Stereocontrolled total synthesis of (+)-vinblastine

Abstract

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

Effects of Ultraviolet A Supplemented with Red Light Irradiation on Vinblastine Production in <i>Catharanthus roseus</i>

“…A coupling reaction of vindoline and catharanthine rarely occurs in nature. Although many researchers have studied total or semi-synthetic techniques for DIAs production by chemical and enzymatic methods Misawa et al, 1988;Kuehne et al, 1991;Yokoshima et al, 2002;Shirahama et al, 2006;Ishikawa et al, 2009), these techniques have not resulted in sufficient benefit. These drugs, derived from DIAs, can still be extracted and purified from large amounts of C. roseus plants, which are cultivated in large fields (Roepke et al, 2010).…”

5,5’-Biindole

“…Furthermore, indomethacin [7], a non-steroidal anti-inflammatory agent, and pindolol [8], a b-adrenergic blocker, are clinically proven indole compounds. Several naturallyoccurring indoles are also of clinical relevance; vincristine, a dimeric indole alkaloid, and related compounds, were the first of the antimitotic class of chemotherapeutic agents for cancer [9]. The mitomycins [10] and derivatives of ellipticine [11] are other examples of compounds having antitumor activity.…”

Conversion of Vindoline into 11-Mesyloxytabersonine

“…In our synthetic studies of dimeric indole alkaloids and their analogs, [10][11][12] 11-mesyloxytabersonine (3) was used as the key intermediate. Our reported synthetic route toward 3 features synthesis of the indole unit via a radical cyclization and facile deprotection of a secondary amine by employing a 2,4-dinitrobenzenesulfonyl group as a protective group.…”