Regioselective ring-opening metathesis - Cross metathesis of bridgehead-substituted 7-azanprbornene

Article abstract of DOI:10.1021/ol0631051

Figure presented In this paper we describe a highly regioselective ring-opening metathesis-cross metathesis (ROM-CM) process between methyl N-Boc-7-azabicyclo[2.2.1]hept-2-en-1-carboxylate, a bridgehead-substituted 7-azanorbornene system, and electron-poo

Full text of DOI:10.1021/ol0631051

ORGANIC
LETTERS
2007
Vol. 9, No. 7
1235-1238
Regioselective Ring-Opening
Metathesis Cross Metathesis of
−
Bridgehead-Substituted
7-Azanorbornene†
J. Carreras, A. Avenoza,* J. H. Busto,* and J. M. Peregrina
Departamento de Qu´ımica, UniVersidad de La Rioja, Grupo de S´ıntesis Qu´ımica de La
Rioja, UA-CSIC, 26006 Logron˜o, Spain
alberto.aVenoza@unirioja.es; hector.busto@unirioja.es
Received December 22, 2006 (Revised Manuscript Received March 1, 2007)
ABSTRACT
In this paper we describe a highly regioselective ring-opening metathesis−cross metathesis (ROM−CM) process between methyl N-Boc-7-
azabicyclo[2.2.1]hept-2-en-1-carboxylate, a bridgehead-substituted 7-azanorbornene system, and electron-poor olefins. The reaction opens the
way to the synthesis of interesting -amino diacids and pyrrolizinone derivatives that incorporate quaternary stereocenters.
r
The metathesis reaction has appeared in recent times as a
powerful tool for the construction of complex organic
molecules.1 This reaction allows the production of highly
functionalized unsaturated polymers and small molecules.
The development of new, well-defined catalysts tolerant to
most functional groups has allowed this reaction to be carried
out on new substrates.2 In this sense, the ring-opening
metathesis-cross metathesis (ROM-CM or ROCM) reac-
tion of norbornene or oxanorbornene derivatives has received
a great deal of attention because it is a powerful entry for
the synthesis of highly substituted five-membered rings.3
When azanorbornenes are used in ROCM reactions with the
aim to synthesize polysubstituted pyrrolidines, particular
attention must be rendered on regioselectivity of this process.4
Nevertheless, in this context little is known about the use of
7-azanorbornenes as starting materials. Indeed, we have only
found four recent examples in the literature.5
As a part of our research project on the chemistry of
azanorbornanes,6 we planned to apply the ROCM reaction
to methyl N-Boc-7-azabicyclo[2.2.1]hept-2-en-1-carboxylate
(6) to study the metathesis reaction in bridgehead-substituted
systems to give interesting pyrrolidine derivatives. In par-
(3) (a) Schneider, M. F.; Blechert, S. Angew. Chem., Int. Ed. Engl. 1996,
35, 411-412. (b) Arjona, O.; Csa´ky¨, A. G.; Murcia, M. C.; Plumet, J. J.
Org. Chem. 1999, 64, 9739-9741. (c) Mayo, P.; Tam, W. Tetrahedron
2002, 58, 9513-9525. (d) Morgan, J. P.; Morril, C.; Grubbs, R. H. Org.
Lett. 2002, 4, 67-70. (e) Katayama, H.; Nagao, M.; Ozawa, F. Organo-
metallics 2003, 22, 586-593. (f) Schrock, R. R.; Hoveyda, A. H. Angew.
Chem., Int. Ed. 2003, 42, 4592-4633.
(4) (a) Schneider, M. F.; Lucas, N.; Velder, J.; Blechert, S. Angew. Chem.,
Int. Ed. Engl. 1997, 36, 257-259. (b) Arjona, O.; Csa´ky¨, A. G.; Plumet, J.
Synthesis 2000, 857-861. (c) Arjona, O.; Csa´ky¨, A. G.; Plumet, J. Eur. J.
Org. Chem. 2003, 611-622. (d) Ishikura, M.; Saijo, M.; Hino, A.
Heterocycles 2002, 57, 241-244. (e) Ishikura, M.; Saijo, M.; Hino, A.
Heterocycles 2003, 59, 573-579. (f) Ishikura, M.; Hasunuma, M.; Saijo,
M. Heterocycles 2004, 63, 5-8. (g) Ishikura, M.; Hasunuma, M.; Yanada,
K. Heterocycles 2005, 65, 2587-2592. (h) Felpin, F.-X.; Lebreton, J. Eur.
J. Org. Chem. 2003, 3693-3712.
† Dedicated to Prof. Miguel Yus on the occasion of his 60th birthday.
* To whom correspondence should be addressed. Fax (A.A.): +34 941
299621.
(1) (a) Chauvin, Y. Angew. Chem., Int. Ed. 2006, 45, 3740-3747. (b)
Schrock, R. R. Angew. Chem., Int. Ed. 2006, 45, 3748-3759. (c) Grubbs,
R. H. Angew. Chem., Int. Ed. 2006, 45, 3760-3765. (d) Deiters, A.; Martin,
S. F. Chem. ReV. 2004, 104, 2199-2238.
(2) Trnka, T. M.; Grubbs, R. H. Acc. Chem. Res. 2001, 34, 18-29.
10.1021/ol0631051 CCC: $37.00
© 2007 American Chemical Society
Published on Web 03/09/2007

ticular, we became interested in the participation of electron-
poor olefins, such as methyl acrylate, in the cross metathesis
process to obtain amino diacids with the pyrrolidine sub-
structure.7
In order to prepare compound 6 on a multigram scale, we
designed a synthetic pathway (Scheme 1) starting from
From this compound 2 and following a previously
published protocol8a,b that involves several steps, the corre-
sponding 7-azabicyclic system was obtained, which was
protected with (Boc)2O to obtain the new compound 3.
Deprotection of the O-acetyl group in derivative 3 with DBU,
followed by oxidation with Dess-Martin periodinane gave
the required ketone 4.
The enol triflate 5 was obtained from 4 by treatment with
LHMDS as a base and Comins triflating reagent.12 In an
effort to obtain the required olefin 6, we tried the reduction
of the enol triflate with Bu3SnH in the presence of lithium
chloride and palladium(0),13 which gave the desired com-
pound in good yield but accompanied by an excess of
organotin byproducts. We attempted to avoid the presence
of these byproducts by carrying out the reduction using
tributylammonium formate and Pd(OAc)2(PPh3)2 in DMF.14
In this case compound 6 was obtained in good yield on a
multigram scale (Scheme 1).
Scheme 1. Synthetic Route To Obtain Compound 6
When 6 was exposed to ROCM reaction conditions with
methyl acrylate (10 equiv) in dichloromethane using Grubbs
second generation catalyst, pyrrolidine 7a was exclusively
obtained but with a poor yield (Table 1, entry 1). Some
Table 1. Highly Regio- and Stereoselective ROCM Process for
Compound 6 and Methyl Acrylate
ketone 4, which was obtained by using an improved route
based on our previously reported method8 (see Supporting
Information).
The synthesis of ketone 4 started from commercially
available methyl 2-acetamidoacrylate (1), whose Diels-Alder
reaction with 1,3-butadiene to give cleanly compound 2 was
optimized for a multigram scale using methylaluminoxane
(MAO) instead of TiCl4 as a Lewis acid. In this sense, it is
important to notice that MAO is not an usual Lewis acid for
these processes; rather it was found to be an efficient
cocatalyst for olefin polymerization reactions.9 To the best
of our knowledge, only Yamamoto described its use as a
very strong and quite bulky Lewis acid in Diels-Alder
reactions,10 and recently, it has been used for the synthesis
of cyclobutanes by a formal [2 + 2] process.11
entry catalysta (equiv) solvent temp
time
yield (%)b
1
2
3
4
G (0.08)
G (0.08)
G (0.04)
CH2Cl2 rt
CHCl3
PhCH3 80 °C 24 h
PhCH3 80 °C 4 h
6 days
15
50
76
92
55 °C 48 h
H-G (0.04)
a G: Grubbs second generation catalyst, H-G: Hoveyda-Grubbs second
generation catalyst.
b Reaction followed by GC-MS and yield obtained from isolated product
after column chromatography.
(5) (a) Weeresakare, G. M.; Liu, Z.; Rainier, J. D. Org. Lett. 2004, 6,
1625-1627. (b) Liu, Z.; Rainier, J. D. Org. Lett. 2005, 7, 131-133. (c)
Liu, Z.; Rainier, J. D. Org. Lett. 2006, 8, 459-462. (d) Bu¨chert, M.; Meinke,
S.; Prenzel, A. H. G. P.; Deppermann, N.; Maison, W. Org. Lett. 2006, 8,
5553-5556.
(6) (a) Avenoza, A.; Cativiela, C.; Busto, J. H.; Peregrina, J. M.;
Tetrahedron Lett. 1995, 36, 7123-7126. (b) Avenoza, A.; Cativiela, C.;
Busto, J. H.; Ferna´ndez-Recio, M. A.; Peregrina, J. M.; Rodr´ıguez, F.
Tetrahedron 2001, 57, 545-548. (c) Avenoza, A.; Barriobero, J. I.; Busto,
J. H.; Cativiela, C.; Peregrina, J. M. Tetrahedron: Asymmetry 2002, 13,
625-632. (d) Avenoza, A.; Barriobero, J. I.; Busto, J. H.; Peregrina, J. M.
J. Org. Chem. 2003, 68, 2889-2894.
changes of solvent, temperature, and equivalents of Grubbs
catalyst led to an increase in the yield of the ROCM reaction.
Indeed, the use of chloroform at 55 °C and toluene at 80 °C
(10) Akakura, M.; Yamamoto, H. Synlett 1997, 277-278.
(11) Avenoza, A.; Busto, J. H.; Canal, N.; Peregrina, J. M.; Pe´rez-
Ferna´ndez, M. Org. Lett. 2005, 7, 3597-3600.
(12) (a) Comins, D. L.; Dehghani, A.; Foti, C. J.; Joseph, S. P. Org.
Synth. 1997, 74, 77-83. (b) Comins, D. L.; Dehghani, A. Tetrahedron Lett.
1992, 33, 6299-6302.
(13) Scott, W. J.; Crisp, G. T.; Stille, J. K. J. Am. Chem. Soc. 1984,
106, 4630-4632.
(14) Cacchi, S.; Morera, E.; Ortar, G. Tetrahedron Lett. 1984, 25, 4821-
4824.
(7) (a) Ma, D.; Yang, J. J. Am. Chem. Soc. 2001, 123, 9706-9707. (b)
Watanabe, H.; Okue, M.; Kobayashi, H.; Kitahara, T. Tetrahedron Lett.
2002, 43, 861-864.
(8) (a) Avenoza, A.; Cativiela, C.; Ferna´ndez-Recio, M. A.; Peregrina,
J. M. Synlett 1995, 891-892. (b) Avenoza, A.; Cativiela, C.; Ferna´ndez-
Recio, M. A.; Peregrina, J. M. Synthesis 1997, 165-167. (c) Avenoza, A.;
Cativiela, C.; Ferna´ndez-Recio, M. A.; Peregrina, J. M. Tetrahedron:
Asymmetry 1999, 10, 3999-4007.
(9) Zurek, E.; Ziegler, T. Prog. Polym. Sci. 2004, 29, 107-148.
1236
Org. Lett., Vol. 9, No. 7, 2007

gave yields of 50% and 76%, respectively (Table 1, entries
2 and 3). However, the best conditions involved the use of
Hoveyda-Grubbs catalyst,15 highly indicated for cross
metathesis reaction with electron-poor olefins. Indeed, the
use of toluene and 4 mol % of catalyst gave a 92% yield
(Table 1, entry 4).
gave only a moderate yield of the metathesis product (Table
2, entry 4).
Under the same reaction conditions, ketones such as
methyl vinyl ketone and ethyl vinyl ketone and aldehydes
as acrolein afforded poor yields of the required products (7f-
h), probably due to their high reactivity (i.e., auto-cross
metathesis). To prevent these side reactions, fewer equiva-
lents (2 equiv) of electron-poor olefin and 8 mol % (instead
of 4 mol %) of catalyst were used, obtaining good yields
(Table 2, entries 5-7).
Compound 7a and related systems (7b-h) are interesting
substrates to obtain amino diacids. Consequently, hydrogena-
tion with Pd-C as a catalyst, subsequent hydrolysis of the
Boc group with TFA, and final acid hydrolysis of the methyl
ester group afforded an interesting amino acid with a
quaternary stereocenter at the R carbon. This R-amino diacid
8 is a “chimera” of natural amino acids proline and
2-aminosuberic acid (Scheme 2). Moreover, it is important
In all conditions tested the reaction gave a single product.
However, the 1H NMR spectra are complex due the presence
of two conformers for the tert-butoxycarbonyl group (Boc).16
When the 1H NMR spectra were recorded at different
temperatures, we observed a single compound at 340 K
(Supporting Information). Therefore, it is important to notice
that this reaction gave a single regio- and stereoisomer and
the (Z) isomer was not detected. Although a few studies on
the effect of a remote substituent on the regioselectivity of
the ROCM reactions of unsymmetrical bicyclic systems have
been reported,3b,4c,5a,b,17 to the best of our knowledge, this is
the second time that a substituent in an allylic position
induced a complete regioselectivity, since we have only
found a single case in the literature and it refers to
unpublished work cited in a review.4c
Scheme 2. Synthesis of Amino Diacid 8
To expand the reactivity of compound 6 to other electron-
poor olefins, we examined the ROCM reaction with several
acrylates. Isobutyl, tert-butyl, and ethyl acrylates reacted
under the same conditions to give excellent yields of a single
stereoisomer (Table 2, entries 1-3), meaning that the size
Table 2. ROCM Reaction of Compound 6 with Electron-Poor
Olefins, Using Hoveyda-Grubbs Second Generation Catalyst
to note that compound 8 incorporates the substructure of
GABA,18 an inhibitory neurotransmitter found in the nervous
system, with a limited flexibility due to the restriction
imposed by the five-membered ring.
â,γ-Unsaturated amino acid derivatives have received a
great deal of attention since they are potential precursors to
new R-branched R-amino acids as building blocks for de
novo peptide design.19 Moreover, they are also important
enzyme inhibitors;20 for example, R-vinyl-R-amino acids are
known to inhibit amino acid decarboxylases.21 Therefore,
given the stability of these compounds to racemization, in
order to apply a similar vinyl-triggering strategy to the
mechanism-based inactivation of amino acid decarboxylase
enzymes, quaternary â,γ-unsaturated amino acids become
attractive targets.22 Given this background and the fact that
there are few methods available for the stereocontrolled
entry
R (equiv)
product
time (h)
yield (%)a
1
2
3
4
5
6
7
OiBu (10)b
OtBu (10)b
OEt (10)b
OH (10)c
Me (2)c
Et (2)c
H (2)c
7b
7c
7d
7e
7f
4
4
4
48
24
24
48
89
90
93
23
87
89
76
7g
7h
(17) Cuny, G. D.; Cao, J.; Shidu, A.; Hauske, J. R. Tetrahedron 1999,
55, 8169-8178.
(18) (a) GABA: Chebib, M.; Johnston, G. A. R. J. Med. Chem. 2000,
43, 1427-1447. (b) GABA-3-substituted: Bryans, J. S.; Wustrow, D. J.
Med. Res. ReV. 1999, 19, 149-177.
a Yield obtained from isolated product after column chromatography.
b Equivalents of electron-poor olefin used in the conditions: toluene at 80
°C and 4 mol % of catalyst. c Another addition of 4 mol % was made.
(19) (a) Altmann, E.; Nebel, K.; Mutter, M. HelV. Chim. Acta 1991, 74,
800-806, and references cited therein. (b) Baldwin, J. E.; Haber, S. B.;
Hoskins, C.; Kruse, L. I. J. Org. Chem. 1977, 42, 1239-1241. (c) Rose,
N. G. W.; Blaskovich, M. A.; Wong, A.; Lajoie, G. A. Tetrahedron 2001,
57, 1497-1507.
of the ester group does not affect the regioselectivity of
ROCM reaction. Acrylic acid was also tested, but the reaction
(20) (a) Rando, R. R. Biochemistry 1974, 13, 3859-3863. (b) Metcalf,
B. W.; Jund, K. Tetrahedron Lett. 1977, 41, 3689-3692.
(21) (a) Maycock, A. L.; Aster, S. D.; Patchett, A. A. DeV. Biochem.
1979, 6, 115-129. (b) Danzin, C.; Casara, P.; Claverie, N.; Metcalf, B. W.
J. Med. Chem. 1981, 24, 16-20. (c) Tendler, S. J. B.; Threadgill, M. D.;
Tisdale, M. J. J. Chem. Soc., Perkin Trans. 1 1987, 2617-2623.
(15) (a) Garber, S. B.; Kingsbury, J. S.; Gray, B. L.; Hoveyda, A. H. J.
Am. Chem. Soc. 2000, 122, 8168-8179. (b) Randl, S.; Gessler, S.;
Wakamatsu, H.; Blechert, S. Synlett 2001, 3, 430-432.
(16) Avenoza, A.; Busto, J. H.; Corzana, F.; Jime´nez-Ose´s, G.; Peregrina,
J. M. Tetrahedron 2003, 59, 5713-5718.
Org. Lett., Vol. 9, No. 7, 2007
1237

synthesis of quaternary â,γ-unsaturated amino acids,22 the
unsaturated quaternary amino diacid 10 is particularly
attractive (Scheme 3). This compound is a proline-derived
Scheme 4. Synthesis of Pyrrolizinone Core
Scheme 3. Synthesis of Unsaturated Amino Diacid 10
this pyrrolizinone core is present in azabicyclo[3.3.0]octanone
amino acids, particularly in 3-amino-2-oxo-1-azabicyclo-
[3.3.0]octane-8-carboxylic acid derivatives,25 which have
been used as restricted dipeptide surrogates in which the
peptide backbone is constrained within a fused bicyclic
skeleton.
In conclusion, we have achieved a highly regioselective
ROCM process between compound 6, a bridgehead-
substituted 7-azanorbornene, and electron-poor olefins. The
reaction opens the way to obtain interesting quaternary amino
diacids and the pyrrolizidinone core. In future works, we
aim to study the role of the bridgehead methyl ester in the
regiochemistry of this reaction.
R-vinyl-R-amino acid, whose synthesis was achieved by a
simple acid hydrolysis of compound 9, which was obtained
from compound 7a. Therefore, the tert-butoxycarbonyl group
of 7a was removed using TFA to give compound 9, whose
structure was confirmed by COSY, HSQC, and 2D-NOESY
experiments (see Supporting Information).
Hydrogenation of compound 7c, using Pd(OH)2/C as
catalyst in MeOH, gave the corresponding saturated com-
pound. Selective hydrolysis of the tert-butyl ester group of
this saturated compound was possible, and the use of TFA
allowed the concomitant hydrolysis of the N-Boc group to
give the corresponding γ-amino acid. Subsequent cyclization
using Mukaiyama’s reagent gave lactam 11 (Scheme 4).
This compound 11 is a pyrrolam23 derivative and contains
the pyrrolizinone core that is present in bioactive compounds
such as the telomerase inhibitor UCS1025A.24 In addition,
Acknowledgment. We thank the Ministerio de Educacio´n
y Ciencia and FEDER (project CTQ2006-05825/BQU and
Ramo´n y Cajal contract to J.H.B.) and the Gobierno de La
Rioja (ANGI-2004/03 and ANGI-2005/01 projects and a
grant to J.C.).
Supporting Information Available: Experimental de-
tails, spectroscopic characterization of all compounds, and
variable temperature NMR experiments. This material is
available free of charge via the Internet at http://pubs.acs.org.
(22) (a) Avenoza, A.; Cativiela, C.; Peregrina, J. M.; Sucunza, D.;
Zurbano, M. M. Tetrahedron: Asymmetry 1999, 10, 4653-4661. (b)
Berkowitz, D. B.; Chisowa, E.; McFadden, J. M. Tetrahedron 2001, 57,
6329-6343.
(23) (a) Majik, M. S.; Shet, J.; Tilve, S. G.; Parameswaran, P. S. Synthesis
2006, 663-665. (b) Watson, R. T.; Gore, V. K.; Chandupatla, K. R.; Dieter,
R. K.; Snyder, J. P. J. Org. Chem. 2004, 69, 6105-6114.
(24) (a) Lambert, T. H.; Danishefsky, S. J. J. Am. Chem. Soc. 2006,
128, 426-427. (b) Hoye, T. R.; Dvornikovs, V. J. Am. Chem. Soc. 2006,
128, 2550-2551. (c) Hoye, T. R.; Dvornikovs, V.; Sizova, E. Org. Lett.
2006, 8, 5191-5194.
OL0631051
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6996. (b) Salvati, M.; Cordero, F. M.; Pisaneschi, F.; Bucelli, F.; Brandi,
A. Tetrahedron 2005, 61, 8836-8847. (c) Cordero, F. M.; Pisaneschi, F.;
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Org. Lett., Vol. 9, No. 7, 2007