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.The seminal example of the reversal of functional group polarity, the benzoin reaction, dates to 1832, when Wöhler and Liebig reported that cyanide catalyzes the formation of benzoin from two equivalents of benzaldehyde (eq. 1). 1,2 In 1943, Ukai et al showed that thiazolium salts catalyze the homodimerization of aldehydes in the presence of base. 3 A related Umpolung 4 transformation is the Stetter reaction, the conjugate addition of the aldehyde into a Michael acceptor. 5 Utilizing cyanide or thiazolylidene carbenes as catalysts, Stetter demonstrated that a variety of aromatic and aliphatic aldehydes are competent nucleophilic coupling partners with a wide range of α, β-unsaturated ketones, esters, and nitriles. 6 The ability to bring two different electrophilic partners together and form a new carbon-carbon bond enhances the potential utility of this transformation.Our group has developed chiral triazolinylidene carbenes and precursors, 1-3, for a variety of carbene mediated transformations. 7 We have shown that the carbenes derived from 1 and 2 are capable of inducing the cyclization of aromatic and aliphatic aldehydes to α,β-unsaturated esters, ketones, thioesters, amides, aldehydes, and nitriles. 8 Mechanistic insight into organocatalytic reactions is important for the development of general transformations. 11 To the best of our knowledge a detailed study probing the mechanism of the Stetter reaction has not been reported. In the absence of such a study the working model of the Stetter reaction is based on the Breslow mechanism for the thiamincatalyzed benzoin reaction. 12,13 The mechanism is closely related to Lapworth's mechanism for cyanide anion catalyzed benzoin reaction. 14 As with the cyanide catalyzed benzoin reaction, the thiazolinylidene catalyzed reaction is reversible. 15 The proposed catalytic cycle is as follows: the carbene I (Scheme 1), formed in situ by base deprotonation of the corresponding azolium salt, adds to the aldehyde to form II. A proton transfer event generates acyl anion equivalent III, termed the nucleophilic alkene or Breslow intermediate. Subsequent addition into the Michael acceptor forms a new carbon-carbon bond to generate IV. A second proton transfer event then provides V. Finally, collapse of this tetrahedral intermediate V to form Stetter product is accompanied by liberation of the active catalyst. As we strive to understand differences in catalysts and continue to ...

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Peptide macrocycles are widely utilized in the development of high affinity ligands, including stapled α-helices. The linear rigidity of a 1,3-diynyl linkage provides an optimal distance (7 Å) between β-carbons of the i,i+4 amino acid side chains, thus suggesting its utility in stabilizing α-helical structures. Here, we report the development of an on-resin strategy for an intramolecular Glaser reaction between two alkyne-terminated side chains by using copper chloride, an essential bpy-diol ligand, and diisopropylethylamine at room temperature. The efficiency of this ligation was illustrated by the synthesis of (i,i+4)-, (i,i+5)-, (i,i+6)-, and (i,i+7)-stapled BCL-9 α-helical peptides using the unnatural amino acid propargyl serine. Overall, this procedurally simple method relies on inexpensive and widely available reagents to generate low molecular weight 23-, 26-, 29-, and 32-membered peptide macrocycles.

A bimetallic Rh(II) catalyst promoted the C-H alkenylation of simple arenes at 1.0 equivalent without the use of a directing group. A phosphine ligand as well as cooperative reoxidation of Rh(II) with Cu(TFA)2 and V2O5 proved essential in providing monoalkenylated products in good yields and selectivities, especially with di- and trisubstituted arenes.

Certain lipid injectable emulsions packaged in plastic containers have baseline abnormal GSD profiles compared with those packaged in glass containers. When used to compound TNAs, the abnormal profile worsens and produces less stable TNAs than those compounded with lipid injectable emulsions packaged in glass containers.