IMPORTANCEWhether intravenous thrombolysis is needed in combination with mechanical thrombectomy in patients with acute large vessel occlusion stroke is unclear.OBJECTIVE To examine whether mechanical thrombectomy alone is noninferior to combined intravenous thrombolysis plus mechanical thrombectomy for favorable poststroke outcome. Investigator-initiated, multicenter, randomized, open-label, noninferiority clinical trial in 204 patients with acute ischemic stroke due to large vessel occlusion enrolled at 23 hospital networks in DESIGN, SETTING, AND PARTICIPANTS

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Stereocontrolled total synthesis of (+)-vinblastine (1) has been achieved using a novel radical-mediated indole synthesis developed in our laboratories. The isothiocyanate 18, prepared readily from quinoline 17, underwent a facile addition of the malonate anion to give 19. The o-alkenylthioanilide 19 was then converted to indole 20 by radical cyclization and protection. (-)-Vindoline (2) was prepared from this key intermediate 20 in a highly efficient manner. The indole core of the 11-membered intermediate 3 was constructed similarly from quinoline. The critical coupling reaction between 2 and the chloroindolenine derived from 3 proceeded with complete control of stereochemistry to give the desired product 66 in 97 % yield, which could be successfully converted to (+)-vinblastine (1).Vinblastine (1), isolated from Catharanthus roseus [1], has been widely known as a prominent agent for cancer chemotherapy. Since chemical modifications of the natural product have been the major means for exploration of the more potent analogs, a limited number of its derivatives have so far been accessible [2a]. Total synthesis of vinblastine, on the other hand, has been the subject of intensive investigations in the area of alkaloid synthesis [2b]. Despite the endeavors spanning the past three decades, only four syntheses have been reported to date [3]. In all cases, however, the supply of the lower half of vinblastine (i.e., vindoline) relied upon the natural sources. The major challenges in the total synthesis of 1 include controlling the stereochemistry of C18′ as well as establishment of efficient routes to the two halves of the indole units.Our synthetic plan is shown in Scheme 1. Model studies by Schill [4] as well as our molecular modeling study strongly suggested that a stereocontrolled coupling with vindoline (2) could be per-*Lecture presented at the

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