Jeffrey W. Bode

Rethinking amide bond synthesis

One of the most important reactions in organic chemistry—amide bond formation—is often overlooked as a contemporary challenge because of the widespread occurrence of amides in modern pharmaceuticals and biologically active compounds. But existing methods are reaching their inherent limits, and concerns about their waste and expense are becoming sharper. Novel chemical approaches to amide formation are therefore being developed. Here we review and summarize a new generation of amide-forming reactions that may contribute to solving these problems. We also consider their potential application to current synthetic challenges, including the development of catalytic amide formation, the synthesis of therapeutic peptides and the preparation of modified peptides and proteins.

An Enantioselective Claisen Rearrangement Catalyzed by N-Heterocyclic Carbenes

In the presence of a chiral azolium salt (10 mol %), enols and ynals undergo a highly enantioselective annulation reaction to form enantiomerically enriched dihydropyranones via an N-heterocyclic carbene catalyzed variant of the Claisen rearrangement. Unlike other azolium-catalyzed reactions, this process requires no added base to generate the putative NHC-catalyst, and our investigations demonstrate that the counterion of the azolium salt plays a key role in the formation of the catalytically active species. Detailed kinetic studies eliminate a potential 1,4-addition as the mechanistic pathway; the observed rate law and activation parameters are consistent with a Claisen rearrangement as the rate-limiting step. This catalytic system was applied to the synthesis of enantioenriched kojic acid derivatives, a reaction of demonstrated synthetic utility for which other methods for catalytic enantioselective Claisen rearrangements have not provided a satisfactory solution.

Catalytic Selective Synthesis

Complete control of the product of a catalytic reaction can be achieved on the basis of catalyst structure, even when the reaction conditions are nearly identical. Catalyst-controlled selectivity is well established for enantioselective catalysis but less formulated for catalytic regio-, chemo-, or product-selective reactions. This Review describes selective transformations of the same starting materials into two or more different products simply by the choice of catalyst. By collecting and highlighting examples of selective catalysis, we hope that the field will be encouraged by the progress that has been made while bringing attention to unmet needs in the design and mechanistic understanding of selective catalysts.

The effect of the N-mesityl group in NHC-catalyzed reactions.

The majority of N-heterocyclic carbene catalyzed reactions of α-functionalized aldehydes, including annulations, oxidations, and redox reactions, occur more rapidly with N-mesityl substituted NHCs. In many cases, no reaction occurs with NHCs lacking ortho-substituted aromatics. By careful competition studies, catalyst analogue synthesis, mechanistic investigations, and consideration of the elementary steps in NHC-catalyzed reactions of enals, we have determined that the effect of the N-mesityl group is to render the initial addition of the NHC to the aldehyde irreversible, thereby accelerating the formation of the Breslow intermediate. These studies rationalize the experimentally observed catalyst preference for all classes of NHC-catalyzed reactions of aldehydes and provide a roadmap for catalyst selection and design.

Cyclic ketimines as superior electrophiles for NHC-catalyzed homoenolate additions with broad scope and low catalyst loadings.

Cyclic sulfonyl imines derived from ketones were identified as stable and readily prepared compounds that serve as superior electrophiles for N-heterocyclic carbene (NHC)-catalyzed annulations with alpha,beta-unsaturated aldehydes to afford highly substituted gamma-lactams. Their superior reactivity and properties are highlighted by the first example of NHC-catalyzed reactions of enals with low catalyst loadings (0.5 mol %) and broad substrate scope encompassing alkyl, aryl, and heteroaromatic substituents. These findings and supporting studies suggest an alternative, ene-like mechanism rather than the catalytic generation of a catalyst-bound homoenolate equivalent.

Chiral N-heterocyclic carbene-catalyzed generation of ester enolate equivalents from α,β-unsaturated aldehydes for enantioselective Diels–Alder reactions

The catalytic generation of chiral ester enolate equivalents from α,β-unsaturated aldehydes with chiral N-hetereocyclic carbene catalysts makes possible highly enantioselective hetero-Diels–Alder reactions. The reactions proceed under simple, mild conditions with both aliphatic and aromatic substituted enals as substrates. Previous attempts to employ these starting materials as enolate precursors gave structurally different products via catalytically generated homoenolate equivalents. Critical to the success of the enolate generation was the strength of the catalytic base used to generate the active N-heterocyclic carbene catalyst. To complement these studies, we have investigated the enolate structure using computational methods and find that it prefers conformations perpendicular to the triazolium core.

α,β-Unsaturated Acyl Azoliums from N-Heterocyclic Carbene Catalyzed Reactions: Observation and Mechanistic Investigation

Catalytically generated acyl azoliums I and their a,b-unsaturated counterparts II are thought to be key reactive intermediates in a rapidly growing number of transformations promoted by N-heterocyclic carbene (NHC) catalysts. Acyl azoliums are invoked in the postulated catalytic cycles of nearly all of the new NHC-catalyzed reactions of a-functionalized aldehydes reported since 2004, in which they are generally assumed to possess the reactivity of an activated carboxylic acid, that is, analogous to an activated ester. In NHC-catalyzed processes, they are most often obtained through internal redox reactions of functionalized aldehydes but have also been prepared by oxidations of the Breslow intermediates or additions to ketenes. Acyl azoliums I are important intermediates in thiamine pyrophosphate (ThPP) dependent enzymatic reactions. Townsend et al. have recently proposed that unsaturated acyl azolium III is the key intermediate in clavulanic acid biosynthesis; despite careful efforts, III or its analogues II have never been characterized or independently synthesized. Here, we document the observation and characterization of a,b-unsaturated acyl azoliums 1 and 2 (Scheme 1) and demonstrate that their corresponding hemiacetals (1’ and 2’) are the kinetically important intermediates in both their acylation and annulation reactions. Simple acyl azoliums prepared under stoichiometric conditions were extensively studied in a seminal work by Breslow and continued by Daigo, White and Ingraham, Bruice, Lienhard, and Owen. These investigations revealed the unique and rich chemistry of acyl azoliums, including their remarkable reluctance to acylate amines and high preference for reactions with water or alcohols. Despite the more than 120 publications since 2004 that feature acyl azoliums, including the rediscovery of their unusual chemoselectivity, there have been no reports of the isolation, detection, or properties of novel acyl azoliums thought to be generated under catalytic conditions. Even at high catalyst loadings, most NHC-catalyzed reactions do not give any detectable intermediates that can be observed with conventional techniques such as UV, IR, NMR spectroscopy, or MS methods. For example, no intermediates could be observed during the redox esterification of cinnamaldehyde, even when the reaction was run with high catalyst loadings or in the absence of base to ensure slow reaction. This is consistent with NMR studies of the redox esterification of ynals by Zeitler, in which the postulated a,bunsaturated acyl azolium II was not observed. Our recent studies of reactions of ynals catalyzed by azolium salts revealed that the rate-limiting step of the catalytic cycle occurs after the formation of the acyl azolium. These findings strongly suggested that generation of substantial amounts of the a,b-unsaturated acyl azolium intermediate should be possible in the absence of a nucleophile. Careful preparation of a mixture of triazolium 3 and para-chlorophenyl ynal 4 in anhydrous CDCl3 gives a clear solution (Figure 1). Upon addition of NaOAc, the solution rapidly becomes yellow, and turns deep red within 20 minutes. The color change was monitored by UV/Vis spectroscopy, and we observed a maximum absorption at 355 nm, with a significantly smaller absorption at 520 nm, for the solution containing acyl azolium 1 (Figure 2). Townsend et al. have speculated that the related protein-bound species III (Scheme 1) has a characteristic UV/Vis absorption at 310– 320 nm. Our mixture was further investigated by electrospray ionization–high resolution mass spectrometry (ESIHRMS), which verified the molecular formula of 1 (Figure 2). Scheme 1. Various acyl azoliums and the hemiacetals.

Synthesis of Saturated N-Heterocycles

Saturated N-heterocycles are prevalent in biologically active molecules and are increasingly attractive scaffolds in the development of new pharmaceuticals. Unlike their aromatic counterparts, there are limited strategies for facile construction of substituted saturated N-heterocycles by convergent, predictable methods. In this Synopsis, we discuss recent advances in the synthesis of these compounds, focusing on approaches that offer generality and convenience from widely available building blocks.

Stereodivergency of Triazolium and Imidazolium-Derived NHCs for Catalytic, Enantioselective Cyclopentane Synthesis

Chiral triazolium- and imidazolium-derived N-heterocyclic carbene catalysts promote the direct annulation of alpha,beta-unsaturated aldehydes and achiral alpha-hydroxy enones to afford cyclopentane-fused lactones with high enantioselectivity. Remarkably, otherwise structurally identical imidazolium and triazolium precatalysts afford different major products. These studies provide both an efficient entry to valuable chiral structures and a dramatic demonstration of stereodivergency of chiral imidazolium versus triazolium-derived N-heterocyclic carbene catalysts.

Catalytic kinetic resolution of cyclic secondary amines.

The catalytic resolution of racemic cyclic amines has been achieved by an enantioselective amidation reaction featuring an achiral N-heterocyclic carbene catalyst and a new chiral hydroxamic acid cocatalyst working in concert. The reactions proceed at room temperature, do not generate nonvolatile byproducts, and provide enantioenriched amines by aqueous extraction.