Synthesis of isocyano peptides by dehydration of the N-formyl derivatives

Article abstract of DOI:10.1055/s-2003-39898

Phosphoryl chloride in combination with triethylamine dehydrates N-formyl peptides to provide the corresponding isocyano peptides in excellent yields.

Full text of DOI:10.1055/s-2003-39898

LETTER
1153
Synthesis of Isocyano Peptides by Dehydration of the N-Formyl Derivatives
S
ynthesis of Isocy
a
a
no Peptide
n
s
g Zhao,a Carine Bughin,a Hugues Bienaymé,b Jieping Zhu*a
a
Institut de Chimie des Substances Naturelles, CNRS, 91198 Gif-Sur-Yvette Cedex, France
Fax +33(1)69077247; E-mail: zhu@icsn.cnrs-gif.fr
b
Chrysalon, 11 Avenue Albert Einstein, 69100 Villeurbanne, France
Received 4 April 2003
Abstract: Phosphoryl chloride in combination with triethylamine
dehydrates N-formyl peptides to provide the corresponding iso-
cyano peptides in excellent yields.
Key words: dehydration, N-formyl, isocyanide, isocyano peptide,
phosphoryl chloride
Scheme 1
equiv) in the presence of triethylamine (5 equiv) at –20 °C
provided the corresponding isocyano dipeptide 2 in 97%
yield (Scheme 1). The procedure is applicable to other
peptides with a variety of side chains and some represen-
tative examples were listed in Figure 1.
Isocyanides participate in a wide range of synthetically
important transformations, mainly due to their profound
ability to undergo a-addition with both electrophiles and
nucleophiles.1 The Ugi four-component2 and Passerini3
three-component reactions are notable examples that use
this unique compound as a key input. Although a variety
of isocyanides, including a-isocyano acetate4 and tosyl
methylisocyanide (TosMIC)5 have been synthesized and
widely used in organic syntheses, the chemistry of isocy-
ano peptides remained underdeveloped. They have been
synthesized by coupling of the a-isocyano acetic acid with
C-terminal protected amino acids.6 However, the yield
was only low to moderate. Direct dehydration of N-formyl
dipeptide with a large excess of tosyl chloride in pyridine7
and with Burgess’s reagent8 have been reported in a spo-
radical case, without demonstrating the generality of the
method. To the best of our knowledge, phosgene in com-
bination with N-methyl morpholine9 developed by Ugi
and co-workers is the only general method for the dehy-
dration of N-formyl dipeptides. However, the toxicity and
cumbersome handling of phosgene may hamper its large-
scale application.
Since the combination of POCl3/diisopropylamine was re-
ported to cause the complete racemization of chiral meth-
yl N-formylvalinate,14 the extent of epimerization under
the present conditions needed to be evaluated. Therefore,
we synthesized the N-formyl L-phenylanine-L-phenyl-
anine methyl ester (3) and its (L,D)-diastereomer 5. Both
compounds were smoothly converted to the correspond-
ing isocyano derivatives 4 and 6 in 97% and 95% yield,
respectively.15 Analysis of the 1H NMR spectra indicated
that epimerization during the dehydration is less than 5%.
Significantly, even with dipeptide 9 containing racemiza-
tion-prone phenylglycine, the epimerization remained
minimum. No chain-ring tautomerization leading to 5-
aminooxazole occurred regardless of the nature of the in-
ternal amide bond (secondary or tertiary amide) thanks to
the mild conditions used.16 Extension of this chemistry to
N-formyl tripeptide 19 was successful and isocyanide 20
was obtained in 95% yield. Partial decomposition of iso-
cyanide 18 during purification was observed that might
account for its reduced yield.
In connection with our ongoing project aiming at the
development of novel isocyanide-based multicomponent
reactions,10 we required a facile and reliable access to iso-
cyano peptides.11 After having screened various dehydrat-
ing agents, including triphosgene, p-TsCl/pyridine, Tf2O/
Hünig’s base,12 we found that easily available and cheap
phosphoryl chloride13 in combination with triethylamine
is a mild and high-yielding alternative for the synthesis of
a-isocyano peptide and report herein our results.
The reaction is easy to perform experimentally and all the
isocyano peptides synthesized were odorless and can be
purified by flash chromatography. The following proce-
dure is typical. To a stirred solution of N-formylpeptide
(2.0 mmol) and triethylamine (10.0 mmol) in dry CH2Cl2
(20.0 mL) cooled to –20 ºC was added drop wise the phos-
phoryl chloride (3.0 mmol) under argon. After being
stirred at the same temperature for 2 hours, the reaction
mixture was quenched by addition of saturated aqueous
NaHCO3 and was extracted with CH2Cl2. The combined
organic extracts were washed with brine, dried over anhy-
drous Na2SO4 and evaporated to dryness under reduce
pressure. The crude residue was subjected to flash chro-
matography on silica gel to give the pure isocyanide.
Treatment of a dichloromethane solution of N-formyl L-
phenylalanine-glycine (1) with phosphoryl chloride (1.5
Synlett 2003, No. 8, Print: 24 06 2003.
Art Id.1437-2096,E;2003,0,08,1153,1154,ftx,en;G07203ST.pdf.
© Georg Thieme Verlag Stuttgart · New York

1154
G. Zhao et al.
LETTER
(5) Van Leusen, D.; Van Leusen, A. M. Org. React. 2001, 57,
417.
(6) Nunami, K.-I.; Suzuki, M.; Matsumoto, K.; Yoneda, N.;
Takiguchi, K. Agric. Biol. Chem. 1984, 48, 1073.
(7) Sakiyama, F.; Witkop, B. J. Org. Chem. 1965, 30, 1905.
(8) Creedon, S. M.; Crowley, H. K.; McCarthy, D. G. J. Chem.
Soc., Perkin Trans 1 1998, 1015.
(9) Urban, R.; Marquarding, D.; Seidel, P.; Ugi, I.; Weinelt, A.
Chem. Ber. 1977, 110, 2012.
(10) For recent reviews on the isocyanide-based MCR, see:
(a) Weber, L. Curr. Med. Chem. 2002, 9, 2085.
(b) Dömling, A. Curr. Opin. Chem. Biol. 2002, 6, 306.
(c) Hulme, C.; Gore, V. Curr. Med. Chem. 2003, 10, 51.
(d) Zhu, J. Eur. J. Org. Chem. 2003, 1133.
(11) For an application of isocyano dipeptides in the synthesis of
cyclodepsipeptides, see: Zhao, G.; Sun, X.; Bienaymé, H.;
Zhu, J. J. Am. Chem. Soc. 2001, 123, 6700.
(12) Baldwin, J. E.; O’Neil, I. A. Synlett 1990, 603.
(13) POCl3 in combination with a tertiary amine is a well-known
dehydrating agent, see ref.1, and ref. 2. For the dehydration
of a-formylamino acrylic acid to a-isocyano acrylic acid
under mild conditions, see: (a) Schöllkopf, U.; Schröder, R.;
Stafforst, S. Liebigs Ann. Chem. 1974, 44. (b) Nunami, K.-
I.; Suzuki, M.; Yoneda, N. Synthesis 1978, 840.
(14) Obrecht, R.; Herrmann, R.; Ugi, I. Synthesis 1985, 400.
(15) Compound 4: Rf = 0.43 (EtOAc/heptane = 1/1);
[a]D = +13.8 (c 0.3, CHCl3). IR (CHCl3): n = 3422, 2138,
1744, 1684, 1603, 1522, 1497, 1437, 1363, 1180 cm–1.
1H NMR (250 MHz, CDCl3, ppm): d = 3.08–3.30 (m, 4 H),
3.69 (s, 3 H,), 4.37 (dd, J = 4.5 Hz, 7.3 Hz, 1 H), 4.84 (dt,
J = 5.7 Hz, 7.8 Hz, 1 H), 6.73 (d, J = 5.7 Hz, 1 H), 7.20–7.33
(m, 10 H). 13C NMR (62.5 MHz, CDCl3, ppm): d = 37.6,
38.3, 52.4, 53.1, 59.4, 127.3, 127.6, 127.7, 129.6, 129.0,
134.4, 134.8, 164.1, 170.7. MS (EI): m/z = 336 (M+), 227,
245. Anal. Calcd for C20H20N2O3: C, 71.43; H, 5.95; N, 8.33.
Found: C, 71.44; H, 5.98; N, 8.30. Compound 6: Rf = 0.48
(EtOAc/heptane = 1/1.5); [a]D = +17.5 (c 0.5, CHCl3). IR
(CHCl3): n = 3421, 3012, 2138, 1745, 1685, 1603, 1521,
1497, 1455, 1362, 1210, 1280, 1120 cm–1. 1H NMR (250
MHz, CDCl3, ppm): d = 3.00–3.30 (m, 4 H), 3.72 (s, 3 H),
4.35 (dd, J = 4.2 Hz, 7.8 Hz, 1 H), 4.84 (dd, J = 6.7 Hz, 12.7
Figure 1
In conclusion, we have developed a reliable procedure for
the synthesis of isocyano peptides from the corresponding
N-formyl derivatives. Application of these isocyanides in
diversity-oriented synthesis will be reported in due
course.17
Hz, 1 H), 6.72 (d, J = 6.7 Hz, 1 H), 7.15–7.32 (m, 10 H). 13
C
NMR (62.5 MHz, CDCl3, ppm): d = 37.8, 38.9, 52.6, 53.6,
59.9, 127.5, 127.8, 128.8, 129.2, 129.5, 134.7, 135.2, 164.7,
170.9. MS (EI): m/z = 336 (M+), 277, 245. Anal. Calcd for
C20H20N2O3: C, 71.43; H, 5.95; N, 8.33. Found: C, 69.92; H,
6.05; N, 8.15.
Acknowledgment
C. Bughin thanks the Ministère de l’Enseignement Supérieur et de
la Recherche for a doctoral fellowship. Financial supports from
CNRS and Rhodia (post-doctoral fellowship to GZ) are gratefully
acknowledged.
(16) Mazurkiewicz, R. Synthesis 1992, 941.
(17) Recent examples from our group: (a) González-Zamora, E.;
Fayol, A.; Bois-Choussy, M.; Chiaroni, A.; Zhu, J. Chem.
Commun. 2001, 1684. (b) Janvier, P.; Sun, X.; Bienaymé,
H.; Zhu, J. J. Am. Chem. Soc. 2002, 124, 2560. (c) Gámez-
Montaño, R.; Zhu, J. Chem. Commun. 2002, 2448.
(d) Fayol, A.; Zhu, J. Angew. Chem. Int. Ed. 2002, 41, 3633.
(e) Janvier, P.; Bienaymé, H.; Zhu, J. Angew. Chem. Int. Ed.
2002, 41, 4291. (f) Gámez-Montaño, R.; González-Zamora,
E.; Potier, P.; Zhu, J. Tetrahedron 2002, 58, 6351.
(g) Janvier, P.; Bois-Choussy, M.; Bienaymé, H.; Zhu, J.
Angew. Chem. Int. Ed. 2003, 42, 811.
References
(1) Isonitrile Chemistry; Ugi, I., Ed.; Academic Press Inc.: New
York, 1971.
(2) Dömling, A.; Ugi, I. Angew. Chem. Int. Ed. 2000, 39, 3168.
(3) (a) Passerini, M. Gazz. Chim. Ital. 1922, 52, 126.
(b) Passerini, M. Gazz. Chim. Ital. 1922, 52, 181.
(4) (a) Hoppe, D. Angew. Chem., Int. Ed. Engl. 1974, 13, 789.
(b) Marcaccini, S.; Torroba, T. Org. Prep. Proced. Int. 1993,
25, 141.
Synlett 2003, No. 8, 1153–1154 ISSN 1234-567-89 © Thieme Stuttgart · New York