Diels-Alder reactions enamine catalysis

Diels-Alder Reactions The organocatalytic Diels-Alder reaction of a,P-unsaturated carbonyl compounds can be performed either via iminium (see Section 11.3) or enamine catalysis. The first highly selective enamine-promoted cycloaddition reaction was reported by Jprgensen and coworkers, who developed an amine-catalyzed inverse-electron-demand hetero-Diels-Alder (HDA) reaction (Scheme ll.lOa). ... 

The term aminocatalysis has been coined [4] to designate reactions catalyzed by secondary and primary amines, taking place via enamine and iminium ion intermediates. The field of asymmetric aminocatalysis, initiated both by Hajos and Parrish [5] and by Eder, Sauer, and Wiechert [6] in 1971, has experienced a tremendous renaissance in the past decade [7], triggered by the simultaneous discovery of proline-catalyzed intermolecular aldol [8] and Mannich [9] reactions and of asymmetric Diels-Alder reactions catalyzed by chiral imidazolidinones [10]. Asymmetric enamine and iminium catalysis have been influential in creating the field of asymmetric organocatalysis [11], and probably for this reason aminocatalytic processes have been the object of the majority of mechanistic smdies in organocatalysis. 

Enamine/metal Lewis acid bifunctional catalysis has been used to achieve good yields, des, and excellent ees in hetero-Diels-Alder reactions of six-membered cyclic ketones ... 

The self-assembly of cinchona alkaloid-derived thioureas and proline, which enables the inverse-electron-demand hetero-Diels-Alder reactions between aldehydes R R CHCH=0 and electron-deficient enones R CH=CHCOR", affording (260), has been discussed in the paragraph covering enamine catalysis. ... 

Scheme 38.46 Enamine catalysis of aza-hetero-Diels-Alder reactions.

When using aliphatic aldehydes tethered to arene motifs as substrates, an enan-tioselective sequential aza-hetero-Diels-Alder and Friedel-Crafts reaction was successfully achieved by the same group [63]. Similarly, optically active lactone[3,3-b] piperidine skeletons 140 can be obtained by tandem aza-hetero-Diels-Alder reaction-hemiacetal formation-oxidation from a,P-unsaturated imines 136 and glutaraldehyde (139) (Scheme 38.41) [64]. Enamine catalysis of the inverse-electron-demand aza-hetero-Diels-Alder reaction was further extended to o-benzoquinone diimide 141 by Chen s group [65]. Various hydroquinoxalinones 142 can be obtained in high yields with excellent enantioselectivities (Scheme 38.42). 

Over the past decade, rapid growth has been achieved in organocatalytic asymmetric Diels-Alder and hetero-Diels-Alder reactions. Numerous organocatalysts such as chiral amines, guanidines, N-heterocyclic carbenes, Bronsted acids, and bifunctional catalysts have been successfully developed. The activation modes for these catalysts, such as imine-catalysis, enamine-catalysis, dienamine catalysis. 

In addition to the consecutive aldol reactions of aldehydes, Barbas s group also reported enamine-activated Diels-Alder reactions (or double Michael reactions) between a,P-unsaturated ketones and nitroolefm (Scheme 1.15) for the first time in 2002 [17], hi contrast to MacMillan s iminium catalysis for Diels-Alder reactions, wherein a,P-unsaturated carbonyl compounds were activated as dienophiles in a LUMO-lowering strategy based on iminium formation [3], an alternative strategy involving the in situ generation of 2-amino-1,3-dienes from a,P-unsaturated ketones... 

Schreiber utilized oxazolidine 220, derived from ephedrine, as an auxiliary for asymmetric hetero-Diels-Alder reactions (Scheme 17.31) [113]. In an experiment that anticipates subsequent developments in organic catalysis, condensation of 220 with aldehyde 219 led to covalent attachment of the auxiliary to the substrate, generating enamine 221. The stage was thus set for intramolecular cycloaddition, which afforded 222 as a 17 1 mixture of diaster-eomers. The dihydropyran 222 served as a key intermediate in the synthesis of the macrolide antibiotic brefeldin C (223). 

In this transformation two new C-C-rr-bonds are formed from three different components. The enantioselectivity of this reaction is generally low (< 5%). With cyclic ketones the corresponding products were obtained as single diastereomers. It is proposed that this reaction involves a Knoevenagel-hetero-Diels-Alder sequence where proline utilizes both iminium and enamine catalysis (Scheme 9.20). 

Even though the use of (S)-proline (1) for the synthesis of the Wieland-Miescher ketone, a transformation now known as the Hajos-Parrish-Eder-Sauer-Wiechert reaetion, was reported in the early 1970s, aminocatalysis - namely the catalysis promoted by the use of chiral second-aiy amines - was rediscovered only thirty years later. The renaissance of aminocatalysis was prompted by two independent reports by List et al. on the asymmetric intermolecular aldol addition catalysed by (S)-proline (1) and by MacMillan et al. on the asymmetric Diels-Alder cycloaddition catalj ed by a phenylalanine-derived imidazolidinone 2. These two reactions represented the archetypical examples of asymmetric carbonyl compound activation, via enamine (Figure ll.lA) and iminium-ion (Figure 11.IB), respectively. 

---