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Logo of nihpaAbout Author manuscriptsSubmit a manuscriptHHS Public Access; Author Manuscript; Accepted for publication in peer reviewed journal;
Tetrahedron Lett. Author manuscript; available in PMC 2010 December 14.
Published in final edited form as:
Tetrahedron Lett. 2007 September 3; 48(36): 6364–6367.
doi:  10.1016/j.tetlet.2007.07.040
PMCID: PMC3001619

Studies towards the synthesis of the marine alkaloid chartelline C


The 2,6-dibromoindole 5 underwent regioselective Sonogashira coupling at the 2 position with simple acetylenic partners. While, the imidazole-acetylene 16 failed to couple to 5, the cyclic carbonate 19 succeeded to give 20, which was further elaborated into the indole-imidazole 23.

Keywords: Chartelline C, securines, securamines, biogenetic, Sonogashira coupling

The chartelline marine alkaloids were isolated from the bryozoan Chartella papyracea and characterized in the 1980’s.13 A related bryozoan Securiflustra securifrons also produces the securines and securamines,4,5 and they are plausible biogenetic precursors to the chartellines. It was reported that solutions of securine B 1 in DMSO-d6 converted into securamine B 2, presumably via 1a, Scheme 1.4 Redissolving 2 in CDCl3 converted 2 back into 1. One could imagine that if this isomerization were carried out in the presence of an electropositive source of chlorine, 1 could be converted into chartelline C 3 through the intermediacy of 1b and 1c. 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 6,811 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.

Indole-3-acetonitrile 415,16 was regioselectively brominated using a known protocol17 to give 5 (after t-butyl carbamate protection), Scheme 2. Exposure of 5 to standard Sonogashira coupling reaction conditions proceeded with complete regioselectivity to give the 2-coupled indoles 6, 7 and 8 respectively. It was found that the choice of protecting group on the indole nitrogen atom was essential to achieving regioselectivity in the Sonogashira coupling reaction. For example, when an N-benzyl-2,6-dibromo indole 9 was subjected to the coupling reaction conditions with triisopropylsilylacetylene, a mixture of 10a, 10b and 10c was obtained in a ratio of 1:2:1.5 and in an overall yield of 72%.

Scheme 2
(a) NBS, SiO2, CH2Cl2, (b) Boc2O, NEt3, DMAP, CH2Cl2 54% over two steps. (c) Acetylene, PdCl2(PPh3)2, CuI, NEt3, 45 °C. (d) triisopropylsilylacetylene, PdCl2(PPh3)2, CuI, NEt3, MeCN, 25 °C, 72%, 10a, 10b and 10c in a 1 : 2 : 1.5 ratio ...

With the indole portion in hand, synthesis of the imidazole 16 was undertaken, Scheme 3. The aldehyde 1118 was converted into the α,β-unsaturated ester 1219 (90%) and subjected to deconjugative dimethylation to give 13 (96%). Reduction of 13 followed by oxidation and treatment of the resulting aldehyde with Ohira’s reagent [MeCOCN2PO(OEt)2],20,21 gave the terminal acetylene 14 in 90% yield over three steps.

Scheme 3
Reagents and conditions: (a) triethylphosphonoacetate, NaH, THF, 0 °C, 90%; (b) LiHMDS, HMPA, THF at −78 °C, then MeI and LiHMDS, HMPA, THF at −78 °C, then MeI, 96% for one-pot procedure. (c) LiAlH4, THF, −78 ...

Dihydroxylation of the internal alkene in 14 followed by oxidation of the resulting diol with SO3•pyridine, NEt3, DMSO in CH2Cl2 gave the -diketone 15 (83%). Treatment of 15 with NH4OAc, (CH2O)n in acetic acid at 100 °C, followed by protection of the imidazole NH gave 16 in reproducible yields of 74% from 15.22

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 work6,7 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. It was therefore decided to construct the imidazole portion after the acetylenic coupling process.

The cyclic carbonate 18 (made from 14 by vic-dihydroxylation followed by triphosgene/pyridine) was treated with BCl3/CH2Cl2 and the resulting alcohol protected as its TIPS ether 19 (89% over two steps), Scheme 5. It was necessary to conduct the exchange of the benzyl ether since the benzyl analogue of 20 was not compatible with the cis-hydrogenation of the acetylene. The indole 5 could now be successfully coupled with the terminal acetylene 19 under standard Sonogashira reaction conditions to give 20 (67%).

Scheme 5
Reagents and conditions: (a) BCl3, CH2Cl2, 0 °C. (b) TIPSCl, imidazole, ClCH2CH2Cl, 85 °C, 89% over two steps. (c) 5, PdCl2(PPh3)2, CuI,NEt3, 25 °C, 67%. (d) H2, PtO2 (cat.), EtOH, 60%. (e) NaOH (aq.), dioxane, (f) Dess-Martin ...

Hydrogenation of 20 over Adam’s catalyst (PtO2/H2/EtOH) reduced the acetylenic bond stereoselectively to the cis-alkene 21 without competing hydrogenolysis of the 6-Br substituent in the indole ring. Hydrogenation of 20 over 10%Pd/C or Raney Ni reduced the acetylenic bond to the cis-alkene but also removed the 6-Br atom. Standard hydrogenation catalysts such as Lindlar’s catalyst, Wilkinson’s catalyst and Pt/C proved too unreactive, as were transfer hydrogenation and diimide (generated in situ).

Treatment of 21 with NaOH (aq.) in dioxane by followed oxidation of the resulting diol with the Dess-Martin periodinane reagent gave the -diketone 22 (43% yield). When 22 was subjected to the earlier imidazole formation conditions, the starting material was destroyed without any imidazole formation. However, by maintaining a lower reaction temperature, with the same reagents (NH4OAc, paraformaldehyde, AcOH) the imidazole 23 could be obtained in a 50% yield.

In summary, the regioselective Sonogashira of the 2,6-dibromoindole 5 can be used to synthesize the 2-isoprene-imidazole chain provided the imidazole is constructed after the coupling reaction.


The NIH (GM 32718) and the Welch Chair (F-0018) are thanked for their support of this research. Kevin Williamson is thanked for his contributions.


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