Allocolchicines via intramolecular Nicholas reactions: The synthesis of NSC 51046

Article abstract of DOI:10.1021/ol7024422

Biaryl propargyl acetate hexacarbonyldicobalt complexes (4) undergo Lewis acid mediated Nicholas reactions with a remote arene function to afford dibenzocycloheptyne complexes (9). Reductive decomplexation based on a hydrosilylation-protodesilylation prot

Full text of DOI:10.1021/ol7024422

ORGANIC
LETTERS
2007
Vol. 9, No. 26
5505-5508
Allocolchicines via Intramolecular
Nicholas Reactions: The Synthesis of
NSC 51046
Sinisa Djurdjevic†,‡ and James R. Green*,†
Department of Chemistry and Biochemistry, UniVersity of Windsor,
Windsor, ON, Canada N9B 3P4, and St. Clair College of Applied Arts and
Technology, Windsor, ON, Canada N9A 6S4
jgreen@uwindsor.ca
Received October 7, 2007
ABSTRACT
Biaryl propargyl acetate hexacarbonyldicobalt complexes (4) undergo Lewis acid mediated Nicholas reactions with a remote arene function to
afford dibenzocycloheptyne complexes (9). Reductive decomplexation based on a hydrosilylation protodesilylation protocol is facile, and the
1,2,3,9-tetramethoxy case can be converted to NSC 51046 ((S)-N-acetylcolchicinol methyl ether, 3).
−
The allocolchicines are a series of compounds featuring a
6,7,6-ring system and a highly oxygenated A ring. Several
of these compounds have been found to be active against a
variety of cancer cell lines, including drug-resistant ones,
operating by inhibition of tubulin assembly and polymeri-
zation, resulting in the arrest of cell mitosis.1 Individual
members of this class of compounds have been the subject
of increased recent synthetic interest. Examples include
Wulff’s Diels-Alder C ring construction approach to (S)-
allocolchicine (1),2a Fagnou’s formal (S)-allocolchicine syn-
thesis featuring formation of the B ring by palladium-
catalyzed direct C-H arylation,2b Chong’s,2c Kocienski’s,2d
and Leonard’s2e (S)-N-acetylcolchinol (2) syntheses based
on inter-3 or intramolecular oxidative coupling protocols, and
DeShong’s siloxane coupling-ring expansion route to ra-
cemic N-acetylcolchinol-O-methyl ether (3).4 By contrast,
all preparations of enantiomerically pure 3 (NSC 51046)
derive from oxidative degradation of colchicine itself5 or rely
upon resolution (Figure 1).6
We7 and others8 have developed several methods to
construct seven-membered ring systems featuring cyclohep-
† University of Windsor.
‡ St. Clair College.
(2) (a) Vorogushin, A. V.; Predeus, A. V.; Wulff, W. D.; Hansen, H.-J.
J. Org. Chem. 2003, 68, 5826. (b) Leblanc, M.; Fagnou, K. Org. Lett. 2005,
7, 2849. (c) Wu, T. R.; Chong, J. M. Org. Lett. 2006, 8, 15. (d) Besong,
G.; Jarowicki, K.; Kocienski, P. J.; Sliwinski, E.; Boyle, F. T. Org. Biomol.
Chem. 2006, 4, 2193. (e) Broady, S. D.; Golden, M. D.; Leonard, J.; Muir,
J. C.; Maudet, M. Tetrahedron Lett. 2007, 48, 4627.
(1) (a) Perez-Ramirez, B.; Gorbunoff, M. J.; Timasheff, S. N. Biochem-
istry 1998, 37, 1646. (b) Guan, J.; Zhu, X.; Brossi, A.; Tachibana, Y.;
Bastow, K. F.; Verdier-Pinard, P.; Hamel, E.; McPhail, A. T.; Lee, K.
Collect. Czech. Chem. Commun. 1999, 64, 217. (c) Bu¨ttner, F.; Bergemann,
S.; Gue´nard, D.; Gust, R.; Seitz, G.; Thoret, S. Bioorg. Med. Chem. 2005,
13, 3497. (d) Nakagawa-Goto, K.; Jung, M. K.; Hamel, E.; Wu, C.-C.;
Bastow, K. F.; Brossi, A.; Ohta, S.; Lee, K.-H. Heterocycles 2005, 65, 541.
(3) Sawyer, J. S.; Macdonald, T. L. Tetrahedron Lett. 1988, 29, 4839.
(4) Seganish, W. M.; DeShong, P. Org. Lett. 2006, 8, 3951.
10.1021/ol7024422 CCC: $37.00
© 2007 American Chemical Society
Published on Web 11/29/2007

tyne-Co2(CO)6 complexes, based on propargyl cation-Co2-
(CO)6 (Nicholas reaction) chemistry and other reactions on
intact alkyne-Co2(CO)6 complexes.9 Most pertinently, we
acetate-Co2(CO)6 complexes (4) as an attractive choice for
a general approach to the 6,7,6-ring system. Moreover, our
interest was drawn to 3, given its limited synthetic attention
and the ready availability of precursors by way of Suzuki-
Miyaura coupling and Corey-Fuchs reaction chemistry.
For all but one of the cyclization substrates (4), the
synthesis therefore commenced with 2-bromobenzaldehydes
(5). Suzuki-Miyaura cross-coupling occurs readily with
arylboronic acids (6) under conventional conditions as
reported by Fu¨rstner,10 affording biaryl-2-carboxaldehydes
(7) in good to excellent yields (Scheme 1 and Table 1). In
addition to the precedented cases with 2,3,4-trimethoxyphe-
nylboronic acid (6a f 7a, 7b),10 analogous cross-coupling
reactions were similarly successful with 3,5-dimethylphe-
nylboronic acid (6b f 7c) and 3-thiopheneboronic acid (6c
f 7d).
Figure 1. Selected allocolchicines.
have demonstrated that aryl (Z)-enyne propargyl acetate-
Co2(CO)6 complexes undergo ready Lewis acid mediated
cyclization onto electronically neutral or electron-rich arenes
to afford benzocycloheptyne complexes.7a
Scheme 2. Preparation of Propargyl Acetate Complexes 4a
Scheme 1. Suzuki-Miyaura Synthesis of 7
a Compound 8e was prepared by Sonogashira reaction of
2-iodobiphenyl with propargyl alcohol.
Given this facile ring closing process and the electron-
rich A ring of the allocolchicines, we viewed the intramo-
lecular Nicholas reaction protocol on biaryl-2-propargyl
(5) (a) Iorio, M. A. Heterocycles 1984, 22, 2207. (b) Brecht, R.; Haenel,
F.; Seitz, G. Liebigs Ann./Recl. 1997, 2275. (c) Diler, U.; Franz, B.; Roettele,
H.; Schroeder, G.; Herges, R. J. Prakt. Chem./Chem.-Ztg. 1998, 340, 468.
(6) Cook, J. W.; Jack, J.; Loudon, J. D.; Buchanan, G. L.; Macmillan, J.
J. Chem. Soc. 1951, 1397.
(7) (a) Ding, Y.; Green, J. R. Synlett 2005, 271. (b) Green, J. R. Synlett
2001, 353. (c) Lu, Y.; Green, J. R. Synlett 2001, 243. (d) Patel, M. M.;
Green, J. R. Chem. Commun. 1999, 509. (e) Green, J. R. Chem. Commun.
1998, 1751.
The aldehyde function on the biaryl system was central
to the attachment of the propargyl acetate cobalt complex.
The Corey-Fuchs protocol was accomplished without
purification of the dibromoalkene intermediate; quenching
the BuLi-derived acetylide ion with paraformaldehyde
ultimately resulted in the conversion of the biaryl-2-carbox-
(8) (a) Schreiber, S. L.; Sammakia, T.; Crowe, W. E. J. Am. Chem. Soc.
1986, 108, 3128. (b) Iwasawa, N.; Satoh, H. J. Am. Chem. Soc. 1999, 121,
7951. (c) Tanino, K.; Shimizu, T.; Miyama, M.; Kuwajima, I. J. Am. Chem.
Soc. 2000, 122, 6116. (d) Iwasawa, N.; Sakurada, F.; Iwamoto, M. Org.
Lett. 2000, 2, 871. (e) Tanino, K.; Kondo, F.; Shimizu, T.; Miyashita, M.
Org. Lett. 2002, 4, 2217. (f) Tanino, K.; Onuki, K.; Asano, K.; Miyashita,
M.; Nakamura, T.; Takahashi, Y.; Kuwajima, I. J. Am. Chem. Soc. 2003,
125, 1498. (g) Young, D. G. J.; Burlison, J. A.; Peters, U. J. Org. Chem.
2003, 68, 3494. (h) Iwasawa, N.; Inaba, K.; Nakayama, S.; Aoki, M. Angew.
Chem., Int. Ed. 2005, 44, 7447. (i) Olier, C.; Gastaldi, S.; Christie, S. D.
R.; Bertrand, M. P. Synlett 2007, 423. (j) Kennichi; Takaya, J.; Iwasawa,
N. Chem. Lett. 2007, 36, 474. (k) For the corresponding ethers, see: Baba,
T.; Huang, G.; Isobe, M. Tetrahedron 2003, 59, 6851 and references therein.
(9) For recent reviews on the Nicholas reaction, see: (a) Diaz, D. D.;
Betancort, J. M.; Martin, V. S. Synlett 2007, 343. (b) Teobald, B. J. Tetra-
hedron 2002, 58, 4133. (c) Green, J. R. Curr. Org. Chem. 2001, 5, 809.
(10) Mamane, V.; Hannen, P.; Fu¨rstner, A. Chem.sEur. J. 2004, 10,
4556.
Table 1. Preparation of Propargyl Acetate Complexes 4
yield
(%)
yield
(%)
yield
(%)
compd
compd
compd
7a
7b
7c
7d
84a
92b
72
8a
8b
8c
8d
8e
82
78
57
38c
87
4a
4b
4c
4d
4e
86
84
91
77
86
80
a Literature yield, 89%.10 b Literature yield, 85%.10 c 7-Methoxynaph-
tho[2,1-b]thiophene was isolated in 50% yield.
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Org. Lett., Vol. 9, No. 26, 2007

aldehydes (7) into the corresponding propargyl alcohols (8)
in good yields (Scheme 2 and Table 1), except in the thienyl
case (8d), which was formed in modest yield.11 In addition,
unsubstituted biphenyl case 8e was prepared by Sonogashira
coupling of 2-iodobiphenyl with propargyl alcohol in 87%
yield. Straightforward acetylation of the alcohol and com-
plexation of the alkyne function with Co2(CO)8 then afforded
the propargyl acetate-Co2(CO)6 complexes (4) in good
yields (Table 1).12
Scheme 3. Intramolecular Nicholas Reactions of 4
With the precursor propargyl acetate complexes (4) in
hand, attention was turned to the cyclization reactions. At 5
× 10-3 M concentration (CH2Cl2), tetramethoxy-substituted
complex 4a underwent reaction mediated by BF3-OEt2 (3
equiv) to give tricyclic product 9a in 56% yield after 2.5 h
at room temperature (Table 2, entry 1). With the intent to
Table 2. Intramolecular Nicholas Reactions of 4
yielda
entry
biaryl
rxn time
product
(%)
of cations derived from 4 in a reactive rotamer in addition
to the degree that the reacting arene is electron-rich.
Nevertheless, formation of dibenzocycloheptyne complexes
was possible in all cases and included both electron-rich and
unactivated arenes as the nucleophilic fragment.13
As the transformation of 9a into NSC 51046 required
conversion of the cycloheptynedicobalt unit into an appropri-
ate synthetic handle, a number of reductive decomplexation
reaction protocols were investigated. It was quite gratifying
to find that employing the hydrosilylation conditions devel-
oped by Isobe,14 followed by in situ desilylation by the
addition of CF3CO2H, resulted in the formation of dibenzo-
cycloheptene 10 in excellent yield (97%) (Scheme 4). A
1
2
3
4
5
6
4a
4a
4b
4c
4d
4e
2.5 h
6 h
16 h
6 h
5 h
16 h
9a
9a
9b
9c
9d/9d′
9e
56b
71
59 (66)
85
82c
59
a Number in parentheses is the yield based on recovered starting material.
i
b No Pr2NEt added. c 9d/9d′ ) 45:55.
scavenge acid liberated during the reaction process, 1.5 equiv
of iPr2NEt was added to the mixture in addition to the Lewis
acid. While a slightly longer reaction time (6 h) was required
for complete consumption of 4a, compound 9a was formed
in increased yield (71%, entry 2). This 3 equiv of BF3-
OEt2/1.5 equiv of Pr2NEt (CH2Cl2, 5 × 10-3 to 1 × 10-2
i
Scheme 4. Conversion of 9a to Dibenzosuberone 11
M) protocol was therefore adopted as the standard one for
4b-e. Each substrate gave the corresponding dibenzocyclo-
heptyne (9b-e) in synthetically useful yields (Scheme 3 and
Table 2).
There are several significant points for these Nicholas
reaction based cyclizations. The 3-thienyl-substituted sub-
strate 4d afforded 9d as an approximately 1:1 ratio of
regioisomers resulting from attack at the 2- and 4-positions
of the thiophene ring (entry 5). In addition, it is also worthy
of note that there was very limited correlation between the
nucleophilicity of the ring at which reaction occurs (i.e., entry
3 vs 4), and that all the cyclizations were considerably slower
than the analogous benzocycloheptenyne formation reactions.7a
Taken together, it is clear that the rate at which ring closing
occurs in the current system is dependent upon the proportion
conventional hydroboration/oxidation reaction, followed by
further oxidation under Swern conditions, gave ketone 11
(80% yield), with only a trace of the isomeric hydrobora-
tion-oxidation product observable in the crude reaction
product.15
(11) In this case, the major product was 7-methoxynaphtho[2,1-b]-
thiophene (50% yield), consistent with vinyl carbene insertion into the
thiophene C(2)-H bond. For related chemistry, see: (a) Imamura, K.;
Hirayama, D.; Yoshimura, H.; Takimiya, K.; Aso, Y.; Otsubo, T. Tetra-
hedron Lett. 1999, 40, 2789. (b) Merlic, C. A.; Pauly, M. E. J. Am. Chem.
Soc. 1996, 118, 11319.
(13) The complexes with substitution ortho to the biaryl juncture or to
the cycloheptyne on the A ring (4a,b, 9a-c) possess a diastereotopic
methylene in the 1H NMR spectrum, reflecting biaryl restricted rotation.
(14) Kira, K.; Tanda, H.; Hamajima, A.; Baba, T.; Takai, S.; Isobe, M.
Tetrahedron 2002, 58, 6485.
(12) Acetates were chosen over alcohol leaving groups due to their
superiority in benzocycloheptenyne complex syntheses; see ref 7a.
Org. Lett., Vol. 9, No. 26, 2007
5507

diisopropyl azodicarboxylate (DIAD) gave 13 (64%), and
subsequent reduction of the azide and acetylation of the
intermediate amine afforded target NSC 51046 (3) (88%
yield, 93% ee). A single recrystallization of 3 resulted in its
isolation in >99% ee.
Scheme 5. Completion of Synthesis of NSC 51046a
In summary, we have demonstrated that biaryl-2-propargyl
acetate-Co2(CO)6 complexes (4) undergo cyclization to
afford dibenzocycloheptyne-Co2(CO)6 complexes (9) under
mild, Lewis acid mediated conditions in fair to good yields.
The appropriate dibenzocycloheptyne complex (9a) may be
converted readily into allocolchicine NSC 51046 (3); to our
knowledge, this is the first de novo synthesis of this
allocolchicine in enantiomerically enriched form. The ap-
plication of the cyclization protocol to other allocolchicine
natural products is in progress and will be reported in due
course.
Acknowledgment. The authors wish to thank Michael
J. Siwek (St. Clair College), Nancy Mitrevski (St. Clair
College), and Juekang Liu (University of Windsor) for
preliminary experiments. We are grateful to NSERC (Canada),
the Canada Foundation for Innovation (CFI), and Ontario
Innovation Trust (OIT) for support of this research.
a Isolated with 7% of alkene 10.
While 11 has been converted previously to racemic 3,4,6
no fully synthetic enantioselective approach has been re-
ported. Therefore, adapting Wulff’s approach to (S)-allo-
colchicine to the current system, we subjected ketone 11 to
reaction with LiBH4-TARB-NO2, giving 12 in good yield
(96%) and enantiomeric purity (95% ee) (Scheme 5).
Substitution of the alcohol function with zinc azide16 and
Supporting Information Available: Experimental pro-
cedures and spectroscopic data for all new compounds. This
material is available free of charge via the Internet at
http://pubs.acs.org.
(15) Both 10 and 11 themselves also have significant tubulin assembly
inhibitory activity. See refs 1b,c and: (a) Polan´ski, J. Acta Biochim. Pol.
2000, 47, 37. (b) Han, S.; Hamel, E.; Bastow, K. F.; McPhail, A. T.; Brossi,
A.; Lee, K.-H. Bioorg. Med. Chem. Lett. 2002, 12, 2851.
OL7024422
(16) Viaud, M. C.; Rollin, P. Synthesis 1990, 130.
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