Total Synthesis of (±)-Chartelline C

Abstract

The first total synthesis of (±)-chartelline C in a concise 10-step sequence is reported. Highlights of the completion of this decades-old puzzle include (1) chemo- and position-selective installation of the heteroaromatic halogens, (2) halogen-sparing monoreduction of an alkyne linker, (3) a simple strategy for placement of the sensitive β-chloroenamide, (4) an unusually facile thermolysis of a vinyl carboxylic acid, and (5) a powerful ring contraction whose potential utility in heterocyclic chemistry merits further investigation.

Synthesis and reactivity of spiro-fused β-lactams

“…5 It is worth mentioning that chartellines A, B, and C 1-3 (Figure 2) have been isolated in the 1980s from the marine bryozoans, Chartella papyracea, collected from the North sea. 50 Although the chartellines lacked biological activity, they remained targets of interest, due to their novel and complex structure.…”

“…34 The reaction of 9H-xanthene-9-carboxylic acid 53 was extended to some bis-imines, derived from treatment of anthracene-9-carbaldehyde with diamines, forming novel bis-spiro-fused 2-azetidinones 56a-e (Figure 3). The -oxoketenes, generated by pyrolysis of 2-aryl-substituted 1,5,7-trioxaspiro [2,5]octane-4,8-diones 57, reacted with imines 30 to give diastereomeric 2-azetidinones, spiro-fused to 1,3-dioxolan-4-ones 59 and 60 ( Table 2). 35 The proposed mechanism for the generation of ketenes involves an intramolecular rearrangement between the oxirane ring and the carbonyl group in compounds 57 forming bicycles 58, which undergo another intramolecular rearrangement under anhydrous conditions forming -oxoketenes (Scheme 19).…”

Studies towards the synthesis of the marine alkaloid chartelline C

“…22 Unfortunately, attempts to couple 5 and 16 to give 17, under a variety of Sonogashira and Castro-Stephens reaction conditions failed, Scheme 4. In light of Baran's reported work 6,7 we revisited this reaction applying their reaction conditions, but no coupling product 17 was observed. Presumably, the more reactive 2-iodo analog of 5 would have been successful.…”

“…The transformation of 1c into 3 can be written as a [1,5]-shift and is a key step in the recently reported biogenetically inspired strategy for the synthesis of 3 by Baran and Shenvi. 6,7 Several other groups have reported on synthetic approaches to chartelline C 6,[8][9][10][11] as well as related alkaloids. 12,13 Our plan was also based on the supposition that the spiro-β-lactam in 3 could arise from a late stage oxidative cyclization of a suitable macrolactam.…”

“…14 The macrolactam precursor to 1c, namely 1, was envisioned as arising from macrolactamization, and to eventually achieve this a regioselective Sonogashira coupling at the 2-position of a 2-halo-6-bromoindole was required as a starting point. The only selective coupling of an acetylene at the 2-position of an indole that has a 6-bromo substituent was a 2-iodo-6-bromoindole, 7 and since this compound required a six step synthesis from 6-bromoindole, we were interested to see if a 2,6-dibromoindole exhibited any selectivity in a Sonogashira coupling reaction.…”