Nitrone and Alkyne Cascade Reactions for Regio‐ and Diastereoselective 1‐Pyrroline Synthesis

Abstract

The synthesis of 1-pyrrolines from N-alkenylnitrones and alkynes has been explored as ar etrosynthetic alternative to traditional approaches.T hese cascade reactions are formal [4 + 1] cycloadditions that proceed through ap roposed dipolar cycloaddition and N-alkenylisoxazoline [3,3']sigmatropic rearrangement. Av ariety of cyclic alkynes and terminal alkynes have been shown to undergo the transformation with N-alkenylnitrones under mild conditions to provide the corresponding spirocyclic and densely substituted 1-pyrrolines with high regio-and diastereoselectivity.M echanistic studies provide insight into the balance of steric and electronic effects that promote the cascade process and control the diastereo-and regioisomeric preferences of the 1-pyrroline products.D iastereoselective derivatization of the 1-pyrrolines prepared by the cascade reaction demonstrate the divergent synthetic utility of the new method.Scheme 1. N-Alkenylisoxazoline approach to 1-pyrroline synthesis.LG = leaving group. EWG = electron-withdrawing group.

Nitrone and Alkyne Cascade Reactions for Regio‐ and Diastereoselective 1‐Pyrroline Synthesis

“…[37] This reactivity pattern was not accessible for 12 a.T he connectivity and stereochemistry of 26 and 27 were confirmed by X-ray crystallographic analysis of 27. [18] Finally,a ni nteresting transformation was observed with extended reaction times for the formation of 12 b.Asshown in Scheme 8B,lactone 28 is formed in good yield and high diastereoselectivity.Further experimentation showed that 28 could also be obtained directly from 12 b by treatment with K 2 CO 3 under the cascade reaction conditions.T he transformations illustrated in Scheme 8showcase the utility of cascade reaction for accessing highly substituted and stereodefined pyrrolines that can be easily converted into avariety of molecules with increased complexity using simple procedures.…”

“…Ther elative stereochemistry of these compounds was confirmed by X-ray crystallographic analysis of 14 j. [18] In contrast to 14 c,1 -pyrroline 14 l was resistant to isomerization in solution. Nitrones prepared from N-methylisatin and acenapthylenedione were unreactive with terminal alkynes suggesting that some amount of strain release is required to initiate the cascade reaction for these substrates.…”

“…Them ajor diastereomer of the product was identified by X-ray crystallography and has a trans-relationship between the substituents at the 3-and 4-positions of the 1-pyrroline ring. [18] The trans/cis-diastereomeric ratio between these two positions was shown to be dependent on the selection of the reaction medium as well as the concentration of phenylacetylene (entries 1-5 and 10). While 14 a can be purified by column chromatography,i solated as as ingle trans-diastereomer,a nd crystallized as asingle trans-diastereomer,solutions of 14 a in CDCl 3 and [D 4 ]MeOH isomerize over time to mixtures of trans-14 a and cis-14 a as illustrated in Table 3.…”

“…When cyclohexyne was generated in the presence of malonate- Entry [a] derived nitrones with cyclic,styrenyl, linear, and heterocyclic N-alkenyl substituents,p yrrolines 12 a-12 e were formed in good yield with high diastereoselectivity.T he cis-relationship between the alkyl substituent at the 3-position and the ketone at the 4-position was initially assumed in analogy to benzyne cascade products 10 but later confirmed by X-ray crystallography (see 12 i). [18] Similarly,when the cyclohexyne precursor was exchanged for pyranyne precursor 11 b and piperidyne precusor 11 c,s pirocyclicp yrrolines 12 f and 12 g were generated smoothly.T hese single regioisomeric products corresponded to the preferred dipolar cycloaddition regioselectivity predicted by the torsion-distortion model previously reported by Garg and Houk. [19] Thes ynthesis of 12 g could also be combined with adeprotection process to give 12 q over two steps (Scheme 3B).…”

“…Thes tereochemical relationship of the three stereocenters was confirmed by an X-ray crystal structure of 12 i and is consistent with the cascade reaction being as tereospecific process dependent on the stereochemistry of 7. [18] Thei solation of 12 h-12 j are noteworthy since analogous cascade reactions between N-alkenylnitrones derived from benzoylformate esters and benzyne give dihydrobenzofurans through ap roposed spontaneous rearomatization process. [12] Further attempts at controlling stereochemical information using ac hiral non-racemic ester substituent on the nitrone showed only moderate selectivity (12 k) suggesting that the stereochemical information is likely too far removed from the initial C À Cb ond forming event to be influential.…”