Pyrrolidine-derived catalysts

By surveying 72 catalysts from the proline family, including piperidine- and pyrrolidine-derived catalysts, amino acids and diamines investigated over the past decade (Appendices 7.B-D), we may better understand both the structural features that are compatible with a successful catalyst and those which are detrimental and preferably avoided. 

The use of different acid functionalities on pyrrolidine-derived catalysts has improved the reaction rate of some aldol reactions. For example, pyrrolidine-based tetrazole derivative 9 (Fig. 2.2) catalyzed many aldol reactions with rates faster than proline, with similar stereocontrol [16, 18b, 24, 55]. The faster reaction rates with tetrazole derivative 9 in DM SO as compared with proline were attributed to the lower pKa of the tetrazole moiety as compared to the carboxylic acid group in DMSO (tetrazole pKa(DMSO) 8.2 acetic acid pKa(DMSO) 12.3) [55, 56]. In addition, tetrazole derivative 9 is more soluble than proline in many organic solvents. A higher actual concentration of the catalyst in the solution phase of a reaction mix-... 

Scheme 2.38 Chiral pyrrolidine-derived catalysts for Michael-type addition of ketones to activated olefins.

In the pioneering studies of Melchiorre and Jorgensen and colleagues, a variety of pyrrolidine-derived catalysts was tested (Scheme 2.51) [40]. Whilst modest selectivity was obtained with proline, and unhindered prolinol derivatives, (S)-2-(bis(phenyl)methyl)pyrrolidine derivative, 45c, allowed good conversion and enantio selectivity in the addition of linear aldehydes to methyl-vinyl ketone (MVK) (revalues up to 85%). Cyclic enones as well as -substituted enones afforded no, or perhaps poor, results. 

In 2002 and 2003, the Rovis group developed ehiral triazolium salts with amino indanoi and pyrrolidine frameworks whieh were found to be excellent eatalysts for intramolecular Stetter reaetions (up to 98% yield, 99% ee). The amino indanoi derived eatalysts and pyrrolidine derived catalysts, developed by Rovis and co-workers, turn out to be the most efficient catalysts so far for the intramolecular Stetter reaetions, providing the desired products in high yields and excellent enantioseleetivity. 

Unfortunately, these results could not be readily reproduced in related reactions. Further studies by the same group led to the design of the pyrrolidine-derived catalyst 36 to catalyze the reaction of ketones 7 with iV-PMP-protected glyoxylate ester 10a (Scheme 5.20) [27]. The corresponding P-formyl-functionalized amino acid derivatives 37 were produced in high yields and excellent anh-selectivities. 

Scheme 5.20 Pyrrolidine-derived catalyst to react ketones with iV-PMP-protected glyoxylate ester 10a...

Recently, other research groups have developed the addition of 1,3 dicarbonyl or related compounds to enones. For example, Lattanzi reported the addition of malononitriles to enones catalyzed by cinchona alkaloids with good yields and enantioselectivities [84], Jaszay reported the addition of diethylcyanomethyl phos-phonate to enones using thiourea catalysts with moderate yields and enantioselectivities [85], and Wang reported the Michael addition of ketones to chalcones using pyrrolidine-derived catalysts with good yields and excellent enantioselectivities [86]. 

The chiral titanocene catalyst 34 is very effective for the kinetic resolution of racemic 2,5-disubstituted 1-pyrrolines. When hydrogenation of racemic 5-methyl-2-phenyl-1-pyrroline with (Y)-34 is interrupted at ca. 50% conversion, unreacted R substrate with 99% ee is obtainable with a (2S,5S)-cA-pyrrolidine derivative with 99% ee (Scheme 1.98) [353], As summarized in the table, some other racemic substrates can be resolved in >95% optical yield. 

N-terminal L-proline, again in DMSO as solvent [40], In this study the maximum ee in the addition of acetone to trans-2-nitrostyrene was 31%. Alexakis and Andrey successfully employed the bis-pyrrolidine 52 as catalyst for the addition of aldehydes and ketones to trans-fi-nitrostyrene [41], whereas Barbas and Betancort [42] were able to perform the Michael addition of unprotected aldehydes to nitroolefins using the pyrrolidine derivative 53 as catalyst (Scheme 4.24). 

The existence of the enamine intermediate of proline-catalyzed reaction with acetone as a donor was detected by mass analysis [54], but not by aH NMR. The formation of the presumed enamine intermediate generated from pyrrolidine-acetic acid and isobutyraldehyde was confirmed by 1H NMR [29a]. In this study, the enamine formation in the presence of pyrrolidine-acetic acid was observed within 5 min, but the enamine was shown to form only very slowly in the absence of acid. In these pyrrolidine derivative-acid combination catalysts, the acid component was shown to be important both for faster enamine formation and for the stereocontrol in the C-C bond-forming step. These catalyst systems are essentially split-proline systems that allow for the contributions of the pyrrolidine and carboxylate functionalities of proline to be probed independently. 

Cyclic nitrones generated by [4+ 2]-cycloaddition of nitroalkenes undergo various, synthetically very valuable reactions. Thus, Denmark et al. have developed an elegant access to different enantiopure, 3- and 3,4-substituted pyrrolidine derivatives by reductive ring contraction of the cyclic nitrone resulting from a hetero Diels-Alder reaction [389,390]. Upon reaction of -2-nitrostyrene 4-51 with the chiral enol ether 4-52 in the presence of the bulky Lewis acid MAPh (4-53), three diastereomeric cycloadducts 4-54, 4-55 and 4-56 were formed. Hydrogenolysis of the main product 4-54 yielded the desired pyrrolidine 4-57 in excellent optical purity and allowed nearly quantitative recovery of the chiral auxiliary (Fig. 4-12) [391]. It is noteworthy that the nature of the Lewis acid catalyst, especially its steric demand, decisively influences the stereochemical course of such cycloadditions [392]. 

The palladium-catalyzed [3 + 2] cycloaddition of vinylic oxirane 20a [42] and aziridine 20b [39] with the activated olefin 4a for the formation of five membered cyclic ether 21a and pyrrolidine derivative 21b has also been reported in our laboratories. The mechanistic issue is very much similar to that discussed in Scheme 9. Pd(0) catalyst added oxidatively to 20 to produce the 7r-allylpalladium complex 22. The Michael addition of a hetero nucleophile in 22 to the activated olefin 4a gives 23 which undergoes intramolecular nucleophilic attack on the inner 7r-allylic carbon atom to give the cy-clized products 21 and Pd(0) species is generated (Scheme 10). Similarly, the palladium-catalyzed [3 + 2] cycloaddition of vinylic oxirane 20a with the N-losylimincs 24 is also known (Scheme 11) [43]. Intermolecular cycloaddition of vinyl epoxides and aziridines with the heterocumulenes such as isocyanates, carbodiimides and isothiocyanates is also known [44,45]. Alper et al. reported the regio- and enatioselective formation of the thiaolidine, oxathiolane, and dithiolane derivatives by the palladium-catalyzed cyclization reaction of 2-vinylthiirane with heterocumulenes [46]. 

Cycloaddition of nitrones and pyrazolinones with a copper catalyst and a chiral ligand leads to pyrrolidine derivatives with good enantioselectivity. 

Not only diazo compounds, but also )8-ketosulfoxonium ylides can be converted to carbenoids capable of undergoing intramolecular N—H insertion to form pyrrolidine derivatives. Thus, ylide 60 (n = 1) was treated with a rhodium(II) catalyst in boiling benzene to give proline derivative... 

Zhang et al. investigated the asymmetric 1,3-dipolar cycloaddition of tert-butyl 2-(diphenylmethyleneamino)acetate and nitroalkenes promoted by bifunctional thiourea compounds derived from cinchona alkaloids, affording chiral pyrrolidine derivatives 13 with multisubstitutions. Catalyst lm delivered the best results in terms of catalytic activity, diastereoselectivity and enantioselectivity. Nevertheless, only moderate ee values could be obtained while the diastereoselectivities were generally good (Scheme 10.18) [22]. 

We examined optically active pyrrolidine derivatives as efficient chiral catalysts in the asymmetric 1,4-addition of thiols to a,j3-unsaturated ketones. Thus, benzenethiol in the presence of 1 mol% of a chiral diamino alcohol, 3a-f, as catalyst was added to 2-cyclohexen-l-one in toluene at —20 °C. The results are listed in Table IS . 

A. Armstrong, G. Ahmed, 1. Garnett, K. Goacolou, Pyrrolidine-Derived iminium salts as catalysts for alkene epoxidation by Oxone , Synlett (1997) 1075. 

Another interesting and synthetically useful behavior of aziridines is their tendency to open thermally to azomethine ylides, a process which can also be facilitated by Lewis acid catalysts. These reactive intermediates can be trapped by a variety of dipolarophiles to give new heterocyclic species. Methyl vinyl ethers convert aziridines such as 172 into a pyrrolidine derivative (i.e., 174) in the presence of a zinc(salen) Lewis acid catalyst 171 <04JA2294>. Similarly, nitriles (e.g., 175) lead to the formation of 2,4-disubstituted 177-imidazolines (e.g., 176) under the catalysis of boron triethyloxonium tetrafluoroborate <04TL 1137>. Under almost... 

Addition and cyclization reactions. Chiral propargylic amines are obtained from aUcynylation of imines by catalysis of the silver salt of IB. The enantiomer of phosphate ID also finds use in the addition of indole to a-acetaminostyrenes. One more catalyst for intramolecular hydroamination to form pyrrolidine derivatives is the silylated 3. The... 

---