Total Synthesis of (±)-Cylindricine C

Abstract

A concise synthesis of (±)-cylindricine C and its C(13)-epimer is described. Starting from 1-octyne, cylindricine C and 13-epi-cylindricine C were prepared in 11% and 15% yields, respectively. The synthesis involves the preparation of the central tricyclic moiety via a radical α-iodoketone carboazidation/bis-reductive amination sequence. Inversion of the stereochemistry at C(13) and C(5) was efficiently achieved on late stage intermediates.

Au(I)‐Catalyzed Hydration of 1‐Iodoalkynes Leading to α‐Iodoketones

“…[ 4 ] As a result of this versatility, the use of α‐iodomethyl ketones in total synthesis is nowadays a valuable approach to increase molecular complexity. For example, the preparation of certain pharmacological substances, such as (–)‐trachelanthamidine, [ 5 ] dendrobine [ 6 ] or cylindricine C, [ 7 ] among others, [ 8 ] has benefited from the use of iodoketones as key intermediates (Figure 1). These molecules can be prepared in various ways, with the direct iodination of methyl ketones being the most common approach [ 9 ] due to the availability of the corresponding substrates and the high atom economy of this reaction.…”

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

“…α‐Iodoketones were also used in intermolecular carboazidation reactions employed as a key step in monomorine I and cylindricine C synthesis (Scheme a). The radical carboazidation between 2‐iodohexan‐2‐one ( 7 ) and hept‐6‐en‐2‐one proceeded in good yield, and bis‐reductive amination of the azide 8 afforded the natural product as a single diastereoisomer.…”

Synthesis of Tricyclic Marine Alkaloids, Cylindricines, Lepadiformines, Fasicularin, and Polycitorols: A Recent Update

“…Renaud and co-workers reported the synthesis of (±)-cylindricine C [(±)-5] using double reductive amination for the construction of the tricyclic core (Scheme 19). 57 Their synthesis utilized the radical carboazidation of alkene 129 and α-iodo ketone 130 in the presence of 3-pyridinesulfonyl azide for the synthesis of tertiary azide 131 (trans/cis = 7:3). The resulting two diastereomers were separable and trans-131 was utilized for the next double reductive amination, which was initiated by reduction of azide 131 with SnCl 2 58 to give cyclic imine 132 followed by the treatment with NaBH(OAc) 3 to afford azaspirocycle 133 in diastereoselective manner, in which hydride was delivered from the less hindered β-face of the C=N bond of 132.…”