Combinatorial chemistry for ligand development in catalysis: Synthesis and catalysis screening of peptidosulfonamide tweezers on the solid phase

Article abstract of DOI:10.1021/jo991628z

On the basis of a pyrrolidine tweezer 1, a library of peptidosulfonamide tweezers (15a-e, 16a-e was synthesized on the solid phase. This library was screened in a simultaneous substrate screening procedure for the ability to enantioselectively catalyze the Ti(O-i-Pr)4-mediated addition of diethylzinc to aldehydes. One of the best solid-phase tweezer catalyst (i.e., 16d, giving an ee of 32% in solid-phase catalysis) was resynthesized in solution (compounds 20 and 21). The now homogeneous solution-phase catalysis showed even better enantioselectivity (i.e., up to 66%).

Full text of DOI:10.1021/jo991628z

1750
J . Org. Chem. 2000, 65, 1750-1757
Com bin a tor ia l Ch em istr y for Liga n d Develop m en t in Ca ta lysis:
Syn th esis a n d Ca ta lysis Scr een in g of P ep tid osu lfon a m id e
Tw eezer s on th e Solid P h a se
Arwin J . Brouwer, Heiko J . van der Linden, and Rob M. J . Liskamp*
Department of Medicinal Chemistry, Utrecht Institute for Pharmaceutical Sciences, Utrecht University,
P.O. Box 80082, NL-3508 TB Utrecht,The Netherlands
Received October 19, 1999
On the basis of a pyrrolidine tweezer 1, a library of peptidosulfonamide tweezers (15a -e, 16a -e)
was synthesized on the solid phase. This library was screened in a simultaneous substrate screening
procedure for the ability to enantioselectively catalyze the Ti(O-i-Pr)4-mediated addition of
diethylzinc to aldehydes. One of the best solid-phase tweezer catalyst (i.e., 16d , giving an ee of
32% in solid-phase catalysis) was resynthesized in solution (compounds 20 and 21). The now
homogeneous solution-phase catalysis showed even better enantioselectivity (i.e., up to 66%).
In tr od u ction
tweezer structure led to a considerable increase in
binding affinity.2b One of these tweezers was the pyrro-
lidine containing synthetic receptor 1 (Figure 1). There
is clear similarity between the amine-sulfonamide part
of this compound with the very well-known bisulfonamide
ligand derived from 1,2-diaminocyclohexane3 2. This
ligand has been used in the very efficient enantioselective
addition of diethylzinc to aldehydes (e.g., benzaldehyde).3
The pyrrolidine tweezer-like synthetic receptor has an
additional handle for attachment of a dye2 or to a solid-
phase bead. In this paper, the handle is attached to a
solid-phase bead enabling solid-phase synthesis of the
peptidosulfonamide tweezer-ligand as well as a facile
screening of enantioselective catalytic properties. Advan-
tages of a solid-phase ligand are easy removal after
completion of the reaction and catalyst reuse.
Combinatorial chemistry is now widely integrated in
the drug discovery and optimization processes, and it is
now progressing rapidly in a number of other molecular
areas.1a The possibilities to generate and screen a number
of compounds as well as optimize conditions for studying
these compounds (e.g., reaction conditions) in an iterative
manner make combinatorial chemistry extremely attrac-
tive for finding and optimizing ligands for catalysis.1b
In principle, there are two approaches for screening of
a catalyst ligand: screening in solution1a-c or screening
on the solid phase.1a,b,d-f Although screening an im-
mobilized solid-phase catalyst ligand clearly has disad-
vantages compared to solution screening, such as the
heterogeneous nature of a solid-phase bead causing
unfavorable kinetics and possible interactions of the
reactants with the solid phase, the very same heteroge-
neous nature of the bead has the advantages that catalyst
and product can be easily separated and the catalyst
recovered. In addition, solid-phase chemistry enables, in
principle, the convenient preparation of libraries of
compounds.
Therefore, our approach was to synthesize ligands for
catalysis on the solid phase, screen them for catalytic
activity, and resynthesize the best ligand in solution and
determine its catalytic activity. Thus, the solid-phase
approach is used here for synthesis and screening of
ligands, which will be applied in solution.
Recently, we found that peptidosulfonamide-containing
tweezer-like molecules were capable of selective binding
of tripeptides from a combinatorial library.2a In addition,
we found that a more rigid hinge preorganized toward a
Resu lts a n d Discu ssion
To determine if the pyrrolidine hinge would give rise
to a catalytically active ligand showing at least some
degree of enantioselectivity, the triflate containing hinge
3 was first synthesized in solution. Indeed, it was found
that the triflate pyrrolidine ligand gave rise to catalysis,
and to some degree of enantioselectivity. The next step
was to introduce a linker for attachment to a solid-phase
resin to give compound 4. This compound, as well as a
compound containing a different sulfonamide (5), was
catalytically active showing that the pyrrolidine hinge
containing a linker can, in principle, be used for different
catalytically active ligands and that a linker is compatible
with catalytic activity (Figure 1).
Before moving to a solid-phase synthesis of the pepti-
dosulfonamide ligands, it was necessary to evaluate if
* To whom correspondence should be addressed Fax: (+31)30-
2536655. E-mail: R.M. J .Liskamp@pharm.uu.nl.
(2) (a) Lo¨wik, D. W. P. M.; Mulders, S. J . E.; Cheng, Y.; Shao, Y.;
Liskamp, R. M. J . Tetrahedron Lett. 1996, 37, 8253-8256. (b) Lo¨wik,
D. W. P. M.; Weingarten, M. D.; Broekema, M.; Brouwer, A. J .; Still,
W. C.; Liskamp, R. M. J . Angew. Chem., Int. Ed. Engl. 1998, 37, 1846-
1850.
(3) See e.g. Takahashi, H.; Kawakita, T.; Yoshioka, M.; Kobayashi,
S.; Ohno, M. Tetrahedron Lett. 1989, 30, 7095; Takahashi, H.;
Kawakita, T.; Ohno, M.; Yoshioka, M.; Kobayashi, S. Tetrahedron 1992,
48, 5691. A modified bissulfonamide ligand derived from 2 has been
used as a cross-linker in the successfull preparation of a polymeric
catalytically active ligand for the enantioselective alkylation of ben-
zaldehyde: Halm, C.; Kurth, M. J . Angew. Chem., Int. Ed. Engl. 1998,
37, 510-512.
(1) (a) For a recent review, see: J andeleit, B.; Scheafer, D. J .;
Powers, T. S.; Turner, H. W.; Weinberg, W. H. Angew. Chem., Int. Ed.
Engl. 1999, 38, 2495-2532. (b) For a nice overview of seminal work of
several researchers, see, e.g.: Shimizu, K. D.; Snapper, M. L.; Hoveyda,
A. H. Chem. Eur. J . 1998, 4, 1885 and references therein. (c) Cole, B.
M.; Shimizu, K. D.; Krueger, C. A.; Harrity, J . P. A.; Snapper, M. L.;
Hoveyda, A. H. Angew. Chem., Int. Ed. Engl. 1996, 35, 1668. (d)
Shimizu, K. D.; Cole, B. M.; Krueger, C. A.; Kuntz, K. W.; Snapper,
M. L.; Hoveyda, A. H. Angew. Chem., Int. Ed. Engl. 1997, 36, 1704-
1707. (e) Taylor, S. J .; Morken, J . P Science 1998, 280, 267-270. (f)
Sigman, M. S.; J acobsen, E. N. J . Am. Chem. Soc. 1998, 120, 4901-
4902.
10.1021/jo991628z CCC: $19.00 © 2000 American Chemical Society
Published on Web 02/23/2000

Peptidosulfonamide Tweezers in Catalysis
J . Org. Chem., Vol. 65, No. 6, 2000 1751
F igu r e 1. Pyrrolidine-containing synthetic receptor 1 and bistriflate catalyst 2 as starting points for the development of solid-
phase attached tweezer catalysts.
these ligands showed at least some catalytic activity in
solution. Therefore, taurine-containing tweezer 6 as well
as the phenylalanine sulfonamide (Phes) containing
tweezer 7 were synthesized. The latter displayed a
promising ee of 30% in preliminary experiments in the
catalyzed diethylzinc addition (vide infra).
lidine diol 9.6 This diol was converted into the diazide7
and reduced, and the resulting amino groups were
protected to afford 10. The spacer was introduced after
hydrogenolysis of the benzyl group8 by treatment with
succinic anhydride. Coupling of the resulting pyrrolidine
ring containing system 11 to the Argonaut resin was
achieved in a BOP coupling to give 12. After removal of
the Boc-protecting groups, the peptidosulfonamide moi-
eties were introduced in 13 by the sulfonyl chloride
approach (Scheme 1). The required Fmoc-protected â-
aminosulfonyl chlorides 14a -e were synthesized as
described.9 By cleavage of the Fmoc group, the loading
of the resin was determined followed by introduction of
the base-stable Boc group.10 According to this procedure,
a library of 10 peptidosulfonamide tweezers 15a -e and
16a -e on the solid phase was obtained.
Instead of screening each resin-bound peptidosulfon-
amide tweezer with one substrate, we decided to use a
mixture of substrates (Scheme 2). This mixture was
chosen in such a way that (a) the GC retention times of
the individual substrates were different, (b) the retention
times of the individual enantiomeric mixtures of the
products were different, and (c) the retention times of
the substrates and products were different. In this way,
in a single run four data points were obtained with
However, in initial experiments with the sulfonamide
ligand attached to the solid phase, it was found that the
resin type and the amount of the used catalyst was quite
essential. In these experiments, benzaldehyde was used
as the substrate in the Ti(O-i-Pr)4-mediated addition of
diethylzinc. The sulfonamide ligand attached to a Mer-
rifield resin (8a ) was completely devoid of catalytic ac-
tivity. After changing the resin to a poly(ethylene glycol)-
polystyrene (Argonaut resin) to give 8b, catalysis did take
place using 16 mol % of ligand. Based on a loading of
0.30 mmol/g resin, this amounted to 40 mg of resin.
These encouraging results justified the solid-phase
preparation and screening for catalytic activity of pep-
tidosulfonamide tweezers.4 Five â-amino sulfonic acid
derivatives were selected for solid-phase synthesis of
pyrrolidine-containing peptidosulfonamides. To deter-
mine the influence of ligand handedness on enantiose-
lectivity, the pyrrolidine ring was synthesized starting
from L- as well as D-tartaric acid (Scheme 1). Thus, the
pyrrolidine hinge5 was prepared as follows, from pyrro-
(6) Nagel, U.; Kinzel, E.; Andrade, J .; Prescher, G. Chem. Ber. 1986,
119, 3326-3343.
(4) While this work was in progress, the synthesis in solution and
parallel screening of chiral sulfonamide containing diamines was
described: Gennari, C.; Ceccarelli, S.; Piarulli, U.; Montalbetti, C. A.
G. N.; J ackson, R. F. W. J . Org. Chem. 1998, 63, 5312-5313.
(5) This hinge was successfully applied in the synthetic receptors
of Still et al.; see, e.g.: (a) Yoon, S. S.; Still, W. C. Tetrahedron 1995,
51, 567-578. (b) Shao, Y.; Still, W. C. J . Org. Chem. 1996, 62, 6086-
6087. (c) Pan, Z.; Still, W. C.Tetrahedron Lett. 1996, 37, 8699-8702.
(d) Torneiro, M.; Still, W. C.Tetrahedron 1997, 53, 8739-8750.
(7) Skarzewski, J .; Gupta, A. Tetrahedron: Assymetry 1997, 8, 1861-
1867.
(8) See ref 5a.
(9) (a) De Bont, D. B. A.; Dijkstra, G. D. H.; Den Hartog, J . A. J .;
Liskamp, R. M. J . Bioorg. Med. Chem. Lett. 1996, 6, 3035-3040. (b)
Brouwer, A. J .; Monnee, M. C. F.; Liskamp, R. M. J . Manuscript in
preparation.
(10) We have now shown that although upon storage the Fmoc group
is less stable, it gave rise to comparable conversions and ee.

1752 J . Org. Chem., Vol. 65, No. 6, 2000
Brouwer et al.
Sch em e 1. Syn th esis of a Libr a r y of
P ep tid osu lfon a m id e Tw eezer s on th e Solid P h a se
Sch em e 2. Libr a r y Scr een in g in a Sim u lta n eou s
Su bstr a te Scr een in g P r oced u r e for th e Ability To
En a n tioselectively Ca ta lyze th e Ti(O-i-P r )4
Med ia ted Ad d ition of Dieth ylzin c
Sch em e 3. Resyn th esis in Solu tion of Solid P h a se
Atta ch ed P ep tid osu lfon a m id e Tw eezer 16d
respect to the conversion and four data points were
obtained with respect to the enantioselectivity (expressed
as ee).
The Ti(O-i-Pr)4-mediated diethylzinc addition reactions
were carried out in toluene on a 0.0125 mmol scale, for
each substrate, using 20 mg of resin corresponding to 10-
16 µmol of resin bound chiral peptidosulfonamide ligand.
The substrates were benzaldehyde, p-Cl-benzaldehyde,
cyclohexylaldehyde, and phenylacetaldehyde. The reac-
tions were run overnight at -20 °C, quenched, and
analyzed by GC using a chiral capillary GC column. A
typical GC trace of a reaction mixture is shown in Figure
2.
From a comparison of the bargraphs in Figures 3 and
4, it is immediately apparent that high conversion was
paralleled by high ee. Furthermore, the two aromatic
The results of the conversion and ee values are shown
in Figures 3 and 4, respectively.

Peptidosulfonamide Tweezers in Catalysis
J . Org. Chem., Vol. 65, No. 6, 2000 1753
F igu r e 2. Typical GC-trace (CP-Chiracil-Dex CB column) of the enantioselective addition of diethylzinc to a mixture of
benzaldehyde (a), 4-chlorobenzaldehyde (b), phenylacetaldehyde (c), and cyclohexylaldehyde (d) catalyzed by solid-phase tweezer
16d giving rise to the corresponding enantiomeric mixtures of alcohols (aa-dd).
Ta ble 1
pyrrolidine is not sufficient for a high enantioselectivity
since taurine-containing pyrrolidine tweezers 15a and
16a did not show an appreciable ee. The best ee’s were
observed with the aromatic substrates using the leucine-
derived peptidosulfonamide (Leus) pyrrolidine tweezers
15d and 16d . The ee’s are largely determined by the side
chains in the peptidosulfonamide, since both pyrrolidine
enantiomers give rise to a similar ee. Apparently, size of
the side chain is not the only factor, since the phenyl-
alanine-derived peptidosulfonamide 15e and 16e do not
give rise to the highest ee. The less the influence of the
side chain, the more distinct the influence of the pyrro-
lidine ring on the ee as is nicely illustrated by the
phenylalanine derived peptidosulfonamide containing
tweezers (Figure 4).
Not unexpectedly, both the ee and the conversions
using the resin-bound tweezer are lower than in solution.
Therefore, it was expected once the best catalytically
resin-bound tweezer was found, the corresponding “solu-
tion” tweezer would give better enantiomeric ratio’s and
higher yields. There are literature data1d supporting this
assumption. Thus, the resin-bound tweezer containing
the leucine-derived peptidosulfonamide, which gave the
best ee, was synthesized in solution (Scheme 3). Instead
of attaching the pyrrolidine-spacer molecule to the resin,
the methyl amide 17 was now prepared, followed by
removal of the Boc group to 18 and preparation of the
peptidosulfonamide 19. Surprisingly, removal of the
aldehydes showed the highest conversions and highest
ee’s. It is also important to emphasize that the same
enantiomer is always formed in excess, irrespective of
the peptidosulfonamide and the chirality of the pyrroli-
dine moiety.
The influence of the configuration of the chiral centers
in pyrrolidine is not very great. However, the highest ee’s
are generally observed with the RR-pyrrolidine. This is
paralleled by the conversions, which are generally greater
for the RR-pyrrolidine with the distinct exception of the
valine-derived sulfonamide. Here, the SS diastereomer
resulted in a higher conversion, whereas the RR diaste-
reomer gave a higher ee. Clearly, the chirality of the

1754 J . Org. Chem., Vol. 65, No. 6, 2000
Brouwer et al.
F igu r e 3. Aldehyde conversions catalyzed by peptidosulfonamide tweezers on the solid phase.
F igu r e 4. Ee of the diethylzinc addition products catalyzed by peptidosulfonamide tweezers on the solid phase.
Fmoc group followed by introduction of the Boc group to
give 20 was accompanied by formation of a product (21)
resulting from cleavage of the spacer-pyrrolidine amide.
Be this as it may, both products 20 and 21 were tested
for their ability to catalyze the diethylzinc addition.
Indeed, it was found that under homogeneous conditions

Peptidosulfonamide Tweezers in Catalysis
J . Org. Chem., Vol. 65, No. 6, 2000 1755
was added a diazomethane solution in diethyl ether until the
reaction mixture remained yellow. After the mixture was
stirred for 5 min, a few drops of glacial acetic acid were added
to destroy the excess diazomethane. Subsequently, the solvent
was evaporated, and the Boc groups were removed by dissolv-
ing the residue in DCM (20 mL) and TFA (20 mL) and by
stirring for 5 min. Evaporation to dryness gave a yellow oil
that was dried on KOH under reduced pressure. The oil was
dissolved in DCM (4 mL), and DIPEA (1.07 mL, 6.15 mmol)
was added. After the mixture was cooled to -40 °C, trifluo-
romethanesulfonyl chloride (201 µL, 1.89 mmol) in DCM (0.5
mL) was slowly added. Stirring was continued at 4 °C for 2 h.
Then the solvent was evaporated, and EtOAc (40 mL) was
added. The resulting solution was washed with KHSO4, water,
and brine and dried on Na2SO4 followed by concentration. After
purification by column chromatography (eluent: 5% MeOH/
DCM, v/v), the product was obtained as a white foam (185 mg,
44%, 0.414 mmol): Rf 0.37 (eluent: 10% MeOH in DCM, v/v);
1H NMR (CDCl3) δ 2.54-2.67 (2m, 4H), 3.28-3.47 (m, 2H),
3.70 (s, 3H), 3.87-4.13 (m, 4H); 13C NMR (CDCl3/CD3OD) δ
28.1, 28.2, 47.9, 49.2, 51.7, 56.3, 57.8, 113.1, 117.4, 121.6, 125.9,
171.0, 174.0.
the tweezer containing leucine-derived peptidosulfon-
amides gave rise to notably increased ee values (56-66%)
as compared to the resin-bound ligand (32%), thus
confirming the earlier assumption (Table 1).
Con clu sion
We have shown that the solid-phase synthesis ap-
proach is a versatile approach to rapidly prepare a library
of peptidosulfonamide tweezers, which can be conve-
niently screened in a simultaneous screening procedure
for finding the optimal tweezer as well as determination
of the substrate specificity. Furthermore, it was shown
that the best ligand in the solid-phase catalysis is even
better in solution-phase catalysis. Since this approach is
amenable to additional combinatorial chemistry applica-
tions, it offers perspectives for further optimization of the
tweezer, determination of substrate range, and reuse of
the library in other catalytic reactions.
Liga n d 5. To a solution of N-succinyl-3,4-di(Boc-amino)-
pyrrolidine 11-RR (385 mg, 0.958 mmol) in MeOH (9.6 mL)
was added a diazomethane solution in diethyl ether until the
reaction mixture remained yellow. After the mixture was
stirred for 5 min, a few drops of glacial acetic acid were added
to destroy the excess of diazomethane. Evaporation of the
solvent gave a colorless oil (417 mg) that was dissolved in DCM
(3.0 mL), followed by addition of diethyl ether (3.0 mL),
saturated with HCl. After the mixture was stirred for 10 min,
the solvent was removed, and the product was dried on KOH
under reduced pressure, which gave a sticky white solid (290
mg, 0.964 mmol, 101%). To a solution of this residue (86.5 mg,
0.3 mmol) in DCM (3 mL) were added Et3N (167.3 µL, 1.2
mmol) and 4-nitro-phenylsulfonyl chloride (133 mg, 0.6 mmol).
After the mixture was stirred for 3 h, the solvent was
evaporated and the product was purified by column chroma-
tography (eluent: 5% MeOH in DCM, v/v) affording a yellow
foam (89 mg, 0.152 mmol, 51%): Rf 0.37 (eluent: 7% MeOH
Exp er im en ta l Section
Gen er a l Meth od s. Solvents were distilled prior to use. If
necessary, the commercial reagents were purified according
to Perrin and Armarego.11 Et2Zn was obtained as a 1 M
solution in hexanes (Aldrich, Zwijndrecht, The Netherlands).
N-Methylmorpholine (NMM) was distilled from CaH2. Argogel-
NH2 resin was purchased from Argonaut Technologies Inc.
(San Carlos, CA). The aldehydes, Ti(O-i-Pr)4, and methylamine
in THF (2 M) were obtained from Aldrich; the Ti(O-i-Pr)4 was
distilled. Reactions were carried out at ambient temperature
unless stated otherwise. TLC analysis was performed on Merck
precoated silicagel 60 F-254 (0.25 mm) plates. Spots were
visualized with UV light, ninhydrin, or Cl2-TDM.12 Solvents
were evaporated under reduced pressure at 40 °C. Column
chromatography was performed on Merck Kieselgel 60 (40-
63 µm). Electrospray mass spectra were recorded on a LCMS
spectrometer. Elemental analyses were carried out at J anssen
Pharmaceutica (Beerse, Belgium). For gas chromatography,
a gas chromatograph with split injector and a CP-Chirasil-
Dex CB column was used. 1H NMR and 13C NMR spectra were
1
in DCM, v/v); H NMR (CDCl3/CD3OD) δ 2.41-2.63 (m, 4H),
3.16 (dd, 1H), 3.33 (dd, 1H), 3.50 (dd, 1H), 3.66 (s, 3H), 3.71 (4
lines, 1H), 3.78 (dd, 1H), 3.89 (4 lines, 1H), 8.08 (m, 4H, 8.36
(m, 4H); 13C NMR (CDCl3/CD3OD) δ 28.4, 48.0, 51.9, 55.9, 57.5,
124.5, 128.2, 128.3, 145.5, 145.6, 150.2, 170.9, 173.9.
recorded on
a
300 MHz spectrometer. 13C spectra were
recorded using the attached proton test (APT) pulse sequence.
Compounds were pure according to TLC.
Liga n d 6. TFA salt (0.30 mmol), prepared from 11-R R
according to the procedure described for 4, was dissolved in
DCM (2.2 mL). NMM was added, until the apparant pH of
the solution was 8, and then Boc-tauryl chloride was added
(168 mg, 0.69 mmol). After the mixture was stirred for 12 h,
the solvent was removed in vacuo. Purification by column
chromatography (eluent: 6% MeOH in DCM, v/v) afforded a
colorless oil (80 mg, 43%, 0.129 mmol): Rf 0.44 (eluent: 10%
MeOH in DCM); 1H NMR (CDCl3/CD3OD) δ 1.43 (s, 18H), 2.55,
2.64 (2m, 4H), 3.31 (m, 5H), 3.43 (m, 1H), 3.56 (m, 4H), 3.68
(s, 3H), 3.90-4.02 (m, 4H), 5.56 (m, 2H), 6.64 (bs, 2H); 13C
NMR (CDCl3) δ 28.2, 28.5, 48.6, 50.1, 51.8, 52.4, 52.7, 55.5,
56.9, 80.1, 156.2, 170.8, 173.8; [M + H]+ ) 630.25.
Liga n d 7. TFA salt (0.30 mmol), prepared from 11-R R
according to the procedure described for 4, was dissolved in
DCM (2.2 mL). NMM was added, until the apparent pH of the
solution was 8, and then Boc-benzyltauryl chloride was added
(230 mg, 0.69 mmol). After the mixture was stirred for 12 h,
the solvent was removed in vacuo. Purification by column
chromatography (eluent: 4% MeOH in DCM, v/v) afforded a
white foam (46 mg, 19%, 0.057 mmol): Rf 0.53 (eluent: 10%
MeOH in DCM); 1H NMR (CDCl3) δ 1.40, 1.41 (2s, 18H), 2.52,
2.66 (2m, 4H), 2.83-3.04 (2m, 4H), 3.10-3.42 (m, 6H), 3.68
(s, 3H), 3.70-3.92 (m, 2H), 4.11-4.24 (m, 4H), 4.91 (bs, 2H),
7.15-7.33 (m, 12H); 13C NMR (CDCl3) δ 28.2, 28.5, 38.7, 48.2,
50.0, 51.7, 54.0, 81.4, 127.2, 129.0, 129.4, 129.5, 136.3, 155.8,
170.1, 173.5; [M + H]+ ) 810.40.
Liga n d 3. 1-Mesyl-3,4-di(Boc-amino)pyrrolidine (688 mg,
1.98 mmol), obtained by hydrogenolysis and subsequent me-
sylation of 10-RR, was dissolved in 4 mL of DCM, and 4 mL
of ether, saturated with HCl, was added. After the mixture
was stirred for 10 min, the solvent was removed in vacuo, and
the residue was dried on KOH under reduced pressure. The
HCl salt was obtained in 95% as a white solid (474 mg, 1.88
mmol). To a suspension of HCl salt (252 mg, 1.0 mmol) in DMF
(10 mL) at 0 °C was added DIPEA (766 µL, 4.4 mmol), under
a nitrogen atmosphere. After being stirred for 10 min, the
mixture was cooled to -40 °C and trifluoromethanesulfonyl
chloride (212 µL, 2.0 mmol) was added slowly. The mixture
was stirred for 1 h at room temperature. The solvent was
evaporated, and the residue was dissolved in EtOAc. After
being washed with 1 M KHSO4, water, and brine, the organic
layer was dried on Na2SO4 and evaporated to dryness in vacuo.
Column chromatography (eluent 10% MeOH in DCM, v/v)
afforded 3 as a white solid (82 mg, 19%, 0.185 mmol): Rf 0.19
(eluent: 10% MeOH in DCM, v/v); 1H NMR (CDCl3/CD3OD) δ
2.92, 2.93 (2s, 3H), 3.21 (m, 2H), 3,76 (m, 2H), 4.03 (m, 2H),
4.33 (bs, 2H); 13C NMR (CDCl3/CD3OD) δ 35.3, 49.8, 57.5,
113.1, 118.0, 121.6, 125.9.
Liga n d 4. To a solution of N-succinyl-3,4-di-(Boc-amino)-
pyrrolidine 11-RR (380 mg, 0.946 mmol) in MeOH (10 mL)
(11) Perrin, D. D.; Armarego, W. L. F. Purification of Laboratory
Chemicals, 3rd ed,; Pergamon Press: Oxford, 1988.
(12) Arx, E. von; Faupel, M.; Bruggen, M., J . Chromatogr. 1976,
120, 224.
N-Ben zyl-3,4-d i(Boc-a m in o)p yr r olid in e 10-RR a n d 10-
SS. A solution of N-benzyl-3,4-diazidopyrrolidine (2.4 g, 9.9
mmol), prepared from 9-RR according to Skarzewski and

1756 J . Org. Chem., Vol. 65, No. 6, 2000
Brouwer et al.
Gupta,7 in dried THF (9.9 mL), was added dropwise to a
stirring mixture of LiAlH4 (992 mg, 26.1 mmol) in THF (9.9
mL). The mixture was refluxed for 30 min, followed by cooling
to 0 °C in an ice bath. NaOH (1 M, 6.4 mL) and water (6.4
mL) were carefully added. The mixture was filtrated and
concentrated to ca. 15 mL. Then dioxane (15 mL) and Boc2O
(4.3 g, 19.8 mmol) in dioxane (15 mL) were added. After the
mixture was stirred for 2 h at room temperature, the solvent
was removed and EtOAc was added. The organic layer was
washed with water (twice) and brine, dried (Na2SO4), and
evaporated. Crystallization from EtOAc afforded a white
crystalline solid (1.5 g, 79%, 7.82 mmol): 1H NMR (CDCl3) δ
1.43 (s, 18H), 2.40 (m, 2H), 2.99 (m, 2H), 3.58 (s, 2H), 3.85 (m,
2H), 4.89 (bs, 2H), 7.29 (m, 5H); 13C NMR (CDCl3) δ 28.4, 57.2,
59.0, 59.8, 79.6, 127.2, 128.3, 128.7, 138.0, 155.5.
DCM, v/v) yielding pyrrolidine 17 (435 mg, 1.05 mmol, 84%)
as a white foam: Rf 0.19 (eluent: 6% MeOH in DCM, v/v); 1H
NMR (CDCl3) δ 1.43 (s, 18H, 2 × C(CH3)3), 2.53 (m, 4H,
CH2CH2), 2.75 (d, 3H, NCH3), 3.20-3.40 (m, 2H, 2 × NCHaCH),
3.84-4.06 (m, 4H, 2 × NCHbCH, 2 × NCH2CH), 5.89 (bd, 2H,
2 × NHBoc), 6.93 (bs, 1H, NHCH3); 13C NMR (CDCl3) δ 26.1
(NCH3), 28.2 (C(CH3)3), 29.1, 30.5 (CH2CH2), 48.3, 49.9, (NCH2-
CH), 53.2, 55.4 (NCH2CH), 79.6 (C(CH3)3), 155.8 (NHCO2),
171,0 (CH2C)O), 172.7 (CH3NHC)O); [M + Na]+ ) 437.40,
[2M + Na]+ ) 851.20. Anal. Calcd for C19H34N4O6‚H2O: C,
52.76; H, 8.39; N, 12.95. Found: C, 52.66; H, 7.94; N, 12.71.
Liga n d 19. To a solution of N-methylamidosuccinyl-3,4-di-
(Boc-amino)pyrrolidine 17 (145 mg, 0.35 mmol) in DCM (1.0
mL) was added diethyl ether (1.0 mL), saturated with HCl.
The mixture was stirred for 30 min followed by the evaporation
of the solvent and drying of the residue in vacuo. Then, to a
solution of this residue in DCM (3.0 mL) were added NMM
(169 µL, 1.54 mmol) and Leucine derived sulfonyl chloride 14d
(409 mg, 1.05 mmol). After the mixture was stirred for 2 h,
the solvent was evaporated and the product was purified by
column chromatography (eluent: 6% MeOH in DCM v/v)
affording 19 (335 mg, 0.32 mmol, 97%) as a white foam: Rf
N-Su ccin yl-3,4-d i(Boc-a m in o)p yr r olid in e 11-R R a n d
11-SS. To a solution of N-benzyl-3,4-di(Boc-amino)pyrrolidine
10-RR (3.95 g, 10.1 mmol) in t-BuOH/H2O (4:1, v/v, 150 mL)
was added Pd(OH)2/C (10%, 250 mg). The mixture was shaken
overnight under a 3 Bar hydrogen atmosphere in a Parr
apparatus. The catalyst was removed by filtration over Hyflo.
Evaporation of the solvent followed by coevaporation of the
residue with benzene (three times) afforded the amine as a
white solid (2.96 g, 97%, 9.80 mmol). This amine was dissolved
in DCM (93 mL), and succinic anhydride (936 mg, 9.35 mmol)
and Et3N (1.56 mL, 11.22 mmol) were added. After the mixture
was stirred for 1 h at room temperature, the solvent was
removed and EtOAc was added. The organic layer was washed
with 1 M KHSO4 (twice), water, and brine and dried (Na2SO4).
Removal of the solvent gave a white foam (4.0 g, 102%, 9.54
mmol) that contained unexplained varying amounts (2-8%)
1
0.38 (eluent: 10% MeOH in DCM); H NMR(CDCl3) δ 0.74-
0.88 (m, 12H, 2 × CH(CH3)2), 1.43-1.57 (m, 6H, 2 × CH2CH-
(CH3)2), 2.32 (bs, 4H, CH2CH2), 2.64 (d, 3H, NCH3), 3.00-3.30
(m, 6H, 2 × SCH2, NCH2CH, 3.82 (m, 4H, NCH2CH, 2 ×
NCH2CH) 4.15 (m, 4H, 2 × NCH, 2 × CH (Fmoc)), 4.35-4.55
(2m, 4H, 2 × CH2 (Fmoc)), 5.51, 5.67, 5.96, 6.02, 6.25, 6.45,
6.60, (7 × bs), 5H, 2 × NHFmoc, NHCH3, 2 × SNH), 7.26 (m,
8H, Ar-CH (Fmoc)), 7.56 (t, 4H, Ar-CH (Fmoc)), 7.72 (d, 4H,
Ar-CH (Fmoc)); 13C NMR (CDCl3) δ 21.5, 21.6, 23.0, 23.1
(CHCH3), 24.6 (CHCH3), 26.3 (NHCH3), 28.8, 30.1 (CH2CH2),
43.3 (CH2CHCH3), 46.1 (FmocNHCH), 47.1 (CH (Fmoc)), 48.7,
49.8 (NCH2CH), 56.0 (NCH2CH), 57.3 (SCH2), 119.9, 126.1,
127.0, 126.6 (Ar-CH (Fmoc)), 141.2, 143.6, 143.9 (Ar-C (Fmoc)),
156.2 (NHCO2), 171.2 (CH2NCdO), 172.9 (CH3NHCdO); [M
+ H]+ ) 985.20, [M + Na]+ ) 1007.00. Anal. Calcd for
1
of 1-butanol; H NMR (CDCl3) δ 1.4 (s, 18H), 1.6 (m, 4H), 3.2
(bs, 2H), 3.8-4.1 (m, 4H), 5.5, 5.6 (2bs, 2H); 13C NMR (CDCl3)
δ 28.3, 28.3, 28.6, 28.9, 48.4, 50.3, 55.9, 80.2, 156.1, 171.1,
175.6; [M + Na]+ ) 424.15, [M - H + 2Na]+ ) 446.10.
Resin 12a ,b. Argogel-NH2 (600 mg, 0.41 mmol/g) was
loaded with pyrrolidine 11-RR or 11-SS (296 mg, 0.738 mmol)
using BOP (327 mg, 0.738 mmol) and DIPEA (514 µL, 2.95
mmol) dissolved in DCM (7 mL). The resin was gently shaken
overnight, filtrated, and washed three times with DCM (2 min
each).
C
51H64N6O10S2‚H2O: C, 61.06; H, 6.63; N, 8.38; S, 6.39.
Found: C, 60.93; H, 6.61; N, 8.26; S, 6.09.
Liga n d 20. Fmoc-ligand 19 (197 mg, 0.20 mmol) was
dissolved in Tesser’s base (dioxane/MeOH/4M NaOH 14:5:2,
v/v/v, 2 mL) and was stirred for 2.5 h. Then 1 M HCl was added
until pH ≈ 6, and the solvents were evaporated. Ether was
added to the solid residue, and after being stirred overnight,
the mixture was filtrated. To the resulting solid, dioxane (2
mL), 1 M NaOH (2 mL) and Boc2O (98 mg, 0.44 mmol) were
added. After being stirred overnight, the mixture was concen-
trated and dissolved in DCM. The solution was extracted with
1 M KHSO4, H2O, and brine and dried on Na2SO4. Evaporation
of the solvent and column chromatography (eluent: 6% MeOH
in DCM, v/v) gave a white foam (54 mg, 0.08 mmol, 40%): Rf
0.28 (eluent: 10% MeOH in DCM, v/v); 1H NMR (CDCl3) δ
0.89 (d, 12H, 2 × CH(CH3)2), 1.42 (m, 22H, 2 × C(CH3)3, 2 ×
CH2CH(CH3)2, 1.67 (bs, 2H, 2 × CHCH3), 2.50 (m, 4H,
CH2CH2), 2,73 (d, 3H, NHCH3), 3.22-3.49 (m, 6H, 2 × SCH2,
2 × NCHaCH), 3.86-4.11 (m, 6H, 2 × NCHbCH, 2 × NCH2CH,
2 × BocNHCH), 5.23, 5.29, 5.34 (bs (3 ×), 2H, 2 × NHBoc),
6.37, 6.62, 6.91 (bs (3 ×), 3H, NHCH3, 2 × NHSO2); 13C NMR
(CDCl3) δ 21.6, 23.0 (CHCH3), 24.6 (CHCH3), 26.3 (NHCH3),
28.4 (C(CH3)3), 29.1, 30.5 (CH2CH2), 43.4 (CH2CHCH3), 45.7
(BocNHCH), 49.1, 50.3 (NCH2CH), 56.0, NCH2CH), 57.3
(SCH2), 79.9 (C(CH3)3), 155.9 (NHCO2), 171.3 (CH2NCdO), 173
(CH3NHCdO); [M + H]+ ) 741.20, [M + Na]+ ) 763.20. Anal.
Calcd for C31H60N6O10S2: C, 50.25; H, 8.16; N, 11.34; S, 8.65.
Found: C, 49.95; H, 8.26; N, 11.04; S, 8.12.
Gen er a l P r oced u r e for Libr a r y Syn th esis 15a -e, 16a -
e. DCM (1 mL) and TFA (1 mL) were added to resin 12a ,b
(100 mg, 0.041 mmol), and the mixture was gently shaken for
30 min. The resin was filtrated and washed three times with
DCM (2 min each), three times with 10% Et3N/DCM (2 min
each), and three times with DCM (2 min). To the resin were
added 8 equiv of sulfonyl chloride 14a -e9 (0.32 mmol), NMM
(30 µL, 0.32 mmol), and DCM (0.5 mL). After the mixture was
shaken for 4-16 h, the resin was washed with DCM three
times (2 min each). The resin was dried overnight on P2O5,
and the loading of the resin was determined from the absor-
bance of the dibenzofulvene-piperidine adduct at 301 nm.13 The
Fmoc groups were cleaved by adding 20% piperidine in DCM
(2 mL) and shaking for 30 min. The resin was filtrated, washed
with DCM three times (2 min each), and Boc2O (0.32 mmol)
and NMM (0.32 mmol) in DCM (0.5 mL) were added followed
by gentle shaking of the resin overnight. After being washed
with DCM three times (2 min each), the resin was dried on
P2O5.
N -Me t h yla m in osu ccin yl-3,4-d i(Boc-a m in o)p yr r oli-
d in e 17. To a solution of N-succinyl-3,4-di(Boc-amino)pyrroli-
dine 11-SS (502 mg, 1.25 mmol), BOP (608 mg, 1.37 mmol),
and DIPEA (479 µL, 2.75 mmol) in DCM (2.5 mL) was added
dropwise a solution of methylamine in THF (2 M, 3.13 mL,
6.25 mmol) at 0 °C. After the mixture was stirred for 1 h at 0
°C, the solvent was evaporated and the residue redissolved in
EtOAc. This solution was washed twice with 1 M KHSO4, twice
with 1 M NaOH, and once with brine and dried on Na2SO4.
The EtOAc was removed in vacuo, and the product was
purified by column chromatography (eluent: 6% MeOH in
Liga n d 21. Ligand 21 was obtained as an unexpected
product from Fmoc-ligand 19 (197 mg, 0.20 mmol) according
to the procedure described for 20. The product was purified
by column chromatography (eluent: 6% MeOH in DCM, v/v)
which gave a white foam (42 mg, 0.058 mmol, 29%): Rf 0.70
(eluent: 10% MeOH in DCM); 1H NMR (CDCl3) δ 0.91 (d, 12H,
1.42 (bs, 31H), 1.67 (bs, 2H), 3.23 (m, 6H), 3.83 (m, 4H), 4.15
(bs, 2H), 4.93, 5.60, 6.12 (bs (3×), 4H); 13C NMR (CDCl3) δ
21.6, 23.0, 24.7, 28.4, 43.5, 45.7, 49.0, 56.3, 58.4, 80.1, 153.9,
156.2; [M + Na]+ ) 750.20.
(13) Meienhofer, J .; Waki, M.; Heimer, E. P.; Lambros, T. J .;
Makofske, R. C.; Chang, C.-D., Int. J . Peptide Protein Res. 1979, 13,
35-42.

Peptidosulfonamide Tweezers in Catalysis
J . Org. Chem., Vol. 65, No. 6, 2000 1757
Gen er a l P r oced u r e for th e En a n tioselective Ad d ition
of Dieth ylzin c to Ald eh yd es. Under an argon atmosphere
Ti(O-i-Pr)4 solution in toluene (1 M, 0.06 mL, 0.06 mmol) was
added to the ligand (0.002 mmol) (ligand on resin: 20 mg,
0.010-0.016 mmol, additional toluene (0.04 mL) was added).
After being stirred at 40 °C for 30 min, the mixture was cooled
to -78 °C and Et2Zn in hexanes (1 M solution, 110 µL, 0.110
mmol) was added followed by a mixture of benzaldehyde,
4-chlorobenzaldehyde, phenylacetaldehyde, and cyclohexyl-
aldehyde (50 µL, 0.0125 mmol each, in toluene). The reaction
mixture was stirred overnight at -20 °C and quenched by
adding 1 M HCl (0.5 mL) and EtOAc (1 mL). The EtOAc layer
was removed and dried on Na2SO4. This solution was directly
used for GC analysis.
Su p p or tin g In for m a tion Ava ila ble: Experimental pro-
cedures containing NMR peak assignments. Copies of 1H NMR
and 13C NMR spectra for compounds 3, 5, 6, 7, 10, 11, and 21,
a
13C NMR spectrum for 4, and COSY spectra for 17, 19, and
20. This material is available free of charge via the Internet
at http://pubs.acs.org.
J O991628Z