Published papers

Since their discovery, carbon nanotubes (CNTs) continue to attract growing interest from scientists in a wide range of fields, likely due to their fascinating nanoarchitecture as well as their electronic and physical properties. From the viewpoint of synthetic chemistry, the chemical and physical stability, high surface area, and -stacking nature of CNTs are attractive features for their application as solid supports for molecular catalysts. The chemical functionalization of CNTs has been explored for various applications, including covalent and noncovalent grafting of molecular catalysts. Although noncovalent grafting provides less stable immobilized catalysts compared with covalently grafted hybrid molecular catalysts and CNTs, the preparation protocol is expeditious and repetitive use of the catalysts is well demonstrated, confirming their potential broad utility in synthetic organic chemistry.

Organofluorine compounds are found in several important classes of chemicals, such as pharmaceuticals, agrochemicals, and functional materials. Chemists have been immensely interested in the development of methodologies for expeditious access to fluorine containing building blocks. In this study, we report a new method for the catalytic asymmetric synthesis of CF3-substituted tertiary propargylic alcohols with two contiguous stereogenic centers via the direct aldol reaction of an alpha-N-3 amide to trifluoromethyl ketones. The key to the success of this method is the identification of a catalyst comprising Cu(II)/chiral hydroxamic acid to promote the desired aldol reaction, constructing a tetrasubstituted carbon in a highly stereoselective fashion. Despite substantial prior advances in asymmetric catalysis, this class of catalysts has not been utilized for the formation of carbon-carbon bond-forming reactions. Our mechanistic study sheds light on the unique profile of this catalytic system, where the Cu(II) complex plays a bifunctional role of serving as a Lewis acid and a Bronsted base. Furthermore, the densely functionalized aldol adducts undergo chemoselective transformations, affording a series of fluorine containing chiral building blocks with widespread application.

Despite the burgeoning demand for fluorine-containing chemical entities, the construction of CF3-containing stereogenic centers has remained elusive. Herein, we report the strategic merger of CuI/base-catalyzed enolization of an alpha-CF3 amide and Pd-0-catalyzed allylic alkylation in an enantioselective manner to deliver chiral building blocks bearing a stereogenic carbon center connected to a CF3, an amide carbonyl, and a manipulable allylic group. The phosphine complexes of Cu-I and Pd-0 engage in distinct catalytic roles without ligand scrambling to render the dual catalysis operative to achieve asymmetric alpha-allylation of the amide. The stereoselective cyclization of the obtained alpha-CF3-gamma, delta-unsaturated amides to give tetrahydropyran and g-lactone-fused cyclopropane skeletons highlights the synthetic utility of the present catalytic method as a new entry to non-racemic CF3-containing compounds.

The expansion of molecular diversity beyond what nature can produce is a fundamental objective in chemical sciences. Despite the rich chemistry of boron-containing heterocycles, the 1,3-dioxa-5-aza-2,4,6-triborinane (DATB) ring system, which is characterized by a six-membered B3NO2 core, remains elusive. Here, we report the synthesis of m-terphenyltemplated DATB derivatives, displaying high stability and peculiar Lewis acidity arising from the three suitably arranged boron atoms. We identify a particular utility for DATB in the dehydrative amidation of carboxylic acids and amines, a reaction of high academic and industrial importance. The three boron sites are proposed to engage in substrate assembly, lowering the entropic cost of the transition state, in contrast with the operative mechanism of previously reported catalysts and amide coupling reagents. The distinct mechanistic pathway dictated by the DATB core will advance not only such amidations, but also other reactions driven by multisite activation.

In contrast to recent significant progress in the development of catalytic methodologies for nitrogen acylations, syntheses of N-acyl sulfoximines have been slow to evolve, and still largely rely on the use of stoichiometric amounts of activating reagents. Here we describe the direct acylation of the nitrogen atom in sulfoximines with carboxylic acids promoted by a heterocyclic catalyst featuring the B3NO2 ring system. The protocol used was found to be operationally simple and to tolerate a wide range of functional groups, furnishing the N-acylated sulfoximines in good yield. The multiboron catalyst tamed previously intractable nitrogen nucleo-philes, allowing for the short synthesis of a factor Xa inhibitor by catalyzing two consecutive nitrogen acylations in the same pot.

Direct coupling of ethers and acyl halides was promoted by a binary catalytic Sytem comprising an Ir-based photocatalyst and a Ni complex under blue-light irradiation. Photocatalysts with high triplet energy directed the catalysis, and the reaction likely proceeded by triplet-triplet energy transfer from the excited photocatalysts. chlorine radicals generated from an excited Ni Complex bearing, a Ni-Cl bond would be responsible for generating alpha-oxy radicals leading to the alpha-acylated ethers.

Direct asymmetric aldol addition of an alpha-CF3 amide to arylglyoxal hydrates was promoted by a chiral catalyst comprising a soft Lewis acidic Cu(I), a chiral bisphosphine ligand, and DBU. The 7-azaindoline moiety of the amide facilitates its enolization and stabilizes the thus-generated Cu enolate, furnishing enantioenriched aldol adducts.

1,3-Dipolar cycloaddition is a commonly exploited method to access 5-membered chemical entities with a variety of peripheral functionalities and their stereochemical arrangements. Nitrones are isolable 1,3-dipoles that exhibit sufficient reactivity toward electron-deficient olefins in the presence of Lewis acids to deliver highly substituted isoxazolidines. Herein we document that ,-unsaturated amides, generally regarded as barely reactive in a 1,3-dipolar reaction manifold, were effectively activated using the designed 7-azaindoline auxiliary in an In(OTf)(3)/bishydroxamic acid catalytic system. The broad substrate scope and clean removal of the 7-azaindoline auxiliary from the product highlight the synthetic utility of the present catalysis.

Viridiofungins are alkyl citrate natural products characterized by their inhibitory effects on squalene synthase and serine palmitoyl transferase. Their activities as broad-spectrum antifungal agents as well as blocking agents for the biosynthesis of sphingolipids have inspired the development of several approaches toward their stereoselective total synthesis. Structurally, these natural products are a family of hybrid molecules comprising a longer alkyl chain and a citric acid unit, rendering an asymmetric structure that is difficult to access. Herein, we summarize the synthetic approaches to this attractive class of natural products, including proficient synthetic strategies for constructing the densely and chirally functionalized citric acid unit with high polarity. Particular emphasis is placed on methods for furnishing stereogenic centers in the highly constrained carbon framework.

A highly anti-selective catalytic asymmetric nitroaldol reaction of trifluoromethyl ketones based on Nd/Na and Pr/Na heterobimetallic catalysts was developed. These catalysts function as heterogeneous catalysts to engage nitroethane and a range of trifluoromethyl ketones in a stereoselective assembly to afford CF3-appended vic-nitroalkanols that could be readily converted to enantioenriched vic-amino alcohols, which are privileged structural motifs in medicinal chemistry.

A direct catalytic Mannich-type reaction of α-oxygen-functionalized amides was achieved. The use of 7-azaindoline amide was crucial to facilitate direct enolization and subsequent stereoselective addition to imines in a cooperative catalytic system comprising a soft Lewis acid and Brønsted base. The operationally simple room-temperature protocol furnished a syn-Mannich adduct with high stereoselectivity. Divergent functional group transformation of the amide moiety of the product allowed for expeditious access to enantioenriched syn-configured α-hydroxy-β-amino carboxylic acid derivatives, highlighting the synthetic utility of the present catalysis.

Waste-free catalytic assembly of α-amino acids is fueled by a multiboron catalyst that features a characteristic B3NO2 heterocycle, providing a versatile catalytic protocol wherein functionalized natural α-amino acid units are accommodated and commonly used protecting groups are tolerated. The facile dehydrative conditions eliminate the use of engineered peptide coupling reagents, exemplifying a greener catalytic alternative for peptide coupling. The catalysis is sufficiently robust to enable pentapeptide synthesis, constructing all four amide bond linkages in a catalytic fashion.

Mild solvolytic cleavage of bis(2-pyridyl)amide under neutral and room-temperature conditions is described. The inherently stable amide was readily activated by catalytic amounts of metal cations to react with alcohols. Based on X-ray crystallographic analysis, the primary driving force was considered to be amide distortion induced by the metal coordination of two pyridyl groups in a bidentate fashion without affecting the amide functionality. The compatibility of the acid/base-sensitive functionalities and the absence of racemization during solvolysis highlight the mildness of the present protocol.

Novel fluorinated N1-acylated 7-azaindolines have been synthesized and their conformations analyzed by X-ray diffraction and NMR spectroscopy: Unusual intramolecular interactions between the 7-nitrogen and amide α-hydrogen atoms were identified. The strength of these interactions correlate with the electron-withdrawing character of the amide α substituents. A combination of experimental and computational approaches revealed a significant substituent effect when the substituent (H, OMe, F, CN) at the 4-position of the 7-azaindoline scaffold was varied. As these intramolecular interactions also occur in non-fluorinated N1-acylated 7-azaindolines and similar heterocycles, this study is relevant to medicinal chemistry: The results will facilitate the prediction of the predominant conformations of N1-acylated-7-azaindoline-containing bioactive molecules and thus potentially contribute to drug discovery programs.

The direct catalytic asymmetric aldol reaction is an emerging catalytic methodology that provides atom-economical access to functionalized chiral building blocks. Thioamides are useful aldol donors due to their high-fidelity chemoselective enolization and divergent post-aldol transformations. Herein we describe the incorporation of an α-vinyl appendage on a thioamide, which expands the utility of aldol adducts for natural product synthesis. This vinylated thioamide was not accommodated under the previously identified catalyst settings, but the newly developed catalytic conditions furnished aldol products containing the pendant vinyl group.

Amides are generally considered as a low-reactive chemical entity among the carbonyl group, and therefore fewer opportunities to be involved in catalytic transformations as substrates. The origin of the stable nature of amides is resonance stabilization in the planar structure, which has drawn considerable attention from organic and physical chemists, leading to the discovery of distorted amides that exhibit a substantially reactive nature. Recent focus in this field is on the catalytic transformation of designed amides with moderate distortion or reduced resonance stabilization. This digest reviews the brief history of the quest for highly distorted amides and introduces a collection of recent studies on catalytic transformations of designed amides.

Enantioenriched CF3-substituted tertiary alcohols have been applied in a broad range of chemical disciplines, including medicinal chemistry and agrochemistry. The widely prescribed anti-HIV pharmaceutical efavirenz is one particular example of the application of these chiral building blocks. Because the typical synthetic route to this small drug molecule involves the stoichiometric use of a chiral promoter, significant effort has been devoted to the development of catalytic alternatives for accessing this building block. In this Focus Review, we summarize the catalytic asymmetric synthesis of CF3-substituted tertiary propargylic alcohols based on three retrosynthetic approaches, namely one trifluoromethylation approach and two building-block strategies. The general challenges that are involved in the construction of a CF3-substituted tetrasubstituted stereogenic carbon species are highlighted and possible future directions in the field are discussed.

A direct catalytic asymmetric aldol addition of an α-vinyl 7-azaindoline amide to both aromatic and aliphatic aldehydes was promoted by a cooperative acid/base catalyst in a stereodivergent manner. The key structural element, a 7-azaindoline moiety, facilitated catalytic enolization, allowing for subsequent stereoselective aldol addition. Enantioselective synthesis of the key intermediate of blumiolide C and kainic acid supported the synthetic utility of this protocol.

Amide pronucleophiles were successfully incorporated into a 1,6-conjugate addition reaction manifold using p-quinone methides (p-QMs) as electrophiles. Four different types of functionalities were tolerated as α-substituents of the amides, allowing for expeditious access to a range of enantiomerically enriched diarylmethine products. The 7-azaindoline unit is critically important for in situ catalytic enolization of the amide pronucleophile, engaging in 1,6-conjugate addition to p-QMs with readily available catalyst components.