Studies of a Diazo Cyclopropanation Strategy for the Total Synthesis of (−)‐Lundurine A

Abstract

The bioactive Kopsia alkaloids lundurines A-D are the only natural products known to contain indolylcyclopropane. Achieving their syntheses can provide important insights into their biogenesis, as well as novel synthetic routes for complex natural products. Asymmetric total synthesis of (-)-lundurine A has previously been achieved through a Simmons-Smith cyclopropanation strategy. Here, the total synthesis of (-)-lundurine A was carried out using a metal-catalyzed diazo cyclopropanation strategy. In order to avoid a carbene CH insertion side reaction during cyclopropanation of α-diazo- carboxylates or cyanides, a one-pot, copper-catalyzed Bamford-Stevens diazotization/diazo decomposition/cyclopropanation cascade was developed, involving hydrazone. This approach simultaneously generates the C/D/E ring system and the two chiral quaternary centers at C2 and C7.

Catalytic Function of Cu (I) and Cu (II) in Total Synthesis of Alkaloids

“…Total synthesis of murrastifoline-C (199) was started from 2hydroxy-3-methylcarbazole (197), [145] which itself is a natural product [148] and after several steps transformed into framework 198, which under Ullmann-type coupling reaction with 186 in the presence of catalytic amounts of copper(I) bromide, pyrrole-2-carboxylic acid, and potassium phosphate provided compound 199. Therefore, the total synthesis of murrastifoline-C (199) was completed in nine steps with 8 % overall yields (Scheme 26).…”

“…[195e,196] Nishida and co-workers completed the first total synthesis of (�)-lundurine A and B. [127] Zhang and co-workers in 2015 [197] reported the synthesis of (À )-lundurine A starting from the stereoselective synthesis of intermediate 302. Heating iodide 301 (prepared in six steps from the reaction of indole derivative 299 and (S)pyrrolidinone (300) [198] in MeCN formed an iminium cation intermediate, that was then directly attacked using organometallic nucleophiles in THF at À 78°C to give compound 302.…”

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

“…The unique structures and interesting biological activities of these Kopsia alkaloids have prompted their synthetic studies from a number of research groups . As a result, Nishida,– Qin, and Echavarren, groups have achieved the total synthesis of lundurine‐type alkaloids by using radical cyclization, an intramolecular Simmons–Smith reaction, and gold‐catalyzed cyclization as the key steps, respectively. Zu and co‐workers accomplished the first total synthesis of grandilodine B ( 6 ) via construction of the key spiro‐indoline intermediate with a Diels–Alder reaction.…”

Rh(III)‐Catalyzed Csp2−Csp3 Bond Cleavage/Carbonylethylation of α‐Indolyl Alcohols

“…However, the synthetic access to 2‐carbonylethylindoles has been rarely reported, the existed protocols mainly focus on the direct C sp 2 −H and C sp 2 −Br bond carbonylethylation. For examples, traditional transition metal‐catalyzed cross‐coupling of 2‐bromoindoles with α,β‐unsaturated ketones could efficiently install carbonylethyl group into 2‐position of highly congested and substituted indoles (Scheme 1a) [3b,4] . As for simple‐structure indoles, ligand‐directed coupling reaction of indolyl C sp 2 −H with cyclopropanols [5] or diazo compounds [6] may regioselectively realize indolyl C2‐carbonylethylation (Scheme 1b).…”