No data for acidity of isocyanoacetates are given in literature;
however, its pKa can be estimated in the range of 9-11.3 But
their main disadvantage is racemization occurring easily under
conditions of U-4CR due to basicity of the amine.4 Also, special
conditions are required for the synthesis of isocyanides 1 in
optically pure form.5
We decided to develop another type of R-amino acid
isocyanides for the synthesis of peptides by U-4CR, which
would be configurationally stable in basic conditions. We
assumed that transformation of a carboxyl group into an OBO-
ester (4-methyl-2,6,7-trioxabicyclo[2.2.2]octyl derivatives) would
avoid all aforementioned problems and open a way to protected
peptides 4 with preserved configuration of the C-terminal amino
acid. Furthermore, reaction with ortho esters opens a way to
peptides with an OBO-protective group, which is stable to
nucleophiles and bases and can be easily removed under mild
conditions without racemization.6 We report herein large-scale
oriented synthesis of new chiral OBO-esters of R-isocyano acids
3 and our studies on their stability toward racemization and
behavior in the Ugi reaction.
OBO-esters are synthesized by BF3-catalyzed rearrangement
of the corresponding 3-methyl-3-(hydroxymethyl)oxetane es-
ters.7 For this rearrangement to take place, amino group has to
be protected. However, under reaction conditions, N-formylg-
lycine ester gave only insoluble precipitate instead of the desired
OBO-ester, the immediate precursor for the corresponding
isocyanide. A possible reason is Lewis acid/base reaction of
the BF3 with the amide moiety.8 Experiments with other Lewis
and Bro¨nsted acids (AlCl3, TiCl4, Yb(OTf)3, CF3COOH,
CF3SO3H, H2SO4) were unsuccessful. Therefore, we used Cbz
derivatives because of their high efficiency of introduction/
removal processes and availability of the corresponding Cbz-
amino acids. Also, the synthesis of the OBO-ester of glycine
11a via the Cbz derivative has been recently reported.9
Nonracemizable Isocyanoacetates for
Multicomponent Reactions
Alexander G. Zhdanko and Valentine G. Nenajdenko*
Department of Chemistry, Moscow State UniVersity,
Moscow, Russia
ReceiVed September 15, 2008
Chiral ortho esters of R-isocyano acids were synthesized from
commercially available Cbz-protected R-amino acids. These
compounds are stable toward racemization in the Ugi 4CC
in contrast to known esters of R-isocyano acids. Applying
them in Ugi 4CC with subsequent deprotection gives access
to dipeptides with preserved configuration at the C-terminal
amino acid.
The Ugi multicomponent reaction (U-MCR) is one of the
most important tools for creating substances with high levels
of molecular diversity.1a-c In particular, U-MCR is used to
construct molecules with two amide bonds and, consequently,
represents a general efficient method for the synthesis of
peptidomimetics.1d This method permits the replacement of
natural amino acids in biologically relevant peptides with
nonproteinogenic derivatives that may influence their properties
dramatically.1e,f This promising approach has attracted attention
for years, but it still needs improvement in many aspects.
R-Isocyano esters (isocyanoacetates) 1 easily accessible from
R-amino acids are the simplest isocyanide derivatives of
R-amino acids. These building blocks have been used to date
in U-MCR to introduce a C-terminal amino acid into the
structure of desired peptide 2 (Scheme 1). However, there are
some disadvantages of the method. Reactivity of 1 is lowered
due to strong electron-withdrawing effects of the carboxyl group
(especially in reactions with ketones). Isocyano and carboxyl
groups together increase significantly the acidity of the R-hy-
drogen atom; hence, side reactions involving this site of the
molecule are possible.2
(2) Some isocyanoacetates are widely used in organic synthesis, where
enhanced CH-acidity of them plays key role; see, for example: (a) Suzuki, M.;
Nunami, K.; Moriya, T.; Matsumoto, K.; Yoneda, N J. Org. Chem. 1978, 43,
4933–4935. (b) Bon, R. S.; Hong, C.; Bouma, M. J.; Schmitz, R. F.; de Kanter,
F. J. J.; Lutz, M.; Spek, A. L.; A. Orru, R. V Org. Lett. 2003, 5, 3759–3762. (c)
Ito, Y.; Sawamura, M.; Hayashi, T. J. Am. Chem. Soc. 1986, 108, 6405–6406.
(d) Schro¨der, R.; Scho¨llkopf, U.; Blume, E.; Hoppe, I. Liebigs. Ann. Chem. 1975,
3, 533–546.
(3) Green, J. A.; Hoffman, P. T. In Isonitrile chemistry; Ugi, I., Ed.; Academic
Press: New York, 1971; pp 1-7.
(4) Bayer, T.; Riemer, C.; Kessler, H. J. Peptide Sci. 2001, 7, 250–261.
However, the ennantiomerically enriched R-isocyano acetamide is known to
undergo the oxidative Ugi reaction without significant racemization, but amides
are weaker CH-acids than esters; see: Ngouansavanh, T.; Zhu, J. Angew. Chem.,
Int. Ed. 2007, 46, 5775.
(5) (a) Skorna, G.; Ugi, I. Angew. Chem. 1977, 89, 267–268. (b) Seebach,
D.; Adam, G.; Gees, T.; Schiess, M.; Weigand, W. Chem. Ber. 1988, 121, 507–
517. (c) Giesemann, G.; Von Hinrichs, E.; Ugi, I. J. Chem. Res. 1982, 79. (d)
Porcheddu, A.; Giacomelli, G.; Salaris, M. J. Org. Chem. 2005, 70, 2361–2363.
(e) Ugi, I.; Fetzer, U.; Eholzer, U.; Knupfer, H.; Offermann, K. Angew. Chem.
1965, 77, 492–504.
(1) (a) Do¨mling, A.; Ugi, I. Angew. Chem., Int. Ed. 2000, 39, 3168. (b)
Do¨mling, A. Chem. ReV. 2006, 106, 17. (c) Ramo´n, D. J.; Yus, M. Angew. Chem.,
Int. Ed. 2005, 44, 1602–1634. (d) Ugi, I.; Do¨mling, A.; Ebert, B. In Combinatorial
Chemistry; Jung, G., Ed.; Wiley-VCH, Weinheim, 1999; pp 125-165. (e) Hruby,
V. J. Acc. Chem. Res. 2001, 34, 389–397. (f) Roy, R. S.; Balarm, P. J. Peptide
Res. 2004, 63, 279–289.
(6) Blaskovich, M. A.; Lajoie, G. A. J. Am. Chem. Soc. 1993, 115, 5021–
5030.
(7) Corey, E. J.; Raju, N. Tetrahedron Lett. 1983, 24, 5571–5574.
(8) Herdeis, C.; Kelm, B. Tetrahedron 2003, 59, 217.
(9) Raghavan, B.; Johnson, R. L. J. Org. Chem. 2006, 71 (5), 2151–2154.
884 J. Org. Chem. 2009, 74, 884–887
10.1021/jo802420c CCC: $40.75 2009 American Chemical Society
Published on Web 12/19/2008