Catalysts pyrrolidine

The same system was used by Frechet s group of to achieve a multicomponent one-pot cascade reaction with mutually interfering acid and proline-derived pyrrolidine catalysts [31]. The concept is illustrated in Figure 5.1. The protonation of imidazo-lidone (3) by the immobilized PSTA (5) gives the desired iminium catalyst (6), while... 

The catalytic asymmetric epoxidation of a,p-unsaturated aldehydes has also been an important challenge in iminium catalysis and for chemical synthesis in general. More recently, Jprgensen and coworkers have developed an asymmetric organocatalytic approach to ot, (3-epoxy aldehydes using pyrrolidine catalyst 20 and H2O2 as the stoichiometric oxidant. The reaction appears to be extremely general and will likely receive wide attention from the chemical synthesis community (Scheme 11.6b). 

I, 10mol% chiral pyrrolidine catalyst, NEts, CH2CI2, -40 °C, overnight... 

Modification of the proline structure leads to more efficient chiral pyrrolidine catalysts, showing better selectivity and improved synthetic scope. 

Fig. 2.12 The rationale of enantioselectivity of the pyrrolidine catalyst-mediated additions of aldehydes to nitroolefins.

To a solution of pyrrolidine catalyst (0.05 mmol, 15 mol%) in CHCI3 (3 mL) was added at r.t. the ketone (3.35 mmol) and the nitroolefin (0.335 mmol). The evolution of the reaction was monitored by TLC. The solution was then hydrolyzed with 1 M HCl (2 mL). The layers were separated and the aqueous phase was extracted with CH2CI2 (2 x 3 mL). The combined organic phases were dried over MgS04, filtered, concentrated and purified by flash column chromatography on silica gel using a mixture of cyclohexane and ethyl acetate as eluent. 

Tetrahydroxanthen-l-ones have been obtained through enantioselective domino oxa-Michael - aldol reactions between salicylaldehydes and cyclohexenones using a chiral pyrrolidine catalyst in the presence of 2-nitrobenzoic acid <07TL2181>. A similar approach using chiral 4-hydroxycyclohexenones and V-methylimidazole as catalyst leads to a diastereomeric mixture of the reduced xanthones (Scheme 40) <07S2175>. Dimeric... 

Table 6 Pyrrolidine catalysts for asymmetric epoxidation of cycloalkenes...

Aromatic nitrogen heterocycles, especially triazoles and tetrazoles are the most common nucleophiles used in the organocatalysed aza-Michael reaction. 5-Phenyltetrazole undergoes conjugate addition with acyclic enals using the tri-fluoracetate salt of imidazolidinone (11.127), while the 1,4-addition of phenyl-tetrazole and 1,2,4-triazole (11.130) occurs with high ee using the enantiopure pyrrolidine catalyst (11.79). ... 

The first asymmetric direct a-iodination of aldehydes has also been described to provide products in moderate to good enan-tioselectivities using an organocatalyst. 3-Methyl-1-butanal was reacted with NIS in the presence of a chiral pyrrolidine catalyst to provide the halogenated product in 78% yield with 89% ee (eq 27). 

Shortly after MacMillan s publication, the Zhao group reported an extension of the asymmetric Diels—Alder approach to include a,P-unsaturated aldehydes using pyrrolidine catalysts (Scheme 10). ... 

Alexakis and coworkers, reported that an unprecedented rearrangement of the sulfone group involving the aminal-pyrrolidine catalyst Ik caused the formation of gem-disulfones when aldehydes were reacted with 1,2-bissul-fonyl alkenes. The rearrangement products were obtained in good to high yields and usually with high enantioselectivities (Scheme 9.48). 

Three secondary amine catalysts have been utilized in the a-bromination of aldehydes (Scheme 13.31). J0rgensen reported the use of two different chiral pyrrolidine catalysts that generated the S enantiomer of the product, while Mamoka reported the use of a binaphthyl-based catalyst that generated the R enantiomer of the product [67-69]. Both employed the same bromine source, 4,4-dibromo-2,6-di-tcrt-butyl-cyclohexa-2,5-dienone (inset in Scheme 13.31), and both reduced the aldehyde products in situ to facilitate product isolation and analysis. 

A BINAP-sulfonamide gives delee up to 98/97% in additions of ketones to nitroolefins in water. Up to all-98% performance (yield/tfe/cc) has been achieved by sugar-based pyrrolidine catalysts of addition of ketones to nitrostyrenes, without solvent. ... 

A series of pyrrolidine catalysts has been investigated for the asymmetric Michael addition of cyclohexanone to nitroalkenes, which is the classical model commonly used. When an aminal-pyrrolidine, developed by Alexakis et al. was employed as an organocatalyst for the conjugate addition of cyclohexanone to nitrostyrene, it led quantitatively to the Michael product with 84% de and 87% ee (Scheme 1.48). Better stereoselectivities for this reaction were... 

Scheme 7.18. Supported pyrrolidine catalysts in asymmetric synthesis of chromanes.

A 1,2,3-triazole-based solid-phase click linker was developed with an aldehyde functionality or a regenerative Michael acceptor (REM) functionality (Figure 11.1). In addition, a chiral pyrrolidine catalyst was grafted to the resin with a 1,2,3-triazole linker, enabling enantioselective Michael addition of ketones to nitroolefins... 

In the same year, Xu et al developed an efficient example of asymmetric cooperative catalysis applied to a domino oxa-Michael-Mannich reaction of salicylaldehydes with cyclohexenones. The proeess was eatalysed by a combination of two chiral catalysts, such as a chiral pyrrolidine and amino acid D-tert-leucine. The authors assumed that there was protonation of the aromatic nitrogen atom of the pyrrolidine catalyst by u-te/t-leucine, which spontaneously led to the corresponding ion-pair assembly (Scheme 2.6). This self-assembled catalyst possessed dual activation centres, enabling the catalysis of the electrophilic and nucleophilic substrates simultaneously. The domino oxa-Michael-Mannich reaction provided a range of versatile chiral tetrahydroxanthenones in high yields and high to excellent enantioselectivities of up to 98% ee, as shown in Scheme 2.6. 

Chiral 1,2,3-triazolium ionic liquid tethered pyrrolidine catalysts built from (S)-proline and its derivatives have been successfully ap>plied in various catalytic reactions (Khan, Shah et al. 2010 Khan, Shah et al. 2010 Maltsev, Kucherenko et al. 2010 Yacob, Shah et al. 2008). The 1,2,3-triazolium ionic liquid-tagged organocatalysts derived from proline and its derivatives are mostly viscous liquids at room temperature and are completely miscible with polar solvents such as methanol, chloroform, acetonitrile, dimethylsulfoxide, dimethylformamide and water. They are insoluble in less-polar solvents such as n-hexane and diethyl ether. In some cases, the ionic liquid sub-unit serves not only as a phase tag for efficient recycling but also as an effective chiral amplifier through polar interactions and steric shielding. 

The direct application of unmodified aldehydes in catalytic Michael additions can be severely hindered due to the presence of undesirable intermolecular self-aldol reactions (Hagiwara, Komatsubara et al. 2001 Hagiwara, Okabe et al. 2001). Barbas and co-workers achieved the first direct catalytic asymmetric Michael reaction between unmodified aldehydes and nitroolefins. The usage of an (S)-2-(morphohnomethyl) pyrrolidine catalyst in 20 % furnished the Michael addition products in 72 % enantioselectivity, 12 1 diastereoselectivity and 78 % yield (Betancort and Barbas 2001 Betancort, Sakthivel et aL 2004 Mosse, Andrey et al. 2006). The utilization of the ionic hquid tagged catalysts 25 and 26 in the Michael reactions of frans- -nitrostyrenes to aldehydes resulted in high yields but... 

In Section 31.6 we mentioned the enantioselective reduction of itaconic acid by a number of entrapped chiral organometallic catalysts [25]. A follow-up and major improvement of that study was reported by Volovych et al. [30]. These authors hydrogenated itaconic acid with sol-gel-entrapped Rh complexed with (2S,4S)-l-tert-butoxycarbonyl-4-diphenylphosphino-2-(diphe-nylphosphinomethyl)pyrrolidine catalyst in methanol solutions. The immobilization process was carried out with different sol-gel precursors TMOS, TEOS, triethoxyphenylsilane PhSi(OEt)3/TMOS, and trimethoxy (octyl)silane OcSi(OMe)3/TMOS. The choice of the precursor was found to influence the enantioselectivity and the rate of the reaction. The immobilized catalyst could be recovered and recycled several times under N2 atmosphere. About 90-99% ee was achieved for the hydrogenation of itaconic acid to (S)-(+)-2-methyl succinic acid. 

After MacMillan s pioneering work on the VMM-type reaction, a number of oiganocatalysts were applied to similar reaction systems. Among these, direct vinylogous Michael reaction attracted much attention. For example, Alexakis reported that diphenylprolinol silyl ether 142 and aminal-pyrrolidine catalyst 143 are effective for the direct reaction of angelica lactone 140a with a,p-enal 137b (Scheme 59) [101]. In this case, it was also mentioned that furan-2(5H)-one itself does not work as a suitable nucleophile. 

For the same purpose, various chiral pyrroUdine catalysts such as 50-54 have also been introduced [242-250]. The versatile nature of pyrrolidine catalysts has been recognized by other transformations aldol reaction [251], Mannich-type reaction [252, 253], and oxa-Michael reaction [254]. Among these, Maruoka s work on anti-selective Mannich reactions is noteworthy (Scheme 1.19, compare with Scheme 1.8) [253]. In this case, the remote hydrogen-bonding form 57 derived from catalyst 56 can overcome the steric preference so that the opposite sense of stereochemistry should be observed. 

In 2003, Juhl and Jorgensen found that, after screening a series of pyrrolidine catalysts, catalyst 48 is again of great value for the inverse-electron-demand hetero-Diels-Alder reaction after pyridinium chlorochromate (PCC) oxidation, lactone products could be obtained as a single diastereomer in excellent enantioselectivity (Scheme 1.20) [255]. The proposed transition state model 58 indicates effective shielding of the Si-face of the enamine double bond by the diaryhnethyl substituent on the pyrrolidine ring of the catalyst. 

With a-substituted pyrrolidine catalysts, there are a few mechanistic issues that deserve to be mentioned. Firstly, the formation of pyrrolidine enamine with the nucleophilic partner could encounter increased steric encumbrance near the amino nitrogen that can result in reduced efficiency. Secondly, alternative mechanisms without the involvement of enamines could also be operating [40]. However, among the limited set of available computational studies on a-substituted pyrrolidines, the enamine pathway has been effective towards rationalizing the stereochemical outcome of the reaction. In most of these, a steric control driven transition state model has been invoked wherein the incoming electrophile is guided towards the enamine double bond from the face opposite to that of the bulky a-substituent. 

Scheme 17.15 Bicydic pyrrolidine catalysts and the corresponding enantiomeric excess computed using transition state modeling. The higher and lower ee s are indicated.

In 2008, Chi et al. reported a tandem reaction of indoles, a,P-unsaturated aldehydes, and methyl vinyl ketone (MVK) for the synthesis of chiral indole derivatives with two stereogenic centers [ 19]. To avoid the interference of the two secondary amine catalysts and cocatalyst acid, the soluble star polymer-based site isolatbn method was adopted, whereby the supported imidazolidinone catalyst promoted initial Friedel-Crafts alkylation and the supported pyrrolidine derivative promoted the following Michael addition to MVK (Scheme 9.19). Notably, simple combination of these catalysts in one pot didn t mediate the cascade reaction efficiently despite the fact that the MacMillan imidazolidinone and pyrrolidine catalyst can efficiently promote separate Friedel-Crafts reaction and Michael addition, respectively. Moreover, when the pyrrolidine catalyst was replaced by its enantiomer, a diaste-reomer of the product could be obtained with high enantioselectivity. This smdy presented a novel solution to the efficient combination of incompatible substrates and catalysts. 

Reversing the position of the aldol electrophile, Enders and coworkers developed a type ce approach to complex 3-pyrrolin-2-ones that involved a quadruple cascade process (Scheme 91 2014S1539). Treatment of cinnamaldehyde (353) and the a-ketoamide 354 with pyrrolidine catalyst 355 and NaOAc gives the fused 3-pyrrolin-2-one 357. The mechanism of the reaction includes a Michael addition by the amide followed by aldol condensation to generate the 3-pyrrolin-2-one intermediate 356 subsequent Michael and aldol transformations with a second equivalent of 353 then gives the fused cyclopentene ring. 

In 2005, J0rgensen and co-workers introduced 1-benzyl-sulfanyl[ 1,2,4] triazole 416 as an electrophilic sulfur source for the catalytic enantioselective a-sulfenylation of aldehydes (Scheme 46.47). ° The products 418 were obtained in high yields and excellent enantioselectivities, and more importantly, these products obtained by enamine catalysis were not racemized by the action of a chiral pyrrolidine catalyst 417. 

These two examples, of aldol and a-amination, evidently illustrate that a generalized transition state model demands additional refinements, taking the reaction conditions as well into account While the hydrogen bonding transition state models remained successful for many prohne-catalyzed reactions, the appHcabihty of the same to specialized reaction conditions tends to surest the need for more investigations. Similarly, with a different series of pyrroHdine catalysts devoid of a<arboxylic acid, the need for alternative transition state models to the general hypothesis of carboxylic acid directed approach of the electrophile, is more readily evident For example, one of the most popular pyrrolidine catalysts in use today carries bulkier a-substituents. 

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