Total synthesis of colchicine. α-methoxy-substituted oxyally [4 + 3] cycloaddition approach

Full text of DOI:10.1021/jo980220j

2804
J . Org. Chem. 1998, 63, 2804-2805
colchicine (1), which is also anticipated to provide a unified
Tota l Syn th esis of Colch icin e.
r-Meth oxy-Su bstitu ted Oxya llyl [4 + 3]
Cycloa d d ition Ap p r oa ch
approach to structurally related tropoloisoquinoline alka-
loids, such as gradirubrine (4), isoimerubrine (5), and
imerubrine (6).4
J ae Chol Lee, Shu-juan J in, and J in Kun Cha*
Department of Chemistry, University of Alabama
Tuscaloosa, Alabama 35487
Received February 10, 1998
Colchicine (1), the principal alkaloid constituent of Colchi-
cum autumnale, possesses interesting biological features in
arresting cell division during mitosis.1 The antimitotic
effects of colchicine result from its binding to tubulin and
interference with microtubule-dependent cell functions.
Although its high toxicity has precluded clinical utilization
as a potential antitumor agent, it remains an important
biochemical probe. Over the past three decades, colchicine
has been the target of an unusually large number of
synthetic studies, culminating in several elegant total
syntheses.2,3 Despite a deceptibly straightforward structure,
1 poses considerable synthetic challenges, which are in part
due to the paucity of general synthetic methods for the
tropolone ring. All of the previous syntheses, with a sole
exception,3d involve the penultimate intermediacy of colchi-
ceine (2). Consequently, they suffer from lack of regiocontrol
in the final methylation, resulting in equal amounts of 1 and
3. Herein, we report a regioselective synthesis of (-)-
A general approach to these tropolone target structures
was found in the [4 + 3] cycloaddition of the R-methoxy-
substituted oxyallyl 8 to furan 9, which was expected to
afford stereo- and regioselectively the cycloadduct 7 (Scheme
1).5,6 Subsequent double elimination would then give colchi-
cine (1), free from isocolchicine (3), by obviating the inter-
mediacy of colchiceine (2). The requisite substrate 9 should
be readily available by the intramolecular Diels-Alder
reaction of the acetylenic oxazole 10,7 which would in turn
be prepared from the alcohol 11. This synthetic plan
stemmed from our ongoing interest in the applications of
oxyallyl [4 + 3] cycloaddition reactions in natural product
synthesis.8 In particular, we became interested in a key
variant of utilizing R-heteroatom-substituted oxyallyls;6
while a few methods for their generation are known, to our
knowledge, no synthetic application has been reported.
The acetylenic alcohol 11 was first prepared from the
alcohol 12 by means of the Sonogashira coupling of the
corresponding aryl iodide (Scheme 2).9 Swern oxidation,
followed by addition of the anion prepared in situ from the
(1) For general reviews, see: (a) Wildman, W. C.; Pursey, B. A. Alkaloids
1968, 11, 407. (b) Capraro, H.-G.; Brossi, A. Alkaloids 1984, 23, 1. (c) Boye´,
O.; Brossi, A. Alkaloids 1992, 41, 125.
(2) In the previous syntheses, deacetamidocolchicine was employed as
the key intermediate, which was subsequently converted to 1 by the
introduction of an amino group at C-7: (a) Schreiber, J .; Leimgruber, W.;
Pesaro, M.; Schudel, P.; Threlfall, T.; Eschenmoser, A. Helv. Chim. Acta
1961, 44, 540. (b) van Tamelen, E. E.; Spencer, T. A.; Allen, D. S.; Orvis, R.
L. Tetrahedron 1961, 14, 8. (c) Scott, A. I.; McCapra, F.; Buchanan, R. L.;
Day, A. C.; Young, D. W. Tetrahedron 1965, 21, 3605. (d) Martel, J .;
Toromanoff, E.; Huynh, C. J . Org. Chem. 1965, 30, 1752. (e) Kato, M.; Kido,
F.; Wu, M. D.; Yoshikoshi, A. Bull. Chem. Soc. J pn. 1974, 47, 1516. (f) Boger,
D. L.; Brotherton, C. E. J . Am. Chem. Soc. 1986, 108, 6713 and references
therein.
(3) (a) Nakamura, T. Murase, Y.; Hayashi, R.; Endo, Y. Chem. Pharm.
Bull. 1962, 10, 281. (b) Woodward, R. B. The Harvey Lectures Series 59;
Academic Press: New York, 1965; p 31. (As cited in: Fleming, I. Selected
Organic Syntheses; Wiley: New York, 1973; pp 202-207.) (c) Evans, D. A.;
Tanis, S. P.; Hart, D. J . J . Am. Chem. Soc. 1981, 103, 5813. (d) Banwell,
M. G. Pure Appl. Chem. 1996, 68, 539.
(4) For a general review, see: (a) Buck, K. T. Alkaloids 1984, 23, 301.
For successful total syntheses, see: (b) Banwell, M. G.; Hamel, E.; Ireland,
N. K.; Mackay, M. F. Heterocycles 1994, 39, 205. (c) Banwell, M. G.; Ireland,
N. K. J . Chem. Soc., Chem. Commun. 1994, 591. (d) Boger, D. L.; Takahashi,
K. J . Am. Chem. Soc. 1995, 117, 12452.
Sch em e 1
(5) For general reviews of oxyallyl cations, see: (a) Noyori, R.; Hayakawa,
Y. Org. React. 1983, 29, 163. (b) Hoffmann, H. M. R. Angew. Chem., Int.
Ed. Engl. 1984, 23, 1. (c) Mann, J . Tetrahedron 1986, 42, 4611. (d) Hosomi,
A.; Tominaga, Y. In Comprehensive Organic Synthesis; Trost, B. M.,
Fleming, I., Eds.; Pergamon: Oxford, 1991; Vol. 5, Chapter 5.1.
(6) Only a handful of reports appeared for the preparation R-alkoxy-
substituted oxyallyl cations: (a) Fo¨hlisch, B.; Krimmer, D.; Gehrlach, E.;
Ka¨shammer, D. Chem. Ber. 1988, 121, 1585. (b) Murray, D. H.; Albizati,
K. F. Tetrahedron Lett. 1990, 31, 4109. (c) More recently, the first report
on R-nitrogen-substituted oxyallyl cations appeared: Walters, M. A.; Arcand,
H. R.; Lawrie, D. J . Tetrahedron Lett. 1995, 36, 23.
(7) An intramolecular Diels-Alder reaction of acetylenic oxazoles for the
preparation of fused-ring furans has been popularized and termed as bis-
heteroannulation by J acobi and co-workers: J acobi, P. A.; Blum, C. A.;
DeSimone, R. W.; Udodong, U. E. S. J . Am. Chem. Soc. 1991, 113, 5384
and references therein.
(8) By embedding the oxyallyl function in a ring, we recently developed
the useful variant of employing cyclic oxyallyls, which broaden the scope
and synthetic utility of the [4 + 3] oxyallyl cycloadditions: (a) J in, S.-j.;
Choi, J .-R.; Oh, J .; Lee, D.; Cha, J . K. J . Am. Chem. Soc. 1995, 117, 10914.
(b) Lee, J .; Oh, J .; J in, S.-j.; Choi, J .-R.; Atwood, J . L.; Cha, J . K. J . Org.
Chem. 1994, 59, 6955 and references therein.
(9) This conversion was achieved by standard methods in 84% overall
yield: (1) TIPSOTf, 2,6-lutidine; (2) I2, CF3CO2Ag, CHCl3; (3) HCtCTMS,
Et2NH, (Ph3P)2PdCl2, CuI, DMSO; (4) TBAF, THF.
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Published on Web 04/09/1998

Communications
J . Org. Chem., Vol. 63, No. 9, 1998 2805
Sch em e 2
Sch em e 3
oxazole-borane complex using the method of Vedejs, af-
forded the oxazole 13.10 For the enantioselective installation
of the C-7 acetamido group, the (R)-alcohol 14 was first
prepared by Itsuno reduction in 64% yield and 85-90% ee
(estimated by the NMR studies with a chiral shift re-
agent).11,12 Subsequent conversion to the azide 15 was
achieved with inversion of configuration by means of Mit-
sunobu chemistry.13 Reduction of the azide functionality
and acetylation then afforded the acetylenic oxazole 10a
(where R1 ) Me) in nearly quantitative yield. Thermolysis
(o-dichlorobenzene, reflux) provided the furan 9a (where R1
) Me) in 60∼70% yield and with little racemization.
Interestingly, “bis-heteroannulation” of 10a was found to
proceed more slowly than that of the isomeric oxazole 10b.14
The key [4 + 3] cycloaddition of the furan 9a was carried
out by adaptation of Albizati’s procedure involving in situ
generation (with TMSOTf) of R-methoxy(trimethylsiloxy)-
allyl cation (e.g., 8) from the trimethylsilyl enol ether 16 of
pyruvic aldehyde dimethyl acetal (Scheme 3).6b Surpris-
ingly, the undesired regioisomer 17 was isolated as the sole
product (60% yield based on 50% conversion of the starting
material). On the other hand, the cycloaddition of the
carbamate 9b (R1 ) O-t-Bu), which was readily prepared
from 9a by standard methods,15 furnished the desired
cycloadduct 7 (R1 ) O-t-Bu) as a single diastereomer in 45%
yield (based on 50% conversion of the starting material). Its
structure rests on 1H NMR analysis; regiochemistry was
unequivocally established by the splitting pattern of meth-
ylene protons at C-8 (colchicine numbering). While incon-
sequential, the stereochemical assignment was tentatively
made based on the expected approach of the W-shaped
oxyallyl cation from the less hindered, â-face of the furan in
a “compact” (endo-like) mode.5 It is presently unclear what
factors are responsible for the remarkable divergence in the
regioselectivity of the [4 + 3] cycloadditions of 9a and 9b.
Subsequent double elimination of the oxa bridge proved to
be challenging. Ultimately, the 2-methoxytropone 18, a fully
assembled colchicine derivative, was prepared (62%) in one
step by a slightly modified procedure of Fo¨hlisch and Mann
employing an excess of TMSOTf and Et3N in CH2Cl2.16
Finally, the BOC amino protecting group was replaced by
the N-acetyl group to complete a total synthesis of (-)-1 in
∼90% ee.17
In summary, the [4 + 3] cycloaddition of an R-alkoxy-
substituted oxyallyl cation to a suitable furan provides an
effcient, regioselective entry to colchicine (1). This [4 + 3]
cycloaddition methodology is anticipated to also offer a
unified approach to structurally related tropoloisoquinoline
alkaloids 4-6. Mechanistic studies to elucidate the origin
of the regioselective cycloadditions of 9a ,b are currently
underway and will be reported in due course.
(10) Vedejs, E.; Monahan, S. D. J . Org. Chem. 1996, 61, 5192.
(11) (a) Itsuno, S.; Ito, K.; Hirao, A.; Nakahama, S. J . Chem. Soc., Chem.
Commun. 1983, 469. (b) Itsuno, S.; Ito, K. J . Org. Chem. 1984, 49, 555. (c)
Itsuno, S.; Sakurai, Y.; Ito, K.; Hirao, A.; Nakahama, S. Bull. Chem. Soc.
J pn. 1987, 60, 395. See also: (d) Whang, K.; Cooke, R. J .; Okay, G.; Cha, J .
K. J . Am. Chem. Soc. 1990, 112, 8985.
(12) Cf. (a) Corey, E. J .; Bakshi, R. K.; Shibata, S. J . Am. Chem. Soc.
1987, 109, 5551. (b) Follet, M. Acros Org. Acta 1996, 2, 12. (c) Mathre, D.
J .; Thompson, A. S.; Douglas, A. W.; Hoogsteen, K.; Carroll, J . D.; Corley,
E. G.; Grabowski, E. J . J . J . Org. Chem. 1993, 58, 2880.
Ack n ow led gm en t. We are grateful to the National
Institutes of Health (GM35956) for generous financial
support and a Research Career Development Award
(GM00575 to J .K.C.).
Su p p or tin g In for m a tion Ava ila ble: Experimental proce-
dures and characterization/spectral data (27 pages).
(13) Lal, B.; Pramanik, B. N.; Manhas, M. S.; Bose, A. K. Tetrahedron
Lett. 1977, 23, 1977.
J O980220J
(14) The acetamido oxazole moiety of 10b was prepared by the introduc-
tion of the (trichloromethyl)carbinol, followed by its conversion to the R-azido
ester by the method of Corey (Corey, E. J .; Link, J . O. J . Am. Chem. Soc.
1992, 114, 1906) and subsequent treatment with TosMIC (van Leusen, A.
M.; Hoogenboom, B. E.; Siderius, H. Tetrahedron Lett. 1972, 23, 2369).
Complete details will be reported in a full paper.
(16) (a) Fo¨hlisch, B.; Sendelbach, S.; Bauer, H. Liebigs Ann. Chem. 1987,
1. (b) Barbosa, L. C. A.; Mann, J .; Wilde, P. D. Tetrahedron 1989, 45, 4619.
(17) The synthetic substance was found to be identical with an authentic
sample of natural colchicine: mp 153-154 °C; [R]D ) -143.5° (c ) 0.4,
CHCl3) [[R]D ) -161.4° (c ) 0.43, CHCl3) for natural colchicine].
(15) Flynn, D. L.; Zelle, R. E.; Grieco, P. A. J . Org. Chem. 1983, 48, 2424.