Enantiodivergent Preparation of Optically Active Oxindoles Having a Stereogenic Quaternary Carbon Center at the C3 Position via the Lipase-Catalyzed Desymmetrization Protocol: Effective Use of 2-Furoates for Either Enzymatic Esterification or Hydrolysis

Article abstract of DOI:10.1021/jo035749h

Both enantiomers of oxindoles 2a-h, having a stereogenic quaternary carbon center at the C3 position and a different N-protective group, were readily prepared by the lipase-catalyzed desymmetrization protocol. Thus, the transesterification of the prochiral diols 3a-h with 1-ethoxyvinyl 2-furoate 5 was catalyzed by Candida rugosa lipase to give (R)-(+)-2a-h (68-99% ee), in which the use of a mixed solvent, {%N}i{%N}Pr₂O (diisopropyl ether)-THF, was crucial. The same lipase also effected the enantioselective hydrolysis of the difuroates 4a-h in a mixture of {%N}i{%N}Pr₂O, THF, and H₂O to provide the enantiomers (S)-(-)-2a-h (82-99% ee). The products 2 obtained by both methods were stable against racemization. These enzymatic desymmetrization reactions were also applicable for other typical symmetrical difuroates 12b and 15b to provide the racemization-resistant products 13b and 16b.

Full text of DOI:10.1021/jo035749h

En a n tiod iver gen t P r ep a r a tion of Op tica lly Active Oxin d oles
Ha vin g a Ster eogen ic Qu a ter n a r y Ca r bon Cen ter a t th e C3
P osition via th e Lip a se-Ca ta lyzed Desym m etr iza tion P r otocol:
Effective Use of 2-F u r oa tes for Eith er En zym a tic Ester ifica tion or
Hyd r olysis
Shuji Akai, Toshiaki Tsujino, Emi Akiyama, Kouichi Tanimoto, Tadaatsu Naka, and
Yasuyuki Kita*
Graduate School of Pharmaceutical Sciences, Osaka University, 1-6, Yamadaoka, Suita,
Osaka 565-0871, J apan
kita@phs.osaka-u.ac.jp
Received November 29, 2003
Both enantiomers of oxindoles 2a -h , having a stereogenic quaternary carbon center at the C3
position and a different N-protective group, were readily prepared by the lipase-catalyzed
desymmetrization protocol. Thus, the transesterification of the prochiral diols 3a -h with 1-ethoxy-
vinyl 2-furoate 5 was catalyzed by Candida rugosa lipase to give (R)-(+)-2a -h (68-99% ee), in
i
which the use of a mixed solvent, Pr2O (diisopropyl ether)-THF, was crucial. The same lipase
i
also effected the enantioselective hydrolysis of the difuroates 4a -h in a mixture of Pr2O, THF,
and H2O to provide the enantiomers (S)-(-)-2a -h (82-99% ee). The products 2 obtained by both
methods were stable against racemization. These enzymatic desymmetrization reactions were also
applicable for other typical symmetrical difuroates 12b and 15b to provide the racemization-resistant
products 13b and 16b.
In tr od u ction
easy and safe operations, mild reaction conditions, and
high chemical and optical yields of the products.6 How-
ever, the potential of the approaches in Scheme 1 was
hardly exploited. The only successful example was the
enantioselective hydrolysis of the dipropanoate 4 (R1 )
MOM, R2 ) H, R3 ) Et) in which the product 2 (R1 )
MOM, R2 ) H, R3 ) Et) (95% ee, 38% yield) was obtained
after a 5 day reaction, whereas the enantioselective
esterification of the corresponding diol 3 (R1 ) MOM, R2
) H) did not proceed.7,8
In addition to the above-mentioned low reactivity of
the sterically congested substrates (3 and 4), the enzy-
matic desymmetrization of the prochial 2,2-disubstituted
1,3-propanediols I and the hydrolytic desymmetrization
of their diesters II have often suffered from the easy
Oxindole- and indoline-skeletons 1 having a stereo-
genic quaternary carbon center at the C3 position are
found in many biologically important indole alkaloids
such as spirotryprostatins A and B, (-)-physostigmine,
and (-)-esermethole.1-5 Effective construction of their
stereogenic quaternary carbon center has been one of the
pivotal issues for their asymmetric total synthesis, and
a variety of methodologies have been developed via
enantio- or diastereoselective carbon-carbon bond-form-
ing reactions at the C3 position.1-5
On the other hand, the biocatalytic enantioselective
desymmetrization of the prochiral substrates (3 and 4)
by (trans)esterification and hydrolysis, respectively, could
offer an attractive alternative (Scheme 1) with regard to
(5) For some other recent examples, see: (a) Lakshmaiah, G.;
Kawabata, T.; Shang, M.; Fuji, K. J . Org. Chem. 1999, 64, 1699-1704.
(b) Yokoshima, S.; Tokuyama, H.; Fukuyama T. Angew. Chem., Int.
Ed. 2000, 39, 4073-4075. (c) Oestreich, M.; Dennison, P. R.; Kodanko,
J . J .; Overman, L. E. Angew. Chem., Int. Ed. 2001, 40, 1439-1442.
(d) Hills, I. D.; Fu, G. C. Angew. Chem., Int. Ed. 2003, 42, 3921-3924.
(e) Takayama, H.; Fujiwara, R.; Kasai, Y.; Kitajima, M.; Aimi, N. Org.
Lett. 2003, 5, 2967-2970.
(6) For recent reviews, see: Schoffers, E.; Golebiowski, A.; J ohnson,
C. R. Tetrahedron 1996, 52, 3769-3826. Bornscheuer, U. T.; Kazlaus-
kas, R. J . In Hydrolases in Organic Synthesis; Wiley: Weinheim, 1999.
Theil, F. Tetrahedron 2000, 56, 2905-2919. Faber, K. In Biotransfor-
mations in Organic Chemistry, 4th ed.; Springer-Verlag: Berlin, 2000.
Roberts, S. M. J . Chem. Soc., Perkin Trans. 1 2001, 1475-1499.
Hanefeld, U. Org. Biomol. Chem. 2003, 1, 2405-2415.
(1) For recent reviews, see: Saxton, J . E. In The Alkaloids: Chem-
istry and Biology; Cordell, G. A., Ed.; Academic Press: San Diego, 1998;
Vol. 51, Chapter 1. Toyota, M.; Ihara, M. Nat. Prod. Rep. 1998, 327-
340. Gribble, G. W. J . Chem. Soc., Perkin Trans. 1 2000, 1045-1075.
Marti, C.; Carreira, E. M. Eur. J . Org. Chem. 2003, 2209-2219.
(2) For some recent examples of the asymmetric total syntheses of
spirotryprostatins, see: Overman, L. E.; Rosen, M. D. Angew. Chem.,
Int. Ed. 2000, 39, 4596-4599. Bagul, T. D.; Lakshmaiah, G.; Kawabata,
T.; Fuji, K. Org. Lett. 2002, 4, 249-251. Meyers, C.; Carreira, E. M.
Angew. Chem., Int. Ed. 2003, 42, 694-696. Onishi, T.; Sebahar, P. R.;
Williams, R. M. Org. Lett. 2003, 5, 3135-3137.
(3) For recent examples of the asymmetric total synthesis of
physostigmine, see: Matsuura, T.; Overman, L. E.; Poon, D. J . J . Am.
Chem. Soc. 1998, 120, 6500-6503. Kawahara, M.; Nishida, A.; Naka-
gawa, M. Org. Lett. 2000, 2, 675-678.
(4) For an example of the asymmetric total synthesis of esermethole,
see: Fuji, K.; Kawabata, T.; Ohmori, T.; Shang, M.; Node, M.
Heterocycles 1998, 47, 951-964.
(7) Nakazawa, K.; Hayashi, M.; Tanaka, M.; Aso, M.; Suemune, H.
Tetrahedron: Asymmetry 2001, 12, 897-901.
(8) Nonenzymatic desymmetrization of the oxindoles or indolines
having two identical substituents at the C3 position has never been
reported to the best of our knowledge.
10.1021/jo035749h CCC: $27.50 © 2004 American Chemical Society
Published on Web 03/06/2004
2478
J . Org. Chem. 2004, 69, 2478-2486

Enantiodivergent Preparation of Optically Active Oxindoles
SCHEME 1
SCHEME 2
i
solvent, Pr2O (diisopropyl ether)-THF.11 We also have
achieved the first lipase-catalyzed hydrolysis of the
prochiral difuroate 4 (R3 ) 2-furyl). By these two meth-
ods, both enantiomers of the oxindoles 2 (g97% ee in
most cases) having various types of N-protective groups
were prepared. The efficiency of the hydrolytic desym-
metrization strategy using the difuroates was also dem-
onstrated in the typical substrates (12, 15) for which the
existing methods caused easy racemization of the prod-
ucts.
Resu lts a n d Discu ssion
P r ep a r a tion of P r och ir a l Diols 3 a n d P r och ir a l
Difu r oa tes 4. The core indole (or indoline) skeletons of
most natural indole alkaloids are classified as either
compounds having no substituent at the C4-C7 positions
or those having an oxygen substituent at the C5 or C6
position. Aiming at the preparation of chiral synthons
useful for the total synthesis of natural products, we
planned to examine the enzymatic desymmetrization of
the prochiral diols 3a -h and the difuroates 4a -h having
various N-protective groups.
The diols 3a -h were prepared from commercially
available 6a and 7f or the known compounds (6b,5a 6c,12
7a ,13 7b,14 7e,14 7g,7 and 7h 15). New compounds (7c and
7d ) were prepared by the N-protection of 6b and 6c,
respectively. The bis-hydroxymethylation at the C3 posi-
tion of 7 was performed with an aqueous 37% solution
of formaldehyde16 and Na2CO3 to give the diols 3a -h .
racemization of the products (III and ent-III). This is
because lower aliphatic acyl groups (COR3) such as an
acetyl group are prone to easily migrate to the neighbor-
ing hydroxyl group under various conditions (Scheme 2).9
Therefore, to make both approaches in Scheme 1 useful,
other acyl groups (COR3) having a high reactivity for the
enzymatic reaction and resistance against the migration
needed to be developed.
Recently, we have developed a new prominent acyl
donor, 1-ethoxyvinyl 2-furoate 5, for the lipase-catalyzed
desymmetrization of the prochiral 2,2-disubstituted 1,3-
propanediols I.10 The reagent 5 offers advantages such
as high reactivity, high enantioselectivity, and the pro-
duction of racemization-resistant products III (R3
)
2-furyl). In this paper, the successful application of 5 for
the desymmetrization of 3 is presented using a mixed
(10) (a) Akai, S.; Naka, T.; Fujita, T.; Takebe, Y.; Kita, Y. Chem.
Commun. 2000, 1461-1462. (b) Akai, S.; Naka, T.; Fujita, T.; Takebe,
Y.; Tsujino, T.; Kita, Y. J . Org. Chem. 2002, 67, 411-419. For synthetic
applications, see: (c) Akai, S.; Tsujino, T.; Fukuda, N.; Iio, K.; Takeda,
Y.; Kawaguchi, K.; Naka, T.; Higuchi, K.; Kita, Y. Org. Lett. 2001, 3,
4015-4018.
(9) Acyl group migration was reported to proceed during the
enzymatic reactions, the purification by SiO2 chromatography, and the
subsequent chemical transformations. For migrations on the hydrolysis
approaches, see: (a) Crout, D. H. G.; Gaudet, V. S. B.; Laumen, K.;
Schneider, M. P. J . Chem. Soc., Chem. Commun. 1986, 808-810. (b)
Xie, Z.-F.; Nakamura, I.; Suemune, H.; Sakai, K. J . Chem. Soc., Chem.
Commun. 1988, 966-967. (c) Wang, Y.-F.; Lalonde, J . J .; Momongan,
M.; Bergbreiter, D. E.; Wong, C-H. J . Am. Chem. Soc. 1988, 110,
7200-7205. (d) Suemune, H.; Harabe, T.; Xie, Z.-F.; Sakai, K. Chem.
Pharm. Bull. 1988, 36, 4337-4344. (e) Liu, K. K.-C.; Nozaki, K.; Wong,
C.-H. Biocatalysis 1990, 3, 169-177. (f) Prasad, K.; Estermann, H.;
Underwood, R. L.; Chen. C.-P.; Kucerovy, A.; Repic, O. J . Org. Chem.
1995, 60, 7693-7696. (g) Bo´dai, V.; Nova´k, L.; Poppe, L. Synlett 1999,
759-761. (h) Egri, G.; Ba´lint, J .; Peredi, R.; Fogassy, E.; Nova´k, L.;
Poppe, L. J . Mol. Cat. B 2000, 10, 583-596. For migrations on the
esterification approaches, see: (i) Nicolosi, G.; Patti, A.; Piattelli, M.;
Sanfilippo, C. Tetrahedron: Asymmetry 1994, 5, 283-288. (j) Nicolosi,
G.; Patti, A.; Piattelli, M.; Sanfilippo, C. Tetrahedron: Asymmetry 1995,
6, 519-524. (k) Fadel, A.; Arzel, P. Tetrahedron: Asymmetry 1997, 8,
283-291.
(11) Part of this study was reported in a preliminary communication,
see: Akai, S.; Tsujino, T.; Naka, T.; Tanimoto, K.; Kita, Y. Tetrahedron
Lett. 2001, 42, 7315-7317.
(12) Beckett, A. H.; Daisley, R. W.; Walker, J . Tetrahedron 1968,
24, 6093-6109. See also: Hennessy, E. J .; Buchwald, S. L. J . Am.
Chem. Soc. 2003, 125, 12084-12085.
(13) Bordwell, F. G.; Fried, H. E. J . Org. Chem. 1991, 56, 4218-
4223.
(14) Preparation of 7b was carried out at a temperature (65 °C)
higher than that in the reported method (Rajeswaran, W. G.; Cohen,
L. A. Tetrahedron 1998, 54, 11375-11380) because of the tardy
reaction.
(15) Crestini, C.; Saladino, R. Synth. Commun. 1994, 24, 2835-2841.
For the preparation of N-benzylisatin, see: Singh, R. P.; Majumder,
U.; Shreeve, J . M. J . Org. Chem. 2001, 66, 6263-6267.
J . Org. Chem, Vol. 69, No. 7, 2004 2479

Akai et al.
SCHEME 3
acetonitrile, the lipase MY-catalyzed reaction did not
proceed. After investigation of a range of solvents, the
use of a 1:1 mixture of iPr2O and THF was found to give
2a (33% ee) after 7 days. On the other hand, the use of
a 1:1 mixture of iPr2O and either dioxane or acetonitrile
resulted in a very poor selectivity and reactivity. Next,
i
we examined several lipases in the 1:1 mixture of Pr2O
and THF, and a C. rugosa lipase (Meito OF) was found
to be more effective to give (+)-2a (77% ee, 21% yield)
and 4a (79% yield) after 4 days (Table 1, entry 2).17
Investigation of the reaction conditions was continued by
i
changing the ratio of Pr2O to THF. Each reaction was
carried out using a minimal volume of the solvent to
dissolve 3a and quenched by filtering the lipase through
a Celite pad when 3a was consumed (Table 1). The
reaction proceeded faster in solvent mixtures with a
i
higher ratio of Pr2O to THF; however, a considerable
amount of 4a was produced in all cases. Good optical
purities (79-87% ee) and acceptable yields (53-60%) of
i
2a were obtained in a 5:1 or 10:1 mixture of Pr2O and
THF (entries 4 and 5).
With the profile of the desymmetrization reaction of
3a in hand, various prochiral diols 3b-h were next
subjected to the desymmetrization. Among the different
i
i
ratios of Pr2O to THF, only a few, i.e., neat Pr2O, 10:1,
5:1, and 2:1, were examined for each substrate, and the
best results are summarized in the left column of Table
2.18 Some features are worth noticing. First, the 5:1 ratio
of iPr2O to THF was generally the best choice, while the
other ratio of the solvents resulted in a decrease of both
optical and chemical yields of 2. In the case of 3c, the
i
best result was obtained using Pr2O alone (entry 4),
SCHEME 4
although the use of a 10:1 mixture of iPr2O and THF also
afforded a similar result (24 h, 97% ee, 75% yield).
Second, the N-acyl derivatives 3b-f generally produced
(+)-2b-f with high optical (91-99% ee) and chemical
yields (71-93%) irrespective of the structure of the acyl
group (entries 2-7). On the contrary, the desymmetri-
zation of the N-alkyl derivatives (3g and 3h ) resulted in
lower optical and chemical yields (entries 8 and 9). Third,
this method was scarcely affected by the reaction scale
and was suitable for multigram synthesis of chiral
products. For instance, under identical reaction condi-
tions using the same ratio of 3b, 5, lipase OF, and the
solvent mixture, the reactions of 3b (100 mg and 2.0 g)
afforded similar results (entries 2 and 3). Fourth, recrys-
tallization was effective for obtaining the optically pure
products 2 from those with unsatisfactory optical purities.
The prochiral difuroates 4a -h were prepared from 3a -h
by the condensation with 2-furoic acid using either DCC
or DEC (1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide
hydrochloride) and DMAP (Scheme 3).
(17) Following lipases were inactive in the 1:1 mixture of iPr2O and
THF at 30 °C: C. rugosa lipases (Amano AY and Roche Diagnostics
CHIRAZYME L-3), C. antarctica lipase (Roche Diagnostics CHIRA-
ZYME L-2), Mucor miehei lipase (Roche Diagnostics CHIRAZYME L-9),
Pseudomonas aeruginosa lipase (Toyobo LIP), Pseudomonas sp. lipase
(Amano AK), Pseudomonas cepacia lipases (Amano AH and PS),
porcine pancreas (Amano), and pig liver esterase (Amano).
(18) Ca u tion : During the workup of the transesterification reaction
of 3, viz., the filtration of the reaction mixture through a Celite pad
followed by concentration of the filtrate in vacuo, we occasionally
observed the formation of 3-acetoxymethyl-3-(furoyloxymethy)oxindoles
in variable yields. This often occurred when we used a large excess of
5 (for instance, 5 equiv), which resulted in decreasing yields of 2. The
side-product seemed to be generated by the acetylation of the optically
active 2. The remaining 5 was likely to be involved to some degree,
although we have not specified the exact factor that induces the
undesired reaction. The side-reaction could be suppressed by stirring
the above-mentioned filtrate with water for 30 min to decompose 5
and to extract the resultant 2-furoic acid with the aqueous phase (for
details, see Experimental Section).
Desym m etr iza tion of P r och ir a l Diols 3 by Lip a se-
Catalyzed En an tioselective Tr an sester ification . The
transesterification of 3a using 5 was at first investigated
by applying the reaction conditions [C. rugosa lipase
(Meito MY), wet iPr2O] used in our previous study.10
However, the very poor solubility of 3a hampered its fast
esterification and resulted in enhancement of the further
esterification of the soluble product 2a to exclusively
provide the diester 4a (Scheme 4). Although 3a was
soluble in polar solvents such as THF, dioxane, and
(16) For previous examples of bis-hydroxymethylation at the R-posi-
tion of the ketones, see: Schneider, G.; Wo¨lfling, J .; Hackler, L.; Mesko´,
E.; Dombi, G. Synthesis 1985, 194-197.
2480 J . Org. Chem., Vol. 69, No. 7, 2004

Enantiodivergent Preparation of Optically Active Oxindoles
TABLE 1. Lip a se OF -Ca ta lyzed Tr a n sester ifica tion of 3a w ith 5 u n d er Va r iou s Con d ition sa
entry
ratio of iPr2O to THF (solvent volume)b
reaction timec
2a d
4a
1
2
3
4
5
6
1:2 (5 mL)
1:1 (10 mL)
2:1 (15 mL)
5:1 (20 mL)
10:1 (40 mL)
4 days
4 days
4 days
22 h
7 h
7 h
76% ee, 15%e
77% ee, 21%e
75% ee, 16%
79% ee, 60%
87% ee, 53%
62% ee, 30%
76%e
79%e
76%
40%
47%
65%
i
neat Pr2O (40 mL)
a
b
Reagent amounts: 3a (30 mg), 5 (80 mg, 3 equiv), and lipase OF (75 mg). Minimal volume of the mixed organic solvent to dissolve
3a (30 mg) was used in the presence of water (0.1 v/v % to the combined volume of the organic solvents). c Reaction was quenched when
3a was consumed. Optical purity was determined by HPLC using a chiral column, Daicel Chiralcel OD. e Yields based on 1H NMR data.
d
TABLE 2. En zym a tic Desym m etr iza tion of 3a -h a n d 4a -h a
(1) enzymatic transesterification of 3a -h a
(2) enzymatic hydrolysis of 4a -h
(-)-2
(+)-2
3
ratio of
time,
hb
ee, yield,
yield,
%
time,
hb
ee, yield,
yield,
%
c
c
c
c
entry
R1
3a Me
R2
iPr2O to THF
%
%
4,
entry
10d 4a
11 4b
12d 4b
4
%
%
3,
1
H
H
H
10:1
5:1
5:1
7
(+)-2a 87
53
83
93
77
4a
4b
4b
4c
47
15
6
4.5 (-)-2a >99
46
33
34
40
3a
3b
3b
3c
50
63
64
51
2
3b Boc
3b Boc
3c Boc
23 (+)-2b 97
72
24
4c 120
(-)-2b >99
(-)-2b >99
(-)-2c >99
3d
4
22 (+)-2b 99
5-OMe
neat
iPr2O
5:1
3
(+)-2c 98
20
13
5
6
7
8
9
3d Boc
3e Cbz
3f Ac
3g MOM
3h Bn
6-OMe
19 (+)-2d 91
58 (+)-2e 98
48 (+)-2f 97
64 (+)-2g 86
144 (+)-2h 68
79
71
90
34
59
4d
4e
4f
4g
4h
13
28
5
38
24
14
15
16
17
18
4d
4e
4f
4g
4h
72
48
24
39
24
(-)-2d
82
12
29
34
57
40
3d
3e
3f
3g
3h
79
61
61
43
58
H
H
H
H
5:1
5:1
5:1
5:1
(-)-2e >99
(-)-2f
(-)-2g
(-)-2h
97
98
98
a
Substrate amount was 20-100 mg unless otherwise noted. For a detailed reaction procedure and the determination of the optical
purity of the product, see Experimental Section. Reaction was quenched when the starting material was consumed. c Isolated yield by
flash column chromatography on SiO2. Substrate amount was 2.0 g for entries 3 and 12 and 0.50 g for entry 10.
b
d
For instance, 2d was obtained in >99% ee after a single
recrystallization step from the optically impure (91% ee)
material.
The products (+)-2a -h were easily isolated by stan-
dard flash column chromatography on silica gel and
stored in a refrigerator for several months without any
loss of optical purity.
Desym m etr iza tion of th e P r och ir a l Difu r oa tes 4
by Lip a se-Ca ta lyzed En a n tioselective Hyd r olysis.
In general, hydrolytic desymmetrization of prochiral
diacetates II (Scheme 2) also suffers from racemization
during the enzymatic resolution due to concomitant
nonenzymatic acetyl group migration. This is aggravated
by the phosphate buffer (pH 7) typically used as the
reaction medium.9 Although desymmetrization trials of
any aromatic diesters II (R3 ) aryl group) have attained
no success,7 we were interested in the applicability of the
difuroates 4 (R3 ) 2-furyl) for the enzymatic hydrolysis
as a means to solve the above-mentioned racemization
problem.
was examined, and we found that the use of a mixture
of Pr2O-THF-water (5:1:6) gradually caused the hy-
i
drolysis of 4b along with the simultaneous hydrolysis of
2b to 3b. When 4b was consumed after 3 days, (-)-2b
(99% ee, 33% yield) and 3b (63% yield) were isolated
(Table 2, entry 11). Using this solvent mixture, (-)-2 with
more than 97% ee was obtained in most cases; however,
the chemical yields were always unsatisfactory due to the
formation of substantial amounts of 3 (entries 10-18).
The applicability of this method for multigram synthesis
was also approved without any change of the optical and
chemical yields of the product (entry 12). The use of a
i
1:1 mixture of Pr2O-water caused a faster hydrolysis
but gave (-)-2 in slightly lower chemical and/or optical
i
yields than that of a mixture of Pr2O-THF-water (5:
1:6) due to the rapid hydrolysis of the products 2 [for
example, 4a : 3 h, >99% ee, 22% yield, 4c: 24 h, 80% ee,
35% yield]. On the other hand, the reaction in THF-
water (1:1) did not take place. On the basis of their
specific rotations, the products 2 of the hydrolysis had
opposite absolute stereochemistry to those of the above-
mentioned transesterification.
A preliminary study of the hydrolysis of 4b was started
by using lipase OF in water or an alcohol (MeOH, EtOH,
i
i
nPrOH, PrOH, nBuOH, BuOH, and tBuOH) at 30 °C;
however, no reaction took place over 6 days in every case.
Next, the use of the mixed solvent (iPr2O-THF, 5:1) in
the presence of water or the above-mentioned alcohols
Remarkably, the desymmetrization of N-MOM difu-
roate 4g proceeded faster and in higher yields of (-)-2g
(entry 17) compared to the corresponding N-MOM dipro-
panoate.7 Contrary to the precedent literature,7 diben-
J . Org. Chem, Vol. 69, No. 7, 2004 2481

Akai et al.
SCHEME 5
zoate 4i was also susceptible to the hydrolytic desym-
metrization to give (-)-2i (98% ee, 37% yield) (Scheme
5). Nevertheless, furoate (-)-2g was perfectly stable
under acidic conditions (0.1 equiv of camphorsulfonic
acid, 0.4 M in CH2Cl2, room temperature, 30 h), whereas
benzoate (-)-2i sustained partial racemization, thus
suggesting distinct advantages of using furoates instead
of benzoates (Figure 1).
F IGURE 1. Comparison of the stability of 2g and 2i under
acidic conditions.
Det er m in a t ion of Ab solu t e St er eoch em ist r y of
P r od u cts. The absolute stereochemistry of (-)-2a was
determined to be S as follows. The hydroxymethyl group
of (-)-2a was converted to the methyl group (8) via the
radical reduction of the corresponding iodide using 2,2′-
azobis(2,4-dimethyl-4-methoxyvaleronitrile) (V-70L)19 and
(Me3Si)3SiH,20 and its furoyloxy group was cleaved by
Dibal-H to give 9.21 The hydroxyl group of 9 was
converted to the nitrile group (10), which was in turn
transformed to the known aldehyde 11 (Scheme 6).
SCHEME 6a
29
Comparison of its specific rotation ([R]D +41.3 (c 0.35,
24
CHCl3)) with the reported value, [R]D +20.2 (c 0.50,
CHCl3) for (S)-11 with 45% ee,22a clearly disclosed that
its absolute stereochemistry was S; therefore, (-)-2a has
S-chirality at the C3 position. The optical purity of 11
was determined to be 99% by the HPLC analysis using
a chiral column, Daicel Chiralcel OD, and confirmed
complete retention of the chiral integrity during these
transformations. The absolute stereochemistries of all
other products (-)-2b-h were tentatively assigned to be
S on the basis of the similarity of their specific rotation
to that of (-)-2a .
Because the conversion of (R)-11 to (+)-esermethole
and (+)-physostigmine has already been attained,22b (S)-
11 can lead to natural (-)-esermethole and (-)-physo-
stigmine.
a
Reagents and conditions: (a) (1) MeP(OPh)3I, DMF, 120 °C;
Lip a se-Ca ta lyzed Hyd r olytic Desym m etr iza tion
of P r och ir a l P r op a n e-1,3-d iyl Difu r oa te a n d m eso-
Cycloh exa n e-1,2-d iyl Difu r oa te. The desymmetriza-
tion of prochiral 2-substituted propane-1,3-diyl diacetates
such as 12a has been known to be troublesome, because
the racemization of the product 13a gradually took place
during the enzymatic reaction in phosphate buffer (pH
7).9c,e,g,h We briefly investigated the applicability of the
newly developed difuroate protocol to this system. The
hydrolysis of the corresponding difuroate 12b was at-
(2) 2,2′-azobis(2,4-dimethyl-4-methoxyvaleronitrile) (V-70L),
(Me3Si)3SiH, C6H6, 50 °C. (b) Dibal-H, toluene -78 °C. (c) (1) I2,
35% NaOH, MeOH, room temp; (2) BH3‚Me2S, THF, room temp;
(3) Dess-Martin periodinane, CH2Cl2, 0 °C.
tained using CAL-B (Candida antarctica lipase, fraction
i
B) in a 1:1 mixture of Pr2O and water to give 13b (75%
ee, 55% yield) (Scheme 7). The comparison of the stability
of 13b and the acetate 13a in a phosphate buffer (pH
7.2) revealed the efficacy of our furoate method (Figure
2). The superior stability of 13b over 13a was also
apparent under acidic conditions [0.1 equiv of camphor-
sulfonic acid, CH2Cl2, room temperature, 30 h] (Figure
3).
(19) Matsugi, M.; Gotanda, K.; Ohira, C.; Suemura, M.; Sano, A.;
Kita, Y. J . Org. Chem. 1999, 64, 6928-6930.
(20) Chatgilialoglu, C.; Griller, D.; Lesage, M. J . Org. Chem. 1988,
53, 3641-3642.
(21) Alkaline hydrolysis of 8 (99% ee) using K2CO3 in MeOH at room
temperature caused a significant racemization of 9 (12% ee) probably
via the retro-aldol-aldol reaction.10c The use of Dibal-H successfully
cleaved the ester bonding of 8 to give 9 (99% ee, 50% yield, 77% yield
based on the consumed 8) and the recovered 8 (35% yield).
(22) (a) Ashimori, A.; Bachand, B.; Overman, L. E.; Poon, D. J . J .
Am. Chem. Soc. 1998, 120, 6477-6487. (b) Ashimori, A.; Bachand, B.;
Calter, M. A.; Govek, S. P.; Overman, L. E.; Poon, D. J . J . Am. Chem.
Soc. 1998, 120, 6488-6499.
The hydrolysis of the meso-diacetates 15a is another
example of the easy racemization of the product 16a .9a,b,j
The desymmetrization of the corresponding difuroate 15b
proceeded slowly in a 1:1 mixture of Pr2O and water at
50 °C to give optically pure 16b (20% yield) after 24 h
(Scheme 8). The satisfactory stability of 16b was again
i
2482 J . Org. Chem., Vol. 69, No. 7, 2004

Enantiodivergent Preparation of Optically Active Oxindoles
SCHEME 7
SCHEME 8
F IGURE 2. Comparison of the stability of 13a and 13b in
phosphate buffer.
certified by the comparison with the acetate 16a under
acidic conditions (Figure 4).23
Con clu sion
The efficient preparation of either enantiomer of the
oxindoles 2 bearing a stereogenic quaternary carbon
center at the C3 position was developed by two comple-
mentary methods, viz., the enantioselective transesteri-
fication of the prochiral diols 3 and the enantioselective
hydrolysis of the prochiral difuroates 4. These methods
conveniently give access to indole derivatives 2a -h , with
various N-protective groups such as Boc, Cbz, Ac, Me,
MOM, and Bn, in excellent optical purity, from readily
available starting materials in few steps. The formation
of the racemization-resistant monofuroates 2 is another
noticeable advantage of both methods, for which the use
of the furoyl donor 5 (for the transesterification) and the
difuroates 4 (for the hydrolysis) is crucial.
F IGURE 3. Comparison of the stability of 13a and 13b under
acidic conditions.
The transesterification approach is more advantageous
than the hydrolysis approach in terms of the fewer steps
and generally higher chemical yields. An example is the
preparation of (+)-2b (99% ee, 69% overall yield) in three
steps from commercial 6a . In this study, the effective use
of a mixed solvent system, Pr2O-THF for polar sub-
strates was elucidated, and this method would be ap-
plicable for a wide range of substrates.
Additionally, the first successful examples of the use
of aromatic diesters for the enzymatic hydrolytic desym-
metrization were discovered in this study. Although the
reaction is usually slow and the overhydrolysis from the
monofuroates to the diols resulted in the decreased yields
of the products, this method has opened an alternative
approach for the preparation of racemization-resistant
products by enzymatic hydrolysis.
F IGURE 4. Comparison of the stability of 16a and 16b under
acidic conditions.
i
Exp er im en ta l Section
Ma ter ia ls. Lipases MY (from C. rugosa) and OF (from C.
rugosa) were gifts from Meito Sangyo Co., Ltd., J apan. CAL-B
(C. antarctica lipase, fraction B) and CHIRAZYME L-9 (from
Mucor miehei) were gifts from Roche Diagnostics. Yields refer
1
to the isolated material of g95% purity as determined by H
NMR. The known compounds (5,10b 6b,5a 6c,12 7a ,13 7b,14 7e,14
7g,7 7h ,15 13a ,9e,h and 16a 9b,j) were prepared according to the
reported procedure. The compounds (6a , 7f, 14, and 17) were
commercially available and used as purchased.
5-Meth oxy-1-(ter t-bu toxyca r bon yl)oxin d ole (7c). Under
a nitrogen atmosphere, a mixture of 6b (0.20 g, 1.23 mmol),
(Boc)2O (0.67 g, 3.1 mmol), and NaHCO3 (0.92 g, 11 mmol) in
anhydrous THF (17 mL) was heated at refluxing temperature
(23) We have reported the higher stability of 16b in comparison to
that of 16a during the standard SiO2 column chromatography.10b
J . Org. Chem, Vol. 69, No. 7, 2004 2483

Akai et al.
for 2.5 h. After cooling, the reaction mixture was filtered, and
the filtrate was concentrated in vacuo. The residue was
purified by column chromatography (hexanes-EtOAc, 4:1) to
give 7c (0.25 g, 78% yield) as white crystals; mp 124-125 °C.
1H NMR (CDCl3, 270 MHz): δ 1.64 (9H, s), 3.62 (2H, s), 3.80
(3H, s), 6.80-6.82 (2H, m), 7.70 (1H, d, J ) 9.5 Hz). 13C NMR
(CDCl3, 68 MHz): δ 28.2, 36.9, 55.6, 84.1, 110.4, 112.7, 115.8,
124.4, 134.3, 149.1, 156.5, 172.9. IR (KBr): 1790-1770, 1713
cm-1. Anal. Calcd for C14H17NO4: C, 63.87; H, 6.51; N, 5.32.
Found: C, 63.78; H, 6.50; N, 5.30.
and concentrated in vacuo. The residue was purified by column
chromatography (hexanes-EtOAc, 3:1 to 2:1)24 to give the
monoester (R)-2b (109 mg, 83% yield) and the diester 4b (24
mg, 15% yield). The reaction conditions, the isolated yield, and
the optical purity of other products (R)-2a ,c-h are listed in
Table 2. The 2 g-scale reaction (entry 3) was carried out by
the same procedure using the same ratio of the substrate, the
reagents, and the solvent. The optical purity of (R)-2 was
determined by HPLC using chiral columns: Daicel Chiralcel
OD for 2a -d ,f, Chiralpak AD for 2e,g, and Chiralcel OJ for
2h .
6-Meth oxy-1-(ter t-bu toxyca r bon yl)oxin d ole (7d ). Simi-
larly to the preparation of 7c, 7d (0.33 g, 81% yield) was
obtained from 6c (0.26 g, 1.56 mmol). White crystals; mp 77-
(R)-(+)-[3-(Hyd r oxym eth yl)-1-m eth yloxin d ol-3-yl]m e-
27
th yl 2-F u r oa te (2a ). A pale yellow oil, 87% ee; [R]D +63.3
(c 1.1, CHCl3). 1H NMR (CDCl3, 300 MHz): δ 3.19 (3H, s), 3.82
(1H, d, J ) 11.0 Hz), 3.99 (1H, d, J ) 11.0 Hz), 4.46 (1H, d, J
) 11.0 Hz), 4.77 (1H, d, J ) 11.0 Hz), 6.40 (1H, d, J ) 3.0 Hz),
6.83 (1H, d, J ) 7.5 Hz), 6.96 (1H, d, J ) 3.0 Hz), 7.01 (1H, t,
J ) 7.5 Hz), 7.25 (1H, d, J ) 7.5 Hz), 7.29 (1H, t, J ) 7.5 Hz),
7.48 (1H, s). 13C NMR (CDCl3, 75 MHz): δ 26.3, 29.6, 63.8,
64.4, 108.4, 111.8, 118.3, 123.0, 124.1, 127.5, 129.1, 143.9,
144.0, 146.6, 158.0, 176.5. IR (KBr): 3700-3200, 1713, 1693
cm-1. High-resolution EIMS calcd for C16H15NO5 (M+), 301.0950;
found, 301.0979.
1
78 °C. H NMR (CDCl3, 300 MHz): δ 1.65 (9H, s), 3.28 (2H,
s), 3.82 (3H, s), 6.67 (1H, dd, J ) 2.0, 8.0 Hz), 7.11 (1H, d, J
) 8.0 Hz), 7.43 (1H, d, J ) 2.0 Hz). 13C NMR (CDCl3, 75
MHz): δ 28.0, 35.9, 55.5, 84.3, 101.9, 109.7, 114.8, 124.6, 141.8,
149.1, 159.6, 173.7. IR (KBr): 1800-1770, 1728 cm-1. Anal.
Calcd for C14H17NO4: C, 63.87; H, 6.51; N, 5.32. Found: C,
63.73; H, 6.50; N, 5.14.
3,3-Bis(h ydr oxym eth yl)-1-m eth yloxin d ole (3a ). A Typ i-
ca l P r oced u r e for P r ep a r a tion of Diols 3 fr om 7. An
aqueous 37% HCHO solution (1.7 mL) was added to a mixture
of 7a (1.15 g, 7.8 mmol) and Na2CO3 (170 mg, 1.6 mmol) in
dioxane (6.5 mL). After the mixture was stirred at room
temperature for 17 h, an aqueous 37% HCHO solution (0.22
mL) was added. The stirring was continued for further 2.5 h,
and the reaction mixture was filtered. The filtrate was
concentrated in vacuo, and the residue was purified by column
chromatography (hexanes-EtOAc) to give 3a (1.18 g, 73%
yield) as white crystals; mp 161-162 °C. 1H NMR (CD3OD,
300 MHz): δ 3.20 (3H, s), 3.80 (2H, d, J ) 11.0 Hz), 3.90 (2H,
d, J ) 11.0 Hz), 6.98 (1H, d, J ) 7.5 Hz), 7.10 (1H, dt, J ) 1.0,
7.5 Hz), 7.31 (1H, dt, J ) 1.0, 7.5 Hz), 7.42 (1H, d, J ) 7.5
Hz). 13C NMR (CD3OD, 75 MHz): δ 26.4, 59.2, 64.7, 109.3,
123.7, 125.0, 129.4, 130.9, 146.0, 179.6. IR (KBr): 3700-3100,
1695-1610 cm-1. Anal. Calcd for C11H13NO3: C, 63.76; H, 6.32;
N, 6.76. Found: C, 63.66; H, 6.32; N, 6.74.
3,3-Bis(2-fu r oyloxym eth yl)-1-m eth yloxin dole (4a). Typi-
ca l P r oced u r e for P r ep a r a tion of Difu r oa tes 4 fr om 3.
Under a nitrogen atmosphere, a mixture of 3a (0.81 g, 3.9
mmol), furan-2-carboxylic acid (1.31 g, 11.7 mmol), DCC (2.4
g, 11.7 mmol), and DMAP (0.24 g, 2.0 mmol) in anhydrous THF
(23 mL) was stirred at room temperature for 15 h. Water (10
mL) was added, and the mixture was stirred vigorously. The
product was extracted with EtOAc three times, and the
combined organic layer was washed with brine, dried with Na2-
SO4, and concentrated in vacuo. The residue was purified by
column chromatography (hexanes-EtOAc, 1:1) to give 4a (1.48
g, 96% yield) as white crystals; mp 106.5-107 °C. 1H NMR
(CDCl3, 300 MHz): δ 3.29 (3H, s), 4.55 (2H, d, J ) 11.0 Hz),
4.88 (2H, d, J ) 11.0 Hz), 6.47 (2H, dd, J ) 2.0, 3.5 Hz), 6.90
(1H, dd, J ) 1.0, 7.5 Hz), 7.05 (2H, dd, J ) 1.0, 3.5 Hz), 7.06
(1H, dt, J ) 1.0, 7.5 Hz) 7.33 (1H, dt, J ) 1.0, 7.5 Hz), 7.45
(1H, dd, J ) 1.0, 7.5 Hz). 7.56 (2H, dd, J ) 1.0, 2.0 Hz). 13C
NMR (CDCl3, 75 MHz): δ 26.4, 51.9, 64.7, 108.2, 111.8, 118.4,
122.9, 124.6, 127.0, 129.3, 143.8, 143.9, 146.7, 157.8, 174.3.
IR (KBr): 1730-1710 cm-1. Anal. Calcd for C21H17NO7: C,
63.80; H, 4.33; N, 3.54. Found: C, 63.89; H, 4.52; N, 3.53.
(R)-(+)-[3-(Hyd r oxym eth yl)-1-(ter t-bu toxyca r bon yl)ox-
in d ol-3-yl]m eth yl 2-F u r oa te (2b). White crystals, 97% ee;
27
1
mp 125-126 °C; [R]D +56.3 (c 1.1, CHCl3). H NMR (CDCl3,
300 MHz): δ 1.64 (9H, s), 3.96 (1H, d, J ) 11.0 Hz), 4.04 (1H,
d, J ) 11.0 Hz), 4.57 (1H, d, J ) 11.0 Hz), 4.79 (1H, d, J )
11.0 Hz), 6.45 (1H, dd, J ) 1.5, 3.5 Hz), 6.99 (1H, d, J ) 3.5
Hz), 7.17 (1H, t, J ) 7.5 Hz), 7.34 (1H, t, J ) 7.5 Hz), 7.40
(1H, d, J ) 7.5 Hz), 7.54 (1H, d, J ) 1.5 Hz), 7.86 (1H, d, J )
7.5 Hz). 13C NMR (CDCl3, 75 MHz): δ 27.9, 54.3, 64.2, 64.9,
84.7, 111.8, 115.0, 118.4, 123.7, 124.6, 126.4, 129.0, 140.0,
143.6, 146.7, 148.8, 157.8, 175.1. IR (KBr): 3700-3200, 1790-
1720 cm-1. Anal. Calcd for C20H21NO7: C, 62.01; H, 5.46; N,
3.62. Found: C, 61.71; H, 5.46; N, 3.60.
(R)-(+)-[3-(Hyd r oxym eth yl)-5-m eth oxy-1-(ter t-bu toxy-
ca r bon yl)oxin d ol-3-yl]m eth yl 2-F u r oa te (2c). White crys-
tals, 98% ee; mp 140-140.5 °C; [R]D27 +49.8 (c 1.1, CHCl3). 1H
NMR (CDCl3, 300 MHz): δ 1.65 (9H, s), 3.78 (3H, s), 3.95 (1H,
d, J ) 11.0 Hz), 4.07 (1H, d, J ) 11.0 Hz), 4.59 (1H, d, J )
11.0 Hz), 4.79 (1H, d, J ) 11.0 Hz), 6.47 (1H, dd, J ) 1.5, 3.5
Hz), 6.87 (1H, dd, J ) 2.5, 9.0 Hz), 6.96 (1H, d, J ) 2.5 Hz),
7.04 (1H, d, J ) 3.5 Hz), 7.56 (1H, br s), 7.81 (1H, d, J ) 9.0
Hz). 13C NMR (CDCl3, 75 MHz): δ 28.1, 54.4, 55.6, 64.4, 64.8,
84.7, 110.0, 111.9, 114.0, 116.0, 118.5, 127.6, 133.4, 143.8,
146.7, 148.9, 157.0, 157.9, 175.2. IR (KBr): 3625-3250, 1786,
1770, 1732 cm-1. Anal. Calcd for C21H23NO8: C, 60.43; H, 5.55;
N, 3.36. Found: C, 60.28; H, 5.58; N, 3.28.
(R)-(+)-[3-(Hyd r oxym eth yl)-6-m eth oxy-1-(ter t-bu toxy-
ca r bon yl)oxin d ol-3-yl]m eth yl 2-F u r oa te (2d ). White crys-
tals. Recrystallization from benzene gave 2d (99% ee); mp
136-136.5 °C; [R]D26 +69.6 (c 1.0, CHCl3) for 99% ee. 1H NMR
(CDCl3, 300 MHz): δ 1.65 (9H, s), 3.83 (3H, s), 3.91 (1H, d, J
) 11.0 Hz), 4.03 (1H, d, J ) 11.0 Hz), 4.56 (1H, d, J ) 11.0
Hz), 4.78 (1H, d, J ) 11.0 Hz), 6.48 (1H, dd, J ) 1.5, 3.5 Hz),
6.71 (1H, dd, J ) 2.5, 8.0 Hz), 7.05 (1H, d, J ) 3.5 Hz), 7.27
(1H, d, J ) 8.0 Hz), 7.53 (1H, d, J ) 2.5 Hz), 7.56 (1H, d, J )
2.0 Hz); 13C NMR (CDCl3, 75 MHz): δ 28.1, 53.8, 55.5, 64.5,
64.9, 84.9, 102.2, 110.2, 111.9, 117.6, 117.9, 118.5, 124.4, 141.2,
143.8, 146.7, 157.9, 160.6, 175.7. IR (KBr): 3625-3250, 1790,
1775, 1732 cm-1. Anal. Calcd for C21H23NO8: C, 60.43; H, 5.55;
N, 3.36. Found: C, 60.70; H, 5.70; N, 3.56.
Typ ica l P r oced u r e for Lip a se-Ca ta lyzed Desym m e-
tr iza tion of P r och ir a l Diols 3a -h Usin g 5. To a resealable
i
vessel were added Pr2O (55 mL), THF (11 mL), and water
(0.07 mL). The diol 3b (100 mg, 0.34 mmol), 5 (187 mg, 1.0
mmol), and lipase OF (180 mg) were added in this order, and
the vessel was sealed. The reaction mixture was stirred at 30
°C with monitoring the reaction by TLC. When 3b was
consumed, the reaction mixture was filtered through a Celite
pad. Water (100 mL) was added to the filtrate, and the mixture
was stirred vigorously at room temperature until 5 disap-
peared (TLC analysis; usually for 30 min to 5 h). The organic
layer was separated, and the aqueous layer was extracted with
EtOAc. The combined organic layer was dried with Na2SO4
(R)-(+)-[1-Ben zyloxyca r bon yl-3-(h yd r oxym eth yl)oxin -
d ol-3-yl]m eth yl 2-F u r oa te (2e). White crystals, 98% ee; mp
136-137 °C; [R]D +56.4 (c 1.04, CHCl3). 1H NMR (CDCl3,
28
300 MHz): δ 3.89 (1H, d, J ) 11.0 Hz), 4.00 (1H, d, J ) 11.0
Hz), 4.53 (1H, d, J ) 11.0 Hz), 4.74 (1H, d, J ) 11.0 Hz), 5.39
(24) Occasionally, a product was obtained with a small amount of
furan-2-carboxylic acid as a contaminant after standard SiO2 flash
chromatography. Use of the eluent containing 1 v/v % of Et3N for the
chromatography was effective to prevent the contamination.
2484 J . Org. Chem., Vol. 69, No. 7, 2004

Enantiodivergent Preparation of Optically Active Oxindoles
(2H, s), 6.35 (1H, dd, J ) 2.0, 3.5 Hz), 6.88 (1H, d, J ) 3.5
Hz), 7.13 (1H, t, J ) 7.5 Hz), 7.26-7.36 (5H, m), 7.43-7.46
(3H, m), 7.87 (1H, d, J ) 8.0 Hz). 13C NMR (CDCl3, 75 MHz):
δ 54.5, 64.5, 64.8, 68.9, 111.9, 115.3, 118.6, 123.8, 125.1, 128.2,
128.6, 128.7, 129.4, 134.7, 139.7, 143.6, 146.8, 150.5, 157.8,
175.0. IR (KBr): 3700-3200, 1790, 1760, 1730 cm-1. Anal.
Calcd for C23H19NO7: C, 65.55; H, 4.54; N, 3.32. Found: C,
65.37; H, 4.70; N, 3.30.
(S)-(-)-[3-(Hyd r oxym eth yl)-1-(ter t-bu toxyca r bon yl)ox-
28
in d ol-3-yl]m eth yl 2-F u r oa te (2b): >99% ee; [R]D -53.8 (c
0.80, CHCl3).
(S)-(-)-[3-(Hyd r oxym eth yl)-5-m eth oxy-1-(ter t-bu toxy-
ca r bon yl)oxin d ol-3-yl]m eth yl 2-F u r oa te (2c): >99% ee;
27
[R]D -46.1 (c 1.1, CHCl3).
(S)-(-)-[3-(Hyd r oxym eth yl)-6-m eth oxy-1-(ter t-bu toxy-
ca r bon yl)oxin d ol-3-yl]m eth yl 2-F u r oa te (2d ): 82% ee;
28
[R]D -41.4 (c 0.91, CHCl3).
(R)-(+)-[1-Acetyl-3-(h yd r oxym eth yl)oxin d ole-3-yl]m e-
th yl 2-F u r oa te (2f). White crystals, 97% ee; mp 122-122.5
(S)-(-)-[1-Ben zyloxyca r bon yl-3-(h yd r oxym eth yl)oxin -
28
d ol-3-yl]m eth yl 2-F u r oa te (2e): >99% ee; [R]D -56.3 (c
27
1
°C; [R]D +20.1 (c 1.1, CHCl3). H NMR (CDCl3, 270 MHz): δ
2.71 (3H, s), 4.00 (1H, d, J ) 11.0 Hz), 4.08 (1H, d, J ) 11.0
Hz), 4.61 (1H, d, J ) 11.0 Hz), 4.80 (1H, d, J ) 11.0 Hz), 6.46
(1H, dd, J ) 1.5, 3.5 Hz), 6.70 (1H, d, J ) 3.5 Hz), 7.21-7.26
(1H, m), 7.35-7.42 (2H, m), 7.55 (1H, s), 8.27 (1H, d, J ) 7.5
Hz). 13C NMR (CDCl3, 68 MHz): δ 26.8, 54.8, 64.6, 64.8, 111.9,
116.7, 118.5, 123.3, 125.4, 126.3, 129.4, 140.6, 143.8, 146.7,
157.7, 170.5, 177.3. IR (KBr): 3600-3180, 1770-1740, 1725,
1713 cm-1. High-resolution FABMS calcd for C17H16NO6 [(M
+ H)+], 330.0978; found, 330.0959.
0.97, CHCl3).
(S)-(-)-[1-Acetyl-3-(h yd r oxym eth yl)oxin d ole-3-yl]m e-
27
th yl 2-F u r oa te (2f): 97% ee; [R]D -21.8 (c 0.63, CHCl3).
(S)-(-)-[3-Hyd r oxym eth yl-1-(m eth oxym eth yl)oxin d ol-
27
3-yl]m eth yl 2-F u r oa te (2g): 98% ee; [R]D -26.0 (c 0.73,
CHCl3).
(S)-(-)-[1-Ben zyl-3-(h yd r oxym et h yl)oxin d ol-3-yl]m e-
27
th yl 2-F u r oa te (2h ): 98% ee; [R]D -45.0 (c 1.1, CHCl3).
(S)-(-)-[3-(Hydr oxym eth yl)-1-(m eth oxym eth yl)oxin dol-
3-yl]m eth yl 2-Ben zoa te (2i). Similarly to the typical proce-
dure for the desymmetrization of 4a -h , 4i (20 mg, 0.040 mmol)
(R)-(+)-[3-Hyd r oxym eth yl-1-(m eth oxym eth yl)oxin d ol-
27
3-yl]m eth yl 2-F u r oa te (2g). Colorless oil, 86% ee; [R]D
i
and lipase OF (40 mg) were stirred in a mixture of Pr2O-
+19.7 (c 0.89, CHCl3). 1H NMR (CDCl3, 300 MHz): δ 3.34 (3H,
s), 3.95 (1H, d, J ) 11.0 Hz), 4.08 (1H, d, J ) 11.0 Hz), 4.60
(1H, d, J ) 11.0 Hz), 4.87 (1H, d, J ) 11.0 Hz), 5.15 (1H, d, J
) 11.0 Hz), 5.21 (1H, d, J ) 11.0 Hz), 6.46 (1H, dd, J ) 1.5,
3.5 Hz), 7.02 (1H, d, J ) 3.5 Hz), 7.08-7.15 (2H, m), 7.34 (1H,
dt, J ) 1.0, 7.5 Hz), 7.39 (1H, d, J ) 7.5 Hz), 7.53 (1H, d, J )
1.5 Hz). 13C NMR (CDCl3, 68 MHz): δ 54.2, 56.3, 64.3, 64.6,
71.2, 109.8, 111.8, 118.3, 123.4, 123.9, 126.8, 129.1, 142.2,
143.8, 146.5, 157.8, 177.0. IR (KBr): 3600-3200, 1730-1710
cm-1. Anal. Calcd for C17H17NO6: C, 61.63; H, 5.17; N, 4.23.
Found: C, 61.50; H, 5.25; N, 4.16.
THF (5:1, 4.0 mL) and water (2.0 mL) at 30 °C for 24 h. The
reaction mixture was filtered through a Celite pad, and the
filtrate was concentrated in vacuo. The residue was purified
by column chromatography (hexanes-EtOAc, 2:1) to give (S)-
2i (5.8 mg, 37% yield) and 3g (6.0 mg, 63% yield). (S)-2i was
obtained as a colorless oil. The optical purity was determined
to be 98% ee by HPLC using a Daicel Chiralpak AS. The
absolute
stereochemistry
is
tentatively
presumed
to be S on the basis of the similarity of its specific rotation
{[R]D27 -37.2 (c 1.0, CHCl3)} to that of (S)-2a . 1H NMR (CDCl3,
300 MHz): δ 3.32 (3H, s), 3.97 (1H, d, J ) 11.0 Hz), 4.10 (1H,
d, J ) 11.0 Hz), 4.70 (1H, d, J ) 11.0 Hz), 4.84 (1H, d, J )
11.0 Hz), 5.16 (1H, d, J ) 11.0 Hz) 5.21 (1H, d, J ) 11.0 Hz),
7.05 (2H, t, J ) 7.5 Hz), 7.30 (4H, dt, J ) 2.5, 7.5 Hz), 7.45
(1H, t, J ) 7.5 Hz), 7.75 (2H, d, J ) 7.5 Hz). 13C NMR (CDCl3,
75 MHz): δ 54.4, 56.4, 64.3, 64.9, 71.3, 109.9, 123.5, 123.9,
127.1, 128.4, 129.2, 129.5, 133.2, 142.4, 166.0, 177.4. IR
(KBr): 3650-3200, 1724, 1614 cm-1. High-resolution FABMS
calcd for C19H20NO5 [(M + H)+], 342.1341; found, 342.1353.
(S)-(+)-3-(2-Oxoeth yl)-1,3-d im eth yoxin d ole (11). A mix-
ture of (S)-10 (100 mg, 0.50 mmol), an aqueous 35% NaOH
solution (2.0 mL), and MeOH (2.0 mL) was stirred at room
temperature for 3 h, which was acidified with 2 N HCl. The
product was extracted with EtOAc three times, and the
combined organic layer was washed with brine, dried with Na2-
SO4, and concentrated in vacuo. The residue was purified by
column chromatography (hexanes-EtOAc, 2:1 to 1:1) to give
(S)-1,3-dimethyloxindol-3-yl acetic acid (107 mg, 97% yield) as
(R)-(+)-[1-Ben zyl-3-(h yd r oxym et h yl)oxin d ol-3-yl]m e-
25
th yl 2-F u r oa te (2h ). A colorless oil, 68% ee; [R]D +33.9 (c
1.1, CHCl3). 1H NMR (CDCl3, 300 MHz): δ 3.95 (1H, d, J )
11.0 Hz), 4.08 (1H, d, J ) 11.0 Hz), 4.64 (1H, d, J ) 11.0 Hz),
4.83 (1H, d, J ) 16.0 Hz), 4.92 (1H, d, J ) 11.0 Hz), 5.08 (1H,
d, J ) 16.0 Hz), 6.41 (1H, dd, J ) 1.5, 3.5 Hz), 6.76 (1H, d, J
) 7.5 Hz), 6.87 (1H, d, J ) 3.5 Hz), 7.03 (1H, t, J ) 7.5 Hz),
7.19 (1H, dt, J ) 1.0, 7.5 Hz), 7.24-7.31 (5H, m), 7.37 (1H, d,
J ) 7.5 Hz), 7.52 (1H, d, J ) 1.5 Hz). 13C NMR (CDCl3, 75
MHz): δ 43.8, 53.8, 64.3, 64.7, 109.4, 111.8, 118.3, 123.0, 127.2,
127.5, 127.6, 128.8, 128.9, 135.4, 143.1, 143.9, 146.6, 158.0,
176.7. IR (KBr): 3700-3200, 1740-1690 cm-1. High-resolution
FABMS calcd for C22H20NO5 [(M + H)+], 378.1342; found,
378.1342.
Typ ica l P r oced u r e for Lip a se-Ca ta lyzed Desym m e-
tr iza tion of Difu r oa tes 4a -h . A solution of 4a (500 mg, 1.26
1
i
pale yellow crystals; mp 175-175.5 °C. H NMR (CDCl3, 300
mmol) in a 5:1 mixture of Pr2O-THF (50 mL) was placed in
MHz): δ 1.30 (3H, s), 2.73 (1H, d, J ) 16.5 Hz), 2.91 (1H, d,
J ) 16.5 Hz), 3.14 (3H, s), 6.78 (1H, br d, J ) 7.5 Hz), 7.00
(1H, br t, J ) 7.5 Hz), 7.12 (1H, br d, J ) 7.5 Hz), 7.21 (1H,
dt, J ) 1.0 Hz, 7.5 Hz). 13C NMR (CDCl3, 75 MHz): δ 23.9,
26.5, 41.3, 45.3, 108.4, 122.3, 122.8, 128.3, 132.7, 143.1, 174.0,
180.3. IR (KBr): 3350-2800, 1730-1675, 1614 cm-1. High-
resolution FABMS calcd for C12H14NO3 [(M + H)+], 220.0974;
found, 220.0974.
Under a nitrogen atmosphere, BH3‚Me2S (2.0 M in THF,
0.070 mL, 0.14 mmol) was added to an ice-cooled solution of
the above product (30 mg, 0.14 mmol) in anhydrous THF (0.3
mL). The reaction mixture was stirred at room temperature
for 9 h and quenched with MeOH (1 mL). The whole mixture
was concentrated in vacuo, and the residue was purified by
column chromatography (hexanes-EtOAc, 1:1 to EtOAc) to
give (S)-3-(2-hydroxyethyl)-1,3-dimethyloxindole (25 mg, 89%
yield) as a yellow oil. 1H NMR (CDCl3, 270 MHz): δ 1.34 (3H,
s), 1.89-2.00 (1H, m), 2.04-2.14 (1H, m), 3.15 (3H, s), 3.30-
3.42 (1H, m), 3.54-3.62 (1H, m), 6.79 (1H, br d, J ) 8.0 Hz),
7.01 (1H, dt, J ) 1.0, 8.0 Hz), 7.10 (1H, br d, J ) 8.0 Hz), 7.21
a resealable vessel, and water (50 mL) and lipase OF (500 mg)
were added. The vessel was sealed, and the reaction mixture
was stirred at 30 °C with monitoring the reaction by TLC.
When 4a was consumed, water (20 mL) and EtOAc (80 mL)
were added to the reaction mixture. The organic layer was
separated, and the aqueous layer was extracted with EtOAc
three times. The combined organic layer was washed with
brine, dried with Na2SO4, and concentrated in vacuo. The
residue was purified by column chromatography (hexanes-
EtOAc with 1 v/v % of Et3N)24 to give (S)-2a and 3a . The
reaction conditions, the isolated yield, and the optical purity
of (S)-2b-h are listed in Table 2. The 2 g-scale reaction (entry
12) was carried out by the same procedure using the same ratio
of substrate, reagents, and solvent. The optical purity of (S)-
2a -h was determined as described for (R)-2 obtained by the
desymmetrization of 3. The spectroscopic data of (S)-2a -h
were identical with those of (R)-2a -h .
(S)-(-)-[3-(Hyd r oxym eth yl)-1-m eth yloxin d ol-3-yl]m e-
25
th yl 2-F u r oa te (2a ): >99% ee; [R]D -66.6 (c 0.79, CHCl3).
J . Org. Chem, Vol. 69, No. 7, 2004 2485

Akai et al.
(1H, dt, J ) 1.0, 8.0 Hz). 13C NMR (CDCl3, 75 MHz): δ 23.5,
26.3, 39.9, 46.9, 59.3, 108.3, 122.4, 122.8, 128.0, 134.0, 142.8,
181.6. IR (KBr): 3550-3300, 1720-1690 cm-1. High-resolution
FABMS calcd for C12H16NO2 [(M + H)+], 206.1181; found,
206.1191.
A mixture of the above product (20 mg, 0.10 mmol) and
Dess-Martin periodinane (124 mg, 0.30 mmol) in CH2Cl2 (0.80
mL) was stirred at 0 °C for 30 min, and the reaction mixture
was quenched with saturated aqueous Na2S2O3 solution. After
vigorous stirring for 10 min, the reaction mixture was parti-
tioned between saturated aqueous NaHCO3 and EtOAc. The
organic layer was separated, and the aqueous layer was
extracted with EtOAc twice. The combined organic layer was
washed with brine, dried with Na2SO4, and concentrated in
vacuo. The residue was purified by column chromatography
(hexanes-EtOAc, 1:1) to give (S)-(+)-11 (18 mg, 92% yield)
as a pale yellow oil. The optical purity of the product was
determined to be 99% ee on the basis of HPLC analysis using
63.4, 72.2, 77.0, 111.9, 118.3, 127.8, 127.9, 128.4, 137.7, 144.2,
146.5, 158.5. IR (KBr): 3550-3200, 1730-1710 cm-1. Anal.
Calcd for C15H16O5: C, 65.21; H, 5.84. Found: C, 64.80; H,
5.95.
(1S,2R)-2-Hyd r oxycycloh ex-1-yl 2-F u r oa te (16b). Simi-
larly to the typical procedure for the enzymatic hydrolysis of
4, a mixture of 15b (40 mg, 0.13 mmol) and CHIRAZYME L-9
(80 mg) was stirred in a 1:1 mixture of iPr2O and water (total
2.0 mL) at 50 °C for 24 h. The workup and the purification
were similarly performed to give 16b (5.4 mg, 20% yield), 17
(2.3 mg, 15% yield), and recovered 15b (24 mg, 61% yield).
The optical purity of 16b was determined to be 99% ee on the
basis of HPLC analysis using Daicel Chiralcel OJ . Colorless
oil; [R]D27 +2.5 (c 0.79, CHCl3) {lit.10b [R]D22 -2.5 (c 1.0, CHCl3)
1
for (1R,2S)-16b with 97% ee}. H NMR (CDCl3, 300 MHz): δ
1.25-2.05 (9H, m), 3.97 (1H, d, J ) 6.0 Hz), 5.17 (1H, dt, J )
3.0, 8.0 Hz), 6.52 (1H, dd, J ) 1.0, 3.0 Hz), 7.21 (1H, d, J )
3.0 Hz), 7.60 (1H, d, J ) 1.0 Hz). 13C NMR (CDCl3, 75 MHz):
δ 21.1, 21.9, 27.1, 30.3, 69.2, 74.8, 111.8, 118.0, 144.7, 146.3,
158.3. High-resolution FABMS calcd for C11H15O4 [(M + H)+],
211.0970; found, 211.0966.
Daicel Chiralcel OD. [R]D29 +41.3 (c 0.35, CHCl3) {lit.22a [R]D
24
+20.2 (c 0.50, CHCl3) for (S)-11 with 45% ee}. 1H NMR (CDCl3,
300 MHz): δ 1.35 (3H, s), 2.91 (2H, s), 3.20 (3H, s), 6.81 (1H,
d, J ) 7.5 Hz), 7.00 (1H, t, J ) 7.5 Hz), 7.12 (1H, d, J ) 7.5
Hz), 7.21 (1H, t, J ) 7.5 Hz), 9.45 (1H, s). 13C NMR (CDCl3,
75 MHz): δ 23.9, 26.4, 45.0, 50.5, 108.4, 122.4, 122.7, 128.3,
Ack n ow led gm en t. This work was supported by
Grants-in-Aid for Scientific Research (S and C) and for
Scientific Research on Priority Area (A) from the
Ministry of Education, Culture, Sports, Science, and
Technology, J apan. S.A. thanks the Takeda Science
Foundation, J apan, for a research fellowship. The Meito
Sangyo Co., Ltd., J apan, and Roche Diagnostics K. K.,
J apan, are thanked for their generous gifts of the
lipases.
132.7, 143.2, 179.5, 198.7. IR (KBr): 1720-1690, 1614 cm-1
.
High-resolution FABMS calcd for C12H14NO2 [(M + H)+],
204.1028; found, 204.1028.
(-)-2-Ben zyloxy-3-h ydr oxypr opan -1-yl 2-Fu r oate (13b).
Similarly to the typical procedure for the enzymatic hydrolysis
of 4, a mixture of 12b (40 mg, 0.108 mmol) and CALB (80 mg)
was stirred in a 1:1 mixture of iPr2O and water (total 2.0 mL)
at 30 °C for 84 h. The reaction mixture was filtered through a
Celite pad, and the filtrate was concentrated in vacuo. The
residue was purified by column chromatography (hexanes-
EtOAc, 2:1) to give (-)-13b (14.9 mg, 55% yield) and 14 (4.8
mg, 26% yield). The optical purity of (-)-13b was determined
to be 75% ee on the basis of HPLC analysis using Daicel
Su p p or tin g In for m a tion Ava ila ble: General methods;
preparation of 3b-h , 4b-i, 12b, and 15b and the conversion
1
of (S)-(-)-2a to (S)-(+)-10; H NMR and 13C NMR spectra for
compounds 3c,g, (+)-2a , (+)-2f, (+)-2h , (-)-2i, (S)-3-(iodo-
methyl)-1,3-dimethyoxindole, (S)-10, (S)-1,3-dimethyloxindol-
3-yl acetic acid, (S)-3-(2-hydroxyethyl)-1,3-dimethyloxindole,
(S)-11, 12b, 15b, and (1S,2R)-16b. This material is available
free of charge via the Internet at http://pubs.acs.org.
Chiralcel OD. Colorless oil; [R]D -10.0 (c 0.74, CHCl3). 1H
27
NMR (CDCl3, 300 MHz): δ 3.60-3.75 (3H, m), 4.34 (1H, dd,
J ) 5.5, 11.5 Hz), 4.39 (1H, dd, J ) 5.5, 11.5 Hz), 4.56 (1H, d,
J ) 11.5 Hz), 4.67 (1H, d, J ) 11.5 Hz), 6.43 (1H, dd, J ) 2.0,
3.5 Hz), 7.10 (H, dd, J ) 1.0, 3.5 Hz), 7.18-7.26 (5H, m), 7.50
(1H, dd, J ) 1.0, 2.0 Hz). 13C NMR (CDCl3, 75 MHz): δ 61.8,
J O035749H
2486 J . Org. Chem., Vol. 69, No. 7, 2004