Anslyn, Eric V; Liu, Hung-WenThe development of more efficient carbon-carbon bond transformation is of great significance. One of the more common approaches to forging carbon-carbon bonds is the addition of carbon- based nucleophiles to carbonyl compounds, exploiting classical electrophile-nucleophile pairing. In an effort to minimize nucleophile pre-activation and organometallic byproducts, my research in the Krische group focuses on the development of efficient methods for the in-situ formation of alkyl-metal nucleophiles from π- unsaturated compounds via transition metal catalysis. With the use of Ruthenium or Osmium we can use readily abundant a-olefins such as ethylene gas and couple it with various secondary alcohols via transfer hydrogenative C-C coupling in a proposed oxidative coupling pathway.Item Enantioselective iridium-catalyzed carbon–carbon and carbon–nitrogen bond formations(2020-08-07) Schwartz, Leyah Ashley; Krische, Michael J.; Hull, Kami; Rose, Michael; Whitman, Christian PFormation of new C–C bonds is a mainstay of modern molecule construction, however methods for the asymmetric construction of these scaffolds has been limited by the use of premetalated reagents or the use of catalytic methods that still require the use of stoichiometric metallic reductants. The Krische group’s approach to this bond formation utilizes the concepts of transfer hydrogen and carbonyl addition to form C–C bonds. These processes proceed through the in situ formation of a transient allylmetal species which then undergoes carbonyl addition. The research presented herein describes the development of several methods for the enantioselective construction of new C–C bonds, utilizing allenes to form nucleophilic allylmetal complexes that react with carbonyl electrophiles. Additionally, a method for the enantioselective construction of new C–N bonds is described, utilizing branched allylic acetates to form allylmetal complexes that react in an electrophilic manner with non-redox active primary and secondary amine nucleophiles.Item Iridium-catalyzed C-C bond formation : development of crotylation and methallylation reactions through transfer hydrogenation(2012-05) Townsend, Ian A.; Krische, Michael J.; Anslyn, Eric V.Under the conditions of transfer hydrogenation utilizing chromatographically purified ortho-cyclometallated iridium C,O-benzoate precatalysts, enantioselective carbonyl crotylation and methallylation can be performed in the absence of stoichiometric metallic reagents and stoichiometric chiral modifiers. In the case of carbonyl crotylation, use of a preformed precatalyst rather than an in situ generated catalyst results in lower reaction temperatures, providing generally higher diastereoselectivity and yields. By utilizing a more reactive leaving group in chloride over acetate on our methallyl donor, the inherently shorter lifetime of the olefin π-complex is compensated for, giving our group’s first report of reactivity utilizing 1,1-disubstituted allyl donors.Item Total synthesis of the acetyl CoA carboxylase allosteric inhibitor soraphen A and the development of new catalytic methods using palladium, iridium and rhodium(2022-07-14) Schempp, Tabitha Taylor; Krische, Michael J.; Hull, Kami L; Keatinge-Clay, Adrian T; Whitman, Christian PMetal catalysis with palladium, iridium, and rhodium has provided a lexicon of synthetic transformations extensively utilized in the construction of complex molecules. The total synthesis of soraphen A, a type 1 polyketide allosteric inhibitor of Acetyl-CoA carboxylase, was completed in 11 steps (LLS), less than half the previously required steps. The synthesis maximizes convergency by exploiting the catalytic reactivity of transition metals to facilitate five asymmetric processes and four carbon-carbon bond formations. A key strategic element involves the development of a new synthetic method: a palladium-AntPhos catalyst directed diastereoselective hydrogenolysis of allylic carbonates to reveal a terminal olefin for successive olefin cross-metathesis. The development of palladium-catalyzed hydrogenolysis of allylic compounds, current asymmetric methods, and their application in the total synthesis of complex natural products will be described. In addition, an iridium-catalyzed enantioselective allylation of indoles and various azoles to access products with complete N- and branched-regioselectivity and a rhodium-catalyzed reductive coupling-internal redox isomerization of vinyl triflates and aldehydes to furnish ketones were developed.Item Transition metal catalyzed redox triggered C–C bond forming reactions of alcohols via transfer hydrogenation(2016-05) Park, Boyoung; Krische, Michael J.; Willson, Grant; Dong, Guangbin; Liu, Hung-Wen; Humphrey, SimonCarbonyl addition is one of the fundamental reactions forming C–C bonds in organic chemistry to construct structurally complex organic molecules, in particular natural products, from small molecules. For this useful carbonyl addition, transition metal catalyzed redox-triggered C–C bond forming reactions of alcohols have been developed via transfer hydrogenation. Combined redox events are more efficient in terms of step- and atom-economy by delivering nucleophile-electrophile pairs in situ from π-unsaturates and alcohols, respectively. Furthermore, transition metal catalyzed redox-triggered C–C couplings bypass the need of stoichiometric (organo)metallic reagents. This dissertation shows the development of new methodologies for this goal including prenylation, vinylation, alkylation and allylation using various ruthenium, osmium and iridium catalysts.Item Transition metal catalyzed reductive couplings under hydrogenative and transfer hydrogenative conditions(2010-08) Williams, Vanessa Monet; Krische, Michael J.; Martin, Stephen F.; Magnus, Philip D.; Laude, David A.; Liu, Hung-WenEnvironmental concerns have birthed an awareness of how we conduct ourselves as citizens of this planet. To reduce environmental impact, we have learned that we must be responsible stewards in all ranges of life: from buying locally grown food to how scientific research and industrial processes are executed. In the realm of chemical research, "green chemistry" has initiated the development of new, sustainable methods that make use of atom economy, step economy, and utilize renewable materials to minimize waste and production of toxic by-products. The formation of carbon-carbon bonds lies at the very heart of organic synthesis, and traditional methods for forming such bonds generally require the use of at least one stoichiometrically preformed organometallic reagent. This corresponds to at least one equivalent of metallic waste byproduct. The in situ formation of alkyl metal nucleophiles for carbonyl additions via hydrogenation of [pi]-unsaturates represents an alternative to use of preformed organometallic reagents. Comprising nearly 90% of the atoms in the universe, hydrogen is vastly abundant and very cheap. The Krische group seeks to contribute new technologies which make use of catalytic hydrogenation and transfer hydrogenation in the reductive coupling of basic chemical feedstocks.Item Transition metal-catalyzed carbon-carbon bond formation utilizing transfer hydrogenation(2015-05) Montgomery, Timothy Patrick; Krische, Michael J.; Anslyn, Eric V; Dong, Guangbon; Brodbelt, Jennifer S; Liu, Hung-wenA central tenant of organic synthesis is the construction of carbon-carbon bonds. One of the traditional methods for carrying out such transformations is that of carbonyl addition. Unfortunately, traditional carbonyl addition chemistry suffers various drawbacks: preactivation, moisture sensitivity, and the generation of stoichiometric organometallic waste. The research presented in this dissertation focuses on the development of methods that make use of nucleophile-electrophile pairs generated in situ via transfer hydrogenation, which allow the formation of carbonyl or imine addition products from the alcohol or amine oxidation level; streamlining the construction of complex molecules from simple, readily available starting materials. Additionally, studies toward the total synthesis of the fibrinogen receptor inhibitor tetrafibricin, utilizing the methods developed in catalytic carbon-carbon bond formation through the addition, transfer or removal of hydrogen, are presented.Item Transition metal-catalyzed redox-triggered C-C couplings of alcohols via transfer hydrogenation(2018-01-26) Xiao, Hongde, M.A.; Krische, Michael J.In the first chapter, the first example of transfer hydrogenative cross-couplings of styrene with primary alcohols is reported. Using RuHCl(CO)(PCy₃)₂ as the precatalyst, AgOTf or HBF₄ as additives, branched or linear adducts with styrene would be generated from benzylic or aliphatic alcohols respectively. In the second chapter, a strategy for asymmetric construction of cyclopropanes is developed. In the presence of phosphine ligand, the nickel(0) catalyst react with enantiomerically enriched 3-aryl-4-vinyl-1,3-dioxanones to form (cyclopropylcarbinyl)nickel(II) species, which then couples with organoboron reagents to generate the cyclopropane in a stereospecific way. In this way, the enantioselective synthesis of tetra-substituted cyclopropanes bearing all-carbon quaternary stereocenters is achieved.Item Transition metal-catalyzed reductive C-C bond forming hydrogenation/transfer hydrogenation and applications in the total synthesis of (+)-roxaticin(2010-12) Han, Soo Bong, 1975-; Krische, Michael J.; Magnus, Philip D.; Cowley, Alan H.; Kerwin, Sean M.; Siegel, Dionicio R.By simply hydrogenating enones in the presence of aldehydes at ambient temperature and pressure, aldol adducts are generated under neutral conditions in the absence of any stoichiometric byproducts. Using cationic rhodium complexes modified by tri(2-furyl)phosphine, highly syn-diastereoselective reductive aldol additions of vinyl ketones are achieved. Finally, using novel monodentate TADDOL-like phosphonite ligands, the first highly diastereo- and enantioselective reductive aldol couplings of vinyl ketones were devised. These studies, along with other works from our laboratory, demonstrate that organometallics arising transiently in the course of catalytic hydrogenation offer byproduct-free alternatives to preformed organometallic reagents employed in classical carbonyl addition processes. Existing methods for enantioselective carbonyl allylation, crotylation and tert-prenylation require stoichiometric generation of pre-metallated nucleophiles, and often employ stoichiometric chiral modifiers. Under the conditions of transfer hydrogenation employing an ortho-cyclometallated iridium C,O-benzoate catalyst, enantioselective carbonyl allylations, crotylations and tert-prenylations are achieved in the absence of stoichiometric metallic reagents or stoichiometric chiral modifiers. Moreover, under transfer hydrogenation conditions, primary alcohols function dually as hydrogen donors and aldehyde precursors, enabling enantioselective carbonyl addition directly from the alcohol oxidation level.Item Transition-metal-catalyzed C-C bonds formation via transfer hydrogenation : from methodology development to (+)-SCH 351448 synthesis(2017-08) Wang, Gang, Ph. D.; Krische, Michael J.; Martin, Stephen F.; Anslyn, Eric V.; Rose, Michael J.; Liu, Hung-WenRedox-triggered carbonyl addition via transfer hydrogenation, which enables direct primary alcohol C-H functionalization to form C-C bond, avoids usage of premetalated reagents or discrete alcohol to aldehyde redox reactions. Moreover, step-economy could be greatly improved by site-selective transformations of polyfunctional molecules due to bypassing the need to install and remove protecting groups. However, the redox site-selective transformations still pose a significant challenge in the area of synthetic organic chemistry. Efforts have been focused on the development of iridium catalyzed transfer hydrogenative coupling reactions of primary alcohols with different allyl donors through carbonyl addition in a site-selective manner as well as ruthenium catalyzed regioselective hydrohydroxyalkylation of primary alcohols with a basic feedstock-styrene. Additionally, studies towards the total synthesis of type I polyketide natural product (+)-SCH 351448 in the most concise route is presented.