Asymmetric Ion-Pairing Catalysis Brak, Katrien; Jacobsen, Eric N.
Angewandte Chemie (International ed.),
January 7, 2013, Letnik:
52, Številka:
2
Journal Article
Recenzirano
Odprti dostop
Charged intermediates and reagents are ubiquitous in organic transformations. The interaction of these ionic species with chiral neutral, anionic, or cationic small molecules has emerged as a ...powerful strategy for catalytic, enantioselective synthesis. This review describes developments in the burgeoning field of asymmetric ion‐pairing catalysis with an emphasis on the insights that have been gleaned into the structural and mechanistic features that contribute to high asymmetric induction.
Framing the field, this review provides an overview of four ion‐pairing strategies that have emerged for asymmetric catalysis of transformations proceeding through charged intermediates or reagents (see picture). Particular emphasis is placed on the mechanistic features that enable high asymmetric induction in these systems.
Disease overview
Follicular lymphoma (FL) is generally an indolent B cell lymphoproliferative disorder of transformed follicular center B cells. Follicular lymphoma is characterized by diffuse ...lymphadenopathy, bone marrow involvement, and splenomegaly. Extranodal involvement is less common. Cytopenias are relatively common but constitutional symptoms of fever, night sweats, and weight loss are uncommon in the absence of transformation to diffuse large B cell lymphoma.
Diagnosis
The diagnosis is based on histology from a biopsy of a lymph node or other affected tissue. Incisional biopsy is preferred over needle biopsies in order to give adequate tissue to assign grade and assess for transformation. Immunohistochemical staining is positive in virtually all cases for cell surface CD19, CD20, CD10 and monoclonal immunoglobulin, as well as cytoplasmic expression of bcl‐2 protein. The overwhelming majority of cases have the characteristic t(14;18) translocation involving the IgH/bcl‐2 genes.
Risk stratification
The Follicular Lymphoma International Prognostic Index (FLIPI) uses five independent predictors of inferior survival: age > 60 years, hemoglobin <12 g/dL, serum LDH > normal, Ann Arbor stage III/IV, number of involved nodal areas >4. The presence of 0‐1, 2, and ≥ 3 adverse factors defines low, intermediate, and high‐risk disease. There are other clinical prognostic models but the FLIPI remains the most common. Other factors such as time to relapse of less than 2 years from chemoimmunotherapy and specific gene mutations may also be useful for prognosis. Regardless of the prognostic model used, modern therapies have demonstrably improved prognosis.
Risk‐adapted therapy
Observation continues to be appropriate for asymptomatic patients with low bulk disease and no cytopenias. There is no overall survival advantage for early treatment with either chemotherapy or single agent rituximab. For patients needing therapy, most patients are treated with chemoimmunotherapy, which has improved response rates, duration of response and overall survival (OS). Randomized studies have shown additional benefit for maintenance rituximab. Lenalidomide was non‐inferior to chemoimmunotherapy in a randomized front‐line study and, when combined with rituximab, was superior to rituximab alone in relapsed FL. Kinase inhibitors, other immunotherapies, and stem cell transplantation (SCT) are also considered for recurrent disease.
Difluoromethyl groups possess specific steric and electronic properties that invite their use as chemically inert surrogates of alcohols, thiols, and other polar functional groups important in a wide ...assortment of molecular recognition processes. We report here a method for the catalytic, asymmetric, migratory geminal difluorination of β-substituted styrenes to access a variety of products bearing difluoromethylated tertiary or quaternary stereocenters. The reaction uses commercially available reagents (m-chloroperbenzoic acid and hydrogen fluoride pyridine) and a simple chiral aryl iodide catalyst and is carried out readily on a gram scale. Substituent effects and temperature-dependent variations in enantioselectivity suggest that cation-π interactions play an important role in stereodifferentiation by the catalyst.
We describe a direct, catalytic approach to the 1,2-difluorination of alkenes. The method utilizes a nucleophilic fluoride source and an oxidant in conjunction with an aryl iodide catalyst and is ...applicable to alkenes with all types of substitution patterns. In general, the vicinal difluoride products are produced with high diastereoselectivities. The observed sense of stereoinduction implicates anchimeric assistance pathways in reactions of alkenes bearing neighboring Lewis basic functionality.
Catalysis by small molecules (≤1000 Da, 10−9 m) that are capable of binding and activating substrates through attractive, noncovalent interactions has emerged as an important approach in organic and ...organometallic chemistry. While the canonical noncovalent interactions, including hydrogen bonding, ion pairing, and π stacking, have become mainstays of catalyst design, the cation–π interaction has been comparatively underutilized in this context since its discovery in the 1980s. However, like a hydrogen bond, the cation–π interaction exhibits a typical binding affinity of several kcal mol−1 with substantial directionality. These properties render it attractive as a design element for the development of small‐molecule catalysts, and in recent years, the catalysis community has begun to take advantage of these features, drawing inspiration from pioneering research in molecular recognition and structural biology. This Review surveys the burgeoning application of the cation–π interaction in catalysis.
Positive effects: This Review discusses the burgeoning role of the cation–π interaction in the small‐molecule catalysis of organic and organometallic reactions. An extensive survey of the state‐of‐the‐art research emphasizes how unexpected discoveries and systematic mechanistic studies have begun to enable rational applications of the cation–π interaction in catalyst design.
Nucleophilic aromatic substitution (S
Ar) is one of the most widely applied reaction classes in pharmaceutical and chemical research, providing a broadly useful platform for the modification of ...aromatic ring scaffolds. The generally accepted mechanism for S
Ar reactions involves a two-step addition-elimination sequence via a discrete, non-aromatic Meisenheimer complex. Here we use
C/
C kinetic isotope effect (KIE) studies and computational analyses to provide evidence that prototypical S
Ar reactions in fact proceed through concerted mechanisms. The KIE measurements were made possible by a new technique that leverages the high sensitivity of
F as an NMR nucleus to quantitate the degree of isotopic fractionation. This sensitive technique permits the measurement of KIEs on 10 mg of natural abundance material in one overnight acquisition. As a result, it provides a practical tool for performing detailed mechanistic analyses of reactions that form or break C-F bonds.
Catalysis by neutral, organic, small molecules capable of binding and activating substrates solely via noncovalent interactions—particularly H-bonding—has emerged as an important approach in ...organocatalysis. The mechanisms by which such small molecule catalysts induce high enantioselectivity may be quite different from those used by catalysts that rely on covalent interactions with substrates. Attractive noncovalent interactions are weaker, less distance dependent, less directional, and more affected by entropy than covalent interactions. However, the conformational constraint required for high stereoinduction may be achieved, in principle, if multiple noncovalent attractive interactions are operating in concert. This perspective will outline some recent efforts to elucidate the cooperative mechanisms responsible for stereoinduction in highly enantioselective reactions promoted by noncovalent catalysts.
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