Total synthesis of (3R,9R,10R)-panaxytriol via tandem metathesis and metallotropic [1,3]-shift as a key step

Article abstract of DOI:10.1021/ol702651s

(Chemical Equation Presented) Enyne metathesis is unique for its capacity to carry out multiple bond formation in tandem fashion. Its combined use with metallotropic [1,3]-shift allowed for the development of a novel strategy for the total synthesis of a conjugated 1,3-diyne-containing natural product (3R,9R,10R)-panaxytriol.

Full text of DOI:10.1021/ol702651s

ORGANIC
LETTERS
2008
Vol. 10, No. 2
257-259
Total Synthesis of
(3R,9R,10R)-Panaxytriol via Tandem
Metathesis and Metallotropic [1,3]-Shift
as a Key Step
Eun Jin Cho† and Daesung Lee*
Department of Chemistry, UniVersity of Illinois at Chicago, 845 West Taylor Street,
Chicago, Illinois 60607
dsunglee@uic.edu
Received November 1, 2007
ABSTRACT
Enyne metathesis is unique for its capacity to carry out multiple bond formation in tandem fashion. Its combined use with metallotropic
[1,3]-shift allowed for the development of a novel strategy for the total synthesis of a conjugated 1,3-diyne-containing natural product (3R,9R,-
10R)-panaxytriol.
The most unique aspect of synthetic chemistry stems from
its capacity to create molecules crucial to addressing
problems ranging from fundamental science to human health.
The practical synthesis1 of these target molecules is contin-
gent upon the availability of effective synthetic methods, and
thus, the development of tandem reactions2 draws great deal
of attention as it induces a significant increase in molecular
complexity within a given step.
is juxtaposed with one or more metallotropic [1,3]-shift
followed by another RCM step.3 In this paper, we describe
a powerful tandem reaction sequence initiated by relay
metathesis,4 which is followed by metallotropic [1,3]-shift
and cross-metathesis,5 as a unique and efficient way for the
synthesis of a 1,3-diyne-containing natural compound.6
(3R,9R,10R)-Panaxytriol 1 was isolated as one of the
characteristic constituents of Panax ginseng C. A. Meyer in
1983.7 It exhibits inhibitory activity against a range of tumor
cell types, including human gastric adenocarcinoma (MK-
Recently, we have introduced a metathesis-based tandem
reaction sequence, where an enyne ring-closing metathesis
† University of WisconsinsMadison.
(3) (a) Kim, M.; Lee, D. J. Am. Chem. Soc. 2005, 127, 18024. (b) Hansen,
E. C.; Lee, D. Acc. Chem. Res. 2006, 39, 509. For a review of metallotropic
[1,3]-shift, see: (c) Lee, D.; Kim, M. Org. Biomol. Chem. 2007, 5, 3418.
(4) (a) Hansen, E. C.; Lee, D. Org. Lett. 2004, 6, 2035. (b) Hoye, T. R.;
Jeffrey, C. S.; Tennakoon, M. A.; Wang, J.; Zhao, H. J. Am. Chem. Soc.
2004, 126, 10210.
(1) Atom-economy: (a) Trost, B. M. Science 1991, 254, 1471. Step-
economy: (b) Trost, B. M. Acc. Chem. Res. 2002, 35, 695. (c) Wender, P.
A.; Bi, F. C.; Gamber, G. G.; Gosselin, F.; Hubbard, R. D.; Scanio, M. J.
C.; Sun, R.; Williams, T. J.; Zhang, L. Pure Appl. Chem. 2002, 74, 25. (c)
Wender, P. A.; Miller, B. L. Toward the Ideal Synthesis. In Organic
Synthesis: Theory and Application; JAI Press: London, 1993; Vol. 2, pp
27-66.
(5) A review on cross-metathesis, see: Connon, S. J.; Blechert, S. Angew.
Chem., Int. Ed. 2003, 42, 1900.
(2) (a) Ho, T.-L. Tandem Organic Reactions; Wiley: New York, 1992.
(b) Tietze, L. F. Chem. ReV. 1996, 96, 115. (c) Wasilke, J.-C.; Obrey, S. J.;
Baker, R. T.; Bazan, G. C. Chem. ReV. 2005, 105, 1001. (d) Nicolaou, K.
C.; Edmonds, D. J.; Bulger, P. G. Angew. Chem., Int. Ed. 2006, 45, 7134.
(6) For a review of naturally occurring polyynes, see: Shi, Shun, A. L.
K.; Tykwinski, R. R. Angew. Chem., Int. Ed. 2006, 45, 1034.
(7) Kitagawa, I.; Yoshikawa, M.; Yoshihara, M.; Hayashi, T.; Taniyama,
T. Yakugaku Zasshi. 1983, 103, 612.
10.1021/ol702651s CCC: $40.75
© 2008 American Chemical Society
Published on Web 12/13/2007

1),8 human breast carcinoma (breast M25-SF),9 and mouse
lymphoma (P388D1).10 The structure of panaxytriol was
established as heptadec-1-ene-4,6-diyne-3,9,10-triol in 1989,11
and its absolute configuration was determined as 3R,9R,-
10R by circular dichroism (CD) analysis12 and confirmed
by total syntheses.13
Scheme 2
Our strategy for the synthesis of 1 is outlined in Scheme
1. We envisioned that the main carbon framework of the
Scheme 1
metric dihydroxylation,17 which selectively took place on the
disubstituted trans-double bond of 8 in 95% yield. The
resulting diol was then protected as its acetonide by treatment
with 2,2-dimethoxypropane (cat. PTSA, THF) to give 9 in
98% yield. In turn, 9 was converted to enyne 10 in 93%
overall yield through deacetylation (DIBAL-H, THF,
-78 °C), desilylation (TBAF, 10 mol % of AcOH, THF),
and O-allylation (NaH, allyl bromide, DMF). Addition of a
small amount of acetic acid to the reaction in the desilyation
minimizes undesired side reactions that lead to extensive
decomposition. For the etherification of the subsequent allylic
alcohol, we found that preformation of alkoxide increased
the extent of the undesired intramolecular addition of the
alkoxide to the nearby triple bond. This undesired byproduct
could be suppressed by adding sodium hydride to the mixture
of the alcohol and allyl bromide. The elongation of enyne
10 to diyne 4 was achieved in 92% yield employing the
Cadiot-Chodkiewicz reaction14 with silylated bromoalkyne
7 followed by desilylation (TBAF, 10 mol % AcOH, THF).
With the key substrate 4 in hand, we explored the tandem
ring-closing metathesis, metallotropic [1,3]-shift, and cross-
metathesis. When 4 was treated with Grubbs’ second-
generation catalyst18 (Grubbs II, 10 mol %, CH2Cl2, 40 °C)
in the presence of 2.0 equiv of alkene 3, the expected product
2 was obtained in 61% yield as a mixture of Z/E-isomers
(5:1)4a,19 together with ruthenium alkylidene 11′ (10%). The
isolated complex 11′ could be turned over to 2 upon
treatment with 3, which implies that this complex is a
catalytically viable intermediate in the catalytic cycle. The
yield of 11′ was increased up to 40% with stoichiometric
amount of Grubbs complex. We speculate that the stability
target molecule could arise from a tandem reaction sequence
of relay metathesis, metallotropic [1,3]-shift, and cross-
metathesis with enediyne 4 in the presence of an excess
amount of external alkene 3. The intricate array of multiply
unsaturated functional groups in 4 could be orchestrated by
the recently developed regioselective Alder ene reaction of
multiyne 514 with terminal alkene 6 followed by alkyne
homologation via the Cadiot-Chodkiewicz reaction15 with
bromoalkyne 7.
The eight-step synthesis of endiyne 4 was initiated by the
Ru-catalyzed Alder ene reaction of silylated diyne 5 and
1-decene to provide enyne 8 in 81% yield (Scheme 2).16 The
required (9R,10R)-diol was installed by the Sharpless asym-
(8) Saita, T.; Katano, M.; Matsunaga, H.; Kouno, I.; Fujito, H.; Mori,
M. Bio. Pharm. Bull. 1995, 18, 933.
(9) Matsunaga, H.; Saita, T.; Naguo, F.; Mori, M.; Katano, M. Cancer
Chemother. Pharmacol. 1995, 35, 291.
(10) Kim, J. Y.; Lee, K. W.; Kim, S. H.; Wee, J. J.; Kim, Y. S.; Lee, H.
J. Planta Med. 2002, 68, 119.
(11) Matsunaga, H.; Katano, M.; Yamamoto, H.; Mori, M.; Takata, K.
Chem. Pharm. Bull. 1989, 37, 1279.
(12) Kovayashi, M.; Mahmund, T.; Umezome, T.; Wang, W.; Murakami,
N.; Kitagawa, I. Tetrahedron 1997, 53, 15691.
(13) Total Syntheses: (a) Lu, W.; Zheng, G.; Cai, J. Synlett 1998, 737.
(b) Lu, W.; Zheng, G.; Gao, D.; Cai, J. Tetrahedron 1999, 55, 7157. (c)
Gurjar, M. K.; Kumar, V. S.; Rao, B. V. Tetrahedron 1999, 55, 12563. (d)
Yadav, J. S.; Maiti, A. Tetrahedron 2002, 58, 4955. (e) Mayer, S. F.;
Steinreiber, A.; Orru, R. V. A.; Faber, K. J. Org. Chem. 2002, 67, 9115.
(f) Yun, H.; Danishefsky, S. J. J. Org. Chem. 2003, 68, 4519. (g) Yun, H.;
Chou, T.-C.; Dong, H.; Tian, Y.; Li, Y.; Danishefsky, S. J. J. Org. Chem.
2005, 70, 10375.
(14) (a) Cho, E. J.; Lee, D. J. Am. Chem. Soc. 2007, 129, 6692. For
reviews on ruthenium-catalyzed Alder ene reaction, see: (b) Trost, B. M.;
Frederiksen, M. U.; Rudd, M. T. Angew. Chem., Int. Ed. 2005, 44, 6630.
(c) Trost, B. M.; Toste, F. D.; Pinkerton, A. B. Chem. ReV. 2001, 101,
2067.
(17) (a) Sharpless, K. B.; Amberg, W.; Bennani, Y. L.; Crispino, G. A.;
Hartung, J.; Jeong, K.-S.; Kwong, H.-L.; Morikawa, Wang, K. Z.-M.; Xu,
D.; Zhang, X.-L. J. Org. Chem. 1992, 57, 2768. (b) Kolb, H. C.;
VanNieuwenhze, M. S.; Sharpless, K. B. Chem. ReV. 1994, 94, 2483.
(18) Scholl, M.; Ding, S.; Lee, C. W.; Grubbs, R. H. Org. Lett. 1999, 1,
953.
(19) Z-preference in cross-metathesis of enynes and acrylonitrile, see:
(a) Crowe, W. E.; Goldberg, D. R. J. Am. Chem. Soc. 1995, 117, 5162. (b)
Randl, S.; Gessler, S.; Wakamatsu, H.; Blechert, S. Synlett 2001, 430. (c)
Kang, B.; Kim, D.-h.; Do, Y.; Chang, S. Org. Lett. 2003, 5, 3041. (d) Kang,
B.; Lee, J. M.; Kwak, J.; Lee, Y. S.; Chang, S. J. Org. Chem. 2004, 69,
7661. (e) Love, J. A.; Morgan, J. P.; Trnka, T. M.; Grubbs, R. H. Angew.
Chem., Int. Ed. 2002, 41, 4035.
(15) (a) Marino, J. P.; Nguyen, H. N. J. Org. Chem. 2002, 67, 6841 and
Supporting Information. (b) Supporting Information of ref 3a for a slightly
modified reaction protocol.
(16) The transformation of 5 and 6 to 8 was reported in ref 13a.
258
Org. Lett., Vol. 10, No. 2, 2008

(low reactivity) of 11′ is the consequence of the low steric
pressure of the alkynyl group and the hydrogen on the
carbenic carbon, which ultimately lowers the rate of phos-
phine dissociation from the ruthenium center (Scheme 3).
The completion of total synthesis of (3R,9R,10R)-panax-
ytriol 1 was achieved in six steps from 2 as shown in Scheme
5. Removal of the acyl group of 2 (cis/trans ) 5:1) with
Scheme 5
Scheme 3
To make the synthetic sequence more convergent, the
Alder ene reaction was carried out with triyne 12 and
1-decene 6, providing diyne 13 in 70% yield (Scheme 4).20
DIBAL-H afforded allylic alcohol 18, which was converted
to the required hydroxyl group at C3 through epoxidation
followed by ring opening reaction. trans-18 was founded to
react much faster than the corresponding cis-isomer in the
Sharpless asymmetric epoxidation (SAE)23 leading to the
formation of a 2.8:1 mixture of epoxide 19 with mostly
recovered cis-18. To exploit the faster SAE reaction of trans-
18, the C2-C3 double bond of 18 was isomerized with
iodine,24 resulting in a 1.6:1 ratio of trans/cis isomers. The
Sharpless asymmetric epoxidation of this mixture provided
a 8.8:1 mixture of diasteromers 19 in 55% yield together
with 15% of unreacted cis-18. The conversion of the primary
alcohol to the corresponding iodoepoxide followed by its
reductive ring opening with Zn dust25 gave the (3R)-
secondary allylic alcohol. Finally, deprotection of the ac-
etonide provided (3R,9R,10R)-panaxytriol 1 the spectroscopic
data of which are identical to those reported for natural 1.
In conclusion, we have developed a novel strategy for a
total synthesis of (3R,9R,10R)-panaxytriol (1) based on the
tandem sequence of relay metathesis-metallotropic [1,3]-
shift-cross-metathesis. This powerful multiple bond-forming
reaction allowed an efficient synthesis of the target molecule
in 15 steps with 15% overall yield, highlighting its utility
for the synthesis of natural products with highly unsaturated
carbon skeletons.
Scheme 4
Through the standard sequence, 13 was elaborated to 15 via
intermediate 14. Unfortunately, due to the facile formation
of the cyclic ether in basic conditions,21 the desired allyl ether
4 could not be prepared from 15, which, however, could be
converted to the corresponding allyl silyl ether 17 under less
basic conditions. Upon isolation, 17 was directly subjected
to the metathesis conditions without purification due to its
instability, yielding 2 in 40% overall yield.22
Acknowledgment. We thank the NIH (CA106673) for
financial support of this work as well as the NSF and NIH
for NMR and mass spectrometry instrumentation.
Supporting Information Available: General procedures
and characterization data of new compounds. This material
is available free of charge via the Internet at http://pubs.acs.org.
OL702651S
(20) The transformation of 12 and 6 to 13 was reported previously in
ref 13a.
(21) For the addition of alkoxide to an alkyne followed by [3,3]-
sigmatropic rearrangement, see: (a) Li, X.; Ovaska, T. V. Org. Lett. 2007,
9, 3837. (b) Li, X.; Kyne, R. E.; Ovaska, T. V. Org. Lett. 2006, 8, 5153.
(c) Martinez, I.; Alford, P. E.; Ovaska, T. V. Org. Lett. 2005, 7, 1133.
(22) To the best of our knowledge, this is the first example of using
silyl ether as a relay tether.
(23) (a) Katsuki, T.; Sharpless, K. B. J. Am. Chem. Soc. 1980, 102, 5974.
(b) Bellina, F.; Carpita, A.; Mannocci, L.; Rossi, R. Eur. J. Org. Chem.
2004, 2610.
(24) Giacomelli, G.; Lardicci, L.; Saba, A. J. Chem. Soc., Perkin Trans.
1 1978, 314.
(25) Bernet, B.; Vasella, A. HelV. Chim. Acta 1979, 62, 1990.
Org. Lett., Vol. 10, No. 2, 2008
259