Synthesis of allocolchicines using sequential ring-closing enyne metathesis - Diels - Alder reactions

Article abstract of DOI:10.1021/ol0630548

New allocolchinoids having functionality in the C ring at position C10 or C11 have been synthesized using the enyne ring-closing metathesis (RCM) reaction for construction of the seven-membered ring and a Diels-Alder-aromatization sequence for the elabora

Full text of DOI:10.1021/ol0630548

ORGANIC
LETTERS
2007
Vol. 9, No. 4
715-718
Synthesis of Allocolchicines Using
Sequential Ring-Closing Enyne
Metathesis−Diels−Alder Reactions
Franc¸
ois-Didier Boyer† and Issam Hanna*,‡
Unite´ de Chimie Biologique, INRA, F-78026 Versailles, France, and Laboratoire de
Synthe`se Organique associe´ au CNRS, Ecole Polytechnique, F-91128 Palaiseau,
France
hanna@poly.polytechnique.fr
Received December 18, 2006
ABSTRACT
New allocolchinoids having functionality in the C ring at position C10 or C11 have been synthesized using the enyne ring-closing metathesis
(RCM) reaction for construction of the seven-membered ring and a Diels−Alder−aromatization sequence for the elaboration of the aromatic
ring C.
Colchicine (1), present as the major alkaloid in Colchicum
autumnale, is an old drug used in medicine in acute gout
attacks and in familial Mediterranean fever. It is also effective
in chronic myelocytic leukemia, but the therapeutic effects
are only observed at toxic or nearly toxic doses. The
biological activity of 1 depends mainly on its selective
binding to tubulin which disturbs the microtubule-dependent
functions in the cell and thereby inhibits cellular mitosis.1,2
A significant development in cancer chemotherapy was the
discovery that allocolchinoids, with a benzene ring in place
of the tropolone ring, also arrest mitosis by inhibiting tubulin
polymerization. Examples include natural allocolchicine 2,
N-acetylcolchinol 3, and its methyl ether which bind to
tubulin more strongly than colchicine itself.3
For a long time, allocolchinoids were obtained by trans-
formation of colchicine itself, thus limiting the range of
structural variations. Recently, the total syntheses of various
allocolchinoids, including 2 and 3, have been published.4
Although most approaches have a strategy involving
construction of the seven-membered ring by an intramolecu-
lar biaryl-coupling reaction (AC f ABC approach), a
different route was developed by Wulff and co-workers
which distinguished itself by constructing the aromatic ring
C by a Diels-Alder reaction on a suitably substituted diene
(3) For a review on microtubule-targeted drugs, see: Jordan, M. A.;
Wilson, L. Nat. ReV. Cancer 2004, 59, 163.
† Unite´ de Chimie Biologique, INRA.
‡ Ecole Polytechnique.
(4) For recent references, see: (a) Besong, G.; Jarowski, K.; Kocienski,
P. J.; Sliwinski, E.; Boyle, F. T. Org. Biomol. Chem. 2006, 4, 2193 and
references therein. (b) Leblanc, M.; Fagnou, K. Org. Lett. 2005, 7, 2849.
Bu¨ttner, F.; Bergemann, S.; Gue´nard, D.; Gust, R.; Seitz, G.; Thoret, S.
Bioorg. Med. Chem. 2005, 13, 3497. (c) Wu, R. T.; Chong, J. M. Org.
Lett. 2006, 8, 15.
(1) For a summary of the synthesis and biological activity of colchicine
and allocongeners, see: Brossi, A. J. Med. Chem. 1990, 33, 2311 and
references therein.
(2) For a recent review on the total syntheses of colchicines, see:
Graening, T.; Schmalz, H.-G. Angew. Chem., Int. Ed. 2004, 43, 3230.
10.1021/ol0630548 CCC: $37.00
© 2007 American Chemical Society
Published on Web 01/24/2007

containing the seven-membered ring (AB f ABC ap-
proach).5 In all these approaches, the allocolchinoids de-
scribed bear functionalities at the C9 position of the C ring.6
Here, we report a versatile synthesis of allocolchicines 4 and
5 (Figure 1), analogues of 2 having the ester group located
(RCM) reaction on enyne 10.8,9 This precursor would be
obtained from the cheap and commercially available acid
11.
In accord with our plan, the synthesis commenced with
conversion of the acid functionality in 11 into the methyl
ester and subsequent formylation using dichloromethyl
methyl ether in the presence of SnCl4 to afford aldehyde 12
(Scheme 2) which was alkynylated with lithiated trimeth-
Scheme 2
Figure 1.
at positions C11 and C10, respectively.7 Our retrosynthetic
analysis is outlined in Scheme 1. Thus, target compounds 4
Scheme 1. Retrosynthetic Analysis
ylsilylacetylene. The resulting propargylic alcohol was
converted into its tert-butyldimethylsilyl-protected derivative
under standard conditions. To elaborate the “upper” carbon
chain, ester 13 was reduced with LiAlH4 and the resulting
primary alcohol was treated with PDC to furnish aldehyde
14 which was converted into enyne 15 using a Wittig reaction
followed by selective desilylation with K2CO3 in MeOH.
Treatment of 15 with 5% of the second-generation Grubbs
catalyst10 in refluxing dichloromethane for 4 h smoothly
afforded diene 16 in 92% yield. Complete deprotection of
the tertiary alcohol was achieved by stirring 16 with 1 M
(5) Voroguishin, A. V.; Predeus, A. V.; Wulff, W. D.; Hansen, H.-G. J.
Org. Chem. 2003, 68, 5826.
(6) The colchicine numbering has been used throughout this paper.
(7) To our knowledge, although compound 4 is unknown, only one report
has hitherto been published describing 5 by transformation of colchicine:
Vaterlaus, B. P.; Muller, G. Bull. Soc. Chim. Fr. 1957, 1329.
(8) For recent reviews on enyne metathesis, see: (a) Mori, M. In
Handbook of Metathesis; Grubbs, R. H., Ed.; Wiley-VCH: Weinheim, 2003;
Vol. 2, p 176. (b) Poulsen, C. S.; Madsen, R. Synthesis 2003, 1. (c) Diver,
S. T.; Giessert, A. J. Chem. ReV. 2004, 104, 1317.
and 5 were to be obtained by direct reductive amination of
ketones 6 and 7 which could be prepared by a Diels-Alder-
aromatization sequence from the same intermediate 9. This
diene could be traced back to 8 (R ) H) which, in turn,
could potentially be derived from a ring-closing metathesis
(9) For a related example, see: Royer, F.; Villain, C.; Elkaim, L.;
Grimaud, L. Org. Lett. 2003, 5, 2007.
(10) Scholl, M.; Ding, S.; Lee, C. W.; Grubbs, R. H. Org. Lett. 1999, 1,
953.
716
Org. Lett., Vol. 9, No. 4, 2007

tetra-n-butylammonium fluoride (TBAF) solution in THF for
2 days at room temperature.
With the bicyclic conjugated diene 17 in hand, we turned
next to construction of the aromatic ring.
148 °C). It is worth noting that allocolchicinoids 19 and 20
occurred as a mixture of atropoisomers which were not only
characterized by different 1H and 13C NMR spectra but also
separable on silica gel column chromatography. For these
compounds, the barrier for interconversion is so high that
the individual conformers can be separated at room temper-
ature.14
To place the ring C in the correct position by a Diels-
Alder reaction, rearrangement of the allylic alcohol had to
be achieved at this stage. To this end, treatment of 17 under
Dauben’s tertiary allylic rearrangement conditions was
considered.11a When a solution of 17 in dichloromethane was
stirred with 2 equiv of pyridinium chlorochromate (PCC) at
room temperature for 30 min, dienone 9 was obtained as
the sole product in 55% yield.11b Sequential reduction of 9
under Luche conditions12 and protection of the resulting
alcohol as its tert-butyldimethylsilyl ether led to 18 in high
yield (Scheme 3).
To shorten the synthesis, the Diels-Alder reaction of
methyl propiolate was attempted directly on dienone 9. We
were pleased to observe that this reaction occurred readily
under the same conditions affording only one regioisomer
as with diene 18. Treatment of the crude cycloadduct with
DDQ led to 7 in 85% overall yield. By this method, the
synthesis of allocolchicinoid 7 was achieved in two steps
from ketone 9 instead of in six for the previous sequence.
Reductive amination of ketone 7, using ammonium acetate
and sodium cyanoborohydride,15 followed by N-acylation of
the resulting amino ester produced 4 (mp 206-209 °C) in
Scheme 3
1
69% yield as a 2:1 mixture of rotamers as shown by H
NMR.
Next, we turned to the synthesis of allocolchicinoids
bearing functionality at C-10. On the basis of the regiose-
lectivity observed above, we reasoned that methyl â-ni-
troacrylate 2116 would provide the reverse regiochemistry
relative to that with methyl propiolate from the Diels-Alder
reaction with diene 18. Indeed, 21 readily reacted with diene
9 at room temperature affording cycloadduct 22 in 97%
yield. NMR spectra revealed that 22 is a mixture of two
stereoisomers (4:1 ratio) confirming the complete regiose-
lectivity of this reaction (Scheme 4).17 The elimination of
Scheme 4
The Diels-Alder reaction of diene 18 was first performed
with methyl propiolate. When a mixture of 18 and an excess
of the dienophile was heated in toluene at 115 °C for 24 h,
only one regioisomer was obtained as indicated by NMR
analysis (Scheme 3). The regioselectivity of this cycloaddi-
tion was confirmed in the next step: DDQ aromatization of
the crude cycloadduct afforded the protected allocolchicinoid
19 as only one isomer. It is likely that electronic factors
prevail upon the steric interaction in 18 and are responsible
for this complete regiocontrol. Deprotection by TBAF led
to alcohol 20, which was oxidized with Dess-Martin
periodinane13 to give ketone 7 as a white solid (mp 147-
nitrous acid using DBU and the subsequent aromatization
by DDQ furnished ketone 6 as the sole product in 50%
overall yield. As for ketone 7, reductive amination of
compound 6, followed by N-acylation of the resulting amino
ester produced 5 (mp 181-183 °C) in 57% yield as a 2:1
(11) (a) Dauben, W. G.; Michno, D. M. J. Org. Chem. 1977, 42, 682.
(b) Although the oxidative rearrangement of tertiary alcohols with PCC is
widely used in synthesis, the application of such a reaction to secondary
alcohols is unprecedented to our knowledge.
(12) Gemal, A. L.; Luche, J. L. J. Am. Chem. Soc. 1981, 103, 5454.
(13) (a) Dess, D. B.; Martin, J. C. J. Org. Chem. 1983, 48, 4155. (b)
Meyer, S. D.; Schreiber, S. L. J. Org. Chem. 1994, 59, 7549.
1
mixture of rotamers as shown by H NMR.
Org. Lett., Vol. 9, No. 4, 2007
717

In conclusion, we have achieved the total syntheses of (()-
allocolchicines 4 and 5 using the enyne ring-closing me-
tathesis (RCM) reaction for the construction of the seven-
membered ring and a Diels-Alder-aromatization sequence
for the elaboration of the aromatic ring C. These new
allocolchicines will be subjected to a tubulin binding assay
to gain some indication of their ability to function as
antimitotic agents; the results will be reported in due course.
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.
(14) For reviews on atropoisomerism, see: (a) Oki, M. In Topic in
Stereochemistry; Alinger, N. L., Eliel, E. L., Wilen, S. H., Eds.; Wiely:
New York, 1983; Vol. 14, pp 1-82. (b) Eliel, E. L.; Wilen, S. H.
Stereochemistry of Organic Compounds; Wiley: New York, 1994; p 1142.
For a recent review on atroposelective synthesis of axially chiral biaryl
compounds, see: Bringmann, G.; Mortimer, A. J. P.; Keller, P. A.; Gresser,
M. L.; Garner, G.; Breuning, M. Angew. Chem., Int. Ed. 2005, 44, 5384
and references cited therein.
OL0630548
(16) Methyl â-nitroacrylate was prepared according to the procedure
described by Pritchard et al.: Pritchard, R. G.; Stoodly, R. J.; Yuen, W.-H.
Org. Biomol. Chem. 2005, 3, 162.
(17) For selected examples on the use of methyl and ethyl â-nitroacrylate
as dienophiles in the Diels-Alder reaction, see: Danishefsky, S.; Prisbylla,
M. P.; Hiner, S. J. Am. Chem. Soc. 1978, 100, 2918. Ref 5 and references
cited therein.
(15) Borch, R. F.; Bernstein, M. D.; Durst, H. D. J. Am. Chem. Soc.
1971, 93, 2829. Banwell, M. G.; Fam, M.-A.; Gable, R. W; Hamel, E.
Chem. Commun. 1994, 2647. Ref. 5.
718
Org. Lett., Vol. 9, No. 4, 2007