The total synthesis of 4-hydroxydictyolactone

2009 2009

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Abstract (summary)

The xenicane family of marine diterpenoid secondary metabolites is comprised of over 100 natural products that generally share a cyclononene carbocyclic framework. Indigenous to many of these compounds is an endocyclic trans olefin that imparts considerable ring strain within the nine-membered ring. This strain allows for elevated levels of reactivity that are believed to be fundamental to the biological activities displayed within family. Furthermore, difficulties associated with the construction of this motif have resulted in little synthetic advancement toward its members. Efforts within the Williams research laboratories have focused on 4-hydroxydictyolactone, an archetypal member of the family. The synthetic route succeeded in developing of a highly diastereoselective Ireland-Claisen rearrangement for installation of the contiguous all-carbon stereotriad intrinsic to the backbone of the natural product. The product of the rearrangement was strategically designed to provide a highly versatile scaffold around which a number of strategies for completion of the molecule could be explored. Ultimately, the fused butyrolactone motif was secured via a novel intramolecular Nozaki-Hiyama SE' allylation, which employed a formate ester as the electrophilic component in the reaction. The difficult C4 stereochemistry was achieved via a γ-chelation-controlled addition of allenylmagnesium bromide to an aldehydic precursor. This reaction is believed to proceed through a closed six-membered transition state to provide a homopropargylic product with good levels of diastereoselectivity. Extensive optimization studies have provided the first example of an intramolecular B-alkyl Suzuki cross-coupling for direct closure of the (E)-cyclononene carbocyclic core. Despite overwhelming literature evidence to the contrary, our studies found Pd(PPh3)4 to be far superior to PdCl2(dppf) as a catalyst for this reaction. Finally, diastereoselective α-phenylselenylation of the butyrolactone and subsequent oxidation allowed for syn-oxidative elimination to install the reactive enoate functionality of the natural product. In summary, the first total synthesis of 4-hydroxydictyolactone has been achieved in 28 steps and 4.2% overall yield from a known intermediate. Furthermore, the completion of the molecule has provided supporting evidence for the proposed absolute stereochemical assignment, which was originally assigned by an advanced Mosher ester analysis.

Indexing (details)

Organic chemistry
0490: Organic chemistry
Identifier / keyword
Pure sciences; B-alkyl suzuki reaction; Cyclononene; Hydroxydictyolactone; Ireland-Claisen rearrangement; Xenicanes
The total synthesis of 4-hydroxydictyolactone
Walsh, Martin J.
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
Williams, David R.
Committee member
Cook, Silas; Lee, Dongwhan; VanNieuwenhze, Michael S.
Indiana University
University location
United States -- Indiana
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.
Document URL
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