Enantioselective pyrrolidine formation

SCHEME 5 Enantioselective pyrrolidine formation from the Xiao group. 

Paderes and Chemler developed an intramolecular diastereoselective aminooxygenation of unactivated alkenes to pyrrolidines. Cu(EH)2/02 catalytic system could lead to 2,5-cis- and 2,5-fra s-pyrrolidines formation from a-substituted 4-pentenylsulfonamides in good to excellent yields and >20 1 selectivity. For P- and /-substituted 4-pentenylsulfonamides, Cu(OTf)2-bis(oxazoline) with O2 catalytic system could give higher diastereoselectivities. Furthermore, enantioselective desymmetrization could be achieved (up to 98% ee) with /l-allyl-4-pentenylsulfonamide [26] (Scheme 8.13). 

The key to the success of the synthesis was the development of a novel method for enantioselective formation of a-arylpyrrolidines. In this method, (-)-sparteine-mediated, enantioselective lithiation of N-Boc-pyrrolidine 19 was followed by an in situ transmetallation to zinc and Pd-catalyzed coupling reaction with aryl bromide 3, which afforded 2-arylpyrrolidine in 63% isolated yield and 92% ee. Notably, the acidic aniline NH2 group was tolerated under the coupling reaction conditions. 

A chair-like amino-zinc-enolate transition state has been used to explain how substituents on the ring affect the diastereoselective and enantioselective formation of polysubstituted pyrrolidines during intramolecular amino-zinc-enolate carbometalla-tion reactions. ... 

Enantioselective aldolization using 5-pyrrolidin-2-yltetrazole (26) - in which the carboxylic acid of proline has been replaced by its well-known pharmacophore - has been modelled by DFT.112 The calculations indicate that the large charge buildup on the carbonyl oxygen during C-C bond formation is stabilized by hydrogen bonding by the tetrazole NH. 

In the area of [3 + 2]-cycloadditions (1,3-dipolar cycloadditions), chiral silver catalysts have been utilized extensively for the enantioselective formation of five-membered rings from prochiral substrates. For example, Zhang and co-workers360 have reported the highly enantioselective Ag(i)-catalyzed [3 + 2]-cycloaddition of azomethine ylides to electron-deficient alkenes. Thus, reaction of ct-imino esters 442 with dimethyl maleate in the presence of catalytic amounts of silver(i) acetate and the chiral bisferrocenyl amide phosphine 443 provided the chiral pyrrolidines 444 with high stereoselectivities and chemical yields (Scheme 131). Only the endo-products were isolated in all cases. 

Internal 1,1 or 1,2 disubstituted olefins 26 and 28 are much less reactive for hydroamination and require significantly harsher reaction conditions [39, 41 44]. The formation of pyrrolidines and piperidines often proceeds at comparable rates (Eq. 11.7), contrasting the general trend of significantly faster five membered ring formation observed with terminal aminoalkenes [39]. Despite these harsh reaction conditions, moderate enantioselectivities of up to 58% ee at 100 "C (up to 68% at 60 °C) were observed. 

However, at this stage relatively little progress has been made in research on asymmetric catalytic carbene transfer to imines. In 1995, Jacobsen and Jorgensen reported independently that reaction of ethyl diazoacetate with selected imines can be catalyzed by copper salts [27,28]. In the former case [27], moderate levels of enantioselection were found to be imparted by bisoxazoline ligands associated with the copper catalyst (Scheme 11). The observation of racemic pyrrolidine byproducts in the reaction was taken to support a mechanism of catalysis involving initial formation of a copper-bound azomethine yhde intermediate (Scheme 12 ). Collapse of this intermediate to the optically active aziridine apparently competes with dissociation of the copper to a free azomethine ylide. The latter can react with fumarate formed by diazoester decomposition in a dipolar cycloaddition to afford racemic pyrrolidine. 

The a.a-dimethyl derivative 23 was used in the formation of amides 30 with carboxylic acids and thus applied to the enantioselective a-alkylation of carbanions (Section D.1.1.1.3.1.). The amides are obtained either by Ar-acylation of 2-(l-hydroxy-l-methylethyl)pyrrolidine or by first acylating an ester of proline and subsequent treatment with a Grignard reagent which reacts selectively with the ester group, leaving the amide intact. 

Wang et al. further used pyrrolidine-sulfonamide 3a to develop a highly enantioselective Michael reaction of cyclic ketones to a,p-unsaturated ketones (chalcones). The synthetically useful 1,5-dicarbonyl compounds were obtained in good yields and with high stereoselectivities (>40 1 dr, up to 97% ee). The most satisfactory results were achieved for six-membered cyclic ketones, whereas cyclopentanone appeared to be a more challenging substrate for this reaction (Scheme 9.26). A possible transition-state model was presented to rationalise the stereochemical outcome in which hydrogen-bond formation between the NH in 3a and the carbonyl group of chalcone caused the increase in reactivity. 

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). 

Enantioselective 1,3-dipolar cycloadditions employing azomethine ylides and asymmetric catalysis are discussed in the next chapter. The formation of chiral non-racemic pyrrolidine derivatives via dipolar cycloadditions presents an important challenge that has been successfully overcome. The role of catalysis involving different metals is also highUghted. 

Higher levels of chiral induction were achieved with (/ )-xylyl-BINAP(Au-/i-nitrobenzoate)2 or (/ )-ClMeOBIPHEP(Au-p-nitrobenzoate)2 as catalyst (Scheme 4-63). These allow the smooth formation of chiral pyrrolidines or piperidines with up to 99% ee and high chemical yield from the corresponding trisubstituted tosyl-protected y- or 5-aminoallene. Gold catalysts with a chiral counterion can also be employed for the highly enantioselective intramolecular exo-hydroamination of aminoallenes. ... 

As an extension of this methodology, these authors employed the same catalyst to induce a three-component synthesis of chiral pyrrolidines [350]. The first step of the domino process consisted in an imine formation between 2-aminomalonate and an aldehyde. Its corresponding azomethine yUde, prepared in situ, reacted with a,P-unsaturated aldehydes, furnishing the final products in good yields (51-63%) and diastereo- and enantioselectivities of 50-82% de and 92-98% ee, respectively. Various aromatic and ahphatic enals were compatible acceptors in this process, as were a broad range of berrzaldehydes. In 2008, a three-component reaction of aldehydes, diaUcyl maleates, and a-amino esters was described by Gong et al. [351]. The... 

The amine-catalysed asymmetric conjugate addition of aldehydes to nitroalkenes is a powerful tool for stereoselective carbon-carbon bond formation, and hence, a large number of chiral amine catalysts have been developed to date. ° In most amine-catalysed reactions, q n-conjugate adducts were obtained as major diastereomers. For instance, the reaction catalysed by a chiral pyrrolidine (5 )-6 gave a sy -conjugate adduct with excellent enantioselectivity (Scheme 17.13). In contrast, the reaction using a biphenyl-based amine catalyst (S)-7 is complementary to most amine-catalysed... 

---