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1.1.7 Iminium Catalysis

DOI: 10.1055/sos-SD-204-00129

MacMillan, D. W. C.; Watson, A. J. B.Science of Synthesis: Asymmetric Organocatalysis, (20121309.

General Introduction

α,β-Unsaturated carbonyl compounds are one of the most synthetically valuable classes of substrates available to the preparative chemist. These species have enjoyed such a distinguished position for over 120 years due to the reactivity imparted to the alkenic moiety by the electron-withdrawing carbonyl vector, which enables fundamental synthetic transformations such as the 1,4-addition category of chemical bond formations.[‌1‌] Since the discovery of the first conjugate addition process by Komnenos in 1883,[‌1‌‌3‌] the 1,4-addition reaction has become a mainstay of chemical synthesis, affording a host of powerful carboncarbon and carbonheteroatom bond-forming technologies. The potential to develop asymmetric processes was quickly realized, using a number of different approaches, and continues to be an area of intense research activity.[‌1‌,‌4‌‌13‌]

The synthetic flexibility of asymmetric 1,4-addition reactions in terms of both the α,β-unsaturated substrate and the nucleophilic component has provided the chemical community with a generic, yet extensively versatile, method for the rapid installation of carboncarbon and carbonheteroatom stereogenicity. Additionally, since the products retain the activating carbonyl group functionality, which can subsequently be further functionalized using a variety of established protocols, enantioselective 1,4-addition reactions provide access to a bank of products with substantially greater intrinsic value and broader utility. Accordingly, the continued development of new synthetic technologies that enhance this key bond-forming strategy is of global interest.

In this context, with its foundations in the pioneering work of Knoevenagel described over 100 years ago[‌14‌,‌15‌] and based upon the seminal work of Langenbeck in the 1930s,[‌16‌] activation of an α,β-unsaturated compound by condensation with a chiral amine catalyst, to provide the corresponding iminium species which can then participate in enantioselective 1,4-addition processes, has been known for over 20 years. Yamaguchi first described the potential for prolinate salts to perform effectively as catalysts in this role through a series of publications in the 1990s.[‌17‌‌21‌] In addition to this, several other scattered reports of what has come to be generally known as iminium activation have been documented.[‌22‌,‌23‌] However, it was not until 2000 and the launch of organocatalysis that iminium catalysis[‌24‌‌26‌] was identified as a general activation mode for asymmetric catalysis through MacMillanʼs chiral, amine-catalyzed enantioselective DielsAlder reaction.[‌27‌]

This organocatalytic manifold was founded on the mechanistic hypothesis that the reversible formation of iminium ions, from α,β-unsaturated carbonyl compounds and chiral secondary amines, might emulate the equilibrium dynamics and π-orbital electronics that are inherent to Lewis acid catalysis, i.e. LUMO-lowering activation (Scheme 1).[‌27‌]

Scheme 1 Lewis Acid Catalysis and Iminium Catalysis: Enantioselective 1,4-Addition via LUMO-Lowering Activation

This key initial publication provided the inspiration for a new wave of research within the enantioselective 1,4-addition arena and has since seen extensive exploitation.[‌24‌‌26‌] Considerable efforts have also been directed toward the identification of new categories of organocatalyst to broaden the substrate scope and reaction classes amenable to the iminium catalysis paradigm, providing a spectrum of highly enantioselective bond-forming reaction types. Additionally, iminium catalysis technologies (and, indeed, organocatalysis in general) are receiving continually increasing application within complex molecule synthesis.[‌28‌]

This chapter describes the application of iminium catalysis toward the enantioselective construction of carboncarbon and carbonheteroatom bonds. Included in this are cycloaddition processes (Section and β-functionalization with nucleophilic agents (Section While there is an extensive array of cascade processes that employ iminium catalysis as a central feature, this overall very expansive topic is beyond the scope of this chapter. However, iminium-initiated formal [2+1]-cascade cycloaddition processes (cyclopropanation, aziridination, and epoxidation) have been included (Section

There are several general aspects of iminium catalysis that should be noted and care should be taken to address these prior to employing this activation mode, specifically on substrates that are untested (or at least that have not been communicated in the chemical literature). These general points are detailed below and are supplemented with more specific analyses within the relevant subject section.

Catalyst Selection: Selection of a suitable catalyst is crucial to the successful outcome of the cycloaddition or 1,4-addition reaction. While many amines are able to catalyze the iminium-based bond-forming event, the reaction efficiency/output and stereochemical induction capabilities of catalysts can vary widely. As will be seen, there are several privileged catalyst categories, many of which are now commercially available or can be made in several straightforward steps. However, it should be noted that some of the more reaction-specific catalysts can require a more laborious preparation. In addition, acid cocatalysts are necessary for some catalysts and this ancillary component can also profoundly impact the reaction outcome. Indeed, it is not unusual for reactions in which acid cocatalysts are necessary to use the same amine catalyst but as a different acid salt. Selections of the general catalysts that have been shown to effectively mediate a particular transformation are provided for each reaction type.

Catalyst Loading: Organocatalyst loadings can vary substantially depending on the desired transformation. Loadings can be usefully low [e.g., 5mol% (0.05 equiv) and some have been described with yet lower levels] or considerably higher [e.g., 50mol% (0.5 equiv)]. In general, a loading of 20mol% (0.2 equiv) would be a suitable starting point when attempting a transformation on an unknown substrate.

Scale: Most iminium-catalyzed reactions are performed on a millimolar scale or below, although some have been described on a considerably larger (multigram) scale.

Reagent Economy: This can vary significantly depending on the transformation and care should be taken to note the relative quantities of a particular component. Potential users should pay particular attention to the equivalents of the α,β-unsaturated carbonyl substrate employed since many processes use the carbonyl component in excess. This may be especially prohibitive when considering use on an advanced intermediate enal or enone that has required multiple steps to prepare. Reaction molarities are also highly dependent on the specific conditions employed and the values quoted in the example procedures for this chapter are based on the limiting reagent.

Reaction Temperature: Generally reaction specific, some reactions can be carried out conveniently at room temperature while many are cooled and a few are heated. Temperatures for the examples surveyed for this chapter range from 88 to +50°C.

Reaction Time: Many iminium-catalyzed reactions are usefully fast and are complete within a few hours or less, while others can require significantly longer time periods. Reactions are typically monitored by TLC, 1HNMR, GC, HPLC, or SFC for consumption of the limiting reagent.

Product Isolation: Where possible, the direct products of a particular transformation have been isolated, although derivatization steps are not uncommon, particularly with aldehydes in which reduction to the alcohol (typically with NaBH4) is the transformation most often employed. Additionally, there are examples in which only the instrument yield is given, i.e. the yield as obtained from a particular analytical instrument, typically estimated using an internal standard.

Analysis: Analyses of conversion and enantioselectivity are achieved using a combination of NMR, GC, HPLC, and/or SFC techniques. For convenience, and where possible, the method of analysis of selectivity for a specific example has been noted. Determination of enantioselectivity often requires derivatization, e.g. to the corresponding alcohol.

Utility: A priori determination of whether or not a transformation will be successful on an untested (or unpublished) substrate is difficult. Authors of the parent research typically include commonly encountered functional groups such as esters, carbamates, alkenes, and aromatic/heteroaromatic residues within their example sets; however, many manuscripts detail only very simple substrates. Discussion of unsuccessful reactions within research articles is also particularly useful in gauging the likelihood of success on new substrates although, it must be said, such discussions of the limitations of new synthetic technologies (not exclusively within this area) can be disappointingly low in frequency.

Waste Output: Waste associated with iminium catalysis can be relatively high, especially when catalyst loadings are around 0.2 equivalents or greater. However, it is possible to recover catalysts at the end of the reaction and polymer-supported catalysts have been the subject of much interest. Perhaps more significantly, many transformations operate with excesses of a particular reagent. However, the waste output should be considered in context with more conventional chemical strategies that would otherwise be employed to access the same product.

For illustrative purposes, a general iminium-catalyzed β-functionalization catalytic cycle, employing an imidazolidinone organocatalyst, is shown in Scheme 2.

Scheme 2 General Iminium-Catalyzed Enantioselective β-Functionalization