Proline derivatives asymmetric diastereoselectivity

The chiral auxiliaries anchored to the substrate, which is subjected to diastereoselective catalysis, is another factor that can control these reactions. These chiral auxiliaries should be easily removed after reduction without damaging the hydrogenated substrate. A representative example in this sense is given by Gallezot and coworkers [268], They used (-)mentoxyacetic acid and various (S)-proline derivates as chiral auxiliaries for the reduction of o-cresol and o-toluic acid on Rh/C. A successful use of proline derivates in asymmetric catalysis has also been reported by Harada and coworkers [269,270], The nature of the solvent only has a slight influence on the d.e. [271],... 

In late 1975, Enders et al.156) started a research project directed towards the development of a new synthetic method for asymmetric carbon-carbon bond formation. A new chiral auxiliary, namely the (S)-proline derivative SAMP (137), was allowed to react with aldehydes and ketones to give the hydrazones (138), which can be alkylated in the a-position in an diastereoselective manner 157,158). Lithiation 159) of the SAMP hydrazones (138), which are formed in excellent yields, leads to chelate complexes of known configuration 160). Upon treatment of the chelate complexes with alkyl halogenides the new hydrazones (139) are formed. Cleavage of the product hydrazones (139) leads to 2-alkylated carbonyl compounds (140). 

Another substrate class, for which the outcomes of a radical and a carbocationic process are opposite, are indoles (Fig. 85) [418], Indeed, when oxaziridines 315a or 315c were treated with indoles 314c in the presence of 2 or 10 mol% of C11CI2/ TBAC oxazolidinoindolines 316c were obtained as the exclusive products in 53-90% yield. The reaction is applicable to 2-, 3-, and 2,3-disubstituted indoles. Chiral indole derivatives acylated with (S)-proline units at nitrogen underwent asymmetric diastereoselective aminohydroxylation reactions with 86-91% de. Tricyclic hemiaminals derived from tryptamine derivatives could be transformed to pyrrolidinoindolines, which are core structures of a number of alkaloids. 

In addition to proline-derived organocatalysts, a large number of chiral primary amines have been successfully used to catalyse asymmetric aldolisations. Thus, several primary amine catalysts derived from chiral 1,2-cyclohexyldi-amine have been applied as organocatalysts to promote the aldolisation of ketones. Remarkable combinations of both excellent yields and enantioselectivities associated to high diastereoselectivities of up to 94% de were obtained by Maruoka and Nakayama for the asymmetric aldolisation of various cyclic ketones with benzaldehydes by using a common substituted cw-cyclohex-yldiamine in a 1 1 THF/H2O mixture as the solvent (Scheme 2.29). ... 

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). 

Asymmetric addition to a chiral a-keto amide. The Lewis acid-catalyzed addition of allyltrimethylsilane to a chiral a-keto amide (1) derived from methyl (S)-prolinate proceeds with good to high diastereoselectivity, probably because of chelation with the ester group of 1. SnBrj, SnCU. and TiCU are the most effective catalysts. 

In 2001, Tungler and coworkers described the diastereoselective hydrogenation of N (1 methylpyrrole 2 acetyl) (S) proline methyl ester (32) using the Rh/C as cata lyst [40]. By introducing (S) proline moiety as chiral auxiliary, high asymmetric induction was obtained. When 32 was subjected to 5% Rh/C catalyst in methanol with 20 bar H2, the reduced product 33 was obtained with full conversion and 95% de. This substrate induced asymmetric reduction and was effective only to (2 pyrrolyl) acetic acid derivatives (Scheme 10.30). 

In the past Lewis acid-catalyzed [4+2] cycloaddition reactions of chiral alkyl acrylates have been systematically studied. Chiral auxiliaries derived from camphor, menthol and amino acids or from carbohydrates have been developed. Stereochemical and theoretical aspects of these chiral inductors have been intensively reviewed (see. Chapter 6). Asymmetric Diels-Alder reactions of chiral acrylamides derived from Ca-symmetrical secondary amines lead selectively to the cycloadducts in the presence of Lewis acids such as AICI3. In reactions of chiral auxiliaries derived from (iS)-proline and (iS)-prolinol excellent endo/exo selectivities and diastereoselectivities were obtained in the presence of catalytic amounts of Et2AlCl or TiCL. Cycloadducts of chiral crotonoyl derivatives derived from oxazolidinones 62, sultam 63 or for example (S)-lactate IS were obtained with high selectivities in the presence of Lewis acids such as Et2AICl. 

Importantly, prolinamide catalysts (Figure 6.3) work well in Michael addition reactions using nitro-olefins as acceptors. iV-Tritylprolinamide 33 and aminonaphthyridine-derived ProNap 34 served as organocatalysts in asymmetric Michael additions of aldehydes and cyclohexanone to nitro-alkenes. Proline-functionalised C3-symmetric 1,3,5-triallq lbenzene 35 was screened in the reaction of cyclohexanone to nitrostyrene to afford the Michael adducts in good yields and diastereoselectivity but low enantioselectivity. 

By contrast, very high diastereoselectivities have been observed by the use of chiral hydrazones prepared from the C2 symmetric hydrazine 2,5-dimethyl-pyrrolidin-l-ylamine. The asymmetric induction comes at a price, however The hydrazine is not commercially available, and it cannot be recovered as such following oxidative cleavage from the P-lactam. More readily available, and therefore more expendable, hydrazines are SAMP analogs derived from L-proline. ... 

The synthesis of a novel Merrifield resin-supported dipeptide Pro-Ala-O-P, derived from proline and alanine, was reported by Wang and Yan with the aim of being used as an organocatalyst in asymmetric aldol reactions of ketones with aldehydes. " Indeed, this supported dipeptide was found to be an efficient catalyst to promote the asymmetric aldol reaction under neat conditions between aromatic aldehydes and cyclic ketones, generating the corresponding aldol products with moderate to high yields and diastereoselectivities of up to 80% de combined with good enantioselectivities of up to 95% ee, as shown in Scheme 2.18. Moreover, this catalyst could be used for seven times with only a minor decrease in product yields, but maintained stereoselectivities. 

A one-pot synthesis of 1,3-diamines was described in 2009 by Cordova and coworkers [17]. An asymmetric cascade aza-Michael/Mannich reaction was developed using a combination of diphenylprolinol trimethylsilyl ether 5 and proline as catalysts (Scheme 12.13). The cascade was possible because of the complete difference in reactivity between chiral pyrrolidine 5 and proline in the separate reactions. The conjugate addition of a protected methoxyamine to hex-2-enal was coupled to a three-component Mannich reaction, giving direct access to orthogonally protected chiral diamine derivatives with excellent chemo and enantioselectivities (yield 60-62%, ee 98-99%). The use of l-Pto as a catalyst for the Mannich reaction afforded the 6yn-l,3-diamine 30 (dr > 19/1), while the use of the antipode D-proline gave the anti derivative 31 with similar levels of diastereoselectivity. 

Following immediately the initial efforts on primary amino acids catalyzed aldol reactions, the application of primary amine acid in Mannich reaction has also been attempted. Cordova reported that simple primary amino acids and their derivatives could catalyze the asymmetric Mannich reactions of ketones with comparable results to those obtained in the catalysis of proline[28]. Later, Barbas [29] and Lu [30] independently reported that L-Trp or 0-protected L-Thr could catalyze anti-selective asymmetric Mannich reactions of a-hydroxyacetones with eiflier preformed or in-situ generated imines. The preference of anii-diastereoselectivity was ascribed to the formation of a Z-enamine, with the assistance of an intramolecular H-bond (Scheme 5.15). 

The investigations of Enders, Evans, and others have demonstrated the versatility of chiral auxiliaries based on the proline skeleton [80]. Katsuki designed and utilized a C2-symmetric, 2,5-disubstituted pyrrolidine auxiliary for asymmetric enolate alkylations (Equation 10) [81]. Enolates prepared from 112 generally undergo alkylations with superb diastereoselectivity dr >95 5). However, in contrast to the prolinol amide-derived systems described above, accessibility of the chiral auxiliary hinged upon a multi-step synthetic preparation involving resolution, and the hydrolytic removal of the auxiliary necessitated considerably harsher reaction conditions. 

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