- The inner-sphere process in the enantioselective Tsuji allylation reaction with (S)-t-Bu-phosphinooxazoline liqands
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We propose an inner-sphere mechanism explaining the unique performance of the Tsuji asymmetrical allylation reaction using hard prochiral enolate nucleophiles and non-prochiral allyl groups. Using first principles quantum mechanics (B3LYP density function
- Keith, John A.,Behenna, Douglas C.,Mohr, Justin T.,Ma, Sandy,Marinescu, Smaranda C.,Oxgaard, Jonas,Stoltz, Brian M.,Goddard III, William A.
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Read Online
- The Enantioselective Intermolecular Saegusa Allylation
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A simple procedure for the intermolecular enantioselective palladium-catalyzed decarboxylative allylation of β-ketoacids is described. This method, inspired by a stoichiometric control experiment performed by Saegusa and co-workers some 40+ years ago, makes use of allyl carbonates as the coupling substrates and enables direct access to α-allylated ketones bearing newly formed quaternary stereocenters. Experiments suggest that the transformation proceeds via an inner-sphere mechanism and not the traditional outer-sphere process proposed. The reaction should be highly useful and its application is demonstrated by a short enantioselective synthesis of (+)-adalinine.
- Liu, Ji,Laguna, Edward M.,Kizhakkayil Mangadan, Arun Raj,Kang, Kyoungmin,Aponick, Aaron
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p. 14842 - 14847
(2021/12/09)
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- Asymmetric Catalysis with CO2: The Direct α-Allylation of Ketones
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Quaternary stereocenters are found in numerous bioactive molecules. The Tsuji-Trost reaction has proven to be a powerful C-C bond forming process, and, at least in principle, should be well suited to access quaternary stereocenters via the α-allylation of ketones. However, while indirect approaches are known, the direct, catalytic asymmetric α-allylation of branched ketones has been elusive until today. By combining "enol catalysis" with the use of CO2 as a formal catalyst for asymmetric catalysis, we have now developed a solution to this problem: we report a direct, highly enantioselective and highly atom-economic Tsuji-Trost allylation of branched ketones with allylic alcohol. Our reaction delivers products bearing quaternary stereocenters with high enantioselectivity and water as the sole by-product. We expect our methodology to be of utility in asymmetric catalysis and inspire the design of other highly atom-economic transformations.
- Pupo, Gabriele,Properzi, Roberta,List, Benjamin
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supporting information
p. 6099 - 6102
(2016/05/19)
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- ASYMMETRIC CATALYTIC DECARBOXYLATIVE ALKYL ALKYLATION USING LOW CATALYST CONCENTRATIONS AND A ROBUST PRECATALYST
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This invention provides efficient and scalable enantioselective methods that yield 2-alkyl-2-allylcycloalkyanone compounds with quaternary stereogenic centers. Methods include the method for the preparation of a compound of formula (I): comprising treatin
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Paragraph 0150-0151
(2016/10/17)
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- An Efficient Protocol for the Palladium-Catalyzed Asymmetric Decarboxylative Allylic Alkylation Using Low Palladium Concentrations and a Palladium(II) Precatalyst
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Enantioselective catalytic allylic alkylation for the synthesis of 2-alkyl-2-allylcycloalkanones and 3,3-disubstituted pyrrolidinones, piperidinones and piperazinones has been previously reported by our laboratory. The efficient construction of chiral all
- Marziale, Alexander N.,Duquette, Douglas C.,Craig, Robert A.,Kim, Kelly E.,Liniger, Marc,Numajiri, Yoshitaka,Stoltz, Brian M.
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supporting information
p. 2238 - 2245
(2015/07/27)
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- Development of (trimethylsilyl)ethyl ester protected enolates and applications in palladium-catalyzed enantioselective allylic alkylation: Intermolecular cross-coupling of functionalized electrophiles
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The development of (trimethylsilyl)ethyl ester protected enolates is reported. The application of this class of compounds in palladium-catalyzed asymmetric allylic alkylation is explored, yielding a variety of α-quaternary six- and seven-membered ketones and lactams. Independent coupling partner synthesis engenders enhanced allyl substrate scope relative to traditional β-ketoester substrates; highly functionalized α-quaternary ketones generated by the union of (trimethylsilyl)ethyl β-ketoesters and sensitive allylic alkylation coupling partners serve to demonstrate the utility of this method for complex fragment coupling.
- Reeves, Corey M.,Behenna, Douglas C.,Stoltz, Brian M.
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p. 2314 - 2317
(2014/05/20)
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- Formal total syntheses of classic natural product target molecules via palladium-catalyzed enantioselective alkylation
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Pd-catalyzed enantioselective alkylation in conjunction with further synthetic elaboration enables the formal total syntheses of a number of "classic" natural product target molecules. This publication highlights recent methods for setting quaternary and tetrasubstituted tertiary carbon stereocenters to address the synthetic hurdles encountered over many decades across multiple compound classes spanning carbohydrate derivatives, terpenes, and alkaloids. These enantioselective methods will impact both academic and industrial settings, where the synthesis of stereogenic quaternary carbons is a continuing challenge.
- Liu, Yiyang,Liniger, Marc,McFadden, Ryan M.,Roizen, Jenny L.,Malette, Jacquie,Reeves, Corey M.,Behenna, Douglas C.,Seto, Masaki,Kim, Jimin,Mohr, Justin T.,Virgil, Scott C.,Stoltz, Brian M.
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p. 2501 - 2512
(2015/02/19)
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- Enantioselective decarboxylative alkylation reactions: Catalyst development, substrate scope, and mechanistic studies
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α-Quaternary ketones are accessed through novel enantioselective alkylations of allyl and propargyl electrophiles by unstabilized prochiral enolate nucleophiles in the presence of palladium complexes with various phosphinooxazoline (PHOX) ligands. Excellent yields and high enantiomeric excesses are obtained from three classes of enolate precursor: enol carbonates, enol silanes, and racemic β-ketoesters. Each of these substrate classes functions with nearly identical efficiency in terms of yield and enantioselectivity. Catalyst discovery and development, the optimization of reaction conditions, the exploration of reaction scope, and applications in target-directed synthesis are reported. Experimental observations suggest that these alkylation reactions occur through an unusual inner-sphere mechanism involving binding of the prochiral enolate nucleophile directly to the palladium center. Sly as a PHOX: The development of an enantioselective decarboxylative palladium-catalyzed allylic alkylation reaction, utilizing phosphinooxazoline ligands, is described. The catalyst is applied to a range of allyl enol carbonate, silyl enol ether, and allyl β-ketoester substrates to provide alkylated ketone products in excellent yield and good ee (see scheme). The utility of these products is demonstrated by their use in several asymmetric syntheses. Mechanistic studies are reported suggesting an unusual inner-sphere mechanism. Copyright
- Behenna, Douglas C.,Mohr, Justin T.,Sherden, Nathaniel H.,Marinescu, Smaranda C.,Harned, Andrew M.,Tani, Kousuke,Seto, Masaki,Ma, Sandy,Novak, Zoltan,Krout, Michael R.,McFadden, Ryan M.,Roizen, Jennifer L.,Enquist Jr., John A.,White, David E.,Levine, Samantha R.,Petrova, Krastina V.,Iwashita, Akihiko,Virgil, Scott C.,Stoltz, Brian M.
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p. 14199 - 14223
(2012/02/01)
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- Palladium-catalyzed decarboxylative asymmetric allylic alkylation of enol carbonates
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Palladium-catalyzed decarboxylative asymmetric allylic alkylation (DAAA) of allyl enol carbonates as a highly chemo-, regio-, and enantioselective process for the synthesis of ketones bearing either a quaternary or a tertiary R-stereogenic center has been investigated in detail. Chiral ligand L4 was found to be optimal in the DAAA of a broad scope of cyclic and acyclic ketones including simple aliphatic ketones with more than one enolizable proton. The allyl moiety of the carbonates has been extended to a variety of cyclic or acyclic disubstituted allyl groups. Our mechanistic studies reveal that, similar to the direct allylation of lithium enolates, the DAAA reaction proceeds through an "outer sphere" S N2 type of attack on the π-allylpalladium complex by the enolate. An important difference between the DAAA reaction and the direct allylation of lithium enolates is that in the DAAA reaction, the nucleophile and the electrophile were generated simultaneously. Since the π-allylpalladium cation must serve as the counterion for the enolate, the enolate probably exists as a tight-ion-pair. This largely prevents the common side reactions of enolates associated with the equilibrium between different enolates. The much milder reaction conditions as well as the much broader substrate scope also represent the advantages of the DAAA reaction over the direct allylation of preformed metal enolates.
- Trost, Barry M.,Xu, Jiayi,Schmidt, Thomas
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supporting information; experimental part
p. 18343 - 18357
(2010/04/25)
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- A facile and modular synthesis of phosphinooxazoline ligands
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The copper(I) iodide catalyzed phosphine/aryl halide coupling procedure of Buchwald et al. provides modular, robust, and scaleable access to phosphinooxazoline (PHOX) ligands. The advantages of this method are highlighted by the convenient synthesis of PH
- Tani, Kousuke,Behenna, Douglas C.,McFadden, Ryan M.,Stoltz, Brian M.
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p. 2529 - 2531
(2008/02/05)
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- Enantioselective, catalytic allylation of ketones and olefins
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Compounds containing a substituted or unsubstituted allyl group directly bound to a chiral carbon atom are prepared enantioselectively. Starting reactants are either chiral or achiral, and may or may not contain an attached allyloxycarbonyl group as a sub
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Page/Page column 17
(2008/06/13)
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- Deracemization of quaternary stereocenters by Pd-catalyzed enantioconvergent decarboxylative allylation of racemic β-ketoesters
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(Chemical Equation Presented) Stereochemical alchemy! Racemic allyl β-ketoesters allow the regiocontrolled formation of enolates, where the same catalyst is intimately involved in both the stereoablative (C-C bond-breaking) and stereoselective (C-C bond-f
- Mohr, Justin T.,Behenna, Douglas C.,Harned, Andrew M.,Stoltz, Brian M.
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p. 6924 - 6927
(2007/10/03)
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- Regio- and enantioselective Pd-catalyzed allylic alkylation of ketones through allyl enol carbonates
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The Pd-catalyzed reorganization of enol allyl carbonates to allylated ketones occurs asymmetrically in the presence of chiral ligands previously developed in this group. With 2-methylcyclohexanone, asymmetric regioselective alkylation occurs at the more s
- Trost, Barry M.,Xu, Jiayi
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p. 2846 - 2847
(2007/10/03)
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- The enantioselective Tsuji allylation
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The first catalytic enantioselective examples of the Tsuji allylation using enol carbonates and enol silanes are described. The products possess a quaternary stereogenic center and are useful building blocks for synthetic chemistry. Copyright
- Behenna, Douglas C.,Stoltz, Brian M.
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p. 15044 - 15045
(2007/10/03)
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