the intramolecular cyclization strategy used to build ana-
logues such as 1b,5 3, and 4 (Scheme 2). In this route, amino
chemoselective formation of an N-acyliminium ion, and
allow for the approach to peptidomimetics outlined in
Scheme 2.
To test the feasibility of this approach, the chemistry
outlined in Scheme 3 was investigated. This example was
Scheme 2
Scheme 3
acid starting materials are converted into N-acyliminium ion
precursor 8b. Peptide 8b is then cyclized to form the desired
constrained peptidomimetic. On the surface, the strategy
appears ideal for synthesizing libraries of constrained
molecules. However, synthesizing substrate 8b can be a
challenging task. If the leaving group needed to make
N-acyliminium ion 7 is introduced into the initial monomer
(5b), then it is readily eliminated during the deprotection
and coupling steps needed to incorporate the functionalized
amino acid into 8b. On the other hand, introduction of the
leaving group following construction of the polypeptide 8a
requires the selective oxidation of a substrate having more
than one nitrogen atom. While such oxidation reactions can
be accomplished for specific dipeptides,4c,d they are highly
dependent on the nature of the substrate. There is little hope
for chemoselectively oxidizing just one nitrogen in a
polypeptide like 8a.6
selected as a starting point for the study because the anodic
oxidation of a dipeptide analogous to 9 having no silyl
substituent had failed to afford any methoxylated product.10
Substrate 9 was synthesized by first oxidizing a simple
proline derivative in order to form the methoxylated product
and then converting the product into the phenyl sulfonyl
proline derivative in 85% yield.11 A cuprate reagent was then
employed to introduce the silyl moiety.12 Once the silyl group
was in place, the Cbz group was removed and the amino
acid was coupled to a t-Boc protected phenylalanine. The
oxidation of 9 was performed in an undivided cell using a
reticulated vitreous carbon anode, a 0.03 M Et4NOTs in
MeOH electrolyte solution, and constant current conditions.
Current was passed until 2.0 F/mol of charge had been
passed.13 The reaction led to the formation of the methoxy-
lated product in an 82% yield along with 4.4% of the
recovered starting material. The intramolecular cyclization
was then completed with the use of BF3‚Et2O and the
stereochemistry of the bicyclic product assigned with the use
of a NOESY experiment.
Fortunately, chemistry developed by Yoshida and co-
workers would appear to provide an ideal solution to this
dilema.7-9 These authors showed that the presence of a silyl
substituent on the carbon R to an amide nitrogen lowered
the oxidation potential of the amide by +0.5 V. Oxidation
of the R-silated amide led to loss of the silyl group and
generation of an N-acyliminium ion. Hence, if a silyl group
could be selectively incorporated into 8b (X ) SiR3), then
a subsequent oxidation reaction would in principle selectively
oxidize the nitrogen proximal to the silyl group, lead to the
A similar oxidation-cyclization sequence was accom-
plished using substrate 12a (another case in which the
unsilated alternative failed to afford a bicyclic product). In
this experiment the oxidation afforded a methoxylated
product (76%) that was cyclized using TFA in dichloro-
(5) For intramolecular cyclizations leading to stereoselective syntheses
of peptidomimetics such as 1b, see: (a) Robl, J. A. Tetrahedron Lett. 1994,
35, 393. (b) Flynn, G. A.; Beight, D. W.; Mehdi, S.; Koehl, J. R.; Giroux,
E. L.; French, J. F.; Hake, P. W.; Dage, R. C. J. Med. Chem. 1993, 36,
2420. Flynn, G. A.; Giroux, E. L.; Dage, R. C. J. Am. Chem. Soc. 1987,
109, 7914.
(6) Murahashi, S.-I.; Mitani A.; Kitao, K. Tetrahedron Lett. 2000, 41,
10245.
(7) (a) Yoshida, J.; Isoe, S. Tetrahedron Lett. 1987, 28, 6621. (b) For a
review, see: Yoshida, J. Topics Curr. Chem. 1994, 170, 39.
(8) (a) For a recent application to a simple amide, see: Kamada, T.;
Oku, A. J. Chem. Soc., Perkin Trans. 1 1998, 3381.
(10) For an experimental procedure, see ref 4b.
(11) Brown, D. S.; Charreau, P.; Hansson, T.; Ley, S. V. Tetrahedron
1991, 47, 1311.
(12) For a review, see: Fleming, I. In Organocopper Reagents; Taylor,
R. J. K., Ed.; Oxford University Press: Oxford, 1994; pp 257-292.
(13) The oxidations were conducted using a model 630 coulometer, a
model 410 potentiostatic controller, and a model 420A power supply
purchased from The Electrosynthesis Co., Inc.
(9) For the use of R-silylamines to direct the generation of iminium ions,
see: (a) Yoon, U. C.; Mariano, P. S. Acc. Chem. Res. 1992, 25, 233.
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Org. Lett., Vol. 4, No. 9, 2002