ORGANIC
LETTERS
2002
Vol. 4, No. 4
597-598
A Solid-Phase Route to N-Cyanoamides
Trevor Morgan, Nicholas C. Ray,* and David M. Parry
Celltech R&D Ltd., Granta Park, Great Abington, Cambridge CB1 6GS, U.K.
Received December 10, 2001
ABSTRACT
A new method for the solid-phase synthesis of cyanamides is described. The attachment of a secondary amine to solid support is accomplished
using Merrifield resin. After functionalization, cleavage is readily achieved with cyanogen bromide to afford the desired cyanamide.
The cysteine proteinases are one of four major classes of
proteinase enzymes1 that selectively catalyze the hydrolysis
of polypeptide bonds. They are involved in a variety of
physiological processes such as apoptosis, inflammation, and
cell signaling and migration. Inhibitors of such enzymes
therefore have promising therapeutic application in the
treatment of, for instance, tumor metastasis, myocardial
infarction, inflammation, and bone disease. Most cysteine
proteinase inhibitors contain electrophilic isosteres (the
“warhead”) that interact with the cysteine thiol group at the
enzyme catalytic site, and a key feature in the development
of inhibitors to this enzyme class has been the design of
warheads that react selectively without the toxicity problems
associated with alkylation/acylation of other functionalities.
Nitrile groups are known to be suitable warheads with
selectivity toward cysteine proteinases over other classes,2
and recently workers at Merck have disclosed N-cyanamides
(Figure 1) as inhibitors of the cysteine proteinases cathepsins
We hypothesized that secondary amines loaded onto
suitable resins should be cleavable through quaternization
with cyanide and loss of a benyzl group (from the linker) in
one step (the von Braun reaction4). To test this methodology
we prepared suitably substituted 1-cyano-3-aminopyrrolidines
and 1-cyano-4-aminopiperidines as disclosed by the Merck
workers.
Thus Merrifield resin5 was loaded with 3-(tert-butoxycar-
bonylamino)pyrrolidine (Scheme 1) in DMF with catalytic
tetrabutylammonium iodide. Loading was judged qualita-
tively by IR (carbonyl stretch at 1650-1680 cm). Depro-
tection with 20% trifluoroacetic acid in dichloromethane
followed by a triethylamine wash afforded compound 1 as
the free base. Disappearance of the carbonyl stretch indicated
complete deprotection of the primary amine. At this point
the amino group was derivatized in a number of ways.
Carboxylic acids were coupled using an HBTU protocol to
afford compounds 2a,b, while the urea was prepared through
reaction with excess phenyl isocyanate to yield 3. To prepare
sulfonamide 4, pyridine was chosen as the base rather than
triethylamine or diisopropylethylamine, as the latter often
led to the formation of significant amounts of the bis-
sulfonamide. The chemistry was repeated using 4-(tert-
butoxycarbonylamino)piperidine attached to the resin to give
the appropriately functionalized aminopiperidines.
Figure 1. Merck cathepsin inhibitors.
Cleavage from the resin was achieved with a slight excess
of cyanogen bromide, the excess of which was then
scavenged out from solution using polymer-supported trisamine
K and L.3 Herein we disclose our work toward the prepara-
tion of such compounds on the solid phase.
(3) Falgueyrat, J.-P.; Oballa, R. M.; Okamoto, O.; Wesolowski, G.;
Aubin, Y.; Rydzewski, R. M.; Prasit, P.; Riendau, D.; Rodan, S. B.; Percival,
M. D. J. Med. Chem. 2001, 44, 94-104.
(4) For a review, see: Cooley, J. H.; Evain, E. J. Synthesis 1989, 1.
(5) Merrifield resin from Novabiochem, loading 1.19 mmol/g.
(1) Leung, D.; Abbenante, G.; Fairlie, D. P. J. Med. Chem. 2000, 43,
305-341.
(2) Hanzlik, R. P.; Zygmunt, J.; Moon, J. B. Biochim. Biophys. Acta
1990, 1035, 62-70.
10.1021/ol0172020 CCC: $22.00 © 2002 American Chemical Society
Published on Web 01/29/2002
Morgan, Trevor
