Total Synthesis of Lapidilectine B Enabled by Manganese(III)‐Mediated Oxidative Cyclization of Indoles

Abstract

A novel manganese(III)-mediated oxidative cyclization of readily accessible 1,2,3-trisubstituted indoles is described. This unprecedented method enabled the efficient construction of a complex polycyclic scaffold bearing a spiro-indoline motif and a lactone moiety in one step. Its synthetic utility was demonstrated in the total synthesis of lapidilectine B (in 18 steps) by employing a strategic regioselective ring-expansion and a silver-promoted allenic amine cyclization as the additional key elements.

Thiourea‐Catalyzed Asymmetric Michael Addition of Carbazolones to 2‐Chloroacrylonitrile: Total Synthesis of 5,22‐Dioxokopsane, Kopsinidine C, and Demethoxycarbonylkopsin

“…We noticed that this reaction was relatively fast, and therefore decided to reduce the reaction temperature to improve the enantioselectivity.T oour delight, complete conversion was observed within 42 ha tÀ10 8 8Ct o afford 1a in 91 %yield with 95 % ee (entry 11). Changing the methyl group in catalyst J to an ethyl, n-propyl, or n-butyl substituent provided similar results (entries [11][12][13][14]. Theb est outcome in enantioselectivity was observed when the npentyl-substituted catalyst N was used (Table 1, entry 15).…”

“…Zuschriften radical attacked at either the 2-position or the 4-position of the substituted indole to afford the corresponding cyclization products. [14] On the basis of these studies,wee nvisioned that the b-ketoamide moiety in 19 might produce radical A under the action of Mn III ,a nd the radical might attack the neighboring indole 3-position to provide radical B.Oxidation of this intermediate would give carbocation C,w hich could trap MeOH or water to deliver the desired cyclization product. Accordingly,w et reated 19 in methanol with Mn-(OAc) 3 as the single-electron oxidant and Cu(OAc) 2 as the co-oxidant, and obtained two cyclization products 20 and 21 in 76 and 10 %y ield, respectively.N otably, b-ketoamide 20 could be readily transformed under acidic conditions into hemiacetal 21,w hose structure was confirmed by X-ray crystallographic analysis.…”

Radical Reactions in Alkaloid Synthesis: A Perspective from Carbon Radical Precursors

“…In Ma's synthesis of lapidilectine B, a Mn(III)‐mediated oxidative cyclization ( 197 → 198 ) of readily accessible 1,2,3‐trisubstituted indoles enabled the efficient one‐step construction of a complex polycyclic scaffold bearing a spiro‐indoline motif and a lactone moiety (Scheme d).…”

Arthur C. Cope Scholar Awards: E. P. Balskus, N. Chatani, W. F. DeGrado, F. Glorius, R. R. Knowles, D. Ma, H. D. Maynard, J. P. Morken, G. K. S. Prakash, K. A. Woerpel / Priestley‐Medaille: K. B. Sharpless

“…Sie entwickeln neue Methoden und wenden dieser in der Synthese von Verbindungen mit biologischer und pharmazeutischer Relevanz an. Chemistry—A European Journal veröffentlichte einen ihrer Beiträge über eine Mangan(III)‐vermittelte oxidative Cyclisierung in der Totalsynthese von Lapidilectin B . Ma ist Mitglied der Redaktionsbeiräte von Chemistry—An Asian Journal und Advanced Synthesis & Catalysis .…”