Concise Synthesis of (−)-Cycloclavine and (−)-5-epi-Cycloclavine via Asymmetric C–C Activation

Abstract

To illustrate the synthetic significance of C-C activation methods, here we describe an efficient strategy for the enantioselective total syntheses of (-)-cycloclavine and (-)-5- epi-cycloclavine, which is enabled by an asymmetric Rh-catalyzed "cut-and-sew" transformation between benzocyclobutenones and olefins. Despite the compact structure of cycloclavine with five-fused rings, the total synthesis was accomplished in 10 steps with a 30% overall yield. Key features of the synthesis include (1) a Pd-catalyzed tandem C-N bond coupling/allylic alkylation sequence to construct the nitrogen-tethered benzocyclobutenone, (2) a highly enantioselective Rh-catalyzed carboacylation of alkenes to forge the indoline-fused tricyclic structure, and (3) a diastereoselective cyclopropanation for preparing the tetrasubstituted cyclopropane ring. Notably, an improved catalytic condition has been developed for the nitrogen-tethered cut-and-sew transformation, which uses a low catalyst loading and allows for a broad substrate scope with high enantioselectivity (94-99% e.e.). The C-C activation-based strategy employed here is anticipated to have further implications for syntheses of other natural products that contain complex fused or bridged rings.

Asymmetric Total Synthesis and Biological Evaluation of (+)-Cycloclavine

“…to be +61.4 (c 0.2, CHCl 3 ), which was consistent with the literature value +63 (c 1, CHCl 3 ). 4 Mass spectra, IR, 1 H, and 13 C NMR data were also consistent with the previously reported data for the natural product as well as its enantiomer. 4,11 Scheme 9 Completion of total synthesis of (+)-cycloclavine…”

“…12 Most recently, Dong and co-workers developed a benzyne cycloaddition/alkene carboacylation route to both (-)-5-epi-cycloclavine and (-)-cycloclavine, utilizing a ring-enlargement of a benzocyclobutenone intermediate as a key reaction. 13 The impressive publication surge and the diverse strategies of these synthetic approaches illustrate the high level of current interest in architecturally novel alkaloid natural products. We now report the details of the first enantioselective total synthesis of (+)-cycloclavine.…”

Transition Metal‐Mediated C−C Single Bond Cleavage: Making the Cut in Total Synthesis

“…These synthetic challenges,a long with its biological activity, have made cycloclavine an intriguing target for synthetic chemists.H erein, we discuss the 2018 asymmetric total synthesis of (À)-cycloclavine by Dong and co-workers, which was accomplished through an enantioselective CÀC activation/functionalization of acyclobutanone. [30] Forclarity, C À Ca ctivation in this Review will be defined as as pecific form of C À Cb ond cleavage that is accomplished by an oxidative addition of atransition metal into aC ÀCb ond.…”

Ruthenium(ii)-catalyzed chemoselective deacylative annulation of 1,3-diones with sulfoxonium ylides via C–C bond activation

“…The selective cleavage of C–C bonds in a constructive manner enables the reconstitution of the molecular skeleton and introduction of new functional groups, thus attracting great attention 1. In the past decade, chemoselective C–C(CO) bond cleavage has been extensively studied by employing the strategies of chelation assistance,2 ring-strain release,3 and aromatization 4. However, the selective cleavage of unstrained C–C(CO) moieties without an auxiliary directing group still remains an unmet challenge 5,6.…”