2012 – 2008

Current – 2013 ⋅   2012 – 2008   ⋅   2007 – 2002

2012


Biotinylated Rh(III) Complexes in Engineered Streptavidin for Accelerated Asymmetric C-H Activation
Todd K. Hyster; Livia Knörr; Thomas R. Ward; Tomislav Rovis
SCIENCE,  2012, 338, 500-503

Enzymes provide an exquisitely tailored chiral environment to foster high catalytic activities and selectivities, but their native structures are optimized for very specific biochemical transformations. Designing a protein to accommodate a non-native transition metal complex can broaden the scope of enzymatic transformations while raising the activity and selectivity of small-molecule catalysis. Here, we report the creation of a bifunctional artificial metalloenzyme in which a glutamic acid or aspartic acid residue engineered into streptavidin acts in concert with a docked biotinylated rhodium(III) complex to enable catalytic asymmetric carbon-hydrogen (C-H) activation. The coupling of benzamides and alkenes to access dihydroisoquinolones proceeds with up to nearly a 100-fold rate acceleration compared with the activity of the isolated rhodium complex and enantiomeric ratios as high as 93:7.

An Asymmetric Synthesis of 1,2,4-Trioxane Anticancer Agents via Desymmetrization of Peroxyquinols through a Bronsted Acid Catalysis Cascade
David M. Rubush; Michelle A. Morges; Barbara J. Rose;  Douglas H. Thamm; Tomislav Rovis
JOURNAL OF THE AMERICAN CHEMICAL SOCIETY, 2012, 134, 13554-13557

The desymmetrization of p-peroxyquinols using a Bronsted acid-catalyzed acetalization/oxa-Michael cascade was achieved in high yields and selectivities for a variety of aliphatic and aryl aldehydes. Mechanistic studies, suggest that the reaction proceeds through a dynamic kinetic resolution of the peroxy hemiacetal intermediate. The resulting 1,2,4-trioxane products were derivatized and show potent cancer cell-growth inhibition.

Exploiting Acyl and Enol Azolium Intermediates via N-Heterocyclic Carbene-Catalyzed Reactions of α-Reducible Aldehydes
Harit U. Vora; Philip Wheeler; Tomislav Rovis
ADVANCED SYNTHESIS & CATALYSIS, 2012, 354, 1617-1639

N-heterocyclic carbenes (NHC) are well known for their role in catalyzing benzoin and Stetter reactions: the generation of acyl anion equivalents from simple aldehydes to react with a variety of electrophiles. However, when an aldehyde bearing a leaving group or unsaturation adjacent to the acyl anion equivalent is subjected to an NHC, a new avenue of reactivity is unlocked, leading to a number of novel transformations which can generate highly complex products from simple starting materials, many of which are assembled through unconventional bond disconnections. The field of these new reactions those utilizing a-reducible aldehydes to access previously unexplored catalytic intermediates has expanded rapidly in the past eight years. This review aims to provide the reader with a historical perspective on the underlying discoveries that led to the current state of the art, a mechanistic description of these reactions, and a summary of the recent advances in this area.

Catalytic Asymmetric alpha-Acylation of Tertiary Amines Mediated by a Dual Catalysis Mode: N-Heterocyclic Carbene and Photoredox Catalysis
Daniel A. DiRocco; Tomislav Rovis
JOURNAL OF THE AMERICAN CHEMICAL SOCIETY, 2012, 134, 8094-8097

Cross-coupling reactions are among the most widely utilized methods for C-C bond formation; however, the requirement of preactivated starting materials still presents a major limitation. Methods that take direct advantage of the inherent reactivity of the C-H bond offer an efficient alternative to these methods, negating the requirement for substrate preactivation. In this process, two chemically distinct activation events culminate in the formation of the desired C-C bond with loss of H-2 as the only byproduct. Herein we report the catalytic asymmetric alpha-acylation of tertiary amines with aldehydes facilitated by the combination of chiral N-heterocyclic carbene catalysis and photoredox catalysis.

Isolable Analogues of the Breslow Intermediate Derived from Chiral Triazolylidene Carbenes
Daniel A. DiRocco; Kevin M. Oberg, Tomislav Rovis
JOURNAL OF THE AMERICAN CHEMICAL SOCIETY, 2012, 134, 6143-6145

Since Breslow’s initial report on the thiamine mode of action, the study of catalytic acyl carbanion processes has been an area of immense interest. With the advent of azolylidene catalysis, a plethora of reactivtiy has been harnessed, but the crucial nucleophilic intermediate proposed by Breslow had never been isolated or fully characterized. Herein, we report the isolation and full characterization of nitrogen analogues of the Breslow intermediate. Both stable and catalytically relevant, these species provide a model system for the study of acyl carbanion and homoenolate processes catalyzed by triazolylidene carbenes.

N-Heterocyclic-Carbene-Catalyzed Asymmetric Oxidative Hetero-Diels-Alder Reactions with Simple Aliphatic Aldehydes
Xiaodan Zhao; Kyle E. Ruhl; Tomislav Rovis
ANGEWANDTE CHEMIE-INTERNATIONAL EDITION, 2012, 51, 12330-12333

An efficient enantioselective approach to form trans lactams and cis lactones in up to 98 % yield with greater than 99 % ee, and greater than 20:1 d.r. using simple aliphatic aldehydes has been developed. The process involves a new pathway to generate enolate intermediates from aliphatic aldehydes by oxidation and deprotonation. NHC=N-heterocyclic carbene, Ts=4-toluenesulfonyl.

Catalytic Asymmetric Cross-Aza-Benzoin Reactions of Aliphatic Aldehydes with N-Boc-Protected Imines
Daniel A. DiRocco; Tomislav Rovis
ANGEWANDTE CHEMIE-INTERNATIONAL EDITION, 2012, 51, 5904-5906

A catalyst system has been developed that allows the direct asymmetric coupling of aliphatic aldehydes and N-Boc-protected imines in a cross-aza-benzoin reaction (see scheme; Boc=tert-butoxycarbonyl). The active catalyst is shown to react rapidly with the imine, however, the presence of an acid as co-catalyst renders this process reversible and allows the regeneration of the catalyst.

Catalytic Asymmetric Intermolecular Stetter Reactions of Enolizable Aldehydes with Nitrostyrenes: Computational Study Provides Insight into the Success of the Catalyst
Daniel A. DiRocco; Elizabeth L. Noey; K. N. Houk; Tomislav Rovis
ANGEWANDTE CHEMIE-INTERNATIONAL EDITION, 2012, 51, 2391-2394

A fluorinated triazolium salt precatalyst has been developed that efficiently promotes the asymmetric intermolecular Stetter reaction of enolizable aldehydes and nitrostyrenes (see scheme). Trans fluorination of the catalyst architecture results in unparalleled reactivity and enantioselectivity in the desired transformation. A DFT study provides evidence of an electrostatic interaction as the source of the increased enantio-induction.

2011

N-Heterocyclic Carbene and Bronsted Acid Cooperative Catalysis: Asymmetric Synthesis of trans-γ-Lactams
Xiaodan Zhao; Daniel A. DiRocco ; Tomislav Rovis
JOURNAL OF THE AMERICAN CHEMICAL SOCIETY, 2011, 133, 12466-12469

In efficient enantioselective approach to form trans-gamma-lactams in up to 99% yield, 93% ee, and >20/1 dr using unactivated imines has been developed. The cyclohexyl-substituted azolium and the weak base sodium o-chlorobenzoate are most suitable for this transformation. Notably, the process involves cooperative catalysis by an N-heterocyclic carbene and a Bronsted acid.

Catalytic Asymmetric Intermolecular Stetter Reaction of Enals with Nitroalkenes: Enhancement of Catalytic Efficiency through Bifunctional Additives
Daniel A. DiRocco; Tomislav Rovis
JOURNAL OF THE AMERICAN CHEMICAL SOCIETY, 2011, 133, 10402-10405

An asymmetric intermolecular Stetter reaction of enals with nitroalkenes catalyzed by chiral N-heterocyclic carbenes has been developed. The reaction rate and efficiency are profoundly impacted by the presence of catechol. The reaction proceeds with high selectivities and affords good yields of the Stetter product. Internal redox products were not observed despite of the protic conditions. The impact of catechol has been found to be general, facilitating far lower catalyst loadings than were previously achievable.

Quantum Mechanical Investigation of the Effect of Catalyst Fluorination in the Intermolecular Asymmetric Stetter Reaction
Joann M. Um; Daniel A. DiRocco; Elizabeth L. Noey; Tomislav Rovis; K. N. Houk
JOURNAL OF THE AMERICAN CHEMICAL SOCIETY, 2011, 133, 11249-11254

The asymmetric intermolecular Stetter reaction was investigated using the B3LYP and M06-2X functionals. Fluorination of a triazolium bicyclic catalyst had been found to significantly influence reaction yields and enantiomeric ratios. Computations indicate that the improved reactivity of the fluorinated catalyst is due to better electrostatic interactions between the nitroalkene and catalyst. Computational investigations of preferred conformations of the ground state catalyst and acyl anion equivalent, and the transition structures leading to both enantiomers of the products, are reported.

Enantioselective Rhodium-Catalyzed [4+2] Cycloaddition of α,β-Unsaturated Imines and Isocyanates
Kevin M. Oberg; Tomislav Rovis
JOURNAL OF THE AMERICAN CHEMICAL SOCIETY, 2011, 133, 4785-4787

A [4 + 2] cycloaddition of alpha,beta-unsaturated imines and isocyanates catalyzed by a phosphoramidite rhodium complex provides pyrimidinones in good yields and high enantioselectivities.

Mechanistic Investigation of the Enantioselective Intramolecular Stetter Reaction: Proton Transfer Is the First Irreversible Step
Jennifer L. Moore; Anthony P. Silvestri; Javier Read de Alaniz; Daniel A. DiRocco; Tomislav Rovis
ORGANIC LETTERS, 2011, 13, 1742-1745

A study on the mechanism of the asymmetric intramolecular Stetter reaction is reported. This investigation includes the determination of the rate law, kinetic isotope effects, and competition experiments. The reaction was found to be first order in aldehyde and azolium catalyst or free carbene. A primary kinetic isotope effect was found for the proton of the aldehyde. Taken together with a series of competition experiments, these results suggest that proton transfer from the tetrahedral intermediate formed upon nucleophilic attack of the carbene onto the aldehyde is the first irreversible step.

Organocatalytic Hydroacylation of Unactivated Alkenes
Daniel A. DiRocco; Tomislav Rovis
ANGEWANDTE CHEMIE-INTERNATIONAL EDITION, 2011, 50, 7982-7983

N-Heterocyclic carbenes interact with aldehydes to generate the Breslow intermediate, a rendering of the prototypical electrophile into a nucleophile (umpolung). Recent work has indicated that these intermediates may also add to simple, unpolarized alkenes. The use of a chiral precatalyst leads to the generation of the derived adducts with high yields and very high selectivities.

Rhodium(III)-catalyzed oxidative carbonylation of benzamides with carbon monoxide
Ya Du; Todd. K. Hyster; Tomislav Rovis
CHEMICAL COMMUNICATIONS, 2011, 47, 12074-12076

An efficient strategy for the oxidative carbonylation of aromatic amides via C-H/N-H activation to form phthalimides using an Rh(III) catalyst has been developed. The reaction shows a preference for C-H bonds of electron-rich aromatic amides and tolerates a variety of functional groups.

Pyridine synthesis from oximes and alkynes via rhodium(III) catalysis: Cp* and Cp-t provide complementary selectivity
Todd. K. Hyster; Tomislav Rovis
CHEMICAL COMMUNICATIONS, 2011, 47, 11846-11848

The synthesis of pyridines from readily available alpha,beta-unsaturated oximes and alkynes under mild conditions and low temperatures using Rh(III) catalysis has been developed. It was found that the use of sterically different ligands allows for complementary selectivities to be achieved.

Enamine/carbene cascade catalysis in the diastereo- and enantioselective synthesis of functionalized cyclopentanones
Kerem E. Ozboya; Tomislav Rovis
CHEMICAL SCIENCE, 2011, 2, 1835-1838

Herein we report an enantioselective synthesis of complex cyclopentanones using aliphatic aldehydes and activated enones. With the combination of a chiral secondary amine and a chiral triazolium catalyst, high diastereoselectivity and excellent enantioselectivity can be achieved. We present evidence of a clear cooperative effect when these two catalysts are present simultaneously in the system

An improved catalyst architecture for rhodium(III) catalyzed C-H activation and its application to pyridone synthesis
Todd. K. Hyster; Tomislav Rovis
CHEMICAL SCIENCE, 2011, 2, 1606-1610

We have developed a method for preparing pyridones from the coupling reaction of acrylamides and alkynes with either stoichometric Cu(OAc)(2) or catalytic Cu(OAc)(2) and air as oxidants. In the course of these studies, it was found that a larger ligand, 1,3-di-tert-butylcyclopentadienyl (termed Cp(t)) results in higher degrees of regioselectivity in the alkyne insertion event. The transformation tolerates a broad variety of alkynes and acrylamides. Furthermore, Cp(t) and Cp* demonstrate similar catalytic activity. This similarity allows for mechanistic studies to be undertaken which suggest a difference in mechanism between this reaction and the previously studied benzamide system.

Multicatalytic, asymmetric Michael/Stetter reaction of salicylaldehydes and activated alkynes
Claire M. Filloux; Stephen P. Lathrop; Tomislav Rovis
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 2011, 107, 20666-20671

We report the development of a multicatalytic, one-pot, asymmetric Michael/Stetter reaction between salicylaldehydes and electron-deficient alkynes. The cascade proceeds via amine-mediated Michael addition followed by an N-heterocyclic carbene-promoted intramolecular Stetter reaction. A variety of salicylaldehydes, doubly activated alkynes, and terminal, electrophilic allenes participate in a one-step or two-step protocol to give a variety of benzofuranone products in moderate to good yields and good to excellent enantioselectivities. The origin of enantioselectivity in the reaction is also explored; E/Z geometry of the reaction intermediate as well as the presence of catalytic amounts of catechol additive are found to influence reaction enantioselectivity.

2010

Stereospecific Polymerization of Chiral Oxazolidinone-Functionalized Alkenes
Garret M. Miyake; Daniel A. DiRocco; Qin Liu; Kevin M. Oberg; Ercan Bayram; Richard G. Finke; Tomislav Rovis; Eugene Y. -X. Chen
MACROMOLECULES, 2010, 43, 7504-7514

Acryloyl and vinyl monomers functionalized with a chiral oxazolidinone auxiliary have been successfully polymerized in a stereospecific fashion to highly isotactic, optically active polymers, through either the previously established isospecific coordination polymerization (for acryloyl monomers) or a novel isospecific cationic polymerization (for vinyl monomers). Specifically, conjugated chiral acryloyloxazolidinones, N-acryloyl(R or S)-4-phenyl-2-oxazolidinone [(R or S)-AO] are readily polymerized by chiral ansa-zirconocenium coordination catalysts, (R,R-, S,S-, or RR/S,S)-[C(2)H(4)(eta(5)-Ind)(2)]Zr(+)(THF)OC(O(i)Pr)=CME(2)][MeB(C(6)F(5))(3)](-) (1), in an isospecific manner through a catalyst-site-controlled mechanism, producimi, the corresponding optically active chiral polymers, (R or S)-PAOZ. Owing to the nature of stereocontrol dictated by the chiral catalyst site, even the coordination polymerization of the parent AOZ, without the chiral side group, also affords PAOZ with nearly quantitative isotact icily. A series of experiments have shown that the chiral polymers (R or S)-PAOZ exhibit no chiral amplifications, despite having stercoregularly placed stereogenic centers in the main chain, and the optical activity of the polymers arises solely from their chiral auxiliary, a consequence of adopting a random-coil secondary structure and thus having a cryptochiral chain. In sharp contrast, the chiral isotactic polymers derived from nonconjugated chiral vinyl oxazolidinones, N-vinyl-(R)-4-phenyl-2-oxazolidinone [(R)-VOZI and its p-hexyloxyphenyl derivative (R)-HVOZ (designed to solve the solubility issue of the resulting polymer), exhibit substantial chiral amplifications by virtue of adopting a solution-stable, one-handed helical conformation. The synthesis of such helical vinyl polymers has been accomplished by the development of a novel isospecific cationic polymerization using Lewis and Bronsted acids, such as [Ph(3)C][13(C(6)F(5))(4)], BF(3)center dot Et(2)O, and [H(Et(2)O)(2)][(C(6)F(5))(4)], through a chiral auxiliary-controlled mechanism. Noteworthy is the combination of the near-quantitative isotactic placement of the stereogenic centers of the polymer main chain with the chiral side groups located near those stereocenters that renders one-handed helicity of (R)-PVOZ and (R)-PHVOZ. Significantly, this novel cationic polymerization process, operating at ambient temperature, effectively assembles two elements of polymer local chirality side-chain chirality and main-chain chirality into global chirality in the form of excess one-handed helicity. Furthermore, the resultimg chiral helical vinyl polymers exhibit considerably higher thermal decomposition temperatures and polymer crystallinity, in comparison to the random-coil chiral acryloyl polymers, having a similarly high deuce of main-chain stereoreizularity.

ORGANOMETALLIC CHEMISTRY C-H carboxylation takes gold
Derek M. Dalton; Tomislav Rovis
NATURE CHEMISTRY, 2010, 2, 710-711

A highly basic gold catalyst has been shown to mediate the reaction of aromatic C–H bonds with carbon dioxide. The reaction provides a potential method of fixing atmospheric carbon dioxide and producing valuable chemical products.

Rhodium-Catalyzed Oxidative Cycloaddition of Benzamides and Alkynes via C-H/N-H Activation
Todd K. Hyster; Tomislav Rovis
JOURNAL OF THE AMERICAN CHEMICAL SOCIETY, 2010, 132, 10565-10569

The oxidative cycloaddition of benzamides and alkynes has been developed. The reaction utilizes Rh(III) catalysts in the presence of Cu(II) oxidants, and is proposed to proceed by N-H metalation of the amide followed by ortho C-H activation. The resultant rhodacycle undergoes alkyne insertion to form isoquinolones in good yield. The reaction is tolerant of extensive substitution on the amide, alkyne, and arene, including halides, silyl ethers, and unprotected aldehydes as substituents. Unsymmetrical alkynes proceed with excellent regioselectivity, and heteroaryl carboxamides are tolerated leading to intriguing scaffolds for medicinal chemistry. A series of competition experiments shed further light on the mechanism of the transformation and reasons for selectivity.

Phosphoramidite-rhodium complexes as catalysts for the asymmetric [2+2+2] cycloaddition of alkenyl isocyanates and alkynes
Rebecca Keller-Friedman; Kevin M. Oberg; Derek M. Dalton; Tomislav Rovis
PURE AND APPLIED CHEMISTRY, 2010, 82, 1353-1364

The discovery and development of the asymmetric rhodium-catalyzed [2 + 2 + 2] cycloaddition of alkenyl isocyanates and exogenous alkynes to form indolizinone and quinolizinone scaffolds is described. This methodology has been expanded to include substituted alkenes and dienes, a variety of sterically and electronically diverse alkynes, and carbodiimides in place of the isocyanate. Through X-ray analysis of Rh(cod)/phosphoramidite complexes additives that modify the enantio-determining step, and other experimental data, a mechanism has been proposed that explains lactam, vinylogous amide, and pyridone products and the factors governing their formation. Finally, we have applied this methodology to the synthesis of (+)-lasubine II and (-)-209D.

N-Heterocyclic Carbene Catalyzed Asymmetric Hydration: Direct Synthesis of alpha-Protio and alpha-Deuterio alpha-Chloro and alpha-Fluoro Carboxylic Acids
Harit U. Vora; Tomislav Rovis
JOURNAL OF THE AMERICAN CHEMICAL SOCIETY, 2010, 132, 2860-2861

Asymmetric hydration of alpha,alpha-dichloro aldehydes and alpha-halo enals via a NHC-catalyzed redox process to yield enantioenriched alpha-chloro and alpha-fluoro carboxylic acids is described herein. The developed reaction allows for installation of an alpha-deuterium to give rise to enantioenriched alpha-deutero alpha-halo acids Using D(2)O as the deuteron source.

2009

Excess Substrate is a Spectator Ligand in a Rhodium-Catalyzed Asymmetric [2 + 2 + 2] Cycloaddition of Alkenyl Isocyanates with Tolanes
Mark E. Oinen, Robert T. Yu, Tomislav Rovis
ORGANIC LETTERS, 2009, 11, 4934-4937

Excess substrate has been identified as an unintended spectator ligand affecting enantioselectivity in the [2 + 2 + 2] cycloaddition of alkenyl isocyanates with tolanes. Replacement of excess substrate with an exogenous additive affords products with consistent and higher ee’s. The increase in enantioselectivity is the result of a change in composition of a proposed rhodium(III) intermediate on the catalytic cycle. The net result is a rational probe of a short-lived rhodium(III) intermediate and gives insight that may have applications in many rhodium-catalyzed reactions.

Enantioselective Rhodium-Catalyzed [2 + 2 + 2] Cycloadditions of Terminal Alkynes and Alkenyl Isocyanates: Mechanistic Insights Lead to a Unified Model that Rationalizes Product Selectivity
Derek M. Dalton, Kevin M. Oberg, Robert T. Yu, Ernest E. Lee, Stephane Perreault, Mark E. Oinen, Melissa L. Pease, Guiome Malik, Tomislav Rovis
JOURNAL OF THE AMERICAN CHEMICAL SOCIETY, 2009, 131, 15717-15728

This manuscript describes the development and scope of the asymmetric rhodium-catalyzed [2 + 2 + 2] cycloaddition of terminal alkynes and alkenyl isocyanates leading to the formation of indolizidine and quinolizidine scaffolds. The use of phosphoramidite ligands proved crucial for avoiding competitive terminal alkyne dimerization. Both aliphatic and aromatic terminal alkynes participate well, with product selectivity a function of both the steric and electronic character of the alkyne. Manipulation of the phosphoramidite ligand leads to tuning of enantio- and product selectivity, with a complete turnover in product selectivity seen with aliphatic alkynes when moving from Taddol-based to biphenol-based phosphoramidites. Terminal and 1,1-disubstituted olefins are tolerated with nearly equal efficacy. Examination of a series of competition experiments in combination with analysis of reaction outcome shed considerable light on the operative catalytic cycle. Through a detailed study of a series of X-ray structures of rhodium(cod)chloride/phosphoramidite complexes, we have formulated a mechanistic hypothesis that rationalizes the observed product selectivity.

Asymmetric Synthesis of Functionalized Cyclopentanones via a Multicatalytic Secondary Amine/N-Heterocyclic Carbene Catalyzed Cascade Sequence
Stephen P. Lathrop, Tomislav Rovis
JOURNAL OF THE AMERICAN CHEMICAL SOCIETY, 2009, 131, 13628-13630

A one-pot, asymmetric multicatalytic formal [3+2] reaction between 1,3-dicarbonyls and α,β-unsaturated aldehydes is described. The multicatalytic process involves a secondary amine catalyzed Michael addition followed by a N-heterocyclic carbene catalyzed intramolecular crossed benzoin reaction to afford densely functionalized cyclopentanones with high enantioselectivities. The reaction proceeds with a variety of alkyl and aryl enals as well as a range of 1,3-dicarbonyls (diketones and β-ketoesters). The functionalized products are obtained from cheap, readily available starting materials in a rapid and efficient manner in a one-pot, one-step operation.

Enantioselective Rhodium-Catalyzed [4+2+2] Cycloaddition of Dienyl Isocyanates for the Synthesis of Bicyclic Azocine Rings
Robert. T. Yu, Rebecca K. Friedman, Tomislav Rovis
JOURNAL OF THE AMERICAN CHEMICAL SOCIETY, 2009, 131, 13250-13251

A highly enantioselective rhodium-catalyzed [4+2+2] cycloaddition of terminal alkynes and dienyl isocyanates has been developed. The cycloaddition provides a rapid entry to highly functionalized and enantioenriched bicyclic azocines. This reaction represents the first [4+2+2] cycloaddition strategy to construct nitrogen-containing eight-membered rings.

Catalytic Asymmetric Intermolecular Stetter Reaction of Heterocyclic Aldehydes with Nitroalkenes: Backbone Fluorination Improves Selectivity
Daniel A. DiRocco, Kevin M. Oberg, Derek M. Dalton, Tomislav Rovis
JOURNAL OF THE AMERICAN CHEMICAL SOCIETY, 2009, 131, 10872-10874

The catalytic asymmetric intermolecular Stetter reaction of heterocyclic aldehydes and nitroalkenes has been developed. We have identified a strong stereoelectronic effect on catalyst structure when a fluorine substituent is placed in the backbone. X-ray structure analysis provides evidence that hyperconjugative effects are responsible for a change in conformation in the azolium precatalyst. This new N-heterocyclic carbene precursor bearing fluorine substitution in the backbone results in significantly improved enantioselectivities across a range of substrates.

Predictable and Regioselective Insertion of Internal Unsymmetrical Alkynes in Rhodium-Catalyzed Cycloadditions with Alkenyl Isocyanates
Rebecca K. Friedman, Tomislav Rovis
JOURNAL OF THE AMERICAN CHEMICAL SOCIETY, 2009, 131, 10775-10782

A regioselective, rhodium-catalyzed cycloaddition between a variety of internal, unsymmetrical alkynes is described. We document the impact of both steric and electronic properties of the alkyne on reaction course, efficiency, and enantioselectivity. The substituent that better stabilizes a positive charge or the larger group, all else being equal, inserts distal to the carbonyl moiety in a predictable and controllable fashion. The reaction scope is broad and the enantioselectivities are high, providing an “instruction manual” for substrate choice when utilizing this reaction as a synthetic tool.

Enantio- and Diastereoselective Intermolecular Stetter Reaction of Glyoxamide and Alkylidene Ketoamides
Qin Liu, Tomislav Rovis
ORGANIC LETTERS, 2009, 11, 2856-2859

A triazolinylidene carbene catalyzed intermolecular Stetter reaction of glyoxamide and alkylidene ketoamides has been developed. 1,4-Dicarbonyl products are afforded in good to excellent yields, enantioselectivities, and diastereoselectivities. Further derivatization of the products affords useful intermediates for organic synthesis.

Regioselective rhodium-catalyzed intermolecular [2+2+2] cycloaddition of alkynes and isocyanates to form pyridones
Kevin M. Oberg, Ernest E. Lee, Tomislav Rovis
TETRAHEDRON, 2009, 65, 5056-5061

A highly regioselective rhodium-catalyzed intermolecular [2+2+2] cycloaddition of terminal alkynes with a variety of isocyanates to provide 2- and 4-pyridones has been developed. This reaction proceeds in good to excellent yields and overcomes the problem of dimerization and trimerization through the use of phosphoramidite ligands. A CO migration in the metallacycle is proposed to account for the formation of 4-pyridone.

The Catalytic Asymmetric Intramolecular Stetter Reaction
Javier Read de Alaniz, Tomislav Rovis
SYNLETT, 2009, 1189-1207

This Account chronicles our efforts in the development of the catalytic asymmetric Stetter reaction using chiral triazolium salts as small molecule organic catalysts. Advances in the mechanistically related azolium-catalyzed asymmetric benzoin reaction are discussed, particularly as they apply to catalyst design. A chronological treatise of reaction discovery, catalyst optimization and reactivity extension follows.

Ligand differentiated complementary Rh-catalyst systems for the enantioselective desymmetrization of meso-cyclic anhydrides
Jeffrey B. Johnson, Matthew J. Cook, Tomislav Rovis
TETRAHEDRON, 2009, 65, 3202-3210

Two distinct systems for the rhodium-catalyzed enantioselective desymmetrization of meso-cyclic anhydrides have been developed. Each system has been optimized and are compatible with the use of in situ prepared organozinc reagents. Rhodium/PHOX species efficiently catalyze the addition of alkyl nucleophiles to glutaric anhydrides, while a rhodium/phosphoramidite system is effective in the enantioselective arylation of succinic and glutaric anhydrides.

Enantioselective Rhodium-Catalyzed Alkylative Desymmetrization of 3,5-Dimethylglutaric Anhydride
Matthew J. Cook, Tomislav Rovis
SYNTHESIS, 2009, 335-338

A rhodium-catalyzed enantioselective cross-coupling of sp³ organozinc reagents and 3,5-dimethylglutaric anhydride has been developed to afford the corresponding products, syn-deoxypolypropionates, in excellent yields and enantioselectivities. This reaction has been developed so that both commercially available and in situprepared organozinc reagents are competent coupling partners.

Total Synthesis of Indolizidine Alkaloid (−)-209D: Overriding Substrate Bias in the Asymmetric Rhodium-Catalyzed [2+2+2] Cycloaddition
Robert T. Yu, Ernest E. Lee, Goume Malik, Tomislav Rovis
ANGEWANDTE CHEMIE INTERNATIONAL EDITION, 2009, 48, 2379-2382

The use of chiral biphenyl-based phosphoramidite ligands on rhodium provides an efficient [2+2+2] cycloaddition between terminal alkyl alkynes and alkenyl isocyanates (see scheme). The cycloaddition proceeds through a CO migration pathway, and facilitates a rapid four-step asymmetric synthesis of indolizidine (−)-209D.

Beyond Reppe: Building Substituted Arenes by [2+2+2] Cycloadditions of Alkynes
Brandon R. Galan, Tomislav Rovis
ANGEWANDTE CHEMIE INTERNATIONAL EDITION, 2009, 48, 2830-2834

The transition-metal-catalyzed [2+2+2] cycloaddition is an established method for the construction of carbocyclic frameworks but is often plagued by poor selectivity. Recent literature paints a promising picture—a more general metal-catalyzed [2+2+2] cycloaddition can be accomplished intermolecularly using three separate alkynes to furnish highly substituted arenas (see scheme).

Carbene Catalysts
Jennifer L. Moore, Tomislav Rovis
TOPICS IN CURRENT CHEMISTRY, 2009, 291, 77-144

The use of N-heterocyclic carbenes as catalysts for organic transformations has received increased attention in the past 10 years. A discussion of catalyst development and nucleophilic characteristics precedes a description of recent advancements and new reactions using N-heterocyclic carbenes in catalysis.

Multi-component cycloaddition approaches in the catalytic asymmetric synthesis of alkaloid targets
Stephane Perreault, Tomislav Rovis
CHEMICAL SOCIETY REVIEWS, 2009, 38, 3149-3159

Cycloaddition reactions are attractive strategies for the rapid formation of molecular complexity in organic synthesis, as multiple bonds are formed in a single process. To this end, several research groups have been actively involved in the development of catalytic methods to activate readily accessible π-components to achieve cycloadditions. However, the use of C–N π-components for the formation of heterocycles by these processes is less well developed. It has been previously demonstrated that the combination of different isocyanates with two alkynes yields pyridones of several types by metal-catalyzed [2 + 2 + 2] cycloadditions. The potential of this chemistry has been extended to alkenes as C–C π-components, allowing the formation of sp3-stereocenters. In this tutorial review directed towards [n + 2 + 2] cycloadditions of heterocumulenes, alkynes and alkenes, the recent advances in the catalytic asymmetric synthesis of indolizidine, quinolizidine and azocine skeletons are discussed.

2008

Nucleophilic Carbene Catalyzed Synthesis of 1,2 Amino Alcohols Via Azidation of Epoxy Aldehydes
Harit U. Vora, Johannah R. Moncecchi, Oleg Epstein, Tomislav Rovis
JOURNAL OF ORGANIC CHEMISTRY, 2008, 73, 9727-9731

We report herein a nucleophilic carbene catalyzed redox azidation of epoxyaldehydes. The intermediate β-hydroxy acyl azides undergo thermal Curtius rearrangement followed by trapping with excess azide to form carbamoyl azides or, in a complementary sequence, by the hydroxy group to form oxazolidinones. Both products are formed in modest to good yields and diastereoselectivities. The use of an enantioenriched triazolium catalyst leads to modest asymmetric induction.

Nickel-Catalyzed Reductive Carboxylation of Styrenes Using CO2
Catherine M. Williams, Jeffrey B. Johnson, Tomislav Rovis
JOURNAL OF THE AMERICAN CHEMICAL SOCIETY, 2008, 130, 14936-14397

A nickel-catalyzed reductive carboxylation of styrenes using CO2 has been developed. The reaction proceeds under mild conditions using diethylzinc as the reductant. Preliminary data suggests the mechanism involves two discrete nickel-mediated catalytic cycles, the first involving a catalyzed hydrozincation of the alkene followed by a second, slower nickel-catalyzed carboxylation of the in situ formed organozinc reagent. Importantly, the catalyst system is very robust and will fixate CO2 in good yield even if exposed to only an equimolar amount introduced into the headspace above the reaction.

Catalytic Asymmetric Intermolecular Stetter Reaction of Glyoxamides with Alkylidenemalonates
Qin Liu, Stephane Perreault, Tomislav Rovis
JOURNAL OF THE AMERICAN CHEMICAL SOCIETY, 2008, 130, 14066-14067

An asymmetric intermolecular Stetter reaction of glyoxamide and alkylidenemalonates has been developed. Catalyzed by a novel N-heterocyclic carbene, the Stetter adducts are formed in good yield and excellent enantioselectivity. The presence of a sensitive epimerizable stereocenter is tolerated under these mildly basic reaction conditions if a bulky amine base is used. The products may be further elaborated to provide synthetically useful intermediates.

Catalytic Asymmetric Stetter Reaction Onto Vinylphosphine Oxides and Vinylphosphonates
Stephen C. Cullen, Tomislav Rovis
ORGANIC LETTERS, 2008, 10, 3141-3144

An intramolecular Stetter reaction of vinylphosphine oxides and vinylphosphonates has been developed. Treatment of an aldehyde with a nucleophilic N-heterocyclic carbene catalyst allows for addition of an acyl anion equivalent into a vinylphosphine oxide or vinylphosphonate Michael acceptor in yields up to 99% and ee values up to 96%.

Scope of the Asymmetric Intramolecular Stetter Reaction Catalyzed by Chiral Nucleophilic Triazolinylidene Carbenes
Javier Read de Alaniz, Mark S. Kerr, Jennifer L. Moore, Tomislav Rovis
JOURNAL OF ORGANIC CHEMISTRY, 2008, 73, 2033-2040

A highly enantioselective intramolecular Stetter reaction of aromatic and aliphatic aldehydes tethered to different Michael acceptors has been developed. Two triazolium scaffolds have been identified that catalyze the intramolecular Stetter reaction with good reactivity and enantioselectivity. The substrate scope has been examined and found to be broad; both electron-rich and -poor aromatic aldehydes undergo cyclization in high yield and enantioselectivity. The tether can include oxygen, sulfur, nitrogen, and carbon linkers with no detrimental effects. In addition, the incorporation of various tethered Michael acceptors includes amides, esters, thioesters, ketones, aldehydes, and nitriles. The catalyst loading may be reduced to 3 mol % without significantly affecting the reactivity or selectivity of the reaction.

Enantioselective Synthesis of Indolizidines Bearing Quaternary Substituted Stereocenters via Rhodium-Catalyzed [2 + 2 + 2] Cycloaddition of Alkenyl Isocyanates and Terminal Alkynes
Ernest E. Lee, Tomislav Rovis
ORGANIC LETTERS, 2008, 10, 1231-1234

An enantioselective synthesis of indolizidines bearing quaternary substituted stereocenters by way of a rhodium-catalyzed [2 + 2 + 2] cycloaddition of substituted alkenyl isocyanates and terminal alkynes is described. The reaction provides lactam products using aliphatic alkynes, whereas aryl alkynes give rise to vinylogous amide products. Through modification of the phosphoramidite ligand, high levels of enantioselectivity, regioselectivity, and product selectivity are obtained for both products.

Asymmetric Synthesis of Bicyclic Amidines via Rhodium-Catalyzed [2+2+2] Cycloaddition of Carbodiimides
Robert T. Yu, Tomislav Rovis
JOURNAL OF THE AMERICAN CHEMICAL SOCIETY, 2008, 130, 3262-3263

A highly enantioselective rhodium-catalyzed [2+2+2] cycloaddition of terminal alkynes and alkenyl carbodiimides has been developed. This reaction demonstrates the feasibility of olefin insertion into carbodiimide-derived metalacycles and provides a new class of chiral bicyclic amidines as the major products. An isonitrile migration process responsible for the formation of the minor cycloadduct can be observed and is highly sensitive to the electronics of alkynyl substrates.

Enantioselective Cross-Coupling of Anhydrides with Organozinc Reagents: The Controlled Formation of Carbon−Carbon Bonds through the Nucleophilic Interception of Metalacycles
Jeffrey B. Johnson, Tomislav Rovis
ACCOUNTS IN CHEMICAL RESEARCH, 2008, 41, 327-338

The construction of carbon−carbon bonds, particularly with concomitant control of newly formed asymmetric centers, is of paramount importance for the development of synthetic routes to complex organic molecules. While cross-coupling reactions for the generation of sp2 carbon centers are well established, similar methodology for the formation and control of sp3-hydridized carbon stereocenters is extremely limited. We suggest that the nucleophilic interception of metalacycles provides the means to achieve such a transformation, wherein the metal complex serves to activate electrophiles, facilitate nucleophile addition, and ultimately control stereochemistry. One means of accessing these intermediates is through the use of simple meso-carboxylic anhydrides, which upon reaction with transition metals readily generate the desired metalacycles. Interception of the metalacycle with an appropriate carbon-based nucleophile generates an enantioenriched ketoacid, the product of the asymmetric desymmetrization of achiral starting materials.

A Diastereoselective Ring Contraction of 1,3-Dioxepins to 2,3,4-Trisubstituted and Tetrasubstituted Tetrahydrofurans
Christopher G. Nasveschuk, Tomislav Rovis
JOURNAL OF ORGANIC CHEMISTRY, 2008, 73, 612-617

A modular and diastereoselective approach to 2,3,4-trisubstituted and tetrasubstituted tetrahydrofurans is reported. The use of dioxepins containing an embedded vinyl acetal functionality leads to a Lewis acid-mediated [1,3] ring contraction to afford tetrahydrofurans in good yield and excellent diastereoselectivity. The use of TMSOTf in MeCN leads to the 2,3-cis/3,4-trans diastereomer while SnCl4 in CH2Cl2 provides the 2,3-trans/3,4-cis diastereomer. A variety of substituents are tolerated at each position. The presence of Lewis basic functionality under the SnCl4 conditions alters the reaction favoring the diastereomer formed under the TMSOTf conditions. We present conclusive evidence that the products of each of these reactions are formed under kinetic control. We further provide stereochemical models consistent with each of these rearrangement reactions that account for the formation of the major diastereomer in each case.

Development of Chiral Bicyclic Triazolium Salt Organic Catalysts: The Importance of the N-Aryl Substituent
Tomislav Rovis
CHEMICAL LETTERS, 2008, 37, 2-7

The development of a family of chiral bicyclic triazolium salts is described. Treatment of these salts with base provides a nucleophilic carbene which may be used as an organic catalyst for asymmetric acyl anion chemistry including the benzoin and Stetter reactions, and some recently developed redox chemistry. Throughout the development of these reactions, the nature of the N-aryl substituent on the triazole ring has proven to have a profound effect on both reactivity and selectivity. These observations have also paralleled those made by others using our family of catalysts.

A Rapid Total Synthesis of (±)-Sylvone
Christopher G. Nasveschuk, Tomislav Rovis
SYNLETT, 2008, 126-128

We report a convergent and diastereoselective synthesis of (±)-sylvone that utilizes a diastereoselective [1,3] ring contraction.

More than Bystanders: The Effect of Olefins on Transition-Metal-Catalyzed Cross-Coupling Reactions
Jeffrey B. Johnson, Tomislav Rovis
ANGEWANDTE CHEMIE INTERNATIONAL EDITION, 2008, 47, 840-871

Olefins and alkynes are ubiquitous in transition-metal catalysis, whether introduced by the substrate, the catalyst, or as an additive. Whereas the impact of metals and ligands is relatively well understood, the effects of olefins in these reactions are generally underappreciated, even though numerous examples of olefins influencing the outcome of a reaction, through increased activity, stability, or selectivity, have been reported. This Review provides an overview of the interaction of olefins with transition metals and documents examples of olefins influencing the outcome of catalytic reactions, in particular cross-coupling reactions. It should thus provide a basis for the improved understanding and further utilization of olefin and alkyne effects in transition-metal-catalyzed reactions.

Towards the total synthesis of FD-838: modular enantioselective assembly of the core
Arturo Orellana, Tomislav Rovis
CHEMICAL COMMUNICATIONS, 2008, 730-732

A rapid assembly of the tetracyclic core of FD-838, featuring a catalytic asymmetric Stetter reaction, is described.

The [1,3] O-to-C rearrangement: opportunities for stereoselective synthesis
Christopher G. Nasveschuwk, Tomislav Rovis
ORGANIC AND BIOMOLECULAR CHEMISTRY, 2008, 6, 240-254

The relay of stereochemistry of a breaking C–O bond into a forming C–C bond is well-known in the context of [3,3] sigmatropic shifts; however, this useful strategy is less well-known in other types of molecular rearrangements. Though the first successful example of a [1,3] O-to-Crearrangement was reported more than 100 years ago, this class of reactions has received less attention than its [3,3] counterpart. This perspective analyzes the various methods used for theactivation and [1,3] rearrangement of vinyl ethers with an emphasis on mechanism and applications to stereoselective synthesis. We also highlight our own contributions to this area.

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