One-pot synthesis of macrocycles by a tandem three-component reaction and intramolecular [3+2] cycloaddition

Article abstract of DOI:10.1021/ol061782p

By combining three appropriately designed simple substrates, a programmed sequence involving an α-isocyano acetamide-based three-component reaction followed by a copper-catalyzed intramolecular [3+2] cycloaddition of alkyne and azide took place to afford complex macrocycles in moderate to good yields. One macrocycle and two heterocycles were produced with concurrent formation of five chemical bonds in this operationally simple process.

Full text of DOI:10.1021/ol061782p

ORGANIC
LETTERS
2006
Vol. 8, No. 18
4145-4148
One-Pot Synthesis of Macrocycles by a
Tandem Three-Component Reaction and
Intramolecular [3+2] Cycloaddition
Tracey Pirali,† Gian Cesare Tron,*,† and Jieping Zhu‡
Dipartimento di Scienze Chimiche, Alimentari, Farmaceutiche e Farmacologiche and
Drug and Food Biotechnology Center, UniVersita` degli Studi del Piemonte Orientale
“A. AVogadro”, Via BoVio 6, 28100 NoVara, Italy, and Institut de Chimie des
Substances Naturelles, CNRS, 91198 Gif-sur-YVette Cedex, France
tron@pharm.unipmn.it
Received July 20, 2006
ABSTRACT
By combining three appropriately designed simple substrates, a programmed sequence involving an
r
-isocyano acetamide-based three-
component reaction followed by a copper-catalyzed intramolecular [3+2] cycloaddition of alkyne and azide took place to afford complex
macrocycles in moderate to good yields. One macrocycle and two heterocycles were produced with concurrent formation of five chemical
bonds in this operationally simple process.
Macrocycles often display remarkable biological activities
and many of them are used as drugs.1 Several factors are
responsible for this attractive behavior. For example, mac-
rocycles, unlike their linear counterparts, possess a smaller
number of accessible energetic conformations. This effect
reduces the entropic penalty related to the binding to the
target increasing the biological activity.2 Nevertheless, they
still show enough mobility to use different conformations
during the pharmacokinetic and pharmacodynamic phases.
This is particularly useful as true rigid analogues might show
an increased biological activity in vitro with respect to their
linear counterpart, but turn out to be poorly active in vivo
on account of pharmacokinetic problems.3 Macrocycles
might, therefore, pass over this problem by the fact that they
constitute a compromise between conformational preorga-
nization and flexibility. A classic pathway leading to macro-
cycles consists of a stepwise construction of a linear substrate
followed by a ring closure.4 While this approach has been
extensively employed in target-oriented synthesis of single
compounds, its limitation in diversity-oriented synthesis of
macrocyclic libraries is self-evident.5 An alternative and high-
ly efficient strategy involving a sequence of a multicompo-
nent reaction-post functionalization has attracted much
6,7
attention over the past decade
and indeed several types
of complex macrocycles are now readily accessible in only
a few steps by applying this strategy.8 On the other hand, a
(3) (a) Navia, M. A.; Chaturvedi, P. R. Drug DiscoVery Today 1996, 1,
179-189. (b) Veber, D. F.; Johnson, S. R.; Cheng, H. Y.; Smith, B. R.;
Ward, K. W.; Kopple, K. D. J. Med. Chem. 2002, 43, 2615-2623.
(4) For reviews: (a) Parenty, A.; Moreau, X.; Campagne, J.-M. Chem.
ReV. 2006, 106, 911-939. (b) Gibson, S. E.; Lecci, C. Angew. Chem., Int.
Ed. 2006, 45, 1364-1377.
(5) Burke, M. D.; Schreiber, S. L. Angew. Chem., Int. Ed. 2004, 43,
46-58.
(6) Marcaccini, S.; Torroba, T. In Multicomponent Reaction; Zhu, J.,
Bienayme´, H., Eds.; Wiley-VCH: Weinheim, Germany, 2005; pp 33-75.
† Universita` degli Studi del Piemonte Orientale “A. Avogadro”.
‡ Institut de Chimie des Substances Naturelles.
(1) Wessjohann, L. A.; Ruijter, E.; Garcia-Rivera, D.; Brandt, W. Mol.
DiVersity 2005, 9, 171-186.
(2) (a) Tyndall, J. D. A.; Fairlie, D. P. Curr. Med. Chem. 2001, 8, 893-
907. (b) Wermuth, C. G. The Practice of Medicinal Chemistry; Academic
Press: New York, 2003. (c) Silverman, R. B. The organic chemistry of
drug design and drug action; Academic Press: New York, 2004.
10.1021/ol061782p CCC: $33.50
© 2006 American Chemical Society
Published on Web 08/09/2006

one-step multicomponent synthesis of macrocycles from
readily accessible starting materials remains elusive and only
a very few examples exist in the literature.9 In connection
with our ongoing project, we were interested in developing
a one-pot synthesis of macrocycle 1 from appropriately
functionalized isocyanoacetamides,10 aldehydes, and amines.
The underlying principle is shown in Scheme 1.
capable of promoting the formation of 5a in excellent yield,
efforts were concentrated on the subsequent intramolecular
[3+2] azide-alkyne cycloaddition of analyticly pure oxazole
5a (R1 ) n-C6H13, R2 ) Bn, R3 ) Bn, m ) 1, n ) 2, Scheme
1). After extensive screening of reaction parameters varying
the copper sources, solvents, bases, and temperatures, it was
found that intramolecular alkyne/azide cycloaddition took
place smoothly in tetrahydrofuran at room temperature in
the presence of freshly purified copper iodide12 and an excess
of diisopropylamine to produce 1a (R1 ) n-C6H13, R2 ) Bn,
R3 ) Bn, m ) 1, n ) 2, Scheme 1) in over 90% yield.13
With this result, the synthesis of 1a from 2a, 3a, and 4a,
without isolation of 5-aminooxazole 5a, was realized as
follows: heating a toluene solution of 2a, 3a, and 4a in the
presence of ammonium chloride (1.5 equiv) at 80 °C for 4
h was followed, after removal of inorganic salt by filtration,14
by addition of CuI (2.0 equiv), diisopropylamine (20 equiv),
and tetrahydrofuran (c ) 0.001 M). After being stirred at
room temperature for 15 h, the desired macrocycle (1a) was
isolated in 76% yield after column chromatography. It is
worth noting that this procedure did not give the dimerization
product during the ring closure step as reported for analogue
ring closures.
Scheme 1. One-Pot Synthesis of Macrocycles by a
Three-Component Reaction/[3+2] Cycloaddition
The scope of this novel tandem three-component reaction/
[3+2]cycloaddition reaction was next examined. Five alde-
hydes, four amines (Figure 1), and three isocyanoacetamides
The reaction between an aldehyde (2), an ω-azido amine
(3), and an isocyanoacetamide (4) would give 5-aminoox-
azole (5).11 We hypothesized that the rigidifying effect of
the oxazole should render 5 more susceptible to the intramo-
lecular [3+2] cycloaddition of tethered alkyne and azide to
afford macrocycle 1 directly under appropriate conditions.
The realization of this transformation is the subject of the
present Letter.
With use of heptanal (2a), 4-azido-N-benzyl-1-butanamine
(3a), and 2-isocyano-N-methyl-3-phenyl-N-(prop-2-ynyl)pro-
panamide (4a) as test substrates, initial experiments indicated
that copper(I) salts were unable to catalyze the entire reaction
sequence shown in Scheme 1. Since ammonium chloride was
(7) (a) Hulme, C.; Gore, V. Curr. Med. Chem. 2003, 10, 51-80. (b)
Orru, R. V. A.; De Greef, M. Synthesis 2003, 1471-1499. (c) Jacobi von
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4957-4980. (g) Do¨mling, A. Chem. ReV. 2006, 106, 17-89.
Figure 1. Aldehyde and amine building blocks.
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5, 4125-4127. (d) Hebach, C.; Kazmaier, U. Chem. Commun. 2003, 596-
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Riva, R. Org. Biomol. Chem. 2005, 3, 97-106. (f) Bughin, C.; Zhao, G.;
Bienayme´, H.; Zhu, J. Chem-A. Eur. J. 2006, 12, 1174-1184.
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3261. (b) Janvier, P.; Bois-Choussy, M.; Bienayme, H.; Zhu, J. Angew.
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Rivera, D. G. Angew. Chem., Int. Ed. 2005, 44, 4785-4790. (d) Wessjohan,
L. A.; Ruijter, E. Mol. DiVersity 2005, 9, 159-169. (e) Rivera, D. G.;
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O.; Westermann, B.; Rivera, D. G.; Johnson, D. V.; Orru, R. V. A.;
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were used. Isocyanoacetamides were synthesized in a
straightforward manner starting from the corresponding form-
ylamine derivatives which were subsequently coupled with
the desired secondary amine under classical EDCI/DMAP
protocol. Final dehydration with phosphorus oxychloride in
(12) Armarengo, W. L. F.; Perrin, D. D. Purification of Laboratory
Chemicals, 4th ed.; Butterworth: Heinemann, UK, 1996
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Tornøe, C. W.; Christensen, C.; Meldal, M. J. Org. Chem. 2002, 67, 3057-
3064. (d) For a recent review see: Bock, V.; Hiemstra, H.; van Maarseveen,
J. H.; et al. Eur. J. Org. Chem. 2006, 11, 51-68.
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(14) Filtration of ammonium chloride is important as without filtration
we registered a drop of yield (45% vs 76%).
4146
Org. Lett., Vol. 8, No. 18, 2006

the presence of an excess of triethylamine15 afforded the
isocyanoacetamides in excellent yields. (Scheme 2).
Scheme 2. Synthesis of Isocyanoacetamides Building Blocks
The macrocycles 1a-j synthesized are listed in Figure 2.
As is seen, the reaction turned out to be quite general and
14-, 15-, and 16-membered rings were readily accessible.
Since 5-aminooxazole is a surrogate of dipeptide16 and
triazole is considered as a bioisostere of an amide,17
compounds 1e-g, resulting from the reaction of azido amine
3c and appropriate reaction partners, could be regarded as
cyclopeptide mimics. While the diversity can be easily
introduced by varying the R1 to R4 residues, further structural
ramification can be made by simply reversing the tethering
position of alkyne and azide (1h vs 1i). Even more
significantly, when azide and alkyne units were tethered to
aldehyde and isocyanide, respectively, macrocycles having
an exo-tertiary amine function (1i, 1j) instead of endo-tertiary
amine (1a-h) were produced. Although the overall yield
was moderate, it has to be stressed that one macrocycle and
two heterocyles were produced in this experimentally simple
process with the creation of five chemical bonds.
Figure 2. 14-, 15-, and 16-membered macrocycles.
The efficiency of this multicomponent domino process for
the construction of macrocycle 1 is thus truly remarkable.
To explore the possible conformational preorganization effect
of oxazole,19 dipeptides 6 and 7 (Figure 3) were synthesized
by a Ugi four-component reaction.20 Indeed, no reaction
occurred when 6 and 7 were submitted to the established
cycloaddition conditions, indicating the pivotal role of
oxazole in the production of macrocycles 1a to 1j.
Consequently, the yield per chemical bond produced
remains excellent. While the “click” [3+2] cycloaddition
reaction has been extensively used for the preparation of
triazole as well as bicyclic ring systems, examples dealing
with the concurrent formation of a macrocycle are still rare.18
(15) Obrecht, R.; Hermann, R.; Ugi, I. Synthesis 1985, 400-402.
(16) (a) Clern, D.; Fleury, J. P. Bull. Soc. Chim. Fr. 1974, 211-217. (b)
Clern, D.; Kille, G.; Fleury, J. P. Tetrahedron 1974, 30, 469-474.
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Olson, A. J.; Fokin, V. V.; Sharpless, K. B.; Wong, C. H. ChemBioChem
2003, 4, 1246-1248. (b) Horne, W. S.; Yadav, M. K.; Stout, C. D.; Ghadiri;
M. R. J. Am. Chem. Soc. 2004, 126, 15366-1537. (c) Tornøe, C. W.;
Sanderson, S. J.; Mottram, J. C.; Coombs, G. H.; Meldal, M. J. Comb.
Chem. 2004, 6, 312-324. (d) Brik, A.; Alexandratos, J.; Lin, Y. C.; Elder,
J. H.; Olson, A. J.; Wlodawer, A.; Goodsell, D. S.; Wong, C. H.
ChemBioChem 2005, 6, 1167-1169.
(18) (a) Bodine, K. D.; Gin, D. Y.; Gin, M. S. J. Am. Chem. Soc. 2004,
126, 1638-1639. (b) Billing, J. F.; Nilsson, U. J. J. Org. Chem. 2005, 70,
4847-4850. (c) Punna, S.; Kuzelka, J.; Wang, Q.; Finn, M. G. Angew.
Chem., Int. Ed. 2005, 44, 2215-2220. (d) Angell, Yu; Burgess, K. J. Org.
Chem. 2005, 70, 9595-9298. (e) Maarseveen, J. H.; Horne, W. S.; Ghadiri,
M. R. Org. Lett. 2005, 7, 4503-4506. (f) Bock, V. D.; Perciaccante, R.;
Jansen, T. P.; Hiemstra, H.; Van Maarseveen, J. H Org. Lett. 2006, 8, 919-
922. (g) Looper, R. E.; Pizzirani, D.; Schreiber, S. L. Org. Lett. 2006, 8,
2063-2066.
Figure 3. Dipeptides obtained via Ugi reaction.
In conclusion, we documented a very straightforward
synthesis of complex macrocycles from readily accessible
Org. Lett., Vol. 8, No. 18, 2006
4147

starting materials by a tandem three-component reaction/
intramolecular [3+2] cycloaddition of alkyne and azide.
Work is in progress to expand the number of macrocycle
scaffolds synthesizable with this procedure as well as to
evaluate potential biological properties of these compounds.
Acknowledgment. We are grateful to Giampiero Co-
lombano of the Univerisita` del Piemonte Orientale for
technical assistance. Financial support from the Universita`
del Piemonte Orientale and CNRS is gratefully acknowl-
edged.
Supporting Information Available: Experimental pro-
cedures and characterization data for all new compounds
synthesized. This material is available free of charge via the
Internet at http://pubs.acs.org.
(19) For a review on conformation-directed macrocyclization, see:
Blankenstein, J.; Zhu, J. Eur. J. Org. Chem. 2005, 10, 1949-1964.
(20) Two-step synthesis of a fused bicyclic ring system by a Ugi-4CR
followed by intramolecular click chemistry has been developed; see:
Akritopoulou-Zanze, I.; Gracias, V.; Djuric, S. W. Tetrahedron Lett. 2004,
45, 8439-8442.
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