2007 – 2002

Current – 2013 ⋅   2012 – 2008   ⋅   2007 – 2002

2007

A Diastereoselective Intermolecular Heck Reaction of 1,3-Dioxepins
Christopher G. Nasveschuk, Jeffrey D. Frein, Nathan T. Jui, Tomislav Rovis
ORGANIC LETTERS, 2007, 9, 5509-5512

A highly diastereoselective intermolecular Heck reaction of 1,3-dioxepins is reported. Substitution at both the 2- and 4-positions of the dioxepin directs the Pd coordination and subsequent olefin insertion to provide the trans-disubstituted adduct in good yield and high diastereoselectivity. Chemoselective Heck reaction occurs at the dioxepin alkene in the presence of other olefinic functional groups. A labeling study has been conducted which suggests that the reaction is under kinetic control.

Nucleophilic Carbene and HOAt Relay Catalysis in an Amide Bond Coupling:  An Orthogonal Peptide Bond Forming Reaction
Harit U. Vora, Tomislav Rovis
JOURNAL OF THE AMERICAN CHEMICAL SOCIETY, 2007, 129, 13796-13797

A catalyzed internal redox process provides a route from α-reducible aldehydes and amines to α-reduced amides. The chemistry is catalyzed by nucleophilic carbenes and common peptide cocatalysts such as HOBt and HOAt in a relay fashion. The transformation proceeds in excellent yields using a variety of primary and secondary alkyl and aryl amines. The aldehyde component may be varied from haloaldehydes to epoxy and aziridino aldehydes as well as enals. The latter three substrates provide for a waste-free amide bond forming reaction.

Rhodium-Catalyzed Enantioselective Desymmetrization of meso-3,5-Dimethyl Glutaric Anhydride:  A General Strategy to syn-Deoxypolypropionate Synthons
Matthew J. Cook, Tomislav Rovis
JOURNAL OF THE AMERICAN CHEMICAL SOCIETY, 2007, 129, 9302-9303

A rhodium phosphinooxazoline system allows for an efficient enantioselective desymmetrization of dimethyl glutaric anhydride. Both commercially available and in situ generated sp3-organozinc nucleophiles couple efficiently in high enantiomeric excess. This chemistry has also been extended to other 3,5-disubstituted anhydrides, and further elaboration has enabled the synthesis of potentially useful syn-deoxypolypropionate fragments.

Enantioselective Synthesis of Hydrobenzofuranones Using an Asymmetric Desymmetrizing Intramolecular Stetter Reaction of Cyclohexadienones
Qin Liu, Tomislav Rovis
ORGANIC PROCESS RESEARCH AND DEVELOPMENT, 2007, 11, 598-604

A series of cyclohexadienones were synthesized by dearomatization of phenols followed by Dess−Martin oxidation. Asymmetric intramolecular Stetter reactions of these substrates provide hydrobenzofuranones in good to excellent yields and excellent stereoselectivities. Up to three stereocenters as well as a quaternary stereocenter are formed from polysubstituted substrates. A scale-up experiment demonstrates the utility of this transformation.

Ligand-Dependent Catalytic Cycle and Role of Styrene in Nickel-Catalyzed Anhydride Cross-Coupling:  Evidence for Turnover-Limiting Reductive Elimination
Jeffrey B. Johnson, Eric A. Bercot, John M. Rowley, Geoffrey W. Coates, Tomislav Rovis
JOURNAL OF THE AMERICAN CHEMICAL SOCIETY, 2007, 129, 2718-2725

Results from a mechanistic study on the Ni(COD)2−bipy-catalyzed alkylation of anhydrides are consistent with turnover-limiting reductive elimination at high Et2Zn concentrations. While the presence of styrene does not affect the initial rate of alkylation, it appears to inhibit catalyst decomposition and provides higher product yield at long reaction times. In contrast, Ni(COD)2iPrPHOX-catalyzed anhydride alkylation proceeds through two competing catalytic cycles differentiated by the presence of styrene. The presence of styrene in this system appears to accelerate rate-limiting oxidative addition and promotes the cycle which proceeds 4 times more rapidly and with much higher enantioselectivity than its styrene-lacking counterpart.

A Concise Synthesis of Eupomatilones 4, 6, and 7 by Rhodium-Catalyzed Enantioselective Desymmetrization of Cyclic meso Anhydrides with Organozinc Reagents Generated In Situ
Jeffrey B. Johnson, Eric A. Bercot, Catherine M. Williams, Tomislav Rovis
ANGEWANDTE CHEMIE INTERNATIONAL EDITION, 2007, 46, 4514-4518

The development of a phosphoramidite-ligated rhodium catalyst allows the enantioselective desymmetrization of cyclic anhydrides with organozinc nucleophiles formed in situ. This methodology has been utilized for a concise synthesis of eupomatilones 4 and 7 and of the putative structure of eupomatilone 6, each of which is completed in four steps in greater than 50 % overall yield.

Alkene-Directed Regioselective Nickel-Catalyzed Cross-Coupling of Cyclic Anhydrides with Diorganozinc Reagents
Rebecca L. Rogers, Jennifer L. Moore, Tomislav Rovis
ANGEWANDTE CHEMIE INTERNATIONAL EDITION, 2007, 46, 9301-9304

A resident alkene directs a nickel-catalyzed cross-coupling of cyclic anhydrides with diorganozinc reagents. Relative directing effects parallel the stability of nickel–alkene complexes, with less-hindered terminal olefins dominating over internal olefins.

2006

A Sakurai−Prins−Ritter Sequence for the Three-Component Diastereoselective Synthesis of 4-Amino Tetrahydropyrans
Oleg L. Epstein, Tomislav Rovis
JOURNAL OF THE AMERICAN CHEMICAL SOCIETY, 2006, 128, 16480-16481

A simple one-pot procedure for the Sakurai−Prins−Ritter sequence allows rapid assembly of 4-acylamino-2,6-substituted tetrahydropyrans in high yields and with excellent diastereoselectivity from readily available 4-acetoxy-1,3-dioxanes, allylsilanes, and nitriles. A variety of nitriles have been shown to participate. Diastereoselectivities are uniformly high and observed stereochemistry of cation trapping proceeds according to Alder’s model of the 4-tetrahydropyranyl cation.

Enantioselective formation of quaternary stereocenters using the catalytic intramolecular Stetter reaction
Jennifer L. Moore, Mark S. Kerr, Tomislav Rovis
TETRAHEDRON, 2006, 62, 11477-11482

Asymmetric formation of quaternary stereocenters has been accomplished using the catalytic intramolecular Stetter reaction. A variety of tethered aldehydes and Michael acceptors are cyclized in excellent yields and enantioselectivities.

Enantioselective Rhodium-Catalyzed [2+2+2] Cycloaddition of Alkenyl Isocyanates and Terminal Alkynes:  Application to the Total Synthesis of (+)-Lasubine II
Robert T. Yu, Tomislav Rovis
JOURNAL OF THE AMERICAN CHEMICAL SOCIETY, 2006, 128, 12370-12371

The use of TADDOL-based phosphoramidite ligands on rhodium allows for the incorporation of terminal alkynes in the [2+2+2] cycloaddition with alkenyl isocyanates. Terminal aliphatic alkynes provide bicyclic lactams, while the use of aryl alkynes provides complementary access to vinylogous amides. Product selectivity seems to be governed by a combination of electronics and sterics, with smaller and/or more electron-deficient substituents favoring lactam formation. The use of homologous alkenyl isocyanates leads to an expedient asymmetric total synthesis of the alkaloid lasubine II.

Selective Substituent Transfer from Mixed Zinc Reagents in Ni-Catalyzed Anhydride Alkylation
Jeffrey B. Johnson, Robert T. Yu, Paul Fink, Eric A. Bercot, T. Rovis*
ORGANIC LETTERS, 2006, 8, 4307-4310

The use of mixed zinc reagents in Ni-catalyzed anhydride alkylation results in preferential transfer of substituents (Ph > Me > Et  iPr  TMSCH2) for the ligands bipy, dppe, andiPrPHOX. Utilization of such mixed species allows the use of 0.55 equiv of the diorganozinc reagent, effectively transferring both desired substituents when used in conjunction with a suitable second zinc reagent.

Surveying approaches to the formation of carbon–carbon bonds between a pyran and an adjacent ring
Jeffrey D. Frein, Tomislav Rovis
TETRAHEDRON, 2006, 62, 4573-4583

We have examined several methods for the stereoselective formation of carbon–carbon bonds between contiguous rings where a stereogenic center is already present. The approaches investigated were a [1,3] oxygen to carbon rearrangement of cyclic vinyl acetals, an intermolecular enolsilane addition into an in situ generated oxocarbenium ion, an intramolecular conjugate addition of tethered alkoxyenones, and epimerization of several a-pyranyl cycloalkanones. These routes have been found to be complementary in several cases and have enabled formation of both the trans:anti and cis:anti stereoisomers in good to excellent yields and varying diastereoselectivities. We have proven C2–C2 0relative stereochemistry of 1–2 via a chemical correlation.

Rhodium-Catalyzed [2 + 2 + 2] Cycloaddition of Alkenyl Isocyanates and Alkynes
Robert T. Yu, Tomislav Rovis
JOURNAL OF THE AMERICAN CHEMICAL SOCIETY, 2006, 128, 2782-2783

A rhodium(I)-catalyzed [2 + 2 + 2] cycloaddition between alkenyl isocyanates and alkynes has been developed. Heating a mixture of an alkenyl isocyanate and a symmetrical internal alkyne in the presence of [Rh(ethylene)2Cl]2/P(4-OMe-C6H4)3 in toluene delivers substituted indolizinones and quinolizinones. Depending on the substrates, a rare fragmentation of the isocyanate unit can be involved within the cycloaddition process to furnish a vinylogous amide embedded in the indolizinone.

Asymmetric Synthesis of Hydrobenzofuranones via Desymmetrization of Cyclohexadienones Using the Intramolecular Stetter Reaction
Qin Liu, Tomislav Rovis
JOURNAL OF THE AMERICAN CHEMICAL SOCIETY, 2006, 128, 2552-2553

Dearomatization of phenols followed by oxidation affords cyclohexadienyloxyacetaldehydes, which produce hydrobenzofuranones via asymmetric intramolecular Stetter reaction in good to excellent yield. Quaternary as well as up to three contiguous stereocenters may be formed in good to excellent enantioselectivities and high diastereoselectivities.

A modular approach to the synthesis of 2,3,4-trisubstituted tetrahydrofurans
Christopher G. Nasveschuk, Nathan T. Jui, Tomsilav Rovis
CHEMICAL COMMUNICATIONS, 2006, 3119-3121

A highly diastereoselective Lewis acid-mediated [1,3] rearrangement of 1,3-dioxepins is the key step along a modular route to 2,3,4-trisubstituted tetrahydrofurans.

2005

Enantioselective protonation of catalytically generated chiral enolates as an approach to the synthesis of alpha-chloroesters
Nathan T. Reynolds; Tomislav Rovis
JOURNAL OF THE AMERICAN CHEMICAL SOCIETY, 2005, 127, 16406-16407

Treatment of α,α-dichloroaldehydes with various phenols in the presence of chiral triazolium salt catalysts and excess base results in the synthesis of α-chloro aryl esters in good yield and enantioselectivity. The reaction is tolerant of various functionality on the aldehyde as well as several electronically diverse phenols. The product chloroesters were further transformed into chloroacid, chlorohydrin, and azidoesters with nearly complete retention of enantioselectivity.

An efficient synthesis of achiral and chiral 1,2,4-triazolium salts: Bench stable precursors for N-heterocyclic carbenes
Mark S. Kerr; Javier Reid de Alaniz; Tomislav Rovis
JOURNAL OF ORGANIC CHEMISTRY, 2005, 70, 5725-5728

The promising utility of triazolyl N-heterocyclic carbene catalysts in umpolung aldehyde chemistry requires a straightforward reliable synthesis from readily available materials. Herein, we describe the synthesis of a variety of triazolyl N-heterocyclic carbene precursors. The reactions commence from commercially available amino acids and proceed in 44-68% overall yields. The N-heterocyclic salts are air-stable crystalline solids that can be stored with no special precaution and can generate the active catalyst when treated with an appropriate base.

The effect of pre-existing stereocenters in the intramolecular asymmetric Stetter reaction
Nathan T. Reynolds; Tomislav Rovis
TETRAHEDRON, 2005, 61, 6368-6378

A series of disubstituted cyclopentanones have been synthesized by the intramolecular Stetter reaction. Racemic substrates containing one chiral center were used, allowing us the opportunity to observe a parallel kinetic resolution in the synthesis of 2,3- and 2,4disubstituted cyclopentanones. The Stetter reaction of 2,5-disubstituted cyclopentanones proved to be substrate controlled, resulting in the selective formation of the cis-diasteroiners with low ee.

Regioselective Lewis acid-mediated [1,3] rearrangement of allylvinyl ethers
Christopher G. Nasveschuk; Tomislav Rovis
ORGANIC LETTERS, 2005, 7, 2173-2176

Aluminum and copper Lewis acids were implemented to effect a regioselective [1,3] rearrangement of allylvinyl ethers in moderate to good yields. The use of trisubstituted alkenes leads to depressed levels of Claisen products.

A highly enantio- and diastereoselective catalytic intramolecular stetter reaction
Javier Reid de Alaniz; Tomislav Rovis
JOURNAL OF THE AMERICAN CHEMICAL SOCIETY, 2005, 127, 6284-6289

A highly enantio- and diastereoselective intramolecular Stetter reaction has been developed. Subjection of alpha,alpha-disubstituted Michael acceptors to an asymmetric intramolecular Stetter reaction results in a highly enantioselective conjugate addition and a diastereoselective proton transfer. Available evidence suggests the diastereoselective protonation occurs via intramolecular delivery to the sterically more hindered face of the enolate. The scope of the trisubstituted Michael acceptors has been examined and found to be broad with respect to the size of the alpha-substituent and nature of the Michael acceptor. Aliphatic and aromatic aldehydes were examined and found to afford the desired product in good overall yield with high enantio-and diastereoselectivity.

Highly efficient nickel-catalyzed cross-coupling of succinic and glutaric anhydrides with organozinc reagents
Eric A. Bercot; Tomislav Rovis
JOURNAL OF THE AMERICAN CHEMICAL SOCIETY, 2005, 127, 247-254

A nickel-catalyzed alkylation of succinic and glutaric anhydrides with alkyl- and arylzinc reagents has been developed. A dramatic olefin effect has been investigated resulting in the identification of several styrene-based promoters which show pronounced enhancements in reaction rate. The substrate scope with respect to electrophilic and nucleophilic coupling partners has been examined and found to be remarkably broad, allowing for rapid introduction of molecular complexity through the use of functionalized coupling partners. Regioselective alkylation of an unsymmetrical succinic anhydride and a profound effect of pendent coordinating olefins on reaction rate suggest a mechanism involving discrete oxidative addition of the nickel complex into the cyclic anhydride followed by a transmetalation event.

Complementary diastereoselective reduction of cyclic gamma-keto acids: Efficient access to trisubsituted gamma-lactones
Eric A. Bercot; David E. Kindrachuk; Tomislav Rovis
ORGANIC LETTERS, 2005, 7, 107-110

Complementary reduction conditions have been identified that provide ready access to each respective diastereomer of bi- and tricyclic, trisustituted gamma-lactones starting from the corresponding cyclic gamma-keto acids. Subjection of cyclic gamma-keto acids to silane reagents in the presence of trifluoroacetic acid provides all syn-gamma-lactones, while reduction with trialkylborohydrides furnishes the syn,anti-gamma-lactones. The conditions are mild and provide the product lactones in good yields and modest to excellent selectivity.

Stereoselective Lewis acid mediated [1,3] ring contraction of 2,5-dihydrooxepins as a route to polysubstituted cyclopentenes
Christopher G. Nasveschuk; Tomislav Rovis
ANGEWANDTE CHEMIE-INTERNATIONAL EDITION, 2005, 44, 3264-3266

A room-temperature diastereoselective [1,3] rearrangement results from treatment of 2,5-dihydrooxepins with EtAlCl2 (see scheme). A modular synthesis of dihydrooxepins allows substituents to be incorporated at any position on the ring, which means that various polysubstituted cyclopentenes can be prepared through this Lewis acid mediated [1,3] ring contraction.

2004

A unique catalyst effects the rapid room-temperature cross-coupling of organozinc reagents with carboxylic acid fluorides, chlorides, anhydrides, and thioesters
Yongda Zhang; Tomislav Rovis
JOURNAL OF THE AMERICAN CHEMICAL SOCIETY, 2004, 126, 15964-15965

We have identified a catalyst capable of effecting the rapid, room-temperature cross-coupling between acid fluorides and diorganozinc reagents. The use of acid fluorides as electrophilic partners allows this reaction to tolerate epimerizable functionality as well as β leaving groups. The same catalyst is also capable of cross-coupling acid chlorides, acyl cyanides, anhydrides, thioesters, and pyridyl esters. Noteworthy is the ability of the reaction to successfully transfer both groups from the organometalic fragment.

A palladium-catalyzed enantioselective alkylative desymmetrization of meso-succinic anhydrides
Eric A Bercot; Tomislav Rovis
JOURNAL OF THE AMERICAN CHEMICAL SOCIETY, 2004, 126, 10248-10249

Monoalkylation of cyclic anhydrides provides an opportunity to couple a carbon−carbon bond-forming event with the control of backbone stereochemistry. We have developed a palladium-JOSIPHOS catalyst system that desymmetrizes meso-succinic anhydrides using organozinc reagents as nucleophiles, and have found that, in many cases, this reaction proceeds at ambient temperature.

Conversion of alpha-haloaldehydes into acylating agents by an internal redox reaction catalyzed by nucleophilic carbenes
Nathan T. Reynolds; Javier Reid de Alaniz; Tomislav Rovis
JOURNAL OF THE AMERICAN CHEMICAL SOCIETY, 2004, 126, 9518-9519

A new electron-deficient chiral triazolium salt has been shown to catalyze the formation of quaternary stereocenters by an asymmetric intramolecular Stetter reaction. Pentafluorophenyl substitution on an aminoindanol-derived catalyst affords tertiary ether, thioether, and quaternary stereocenters in typically greater than 90% ee and very good chemical yield. Aromatic and aliphatic aldehydes are equally competent substrates for this reaction. The reaction proceeds at room temperature under mild conditions to provide quaternary stereocenters with functional group relationships that are particularly difficult to access by other methods.

Enantioselective synthesis of quaternary stereocenters via a catalytic asymmetric Stetter reaction
Mark S. Kerr; Tomislav Rovis
JOURNAL OF THE AMERICAN CHEMICAL SOCIETY, 2004, 126, 8876-8877

A new electron-deficient chiral triazolium salt has been shown to catalyze the formation of quaternary stereocenters by an asymmetric intramolecular Stetter reaction. Pentafluorophenyl substitution on an aminoindanol-derived catalyst affords tertiary ether, thioether, and quaternary stereocenters in typically greater than 90% ee and very good chemical yield. Aromatic and aliphatic aldehydes are equally competent substrates for this reaction. The reaction proceeds at room temperature under mild conditions to provide quaternary stereocenters with functional group relationships that are particularly difficult to access by other methods.

Use of acid fluorides increases the scope of the reductive acylation of esters
Yongda Zhang; Tomislav Rovis
ORGANIC LETTERS, 2004, 6, 1877-1879

The use of acyl fluorides in the Rychnovsky reductive acylation of esters allows a variety of esters to be converted to their corresponding alpha-acyloxy ethers in good to excellent yields, without the need to sacrifice an extra equiv of carboxylic acid functionality.

2003

1,3-polyol arrays via the stereoselective rearrangement of vinyl acetals
Yongda Zhang, Tomislav Rovis
TETRAHEDRON, 2003, 59, 8979-8987

A series of 1,3-dioxanyl vinyl acetals were readily synthesized from the corresponding dioxanone by a reduction and in situ acylation followed by Petasis olefination. Treatment of these vinyl acetals with BF3 . OEt2 results in an O to 5 rearrangement to form anti-3,5-dihydroxyketones while a mixture of Me3Al and BF3.OEt2 provides the corresponding syn relationship via a stereoretentive rearrangement.

Effect of the Michael acceptor in the asymmetric intramolecular Stetter reaction
Mark. S. Kerr; Tomislav Rovis
SYNLETT, 2003, 12, 1934-1936

The effect of different Michael acceptors was evaluated in the catalytic asymmetric intramolecular Stetter reaction. Utilizing a readily prepared chiral triazolium salt as a nucleophilic carbene precursor, the reactivity and selectivity of substrates containing different electron-deficient double bonds was shown to vary significantly under identical reaction conditions.

Decarbonylative cross-coupling of cyclic anhydrides: Introducing stereochemistry at an sp(3) carbon in the cross-coupling event
Erin M. O’Brien; Eric A. Bercot; Tomislav Rovis
JOURNAL OF THE AMERICAN CHEMICAL SOCIETY, 2003, 125, 10498-10499

Treatment of cyclic anhydrides with stoichiometric amounts of nickel−neocuproine complex generates alkylcarboxylato−nickelalactones upon extrusion of CO. These metalacycles undergo cross-coupling with arylzinc reagents. The generated CO is sequestered in situ by a nickel−dppb complex. The overall sequence effects a secondary sp3(electrophile)−sp2(nucleophile) cross-coupling and allows for control of stereochemistry during the bond-forming event.

2002

A highly enantioselective catalytic intramolecular Stetter reaction
Mark S. Kerr; Javier Reid de Alaniz; Tomislav Rovis
JOURNAL OF THE AMERICAN CHEMICAL SOCIETY, 2002, 124, 10298-10299

A family of chiral triazolium salts has been developed for inducing the asymmetric intramolecular Stetter reaction. The use of an aminoindanol-derived catalyst affords optimal results, with the product keto esters formed in 82−97% ee and very good chemical yield. Aromatic and aliphatic aldehydes are equally competent substrates for this reaction. The reaction conditions are reasonably mild and allow the isolation of the newly formed stereocenter without epimerization, although the presumed carbenic intermediates are strong bases.

Stereoretentive O-to-C rearrangement of vinyl acetals: Solvent cage effects as a stereocontrol element
Yongda Zhang; Nathan T. Kavita Manju; Tomislav Rovis
JOURNAL OF THE AMERICAN CHEMICAL SOCIETY, 2002, 124, 9720-9721

The Lewis acid-mediated rearrangement of chiral vinyl acetals may be induced to provide the product of stereoretention using Me3Al and BF3·OEt2 in concert. The selectivities obtained in this reaction (86:14 to 96:4) are complementary to that observed when relying on oxocarbenium facial bias to control the newly formed stereocenter. Evidence is presented that this reaction occurs by tight ion-pair binding in the solvent cage. The relay of C−O bond stereochemistry to a C−C bond stereocenter via ionic intermediates is an addition to similar established methods such as the Claisen rearrangement.

A mild and efficient catalytic alkylative monofunctionalization of cyclic anhydrides
Eric A. Bercot; Tomislav Rovis
JOURNAL OF THE AMERICAN CHEMICAL SOCIETY, 2002, 124, 174-175

Substituted succinic and glutaric anhydrides undergo a nickel-catalyzed monofunctionalization with organozinc reagents as nucleophiles. The reaction proceeds readily with a variety of substrates, employs commercially available or readily attainable reagents, tolerates sensitive functionality on both partners, and affords the product ketoacids in moderate to high yields. The use of a chiral phosphinooxazoline results in a desymmetrization of a meso anhydride to provide the ketoacid in 85% yield and 79% ee.

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