Parallel kinetic resolution under catalytic conditions: A three-phase system allows selective reagent activation using two catalysts

Full text of DOI:10.1021/ja0035405

2428
J. Am. Chem. Soc. 2001, 123, 2428-2429
ChiroCLEC-PC has the standard lipase reactivity preference for
the formation of the R-ester (for example, 3a with s ) 83).
Parallel Kinetic Resolution under Catalytic
Conditions: A Three-Phase System Allows Selective
Reagent Activation Using Two Catalysts
Edwin Vedejs* and Eriks Rozners
Department of Chemistry, UniVersity of Michigan
Ann Arbor Michigan 48109
ReceiVed September 29, 2000
Furthermore, lipase selectivity or reactivity were not significantly
affected when the phosphine 1 was present together with the vinyl
pivalate. On the other hand, the usual phosphine catalyzed
isobutyric anhydride acylation7 of the alcohol could not be
performed in the presence of ChiroCLEC-PC because the latter
also activates the anhydride. To avoid this problem, and to ensure
selective activation of a unique acyl donor by the lipase, we
considered a polymer-bound reagent to serve as the phosphine-
specific acyl donor. Insoluble activated esters of the general
formula 4 cannot interact with ChiroCLEC-PC because the latter
does not dissolve in organic solvents. The catalytic PKR experi-
ment would then consist of three phases,8 (1) ChiroCLEC-PC
(insoluble catalyst), (2) insoluble acyl donor 4, and (3) soluble
catalyst 1 and soluble acyl donor (vinyl pivalate). The three-phase
system should allow contact between 1 and 4 to generate 5, as
well as the usual interaction between ChiroCLEC-PC and the vinyl
ester to produce the acylated lipase intermediate 6. Since the
reactive acylphosphonium salt 5 is insoluble, there is no possibility
that it would modify or deactivate the lipase. Furthermore, the
eventual ester product 7 is attached to the solid phase and would
be easy to separate from the quasi-enantiomeric lipase-derived
ester R-3 because the latter is formed in solution.
We have been interested in experiments where two different
catalysts are present, each of which must activate a unique
substrate. This situation would arise in some of the conceivable
catalytic adaptations of parallel kinetic resolution (PKR).1-3 As
reported in the initial publication describing a stoichiometric
version of the PKR experiment, two quasi-enantiomeric reagents
can be used to simultaneously derivatize each enantiomer of a
racemic mixture to give two distinct quasi-enantiomeric products.
In the optimal case where the competing derivatizations occur
with similar rates and complementary enantioselectivities, product
ee is near the theoretical limit calculated from the inherent
enantioselectivities4 regardless of % conversion, and recovery can
exceed 90%.
PKR experiments that rely on two parallel catalytic reactions
would be especially attractive. Related examples are known for
the special case where a single chiral catalyst induces the
formation of a distinct product from each substrate enantiomer.5
However, a unique scenario should be possible where two
different catalysts are used to promote the selective derivatization
of each enantiomer. Such an experiment allows interesting options
for the separation of the quasi-enantiomeric products as discussed
later, but it requires that each catalyst must selectively activate
only one of the two derivatizing reagents. To achieve the required
selectivity in a fully catalytic version of PKR, we have used a
technique based on phase isolation as described below.
The experimental design features the simultaneous use
of
a commercial cross-linked lipase acylation catalyst
(ChiroCLEC-PC)6a together with a lipase-specific acyl donor, a
complementary chiral phosphine acylation catalyst 1,7 and a
phosphine-specific acyl donor to derivatize enantiomeric alcohols
2. Control experiments with aryl carbinol substrates identi-
fied vinyl pivalate as an acyl donor that is activated by
ChiroCLEC-PC,6 but not by the phosphine 1, and confirmed that
(1) Vedejs, E.; Chen, X. J. Am. Chem. Soc. 1997, 119, 2584.
(2) (a) Review: Eames, J. Angew. Chem., Int. Ed. 2000, 39, 885. (b) Early
analogy: Horeau, A. Tetrahedron Lett. 1961, 2, 506. (c) Pietrusiewicz, K.
M.; Holody, W.; Koprowski, M.; Cicchi, S.; Goti, A.; Brandi, A. Phosphorus,
Sulfur Silicon Relat. Elem. 1999, 144-146, 389. Cardona, F.; Valenza, S.;
Goti, A.; Brandi, A. Eur. J. Org. Chem. 1999, 1319. Guo, J.; Wu, J.; Siuzdak,
G.; Finn, M. G. Angew. Chem., Int. Ed. 1999, 38, 1755. Pedersen, T. M.;
Jensen, J. F.; Humble, R. E.; Rein, T.; Tanner, D.; Bodmann, K.; Reiser, O.
Org. Lett. 2000, 2, 535.
Several structural options were evaluated for the phosphine-
selective acyl donor. According to preliminary experiments under
homogeneous conditions, the nature of the leaving group X is
important for enantioselectivity as well as reactivity. Best results
were obtained when X is carboxylate, but the corresponding
polymer bound reagent 4 would then contain mixed anhydride
functionality with the potential for reaction at either carbonyl
(3) For a precedent involving two or more enzymatic catalysts and
conversion of one of the enantiomers into an achiral product, see: Brooks,
D. W.; Wilson, M.; Webb, M. J. Org. Chem. 1987, 52, 2244.
(4) Kagan, H. B.; Fiaud, J. C. Top. Stereochem. 1988, 18, 249.
(5) (a) El-Baba, S.; Poulin, J.-C.; Kagan, H. B. Tetrahedron 1984, 40, 4275.
Martin, S. F.; Spaller, M. R.; Liras, S.; Hartmann, B. J. Am. Chem. Soc. 1994,
116, 4493. Doyle, M. P.; Dyatkin, A. B.; Kalinin, A. V.; Ruppar, D. A.; Martin,
S. F.; Spaller, M. R.; Liras, S. J. Am. Chem. Soc. 1995, 117, 11021. Visser,
M. S.; Hoveyda, A. H. Tetrahedron 1995, 51, 4383. Bolm, C.; Schlinghoff,
G. J. Chem. Soc., Chem. Commun. 1995, 1247. (b) Overview: Kagan, H.
Croat. Chem. Acta 1996, 69, 669. (c) Parallel reactions involving steady-
state partitioning of diastereomeric intermediates: DeMello N. C.; Curran D.
P. J. Am. Chem. Soc. 1998, 120, 329.
(8) (a) Rebek, J.; Brown, D.; Zimmerman, S. J. Am. Chem. Soc. 1975, 97,
454. Pittman, C. U., Jr.; Smith, L. R. J. Am. Chem. Soc. 1975, 97, 1749.
Regen, S. L. Angew. Chem. 1979, 91, 464. (b) Related multiphase chemistry:
Cohen, B. J.; Kraus, M. A.; Patchornik, A. J. Am. Chem. Soc. 1981, 103,
7620. Bessodes, M.; Antonakis, K. Tetrahedron Lett. 1985, 26, 1305.
Bergbreiter, D. E.; Zhang, L. J. Chem. Soc., Chem. Commun. 1993, 596.
Parlow, J. J. Tetrahedron Lett. 1995, 36, 1395. Flynn, D. L.; Crich, J. Z.;
Devraj, R. V.; Hockerman, S. L.; Parlow, J. J.; South, M. S.; Woodard, S. J.
Am. Chem. Soc. 1997, 119, 4874. Booth, R. J.; Hodges, J. C. J. Am. Chem.
Soc. 1997, 119, 4882. Gerritz, S. W.; Trump, R. P.; Zuercher, W. J. J. Am.
Chem. Soc. 2000, 122, 6357.
(6) (a) Khalaf, N.; Govardhan, C. P.; Lalonde, J. J.; Persichetti, R. A.; Wang,
R.-F.; Margolin, A. L. J. Am. Chem. Soc. 1996, 118, 5494. (b) Use of vinyl
esters with lipases: Degueil-Castaing, M.; De Jeso, B.; Drouillard, S.; Maillard,
B. Tetrahedron Lett. 1987, 28, 953; Wang, Y.-F.; Wong, C.-H. J. Org. Chem.
1988, 53, 3128.
(7) Vedejs, E.; Daugulis, O. J. Am. Chem. Soc. 1999, 121, 5813.
10.1021/ja0035405 CCC: $20.00 © 2001 American Chemical Society
Published on Web 02/15/2001

Communications to the Editor
J. Am. Chem. Soc., Vol. 123, No. 10, 2001 2429
group. Sterically differentiated mixed anhydride 13 (4 with X )
mesitoate) should allow selective carbonyl activation, but the
mesitoate anion would also play a role in proton transfer and
enantioselectivity in the phosphine-catalyzed acylation. This issue
was probed under homogeneous conditions. The model mixed
anhydride 8 was generated by the reaction of cyclohexane-
carboxylic acid chloride with mesitoic acid and triethylamine.
Anhydride 8 could not be purified, but promising enantioselec-
tivity was determined when crude 8 was used in a simple kinetic
resolution of 2a with phosphine 1 as the catalyst at room
temperature (s > 25).9 Mesitoate ester formation was not detected,
and the S-enantiomer of 2a was more reactive, as required for a
complementary match with the enantioselectivity of the lipase
catalyst in PKR.
A polymer-bound cyclohexanecarboxylic acid 12 was then
prepared from phosphonium salt 9 using standard methods.10 Thus,
9 was converted to the ylide 10 with n-butyllithium and
4-oxocyclohexanecarboxylic acid was added as the lithium salt
in THF-DMPU. The resulting 11 was reduced using Et3SiH/
CF3CO2H to afford 12 and conversion into the mixed anhydride
13 was performed by reaction with ethylchloroformate, N,N-
diisopropylethylamine, and mesitoic acid.
Good enantiomeric purity in both products R-3a and S-7a was
obtained even though the enantioselectivities of the two catalysts
were not closely matched (2a with ChiroCLEC-PC/vinyl pivalate:
s ) 83; 2a with phosphine 1/mixed anhydride 13: s ) 34). This
is possible because the more important variable in PKR is the
rate of each of the major pathways from R/S-2a to the products
R-3a and S-7a. If catalyst 1 consumes S-2a at nearly the same
rate that Chiroclec-PC consumes R-2a, then the ratio of unreacted
S-2a:R-2a will remain close to unity, provided that the rates
leading to the minor products S-3a and R-7a are sufficiently slow.
This condition must have been satisfied because R-3a and S-7a
were obtained with ee values near the theoretical limits (defined
as the ee expected at <1% conversion in a simple kinetic
resolution, 98% ee for R-3a with s ) 83, and 94% ee for S-7a
with s ) 34). The limits were not reached because enantioselec-
tivities for the two parallel reactions were not identical.
The ratio of unreacted S-2a:R-2a in the catalytic PKR experi-
ments was assayed at varying conversions. In all three experi-
ments, unreacted alcohol developed a small initial excess of R-2a
with the maximum (6-13% ee) found at 40-70% conversion.
As % conversion increased beyond .∼70%, the ee value of
unreacted 2a decreased and eventually inverted in favor of S-2a.
The empirical results indicate that the phosphine-catalyzed
acylation with 13 becomes relatively less efficient compared to
the ChiroCLEC-PC acylation as % conversion increases.
It is instructive to compare the ee values of unreacted starting
material and products in the PKR experiment vs the simple kinetic
resolution of 2b, a substrate that reacts with relatively modest
enantioselectivity at room temperature using either catalyst (2b
with ChiroCLEC-PC/vinyl pivalate: s ) 37; 2b with phosphine
1/mixed anhydride 13: s ) 23). The PKR experiment gave S-7b
with 89% ee and R-3b with 94-5% ee and >80% recovery.
According to Kagan’s equation,4 the simple kinetic resolution
experiment at 50% conversion using 1 as the catalyst (s ) 23)
would afford unreacted R-2b and product S-3b, each with 81%
ee. At 54% conversion, the unreacted R-2b (46% recovery limit)
would have the same 89% ee as in the PKR experiment, but the
product S-3b would have 77% ee, too low for most purposes.
Increased conversion to 56% would increase the ee of unreacted
R-2b to 94%, but recovery of useful material would decrease (44%
maximum) and the ee of S-3b would drop further to 74%.13
The above findings constitute a proof for the concept of PKR
using two different chiral catalysts to selectively activate two
different achiral stoichiometric reagents. The results also show
that PKR succeeds even when the enantioselectivities of the
competing simultaneous reactions are not closely matched and
when the ratio of unreacted enantiomers deviates from the ideal
1:1 ratio in a nonlinear manner.
The polymer-bound anhydride 13 was tested in a simple kinetic
resolution at room temperature with 2a as the substrate and 1 as
the catalyst. A satisfactory value of s ) 34 was determined after
cleavage of the ester 7a using Bu4NOH/THF, and a preference
for acylation of S-2a was confirmed. Such high enantioselectivity
requires that transport of both enantiomers of 2a into and out of
the polymer is fast on the time scale of the acyl transfer process.
A positive result was anticipated because there are prior examples
of kinetic resolution using polymeric reagents.11
With all of the preliminary conditions for catalytic PKR
satisfied, the key experiment could be examined. Both catalysts
(1 and ChiroCLEC-PC) were used together with R/S 2a and the
catalyst-specific acyl donors, 13 and vinyl pivalate. Based on three
experiments with conversions in the range of ∼85-90%, PKR
was clearly demonstrated. Thus, S-2a was recovered after cleavage
of polymer-bound 7a with ee values of 93, 91, and 92%, while
the (soluble) pivalate R-3a was obtained with 97, 94, and 96%
ee, respectively.12 In view of the high (g85%) conversions,
product recoveries, and enantiomeric purities, the conditions
required for catalytic PKR must have been satisfied.
Phase isolation provides one way to control which reagent is
activated by a given catalyst. Several variations on the phase
isolation theme remain to be explored, including the case where
each catalyst is placed in separate imiscible phases. In principle,
however, catalytic PKR experiments need not be performed using
phase isolation. Parallel reactions based on two mechanistically
distinct catalytic derivatizations should be feasible using two
different catalysts under homogeneous conditions. Efforts are
under way to identify PKR examples where this might be possible.
Similar considerations apply to any set of four potentially
competing catalytic reactions induced by two catalysts, and the
same principle could be used to differentiate or separate two
diastereomers, regioisomers, or components of a mixture.
(9) The empirical selectivity is listed in all cases without correcting for
the enantiomeric purity of catalyst 1 (99%).
(10) Frechet, J. M.; Schuerch, C. J. Am. Chem. Soc. 1971, 93, 492.
(11) Annis, D. A.; Jacobsen, E. N. J. Am. Chem. Soc. 1999, 121, 4147.
Coisne, J. M.; Pecher, J. Chimia 1981, 35, 97. Annunziata, R.; Borgogno, G.;
Montanari, F.; Quici, S.; Cucinella, S. J. Chem. Soc., Perkin Trans. 1 1981,
113.
(12) A fourth experiment was interrupted at 75% conversion, resulting in
R-3a (97% ee) and S-7a, 89% ee after cleavge.
Acknowledgment. This work was supported by the National Science
(13) Leading references to recent nonenzymatic catalysts for simple kinetic
resolution: (a) Review: Spivey, A. C.; Maddaford, A.; Redgrave, A. J. Org.
Prep. Proced. Int. 2000, 32, 331. (b) Bellemin-Laponnaz, S.; Tweddell, J.;
Ruble, J. C.; Breitling, F. M.; Fu, G. C. Chem. Commun. (Cambridge) 2000,
1009. (c) Spivey, A. C.; Fekner, T.; Spey, S. E. J. Org. Chem. 2000, 65,
3154. (d) Sano, T.; Miyata, H.; Oriyama, T. Enantiomer 2000, 5, 119. (e)
Jarvo, E. R.; Copeland, G. T.; Papaioannou, N.; Bonitatebus, P. J., Jr.; Miller,
S. J. J. Am. Chem. Soc. 1999, 121, 11638.
Foundation.
Supporting Information Available: Preparation of solid-phase
reagents; general procedures (PDF). This material is available free of
charge via the Internet at http://pubs.acs.org.
JA0035405