Amino esters, azomethine ylides 1,3-dipolar cycloadditions

Synthetic work commenced with evaluation of an azomethine ylide dipole for the proposed intramolecular dipolar cycloaddition. A number of methods exist for the preparation of azomethine ylides, including, inter alia, transformations based on fluoride-mediated desilylation of a-silyliminium species, electrocyclic ring opening of aziridines, and tautomerization of a-amino acid ester imines [37]. In particular, the fluoride-mediated desilylation of a-silyliminium species, first reported by Vedejs in 1979 [38], is among the most widely used methods for the generation of non-stabilized azomethine ylides (Scheme 1.6). 

Microwave-induced 1,3-dipolar cycloadditions involving azomethine ylides have been widely reported in the literature. Bazureau showed that imidates derived from a-amino esters 120, as potential azomethine ylides, undergo 1,3-dipolar cyclo-additions with imino-alcohols 121 in the absence of solvent under microwave irradiation. This reaction leads to polyfunctionalized 4-yliden-2-imidazolin-5-ones 122 (Scheme 9.36) [87]. 

The synthesis of proline-fused heterocyclic systems by 1,3-dipolar cycloaddition has been well-established in solution-phase synthesis (Scheme 14) [42]. It is usually performed as a one-pot, three-component reaction of a dipo-larophile with an in situ prepared azomethine ylide. Perfluoroalkanesulfonyl protected hydroxybenzaldehydes [43] or fluorous alcohol protected amino esters [44] have been developed as two different fluorous components for the synthesis of proline derivatives 11 and 12. 

A one-pot, double intramolecular 1,3-dipolar cycloaddition reaction of azomethine ylides was developed by reaction of 4 equiv of an O-allyl salicyl-adehyde with a fluorous amino ester under microwave heating to generate a novel hexacyclic ring system 13 that contains seven stererocenters (Scheme 15) [45]. 

The first evidence for the existence of acyclic N-unsubstituted azomethine ylides as tautomers of imines was reported by Grigg (77CC125 78CC109). When the imines of a-amino esters are heated in benzene or toluene in the presence of a variety of dipolarophiles, pyrrolidine- or 3-pyrroline-2-carboxylates are isolated in high yields. These heterocycles correspond to the products produced by the 1,3-dipolar cycloadditions of N-unsubstituted azomethine ylides, indicating the thermal equilibrium between the imine esters... 

An intramolecular allyl silane/N-sulfonyl iminium ion cyclization has also been used as a pivotal step in an approach to the tricyclic core of the unique marine alkaloid sarain A [46]. The starting material was aziridine ester 129 (Scheme 25) which was elaborated to amide 130. An important step in the synthetic strategy was thermolysis of 130 to an azomethine ylide, which underwent stereospecific intramolecular 1,3-dipolar cycloaddition with the Z-alkene to produce bicyclic lactam 131 [47]. This compound was then elaborated into allyl silane 132. It was then possible to replace the lactam N-benzyl functionality with a tosyl moiety, leading to 133, and subsequent reduction of the carbonyl group afforded the desired cyclization precursor a-hydroxy sulfonamide 134. Exposure of 134 to ferric chloride promoted cyclization to a single stereoisomeric tricyclic amino alkene 136 having the requisite sarain A nucleus. It is believed that the intermediate N-sulfonyl iminium ion cyclizes via the conformation shown in 135. 

The 1,3-dipolar cycloaddition reaction of azomethine ylides with thioketones has been used to prepare 1,3-thiazoIidines. The metallated azomethine ylides 67 were generated in situ by treating a-amino acid ester imines 66 with lithium bromide and DBU. The ylides were then treated with highly reactive thioketones such as thiobenzophenone or fluorene-9-thione, to afford 1,3-thiazolidine derivatives 68 (main isomer) and 69 (minor isomer) in good yield and in diastereoisomeric ratios of between 2 1 and 4 1 <01H(55)691>. 

The 1,3-dipolar cycloadditions of azomethine ylides with aldehydes readily produced high yields of oxazolidines, which hydrolysed to anti a-amino-y -hydroxy esters." Non-stabilized azomethine ylides with isotonic anhydrides produced oxa-zolidine intermediates, which were converted into l,3-benzodiazepin-5-ones via ringopening-decarboxylation-ring-closing reaction cascades." ... 

Dipolar [3 + 2] cycloadditions are one of the most important reactions for the formation of five-membered rings [68]. The 1,3-dipolar cycloaddition reaction is frequently utilized to obtain highly substituted pyrrolidines starting from imines and alkenes. Imines 98, obtained from a-amino esters and nitroalkenes 99, are mixed together in an open vessel microwave reactor to undergo 1,3-dipolar cycloaddition to produce highly substituted nitroprolines esters 101 (Scheme 35) [69]. Imines derived from a-aminoesters are thermally isomerized by microwave irradiation to azomethine ylides 100,... 

The 3 + 2-cycloaddition reaction of azomethine ylides with c-deficient alkenes produced polysubstituted l- and D-unnatural prolines. Also, phosphoramidite-(7u(OTf)2 complexes catalyse the 1,3-dipolar cycloaddition reactions of azomethine ylides with nitroalkenes to yield exo-tetrasubstituted proline esters." The 1,3-dipolar cycloaddition of non-stabilized azomethine ylides, from iV-alkyl-a-amino acids and aldehydes, with 3-substituted coumarins provides l-benzopyrano[3,4-c]pyrrolidines in good yields and high regio- and stereo-selectivity." The organocatalytic 1,3-dipolar cycloaddition of azomethine ylides, derived from azlactones, with methyleneindolinones produced spirooxindoles with high yields (up to 95%) and high diastereo- (93 7 dr) and enantioselectivity (98% ee). ... 

Nine substituted hydroxybenzaldehydes were coupled to a Wang resin with a Mitsu-nobu coupling (Scheme 11.4). Treatment of the aldehydes with amino acid methyl esters produced resin-bound azomethine ylides that reacted with maleimide in a 1,3-dipolar cycloaddition. Ether-linked cycloadducts were cleaved from the resin as phenols with 50% trifluoroacetic acid. The compounds were retained as a mixture and were not isolated. 

This group also presented the first catalytic asymmetric 1,3-dipolar cycloaddition of azomethine ylides to imines, which converted aldehydes 3, amino esters 45a, and anilines 7 into chiral imidazolidines 58 with high levels of enantioselectivity (Scheme 2.16) [27],... 

Gong et al. have confirmed that oxygen-linked bisphosphoric acid (274) provided the highest level of stereoselectivity for the 1,3-dipolar cycloaddition reaction tolerating a wide range of substrates including azomethine ylides, generated in situ from a broad scope of a-amino esters (275), aldehydes (276), and various electron deficient dipolarophiles (277). This reaction actually represents one of the most enantioselective catalytic... 

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