Diels-alder cycloaddition strategy for kinetic resolution of chiral pyrazolidinones

Article abstract of DOI:10.1021/ol901504p

A rare example of the application of a catalytic, enantioselective Diels-Alder cycloaddition to affect a kinetic resolution has been developed. Chiral pyrazolidinones are resolved with high selectivity through a process that utilizes a relay of stereochemical information from a permanent chiral center to a fluxional chiral center to enhance the inherent selectivity of the chiral Lewis acid catalyst.

Full text of DOI:10.1021/ol901504p

ORGANIC
LETTERS
2009
Vol. 11, No. 17
3894-3897
Diels-Alder Cycloaddition Strategy for
Kinetic Resolution of Chiral
Pyrazolidinones
Mukund P. Sibi,* Keisuke Kawashima, and Levi M. Stanley
Department of Chemistry and Molecular Biology, North Dakota State UniVersity,
NDSU Department 2735, P.O. Box 6050, Fargo, North Dakota 58108-6050
mukund.sibi@ndsu.edu
Received July 1, 2009
ABSTRACT
A rare example of the application of a catalytic, enantioselective Diels-Alder cycloaddition to affect a kinetic resolution has been developed.
Chiral pyrazolidinones are resolved with high selectivity through a process that utilizes a relay of stereochemical information from a permanent
chiral center to a fluxional chiral center to enhance the inherent selectivity of the chiral Lewis acid catalyst.
Enantioselective, metal-catalyzed asymmetric synthesis is
among the most powerful means to access enantioenriched
compounds.1 However, many cases exist in which catalyst
limitations preclude direct access to a full complement of
compounds within a product class. Thus, the kinetic resolu-
tion of racemic mixtures remains a prominent and often
complementary approach to access enantioenriched com-
pounds.2 The pyrazolidinones represent a class of hetero-
cycles that highlight the complementarity of direct asym-
metric synthesis3 and kinetic resolution4 approaches.
Furthermore, the pyrazolidinones remain attractive targets
due to their bioactivity5 and the challenges associated with
their synthesis in enantioenriched form.
We recently reported chiral Mg(II)-catalyzed, enantiose-
lective conjugate additions of hydrazines to R,ꢀ-unsaturated
(2) For reviews, see: (a) Pellissier, H. Tetrahedron 2008, 64, 1563. (b)
Vedejs, E.; Jure, M. Angew. Chem., Int. Ed. 2005, 44, 3974. (c) Kagan,
H. B.; Fiaud, J. C. Top. Stereochem. 1998, 18, 249. (d) Cardona, F.; Goti,
A.; Brandi, A. Eur. J. Org. Chem. 2001, 2999. (e) Wegener, B.; Hansen,
M.; Winterfeldt, E. Tetrahedron: Asymmetry 1993, 4, 345. (f) Keith, J. M.;
Larrow, J. F.; Jacobsen, E. N. AdV. Synth. Catal. 2001, 1, 5. (g) Robinson,
D. E. J. E.; Bull, S. D. Tetrahedron: Asymmetry 2003, 14, 1407. (h)
Jacobsen, E. N. Acc. Chem. Res. 2000, 33, 421.
(3) (a) Sibi, M. P.; Soeta, T. J. Am. Chem. Soc. 2007, 129, 4522. (b)
Shintani, R.; Fu, G. C. J. Am. Chem. Soc. 2003, 125, 10778. (c) Chen, W.;
Yuan, X.-H.; Li, R.; Du, W.; Wu, Y.; Ding, L.-S.; Chen, Y.-C. AdV. Synth.
Catal. 2006, 348, 1818. (d) Suga, H.; Funyu, A.; Kakehi, A. Org. Lett.
2007, 9, 97. (e) Sibi, M. P.; Rane, D.; Stanley, L. M.; Soeta, T. Org. Lett.
2008, 10, 2971.
(4) Sua´rez, A.; Downey, C. W.; Fu, G. C. J. Am. Chem. Soc. 2005,
127, 11244.
(1) For recent reviews see: (a) Kocovsky, P.; Malkov, A. V. Pure Appl.
Chem. 2008, 80, 953. (b) Lu, Z.; Ma, S. Angew. Chem., Int. Ed. 2008, 47,
258. (c) Glueck, S. D. Synlett 2007, 2627. (d) Ikariya, T.; Blacker, A. J.
Acc. Chem. Res. 2007, 70, 1300. (e) Christoffers, J.; Koripelly, G.; Rosiak,
A.; Roessle, M. Synthesis 2007, 1279. (f) Guo, H.-C.; Ma, J.-A. Angew.
Chem., Int. Ed. 2006, 45, 354. (g) Hultzsch, K. C. AdV. Synth. Catal. 2005,
347, 367.
(5) (a) Hlasta, D. J.; Casey, F. B.; Ferguson, E. W.; Gangell, S. J.;
Heimann, M. R.; Jaeger, E. P.; Kullnig, R. K.; Gordon, R. J. J. Med. Chem.
1991, 34, 1560. (b) Perri, S. T.; Slater, S. C.; Toske, S. G.; White, J. D. J.
Org. Chem. 1990, 55, 6037. (c) White, J. D.; Toske, S. G. Tetrahedron
Lett. 1993, 34, 207. (d) Panfil, I.; Urbanczyk-Lipkowska, Z.; Suwinska,
K.; Solecka, J.; Chmielewski, M. Tetrahedron 2002, 58, 1192.
10.1021/ol901504p CCC: $40.75
Published on Web 08/03/2009
 2009 American Chemical Society

imides as a direct method to synthesize enantioenriched
pyrazolidinones.3a The method allows for the synthesis of
C5-substituted pyrazolidinones with good to excellent enan-
tioselectivity when the C5-substituent is of relatively small
steric volume. However, the enantioselectivity decreases
significantly in reactions that form pyrazolidinones with
larger C-5 substituents. Thus, we required an improved
strategy to access pyrazolidinones bearing C5-substituents
of larger steric volume.
Achiral pyrazolidinones have proven to be exceptionally
effective as templates in enantioselective conjugate addition,6
dipolar cycloaddition,3e,7 and Diels-Alder (DA) cycload-
dition reactions8 involving R,ꢀ-unsaturated pyrazolidinone
imide electrophiles. We hypothesized that the use of racemic
5-substituted pyrazolidinones as the templates in such
reactions might lead to a kinetic resolution of the C5-
pyrazolidinone stereocenter. We surmised that DA cycload-
ditions of a diene with racemic, 5-substituted, R,ꢀ-unsaturated
pyrazolidinone imides were particularly promising as a
strategy for kinetic resolution since C5-substituent size exerts
a significant influence on the enantioselectivity of chiral
Cu(II) Lewis acid-catalyzed DA cycloadditions with achiral
pyrazolidinone imides.8b
Although kinetic resolutions based on DA cycloaddition
reactions are known,2d,9 the majority employ an enantioen-
riched diene or dienophile as a reagent to accomplish the
resolution. In contrast, kinetic resolutions based on catalytic,
enantioselective DA cycloadditions are rare. Herein we report
a strategy for the resolution of racemic R,ꢀ-unsaturated
pyrazolidinone imides by catalytic, enantioselective DA
cycloadditions.
An initial study of reaction conditions for the kinetic
resolution of racemic R,ꢀ-unsaturated pyrazolidinone imide
1a led to the identification of Cu(OTf)2 and aminoindanol-
derived bisoxazoline ligand 2 as the most promising catalyst
precursors (Scheme 1). When the resolution of 1a was
C5-substitution plays a pivotal role in the enantioselectivity
of the chiral Cu(II)-catalyzed DA cycloadditions involving
R,ꢀ-unsaturated pyrazolidinone imides. Thus, the kinetic
resolution of C5-substituted, R,ꢀ-unsaturated pyrazolidinone
imides based on Cu(OTf)2/2-catalyzed DA cycloadditions
was selected for further optimization.
Although pyrazolidinone (S)-1a can be isolated with
excellent enantiomeric excess under the reaction conditions
presented in Scheme 1, the DA kinetic resolution strategy
presented operational challenges not commonly associated
with other kinetic resolution strategies. Foremost among the
challenges was the use of excess cyclopentadiene as a
reactant in the resolving cycloaddition. In contrast to the
many kinetic resolution protocols that utilize 0.5-0.6 equiv
of a reactive reagent to eliminate the potential for overcon-
version of the starting material, our kinetic resolution
approach based on the DA cycloaddition often led to
conversions of greater than 60% due to the presence of excess
cyclopentadiene. Unfortunately, the logical solution of adding
a limiting quantity of the diene proved impractical due to
dimerization of the cyclopentadiene to dicyclopentadiene
under the reaction conditions. Furthermore, the use of dienes
that are less prone to dimerization led to less selective
resolutions.
Thus, a more controllable set of reaction conditions was
necessary to minimize the conversion of the dienophile past
50% in the presence of excess cyclopentadiene. Two
parameters were evaluated to accomplish this goal. First, the
loading of the chiral Lewis acid catalyst was reduced to 5
mol % (Table 1, entry 1). This modification led to a more
controllable reaction of cyclopentadiene with pyrazolidinone
crotonimide 1a (56% conversion over 9 h, 98% ee for
the remaining (S)-1a. Second, the effect of substitution at
the ꢀ-position of the enoyl fragment of the dienophile was
studied. Not surprisingly, the cycloaddition of pyrazolidinone
acrylimide 1b was essentially uncontrollable (entry 2). The
Cu(OTf)2/2-catalyzed cycloaddition of 1b with cyclopenta-
diene proceeded to 100% conversion in less than 1 h at room
temperature. In contrast, the corresponding resolution of
pyrazolidinone cinnamimide 1c was extremely slow (entry
3). The cycloaddition of 1c with cyclopentadiene occurred
to only 36% conversion after 54 h and with reduced
selectivity (s ) 8). Given these results, we chose to proceed
Scheme 1. Cu(OTf)2/2-Catalyzed Kinetic Resolution of
R,ꢀ-Unsaturated Pyrazolidinone Imide 1a
(6) (a) Sibi, M. P.; Prabagaran, N. Synlett 2004, 2421. (b) Sibi, M. P.;
Liu, M. Org. Lett. 2001, 3, 4181.
(7) (a) Sibi, M. P.; Stanley, L. M.; Soeta, T. Org. Lett. 2007, 9, 1553.
(b) Sibi, M. P.; Stanley, L. M.; Soeta, T. AdV. Synth. Catal. 2006, 348,
2371. (c) Sibi, M. P.; Ma, Z.; Jasperse, C. P. J. Am. Chem. Soc. 2004, 126,
718.
(8) (a) Sibi, M. P.; Nie, X.; Shackleford, J. P.; Stanley, L. M.; Bouret,
F. Synlett 2008, 2655. (b) Sibi, M. P.; Stanley, L. M.; Nie, X.; Venkatraman,
L.; Liu, M.; Jasperse, C. P. J. Am. Chem. Soc. 2007, 129, 395. (c) Sibi,
M. P.; Venkatraman, L.; Liu, M.; Jasperse, C. P. J. Am. Chem. Soc. 2001,
123, 8444.
(9) For an example of an enantioselective Diels-Alder reaction leading
to kinetic resolution of a chiral diene using a stoichiometric quantity of a
chiral Lewis acid, see: (a) Landells, J. S.; Larsen, D. S.; Simpson, J.
Tetrahedron Lett. 2003, 44, 5193. For the use of chiral dienophiles or dienes
for kinetic resolutions based on Diels-Alder cycloadditions, see: (b)
Carren˜o, M. C.; Urbano, A.; Di Vitta, C. J. Org. Chem. 1998, 63, 8320. (c)
Carren˜o, M. C.; Garcia-Cerrada, S.; Urbano, A.; Di Vitta, C. Tetrahedron:
Asymmetry 1998, 9, 2965. (d) Carren˜o, M. C.; Urbano, A.; Fischer, J. Angew.
Chem., Int. Ed. Engl. 1997, 36, 1621.
conducted with 10 equiv of cyclopentadiene, 11 mol % of
2, and 10 mol % of Cu(OTf)2, the enantioenriched R,ꢀ-
unsaturated pyrazolidinone imide (S)-1a was isolated with
99% ee at 66% conversion (s ) 15). This result served to
further support our previous observation that pyrazolidinone
Org. Lett., Vol. 11, No. 17, 2009
3895

with further studies on the scope of the kinetic resolution
with pyrazolidinone crotonimide dienophiles.
Table 2. Effect of Substitution on the Selectivity of the Kinetic
Resolution Reactionsa
Table 1. Effect of Enoyl ꢀ-Substitution on the Kinetic
Resolutiona
time conv ee (S)-1 yield
(h)
entry
R1
R2
1
(%)b
(%)c
1 (%)d se
entry
R (1)
time (h) conversion (%)b ee (S)-1a (%)c sd
1
2
3
4
5
i-Pr Ph
t-Bu Ph
1a
1d
1e
8
18
2
20
7
56
60
57
57
63
98
97
98
99
86
40
39
34
35
40
34
19
30
35
8
1
2
3
Me (1a)
H (1b)
Ph (1c)
9
1
54
56
100
36
98
--
39
34
--
8
Ph
Ph
i-Pr 1-Naph 1f
i-Pr Me 1g
a For experimental details, see the Supporting Information. b Determined
by 1H NMR spectroscopy of the crude reaction mixture with triphenyl-
methane as the internal standard. c Determined by chiral HPLC. d Selectivity
factor (s) ) ln{(1 - c)(1 - ee)}/ln{(1 - c)(1 + ee)} where c is the
conversion and ee is the enantiomeric excess of remaining 1.
a For experimental details, see the Supporting Information. b Determined
by 1H NMR spectroscopy of the crude reaction mixture with triphenyl-
methane as the internal standard. c Determined by chiral HPLC. d Isolated
yield of (S)-1. e Selectivity factor (s) ) ln{(1 - c)(1 - ee)}/ln{(1 - c)(1
+ ee)} where c is the conversion and ee is the enantiomeric excess of
remaining 1.
We next set out to determine whether the reaction
conditions for the kinetic resolution of pyrazolidinone
crotonimide 1a would also be effective for the resolutions
of additional pyrazolidinones bearing a chiral center at the
5-position of the pyrazolidinone ring (Table 2). As previously
illustrated, the resolution of pyrazolidinone crotonimide 1a
occurred with high selectivity (entry 1, s ) 34). We were
further pleased to observe that the resolutions of pyrazoli-
dinone crotonimides 1d (R1 ) t-Bu, R2 ) Ph) and 1e (R1 )
Ph, R2 ) Ph) occurred with high selectivities (entries 2 and
3; s ) 19 and 30, respectively). Entries 1-3 in Table 2
clearly demonstrate the feasibility of using our DA strategy
for highly selective kinetic resolutions of pyrazolidinone
crotonimides, but these results provide minimal insight into
the origin of the observed selectivity.
chirality of the pyrazolidinone to the fluxional chirality of
the N1 nitrogen plays a prominent role in the selectivity of
the resolution.
Scheme 2 presents an explanation for the influence of N1
substituent size on the selectivity of the kinetic resolution
reactions reported in Table 2. Initial coordination of the chiral
Cu(II) Lewis acid to the racemic starting material establishes
an equilibrium population of complexes 4 and 5. Complex
4, which is formed from the (S)-enantiomer of the pyrazo-
lidinone crotonimide, likely leads to a dissonant stereochem-
ical interaction between the ligand chirality and the chirality
of the fluxional nitrogen configuration at C5. Such a situation
would result in both faces of the dienophile being blocked
from approach of the diene and a relatively slow rate of
reaction through complex 4. Complex 5, which is formed
from the (R)-enantiomer of the pyrazolidinone crotonimide,
would lead to a consonant interaction between the ligand
chirality and the chirality of the fluxional nitrogen center.
Thus, the ligand chirality and the chirality of the fluxional
nitrogen center reinforce each other and effectively shield
the bottom face of the dienophile, leaving the top face open
to approach of the diene and a relatively fast rate of reaction
for complex 5 relative to complex 4. The poor selectivity
for the kinetic resolution of pyrazolidinone crotonimide 1g
(R2 ) Me) compared with those for pyrazolidinone croton-
imides 1a (R2 ) Ph) and 1f (R2 ) 1-naphthyl) offers support
for the hypothesis presented in Scheme 2. The small size of
the fluxional N1 substituent in 1g prevents efficient shielding
of the top face of the dienophile by the fluxional group,
rendering the cycloaddition with complex 4 competitive with
the corresponding cycloaddition with complex 5.
We next synthesized pyrazolidinone crotonimides 1f (R1
) i-Pr, R2 ) 1-naphthyl) and 1g (R1 ) i-Pr, R2 ) Me) to
evaluate whether the size of the substituent on the fluxional
N1 nitrogen impacts the selectivity of the resolution. Pyra-
zolidinone crotonimide 1f (R2 ) 1-naphthyl) was resolved
efficiently and controllably (entry 4, s ) 35). The nearly
identical selectivity factors observed for the resolutions of
1a (R1 ) Ph) and 1f (R1 ) 1-naphthyl, compare entries 1
and 4) led us to initially conclude that the selectivity of the
kinetic resolution was primarily controlled by the catalyst
and the identity of the C5 substitution. However, the
resolution of an additional pyrazolidinone crotonimide 1g
bearing a relatively small N1 substituent (R2 ) Me) was
markedly less selective. The selectivity factor for resolution
of 1g (R2 ) Me) was 8, and enantiomerically enriched (S)-
1g was isolated in only 86% ee (entry 5). The lower
selectivity observed for the resolution of 1g compared with
1a and 1f (compare entry 5 with entries 1 and 4) suggests
that a relay of stereochemical information from the fixed
3896
Org. Lett., Vol. 11, No. 17, 2009

Scheme 2. Proposed Explanation for the Influence of C5 and N1 Substituent Size on the Selectivity of the Kinetic Resolution
With an efficient method to access enantiomerically
enriched, N2 acylated pyrazolidinones in hand, it remained
to develop conditions that would provide access to both
enantiomers of the N-H pyrazolidinones 6 (Scheme 3).10
nones 6a and 6f are liberated by reaction of 1a and 1f with
the lithium alkoxide of p-methoxybenzyl alcohol (Scheme
3). The parent pyrazolidinones (S)-6a and (S)-6f were isolated
in moderate to good yields with minimal erosion of the
enantiomeric excess (eq 1). The enantiomeric (R)-N-H
pyrazolidinones (R)-6a and (R)-6f could also be isolated in
good yields, albeit with lower enantiomeric purity from the
reaction of the DA adducts 3a and 3f with the lithium
alkoxide of p-methoxybenzyl alcohol (eq 2).
Scheme 3
.
Conversion of N2-Acylated Pyrazolidinones to N-H
Pyrazolidinonesa
In conclusion, we have developed a practical DA cycload-
dition strategy for the kinetic resolution of chiral pyrazoli-
dinones that could not be obtained in high enantiomeric
excess from direct methods. Our approach represents a rare
example of a catalytic, enantioselective DA cycloaddition
reaction as a means to effect a kinetic resolution. Further-
more, this strategy highlights the role that fluxional chirality
at nitrogen centers may play in influencing stereochemical
outcomes, and further demonstrates the potential to relay
stereochemical information from a remote stereocenter to a
fluxional nitrogen center near the site of reaction. The
extension of the present strategy to access enantiomerically
enriched 4-substituted, 4,5-disubstituted, and 4,4-disubstituted
pyrazolidinones is currently underway.
a PMB ) para-methoxybenzyl.
Acknowledgment. We thank the NSF (NSF-CHE-
0709061) for financial support of this work.
After separation of the enantiomerically enriched starting
material and the DA cycloadduct, the (S)-N-H pyrazolidi-
Supporting Information Available: Experimental pro-
cedures and characterization data for new compounds. This
material is available free of charge via the Internet at
http://pubs.acs.org.
(10) For procedures and additional data on the cleavage of R,ꢀ-
unsaturated pyrazolidinone imides 1a, 1d-g, and Diels-Alder adducts 3a
and 3d-g with the lithium alkoxide of p-methoxybenzyl alcohol, see Table
1 and Table 2 in the Supporting Information.
OL901504P
Org. Lett., Vol. 11, No. 17, 2009
3897