Ketene Aza-Claisen Rearrangements

Another type of rearrangement involving 1,5-asymmetric induction is the ketene aza-Claisen rearrangement, used in the stereoselective synthesis of intermediate 16, a common precursor for the synthesis of monoterpene alkaloids (-)-a-skytanthine, (-)-jV-demethyl-<5-skytamhine, and (+ )-epidihydrotecomanine 649. 

The ketene aza-Claisen rearrangement seemed to fulfiU these prerequisites using I-(-) proHne derivatives 303 as chiral auxiharies [50], Several N-aUyl pyrroh-dines 306 were synthesized via a Pd(0)-catalyzed amination of the corresponding allyhnesylates 304 and 305, respectively. The double bond was always E configured. The treatment with chloro- and suitably protected a-amino acetyl fluorides 307, respectively, in the presence of soUd K2CO3 and trimethyl aluminum in... 

Chiral pyrrolidine substituents serve as efficient auxiliaries in diastereoselective zwit-terionic ketene aza-Claisen rearrangements (Scheme 18). ... 

Further information concerning the stereochemical properties of the rearrangement were evaluated by submitting rigid cyclohexane derivatives 254/255 to the reaction conditions. In 1975, House described the allylation of a cyclohexyl cyanide 248 [53]. The initial deprotonation with LDA led to a ketene imine anion 249, which was then treated with allyl bromide. Two potential paths rationalized the outcome an AT-allylation generated the intermediate ketene imines 250/251, which underwent aza-Claisen rearrangement to deliver the nitriles 252/253 alternatively, the direct C-allylation of249 produced the nitriles. 

Most [3,3]-sigmatropic rearrangements take place thermally, and the Cope, oxy-Cope and Claisen rearrangements are among the most important rearrangements in this class. Important variants of the Claisen rearrangement include the Johnson modification via orthoesters, the Eschenmoser modification via ketene N,O-acetals, the Ireland modification via ketene silylacetals and the Corey modification via boron ester enolates [696], The aza-Claisen rearrangement has also seen... 

Tsunoda has rationalized a role for chelation with preferential formation of the Z-enolate 397 from Y-crotyl glycolamide 395 and glycinamide 396. At elevated temperature, the (. -ketene iV, 0-acetal 397 exhibits a facile aza-Claisen rearrangement with excellent syn selectivity. ... 

This case study highlights the formidable challenge posed by epimerization en route to the synthesis of nonpeptidic fragments of cyclic peptide natural products. (3S,4R,7S)-HTMMD was prepared from (R)-4-methyl-5-valerolactone 74 in nine steps (Scheme 8.6a). After convenient synthesis of aldehyde 77 and its asymmetric aldol condensation with the ketene acetal 79, HTMMD skeleton 80 was isolated as a single isomer. After installation of allyl ester, the alcohol was coupled with Fmoc-Ala-Cl in the presence of DMAP/DIPEA (4-dimethylaminopyridine/diisopropylethylamine) followed by fluorenylmethyloxy-carbonyl (Fmoc) deprotection to afford the ester segment 81b in excellent yield. The amount of DMAP and temperature (—15 °C) were critical to avoid racemiza-tion. Modified Tsunoda s diastereoselective aza-Claisen rearrangement [145] was used as the key step in the 13-step synthesis of N-methylhydroxyisoleucine 86b... 

---