Ammonium chloride promoted three-component synthesis of 5-iminooxazoline and its subsequent transformation to macrocyclodepsipeptide

Article abstract of DOI:10.1021/ol7024372

(Chemical Equation Presented) A three-component reaction of an α,α-disubstituted α-isocyanoacetamide, an aldehyde and an amino alcohol afforded the 5-iminooxazoline, which, upon saponification, cyclized under acidic conditions to provide the macrocyclodepsipeptide in good overall yield.

Full text of DOI:10.1021/ol7024372

ORGANIC
LETTERS
2007
Vol. 9, No. 25
5275-5278
Ammonium Chloride Promoted
Three-Component Synthesis of
5-Iminooxazoline and Its Subsequent
Transformation to
Macrocyclodepsipeptide
Tracey Pirali,† Gian Cesare Tron,*,† Ge´raldine Masson,‡ 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, Institut de Chimie des Substances
Naturelles, CNRS, 91198 Gif-sur-YVette Cedex, France
zhu@icsn.cnrs-gif.fr
Received October 5, 2007
ABSTRACT
A three-component reaction of an
r,r-disubstituted r-isocyanoacetamide, an aldehyde and an amino alcohol afforded the 5-iminooxazoline,
which, upon saponification, cyclized under acidic conditions to provide the macrocyclodepsipeptide in good overall yield.
Over the past decades, a multitude of efficient synthesis
strategies have been developed enabling the rapid construc-
tion of complex structures under mild conditions.1 At the
forefront of these chemical methodologies are multicompo-
nent reactions (MCRs),2 which create molecular complexity
and diversity from readily accessible starting materials in
one single operation. The isocyanide capable of reacting with
both nucleophile and electrophile is an ideal starting material
for the development of novel MCRs2 and indeed formed the
basis of the well-known Passerini3 and Ugi reactions.4 A
conceptually simple approach to further increase the versatil-
ity of these powerful transformations is the use of function-
alized isocyanides. We have been exploiting the peculiar
reactivity profiles of R-isocyanoacetamides,5 R-isocyanoace-
tic acids,6 O-isocyanobenzamides,7 and R-isocyanoacetates8,9
and have developed a number of MCRs allowing rapid access
to the medicinally relevant heterocycles.10 As a logical
extension of our work in this field, we report herein a three-
† Universita` degli Studi del Piemonte Orientale “A. Avogadro”.
‡ CNRS.
(1) For reviews see: (a) Trost, B. M. Angew. Chem., Int. Ed. Engl. 1995,
34, 259-281. (b) Tietze, L. F. Chem. ReV. 1996, 96, 115-136. (c) Wender,
P. A.; Handy, S. T.; Wright, D. L. Chem. Ind. 1997, 765-769. (d) Schreiber,
S. L. Science 2000, 287, 1964-1969. (e) Nicolaou, K. C.; Edmonds, D. J.;
Bulger, P. G. Angew. Chem., Int. Ed. 2006, 45, 7134-7186.
(2) (a) For a monograph see: Multicomponent Reaction: Zhu, J.;
Bienayme`, H. Eds.; Wiley-VCH: Weinhein, Germany, 2005. For recent
reviews: (b) Hulme, C.; Gore, V. Curr. Med. Chem. 2003, 10, 51-80. (c)
Zhu, J. Eur. J. Org. Chem. 2003, 1133-1144. (d) Orru, V. A.; De Greef,
M. Synthesis 2003, 1471-1499. (e) Simon, C.; Constantieux, T.; Rodriguez,
J. Eur. J. Org. Chem. 2004, 4957-4980. (f) Do¨mling, A. Chem. ReV. 2006,
106, 17-89. (g) D’Souza, M.; Mu¨ller, T. J. J. Chem. Soc. ReV. 2007, 36,
1095-1108. (h) Ramo´n, D. J.; Yus, M. Angew. Chem., Int. Ed. 2005, 44,
1602-1634. (i) Enders, D.; Grondal, C.; Hu¨ttl, M. R. M. Angew. Chem.,
Int. Ed. 2007, 46, 1570-1581.
(3) (a) Banfi, L.; Riva, R. Organic Reactions; Charette, A. B., Ed.; John
Wiley & Sons Inc.: New York, 2005; 65, pp 1-140. (b) Oxidative P-3CR,
see: Ngouansavanh, T.; Zhu, J. Angew. Chem., Int. Ed. 2006, 45, 3495-
3497.
(4) (a) Do¨mling, A.; Ugi, I. Angew. Chem., Int. Ed. 2000, 39, 3168-
3210. (b) Wessjohann, L. A.; Voigt, B.; Rivera, D. G. Angew. Chem., Int.
Ed. 2005, 44, 4785-4790. (c) El Kaim, L.; Grimaud, L.; Oble, J. Angew.
Chem., Int. Ed. 2005, 45, 7961-7964. (d) Giovenzana, G. B.; Tron, G. C.;
Di Paola, S.; Menegotto, I. G.; Pirali, T. Angew. Chem., Int. Ed. 2006, 45,
1099-1102. (e) Ngouansavanh, T.; Zhu, J. Angew. Chem., Int. Ed. 2007,
46, 5775-5778.
10.1021/ol7024372 CCC: $37.00
© 2007 American Chemical Society
Published on Web 11/09/2007

component reaction of R,R-disubstituted R-isocyanoacet-
amides (1)11 with an aldehyde and an amine leading to
5-iminooxazoline (2) (Figure 1). The structural features
of formamide 7 (POCl3, TEA, CH2Cl2, -30 °C)12 yielded
the desired isocyanide (1) in excellent yield (Scheme 1). Four
dipeptidic R,R-dialkyl R-isocyanoacetamides were synthe-
sized following this two-step sequence with overall yields
ranging from 45% to 60%. It is interesting to note that the
Ugi reaction does not suffer from steric effects13 and that
this protocol could potentially constitute a very efficient way
for the synthesis poly-Aib (R-aminoisobutyric acid) peptides,
not easily accessible by conventional peptide chemistry.14
The reaction of 1a with heptanal (8a) and morpholine (9a)
was next examined. In methanol, the undesired isomerization
of 1a took place predominantly to afford the 5-iminooxazo-
line 10 in 47% yield. Gratifyingly, when the reaction was
performed in toluene in the presence of ammonium chlo-
ride,5,15 a three-component condensation occurred to provide
Figure 1. From R,R-disubstituted R-isocyanoacetamide to 5-imi-
nooxazoline and macrocyclodepsipeptide.
the 5-iminooxazoline (2a) in 62% isolated yield.16
A
plausible reaction scenario that accounts for the formation
of 2a is shown in Scheme 2. Thus, condensation of 8a and
incorporated in 1, that is, a secondary amide and a double
substitution at the R-position, were designed to guarantee
the occurrence of the projected reaction sequence. We
document also the subsequent transformation of 2 to mac-
rocyclodepsipeptide (3) under mild acidic conditions by using
the 5-iminooxazoline as an internal activator of the vicinal
carboxylic acid.
Scheme 2. Three-Componenent Synthesis of 5-Iminooxazoline
The requisite R,R-disubstituted R-isocyanoacetamides (1)
are prepared as shown in Scheme 1. The Ugi reaction of
Scheme 1. Synthesized R,R-Disubstitued
R-Isocyanoacetamides
9a would give the iminium ion 11, which would react with
isonitrile (1a) to afford the nitrilium intermediate (12).
(10) (a) Ga´mez-Montan˜o, R.; Zhu, J. J. Chem. Soc., Chem. Commun.
2002, 2448-2449. (b) Fayol, A.; Zhu, J. Angew. Chem., Int. Ed. 2002, 41,
3633-3635. (c) Janvier, P.; Bienayme´, H.; Zhu, J. Angew. Chem., Int. Ed.
2002, 41, 4291-4294. (d) Ga´mez-Montan˜o, R.; Gonza´lez-Zamora, E.;
Potier, P.; Zhu, J. Tetrahedron 2002, 58, 6351-6358. (e) Fayol, A.; Zhu,
J. Org. Lett. 2005, 7, 239-242.
(11) (a) Bossio, R.; Marcaccini, S.; Paoli, P.; Papaleo, S.; Pepino, R.;
Polo, C. Liebigs Ann. Chem. 1991, 843-849. (b) Costa, S. P. G.; Maia, H.
L. S.; Peerira-Lima, S. M. M. A. Org. Biomol. Chem. 2003, 1, 1475-1479.
(12) (a) Obrecht, R.; Hermann, R.; Ugi, I. Synthesis 1985, 400-402.
(b) Zhao, G.; Bughin, C.; Bienayme´, H.; Zhu, J. Synlett 2003, 1153-1154.
(13) For an interesting exemple see: Yamada, T. Synthesis 1998, 991-
998.
ketone (4), ammonium formate (5), and isocyanoacetate (6)
in methanol at 60 °C11 afforded the adduct 7. Dehydration
(5) (a) Sun, X.; Janvier, P.; Zhao, G.; Bienayme`, H.; Zhu, J. Org. Lett.
2001, 3, 877-880. (b) Janvier, P.; Sun, X.; Binayme`, H.; Zhu, J. J. Am.
Chem. Soc. 2002, 124, 2560-2567. (c) Fayol, A.; Housseman, C.; Sun,
X.; Janvier, P.; Bienayme`, H.; Zhu, J. Synthesis 2005, 161-165. (d) Tron,
G. C.; Zhu, J. Synlett 2005, 532-534. (e) Janvier, P.; Bois-Choussy, M.;
Bienayme`, H.; Zhu, J. Angew. Chem., Int. Ed. 2003, 42, 811-814. (f) Pirali,
T.; Tron, G. C.; Zhu, J. Org. Lett. 2006, 8, 4145-4148.
(6) (a) Bonne, D.; Dkhane, M.; Zhu, J. Org. Lett. 2004, 6, 4771-4774.
(b) Bonne, D.; Dekhane, M.; Zhu, J. J. Am. Chem. Soc. 2002, 124, 2560-
2567.
(7) Bonne, D.; Dekhane, M.; Zhu, J. Org. Lett. 2005, 7, 5285-5288.
(8) Bonne, D.; Dekhane, M.; Zhu, J. Angew. Chem., Int. Ed. 2007, 46,
2485-2488.
(9) (a) Bon, R. S.; Hong, C.; Bouma, M. J.; Schmitz, R. F.; De Kanter,
F. J. J.; Lutz, M.; Spek, A. L.; Orru, R. V. A. Org. Lett. 2003, 5, 3759-
3762. (d) Marcaccini, S.; Torroba, T. Org. Prep. Proc. Int. 1993, 25, 141-
208.
(14) Toniolo, C.; Formaggio, F.; Kaptein, B.; Broxterman, Q. B. Synlett
2006, 1295-1310.
(15) (a) Cristau, P.; Vors, J. P.; Zhu, J. Org. Lett. 2001, 3, 4079-4082.
(b) Cristau, P.; Vors, J. P.; Zhu, J. Tetrahedron 2003, 59, 7859-7870. (c)
Parchinsky, V. Z.; Shuvalova, O.; Ushakova, O.; Kravchenko, D. V.;
Krasavin, M. Tetrahedron Lett. 2006, 47, 947-951. (d) Neo, A. G.; Carrillo,
R. M.; Barriga, S.; Moma´n, E.; Marcaccini, S.; Marcos, C. F. Synlett 2007,
327-329. (e) Umkehrer, M.; Ross, G.; Ja¨ger, N.; Burdack, C.; Kolb, J.;
Hu, H.; Alvim-Gaston, M.; Hulme, C. Tetrahedron Lett. 2007, 48, 2213-
2216.
5276
Org. Lett., Vol. 9, No. 25, 2007

Trapping of the latter by the internal amide oxygen would
produce the 5-iminooxazoline (2a). The alternative nucleo-
philic attack by nitrogen leading to imidazolinone 13 was
not observed, probably due to the hard electropilic nature of
the nitrilium intermediate.7,17 The structure of 2a was
confirmed by its hydrolysis under mild acidic conditions (1
N HCl, acetone, room temperature) affording the tripeptide
14 in a quantitative yield (Scheme 3).18 Only one isomeric
NMR analysis of the crude reaction mixture. The moderate
isolated yields were due to their partial degradation during
purification. Indeed, 5-iminooxazolines are known to be very
sensitive to the acid, and flash chromatography has to be
performed using neutral alumina (Brockmann grade III) as
support. Nine other iminooxazolines were synthesized and
were engaged, without purification, in the subsequent
transformations (cf. Figure 3).
Scheme 3. Acidic Hydrolysis of 5-Iminooxazoline
1
form of 2a was detected in its H NMR spectrum and the
Z-geometry was tentatively assigned for the imidate unit
based on the steric consideration. We stress the importance
of R,R-disubstitution pattern in 1 since the reaction of
secondary amide derived from R-mono substituted R-isocy-
anoacetamide with aldehyde and amine led only to a complex
reaction mixture.
The scope of this protocol was next examined by varying
the structure of aldehydes, amines, and isocyanides. The
reaction turned out to be quite general and a variety of
functionalities such as acetate, free hydroxy group, carbam-
ate, and esters are tolerated. The spiro iminooxazoline was
readily accessible starting from isocyanides 1c and 1d (Figure
2). The reaction appeared to be clean and proceeded with
Figure 3. Synthesized macrocyclodepsipeptides.
A hydrochloride salt of amine can be used as a starting
material in the presence of triethylamine. We assumed that
the stoichiometric amount of Et3N‚HCl generated in situ
played the same role as ammonium chloride in promoting
the three-component reaction.
Besides its hydrolysis to peptide, little is known about the
chemistry of 5-iminooxazoline. In analogy to the 5-amino
oxazole, we speculated that we might be able to use this
heterocycle as an internal activator of the vicinal carboxylic
acid and consequently, develop an efficient macrocyclization
protocol (Scheme 4).19 The projected reaction sequence is
Figure 2. Three-component synthesis of 5-iminooxazoline.
(17) The attack of the amide nitrogen to isocyanide to yield imidazolinone
has been reported under strong basic conditions see: (a) Matsumoto, K.;
Suzuki, M.; Yoneda, N.; Miyoshi, M. Synthesis 1977, 249-250. (b) Bossio,
R.; Marcaccini, S.; Papaleo, S.; Pepino, R. J. Heterocycl. Chem. 1994, 31,
397-399.
(18) Imidazolinones are stable under acidic conditions, see: Rouchaud,
J.; Gustin, F.; Moulard, C. Bull. Soc. Chim. Belg. 1992, 101, 959-968.
(19) (a) Zhao, G.; Sun, X.; Bienayme´, H.; Zhu, J. J. Am. Chem. Soc.
2001, 123, 6700-6701. (b) Bughin, C.; Zhao, G.; Bienayme`, H.; Zhu, J.
Chem. Eur. J. 2006, 12, 1174-1184. (c) Bughin, C.; Masson, G.; Zhu, J.
J. Org. Chem. 2007, 72, 1826-1829.
complete conversion of the substrates as demonstrated by
(16) Only fewer syntheses of iminooxazoline are known, see : (a)
Middleton, W. J.; Krespan, C. G. J. Org. Chem. 1968, 3625-3627. (b)
Jackson, B.; Gakis, N.; Ma¨rky, M.; Hanse, H.-J.; von Philipsborn, W.;
Schmid, H. HelV. Chim. Acta 1972, 55, 916-918. (c) Grutzmacher, H.;
Roesky, H. W. Chem. Ber. 1986, 119, 2127-2134. (d) Koksch, B.; Mutze,
K.; Osipov, S. N.; Golubev, A. S.; Burger, K. Tetrahedron Lett. 2000, 41,
3825-3838.
Org. Lett., Vol. 9, No. 25, 2007
5277

our delight, stirring an acetonitrile solution of the crude
carboxylic acid (c ) 0.001 M) in the presence of trifluoro-
actetic acid (50 equiv) afforded the macrocyclodepsipeptide
3a in 46% overall yield.
Scheme 4. Macrocyclization Using 5-Iminooxazoline as an
Internal Activator of the Terminal Carboxylic Acid
The macrocycles synthesized by this three-step sequence
are listed in Figure 3. As is seen, the 14-, 15-, and
16-membered macrocycles (3b-j) with different substituents
at the peripheral of the cycle were readily synthesized starting
from simple aldehydes, amines, and dipeptidic isocyanides
in overall yields ranging from 27 to 54%. Even with sterically
very hindered substrates, cyclization still worked to provide
the desired macrocycles (3d,g). Although the overall yield
was moderate, the chemical yield per chemical bond
produced remained excellent (1 C-C, 1 C-N, 1 C-O in
3CR and 1 C-O in macrocyclization).
In summary, we have developed a new three-component
synthesis of 5-iminooxazolines starting from aldehydes,
amines, and R,R-disubstituted R-isocyanoacetamides and
documented their subsequent transformation to macrocycles.
The entire sequence was realized under very mild conditions
without using exotic reagents. In the macrocyclization step,
the 4,4-disubstituted 5-iminooxazoline, after serving as an
internal activator of the vicinal carboxylic acid, was concur-
rently converted to R,R-disubstituted amino acid and became
an integral part of the resulting peptide backbone. The
chemistry developed herein could be particularly efficient
for the synthesis of macrocyclopeptides having Aib residues
that are otherwise not easily accessible.22
depicted in Scheme 4. Thus protonation of exocyclic imine
would provide the iminium species 16 that could be trapped
either by an external nucleophile (H2O) leading to simple
hydrolysis or under favorable circumstance, by the neighbor-
ing carbonyl oxygen leading to spirolactone (17). Being
highly electrophilic, the carbonyl carbon of intermediate 17
could subsequently be attacked by the tethered nucleophile
leading to, after fragmentation, the desired macrocyclodep-
sispeptide (3).20 The formation of spirolactone could in
principle reduce the entropy loss during the cyclization and
consequently favor the macrocyclization.21
The realization of this transformation is shown in Scheme
5. The three-component reaction of 1a, 8a, and amino alcohol
Acknowledgment. Financial support from CNRS, France,
and M.I.U.R.-PRIN 2006, Italy, are 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.
Scheme 5. Macrolactonization under Acidic Conditions
OL7024372
(20) (a) Ballard, C. E.; Yu, H.; Wang, B. Curr. Med. Chem. 2002, 9,
471-498. (b) Sarabia, F.; Chammaa, S.; Ruiz, A. S.; Ortiz, L. M.; Herrera,
F. J. L. Curr. Med. Chem. 2004, 11, 1309-1332. (c) Wessjohann, L. A.;
Ru¨ijter, E. Top. Curr. Chem. 2005, 243, 137-184.
(21) For a review on the conformation-directed macrocyclization, see:
Blankenstein, J.; Zhu, J. Eur. J. Org. Chem. 2005, 1949-1964.
(22) For an elegant synthesis of macrocyclodepsipeptide containing Aib
residues see: (a) Heimgartner, H.; Arnhold, F. S.; Fritschi, S. P.; Koch, K.
N.; Margirius, J. E. F.; Linden, A. J. Heterocycl. Chem. 1999, 36, 1539-
1547. (b) Jeremic, T.; Linden, A.; Heimgartner, H. Chem BiodiVersity 2004,
1, 1730-1761.
9b afforded the expected 5-iminooxazoline which, without
purification, was hydrolyzed (1.0 equiv KOH, MeOH-H2O,
room temperature) to the corresponding carboxylic acid. To
5278
Org. Lett., Vol. 9, No. 25, 2007