Total Synthesis of (+)-Condylocarpine, (+)-Isocondylocarpine, and (+)-Tubotaiwine

Abstract

The first enantioselective total syntheses of indolealk aloids of the condylocarpine type are reported. (+)-Condylocarpine, (+)-isocondylocarpine, and (+)-tubotaiwine were prepared in high enantiomeric purity (er >99:1) from (1 S,5 R) -hexahydro-1,5-methano-1 H-azocino[4,3 -b]indole-12-one 7b by way of five or six isolated intermediates.The hexahydro-1,5-methano-1H-azocino [4,3-b]indole ring system 1 is a major fragment of Strychnos alkaloids of the strychnan and aspidopermatan types (e.g., 2-4, Figure 1) and the ring system of indole alkaloids of the uleine group (e.g., 5, Figure 1).1 During our recent total synthesis of the structurally unique indole alkaloid (−)-actinophyllic acid, we developed a concise synthesis of the hexahydro-1,5-methano-1H-azocino [4,3-b]indole ring system.2 , 3 A central step in this synthesis is an iron(III)-promoted intramolecular oxidative coupling of malonate and ketone enolates generated from indole piperidones 6 to deliver hexahydro-1,5-methano-1H-azocino [4,3-b]indole-12-ones 7 (eq 1). Ketone (1S,5R)-7b was prepared in enantioenriched form (er = 95:5) in 26% overall yield from 4-(tertbutoxycarbonylamino)butyric acid by way of six isolated intermediates.2 , 4 Herein we report the use of tetracyclic intermediate (1S,5R)-7b for the enantioselective synthesis of three representative members of the condylocarpine subtype of the aspidospermatan group of alkaloids.5 , 6(1) leoverma@uci.edu. Supporting Information Available: Experimental details and copies of 1 H and 13 C NMR spectra of new compounds (PDF); CIF files for compounds (±)-20 and (±)-iii. This material is available free of charge via the Internet at http://pubs.acs.org. Transformation of hexahydro-1,5-methano-1H-azocino [4,3-b]indole-12-ones 7 to the condylocarpine skeleton requires introduction of a two-carbon unit at C12, installation of a two-carbon bridge between C11b and N2, and dealkoxycarboxylation of the malonate unit. Our early exploratory investigations were carried out in the racemic series and focused on elaboration of C12 and N2. Several observations made during these studies provided essential insight into the chemical reactivity of the hexahydro-1,5-methano-1H-azocino [4,3-b]indole ring system (Scheme 1). Wittig reaction of ketone (±)-7a with ethylidenetriphenylphosphorane delivered ethylidene derivative (±)-8 as a single stereoisomer in 73% yield, with the Z configuration of the double bond being readily secured by 1 H NMR NOE analysis. To our surprise, this product was extremely acid sensitive. For example, (±)-8 rearranged to hexahydro-6H-pyrido [4,3-b]carbazole isomer 9 when stored in CDCl 3 for several days, or within 2 h at room temperature in the presence of 10 mol % of DCl (0.004 M). Related instability was observed with hexahydro-1,5-methano-1H-azocino [4,3-b]indole-12-one (±)-7b, which when exposed in CDCl 3 to 0.15 M DCl for 2 h gave dihydropyrrolo[3,2-b]carbazole 10 in 55% yield.7 Under stronger acidic conditions (neat TFA), ketone (±)-7b yielded 3-hydroxycarbazole-1-carboxylic acid 11 as t...

Concise total synthesis of (±)-actinophyllic acid

“…Two possible strategies to increase the stability of intermediates derived from 26 were thus considered: We could either reduce the ketone, a tactic with some precedent, 13,26 or place an electron withdrawing group on the nitrogen atom of the indole ring. Because we had encountered some difficulties in preliminary attempts to introduce an electron withdrawing group on the indole nitrogen atom of 26 , we elected instead to reduce the ketone function in 26 with lithium borohydride and obtained 28 as a single diastereomer in 82% yield (Scheme 5).…”

Synthesis and stereochemical determination of an antiparasitic pseudo-aminal type monoterpene indole alkaloid

“…This structure has a “push–pull” nature, which is stabilized by electron-donating or electron-withdrawing groups. For example, the aliphatic carbon–nitrogen bond of the gramine type (or vinamidine type) is easily cleaved by retro-Mannich reaction under acid [ 45 ], base [ 46 – 48 ], and thermal [ 49 ] conditions, and with various reagents (e.g., trialkylphosphine [ 50 – 55 ], Lewis acid [ 56 ], phthalimide [ 57 ], thiol [ 58 , 59 ], and activated ester [ 60 , 61 ]) to generate the indolinium cation. We, therefore, anticipated that the propendiamine moiety was an indicator of reactivity similar to the aminal, leading us to suppose the framework as a “ pseudo -aminal type structure”.…”

Structure Determination and Total Synthesis of (+)‐16‐Hydroxy‐16,22‐dihydroapparicine

“…The pseudo‐aminal‐type skeleton could convert into the corresponding 3‐methylene‐3‐ H ‐indolinium cations, which have proven synthetic utility. The aliphatic nitrogen–carbon bond as a pseudo‐aminal‐type moiety could be easily cleaved by a retro‐Mannich reaction under acidic,5 basic,6 or thermal conditions7 or by using various reagents (e.g., trialkylphosphanes,8 Lewis acids,9 phthalimides,10 thiols,11 and activated esters)12 to generate the indolinium cation, which reacts with the various nucleophiles at the 3‐methylene position. Therefore, such reactivity and instability for the apparicines, including our target compound, can be predicted.…”

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under acidic, [5] basic, [6] or thermal conditions [7] or by using various reagents (e.g., trialkylphosphanes, [8] Lewis acids, [9] phthalimides, [10] thiols, [11] and activated esters) [12] to generate the indolinium cation, which reacts with the various nucleophiles at the 3-methylene position. Therefore, such reactivity and instability for the apparicines, including our target compound, can be predicted.

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