A concise, biomimetic total synthesis of (+)-davanone

Article abstract of DOI:10.1021/ol900697w

A concise, biomimetic synthesis of the antifungal and antispasmodic natural product (+)-davanone is described. The key stereoselective reactions are a Sharpless asymmetric epoxidation, a thiazolium-catalyzed esterification, and a palladium-mediated cycliz

Full text of DOI:10.1021/ol900697w

ORGANIC
LETTERS
2009
Vol. 11, No. 10
2217-2218
A Concise, Biomimetic Total Synthesis
of (+)-Davanone
Karen C. Morrison, Jonathan P. Litz, Kathryn P. Scherpelz, Paul D. Dossa, and
David A. Vosburg*
Department of Chemistry, HarVey Mudd College, 301 Platt BouleVard,
Claremont, California 91711
daVid_Vosburg@hmc.edu
Received April 2, 2009
ABSTRACT
A concise, biomimetic synthesis of the antifungal and antispasmodic natural product (+)-davanone is described. The key stereoselective
reactions are a Sharpless asymmetric epoxidation, a thiazolium-catalyzed esterification, and a palladium-mediated cyclization. All carbons are
derived from isoprene units and no protecting groups are used, permitting an atom- and redox-economical synthesis.
Davanone, a sesquiterpene first isolated from Artemisia
pallens in 1968,1 is the principle component of davana oil
and exhibits both antifungal2 and antispasmodic3 properties.
The core of its structure is shared with several other
secondary metabolites present in davana oil, some of which
are shown in Figure 1.4 Davanone has attracted significant
synthetic interest over the years,5 with noteworthy racemic
syntheses by Bartlett5d and Molander.5f Fully aware that the
only enantioselective synthesis exceeds 20 steps and gener-
ates a mixture of davanone and artemone,5e we sought a
Figure 1. Natural products related to davanone.
novel, concise, and enantioselective route to this natural
product.
Our synthetic planning was guided by the proposed
biosynthesis of davanone shown in Scheme 1. Feeding
studies have confirmed that davanone and artemone derive
from farnesyl diphosphate,6 and we hypothesized that allylic
oxidation and alkene hydration could generate hydroxyketone
1. Cyclization of such a substrate, with loss of diphosphate,
would then directly produce davanone.7
(1) Sipma, G.; Van der Wal, B. Recl. TraV. Chim. Pays-Bas. 1968, 87,
715–720.
Our synthesis began with the known epoxyalcohol 2,8
available in two steps from geranyl acetate via allylic
hydroxylation9 and Sharpless asymmetric epoxidation.8
Oxidation to epoxyaldehyde 3 proceeded smoothly with
DMSO/SO3/pyridine; however, generating anti-hydroxyester
(2) Vajs, V.; Trifunovic, S.; Janackovic, P.; Sokovic, M.; Milosavljevic,
S.; Tesevic, V. J. Serb. Chem. Soc. 2004, 69, 969–972.
(3) Perfumi, M.; Paparelli, F.; Cingolani, M. L. J. Essent. Oil Res. 1995,
7, 387–392.
(4) Misra, L. N.; Chandra, A.; Thakur, R. S. Phytochemistry 1991, 30,
549–552.
(5) (a) Naegeli, P.; Weber, G. Tetrahedron Lett. 1970, 959–962. (b)
Ohloff, G.; Giersch, W. HelV. Chim. Acta 1970, 53, 841–843. (c) Birch,
A. J.; Corrie, J. E. T.; Subba Rao, G. S. R. Aust. J. Chem. 1970, 23, 1811–
1817. (d) Bartlett, P. A.; Holmes, C. P. Tetrahedron Lett. 1983, 24, 1365–
1368. (e) Honda, Y.; Ori, A.; Tsuchihashi, G. Chem. Lett. 1987, 1259–
1262. (f) Molander, G. A.; Haas, J. Tetrahedron 1999, 55, 617–624.
(6) Akhila, A.; Sharma, P. K.; Thakur, R. S. Tetrahedron Lett. 1986,
27, 5885–5888.
(7) Most likely via an allylic cation as in linalool synthase and
methylbutenol synthase; see: Dewick, P. M. Nat. Prod. Rep. 2002, 19, 181–
222.
10.1021/ol900697w CCC: $40.75
Published on Web 04/14/2009
 2009 American Chemical Society

In summary, we have achieved the shortest enantioselec-
tive synthesis of davanone to date, requiring merely seven
steps from geranyl acetate and proceeding with a yield of
18% over five steps from epoxyalcohol 2. The atom
Scheme 1. Proposed Biosynthesis of Davanone
Scheme 2. Synthesis of Davanone
5 was more difficult. While other methods were unsatisfac-
tory, Bode’s thiazolium salt 410 was quite effective at
providing 5 using a non-aldol approach. To the best of our
knowledge, this is the first use of Bode’s carbene-catalyzed
epoxide-opening reaction in a total synthesis.
Our next concern was the formation of the final stereo-
center, as there are few examples of stereoselective allylic
O-alkylations at tertiary centers with aliphatic alcohols.11 We
anticipated that the inherent diastereofacial preference of 5
would be to form trans-6 rather than the desired cis
product.12 After screening a range of chiral catalysts and
reaction conditions, we found that Pd2dba3 with (S)-C3-
TunePhos13 enabled us to overcome the substrate’s diaste-
reofacial bias and favor cis-davana acid ethyl ester (6), itself
a trace natural component of davana oil.4,14 (R)-C3-TunePhos
gave substantial (>12:1) selectivity for the undesired trans
product.
Our route converged with the racemic synthesis of Haas
and Molander5f at anti,cis-Weinreb amide 7, which we
prepared with a three-step isolated yield of 31% from
aldehyde 3. Other than optical rotation, the physical proper-
ties of (+)-7 matched those reported for (()-7,5f and reaction
of this Weinreb amide with prenylmagnesium chloride
proceeded smoothly to produce (+)-davanone and complete
the synthesis.
economy15 and redox economy16 are considerable, as each
carbon in the final product derives from an isoprene unit,
no protecting groups are used, and superfluous redox
manipulations are avoided. Our route parallels the biosyn-
thetic proposal in Scheme 1 and features the first use of a
thiazolium-catalyzed epoxide opening in the synthesis of a
natural product.
Acknowledgment. This work was supported by a Camille
and Henry Dreyfus Foundation Faculty Startup Award,
National Science Foundation REU grant CHE-0353662, the
Beckman Foundation, the Harvey Mudd College (HMC) and
Pomona College Chemistry Departments, the Christian
Scholars Foundation, and Pfizer Summer Undergraduate
Research Fellowships (to K.C.M. and J.P.L.). We thank Ryan
J. Pakula and Kanny K. Wan from HMC for their contribu-
tions to this project.
(8) Katsuki, T.; Sharpless, K. B. J. Am. Chem. Soc. 1980, 102, 5974–
5976.
(9) (a) Umbreit, M. A.; Sharpless, K. B. J. Am. Chem. Soc. 1977, 99,
5526–5528. (b) Tanis, S. P.; Chuang, Y.-H.; Head, D. B. J. Org. Chem.
1988, 53, 4929–4938.
Supporting Information Available: Experimental pro-
cedures and compound characterization data. This material
is available free of charge via the Internet at http://pubs.acs.org.
(10) Chow, K.Y.-K.; Bode, J. W. J. Am. Chem. Soc. 2004, 126, 8126–
8127.
(11) (a) Fournier-Nguefack, C.; Lhoste, P.; Sinou, D. Tetrahedron 1997,
53, 4353–4362. (b) Trost, B. M.; Crawley, M. L. Chem. ReV. 2003, 103,
2921–2943. (c) Haight, A. R.; Stoner, E. J.; Peterson, M. J.; Grover, V. K.
J. Org. Chem. 2003, 68, 8092–8096.
OL900697W
(12) For related cyclizations with achiral catalysts, see ref.11a
(13) (a) Zhang, Z.; Qian, H.; Longmire, J.; Zhang, X. J. Org. Chem.
2000, 65, 6223–6226. (b) Raghunath, M.; Zhang, X. Tetrahedron Lett. 2005,
46, 8213–8216.
(15) Trost, B. M. Science 1991, 254, 1471–1477.
(16) (a) Richter, J. M.; Ishihara, Y.; Masuda, T.; Whitefield, B. W.;
Llamas, T.; Pohjakallio, A.; Baran, P. S. J. Am. Chem. Soc. 2008, 130,
17938–17954. (b) Burns, N. Z.; Baran, P. S.; Hoffmann, R. W. Angew.
Chem., Int. Ed. 2009, 48, 2854–2867.
(14) Dibenzylideneacetone co-elutes with 6 but can be chemoselectively
reduced with sodium borohydride or removed after the following step.
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