Synthesis of the Tetracyclic ABCD Ring Domain of Calyciphylline A-Type Alkaloids via Reductive Radical Cyclizations

Abstract

A tetracyclic compound with the ABCD ring framework of calyciphylline A-type alkaloids was synthesized from a cis-3a-methyloctahydroindole triggered by a 5-endo radical cyclization. The synthesis required two additional ring-forming steps: the construction of a seven-membered ring by aldol cyclization and the azabicyclic fragment by a radical ring closure of a trichloroacetamide-tethered enol acetate followed by a diastereoselective α-methylation of the lactam group.

Synthesis of Azabicyclic Building Blocks for Daphniphyllum Alkaloid Intermediates Featuring N‐Trichloroacetyl Enamide 5‐endo‐trig Radical Cyclizations

“…The configuration of 6b ( Figure ), both in the solid state and solution, showed that the conformational preference of the mobile cis ‐fused hydroindole moiety embedded in the tricyclic ring system located the methine proton at C(3a) in an axial disposition ( δ (H) 3.17, dd , J =11.5, 4.5). This conformational behavior differs from that observed in the analogous compound lacking the arene ring, in which the methine proton of the lactam ring appears at δ (H) 3.03 as a triplet with small coupling constants (3.2 Hz). …”

“…When trichloroacetamide 24 was subjected to a radical cyclization under reductive conditions, the process was very successful, leading to the tetracyclic compound 26 in 81 % yield. The latter was elaborated into the valuable keto lactam 27 through a three‐step sequence (diastereoselective methylation of lactam, oxidative hydrolysis of enol acetate, and Burgess dehydration) …”

“…The generation of the C(3)−C(3a) bond through an intramolecular Michael addition was reported by Dixon . The radical cyclization strategy described here is an example of the second approach, which was preliminarily applied in the synthesis of the ABCD ring framework of calyciphylline A‐type alkaloids …”

“…Ethyl (3 RS ,3a SR ,8a SR )‐1‐Benzyl‐3a‐methyl‐2,5‐dioxo‐3‐(prop‐2‐en‐1‐yl)decahydrocyclohepta[ b ]pyrrole‐6‐carboxylate ( 28a ). A solution of acetal 6a (0.5 g, 1.46 mmol) in a mixture of THF/4 n HCl (3 : 1; 33 ml) was stirred at room temperature overnight. The reaction was quenched with a saturated solution of Na 2 CO 3 and extracted with CH 2 Cl 2 (4×10 ml).…”

“…Prior to our initial report in this field, the radical cyclization of a trichloroacetamide embedded in an enamide structure, providing hydroindoles with a methyl group at the ring junction ( Scheme ), had only been described by Zard . Parsons reported the cyclization of a dichloroacetamide with a methoxycarbonyl at the α ‐position, using either CuCl in an atom transfer radical cyclization (ATRC) or Mn(OAc) 3 in an oxidative procedure .…”