Lipase-catalyzed enantioselective desymmetrization of prochiral 3,3-bis(hydroxymethyl)oxindoles

Article abstract of DOI:10.1016/S0040-4039(01)01547-7

Oxindoles 3b-d (91-98% ee) having a chiral quaternary carbon center at the C-3 position were prepared from readily available oxindoles 5a-c in 50-64% overall yields, in which an enantioselective desymmetrization of prochiral 1,3-diols 2b-d using a Candida rugosa lipase (Meito OF) and 1-ethoxyvinyl 2-furoate 1 was employed as the key step.

Full text of DOI:10.1016/S0040-4039(01)01547-7

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 42 (2001) 7315–7317
Lipase-catalyzed enantioselective desymmetrization of prochiral
3,3-bis(hydroxymethyl)oxindoles
Shuji Akai, Toshiaki Tsujino, Tadaatsu Naka, Kouichi Tanimoto and Yasuyuki Kita*
Graduate School of Pharmaceutical Sciences, Osaka University 1-6, Yamadaoka, Suita, Osaka 565-0871, Japan
Received 2 July 2001; revised 30 July 2001; accepted 17 August 2001
Abstract—Oxindoles 3b–d (91–98% ee) having a chiral quaternary carbon center at the C-3 position were prepared from readily
available oxindoles 5a–c in 50–64% overall yields, in which an enantioselective desymmetrization of prochiral 1,3-diols 2b–d using
a Candida rugosa lipase (Meito OF) and 1-ethoxyvinyl 2-furoate 1 was employed as the key step. © 2001 Elsevier Science Ltd.
All rights reserved.
Many biologically important indole alkaloids such as
spirotryprostatins A and B, (−)-physostigmine, and (−)-
esermethole, have a common structure; viz., indoline I
with a chiral, nonracemic quaternary carbon center at
the C-3 position.1–3 Effective construction of the chiral
quaternary carbon has been one of the pivotal issues
for their asymmetric total synthesis, for which a variety
of methodologies have been developed based on the
enantio- or diastereoselective carbonꢀcarbon bond for-
mation at the C-3 position.4 On the other hand, neither
chemical nor biocatalytic enantioselective desym-
metrization of the prochiral substrates II having two
identical carbon substituents at the C-3 position has
been reported. Especially an effective enzymatic desym-
metrization of a diol II (R5=CH2OH) must provide a
useful alternative for the preparation of optically active
I having the advantages of the easy, safe operation and
the divergent derivatization to either enantiomer as
have often been emphasized in many successful enzy-
matic reactions5 (Scheme 1).
Very recently, the first attempt on the desymmetrization
of II (R5=CH2OH) was reported; however, the reac-
tion did not proceed.6 Alternatively, the authors have
O
X
N
N
H
O
Y
3
*
O
N
H
R
R5
N
R3
R5
desymmetrization
R = OMe, X–Y = CH2CH spirotryprostatin A
R4
R = H, X–Y = CH=C
spirotryprostatin B
R2
*
N
R1
O
R2
O
Me
RO
R1
II
I
N
Me
H
*
R5 = CH2OH, CO2R, etc.
N
Me
R = CONHMe (–)-physostigmine
R = Me (–)-esermethole
Scheme 1.
Keywords: lipase-catalyzed desymmetrization; prochiral 1,3-diol; oxindole; quaternary carbon center.
* Corresponding author. Tel.: (+81) 6-6879-8225; fax: (+81) 6-6879-8229; e-mail: kita@phs.osaka-u.ac.jp
0040-4039/01/$ - see front matter © 2001 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(01)01547-7

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S. Akai et al. / Tetrahedron Letters 42 (2001) 7315–7317
(entry 3). Optically pure 3d (>99% ee) was obtained by
single recrystallization of 3d (91% ee) from benzene.9
achieved the desymmetrization by an enantioselective
hydrolysis of a prochiral diester II (R5=CH2OCOEt)
to give the product with 95% ee in 38% yield after 5
days. We present herein a highly effective desym-
metrization of the diols 2 using a prominent acyl donor,
The diols 2a–d were readily prepared from commercial
5a or the known oxindoles 5b4a and 5c10 in good yields
(Scheme 2).11–13 The presented method is useful,
because 3b and 3c (97–98% ee), for instance, were
obtained in three steps in 50–53% overall yields from 5a
and 5b, respectively.
1-ethoxyvinyl 2-furoate 1.7 The products
3 were
obtained with 91–98% ee in 68–79% yields. The pre-
sented desymmetrization method is quite useful in
terms of the short step and the good overall yield from
readily available oxindoles 5a–c.
Acknowledgements
The majority of the natural indole alkaloids are
classified as either compounds having no substituent at
the C-4 through C-7 positions of the indole skeleton or
those having an oxygen substituent at the C-5 or C-6
position. Aiming at production of chiral synthons use-
ful for total synthesis of these natural products, the
substrates 2a–d were subjected to the desymmetrization.
However, we encountered a serious problem when we
applied the reaction conditions [Candida rugosa lipase
(Meito MY), wet iPr2O] used in our previous work7a to
2a. Thus, the very poor solubility of 2a in iPr2O
became an obstacle to its fast esterification and resulted
in enhancement of the further esterification of the solu-
ble product 3a to provide the diester 4a exclusively.
Although 2a was soluble in polar solvents such as THF,
dioxane and acetonitrile, the lipase MY-catalyzed reac-
tion did not proceed. After investigation of the solvent
system and the lipase, the use of a Candida rugosa
lipase (Meito OF) in a mixed solvent (iPr2O–THF) was
found to be effective.8 Some different ratios of these
two solvents were examined in each case of 2a–d, and
the best results were summarized in Table 1. The ratio
of iPr2O to THF around 5:1 was usually the best
choice, and the N-Boc derivatives 2b–d were found to
be suitable substrates (entries 2–4). In the case of 2c,
use of iPr2O alone gave a better result than the mixed
solvent providing 3c (98% ee, 77% yield) within 3 h
This work was supported by Grant-in-Aids for Scien-
tific Research [Priority Areas (A) ‘Exploitation of
a or b
R2
R2
O
O
N
H
N
R1
6a R1 = Me, R2 = H (68%)11
6b R1 = Boc, R2 = H (83%)12
6c R1 = Boc, R2 = 5-OMe (78%)
6d R1 = Boc, R2 = 6-OMe (85%)
5a R2 = H
5b R2 = 5-MeO
5c R2 = 6-MeO
OH
OH
c
R2
O
N
R1
2a R1 = Me, R2 = H (99%)
2b R1 = Boc, R2 = H (89%)
2c R1 = Boc, R2 = 5-OMe (89%)
2d R1 = Boc, R2 = 6-OMe (95%)
Scheme 2. (a) NaH, Me2SO4, xylene, reflux; (b) (Boc)2O,
NaHCO3, THF, 45°C–reflux; (c) aq. 37% HCHO, Na2CO3,
dioxane, room temp.–40°C. Boc=t-butoxycarbonyl.
Table 1. Lipase OF-catalyzed desymmetrization of 2 using 1
OCO-2-Fr
OH
O
OH
O
OCO-2-Fr
OCO-2-Fr
OH
EtO
O
1
*
R2
R2
O
O
R2
+
O
N
N
lipase OF
wet iPr2O–THFa
30 °C
N
R1
R1
R1
2a–d
3a–d
4a–d
O
2-Fr =
Entry
2
R1
R2
Ratio of
iPr2O–THF
Reaction Time
(h) b
3
Ee (%) c
Yield (%) d
Mp (°C)
[h]2D7 (c=1.0, CHCl3)
1
2
3
4
2a Me
2b Boc
2c Boc 5-OMe
2d Boc 6-OMe
H
H
5:1
5:1
100:0
5:1
20
20
3
3a 79
60
68
77
79
Oil
+63.3
+56.3
+49.8
+69.6 e
3b 97
3c 98
3d 91
125–126
140–140.5
136–136.5
19
a Water (0.1%) was added to a mixture of iPr2O and THF. b The reaction was quenched when 2 was consumed. c Determined by HPLC using
Daicel CHIRALCEL OD (hexane–iPrOH). d Isolated by column chromatography on SiO2. The rest of the product was the corresponding 4 in
each case. e For 3d (>99% ee) after recrystallization.

S. Akai et al. / Tetrahedron Letters 42 (2001) 7315–7317
7317
Multi-Element Cyclic Molecules’ and No. 11672102]
from the Ministry of Education, Culture, Sports, Sci-
ence, and Technology, Japan and the Takeda Science
Foundation, Japan. The Meito Sangyo Co., Ltd., Japan
is thanked for their generous gifts of the lipases.
8. The following lipases were examined in a 1:1 mixture of
iPr2O and THF at 30°C: The reaction using Meito OF
gave 3a (33% ee) after 7 days, whereas Candida rugosa
lipases (Meito MY, Amano AY, and Novo L3), Candida
antarctica lipase (Novo L2), Mucor miehei lipase (Novo
L9), Pseudomonas aeruginosa lipase (Toyobo LIP), Pseu-
domonas sp. lipase (Amano AK), Pseudomonas cepacia
lipases (Amano AH and PS), porcine pancreas (Amano),
and pig liver esterase (Amano) were not reactive. Use of
a 1:1 mixture of iPr2O and either dioxane or acetonitrile
resulted in very poor selectivity and reactivity.
9. A typical procedure for the desymmetrization of 2: In a
resealable tube, a solution of 2b (150 mg, 0.50 mmol) and
1 (280 mg, 1.50 mmol) in a 5:1:0.006 mixture of iPr2O–
THF–H2O (100 mL) was placed, and lipase OF (275 mg)
was added to it. The tube was sealed and the reaction
mixture was stirred at 30°C for 20 h. The reaction
mixture was filtered through a Celite pad, and the filtrate
was concentrated in vacuo. The residue was purified by
flash column chromatography on SiO2 (hexane–EtOAc,
3:1“2:1) to give 3b (134 mg, 68%). The optical purity
was determined to be 97% ee by HPLC using Daicel
CHIRALCEL OD (hexane–iPrOH, 90:10; flow rate 1.0
mL/min; 10°C). All new compounds (2a–d, 3a–d, and
6c–d) were fully characterized by spectroscopic means
and combustion analysis.
References
1. For recent reviews, see: (a) Saxton, J. E. In The Alkaloids:
Chemistry and Biology; Cordell, G. A., Ed.; Academic
Press: San Diego, 1998; Vol. 51, Chapter 1; (b) Toyota,
M.; Ihara, M. Nat. Prod. Rep. 1998, 327; (c) Gribble, G.
W. J. Chem. Soc., Perkin Trans. 1 2000, 1045.
2. For an example of asymmetric total syntheses of spiro-
tryprostatins, see: Overman, L. E.; Rosen, M. D. Angew.
Chem., Int. Ed. 2000, 39, 4596.
3. For an example of asymmetric total synthesis of (−)-
physostigmine, see: Kawahara, M.; Nishida, A.; Naka-
gawa, M. Org. Lett. 2000, 2, 675.
4. For some recent reports, see: (a) Lakshmaiah, G.; Kawa-
bata, T.; Shang, M.; Fuji, K. J. Org. Chem. 1999, 64,
1699; (b) Yokoshima, S.; Tokuyama, H.; Fukuyama, T.
Angew. Chem., Int. Ed. 2000, 39, 4073; (c) Oestreich, M.;
Dennison, P. R.; Kodanko, J. J.; Overman, L. E. Angew.
Chem., Int. Ed. 2001, 40, 1439.
5. For a recent review, see: Bornscheuer, U. T.; Kazlauskas,
R. J. Hydrolases in Organic Synthesis; Wiley: Weinheim,
1999.
6. Nakazawa, K.; Hayashi, M.; Tanaka, M.; Aso, M.; Sue-
mune, H. Tetrahedron: Asymmetry 2001, 12, 897.
7. (a) Akai, S.; Naka, T.; Fujita, T.; Takebe, Y.; Kita, Y.
Chem. Commun., 2000, 1461. A recipe for 1 is available
via the internet at http://www.rsc.org/suppdata/cc/b0/
b003871g/; (b) See also: Kita, Y.; Takebe, Y.; Murata,
K.; Naka, T.; Akai, S. J. Org. Chem. 2000, 65, 83.
10. Beckett, A. H.; Daisley, R. W.; Walker, J. Tetrahedron
1968, 24, 6093.
11. Bordwell, F. G.; Fried, H. E. J. Org. Chem. 1991, 56,
4218.
12. Compound 6b was prepared at higher temperature than
the reported method: Rajeswaran, W. G.; Cohen, L. A.
Tetrahedron Lett. 1998, 54, 11375.
13. For examples of bis-hydroxymethylation at the a-position
of ketones, see: Schneider, G.; Wo¨lfling, J.; Hackler, L.;
Mesko´, E.; Dombi, G. Synthesis 1985, 194.