A proline-catalyzed

List and Castello discovered a proline-catalyzed three-component domino reaction between ketones, aldehydes, and Meldrum s acid forming corresponding ketoesters (Scheme 9.19) [30],... 

Bpgevig A, Poulsen TB, Zhuang W, Jprgensen KA (2003) Formation of optically active functionalized 3-hydroxy nitrones using a proline catalyzed aldol reaction of aldehydes with carbonyl compounds and hydroxylamines. Synlett 2003 1915-1918... 

Bui, T., Barbas, C. F. A proline-catalyzed asymmetric Robinson annulation reaction. Tetrahedron Lett. 2000, 41, 6951-6954. 

The diastereoselectivity of the Baylis-Hillman reaction was investigated by attaching chiral auxiliaries to a,-unsaturated ketones [216]. The use of the 4-isopropyloxazoladinone chiral auxiliary in [EMIM][OTf] gave rise to very low di-astereomer ratios (45 55) (Scheme 5.2-88). The authors also describe a proline -catalyzed aldol reaction of acetone, butanone, hydroxyacetone and chloroacetone with a chiral imine and obtain up to 9 1 diastereomer ratios. 

Aznar, et al. reported a proline-catalyzed imino-Diels-Alder reactions of acyclic a,p-unsaturated ketones 96 with imines 92 for the synthesis of mc50-2,5-diaryl-4-piperidones 98, Scheme 3.35 [50], The 2-amino-1,3-butadiene was generated in situ by the reaction of a,p-unsaturated ketones 96 with L-proline, followed by Diels-Alder cycloaddition with imine 92 to provide tetrahydropyridine adduct which was then hydrolyzed to the 4-piperidone 98. 

Ramachary and his co-workers reported a proline-catalyzed cascade [3h-2]-cycloaddition/hydrolysis reactions for the synthesis of highly functionalized ATH-1,2,3-triazoles, Scheme 3.76 [94],... 

Using a ball milling technique, the desired aldols 58a can be synthesized in a proline-catalyzed reaction (10 mol% catalyst loading) with no solvent added [77]. In addition to proline, a variety of primary amino acids catalyze this reaction, indicating that the five-membered ring is not crucial to catalytic efficacy [62, 78, 79, 80]. The results are very impressive for aldehyde 2a but less so for benzaldehydes with electron-donating groups. 

In 2008, MacMillan and co-workers [13] reported the first total synthesis and structure revision of callipeltoside C (38), a cytotoxic marine macrolide, with amino acid proline as a suitable organocatalyst for the construction of three key intermediates. This elegant synthesis (18 steps, 12% overall yield) demonstrated the power of organocatalysis with unprecedented level of ease and efficiency, which involved a proline-catalyzed double diastereo-differentiating aldol reaction between propionaldehyde 18 and the Roche ester-derived aldehyde 28 to achieve 29 (12 1 dr, 99% ee), an organocatalytic a-oxyamination to afford 32 (99% ee), and proline-... 

Enders also applied a proline-catalyzed strategy to develop a direct biomimetically inspired route towards precursors of ulosonic and sialic acids (60) as demonstrated in... 

Total synthesis of the potential anticancer drug salinosporamide A (56) represents an example where a proline-catalyzed aldol reaction between an achiral ketone donor and an a-chiral aldehyde was carried out with high selectivity. 

Pihko PM, Erkkila A (2003) Enantioselective Synthesis of Prelactone B Using a Proline-Catalyzed Crossed-Aldol Reaction. Tetrahedron Lett 44 7607... 

Itoh T, Yokoya M, Miyauchi K, Nagata K, Ohsawa A (2006) Total Synthesis of ent-Dihydrocorynantheol by Using a Proline-Catalyzed Asymmetric Addition Reaction. Org Lett 8 1533... 

Comparably, Barbas HI et al. observed interesting results employing the quite similar ionic liquid 40 as solvent in a proline-catalyzed Mannich reaction (Scheme 2.11a, up to 95% ee) [32], whereas, Wang s group examined the properties of more complex ionic liquids as enamine activation catalysts (Scheme 2.1 lb). The best outcome in terms of yield (up to 99%) and stereoselectivities (91-99% ee) was observed performing the reaction in DMF at -20 °C and using 30 mol% of[EMlm][Pro] 41 [33]. 

Jiang et al. described the proline-catalyzed reaction of several amines 143 with alkynes 141, various aldehydes 142, and 1,3-dicarbonyl compounds 144 to afford 1,4-dihydro-pyridines 145 in moderate to good yields (65-85%) (Scheme 13.37) [62]. Mainly three reactions are involved in the production of those products the first one is a proline-catalyzed Knoevenagel reaction between the aldehydes 142 and the 1,3-dicarbonyl compounds 144 to give Michael acceptors. The second one is a hydroamination reaction of the alkyne 141 to yield enamines, which in the third reaction undergo an enamine-Michael addition/cyclization sequence to provide the desired products. 

The reaction combines a proline-catalyzed Knoevenagel condensation with the Michael addition of the electron-rich heterocycle (Scheme 13.73). Proline 170 initially condenses with the aldehyde 328 to form an imininm intermediate 331. This is attacked by the CH-acidic Meldrum s acid 112 with subseqnent elimination of proline to provide the Knoevenagel condensation prodnct 332. Nucleophilic 1,4-addition of the indole 327 followed by tautomerizations of the rather unstable intermediate 333 liberates the desired products 330. 

By aiming at BRMs within MBFTs and organocatalysis, this section is limited to a small field of research. Nonetheless, the method is very productive, and the number of interesting examples extends far beyond the number that will be discussed in this section. Therefore, we will start, without further introduction, with the first example by Itoh and coworkers, who reported a proline-catalyzed asymmetric addition reaction for the synthesis of mf-dihydrocomynantheol in 2006 [6]. The reaction commences with activation of methyl vinyl ketone derivative 1 to form the intermediate enamine 4. Simultaneously, the acidic carboxyl group allows activation of the imine 2 and directs the newly formed nucleophile to add stereoselectively on iminium ion 5. The resulting o,p-unsaturated iminium is prone to diastereoselective cyclization by aza-Michael addition of the liberated secondary amine (Scheme 14.1). 

Itoh, T., Yokoya, M., Miyauchi, K., Nagata, K., Ohsawa, A. (2006). Total synthesis of ent-dihydrocorynantheol by using a proline-catalyzed asymmetric addition reaction. Organic Letters, 8, 1533-1535. 

A proline-catalyzed cyclization of ketone 107 to give enone 109 directly tvithout added acid tvas described by Fiirst et al. [28]. 

Application of a proline-catalyzed intermolecular aldolization in the synthesis of carbohydrate derivatives. 

Formal total synthesis of brasinolide featuring a proline-catalyzed aldol reaction. 

In 2002, Satoshi Omura s group used a proline-catalyzed Knoevenagel condensation between a,p-unsaturated aldehyde 78 and 4-hydroxy-2-pyrone 77 to form dienone 79, which underwent a spontaneous On-electron electrocyclization to form 80, which contains the pentacyclic core of arisugacin A (81)/ ... 

In what can be regarded as the earliest evidence for the participation of enamines in a proline-catalyzed aldol reaction and its in situ detection was provided by Metzeger and coworker. A combination of high-resolution MS/MS and ESI-MS methods could detect the condensahon product between prohne and acetone [9]. Furthermore, the evidence was strongly in favor of enamine as compared to the isomeric oxazolidinone. In a subsequent study, Seebach and coworkers using NMR and IR studies proposed that an oxazolidinone intermediate plays a vital role in asymmetric organocatalytic Michael reactions. Evidence for participation of bicychc as well as spirocyclic oxazolidinones in proline-catalyzed reachons was presented [10]. 

In a closely related study, Sharma and Sunoj examined the validity of transition state models based on sy -face and anti-face additions under base free as well as basic conditions in a proline-catalyzed a-amination reaction (Scheme 17.8) [36]. Mechanistic investigation using the PCM(CH2cu)/mPWlK/6-31-i-G computational method revealed that the addition of enamine carboxyUc add to DEAD... 

Figure 17.9 Transition state models (a) and (b) employed to rationalize the reversal of stereoselectivity in the presence of DBU in a proline-catalyzed a-amination reaction.

The use of ball mills to assist solvent-free asymmetric organocatalytic processes is still very rare. In 2006 Bohn and coworkers [59] reported the first examples of such applications. This technique was used in a proline catalyzed aldol reaction between ketones and aromatic aldehydes. The asymmetric organocatalytic aldol reaction was very intensively studied since the pioneering work by list and Barbas in 2000/2001 [21]. In the vast majority of cases it was performed in different organic solvents (e.g., DMSO, DMF), but in recent years several eco-friendly solvent-free, or using water, protocols have been reported. Such reactions, avoiding the use of organic solvents, are especially preferred in industrial-scale processes and the synthesis of pharmaceuticals. 

Other liquid ketones such as cyclopentanone and acetone, as weU as solid ketones (e.g., 4-tert-butylcyclohexanone, tetrahydro-4H-thiopyran-4-one, and 1-Boc-4-piperidone) were also examined in a proline catalyzed aldol reaction with p-nitrobenzaldehyde (Scheme 21.29). 

Since the early example of a proline-catalyzed asymmetric domino Michael-aldol reaction reported by Bui and Barbas in 2000 [57], a number of these reactions have been successfully developed by several groups. For example, Wang et al. have reported the synthesis of chiral densely functionalized cyclopentenes on the basis of a domino Michael-aldol reaction followed by dehydration between aromatic enals and dimethyl 2-oxoethylmalonate [67]. High yields (63-89%) and enanhose-lectivities (91-97% ee) were obtained by using (S)-diphenylprolinol sUyl ethers as catalysts. On the other hand, the condensation of P-nitroketones 36 onto enals in the presence of 8 was shown by Hong et al. to afford the corresponding domino Michael-aldol products 37 through the iminium-enamine activation mode [68]. 

In 2003, a proline-catalyzed enamine-enamine activation sequence was used to develop a three-component reaction leading to functionalized P-amino alcohols 35 [29, 30]. The reaction used both ketones (specifically, acetone) and aldehydes 33 as donors, together with azodicarboxylate 34 (Scheme 42.9) [30]. The first step is the pro line-catalyzed amination of aldehydes [31], leading to intermediate 36, which represents the electrophiUc substrate for the subsequent aldol reaction with acetone. Both intermolecular steps proceed under enamine catalysis by proline 1. A key factor in the high level of chemoselectivity observed was the much higher reactivity of aldehyde over ketone in the proline-catalyzed a-amination reaction, which selectively forms 36. 

Moreover, enamine catalytic in situ sequences of acetaldehyde with two electrophiles can be envisioned (Scheme 1.11). The first successful realization of this concept with a proline-catalyzed double Mannich reaction of acetaldehyde with N-Boc-imines 36 was developed to give pseudo-Cj-symmetric p,p -diaminoaldehydes 37 with extremely high stereoselectivities (>99 1 dr, >99% ee) [13], A similar approach with ketones was also realized [14],... 

Hubin PO, Jacquemin D, Leherte L, Andre JM, van Duin ACT, Vercauteren DP (2012) Ab initio quantum chemical and ReaxFF-based study of the intramolecular iminium-enamine conversion in a proline-catalyzed reaction. Theor Chem Acc 131 1261... 

Ab initio quantum chemical and ReaxFF-based study of the intramolecular iminium-enamine conversion in a proline-catalyzed reaction... 

Our theoretical investigation regarding the understanding of the conversion of iminium into enamine in the framework of a proline-catalyzed aldol reaction emphasizes that the reactive force field (FF), ReaxFF, used in combination with molecular dynamics (MD) simulations is a relevant method to investigate the mechanism of proton transfers in iminium-enamine conversions. This approach should be extended to model other steps of proline-catalyzed... 

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