A concise asymmetric route to the bridged bicyclic tropane alkaloid ferruginine using enyne ring-closing metathesis

Article abstract of DOI:10.1021/ol049665m

Enyne metathesis has been used to prepare bridged azabicycles and applied in a short asymmetric synthesis of the tropane ferruginine. A Grubbs first generation catalyst proved to be superior to the second generation catalyst in the enyne metathesis reaction.

Full text of DOI:10.1021/ol049665m

ORGANIC
LETTERS
2
004
Vol. 6, No. 9
469-1471
A Concise Asymmetric Route to the
Bridged Bicyclic Tropane Alkaloid
Ferruginine Using Enyne Ring-Closing
Metathesis
1
Varinder K. Aggarwal,* Christopher J. Astle, and Mark Rogers-Evans†
School of Chemistry, Bristol UniVersity, Cantock’s Close, Bristol BS8 1TS, U.K.
V.aggarwal@bristol.ac.uk
Received February 25, 2004
ABSTRACT
Enyne metathesis has been used to prepare bridged azabicycles and applied in a short asymmetric synthesis of the tropane ferruginine. A
Grubbs first generation catalyst proved to be superior to the second generation catalyst in the enyne metathesis reaction.
Bridged azabicycles, like the well-known compound cocaine,
show a broad range of neurochemical activity. For example,
(between the carbonyl oxygen and substituents R to the
nitrogen) will result in the diaxial conformer being favored.
1
5
both anatoxin and ferruginine have potential in the treatment
2
of the neurodegenerative disorder Alzheimer’s disease. Their
biological activity coupled with an interesting architecture
has stimulated considerable synthetic activity, and aza-
bicycles have acted as important vehicles for the development
1
of new methods and strategies. As a novel strategy, we
considered the possibility of carrying out RCM of a suitable
precursor to assemble the bridged azabicycle. Although RCM
has been widely employed to construct cyclic and fused
bicyclic compounds, the construction of bridged bicycles
is much less common.4
3
Figure 1.
For successful RCM, it is important that the substrate
should easily be able to adopt the conformation required for
cyclization. Thus, to construct bridged azabicycles, the
precursor must be able to adopt a conformation in which
the two substituents are diaxial. This can best be achieved
Indeed, during the course of our work, Martin described such
a strategy utilizing disconnection A (Scheme 1). As we
wanted to access tropane alkaloids, e.g., ferruginine 1, we
6
1,3
using acyl or alkoxycarbonyl groups on nitrogen as A strain
Scheme 1. Retrosynthetic Analysis of the Tropane Bicycle
†
Based on Ring-Closing Metathesis
F. Hoffmann-La Roche Ltd., Pharmaceuticals Division, Lead Genera-
tion, PRBC-CI, Bldg 65/416, CH-4070 Basel, Switzerland.
(1) For a general review, see: Lounasmaa, M.; Tamminen, T. The
Alkaloids, The Tropane Alkaloids; Academic Press: New York, 1993; Vol.
4
4, pp 1-114.
2) Swanson, K. L.; Albuquerque, E. X. Handb. Exp. Pharmacol. 1992,
02, 620-621.
(
1
1
0.1021/ol049665m CCC: $27.50 © 2004 American Chemical Society
Published on Web 03/31/2004

needed to be able to introduce functionality in the six-
membered ring, and clearly this could most easily be done
through disconnection B with suitably substituted alkenes.
Furthermore, unlike disconnection A, disconnection B would
enable us to easily access enantiomerically pure material as
Scheme 3. Enol Ether Preparation and Attempts at RCMa
4
could potentially be obtained from L-pyroglutamic acid.
Pyroglutamic acid was first converted into the known
7
j
aminal 6 in four steps. Treatment with BF
3 2
‚OEt and
a
(
i) TiCl
4
(4.0 equiv), TMEDA (8 equiv), Zn (9 equiv), PbCl
Br (2.2 equiv), 25 °C, 4.5 h, THF, 45%. (ii)
2
allyltrimethylsilane gave the required cis product as the major
diastereomer (Scheme 2).7
(
0.046 equiv), CH
RCM.
2
2
13
to effect RCM using the Ru and Mo catalysts I, II, III,11
9
10
Scheme 2. Preparation of Allyl-ester 7a
1
2
13
and IV (Figure 2). Only unreacted starting material was
a
i
(
i) Pr
h. (ii) BOC
h, 92% over two steps. (iii) LiEt
h, 88%. (iv) MeOH, pTSA (0.1 equiv), 25 °C, 5 h, 98%. (v)
BF .OEt (1.03 equiv), allyltrimethylsilane (4.5 equiv), -78 to 25
C, Et O, 15 h, 93% (80:20, cis:trans).
2
EtN (1.2 equiv), BnBr (1.0 equiv), 0 to 55 °C, CH
O (1.2 equiv), DMAP (0.1 equiv), 25 °C, MeCN, 3
BH (1.2 equiv), -78 °C, THF, 2
2 2
Cl ,
5
2
3
3
2
°
2
The ester was converted into the enol ether 8 by the
8
modified Takai procedure (Scheme 3), but we were unable
Figure 2. Structures of the 1st, 2nd, and 3rd generation Grubbs
and Schrocks catalysts.
(3) For reviews of RCM, see: (a) Grubbs, R. H.; Chang, S. Tetrahedron
1
1
3
998, 54, 4413-4450. (b) Armstrong, S. K. J. Chem. Soc., Perkin Trans.
1998, 371-388. (c) Phillips, A. J.; Abell, A. D. Aldrichimica Acta 1999,
2, 75-89. (d) F u¨ rstner, A. Angew. Chem., Int. Ed. 2000, 39, 3012-3043.
observed. To determine whether active catalyst was still
present, dimethyl diallymalonate was added to the reaction
mixture after 1 h. Rapid ring closure of the malonate proved
that the catalyst had not become deactivated by the enol ether
or other adventitious impurities.
(e) Maier, M. E. Angew. Chem., Int. Ed. 2000, 39, 2073-2077. (f) Trnka,
T. M.; Grubbs, R. H. Acc. Chem. Res. 2001, 34, 18-29. (g) Semeril, D.;
Bruneau, C.; Dixneuf, P. H. AdV. Synth. Catal. 2002, 344, 585-595. (h)
Poulsen, C. S.; Madsen, R. Synthesis 2003, 1, 1-18. (i) Hoveyda A. H.;
Gillingham D. G.; Van Veldhuizen J. J.; Kataoka O.; Garber S. B.;
Kingsbury J. S.; Harrity J. P. A. Org. Biomol. Chem. 2004, 2, 8-23.
(
4) Neipp, C. E.; Martin, S. F. J. Org. Chem. 2003, 68, 8867-8878 and
references therein.
5) For a review, see: Hoffman, R. W. Chem. ReV. 1989, 89, 1841-
860.
To test whether the problem lay with enol ether metathesis
(which is known to be a more difficult cyclization than
(
1
14
simple diene metathesis) or substrate conformation, we
(
6) Neipp, C. E.; Martin, S. F. Tetrahedron Lett. 2002, 43, 1779-1782.
(7) Although this reaction has been described to furnish a 95:5 (cis:trans)
prepared diene 10, and this time RCM occurred uneventfully
to give the bridged azabicycle 11 in good yield (Scheme 4).
This showed that our strategy for controlling the diaxial
conformation had been successful, but to easily access the
enone required for the synthesis of ferruginine we needed a
ratio of diastereomers we have not been able to reproduce this result (80:
0, cis:trans obtained). See: (a) Shono, T.; Fujita, T.; Matsumura, Y. Chem.
Lett. 1991, 81-84. (b) Ma, D.; Yang, J. J. Am. Chem. Soc. 2001, 123,
706-9707. Other workers have also reported levels of selectivity similar
to our own. See: (c) Chiesa, M. V.; Manzoni, L.; Scalastico, C. Synlett
2
9
1
3
1
2
996, 441-443. (d) Beal, L. M.; Moeller, K. D. Tetrahedron Lett. 1998,
9, 4639-4642. (e) Grossmith, C. E.; Senia, F.; Wagner, J. Synlett 1999,
0, 1660-1662. (f) Mulzer, J.; Schulzchen, F.; Bats, J.-W. Tetrahedron
000, 56, 4289-4298. (g) Tong, Y.; Forbian, Y. M.; Wu, M.; Boyd, N.
(10) Scholl, M.; Ding, S.; Lee, C. W.; Grubbs, R. H. Org. Lett. 1999, 1,
953-956.
D.; Moeller, K. D. J. Org. Chem. 2000, 65, 2484-2493. (h) Manzoni, L.;
Colombo, M.; May, E.; Scolastico, C. Tetrahedron 2001, 57, 249-255. (i)
Zhang, X.; Schmitt, A. C.; Jiang, W. Tetrahedron Lett. 2001, 42, 5335-
(11) Love, J. A.; Morgan, J. P.; Trnka, T. M.; Grubbs, R. H. Angew.
Chem., Int. Ed. 2002, 41, 4035-4037.
(12) Murdzek, J. S.; Schrock, R. R. Organometallics 1987, 6, 1373-
1374.
5
2
338. (j) Kim, S.; Hayashi, K.; Kitano, Y.; Tada, M.; Chiba, K. Org. Lett.
002, 4, 3735-3737. (k) Harris, P. W. R.; Brimble, M. A.; Gluckman, P.
(13) Grubbs 1st, 2nd, and 3rd generation catalysts in either dichlo-
romethane or benzene, Schrocks catalyst in degassed pentane, at both room
temperature and reflux, with concentrations ranging from 0.005 to 0.1 M.
(14) (a) Louie, J.; Grubbs, R. H. Organometallics 2002, 21, 2153-2164
and references therein. (b) Aggarwal, V. K.; Daly, A. D. Chem. Commun.
2002, 2490-2491.
D. Org. Lett. 2003, 5, 1847-1850.
(
8) Takai, K.; Kataoka, Y.; Miyai, J.; Okazoe, T.; Oshima, K.; Utimoto,
K. Org. Synth. 1996, 73, 73-84.
9) Schwab, P.; France, M. B.; Ziller, J. W.; Grubbs, R. H. Angew. Chem.,
Int. Ed. Engl. 1995, 34, 2039-2041.
(
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Org. Lett., Vol. 6, No. 9, 2004

Scheme 4. Diene Preparation and RCMa
Scheme 6. Enyne RCM and Wacker Oxidationa
a
4
(i) LiAlH (2 equiv), 0 °C, THF, 10 min., 78% (pure cis isomer).
a
(
Cl
i) 1st generation Grubbs I (10 mol %), reflux, 0.01 M in
(
8
1
ii) Dess-Martin periodinane (2.1 equiv), 25 °C, DCM, 30 min,
CH
2
2
, 50 °C, 10 h, 86%. (ii) PdCl
2
(0.1 equiv), CuCl
2
(2.1 equiv),
, 3 h, then
(1.6
5%. (iii) CH
6 h, 93%. (iv) 2nd generation Grubbs II (10 mol %), reflux, 0.005
, 90 min, 87%.
3 3
PPh Br (1.1 equiv), n-BuLi (1.1 equiv), 25 °C, THF,
H
K
2
O, 95 °C, DMF, 6 h, 81%. (iii) TFA, 25 °C, CH
CO (aq) (1 M), 93%. (iv) CH
CN, 15 min, 97%.
2
Cl
2
O (5 equiv), NaCNBH
3
6 6
M in C H
2
3
2
equiv), CH
3
differentially functionalized alkene. We therefore considered
the possibility of enyne metathesis, as this should generate
a diene. However, literature precedent for enyne metathesis
to furnish bridged bicycles was particularly rare. The
required enyne 13 was prepared by reduction of the ester 7
to the aldehyde 12 as described in Scheme 4 followed by
decline. Thus, the active metathesis catalyst was destroying
1
8
the product during the reaction. This led us to test the less
active first generation Grubbs catalyst I. This time the
metathesis reaction resulted in clean buildup of the required
tropane 15 in high isolated yield. Examples where the Grubbs
first generation catalyst is superior to the later generations
are rare. This important example of enyne metathesis adds
1
5
homologation using a modified version of the Gilbert
reagent16 (Scheme 5).
1
9
to this growing list.
Wacker oxidation of the terminal alkene gave methyl
ketone 16 (Scheme 6), which has been deprotected and
N-methylated in 90% yield, thus completing the synthesis
Scheme 5. Enyne Preparation and Attempted RCMa
20
of ferruginine 1.
In summary, we have developed an efficient asymmetric
synthesis of ferruginine (12 steps and 29% overall yield)21
using inexpensive L-pyroglutamic acid. The key step involved
enyne metathesis, which required the first generation Grubbs
catalyst as the more active second generation catalyst caused
subsequent destruction of the diene. The synthesis was
completed with a Wacker oxidation giving the enone 16.
As enones are common motifs in bridged azabicycles and
many other natural products, this strategy could find wide
usage.
a
(
i) CH
3
COCN
2
PO(OEt)
2
(1.2 equiv), K
2
CO
3
(2 equiv), 25 °C,
2
dCH ,
MeOH, 1.5 h, 93%. (ii) Catalysts I-III (10 mol %), CH
reflux, 0.01 M in CH Cl or C
2
2
2
6 6
H .
We began our investigation using conditions that are
commonly used for ring closure of terminal enynes: the
Grubbs second generation catalyst II under an atmosphere
Acknowledgment. We thank Hoffman-La Roche for
17
of ethylene. However, under these conditions and employ-
ing any of the metathesis catalysts I-III, the major product
was triene 14 (Scheme 5). As ethylene was clearly becoming
incorporated, we decided to conduct the metathesis under
an inert atmosphere. Although we obtained clean conversion
by GC-MS to the desired tropane 15 (Scheme 6) with
catalysts II or III, our isolated yields were very low. To
determine whether the problem occurred during product
isolation (active catalyst present with product diene could
cause dimerization) or during the course of the reaction (e.g.,
ring-opening polymerization/acyclic diene polymerization)
the reaction was monitored by GC-MS with an internal
standard. This clearly showed a buildup in the concentration
of the product to a steady-state level followed by a slow
financial support.
Supporting Information Available: Experimental pro-
cedures and full characterization for all compounds. This
material is available free of charge via the Internet at
http://pubs.acs.org.
OL049665M
(
18) GC-MS analysis of the reaction mixture only showed product and
starting material, implying that the byproducts formed are nonvolatile. We
speculate that the active metathesis catalyst was converting the desired
product 15 into the (nonvolatile) homodimer.
(19) For recent examples, see: (a) F u¨ rstner, A.; Thiel, O. R.; Ackermann,
L.; Schanz, H.-J.; Nolan, S. P. J. Org. Chem. 2000, 65, 2204-2207. (b)
Boiteau, J.; Van de Weghe, P.; Eustache, J. Org. Lett. 2001, 3, 2737-
2740. (c) F u¨ rstner, A.; Guth, O.; D u¨ ffels, A.; Seidel, G.; Liebl, M.; Gabor,
B.; Mynott, R. Chem. Eur. J. 2001, 7, 4811-4820. (d) Clark, J. S.;
Elustondo, F.; Trevitt, G. P.; Boyall, D.; Robertson, J.; Blake, A. J.; Wilson,
C.; Stammen, B. Tetrahedron 2002, 58, 1973-1982. (e) Poulsen, C. S.;
Madsen, R. J. Org. Chem. 2002, 67, 4441-4449.
(
15) (a) Rodr ´ı guez, J. R.; Castedo, L.; Mascare n˜ as. J. L. Chem. Eur. J.
2
6
002, 8, 2923-2930. (b) Neipp, C. E.; Martin, S. F. J. Org. Chem. 2003,
8, 8867-8878 and references therein.
(
16) (a) Gilbert, J. C.; Weerasooriya, U. J. Org. Chem. 1982, 47, 1837-
(20) Hernandez, A. S.; Thaler, A.; Castells, J.; Rapoport,H. J. Org. Chem.
1996, 61, 314-323.
1
845. (b) Ohira, S. Synth. Commun. 1989, 19, 561-564. (c) M u¨ ller, S.;
Liepold, B.; Roth, G. J.; Bestmann, H. J. Synlett 1996, 521-522.
17) Mori, M.; Sakakibara, N.; Kinoshita, A. J. Org. Chem. 1998, 63, 3,
082-6083. For a review of enyne metathesis see ref 3h.
(21) For one of the best previous syntheses of ferruginine (8 steps, 11%
overall yield), see: Gauthier, I.; Royer, J.; Husson, H.-P. J. Org. Chem.
1997, 62, 6704-6705.
(
6
Org. Lett., Vol. 6, No. 9, 2004
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