Azabicycloalkenes as synthetic intermediates - Synthesis of azabicyclo[x.3.0]alkane scaffolds

Article abstract of DOI:10.1021/ol062219+

A general method to synthesize functionalized azabicyclo[X.3.0]alkane scaffolds 5 is reported. Key intermediates are azabicycloalkenes such as 1 and 2, which are acylated with unsaturated carboxylic acids and subsequently submitted to tandem olefin metathesis. The resulting bicyclic heterocycles are versatile intermediates for different dipeptide mimetics and can be used as intermediates for natural products with indolizidine scaffolds or analogues thereof.

Full text of DOI:10.1021/ol062219+

ORGANIC
LETTERS
2006
Vol. 8, No. 24
5553-5556
Azabicycloalkenes as Synthetic
Intermediates Synthesis of
Azabicyclo[X.3.0]alkane Scaffolds
−
Marina Bu1chert, Sebastian Meinke, Alexander H. G. P. Prenzel,
Nina Deppermann, and Wolfgang Maison*
Justus-Liebig UniVersita¨t Gieâen, Institut fu¨r Organische Chemie,
Heinrich-Buff-Ring 58, 35392 Gieâen, Germany
maison@chemie.uni-hamburg.de
Received September 7, 2006
ABSTRACT
A general method to synthesize functionalized azabicyclo[X.3.0]alkane scaffolds 5 is reported. Key intermediates are azabicycloalkenes such
as 1 and 2, which are acylated with unsaturated carboxylic acids and subsequently submitted to tandem olefin metathesis. The resulting
bicyclic heterocycles are versatile intermediates for different dipeptide mimetics and can be used as intermediates for natural products with
indolizidine scaffolds or analogues thereof.
Conformationally constrained dipeptide mimetics based on
azabicyclo[X.Y.0]alkane scaffolds have found numerous
applications in medicinal and bioorganic chemistry.1 In
addition, the azabicycloalkane structural motif forms the core
of many natural products with pharmacological relevance
such as indolizidine and quinolizidine alkaloids and aza-
sugars.2 In consequence, a number of groups have developed
efficient syntheses of these bicyclic heterocycles.3
Ring-closing metathesis (RCM) and tandem metathesis4
have been particularly successful strategies for the assembly
of common natural product scaffolds.5 Application of RCM
to the synthesis of peptide mimetics was first described by
Grubbs6 and later extended by several other groups.7 Key
intermediates in these approaches are often alkenyl-
substituted pyrrolidines, which are N-acylated with an
unsaturated carboxylic acid and submitted to ring-closing
metathesis (RCM).
Inspired by the elegant concept of intramolecular ring-
opening/ring-closing metathesis (RORCM) established by the
groups of Blechert, Grubbs, and Hoveyda,8 we wanted to
(5) (a) Martin, W. H. C.; Blechert, S. Curr. Top. Med. Chem. 2005, 5,
1521-1540. (b) Nakamura, I.; Yamamoto, Y. Chem. ReV. 2004, 104, 2127-
2198. (c) Deiters, A.; Martin, S. F. Chem. ReV. 2004, 104, 2199-2238. (d)
Larry, Y. Chem. ReV. 2000, 100, 2963-3008. (e) Phillips, A. J.; Abell, A.
D. Aldrichimica Acta 1999, 32, 75-89. (f) Fuerstner, A. Top. Organomet.
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1998, 371-388. (h) Grubbs, R. H.; Chang, S. Tetrahedron 1998, 54, 4413-
4450. (i) Schuster, M.; Blechert, S. Angew. Chem., Int. Ed. Engl. 1997, 36,
2037-2056.
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150. (b) Belvisi, L.; Colombo, L.; Manzoni, L.; Potenza, D.; Scolastico, C.
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Des. 2003, 9, 1209-1224.
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2003, 3693-3712. (c) Yoda, H. Curr. Org. Chem. 2002, 6, 223-243.
(3) Reviews: (a) Maison, W.; Prenzel, A. H. G. P. Synthesis 2005, 1031-
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45, 5987-5990. (c) Harris, P. W. R.; Brimble, M. A.; Gluckman, P. D.
Org. Lett. 2003, 5, 1847-1850. (d) Hoffmann, T.; Lanig, H.; Waibel, R.;
Gmeiner, P. Angew. Chem., Int. Ed. 2001, 40, 3361-3364. (e) Lim, S. H.;
Ma, S.; Beak, P. J. Org. Chem. 2001, 66, 9056-9062. (f) Beal, L. M.; Liu,
B.; Chu, W.; Moeller, K. D. Tetrahedron 2000, 56, 10113-10125. (g)
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10.1021/ol062219+ CCC: $33.50
© 2006 American Chemical Society
Published on Web 10/24/2006

use N-acylated 2- 9 and 7-azabicycloalkenes 1 and 2 as
precursors for azabicyclo[X.3.0]alkanes 5. This is part of a
general synthetic concept using azabicycloalkenes as masked
analogues of functionalized pyrrolidines or piperidines.10
In particular, symmetrical derivatives of 7-azabicyclo-
alkenes 2 are in this context very interesting substrates
because they can be desymmetrized by either diastereo-
selective or enantioselective metathesis. Both 2- and 7-azabi-
cycloalkenes are easy to synthesize11 via Diels-Alder
reaction, and a stereoselective catalytic approach to 1 has
been recently reported by our group, giving access to
enantiomerically pure scaffolds 5 (Figure 1).12
Scheme 1. Acylation of 2-Azabicycloalkenes 9, 11, and 13
stereomeric mixture 9 and enantiomerically enriched azabi-
cycloalkanes 11 and 13, which were synthesized by an
enantioselective catalytic imino Diels-Alder reaction.12 As
acyl compounds, we chose vinylacetic acid for model studies,
Cbz-vinylglycine, and Boc-allylglycine for the synthesis of
dipeptide mimetics.
Figure 1. Retrosynthetic analysis of indolizidine scaffold 5.
The choice of educt 9 was due to stereochemical reasons
because we wanted to evaluate endo and exo isomers of
3-substituted 2-azabicycloalkene scaffolds. Therefore, azabi-
cycloalkene 9 was an ideal starting material because it can
be synthesized as a racemic mixture of (at this point
unseparable) endo and exo isomers. However, both dia-
stereoisomers are easily separated by column chromatogra-
phy after acylation with vinylacetic acid, giving exo-10 and
endo-10.
Our catalytic approach gives enantiomerically enriched
azabicycloalkenes 11 and 13 with high exo selectivity.
Metathesis precursor 12, resulting from coupling of (S)-
vinylglycine to 11, is therefore an excellent intermediate for
the synthesis of enantiomerically pure dipeptide mimetics
of general structure 5.
Synthesis of suitable metathesis precursors was achieved
according to Scheme 1 by acylation of the racemic dia-
(8) Selected examples of tandem ROM/(R)CM metathesis of alkenylated
strained bicyclic compounds: (a) Hart, A. C.; Phillips, A. J. J. Am. Chem.
Soc. 2006, 128, 1094-1095. (b) Funel, J.-A.; Prunet, J. Synlett 2005, 235-
238. (c) Takao, K.-I.; Yasui, H.; Yamamoto, S.; Sasaki, D.; Kawasaki, S.;
Watanabe, G.; Tadano, K.-I. J. Org. Chem. 2004, 69, 8789-8795. (d)
Lesma, G.; Crippa, S.; Danieli, B.; Sacchetti, A.; Silvani, A.; Virdis, A.
Tetrahedron 2004, 60, 6437-6442. (e) Holtsclaw, J.; Koreeda, M. Org.
Lett. 2004, 6, 3719-3722. (f) Schaudt, M.; Blechert, S. J. Org. Chem. 2003,
68, 2913-2920. (g) Wrobleski, A.; Sahasrabudhe, K.; Aube´, J. J. Am. Chem.
Soc. 2002, 124, 9974-9975. (h) Hagiwara, H.; Katsumi, T.; Endou, S.;
Hoshi, T.; Suzuki, T. Tetrahedron 2002, 58, 6651-6654. (i) Banti, D.;
North, M. Tetrahedron Lett. 2002, 43, 1561-1564. (j) Minger, T. L.;
Phillips, A. J. Tetrahedron Lett. 2002, 43, 5357-5359. (k) Limanto, J.;
Snapper, M. L. J. Am. Chem. Soc. 2000, 122, 8071-8072. (l) Adams, J.
A.; Ford, J. G.; Stamatos, P. J.; Hoveyda, A. H. J. Org. Chem. 1999, 64,
9690-9696. (m) Stragies, R.; Blechert, S. Synlett 1998, 169-170. (n) Burke,
S. D.; Quinn, K. J.; Chen, V. J. J. Org. Chem. 1998, 63, 8626-8627. (o)
Stille, J. R.; Santarsiero, B. D.; Grubbs, R. H. J. Org. Chem. 1990, 55,
843-862.
(9) For a parallel study in the Blechert group, see: N. Rodriguez y
Fischer, Ringumlagerungsmetathesen zu Azacyclen, Dissertation, TU Berlin,
2004. For ROCM of 2-azabicycloalkenes see: Dunne, A. M.; Mix, S.;
Blechert, S. Tetrahedron Lett. 2003, 44, 2733-2736. 2-Azabicycloalkenones
have been studied by Plumet: Arjona, O.; Csa´ky, A. G.; Medel, R.; Plumet,
J. J. Org. Chem. 2002, 67, 1380-1383. For ROM/CM of 2-azabicyclo-
alkenones, see: Ishikura, M.; Saijo, M.; Hino, A. Heterocycles 2003, 59,
573-585.
Olefin metatheses were performed according to Scheme
2. Careful control of reaction conditions was essential for
successful conversions. Ruthenium precatalysts 7 and 8
(Figure 2) gave comparable results and were more effective
Scheme 2. Olefin Metathesis of Bisolefins 10
(10) For other applications of this general strategy, see: (a) Grohs, D.
C.; Maison, W. Amino Acids 2005, 29, 131-138. (b) Grohs, D. C.; Maison,
W. Tetrahedron Lett. 2005, 46, 4373-4376. (c) Maison, W.; Grohs, D. C.;
Prenzel, A. H. G. P. Eur. J. Org. Chem. 2004, 1527-1543. (d) Arakawa,
Y.; Ohnishi, M.; Yoshimura, N.; Yoshifuji, S. Chem. Pharm. Bull. 2003,
51, 1015-1020. (e) Arakawa, Y.; Murakami, T.; Yoshifuji, S. Chem. Pharm.
Bull. 2003, 51, 96-97. (f) Arakawa, Y.; Murakami, T.; Ozawa, F.; Arakawa,
Y.; Yoshifuji, S. Tetrahedron 2003, 59, 7555-7563. (g) Maison, W.;
Ku¨ntzer, D.; Grohs, D. C. Synlett 2002, 1795-1798. (h) Jaeger, M.; Polborn,
K.; Steglich, W. Tetrahedron Lett. 1995, 36, 861-864.
(11) Reviews: (a) Heintzelman, G. R.; Meigh, I. R.; Mahajan, Y. R.;
Weinreb, S. M. Org. React. 2005, 65, 141-599. (b) Chen, Z.; Trudell, M.
L. Chem. ReV. 1996, 96, 1179-1193.
(12) Prenzel, A. H. G. P.; Deppermann, N.; Maison, W. Org. Lett. 2006,
8, 1681-1684.
5554
Org. Lett., Vol. 8, No. 24, 2006

Scheme 3. Synthesis of Dipeptide Mimetics 19 and 20
Figure 2. Ruthenium-based precatalysts for olefin metathesis.
than 6, which gave significantly lower yields. An important
parameter for the synthesis of azabicycloalkanes 15 and 17
is temperature. If substrates 10 are treated with precatalysts
7 or 8 at room temperature, the conversion to 15 or 17 is
clean but yields are low (<20% of 15 or 17 along with
unreacted starting material 10). In refluxing dichloromethane,
yields for indolizidines 15 or 17 are better. However, these
conditions require a relatively high catalyst loading (10 mol
%) and lead to the formation of side products, which have
been identified by NMR as pyridone 16 and products derived
from olefin isomerization of products 15 or 17.
In some cases, the benzylidene ligand of precatalyst 7 was
incorporated by cross metathesis into the olefinic side chain
of target structures 15 or 17.13 Metathesis products derived
from endo-10 were particularly prone to rapid aromatization,
and a substantial amount (∼5%) of pyridone 16 was observed
by NMR immediately following the reaction. Within hours,
the amount of pyridone 16 grows significantly, if the sample
is not strictly excluded from air. Most likely, this type of
aromatization occurs via a peroxide pathway from either 15
or the R,â-unsaturated bicyclic lactam that is generated by
isomerization of 15. In consequence, 15 needs to be stored
under a strict inert atmosphere if it is to be used for further
conversions. Similar side reactions were observed for olefin
metathesis of exo-10, although aromatization to 18 was much
slower in this case.
Concentration is another important parameter because
concentrated solutions of 10 in dichloromethane gave
significant amounts of oligomerized products. However,
educt concentrations of 0.01 M were found to give indoli-
zidines 15 and 17 in good yields for endo and exo precursors.
In addition, it was essential to perform all metatheses of
azabicycloalkenes 10 under an ethylene atmosphere to
enhance catalyst initialization.
Having established suitable reaction conditions for olefin
metathesis, we turned our attention to the synthesis of
bicyclic dipeptide mimetics. As depicted in Scheme 3,
azabicycloalkene dipeptides 12 and 14 were submitted to
the standard conditions for olefin metathesis. Desired bicyclic
dipeptide mimetics 19 and 20 were thus obtained in good
yields, respectively. However, increased amounts of side
products were noted for the metathesis of bisolefin 12
compared to the corresponding reaction starting from exo-
10 depicted in Scheme 2. This is due to a substantial amount
of olefin isomerization of 19 and aromatization to the
corresponding pyridone derivative. These side products were
not isolated, but identified by NMR from the crude mixture.
A much cleaner conversion was observed with educt 14 to
give dipeptide mimetic 20 along with unreacted starting
material. Seven-membered heterocycle 20 was obtained as
a mixture of two diastereoisomers and is less prone to olefin
isomerization than its six-membered analogue 19.
It should be noted that bicyclic compounds 19 and 20 are
ready for structural modification in both parts of the dipeptide
mimetic because the internal double bond at the N-terminus
and the external double bond at the C-terminus are easily
differentiated. Our route thus addresses a major drawback
of known syntheses to azabicycloalkane dipeptide mimetics,
and a number of these useful compounds with various amino
acid side chains at both termini are now accessible.
Different metal-catalyzed protocols for desymmetrization
of 7-azabicycloalkenes or their oxa-analogues have been
shown to be excellent methods for the construction of
valuable chiral synthetic intermediates.14 In this context,
asymmetric tandem metathesis has been achieved with
symmetrical norbornenes and oxanorbornenes as educts.15
A transfer of this reaction to 7-azabicycloalkenes such as
22 and 25 has not been reported so far to the best of our
knowledge.16 However, it would lead to the formation of
extremely interesting chiral scaffolds for the synthesis of
dipeptide mimetics or natural products.
We chose azabicycloalkene 21 for our first studies because
it is easy to synthesize on a large scale and it should give
interesting isoindole scaffolds in the final products.
Conversion of 21 to metathesis precursor 22 was per-
formed in a two-step procedure via deprotection of the Boc
group with HCl17 and coupling of vinylacetic acid to the
resulting free amine with DCC/HOBt to give 22 (Scheme
4). When bisolefin 22 was submitted to the standard
metathesis conditions, the unexpected products were pyri-
dones 23 and 24 in overall 35% yield along with large
(14) For recent examples, see: (a) Cho, Y.-H.; Zunic, V.; Senboku, H.;
Olsen, M.; Lautens, M. J. Am. Chem. Soc. 2006, 128, 6837-6846 and
references cited therein. (b) Namyslo, J. C.; Kaufmann, D. E. Synlett 1999,
804-806.
(15) Review: Arjona, O.; Csa´k, A. G.; Plumet, J. Eur. J. Org. Chem.
2003, 611-622.
(16) For tandem metathesis of unsymmetrical 7-azabicycloalkenes, see:
Liu, Z.; Rainier, J. D. Org. Lett. 2006, 8, 459-462.
(17) Carpino, L. A.; Barr, D. E. J. Org. Chem. 1966, 31, 764-767.
(13) It has been reported that precatalysts 7 and 8 generate reactive
ruthenium species at an elevated temperature promoting a number of
unwanted side reactions: Hong, S. H.; Day, M. W.; Grubbs, R. H. J. Am.
Chem. Soc. 2004, 126, 7414-7415.
Org. Lett., Vol. 8, No. 24, 2006
5555

Scheme 4. Acylation of 21 and Subsequent RORCM
Scheme 5. ROCM of Boc-Protected 7-Azabicycloalkene 21
amount of an additional isoindole 29 resulting from ROCM
of azabicycloalkene 21 and ethylene was observed. The
formation of this side product is due to the relatively low
reactivity of methyl butenoate in these ROCMs and its
homodimerization resulting in small quantities of ethylene
in the reaction mixture.
It should be noted that reaction conditions for metatheses
of 7-azabicycloalkenes such as 21 are significantly milder
(room temperature vs 40 °C) and that catalyst loading can
be substantially lower (can be lowered to 1% with still
acceptable yields) if compared to the corresponding reactions
with 2-azabicycloalkenes (see Schemes 2 and 3).
amounts of unreacted starting material. This is remarkable
because at least a ROCM sequence of azabicycloalkene 21
with ethylene would be expected. With a turnover of only
three, the Grubbs catalyst 7 is thus quite ineffective in this
metathesis reaction. Although the underlying mechanism
leading to the unique product distribution and reactivity for
the conversion of 22 to 23 and 24 were not clear, we assumed
that either the structure of the educt 22 (location of the
exocyclic double bond) or the aromatization was the reason
for the low catalytic efficiency.
We tested this hypothesis with metathesis precursor 25,
which was synthesized according to a known protocol for
one-pot acylation of azabicycloalkene 21 with pentenoyl
chloride.18 As expected, bisolefin 25 was converted smoothly
to the corresponding seven-membered ring system under
standard metathesis conditions. This metathesis product was
difficult to purify and was therefore hydrogenated to give
26, which was isolated in pure form after column chroma-
tography.
Cyclization of 27 to the corresponding lactam should be
easy to perform, and suitable conditions are reported in the
literature for similar substrates.19
In conclusion, we presented our initial studies on tandem
metatheses of 2- and 7-azabicycloalkenes to give function-
alized bicyclic scaffolds useful for the preparation of
dipeptide mimetics and various natural products. As a general
trend, it has been found that 7-azabicycloalkenes are
significantly more reactive than 2-azabicycloalkenes.
A suitable workaround for the corresponding six-mem-
bered ring systems is a sequence of ring opening and cross
metathesis (ROCM) of azabicycloalkene 21 with vinylacetic
acid and subsequent intramolecular cyclization. This type
of ROCM has been accomplished for another 7-azabi-
cycloalkene scaffold by Rainier and co-workers.19 Reactions
can be performed according to Scheme 5 at room temperature
without an ethylene atmosphere to give disubstituted iso-
indoles 27 and 28 in good to excellent yields. In the reactions
with methyl butenoate as the CM partner, a significant
Acknowledgment. We gratefully acknowledge helpful
discussions with Prof. Dr. Chris Meier. We are grateful to
BASF AG, Degussa AG, and Merck KgaA for material
support. We thank the Alexander von Humboldt-Stiftung,
Fonds der Chemischen Industrie, and the Deutsche Fors-
chungsgemeinschaft (DFG MA 2529) for financial support.
Supporting Information Available: Experimental details
and characterization data for all new compounds. This
material is available free of charge via the Internet at
http://pubs.acs.org.
(18) Lautens, M.; Fagnou, K.; Zunic, V. Org. Lett. 2002, 4, 3465-3468.
(19) Liu, Z.; Rainier, J. D. Org. Lett. 2005, 7, 131-133.
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