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AMINE-CATALYZED CASCADE REACTIONS

AIGUO SONG AND WEI WANG

1.1 INTRODUCTION

Chiral amine-mediated organocatalytic cascade reactions have become a benchmark in contemporary organic synthesis, as witnessed by a number of cascade processes developed in the past decade [1]. The great success is attributed to two unique interconvertible activation modes, enamine [2] and iminium activations [3]. Enamine catalysis has been widely applied to the α-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 α-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.

SCHEME 1.1 Enamine-catalyzed nucleophilic substitution (a) and addition (b) reactions.

SCHEME 1.2 Iminium catalysis.

Correspondingly, iminium catalysis involves nucleophilic addition to the β-position of an iminium species 8 derived from an α,β-unsaturated aldehyde or ketone 7 with an amine catalyst (Scheme 1.2).

1.2 ENAMINE-ACTIVATED CASCADE REACTIONS

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.

1.2.1 Enamine–Enamine Cascades

1.2.1.1 Design of Enamine–Enamine Cascades

Three possible active sites (e.g., carbonyl group, nucleophilic α- and Y-positions) of enamine catalysis product 4 or 6 (Figure 1.1) can be further functionalized via a second enamine process in a cascade manner. Taking advantage of the electrophilic carbonyl in 4 and 6, intermolecular enamine–enamine (Scheme 1.3a ) and enamine–enamine cyclization (Scheme 1.3b ) cascades could be possible. In addition, the α-position of the same (Scheme 1.3c ) or different (Scheme 1.3d , e.g., Robinson annulation) carbonyl group can be subjected to a second enamine process.

FIGURE 1.1 Possible sites of enamine catalysis products for a second enamine-activated process.

1.2.1.2 Examples of Enamine–Enamine and Enamine–Enamine Cyclization Cascades

Inspired by a 2-deoxyribose-5-phosphate aldolase (DERA)–catalyzed double-aldol sequence using only acetaldehyde to afford cyclized trimer 23 (Scheme 1.4) [4], Códova et al. conducted L-proline-catalyzed direct asymmetric self-aldolization of acetaldehyde, furnishing a triketide 24, instead of trimer 23, with 90% ee and 10% yield for the first time [5].

SCHEME 1.3 Design of enamine–enamine cascade catalysis.

SCHEME 1.4 Aldolase- and proline-catalyzed self-aldolization of acetaldehyde.

The mechanism proposed suggested that an enamine was involved in an Re-facial attack of the carbonyl group of acetaldehyde (Scheme 1.5). After the carbon–carbon bond-forming step, the resulting reactive iminium ion, instead of being hydrolyzed, underwent a Mannich type of condensation [6] to give 24.

SCHEME 1.5 Mechanism proposed for proline-catalyzed self-aldolization of acetaldehyde.

Although the formation of hemiacetal 23 from acetaldehyde did not result from the use of L-proline, trimeric aldol product 25 was obtained in 12% isolated yield with propionaldehyde [7]. Slow addition of propionaldehyde to the reaction produced 25 in a significantly improved yield (53%) as a 1 : 8 mixture of diastereomers (Scheme 1.6). Subsequent oxidation of the product enabled the synthesis of lactone 26 with modest enantioselectivity (47% ee).

Reactions involving nonequivalent aldehydes were also examined. When 2 equiv of propionaldehyde was added slowly over 24 h to acceptor aldehydes such as isobutyraldehyde or isovaleraldehyde, lactones were formed as single diastereomers in moderate yields (20 to 30%) and poor ee (12%). Improved ee (25%) was observed when the reaction was conducted in an ionic liquid [8].

It was problematic to obtain high enantioselectivity when these consecutive aldol reactions were conducted within a single catalytic system. Two-step synthesis of similar products was developed. In 2004, Northrup and MacMillan reported an elegant synthesis of hexoses based on a proline-catalyzed dimerization of protected α-oxyaldehydes, followed by a tandem Mukaiyama aldol cyclization catalyzed by a Lewis acid (Scheme 1.7) [9]. The products were obtained in modest to good yields, with high diastereoselectivity (10 : 1 to 19 : 1) and enantioselectivity (95 to 99%).

SCHEME 1.6 Proline-catalyzed assembly of propionaldehyde and conversion to lactone.

SCHEME 1.7 Two-step synthesis of hexoses with organo- and Lewis acid catalysis.

To improve the efficiency and selectivity of the tandem aldol process, Córdova’s group also isolated the β-hydroxyaldol intermediate from the first aldol transformation prior to the second aldol reaction. The pure intermediate was subjected to the second aldol reaction with a different catalyst (Scheme 1.8). The two-step synthetic protocol made it possible to investigate both (L)- and (D)-catalysts in stereocontrol. The synthesis of hexoses proceeded with excellent chemo-, diastereo-, and enantioselectivity. In all cases except one, the corresponding hexoses were isolated as single diastereomers with >99% ee [10].

SCHEME 1.8 Two-step direct proline-catalyzed enantioselective synthesis of hexoses.

1.2.1.3 Enamine–Enamine in Three-Component Cascades

As part of a continuing effort, Chowdari et al. reported L-proline-catalyzed direct asymmetric assembly reactions involving three different components–aldehydes, ketones, and azodicarboxylic acid esters—to provide optically active functionalized β-amino alcohols in an enzyme-like fashion. These are the first examples of using both aldehydes and ketones as donors in one pot (Scheme 1.9) [11].

SCHEME 1.9 Proline-catalyzed three-component reaction.

1.2.1.4 Enamine-Activated Double α-Functionalization

Enders et al. reported an organocatalytic domino Michael addition/alkylation reaction between aliphatic aldehydes and (E)-5-iodo-1-nitropent-1-ene 33 involving enamine–enamine activation (Scheme 1.10) [12]. This process is highly stereoselective and leads to the γ-nitro aldehydes, which contain an all-carbon-substituted quaternary stereogenic center.

SCHEME 1.10 ...