1.3- Dipolar cycloaddition amino acid synthesi

Recent research deals with stereoselective 1,3-dipolar cycloadditions of nitrones for the syntheses of alkaloids and aza heterocycles asymmetric synthesis of biologically active compounds such as glycosidase inhibitors, sugar mimetics, /3-lactams, and amino acids synthesis of peptido-mimetics and peptides chemistry of spirocyclopropane heterocycles synthesis of organic materials for molecular recognition and photochemical applications. 

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. 

Owing to flexibility in the substrate, the TycATE was also used to synthesize a variety of novel cyclic structures. Inclusion of a propargylated amino acid into the linear substrate allowed the synthesis of over 247 macrocyclic glycopeptides, where azido-sugars were coupled onto the cyclized alkyne via copper-catalyzed 1,3-dipolar cycloaddition [44] (Figure 13.12). 

A concise and efficient asymmetric synthesis of L-( + )-carbafuranomycin 452, a novel analog of L-( + )-furanomycin, which is an unusual antibiotic amino acid of great interest, due to its activity as an isoleucine antagonist, has been reported (496). The synthesis starts with the 1,3-dipolar cycloaddition of a chiral nitrile oxide (obtained in situ from hydroximinoyl chloride 453 via slow addition of NEt3) with cyclopentadiene. Then methylation of cyclopentenyl acetate 454,... 

Huisgen and coworkers have also described the cycloaddition behavior of the munchnones , unstable mesoionic A2-oxazolium 5-oxides with azomethine ylide character.166 Their reactions closely parallel those of the related sydnones. These mesoionic dipoles are readily prepared by cyclodehydration of N-acyl amino acids (216) with reagents such as acetic anhydride. The reaction of munchnones with alkynic dipolarophiles constitutes a pyrrole synthesis of broad scope.158-160 1,3-Dipolar cycloaddition of alkynes to the A2-oxazolium 5-oxide (217), followed by cycloreversion of carbon dioxide from the initially formed adduct (218), gives pyrrole derivative (219 Scheme 51) in good yield. Cycloaddition studies of munchnones with other dipolarophiles have resulted in practical, unique syntheses of numerous functionalized monocyclic and ring-annulated heterocycles.167-169... 

A number of complex heterocycles have been assembled using dipolar cycloadditions (Fig. 6). The Affymax group [32] published an approach to the synthesis of tetrasubsti-tuted pyrrolidines by the reaction of azomethine ylids with electron-deficient olefins. A similar approach was described by researchers at Monsanto however, the aldehyde component was bound to the resin instead of the amino acid [33]. Kurth and co-workers [34] described a route to 2,5-disubstituted tetrahydrofurans using a nitrile oxide cycloaddition as the key reaction. Mjalli et al. [35] synthesized highly substituted pyrroles using the dipolar cycloaddition of intermediate 5 with mono- or disubstituted acetylenes. 

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. 

The 1,2-dipolar cycloaddition of chlorosulfonyl isocyanate to different cycloalkenes has become a well-known route for the synthesis of cycloalkane-fused p-lactams, and for alicyclic P-amino acids, after hydrochloric acid treatment. The addition takes places regio- and stereospecifically, in accordance with the Markovnikov orientation rule [51-55]. In this manner, a number of homologue and analogue alicyclic P amino acids have been prepared, such as czs-2-amino-2-methylcyclopentanecarboxylic acid [56], m-2-amino-2-methylcyclo-hexanecarboxylic acid [56], (l/ , 2S, 4S )2-amino-4-terMnitylcyclopenta-necarboxylic acid [55, 58], 3-exo-aminobicyclo[2.2.1]heptane-2-exo-carboxylic acid [59, 60] and 3-exo-aminobicyclo[2.2.1]hept-5-ene-2-exo-carboxylic acid [61]. 

Dipolar cycloadditions between nitrones and alkenes are most useful and convenient for the preparation of isoxazolidine derivatives, which are readily converted to 1,3-amino alcohol equivalents under mild reducing conditions (Tufariello 1984, Torssell 1988). In spite of the importance of chiral amino alcohol units for the synthesis of biologically important alkaloids, amino acids, 3-lactams, and amino sugars, etc. (for a review see Frederickson 1997), catalytic enantioselective 1,3-dipolar cycloadditions remain relatively unexplored (Seerden et al. 1994, 1995, Gothelf and Jorgensen 1994, Gothelf et al. 1996, Hori et al. 1996, Seebach et al. 1996, Jensen et al. 1997). Catalytic enantioselective... 

Abstract This review is devoted to the stereoselectivity of intermolecular (intramolecular cycloadditions are not included) 1,3-dipolar cycloadditions of sugar-derived nitrones. Stereoselective cycloaddition (transformation of isoxazolidine followed by reduction of the N O bond to produce both an amino and a hydroxy function) allows the synthesis of tailor-made products of possible biological interest such as pol>4iydroxylated pyrrolidines, pyrrolizidines, indolizidines, fi-aminocarbonyl compounds, and disaccharides. Attention is focused on the preparation of isoxazolidinyl nucleosides and to the catalysis of the cycloaddition by Lewis acids. This review has concentrated on the new developments achieved from 1999 to February 2007. 

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