Intermolecular Regio‐ and Stereoselective Hetero‐[5+2] Cycloaddition of Oxidopyrylium Ylides and Cyclic Imines

Abstract

We have developed the first intermolecular hetero-[5+ +2] cycloaddition reaction between oxidopyrylium ylides and cyclic imines with excellent control of regio-and stereoselectivity.S urprisingly,d ivergent stereochemistry was observed depending on the substitution pattern of the oxidopyrylium ylide.T his new reaction provides quicka ccess to highly substituted nitrogen-containing seven-membered rings-azepanes.N otably,abroad range of oxidopyrylium ylides and cyclic imines participate in this novel hetero-[5+ +2] cycloaddition reaction and the cycloadducts can be readily transformed into the core skeletons of bioactive natural products.D FT calculations revealed that the cycloaddition proceeds through as tepwise pathway and the imine nitrogen atom serves as the nucleophile to initiate the cycloaddition. Cycloadditionisoneofthemostefficientandpowerfulwaysto build molecular complexity.A lthough various cycloaddition reactions have been developed for the synthesis of complex four-, five-, and six-membered rings with excellent control of regio-and stereoselectivity,far fewer methods are available for the formation of highly substituted sevenmembered rings. [1][2][3] Since the first report by Hendrickson in 1980, [4] oxidopyrylium ylide based [5+ +2] cycloaddition [5] has emerged as apowerful transformation for the construction of seven-membered carbocycles. [2,6,7] Most previous studies have focused on intramolecular oxidopyrylium-alkene cycloaddition with the alkene 2p components tethered to C2 or C6 position, that is,type Ioxidopyrylium-alkene cycloaddition. [6] In 2015, Lisg roup demonstrated that type II [5+ +2] cycloaddition is feasible by tethering the alkene to the C5 position of an oxidopyrylium ylide,w hich leads to various highly functionalized bridged seven-membered carbocycles. [8] This reaction was then applied to the construction of the carbon core of eurifoloid A [9] and the total synthesis of isocyclocitrinol. [10] In contrast, the intermolecular version of the oxidopyrylium-based [5+ +2] cycloaddition is much less studied and the substituent effect of the oxidopyrylium ylide on endo/ exo selectivity remained underexplored. [5][6][7] Furthermore, despite the importance of the oxidopyrylium-based [5+ +2] cycloadditions,t he 2p partners have been to date limited to alkenes,d ienamine,t rienamine,a nd alkynes.T ot he best of our knowledge,n oh etero-[5+ +2] cycloaddition of oxidopyrylium ylides with imines has ever been reported.As part of our continuing efforts in developing novel [5+ +2] cycloaddition reactions, [11] we became interested in the synthesis of highly substituted nitrogen-containing sevenmembered heterocycles-azepanes-through hetero-[5+ +2] cycloadditions as shown in Scheme 1A.Azepanes are present in numerous natural products such as rubenine, [12] cadambine, [13] and banistenoside [14] (Scheme 1B), which possess complex penta-and even hexa-substituted azepane cores.The feasibility,regio-, and stereoselectivty of the proposed hetero-[5+ +2] cycloaddition are entirely unknown. We herein des...

Combined Computational and Experimental Study on [5 + 2] Cycloaddition of 2-Trifluoromethylated Oxidopyrylium Species Leading to 1-(Trifluoromethyl)-8-oxabicyclo[3.2.1]oct-3-en-2-ones

“…The corresponding cycloadduct 4ak was exclusively obtained in 31% yield when ethyl propiolate was used as the alkyne dipolarophile. The reaction with dihydroisoquinoline produced endo - 4al in 26% yield . The yields of 4ak and endo - 4al were improved (46 and 34%, respectively) using the slow addition technique.…”

Reductive (3 + 2) Annulation of Benzils with Pyrylium Salts: Stereoselective Access to Furyl Analogues of cis-Chalcones

“…Pyrylium salts have been used as synthetic intermediates in organic chemistry, especially serving as either C4 or C5 units in [4 + 2], [5 + 1], and [5 + 2] cycloadditions. − Although such strong electrophiles have been found to react readily with carbenes and α-carbonyl carbenoids showing the usual 1,1-dipolar reactivity, ,, we found that 2,6-disubstituted pyrylium salts underwent an unprecedented (3 + 2) annulation with the KRAs from benzils, leading to facile concurrent formation of both fully substituted furan rings and the challenging cis α,β-unsaturated carbonyl motifs . Herein, pyrylium ions formally serve as highly electrophilic C2 synthons bearing a Z -enone unit, whereas the KRAs derived from benzils function as C3 synthons for the first time.…”

Hydrogen bonds promote site-selective phenol functionalization enabled by Cl- anion

“…As potential carriers for hydrogen bonds, oxonium ylides provide intramolecular charge balance potentially involving hydrogen bonds, which set the stage for the investigation of new transformations and mechanisms. [7][8][9][10] For example, oxonium ylide intermediates with static hydrogen bonds are likely responsible for the metal carbenoid O-H insertion, reported by Yu's 11 and Fang's 12 group through DFT calculations.…”