Organocatalysts proline-derived

Gruttadauria, M., Giacalone, F. and Noto, R. (2008) Supported proline and proline-derivatives as recyclable organocatalysts. Chemical Society Reviews, 37 (8), 1666-1688. 

A very important development in multicomponent domino reactions is the enan-tioselective approach using organocatalysts which has been recently discussed in an excellent review by Yus and Ramon [2c]. The latest great success in this field stem from Enders and coworkers, presence of an enantiopure proline derivative to give polyfunctionalized cyclohexenes with 99% ee [111]. 

A range of proline derivatives have been employed as enamine-based organocatalysts of direct aldols in water, without organic co-solvent.111 Using the reaction of cyclohexanone with benzaldehydes as a test bed, lipophilic diamine (40) in the presence of TFA proved to be an excellent bifunctional catalyst system, giving performance up to 99/90/99% in terms of conversion/r/c/ee. Alkyl chains of (40) make an organic microphase likely. 

The proline-derived thiourea organocatalyst (154) (20 mol%) in conjunction with n-butyric acid (10 mol%) exhibited high stereoselectivity (<99 1 syn. anti and <98% ... 

Diastereoselectivity and enantioselectivity were observed to increase substantially when proline-derived diamine salts were used as organocatalysts. In particular, the pyrrolidinium salt 41-2HC1 was found to be very useful, furnishing the target molecule 38 in 70% yield with diastereoselectivity of d.r. = 95 5 and enantioselec-... 

Notably, 2-substitution on the indole moiety led to enhaneed selectivity, indicative of beneficial steric effects [e.g. when is H, only 11% enantiomeric excess is observed). Additionally, as solvent polarity decreased, increases in both rate and stereoselectivity were observed. Screening other organocatalysts and other proline derivatives identified L-proline as the optimal catalyst this was suggestive of the important role of proline s carbojylate moiety in generating the iminium-like indole carbocation. It was postulated that proline s carbo>ylate moiety could interact via electrostatic interactions with the carbocation intermediate, which was thought to explain solvent effects. ... 

In 2007 Sun and coworkers reported the use of the proline derived triamine 17 in the presence of weak acids as a highly stereoselective organocatalyst for the asymmetric Michael addition of cyclohexanone to nitroalkenes (Scheme 11.16). All selected aromatic nitroalkenes gave excellent yields and selectivities, with the exception of electron-deficient substrates (Ar = 4-CN-Ph, 4-N02-Ph), which also require much longer reaction times. 

The 1,2,3-triazole-linked fluorous proline organocatalyst 32 was introduced by Pericas and coworkers in 2013 for the asymmetric aldol reactions of acetone with aromatic aldehydes, giving higher enantioselectivities than other proline derivatives (Scheme 11.27). ° The fluorous tag and the use of a per-fluorinated solvent allowed the easy recycling and reuse of 32, for at least six times. 

First studies in relation to the conjugate addition of ketones with alkylidene malonates were performed by Barbas group initially using L-proline [107] and proline-derived diamines such as 31 [49, 138] (Fig. 2.4) as organocatalysts, showing that acetone, cyclohexanones, and cyclopentanone could add to various aryl- and alkylidene malonates with moderate yields and enantioselectivities. Very recently. 

By using a three-component system of acetone, 4-nitrobenzaldehyde (2a) and p-anisidine (3), an electrophihc imine was formed, which reacted with the in situ formed proline-derived chiral enamine 4 to form the adduct 5. Subsequent iminium hydrolysis then led to the Mannich product 6 and regeneration of the organocatalyst. Hydrogen bonding interactions between the carboxylate of the enamine 4 and the... 

Isotetronic acids were readily assembled through an organocatalyzed domino aldol-lactonization reaction starting from a-keto carboxylic acids and aldehydes [5]. As chiral organocatalyst, the proline-derived benzimidazol pyrrolidine 8 was employed, which proved superior to proUne itself Electron-poor aldehydes were both more reactive and selective. Thus, as a typical example, pyruvate was converted into isotetronic acid 10 in 77% yield and 83% ee upon treatment with para-nitrobenzyldehyde (9) and 10mol% 8 (Scheme 8.3). 

It seems appropriate to remember that there are also other classes of molecules that are catalytically active thanks to one of the mentioned mechanisms (ureas, thioureas, phosphoric acids, etc.) as well as molecules with two or more different functional sites (bifunctional organocatalysts) one of which is often an alcoholic/phenolic/carbojqrlic group (amino-alcohols, aminoacids, proline derivatives, aminophenols, etc.) they will be not discussed in this chapter because they have already been examined in previous chapters or because they contain nonsustainable elements. 

A number of other-than-proline-derived organocatalysts have been involved to induce chirality in Michael additions of various C-nucleophiles onto a range of Michael acceptors. Among them, bifunctional organocatalysts possessing a thiourea moiety and a tertiary amino group were designed by Takemoto et al. 

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