A General Synthetic Entry to Strychnos Alkaloids of the Curan Type via a Common 3a-(2-Nitrophenyl)hexahydroindol-4-one Intermediate. Total Syntheses of (±)- and (−)-Tubifolidine, (±)-Akuammicine, (±)-19,20-Dihydroakuammicine, (±)-Norfluorocurarine, (±)-Echitamidine, and (±)-20-Epilochneridine¹

Abstract

A general strategy for the synthesis of pentacyclic Strychnos alkaloids with the curan skeleton has been developed. It utilizes 3a-(2-nitrophenyl)hexahydroindol-4-one (23), which was prepared from 2-allyl-2-(2-nitrophenyl)-1,3-cyclohexanedione (15), as the common, pivotal intermediate. Three different procedures have been employed for the closure of the bridged piperidine D ring from 23: (i) an intramolecular Michael-type conjugate addition; (ii) a Ni(COD)2-promoted biscyclization that assembles B and D rings in a single synthetic step, and (iii) an intramolecular cyclization of an enone−propargylic silane system. When necessary, depending on the procedure used, introduction of the oxidized one-carbon substituent at C-16, closure of the indole ring, and/or adjustment of the functionality of the C-20 two-carbon chain constitute the last stages of the synthetic route to the title alkaloids. The procedure involving the cyclization of a propargylic silane has been successfully extended to the enantiospecific synthesis of (−)-tubifolidine starting from the enantiopure 3a-(2-nitrophenyl)hexahydroindolone (−)-51, which was prepared taking advantage of the prochiral character of cyclohexanedione 15.

Total Synthesis of (±)-Cycloclavine and (±)-5-epi-Cycloclavine

“…We circumvented this problem by a dealkylative protection of the tertiary amine as a carbamate with methyl chloroformate in 71% yield. 16 Saegusa-Ito oxidation (LDA, TMSCl, −78 °C, then Pd(OAc) 2 ) served to cleanly introduce a double bond at the C(11)–C(16) position of 25 . 17 …”

Synthesis of Spirocyclic Indolenines

“…Another elegant multistep sequence was developed by Bonjoch, Bosch and co‐workers in their synthesis of (±)‐dehydrotubifoline; the key tandem cross‐coupling, nitro reduction and condensation sequence was realised by employing a Ni 0 catalyst, furnishing the desired natural product 331 in good yield, considering the number of synthetic operations taking place (Scheme ). Bonjoch, Bosch and co‐workers also demonstrated the enone‐nitro condensation reaction without the initial cross‐coupling . This powerful methodology has also been used to complete the total synthesis of both (±)‐akuammicine and (±)‐norfluorocurarine …”

“…Bonjoch, Bosch and co-workersa lso demonstrated the enone-nitroc ondensation reaction withoutt he initial cross-coupling. [181] This powerful methodology has also been used to complete the total synthesis of both (AE)-akuammicinea nd (AE)-norfluorocurarine. [182] Finally,a nother multistep one-pot procedure was reported by Zhu and co-workers who utilised their iORC (integrated oxidation/reduction/cyclisation) process for the synthesis of (AE)-1,2-dehydroaspidospermidine 339 (Scheme51).…”

“…Scheme50. Ni 0 -promoted tandem cross-coupling, nitro reduction and condensation( Bonjoch,Bosch et al [180][181][182] ).…”

A Novel Alkaloid from Melodinus henryi

“…1) together with ten known compounds: (þ)-eburnamine ((3a,14a,16a); 2 Fig. 1) [5], 14-epieburnamine (¼ (À)-isoeburnamine; (3a,14b,16a)) [5], (AE)-condylocarpine [6], (AE)-isocondylocarpine [6], rhazinilam [7], vincamenine [8], akuammicine [9], norfluorocurarine [9], 10,22-dioxokopsane [10], and stemmadenine [11]. (21), and between CH 2 (1') and Me(2') which allowed the assignment of two Et side chains.…”