Total synthesis of (-)-colchicine via a Rh-triggered cycloaddition cascade

Article abstract of DOI:10.1021/ol051316k

(Chemical Equation Presented) A synthesis of the antimitotic alkaloids (-)-colchicine and (-)-isocolchicine is reported. Important steps are (a) enantioselective transfer-hydrogenation of an alkynone, (b) iodine/magnesium exchange with subsequent aromatic

Full text of DOI:10.1021/ol051316k

ORGANIC
LETTERS
2005
Vol. 7, No. 20
4317-4320
Total Synthesis of (
Rh-Triggered Cycloaddition Cascade
−)-Colchicine via a
Timm Graening, Virginie Bette, Jo
1rg Neudo1rfl, Johann Lex, and
Hans-Gunther Schmalz*
1
UniVersita¨t zu Ko¨ln, Greinstrasse 4, D-50939 Ko¨ln, Germany
schmalz@uni-koeln.de
Received June 6, 2005
ABSTRACT
A synthesis of the antimitotic alkaloids (
hydrogenation of an alkynone, (b) iodine/magnesium exchange with subsequent aromatic acylation, (c) Rh-catalyzed transformation of an
-diazoketone into an oxatetracyclic key intermediate through intramolecular [3 2]-cycloaddition of an in situ generated carbonyl ylide, and
−)-colchicine and (−)-isocolchicine is reported. Important steps are (a) enantioselective transfer-
r
+
(d) regioselective conversion of the cycloadduct into a tropolone derivative. The new synthetic strategy opens an efficient enantioselective
access to colchicine and structural analogues.
Colchicine (1), the major alkaloid and active principle of
the meadow saffron (Colchicum autumnale L.), is an
important antimitotic agent.1 Like other compounds strongly
binding to tubulin, colchicine and structural analogues are
of interest, for instance, as vascular targeting2 and apoptosis-
inducing agents.3
For 50 years, colchicine has been a prominent target
molecule in natural product synthesis, and a considerable
number of very distinct synthetic approaches have been
elaborated.4 However, the search for efficient and general
schemes also opening flexible entries to structural analogues
of 1 still remains a challenging goal, especially with respect
to the construction of the annulated tropolone substructure.
We have recently disclosed a new strategy for the synthesis
of the colchicine skeleton based on the retrosynthetic analysis
sketched in Scheme 1.5 As a central feature, an oxatetracyclic
compound of type 2 serves as a key intermediate, which can
be traced back to a diazoketone of type 4. The idea was to
generate a carbonyl ylide 3, which then undergoes an
intramolecular 1,3-dipolar cycloaddition with the alkyne side
chain in a domino-type process. This way, both seven-
membered rings B and C are formed in one step with
concomitant installation of the oxygen functions in positions
C(9) and C(10). Moreover, the intramolecular mode of the
cycloaddition step would permit the use of an unactivated
dipolarophile and thus allow for the installation of the C(7)
stereocenter prior to cyclization.
(1) (a) Boye´, O.; Brossi, A. In The Alkaloids; Brossi, A., Cordell, G. A.,
Eds.; Academic Press: San Diego, 1992; Vol. 41, p 125. (b) Le Hello, C.
In The Alkaloids; Cordell, G. A., Ed.; Academic Press: San Diego, 2000;
Vol. 53, Chapter 5.
(2) Soltau, J.; Drevs, J. IDrugs 2004, 7, 380.
(3) A few recent examples: (a) Cervinka, M.; Cerman, J.; Rudolf, E.
Cancer Detect. PreV. 2004, 28, 214. (b) Kristensen, B.; Noer, H.;
Gramsbergen, J. B.; Zimmer, J.; Noraberg, J. Brain Res. 2003, 964, 264.
(c) Nakagawa-Yagi, Y.; Choi, D. K.; Ogane, N.; Shimada, S. I.; Seya, M.;
Momoi, T.; Ito, T.; Sakaki, Y. Brain Res. 2001, 909, 8. (d) Zhang, S. X.;
Fengs, J.; Kuo, S. C.; Brossi, A. J. Med. Chem. 2000, 43, 167.
(4) Most recent colchicine syntheses: (a) Banwell, M. G. Pure Appl.
Chem. 1996, 68, 539. (b) Lee, J. C.; Jin, S.-j.; Cha, J. J. Org. Chem. 1998,
63, 2804. For a recent review on the total synthesis of colchicine, see: (c)
Graening, T.; Schmalz, H.-G. Angew. Chem., Int. Ed. 2004, 43, 3230.
In our first communication, we have demonstrated the
general feasibility of this concept by synthesizing a com-
(5) Graening, T.; Friedrichsen, W.; Lex, J.; Schmalz, H.-G. Angew.
Chem., Int. Ed. 2002, 41, 1524. The intention to apply the same strategy
for a colchicine total synthesis was put forward after our first disclosure:
McMills, M.; Wright, D. L.; Weekly, R. M. Synth. Commun. 2002, 32,
2417.
10.1021/ol051316k CCC: $30.25
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subjected to an enantioselective transfer hydrogenation using
Noyori’s Ru-catalyst (R,R)-7 in 2-propanol6 to afford the
propargylic alcohol 8 in virtually enantiopure form (>99%
ee, 96% yield). The absolute configuration of 8 was
confirmed by means of X-ray crystallography and is in
agreement with the expected selectivity. After protection of
the hydroxy group as a tert-butyldimethylsilyl ether (9), the
succinoyl side chain was introduced through iodine/
magnesium exchange under Knochel conditions7,8 and sub-
sequent addition of succinic anhydride. During workup with
K2CO3/MeOH, the acetylenic trimethylsilyl group was
cleaved off and the oxocarboxylic acid 10 was obtained in
good overall yield. In situ activation of the carboxylic acid
function of 10 as a pyrocarbonate followed by reaction with
diazomethane afforded the R-diazoketone 11.9
Scheme 1. Retrosynthetic Analysis
The key cycloaddition was then achieved by slowly adding
a solution of 11 to an intensely stirred suspension of Rh2-
(OAc)4 (3 mol %) in refluxing toluene. Under these condi-
tions, the key intermediate 12 was obtained in 64% yield
with complete diastereoselectivity (1H NMR). The relative
configuration of 12 was established by NOE experiments
and confirmed by X-ray crystallography, and its enantiomeric
purity (99% ee) was verified by HPLC10 using a sample of
the deprotected derivative 13. The remarkable transformation
of 11 to 12 is assumed to be initiated by formation of an
electrophilic Rh-carbene, which is attacked by the benzylic
ketone to form a reactive carbonyl ylide 3 (Scheme 1). This
1,3-dipole is then trapped by intramolecular cycloaddition
with the tethered alkyne.11 It is noteworthy that this reaction
pound related to 2 in the racemic series.5 We here disclose
the completion of the synthesis of both colchicine and
isocolchicine in the nonracemic series. In particular, we
describe possibilities for the conversion of 2 into tropolones
through selective opening of the oxa-bridge and subsequent
functionalization.
An optimized sequence for the enantioselective synthesis
of advanced colchicine precursors following the above-
mentioned strategy is shown in Scheme 2. At first, the readily
available bifunctional building block 55 was reacted with
lithium trimethylsilylacetylide to give the sensitive alkynone
6 in high yield. The very pure crude product was then
Scheme 2
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Org. Lett., Vol. 7, No. 20, 2005

could be successfully performed because an analogous Rh-
catalyzed 7-7 cyclization of a simple (configurationally
unrestrained) model system was reported to have failed.12
Having achieved the synthesis of 12 containing the
complete carbon skeleton of colchicine, the next goal was
to perform the further functionalization of ring C into the
desired tropolone system. For this purpose, we envisioned
that the oxa-bridge would be amenable to a regioselective
cleavage in the benzylic position.13,14
Scheme 4
In a first experiment carried out in the racemic series, we
reacted rac-12 with Et2AlCl in dichloromethane to obtain
the tropone rac-14 as the only isolated product. While this
represents a very convenient access to such tropone ana-
logues of colchicine, the loss of the second oxygen substitu-
ent at ring C prompted us to search for an alternative way
for the conversion of 12. To avoid dehydratization, which
obviously took place subsequently to the opening of the oxa-
bridge during the formation of rac-14, we first reduced the
keto functionality of 12 using L-selectride in THF. The
configuration of the resulting product 15 (formed with high
diastereoselectivity) and its conformation in solution were
determined by NOE experiments (Scheme 2) in conjunction
with an analysis of the H,H NMR coupling constants.
The selective cleavage of the oxa-bridge of 15, which has
a conformation similar to 12 in the crystalline state, was now
accomplished by treatment with TMSOTf as a Lewis-acid
in the presence of NEt3. In this case, the C(10)-O bond was
left unscathed. The cycloheptadienyl-bis-silyl ether, formed
as the primary ring opening product, was found to easily
undergo a 1,5-H shift. Therefore, the reaction product was
immediately desilylated by treatment with K2CO3/MeOH in
the cold to afford the diol 16 in 63% yield.15
The next task was the conversion of the ring-opening
products 14 or 16 into colchicinoids having a tropolone
substructure. At first, we probed the possibility to transform
the easily accessible compound rac-14 into C(10)-C(11)
oxygenated tropolones (Scheme 3). Applying the method of
obtained in good yields after separation (1:1 ratio). Subse-
quent TBS-deprotection and saponification with KOH in
ethanol furnished the corresponding tropolones rac-21 (a
pseudocolchicine-type compound) and rac-22, respectively.
The conversion of compound 16 into the target molecules
started with its oxidation using a modified Swern reagent
(CF3CO)2O/DMSO17 to give the tropolone 23 in good yield
(Scheme 4). As this compound was difficult to purify, it was
Scheme 3
(8) Attempts to utilize an aryllithium species derived from 9 by treatment
with BuLi failed due to deprotonation at the propargylic stereocenter
(intramolecular proton transfer).
(9) Ye, T.; McKervey, M. A. Tetrahedron 1992, 48, 8007.
(10) Diacel Chiralpak AD-H, hexane/i-PrOH ) 9:1.
(11) (a) Padwa, A.; Fryxell, G. E.; Zhi,L. J. Am. Chem. Soc. 1990, 112,
3100. (b) Padwa, A.; Chinn, R. L.; Hornbuckle, S. F.; Zhang, Z. J. J. Org.
Chem. 1991, 56, 3271. (c) Padwa, A.; Weingaren, M. D. Chem. ReV. 1996,
96, 223.
(12) Under the standard reaction conditions introduced by Padwa (cat.
Rh2(OAc)4, PhH, rt), compound 11 only afforded a dihydropyranone side-
product resulting from 1,4 H-shift of the reactive intermediate 3. A similar
side-product has been observed by Padwa in the reaction of a simple model
compound. See: Padwa, A.; Hornbuckle, S. F.; Fryxell, G. E.; Zhang, Z.
J. J. Org. Chem. 1992, 57, 5747.
Nozoe for tropolone R-functionalization with hydrazine,16
the aminotropone regioisomers rac-17 and rac-18 were
(6) Haack, K. J.; Hashiguchi, S.; Fujii, A.; Ikariya, T.; Noyori, R. Angew.
Chem., Int. Ed. Engl. 1997, 36, 285.
(7) Knochel, P.; Dohle, W.; Gommermann, N.; Kneisel, F. F.; Kopp,
F.; Korn, T.; Sapountzis, I. Angew. Chem., Int. Ed. 2003, 42, 4302.
Org. Lett., Vol. 7, No. 20, 2005
4319

removed with Py‚HF to provide compounds 26 and 27
respectively, both in 86% yield. Mesylation and subsequent
SN2 amination using sodium azide in DMSO smoothly
afforded the azides 30 and 31. The syntheses were completed
by reduction of the azides (H2, Pd/C) and final acetylation
to give colchicine (1) and isocolchicine (32). Adequate
crystals of 32 were obtained from EtOAc/ether, and their
crystallographic analysis showed (as expected) the 7S con-
figuration and, correspondingly, the R configuration of the
chiral axis (Figure 1). This nicely demonstrates once again
the induction of the biaryl chirality by the configuration at
the stereocenter C(7).19
Figure 1. Structure of 25 and 2 in the crystalline state.
In conclusion, we have completed new enantioselective
total syntheses of (-)-colchicine (1) and (-)-isocolchicine
(32). Furthermore, an entry to the (unnatural) pseudocolchi-
cine series was opened. Starting from 5, the syntheses reach
the target compounds 1 and 32 in only 15 steps (overall yield
ca. 1%). The success of the synthetic scheme results from a
powerful metal-catalyzed domino transformation as a key
step. We are optimistic that this strategy can also be applied
to the synthesis of novel colchicine analogues with a
modified ring B substructure.
directly converted into the corresponding tropolonemethyl
ethers by treatment with diazomethane. The products (24 and
25) could be separated by column chromatography. The
structural assignment was confirmed by X-ray crystal-
lography of the isocolchicine-type regioisomer 25. Interest-
ingly, the large OTBS residue at the R-configurated stere-
ocenter C(7) in ring B is adopting a pseudoequatorial
position, thus predefining an S configuration of the chiral
biaryl axis (Figure 1).
While the conversion of 24 into colchicine (1) had already
been performed by Banwell,4a,18 we decided to also perform
the conversion of 25 into isocolchicine (32). As shown in
Scheme 4, the TBS protecting groups of 24 and 25 were
Acknowledgment. This work was supported by the
Volkswagen Foundation, the Fonds der Chemischen Indus-
trie, and the Humboldt Foundation (fellowship to V.B.).
Donations of chemicals from Bayer AG and Chemetall are
gratefully acknowledged.
(13) (a) Plu¨g, C.; Friedrichsen, W. Tetrahedron Lett. 1992, 33, 7509.
See also: (b) Baldwin, J. E.; Mayweg, A. V. W.; Neumann, K.; Prithard,
G. J. Org. Lett. 1999, 1, 1933. For a review on ring opening reactions in
oxabicyclic ring systems, see: (c) Chiu, P.; Lautens, M. Top. Curr. Chem.
1997, 190, 1.
(14) The cleavage of the benzylic C-O bond should also be stereoelec-
tronically assisted as the oxa-bridge is aligned with the π-system of the
aromatic ring.
Supporting Information Available: Experimental pro-
cedures and characteristic data of new compounds, as well
as details of the X-ray crystal structure analyses of com-
pounds 8, 12, 25, and 32. This material is available free of
charge via the Internet at http://pubs.acs.org.
(15) Compound 16 also proved to be rather sensitive toward decomposi-
tion and was usually directly further oxidized to the tropolone 23 (Scheme
4).
OL051316K
(16) (a) Nozoe, T. Chem. Ind. 1955, 66. (b) Nozoe, T. Proc. Jpn. Acad.
1953, 29, 169. (c) Boger, D. L.; Brotherton, C. E. J. Org. Chem. 1985, 50,
3425. (d) Boger, D. L.; Brotherton, C. E. J. Am. Chem. Soc. 1986, 108,
6713.
(17) (a) Baldwin, J. E.; Mayweg, A. v. W.; Pritchard, G. J.; Adlington,
R. M. Tetrahedron Lett. 2003, 44, 4543. (b) Celanire, S.; Marlin, F.;
Baldwin, J. E.; Adlington, R. M. Tetrahedron 2005, 61, 3025.
(18) Banwell, M. G.; Lambert, J. N.; Mackay, M. F.; Greenwood, R. J.
J. Chem. Soc., Chem. Commun. 1992, 974.
(19) According to NMR spectroscopic investigations, the rates of (aS)-
(aR) interconversion for colchicine-type compounds were found to be of
the order of 10-4-10-5 s-1 at 22 °C, which corresponds to a free activation
energy of 22-24 kcal‚mol-1. For details, see ref 1a.
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