Palladium and gold catalyzed synthetic strategies: Application to the syntheses of (−)-ushikulide A and 7-<i>epi</i>-FR900482

2009 2009

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Abstract (summary)

The palladium catalyzed dynamic catalytic asymmetric transformation (DYKAT), dinuclear zinc direct aldol reaction and gold catalyzed spiroketalization are powerful methods for the synthesis of complex natural products. The methodology driven syntheses described in this volume were motivated by the desire to understand and utilize these elegant and atom-economical transformations.

The synthesis of 7-epi-FR900482 was achieved in 23 linear steps and 29 total steps from commercially available 1,5-hexadiene-3,4-diol. Application of a palladium catalyzed DYKAT reaction developed in the Trost group set the absolute stereochemistry for this synthesis. A highly chemo- and diastereoselective dihydroxylation of a derivative derived from this DYKAT product allowed preparation of an aziridine fragment that could be united with a suitable aromatic fragment. In order to facilitate Heck coupling, a Polonovski strategy was investigated that allowed preparation of the [3.3.1] bicyclic hydroxylamine hemiketal ring system present in FR900482. A key deoxygenation of C7 was required to complete this synthesis. Deoxygenation was accomplished, however, only the C7 epimer of the natural product was isolated through this route. Testing of this epimer demonstrated that it had similar activity against several human cancer cell lines compared to the natural product. Thus this project resulted in a novel analog of the natural product via a shorter synthetic route than any previously disclosed in the literature.

Our efforts toward the synthesis of ushikulide A determined for the first time the full stereostructure of this spiroketal containing macrolide. Given the uncertainty of this target, a tentative assignment was made based on analogy to cytovaricin, a related macrolide whose full structure was previously established. Several key methodologies were explored: namely a direct aldol reaction catalyzed by the dinuclear zinc ProPhenol complex, a gold catalyzed spiroketalization in which electronic bias of a propargyl benzoate was demonstrated for the first time as a means to control regioselectivity, as well as application of an unprecedented catalytic asymmetric alkynylation of a simple saturated aldehyde with methyl propiolate to prepare the nucleophilic partner for a Marshall-Tamaru propargylation. Related synthetic work is discussed and the synthesis of ushikulide A is the current state of the art for members of the rutamycin family of natural products.

Each of the above mentioned projects has led to further avenues for exploration. An unexpected domino Heck/alkylation reaction observed during the synthesis of FR900482 was investigated and explored. Finally, synthetic studies were undertaken toward NK154183A, a member of the dunaimycin family of natural products whose efficient synthesis may be envisioned based on our previous work. By further optimizing the general strategy developed for the synthesis of ushikulide A, it is possible to envision much more rapid access to natural products of this family than would have been possible before.

Indexing (details)

Organic chemistry
0490: Organic chemistry
Identifier / keyword
Pure sciences; Dinuclear zinc; Gold; Palladium; Spiroletalization; Ushikulide A
Palladium and gold catalyzed synthetic strategies: Application to the syntheses of (−)-ushikulide A and 7-<i>epi</i>-FR900482
O'Boyle, Brendan M.
Number of pages
Publication year
Degree date
School code
DAI-B 70/10, Dissertation Abstracts International
Place of publication
Ann Arbor
Country of publication
United States
Bois, Justin Du
Stanford University
University location
United States -- California
Source type
Dissertations & Theses
Document type
Dissertation/thesis number
ProQuest document ID
Database copyright ProQuest LLC; ProQuest does not claim copyright in the individual underlying works.
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