Organocatalytic cascade

Transfer Hydrogenation of Quinolines Development of a New Organocatalytic Cascade Reaction... 

Scheme 7.5 Organocatalytic cascade featuring reductive amination with TRIP.

In 2009 the MacMillan group reported an enantioselective total synthesis of (-b)-minfiensine (109). The key step in this synthesis expands upon Levy s early work ° and takes advantage of an organocatalytic cascade sequence... 

The triple Michael/Michael/aldol sequence developed by Enders shown in Scheme 7.8 can probably be considered as one of the most impressive demonstrations of the ability and power of enantioselective organocatalytic cascade reactions for the generation of molecular complexity from very simple and cheap starting materials." In this reaction, a nitroalkene, an enolizable aldehyde and an a,p-unsaturated aldehyde reacted with each other in the... 

Several very interesting cascade processes have also been developed under phase-transfer catalysis which are initiated by a conjugate addition reaction, although the number of reports is remarkably more limited compared to other organocatalytic cascades proceeding via other different mechanisms of activation. Representative examples will be presented in the following pages. 

Scheme 8.29 Organocatalytic cascade utilising Pictet-Spengler reaction.

Based on enantioselective epoxidation and subsequent ring opening and closing, the so-called Achmatowicz reaction was developed. This is an organocatalytic one-pot cascade for the annulation of a,(J-unsaturated aldehydes, hydrogen peroxide, p-carbonyl compounds and NBS, which furnish optically active 3-pyrones. Other chiral heterocycles were also assembled by organocatalytic cascade reactions using diaiylprolinol silyl ethers as catalysts. ... 

Similar conformational preferences are expected to apply to iminium ions, one of the key intermediates in many organocatalytic cascades. When snch iminium ions undergo deprotonation, the reactive conformation is the one where the breaking C-H bond is aligned with the iminium jt-system. In the presence of additional stereocenters that make the two sides of the Jt-system diastereotopic, the proton abstraction occurs from the stericaUy more accessible face opposite to the catalyst sidechain. As a result, the opposite enantiomers of chiral aldehydes are transformed into opposite enamine stereoisomer (E- or Z-, Figure 6.39). This stereochemical relationship is maintained in the reverse process which involves protonation on the less hindered face of the enamine. Eventual equihbration of the E and Z enamines is possible but relatively slow. ... 

An example of a lype II process where a cyclic product is generated, came from the group of Barbas, who showed the self-aldoUzation of acetaldehyde to give (+)-5-hydroxy-(2 )-hexenal in 90% ee [60], The trimerization of simple aldehydes 192 to carbohydrates and polyketides was then described (Scheme 1.43) [61]. Although the ees and yields were low, this was one of the first examples of carbohydrate synthesis using an organocatalytic cascade process. 

Scheme 3.51 Organocatalytic cascade aza-ene-type reactions of a, 3-unsaturated aldehydes with enamides and the subsequent transformations.

This section aims to highlight the most representative synthetic applications of enantioselective organocatalytic cascades involving the successive formation of one C-N bond and one C-C bond. As illustrated below, these methodologies are declined as either bi-component or multicomponent transformations. 

The examples depicted so far have made use primarily of single organocatalytic transformations conducted typically quite early in the multi-step sequences applied towards the syntheses of complex natural products. In contrast, more and more reports describing organocatalytic cascade reactions or combined approaches using different organocatalytic key transformations to achieve a complex synthesis have been reported over the last several years (30, 32, 176-178). In this chapter, the application of combined enamine-catalyzed approaches for the syntheses of natural products will be described. Examples using different activation modes (e.g. enamine and iminium activation) will be discussed later. 

Grondal C, Jeanty M, Enders D (2010) Organocatalytic Cascade Reactions as a New Tool in... 

New sulfur-containing spirocyclic scaffords were synthesized by two different enantioselective organocatalytic cascade reactions (13EJ07979). In the first synthesis, benzothiophene-2-one and an enal react in the presence of a secondary amine catalyst via a Michael-Aldol sequence to yield spiro-cyclo-hexenecarbaldehydes with excellent selectivities [20 1 diastereomeric ratios (dr) up to 20 1]. In the second reaction, the double Michael addition of ben-zothiophene-2-one to aromatic dieneones with primary amine catalysts yields the corresponding spiro-cyclohexanones with slighdy lower dr values. 

An organocatalytic cascade reaction involving a Morita-Baylis-Hill-man-Michael cascade reaction of ninhidrin, nitroalkenes, and saturated aldehydes resulted in a series of spiroindanone 6-tetrahydro-2f/-pyran-2-ones, with high chemo-, regio-, enantio-, and diastereoselectivities (Scheme 55) (13CC8692). 

Diunsubstituted coumarins are available from the palladium(II)-catalyzed intermolecular annulation reaction of phenols with methyl acrylate (13AGE12669) and from an organocatalytic cascade reaction of salicylalde-hydes with malonic acid half-thioesters mediated by a combination of ben-zylamine and triethylamine (Scheme 60) (13EJ04499). 

Among all the possible approach to polysubstimted cyclohexane derivatives, Dixon et al. proposed a further and very elegant alternative approach wherein the asymmetric organocatalytic cascade reaction reties on the synergic action of a bifunctional base/Br0nsted acid catalyst 158 and a cyclic secondary amine (5)-76 (Scheme 2.49) [77]. 

P. Galzerano, F. Pesciaioh, A. Mazzanti, G. Bartoli, P. Melchiorre, Angew. Chem. Int. Ed. 2009, 48, 7892-7894. Asymmetric organocatalytic cascade reactions with a-suhstimted a,P-unsaturated aldehydes. 

C. Cassani, X. Tian, E. C. Escudero-Adan, P. Melchiorre, Chem. Commun. 2011, 47, 233-235. Multiple approaches to enantiopure spirocyclic benzofuranones using organocatalytic cascade reactions. 

D. (2010) Organocatalytic cascade reactions as a new tool in total synthesis. 

In 2011, Enders et al. reported a sequential organocatalytic cascade reaction between a,p-unsaturated aldehydes and p-oxosulfones, using a combination of a chiral diaiylprolinol trimethylsilyl ether and an achiral N-heterocyclic carbene as a catalytic system. This sequential... 

Galzerano, P., Pesciaioli, F., Mazzanti, A., Bartoh, G., Melchiorre, P. (2009). Asymmetric organocatalytic cascade reactions with a-substituted a,p-unsaturated aldehydes. Angewandte Chemie International Edition, 48, 7892-7894. 

Another strategy is to use an organocatalytic cascade merging iminium and enamine activation. First, there is a condensation... 

---