Kinetic resolutions of lndolines by a nonenzymatic acylation catalyst

Article abstract of DOI:10.1021/ja0657859

The first method for the kinetic resolution of indolines through catalytic N-acylation is described. To improve the selectivity factor, new planar-chiral PPY-derived catalysts were synthesized, wherein the chiral environment was systematically modified. This work provides a rare example of a nonenzyme-based acylation catalyst for the kinetic resolution of amines. Copyright

Full text of DOI:10.1021/ja0657859

Published on Web 10/18/2006
Kinetic Resolutions of Indolines by a Nonenzymatic Acylation Catalyst
Forrest O. Arp and Gregory C. Fu*
Department of Chemistry, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139
Received August 9, 2006; E-mail: gcf@mit.edu
Table 1. Effect of Reaction Parameters on the Efficiency of the
An indoline subunit that bears a stereocenter in the 2 position is
found in a range of natural products,1 as well as in an array of
biologically active nonnatural products.2 Few catalytic processes
have been reported that generate such indolines in highly enan-
tioenriched form.3
Kinetic Resolution of 2-Methylindolinea
One strategy for achieving this objective is the kinetic resolution4
of a racemic mixture of indolines. A number of enzyme-based meth-
ods for the resolution of amines via N-acylation have been described,5
although not for indolines. Progress in the development of non-
enzymatic N-acylation catalysts for the kinetic resolution of amines
has been extremely limitedsnot only have there been no reports
of success with indolines, but only two effective methods have been
described for amines of any type (certain primary amines6 and 2-oxa-
zolidinones (Birman)7). In this communication, we establish that a
chiral, nonenzymatic catalyst can achieve the kinetic resolution of a
third family of amines, specifically, 2-substituted indolines (eq 1).
entry
change from the optimized conditions
% conversion
s
1
2
3
4
5
6
7
8
(+)-2 instead of (+)-1
(+)-3 instead of (+)-1
none
(+)-4 instead of (+)-1
15-crown-5 instead of 18-crown-6
12-crown-4 instead of 18-crown-6
no 18-crown-6
4
48
54
58
54
43
16
55
49
43
12
49
<2
10
23
19
20
3
6
<2
2
no LiBr
9
Bu4NBr instead of LiBr/18-crown-6
LiCl instead of LiBr
Lil instead of LiBr
10
11
12
14
12
11
room temp instead of 0 °C (2 days)
a All data are the average of two runs.
inactive (entry 1).8,9 Fortunately, replacement of C5Me5 by C5Ph5
leads to a more effective acylation catalyst that can achieve the
desired kinetic resolution with a useful selectivity factor (entry 2).
In a study of desymmetrizations of meso epoxides catalyzed by
planar-chiral pyridine-N-oxides,10 we determined that increasing the
steric demand of a C5Ph5 group of the catalyst via meta substitution11
provided a more effective chiral environment,12 as manifested by
enhanced enantioselectivity. We attempted to exploit this strategy
for the first time in the context of planar-chiral PPY derivatives, to
enhance the efficiency of these kinetic resolutions of indolines. We
were pleased to determine that the incorporation of methyl substi-
tuents in the meta positions of the phenyl rings does indeed lead to
an improvement in the selectivity factor (entry 2 vs entry 3). How-
ever, a further increase in the bulk of the “bottom” cyclopentadienyl
ring (Me f Et) is not beneficial for stereoselection (entry 4).
On the basis of exploratory studies of kinetic resolutions of indo-
lines by stoichiometric chiral reagents (e.g., higher s values when N-
acylated 3 with a halide counterion13 was employed), we hypothe-
sized that the addition of halide salts might be advantageous for
selectivity.14 This has proved to be the case; in particular, the
presence of LiBr/18-crown-6 leads to the highest s value that we
have observed to date (entry 3). The use of smaller crown ethers
results in lower selectivity (entries 5 and 6),15 as does the omission
of 18-crown-6 (entry 7). Under otherwise identical conditions but
in the absence of LiBr (entry 8) or in the presence of other halide
sources (e.g., entries 9-11), the kinetic resolution proceeds with
diminished efficiency.
In an earlier study, we reported that planar-chiral PPY derivative
2 serves as a catalyst for the kinetic resolution of benzylic primary
amines (eq 2; s ) selectivity factor ) (rate of fast-reacting
enantiomer)/(rate of slow-reacting enantiomer)4).6 Disappointingly,
when we applied these conditions to indolines, we observed no
reaction even at 0 °C, because of the comparatively low nucleo-
philicity of the indoline.
After considerable effort we were able to develop a process by
which a 2-substituted indoline can be kinetically resolved with good
selectivity (Table 1). Under these conditions, as for those depicted
in eq 2, the C5Me5-substituted PPY derivative (2) is virtually
By conducting the acylation at room temperature, the reaction
time can be shortened,16 at the expense of a lower s value (entry
12). In the presence of commercially available acylating agents,
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J. AM. CHEM. SOC. 2006, 128, 14264-14265
10.1021/ja0657859 CCC: $33.50 © 2006 American Chemical Society

C O M M U N I C A T I O N S
Table 2. Kinetic Resolutions of Indolinesa
challenge. Future work will be directed at gaining an improved
understanding of this process and applying that knowledge to the
design of more versatile and efficient catalysts for the kinetic
resolution of amines and related compounds.
Acknowledgment. We thank Luke Firmansjah and Dr. Peter Mueller
for assistance with X-ray crystallography. Support has been provided by
the NIH (National Institute of General Medical Sciences, Grant R01-
GM57034), Merck Research Laboratories, and Novartis. Funding for the
MIT Department of Chemistry Instrumentation Facility has been furnished
in part by NSF Grant CHE-9808061 and NSF Grant DBI-9729592.
Supporting Information Available: Experimental procedures and
compound characterization data. This material is available free of charge
via the Internet at http://pubs.acs.org.
References
(1) For example, see: Gueritte, F.; Fahy, J. In Anticancer Agents from Natural
Products; Cragg, G. M., Kingston, D. G. I., Newman, D. J., Eds.; CRC
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(2) For leading references to drug candidates that bear a 2-methylindoline
subunit, see: Nicolaou, K. C.; Roecker, A. J.; Pfefferkorn, J. A.; Cao,
G.-Q. J. Am. Chem. Soc. 2000, 122, 2966-2967.
(3) For example, see: (a) Ruthenium-catalyzed hydrogenation of N-protected
indoles: Kuwano, R.; Sato, K.; Kurokawa, T.; Karube, D.; Ito, Y. J. Am.
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Palladium-catalyzed cyclization of N-acyl anilines: Yip, K.-T.; Yang, M.;
Law, K.-L.; Zhu, N.-Y.; Yang, D. J. Am. Chem. Soc. 2006, 128,
3130-3131. (c) Enzyme-catalyzed hydrolysis of racemic N-Boc-indoline-
2-carboxylic esters: Kurokawa, M.; Sugai, T. Bull. Chem. Soc. Jpn. 2004,
77, 1021-1025.
(4) For reviews, see: (a) Kagan, H. B.; Fiaud, J. C. Top. Stereochem. 1988,
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a The selectivity factor is the average of two runs. The ee and percent
conversion are for a particular run.
(5) For examples and leading references, see: van Rantwijk, F.; Sheldon, R.
A. Tetrahedron 2004, 60, 501-519.
(6) Arai, S.; Bellemin-Laponnaz, S.; Fu, G. C. Angew. Chem., Int. Ed. 2001,
40, 234-236.
essentially no selectivity (acetic anhydride, acetyl chloride, and
methyl chloroformate) or no reactivity (vinyl acetate) is observed.
Finally, Birman’s method, which is outstanding for the kinetic reso-
lution of 2-oxazolidinones,7 is not effective for indolines (s < 1.1).
We have established that an array of 2-substituted indolines,
including functionalized compounds, can be kinetically resolved
with good selectivity factors under the optimized reaction conditions
(Table 2, entries 1-4).17 Furthermore, 2,3-disubstituted indolines
are suitable substrates (entries 5-9); as might be anticipated, the
process is more efficient for the cis isomer than for the correspond-
ing trans isomer (entry 7 vs entry 8). It is worth noting that 2,3-
disubstituted indolines cannot be accessed in high ee via the
asymmetric hydrogenation of indoles.3a Finally, substituents in the
5 position are tolerated (entries 9-11).18,19
There are a number of features of this process that warrant future
mechanistic investigation, such as the critical role played by LiBr
and 18-crown-6. In addition, we are intrigued by the fact that
catalyst 1, but not 2, is effective for the kinetic resolution of
indolines, whereas 2, but not 1, is useful for the resolution of
primary benzylic amines (eq 2). Through 1H NMR studies, we have
made the interesting observation that the resting state of the catalyst
during indoline resolutions is the free catalyst, which contrasts with
the process depicted in eq 2, for which the resting state is the
N-acylated catalyst.6,20,21
(7) Birman, V. B.; Jiang, H.; Li, X.; Guo, L.; Uffman, E. W. J. Am. Chem.
Soc. 2006, 128, 6536-6537.
(8) A preliminary study suggests that, when catalyst 2 is N-acetylated, it is a
poor electrophile for an indoline.
(9) In the absence of a catalyst, <1% acetylation is observed.
(10) Tao, B.; Lo, M. M.-C.; Fu, G. C. J. Am. Chem. Soc. 2001, 123, 353-354.
(11) Pentaarylcyclopentadienes (C5Ar5H) can be synthesized from Ar-Br in
a single step: Dyker, G.; Heiermann, J.; Miura, M.; Inoh, J.-I.; Pivsa-
Art, S.; Satoh, T.; Nomura, M. Chem.sEur. J. 2000, 6, 3426-3433.
(12) For a discussion of catalyst design, see: Fu, G. C. Acc. Chem. Res. 2000,
33, 412-420.
(13) For an earlier study of kinetic resolutions of 1-phenylethylamine by such
stoichiometric chiral acylating agents, see: Ie, Y.; Fu, G. C. Chem.
Commun. 2000, 119-120.
(14) Mioskowski and Wagner have reported a spectacular salt effect (n-Oct3-
NMeCl) for N-acetylations of racemic 1-phenylethylamine by a stoichio-
metric chiral acylating agent: Arseniyadis, S.; Subhash, P. V.; Valleix,
A.; Mathew, S. P.; Blackmond, D. G.; Wagner, A.; Mioskowski, C. J.
Am. Chem. Soc. 2005, 127, 6138-6139.
(15) For an interesting compilation of log Ka values for various crown ethers
and alkali-metal cations, see: Anslyn, E. V.; Dougherty, D. A. Modern
Physical Organic Chemistry; University Science Books: Sausalito, CA,
2006; p 227. See also: Izatt, R. M.; Pawlak, K.; Bradshaw, J. S. Chem.
ReV. 1991, 91, 1721-2085.
(16) Clearly, long reaction times are not ideal. On the other hand, this kinetic-
resolution method avoids protection/deprotection of the indole, which is
necessary for the most general alternative approach to the catalytic
synthesis of enantionriched indolines (ref 3a).
(17) Acylation of 2-isopropylindoline proceeds extremely slowly and with
moderate selectivity (s ≈ 8). Initial studies indicate that, if the 2-substituent
is sp2-hybridized, low selectivity is observed.
(18) (a) However, an indoline that bears two electronegative fluorine substit-
uents (4,5-difluoro-2-methylindoline) reacts very slowly and with moderate
selectivity (s ≈ 7). (b) Catalyst 1 can be recovered in good yield (>80%).
(19) We have been able to achieve the kinetic resolution of a 2-substituted
pyrrolidine with s ≈ 4. To the best of our knowledge, this is the first
example of a kinetic resolution of a dialkylamine with promising selectivity
by a nonenzymatic acylation catalyst.
(20) Preliminary studies of the dependence of the selectivity factor on the
catalyst ee provide no evidence for the presence of species that contain
more than one catalyst molecule. (a) Johnson, D. W., Jr.; Singleton, D.
A. J. Am. Chem. Soc. 1999, 121, 9307-9312. (b) Kagan, H. B.; Luukas,
T. O. In ComprehensiVe Asymmetric Catalysis; Jacobsen, E. N., Pfaltz,
A., Yamamoto, H., Eds.; Springer: New York, 1999; Chapter 4.1.
(21) This may be a consequence of the enhanced acidity of the N-bound proton
of an indoline, relative to a primary benzylic amine.
In conclusion, we have reported the first method, enzymatic or
nonenzymatic, for the kinetic resolution of indolines through
catalytic N-acylation. To improve the selectivity factor, we
synthesized a new planar-chiral PPY derivative (1) wherein the
chiral environment was tuned through the use of a more bulky
cyclopentadienyl group. In light of the very limited success that
has been described in the development of nonenzymatic acylation
catalysts for the resolution of amines, we believe that our study
represents an interesting step forward in addressing this difficult
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