Convergent synthesis of fully functionalized ringC C allocolchicinoids. Benzannulation approach

Article abstract of DOI:10.1021/ol0100881

(Equation presented) A novel convergent approach to fully functionalized ring C allocolchicinoids is developed which is based on the benzannulation reaction of Fischer carbene complexes with alkynes. The efficacy of this strategy was established with the

Full text of DOI:10.1021/ol0100881

ORGANIC
LETTERS
2
001
Vol. 3, No. 17
641-2644
Convergent Synthesis of Fully
Functionalized Ring C Allocolchicinoids.
Benzannulation Approach
2
Andrei V. Vorogushin,†,‡ William D. Wulff,* and Hans-J u1 rgen Hansen‡
,†
Department of Chemistry, Michigan State UniVersity, East Lansing, Michigan 48824,
and Institute of Organic Chemistry, UniVersity of Z u¨ rich, Winterthurerstrasse 190,
CH-8057, Z u¨ rich, Switzerland
wulff@cem.msu.edu
Received April 30, 2001
ABSTRACT
A novel convergent approach to fully functionalized ring C allocolchicinoids is developed which is based on the benzannulation reaction of
1
2
Fischer carbene complexes with alkynes. The efficacy of this strategy was established with the conversion of bromide 1a (R ) Me, R ) H)
1
2
to the biaryl phenol 3a (R ) Me, R
analogous preparation of the diastereomeric allocolchicinoids 3b (R ) Me, R
L
) Pr, R
S
) H) via the carbene complex 2a. Bromide 1b (R ) t-Bu, R ) OMe) was then used for the
) Pr, R ) H).
L
S
(
-)-Colchicine 4 (Figure 1), the major alkaloid from
Colchicum autumnale, is one of the oldest known natural
1
products. It binds to the cytoskeletal protein tubulin,
therefore interfering with the normal microtubule assembly-
disassembly in the cell and thereby suppressing the cell
2
division process. Several other active colchicine analogues
have been developed or found in nature, including C10-
3
functionalized colchicinoids, C7-functionalized colchicino-
3
ids, and also colchicine analogues with ring systems different
from that of colchicine: the family of compounds with an
aryl ring C, such as allocolchicine 5, N-acetylcolchinyl-O-
methyl ether 6, and their derivatives.4 Several active
,5
Figure 1. (-)-Colchicine and its active analogues.
†
Michigan State University.
University of Z u¨ rich.
‡
allocolchicine-like biaryl compounds, which do not have ring
B, for example, TCB 7, have been developed, but their
activity is usually lower than that of the corresponding
(
1) (a) Capraro, H.-G.; Brossi. A. In The Alkaloids; Brossi, A. Ed.;
Academic Press: New York, 1984; Vol. 23, p 1, and references therein.
b) Boye, O.; Brossi, A. In The Alkaloids; Brossi, A., Cordell, G. A., Eds.;
Academic Press: New York, 1992; Vol. 41, p 125, and references therein.
(
6
allocolchicinoids. Some other allocolchicine analogues with
(
2) Brossi, A. J. Med. Chem. 1990, 33, 2311, and references therein.
3) Shi, A.; Verdier-Pinard, P.; Brossi, A.; Hamel, E.; McPhail, A. T.;
7
8
a five-membered and eight-membered ring B, as well as
(
Lee, K.-H. J. Med. Chem. 1997, 40, 961.
4) Shi, Q.; Chen, K.; Chen, X.; Brossi, A.; Verdier-Pinard, P.; Hamel,
E.; McPhail, A. T.; Tropsha, A.; Lee, K.-H. J. Org. Chem. 1998, 63, 4018.
(
(5) Shi, Q.; Chen, K.; Brossi, A.; Verdier-Pinard, P.; Hamel, E.; McPhail,
A. T.; Lee, K.-H. HelV. Chim. Acta 1998, 81, 1023.
1
0.1021/ol0100881 CCC: $20.00 © 2001 American Chemical Society
Published on Web 08/03/2001

9
compounds with the functionality at C7 moved to C5, have
and C-10 positions of allocolchicinoids from a common
starting material, namely, carbene complexes of type 2b.
Furthermore, the presence of oxygen functionalities in the
C-8 and C-11 positions on ring C of the allocolchicinoids
of type 3b allows for the preparation of the corresponding
triflates, which can be either catalytically coupled with
been recently prepared but found not to affect the tubulin
polymerization process, despite their narrow structural
similarity with the active allocolchicinoids. It was also shown
that any alteration to the trioxygenated moiety of ring A leads
to compounds with decreased tubulin-binding ability. In
contrast, the biological activity of ring C substituted allo-
colchicinoids varies with size, position, and nature of the
substituents.6
1
0
1
4
15
organometallic reagents or reduced, giving a variety of
C-8 and C-11 functionalized allocolchicinoids. In addition,
it should be possible to readily access optically pure
substrates of type 1b. A straightforward approach would be
,11
It was found that only natural (-)-(7S)-colchicine, which
adopts an aR biaryl configuration, binds effectively to tubulin.
The aS,7R-enantiomer does not interfere with the tubulin
polymerization process. Although 7S-allocolchicinoids prefer
an aR biaryl configuration, they exist in solvent-dependent
equilibrium between aR and aS forms and several active 7R
1
6
an oxidation-asymmetric reduction sequence on the cor-
responding alcohol, followed by alkylation. The presence of
a C-11 substituent, which is introduced in the ring C
annulation process, will stop the epimerization about the
chiral axis. Therefore, aR and aS forms of such allocolchi-
cinoids could be isolated and separately subjected to biologi-
cal testing. The development of a successful protection-
deprotection routine for the hydroxy group at C-7 will be
critical for the introduction of other functional groups at C-7
which are not compatible with the carbene complex prepara-
tion conditions. This would include the acyl, aroyl, or
acetamido groups that occur in natural allocolchicinoids.
The proposed reaction sequence was first tested on the
unsubstituted ring C model compounds 1a-3a (Scheme 1).
5
allocolchicinoids are known. It is still not clear whether the
aR,7S form or the small amount of the aS,7S form, present
in solution in equilibrium, is active in the tubulin-binding
process. Because of its high toxicity, colchicine cannot be
used as a therapeutic drug for treatment of human cancers.
Despite the amount of work that has been directed to
structural modification and synthesis of new colchicinoids
and allocolchicinoids, greatly improved active compounds
have not been identified, mainly because of the difficulties
associated with the construction of highly functionalized ring
C derivatives. To date, only a limited number of reports
describe synthetic pathways toward the preparation of
Scheme 1. Synthesis of Biaryl Phenol 3aa
1
1,12
allocolchicinoids,
and the vast majority of these com-
pounds are still being prepared from natural (-)-colchicine.
No general methodology exists for the efficient construction
of different ring C functionalized allocolchicinoids, which
would be desirable in the search to find more active and
less toxic antimitotic agents and to acquire structure-activity
information about the requirements for binding to tubulin.
We now report a novel approach toward the highly
convergent construction of allocolchicinoids of type 3 which
have the natural substitution pattern on ring A and which
provide for a controlled variability of functionalization on
ring C. This family of allocolchicinoids should be accessible
in one step from Fischer carbene complexes of type 2 by
their benzannulation reaction13 with acetylenes, where the
regiochemistry of the acetylene incorporation is controlled
a
(
i) AgBF
ether, 15 min, (2) Cr(CO)
MeOTf, CH Cl , 25 °C, 1.5 h, 66%; (iii) (1) 3 equiv of 1-pentyne,
4
, MeOH, reflux 24 h, 92%; (ii) (1) t-BuLi, -78 °C,
6
, ether, 0 °C 0.5 h, 25 °C, 1.5 h, (3)
2
2
hexane, 50 °C, 24 h, (2) air, 25 °C, 12 h, 65%.
L S
by the steric size of large (R ) and small (R ) groups on the
acetylene. This methodology will provide for a rapid
introduction of a variety of different substituents in the C-9
Access to 1a was achieved by electrophilic ring opening of
1
7
the known dibromocyclopropane 8a mediated by a silver
salt in methanol which readily provided bromide 1a. Ap-
plication of the modified Fischer procedure to the substrate
(6) Banwell, M. G.; Cameron, J.; Corbett, M.; Dupuche, J. R.; Hamel,
E.; Lambert, J. N.; Lin, C. M.; Mackay, M. F. Aust. J. Chem. 1992, 45,
1
967.
(
(
7) Berg, U.; Bladh, H. Acta Chem. Scand. 1998, 52, 1380.
8) Brecht, R.; Seitz, G.; Guenard, D.; Thoret, S. Bioorg. Med. Chem.
(14) For successful coupling, in situ triflation of the intermediate
chromium tricarbonyl complex of 3 must be performed, which can be
isolated and subjected to Suzuki or Stille coupling conditions as we have
previously reported. The free allocolchicinoids can then be generated by
oxidative removal of the Cr(CO)3 group using iodine. Gilbert, A. M.; Wulff,
W. D. J. Am. Chem. Soc. 1994, 116, 7449.
(15) For example, HCOOH in the presence of Pd(dppf)Cl2 catalyst and
Et3N has previously been used in a synthesis of the tricyclic core of olivin.
Miller, R. A.; Gilbert, A. M.; Xue, S.; Wulff, W. D. Synthesis 1998, 80.
(16) For asymmetric catalytic reduction of R-bromoenones with the CBS
reagent, see: Corey, E. J.; Bakshi, R. K.; Shibata, S.; Chen, Ch.-P.; Singh,
V. K. J. Am. Chem. Soc. 1987, 109, 7925.
2
000, 8, 557.
9) Boye, O.; Brossi, A.; Yeh, H. J. C.; Hamel, E.; Wegrzynski, B.;
Toome, V. Can. J. Chem. 1992, 70, 1237.
10) Banwell, M. G.; Cameron, J. M.; Collins, M. P.; Crisp, G. T.; Gable,
R. W.; Hamel, E. Aust. J. Chem. 1991, 44, 705.
11) Banwell, M. G.; Fam, M.-A.; Gable, R. W.; Hamel, E. J. Chem.
Soc., Chem. Commun. 1994, 2647.
(
(
(
(
12) Sawyer, J. S.; Macdonald, T. L. Tetrahedron Lett. 1988, 29, 4839.
(13) For reviews on Fisher carbene complexes and their transformations,
see: (a) Herndon, J. W. Coord. Chem. ReV. 1999, 181, 177. (b) Wulff, W.
D. In ComprehensiVe Organometallic Chemistry II; Elsevier Science Ltd.:
Oxford, England; 1995; Vol. 12, p 469.
(17) Riley, P. E.; Davis, R. E.; Allison, N. T.; Jones, W. M. J. Am. Chem.
Soc. 1980, 102, 2458.
2642
Org. Lett., Vol. 3, No. 17, 2001

1a results in the preparation of chromium pentacarbonyl
complex 2a. The pentacarbonyl complex 2a (orange-red) was
observed to slowly undergo conversion in solution or as a
neat solid to a tetracarbonyl complex (dark-red) in which a
methoxy group is coordinated to the chromium. For purposes
of characterization, it was found most convenient to com-
pletely drive this process to the tetracarbonyl complex by
heating in vacuo at 60 °C. Since it has been previously shown
Scheme 3. Preparation of the Protected Substrates 1d-ha
a
(
i) MOMCl, i-Pr
2
NEt, CH
2
Cl
2
, 96%, PG ) MOM; (ii) (1) NaH,
N, ether,
0%, PG ) TMS; (iv) TBSCl, imidazole, DMF, 99%, PG ) TBS;
v) Ph CCl, DBU, CH Cl , 36%, PG ) Ph C.
that chelated complexes and nonchelated complexes give
identical results upon reactions with alkynes,18 the mixture
NaI, THF, (2) MTMCl, 60%, PG ) MTM; (iii) TMSCl, Et
3
7
(
of pentacarbonyl complex 2a and its tetracarbonyl chelated
complex (5-10%) was reacted directly with 1-pentyne. The
reaction gave the expected phenol 3a, establishing the
viability of allocolchicine ring system construction via the
benzannulation reaction.
3
2
2
3
is usually compatible with organolithium reagents. The
success of this approach of course depends on whether the
alkyl protecting group can be easily removed. Therefore, we
decided to use the tert-butyl protecting group since there are
known methods for its efficient and selective cleavage.
The tert-butyl-protected substrate 1b was prepared from
8b by an electrophilic ring opening in t-BuOH, similar to
the one used for the preparation of 1a, but with the following
modifications: (a) higher temperature and longer reaction
time must be applied to improve the conversion; (b) a 10-
Preparation of the trimethoxy-substituted dibromocyclo-
19
propane 8b was achieved starting from the known tetralone
20
9
, which was prepared by a modified route from ethyl 3,4,5-
trimethoxybenzoyl acetate. Reduction of 9, followed by the
dehydration of the intermediate alcohol, readily afforded
dihydronaphthalene 10 (Scheme 2). Dibromocarbene addition
3
fold excess of CaCO per mole of 8b must be added to
quench the acid formation and suppress the elimination of
Scheme 2. Preparation of Alcohol 1ca
tert-butyl alcohol (Scheme 4). A significant amount of the
Scheme 4. Electrophilic Ring Opening Reaction of 8b in
t-BuOHa
a
(
i) (1) NaBH
4
, EtOH, 25 °C, 0.5 h, reflux 40 min, (2) MgSO
, NaOH, CTMAC, hexane,
O, 80 °C 36 h, 82.5%.
4
,
a
benzene, reflux 1.5 h, 89%; (ii) CHBr
reflux 5 h, 55%; (iii) AgBF , DME/H
3
(i) AgBF
4
3
, CaCO , t-BuOH, 80 °C, 36 h; (ii) CCl
3
C(NH)O-t-
Bu, CH
2
Cl /Cy, catalytic BF
2
3
‚Et O, 25 °C, 17 h, 32%.
2
4
2
free alcohol 1c is also formed in this reaction. Fortunately
to 10 under phase-transfer conditions gave the expected
dibromocyclopropane 8b. Electrophilic ring opening of 8b
led to the alcohol 1c, which was then protected with various
protecting groups to give the substrates 1d-h (Scheme 3).
Unfortunately, all of the substrates 1d-h failed to form
the expected carbene complexes under the conditions de-
veloped for the preparation of 2a. Attempts to optimize the
procedure for carbene complex formation with conditions
more appropriate for substrates 1d-h also failed. In this
situation, utilization of an alkyl group as the protecting group
seemed appropriate, given the fact that the alkyl protection
1c can be easily separated and tert-butylated using tert-butyl
2
Et
,2,2-trichloroacetimidate and catalytic amounts of BF
2
O. Although the yield is not high for the tert-butylation
3
‚
2
1
of 1c, 88% of unreacted starting material 1c can be recovered
and recycled. As expected, the desired carbene complex 2b
could be prepared from 1b under the conditions developed
for 2a (Scheme 5). Here again we observed the formation
of small amounts of the tetracarbonyl chelated complex
(dark-red) from the pentacarbonyl complex 2b (orange-red).
However, the chelated complex in this case is too unstable
to be isolated by column chromatography. It was most
convenient to characterize the carbene complex in the form
of the tetramethylammonium salt of its metal acylate
precursor.
(
18) Bos, M. E.; Wulff, W. D.; Miller, R. A.; Brandvold, T. A.;
Chamberlin, S. J. Am. Chem. Soc. 1991, 113, 9293.
19) Haworth, R. W.; Moore, B. P.; Pauson, P. L. J. Chem. Soc. 1949,
271.
20) The sequence from ref 19 was modified in the following way: for
(
3
(
The pentacarbonyl complex 2b (containing ∼5% chelated
20a
the reduction of 3-(3,4,5-trimethoxybenzoyl)propionic acid , Et3SiH was
used instead of N2H4; for the cyclization of 4-(3,4,5-trimethoxyphenyl)-
butanoic acid, polyphosphoric acid (PPA) was used instead of P2O5 or
PCl5. (a) Hamada, A.; An Chang, Y.; Uretsky, N.; Miller, D. D. J. Med.
Chem. 1984, 27, 675. (b) Koo, J. J. Am. Chem. Soc. 1953, 75, 1891.
complex) was subjected to the benzannulation reaction with
2
0b
(21) Armstrong, A.; Brackenridge, I.; Jackson, R. F. W.; Kirk, J. M.
Tetrahedron Lett. 1988, 29, 2483.
Org. Lett., Vol. 3, No. 17, 2001
2643

treatment of the ether with Ac
2
O in the presence of catalytic
2
3
3
amounts of FeCl .
The acetyl group in the intermediate
Scheme 5. Synthesis of the t-Bu-Protected Allocolchicinoids
b and Their Deprotectiona
3
acetates can then be easily liberated to give an alcohol either
reductively or by hydrolysis. Thus, the major diastereomer
of 3b was subjected to the acetylation conditions described
above, followed by the reductive removal of the acetyl groups
4
using LiAlH to give the alcohol 3c as a single diastereomer
in 72% yield. Interestingly, upon similar treatment, the minor
diastereomer of 3b also gives a single diastereomer of 3c,
and furthermore, it was found to be indentical with that
1
obtained from the major diastereomer of 3b. The H NMR
spectrum of 3c correlates with the major diastereomer of 3b
and differs from that of the minor isomer of 3b.
Therefore, it is concluded that the major isomer of 3b is
cleaved to the alcohol 3c with retention and the minor isomer
3
b gives the alcohol 3c with inversion. The relative stere-
ochemistry of 3c is assigned as shown (aR,7S; aS,7R) on
1
a
the basis of a comparison with the H NMR spectra of related
known compounds.
(
i) (1) t-BuLi, ether, -78 °C 15 min, (2) Cr(CO)
.5 h, 25 °C, 1.5 h, (3) MeOTf, CH Cl , 25 °C, 1.5 h, 54%; (ii) (1)
equiv of 1-pentyne, benzene, 55 °C, 24 h, (2) air, 25 °C, 12 h,
6
, ether, 0 °C
4
0
3
4
1
2
2
In conclusion, this work has demonstrated the feasibility
of a highly convergent construction of the fully functionalized
ring C in the potentially biologically relevant allocolchici-
noids via the benzannulation reaction of chromium carbene
complexes. A successful method for the protection of the
C-7 hydroxyl has been identified as well as a method for its
deprotection, providing for access to the allocolchicinoid
alcohol 3c which presents possibilities for further modifica-
tions of the C7 position in this and related compounds.
8%; (iii) (1) Ac
h.
2 3
O, catalytic FeCl , 0 °C, (2) LAH, THF, 25 °C,
1
-pentyne under the conditions developed for the preparation
of 3a. In this reaction, it is expected that two diastereomers
of the phenol product 3b would be possible given that the
hydroxy and methoxy groups ortho to the biaryl linkage
should prevent epimerization about the chiral axis. As
anticipated, the phenol 3b was produced as a mixture of
diastereomers. The 2:1 mixture of isomers could be separated
and each obtained in pure form. The difficulty encountered
in the deprotection of the tert-butyl ether group in 3b is likely
due to the fact that the unsymmetrical ether linkage at the
C-7 group is both tertiary and benzylic. Competing elimina-
tion is possible, which will install a double bond in ring B.
To find a useful deprotection routine, we screened two known
methods which do not involve the use of equimolar amounts
or excess amounts of acidic reagents. The first involves
treatment of the major diastereomer of 3b with catalytic
amounts of TBDMSOTf 22 which led to the formation of
more than five products. The second provides a solution to
the problem via the in situ trapping of the tert-butyl ether
cleavage product by acetate in a procedure that involves
Acknowledgment. This work is supported by a grant
from the National Institutes of Health (NIH GM 33589).
Mass spectral data were obtained at the Michigan State
University Mass Spectrometry Facility, which is supported,
in part, by a grant from the National Institutes of Health
(DRR-00480). This work was started at the Department of
Chemistry, The University of Chicago, and subsequently
carried out at both Michigan State University and the
University of Z u¨ rich.
Supporting Information Available: Full experimental
details and characterization data for compounds 1a-h, 2a,b,
a-c, 8b, and 10. This material is available free of charge
3
via the Internet at http://pubs.acs.org.
OL0100881
(
23) Alexakis, A.; Gardette, M.; Colin, S. Tetrahedron Lett. 1988, 29,
(22) Franck, X.; Figad e` re, B.; Cav e´ , A. Tetrahedron Lett. 1995, 36, 711.
2951.
2644
Org. Lett., Vol. 3, No. 17, 2001