Kraig A. Wheeler

Asymmetric Inverse-Electron-Demand Hetero-Diels–Alder Reaction of Six-membered Cyclic Ketones: An Enamine/Metal Lewis Acid Bifunctional Approach†

The combination of organocatalysis with metal catalysis has emerged as a potentially powerful tool in organic synthesis. This new concept aims to achieve organic transformations that cannot be accessed by organocatalysis or metal catalysis alone. In our effort to combine organo-enamine catalysis with metal Lewis acid catalysis, we have developed a new class of bifunctional enamine/metal Lewis acid catalysts. These bifunctional catalysts displayed unusually high activity and high stereoselectivity in asymmetric direct aldol reactions. The challenge in the development of Lewis acid/Lewis base catalytic systems lies in the acid-base quenching reaction that leads to catalyst inactivation. A common and elegant approach to solving this problem is the use of a soft acid along with a hard base, or vice versa. Based on this approach, organo-enamine catalysis has been successfully combined with Cu, Ag, Pd, and Au. We use a different strategy to solve the acid-base problem. This new strategy complements the mixed soft/hard approach. In our system, the Lewis base (primary or secondary amine) is tethered to a chelating ligand, which serves as a “trap” for the incoming metal. In this way, the base and the metal Lewis acid are brought into close proximity in one molecule without interacting with each other (Figure 1). The bifunctional enamine/metal Lewis acid catalysts have two unique advantages. First, a large number of metals can be introduced. The Lewis acidity can be easily tuned by simply using a different metal, thereby offering great flexibility to this system. For example, stronger Lewis acids, such as La, can be used to activate the enamine acceptor more strongly. Second, the bifunctional catalysts can potentially convert an intermolecular reaction into a much more efficient intramolecular reaction. In addition, the intramolecular bifunctional nature of the catalysts would also enhance the stereoselectivity of the reaction. With these catalysts, we intend to develop new carbon–carbon or carbon–heteroatom bond-forming reactions involving difficult organic transformations. Herein, we report the first example of a highly chemoand enantioselective inverse-electron-demand hetero-Diels–Alder (HDA) reaction of cyclic ketones with b,g-unsaturated-a-ketoesters catalyzed by primary-amine-based enamine/metal Lewis acid bifunctional catalysts. Asymmetric inverse-electron-demand hetero-Diels– Alder (IED/HDA) reactions of electron-rich alkenes with an electron-deficient a,b-unsaturated ketone offers a valuable synthetic entry into dihydropyran derivatives, which are chemically and biologically of significant importance, allowing the construction of up to three stereogenic centers in one operation. In most of the inverse-electron-demand HDA reactions, enol ethers derived from aldehydes act as the electron-rich alkenes (dienophiles). Very recently, enaminebased organocatalytic asymmetric inverse-electron-demand HDA reactions, in which an in situ formed enamine from a chiral pyrolidine and an aldehyde serves as the dienophile, have been made possible. Ketones are much less reactive compared to aldehydes because of electronic and steric reasons. Asymmetric HDA reactions of ketones, in particular cyclic ketones, have remained a long-standing challenge. We are interested in developing a catalytic asymmetric enamine-based IED/HDA reaction of simple ketones with enones, as it would greatly generalize this method, and open it up to much wider exploitation. To achieve this we believe that the activation of enones should extend beyond hydrogen-bond methods, 8] for example, by using a strong metal Lewis acid. In contrast, the formation of a less congested enamine intermediate using a primary amine catalyst may also contribute to or facilitate this transformation. The primary-amine-based enamine/metal Lewis acid bifunctional catalysts developed in our laboratory appear to be ideal candidates to tackle this difficult problem. We envision that the primary amine/metal Lewis acid bifunctional catalyst would engage enone 3 and the cyclic ketone 2 intramolecularly (Scheme 1). The primary amine would form an enamine in situ with the ketone (A) and the Figure 1. Illustration of primary amine/metal Lewis acid bifunctional catalysts.

Phosphine-Catalyzed Asymmetric Synthesis of β-Lactones from Arylketoketenes and Aromatic Aldehydes

In this paper, the development of a chiral phosphine-catalyzed formal [2 + 2] cycloaddition of aldehydes and ketoketenes that provides access to a variety of highly substituted beta-lactones (14 examples) is reported. The BINAPHANE catalytic system displays excellent enantioselectivity (seven examples with ee >or=90%) and high diastereoselectivity favoring formation of the trans-diastereomer (nine examples with dr >or=90:10).

Arylamine-catalyzed enamine formation: Cooperative catalysis with arylamines and acids

The explosive growth of organocatalysis has had a huge impact on asymmetric catalysis in the past decade. Transition-metal catalysis, on the other hand, has been established for a long time as one of the most powerful methods in organic synthesis. Aminocatalysis is a major field in organocatalysis. The combination of organocatalysis with the more traditional metal Lewis acid catalysis has emerged, aiming to achieve organic transformations that cannot be accomplished by organocatalysis or metal catalysis independently. Although it promises huge potential, this research area has grown only slowly. The major challenge lies in the incompatibility of the catalysts, in particular, the combination of enamine catalysis with harder metal Lewis acid is very difficult. The circumvention of this problem would represent an important breakthrough, given the huge number of substrates that can be activated by the large variety of metal Lewis acids. Herein, we present the solution to this longstanding problem by using arylamines as the catalysts in enamine catalysis. Very importantly, we demonstrate that arylamines can serve as efficient amine catalysts in direct asymmetric aldol reactions. Furthermore, we have developed a highly chemoand enantioselective three-component azaDiels–Alder reaction by combining arylamines with metal Lewis acids. The combination of enamine catalysis with metal Lewis acid catalysis was first reported by Ibrahem and Codava in 2006. Since then, considerable progress has been made in this area, leading to a series of exciting discoveries. However, these combinations were limited to soft metals, such as Cu, Ag, Au, Ir, and Pd or Pd, activating either p-allyl electrophiles or alkynes (Scheme 1,A and B). Combining enamine catalysis with harder metal Lewis acid (Scheme 1, C) turned out to be very challenging because of acid–base self-quenching reactions, which render the catalysts inactive. In asymmetric aminocatalysis involving either an enamine or an iminium intermediate, a chiral aliphatic secondary or primary amine serves as the catalyst. Aliphatic amines are hard bases, and thus likely to be compatible with softer metals based on the soft/hard approach, but less likely to be compatible with harder metals. We hoped to find an amine catalyst that is compatible with a large variety of metal Lewis acids to significantly extend the scope of enamine/ metal Lewis acid catalysis, and to facilitate the development of a new research area of iminium/metal Lewis acid catalysis. We considered to use arylamines, such as aniline, because they have a much lower pKa value (4–6) than aliphatic amines (9–11), and should be much softer because of the delocalization of the lone pair to the aromatic p system. It appeared to us that arylamines are ideal candidates for combination with harder metal Lewis acids. Despite their ubiquity in organic chemistry, arylamines have never been used in enamine catalysis. This may be mainly due to the general understanding that the nucleophilicity of arylamines is much lower compared to aliphatic amines. However, List and co-workers suggested the formation of enamine intermediates from arylamines as a step in organocatalytic cascade reactions. In a recent report, Gong and co-workers also suggested that an achiral arylamine played a crucial role in controlling the stereochemistry of a Friedl nder condensation by forming an enamine intermediate. We speculate that arylamines might be suitable to serve as an efficient amine catalyst in enamine catalysis in conjunction with a stronger metal Lewis acid. The lower nucleophilicity of enamines can be compensated by the following factors: 1) facilitated formation of enamine in the presence of a metal Lewis acid; 2) higher activation of the electrophiles by a metal Lewis acid. The asymmetric aza-Diels–Alder reaction (ADAR) is the most convenient and powerful method to form nitrogencontaining heterocycles, which are one of the most important structural motifs in natural products, pharmaceuticals, and biosystems. While the recent progress on normal-electrondemand ADARs based on dienamines and imine dienophiles Scheme 1. Combination of enamine catalysis with metal catalysis.

A Concise Approach to the Synthesis of opp-Dibenzoporphyrins through the Heck Reaction

A concise approach to the synthesis of functionalized opp-dibenzoporphyrins is described. In this method, introduction of alkenyl groups to the porphyrin periphery through the vicinal 2-fold Heck reaction, 6-pi electrocyclization, and subsequent aromatization occur in one pot.

Underpotential Deposition of Aluminum and Alloy Formation on Polycrystalline Gold Electrodes from AlCl3 / EMIC Room‐Temperature Molten Salts

Interfacial processes occurring at polycrystalline gold in acidic 1-ethyl-3-methylimidazolium chloroaluminate melts at room temperature, at potentials more positive than aluminum bulk deposition, include both Al underpotential deposition and the formation of Al/Au alloys. This information complements that reported in the literature for Al electrodeposition on Au in AlCl{sub 3}/NaCl melts at temperatures of 200 C and higher. Cyclic voltammetry and chronopotentiometry suggest that at least two alloys form, and there is fast phase transformation between these intermetallic compounds at room temperature in the aluminum underpotential region. This transformation with thin gold films was slower than that in bulk gold electrodes.

BINAPHANE-Catalyzed Asymmetric Synthesis of trans-β-Lactams from Disubstituted Ketenes and N-Tosyl Arylimines

The development of a BINAPHANE-catalyzed formal [2 + 2]-cycloaddition of disubstituted ketenes and inexpensive N-tosyl arylimines that provides access to a variety of highly substituted β-lactams (16 examples) is described. The BINAPHANE catalytic system displays moderate to excellent enantioselectivity (up to 98% ee) and high diastereoselectivity in most cases, favoring formation of the trans-diastereomer (13 examples with dr ≥ 90:10).

A photoreactive crystalline quasiracemate

Rationally designed racemic and quasiracemic sulfonamidecinnamic acids assemble to give hydrogen-bonded dimers with coplanar alignment of neighboring olefins. The quasiracemate phase contains near inversion-related motifs with chemically distinct components forming supramolecular heterodimers that undergo asymmetric photodimerization.

Chemistry and ethnobotany of commercial incense copals copal blanco, copal oro, and copal negro, of North America

The North American commercial incense copals are derived from species of Bursera, Protium (Burseraceae), and Hymenaea (Caesal-piniaceae) but are also distinguished by the technique of harvesting as well as by species. Sixty-eight compounds were identified in three commercial incense copals. The essential oil of copal bianco (probably from B. bipinnata) is dominated by 14.52 ± 1.28% α-copaene and 13.75 ± 1.06% germacrene D. The essential oil of copal oro (probably from H. courbaril) is dominated by 21.35 ± 5.96% α-pinene and 26.51 ± 1.22% limonene. The essential oil of copal negro (probably from P. copal) is dominated by 17.95 ± 1.35% α-pinene, 12.51 ± 0.08% sabinene, and 16.88 ± 2.02% limonene.ResumenLos copales comerciales norteamericanas del incienso se derivan de las especies de Bursera, Protium (Burseraceae),y Hymenaea (Caesalpi-niaceae)pero también son distinguidos por la técnica de cosechar así como por las especies. Sesenta y ocho compuestos fueron identificados en tres copales comerciales del incienso. El aceite esencial del copal bianco (probablemente de B. bipinnata)es dominado por el α-copae-ne (14.52 ± 1.28%)y el germacrene D (13.75 ± 1.06%).El aceite esencial del copal oro (probablemente de H. courbaril)es dominado por el α-pinene (21.35 ± 5.96%)y el limonene (26.51 ± 1.22%).El aceite esencial del copal negro (probablemente de P. copal)es dominado por el a-pinene (17.95 ± 1.35%),el sabinene (12.51 ± 0.08%),y el limonene (16.88 ± 2.02%).

Electrodeposition and Nucleation of Copper at Nitrogen-Incorporated Tetrahedral Amorphous Carbon Electrodes in Basic Ambient Temperature Chloroaluminate Melts

The electrodeposition of copper on the atomically smooth nitrogen-incorporated tetrahedral amorphous carbon (taC:N) electrode has been studied in basic ambient temperature AlCl 3 /1-ethyl-3-methylimidazolium chloroaluminate melts. A high overpotential for nucleation of copper on taC:N and no underpotential deposition features are observed, comparable to the behavior of boron-doped diamond electrodes. Electrochemical deposition and stripping of copper on taC:N show that most of the deposit is anodically dissolved only when the potential reaches that of Cu(I) oxidation in a system in which Cu(I) and Cu(II) are both stable. The low density of intrinsic active sites for nucleation and its early saturation with increasing overpotential are responsible for the slight deviation from a model of the ideal progressive type of nucleation at high overpotentials.

Aluminum Deposition and Nucleation on Nitrogen‐Incorporated Tetrahedral Amorphous Carbon Electrodes in Ambient Temperature Chloroaluminate Melts

The electrodeposition of aluminum on the atomically smooth nitrogen‐incorporated tetrahedral amorphous carbon (taC:N) electrode in ambient temperature chloroaluminate melts has been interpreted using a prior model of three‐dimensional diffusion controlled nucleation and growth. Aluminum requires an unusually high overpotential for nucleation on taC:N because of the low density of intrinsic active sites, which act as critical nuclei during the initial stage of deposition. The current‐time characteristics of nucleation on taC:N show a strong dependency on overpotential. Generation of additional, overpotential‐induced active sites imposes a partial progressive nature on the overall nucleation process, resulting in a slight deviation from the limiting behavior of an ideal instantaneous nucleation model.