Alkyl-imines, enantioselective reactions

Table 34.4 Selected results for the enantioselective hydrogenation of N-alkyl imines and enamines (for structures, see Fig. 34.7) Catalytic system, reaction conditions, enantioselectivity, productivity and activity.

A highly enantioselective direct Mannich reaction of simple /V-Boc-aryl and alkyl- imines with malonates and /1-kclo esters has been reported.27 Catalysed by cinchona alkaloids with a pendant urea moiety, bifunctional catalysis is achieved, with the urea providing cooperative hydrogen bonding, and the alkaloid giving chiral induction. With yields and ees up to 99% in dichloromethane (DCM) solvent, the mild air- and moisture-tolerant method opens up a convenient route to jV-Boc-amino acids. 

Nucleophilic carbon radicals can C-alkylate imines, a process which is found to be substantially facilitated by an o-phenolic substituent as in e.g. (32).85 The hydroxyl is presumed to stabilize an intermediate aminyl radical. An enantioselective version of the reaction is also reported. 

Some bifunctional 6 -OH Cinchona alkaloid derivatives catalyse the enantioselective hydroxyalkylation of indoles by aldehydes and a-keto esters.44 Indole, for example, can react with ethyl glyoxylate to give mainly (39) in 93% ee. The enan- tioselective reaction of indoles with iV-sulfonyl aldimines [e.g. (40)] is catalysed by the Cu(OTf)2 complex of (S)-benzylbisoxazoline (37b) to form 3-indolylmethanamine derivatives, in up to 96% ee [e.g. (41a)] 45 Some 9-thiourea Cinchona alkaloids have been found to catalyse the formation of 3-indolylmethanamines [e.g. (41b)] from indoles and /V-PhS02-phenyli mines in 90% ee.46 Aryl- and alkyl-imines also give enantioselective reactions. 

Phosphoric acid 25a was successfully employed for mediating enantioselective synthesis of 1,3-disubstituted isoindolines from electrophilic bifunctional substrates (containing an imine and a Michael acceptor site) and indoles [33]. Catalyst 7a was used effectively in an organocatalytic asymmetric F-C alkylation/cyclization cascade reaction between 1-naphthols and a,(i-unsaturated aldehydes to give chro-manes in good yields and select vities (Scheme 3 5.18) [ 10]. Furthermore, 2-naphthols and p,y-unsaturated a-keto ester also reacted in a F-C alkylation/dehydration sequence, in the presence of a thiourea catalyst and a catalytic amount of concentrated sulfuric acid, affording optically active naphthopyran derivatives [54]. 

Mannich Reaction Carbamate-protected alkyl imines are important building blocks in the synthesis of chiral alkyl amines. However, they are usually unstable, and most of them cannot be prepared in pure form. As the optimal substitutes, a-amido sulfones 142 were first used in the PTC-catalyzed enantioselective aza-Henry reaction in 2005 [57]. Subsequently, Song et al. reported a chiral Cinchona alkaloid thiourea (130b)-catalyzed Mannich reaction with in situ generation of... 

Reactions with Active Methylene Compounds. Enolates of ketones," esters," enediolates," 1,3-dicarbonyl compounds," amides and lactams," as well as nitrile-stabilized carbanions," can be alkylated with benzyl bromide. Cyclohexanone may be benzylated in 92% ee using a chiral amide base." Amide bases as well as alkoxides have been employed in the case of nitrile alkylations." Benzylation of metalloenamines may be achieved and enantioselective reactions are possible using a chiral imine (eq 3). However, reactions between benzyl bromide and enamines proceed in low yield. The benzylation of a ketone via its enol silyl ether, promoted by fluoride, has been observed. ... 

Preliminary experiments prove that the substitution pattern of the /V-aryl moiety of imine 1 is crucial for the stereoselectivity of this reaction. The 2-substituent on the aryl group is of special importance. Namely, introduction of a methoxy group leads to a considerable decrease of enantioselectivity compared to the corresponding 2-H derivative, probably due to disfavor-able coordination with the organolithium complex. In contrast, alkyl groups show the reverse effect along with increased bulkiness (e.g., Tabic 1, entries l-3a) but 2,6-dimethyl substitution provides lower ee values. Furthermore, the 4-substituent of the TV-aryl moiety is of minor importance for the stereoselectivity of the reaction [the Ar-phcnyl and the /V-(4-methoxyphenyl) derivatives give similar results], whereas a substituent in the 3-position results in lower stereoselectivities (e.g., Et, Cl, OCHj)41. 

Optically active /3-ketoiminato cobalt(III) compounds based on chiral substituted ethylenedi-amine find use as efficient catalysts for the enatioselective hetero Diels Alder reaction of both aryl and alkyl aldehydes with l-methoxy-(3-(t-butyldimethylsilyl)oxy)-1,3-butadiene.1381 Cobalt(II) compounds of the same class of ligands promote enantioselective borohydride reduction of ketones, imines, and a,/3-unsaturated carboxylates.1382... 

In contrast, testing substrates in Scheme 2-59 demonstrates that alkyl-substituted imines undergo the addition of HCN with considerably lower ee. (For R = cyclohexyl, 57% ee and 37% ee for R = r-butyl.) The A-substituent does not exert a significant influence on the enantioselectivity of the reaction. 

The studies summarized above clearly bear testimony to the significance of Zr-based chiral catalysts in the important field of catalytic asymmetric synthesis. Chiral zircono-cenes promote unique reactions such as enantioselective alkene alkylations, processes that are not effectively catalyzed by any other chiral catalyst class. More recently, since about 1996, an impressive body of work has appeared that involves non-metallocene Zr catalysts. These chiral complexes are readily prepared (often in situ), easily modified, and effect a wide range of enantioselective C—C bond-forming reactions in an efficient manner (e. g. imine alkylations, Mannich reactions, aldol additions). 

Furthermore, a highly efficient route to A-tert-butoxycarbonyl (Boc)-protected p-amino acids via the enantioselective addition of silyl ketene acetals to Al-Boc-aldimines catalyzed by thiourea catalyst 4 has been reported (Scheme 12.2)." From a steric and electronic standpoint, the A-Boc imine substrates used in this reaction are fundamentally different from the A-alkyl derivatives used in the Strecker reaction. 

The acyl-Pictet-Spengler reaction is also catalyzed by chiral thiourea derivative 6 to provide M-acetyl p-carbolines in high enantioselectivities. Notably, thiourea derivatives can activate not only electronically distinct imine derivatives such as N-alkyl and N-Boc imines but also a weakly Lewis basic N-acyhminium ion with high enantioselectivity using a chiral hydrogen bond donor (Scheme 12.4). 

Quite recently, there has been significant expansion and development in the alkylation of imines with organozinc reagents using chiral Lewis acid catalysts. In 2000, Tomioka and co-workers reported a copper(II)-chiral amidophos-phine 4-catalyzed asymmetric process for the addition of diethylzinc to N-sul-fonylimines (Scheme 2) [8]. Excellent enantioselectivities (90-94%) and yields (83-99%) were obtained in reactions of N-sulfonylimines derived from arylal-dehydes. 

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