2538
M. Steger et al. / Bioorg. Med. Chem. Lett. 11 (2001) 2537–2540
ꢀ
Scheme 2. (i) K
87%); (iii) H
2
O
8
S
2
, CH
3
CN, H
2
O, NaHCO
3
, pH 4.5, 80 C, 5 h (82%); (ii) 3,4-dihydro-2H-pyran (1.6 equiv), TsOH, (0.02 equiv), THF, rt, 12 h
(
equiv), DMAP (2 equiv), CH
2
, Pd/C (10%) (0.03 equiv), EtOAc, rt, 4 h (81%); (iv) TCP-resin, N-ethyldiisopropylamine, rt, 15 h; (v) R
0
1 3
-X-Cl (5 equiv), Et N (8
2
Cl
2
, rt, 6 h; (vi) R
R
2 2
NH (8 equiv), Et
3
N (2 equiv), CH Cl
2
2
, rt, 15 h; (vii) 20% TFA, 10% MeOH, CH
2
Cl , rt, 2 h.
2
choice of the attachment point to the resin, but also the
sequence of protecting group manipulations. In a first
approach the secondary alcohol function of 2 was pro-
whilst the compounds still remain on the solid phase.
The initial scaffold 2 had therefore to be pre-modified
again. The DMB protecting group was removed and the
benzyloxycarbonyl protecting group on the pyrrolidine
nitrogen was replaced by an allyloxycarbonyl (aloc)
group. The latter protecting group can be easily
removed on solid phase with tetrakis-(triphenyl-phos-
phine)-palladium. The deprotection of the THP pro-
tected alcohol was carried out by polymer-supported
PPTS, to yield the scaffold 9 in good yield and purity.
The alcohol function was attached to the resin via a 3,4-
dihydro-2H-pyran-2-ylmethoxy-methyl-linker in the
presence of TsOH at room temperature. The standard
literature procedure with PPTS was not successful on
7
tected with a tetrahydropyran-2-yl-group (THP). The
3
,4-dimethoxy-benzyl- (DMB) protective group of the
5
b-lactam nitrogen was oxidatively removed, followed
by the removal of the benzyloxycarbonyl- (Z) protecting
group on the pyrrolidine nitrogen. The latter protecting
group was removed under hydrogenation conditions.
The modified scaffold 4 was attached to the solid phase,
using a commercially available tritylchloride poly-
styrene (TCP) resin. The first reaction, which was car-
ried out on solid support, was the introduction of the
primary diversity vector. The b-lactam nitrogen of 5 was
acylated or sulfonated using acid-chlorides or sulfonyl-
chlorides, respectively, to yield the intermediates 6. This
reaction not only allows the first introduction of build-
ing blocks, but also at the same time facilitates the key
step, the opening of the b-lactam ring with amines. Due
to the large variety of acid chlorides, sulfonyl chlorides
and amines available, we decided to generate a library
of 800 compounds, which was designed to offer max-
imal diversity from a structural point of view (see
below). Therefore the pyrrolidines 7, after the ring-
opening with the amines, were cleaved off the resin, with
simultaneous cleavage of the THP group, to yield a
library of N-unsubstituted-hydroxy-pyrrolidines 8.
8
this particular scaffold.
Then the b-lactam-ring of 10 was activated by the
introduction of the first diversity vector, followed by the
opening of the intermediates 11 with amines to yield
disubstituted pyrrolidines 12 in a similar fashion as
shown in Scheme 2 (steps v–vi). To be able to introduce
a third vector of diversity, it was necessary to initially
deprotect the pyrrolidine nitrogen. This was carried out
efficiently by the use of tetrakis-(triphenylphosphine)
palladium as catalyst in presence of an allyl scavenger.
In our case the most successful reagent to prevent the
re-protection of the nitrogen by the allyl group was
9
found to be the borane dimethylamine complex. The
Using this route (Scheme 2), the production of libraries
of single, purified compounds (>10mg of each) was
use of other standard allyl scavengers such as dimedone
or typically more then 0.05 equivalents of the palladium
catalyst were not successful and led to the allylation of
the pyrrolidine nitrogen. The free amino function of
13, was the ideal intermediate to construct a very large
TM
achieved using the IRORI MicroKans
TM
in connection
10
with the IRORI AutoSort
.
In a second approach, the scaffold 2 was attached via
the alcohol function to a solid support in order to
introduce further diversity at the pyrrolidine nitrogen,
variety of libraries using acid chlorides, sulphonyl chlor-
ides, isocyanates and chloroformates to yield the corre-
sponding amides, sulfonamides, ureas and carbamates
ꢀ
ꢀ
Scheme 3. (i) AlocCl (1.1 equiv), pyridine (2.5 equiv), CH
80%); (iii) DHP resin, TsOH (3 equiv), rt, 15 h; (iv) R -X
Et N (2 equiv), CH Cl , rt, 15 h; (vi) Pd(PPh
equiv), Et N (8 equiv), CH Cl
2
Cl
2
, À15 C to rt, 1 h (93%); (ii) PPTS-polymer bound (1 equiv), EtOH, 60 C, 10h
0
(
1
1
-Cl (5 equiv), Et
3
N (8 equiv), DMAP (2 equiv), CH
, rt, 1 h; (vii) R
2
Cl
2
, rt, 6 h; (v) R
2
R
2
NH (8 equiv),
-N¼C¼O (5
ꢁ
3
2
2
3
)
4
(0.05 equiv), Me
2
NH BH
3
(20equiv), CH
2
Cl
2
3
COCl, R
3
SO
2
Cl or R
3
3
2
2
, rt, 2 h; (viii) 20% TFA, 10% MeOH, CH
2
Cl
2
.