Total Synthesis of the Marine Alkaloid (±)-Lepadiformine via a Radical Carboazidation

Abstract

[reaction: see text] The total synthesis of lepadiformine has been achieved in 10 steps and 15% overall yield from cyclohexanone. The amino-substituted quaternary carbon center is created through a radical carboazidation reaction. The tricyclic core of lepadiformine is built via an efficient hydrogenation process, involving reduction of the azide and intramolecular reductive amination of a ketone, followed by lactamization of the intermediate gamma-aminoester. The hydroxymethyl side chain is introduced according to a modified Takahata procedure after conversion of the lactam into a thiolactam.

Boron: A key element in radical reactions

“…Therefore, it has to be used in stoichiometric amount. Recently, we have developed a radical carboazidation [9][10][11][12] reaction that has found numerous applications for alkaloid synthesis [13][14][15]. The chain process requires the transformation of an arylsulfonyl radical into an alkyl radical.…”

Radical azidation reactions and their application in the synthesis of alkaloids

“…In our first lepadiformine synthesis [16], the late-stage transformation of a lactam to the corresponding hydroxymethyl substituted pyrrolidine required five steps that included the addition of organometallic species and harsh reduction conditions. Recently, we reported a simple way to shorten this sequence by running the radical carboazidation with α-iodoketones.…”

“…In Aubé's synthesis [48], a lactam intermediate closely related to the one of our lepadiformine A intermediate [16] was prepared. As an illustration of the synthetic usefulness of the desulfitative carboazidation, we achieved a concise synthesis of Aubé's intermediate (Scheme 12) [22].…”

“…Alternatively, 3-pyridinesulfonyl azide could be used instead of benzene sulfonyl azide to facilitate the purification of the products [15]. This radical carboazidation was further showcased in the synthesis of lepadiformine A [16] and (+)-hyacinthacine A 1 [17].…”

Studies on Total Synthesis of the Cylindricine/Fasicularin/Lepadiformine Family of Tricyclic Marine Alkaloids

“…40 The synthesis began with cyclohexanone which was converted in a short, straightforward sequence into exo-methylene compound 270 (Scheme 49). Carboazidation of olefin 270 using the conditions shown in the scheme led to a 3:2 mixture of diastereomeric azido esters 271 and 272.…”