Solid-phase synthesis of aspartic peptidase inhibitors: 3-alkoxy-4-aryl piperidines.

Article abstract of DOI:10.1021/ol016280k

[reaction: see text]. The 3-alkoxy-4-aryl piperidines are non-peptide peptidomimetic inhibitors of several aspartic peptidases. The solid-phase functionalization of 3,4-disubstituted piperidine scaffolds using a traceless linker strategy is described. Syn

Full text of DOI:10.1021/ol016280k

ORGANIC
LETTERS
2001
Vol. 3, No. 17
2625-2628
Solid-Phase Synthesis of Aspartic
Peptidase Inhibitors: 3-Alkoxy-4-Aryl
Piperidines
,†,‡
Matthew G. Bursavich† and Daniel H. Rich*
Department of Chemistry, UniVersity of Wisconsin-Madison, 1101 UniVersity AVenue,
Madison, Wisconsin 53706, and School of Pharmacy, UniVersity of
Wisconsin-Madison, 777 Highland AVenue, Madison, Wisconsin 53705
dhrich@facstaff.wisc.edu
Received June 14, 2001
ABSTRACT
The 3-alkoxy-4-aryl piperidines are non-peptide peptidomimetic inhibitors of several aspartic peptidases. The solid-phase functionalization of
3,4-disubstituted piperidine scaffolds using a traceless linker strategy is described. Synthesis of diverse analogues based on this scaffold
provides the potential to generate selective inhibitors of this important class of peptidase.
Roche scientists recently discovered via high throughput
screening that the 3-alkoxy-4-aryl substituted piperidine 1
inhibited human renin.1 By use of structure-based design they
obtained orally bioavailable analogues, e.g., 2, that lowered
blood pressure in primates. In addition, analogues of 1 and
2 were found that inhibited plasmepsin, a potential target
for treatment of malaria. These inhibitors constitute a major
advance in methods for the inhibition of aspartic peptidases.
The compounds are simple, are low molecular weight, and
contain no amide bonds, and some show promising phar-
macokinetic properties. Furthermore, these piperidines are
structurally related to paroxetine,2 a known CNS active drug;
consequently this scaffold may become especially effective
at inhibiting aspartic peptidases located in the CNS.
Following the Roche lead and using structure-based design,
we developed inhibitors of porcine pepsin and R. chenensis
pepsin, two aspartic peptidases not inhibited in the Roche
reports.3 Subtle modifications in the side chain functionality
gave non-peptide peptidomimetic aspartic peptidase inhibitors
with altered specificities, e.g., 3 and 4. In view of the
importance of aspartic peptidases as potential therapeutic
targets (AIDS, Alzheimer’s disease, hypertension, and ma-
laria, with this list expected to grow as the human genome
project continues) we have developed a solid-phase method
for rapidly synthesizing libraries of piperidine analogues
substituted at the 3- and 4′-positions. In designing a solid-
phase functionalization method to prepare an array of 3,4-
† Department of Chemistry.
‡ School of Pharmacy.
(1) (a) Oefner, C.; Binggeli, A.; Breu, V.; Bur, D.; Clozel, J.P.; D’arcy,
A.; Dorn, A.; Fischli, W.; Gruninger, F.; Guller, R.; Hirth, G.; Marki, H.;
Mathews, S.; Miller, M.; Ridley, R. G.; Stadler, H.; Viera, E.; Wilhelm,
M.; Winkler, F.; Wostl, W. Chem. Biol. 1999, 6, 127. (b) Viera, E., Binggeli,
A.; Breu, V.; Bur, D.; Fischli, W.; Gu¨ller, R.; Hirth, G.; Ma¨rki, H. P.; Mu¨ller,
M.; Oefner, C.; Scalone, M.; Stadler, H.; Wilhelm, M.; Wostl, W. Bioorg.
Med. Chem. Lett. 1999, 9, 1397. (c) Gu¨ller, R.; Binggeli, A.; Breu, V.;
Bur, D.; Fischli, W.; Hirth, G.; Jenny, C.; Kansy, M.; Montavon, F.; Mu¨ller,
M.; Oefner, C.; Stadler, H.; Vieira, E.; Wilhelm, M.; Wostl, W.; Ma¨rki, P.
Bioorg. Med. Chem. Lett. 1999, 9, 1403.
(2) For structural comparison, see Figure 2 in Supporting Information.
(3) Bursavich, M. G.; West, C. W.; Rich, D. H. Org. Lett. 2001, 3, 2317.
10.1021/ol016280k CCC: $20.00 © 2001 American Chemical Society
Published on Web 07/21/2001

conversion of tetrahydropyridine 5 to the corresponding diol
6 using Sharpless asymmetric dihydroxylation (AD).5 Sub-
sequent stereoselective reduction of the resulting benzylic
alcohol with Raney-nickel afforded 7 in both high yields and
enantiomeric excesses.6 Removal of the Boc protecting group
or phenol protection followed by removal of the Boc
protecting group provided the desired piperidines 9-11.
Conditions for anchoring 3,4-disubstituted piperidines to
the triazine-based solid support were determined using
piperidine 9 as the model (Scheme 2). The aniline linker 12
Scheme 2a
Figure 1. Piperidine-based aspartic peptidase inhibitors.
disubstituted piperidine derivatives, we decided to utilize a
traceless triazine linker strategy for amines described by
Brase et al.4 This linker was chosen for our solid-phase
functionalization because it provides (1) selective attachment
of the piperidine secondary amine, (2) facile and orthogonal
functionalization of the piperidine core, and (3) traceless
cleavage of the resin-bound final products via mild conditions
to afford products with high purity.
a Conditions: (a) m-hydroxy aniline, NaH, nBu4NI; (b) BF3‚OEt2,
tBuONO; (c) 9, TEA, DCM/DMF; (d) 10% TFA/DCM.
was generated by alkylation of Merrifield resin with the
phenolic anion of m-hydroxyaniline. The aniline nitrogen in
12 was converted to the diazonium resin 13 using a modified
procedure described by Moore and co-workers.7 The dia-
zonium resin was quickly washed with cold DCM and DMF
and treated with piperidine 9 in DCM (or DCM/DMF) to
afford the resin-bound triazine 14 (1.44 mmol/g).
The piperidine cores for the solid-phase synthesis were
constructed using our reported enantioselective syntheses
(Scheme 1).3 Key to the synthesis of these piperidines was
Scheme 1a
Conditions to functionalize the secondary alcohol of
piperidine 14 were then developed. A variety of alkylation
conditions were systematically investigated, including chang-
ing the solvent (DMF or THF), base (NaH or KOtBu), and
additive (nBu4NI and crown ethers). The optimal alkylation
conditions were determined to be KOtBu in THF at ap-
proximately 50 °C with the addition of nBu4NI. The
secondary alcohol of 14 was then alkylated with a variety
of benzyl bromide derivatives using these conditions (Scheme
3) to afford 15. The piperidines were cleaved from the resin
by using mildly acidic conditions to provide the potential
aspartic peptidase inhibitors 16a-e (>98% crude purity).
These methods were applied to generate two other small
libraries of potential aspartic peptidase inhibitors based on
(4) (a) Brase, S.; Enders, D.; Kobberling, J.; Avemaria; F. Angew. Chem.,
Int. Ed. Engl. 1998, 37, 3413. (b) Brase, S.; Kobberling, J.; Enders, D.;
Lazny, R.; Wang, S.; Brandtner, S. Tetrahedron Lett. 1999, 40, 2105.
(5) Sharpless, K. B.; Amberg, W.; Bennani, Y. L.; Crispino, G. A.;
Hartung, J.; Jeong, K. S.; Kwong, H. L.; Morikawa, K.; Wang, Z. M.; Xu,
D.; Zhang, X. L. J. Org. Chem. 1992, 57, 2768.
(6) The silyl-ether must first be removed, as the protected analogue did
not react presumably for steric reasons.
(7) Nelson, J. C.; Young, J. K.; Moore, J. S. J. Org. Chem. 1996, 61,
8160.
a Conditions: (a) AD-mix-R, CH3SO2NH2; (b) Ra-Ni, refluxing
EtOH; (b′) (1) TBAF, (2) Ra-Ni, refluxing EtOH; (c) Allyl-Br,
Cs2CO3; (d) HCl/dioxane.
2626
Org. Lett., Vol. 3, No. 17, 2001

removed by using Pd(PPh3)4 and morpholine in DCM to
Scheme 3a
provide phenol 19.
We envisioned that alkylation of phenol 19 with Cs2CO3
and the appropriate alkyl bromides would generate the
desired array of potential inhibitors. Initial alkylation attempts
in DMF at 40 °C afforded only minimal conversion to the
desired product; a slight increase was obtained when nBu4NI
was added to the reaction. The reported success of a solid-
phase K2CO3-mediated alkylation in a 2:1 mixture of CHCl3/
MeOH8 prompted us to test this solvent system. We were
able to significantly increase our conversion (∼90% in our
model study) by using Cs2CO3 in CHCl3/MeOH. Alkylation
of phenol 19 under these conditions with a variety of alkyl
bromides afforded 20. The difunctionalized piperidines were
cleaved from the resin by using mildly acidic conditions to
provide the array of potential aspartic peptidase inhibitors
21a-l (70-95% crude purity).
The reduced purity of this library resulted from incomplete
alkylation of phenol 19 in the penultimate step. After multiple
unsuccessful attempts to circumvent this problem, we
developed an expedient method to purify the desired final
product by removing unreacted starting material with a
scavanger resin.9,10 The unreacted phenol was removed from
the crude product mixture by reaction with a basic resin.
Incubation with the P-TBD11,12 scavenging resin 22 in DCM
for 1 min and subsequent filtration afforded (Scheme 5) the
potential aspartic peptidase inhibitors 21a-l in g90% purity.
n
a Conditions: (a) KOtBu, R-X, Bu4NI, 50 °C; (b) 10% TFA/
DCM.
functionalizing both the 3- and 4′-positions of the 3,4-
disubstituted piperidine scaffold. The synthesis of the first
library (Scheme 4) began with the attachment of piperidine
Scheme 4a
Scheme 5
The final library of potential aspartic peptidase inhibitors
(Scheme 6) was synthesized via selective functionalizations
without necessitating phenol protection and subsequent
protecting group manipulations. Attachment of piperidine 10
to the solid-phase diazonium resin 13 generated 23 (1.25
mmol/g). Selective alkylation of phenol 23 using our
optimized phenol alkylation conditions with two different
alkyl bromides afforded piperidine 24. The remaining
secondary hydroxyl of 24 was then alkylated with a variety
a Conditions: (a) 11, TEA, DCM/DMF; (b) KOtBu, R1-Br,
nBu4NI, 50 °C; (c) Pd(PPh3)4, morpholine; (d) Cs2CO3, R2-Br; (e)
10% TFA/DCM.
(8) Pavia, M. R.; Whitesides G. M.; Hangauer, D. G.; Hediger, M. E.
Patent Application WO9504277, 1995.
(9) Flynn, D. L. Med. Chem. Res. 1999, 19, 408.
(10) Parlow, J. J.; Devraj, R. V.; South, M. S. Curr. Opin. Chem. Biol.
1999, 3, 320.
(11) Weidner, J. J.; Parlow, J. J.; Flynn, D. L. Tetrahedron Lett. 1999,
40, 239.
(12) Polystyrene-supported 1,5,7-triazabicyclo[4.4.0]dec-5-ene
11 to the solid-phase diazonium resin 13 to give 17 (1.18
mmol/g). The secondary alcohol was then functionalized via
our optimized alkyation conditions using a variety of benzyl
bromide derivatives to generate 18. Following some experi-
mentation the allyl-protecting group was mildly and cleanly
Org. Lett., Vol. 3, No. 17, 2001
2627

conditions to provide the potential aspartic peptidase inhibi-
tors 26a-e (g90% crude purity).
Scheme 6a
In summary, we have developed a solid-phase function-
alization method to generate arrays of 3,4-disubstituted
piperidines via three routes. Already this scaffold has proven
useful in developing novel inhibitors for four different
aspartic peptidases. The methods described in this Letter
should enable preparation of more extensive libraries to
generate the structure-activity relationships that will facili-
tate the design of more active and selective inhibitors. Further
diversification of these libraries via palladium-mediated
chemistries is under investigation. The new derivatives
reported in this Letter are currently being evaluated as
potential inhibitors of a variety of therapeutically interesting
aspartic peptidase targets.
Acknowledgment. This work was supported by the NIH
(GM50113), as well as by instrumentation grants NSF CHE-
9208463 and NIH 1 S1O RR0 8389-01. We thank Dr. Martha
Vestling for obtaining the MS data.
Supporting Information Available: Detailed experi-
mental procedures for the generation of all resins, product
cleavage from resin, purification protocol via solid-phase
extraction including a representative example, and a listing
with crude purities of all final compounds (Tables 1-3)
generated using these methods. This material is available free
of charge via the Internet at http://pubs.acs.org.
a Conditions: (a) 10, TEA, DCM/DMF; (b) Cs2CO3, R2-Br; (c)
n
KOtBu, R1-Br, Bu4NI, 50 °C; (d) 10% TFA/DCM.
of benzyl bromide derivatives to afford piperidine 25. The
piperidines were cleaved from the resin by using mild acidic
OL016280K
2628
Org. Lett., Vol. 3, No. 17, 2001