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. Author manuscript; available in PMC: 2014 Jan 11.
Published in final edited form as: Org Lett. 2012 Jul 11;14(14):3756–3759. doi: 10.1021/ol301614v

Synthesis of Functionalized Cyclohexenone Core of Welwitindolinones via Rhodium- Catalyzed [5+1] Cycloaddition

Min Zhang 1, Weiping Tang 1,✉
PMCID: PMC3480994  NIHMSID: NIHMS393417  PMID: 22783971

Abstract

graphic file with name nihms393417u1.jpg

The cyclohexenone core of welwitindolinones was synthesized by a Rh(I)-catalyzed [5+1]-cycloaddition of an allenylcyclopropane with CO. A penta-substituted cyclopropane was prepared successfully by a Rh(II)-catalyzed intramolecular cyclopropanation of alkenes with chlorodiazoacetates.

Indole alkaloid welwitindolinones (e.g. 1–3, Scheme 1) and related natural products were isolated from blue-green algae Hapalosiphon welwitschii and westiella intricate.1 N-Methylwelwitindolinone C isothiocyanate 1 reversed the drug-resistance of cancer cells in the presence of various anticancer drugs, including actinomycin D, colchicine, daunomycin, taxol, and vinblastine.2 Because of the challenging structures and their interesting biological activity, numerous synthetic efforts have been devoted to the synthesis of welwitindolinone Cs3 and related natural products, such as welwitindolinone A.4 Recently, research groups of Rawal5 and Garg6 independently accomplished elegant syntheses of welwitindolinone Cs and their oxidized congeners.

Scheme 1.

Scheme 1

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Proposed Strategies for Welwitindolinones

In most previous strategies for welwitindolinone Cs, functional groups on the six-membered ring especially the vinyl chloride group were introduced or proposed to be introduced at late stage, which was often challenging.7 We envisioned that a Rh-catalyzed [5+1] cycloaddition of allenylcyclopropane 5 with CO might afford the fully functionalized cyclohexenone core 4 efficiently. Alternatively, [5+1] cycloaddition of allenylcyclopropane 8 may yield cyclohexenone 7. Closing of the sevenmembered ring may be realized by addition to the isopropylidene group in intermediate 4 through strategy a or α-arylation of the ketone group in intermediate 6 through strategy b.

We recently developed a stereoselective method for the synthesis of highly functionalized cyclohexenones via Rhcatalyzed [5+1] cycloaddition of allenylcyclopropanes derived from 1,3-acyloxy migration of propargyl esters.8,9 We examined the regioselectivity for the cleavage of the cyclopropane ring and found that the C-C bond adjacent to an electron-rich aryl group or away from a quaternary carbon was selectively cleaved.8,10 This provided the basis for the proposed regioselective [5+1] cycloaddition of cyclopropanes 5 or 8.

The synthesis began with the preparation of allylic alcohol 11 from commercially available 4-cyanoindole 9 through a sequence of methylation, reduction, olefination, and reduction. Esterification and diazo compound formation were achieved in one step using reagent 12.11 Chlorination of diazo compound 13 yielded an unstable halodiazoacetate that was directly used in the cyclopropanation reaction. Based on a previous report,12 Du Bois’ Rh2(esp)2 was an efficient catalyst for mediating intermolecular cyclopropanation of alkenes and halodiazoacetates.13 We also found that Rh2(esp)2 was superior to other rhodium catalysts such as Rh2(OAc)4 for this intramolecular cyclopropanation. The best isolated yield we obtained for product 15, however, was only about 20%. We suspected that the electron-rich indole ring might interfere with the electrophilic cyclopropanation. Substrates with an electronwithdrawing group on the indole nitrogen were then examined.

Boc-protected indole 16 was prepared in two steps from 4-cyanoindole indole 9 (Scheme 3). Diazoacetate 17 could be synthesized according to protocols described in Scheme 2. Chlorination followed by intramolecular cyclopropanation using Rh2(esp)2 catalyst afforded bicyclic product 19 in 50–60% yield after two steps starting with 1.2–4.4 g of diazo compound 17. This represents the first successful example of intramolecular cyclopropanation of alkenes with chlorodiazoaceates and the reaction could be scaled up to several grams.

Scheme 3.

Scheme 3

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Intramolecular Cyclopropanation of an Alkene Substituted with a N-Boc protected Indole

Scheme 2.

Scheme 2

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Intramolecular Cyclopropanation of an Alkene Substituted with a N-Methyl Indole

Opening of the lactone and protection of the resulting primary alcohol afforded Weinreb amide14 20. Addition of propynyl magnesium bromide to this amide then yielded ynone 21, which was reduced to a mixture of two diastereomeric propargyl alcohols. Attempts to prepare allene 22 through a SN2′ reaction led to either decomposition when the leaving group was mesylates/triflate or no reaction when the leaving was acetate.15 Eventually, displacement of a sulfoxide leaving group16 proved to be fruitful and provided the desired allene 22 in 80% yield from ynone 21.

With allenylcyclopropane 22 in hand, we then tried the [5+1] cycloaddition under different conditions. After screening various solvents (toluene, xylene, DCE, CHCl3, dioxane), catalysts ([Rh(CO)2Cl]2, [Rh(COD)2Cl]2, [RhCl(PPh3)3], Ir(CO)2Cl]2), CO pressure (1 atm, 2 atm, and 5 atm), and temperature, we were able to isolate 60% yield of the desired [5+1] cycloaddition product 23 under conditions shown in Scheme 5. The cyclopropane C-C bond adjacent to the indole ring and away from the quaternary carbon was selectively cleaved during the cycloaddition. The relative stereochemistry of the product and the regioselectivity for the cleavage of cyclopropane C-C σ-bond were determined by nOe and HMBC, respectively.17

Scheme 5.

Scheme 5

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Rh-catalyzed [5+1] cycloaddition of Allenylcyclopropane and CO

In summary, we have developed an efficient strategy to access the cyclohexenone core of welwitindolinone Cs. Highly sterically congested penta-substituted cyclopropanes were prepared successfully by an intramolecular cyclopropanation of trisubstituted alkenes with chlorodiazoacetates. The [5+1] cycloaddition product 23 has a cyclohexenone core with most of the required functionalities for welwitindolinone Cs including a quaternary carbon, a vinylchloride group, an indole ring, and a ketone group with an isopropylidene substituent. Efforts to complete the synthesis of welwitindolinone Cs and their analogues by installing the second quaternary carbon and closing the seven-membered ring are currently underway in our laboratory,18 in addition to the study of [5+1] cycloaddition of other allenylcyclopropanes.

Supplementary Material

1_si_001

Scheme 4.

Scheme 4

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Preparation of Penta-substituted Allenylcyclopropane

Acknowledgments

We thank the University of Wisconsin and the NIH (R01 GM088285) for financial support and a Young Investigator Award (to W.T.) from Amgen.

Footnotes

Supporting Information Available 1HNMR, 13CNMR, IR, HRMS for starting materials and products. This material is available free of charge via the Internet at http://pubs.acs.org.

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Associated Data

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Supplementary Materials

1_si_001
NIHMS393417-supplement-1_si_001.pdf (468.6KB, pdf)

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