Catalytic bimetalic [Pd(0)/Ag(I) Heck-1,3-dipolar cycloaddition cascade reactions accessing spiro-oxindoles. Concomitant in situ generation of azomethine ylides and dipolarophile
Graphical abstract
Introduction
The spiro-oxindole motif is an important structural feature within a range of bioactive indole alkaloids, such as the anti-cancer spirotryprostatins A 1 and B 2 which were isolated from Aspergillus fumigatus,1 and the hemiterpene spiro-oxindole alkaloids2, 3, 3(a), 3(b), 3(c) elacomine 3a and isoelacomine 3b (Fig. 1). Correspondingly, there has been significant interest in the development of efficient synthetic approaches to these systems.4,5 For instance, Danishefsky and co-workers have reported the synthesis of molecules 4 and 5 (Fig. 1), which are potent analogues of the spirotryptostatins, showing significantly enhanced activity when compared to either spirotryprostatin A 1 and B 2 when tested against MDA MB-468 and MC57 human breast cancer cell lines.5
We have previously described a range of palladium-catalysed cyclisation and cycloaddition-based cascades which provide facile, stereo- and regiocontrolled access to a wide range of carbocyclic and heterocyclic systems including spiro- and bridged-ring heterocycles, beta-lactam analogues, isoquinolines, nucleosides, cyclopropyl diindolylmethanes, γ-carbolines AC190- analogues, and various other bioactive compounds.6, 6(a), 6(b), 6(c), 6(d), 6(e), 6(f), 6(g), 6(h), 6(i) As part of this work, we have previously reported the combination of imine → azomethine ylide → cycloaddition with a Heck reaction7 and in a preliminary communication we have reported8 an alternative tactical combination of an intramolecular Heck reaction and a subsequent Ag(I) catalysed imine → azomethine ylide → cycloaddition cascade in order to access novel spiro-oxindoles. In the present paper, in addition to providing full details of our earlier findings, we report the extension of this work to the formation of novel spiro-oxindole analogues containing two new rings and three stereocentres, together with a synthesis of epi-spirotryprostatin A and its analogues, in good to excellent yields.
Section snippets
Results and discussion
Two cascade approaches to spiro-oxindoles have been developed, both involving in situ formation and trapping of a 3-methylene oxindole dipolarophile moiety 6, followed by cycloaddition with in situ generated azomethine ylides derived from imines 9 to form spiro-oxindoles 10 (Scheme 1).
In the first approach, which is based upon a Peterson olefination route to methylene oxindole 6, the spiro-oxindoles 12a/b were obtained from a Peterson olefination - 1,3-dipolar cycloaddition cascade. Thus N
Conclusion
The tactical combination of bimetallic Pd (0)/Ag(I) Heck-1,3-dipolar cycloaddition cascades offers an extremely simple and versatile route to a variety of structurally diverse spiro-oxindole-based systems. Furthermore, this approach is readily amenable to the production of complex biologically active systems as underlined by our facile synthesis of epi-spirotryprostatin A and its analogues as described above. It should be possible to apply this approach in a combinatorial fashion in order to
General information
Melting points were determined on a Reichert hot-stage apparatus and are uncorrected. Mass spectra were recorded on a V.G.-AutoSpec instrument operating at 70 eV as electron impact (EI+) spectra, and accurate molecular weights were determined using perfluorokerosine as an internal standard. Electrospray (ES+) mass spectra were recorded using a Micro Mass LCT Time of Flight “KA111” instrument. Accurate molecular weights were recorded as ES+ spectra using the EPSRC service. IR spectra were
Acknowledgements
The authors thank The University of Leeds UK and Mersin University Turkey for support.
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