Azabicycloalkenes as synthetic intermediates: Application to the preparation of diazabicycloalkane scaffolds

Article abstract of DOI:10.1021/ol060287q

A general method to synthesize bicyclic dipeptide mimetics is reported. Key intermediates are azabicycloalkenes 9 and 17, which are prepared via Diels-Alder reactions and subsequent mild deprotection. These unsaturated bicyclic heterocycles are versatile

Full text of DOI:10.1021/ol060287q

ORGANIC
LETTERS
2006
Vol. 8, No. 8
1681-1684
Azabicycloalkenes as Synthetic
Intermediates: Application to the
Preparation of Diazabicycloalkane
Scaffolds
Alexander H. G. P. Prenzel, Nina Deppermann, and Wolfgang Maison*
Institut fu¨r Organische Chemie, UniVersita¨t Hamburg, Martin-Luther-King-Platz 6,
20146 Hamburg, Germany
maison@chemie.uni-hamburg.de
Received February 2, 2006
ABSTRACT
A general method to synthesize bicyclic dipeptide mimetics is reported. Key intermediates are azabicycloalkenes 9 and 17, which are prepared
via Diels Alder reactions and subsequent mild deprotection. These unsaturated bicyclic heterocycles are versatile intermediates for different
dipeptide mimetics of the aza- and diazabicycloalkane type, which is demonstrated by the synthesis of diazabicycloalkanes 11 and 19 in only
6 steps and good overall yield.
−
3
−
Fused bicyclic systems such as aza[x.y.0]bicycloalkanes 21,2
and diazabicyclo[x.y.0]alkanes 1 in Figure 1 play an impor-
tant role in the field of drug discovery and natural product
synthesis.3 They have been used as turn mimetics4 or
scaffolds for combinatorial chemistry5 and form the core
structures of numerous alkaloids.6
attention has been paid to diazabicyclo[x.y.0]alkane deriva-
tives such as 1.8 However, general protocols for the synthesis
of 1 and 2 were still missing.
Demands for a suitable synthetic route to compounds of
type 1 and 2 are high. Such a route has to be (a) short and
high yielding, (b) compatible with various side-chain func-
tionalities R1 and R2, (c) stereoselective with respect to
several stereocenters, and (d) variable concerning stereo-
chemistry.
An obvious starting point for a retrosynthetic analysis of
peptide mimetics 1 and 2 is the disconnection of the bicyclic
ring system along the tertiary amide. A substituted proline
derivative would thus be a suitable synthetic intermediate.
However, this approach resulted in somewhat lengthy
syntheses so far since the required substituted prolines are
difficult to prepare in enantiomerically pure form.9 Further-
more, introduction of side chains R2 (if feasible at all) is
Although a number of efficient synthetic protocols to
certain dipeptide mimetics of type 2 are known,7 less
(1) (a) Cluzeau, J.; Lubell, W. D. Biopolymers 2005, 80, 98-150. (b)
Hanessian, S.; McNaughton-Smith, G.; Lombart, H.-G.; Lubell, W. D.
Tetrahedron 1997, 53, 12789-12854.
(2) Heteroanalogues: (a) Tremmel, P.; Geyer, A. J. Am. Chem. Soc. 2002,
124, 8548-8549. (b) Qiu, W.; Gu, X.; Soloshonok, V. A.; Carducci, M.
D.; Hruby, V. J. Tetrahedron Lett. 2001, 42, 145-148.
(3) (a) Giannis, A.; Kolter, T. Angew. Chem. 1993, 105, 1303-1326;
Angew. Chem., Int. Ed. Engl. 1993, 32, 1244-1267. (b) Gante, J. Angew.
Chem. 1994, 106, 1780-1802; Angew. Chem., Int. Ed. Engl. 1994, 33,
1699-1720.
(4) Belvisi, L.; Colombo, L.; Colombo, M.; Di Giacomo, M.; Manzoni,
L.; Vodopivec, B.; Scolastico, C. Tetrahedron 2001, 57, 6463-6473.
(5) St.-Denis, Y.; Augelli-Szafran, C. E.; Bachand, B.; Berryman, K.
A.; DiMaio, J.; Doherty, A. M.; Edmunds, J. J.; Leblond, L.; Le´vesque, S.;
Narasimhan, L. S.; Penvose-Yi, J. R.; Rubin, J. R.; Tarazi, M.; Winocour,
P. D.; Siddiqui, M. A. Bioorg. Med. Chem. Lett. 1998, 8, 3193-3198.
(6) Azabicycloalkanes: (a) Michael, J. P. Nat. Prod. Rep. 2004, 21, 625-
649 and previous articles of this series. (b) Yoda, H. Curr. Org. Chem.
2002, 6, 223-243. (c) Felpin, F.-X.; Lebreton, J. Eur. J. Org. Chem. 2003,
3693-3712. Diazabicycloalkanes: (d) Marti, C.; Carreira, E. M. Eur. J.
Org. Chem. 2003, 2209-2219.
(7) (a) Belvisi, L.; Colombo, L.; Manzoni, L.; Potenza, D.; Scolastico,
C. Synlett 2004, 1449-1471. (b) Dietrich, E.; Lubell, W. D. J. Org. Chem.
2003, 68, 6988-6996. (c) Wang, W.; Yang, J.; Ying, J.; Xiong, C.; Zhang,
J.; Cai, C.; Hruby, V. J. J. Org. Chem. 2002, 67, 6353-6360. (d) Mulzer,
J.; Schulzchen, F.; Bats, J.-W. Tetrahedron 2000, 56, 4289-4298. (e)
Grossmith, C. E.; Senia, F.; Wagner, J. Synlett 1999, 1660-1662. (f) Wessig,
P. Tetrahedron Lett. 1999, 40, 5987-5988. (g) Hanessian, S.; Ronan, B.;
Laoui, A. Bioorg. Med. Chem. Lett. 1994, 4, 1397-1400.
10.1021/ol060287q CCC: $33.50
© 2006 American Chemical Society
Published on Web 03/18/2006

functionalized dipeptide analogues that are useful as modular
ligands with micromolar affinities for the prostate specific
membrane antigene (PSMA), a well-known tumor marker.13
In addition, they form the core structure of a number of
fungal metabolites with antimitotic properties such as the
spirotryprostatines, which we are currently synthesizing in
our lab. Although we have prepared a number of different
peptide mimetics 1 using our diastereoselective synthesis,14
it remains somewhat ineffective due to unproductive steps
for introduction and removal of a chiral auxiliary. For large
scale synthesis of scaffolds 1 for the combinatorial search
of cancer specific ligands and natural product syntheses we
were therefore in need of more efficient approaches.
Bicyclic allylamines such as 3 have been shown to be
excellent precursors for numerous attractive target structures
such as amino alcohols for catalysis,15 unnatural amino
acids,16 and other natural products17 and it was therefore
surprising to us, that preparation of enantiomerically pure 9
(Scheme 2) had not been achieved so far.18 The stereose-
lective synthesis of N-terminally deprotected azabicycloalk-
ene 9 is not a trivial task since the bicyclic ring system is
unstable with respect to a range of different deprotection
conditions.19 We were therefore focusing on imino-Diels-
Alder reactions of carbamate protected imines20,21 particularly
the copper-catalyzed protocol of Jørgensen,22 since some
carbamate protecting groups can be removed under mild
Figure 1. Retrosynthetic analysis of diaza[4.3.0]- and aza[4.3.0]-
bicycloalkanes 1 and 2.
performed at an early stage of the syntheses, limiting
structural diversity in this position.
We propose azabicycloalkenes 3 and 4 as synthetic
intermediates for dipeptide mimetics 1 and 2. Compounds 3
and 4 are masked substitutes of substituted prolines: If
submitted to the right cleavage conditions, their alkene
moiety permits the formation of the second ring system in 1
or 2 and generates at the same time a suitable functional
group for the introduction of side chains. This strategy finds
precedent in the work of Steglich, who has used diastereo-
selective imino-Diels-Alder reactions for the introduction
of the azanorbornene scaffold into peptides and its subsequent
conversion into disubstituted proline derivatives.10
The practicability of our strategy is demonstrated by the
synthesis of diazabicyclo[4.3.0]alkanes 1 in this paper. A
complete retrosynthetic analysis is shown in Figure 1.
Following this scheme, diazabicycloalkanes 1 would be
synthesized by an oxidative cleavage of alkenes 3 or 4. The
azabicycloalkene core of 3 and 4 would be synthesized by a
stereoselective imino-Diels-Alder reaction11 of carbamate
protected imines (3) or a known Diels-Alder reaction of
pyrrol (4).
(13) Maison, W.; Frangioni, J. V. Angew. Chem. 2003, 115, 4874-4876;
Angew. Chem., Int. Ed. 2003, 42, 4726-4728.
(14) Maison, W.; Grohs, D. C.; Prenzel, A. H. G. P. Eur. J. Org. Chem.
2004, 1527-1543.
(15) Nordin, S. J. M.; Roth, P.; Tarnai, T.; Alonso, D. A.; Brandt, P.;
Andersson, P. G. Chem. Eur. J. 2001, 7, 1431-1436.
(16) (a) Bertilsson, S. K.; Ekegren, J. K.; Modin, S. A.; Andersson, P.
G. Tetrahedron 2001, 57, 6399-6406. (b) Bailey, P. D.; McDonald, I. M.;
Rosair, G. M.; Taylor, D. Chem. Commun. 2000, 2451-2452.
(17) (a) Ward, S. E.; Holmes, A. B.; McCague, R. Chem. Commun. 1997,
2085-2086. (b) Baxter, E. W.; Labaree, D.; Chao, S.; Mariano, P. S. J.
Org. Chem. 1989, 54, 2893-2904. (c) Mariano, P. S.; Dunaway-Mariano,
D.; Huesmann, P. L. J. Org. Chem. 1979, 44, 124-133.
(18) For a racemic approach see: Hursthouse, M. B.; Malik, K. M. A.;
Hibbs, D. E.; Roberts, S. M.; Seago, A. J. H.; Sik, V.; Storer, R. J. Chem.
Soc., Perkin Trans. 1 1995, 2419-2425.
(19) In fact Grieco has proposed the azanorbornene scaffold as a
protection group for primary amines: Grieco, P. A.; Clark, J. D. J. Org.
Chem. 1990, 55, 2271-2272.
(20) There is little precedent for this reaction in the literature: (a) Yao,
S.; Saaby, S.; Hazell, R. G.; Jørgensen, K. A. Chem. Eur. J. 2000, 6, 2435-
2448. (b) Bunch, L.; Liljefors, T.; Greenwood, J. R.; Frydenvang, K.;
Bra¨uner-Osborne, H.; Krogsgaard-Larsen, P.; Madsen, U. J. Org. Chem.
2003, 68, 1489-1495.
(21) Only a few successful catalytic enantioselective conversions of
imines bearing readily removable carbamate protecting groups have been
reported so far. Mannich reactions: (a) Uraguchi, D.; Terada, M. J. Am.
Chem. Soc. 2004, 126, 5356-5357. (b) Matsunaga, S.; Yoshida, T.;
Morimoto, H.; Kumagai, N.; Shibasaki, M. J. Am. Chem. Soc. 2004, 126,
8777-8785. (c) Nakamura, Y.; Matsubara, R.; Kiyohara, H.; Kobayashi,
S. Org. Lett. 2003, 5, 2481-2484. (d) Wenzel, A. G.; Jacobsen, E. N. J.
Am. Chem. Soc. 2002, 124, 12964-12965. Friedel-Crafts reactions: (e)
Uraguchi, D.; Sorimachi, K.; Terada, M. J. Am. Chem. Soc. 2004, 126,
11804-11805. (f) Saaby, S.; Bayon, P.; Aburel, P. S.; Jørgensen, K. A. J.
Org. Chem. 2002, 67, 4352-4361. Aziridinations: (g) Aggarwal, V. K.;
Alonso, E.; Hynd, G.; Lydon, K. M.; Palmer, M. J.; Porcelloni, M.; Studley,
J. R. Angew. Chem. 2001, 113, 1482-1485; Angew. Chem., Int. Ed. 2001,
40, 1430-1433. Aza-Henry reaction: (h) Nugent, B. M.; Yoder, R. A.;
Johnston, J. N. J. Am. Chem. Soc. 2004, 126, 3418-3419. Addition of
enamides: (i) Matsubara, R.; Nakamura, Y.; Kobayashi, S. Angew. Chem.
2004, 116, 1711-1713; Angew. Chem., Int. Ed. 2004, 43, 1679-1681.
(22) Saaby, S.; Fang, X.; Gathergood, N.; Jørgensen, K. A. Angew. Chem.
2000, 112, 4280-4282; Angew. Chem., Int. Ed. 2000, 39, 4114-4116.
We have been particularly interested in diazabicycloal-
kanes of type 1 and have recently introduced a diastereose-
lective synthesis12 of these heterocycles. Scaffolds 1 are
(8) (a) Tong, Y.; Fobian, Y. M.; Wu, M.; Boyd, N. D.; Moeller, K. D.
J. Org. Chem. 2000, 65, 2484-2493. (b) Fai Chan, M.; Raju, B. G.; Kois,
A.; Varughese, J. I.; Varughese, K. I.; Balaji, V. N. Heterocycles 1999, 51,
5-8.
(9) For a review on the synthesis of aza- and diazabicycloalkanes see:
Maison, W.; Prenzel, A. H. G. P. Synthesis 2005, 1031-1049.
(10) Jaeger, M.; Polborn, K.; Steglich, W. Tetrahedron Lett. 1995, 36,
861-864.
(11) For reviews on stereoselective imino-Diels-Alder reactions see: (a)
Heintzelman, G. R.; Meigh, I. R.; Mahajan, Y. R.; Weinreb, S. M. Org.
React. 2005, 65, 141-599. (b) Buonora, P.; Olsen, J.-C.; Oh, T. Tetrahedron
2001, 57, 6099-6138. (c) Tietze, L. F.; Kettschau, G. Top. Curr. Chem.
1997, 189, 1-120.
(12) Maison, W.; Ku¨ntzer, D.; Grohs, D. C. Synlett 2002, 1795-1798.
1682
Org. Lett., Vol. 8, No. 8, 2006

alkaline conditions that should be compatible with the
bicyclic allylamine in 3.
We have found the preparation of carbamate protected
imines 7 (Scheme 1) to be a critical step in our sequence.
(3S)-8b were obtained in high yields and decent enantiose-
lectivities. It should be noted that the yields for azabicy-
cloalkenes 8 are given for the overall process starting from
serine or threonine derivatives. Fmoc-protected compounds
6 and 7, to the best of our knowledge, have not been reported
so far. However, they were of special interest to us, since
the resulting Diels-Alder adduct (3S)-8a can be deprotected
under mild alkaline conditions which are compatible with
the labile azanorbornene scaffold. Absolute stereochemistry
for compound (3S)-8b was verified by hydrogenation to the
known ethyl ester of azabicyclo[2.2.1]heptane carboxylic
acid28 and comparison of optical rotations.
Scheme 1. Preparation of Imines and Subsequent
imino-Diels-Alder Reaction to Azabicyclo[2.2.1]alkenes 8
With enantiomerically enriched compounds 8 in hand we
tried to establish a synthesis of dipeptide mimetics. Starting
from Fmoc-protected azabicycloalkene 8, deprotection of the
Fmoc group was performed under standard conditions in
DMF with piperidine to give the free amine 9.
Having in mind that a carbamate function provides a
suitable N-nucleophile for the desired ring closure to diaza-
bicycloalkanes,29 amine 9 was coupled to a Boc-protected
aspartate derivative with use of DCC/HOBt to give dipeptide
10 in good yield. The minor diastereoisomer of 10 was
readily separated on this stage by column chromatography
giving pure 10 (dr > 95:5). Oxidative double bond cleavage
of dipeptide 10 was performed with ozone according to
Scheme 2. Dipeptide 10 is thus converted to a bisaldehyde
Different methods for the synthesis of these versatile
synthetic intermediates are known, but in our hands all of
these procedures were either low yielding or gave side
products that were not compatible with our Lewis acid-
catalyzed Diels-Alder protocol.
A suitable strategy is depicted in Scheme 1. We started
from commercially available serine or threonine derivatives,
which were converted quantitatively to aminals 5 by using
a very recent oxidation protocol of Kita.23 Alternative
methods for the preparation of aminals 5 starting from
glyoxylates24 and serine or threonine derivatives25b have been
reported. However, we found the Kita protocol to be the
shortest and most convenient approach. Crude aminals 5 were
then transferred to bromo glycinates 6 again in nearly
quantitative yield. Dehydrohalogenation of R-bromo glyci-
nates to N-acylated imines has been used successfully in the
past.25 However, these dehydrohalogenations have been
performed with an excess of base, which we found not to
be compatible with our Lewis acid catalyzed imino-Diels-
Alder protocol. A suitable workaround is the use of solid
supported bases26 as outlined in Scheme 1. Bromo glycinates
6 were thus converted in high yields to imines 7, which were
transferred with a syringe to a reaction vessel containing a
chiral Cu(I) complex.27 After addition of cyclopentadiene,
enantiomerically enriched azabicycloalkenes (3S)-8a and
Scheme 2. Mild Deprotection of Azabicycloalkene 8 and
Subsequent Conversion of Unsaturated Dipeptide 10 to
Diazabicycloalkanes 11 and 12
intermediate that immediately cyclizes to give bicyclic aminal
11 in almost quantitative yield.
(23) Harayama, Y.; Yoshida, M.; Kamimura, D.; Kita, Y. Chem.
Commun. 2005, 1764-1766.
(24) (a) Williams, R. M.; Aldous, D. J.; Aldous, S. C. J. Org. Chem.
1990, 55, 4657-4663. (b) Zoller, U.; Ben-Ishai, D. Tetrahedron 1975, 31,
863-866.
This intermediate can be used for further derivatization
of the aldehyde function without purification. Wittig reaction
of 11, for example, gives diazabicycloalkane 12 in good yield
for this two- step sequence. Relative stereochemistry of 12
was established by 2D-NOESY NMR. The reaction in
Scheme 2 is illustrating the general applicability of our
(25) For example: (a) Taggi, A. E.; Hafez, A. M.; Lectka, T. Acc. Chem.
Res. 2003, 36, 10-19 and references therein. (b) Apitz, G.; Ja¨ger, M.; Jaroch,
S.; Kratzel, M.; Scha¨ffeler, L.; Steglich, W. Tetrahedron 1993, 49, 8223-
8232. (c) Bretschneider, T.; Miltz, W.; Muenster, P.; Steglich, W.
Tetrahedron 1988, 44, 5403-5414. (d) Malassa, I.; Matthies, D. Liebigs
Ann. Chem. 1986, 1133-1139.
(26) This method has been used in a different context before: see ref
21c.
(27) No loss of the Fmoc-protecting group was detected upon dehydro-
halogenation of bromoglycinate 6 with immobilized piperidine.
(28) Guijarro, D.; Pinho, P.; Andersson, P. G. J. Org. Chem. 1998, 63,
2530-2535.
(29) Grohs, D. C.; Maison, W. Tetrahedron Lett. 2005, 46, 4373-4376.
Org. Lett., Vol. 8, No. 8, 2006
1683

method since we had shown previously that aldehydes such
as 11 are extremely versatile precursors for a number of
different diazabicycloalkane peptide mimetics.30
In contrast to the sequence depicted in Scheme 2, syntheses
of diazabicycloalkanes 1 from alkenes 4 (Figure 1) start from
symmetrical azabicycloalkenes such as 13, 14, and 15 (Figure
2). A variety of these compounds is easily available by
resulting free amine 17 to an aspartate derivative with
standard coupling conditions. The azabicycloalkene was
cleaved oxidatively and the resulting bisaldehyde cyclized
in excellent yield to diazabicycloalkane 19.
It is interesting to note that amide 18 exists as a 1:1 mixture
of isomers (observable by 1H and 13C NMR) most likely due
to hindered rotation around the partial CN-double bond
between the aspartate and the azabicycloalkene core. The
cyclization to 19 proceeds, however, with excellent diaste-
reoselectivity with respect to stereocenters at C3, C6, and
C10b. The aminal at C1 is initially formed as an epimeric
mixture, which is converted to the 1,3-trans-isomer during
purification on silica gel. Aldehyde 19 is an excellent
intermediate for dipeptide mimetics imitating a phenylglycine
moiety in their C-terminal part and can be modified according
to our reported procedures.30 An example is the Wittig
olefination of 19 to give alkene 20 in good yield.
Figure 2. Symmetrical azabicycloalkene scaffolds.
In summary, we have reported an efficient synthesis of
diazabicycloalkane dipeptide mimetics such as 12 and 20 in
four steps from enantiomerically enriched azabicycloalkenes
8 or achiral derivatives 16. The key step in these sequences
is a domino reaction of oxidative cleavage and intramolecular
nucleophilic capture of the resulting bisaldehydes by a
nitrogen nucleophile. Azabicycloalkenes 8 are synthesized
via a catalytic enantioselective imino-Diels-Alder reaction.
Major advantages of our route are the low number of steps
required for the synthesis of dipeptide mimetics such as 11
and 19 and its variability with respect to stereochemistry and
the introduction of different side chains.
known Diels-Alder reactions of alkynes or benzynes with
pyrrole.31 Azabicycloalkene 13, for example, can be syn-
thesized from anthranilic acid (which is in situ converted to
benzyne) and N-Boc-pyrrole in good yield. We were hoping
for a stereoselective desymmetration of these heterocycles
at a later stage of the synthesis as depicted in Scheme 3.
Scheme 3. Formation and Oxidative Cleavage of Dipeptide
18, Spontaneous Intramolecular Ring Formation, and Subsequent
Wittig Olefination of Aldehyde 19
Enantiomerically enriched azabicycloalkenes 8 and achiral
analogues 16 are highly versatile synthetic intermediates.
They are useful for the synthesis of diazabicycloalkane
dipeptide mimetics and are also valuable intermediates for
natural product synthesis. We are currently elaborating a
suitable route to a number of antimitotic fungal metabolites
based on a 1,4-diazabicycloalkane scaffold along these lines.
Acknowledgment. We gratefully acknowledge the sup-
port of Prof. Dr. Chris Meier and Prof. Wittcko Francke.
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
Forschungsgemeinschaft (DFG MA 2529) for financial
support.
Azabicycloalkene 16 was converted to amide 18 by
deprotection with HCl in methanol and coupling of the
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.
(30) Grohs, D. C.; Maison, W. Amino Acids 2005, 29, 131-138.
(31) 13: Lautens, M.; Fagnou, K.; Zunic, V. Org Lett 2002, 4, (20),
3465-3468. 14: Hodgson, D. M.; Bebbington, M. W. P.; Willis, P. Org.
Biomol. Chem. 2003, 1, 3787-3798. 15: Otten, A.; Namyslo, J. C.;
Stoermer, M.; Kaufmann, D. E. Eur. J. Org. Chem. 1998, 1997-2001.
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