Proline derivatives cycloaddition reactions

Isatin derivatives and proline react to give stereospecific formation of an azo-methine ylide intermediate via the decarboxylation route. The resulting 1,3-dipole undergoes a cycloaddition reaction with N-substituted maleimide (6), as a dipolaro-... 

This route relies on 1,3-dipolar cycloaddition reactions a series of dihydropyrrolizines 213 were synthesized by heating the proline derivatives 211 with dimethyl acetylenedicarboxylate (DMAD) at 130-140 °C in the presence of acetic anhydride. Reaction between 211 and AczO provides the mesoionic oxazalone intermediate 212 which adds to dimethyl acetylenedicarboxylate, giving a cycloadduct, which undergoes spontaneous decarboxylation leading to 213 (Scheme 50) <1998JME4744, 1977JME812>. 

Murahashi and co-workers (49) extensively studied the synthesis of nitrones such as 29 by a decarboxylative oxidation of proline derivatives (Scheme 12.12). However, these nitrones were primarily used in nucleophilic addition reactions rather than 1,3-dipolar cycloadditions. Others have synthesized cyclic nitrones 30 and 31 having a chiral center adjacent to the nitrogen atom (50,51). Saito and co-workers (51) applied nitrone 31 in reactions with fumaric and maleic acid... 

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. 

Methyl-(trimethylsilyl)methyhminoacetate, chosen as the azomethine ylid precursor, provides an elegant access to proline derivatives. However, the cycloaddition reaction has a low regiospecificity.386... 

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. 

Asymmetric induction has been observed in some of these cycloaddition reactions with the use of chiral enamines52-54. For example, reaction of L-proline derived enamines (e.g. 95) with methyl vinyl ketone (equation 17) afforded, after hydrolysis, chiral cyclohexenones (e.g. 96) with optical yields up to 50%52. 

Following the seminal work on proline-catalyzed reactions, a range of proline- and proline derivative-catalyzed asymmetric reactions, including the Mannich reaction, Michael reaction, a-functionalization of carbonyl compounds, and cycloaddition reactions, have been developed [33]. 

Seitz et al. prepared various l,2,4-triazine-C -nucleosides 340 via cycloaddition of 3,6-bis(trifluoromethyl)-l,2,4,5-tetrazine 147 to monosaccharide-derived imido esters 339 as intermediates in their quest for new pyridine C-nucleosides <1999ZNB549, 1997ZNB851, 1995AP175>. Similarly, the same group reported the preparation of novel 2-(2 -pyrrolidinyl)pyridines from (3 )- and (R)-proline via cycloaddition of 3,6-bis(trifluoromethyl)-l,2,4,5-tetrazine 147 to heterodienophilic imidates or hydrazones derived from (3)- and (R)-proline <1999TA573>. Reaction of dimethyl l,2,4,5-tetrazine-3,6-dicarboxylate 150 with either 0-methylisourea or cyanamide gave... 

Yebdri and Texier studied cycloaddition reactions of the well-known munch-none 153 (derived from proline and acetic anhydride) with methyl propiolate and methyl 3-phenylpropiolate to give mixtures of pyrrolizines 154 and 155, respectively (Fig. 4.55). 

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. 

Scheme 10.39 1,3-Dipolar cycloaddition-based three-component reaction catalyzed by proline derivative.

Other new syntheses of 14 and/or 15 have been developed using dioxabiqr-clo[3.2.1]octenone chiral block by Ogasawara et al. [293], yeast reduction by Takeuchi et al. [294], 1,3-dipolar cycloaddition by Hatakeyama et al. [295], and the reductive deamination/recyclization reaction of the proline derivative with Sml2 by Honda et al. [299], etc. 

The scope of organocatalyzed cycloaddition reactions was also extended to different syntheses of pyrrolidine derivatives. In this direction, Cdrdova and coworkers explored the combination of diphenylprolinol 76 and simple oxime cocatalyst 77 to promote the synthesis of functionalized proline derivatives bearing four contiguous stereocenters where one is an all-carbon quaternary one (Scheme 2.21) [47]. The success of the transformation relies on a cooperative combination of iminium and H bond activation to afford chemo- and stereoselective [3 + 2] cycloaddition under kinetic control. The reaction proceeds... 

Another example to illustrate the synthesis of proline derivatives 78 was published by Vicario and coworkers in 2013 [48]. Starting from aromatic aldehydes, diethyl malonate, and a,p-unsaturated aldehydes upon catalysis of unprotected diphenylprolinol, the synthesis of polysubstituted pyrrolidines was achieved in a one-pot condensation and [3+2] cycloaddition reaction in aqueous medium. 

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). ... 

Sulfines derived from proline 36 also reacted with 2,3-dimethyl-l,3-butadiene to give the expected cycloadducts 37 . During the cycloaddition reactions, asymmetric induction of up to 40 % is observed. The best results are obtained when one of the sultine substituents is a chloro group and when the reaction is performed at -78 °C. All thiopyran j -oxides obtained in this manner are mixtures of diastereomers. 

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