Enantioselective synthesis of beta-hydroxy acid derivatives via a one-pot aldol reaction-dynamic kinetic resolution.

Article abstract of DOI:10.1021/ol015682p

[reaction: see text]. Combining dynamic kinetic resolution with an aldol reaction provides access to beta-hydroxy ester derivatives with high enantiomeric purity (up to 99% ee) in a one-pot procedure. Only simple starting materials are required in this enantioselective process, and preformation of a silyl enol ether is not necessary.

Full text of DOI:10.1021/ol015682p

ORGANIC
LETTERS
2001
Vol. 3, No. 8
1209-1212
Enantioselective Synthesis of â-Hydroxy
Acid Derivatives via a One-Pot Aldol
Reaction−Dynamic Kinetic Resolution
Fernando F. Huerta and Jan-E. Ba1ckvall*
Department of Organic Chemistry, Arrhenius Laboratory, Stockholm UniVersity,
SE-106 91 Stockholm, Sweden
jeb@organ.su.se
Received February 8, 2001
ABSTRACT
Combining dynamic kinetic resolution with an aldol reaction provides access to â-hydroxy ester derivatives with high enantiomeric purity (up
to 99% ee) in a one-pot procedure. Only simple starting materials are required in this enantioselective process, and preformation of a silyl
enol ether is not necessary.
The aldol reaction is one of the most important methods for
the construction of new carbon-carbon bonds.1 In these
reactions, control of diastereo- and enantioselectivity has
attracted much attention. There are two main routes for
controlling the stereochemical outcome in the aldol reaction;
the use of asymmetrically modified enolates or electrophiles
(chiral auxiliary)2 and the use of chiral Lewis acids (Scheme
1).3 The former method relies on the use of stoichiometric
amounts of chiral material, an obvious drawback due to the
necessity of an additional step to recover the chiral auxiliary.
In the latter method catalytic amounts of a chiral Lewis acid
are sufficient to efficiently control diastereo- and enantio-
selectivity in the aldol process (Mukaiyama type reactions4).
However, the enolate has to be preformed and isolated as a
silyl enol ether prior to the reaction (Scheme 1).4d,5
Herein, we report on a novel combination of an aldol
reaction and a dynamic kinetic resolution (DKR) of the
corresponding adduct.6 This one-pot tandem procedure allows
the enantioselective synthesis of â-hydroxy acid derivatives
from an aldehyde and a ketone and does not require the
isolation of a preformed silyl enol ether (Scheme 2).
(1) Review: (a) Mahrwald, R. Chem. ReV. 1999, 99, 1095-1120. (b)
Machajewski, T. D.; Wong, C.-H. Angew. Chem., Int. Ed. 2000, 39, 1352-
1374. (c) Nelson, S. G. Tetrahedron: Asymmetry 1998, 9, 357-389. (d)
Gro¨ger, H.; Vogl, E. M.; Shibasaki, M. Chem. Eur. J. 1998, 4, 1137-
1141.
(2) See, for example: (a) Solladie´-Cavallo, A.; Csaky, A. G. J. Org.
Chem. 1994, 59, 2585-2589. (b) Ahn, M.; Tanaka, K.; Fuji, K. J. Chem.
Soc., Perkin Trans. 1 1998, 185-192.
(3) Eliel, E. L.; Wilen, S. H. Stereochemistry of Organic Compounds;
Wiley: New York, 1994; p 835.
Scheme 1. Asymmetric Aldol Reactions
(4) (a) Mukaiyama, T. Angew. Chem., Int. Ed. Engl. 1977, 16, 817-
826. (b) Kobayashi, S.; Uchiro, H.; Fujishita, I.; Shiina, I.; Mukaiyama, T.
J. Am. Chem. Soc. 1991, 113, 4247-4252. (c) Kobayashi, S.; Horibe, M.
Chem. Eur. J. 1997, 3, 1472-1481. (d) For an early report on direct catalytic
asymmetric aldol reactions of aldehydes with isocyanoacetate giving high
ee’s, see: Ito, Y.; Sawamura, M.; Hayashi, T. J. Am. Chem. Soc. 1986,
108, 6405-6406.
(5) Recently, procedures for direct catalytic asymmetric aldol reactions
have been reported: (a) Yoshikawa, N.; Yamada, Y. M. A.; Das, J.; Sasai,
H.; Shibasaki, M. J. Am. Chem. Soc. 1999, 121, 4168-4178. (b) List, B.;
Lerner, R. A.; Barbas, C. F., III. J. Am. Chem. Soc. 2000, 122, 2395-
2396. (c) Trost, B. M.; Ito, H. J. Am. Chem. Soc. 2000, 122, 12003-12004.
10.1021/ol015682p CCC: $20.00 © 2001 American Chemical Society
Published on Web 03/20/2001

Scheme 2
To our knowledge, DKR of â-hydroxy esters has not been
(Scheme 2). We therefore focused on a one-pot procedure
in which the aldol adduct is generated in situ and allowed
to reach full conversion, followed by a DKR without prior
isolation of the aldol adduct. For this purpose the best option
is to run the aldol reaction under kinetic control using a
strong base such as lithium diisopropylamine (LDA) to obtain
complete enolate formation followed by reaction with the
aldehyde. This suggests that polar solvents such as tetrahy-
drofuran (THF) or ethyl ether (Et2O) have to be used at low
temperature. On the other hand, the DKR works better in
nonpolar solvents in a temperature range of 60-80 °C.
reported but their kinetic resolution (KR) is known.7,8 This
is mainly due to the problems of isomerizing chiral â-hy-
droxy esters. An obvious limitation with KR is that the
maximum theoretical yield of one enantiomer is 50% vs
100% with DKR.9 Preliminary experiments indicated that
chiral â-hydroxy esters undergo slow ruthenium-catalyzed
isomerization, and it was found that this isomerization could
be combined with enzymatic acylation. Thus, racemic
â-hydroxy ester 1a was transformed to compound 2a in 70%
yield and 93% ee after 72 h using ruthenium catalyst 3,10
Pseudomonas cepacia lipase (PS-C type II from Amano),
and p-chlorophenyl acetate6b as the acyl donor in cyclohexane
at 60 °C (Scheme 3). This result prompted us to develop
conditions for a one-pot synthesis of compound 2a starting
from the aldol precursors.
Another important factor is that, after the aldol reaction,
the â-hydroxy ester has to be in its neutral form. Attempts
to carry out the DKR reaction starting from the alkoxide
resulted in low conversion and poor ee’s; thus, a source of
protons after the aldol coupling is needed.
The desired coupled process in which the aldol adduct
formed is continuously undergoing a dynamic kinetic resolu-
tion (DKR) seemed difficult due to incompatibility of the
reagents and reaction conditions between the two processes.
For example, the ruthenium catalyst 3 would interfere with
the aldehyde, and the use of silyl enol ether would lead to a
â-silylated adduct, which cannot racemize in the DKR
Taking into account all these considerations, various
solvents were tested in the aldol reaction (Table 1). The best
results were obtained with either THF or Pri2O as solvent,
which gave full conversion to the desired compound (Table
1, entries 1 and 3). Et2O gave a slightly lower conversion
(entry 2). In the other cases (entries 4-6), the low conversion
achieved in the coupling reaction made us reject the use of
these solvents for the tandem process.
(6) For examples involving DKR of secondary alcohols, see: (a) Dinh,
P. M.; Howarth, J. A.; Hudnott, A. R.; Williams, J. M. J. Tetrahedron Lett.
1996, 37, 7623-7626. (b) Larsson, A. L. E.; Persson, B. A.; Ba¨ckvall, J.-
E. Angew. Chem., Int. Ed. Engl. 1997, 36, 1211-1212. (c) Persson, B. A.;
Larsson, A. L. E.; LeRay, M.; Ba¨ckvall, J.-E. J. Am. Chem. Soc. 1999,
121, 1645-1650. (d) Persson, B. A.; Huerta, F. F.; Ba¨ckvall, J.-E. J. Org.
Chem. 1999, 64, 5237-5249. (e) Choi, Y. K.; Suh, J. H.; Lee, D.; Lim, I.
T.; Jung, J. Y.; Kim, M.-J. J. Org. Chem. 1999, 64, 8423-8424. (f) Koh,
J. H.; Jung, H. M.; Kim, M.-J.; Park, J. Tetrahedron Lett. 1999, 40, 6281-
6284. (g) Jung, H. M.; Koh, J. H.; Kim, M.-J.; Park, J. Org. Lett. 2000, 2,
409-411. (h) Huerta, F. F.; Laxmi, Y. R. S.; Ba¨ckvall, J.-E. Org. Lett.
2000, 2, 1037-1040.
When combining the aldol reaction with the DKR, two
additional problems have to be overcome: the DKR works
Scheme 3. Dynamic Kinetic Resolution of the â-Hydroxy
Ester 1a
(7) (a) Kaga, H.; Hirosawa, K.; Takahashi, T.; Goto, K. Chirality 1998,
10, 693-698. (b) Akita, H.; Chen, C. Y.; Nagumo, S. Tetrahedron:
Asymmetry 1994, 5, 1207-1210. (c) Akita, H.; Matsukura, H.; Oishi, T.
Jpn. Kokai Tokkyo Koho JP 63063398 A2 19880319 Showa, 1988, 19 pp.
(8) Kazutoshi, M.; Naoyuki, Y. (Chisso Corp., Japan). Eur. Pat. Appl.
EP 451668 A2 19911016, 1991, 12 pp.
(9) For reviews on DKR, see: (a) Ward, R. S. Tetrahedron: Asymmetry
1995, 6, 1475-1490. (b) Noyori, R.; Tokunaga, M.; Kitamura, M. Bull.
Chem. Soc. Jpn. 1995, 68, 36-56. (c) Caddick, S.; Jenkins, K. Chem. Soc.
ReV. 1996, 25, 447-456. (d) Stecher, H.; Faber, K. Synthesis 1997, 1-16.
(e) El Gihani, M. T.; Williams, J. M. J. Curr. Opin. Chem. Biol. 1999, 3,
11-15. (f) Strauss, U. T.; Felfer, U.; Faber, K. Tetrahedron: Asymmetry
1999, 10, 107-117.
(10) (a) Blum, Y.; Czarkie, D.; Rahamim, Y.; Shvo, Y. Organometallics
1985, 4, 1459-1461. (b) Shvo, Y.; Czarkie, D.; Rahamin, Y. J. Am. Chem.
Soc. 1986, 108, 7400-7402. (c) Menashe, N.; Shvo, Y. Organometallics
1991, 10, 3885-3891.
1210
Org. Lett., Vol. 3, No. 8, 2001

Table 1. Solvent Effect in the Synthesis of 1aa
Scheme 4
entry
solvent
convn (%)
1
2
3
4b
5b
6b
THF
Et2O
Pri2O
TBME
PhCH3
hexane
>99
95
>99
46
traces
16
3) were easily recovered. The lipase was filtered off and
washed with TBME several times, without loss of activity.14
The ruthenium catalyst 3 was recovered in 75% yield from
the reaction mixture by crystallization from dichloromethane/
Et2O. This result provides a new and an economical
alternative for the chemoenzymatic enantioselective synthesis
of â-hydroxy esters. These compounds are versatile building
blocks for chiral synthesis,15,16 and compound 2a is a
progenitor for the antidepressant drugs tomoxetine and
fluoxetine (Prozac, Eli Lilly Co.).16
a Unless otherwise noted, all the reactions were carried out by adding
ethyl acetate to a 0.3 M solution of LDA (1 equiv) at -78 °C. After 1 h,
benzaldehyde (1 equiv) was added at the same temperature and the mixture
was stirred for 0.5-1 h. b After the benzaldehyde addition, the reaction
was allowed to reach rt over 2 h.
better in TBME (tert-butyl methyl ether)11 as solvent,
whereas the aldol reaction does not (Table 1, entry 4).
Furthermore, the presence of diisopropylamine (DIPA) as a
base after the deprotonation of the corresponding ester with
LDA has a negative effect on the outcome of the reaction.
Lipase-mediated acetylation of the aldol adduct leads to an
acetate (2a), which is sensitive toward base-catalyzed
â-elimination.12 In fact, the aldol coupling in Pri2O between
ethyl acetate (4) and benzaldehyde (5a) followed by in situ
DKR without neutralizing the base gave the olefin 6 as a
single reaction product.
This new one-pot tandem reaction was applied to different
substrates (Scheme 4, Table 2). The success of the procedure
Table 2. One-Pot Aldol Coupling-DKRa
entry
R
aldol adduct product yield (%)b ee (%)c
1
2
3
4
Ph
1a
1b
1c
1d
2a
2b
2c
2d
73 (76)
69 (74)
75 (80)
71 (82)d
95
99
96
70
p-MeO-C6H4
PhCH2
Cy
a For a typical experiment, see ref 12. b Isolated yield with respect to 5.
In parentheses isolated yields obtained in the DKR from purified 1 are given.
c The ee of product 2 was determined by GC equipped with a CP-Chirasil-
Dex CB column. d Kinetic resolution of 1d with PS-C (60 mg/mmol) and
p-ClC6H4OAc (3 equiv) in TBME (8 mL/mmol) at 60 °C gave 22% yield
1
after 48 h (calculated by H NMR) and 70% ee.
Finally, the combined reaction was carried out by enolate
formation and coupling with the corresponding aldehyde 5a
in THF at low temperature. Once the aldol adduct 1a was
formed, the THF was removed in vacuo and the residue
dissolved in TBME and transferred to a suspension of lipase
(PS-C), acyl donor, and ruthenium catalyst 3 in TBME
(Scheme 4, Table 1).13 Compound 2a was isolated in 73%
yield (from 5a) and 95% ee. Both catalysts (PS-C lipase and
is highly dependent on the enzymatic resolution. The
substrate requirements for an efficient kinetic resolution are
that there are two groups with different sizes next to the
stereocenter.17 Moreover, the size of these geminal groups
cannot exceed the size of the active pocket in the enzyme.
Considering these restrictions, several compounds, 2a-d,
were synthesized from ester 4 and aldehydes 5a-d via the
coupled aldol reaction-DKR process. The results of these
one-pot tandem reactions are summarized in Table 2.
Although the presence of electron-donating groups in the
(11) TBME was chosen as solvent for the DKR due to the high
enantiomeric ratio (E > 200) obtained with the PS-C lipase for our model
substrate in this solvent.
(12) In the case of benzylic acetates, the elimination leads to a highly
conjugated double bond.
(14) The kinetic resolution of compound 1a with the recovered enzyme
gave the same E value. ee ) enantiomeric excess of substrate (S) or product
(P) and E ) enantiomeric ratio
(13) In a typical experiment n-BuLi (1 equiv, 0.625 mL of 1.7 M solution
in hexane) was added over DIPA (1 mmol, 0.166 mL) in THF (3 mL) in
a Schlenk tube. The mixture was cooled to -78 °C, and ethyl acetate (1
equiv, 0.098 mL) was added dropwise. After 50 min benzaldehyde (0.8
equiv, 0.082 mL) was added dropwise to the solution and the reaction stirred
for 30 min. Then, after hydrolysis with a saturated NH4Cl solution at 0 °C
(5.5 M solution, 2 equiv), the solvent was evaporated and the resulting
reaction crude dissolved in TBME (6 mL) and transferred to another Schlenk
containing a suspension of PS-C (48 mg, 60 mg/mmol), p-ClC6H4OAc (3
equiv, 0.409 g), and Ru catalyst 3 (6 mol %, 52 mg) in TBME (2 mL). The
resulting mixture was stirred at 60 °C (bath temperature) during 6 d. The
enzyme was filtered off from the reaction mixture and washed with TBME
(3 × 10 mL), the solvent evaporated, and the catalyst 3 recovered by
crystallization in CH2Cl2/Et2O. 2a was purified by flash chromatography
(pentane/Et2O).
[eep (1 - ees)]
ln
(eep + ees)
E )
[eep (1 + ees)]
ln
(eep + ees)
(15) Rodr´ıguez, S.; Schroeder, K. T.; Kayser, M. M.; Stewart, J. D. J.
Org. Chem. 2000, 65, 2586-2587.
(16) (a) Boaz, N. W. J. Org. Chem. 1992, 57, 4289-4292 and references
therein. (b) Kumar, A.; Ner, D. H.; Dike, S. Y. Tetrahedron Lett. 1991, 32,
1901-1904.
(17) Carrea, G.; Riva, S. Angew. Chem., Int. Ed. 2000, 39, 2226-2254
and references therein.
Org. Lett., Vol. 3, No. 8, 2001
1211

aromatic ring has been observed previously to have a
negative effect on the racemization process,6c the enantio-
selection in this particular case was excellent, >99% ee (entry
2), and compound 2b was isolated in 69% yield (based on
aldehyde 5b). Attempts to obtain enantio- and diastereo-
selection in compounds 2 with a methyl group in the
R-position have so far been fruitless, due to the increased
bulkiness next to the stereocenter (vide supra).7c,18 Substitu-
tion of the phenyl group in benzaldehyde (5a) with a benzyl
group also resulted in an efficient DKR (entry 3). Cyclohexyl
derivative 2d (entry 4) gave a low ee compared to that of
aryl compounds 2a-c. Although the enantioselectivity can
be slightly improved (80% ee) using less enzyme, the
reaction time increased dramatically (50% conversion after
7 days). Comparing the result obtained by DKR with that
obtained by KR of compound 1d (22% yield and 70% ee),
we can note the efficiency of the dynamic process vs the
traditional kinetic resolution.
In summary, we have demonstrated that the ruthenium-
and enzyme-catalyzed DKR in tandem with carbon-carbon
bond-forming reactions such as the aldol addition reaction
is a valuable tool for asymmetric synthesis. The procedure
reported here should be a useful complement to previous
methodology since enantiomerically pure aldol adducts
lacking an R substituent (cf. 2a-d) are difficult to obtain
with catalytic asymmetric aldol reactions19 and also because
this procedure does not require access to preformed silyl
enolates.5 Moreover, the easy handling of the chemicals
employed and recovery of both catalysts makes this system
suitable for upscaling.
(18) Kinetic resolution by acetate hydrolysis of methyl esters similar to
compounds 2 having a methyl group in the R-position is known: Akita,
H.; Chen, C. Y.; Nagumo, S. Tetrahedron: Asymmetry 1994, 5, 1207-
1210.
(19) For recent catalytic aldol reactions with preformed nonsubstituted
silyl enol ethers giving high ee’s, see: (a) Singer, R. A.; Carreira, E. M.
Tetrahedron. Lett. 1997, 38, 927-930. (b) Carreira, E. M. Recent advances
in asymmetric aldol addition reactions. In Catalytic Asymmetric Synthesis,
2nd ed.; Ojima, I. Ed.; Wiley-VCH: New York, 2000; pp 513-541.
Acknowledgment. AstraZeneca R&D, Mo¨lndal, and the
Swedish Foundation for Strategic Research are gratefully
acknowledged for financial support. We thank Amano
Pharmaceutical Co. Ltd. for a generous gift of lipases.
OL015682P
1212
Org. Lett., Vol. 3, No. 8, 2001