Intramolecular Cycloaddition Reactions of Furo[3,4-b]indoles for Alkaloid Synthesis

Abstract

Model studies dealing with the Cu(II)- or Rh(II)-catalyzed carbenoid cyclization/cycloaddition cascade of several α-diazo indolo amido esters have been carried out as an approach to the alkaloid scandine. The Cu(II)-catalyzed reaction of an α-diazo indolo diester that contains a tethered oxa-pentenyl side chain was found to give rise to a reactive benzo[c]furan which undergoes a subsequent [4 + 2]-cycloaddition across the tethered π-bond. The reaction proceeds by the initial generation of a copper carbenoid intermediate which cyclizes onto the adjacent carbonyl group to give a reactive benzo[c]furan which in certain cases can be isolated. Disappointingly, the analogous reaction with the related amido indolo ester failed to take place, even when the tethered π-bond contained an electron-withdrawing carbomethoxy group. It would seem that the geometric requirements for the intramolecular cycloaddition of the furo[3,4-b]indole system with the tethered π-bond imposes distinct restrictions upon the bond angles of the reacting centers to prevent the cycloaddition reaction from occurring. However, the incorporation of another carbonyl group on the nitrogen atom of the tethered alkenyl diazo amido indolo ester seemingly provides better orbital overlap between the reacting π-systems and allows the desired cycloaddition reaction to occur.

RhII‐Catalyzed Cycloaddition of α‐Diazo Homophthalimides and Nitriles Delivers Oxazolo[5,4‐c]isoquinolin‐5(4H)‐one Scaffold

“…The reactivity of 5 is further enhanced by the electron‐withdrawing influence of the second carbonyl group in the conjugated position of the aromatic ring. Thus, from reactivity perspective, substrates 5 should be quite similar to 2‐(alkoxycarbonyl)phenyl acetate esters employed in diazo transfer reactions by Padwa and co‐workers . However, on exposure to a Rh II catalyst, the α‐diazo carbonyl compounds prepared from the latter substrates subsequently gave rise to the respective carbenoid species which were intercepted by the nearby alkoxycarbonyl group, yielding reactive benzo[ c ]furan species (Scheme ).…”

“…Thus, from reactivity perspective, substrates 5 should be quite similar to 2-(alkoxycarbonyl)phenyl acetate esters employed in diazo transfer reactions by Padwa and co-workers. [12] However, on exposure to a Rh II catalyst, the α-diazo carbonyl compounds prepared from the latter substrates subsequently gave rise to the respective carbenoid species which were intercepted by the nearby alkoxycarbonyl group, yielding reactive benzo[c]furan species (Scheme 1). In the case of diazo compounds 6, any similar interference from the nearby carbonyl group (also documented in earlier reports [13] ) would be impossible.…”

“…The fate of carbenoid species generated from 2-(alkoxycarbonyl)phenyl α-diazoacetate esters. [12] Indeed, when diazo compounds 6 were exposed to an excess amount of aliphatic or aromatic nitriles (as well as a cyanamide) in the presence of 1 mol-% of Rh 2 (OAc) 4 The yields of oxazolo [5,4-c]isoquinolin-5(4H)-ones 7 appear to be reduced for olefinic or benzylic (7f, 7g, 7u) as well as sterically hindered (7d) nitriles. The reaction displayed a generally high functional group tolerance in the substrate and the nitrile component.…”

Recent Advances in the Synthesis of 5‐MemberedN‐Heterocycles via Rhodium Catalysed Cascade Reactions

“…Oxygen‐containing lewis bases such as ketones and ethers are generally converted into carbonyl ylides and oxonium ylides respectively with electrophilic carbenes [33h–n] . Cycloaddition/cyclization of highly reactive carbonyl yildes provided oxacycles or epoxides [33h–j,o] . Allyl‐substituted oxonium ylides on [2,3]‐sigmatropic rearrangements forms homoallyl ethers [33k,l] .…”

“…The ylides of aldehydes and ketones are well explored on intermolecular reaction with carbenes. However, intermolecular reactions between carbenes and esters are uncommon, [33o] despite many examples of intramolecular ester ylide formation [33g–j,p] . Wang and co‐workers in 2020 developed a pioneering work on Huisgen cyclization/carbene cascade reaction with intermolecular trapping of the in situ carbene intermediate by esters resulted in Z ‐selectivity in many transformations.…”