Person: Jacobsen, Eric
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Jacobsen
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Eric
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Jacobsen, Eric
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Publication Macrocyclic bis-thioureas catalyze stereospecific glycosylation reactions(American Association for the Advancement of Science (AAAS), 2017-01-12) Park, Yongho; Harper, Kaid; Kuhl, Nadine; Kwan, Eugene; Liu, Richard; Jacobsen, EricCarbohydrates are involved in nearly all aspects of biochemistry, but their complex chemical structures present long-standing practical challenges to their synthesis. In particular, stereochemical outcomes in glycosylation reactions are highly dependent on the steric and electronic properties of coupling partners; thus, carbohydrate synthesis is not easily predictable. Here we report the discovery of a macrocyclic bis-thiourea derivative that catalyzes stereospecific invertive substitution pathways of glycosyl chlorides. The utility of the catalyst is demonstrated in the synthesis of trans-1,2-, cis-1,2-, and 2-deoxy-β-glycosides. Mechanistic studies are consistent with a cooperative mechanism in which an electrophile and a nucleophile are simultaneously activated to effect a stereospecific substitution reaction.Publication Thiourea-Catalyzed Enantioselective Addition of Indoles to Pyrones: Alkaloid Cores with Quaternary Carbons(American Chemical Society, 2014) Yeung, Charles S.; Ziegler, Robert E.; Porco, John A.; Jacobsen, EricWe report the development of a catalytic method for the enantioselective addition of indoles to pyrone-derived electrophiles. Arylpyrrolidino-derived thioureas catalyze the addition with high stereoselectivity in the presence of catalytic quantities of an achiral Brønsted acid. The indole–pyrone adducts feature a quaternary stereocenter and represent an unusual class of indolines bearing structural resemblance to the hybrid natural product pleiocarpamine.Publication Asymmetric Mannich Synthesis of α-Amino Esters by Anion-Binding Catalysis(American Chemical Society, 2014) Wasa, Masayuki; Liu, Richard Y.; Roche, Stéphane P.; Jacobsen, EricWe report a scalable, one-pot Mannich route to enantioenriched α-amino esters by direct reaction of α-chloroglycine ester as a practical imino ester surrogate. The reaction is promoted by a chiral aminothiourea, which is proposed to operate cooperatively by generating an iminium ion by chloride abstraction and an enolate by deprotonation, followed by highly stereoselective C–C bond formation between both reactive intermediates associated non-covalently within the catalyst framework.Publication Synergistic Ion-Binding Catalysis Demonstrated via an Enantioselective, Catalytic [2,3]-Wittig Rearrangement(American Chemical Society, 2016) Kennedy, C. Rose; Guidera, Jennifer A.; Jacobsen, EricSigmatropic rearrangements number among the most powerful complexity-building transformations in organic synthesis but have remained largely insensitive to enantioselective catalysis due to the diffuse nature of their transition structures. Here, we describe a synergistic ion-binding strategy for asymmetric catalysis of anionic sigmatropic rearrangements. This approach is demonstrated with the enantioselective [2,3]-Wittig rearrangement of α-allyloxy carbonyl compounds to afford highly enantioenriched homoallylic alcohol products. Chiral thiourea catalysts are shown to engage reactive anions and their countercations through a cooperative set of attractive, noncovalent interactions. Catalyst structure–reactivity–selectivity relationship studies and computational analyses provide insight into catalyst–substrate interactions responsible for enantioinduction and allude to the potential generality of this catalytic strategy.Publication Quaternary stereocentres via an enantioconvergent catalytic SN1 reaction(Springer Science and Business Media LLC, 2018-04) Wendlandt, Alison E.; Vangal, Prithvi; Jacobsen, EricPublication Concerted nucleophilic aromatic substitutions(Springer Science and Business Media LLC, 2018-07-16) Kwan, Eugene; Zeng, Yuwen; Besser, Harrison; Jacobsen, EricPublication Thiourea-catalysed ring opening of episulfonium ions with indole derivatives by means of stabilizing non-covalent interactions(Nature Publishing Group, 2012) Lin, Song; Jacobsen, EricSmall organic and metal-containing molecules (molecular mass <1,000) can catalyse synthetically useful reactions with the high levels of stereoselectivity typically associated with macromolecular enzymatic catalysts. Whereas enzymes are generally understood to accelerate reactions and impart selectivity as they stabilize specific transition structures through networks of cooperative interactions, enantioselectivity with chiral, small-molecule catalysts is rationalized typically by the steric destabilization of all but one dominant pathway. However, it is increasingly apparent that stabilizing effects also play an important role in small-molecule catalysis, although the mechanistic characterization of such systems is rare. Here, we show that arylpyrrolidino amido thiourea catalysts catalyse the enantioselective nucleophilic ring opening of episulfonium ions by indoles. Evidence is provided for the selective transition-state stabilization of the major pathway by the thiourea catalyst in the rate- and selectivity-determining step. Enantioselectivity is achieved through a network of attractive anion binding, cation-π and hydrogen-bond interactions between the catalyst and the reacting components in the transition-structure assembly.Publication Application of a Catalytic Asymmetric Povarov Reaction using Chiral Ureas to the Synthesis of a Tetrahydroquinoline Library(American Chemical Society, 2012) Gerard, Baudouin; O’Shea, Morgan Welzel; Donckele, Etienne; Kesavan, Sarathy; Akella, Lakshmi B.; Xu, Hao; Jacobsen, Eric; Marcaurelle, Lisa A.A 2328-membered library of 2,3,4-trisubstituted tetrahydroquinolines was produced using a combination of solution- and solid-phase synthesis techniques. A tetrahydroquinoline (THQ) scaffold was prepared via an asymmetric Povarov reaction using cooperative catalysis to generate three contiguous stereogenic centers. A matrix of 4 stereoisomers of the THQ scaffold was prepared to enable the development of stereo/structure-activity relationships (SSAR) upon biological testing. A sparse matrix design strategy was employed to select library members to be synthesized with the goal of generating a diverse collection of tetrahydroquinolines with physicochemical properties suitable for downstream discovery.Publication Asymmetric Ion-Pairing Catalysis(Wiley Blackwell (John Wiley & Sons), 2013) Brak, Katrien; Jacobsen, EricPublication Mechanistic Basis for High Reactivity of (salen)Co–OTs in the Hydrolytic Kinetic Resolution of Terminal Epoxides(American Chemical Society, 2012) Nielsen, Lars P. C.; Zuend, Stephan J.; Ford, David Dearborn; Jacobsen, EricThe (salen)Co(III)-catalyzed hydrolytic kinetic resolution (HKR) of terminal epoxides is a bimetallic process with a rate controlled by partitioning between a nucleophilic (salen)Co–OH catalyst and a Lewis acidic (salen)Co–X catalyst. The commonly used (salen)Co–OAc and (salen)Co–Cl precatalysts undergo complete and irreversible counterion addition to epoxide during the course of the epoxide hydrolysis reaction, resulting in quantitative formation of weakly Lewis acidic (salen)Co–OH, and severely diminished reaction rates in the late stages of HKR reactions. In contrast, (salen)Co–OTs maintains high reactivity over the entire course of HKR reactions. We describe here an investigation of catalyst partitioning with different (salen)Co–X precatalysts, and demonstrate that counterion addition to epoxide is reversible in the case of the (salen)Co–OTs. This reversible counterion addition results in stable partitioning between nucleophilic and Lewis acidic catalyst species, allowing highly efficient catalysis throughout the course of the HKR reaction.
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