Tandem RCM of Dienynes for the Construction of Taxol-Type Carbocyclic Systems

Article abstract of DOI:10.1021/ol036062m

(Matrix presented) Tandem ring-closing metathesis of hydrindanone dienynes allows access to taxosteroids, a new class of compounds that combine the [5.3.1] carbocyclic system of taxanes with rings C and D of the steroid skeleton.

Full text of DOI:10.1021/ol036062m

ORGANIC
LETTERS
2
004
Vol. 6, No. 2
93-196
Tandem RCM of Dienynes for the
Construction of Taxol-Type Carbocyclic
Systems
1
Rebeca Garcia-Fandi n˜ o, Eva M. Codesido, Eduardo Sobarzo-S a´ nchez,
Luis Castedo, and Juan R. Granja*
Departamento de Qu ´ı mica Org a´ nica e Unidade Asociada o´ CSIC, Facultade de
Qu ´ı mica, UniVersidade de Santiago, 15706 Santiago de Compostela, Spain
qojuangg@usc.es
Received October 22, 2003
ABSTRACT
Tandem ring-closing metathesis of hydrindanone dienynes allows access to taxosteroids, a new class of compounds that combine the [5.3.1]
carbocyclic system of taxanes with rings C and D of the steroid skeleton.
Interest in polycyclic systems containing eight-membered
carbocycles stems both from the synthetic challenge of their
construction and from their wide range of biological activi-
ties. We have recently embarked on the preparation of
linearly fused 6-8-6 carbocyclic systems with a view to
step construction of the [5.3.1] system of Taxol (1), within
a “taxosteroid” structure in which the [5.3.1] system is fused
to the [4.3.0] bicycle constructing rings C and D of the steroid
system. Interest in this type of structure derives from the
recently shown ability of synthetic 2-ethoxyestradiol and
steroid analogues to mimic paclitaxel in increasing tubulin
1
obtaining steroid-like compounds that simulate the transition-
4
state structure of the previtamin-vitamin D
process. For these syntheses, we have developed a very
efficient ring-closing metathesis reaction (RCM) that allows
3
isomerization
assembly and stabilizing microtubules.
2
2a
Following our success with dienyne 2a, we wished to
3
5
evaluate the scope of dienyne RCM for the construction of
efficient construction of the desired systems from dienyne
polycarbocyclic systems containing an eight-membered ring.
We envisaged that elongation of the alkynyl chain (n ) 1)
would allow construction of the bicyclo[5.3.1]undecadiene
system characteristic of taxanes (Figure 1). The use of
hydrindanone 3 as a platform would both aid formation of
2a
2a. Here, we report that RCM of dienyne 2b achieves one-
(1) For reviews, see: (a) Oishi, T.; Ohtsuka, Y. In Studies in Natural
6
Products Synthesis; Atta-ur-Rahman, Ed.; Elsevier: Amsterdam, 1989; Vol.
3
5
, pp 73-115. (b) Petasis, N. A.; Patane, M. A. Tetrahedron 1992, 48,
757-5821. (c) Rousseau, G. Tetrahedron 1995, 51, 2777-2849. (d)
Molander, G. A. Acc. Chem. Res. 1998, 31, 603-609. (e) Mehta, G.; Singh,
V. Chem. ReV. 1999, 99, 881-990.
(4) Wang, Z. Q.; Yang, D. L.; Mohanakrishnan, A. K.; Fanwick, P. E.;
Nampoothiri, P.; Hamel, E., Cushman, M. J. Med. Chem, 2000, 43, 2419-
2429. Wu, J. H.; Batist, G.; Zamir, L. O. Anti-Cancer Drug Design 2001,
16, 129-133.
(5) (a) Kim, S.-H.; Bowden, N.; Grubbs, R. H. J. Am. Chem. Soc. 1994,
116, 10801-10802. (b) Kim, S.-H.; Zuercher, W. J.; Bowden, N. B.;
Grubbs, R. H. J. Org. Chem. 1996, 61, 1073-1081. (c) Zuercher, W. J.;
Scholl, M.; Grubbs, R. H. J. Org. Chem. 1998, 63, 4291-4298. (d) F u¨ rstner,
A.; Liebl, M.; Hill, A. F.; Wilton-Ely, J. D. E. T. Chem. Commun. 1999,
601-602. (d) Boyer, F.-D.; Hanna, I.; Ricard, L. Org. Lett. 2001, 3, 3059-
3098.
(2) (a) Codesido, E. M.; Castedo, L.; Granja, J. R. Org. Lett. 2001, 3,
1
4
483-1486. (b) Codesido, E. M.; Castedo, L.; Granja, J. R. Org. Lett. 2002,
, 1651-1654.
(3) For reviews of metathesis, see: (a) F u¨ rstner, A. Angew. Chem., Int.
Ed. 2000, 39, 3012-3043. (b) Chang, S.; Grubbs, R. H. Tetrahedron 1998,
4, 4413-4450. For a recent view of the synthesis of medium-sized rings
by RCM, see: (c) Maier, M. E. Angew. Chem., Int. Ed. 2000, 39, 2073-
077. For a more general review of the synthesis of medium-sized rings,
see: (d) Yet, L. Chem. ReV. 2000, 100, 2963-3007.
5
2
1
0.1021/ol036062m CCC: $27.50 © 2004 American Chemical Society
Published on Web 12/19/2003

Scheme 1a
Figure 1. Retrosynthetic analysis of the construction of the
taxosteroid skeleton by RCM of dienyne 2b.
a
Key: (a) MeI, CO
3
Na, DMF, 77%; (b) LDA, propargyl
2
the eight-membered ring and provide a CD system on which
bromide, THF, 43%; (c) LiAlH
5%; (e) (i) KHMDS, toluene/DMF, -78 °C, (ii) 5a, 79%; (f)
allylMgBr, THF, 95%; (g) 11a, CH Cl , ∆, 44%.
4 2 3
, THF, 94%; (d) I , PPh , imidazole,
the side-chain characteristic of steroids could be introduced.
Like 2a, dienyne 2b would be prepared from ketone 3 by
alkylation of its kinetic enolate followed by ketone allylation.
The alkylating agent, iodide 5a, was prepared in four steps
from 4-hexenoic acid by esterification with methyl iodide
in basic DMF, alkylation of the LDA-generated enolate of
the resulting ester, reduction with lithium aluminum hydride,
and treatment of the resulting alcohol with triphenylphos-
phine, imidazole, and iodine (Scheme 1). Iodide 5a was
reacted with the kinetic enolate of 3 (formed by reaction
8
2
2
We therefore decided to try the more reactive Grubbs
catalyst 11b, which has also been shown to be very useful
for dienyne RCM. To our surprise, none of the previous
compounds containing eight-membered rings were formed
when dienyne 7a was treated with this catalyst; only the
triene 12a was isolated (Scheme 2).
8
5
d
with potassium hexamethyldisilazide in 1:1 DMF/toluene at
7
-
80 °C), and the resulting ketone 6a was allylated, giving
dienyne 7a in 59% yield (from 3) as an inseparable 1:1
mixture of C10-epimers. Treatment of 7a with 15% of
Grubbs catalyst 11a provided a 2:2:1 mixture of RCM
products 8a, 9a, and 10 with a global yield of 44%.
Compound 8a is formed by simple diene RCM. Compound
Scheme 2
10 is a single isomer, suggesting that only one of the
diastereomers of 7a can undergo the double cyclization, the
other giving compound 9a (an hypothesis that was confirmed
by the nonformation of 10 upon treatment of triene 9a with
catalysts 11a or 11b). Although the above results showed
the feasibility of the proposed strategy, the Taxol-like
skeleton was only a minor product.
(6) Taxol: Science and Applications; Suffness, M., Ed.; CRC: Boca
Raton, FL, 1995. Taxane Anticancer Agents: Basic Science and Current
Status; Georg, G. I., Chen, T. T., Ojima, I., Vyaqs, D. M., Eds.; ACS
Symposium Series 583; American Chemical Society: Washington, DC,
1
995. Kingston, D. G. I.; Jagtap, P. G.; Yuan, H.; Samala, L. Prog. Chem.
Org. Prod. 2002, 84, 53-225. Mekhail, T. M.; Markman, M. Expert Opin.
These results suggest a different reaction mechanism for
catalysts 11a and 11b due to their binding to the substrate
at different sites. In the case of 11a, it would appear that
Pharmacother. 2002, 3, 755-766. Miller, M. L. Ojima, I. Chem. Rec. 2001,
1
, 195-211. Kingston, D. G. I. Chem. Commun. 2001, 867-880. Nicolaou,
K. C.; Guy, R. K. Angew. Chem., Int. Ed. Engl. 1995, 34, 2079-2090.
Rowinsky, E. K.; Cazenave, L. A.; Donebower, R. C. J. Natl. Cancer Inst.
1
990, 82, 1247-1259.
7) Palomo, C.; Oiarbide, M.; Mielgo, A.; Gonz a´ lez, A.; Garc ´ı a, J.; Landa,
C.; Lecumberri, A.; Linden, A. Org. Lett. 2001, 3, 3249-3252.
(
(8) Scholl, M.; Ding, S.; Lee, C. W.; Grubbs, R. H. Org. Lett. 1999, 1,
953-956.
194
Org. Lett., Vol. 6, No. 2, 2004

initial reaction of the catalyst with the less-substituted double
bond allows reaction of the resulting intermediate 13a with
either the other olefin (generating enyne 8a) or with the
alkynyl group (affording the new vinylideneruthenium(II)
intermediate 14a); RCM of the R isomer of 14a would then
afford 10, while the S isomer, cyclization of which would
Scheme 3a
9
be prevented by its geometry, would react with another
molecule of 7a (CM), generating a new molecule of 13a
and leaving compound 9a as product. In the case of 11b, on
the other hand, it would seem that initial reaction of the
catalyst with the acetylene group must provide the conjugated
metallovinylidene 15a, in which the Ru would react pref-
erentially to form the cyclopentene 12a (thermodynamically
more stable than the cyclooctene alternative) despite the
formation of the five-membered ring requiring reaction with
the more substituted olefin.
a
Key: (a) NaOEt, BrCH
2
CCH, THF, ∆, 86%; (b) NaOEt,
BrCH
2 4
CHCH-R, 77-85%; (c) NaOEt, EtOH, 32-55%; (d) LiAlH ,
2 3
THF, 89-94%; (e) I , PPh , imidazole, 86-98%.
alkylation of the resulting anion of the diethyl ester of
-propargylmalonate, and then decarboxylation, reduction,
and iodine substitution provided the iodides 5a-c.
2
The results of using the various substrates with 11a or
1
1b are listed in Table 1. Substrates 7a, 7b, and 7c all
afforded the desired taxosteroid 10, but as expected, the yield
Table 1. Results of Subjecting Substrates 6 to RCM
Conditions
increased upon increasing the steric impediment to the diene
1
2
RCM (R or R ) Me, Et, i-Pr; entries 1, 3, and 5). In the
1
0
case of 7b and 7c, it was possible to separate the two C10
diastereomers, and as expected, only one gave the desired
1
1
product 10 (entries 3 and 5). Neither of the substrates with
a disubstituted olefin afforded compound 10. With 7d, the
use of catalyst 11a led to triene 9d as major product (48%),
1
2
while the use of 11b produced 12d. With 7e, in which the
alkynyl group is also methylated, catalyst 11a afforded triene
9
e in 48 % yield as the sole isolable product. These results
show that formation of the [5.3.1] bicyclic-ring system by
RCM is possible, but it also suggests that only one of the
isomers can adopt the conformation necessary for the
annulation. Selection of appropriate substituents on the olefin
allows the tuning of the RCM process.
relative ratiosb
global
In view of the molecular mechanical evidence that only
the R C10 isomers of 14 can cyclize, and in order to establish
the configuration of the taxosteroids, we prepared enantiopure
alkylating agent 5c. Stereoselective alkylation of (4E)-6-
entry 7a R1 R2 R3 catalyst
8
9
10 12 yieldc
1
2
3
4
5
6
7
8
9
7a Me
7a Me
7b1 Et
7b2 Et
H
H
H
H
iPr
iPr
H
H
H
H
H
H
H
H
11a
11b
11a
11a
11a
11a
11a
11b
11a
40
0
50
90
0
0
0
0
0
40 20
0
100
0
10
0
44
20
80
97
90
55
60
20
38
0
0
0
0
50d
0
13
methyl-4-heptenoic acid (16) with 1-bromo-3-trimethylsi-
lylpropyne using (4R,5S)-(+)-4-methyl-5-phenyl-2-oxazoli-
dinone as chiral auxiliary, followed by reduction with lithium
aluminum hydride, desilylation with TBAF, and treatment
with iodine/triphenylphosphine, provided 5c-(S) (Scheme
7c1
7c2
H
H
11 89d
100
80
0
0
0
0
0
0
7d Me Me
7d Me Me
7e Me Me Me
20
100
0
1
4
4
). Alkylation of the kinetic enolate of 3 with iodide
c-(S), followed by allylation of the resulting ketone, then
100
5
a
C10 epimers separated by flash chromatography are differentiated by
gave a 74% yield of compound 7c-(R), the spectroscopic
characteristics of which agreed with those of the reactive 7c
epimer. The stereochemistry of 10 at C10 was confirmed
an arbitrary suffix, where 1 denotes the 10R-isomer and 2 the 10S-isomer.
b
c
Relative ratios were calculated by NMR of crude mixture. Global isolated
d
yields. Higher isolated yields of 10 were obtained when neutral alumina
was used to purify the crude RCM product.
(
9) As is supported by molecular mechanical calculations.
(10) Alkylation of the kinetic enolate of 3 with iodide 5c gave the two
Since the use of catalyst 11b had failed to improve the
yield afforded by substrate 7a, we prepared the alternative
substrates 7b-e (Table 1), which were designed to prevent
the undesired formation of the diene RCM products (8) and/
or the tetraene intermediates 15. The method used to obtain
the alkylating agents needed it to prepare these substrates is
shown in Scheme 3: propargylation of the triethyl meth-
anetricarboxylate, followed by decarboxylation and in situ
C10-diastereomers in 4:1 ratio, the one affording compound 10 being the
minor isomer.
(
11) The other isomer failed to afford 10 even when other conditions
were tried (different solvent, catalyst, etc.).
12) Treatment of compound 9d with 11b for 12 h gave compound 10
in 18% yield.
(
(13) Kaga, H.; Goto, K.; Takahashi, T.; Hino, M.; Tokuhashi, T.; Orito,
K. Tetrahedron 1996, 52, 8451-8470.
(14) The enantiomeric excess was determined by using the Mosher
modified method; see: Dale, J. A.; Dull, D. L.; Mosher, H. S. J. Org. Chem.
1969, 34, 2543-2549.
Org. Lett., Vol. 6, No. 2, 2004
195

of dienynes and have used this approach to construct the
first member of a novel class of compounds that we have
called taxosteroids because they contain both the character-
istic [5.3.1] system of taxanes and the side chain and CD
system of steroids. Studies aimed at introducing additional
functional groups on the taxosteroid skeleton and at estab-
lishing the pharmacological and biological properties of
the new compounds are underway. It is envisaged that this
approach should allow access to other complex polycyclic
systems starting from conformationally locked cycloalka-
nones.
Scheme 4a
Acknowledgment. Financial support from the Ministerio
de Ciencia y Tecnolog ´ı a and the Xunta de Galicia, under
projects SAF2001-3120 and PGIDIT02PXIC20902PN, re-
spectively, is gratefully acknowledged. We also thank the
Xunta de Galicia and Ministerio de Ciencia y Tecnolog ´ı a
a
Key: (a) (i) pivaloyl chloride, Et
+)-4-methyl-5-phenyl-2-oxazolidinone, DMPA, rt, 80%; (b) LiH-
MDS, BrCH CCTMS, THF, -78 °C, 67%; (c) LiAlH , THF, 0
C; (d) TBAF, THF, 90% (two steps); (e) I , PPh , imidazole, 75%;
f) (i) KHMDS, DMF, -78 °C, (ii) 5c-(S), 70%; (g) allylMgBr,
THF, 90%; (h) 11a, CH Cl , ∆, 90%.
3
N, THF, -78 °C, (ii) (4R,4S)-
(
2
4
°
(
2
3
(FPI) for fellowships awarded to R.G.-F.
2
2
Supporting Information Available: Experimental pro-
1
13
cedure as well as H and C NMR spectra of compounds 4,
5
7
a-d, 5c-(S), 6a-e, 6c-(R), 7a, 7b-(R), 7b-(S), 7c-(R),
c-(S), 7e, 17, 19c, and 10. This material is available free
when subjecting 7c-(R) to the RCM condition that with 11a
as catalyst afforded 10 in 80% yield.
of charge via the Internet at http://pubs.acs.org.
In conclusion, we have shown for the first time that [5.3.1]
systems can be constructed by tandem ring-closing metathesis
OL036062M
196
Org. Lett., Vol. 6, No. 2, 2004