Dynamic kinetic resolution via dual-function catalysis of modified cinchona alkaloids: Asymmetric synthesis of α-hydroxy carboxylic acids

Article abstract of DOI:10.1021/ja0255047

A highly enantioselective catalytic transformation of racemic α-hydroxy acids to optically active α-hydroxy acids is reported. A new procedure was developed for the condensation of racemic α-hydroxy acids with trichloromethyl chloroformate (diphosgene) at room temperature in the presence of activated charcoal to form 5-substituted-1,3-dioxolane-2,4-diones in 90-100% yield. An efficient dynamic kinetic resolution of 5-aryl dioxolanediones was realized via a modified cinchona alkaloid-catalyzed alcoholytic opening of the dioxolanedione ring, generating a variety of optically active α-hydroxy esters in 91-96% ee and 61-85% chemical yield. In this dynamic kinetic resolution, the modified cinchona alkaloid was found to serve dual catalytic roles, mediating both the rapid racemization of the 5-aryl dioxolanediones and the enantioselective alcoholytic ring opening of the 5-aryl dioxolanediones. Consequently, both enantiomers of the 5-aryl dioxolanediones were converted to highly enantiomerically enriched aromatic α-hydroxy esters in yields (61-85%), far exceeding the maximum of 50% for a normal kinetic resolution. This development not only represents an expansion of the scope of asymmetric acyl-transfer catalysis of synthetic catalysts but also provides a new approach for the development of efficient chemical dynamic kinetic resolutions promoted by a single catalyst. 5-Alkyl dioxolanediones were resolved by a conventional but highly enantioselective kinetic resolution to provide α-hydroxy acids and esters in high optical purity and good yields. Copyright

Full text of DOI:10.1021/ja0255047

Published on Web 03/05/2002
Dynamic Kinetic Resolution via Dual-Function Catalysis of Modified Cinchona
Alkaloids: Asymmetric Synthesis of r-Hydroxy Carboxylic Acids
Liang Tang and Li Deng*
Department of Chemistry, Brandeis UniVersity, Waltham, Massachusetts 02454-9110
Received January 2, 2002
Scheme 1
Optically active R-hydroxy acids are ubiquitous structural motifs
in numerous biologically interesting natural and unnatural com-
pounds.1 Accordingly, considerable effort has been devoted to the
asymmetric synthesis of R-hydroxy acids.2-5 Catalytic methods
based on chiral transition metal complexes have emerged as
promising nonenzymatic approaches.4,5 We recently reported that
Scheme 2
modified cinchona alkaloids catalyzed highly enantioselective ring-
opening alcoholyses of cyclic anhydrides and N-carboxyanhydrides.6
We envisaged that an efficient cinchona alkaloid-catalyzed kinetic
resolution of 1,3-dioxolane-2,4-diones 2 could provide a new,
straightforward and metal-free catalytic approach toward optically
active R-hydroxy acids from their readily accessible racemic
counterparts (Scheme 1). Furthermore, the acidic nature of the
R-proton of dioxolanediones 2 presented us with an attractive
opportunity to develop an efficient dynamic kinetic resolution.7
Table 1. Preparations of 5-Substituted 1,3-Dioxolane-2,4-dionesa
Ideally the cinchona alkaloids could serve dual catalytic roles to
mediate both the enantioselective alcoholytic ring opening and the
in situ racemization of 2 (Scheme 2). We report here progress
toward achieving these goals.
Condensations of R-hydroxy acids with phosgene or one of its
equivalents represent a direct route for the preparation of diox-
olanediones 2. However, very few such condensations were
reported.8 In the best procedure, reported by Toyooka, reaction of
R-hydroxy acids with trichloromethyl chloroformate (diphosgene)
in refluxing THF produced 2 in 46-78% yield.8a Using this pro-
cedure, we found that R-hydroxy acids 1 reacted with diphosgene
cleanly. However, a significant amount of 4-chlorobutyl chloro-
formate was produced. A yield-compromising recrystalization or
distillation was required for the purification of 2. We performed
the condensation at room temperature with activated charcoal9 and
found that 2 was formed cleanly, while the amount of 4-chlorobutyl
chloroformate in the reaction mixture was reduced nearly 10-fold.
Filtration of the reaction mixture followed by solvent evaporation
afforded dioxolanediones 2a-n in high yield and greater than 95%
purity (Table 1).
We next focused on the kinetic resolution of 5-phenyl-1,3-
dioxolane-2,4-dione (2a). Reaction of racemic 2a with ethanol in
ether in the presence of (DHQD)2AQN (10 mol %) proceeded to
completion within 24 h at -78 °C. The enantiomeric excesses of
the product (3a) and the starting material (2a) were determined at
various conversions and were found to remain constant at 95% and
nearly 0%, respectively. In control experiments, we found that
treatment of optically pure 2a with (DHQD)2AQN generated the
corresponding racemic mixture within minutes. Also the
(DHQD)2AQN-catalyzed alcoholysis of either (R)- or (S)-2a gave
the same product, (R)-3a, in 95% ee. Neither racemization nor
alcoholysis occurred without the amine catalyst. These results
establish that (DHQD)2AQN serves a dual role, mediating both the
in situ racemization of 2a and the enantioselective alcoholysis of
entry
R
yield/% entry
R
yield/%
1
2
3
4
5
6
7
a
b
c
d
e
f
C6H5
100
100
100
100
100
100
100
8
9
h
i
j
k
l
m
n
1-naphthyl
2-Cl-C6H4
2-Me-C6H4
C6H5CH2
C6H5CH2CH2
CH3(CH2)3
(CH3)2CH
100
100
95
95
97
4-Cl-C6H4
4-Br-C6H4
4-F-C6H4
4-CF3-C6H4
4-iPr-C6H4
3,4-F2-C6H3
10
11
12
13
14
92
90
g
a See Supporting Information for experimental details.
(R)-2a. The racemization is much faster than the alcoholysis.
Consequently, both enantiomers of racemic 2a are converted to a
single optically active product (3a) via an efficient dynamic kinetic
resolution mediated by a single catalyst, (DHQD)2AQN.
Efficient dynamic kinetic resolutions by synthetic catalysts are
scarce.10-12 We were pleased to observe that efficient dynamic
kinetic resolutions were achieved for a variety of 5-aryl-1,3-
dioxolane-2,4-diones (2a-h, Table 2), affording esters 3a-h in
90-96% ee and isolated yields (65-85%) far exceeding the
maximum (50%) for a conventional kinetic resolution.13 The use
of (DHQD)2AQN consistently afforded (R)-3 as the only detectable
product by both GC and HPLC analysis. However, a NMR analysis
of the crude reaction mixture revealed the formation of minor side
products which are possibly H(OCHRCO)nOEt.8b The efficiency
of the dynamic kinetic resolution was reduced with dioxolanediones
(2i-j) bearing an o-substituted benzene ring (entry 9-10, Table
2). The ee of esters 3i-j was found to decrease gradually as the
reaction proceeded to completion (90 to 62% for 3i and 85 to 60%
for 3j). The initially high ee indicates that the alcoholyses of 2i-j
are still highly enantioselective. The reduced efficiency of the
9
2870 VOL. 124, NO. 12, 2002 J. AM. CHEM. SOC.
10.1021/ja0255047 CCC: $22.00 © 2002 American Chemical Society

C O M M U N I C A T I O N S
Table 2. Dynamic Kinetic Resolution of
of efficient catalytic dynamic kinetic resolutions, which remain
among the most challenging, yet desirable, goals in catalytic
asymmetric synthesis.11
5-Aryl-1,3-Dioxolane-2,4-Dionesa
Acknowledgment. We are grateful for financial support from
NIH (GM-61591) and the Harcourt General Charitable Foundation
and for a gift from Daiso.
Supporting Information Available: Experimental details (PDF).
This material is available free of charge via the Internet at
http://pubs.acs.org.
d
entry
R
R′OH
T/°C
time/h
yield/%
ee/%
b
1
2
3
4
5
6
7
8
9
a
b
c
d
e
f
g
h
i
C6H5
EtOH
EtOH
EtOH
EtOH
EtOH
EtOH
EtOH
nPrOH
EtOH
EtOH
-78
-78
-78
-78
-78
-20
-78
-40
-60
-20
24
24
24
24
24
8
24
14
10
4
71
70
80
65
85
68
65
74
66
61
95
96
96
95
93
91
94
91
62
60
4-Cl-C6H4
4-Br-C6H4
4-F-C6H4
4-CF3-C6H4
4-iPr-C6H4
3,4-F2-C6H3
1-naphthylc
2-Cl-C6H4
2-Me-C6H4
References
(1) Coppola, G. M.; Schuster, H. F. R-Hydroxy Acids in EnantioselectiVe
Synthesis; VCH: Weinheim, 1997.
(2) For methods using stoichiometric amounts of chiral reagents, see: (a)
D´ıez, E.; Dixon, D. J.; Ley, S. V. Angew. Chem., Int. Ed. 2001, 40, 2906.
(b) Crimmins, M. T.; Emmitte, K. A.; Katz, J. D. Org. Lett. 2000, 2,
2165. (c) Chang, J.-W.; Jang D.-P.; Uang, B.-J.; Liao, F.-L.; Wang, S.-L.
Org. Lett. 1999, 1, 2061. (d) Seebach D.; Jaeschke G.; Gottwald, K.;
Matsuda, K.; Formisano, R.; Chaplin, D. A. Tetrahedron 1997, 53, 7539.
(3) For enzyme-based methods, see: (a) Gro¨ger, H. AdV. Synth. Catal. 2001,
343, 547. (b) Zhang, W.; Wang, P. G. J. Org. Chem. 2000, 65, 4732. (c)
Huerta, F. F.; Laxmi, Y. R. S.; Ba¨ckvall, J.-E. Org. Lett. 2000, 2, 1037.
(d) Persson, B. A.; Larsson, L. E.; Ray, M. L.; Ba¨chvall, J.-E. J. Am.
Chem. Soc. 1999, 121, 1645. (e) Adam, W.; Lazarus, M.; Boss. B.; Saha-
Mo¨ller, C. R.; Humpf, H.-U.; Schreier, P. J. Org. Chem. 1997, 62, 7841.
(4) For catalytic asymmetric synthesis of cyanohydrins (precursors for
R-hydroxy acids), see: (a)Mori, A.; Inoue, S. Cyanation of Carbonyl and
Imino Groups. In ComprehensiVe Asymmetric Catalysis; Jacobsen, E. N.,
Pfaltz, A., Yamamoto, H., Eds.; Springer: Heidelberg, 1999; Chapter 28.
(b) Hamashima, Y.; Sawada, D.; Kanai, M.; Shibasaki, M. J. Am. Chem.
Soc. 1999, 121, 2641. (c) Hamashima, Y.; Kanai, M.; Shibasaki, M. J.
Am. Chem. Soc. 2000, 122, 7412. (d) Yabu, K.; Masumoto, S.; Yamasaki,
S.; Hamashima, Y.; Kanai, M.; Du, W.; Curran, D. P.; Shibasaki, M. J.
Am. Chem. Soc. 2001, 123, 9908. (e) Tian, S.-K.; Deng, L. J. Am. Chem.
Soc. 2001, 123, 6195.
10
j
a Unless noted, the reaction was performed with 2 (1.0 mmol) in ether
(50 mL) and went to completion, see Supporting Information for experi-
mental details. b When the reaction was performed with (DHQ)2AQN (20
mol %), S-3a was obtained in 73% yield and 88% ee. c This reaction was
perfomed in THF. R-3h was obtained in 88% ee with EtOH. d Isolated yield.
Table 3. Kinetic Resolution of 5-Alkyl 1,3-Dioxolane-2,4-dionesa
(5) For methods of asymmetric hydrogenations, see: (a) Burk, M. J. Acc.
Chem. Res. 2000, 33, 363. (b) Burk, M. J.; Kalberg, C. S.; Pizzano, A. J.
Am. Chem. Soc. 1998, 120, 4345. (c) Mashima, K.; Kusano, K.; Sato, N.;
Matsumura, Y.; Nozaki, K.; Kumobayashi, H.; Sayo, N.; Hori, Y.; Ishizaki,
T.; Akutagawa, S.; Takaya, H. J. Org. Chem. 1994, 59, 3064.
(6) (a) Hang, J.; Tian, S.-K.; Tang, L.; Deng, L. J. Am. Chem. Soc. 2001,
123, 12696. (b) Choi, C.; Tian, S.-K.; Deng, L. Synthesis 2001, 1737. (c)
Chen, Y.; Deng, L. J. Am. Chem. Soc. 2001, 123, 11302. (d) Chen, Y.;
Tian, S.-K.; Deng, L. J. Am. Chem. Soc. 2000, 122, 9542.
(7) For a pioneering study of dynamic kinetic resolutions of azlactones, see:
Liang, J.; Ruble, J. C.; Fu, G. C. J. Org. Chem. 1998, 63, 3154.
(8) (a) Toyooka, K.; Takeuchi, Y.; Kubota, S. Heterocycles 1989, 29, 975.
(b) Davies, W. H. J. Chem. Soc. 1951, 1357.
(9) Activated charcoal is known to promote the decomposition of diphosgene
to phosgene, see: Katakai, R.; Iizuka, Y. J. Org. Chem. 1985, 50, 715.
(10) (a) Noyori, R.; Ikeda, T.; Ohkuma, T.; Widhalm, M.; Kitamura, M.;
Takaya, H.; Akutagawa, S.; Sayo, N.; Saito, T.; Taketomi, T.; Kumoba-
yashi, H. J. Am. Chem. Soc. 1989, 111, 9134. (b) Kitamura, M.; Tokunaga,
M.; Noyori, R. J. Am. Chem. Soc. 1993, 115, 144.
ee (yield)b/%
entry
R
R′
Et
Et
Et
time/h
S-1
R-3
sc
1
2
3
4
k
l
m
n
PhCH2
12
24
36
6
95 (39)
85 (40)
95 (36)
93 (32)
96 (47)
93 (46)
92 (46)
90 (48)
133
67
57
PhCH2CH2
CH3(CH2)3
(CH3)2CH
Allyl
49
a The reaction was perfromed with 2 (1.0 mmol) in ether (50 mL), see
Supporting Information for experimental details. b Isolated yield. c The lower
limit of the selectivity factor s was estimated using the equation s ) kf/ks
) ln[1 - C(1 + ee)]/ln[1 - C(1 - ee)], where ee is the percent enantiomeric
excess of the product 3 and the isolated yield of 3 was used as the value
for C (conversion of the reaction).
(11) (a) Faber, K. Chem. Eur. J. 2001, 7, 5005. (a) Caddick, S.; Jenkins, K.
Chem. Soc. ReV. 1996, 25, 447. (b) Ward, R. S. Tetrahedron: Asymmetry
1995, 6, 1475. (c) Noyori, R.; Tokunaga, M.; Kitamura, M. Bull. Chem.
Soc. Jpn. 1995, 68, 36.
(12) For a dynamic kinetic resolution of epichlorohydrin, see: Schaus, S. E.;
Jacobsen, E. N. Tetrahedron Lett. 1996, 37, 7937.
(13) For examples of deracemizations other than dynamic kinetic resolution
processes, see: (a) Feng, X.; Shu, L.; Shi, Y. J. Am. Chem. Soc. 1999,
121, 11002. (b) Trost B. M.; Bunt, R. C.; Lemoine, R. C.; Calkins, T. L.
J. Am. Chem. Soc. 2000, 122, 5968. (c) Trost, B. M.; Toste, F. D. J. Am.
Chem. Soc. 1999, 121, 3543. (d) Trost, B. M.; McEachern, E. J.; Toste,
F. D. J. Am. Chem. Soc. 1998, 120, 12702. (e) Trost B. M. Acc. Chem.
Res. 1996, 29, 355. (f) Orru, R. V. A.; Mayer, S. F.; Kroutil, W.; Faber,
K. Tetrahedron 1998, 54, 859.
(14) The repulsion shown below between the ortho substituent and the dioxo-
lanedione ring renders enolates derived from 2i-j less stable than those
derived from 2a-g. This in turn slows down the racemizations of 2i-j.
dynamic kinetic resolution is therefore caused by the slow racem-
izations of 2i-j relative to their alcoholyses.14 The enantioselectivity
of the reaction remains high when the aryl groups in 2 are replaced
by alkyl groups of various length and bulk (Table 3). Although the
reduced acidity of the R-proton renders 2k-n unepimerizable with
(DHQD)2AQN, the highly enantioselective ring opening of 2
afforded both S-2 and R-3 in high optical purity. The crude mixture
containing 2 and 3 was subjected to hydrolysis to give a mixture
of acid 1 and ester 3. Both 1 and 3 were obtained in excellent ee
and good yields following an extractive purification (Table 3).
In summary, we have developed a new catalytic approach toward
optically active R-hydroxy acid derivatives via a highly enantiose-
lective kinetic resolution of dioxolanediones 2. The reaction
employs accessible substrates, reagents, catalysts, and a simple
protocol with mild conditions. The realization of an efficient
dynamic kinetic resolution of 5-aryl-1,3-dioxolane-2,4-diones with
a chiral amine-catalyzed acyl-transfer reaction is conceptually
interesting. It adds a new dimension to the scope of asymmetric
acyl-transfer catalysis by synthetic catalysts.3c-d,11,15 The demonstra-
tion of a chiral organic Lewis base as a dual-function catalyst
provides experimental proof for a new approach for the development
(15) For dynamic kinetic resolutions with hydrolytic enzymes, see: (a) Pesti,
J. A.; Yin, J.; Zhang, L.-H.; Anzalone, L. J. Am. Chem. Soc. 2001, 123,
11075. (b) Um, P.-J.; Drueckhammer, D, G. J. Am. Chem. Soc. 1998,
120, 5605. (c) Tan, D. S.; Gunter, M. M.; Drueckhammer, D. G. J. Am.
Chem. Soc. 1995, 117, 9093.
JA0255047
9
J. AM. CHEM. SOC. VOL. 124, NO. 12, 2002 2871