Proline-based catalysts

To recycle a valuable amine acylation catalyst, Janda and co-workers10 attached a proline-based catalyst to a polymeric support for the enan-tioselective kinetic resolution of alcohols (entry 6). The resin-bound catalyst behaves similarly to the soluble catalyst, providing good yields of secondary alcohols and their corresponding esters with good to excellent enantioselectivities for various substrates. 

The organocatalytic asymmetric Michael addition of 2,2-dimethyl-l,3-dioxan-5-one (143) to various nitroalkenes (144), using a number of proline-based catalysts, afforded... 

The enantioselective conjugate addition of tetrahydropyran-4-ones and their thio analogues to nitrostyrene is achieved using proline-based catalysts <06JA9624>, as is the asymmetric aldol reaction of these substrates with benzaldehydes (Scheme 27) <06JOC8198>. 

In 2008 Brimble and coworkers examined the effect of a-substitution in proline-based catalysts for the asymmetric aldol addition of acetone to aromatic aldehydes. In the benchmark aldol reaction between acetone and p-nitro-benzaldehyde they observed a remarkable improvement of stereoselectivity using (5 )-a-methyl-tetrazole 9, albeit with longer reaction times caused by the a-geminal disubstitution. Surprisingly 7a afforded a completely racemic product (Scheme 11.7). Using 9 the scope of this reaction was extended efficiently to several other aromatic aldehydes with excellent enantioselectivities (enantiomeric excess — 70-91%). 

Scheme 11.7 Asymmetric aldol addition between acetone and /i-nitro-benzaldehyde catalysed by (S)-proline (1) and proline-based catalysts 7a, 8 and 9.

In 2009, Carter and Yang reported the construction of the novel proline-based catalyst 27, which is soluble in most solvent systems, including industrially attractive solvents such as 2-Me-THF, and is readily made from inexpensive starting materials [23], Several experiments were conducted to validate the scope of this new catalyst (Scheme 5.16). For instance, propionaldehyde (2d) was reacted with A(-Boc-protected aldimine 23k to provide the Mannich product 25j in excellent selectivity (15 1 dr syn/mA, 99% ee), while L-proUne (1) furnished the same product in rather poor diastereoselectivity (1.2 1 dr synlanti), 99% ee). Similar results were obtained for differently substituted aldimines 23a, 23c-d and 231 as well. 

Syn-Aldols. The synthesis of sy/j-aldols via the cross-aldol reaction is not an easy task since the sy -selectivity requires the reaction to proceed through the (Z)-enamine (Scheme 3.24). All proline-based catalysts tend to give ( )-enamines as... 

The direct asymmetric aldol reaction is a powerful tool for C-C bond formation. Enamine-iminium catalysis is the most developed, and it is nicely complimented by other modes of activation that rely on hydrogen bond formation. Mechanistically, all proline-based catalysts activate donors through the formation of an enamine intermediate. Other activation modes rely on enolate formation, ionic interactions, or hydrogen bond formation, though the mechanism is not always known. 

The Hajos and Wiechert research groups looked at a number of other potential proline based catalysts for their intramolecular Robinson annulation. (. -(-)-Hygrinic acid, Af-methylproline 13, was examined, but only the racemic intermediate ketol product 2 was obtained. In a similar manner, the proline methyl ester 14 also produced the racemic ketol intermediate. No reaction was observed with the piperidine analog 15. The homo-proline analog 16 gave the enantiomeric product. An explanation for this change in selectivity has not been provided yet. Please note that the use of (i )-proline provides the enantiomeric product. 

Two examples of unsupported proline-based catalysts are compounds 88 and 89 (Figure 24.30). Dipeptide 88 was used in water in the presence of NaOH in the addition of ketones to nitroalkenes. The presence of sodium hydroxide additive was crucial for the success of the reaction [109]. Catalyst 89 was designed on the structurally rigid hexahydropyrrolo[2,3]indole skeleton and efficiently catalyzed the enantioselective addition of aldehydes to nitroalkenes both in methanol and water [110]. The same catalyst was also used in the addition of aldehydes to vinyl sulfone followed by reduction with sodium borohydride. In this case water was a better reaction medium than methanol [111]. 

Similar results were reported by the Barret group by using stoichiometric amounts of an enantiopure 2-(2-pyridinyl)-2-oxazoline [46], hi 1996, Iseki and Kobayashi achieved a catalytic version of the asymmetric allylation [47], They applied proline-based chiral HMPA derivatives for the allylation. The catalyst 21 proved to be the best one regarding catalyst loading down to 1 mol% (Scheme 16) [48],... 

HayasM et al. achieved high catalytic activity by using axially chiral iV-oxide catalyst 27. As compared to other organic catalysts, the reaction proceeded much faster, and high enantioselectivities were obtained with 0.01-0.1 mol% catalyst loading [53-55]. In 2005, Hoveyda and Snapper used a novel proline-based ahphatic A-oxide 28 for an asymmetric allylation (Scheme 19) [56],... 

This methodology was applied to a concise synthesis of the alkaloid epilupinine (Scheme 18.10) [27]. N-alkylation of proline benzyl ester with bromo diazoketone 25 gave substrate 26. Treatment with either Rh2(OAc)4 or various copper-based catalysts... 

A dimeric proline-derived diamidobinaphthyl dilithium salt has been introduced as the first example of a chiral main group metal-based catalyst for asymmetric hydroami-nation-cyclization reactions of aminoalkenes.256... 

One of the first examples of the covalent imprinting of bulk silica was described by Katz and Davis.58 In this study, an imprint molecule containing an aromatic core and protected 3-aminopropyltrimethoxysilane groups was synthesized. When hydrolyzed and condensed with TEOS followed by removal of the aromatic core, a shape-selective base catalyst was prepared.58 Katz and Defreese also used a similar approach to create proline-amide imprints in bulk microporous silica.59 Additional... 

The scope of the reaction was subsequently expanded to the 1,3-dipolar cycloaddition of nitrones to cyclic a,/ -unsaturated aldehydes, allowing for the formation of fused bicyclic isoxazolidines (Scheme 3.7). Here, the use of catalyst 1 resulted in almost no reaction, whereas a proline-based diamine (9) afforded high levels of enantio-and diastereoselectivity [59, 60]. 

Surprisingly, little follow-up work on this idea of small molecule asymmetric catalysis appeared for the next 25 years. In the late 1980s, Agami reported the asymmetric intramolecular aldol reaction of acyclic diketones with (S)-proline as the catalyst. It was not nntil the twenty-first centnry, however, when this notion of organocatalysts became fnlly exploited. List and Barbas ° pioneered enam-ines as catalysts for aldol and Mannich and related reactions. MacMillan has developed a variety of imininm-based catalysts prodncing large asymmetric indnction for Diels-Alder chemistry, Friedel-Crafts alkylations, Mnkaiyama-Michael and cyclopropanation " reactions. 

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