Enamine catalysis cascade reactions

In addition to imininm-initiated cascade reactions, two of the steps in enamine-activated cascade reactions can also be enforced by cycle-specific catalysis. It is well known that diphenylprolinol silyl ether catalyst 34 is optimal for diverse enamine-mediated transformations to fnmish prodncts with high enantioselectivities. However, similar to imidazolidinone catalysts, it proved to be less effective or ineffective for bifunctional enamine catalysis. Cycle-specific catalysis via an aza-Michael/Mannich sequence by combining 34 and either enantiomer of proline was thus developed to generate 206 in about 60% yields with excellent diastereo- and enantioselectivities (Scheme 1.89) [139]. 

Recently, List has described a cascade reaction promoted by phosphoric acid 1 in combination with stoichiometric amounts of achiral amine, which transforms various 2,6-diketones to the corresponding ds-cyclohexylamines (Scheme 5.28) [50]. This three-step process involves initial aldolization via enamine catalysis to give conjugate iminium ion intermediate A. Next, asymmetric conjugate reduction followed by a diastereoselective 1,2 hydride addition completes the catalytic cycle. 

One of the first highly enantioselective examples of multicomponent cascade reactions in orgnocatalysis was developed by Enders et al. [62] in 2006. In this report they describe an asymmetric organocatalytic triple cascade reaction for the construction of tetrasubstituted cyclohexenecarbaldehydes (93) starting from from enals (15), nitroalkenes (28), and enolizable aldehydes (94) (Scheme 10.27). In this work, they did the sequential creation of three bonds by a high enantioselective combination of enamine-iminium-enamine catalysis for a triple cascade reaction. 

Cascade reactions have attracted considerable interest over the last years as they can facilitate the short-step preparation of complex structural motifs in good yields. It was already shown in Sect. 2.6 that enamine catalysis can be successfully employed in organocascade reactions to access complex natural products. 

The main focus in this chapter will be on combined approaches using enamine catalysis and iminium catalysis especially in one-pot cascade reactions. As discussed in the following examples, the combined use of these two activation modes has led to the development of some of the most impressive and efficient organocatalytic natural product syntheses conducted so far (301-305). 

SCHEME 6.12 Cascade reaction through iminium-enamine catalysis. 

Double Cascade Reactions Amine-based organocatalysis are often employed for these cascade reactions because they can present a dual-activation mode depending the system involved, via enamine or iminium catalysis. 

Cascade Reaction-Merging Iminium and Enamine Catalysis... 

Cascade Reaction-Merging iminium and Enamine Catalysis 187... 

These findings were extended to a set of very useful cascade reactions by the MacMiUan group [111]. In a first series 1,4-hydride additions were combined with aminations, oxidations, or Mannich reactions (Scheme 4.30). The hydride transfer was catalyzed by imidazoHdinone 9, whereas subsequent functionalization was realized by enamine catalysis through the deployment of proline. Depending on the chirality of proline used, optically pure anti- or syu-configured products 84-86 were isolated. 

Cascade Reaction-Merging tminium and Enamine Catalysis 89 fiu02C . /C02fiu... 

Using 2-iodmybenzoic acid (IBX) as the oxidant, Wang et al. achieved one-step formal conjugate addition of active methylene compounds in moderate yield with excellent enantioselectivity (Scheme 7.20). In a related study, Enders applied this p-activation of saturated aldehydes with IBX to amine-catalyzed cascade reactions for the synthesis of cyclohexene derivatives. Furthermore, Xu et al. succeeded in replacing stoichiometric oxidants with dio q gen by combining enamine catalysis with Pd-catalyzed aerobic oxidation. ... 

Chiral amine-mediated organocaialytic cascade reactions have become a benchmaik in contemporary organic synthesis, as wimessed by a number of cascade processes developed in the past decade [1]. The great success is attributed to two unique interconveilible activation modes, enamine [2] and iminium activations [3]. Enamine catalysis has been widely applied to the a-functionalizations of aldehydes and ketones. Mechanistically, dehydration between a chiral amine and the carbonyl of an aldehyde or ketone generates an intermediate, 2, which undergoes an enantioselective a-substitution or nucleophilic addition reaction to produce respective iminium intermediate 3 or 5 (Scheme 1.1). Hydrolysis affords the products and, meanwhile, releases the chiral amine catalyst. 

We define the cascade reactions initiated by enamine catalysis in the initial step as an enamine-activated mode, although an iminium mode might be involved in the following steps. In this regard, several catalytic cascade sequences, including enamine-enamine, enamine-iminium, and enamine cyclization, are discussed here. 

This catalytic cascade is a three-component reaction comprising a linear aldehyde, a nitroaUcene, an a,p-unsaturated aldehyde, and a simple chiral secondary amine. The catalyst mediates the Michael addition of the linear aldehyde to the nitroalkene via enamine catalysis in the first step. Then the catalyst is liberated by hydrolysis to form the iminium ion of the a,P-unsaturated aldehyde to accomplish the conjugate addition... 

In an effort to develop new cascade reactions, Zhang et al. envisioned that a linear aldehyde can also be genaated in situ via an extra iminium catalysis from an ot,p-unsaturated aldehyde prior to the triple cascade reaction. Therefore, there would be a possibility of extending the triple cascade reactions to four-component cascade reactions. Based on this design, a four-component quadruple cascade reaction through iminium-enamine-iminium-enamine sequential activation initiated by oxa-Michael addition of alcohol to acrolein in moderate yield (about 50%), excellent diastereoselectivities (>20 1), and excellent enantioselectivities (>99% ee) was accomplished (Scheme 1.33) [47]. 

Design of Enomine-Cyclization Cascade Reactions The nucleophilic Y in intermediate 6 can react with other electrophiles intermolecularly (Scheme 1.34a) or intramolecularly (Scheme 1.34b) as well as with the iminium ion. Moreover, the carbonyl group of 6 can also undergo intramolecular aldol reaction with nucleophilic X (Scheme 1.34c). These nucleophilic addition reactions after enamine catalysis induce cyclization reactions to produce versatile five- or six-membered ring structures. 

The cascade reactions induced by iminium catalysis in the first step are defined as iminium-activated cascade reactions, although almost all of the iminium-initiated cascade reactions are followed by an enamine-mediated process in the subsequent step. Considerable effort has been directed to construction of diverse cyclic structures via the iminium-enamine catalytic sequence. 

Chiral amine catalysts have also been used in cascade reactions mediated by SOMO catalysis [143] and Lewis base catalysis [144]. MacMillan s group developed a powerful cascade reaction moderated by SOMO catalysis. The radical cation, generated from an enamine in condensation of imidazolidinone catalyst 208 with aldehyde 207 and subsequent oxidation by Cu oxidant, was expected to engage in a series of 6-endo-trig radical cyclizations terminated by a suitable arene to give a cyclohexadi-enyl radical. After a second oxidation, rearomatization, and liberation of the catalyst, the requisite 209 would be generated (Scheme 1.90). 

Beyond the organic chemists initial imagination, two unique interconvertible enamine and iminium activation modes have produced a number of unprecedented powerful cascade processes in the formation of diverse complex stractures with high efficiency and excellent stereoselectivities. This not only expands the scope of amino catalysis significantly, but more important, affords new and efficient synthetic methods in organic synthesis. It is expected that new cascade reactions with activation modes will continue to be developed to meet the synthetic danand. 

Although the first step is mediated by iminium eatalysis, this work was summarized into enamine-activated catalysis as a continuation of triple cascade reactions. Zhang, F., Xu, A., Gong, Y, Wei, M., and Yang, X. (2009) Chem. Eur. J., 15, 6815-6818. 

---