Parallel kinetic resolutions of monosubstituted succinic anhydrides catalyzed by a modified cinchona alkaloid [7]

Full text of DOI:10.1021/ja011766h

11302
J. Am. Chem. Soc. 2001, 123, 11302-11303
Table 1. (DHQD)2AQN-Catalyzed Parallel Kinetic Resolution of
Methylsuccinic Anhydride
Parallel Kinetic Resolutions of Monosubstituted
Succinic Anhydrides Catalyzed by a Modified
Cinchona Alkaloid
Yonggang Chen and Li Deng*
Department of Chemistry, Brandeis UniVersity
Waltham, Massachusetts 02454-9110
ReceiVed July 20, 2001
entry
R′OH
MeOH
EtOH
n-PrOH
i-PrOH
temp/°C % conva 4/5b % ee, 4b % ee, 5b
Efficient kinetic resolution processes continue to play a critical
role in asymmetric synthesis.1 Using two chiral reagents to effect
two parallel running enantioselective resolution reactions, Vedejs
and co-workers demonstrated that, through minimizing a build-
up of the less reactive enantiomer by simultaneously consuming
both enantiomers of the racemic starting material, the two resolu-
tion reactions work synergistically to render the efficiency of the
parallel kinetic resolution dramatically higher than that of each
of the individual enantioselective resolution reactions.2 Parallel
kinetic resolution thus represents an especially attractive strategy
to maximize the enantiomeric excess attainable for a product gen-
erated via kinetic resolution reactions. However, the development
of catalytic parallel kinetic resolutions that affords synthetically
useful efficiency with an extensive range of substrates remains
highly challenging.3-6 We report here a broadly effective parallel
kinetic resolution mediated by a single organic catalyst that trans-
forms readily accessible racemic monosubstituted succinic an-
hydrides into synthetically valuable chiral succinate mono esters
in high enantiomeric excesses.
1
2
3
4
5
6
25
25
25
25
25
100
100
100
<2
100
100
39/61
49/51
45/55
-
49/51
44/56
74
82
81
-
67
67
72
-
CF3CH2OH
CF3CH2OH
85c
91c
72c
80c
-25
a Determined by GC or NMR analysis. b Determined by HPLC
analysis as described in Supporting Information. c The absolute con-
figuration is determined by comparison with an authentic sample (see
Supporting Information).
Scheme 1. Reagent-Controlled Highly Regioselective
Alcoholysis of (R)- and (S)-Methylsuccinic Anhydrides with
Modified Cinchona Alkaloids
We recently discovered that modified cinchona alkaloids are
highly effective chiral Lewis base catalysts for desymmetrization
of cyclic anhydrides.7,8 In view of the synthetic utility of optically
active monosubstituted succinate mono esters (2, 3),9,10 we began
to explore their asymmetric synthesis via a modified cinchona
alkaloid-catalyzed kinetic resolution of racemic monosubstituted
succinic anhydrides (eq 1). Reaction of racemic 2-methylsuccinic
anhydride (1a, R ) Me) with methanol (10 equiv) in ether at
room temperature in the presence of (DHQD)2AQN (10 mol %)
was completed in 4 h to afford mono esters 4 and 5 in a ratio of
39:61 (entry 1, Table 1). Furthermore, 4 and 5 were shown by
GC analyses to be formed at similar rates throughout the course
of the reaction. Surprisingly, we found that 4 and 5 were produced
in 74 and 67% ee, respectively. This data indicated that the two
enantiomers of anhydride 1a were converted to optically active
hemiesters 4 and 5, respectively, at similar rates via two parallel
enantioselective methanolyses of divergent regioselectivities
catalyzed by a common catalyst, (DHQD)2AQN.
Further evaluations of a variety of reaction parameters revealed
that the enantioselectivity of the parallel kinetic resolution is
influenced considerably by the structure of the alcohol (Table
1). Increasing the size of the alcohol from methanol to n-propanol
significantly enhances the enantioselectivity of the reaction (entries
1-3, Table 1). On the other hand, the use of 2-propanol almost
completely halted the reaction. Importantly, the (DHQD)2AQN-
catalyzed parallel kinetic resolution of 1a with triflouroethanol
at -24 °C afforded succinates 4 and 5 in synthetically useful
enantiomeric excesses (entry 6, Table 1).
The divergent regioselectivity of the (DHQD)2AQN-catalyzed
alcoholysis for (R)- and (S)-2-methyl succinic anhydrides (R- and
S-1a), respectively, is demonstrated experimentally (Scheme 1).
Commercially available optically pure R- and S-2-methyl succinic
acids were converted respectively to the corresponding optically
pure 2-methyl succinic anhydrides (R- and S-1a), which were next
individually subjected to (DHQD)2AQN-catalyzed trifluoroetha-
nolysis. While R-1a was converted to succinates R-7a and -6a in
a ratio of 97:3, the alcoholysis of S-1a under the identical
condition affords S-6a and -7a in a ratio of 92:8. We also
demonstrated that, with a given enantiomer of 1a (R- or S-1a),
the regioselectivity of ring-opening alcoholysis can be controlled
by choosing either (DHQD)2AQN or (DHQ)2AQN as the catalyst
* To whom correspondence should be addressed.
(1) For reviews see: (a) Keith, J. M.; Larrow, J. F.; Jacobsen, E. N. AdV.
Synth. Catal. 2001, 343, 5. (b) Kagan, H. B.; Fiaud, J. C. Top. Stereochem.
1988, 18, 249.
(2) (a) Vedejs, E.; Rozners, E. J. Am. Chem. Soc. 2001, 123, 2428. (b)
Vedejs, E.; Chen, X. J. Am. Chem. Soc. 1997, 119, 2584.
(3) For a review, see: Eames, J. Angew. Chem., Int. Ed. 2000, 39, 885.
(4) For examples using chiral metal complexes, see: (a) Bertozzi, F.; Crotti,
P.; Macchia, F.; Pineschi, M.; Feringa, B. L. Angew. Chem., Int. Ed. 2001,
40, 930. (b) 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.
(c) Visser, M. S.; Hoveyda, A. H. Tetrahedron 1995, 51, 4383. (d) Bolm, C.;
Schlingloff, G. J. Chem. Soc., Chem. Commun. 1995, 1247. (e) Martin, S. F.;
Spaller, M. R.; Liras, S.; Hartmann, B. J. Am. Chem. Soc. 1994, 116, 4493.
(5) For examples using enzymes, see: (a) Ozegowski, R.; Kunath, A.;
Sehick, H. Liebigs Ann. 1995, 1699. (b) Mischitz, M.; Faber, K. Tetrahedron
Lett. 1994, 35, 81. (c) Petit, F.; Furstoss, R. Tetrahedron: Asymmetry 1993,
4, 1341. (d) Alphand, V.; Furstoss, R. J. Org. Chem. 1992, 57, 1306.
(6) For a kinetic resolution involving two different reactions for a complete
conversion of starting material to a single optically active product, see: Feng,
X.; Shu, L.; Shi, Y. J. Am. Chem. Soc. 1999, 121, 11002.
(7) Chen, Y.; Tian, S.-K.; Deng, L. J. Am. Chem. Soc. 2000, 122, 9542.
(8) For catalytic desymmetrizations of cyclic anhydrides with natural
cinchona alkaloids, see: (a) Hiratake, J.; Yamamoto, Y.; Oda, J. J. Chem.
Soc., Chem. Commun. 1985, 1717. (b) Bolm, C.; Schiffers, I.; Dinter, C. L.;
Gerlach, A. J. Org. Chem. 2000, 65, 6984.
(9) For select applications of monosubstituted chiral succinates, see: (a)
Sibi, M.; Deshpande, P. K. J. Chem. Soc., Perkin Trans. 1 2000, 1461. (b)
Evans, D. A.; Wu, L. D.; Wiener, J. J. M.; Johnson, J. S.; Ripin, D. H. B.;
Tedrow, J. S. J. Org. Chem. 1999, 64, 6411.
(10) For preparations of chiral succinates via catalytic asymmetric hydro-
genations, see: Burk, M. J.; Bienewald, F.; Harris, M.; Zanotti-Gerosa, A.
Angew. Chem., Int. Ed. 1998, 37, 1931.
10.1021/ja011766h CCC: $20.00 © 2001 American Chemical Society
Published on Web 10/16/2001

Communications to the Editor
J. Am. Chem. Soc., Vol. 123, No. 45, 2001 11303
Table 2. (DHQD)2AQN-Catalyzed Parallel Kinetic Resolution of
the mixture of succinates 9 and 10 was converted to â- and R-aryl-
γ-butyrolactones (11 and 12), which are chromatographically
readily separable. The highly enantioselective generation of â-aryl-
γ-butyrolactones (11) in excellent overall yields from racemic
anhydrides 8 represents a general and new route toward this
versatile and pharmaceutically important class of chiral intermedi-
ates. Compared to other catalytic enantioselective approaches,13
the route described here is particularly attractive for employing
simple and mild experimental protocols involving easily accessible
starting material, cheap reagents, and a readily available and fully
recyclable catalyst. Given that lactone 11c has previously been
converted in excellent yield to baclofen,14 its highly enantiose-
lective generation via the parallel kinetic resolution of racemic
anhydride 8c could serve as a key step for the efficient synthesis
of this effective GABA receptor agonist which is a therapeutic
reagent for muscle spasticity.15 The crucial role played by the
parallel kinetic resolution process in this route can be appreciated,
considering that a conventional kinetic resolution of a selectivity
factor of at least 112 would be required to obtain lactone 11c
from racemic anhydrides 8 with the same ee and yield afforded
by the parallel kinetic resolution process.16 Such an extraordinary
enantioselectivity is beyond the reach of most known chemical
kinetic resolution processes.
2-Alkyl Succinic Anhydridesa,b
% eed
% yielde
entry
substrate
6/7
6
7
6
7
1c
2
3
1a: R ) -Me
44/55 93 80
40/60 91 70
42/56 98 66
36
38
38
40
41
50
41
49
1b: R ) -Et
1c: R ) -n-C8H17
1d: R ) -CH2CHdCH2 46/53 96 82
4
a Unless noted otherwise, the reaction was performed by treatment
of 1 (1.0 mmol) at 0.02 M with CF3CH2OH (10 equiv) and
(DHQD)2AQN (15 mol %). b Catalyst was recovered in quantitative
yield as described in Supporting Information. c 20 mol % catalyst was
used. d See Supporting Information for details of ee analysis. e Isolated
yield.
Table 3. Asymmetric Synthesis of â-Aryl-γ-Lactones (11) via
Parallel Kinetic Resolution of 2-Aryl-Succinic Anhydrides (8)a
In summary, we have developed a new catalytic method for
the synthesis of optically active succinnate mono esters via a
highly efficient parallel kinetic resolution process, which involves
two simultaneous enantioselective and divergently regioselective
alcoholyses of two enantiomers of the monosubstituted succinic
anhydrides promoted by a common bis-cinchona alkaloid deriva-
tive.17 To our knowledge, this is the first case of an efficient cat-
alytic parallel kinetic resolution of racemic bifunctional substrates
mediated by a single organic catalyst. In our studies of modified
cinchona alkaloid-catalyzed asymmetric alcoholysis of cyclic
anhydrides, we have demonstrated that a catalyst that promotes
desymmetrizations of meso or prochiral bifunctional substrates
may also catalyze the parallel kinetic resolution of related racemic
bifunctional substrates. This trend could, in principle, occur with
other catalytic transformations of bifunctional substrates.
% eeb,c
% eeb,c (yieldd)
entry
1e
2
substrate
8a: Ar ) Ph
9
10
11
12
95
96
96
87
83
76
95 (44)
95 (45)
96 (44)
82 (32)
83 (30)
63 (29)
8b: Ar ) 3-MeO-C6H4
8c: Ar ) 4-Cl-C6H4
3
a See footnote a of Table 2 for reaction conditions. b See Supporting
Information for ee determination. c See Supporting Information for
absolute configuration determination. d Isolated yield from 8. e With
(DHQ)2AQN, ent-11a was obtained in 44% yield and 88% ee.
(Scheme 1). The sequence outlined in Scheme 1 thus constitutes
the first example of a reagent-controlled, highly regioselective
catalytic functionalization of optically active monosubstituted
succinic acids and succinic anhydrides.11
The scope of the parallel kinetic resolution was first investigated
with a series of racemic 2-alkyl succinic anhydrides (Table 2).
Racemic succinic anhydrides bearing alkyl groups with a range
of steric properties are effectively resolved to afford the corre-
sponding 3-alkyl succinnates (6) in 91-98% enantiomeric
excesses and 36-40% isolated yields. The 2-alkyl succinnates
(7) are obtained in 66-82% ee and 41-50% isolated yields. It is
important to note that mixtures of hemiesters 6 and 7 can be
separated via normal chromatographic purifications.
Acknowledgment. We gratefully acknowledge the financial support
of NIH (GM-61591), the Harcourt General Charitable Foundation and
Research Corporation (RI-0311).
Supporting Information Available: Experimental details (PDF). This
material is available free of charge via the Internet at http://pubs.acs.org.
JA011766H
(12) For an efficient chiral auxiliary-based approach, see ref 9b.
(13) (a) Takaya, Y.; Senda, T.; Kurushima, H.; Ogasawara, M.; Hayashi,
T. Tetrahedron: Asymmetry 1999, 10, 4047. (b) Bolm, C.; Luong, T. K. K.;
Schlingloff, G. Synlett 1997, 115. (c) Dawson, G. J.; Williams, M. J.
Tetrahedron: Asymmetry 1995, 6, 2535. (d) Doyle, M. P.; Oeveren, A. V.;
Westrum, L. J.; Protopopova, M. N.; Clayton, T. W., Jr. J. Am. Chem. Soc.
1991, 113, 8982.
(14) (a) Mazzini, C.; Lebreton, J.; Alphand, V.; Furstoss, R. Tetrahedron
Lett. 1997, 38, 1195. (b) Schoenfelder, A.; Mann, A.; Coz, S. L. Synlett 1993,
63.
We were particularly pleased to find that the efficiency of the
parallel kinetic resolution remains high with 2-aryl succinic
anhydrides with either an electron-rich or -poor aromatic ring
(Table 3). Optically active 3- and 2-aryl succinate mono esters
(9 and 10), previously inaccessible from catalytic enantioselective
approaches,10,12 are generated in 95-96 and 76-87% ee, respec-
tively. When treated sequentially with LiBEt3H and aqueous HCl,
(15) Olpe, H. R.; Demie´ville, H.; Baltzer, V.; Bencze, E. L.; Koella, W.
P.; Wolf, P.; Haas, H. L. Eur. J. Pharmacol. 1978, 52, 133.
(16) The minimum value of the required stereoselectivity factor (s ) kfast
/
kslow) was calculated using the equation s ) ln[1 - C(1 + ee)]/ln[1 - C(1 -
ee)],1b where the isolated yield of 11c from 8c (44%) is used as the value for
C (conversion of the reaction).
(17) For a resolution of racemic 4-methyl-1,2,3,6-tetrahydrophthalic an-
hydride using a chiral mediator-promoted alcoholysis see: Seebach, D.;
Jaeschke, G.; Gottawald, K.; Matsuda, K.; Formisano, R.; Chaplin, D. A.;
Breuning, M.; Bringmann, G. Tetrahedron 1997, 53, 7539.
(11) For an enzyme-catalyzed regioselective alcoholysis of cyclic anhy-
drides, see: Hiratake, J.; Yamamoto, K.; Yamamoto, Y.; Oda, J. Tetrahedron
Lett. 1989, 30, 1555.