Investigation of a New Family of Chiral Ligands for Enantioselective Catalysis via Parallel Synthesis and High-Throughput Screening

Full text of DOI:10.1021/jo980890p

5312
J . Org. Chem. 1998, 63, 5312-5313
synthesis (as opposed to the “split and pool” methodology)5c
allows one to know the identity of each ligand and keeps
the ligands separate so that screening of individual ligand
metal complexes can be performed.
In vestiga tion of a New F a m ily of Ch ir a l
Liga n d s for En a n tioselective Ca ta lysis via
P a r a llel Syn th esis a n d High -Th r ou gh p u t
Scr een in g
We have developed a new family of chiral ligands based
on a modular building block strategy and on the use of a
disulfonamide as metal chelating unit, for which a number
of examples are already known.6 These ligands are synthe-
sized by coupling commercially available vicinal diamines
1 and a novel class of chiral N-protected â-amino sulfonyl
chlorides of general formula 2 (Scheme 1), obtained in high
yields from L-R-amino acids via a straightforward synthetic
protocol.7 For the construction of the library (30 com-
pounds), we used the sulfonyl chlorides derived from L-
alanine (2g), L-valine (2h ), L-leucine (2i), L-phenylalanine
(2j), and L-proline (2k ).8 As for the diamine part of the
library, we employed two vicinal diamine scaffolds: 1,2-
diaminocyclohexane9 (1a -d ) and 1,2-diphenylethylenedi-
amine10 (1e-f), for which effective use in the fields of
asymmetric synthesis and molecular recognition is well
documented. In the case of 1,2-diaminocyclohexane, besides
the chiral trans-R,R and trans-S,S, we have used the achiral
cis-R,S and the racemic (() trans structures to take into
consideration all the possible stereochemical combinations,
including those that might seem odd at first glance, and to
take advantage of possible cooperative effects arising from
the formation of aggregates.11
In principle, the synthesis and subsequent test of the
library could be accomplished with the ligands bound to a
solid support. However, the need for an additional handle
to attach the diamine scaffold to the support and the
controversial role of the solid matrix on the yields and
enantiomeric ratios (er’s) of the catalyzed reactions5h,12 make
this route less attractive. On the other hand, the classical
synthesis in solution suffers from a major disadvantage, i.e.,
the necessity of workup and purification (chromatography),
which makes parallel chemistry impractical. An answer to
these problems was found with the use of solid-phase
extraction (SPE) techniques.13 For the coupling reactions
(Scheme 1), we treated the vicinal diamines 1 with an excess
of sulfonyl chlorides 2 to ensure complete conversion and
Cesare Gennari,*,† Simona Ceccarelli,†
Umberto Piarulli,*,‡ Christian A. G. N. Montalbetti,§ and
Richard F. W. J ackson§
Universita` di Milano, Dipartimento di Chimica Organica e
Industriale, Centro CNR per lo Studio delle Sostanze Organiche
Naturali, via G. Venezian 21, I-20133 Milano, Italy,
Universita` di Milano, Istituto di Scienze Mat. Fis. e Chimiche,
via Lucini 3, 22100 Como, Italy, and University of Newcastle,
Department of Chemistry, Bedson Building,
Newcastle upon Tyne NE1 7RU, U.K.
Received May 12, 1998
Applications of combinatorial chemistry are widespread
and cover fields as diverse as drug discovery and optimiza-
tion,1 material science,2 studies of molecular recognition,3
and the development of new catalysts.4,5 In particular, the
possibility of high-throughput catalyst screening for the
development and optimization of enantioselective reactions
has generated a lot of excitement.5d-j Two different basic
approaches have been considered: optimization of the reac-
tion conditions (solvents, temperatures, stoichiometries,
different ligands, or metal ions)5e and the synthesis of new
ligands via a modular building block strategy in which the
stereoelectronic properties of a metal binding site (e.g., a
diphosphine5f or a Schiff-base5h-j) are tuned by variation of
the substituents and side chains. In the case of screening
members of a library containing ligands for enantioselective
catalysis, the identification of a hit requires a demanding
selection procedure, since the screen is ultimately catalysis
of a reaction and analysis of its stereochemical outcome. For
this reason, a combinatorial system is usually chosen that
allows the synthesis of discrete isolated compounds. Parallel
* To whom correspondence should be addressed. Tel.: int. + 2-2367-
593. Fax: int. + 2-2364-369. E-mail: cesare@iumchx.chimorg.unimi.it.
† Dipartimento di Chimica Organica e Industriale, Centro CNR per lo
Studio delle Sostanze Organiche Naturali, Universita` di Milano.
‡ Istituto di Scienze Mat. Fis. e Chimiche, Universita` di Milano.
§ Department of Chemistry, University of Newcastle.
(1) (a) Gallop, M. A.; Barrett R. W.; Dower, W. J .; Fodor, S. P. A.; Gordon,
E. M. J . Med. Chem. 1994, 37, 1233. (b) Gordon, E. M.; Barrett R. W.; Dower,
W. J .; Fodor, S. P. A.; Gallop, M. A. J . Med. Chem. 1994, 37, 1385. (c) Terrett,
N. K.; Gardner, M.; Gordon, D. W.; Kobylecki, R. J .; Steele, J . Tetrahedron
1995, 51, 8135. (d) Balkenhol, F.; von dem Bussche-Hu¨nnefeld, C.; Lansky,
A.; Zechel, C. Angew. Chem., Int. Ed. Engl. 1996, 35, 2288. (e) Thompson,
L. A.; Ellman, J . A. Chem. Rev. 1996, 96, 555. (f) Lam, K. S.; Lebl, M.;
Krcn˜a´k, V. Chem. Rev. 1997, 97, 411.
(6) For Et2Zn additions to aldehydes, see: (a) Takahashi, H.; Kawakita,
T.; Yoshioka, M.; Kobayashi, S.; Ohno, M. Tetrahedron Lett. 1989, 30, 7095.
(b) Takahashi, H.; Kawakita, T.; Ohno, M.; Yoshioka, M.; Kobayashi, S.
Tetrahedron 1992, 48, 5691. (c) Zhang, X.; Guo, C. Tetrahedron Lett. 1995,
36, 4947. (d) Lutz, C.; Knochel, P. J . Org. Chem. 1997, 62, 7895. (e) Ramo´n,
D. J .; Yus, M. Tetrahedron: Asymmetry 1997, 8, 2479. (f) Cernerud, M.;
Skrinning, A.; Be´rge`re, I.; Moberg, C. Tetrahedron: Asymmetry 1997, 8,
3437. (g) Halm, C.; Kurth, M. J . Angew. Chem., Int. Ed. Engl. 1998, 37,
510. For cyclopropanation reactions, see: (h) Takahashi, H.; Yoshioka, M.;
Shibasaki, M.; Ohno, M.; Imai, N.; Kobayashi, S. Tetrahedron 1995, 51,
12013 and references therein. (i) Denmark, S. E.; O’Connor, S. P. J . Org.
Chem. 1997, 62, 584. (j) Denmark, S. E.; O’Connor, S. P. J . Org. Chem.
1997, 62, 3390 and references therein. (k) Imai, N.; Sakamoto, K.; Maeda,
M.; Kouge, K.; Yoshizane, K.; Nokami, J . Tetrahedron Lett. 1997, 38, 1423.
(7) (a) Gude, M.; Piarulli, U.; Potenza, D.; Salom, B.; Gennari, C.
Tetrahedron Lett. 1996, 37, 8589. (b) Gude, M.; Piarulli, U.; Potenza, D.;
Gennari, C. Chem. Eur. J . 1998, in press.
(2) (a) Xiang, X.-D.; Sun, X.; Bricen˜o, G.; Lou, Y.; Wang, K.-A.; Chang,
H.; Wallace-Freedman, W. G.; Chen, S.-W.; Schultz, P. G. Science 1995,
268, 1738. (b) Danielson, E.; Devenney, M.; Giaquinta, D. M.; Golden, J .
H.; Haushalter, R. C.; McFarland, E. W.; Poojary, D. M.; Reaves, C. M.;
Weinberg, W. H.; Wu, X. D. Science 1998, 279, 837.
(3) Still, W. C. Acc. Chem. Res. 1996, 29, 155.
(4) For review articles, see: (a) Gennari, C.; Nestler, H. P.; Piarulli, U.;
Salom, B. Liebigs Ann./ Recueil 1997, 637. (b) Stinson, S. C. Chem. Eng.
News 1996, 74 (April 15), 24. (c) Borman, S. Chem. Eng. News 1996, 74
(Nov 4), 37. (d) Wilson, E. K. Chem. Eng. News 1997, 75 (Dec 8), 24. (e)
Brady, P. A.; Sanders, J . K. M. Chem. Soc. Rev. 1997, 26, 327.
(5) For research papers, see: (a) Menger, F. M.; Eliseev, A. V.; Migulin,
V. A. J . Org. Chem. 1995, 60, 6666. (b) Menger, F. M.; West, C. A.; Ding, J .
Chem. Commun. 1997, 633. (c) Taylor, S. J .; Morken, J . P. Science 1998,
280, 267. (d) Liu, G.; Ellman, J . A. J . Org. Chem. 1995, 60, 7712. (e) Burgess,
K.; Lim, H.; Porte, G.; Sulikowski, G. A. Angew. Chem., Int. Ed. Engl. 1996,
35, 220. (f) Gilbertson, S. R.; Wang, X. Tetrahedron Lett. 1996, 37, 6475.
(g) Gilbertson, S. R.; Chang, C. T. Chem. Commun. 1997, 975. (h) 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. (i) 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. (j) Sigman, M. S.;
J acobsen, E. N. J . Am. Chem. Soc. 1998, 120, 4901.
(8) In the case of proline, problems with the preparation of the N-Boc-
protected sulfonyl chloride via the usual route suggested the alternative
use of N-Cbz protection.
(9) Bennani, Y. L.; Hanessian, S. Chem. Rev. 1997, 97, 3161.
(10) (a) Mangeney, P.; Tejero, T.; Alexakis, A.; Grosjean, F.; Normant,
J . Synthesis 1988, 255. (b) Pikul, S.; Corey, E. J . Org. Synth. 1993, 71, 22.
(11) (a) Mikami, K.; Matsukawa, S.; Volk, T.; Terada, M. Angew. Chem.,
Int. Ed. Engl. 1997, 36, 2768. (b) Ohkuma, T.; Doucet, H.; Pham, T.; Mikami,
K.; Korenaga, T.; Tearda, M.; Noyori, R. J . Am. Chem. Soc. 1998, 120, 1086.
(12) Hodge, P. Chem. Soc. Rev. 1997, 26, 417.
(13) (a) Lawrence M. R.; Biller, S. A.; Fryszman, O. M.; Poss, M. A.
Synthesis 1997, 553. (b) Flynn, D. L.; Crich, J . Z.; Devraj, R. V.; Hockerman,
S. L.; Parlow, J . J .; South, M. S.; Woodward, S. J . Am. Chem. Soc. 1997,
119, 4874. (c) Parlow, J . J .; Mischke, D. A.; Woodward, S. S. J . Org. Chem.
1997, 62, 5908. (d) Booth, R. J .; Hodges, J . C. J . Am. Chem. Soc. 1997, 119,
4882.
S0022-3263(98)00890-1 CCC: $15.00 © 1998 American Chemical Society
Published on Web 07/23/1998

Communications
J . Org. Chem., Vol. 63, No. 16, 1998 5313
Sch em e 1
Sch em e 2
scaffold and the sulfonyl chloride derived from L-phenyl-
alanine). With 3bj, excellent enantiomeric ratios were
obtained with both aromatic and aliphatic aldehydes in favor
of the (R)-alcohol [R:S ) 93:7 (5l), 98:2 (5m ), 98:2 (5n ), 97:3
(5o)]. Ligand 3bj was then purified (chromatography) and
fully characterized, and the screening results were confirmed
by reaction with the four separate aldehydes on a prepara-
tive scale (1 mmol). (2) The influence of the different
â-aminosulfonyl side chains in controlling the er’s is as
follows: R1 ) CH2Ph (2j) > CH3 (2g) g i-Bu (2i) > i-Pr (2h )
. (CH2)3 (2k ). (3) The influence of the different scaffolds
in controlling the er’s is as follows: trans-(1S,2S)-diaminocy-
clohexane (1b) > cis-diaminocyclohexane (1c) ≈ (()-racemic-
1,2-diaminocyclohexane (1d ) > (1R,2R)-diphenylethylene-
diamine (1e) ≈ (1S,2S)-diphenylethylenediamine (1f) >
trans-(1R,2R)-diaminocyclohexane (1a ). (4) With the cis and
the racemic scaffolds, moderate enantiomeric ratios were
obtained in favor of the (R)-alcohol [3ci, R:S ) 87:13 (5m ),
88:12 (5o); 3d j, R:S ) 80:20 (5m ), 81:19 (5n ); 3d i, R:S )
80:20 (5o)]. (5) With the (R,R)-diphenylethylenediamine
scaffold, one single reasonably high enantiomeric ratio was
obtained [3ej R:S ) 89:11 (5o)].
used SPE methodology to avoid purification of the sulfon-
amide products 3. The reaction was run in DCM in the
presence of polymer bound “dimethylamino pyridine”13 to
catalyze the coupling reaction and scavenge the liberated
HCl; after all the diamine had been converted into the
disulfonamide derivative, the excess of sulfonyl chloride
was removed by reaction with solid-phase bound tris(2-
aminoethyl)amine.13b
As a first test for the disulfonamide library, we have
chosen the Ti(O-i-Pr)4-mediated addition of Et2Zn to alde-
hydes. In the enantioselective version of this reaction,
catalytic amounts of chiral disulfonamides have given good
to excellent er’s,6a-g and a fine-tuning of the ligand structure
was shown to be necessary for achieving good enantioselec-
tivities starting from different aldehydes. The tests were
run in a parallel format (30 different reaction vessels,
Scheme 2) on a 0.1 mmol scale with 4 µmol of the chiral
ligand on a mixture of four different aldehydes, and the er’s
were determined by analysis of the crude reaction mixtures
using a chiral capillary GC column (120 different results).14
Following a different selection approach for ligand opti-
mization, we used a mixture of the five ligands derived from
every single diamine (e.g., 3a g-3a k ) with a single aldehyde
(six different reaction vessels) for the evaluation of the
influence of the scaffold on enantioselectivity.
The use of the chiral ligand library (3a g-3fk ) in other
enantioselective reactions of synthetic importance is pres-
ently under investigation.
Ack n ow led gm en t. A graduate fellowship is gratefully
acknowledged by S.C. (Pharmacia & Upjohn, Nerviano,
Italy) and a postdoctoral fellowship by C. A. G. N. M. (TMR
Network grant “Combinatorial catalysts” ERB-FMR XCT
96-0011). We thank the Commission of the European Union
(TMR Network grant “Combinatorial catalysts” ERB-FMR
XCT 96-0011) for financial support. We are grateful to
Giovanni Cervi and Federica Pinoia (Universita` di Milano)
for technical assistance.
The screening revealed a number of interesting and
somewhat unexpected results: (1) The best ligand for this
reaction is 3bj (i.e., 1S,2S-diaminocyclohexane as diamine
Su p p or tin g In for m a tion Ava ila ble: Experimental proce-
dures for the library synthesis (30 compounds 3a g-3fk ) and
screening and additional experimental procedures including physi-
cal and spectroscopic data for compounds 2g-2k , 3bj, and 5l-5o
(8 pages).
(14) The GC conditions were optimized in order to have baseline
separation of the racemic mixtures of the four different alcohols (eight
separate peaks).
J O980890P