Olefin Cross-Metathesis as a Tool in Natural Product Degradation. The Stereochemistry of (+)-Falcarindiol

Article abstract of DOI:10.1021/ol027033z

(Matrix Presented) There are conflicting reports in the literature concerning the absolute sterochemistry at C-3 of the common plant polyacetylene oxylipin (+)-falcarindiol. We have employed olefin cross-metathesis using Grubbs' second generation catalyst and ethylene gas to degrade falcarindiol to the symmetrical 1,9-decadiene-4,6-diyne-3,8-diol. The reaction is completely selective for net removal of the aliphatic side chain. Degradation of (+)-falcarindiol from Tetraplasandra hawaiiensis yields a meso product as shown by chiral HPLC. Hence, (+)-falcarindiol from this source has a (3R,8S)-configuration.

Full text of DOI:10.1021/ol027033z

ORGANIC
LETTERS
2002
Vol. 4, No. 26
4667-4669
Olefin Cross-Metathesis as a Tool in
Natural Product Degradation. The
Stereochemistry of (+)-Falcarindiol
Anokha S. Ratnayake and Thomas Hemscheidt*
Department of Chemistry, UniVersity of Hawaii, 2545 McCarthy Mall,
Honolulu, Hawaii 96822
tomh@gold.chem.hawaii.edu
Received October 4, 2002
ABSTRACT
There are conflicting reports in the literature concerning the absolute sterochemistry at C-3 of the common plant polyacetylene oxylipin
(+)-falcarindiol. We have employed olefin cross-metathesis using Grubbs’ second generation catalyst and ethylene gas to degrade falcarindiol
to the symmetrical 1,9-decadiene-4,6-diyne-3,8-diol. The reaction is completely selective for net removal of the aliphatic side chain. Degradation
of (+)-falcarindiol from Tetraplasandra hawaiiensis yields a meso product as shown by chiral HPLC. Hence, (+)-falcarindiol from this source
has a (3R,8S)-configuration.
As part of an ongoing research program on the discovery of
new antitumor agents, we examined the organic extract of
the Hawaiian endemic plant Tetraplasandra hawaiiensis.
Bioassay-guided fractionation using a cytotoxicity assay led
us to a group of oxylipins of which falcarindiol (+)-1 was
the major constituent.
During our efforts to determine the stereochemistry of the
minor oxylipins from this extract we also reviewed the
information available regarding (+)-falcarindiol. The absolute
configuration of (+)-1 from Peucedanum oreoselinum (entry
1, Table 1) had first been assigned as 3R,8S by Lemmich in
1981 on the basis of chemical correlation studies.1 However,
in 1996, a group from the NCI proposed a (3S,8S)-
configuration for a similarly strongly dextrorotatory sample
of (+)-1 isolated from Dendropanax arboreus (entry 2, Table
1).2 The assignment of the stereochemistry of the latter
sample was based on an application of the advanced Mosher
method.3 It should be noted, however, that the analysis of
chemical shift changes in bis-MTPA esters of 1,n-diols may
be fraught with problems as demonstrated by Riguera.4 In
addition, in the case of (+)-1, one has to rely on the analysis
of ∆δ-values from resonances for protons on only one side
of the MTPA-plane, a practice that the developers of the
method and also Riguera have cautioned against.3,5
Table 1. Optical Rotations and Assigned Configurations of
Falcarindiol
entry
[R]D
assigned configuration
ref
1
2
3
4
5
6
+284a
+300b
+219.4c
+302a
+276b
+250c
3R,8S
3S,8S
3R,8S
3R,8S
3R,8S
3R,8S
ref 1
ref 2
refs 6 and 7
this work
this work
this work
(1) Lemmich, E. Phytochemistry 1981, 20, 1419-1420.
(2) Bernart, M. W.; Cardellina, J. H., II; Alexander, M. R.; Shoemaker,
R. H.; Boyd, M. R. J. Nat. Prod. 1996, 59, 748-753.
a (c 1.0, ether). b (c 0.14, ether). c (c 4.6, CHCl3).
10.1021/ol027033z CCC: $22.00 © 2002 American Chemical Society
Published on Web 11/27/2002

Without reference to the report from the NCI, in 1999 Cai
et al. published a chemical synthesis of (+)-(3R,8S)-
falcarindiol.6 The stereocenters were introduced by trans-
formations of L-tartaric acid and D-xylose. The former gave
rise to the C-8 stereochemistry, while the latter was used to
generate the absolute configuration at C-3. The synthetic
product had an optical rotation and other spectroscopic data
reportedly matching those of falcarindiol isolated from
Glehnia littoralis (entry 3, Table 1).7
The sample of 1 that we had isolated from T. hawaiiensis
showed optical rotations (entries 4-6, Table 1) matching
(within experimental error) all of the literature values reported
for either of the diastereomers of 1 for which an absolute
configuration had been proposed. Hence an unambiguous
assignment of the absolute configuration of our sample could
not be made on the basis of the chiroptical data available in
the literature. We therefore decided to pursue a determination
by an independent method. We reasoned that a confirmation
of either of the proposed absolute configurations might be
obtained if it were possible to modify the C-1/C-2 and C-9/
C-10 double bonds present in falcarindiol in such a way that
a symmetrical compound is formed. The degradation product
would either be meso or chiral if (+)-1 possesses a (3R,8S)-
or (3S,8S)-configuration, respectively. However, all attempts
to reduce this idea to practice using oxidative methods on
TBS-protected 1 failed, as no tractable products could be
isolated.8,9
available literature did not reassure us that removal of the
C-11 to C-17 chain, the desired reaction, would prevail over
potential competing ones such as intermolecular enyne
metathesis in the multifunctional environment of 1.11 How-
ever, side reactions proved to be much less of a problem
than we had anticipated. Using the second-generation Grubbs
catalyst (10 mol %, DCM, 16 h, room temperature, ethylene-
filled double balloon, 1 mM (+)-1),12 we observed a
quantitative conversion (1H NMR, TLC) of 1 to a single,
slightly more polar compound. The product was isolated in
81% yield by careful chromatography and shown to be 2
(see Supporting Information). We deemed chromatography
to be necessary due to the large specific rotation of 1.
Potential contamination of 2 by small amounts of 1 not
1
detectable by H NMR or TLC might induce a measurable
optical rotation in samples of 2 and hence might lead to an
erroneous conclusion as to its configuration. In the event,
the crystalline sample of 2 isolated from the cross-metathesis
reaction possessed marginal optically activity [R]D +5 (c 3.8,
CHCl3), which was suspiciously low when compared to that
of (+)-1.
For comparison purposes, we therefore prepared a syn-
thetic sample of (S,S)-2 shown in Scheme 1. Thus, 5-tri-
Scheme 1. Synthesis of
(S,S)-1,9-Decadiene-4,6-diyne-3,8-diola
At this point we considered the use of olefin cross-
metathesis on 1 as an alternative to oxidative degradation
(Figure 1).10
a Reaction conditions: (a) lipase from Pseudomonas fluorescens,
vinyl acetate, 4 Å MS, hexanes, room temperature, 20 h, 35%; (b)
NBS, cat. AgNO3, acetone, 3 h, 55%; (c) CuCl, NH2OH‚H2O,
ethylamine, aqueous MeOH, room temperature, 16 h, 80%.
methylsilylpent-1-en-4-yne-3-ol (()-3 was resolved using
lipase from Pseudomonas.13 The remaining nonacylated (S)-3
Figure 1. Hypothetical stereochemical consequences of the
degradation of diasteroisomers of (+)-1 by cross-metathesis.
(6) Zheng, G.; Lu, W.; Cai, J. J. Nat Prod. 1999, 62, 626-628.
(7) Matsuura, H.; Saxena, G.; Farmer, S. W.; Hancock, R. E. W.; Towers,
G. N. H. Planta Med. 1996, 62, 256-259.
(8) Travis, B. R.; Narayan, R. S.; Borhan, B. J. Am. Chem. Soc. 2002,
124, 3824-3825.
In the simplest implementation of this approach, ethylene
gas would serve as the second olefin in a reaction catalyzed
by one of Grubbs’ ruthenium carbenes. A review of the
(9) Carlsen, P. H. J.; Katsuki, T.; Martin, V. S.; Sharpless, K. B. J. Org.
Chem. 1981, 46, 3936-3938.
(10) Blackwell, H. E.; O’Leary, D. J.; Chatterjee, A. K.; Washenfelder,
R. A.; Bussmann, D. A.; Grubbs, R. H. J. Am. Chem. Soc. 2000, 122, 58-
71 and references therein.
(3) Ohtani, I.; Kusumi, T.; Kashman, Y.; Kakisawa, H. J. Am. Chem.
Soc. 1991, 113, 4092-4096.
(11) Mori, M. In Alkene Metathesis in Organic Synthesis; Fu¨rstner, A.,
Ed.; Springer-Verlag: Berlin, Heidelberg, 1998; pp 133-154.
(12) Scholl, M.; Ding, S.; Lee, C. W.; Grubbs, R. H. Org. Lett. 1999, 1,
953-956.
(13) Burgess, K.; Jennings, L. D. J. Am. Chem. Soc. 1991, 113, 6129-
6139.
(4) Seco, J. M.; Martino, M.; Quin˜oa´, E.; Riguera, R. Org. Lett. 2000,
2, 3261-3264.
(5) Seco, J. M.; Quin˜oa´, E.; Riguera, R. Tetrahedron: Asymmetry 2000,
11, 2781-2791.
4668
Org. Lett., Vol. 4, No. 26, 2002

([R]D +38 (c 2.0, CHCl3), g95% ee) was desilylated and
converted to bromide (S)-4 using Isobe’s convenient one-
pot procedure.14 Dimerization of (S)-4 under Cadiot-
Chodkiewicz conditions yielded (S,S)-2 ([R]D +102 (c 3.8,
CHCl3)).
The assignment of an (S)-configuration to the nonacylated
(+)-enantiomer of 3, and hence to (+)-2, rests on two lines
of evidence. First, the results of an application of the
advanced Mosher method to (+)-3 are in accord with this
assignment (see Supporting Information).3 Compound 3 was
chosen for the analysis because it bears the TMS group,
which yielded one data point on the right side of the MTPA
plane. Second, in resolutions of similarly substituted pro-
pargylic alcohols, the remaining starting material was shown
to have an (S)-configuration.13,15
The low optical rotation of the sample of 2 from the
degradation could be indicative of meso stereochemistry.
However, a stereorandom sample of low or null optical
activity might also result from epimerization of 1 or of 2
during the cross-metathesis by a variant of the hydride shift
mechanism first proposed by Hoye.16 To investigate this
possibility we resorted to analytical HPLC on a chiral
stationary phase.
Upon chromatography on a Chiralcel OD column, a
sample of symmetrical diol 2 derived from (()-4 yielded
three well-resolved peaks in a 1:2:1 ratio. This result, albeit
not necessarily in that elution order, is to be expected in a
successful separation and resolution of a statistical mixture
of meso and chiral diastereomers. Synthetic (+)-(S,S)-2 from
dimerization of (+)-4 showed only one peak, which co-
incided with the last-eluting peak from the stereorandom
sample of 2. Last, 2 obtained from degradation of (+)-1 from
T. hawaiiensis gave rise to only one peak, which eluted at
the same retention time as the large peak due to the meso
diastereomer of 2 in the synthetic sample (see Supporting
Information). This result suggests that epimerization does
not accompany cross-metathesis when (+)-1 is being de-
graded to 2 because the product is the pure meso isomer. It
is important to note that the same meso isomer is also found
exclusively if the crude degradation reaction mixture is
analyzed directly by chiral HPLC without prior purification
and crystallization of 2. In an additional control experiment,
(+)-2 was subjected to the cross-metathesis conditions used
for degradation of (+)-1. This did not result in any noticeable
change in optical purity of (+)-2 as shown by chiral HPLC
analysis of the crude reaction mixture and by polarimetry.
The present results prove unambiguously that (+)-1 from
T. hawaiiensis has the same (3R,8S)-stereochemistry as the
material obtained by Cai et al. through total synthesis. Upon
cross-metathesis with ethylene, a sample of this configuration
is expected to yield the meso isomer of 2, as is observed
experimentally.
validate the advanced Mosher method for application in such
diyne-diol systems. The result of an analysis of the ∆δ(δS
- δR) values of the bis-MTPA esters according to the
established model was in accordance with (3R,8S)-stereo-
chemistry of this sample. The resonances for protons H-9,
H-10, and H-11 all showed positive ∆δ values, while those
of the resonances for H-1E, H-1Z, and H-2 were all negative.
The sample of (+)-1 from D. arboreus (entry 2, Table 1)
had shown all negative ∆δ values, which had been inter-
preted as indicating a (3S,8S)-configuration.2 Our results,
being clearly different, indirectly support this assignment.
Unfortunately, we were not able to obtain a sample of this
material for degradation by our method for a rigorous
confirmation. However, it appears that Nature does indeed
elaborate two diastereomeric forms of (+)-1, which cannot
be distinguished by polarimetry. Hence, all assignments of
stereochemistry to samples of 1 and analogous compounds
using this latter method must be regarded as suspect.
In conclusion, we have demonstrated that olefin cross-
metathesis using ethylene can be a viable alternative to the
classical oxidative degradation procedures for natural prod-
ucts containing double bonds. Olefin metathesis has revo-
lutionized synthetic organic chemistry. This is a consequence
of the outstanding functional group tolerance of Grubbs’ and
Schrock’s metathesis catalysts, which are all commercially
available.17,18 Our results suggest that natural product chem-
ists interested in structure elucidation may derive a similar
benefit especially from the use of the robust and easy-to-
handle Ru-based catalysts.
It is worth noting that our earlier attempts to perform the
metathesis reaction on TBS-protected 1 were unsuccessful.
Furthermore, in the present circumstance, the use of ethylene
as the donor olefin proved to be preferable over the more
nucleophilic allyltrimethylsilane because the latter yielded
an inseparable mixture of olefin geometrical isomers.19
Acknowledgment. This work was supported by a grant
from the US Department of Defense (DAMD17-97-1-7212).
Support of the UH NMR Facility by the NSF (CHE9974921),
the Pardee Foundation, and the US Air Force (F49620-01-
1-0524) is gratefully acknowledged.
Supporting Information Available: Experimental pro-
1
cedures for the preparation of (+)-2, H NMR data for
configuration analysis and optical purity determination of
(+)-3, chiral HPLC chromatograms of 2, Mosher analysis
of (+)-1. This material is available free of charge via the
Internet at http://pubs.acs.org.
OL027033Z
Having established the absolute stereochemistry of (+)-1
from T. hawaiiensis unambiguously, we were then able to
(17) (a) Schwab, P.; France, M. B.; Ziller, J. W.; Grubbs, R. H. Angew.
Chem., Intl. Ed. Engl. 1995, 34, 2039-2041. (b) Schwab, P.; Grubbs, R.
H.; Ziller, J. W. J. Am. Chem. Soc. 1996, 118, 100-110. (c) Belderrain, T.
R.; Grubbs, R. H. Organometallics 1997, 16, 4001-4003.
(18) (a) Bazan, G. C.; Oskam, J. H.; Cho, H.-N.; Park, L. Y.; Schrock,
R. R. J. Am. Chem. Soc. 1991, 113, 6899-6907 and references therein..
(19) Crowe, W. E.; Goldberg, D. R.; Zhang, Z. J. Tetrahedron Lett. 1996,
37, 2117-2120.
(14) Nishikawa, T.; Shibuya, S.; Hosokawa, S.; Isobe, M. Synlett 1994,
485-486.
(15) Burova, S. A.; McDonald, F. E. J. Am. Chem. Soc. 2002, 124, 8188-
8189.
(16) Hoye, T. R.; Zhao, H. Org. Lett. 1999, 1, 1123-1125.
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