A highly chemo- and stereoselective synthesis of β-keto esters via a polymer-supported lipase catalyzed transesterfication

Full text of DOI:10.1021/jo001478o

1906
J . Org. Chem. 2001, 66, 1906-1909
Sch em e 1
A High ly Ch em o- a n d Ster eoselective
Syn th esis of â-Keto Ester s via a
P olym er -Su p p or ted Lip a se Ca ta lyzed
Tr a n sester fica tion
Armando Co´rdova and Kim D. J anda*
informative it was narrow in scope. Expansion on this
theme using methyl or ethyl â-keto esters as the acyl
donors would give a broader range of compounds. Fur-
thermore, these structures could be synthesized in com-
bination with the kinetic resolution of secondary alcohols
so as to achieve a direct route to chiral â-keto esters. We
now report a general method that avoids the use of bulk
solvent wherein a range of alcohols were reacted with
methyl or ethyl â-keto esters to obtain the desired
transesterified products in excellent yield and with high
chemo- and stereoselectivity.
Department of Chemistry and The Skaggs Institute for
Chemical Biology, The Scripps Research Institute, 10550
North Torrey Pines Road, La J olla, California 92037
kdjanda@scripps.edu
Received October 13, 2000
In tr od u ction
A new research effort from our laboratory concerned
the [3,3] sigmatropic rearrangement of allylic â-keto
esters.1 As such, we required a general method of
synthesizing these compounds both as racemates and
single enantiomers. â-Keto esters are noteworthy in that
they represent an important class of organic building
blocks used in the synthesis of complex natural products.2
A seemingly straightforward method to prepare these
molecules is through an alcohol-based transesterifica-
tion.3 Yet the synthesis of allylic and propargylic â-keto
esters is not trivial by this route due to their acid/base
lability and sigmatropic rearrangement of the â-keto
ester.4,5 To circumvent these problems, a report has
appeared describing the heating of alcohols with â-keto
esters in toluene.4 However, the reaction times were
lengthy and yields variable for many of the substrates.
Another mild method uses crystalline microporous nano-
silicates (zeolites) as the catalyst for the transesterifica-
tion in refluxing toluene to avoid potential side reactions,
but here the yields were even lower compared to the
former case.5 Furthermore, none of these or any of the
conventional methods display stereoselectivity or chemose-
lectivity between aliphatic alcohols or phenols.
The catalyst used in our study was Candida antarctica
lipase B (CALB) immobilized on a macroporous resin. We
used an immobilized lipase as it enables ease of handling
and recovery of the catalyst (Scheme 1). The simplicity
of our method is demonstrated in the following typical
experiment. A homogeneous mixture of alcohol (5 mmol)
and â-keto ester (40 mmol) was treated with 10% (w/w
of alcohol) of the catalyst and swirled in a flask connected
to a Bu¨chi rotavapor at 40 °C and 10 Torr.8 After 8 h,
the reaction mixture was filtered, rinsed (CH2Cl2), con-
centrated, and purified by chromatography to yield the
desired product (Table 1). The immobilized lipase could
be reused without loss of activity by first washing the
beads with CH2Cl2 and then drying them in a desiccator.
Because a one-pot operation was used, we were able to
further generalize our studies such that reactions were
also performed in parallel by the use of a vaccum oven.
Furthermore, this strategy could be used to create a
lipase-catalyzed â-keto ester library. In virtually all cases
we investigated, excellent results were obtained, gener-
ally superior to those found in the literature.3-5
Both primary and secondary alcohols were appropiate
substrates for the lipase as were allylic and propargylic
alcohols. Interestingly, the lipase also efficiently acylated
the polymer poly(ethylene glycol) monomethyl ether
(MeO-PEG5000) (entry 6). The ability of CALB to use MeO-
PEG5000 as a substrate is noteworthy in that it can
provide a variety of â-keto ester terminated PEGs that
could be used as starting points in a polymer supported
synthesis of heterocycles.9 Using 8, chemoselectivity
between a phenol and alcohol was examined. The exclu-
sive formation of 24 elucidates CALB’s chemoselectivity
for alkyl alcohols compared to phenols. CALB was also
able to utilize the well-known annelating reagent ethyl
3-oxo-4-pentenoate (15, Nazarov’s reagent) as an acyl
donor to form 27 in excellent yield (entry 11).10 This
procedure could be applied for the one-step preparation
of various annelating agents (3-oxo-4-pentenoate esters),
since they do not have to be individually prepared from
Resu lts a n d Discu ssion
Lipases are a class of serine hydrolases that can exhibit
excellent stereoselectivity and good catalytic activity for
transesterification reactions in organic solvents.6 Hence,
lipases could be viewed as candidates for the preparation
of chiral â-keto esters. Indeed, using diketene as the acyl
donor, the synthesis of chiral acetoacetate esters by lipase
catalysis was recently reported.7 While this study was
* To whom correspondence should be addressed. Tel: (858) 784 2516.
Fax: (858) 784 2595.
(1) Carroll, F. M. J . Chem. Soc. 1940, 1226.
(2) Benetti, S.; Romagnoli, R.; De Risi, C.; Spalluto, G.; Zanirato,
V. Chem. Rev. 1995, 95, 1065.
(3) (a) Gilbert, J . G.; Kelly, T. A. J . Org. Chem. 1988, 53, 449. (b)
Taber, D. F.; Ameido, J . C., J r.; Patel, Y. K. J . Org. Chem. 1985, 50,
3618.
(4) Mottet, C.; Hamelin, O.; Garavel, G.; Depre´s, J .-P.; Greene, A.
J . Org. Chem. 1999, 64, 1380.
(5) Balaji, B. S.; Sashicharan, M.; Kumar, R.; Chanda, R. J . Chem.
Soc. Chem. Commun. 1996, 707.
(6) (a) Wong, C. H.; Whitesides, G. M. Enzymes in synthetic organic
chemistry; Tetrahedron Organic Chemistry Series Vol. 12.; Baldwin,
J . E., Ed.; Pergamon Press: New York, 1994. (b) Faber, K. Biotrans-
formations in Organic Chemistry. A Textbook, 2nd ed; Springer-
Verlag: New York, 1995.
(7) Suginaka, K.; Hayashi, Y.; Yamamoto, Y. Tetrahedron: Asym-
metry 1996, 4, 1153.
(8) Under these conditions, the liberated EtOH or MeOH, known
inhibitors of lipases, are removed by evaporation.
(9) Gordeev, M. F.; Patel, D. V.; Wu, J .; Gordon, E. M. Tetrahedron
Lett. 1996, 37, 4643.
(10) Nazarov, I. N.; Zavyalov, S. I. Zh. Obshch. Khim. 1953, 23, 1703;
Engl. Transl. 1953, 23, 1793.
10.1021/jo001478o CCC: $20.00 © 2001 American Chemical Society
Published on Web 02/02/2001

Notes
J . Org. Chem., Vol. 66, No. 5, 2001 1907
Ta ble 1. Tr a n sester ifica tion s of Alcoh ols a n d Meth yl or Eth yl Acetoa ceta tes Ca ta lyzed by CALBa
a
b
No reaction occurred in the absence of catalyst, and the catalyst could be reused without loss of activity. R ) CH3 or CH2CH3. c All
new compounds gave satisfactory spectral data (1H NMR, 13C NMR, and HRMS). Isolated yield.
d
the corresponding acetate ester (two steps).11 Further-
more, it should be noted that attempts to prepare 27 by
conventional methods using the 5-acyl derivative of
Meldrum’s acid were unsuccessful.12
To investigate CALB’s ability to resolve racemic sec-
ondary alcohols, reactions were run with mixtures of the
alcohol (5 mmol) and â-keto ester (7.5 mmol) to which
10% (w/w of alcohol) of the catalyst was added. After 1.5
h (∼50% conversion of the alcohol), the reaction was
stopped by filtration of the immobilized lipase and
worked up in a similar manner as detailed (vide supra).
CALB displayed good E values13 for all of the tested
alcohols, and the ee values were above 90% (Table 2).
The successful formation of (R)-33 demonstrates that the
method could be a direct starting point for transfer of
chirality in nonracemic cyclic and acyclic systems.1,14
(13) E ) enantiomeric ratio. Chen, C.-S.; Fujimoto, Y.; Girdaukas,
G.; Sih, C. J . J . Am. Chem. Soc. 1982, 104, 7294.
(14) (a) Hill, R. K. Asymmetric Synthesis; Academic Press: Orlando,
1984; Vol. 3, p 503. (b) Ziegler, F. E. Chem. Rev. 1988, 88, 1423. (c)
Tanabe, M.; Hayashi, K. J . Am. Chem. Soc. 1980, 102, 862. (d) Koreeda,
M.; Brown, L. J . Org. Chem. 1983, 48, 2122.
(11) Zibuck, R.; Streiber, J . M. J . Org. Chem. 1989, 54, 4717.
(12) Oikawa, Y.; Sugano, K.; Yonemitsu, O. J . Org. Chem. 1978, 43,
2087.

1908 J . Org. Chem., Vol. 66, No. 5, 2001
Notes
Ta ble 2. Kin etic Resolu tion of sec-Alcoh ol Ra cem a tes w ith Meth yl Acetoa ceta te Ca ta lyzed by CALB
a
b
The absolute configuration was based on the optical rotation, which was in accordance with those in the literature. Determined by
using chiral HPLC on a Chiralcel OD-H column (hexane/ 2-propanol mixtures, λ ) 254 nm). c Determined on the alcohol corresponding
to the acetoacetate formed,7 by using chiral HPLC on a Chiralcel OD-H column. E ) ln[1 - c(1 + eep)/ln[1 - c(1 - eep), c ) ees/ees
+
d
eep.16 e Isolated yield.
a 50-mL flask connected to a Bu¨chi rotavapor at 40 °C and 10
Torr. For entries 9-12 (Table 1), the ratio was 1.2:1 between
alcohol and â-ketoester, respectively. After 8 h, 20 mL of
CH2Cl2 was added and the polymer-supported lipase removed
by filtration. The solvent was removed under reduced pressure
and the crude product purified by silica gel column chromatog-
raphy with increasing amounts of EtOAc in hexane. The spectral
data for 17-19 and 21 were in accordance with those reported
in the literature.3-5,18
Lip a se-Ca ta lyzed P a r a llel Rea ction s. Vials containing
different mixtures of alcohols (1 mmol) and â-ketoesters (8 mmol)
together with 10 mg of CALB were placed in a vaccum oven at
40 °C and 10 Torr. After 24 h, 3 mL of CH2Cl2 was added to
each vial and the lipase filtered. The workup was performed as
described (vide supra).
Furthermore, this protocol presents an additional ad-
vantage to previous methods utilizing diketene as the
acyl donor for the lipase,7,15 since it can accommodate a
greater variety of acyl donors (i.e., â-keto esters).
In summary, we have described the first general route
to prepare â-keto esters by a lipase-catalyzed transes-
terification. We believe our methodology will be of ample
use due to its mild, solvent-free conditions. Moreover, it
also provides a simple scheme to optically active â-keto
esters that are useful building blocks and starting
materials for natural product synthesis.2,14c,d,16
Exp er im en ta l Section
Lip a se-Ca ta lyzed Kin etic Resolu tion s. The reactions were
performed as described for the lipase-catalyzed transesterifica-
tions (vide supra), except with a ratio of 3:2 between â-ketoester
and alcohol and reacted for 1.5 h (∼50% conversion). Due to
solubility problems, the ratio was 4:1 for alcohol 31. The spectral
data for (R)-32 and (R)-34 were in accordance with those
reported in the literature.7
Gen er a l Meth od s. Methyl and ethyl acetoacetate were
obtained from Aldrich Chemical Co. and distilled prior to use.
â-Ketoester 14 and Nazarov’s reagent 15 were synthesized
according to literature procedures.10,17 Chiral HPLC analyses
were carried out using a Daicel Chiralcel OD Column (250 mm,
4.6 mm, eluent: hexane/2-Propanol). Column chromatography
purification was done using Merck 60 silica gel (particle size
0.04-0.063 mm). The lipase (component B) Novozym 435 derived
from C. antarctica is a product of Novo Nordisk A/S Denmark.
Hex-2-yn yl 3-oxobu ta n oa te (20): chromatography, EtOAc/
1
hexane 10:40 f 10:30; H NMR (250 MHz, CDCl3) δ 0.95 (t, J
) 7.3 Hz, 3H), 1.51 (m, 2H, 2.26 (s, 3H), 3.47 (s, 2H), 4.71 (bs,
The enzyme used was an immobilized preparation on
a
2H); 13C NMR (125 MHz, CDCl3) δ 200.3, 166.7, 88.4, 73.7, 53.9,
macroporous poly(propylene) resin, containing 1% (w/w) enzyme,
with a catalytic activity of approximately 25 000 LU/g prepara-
tion. CALB was dried in a desiccator over P2O5 prior to use. All
glassware was oven dried prior to use. High-resolution mass
spectra (HRMS) were recorded on an Ion Spec Fourier transform
mass spectrometer using dihydroxybenzoic acid (DHB) as the
matrix.
Lip a se-Ca ta lyzed Tr a n sester ifica tion s. A homogeneous
mixture of alcohol (5 mmol) and â-ketoester (20 mmol) was
treated with 10% (w/w of alcohol) of the catalyst and swirled in
(15) J eromin, G.; Welsch, V. Tetrahedron Lett. 1996, 37, 6663.
(16) (a) Hudlicky, T.; Tsunoda, T.; Gadamasett, K. G.; Murry, J . A.;
Keck, G. E. J . Org. Chem. 1991, 56, 3619. (b) Landis, Y.; Planchenault,
D. Tetrahedron Lett. 1994, 35, 4565.
(17) Weiler, L. J . Am. Chem. Soc. 1970, 92, 6707.
(18) Doyle, M. P.; Austin, R. E.; Bailey, A. S.; Dwyer, M. P.; Dyatkin,
A. B.; Kalinin, A. V.; Kwan, M. M.; Liras, S.; Oalman, C. J .; Pieters,
R. J .; Protopopova, Raab, C. E.; Roos, G. H. P.; Zhou, Q.-L.; Martin, S.
F. J . Am. Chem. Soc. 1995, 117, 5763.

Notes
J . Org. Chem., Vol. 66, No. 5, 2001 1909
50.1, 30.3, 22.0, 20.9, 13.6; HRMS calcd for C10H14O3 (M + Na+)
205.0835, found 205.0843.
δ 0.95 (t, 3H, J ) 7.3 Hz), 1.50 (m, 2H), 2.96 (m, 4H), 3.47 (s,
2H), 4.72 (bs, 2H), 7-15-7.30 (m, 5H); 201.6, 166.7, 141.3, 140.8,
128.8, 128.6, 126.4, 88.4, 73.8, 54.0, 49.5, 45.5, 29.7, 22.08, 20.9,
13.6; HRMS calcd for C17H20O3 (M + Na+) 295.1306, found
295.1312.
Cin n am yl 3-oxo-4-pen ten oate (27): chromatography, EtOAc/
hexane 20:80 f 10:30; 1H NMR (250 MHz, CDCl3) δ 3.60 (s,
ketonic H at C(2)), 4.78 (d, J ) 5.9 Hz, 2H), 5.10 (s, enolic H at
C(2)), 5.50 (t, 1H), 5.94-6.36 (m 3H), 6.64 (d, J ) 15.7 Hz, 2H),
7.25-7.40 (m, 5H), 11.8 (s, enol OH); HRMS calcd for C14H14O3
(M + Na+) 253.0835, found 253.0846.
Ben zyl 2-oxocyclop en ta n eca r boxyla te (28): chromatog-
raphy, EtOAc/hexane 10:90 f 20:80; 1H NMR (250 MHz, CDCl3)
δ 1.81-1.90 (m, 1H), 2.10-2.14 (m, 1H), 2.2-2.4 (m, 4H), 3.21
(t, J ) 9.2 Hz, 1H), 5.18 (s, 2H), 7.36 (m, 5H); 13C NMR (125
MHz, CDCl3) δ 212.3, 169.5, 135.8, 128.8, 128.5, 128.3, 67.2, 55.0,
38.3, 27.6, 21.3; HRMS calcd for C13H14O3 (M + Na+) 241.0835,
found 241.0837.
MeO-P EG-3-oxobu ta n oa te (22). Poly(ethyleneglycol) mono-
methyl ether (Mw 5000) (5.0 g, 1 mmol) was dissolved in methyl
acetoacetate (10 mL, 80 mmol) and reacted with CALB (500 mg)
according to the general transesterification procedure. After 8
h, the reaction mixture was dissolved in THF (50 mL), filtered,
and precipitated into diethyl ether (800 mL) at 0 °C. The white
precipitate was collected to afford the product as a white solid
(4.98 g, 97%): 1H NMR (500 MHz, CDCl3) δ 2.24 (s, 3H), 3.34 (s,
3H), 3.45 (s, 2H), 3.50-3.70 (bs, 450H), 4.27 (t, J ) 7.1 Hz, 2H);
13C NMR (125 MHz, CDCl3) δ 200.6, 167.3, 72.1, 70.8, 69.1, 64.5,
59.2, 50.2, 30.3.
Eth en yl 3-p h en ylp r op yl-3-oxobu ta n oa te (S)-(23): [R]25
D
) -3.7° (c ) 2.1, CH2Cl2), 90% ee; chromatography, EtOAc/
hexane 10:90 f 20:80; 1H NMR (500 MHz, CDCl3) δ 1.91-2.09
(m, 2H), 2.28 (s, 3H), 2.62-2.77 (m, 2H), 3.47 (s, 2H), 5.26 (d, J
) 10.6 Hz, 1H), 5.33 (d, J ) 12.5 Hz, 1H), 5.36 (m, 1H), 7.17-
7.25 (m, 3H), 7.27-7.34 (m, 2H); 13C NMR (125 MHz, CDCl3) δ
200.6, 166.5, 141.3, 135.9, 128.6, 128.5, 126.2, 117.7, 75.6, 50.4,
35.8, 31.5, 30.3; HRMS calcd for C15H18O3 (M + Na+) 269.1148,
found 269.1155.
Met h yl 3-p h en ylp r op -2-en yl-3-oxob u t a n oa t e ((R)-33):
[R]25 ) +81.1° (c ) 1.1, CH2Cl2), 93% ee; chromatography,
D
EtOAc/hexane 10:90 f 40:60; 1H NMR (250 MHz, CDCl3) δ 1.40
(d, J ) 6.6 Hz, 2H), 2.23 (s, 3H), 3.42 (s, 2H), 5.55 (m, 1H), 6.21-
(dd, J ) 15.9, 6.6 Hz, 1H), 6.58 (d, J ) 16.1 Hz, 1H), 7.21-7.39
(m, 5H); 13C NMR (125 MHz, CDCl3) δ 200.7, 166.6, 136.4, 132.4,
128.8, 128.4, 128.3, 126.8, 72.6, 50.6, 30.3, 20.5; HRMS calcd
for C14H16O3 (M + Na+) 255.0992, found 255.1004.
Meth yl 3-(4-h yd r oxyp h en yl)p r op yl-3-oxobu ta n oa te (24):
chromatography, EtOAc/hexane 10:90 f 50:50; 1H NMR (250
MHz, CDCl3) δ 2.72 (d, J ) 6.6 Hz, 3H), 1.77-1.90 (m, 1H),
1.91-1.97 (m, 1H), 2.28 (s, 3H), 2.52-2.69 (m, 2H), 3.33 (s, 2H),
4.99 (m, 1H), 6.75 (d, J ) 7.8 Hz, 2H), 7.02 (d, J ) 7.8 Hz, 2H);
13C NMR (125 MHz, CDCl3) δ 201.3, 167.2, 154.2, 133.6, 129.7,
115.6, 77.2, 50.7, 37.9, 31.02, 30.5, 20.2; HRMS calcd for
C14H18O4 (M + Na+) 273.1097, found 273.1094.
Ack n ow led gm en t. This work was supported by the
National Institutes of Health (GM56154) and the
Skaggs Institute for Chemical Biology. A.C. acknowl-
edges a fellowship from the Wennergren Foundations,
Sweden. The provision of enzyme by Novo Nordisk A/S,
Denmark, is also gratefully acknowledged.
Cin n a m yl 3-oxo-5-p h en ylp en ta n oa te (25): chromatogra-
1
phy, EtOAc/hexane 20:80 f 10:30; H NMR (250 MHz, CDCl3)
δ 2.82-3.05 (m, 4H), 4.79 (d, J ) 6.2 Hz, 2H), 6.23 (m, 1H), 6.64
(d, J ) 15.8 Hz, 1H), 7.20-7.42 (m, 10H); 13C NMR (125 MHz,
CDCl3) δ 201.8, 167.0, 140.7, 136.2, 135.1, 128.8, 128.7, 128.5,
126.9, 126.4, 122.7, 66.1, 49.6, 44.7, 29.6; HRMS calcd for
Su p p or t in g In for m a t ion Ava ila b le: 1H NMR and 13C
NMR spectra of 22-24, 28, and 33. This material is available
free of charge via the Internet at http://pubs.acs.org.
C
20H20O3 (M + Na+) 331.1305, found 331.1305.
Hex-2-yn yl 5-p h en yl-3-oxop en ta n oa te (26): chromatogra-
1
phy, EtOAc/hexane 10:40 f 10:30; H NMR (250 MHz, CDCl3)
J O001478O