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. 2010 Mar 31;66(31):5852-5862.
doi: 10.1016/j.tet.2010.04.112.

Synthesis and chemical diversity analysis of bicyclo[3.3.1]non-3-en-2-ones

Jared T Hammill  1 , Julia Contreras-García, Aaron M Virshup, David Beratan, Weitao Yang, Peter Wipf
Affiliations

Synthesis and chemical diversity analysis of bicyclo[3.3.1]non-3-en-2-ones

Jared T Hammill et al. Tetrahedron. .

Abstract

Functionalized bicyclo[3.3.1]non-3-en-2-ones are obtained from commercially available phenols by a hypervalent iodine oxidation, enone epoxidation, epoxide thiolysis, and intramolecular aldol reaction sequence. Reaction optimization studies identified room temperature as well as microwave-mediated procedures, providing moderate to good yields (57%-88%) in the thiophenol-mediated epoxide opening and intramolecular aldol reaction. In addition, the isolation of a key intermediate and in situ NMR studies supported the mechanistic hypothesis. The bicyclic ring products occupy novel chemical space according to ChemGPS and Chemaxon chemical diversity and cheminformatics analyses.

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Figures

Figure 1
Figure 1
Structures of the bicyclo[3.3.1]non-3-en-2-ones gymnastatin F and Q.
Figure 2
Figure 2
Rearrangement of spirolactol 1 to bicyclic enone 2.
Figure 3
Figure 3
ORTEP drawing of o-bromo-bicyclo[3.3.1]non-3-en-2-one 14 (with 50% probability atomic displacement parameters).
Figure 4
Figure 4
ChemGPS-NP coordinates of the newly synthesized bicyclic products (blue circles) and the bicyclo[3.3.1]-nonanes in the MLSMR library (crosses). Also shown are the coordinates of bicyclo[3.3.1]non-3-en-2-ones with all hydroxyl groups removed (yellow boxes).
Figure 5
Figure 5
ChemGPS-NP coordinates of the newly synthesized bicyclic products (blue) and the bicyclo[3.3.1]-nonanes in the MLSMR library (crosses). a) PC1 and PC4 highlight size and flexibility, respectively. b) PC5 and PC6, showing electronegative and electropositive atomic content, respectively.
Scheme 1
Scheme 1
Synthesis of diepoxy ketone lactol 7 and conversion to bicycle 8 after reaction optimization (shown in Table 1).
Scheme 2
Scheme 2
Proposed mechanism for the ring-opening and intramolecular aldol reaction of diepoxyketone 7 with thiophenol.
Scheme 3
Scheme 3
Synthesis of naphthoquinone monoacetal 16 by hypervalent iodine oxidation and rearrangement to bicycle 20.
Scheme 4
Scheme 4
Synthesis of m-cresol quinone monoacetal 21 by hypervalent iodine oxidation and rearrangement to bicycle 25.
Scheme 5
Scheme 5
Attempted preparation of bicyclo[3.4.1]dec-3-en-2-one 30.
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References

    1. http://omics.org/index.php/Main_Page.

    1. http://en.wikipedia.org/wiki/Signaling_pathway.

    1. http://mli.nih.gov/mli/. See also: Wipf P, Arnold D, Carter K, Dong S, Johnston PA, Sharlow E, Lazo JS, Huryn D. Curr Top Med Chem. 2009. p. 1194., and references cited therein.

    1. http://www.nigms.nih.gov/Initiatives/CMLD. See, for example: Pierce JG, Kasi D, Fushimi M, Cuzzupe A, Wipf P. J Org Chem. 2008;73:7807.Wipf P, Werner S, Woo GHC, Stephenson CRJ, Walczak MAA, Coleman CM, Twining LA. Tetrahedron. 2005;61:11488..

    1. http://mlsmr.glpg.com/MLSMR_HomePage/.