Xin Li

Asymmetric Binary-Acid Catalysis with Chiral Phosphoric Acid and MgF2: Catalytic Enantioselective Friedel−Crafts Reactions of β,γ-Unsaturated α-Ketoesters

A unique binary chiral phosphoric acid 1a/MgF(2) catalyst that enables effective catalysis of asymmetric Friedel-Crafts reactions of phenols with up to 82% yield and >99% ee is presented. A dramatic synergistic effect has been observed in the combinations of two types of acids, wherein a highly active binary-acid catalyst can be generated from two individually inert acids.

Asymmetric SN1 α‐Alkylation of Cyclic Ketones Catalyzed by Functionalized Chiral Ionic Liquid (FCIL) Organocatalysts

Echoed with the sustainable chemistry concept, the developments of highly efficient and practical asymmetric catalysts have been and continue to be the fore of organic synthesis. Functionalized chiral ionic liquids (FCILs), which combine the green credential of ionic liquids and the catalytic principles of modern asymmetric catalysis, have recently appeared as such a type of asymmetric catalyst. Following the initial work of Howarth and Seddon; the applications of FCILs have moved beyond the use as chiral additives, chiral reagents, or chiral inducing reaction media, and now have reached the stage of asymmetric catalysts. However, the promising potentials of FCILs as asymmetric catalysts still remain largely underdeveloped at present and the current successes have been primarily confined to the reactions like Michael additions and aldol reactions. As such, in our continuing efforts in exploring this type of catal ACHTUNGTRENNUNGysis,[5d–f, n] we have sought new reaction development by taking advantage of the intrinsic properties of ionic liquids. Herein, we report the first FCIL-catalyzed enantioselective SN1 type alkylation of cyclic ketones, in which the ionic liquid moieties are found to be critical for both the catalytic activity and stereocontrol. The catalytic asymmetric direct a-alkylation reaction of carbonyl compounds has long been a daunting challenge in asymmetric catalysis and synthesis. Before the renaissance of organocatalysis, particularly the enamine-based amino ACHTUNGTRENNUNGcatACHTUNGTRENNUNGalysis, asymmetric phase-transfer catalysis was the only successful approach to this end and it was mostly used in the synthesis of a-amino acids through alkylation of glycine derivatives. In 2004, Vignola and List reported the first catalytic intramolecular nucleophilic a-alkylation of aldehydes by means of enamine activation. Later on, several cascade reactions including an intramolecular a-alkylation of aldehydes as the key step were also reported. However, the intermolecular a-alkylation of aldehydes or ketones are still a challenging task due to the depletion of catalytic activity through the N-alkylation of the aminocatalysts and various competing bypaths therewith. The past few years have witnessed notable breakthroughs in the development of asymmetric intermolecular a-alkylations of carbonyl compounds, specifically of aldehydes. Melchiorre and Cozzi have independently reported SN1 type aalkylation of aldehydes by enamine catalysis. This novel approach was based on alkyl donors endowed with suitable leaving groups (Scheme 1, I), which can generate a stabi-

Phosphoric Acid Catalyzed Asymmetric 1,6-Conjugate Addition of Thioacetic Acid to para-Quinone Methides

An asymmetric 1,6-conjugate addition of thioacetic acid with para-quinone methides has been developed by using chiral phosphoric acid catalysis in the presence of water. A series of sulfur-containing compounds were thus obtained in high yields with good to excellent enantioselectivities. Theoretical studies indicated that the water-bridged proton transfer is a potentially favorable reaction pathway. An unprecedented O-H⋅⋅⋅π interaction between water and the aromatic nucleus of chiral phosphoric acid was discovered to contribute significantly to the stereocontrol in the catalysis.

Chiral Amine Thiourea-Promoted Enantioselective Michael Addition Reactions of 3-Substituted Benzofuran-2(3H)-ones to Maleimides

A highly diastereo- and enantioselective Michael addition reaction with respect to prochiral 3-substituted benzofuran-2(3H)-ones and maleimides by a chiral bifunctional thiourea-tertiary amine catalyst was investigated. The corresponding adducts, containing a quaternary center at the C3-position of the benzofuran-2(3H)-one as well as a vicinal tertiary center, were generally obtained in high yields (up to 99%) with very good diastereo- (up to >20:1 dr) and enantioselectivities (up to 97% ee).

Chiral Biscinchona Alkaloid Promoted Asymmetric Allylic Alkylation of 3-Substituted Benzofuran-2(3H)-ones with Morita—Baylis—Hillman Carbonates

A highly diastereo- and enantioselective asymmetric allylic alkylation reaction with respect to prochiral 3-substituted benzofuran-2(3H)-ones and MBH carbonate by a chiral biscinchona alkaloid catalyst was investigated. The corresponding adducts, containing a quaternary center at the C3-position of the benzofuran-2(3H)-one as well as a vicinal tertiary center, were generally obtained in high yields (up to 97%) with very good diastereo- (up to 98:2 dr) and enantioselectivities (up to 95% ee).

Chiral Primary−Tertiary Diamine−Brønsted Acid Salt Catalyzed Syn-Selective Cross-Aldol Reaction of Aldehydes

Highly syn-selective cross-aldol reaction of aldehydes has remained a challenging subject in the field of aminocatalysis. To achieve this end, chiral primary amines have been explored and the primary-tertiary diamine-Brønsted acid salts are found to promote the cross-aldol reactions of aldehydes with high activity and syn selectivity. Among various vicinal diamines screened, l-phenylalanine derived 2a/TfOH conjugate is identified as the optimal catalyst, showing good catalytic activity (up to 97% yield) and high syn selectivities (syn/anti up to 24:1, 87% ee). The current catalysis works selectively with small aliphatic aldehydes donors such as propionaldehyde and isobutyraldehyde, but not with aliphatic aldehydes bearing larger beta-substitute (>Me). In addition, the use of 2a/TfOH conjugate has also enabled the first syn-selective cross-aldol reactions of glycoaldehyde donors.

Enantioselective Organocatalyzed Sulfenylation of 3-Substituted Oxindoles

A highly enantioselective sulfenylation reaction with respect to 3-substituted oxindoles and electrophilic sulfur reagents by a quinidine catalyst was investigated.

Varioxepine A, a 3H-oxepine-containing alkaloid with a new oxa-cage from the marine algal-derived endophytic fungus Paecilomyces variotii.

A new 3H-oxepine-containing alkaloid, varioxepine A (1), characterized by a structurally unprecedented condensed 3,6,8-trioxabicyclo[3.2.1]octane motif, was isolated from the marine algal-derived endophytic fungus Paecilomyces variotii. Due to the low proton/carbon ratio, the unambiguous assignment of the planar structure and relative configuration was precluded by NMR experiments and solved by single crystal X-ray analysis. The absolute configuration was established by DFT conformational analysis and TDDFT-ECD calculations. Compound 1 inhibited plant pathogenic fungus Fusarium graminearum.

Synthesis of Optically Enriched Spirocyclic Benzofuran-2-ones by Bifunctional Thiourea-Base Catalyzed Double-Michael Addition of Benzofuran-2-ones to Dienones

A highly enantioselective catalytic double-Michael addition reaction of substituted benzofuran-2-ones with divinyl ketones promoted by readily accessible tertiary amine-thiourea Cinchona alkaloids has been developed. A number of optically enriched spirocyclic benzofuran-2-ones were prepared in very good yields (up to 99 %), diastereoselectivities (up to 19:1 d.r.), and very good enantioselectivities (up to 92 % ee). Density functional theory (DFT) calculations were performed to investigate the origin of stereoselectivity.

Standard pKa Scales of Carbon-Centered Indicator Acids in Ionic Liquids: Effect of Media and Structural Implication

Energetics of bond dissociation, especially the R-H bond heterolysis free energy (pK(a)), has played a central role in promoting chemistry to become a rational science. Despite the oceans of acidity studies in the literature, the current knowledge is limited to that in the classical molecular solvents and is unable to be extended to anticipate the acidity changes in ionic media. As the latter is now very popular for replacing volatile organic solvents, it becomes highly desirable to know how the driving force of bond cleavage is varied as the medium composition is switched from neutral molecules to the charged ions. Here we describe a general approach to measure absolute pK(a)s in pure ionic liquid (IL). The standard conditions warranting accurate measurement were outlined. The pK(a)s of the selected 18 C-H type indicator acids in four ILs were determined and a convenient indicator platform was constructed for easy expansion of acidity scales. These absolute pK(a)s make possible, for the first time, direct comparisons of bond energies in IL with those in molecular solvent and in the gas phase and should be able to serve as the standard parameters for calibrating computational methods suitable for the studies in ionic media. The effect of cation and anion in IL in relation to structure was analyzed.