J . Org. Chem. 2002, 67, 2263-2265
2263
Tota l Syn th esis of Gibbilim bols A-D
J ames R. Vyvyan,* Christian L. Holst, Allison J . J ohnson, and Cheryl M. Schwenk
Department of Chemistry, Western Washington University, Bellingham, Washington 98225-9150
vyvyan@chem.wwu.edu
Received November 20, 2001
Gibbilimbols A-D (1-4) were synthesized in 32-49% yield over four steps from commercially
available starting materials. A copper-catalyzed coupling of 4-methoxyphenylmagnesium bromide
with various unsaturated alkyl bromides was the key step in assembling the (long-chain alkyl)-
phenol skeleton.
Sch em e 1
In tr od u ction
Nonisoprenoid phenolic lipids exist in a wide variety
of plant species and in a few bacteria. These compounds
are derived from the shikimate and polyketide pathways
and include alkylmonophenols, -catechols, -resorcinols,
and -hydroquinones.1 Several (long-chain alkyl)phenols,
especially the 5-alkylresorcinols and anacardic acids,
have attracted attention due to their biological activities.2
Gibbilimbols A-D (1-4) are 4-alkenylphenols recently
isolated in small quantities from the leaves of Piper
gibbilimbum (Figure 1).3 The gibbilimbols have an (E)-
alkene in the 3′ or 4′ position of their 8- or 10-carbon side
chains and were found to exhibit modest cytotoxicity
toward KB nasopharyngal cancer cells (ED50 2-8 µg/mL)
and antibacterial activity against Staphylococcus epider-
midis and Bacillus cereus (MIC 2-4 µg/mL).3 A similar
alkenylphenol (5) with an (E)-alkene in the 5′ position
of a 16-carbon side chain has been isolated from Piper
hispidum.4 In the case of 5 determining the position of
the alkene in the side chain was not trivial, and the 5′
position was deduced from double-resonance 1H NMR
experiments.4
pepper it produces. Most Piper species have also found
broad application in traditional medicine.6 The leaves of
P. gibbilimbum, a small shrub that grows in the Central
Province of Papua, New Guinea, are used there to treat
fever, abscesses, and ulceration of the skin, and the juice
squeezed from the heated bark is taken for suspected
cancer or internal sores.7,8
The genus Piper consists of more than 1400 species and
includes shrubs, high-climbing woody vines, and small
trees which exist mostly in tropical regions.5,6 The most
well-known member of this family, Piper nigrum, has
been prized in the spice trade for centuries for the black
We were prompted to undertake the synthesis of the
gibbilimbols due to their biological activity and relative
scarcity (2-12 mg each of 1-4 from 1.2 kg of dried P.
gibbilimbum leaves). In designing a synthesis of these
compounds, we wished to minimize not only the number
of linear steps from commercially available materials, but
also the number of different transformations required.
Thus, we settled on a strategy that attaches each side
chain to the aromatic core via a copper-catalyzed Grig-
nard alkylation. We now report the total synthesis of
gibbilimbols A-D (1-4).9,10
* To whom correspondence should be addressed.
(1) (a) Kozubek, A.; Tyman, J . H. P. Chem. Rev. 1999, 99, 1-25. (b)
Tyman, J . H. P. Synthetic and Natural Phenols; Elsevier: Amsterdam,
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Chemistry; Atta-ur-Rahman, Ed.; Elsevier: Amsterdam, 1991; Vol. 9,
pp 313-381.
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12683-12690. (c) Singh, U. S.; Scannell, R. T.; An, H.; Carter, B. J .;
Hecht, S. M. J . Am. Chem. Soc. 1995, 117, 12691-12699. (d) Scannell,
R. T.; Barr, J . R.; Murty, U. S.; Reddy, K. S.; Hecht, S. M. J . Am. Chem.
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35, 3016-3020. (g) Coates, N. J .; Gilpin, M. L.; Gwynn, M. N.; Lewis,
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David, J . M.; Chavez, J . P.; Chai, H.-B.; Pezzuto, J . M.; Cordell, G. A.
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(5) Atal, C. K.; Dhor, K. L.; Singh, J . Lloydia 1975, 38, 256-
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(6) Ray, A. B. Fitoterapia 1987, 58, 147-166.
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(9) This work was presented at the 37th National Organic Sym-
posium, J une 10-14, 2001, Bozeman, MT, and comprises part of the
M.S. thesis of C.L.H.
(10) An alternative synthesis of the gibbilimbols was reported
recently: Abe, Y.; Takikawa, H.; Mori, K Biosci. Biotechnol. Biochem.
2001, 65, 732-5.
(3) Orjala, J .; Mian, P.; Rali, T.; Sticher, O. J . Nat. Prod. 1998, 61,
939-941.
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10.1021/jo0162991 CCC: $22.00 © 2002 American Chemical Society
Published on Web 03/14/2002