Synthetic studies towards Lundurines A-C

Recent advances in transition metal catalyzed C-H activation are revolutionizing synthetic organic chemistry, and application of this powerful synthetic tool in the context of total synthesis of complex natural products is beginning to blossom. This thesis describes synthetic studies towards the total synthesis of lundurines A-C involving Pd(0)-catalyzed C(sp3)-H functionalization methodologies. From a synthetic point of view, the intriguing cyclopropane-fused indoline caged system at the core of lundurines A-C would naturally invoke a C(sp3)-H functionalization of the central cyclopropane moiety. Although methodologies involving cyclopropane activation have been recently reported in literature, their potential in the case of complex substrates is yet to be explored. This approach would allow rapid access to the lundurine scaffold, circumventing an otherwise complicated and tedious preparation of a highly substituted cyclopropane. A C(sp3)-H functionalization closure of the indoline ring in the lundurine scaffold I from precursor II was considered one of the viable options (Scheme I). However, the cyclization precursor II proved to be a difficult synthetic target on its own merit. Various investigated synthetic approaches towards II via intramolecular cyclopropanation reactions were fruitless. Due to the difficulties associated with preparation of II the aforementioned disconnection has not been tested in the variant presented in the Scheme I. Another disconnection, employing this time a more challenging C(sp3)-C(sp3) bond formation on the cyclopropane and closing the 7-membered ring of the lundurine scaffold III, has been also evaluated (Scheme II). The requisite cyclization precursor IV was successfully prepared from the intermediate V utilizing the previously introduced C(sp3)-H functionalization creating the indoline ring. However, the envisioned late-stage cyclization appeared to be incompatible with the conformational rigidity of IV. Although presented studies conducted on the cyclopropane C(sp3)-H functionalization did not deliver the target lundurine alkaloids, the obtained results led to discovery and development of novel C-H activation methodologies.

Cramer, Nicolai
Lausanne, EPFL
Other identifiers:
urn: urn:nbn:ch:bel-epfl-thesis6794-0

Note: The status of this file is: EPFL only

 Record created 2015-11-09, last modified 2018-03-17

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