Synthesis of the tricyclic core of colchicine via a dienyne tandem ring-closing metathesis reaction

Article abstract of DOI:10.1021/ol070708j

The synthesis of the tricyclic framework of colchicine has been achieved using a tandem ring-closing metathesis reaction of dienynes as the key step. In this process, both seven-membered rings B and C were formed in one step. Oxidation of tertiary allylic

Full text of DOI:10.1021/ol070708j

ORGANIC
LETTERS
2007
Vol. 9, No. 12
2293-2295
Synthesis of the Tricyclic Core of
Colchicine via a Dienyne Tandem
Ring-Closing Metathesis Reaction
Franc¸
ois-Didier Boyer† and Issam Hanna*,‡
Unite´ de Chimie Biologique, AgroParisTech, INRA, F-78026 Versailles, and
Laboratoire de Synthe`se Organique associe´ au CNRS, Ecole Polytechnique,
F-91128 Palaiseau, France
hanna@poly.polytechnique.fr
Received March 22, 2007
ABSTRACT
The synthesis of the tricyclic framework of colchicine has been achieved using a tandem ring-closing metathesis reaction of dienynes as the
key step. In this process, both seven-membered rings B and C were formed in one step. Oxidation of tertiary allylic alcohol derived from the
tandem metathesis product furnished an intermediate in the total synthesis of colchicine.
Colchicine (1), present as the major alkaloid in Colchicum
autumnale, is an old drug used in medicine for acute gout
attacks and familial Mediterranean fever. It is also effective
in treating chronic myelocytic leukemia, but the therapeutic
effects are only observed at toxic or nearly toxic doses.1
Colchicine has also long been known for its remarkable
antimitotic activity which results from its specific binding
to tubulin preventing microtubule assembly, spindle forma-
tion, and consequently cell division.2 Although its high
toxicity has precluded clinical utilization as a potential
antitumor agent, it remains an important biochemical probe.
Owing to its biological importance and unique structure,
colchicine has been the target of a large number of synthetic
studies, culminating in several elegant total syntheses.3 One
of the more difficult features of the colchicine synthesis is
undoubtedly the construction of the tropolone C-ring, which
is condensed to a second seven-membered ring (B). The
common feature of early syntheses is that they adopt a
stepwise linear approach to the construction of the tricyclic
ring system (i.e., A f AB f ABC or A f AC f ABC).
Recently, Schmalz and co-workers described a new strategy
based on the simultaneous construction of the rings B and
C by a Rh-tiggered intramolecular [3 + 2] cycloaddition
(A f ABC approach). The resulting oxabicyclic adduct was
then converted to the desired tropolone ring system.4 In a
conceptually similar approach, we herein describe a new
entry to the colchicine carbon skeleton using a tandem
ruthenium-catalyzed dienyne metathesis as a key step.
The tandem ring-closing metathesis (RCM) reaction of
dienynes5 has proved to be a powerful tool for the construc-
† Unite´ de Chimie Biologique, AgroParisTech.
‡ Ecole Polytechnique.
(1) For a summary of the synthesis and biological activity of colchicine
and allo congeners see: Brossi, A. J. Med. Chem. 1990, 33, 2311 and
references therein.
(2) For a review on microtubule-targeted drugs see: Jordan, M. A.;
Wilson, L. Nat. ReV. Cancer 2004, 59, 163.
(3) For a recent review on the total syntheses of colchicines see:
Graening, T.; Schmalz, H.-G. Angew. Chem., Int. Ed. 2004, 43, 3230.
(4) Graening, T.; Friedichsen. W.; Lex, J.; Schmalz, H.-G. Angew. Chem.,
Int. Ed. 2002, 41, 1524. Graening, T.; Bette, V.; Neudo¨rfl, J.; Lex, J.;
Schmalz, H.-G. Org. Lett. 2005, 7, 4317.
10.1021/ol070708j CCC: $37.00
© 2007 American Chemical Society
Published on Web 05/18/2007

tion of polycyclic ring systems from acyclic starting material.
In this highly efficient process, two rings are formed in a
single step generally in high yield. Depending on the length
of the alkene chains, the newly generated bicyclic systems
may contain five, six, seven, or even eight-membered rings.6
In previous reports, we described the application of this
technique for the preparation of various fused bicyclic
systems containing medium-sized rings including a concise
formal synthesis of guanacastepene A.7 Our interest in the
synthesis of colchicine was therefore stimulated by the
possibility that the (6,7,7)-tricyclic framework could be
constructed by using a cascade RCM reaction starting from
a suitably functionalized dienyne such as 4.
by tandem RCM,8 this process should be facilitated by two
favorable factors:9 first, presence of a pre-existing aromatic
ring bearing the alkene and alkyne moieties at adjacent
positions makes the enyne RCM easier and, second, the
Thorpe-Ingold effect of a quaternary carbon center bearing
the trimethylsilyloxy group. The RCM reaction precursor 4
can be traced back to ketone 5 which in turn could be
synthesized from the cheap and commercially available acid
6.
According to this plan, the synthesis commenced with
converting the acid functionality in 6 into the methyl ester
and subsequent formylation using dichloromethyl methyl
ether in the presence of SnCl4 to afford aldehyde 710 (Scheme
2). This aldehyde was treated with the Grignard reagent 8
Our retrosynthetic analysis (Scheme 1) is based on the
Scheme 1. Retrosynthetic Analysis
Scheme 2. Formation of Dienyne 14
recognition that the formation of a metal carbene on dienyne
4 should first occur at the least hindered terminal alkene,
which can cyclize to give the intermediate 3. This intermedi-
ate could then undergo a second RCM reaction to give the
desired tricyclic framework 2. Although there was no
precedent for the construction of a (7,7)-bicyclic ring system
generated from 6-bromo-2-methyl-hex-2-ene11 to afford
alcohol 9. Reduction of 9 with lithium aluminum hydride
(LiAlH4) furnished diol 10 which was oxidized with Dess-
Martin’s periodinane to furnish ketoaldehyde 11. Treatment
of 11 with methylene triphenylphosphorane resulted in a
selective olefination of the aldehyde function affording
(5) (a) Mori, M. AdV. Synth. Catal. 2007, 349, 121. (b) Diver, S. T.;
Giessert, A. J. Chem. ReV. 2004, 104, 1317.
(6) For selected examples of synthesis of polycyclic systems by tandem
metathesis of dienynes, see: (a) Zuercher, W. J.; Scholl, M.; Grubbs, R.
H. J. Org. Chem. 1998, 63, 4291. (b) Kim, S.-H.; Zuercher, W. J.; Bowden,
N. B.; Grubbs, R. H. J. Org. Chem. 1996, 61, 1073. (c) Codesido, E. M.;
Castedo, L.; Granja, J. R. Org. Lett. 2001, 3, 1483. (d) Shimizu, K.;
Takimoto, M.; Mori, M. Org. Lett. 2003, 5, 2323. (e) Garcia-Fandino, R.;
Codesido, E. M.; Sobarzo-Sanchez, E.; Castedo, L.; Granja, J. R. Org. Lett.
2004, 6, 193. (f) Kaliappan, K. P.; Nandurdikar, R. S. Org. Biomol. Chem.
2005, 3, 3613. (g) Gonzalez, A.; Dominguez, G.; Castells, J. P. Tetrahedron
Lett. 2005, 46, 7267.
(8) Attempts to construct fused 7,7-bicyclic compounds from acyclic
dienynes by tandem RCM failed (see ref. 7e).
(9) Jung, M. E.; Piizzi, G. Chem. ReV. 2005, 105, 1735.
(10) McBride, B. J.; Garst, M. E. Tetrahedron 1993, 49, 2839.
(11) 6-Bromo-2-methyl-hex-2-ene was prepared in three steps from
γ-butyrolactone: reduction with DIBAH followed by Wittig reaction and
bromation of the resulting primary alcohol. For details see Supporting
Information.
(7) (a) Boyer, F.-D.; Hanna, I.; Ricard, L. Org. Lett. 2001, 3, 3095. (b)
Boyer, F.-D.; Hanna, I. Tetrahedron Lett. 2002, 43, 7469. (c) Boyer, F.-
D.; Hanna, I.; Ricard, L. Org. Lett. 2004, 6, 1817. (d) Boyer, F.-D.; Hanna,
I. Eur. J. Org. Chem. 2006, 471. (e) Boyer, F.-D.; Hanna, I. J. Organomet.
Chem. 2006, 691, 5181.
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Org. Lett., Vol. 9, No. 12, 2007

ketone 5 in 41% yield over three steps. At this stage, we
planned to prepare propargylic alcohol 14 directly from 5
by addition of a metal acetylide. Unfortunately, all attempts
using ethynyl magnesium bromide, lithium acetylide, or other
nucleophiles prepared from these reagents and cerium(III)
chloride gave only traces of the desired product or left the
starting ketone unchanged. It is likely that both steric and
electronic factors are responsible for this lack of reactivity.
Finally, propargylic alcohol 14 was obtained from 5 using a
three-step sequence as indicated in Scheme 2. One-carbon
homologation of ketone 5 was achieved by treatment with
trimethylsilyl cyanide (TMSCN) in the presence of zinc
iodide to afford nitrile 12 (87% yield) which was reduced
with diisobutylaluminum hydride (DIBALH) to give alde-
hyde 13 (80% yield).12 Treatment of 13 with dimethyl
1-diazo-2-oxopropylphosphonate (the Ohira reagent)13 in the
presence of K2CO3 in MeOH led to the desired propargylic
alcohol 14 albeit in low yield (24-31%). This alcohol was
converted into its trimethylsilyl-protected derivative 4 by
treatment with 1-(trimethylsilyl)imidazole (TMSIm) at 50
°C and was used without purification in the next step.
When the crude dienyne 4 was treated with 20% of
Grubbs’ second-generation catalyst 1514 in refluxing dichlo-
romethane for 4 h, the tandem RCM reaction took place
affording the tricyclic conjugated diene 16 in 74% yield for
the two steps (Scheme 3). Unlike its precursor 4, this
of pyridinium p-toluenesulfonate (PPTS), allylic rearrange-
ment took place affording methyl ether 18 in high yield
(Scheme 4).
Scheme 4. Formation of the Wenkert Intermediate 19
Next, oxidative rearrangement of tertiary alcohol 17,
obtained by desilylation of 16, was attempted.15 When a
solution of 17 in dichloromethane was stirred with 2 equiv
of pyridinium chlorochromate (PCC) in the presence of
molecular sieves of 4 A at room temperature for 2 h, dienone
18 was isolated in 38% yield along with epoxide 20 (12%)
as a mixture of two isomers. Dienone 19, described by
Wenkert and co-workers16 in the synthesis of an advanced
colchicine intermediate, was transformed by catalytic hy-
drogenation into enone 21 which is a key intermediate in
the Nakamura17 total synthesis of colchicine.
Scheme 3. Formation of Tricyclic Compound 16
In conclusion, we have shown for the first time that the
tricyclic core of colchicine can be constructed by dienyne
ring-closing metathesis. In this process, both seven-memberd
rings B and C were formed in one step: formation of the
seven-membered ring B by enyne RCM occurred first,
followed by closure of the second seven-membered ring by
olefin RCM. Our route has the added benefit of installing
the desired oxygen functionalities at C-7 position furnishing
an advanced colchicine intermediate. Currently, we are
focusing on the completion of the synthesis of colchicine.
compound is stable and was isolated as a pure compound
by silica gel column chromatography. It is worth noting that
attempts to achieve the ring-closing metathesis reaction on
alcohol 14 failed. The starting dienyne was recovered
unchanged.
With the tricylic product 16 in hand, we turned next to
the construction of a colchicine intermediate bearing an
oxygen functionality at C-7. When a solution of trimethylsilyl
ether 16 in ether was treated with methanol in the presence
Supporting Information Available: Experimental pro-
cedures, characterization data, and 1H and 13C NMR spectra
for all new compounds. This material is available free of
charge via the Internet at http://pubs.acs.org.
(12) To get the indicated yield, it is important to observe the following
work up. After the completion of the reaction, silica gel was added at -70
°C, and the reaction mixture was allowed to warm to 0 °C. The crude
aldehyde was isolated by filtration and was purified by flash column
chromatography. Otherwise, treatment of the reaction mixture with Roch-
elle’s salt (potassium and sodium tartrate solution) resulted in the complete
degradation of the product.
(13) (a) Ohira, S. Synth. Commun. 1989, 19, 561. (b) For a review see:
Eymery, F.; Iorga, B.; Savignac, P. Synthesis 2000, 185. (c) Roth, G. J.;
Liepold, B.; Muller, S. G.; Bestmann, H. J. Synthesis 2004, 59.
(14) Scholl, M.; Ding, S.; Lee, C. W.; Grubbs, R. H. Org. Lett. 1999, 1,
953.
OL070708J
(15) Dauben, W. G.; Michno, D. M. J. Org. Chem. 1977, 42, 682.
(16) Wenkert, E.; Kim, H.-S. In Studies in Natural Products Chemistry;
Atta-ur-Rhaman, Ed.; Elsevier: Amsterdam, The Netherlands, 1989; Vol.
3, Part B, p 287.
(17) (a) Nakamura, T.; Murase, Y.; Hayashi, R.; Endo, Y. Chem. Pharm.
Bull. 1962, 10, 281. (b) Sunugawa, G.; Nakamura, T.; Nakazawa, J. Chem.
Pharm. Bull. 1962, 10, 291. (c) Nakamura, T. Chem. Pharm. Bull. 1962,
10, 299.
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