Proline derivatives azomethine ylides

Dipolar addition to nitroalkenes provides a useful strategy for synthesis of various heterocycles. The [3+2] reaction of azomethine ylides and alkenes is one of the most useful methods for the preparation of pyrolines. Stereocontrolled synthesis of highly substituted proline esters via [3+2] cycloaddition between IV-methylated azomethine ylides and nitroalkenes has been reported.147 The stereochemistry of 1,3-dipolar cycloaddition of azomethine ylides derived from aromatic aldehydes and L-proline alkyl esters with various nitroalkenes has been reported. Cyclic and acyclic nitroalkenes add to the anti form of the ylide in a highly regioselective manner to give pyrrolizidine derivatives.148... 

Pyridones, as exemplified by ABT-719 (154, Figure 3.8), represent a new class of DNA gyrase inhibitors possessing a broad spectmm of antibacterial activity and, in studies toward such compounds, it was revealed that the C(8) functionality was an important part of the DNA binding action. Azomethine ylide cycloadditions were employed to give a range of proline-type derivatives in order to study stmcture-activity relationships (39). 

Treatment of proline derivative 154 with rhodium acetate (57) originally led to ylide 155. However, this ylide (155) quickly rearranges to the more stable azomethine ylide 156, which undergoes cycloaddition with DMAD to give the unusual adduct 157. Intramolecular trapping experiments (58,59) have also been conducted (Scheme 4.35). 

For intramolecular 1,3-dipolar cycloadditions, the application of nitrones and nitrile oxides is by far most common. However, in increasing frequency, cases intramolecular reactions of azomethine ylides (76,77,242-246) and azides (247-259) are being reported. The previously described intermolecular approach developed by Harwood and co-workers (76,77) has been extended to also include intramolecular reactions. The reaction of the chiral template 147 with the alkenyl aldehyde 148 led to the formation of the azomethine ylide 149, which underwent an intramolecular 1,3-dipolar cycloaddition to furnish 150 (Scheme 12.49). The reaction was found to proceed with high diastereoselectivity, as only one diaster-eomer of 150 was formed. By a reduction of 150, the proline derivative 151 was obtained. 

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. 

In a subsequent study a number of fulleroproline-containing dipeptides and other derivatives, such as 201 and 202 (Scheme 1.15), were prepared and isolated as optically pure diastereoisomers or resolved into the enantiomers.241 The most distinctive feature in the CD spectra of these adducts is a sharp extremum at 428 nm, the sign of which is characteristic of the absolute configuration of the newly generated stereogenic center at the a-C-atom of the proline unit. To establish this relationship, the absolute configuration of the isolated diastereoisomers 201 and 202 (Scheme 1.15), synthesized by reaction of azomethine ylides generated from enantiomerically pure 203 and... 

The group of Gong and coworkers explored a biomimetic 1,3-dipolar cycloaddition between a-ketoester 79 and benzylamine derivatives 80 with electron-deficient olefins 81a,b to devise a straightforward route to proline derivatives 82 in high yields and enantioselectivities [49]. The proposed biomimetic three-component 1,3-dipolar cycloaddition proceeds as illustrated in Scheme 2.22a. The azomethine ylide B is formed, via a transamination from ketimine ester A, which is in turn prepared from a-ketoesters 79 and benzyl-amine derivatives 80 then, the 1,3-dipolar cycloaddition with electron-poor olefins 81a takes place. For this purpose, the bisphosphoric acid 83 was found to be the catalyst of choice to promote such transformation (Scheme 2.22b). Replacing dimethyl maleate (previously used as deficient olefins) by methyleneindolinones, the same approach could be extended to spirooxindoles synthesis in high yields and... 

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). ... 

A library of highly functionalized pyrrolidines was prepared from resin-bound azomethine ylides and electron-deficient olefins (Scheme 11.7). Four amino acids, four aldehydes, five olefins, and three acyl chlorides were used as building blocks to produce a library of diverse cycloadducts for various enzymatic assays. Ester-linked products were cleaved from TentaGel or SASRIN resins as carboxylic acids with diluted trifluoroacetic acid. Structural diversity of the proline derivatives was enhanced with iV-acylation of the pyrrolidines. 

A related method was applied to the synthesis of 18 isoxazolothiohydantoins (Scheme 11.51)/ Hydantoin formation was also applied to the release of proline derivatives that were obtained from the intramolecular cycloadditions of resin-bound azomethine ylides and alkenes. ... 

Targets with one Heteroatom Five-membered heterocycles with one heteroatom, such as pyrrolidine and tetrahydrofiiran skeletons, exist widely in numerous natural products and bioactive compounds. Therefore, intense efforts have been devoted to the synthesis of these five-membered ring systems. Among the various methods existing for the synthesis of chiral pyrrolidine and proline derivatives, few can match the synthetic potential of 1,3-DC reactions of azomethine ylides with alkenes [3]. Generally, azomethine yhdes are unstable species, so they are normally generated in situ and trapped by unsaturated bonds (Scheme 2.1) [2b]. 

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