Indolizidines nitrone 1,3-dipolar cycloadditions

Intramolecular 1,3-dipolar cycloaddition reactions of N -(3-alkenyl)nitrones, as presented in Scheme 2.21 le, led to the synthesis of polyhydroxy derivatives of quinolizidine (474) and indolizidine (475) (Scheme 2.234) (732). 

Dipolarophiles D3. 1,3-Dipolar cycloadditions of suitably functionalized cyclic nitrones with terminal alkenes, which have potential leaving groups X at the end of the alkane chain -(CHo),- (D3), were successfully used for the synthesis of pyrrolozidine, indolizidine and quinolizidine alkaloids, such as (+ )-and (—)-lentiginosine, a potent amyloglucosidase inhibitor (Scheme 2.243) (742). Reductive cleavage of the N-0 bond in the cycloadduct is important for the subsequent cyclization to pyrrolozidines, indolizidines, and quinolizidines. 

Two protected 3-amino acids, containing indolizidine and quinolizidine skeletons (607a,b), have been synthesized by using 1,3-dipolar cycloaddition of nitrones (551) and (552) to methyl ( )-5-mesyloxy-2-pentenoate. The key steps of this approach is demonstrated by novel syntheses of indolizidinone and quino-lizidinone derivatives (606a,b) and by the ring opening of the tricyclic 1,3-dipolar cycloaddition products (605a,b) (Scheme 2.268) (779). 

The dipolar cycloaddition of nitronates has been applied to the synthesis of several natural products in the context of the tandem [4+2] / [3 + 2] nitroalkene cycloaddition process. All of these syntheses have focused on the construction of pyrrolidine, pyrrolizidine, and indolizidine alkaloids. For example, the synthesis of ( )-hastanecine (316), a necine alkaloid, involves the elaboration of a p-benzoy-loxynitroalkene 311 via [4 + 2] cycloaddition with a chiral vinyl ether (312) in the presence of a titanium based Lewis acid, to provide the nitronate 313 with high diastereo- and facial selectivity (Scheme 2.30) (69). The dipolar cycloaddition of... 

Alkenyl nitrones, having the alkene connected to the nitrone nitrogen atom, have been used in another approach to intramolecular reactions (231-235). Holmes and co-workers have this method for the synthesis of the alkaloid (—)-indolizidine 209B 137 (210,231). The alkenyl nitrone 134, was obtained from the chiral hydroxylamine 133 and an aldehyde. In the intramolecular 1,3-dipolar cycloaddition, 135 was formed as the only isomer (Scheme 12.45). The diastereofacial selectivity was controlled by the favored conformation of the cyclohexane-like transition state in which the pentyl group was in a pseudoequatorial position, as indicated by 134. Further transformation of 135 led to the desired product 137. 

Tethering the alkene to the carbon atom of the nitrone allows the preparation of cw-l,2-disubstituted cycloalkanes such as 212. Examples in which the alkene is tethered to the nitrogen atom of the nitrone are also common. Thus, addition of formaldehyde to the hydroxylamine 213 promoted formation of the intermediate nitrone and hence the cycloadduct 214 (3.140). " Subsequent transformations led to the alkaloid luciduline. This synthesis illustrates a useful feature of the 1,3-dipolar cycloaddition reaction of nitrones, in that it provides an alternative to the Mannich reaction as a route to (3-amino-ketones, via reductive cleavage of the N-0 bond in the isoxazolidine and oxidation of the 1,3-amino-alcohol product. In another example of such an intramolecular cycloaddition reaction, the bridged bicyclic product 217, used in a synthesis of indolizidine 209B, was formed by addition of an aldehyde to the hydroxylamine 215, followed by heating the intermediate nitrone 216 (3.141).142... 

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. 

The group of Sas developed a novel synthetic route to polyhydrojqrlated indolizi-dines (Scheme 8). Protected a-D-mannofuranoside 41 was transformed into derivative 43 by reaction with hydroiq lamine 42 (nitrone formation) followed by intramolecular 1,3-dipolar cycloaddition. This compound was transformed into ammonium salt 44, which was then cleaved under the basic conditions, giving the desired indolizidine scaffold 45. Alternatively, compound 43 was transformed into the mesyl ester 46, which cyclized upon treatment with K2CO3, providing the bicyclic compound 47. 

An efficient approach to the synthesis of a novel polyhydroxylated indolizidine derivatives containing an amino group has been developed. The key step of die synthesis involved microwave-assisted 1,3-dipolar cycloaddition of azasugar nitrone and methacrylate for installing a potential amino group and ester group with an extended chain (Li et al., 2009). 

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