Enamine catalysis approach

As discussed above, all of the cinchona-based quaternary ammonium salts used as catalysts gave only poor to moderate diastereoselectivities and enantioselectivities for direct aldol reactions. Quite recently, a highly enantioselective, catalytic, direct aldol reaction was realized by adopting the enamine catalysis approach [12], in which 9-amino-epi-cinchona alkaloids are employed as aminocatalysts [13, 14]. 

In 2007, Connon and McCooey developed highly efficient, asymmetric syn-selective addition reactions of enolizable carbonyl compounds to nitroolefins by adopting the enamine catalysis approach [48]. The 9-epi-amino cinchona alkaloid derivative (160,9 -epi-DHQDA) as an aminocatalyst promoted the addition ofa variety... 

A major advancement for the subfield of enamine catalysis was achieved with the identification of aldehydes as useful donors for similar Mannich reactions.In particular, the addition of mono- or disubstituted aldehydes to ketoi-mines or aldimines, respectively, represents an elegant and highly efficient approach to the enantioselective construction of quaternary a-amino acids (Scheme 11A one-pot, three-component variant of the aldehyde Mannich reaction has also been recently disclosed (Scheme i 296-300... 

In enantioselective enamine catalysis, the enamine can control the approach of the electrophile either by the steric bulk of the enamine or by directing the electrophile with an activating group. As can be readily observed with relatively unreactive electrophiles, such as aldehydes, ketones or imines, additional assistance for catalysis can be provided by suitably positioned hydrogen bond donors and/or other acids (Scheme 6) [46]. 

In fact, this intramolecular version shortly preceded the intermolecular one discussed above, since the first example was disclosed by Kunz and MacMillan in 2005 [89], shortly followed by Jprgensen and co-workers [90]. This approach has proved to be highly versatile, leading to practical enantioselective syntheses of chiral cyclopropanes [89, 91], epoxides [90], and aziridines [92]. Finally, the use of bifunctional synthons in sequential iminium/enamine catalysis provides a very general entry to carbo- and heterocyclic compounds [93]. 

In this reaction, L-proline reacts with a donor component to generate an enamine intermediate, which attacks the acceptor and leads to an iminium adduct. The aldol is released after hydrolysis. Since its discovery, enamine catalysis has been developed into a powerful strategy that complements enzyme and metal catalysis [6, 7]. The attractiveness of this approach is due to the following ... 

Introducing heteroatoms in the a-position of carbonyl groups in a direct approach is one of the types of transformations that have benefitted the most from recent progress in the field of enamine catalysis (105-109). Besides the development of suitable methods for the stereoselective introduction of O- and N-heteroatoms,... 

As depicted in Scheme 7, the synthesis of the mosquito oviposition pheromone (-)-6-acetoxy-5-hexadecanolide (28) via an intermolecular aldol reaction represents a powerful demonstration of the high potential of asymmetric enamine catalysis (45, 46). It is noteworthy that a methodologically different successful organocatalytic approach towards 28, based on an asymmetric a-oxygenation, was reported recently (727). Reaction of aldehyde 136 with dibenzoyl peroxide (BzOOBz) and hydroqui-none (HQ) (722) in the presence of the TMS-protected prolinol catalyst (S)-138 followed by a direct allyation gave the benzoyl-protected 139 in moderate yield and good selectivity. Intermediate 139 could then be further transformed to give (—)-(57 ,65)-6-acetoxy-5-hexadecanolide (28) (Scheme 33). 

When summing up the recent achievements in iminium-activated natural product synthesis, the importance and versatility of this methodology cannot be overemphasized. Besides enamine catalysis, it is due particularly to the considerable achievements made in iminium catalysis that asymmetric organocatalysis has received so much attention over the last few years. As depicted in this chapter, the LUMO-lowering concept originally introduced by MacMillan has found widespread applications in natural product synthesis. In addition, it has been shown, that this activation mode works very well in cascade approaches. This methodology should become more widely utilized in the future (Table 2). 

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). 

It has been shown in this chapter that combined iminium-enamine catalyzed approaches offer the potential to achieve complex (multistep) transformations in a single operational step, thus giving access to high structural complexity combined with excellent effectivity. In addition, it was pointed out also that organocatalysis can be used successfully when combined with metal catalysis e.g. metathesis). Although these complex approaches have been pursued only for the last few years, the results obtained so far are very promising and thus this methodology should be applied more widely in the future (Table 3). 

Nicewicz and MacMillan merged later photoredox catalysis and asymmetric organocatalysis to an efficient approach to the otherwise difficult asymmetric a-alkylation of aldehydes 118 by activated alkyl bromides 117 (Fig. 30) [183]. The concept of face differentiation at the a-position of aldehydes via chiral enamines 121 provides the basis for the method. This allows the formation of functionalized... 

Azole approach. In the cyclocondensation of the l,2,4-oxadiazole-3-enamine (609) with PTSA catalysis the N-2 nitrogen of the azole moiety becomes the bridgehead nitrogen atom <77H(6)107>. 

Addition of HaS to nitriles (73) represents an important method for the synthesis of primary thioamides (74 equation 33). The reaction is carried out under base or acid catalysis. The base-catalyzed process is particularly useful in the preparation of aromatic thioamides, i.e. for R = aryl, hetaryl in (73) triethylamine in molar proportion or pyridine, which at the same time also serves as solvent, are employed most commonly. The approach tolerates the presence of various other functionalities such as an amide, hydrazone, enamine, a-oxo, a-acetoxy ° or a-amino group. Moreover, the reaction has been applied to the synthesis of thioasparagine as such or incorporated into a dipeptide, as shown... 

Type I aldolases activate the aldol donor by the formation of enamines with active site amino acids and an alternate approach to the direct catalytic asymmetric aldol reaction centres on mimicking this process using proline-based organocatalysts. In fact, one of the earliest examples of asymmetric catalysis uses (S)-profine (7.66) as a catalyst for the intramolecular aldol reaction (the Hajos-Eder-Saeur-Wiechert reaction).As an example the achiral triketone (7.67) cyclises to give the aldol product (7.68) with good enantioselectivity. 

Cordova et al. demonstrated in 2005 that the aldol condensation between 4-nitrobenzaldehyde (5 R=p-N02) and cyclic ketones or butanone in the presence of acyclic primary amino acids led to the antz-isomer 6 (Scheme 12.3). One year later, this author described the structure-activity relationship between acyclic amino acids and the aldol derivatives, the synthetic scope of catalysis by acyclic amino acids in aqueous media and water, and studies concerning the reaction mechanism. Excellent enan-tioselectivities (ee up to >99%) were achieved in several cases. As an example of the anh -induction, the (E)-enamine arising from cyclohexanone and the acyclic amino acid could display a proton transfer from the carboxylic acid function to the alkoxide, giving a six-membered chair-like conformation. The favoured approach of the aldehyde would then lead to an anfi-isomer. 

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