Amino acids asymmetric reactions, 1,3-dipolar

Scheeren et al. reported the first enantioselective metal-catalyzed 1,3-dipolar cycloaddition reaction of nitrones with alkenes in 1994 [26]. Their approach involved C,N-diphenylnitrone la and ketene acetals 2, in the presence of the amino acid-derived oxazaborolidinones 3 as the catalyst (Scheme 6.8). This type of boron catalyst has been used successfully for asymmetric Diels-Alder reactions [27, 28]. In this reaction the nitrone is activated, according to the inverse electron-demand, for a 1,3-dipolar cycloaddition with the electron-rich alkene. The reaction is thus controlled by the LUMO inone-HOMOaikene interaction. They found that coordination of the nitrone to the boron Lewis acid strongly accelerated the 1,3-dipolar cycloaddition reaction with ketene acetals. The reactions of la with 2a,b, catalyzed by 20 mol% of oxazaborolidinones such as 3a,b were carried out at -78 °C. In some reactions fair enantioselectivities were induced by the catalysts, thus, 4a was obtained with an optical purity of 74% ee, however, in a low yield. The reaction involving 2b gave the C-3, C-4-cis isomer 4b as the only diastereomer of the product with 62% ee. 

Related a,p-Unsaturated Esters. Similar a,p-unsaturated esters bearing a heterocyclic chiral auxiliary of a-amino acid origin at the p-position are known and have been utilized in asymmetric synthesis. Effective asymmetric conjugate additions of cuprates to (2), (3), and (5)J epoxidations of (3), and dipolar cycloadditions of (2) have been reported. Although oxazoli-dine (4) is only obtained as an 86 14 equilibrating mixture of stereoisomers, reactions with the lithium (Z)-enolate of methyl N-benzylideneglycinate (see Ethyl N-Benzylideneglycinate) are exclusively diastereoselective. 

Mish, M.R., Gnerra, E.M., and Carreira, E.M., Asymmetric dipolar cycloadditions of Me3SiCHN2. Synthesis of a novel class of amino acids azaprolines, J. Am. Chem. Soc. 119 (35), 8379, 1997. Kim, Y., Singer, R.A., and Carreira, E.M., Total synthesis of macrolactin A with versatile catalytic, enantioselective dienolate aldol addition reactions, Angewandte Chemie-Intemational Edition 37 (9), 1261, 1998. 

The 1,3-dipolar cycloaddition reaction of non-stabilized azomethine ylides, derived from A-alkyl-cf-amino acids, with 3-nitro-2-trifluoro(trichloro)methyl-2//-chromenes produced l-benzopyrano[3,4-c]pyrrolidines in good yields." AgOAc-catalysed asymmetric 3 + 2-cycloaddition reactions of azomethine ylides with e-deficient alkenes yielded enr/o-adducts with up to 99% ee. New chiral ferrocenyl P,N-ligands possessing a benzoxazole ring as the Af-donor (35) are effective asymmetric catalysts... 

The 1,3-dipolar cycloaddition reaction of nitrones has been used in a short synthesis of 4-hydroxyproline, and in an asymmetric synthesis of the proline analogue (190) from a protected mannose oxime. Baldwin and his co-workers have reported a total synthesis of another heterocyclic amino-acid, the antitumour agent AT-125 (191). Syntheses of pipecolic acid and its analogues (192), aminopiperidinecarboxylic acids related to nipecotic acid (193), and c/5-3-aminocyclohexane carboxylic acid (194) have also been published. 

A bisphosphoric acid-catalyzed three-component asymmetric 1,3-dipolar addition reaction between aldehydes 98, amino esters 99, and dipolarophiles 100 was established by Gong and coworkers (Scheme 2.26). The new bisphosphoric acid 102 derived from the linked BINOL could efficiently promote the proposed three-component asymmetric reaction and deliver a series of multiply substituted pyrrolidines 101 in high yields with excellent enantioselectivities under mild conditions [41]. 

Also, Gong and co-workers reported a Brpnsted add catalyzed three-component asymmetric 1,3-dipolar cycloaddition reactions between aldehydes 213, amino esters 214, and dipolarphiles 215 by catalyst 216, providing pyrrolidines 217 in high yields with excellent enantioselectivity. Scheme 3.69 [86], The methodology introduced a concept that stereochemistry can be controlled by use of a chiral Br0nsted acid (BH), e.g., phosphoric acid. The chiral BH provided sufficient acidity... 

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