Efficient lipase-catalyzed enantioselective desymmetrization of prochiral 2,2-disubstituted 1,3-propanediols and meso 1,2-diols using 1-ethoxyvinyl 2-furoate

Article abstract of DOI:10.1021/jo010587f

An efficient lipase-catalyzed desymmetrization of prochiral 2,2-disubstituted 1,3-propanediols was developed using 1-ethoxyvinyl 2-furoate 1b, for which the well-known method using vinyl or isopropenyl acetate has had limited success due to low reactivity and easy racemization of the products through acyl group migration. The reagent 1b is highly reactive and converts various prochiral 1,3-diols to the monoesters having a chiral quaternary carbon center with 82-99% ee. These products were stable against racemization under acidic conditions, and their furoyl groups were compatible with oxidative conditions. Prolonging the reaction time led to the kinetic resolution of the monoesters resulting in an increase of their optical purity. The similar desymmetrization of meso cis-1,2-cycloalkanediols gave the monoesters with 82-97% ee without racemization.

Full text of DOI:10.1021/jo010587f

J . Org. Chem. 2002, 67, 411-419
411
Efficien t Lip a se-Ca ta lyzed En a n tioselective Desym m etr iza tion of
P r och ir a l 2,2-Disu bstitu ted 1,3-P r op a n ed iols a n d Meso 1,2-Diols
Usin g 1-Eth oxyvin yl 2-F u r oa te
Shuji Akai, Tadaatsu Naka, Tetsuya Fujita, Yasushi Takebe, Toshiaki Tsujino, and
Yasuyuki Kita*
Graduate School of Pharmaceutical Sciences, Osaka University,
Yamada-oka, Suita, Osaka 565-0871, J apan
kita@phs.osaka-u.ac.jp
Received J une 12, 2001
An efficient lipase-catalyzed desymmetrization of prochiral 2,2-disubstituted 1,3-propanediols was
developed using 1-ethoxyvinyl 2-furoate 1b, for which the well-known method using vinyl or
isopropenyl acetate has had limited success due to low reactivity and easy racemization of the
products through acyl group migration. The reagent 1b is highly reactive and converts various
prochiral 1,3-diols to the monoesters having a chiral quaternary carbon center with 82-99% ee.
These products were stable against racemization under acidic conditions, and their furoyl groups
were compatible with oxidative conditions. Prolonging the reaction time led to the kinetic resolution
of the monoesters resulting in an increase of their optical purity. The similar desymmetrization of
meso cis-1,2-cycloalkanediols gave the monoesters with 82-97% ee without racemization.
Sch em e 1
In tr od u ction
A number of biologically important natural products
contain optically active quaternary carbon center(s).
Highly enantioselective, catalytic syntheses of these
carbon centers have been a challenging area of research
in this decade.1 Though a variety of methods using metal
catalysts have been reported, the enzyme-catalyzed
enantioselective desymmetrization of symmetric com-
pounds are also attractive and have intensively been
investigated.2 The examples include the hydrolysis of
disubstituted malonates,3 the hydrolysis of diesters de-
rived from diols,4 the hydrolysis of diesters of bis-enols,5
and the reduction of 2,2-disubstituted 1,3-diones.6 Whereas
Sch em e 2
these are performed in aqueous media, the enantioselec-
tive transesterification of the 2,2-disubstituted 1,3-pro-
panediols I (Scheme 1) seems to be efficient because of
easy operation in organic solvents, simple workup, reuse
of the lipases, and facile preparation of I. However, this
approach has rarely been reported due to low reactivity
of sterically congested substrates and the easy racemi-
zation of products II through the acyl group migration.7-9
For instance, the reported enzymatic desymmetrization
reactions of a few diols I using well-known acyl donors,
i.e., vinyl and isopropenyl acetates, took several days or
more and suffered from the partial racemization of II in
some cases under acidic7a or hydrogenolysis conditions.9
Likewise meso 1,2-diols III are suitable substrates of
(1) For reviews, see: (a) Fuji, K. Chem. Rev. 1993, 93, 2037-2066.
(b) Corey, E. J .; Guzman-Perez, A. Angew. Chem., Int. Ed. Engl. 1998,
37, 388-401.
(2) For recent reviews, see: (a) Schoffers, E.; Golebiowski, A.;
J ohnson. C. R. Tetrahedron 1996, 52, 3769-3826. (b) Faber, K.
Biotransformations in Organic Chemistry, 3rd ed.; Springer: Berlin,
1997. (c) Schmid, R. D.; Verger, R. Angew. Chem., Int. Ed. Engl. 1998,
37, 1608-1633. (d) Bornscheuer, U. T.; Kazlauskas, R. J . Hydrolases
in Organic Synthesis; Wiley-VCH: Weinheim, Germany, 1999. (e)
Pogorevc, M.; Faber, K. J . Mol. Catal. B 2000, 10, 357-376. (f) Theil,
F. Tetrahedron 2000, 56, 2905-2919.
(3) (a) Canet, J .-L.; Fadel, A.; Salau¨n, J . J . Org. Chem. 1992, 57,
3463-3473. (b) Trost, B. M.; Li, Y. J . Am. Chem. Soc. 1996, 118, 6625-
6633. (c) Fadel, A.; Garcia-Argote, S. Tetrahedron: Asymmetry 1996,
7, 1159-1166. (d) Honda, T.; Ogino, T. Tetrahedron: Asymmetry 1998,
9, 2663-2669. (e) Honda, T.; Koizumi, T.; Komatsuzaki, Y.; Yamashita,
R.; Kanai, K.; Nagase, H. Tetrahedron: Asymmetry 1999, 10, 2703-
2712.
(4) (a) Suemune, H.; Harabe, T.; Xie, Z.-F.; Sakai, K. Chem. Pharm.
Bull. 1988, 36, 4337-4344. For related examples having a heteroatom-
substituent, see: (b) Prasad, K.; Estermann, H.; Chen, C.-P.; Repic,
O.; Hardtmann, G. E. Tetrahedron: Asymmetry 1990, 1, 421-424. (c)
Estermann, H.; Prasad, K.; Shapiro, M. J . Tetrahedron Lett. 1990, 31,
445-448. (d) Watanabe, N.; Sugai, T.; Ohta, H. Chem. Lett. 1992, 657-
660. (e) Ito, T.; Takagi, Y.; Tsukube, H. J . Mol. Catal. B 1997, 3, 259-
270.
(5) Renouf, P.; Poirier, J .-M.; Duhamel, P. J . Chem. Soc., Perkin
Trans. 1 1997, 1739-1745.
(6) Kitahara, T.; Miyake, M.; Kido, M.; Mori, K. Tetrahedron:
Asymmetry 1990, 1, 775-782. Watanabe, H.; Mori, K. J . Chem. Soc.,
Perkin Trans. 1 1991, 2919-2934. See also ref 1a.
(7) (a) Fadel, A.; Arzel, P. Tetrahedron: Asymmetry 1997, 8, 283-
291. (b) Kirihara M.; Takuwa T.; Kawasaki M.; Kakuda H.; Hirokami
S.; Takahata H. Chem. Lett. 1999, 405-406. (c) A similar desymme-
trization of prochiral 2-sila-1,3-propanediols was reported, see: Coelho,
P. J .; Blanco, L. Eur. J . Org. Chem. 2000, 3039-3046.
(8) For similar desymmetrizations of meso 1,5-diols, see: Ihara, M.;
Suzuki, M.; Fukumoto, K.; Kabuto, C. J . Am. Chem. Soc. 1990, 112,
1164-1171. Toyooka, N.; Nishino, A.; Momose, T. Tetrahedron Lett.
1993, 34, 4539-4540.
(9) Racemization of an optically acitve monoacetate like II, obtained
by the enzymatic hydrolysis, was observed during hydrogenolysis using
Pd/C in MeOH.4a
10.1021/jo010587f CCC: $22.00 © 2002 American Chemical Society
Published on Web 12/21/2001

412 J . Org. Chem., Vol. 67, No. 2, 2002
Akai et al.
Sch em e 3
Sch em e 4
Sch em e 5
lipase-catalyzed desymmetrization reactions; however,
easy racemization of products IV has also been an
annoying problem (Scheme 2).10,11
Therefore, to solve these problems, the development
of an acyl donor exhibiting high reactivity and enan-
tiotopic selectivity and generating products stable against
racemization was necessary.
During the course of our research on the lipase-
catalyzed transesterification of alcohols with novel acyl
donors, 1-ethoxyvinyl esters 1,12 we developed 1-ethoxy-
vinyl benzoate 1a as an effective reagent for the desym-
metrization of I.13 The reagent 1a is more useful than
the corresponding reagents having an aliphatic acyl
group in terms of optical purity of the products IIa and
their stability against racemization (Scheme 3). However,
this method was still unsatisfactory for the sterically
congested 1,3-diols such as 2A-D, because the reactions
took 4-7 days and the enantiotopic selectivity was not
very high (up to 70’s % ee) (see Table 2, right column).
Encouraged by our results with the benzoyl donor 1a ,
we continued to search for an ethoxyvinyl aromatic ester
for the desymmetrization of both 1,3-diols I and 1,2-diols
III with improved performance characteristics. Very
recently, we briefly communicated that 1-ethoxyvinyl
2-furoate 1b was such a reagent with satisfactory per-
formance.14 In this paper, we describe the details of our
results with some additional features of 1b about an
increase of the optical purity of the products through
kinetic amplification.
benzoyl group migrates from one hydroxyl group of a
monosaccharide to a neighboring hydroxyl group less
readily than an acetyl group since the formation of the
ortho ester intermediate V from the benzoate involves a
greater loss in resonance energy (Scheme 4).16 Therefore,
we focused our attention to find a highly efficient ethoxy-
vinyl aromatic ester.
According to our method for preparation of the ethoxy-
vinyl esters 1,17 we prepared 19 aromatic esters 1b-t,
most of which were unknown, from commercial carboxylic
acids (Scheme 5). Thus, a mixture of a carboxylic acid
(1.0 equiv), ethoxyacetylene (1.5 equiv), and [RuCl2(p-
cymene)]2 (0.005 equiv) was stirred in toluene at 0 °C to
room temperature for several hours followed by flash
column chromatography on SiO2 to give 1 in more than
80% yield in most cases. The isolated yields of 1r and 1s
were low due to the poor solubility of the carboxylic acid
and the instability of 1r and 1s to the chromatographic
purification conditions.
En a n tioselective Desym m etr iza tion of P r och ir a l
2,2-Disu bstitu ted 1,3-P r op a n ed iols 2. The prelimi-
nary evaluation of these aroyl reagents 1b-t was per-
formed on the desymmetrization of the congested diol 2A
using lipase MY (from Candida rugosa) under the same
conditions as the previous desymmetrization of 2A by
1a .13 Each reaction was quenched when 2A was con-
sumed. The reaction time, the optical purity, and the
isolated yield of the product 3A are summarized in Table
1. These results revealed that 1-ethoxyvinyl 2-furoate 1b
was the best reagent in terms of the reactivity, the
enantioselectivity, and the yield. The 2-furoyl derivatives
Resu lts a n d Discu ssion
P r ep a r a tion of Va r iou s 1-Eth oxyvin yl Ar om a tic
Ester s 1. It is well-known that the structure of the acyl
moiety of an acyl donor highly affects both of the
selectivity and the reactivity of the lipase-catalyzed
transesterification reactions.15 It is also reported that a
(10) (a) Nicolosi, G.; Patti, A.; Piattelli, M.; Sanfilippo, C. Tetrahe-
dron: Asymmetry 1994, 5, 283-288. (b) Idem Tetrahedron: Asymmetry
1995, 6, 519-524. (c) Bremen, U.; Gais, H.-J . Tetrahedron: Asymmetry
1996, 7, 3063-3066. (d) Patti, A.; Sanfilippo, C.; Piattelli, M.; Nicolosi,
G. J . Org. Chem. 1996, 61, 6458-6461.
(11) The the optically active monoacetates IV, obtained by the
enzyme-catalyzed hydrolysis of the diacetates of III, have been reported
to suffer from racemization during the enzymatic reaction and workup;
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.
(12) Kita, Y.; Takebe, Y.; Murata, K.; Naka, T.; Akai, S. Tetrahedron
Lett. 1996, 37, 7369-7372. Kita, Y.; Naka, T.; Imanishi, M.; Akai, S.;
Takebe, Y.; Matsugi, M. Chem. Commun. 1998, 1183-1184. Kita, Y.;
Takebe, Y.; Murata, K.; Naka, T.; Akai, S. J . Org. Chem. 2000, 65,
83-88.
(13) Akai, S.; Naka, T.; Takebe, Y.; Kita, Y. Tetrahedron Lett. 1997,
38, 4243-4246; Chem. Pharm. Bull. 2000, 48, 1519-1523.
(14) Akai, S.; Naka, T.; Fujita, T.; Takebe, Y.; Kita. Y. Chem.
Commun. 2000, 1461-1462. In part, see also: Akai, S.; Tsujino, T.;
Fukuda, N.; Iio, K.; Takeda, Y.; Kawaguchi, K.; Naka, T.; Higuchi, K.;
Kita, Y. Org. Lett. 2001, 3, 4015-4018.
(16) Hough, L.; Richardson, A. C. In Rodd’s Chemistry of Carbon
Compounds; Coffey, S., Ed.; Elsevier: New York, 1967; Vol. I, Part F,
pp 382-386. Fromageot, H. P. M.; Reese, C. B.; Sulston, J . E.
Tetrahedron 1968, 24, 3533-3540.
(17) Kita, Y.; Maeda, H.; Omori, K.; Okuno, T.; Tamura, Y. J . Chem.
Soc., Perkin Trans. 1 1993, 2999-3005. Shibata, N.; Matsugi, M.;
Kawano, N.; Fukui, S.; Fujimori, C.; Gotanda, K.; Murata, K.; Kita,
Y. Tetrahedron: Asymmetry 1997, 8, 303-310.
(15) For recent examples, see: Ema, T.; Maeno, S.; Takaya, Y.;
Sakai, T.; Utaka, M. J . Org. Chem. 1996, 61, 8610-8616. Nakamura,
K.; Takenaka, K.; Ohno, A. Tetrahedron: Asymmetry 1998, 9, 4429-
4439. Kawasaki, M.; Goto, M.; Kawabata, S.; Kometani, T. Tetrahe-
dron: Asymmetry 2001, 12, 585-596.

Desymmetrization of Disubstituted 1,3-Propanediols
J . Org. Chem., Vol. 67, No. 2, 2002 413
Ta ble 1. Desym m etr iza tion of 1,3-Diols 2A Usin g a Va r iety of Ar oyl Don or s 1a -t a
a
The reaction was run using 1 (3.0 equiv) under the identical reaction conditions (for details, see the typical procedure in the Experimental
Section) and was quenched when 2A was consumed. Lipase from Candida rugosa. c Determined by HPLC using Daicel CHIRALCEL
b
d
OD (hexane-i-PrOH), unless otherwise noted. Isolated by flash column chromatography on SiO2. The rest of the product was the
corresponding diester. e Cited from ref 13. f Daicel CHIRALPAK AD (hexane-i-PrOH) was used.
1c,d having a substituent as well as the 3-furoyl 1e and
the 2-thienyl 1f derivatives were also effective, giving the
corresponding products 3Ac-3Af with good enantiose-
lectivity (62-81% ee); however, the reactions took 1 day,
and their yields were not very high (23-60%). The
benzoyl derivatives 1g-j, having a substituent at the
para-position, were also found to give the products 3Ag-
3Aj with good optical purity (67-86% ee) but with
unsatisfactory reactivity (1-3 days) and yield (25-51%).
2-Naphthoyl derivative 1k was reactive, but the selectiv-
ity was not sufficient. Other benzoyl derivatives 1l-n
having a substituent at the ortho-position and some
heteroaromatic derivatives 1o-t were poorly reactive.
F igu r e 1. Time course of the reaction of 2A with 1b.
Further investigation disclosed more advantages of 1b,
viz., (i) applicability to various substrates, (ii) increase
complete mono acylation of 2 was observed when 1b was
of the optical purity of 3 through kinetic amplification,
used. For instance, the optical purity of 3Ab (81% ee) at
5 h was improved to 96% ee at 30 h, although the yield
decreased (Table 2). The time course of this reaction
shown in Figure 1 revealed that even if the enantiotopic
selectivity was not high at the initial stage (63% ee at
15 min), the optical purity easily went up along the
reaction time. Some other examples were obtained in the
(iii) high stability of 3 against racemization, and (iv)
inertness of 3 under oxidative conditions, as follows.
(i) High Ap p lica bility to Va r iou s 1,3-Diols 2 a n d
(ii) In cr ea se of th e Op tica l P u r ity of 3 th r ou gh
Kin etic Am p lifica tion . The applicability of 1b to vari-
ous diols 2B-H was examined under similar conditions,
and the results are summarized in Table 2. Some of the
cases of 3Bb and 3Db. These results were ascribed to
results were compared with similar reactions using 1a
lipase-catalyzed kinetic resolution of 3,18 which was
or a substituted benzoate 1g (Table 2). Several features
confirmed by the reaction of racemic 3Ab with 1b under
of 1b are noteworthy: First, in all cases, 2B-H were
consumed within 5 h when 1b was employed, whereas
the reactions using 1a and 1g required at least 24 h and
similar conditions (Table 3 and Figure 2). Thus, the
reaction proceeded quickly to give (R)-3Ab (51% ee, 44%
usually 100 h or more to consume the diols. Second, the
optical purities and the yields of the products 3Ab-3Hb
were good-to-very high, which were similar to or higher
than those obtained using 1g and generally higher than
those obtained using 1a . Third, increase of the optical
purity of 3 by prolonging the reaction time beyond the
(18) Similar phenomena have been reported on the lipase-catalyzed
transesterification of prochiral 2-monosubstituted 1,3-propanediols and
hydrolysis of meso diacetates.2,18a However, opposite results were also
reported.18b (a) Wang, Y.-F.; Lalonde, J . J .; Momongan, M.; Gergbreiter,
D. E.; Wong, C.-H. J . Am. Chem. Soc. 1988, 110, 7200-7205. (b)
Guanti, G.; Banfi, L.; Brusco, S.; Narisano, E. Tetrahedron: Asymmetry
1994, 5, 537-540.

414 J . Org. Chem., Vol. 67, No. 2, 2002
Ta ble 2. Desym m etr iza tion of Va r iou s 1,3-Diols 2 Usin g 1a ,b,ga
Akai et al.
a
The reaction was run using 1 (3.0 equiv for 2A-E or 1.5 equiv for 2F -H) and was quenched when 2 was consumed. For 3Ab, 3Bb,
and 3Db , the result of the prolonged reaction is shown in the second line. Cited from ref 13. c Determined by HPLC using Daicel
b
CHIRALCEL OD (hexane-i-PrOH). Isolated by flash column chromatography on SiO2. e For the temperature and the concentration,
d
see the Experimental Section. f Not determined. CRL (from Candida rugosa) immobilized on Hyflo Super Cell.
g
Ta ble 3. Kin etic Resolu tion of (()-3Aa , 3Ab, a n d 3Ag Usin g 1a ,b,ga
a
b
For the reaction conditions, see the Experimental Section. Determined by HPLC using Daicel CHIRALCEL OD (hexane-i-PrOH).
c Isolated by flash column chromatography on SiO2.
yield), the same enantiomer obtained by the above-
mentioned desymmetrization of 2A, and the diester 4Ab
(47% yield) for 2 h. It is worth noticing that the similar
reaction of the monobenzoate (()-3Aa with the corre-
sponding benzoyl donor 1a was very tardy, resulting in
less than 10% conversion after 250 h, although we
previously observed a similar kinetic amplification by 1a
for the less congested acyclic 1,3-diol 2G.13 In addition,
the reaction of (()-3Ag with 1g did not proceed at all.
All these results disclosed that the quite high reactivity
and the kinetic resolution of the monofuroate 3b are the
distinguishing features of 1b, affording the highly opti-
cally pure 3b within a reasonable reaction time.
In every case, the diester 4 was the only side product,
which was quantitatively hydrolyzed to the starting diol
2 by alkaline hydrolysis. Therefore, the overall reaction

Desymmetrization of Disubstituted 1,3-Propanediols
J . Org. Chem., Vol. 67, No. 2, 2002 415
F igu r e 2. Time course of the kinetic resolution of (()-3Ab
with 1b.
Sch em e 6
F igu r e 3. Stability of 3G under acidic conditions. Results of
the acetate (R ) Me) and the benzoate 3Ga are cited from ref
13.
Sch em e 7a
provides preparation of optically active 3 without any
significant loss of chemical yield. An example is shown
in Scheme 6.
a
Reagents and conditions: i, Dess-Martin periodinane, CH2Cl2;
ii, NaClO2, NaH2PO4, t-BuOH-H2O; iii, NaOMe, MeOH.
(iii) Stability of th e Mon ofu r oates 3b u n der Acidic
Con d ition s. The stability of the furoate 3b under acidic
conditions was very much improved as noted from the
following example. Thus, 3Gb was inert to racemization
in an acidic medium (0.1 equiv of camphorsulfonic acid,
4 × 10-4 M in CH2Cl2) at room temperature after 1 day,
whereas the same treatment of the corresponding ben-
zoate 3Ga resulted in gradual racemization (t1/2 ) 18 h)
(Figure 3).13 All the products 3Ab-3Hb were easily
isolated by standard column chromatography on SiO2
with retention of the optical purity.
Sch em e 8
(iv) Sta bility of th e Mon ofu r oa tes 3b u n d er Oxi-
d a tive Con d ition s. The furoate moiety was preserved
under oxidizing conditions. For instance, neither a de-
crease in optical purity nor decomposition of the furan
ring was observed in the treatment of 3Gb (88% ee) with
the Dess-Martin periodinane leading to the correspond-
ing aldehyde 5b (88% ee, quant). Further treatment of
5b with NaClO2 afforded the carboxylic acid 6b (quant),
which was subjected to methanolysis giving the hydroxyl
carboxylic acid 7b (89%; Scheme 7).
Sch em e 9
the HPLC analysis using a chiral column, and thereby,
the absolute stereochemistry of 3Ab was determined to
be R. In a similar manner, that of 3Ag was found to be
R (Scheme 8). The absolute stereochemistry of 3Bb-3Eb
has not been established yet.
(v) Th e Absolu te Ster eoch em istr y of 3. The abso-
lute stereochemistry of 7b was determined to be R by
22
comparison of its specific rotation {[R]D ) +14.3 (c )
0.8, CHCl3)} with the reported value for 97% ee of the
(S)-form {[R]D ) -16.5 (c 1.0, CHCl3)},3c and thereby
20
En a n tioselective Desym m etr iza tion of Meso cis-
1,2-Cycloa lk a n ed iols 9 Usin g 1b. The high utility of
1b was also apparent in the desymmetrization of the
meso cis-1,2-cycloalkanediols (9A,B). The reaction of 9A
with 1b using CHIRAZYME L-9 (from Mucor miehei)
provided the monofuroate (1R,2S)-10Ab (97% ee, 77%
yield) (Scheme 9). Likewise, the desymmetrization of the
cyclopentanediol 9B gave (1R,2S)-10Bb (82% ee, 55%
yield). A similar enantioselective desymmetrization of
9A,B was reported using vinyl acetate; however, column
chromatography on SiO2 of the products often suffered
from a decrease of the optical purity.10b On the other
that of 3Gb to be S. Similarity of the specific rotations
of 3F b and 3Hb with that of (S)-3Gb estimated their
absolute stereochemistry to be S.
The absolute stereochemistries of 3Ab and 3Ag were
determined to be the same as that of the known com-
pound (R)-3Aa 13 as follows: Silylation of 3Ab with (t-
Bu)Me2SiCl-pyridine followed by either methanolysis
(method A) or reduction (method B) gave the monosilyl
ether 8 in 88-95% yields. Similarly, (R)-3Aa was con-
verted to (S)-8 by method B. These two products were
found to have the same absolute configuration based on

416 J . Org. Chem., Vol. 67, No. 2, 2002
Akai et al.
Daicel CHIRALCEL OD (250 mm × 4.6 mm, eluent: hexane-
i-PrOH), Daicel CHIRALPAK AD (250 mm × 4.6 mm, eluent:
hexane-i-PrOH), and Daicel CHIRALCEL OJ (250 mm × 4.6
mm, eluent: hexane-i-PrOH) columns. Column chromato-
graphic purification was performed using silica gel 60 (70-
230 mesh, Merck Co., Ltd.) or silica gel BW-300 (200-400
mesh, Fuji Silysia Chemical Co., Ltd.). Lipase MY (from
Candida rugosa) was a gift from Meito Sangyo Co., Ltd..
CHIRAZYME L-9 (from Mucor miehei) was a gift from Roche
Diagnotics. CRL (0.30 g, from Candida rugosa, Lipase Type
VII, Sigma) was immobilized on Hyflo Super Cell (HSC) (0.30
g) using deionized water (20 mL) by a standard freeze-drying
method. Enzymes were dried (0.5 mmHg, room temperature,
overnight) prior to use. Wet i-Pr2O was prepared by vigorously
stirring a 1000:1 mixture of distilled i-Pr2O and water for 20-
30 min using a magnetic stirrer and decanting the ether layer
after settling down. Yields refer to isolated material of g95%
Sch em e 10
1
purity as determined by H NMR.
P r ep a r a tion of th e Rea gen ts a n d th e Diols. Known
ethoxyvinyl esters (1a ,i,j)17 and diols (2A-D,13 2F ,13 2G,13 and
2H19) were prepared by the reported method. Unknown esters
(1b-h ,k -t) and diol 2E were similarly prepared as follows.
We used ethoxyacetylene prepared by the literature method20
(Caution: Quenching the reaction by addition of brine as is
mentioned in the literature is very dangerous. This may cause
ignition even when one adds brine dropwise at -78 °C. We
recommend quenching the reaction with EtOH or a 1:1 mixture
of EtOH and 1,2-propanediol at -78 °C followed by dropwise
addition of brine.). Ethoxyacetylene is available from Acros
as a 50 wt % solution in hexanes, and the use of this solution
as such without purification gave similar results. [RuCl2(p-
cymene)]2 is commercially available from Aldrich and used as
such without purification.
hand, the optical purity of 10Ab and 10Bb did not change
at all during the standard SiO2 column chromatography.
Determination of the absolute stereochemistry of 10Ab
and 10Bb was performed by their derivatization to the
compounds (11A and 11B) and the comparison of their
specific rotations with those of the compounds derived
from the authentic samples (12A,B) prepared by the
reported method10b (Scheme 10).
1-Eth oxyvin yl 2-F u r oa te (1b). A Typ ica l P r oced u r e for
th e P r ep a r a tion of th e Eth oxyvin yl Ester s. Under a
nitrogen atmosphere, a solution of ethoxyacetylene (0.60 mL,
7.2 mmol) in anhydrous toluene (1.5 mL) was added to an ice-
cooled mixture of 2-furoic acid (0.46 g, 4.1 mmol) and [RuCl2-
(p-cymene)]2 (13 mg, 0.020 mmol) in anhydrous toluene (8.0
mL). The reaction mixture was stirred at room temperature.
The remaining carboxylic acid was monitored by SiO2 TLC (it
usually takes about 5 h to consume the carboxylic acid). The
mixture was concentrated in vacuo, and the residue was
purified by flash column chromatography (hexanes-EtOAc-
Et3N ) 100:10:1) to give 1b (0.68 g, 92%) as a colorless oil. 1H
NMR (CDCl3): δ 1.36 (3H, t, J ) 7.0 Hz), 3.88 (1H, d, J ) 3.5
Hz), 3.92 (2H, q, J ) 7.0 Hz), 3.97 (1H, d, J ) 3.5 Hz), 6.56
(1H, dd, J ) 2.0, 3.5 Hz), 7.31 (1H, dd, J ) 1.0, 3.5 Hz), 7.65
(1H, dd, J ) 1.0, 2.0 Hz). IR (CHCl3): 1744, 1674 cm-1. Anal.
Calcd for C9H10O4: C, 59.34; H, 5.53. Found: C, 59.37; H, 5.55.
La r ge-Sca le P r ep a r a tion of 1b. Similarly to the above
procedure, a mixture of ethoxyacetylene (20 mL, 0.24 mol),
2-furoic acid (18.0 g, 0.16 mol), and [RuCl2(p-cymene)]2 (0.20
g, 0.33 mmol) in anhydrous toluene (350 mL) was stirred at
room temperature overnight and concentrated in vacuo. Distil-
lation of the residue gave 1b (22.5 g, 77%). Bp 80-83 °C/0.35
mmHg.
Con clu sion s
The above-mentioned procedure using 1b features the
following four advantages: (1) 1b is readily prepared
from commercially available ethoxyacetylene and 2-furoic
acid in a large scale (20 g or more) in high yield (in detail,
see the Experimental Section). Compound 1b can be
stored in a refrigerator for more than 1 year. (2) The
reaction using 1b is usually complete within several
hours to give the products in high optical and chemical
yields. If necessary, the only side products, diesters, can
be recycled to the starting diols quantitatively. (3)
Prolonging the reaction time increases the optical purity
of the products through kinetic amplification. (4) Products
are sufficiently stable under acidic and/or oxidative
conditions. Therefore, the present procedure provides a
novel, promising synthetic method of optically active
compounds having a quaternary carbon center at the
benzylic position and the optically active cycloalkane 1,2-
diol derivatives.
From a mechanistic point of view, the quite high
reactivity and high enantiotopic selectivity of 1b are
outstanding among a large number of acyl donors. An
evaluation study on the mechanism and its synthetic
application is now in progress in our laboratory.
1-Eth oxyvin yl 5-Br om o-2-fu r oa te (1c). A colorless oil:
81% yield. H NMR (CDCl3): δ 1.35 (3H, t, J ) 7.0 Hz), 3.87
(1H, d, J ) 4.0 Hz), 3.93 (2H, q, J ) 7.0 Hz), 3.97 (1H, d, J )
4.0 Hz), 6.50 (1H, d, J ) 3.5 Hz), 7.24 (1H, d, J ) 3.5 Hz). IR
(CHCl3): 1746, 1678 cm-1. HRMS. Calcd for C9H981BrO4
(M+): 259.9684. Found: 259.9649.
1
1-Eth oxyvin yl 3-Meth yl-2-fu r oa te (1d ). A colorless oil:
92% yield. H NMR (CDCl3): δ 1.36 (3H, t, J ) 7.0 Hz), 2.39
Exp er im en ta l Section
1
(3H, s), 3.87 (1H, d, J ) 3.5 Hz), 3.94 (2H, q, J ) 7.0 Hz), 3.97
(1H, d, J ) 3.5 Hz), 6.40 (1H, d, J ) 1.5 Hz), 7.49 (1H, d, J )
1.5 Hz). IR (CHCl3): 1736, 1676 cm-1. Anal. Calcd for
Gen er a l Meth od s. All melting points (mp) and boiling
points are uncorrected. Gas-liquid chromatography (GLC)
analyses were carried out using a Hewlett Packard HP-5
column (Crosslinked 5% PH ME siloxane, 30 m × 0.32 mm,
0.25 µm film thickness). 1H NMR spectra were measured at
300 MHz with tetramethylsilane (TMS) as an internal stan-
dard. IR spectra were recorded by diffuse reflectance measure-
ment of samples dispersed in a KBr powder or as a CHCl3
solution. Chiral HPLC analyses were carried out using
C
10H12O4: C, 61.22; H, 6.16. Found: C, 61.13; H, 6.19.
(19) Monkovic, I.; Perron, Y. G.; Martel, R.; Simpson, W. J . J . Med.
Chem. 1973, 16, 403-407.
(20) J ones, E. R. H.; Eglinton, G.; Whiting, M. C.; Shaw, B. L. Org.
Synth. 1954, 34, 46-49.

Desymmetrization of Disubstituted 1,3-Propanediols
J . Org. Chem., Vol. 67, No. 2, 2002 417
1-Eth oxyvin yl 3-F u r oa te (1e). A colorless oil: 95% yield.
1H NMR (CDCl3): δ 1.36 (3H, t, J ) 7.0 Hz), 3.85 (1H, d, J )
3.5 Hz), 3.92 (2H, q, J ) 7.0 Hz), 3.93 (1H, d, J ) 3.5 Hz),
6.80 (1H, dd, J ) 1.0, 2.0 Hz), 7.45 (1H, t, J ) 1.5 Hz), 8.10
(1H, dd, J ) 1.0, 1.5 Hz). IR (CHCl3): 1740, 1676 cm-1. Anal.
Calcd for C9H10O4: C, 59.34; H, 5.53. Found: C, 59.30; H, 5.79.
1-Eth oxyvin yl Th iop h en e-2-ca r boxyla te (1f). A colorless
cm-1. Anal. Calcd for C13H12O4: C, 67.23; H, 5.21. Found: C,
66.99; H, 5.26.
1-Eth oxyvin yl P yr id in e-3-ca r boxyla te (1r ). A brown
1
oil: 23% yield. H NMR (CDCl3): δ 1.38 (3H, t, J ) 7.0 Hz),
3.91 (1H, d, J ) 4.0 Hz), 3.97 (2H, q, J ) 7.0 Hz), 3.99 (1H, d,
J ) 4.0 Hz), 7.41-7.45 (1H, m), 8.34-8.38 (1H, m), 8.83 (1H,
dd, J ) 2.0, 5.0 Hz), 9.29 (1H, dd, J ) 1.0, 2.5 Hz). IR
(CHCl3): 1746, 1678 cm-1. HRMS. Calcd for C10H11NO3 (M+):
193.0737. Found: 193.0742.
1
oil: 94% yield. H NMR (CDCl3): δ 1.37 (3H, t, J ) 7.0 Hz),
3.87 (1H, d, J ) 3.5 Hz), 3.94 (2H, q, J ) 7.0 Hz), 3.98 (1H, d,
J ) 3.5 Hz), 7.14 (1H, dd, J ) 4.0, 5.0 Hz), 7.31 (1H, dd, J )
1.5, 5.0 Hz), 7.90 (1H, dd, J ) 1.5, 4.0 Hz). IR (CHCl3): 1734,
1676 cm-1. HRMS. Calcd for C9H10O3S (M+): 198.0351.
Found: 198.0342.
1-Eth oxyvin yl P yr id in e-4-ca r boxyla te (1s). A brown
1
oil: 13% yield. H NMR (CDCl3): δ 1.38 (3H, t, J ) 7.0 Hz),
3.90 (1H, d, J ) 4.0 Hz), 3.96 (2H, q, J ) 7.0 Hz), 3.99 (1H, d,
J ) 4.0 Hz), 7.90 (1H, dd, J ) 1.5, 4.5 Hz), 8.82 (1H, dd, J )
1.5, 4.5 Hz). IR (CHCl3): 1755, 1676 cm-1. HRMS. Calcd for
1-Eth oxyvin yl 4-Br om oben zoa te (1g). A colorless oil:
1
C
10H11NO3 (M+): 193.0748. Found: 193.0742.
82% yield. H NMR (CDCl3): δ 1.37 (3H, t, J ) 7.0 Hz), 3.88
(1H, d, J ) 3.5 Hz), 3.95 (2H, q, J ) 7.0 Hz), 3.96 (1H, d, J )
3.5 Hz), 7.61 (2H, d, J ) 8.5 Hz), 7.96 (2H, d, J ) 8.5 Hz). IR
(CHCl3): 1746, 1676 cm-1. HRMS. Calcd for C11H1181BrO3
(M+): 269.9891. Found: 269.9904.
1-Eth oxyvin yl Qu in olin e-3-ca r boxyla te (1t). Pale brown
powder: 87% yield. Mp 71-72 °C. 1H NMR (CDCl3): δ 1.40
(3H, t, J ) 7.0 Hz), 3.94 (1H, d, J ) 4.0 Hz), 3.98 (2H, q, J )
7.0 Hz), 4.05 (1H, d, J ) 4.0 Hz), 7.65 (1H, t, J ) 7.5 Hz), 7.87
(1H, t, J ) 7.5 Hz), 7.96 (1H, d, J ) 7.5 Hz), 8.19 (1H, d, J )
1-Eth oxyvin yl 4-Meth ylben zoa te (1h ). A colorless oil:
1
7.5 Hz), 8.93 (1H, s), 9.49 (1H, s). IR (CHCl3): 1748, 1676 cm-1
.
87% yield. H NMR (CDCl3): δ 1.36 (3H, t, J ) 7.0 Hz), 2.42
(3H, s), 3.87 (1H, d, J ) 3.5 Hz), 3.95 (2H, q, J ) 7.0 Hz), 3.96
(1H, d, J ) 3.5 Hz), 7.26 (2H, d, J ) 8.0 Hz), 7.99 (2H, d, J )
8.0 Hz). IR (CHCl3): 1744, 1674 cm-1. Anal. Calcd for
Anal. Calcd for C14H13NO3: C, 69.12; H, 5.39; N 5.76. Found:
C, 69.07; H, 5.45; N 5.70.
1,1-Bis(h yd r oxym eth yl)-5-m eth oxyin d a n (2E) was pre-
pared by a standard reduction of the corresponding malonate21
using LiAlH4. Colorless crystals. Mp 118-119 °C. 1H NMR
(CDCl3): δ 1.97 (2H, t, J ) 5.5 Hz), 2.10 (2H, t, J ) 7.5 Hz),
2.92 (2H, t, J ) 7.5 Hz), 3.73-3.88 (4H, m), 3.79 (3H, s), 6.72-
6.81 (2H, m), 7.16 (1H, d, J ) 8.5 Hz). HRMS. Calcd for
C
12H14O3: C, 69.88; H, 6.84. Found: C, 69.84; H, 6.90.
1-Eth oxyvin yl Na p h th a len e-2-ca r boxyla te (1k ). Color-
less powder: 91% yield. Mp 51-52 °C. 1H NMR (CDCl3): δ
1.39 (3H, t, J ) 7.0 Hz), 3.92 (1H, d, J ) 3.5 Hz), 3.99 (2H, q,
J ) 7.0 Hz), 4.02 (1H, d, J ) 3.5 Hz), 7.53-7.68 (2H, m), 7.89
(1H, d, J ) 8.0 Hz), 7.90 (1H, d, J ) 8.0 Hz), 7.97 (1H, d, J )
7.5 Hz), 8.10 (1H, dd, J ) 1.0, 8.0 Hz), 8.69 (1H, s). IR
(CHCl3): 1742, 1674 cm-1. Anal. Calcd for C15H14O3: C, 74.36;
H, 5.82. Found: C, 74.45; H, 5.90.
C
C
12H16O3 (M+): 208.1094. Found: 208.1099. Anal. Calcd for
12H16O3: C, 69.21; H, 7.74. Found: C, 69.27; H, 7.69.
En zym a tic Desym m etr iza tion of th e 1,3-Diols (2A-H).
A Gen er a l P r oced u r e. To a mixture of 1 (0.60 mmol) and
2A-E (0.20 mmol) in wet i-Pr2O (3.0 mL) was added lipase
MY (125 mg). The reaction of 2F ,G was run using 1 (0.26
mmol), 2F -H (0.17 mmol), and CRL/HSC (100 mg) in wet
i-Pr2O (2.0 mL). The reaction mixture was stirred at 30 °C for
the time shown in Tables 1 and 2 and filtered through a Celite
pad. The filtrate was concentrated in vacuo, and the residue
was purified by column chromatography (hexanes-ethyl ac-
etate) to give the monoester 3 and the diester 4. The isolated
yield and the optical purity of the products are listed in Tables
1 and 2. The optical purity of 3 was determined by HPLC using
CHIRALCEL OD or CHIRALPAK AD.
1-Eth oxyvin yl 2-Meth ylben zoa te (1l). A colorless oil:
90% yield. H NMR (CDCl3): δ 1.37 (3H, t, J ) 7.5 Hz), 2.64
1
(3H, s), 3.87 (1H, d, J ) 3.5 Hz), 3.95 (2H, q, J ) 7.5 Hz), 3.96
(1H, d, J ) 3.5 Hz), 7.25-7.29 (2H, m), 7.42-7.48 (1H, m),
8.03-8.06 (1H, m). IR (CHCl3): 1752, 1674 cm-1. Anal. Calcd
for C12H14O3: C, 69.88; H, 6.84. Found: C, 69.80 H, 6.98.
1-Eth oxyvin yl Na p h th a len e-1-ca r boxyla te (1m ). Color-
less powder: 93% yield. Mp 53-54 °C. 1H NMR (CDCl3): δ
1.40 (3H, t, J ) 7.0 Hz), 3.93 (1H, d, J ) 3.5 Hz), 4.00 (2H, q,
J ) 7.0 Hz), 4.03 (1H, d, J ) 3.5 Hz), 7.61-7.67 (3H, m), 7.90
(1H, d, J ) 8.0 Hz), 8.08 (1H, d, J ) 8.5 Hz), 8.36 (1H, d, J )
8.5 Hz), 9.02 (1H, d, J ) 8.5 Hz). IR (CHCl3): 1742, 1674 cm-1
.
(R)-(1-H yd r oxym et h yl-7-m et h oxyin d a n -1-yl)m et h yl
Anal. Calcd for C15H14O3: C, 74.36; H, 5.82. Found: C, 74.29;
H, 5.87.
28
2-F u r oa te (3Ab). A colorless oil: 96% ee; [R]D ) -39.5 (c )
1.2, CHCl3). 1H NMR (CDCl3): δ 2.00-2.23 (2H, m), 2.83-
3.03 (3H, m), 3.83 (3H, s), 3.90-3.99 (2H, m), 4.49 (1H, d, J )
10.5 Hz), 4.66 (1H, d, J ) 10.5 Hz), 6.48 (1H, dd, J ) 2.0, 3.5),
6.73 (1H, d, J ) 8.0 Hz), 6.87 (1H, d, J ) 8.0 Hz), 7.08 (1H,
dd, J ) 1.0, 3.5), 7.21 (1H, t, J ) 8.0 Hz), 7.56 (1H, dd, J )
1.0, 2.0 Hz). IR (KBr): 3600-3200, 1719, 1588 cm-1. HRMS.
Calcd for C17H18O5 (M+): 302.1154. Found: 302.1153.
1-Eth oxyvin yl An th r a cen e-1-ca r boxyla te (1n ). Color-
less powder: 85% yield. Mp 77-79 °C. 1H NMR (CDCl3): δ
1.47 (3H, t, J ) 7.0 Hz), 3.99 (1H, d, J ) 4.0 Hz), 4.06 (2H, q,
J ) 7.0 Hz), 4.16 (1H, d, J ) 4.0 Hz), 7.48-7.61 (4H, m), 8.01-
8.22 (4H, m), 8.56 (1H, s). IR (CHCl3): 1752, 1676 cm-1. Anal.
Calcd for C19H16O3: C, 78.06; H, 5.52. Found: C, 78.21; H,
5.65.
[1-(H yd r oxym et h yl)b en z[e]in d a n -1-yl]m et h yl 2-F u -
r oa te (3Bb). A colorless oil: 91% ee; [R]D23 ) -16.5 (c ) 0.68,
CHCl3). 1H NMR (CDCl3): δ 1.76 (1H, t, J ) 6.5 Hz), 2.29-
2.51 (2H, m), 3.09-3.15 (2H, m), 4.15-4.31 (2H, m), 4.65 (1H,
d, J ) 11.0 Hz), 4.88 (1H, d, J ) 11.0 Hz), 6.48 (1H, dd, J )
2.0, 3.5 Hz), 7.05 (1H, d, J ) 3.5 Hz), 7.38-7.50 (3H, m), 7.57
(1H, dd, J ) 1.0, 2.0 Hz), 7.76 (1H, d, J ) 8.0 Hz), 7.87 (1H,
d, J ) 8.0 Hz), 8.18 (1H, d, J ) 8.0 Hz). IR (KBr): 3750-
3250, 1732, 1582 cm-1. HRMS. Calcd for C20H18O4 (M+):
322.1205. Found: 322.1204.
1-Eth oxyvin yl 1-Meth ylp yr r ole-2-ca r boxyla te (1o). A
colorless oil: 73% yield. H NMR (CDCl3): δ 1.36 (3H, t, J )
1
7.0 Hz), 3.84 (1H, d, J ) 3.5 Hz), 3.91 (2H, q, J ) 7.0 Hz),
3.93 (3H, s), 3.96 (1H, d, J ) 3.5 Hz), 6.14 (1H, dd, J ) 2.5,
4.0 Hz), 6.85 (1H, dd, J ) 1.5, 2.5 Hz), 7.07 (1H, dd, J ) 1.5,
4.0 Hz). IR (CHCl3): 1727, 1674 cm-1. HRMS. Calcd for C10H13
NO3 (M+): 195.0895. Found: 195.0915.
-
1-Eth oxyvin yl 1-Meth ylin d ole-2-ca r boxyla te (1p ). Pale
brown powder: 79% yield. Mp 84-86 °C. 1H NMR (CDCl3): δ
1.38 (3H, t, J ) 7.0 Hz), 3.89 (1H, d, J ) 3.5 Hz), 3.96 (2H, q,
J ) 7.0 Hz), 3.99 (1H, d, J ) 3.5 Hz), 4.09 (3H, s), 7.13-7.19
(1H, m), 7.31-7.47 (2H, m), 7.44 (1H, s), 7.69 (1H, d, J ) 8.0
[(6-Ch lor o-1-(h yd r oxym eth yl)in d a n -1-yl]m eth yl 2-F u -
23
r oa te (3Cb). A colorless oil: 85% ee; [R]D ) +18.6 (c ) 1.4,
1
CHCl3). H NMR (CDCl3): δ 2.02-2.21 (2H, m), 2.30 (1H, t,
Hz). IR (CHCl3): 1727, 1674 cm-1. Anal. Calcd for C14H15
-
J ) 6.0 Hz), 2.95 (2H, t, J ) 7.5 Hz), 3.66-3.77 (2H, m), 4.42
(1H, d, J ) 11.0 Hz), 4. 50 (1H, d, J ) 11.0 Hz), 6.55 (1H, dd,
J ) 2.0, 3.5 Hz), 7.15-7.22 (3H, m), 7.37 (1H, d, J ) 3.5 Hz),
7.62 (1H, dd, J ) 1.0, 2.0 Hz). IR (KBr): 3700-3200, 1715,
NO3: C, 68.56; H, 6.16; N 5.71. Found: C, 68.53; H, 6.18; N
5.71.
1-E t h oxyvin yl Ben zofu r a n -2-ca r b oxyla t e (1q ). White
powder: 95% yield. Mp 44-45 °C. 1H NMR (CDCl3): δ 1.38
(3H, t, J ) 7.0 Hz), 3.92 (1H, d, J ) 3.5 Hz), 3.97 (2H, q, J )
7.0 Hz), 4.03 (1H, d, J ) 3.5 Hz), 7.32 (1H, t, J ) 7.0 Hz), 7.48
(1H, t, J ) 7.0 Hz), 7.52-7.82 (3H, m). IR (CHCl3): 1746, 1678
(21) Citterio, A.; Fancelli, D.; Finzi, C.; Pesce, L. J . Org. Chem. 1989,
54, 2713-2718.

418 J . Org. Chem., Vol. 67, No. 2, 2002
Akai et al.
1601 cm-1. HRMS. Calcd for C16H15ClO4 (M+): 306.0659.
Found: 306.0677.
0.25 mmol) and 3Ab (76 mg, 0.25 mmol) in wet i-Pr2O (4.0
mL) was added lipase MY (150 mg). The reaction mixture was
stirred at 30 °C for 2 h and filtered through a Celite pad. The
filtrate was concentrated in vacuo, and the residue was
purified by column chromatography (hexanes-ethyl acetate)
to give the mono ester (R)-3Ab (33 mg, 44%, 51% ee) and the
diester 4Ab (52 mg, 47%).
En zym a tic Desym m etr iza tion of 2A Usin g 1b for
P r olon ged Tim e (Sch em e 4). To a solution of 1b (14.6 g, 80
mmol) and 2A (3.3 g, 16 mmol) in wet i-Pr2O (1.0 L) was added
lipase MY (10 g). The reaction mixture was stirred at 30 °C
for 30 h and filtered through a Celite pad. The filtrate was
concentrated in vacuo, and the residue was purified by column
chromatography (hexanes-ethyl acetate ) 3:1) to give (R)-
3Ab (1.0 g, 21%, 96% ee) and 4Ab (4.9 g, 78%).
Hyd r olysis of 4Ab. To a solution of 4Ab (95 mg, 0.24 mmol)
in MeOH (1.5 mL) and water (0.5 mL) was added K2CO3 (166
mg, 1.2 mmol). The reaction mixture was stirred at room
temperature for 2 h and concentrated in vacuo. The residue
was extracted with CH2Cl2, and the organic layer was washed
with brine, dried over MgSO4, and concentrated in vacuo. The
residue was purified by column chromatography (hexanes-
ethyl acetate ) 1:1) to give 2A (48 mg, 96%).
(1-Hydr oxym eth yl-1,2,3,4-tetr ah ydr o-1-n aph th yl)m eth -
23
yl 2-F u r oa te (3Db). A colorless oil: 83% ee; [R]D ) +14.5
(c ) 0.52, CHCl3). 1H NMR (CDCl3): δ 1.84-1.93 (5H, m), 1.98
(1H, t, J ) 7.0 Hz), 2.81 (2H, t, J ) 6.0 Hz), 3.83 (2H, d, J )
7.0 Hz), 4.45 (1H, d, J ) 11.0 Hz), 4.51 (1H, d, J ) 11.0 Hz),
6.52 (1H, dd, J ) 2.0, 3.5 Hz), 7.15-7.29 (4H, m), 7.45-7.48
(1H, m), 7.60 (1H, dd, J ) 1.0, 2.0 Hz). IR (KBr): 3700-3200,
1715, 1582 cm-1. HRMS. Calcd for C17H18O4 (M+): 286.1205.
Found: 286.1186.
(1-Hyd r oxym eth yl-5-m eth oxyin d a n -1-yl)m eth yl 2-F u -
r oa te (3Eb). A colorless oil: 92% ee; [R]D23 ) +30.8 (c ) 0.96,
1
CHCl3). H NMR (CDCl3): δ 2.01-2.22 (3H, m), 2.96 (2H, t,
J ) 7.5 Hz), 3.65-3.76 (2H, m), 3.79 (3H, s), 4.42 (1H, d, J )
11.0 Hz), 4.48 (1H, d, J ) 11.0 Hz), 6.53 (1H, dd, J ) 2.0, 3.5
Hz), 6.74 (1H, dd, J ) 2.0, 8.0 Hz), 6.80 (1H, d, J ) 2.0 Hz),
7.20 (1H, br d, J ) 3.5 Hz), 7.26 (1H, d, J ) 8.0 Hz), 7.61 (1H,
dd, J ) 1.0, 2.0 Hz). IR (KBr): 3600-3200, 1732, 1580 cm-1
.
HRMS. Calcd for C17H18O5 (M+): 302.1154. Found: 302.1155.
(S)-3-Hyd r oxy-2-m et h yl-2-p h en yl-1-p r op yl 2-F u r oa t e
20
(3F b). A colorless oil: >99% ee; [R]D ) -4.9 (c ) 0.86,
1
CHCl3). H NMR (CDCl3): δ 1.43 (3H, s), 1.98 (1H, t, J ) 6.5
Hz), 3.83 (2H, d, J ) 6.5 Hz), 4.55 (1 H, d, J ) 11.0 Hz), 4.60
(1H, d, J ) 11.0 Hz), 6.50 (1H, dd, J ) 2.0, 3.5), 7.13 (1H, dd,
J ) 1.0, 3.5), 7.29-7.46 (5H, m), 7.57 (1H, dd, J ) 1.0, 2.0
Hz). IR (CHCl3): 3700-3200, 1728, 1640, 1582 cm-1. HRMS.
Calcd for C15H16O4 (M+): 260.0777. Found: 260.0772.
(S)-2-Eth yl-3-h ydr oxy-2-ph en yl-1-pr opyl2-Fu r oate (3Gb).
A colorless oil: 89% ee; [R]D ) -10.3 (c ) 0.93, CHCl3). H
NMR (CDCl3): δ 0.74 (3H, t, J ) 7.5 Hz), 1.83 (2H, q, 7.5 Hz),
2.01 (1H, t, J ) 6.5 Hz), 3.80-3.96 (2H, m), 4.67 (1H, d, J )
11.0 Hz), 4.72 (1H, d, J ) 11.0 Hz), 6.50 (1H, dd, J ) 1.5, 3.0
Hz), 7.14 (1H, d, J ) 3.0 Hz), 7.24-7.41 (5H, m), 7.58 (1H, d,
J ) 1.5 Hz). IR (CHCl3): 3700-3200, 1720, 1580 cm-1. HRMS.
Calcd for C16H18O4 (M+): 274.1045. Found: 274.1048.
(R)-2-Hyd r oxym eth yl-2-p h en ylbu ta n oic Acid (7b). Un-
der a nitrogen atmosphere, Dess-Martin periodinane (62 mg,
0.15 mmol) was added to a solution of (S)-3Gb (88% ee, 33
mg, 0.12 mmol) in anhydrous CH2Cl2 (4.0 mL) at 0 °C, and
the mixture was stirred at room temperature for 1 h. Saturated
aqueous Na2S2O3 was added to it. The mixture was extracted
with CH2Cl2. The organic layer was successively washed with
saturated aqueous NaHCO3 and brine, dried over MgSO4, and
concentrated in vacuo to give (R)-5b (32 mg, quant, 88% ee).
The optical purity of the product was determined by HPLC
using CHIRALCEL OD. A colorless oil: [R]D22 ) +3.0 (c ) 3.6,
CHCl3). 1H NMR (CDCl3): δ 0.87 (3H, t, J ) 7.5 Hz), 2.04-
2.24 (2H, m), 4.78 (1H, d, J ) 11.5 Hz), 4.86 (1H, d, J ) 11.5
Hz), 6.47 (1H, dd, J ) 2.0, 3.5 Hz), 7.07 (1H, br d, J ) 3.5 Hz),
7.24-7.44 (5H, m), 7.56 (1H, dd, J ) 1.0, 2.0 Hz), 9.65 (1H, s).
20
1
(S)-2-Allyl-3-h ydr oxy-2-ph en yl-1-pr opyl 2-Fu r oate (3Hb).
20
1
A colorless oil: 82% ee; [R]D ) -19.3 (c ) 0.54, CHCl3). H
NMR (CDCl3): δ 2.07 (1H, t, J ) 7.0 Hz), 2.58 (2H, d, J ) 7.0
Hz), 3.82-3.91 (2H, m), 4.64 (1H, d, J ) 11.0 Hz), 4.69 (1H, d,
J ) 11.0 Hz), 4.99-5.09 (2H, m), 5.47-5.60 (1H, m), 6.49 (1H,
dd, J ) 1.5, 3.5), 7.13 (1H, dd, J ) 1.0, 3.5 Hz), 7.23-7.44
(5H, m), 7.57 (1H, dd, J ) 1.0, 1.5 Hz). IR (CHCl3): 3700-
3200, 1728, 1640, 1582 cm-1. HRMS. Calcd for C17H18O4
(M+): 286.1155. Found: 286.1152.
IR (CHCl3): 1728 cm-1
.
NaH2PO4 (44 mg, 0.37 mmol), 2-methyl-2-butene (0.070 mL,
0.66 mmol), and NaClO2 (20 mg, 0.18 mmol) were successively
added to a solution of (R)-5b (32 mg, 0.12 mmol) in tert-BuOH
(5.0 mL) and water (1.0 mL). The reaction mixture was stirred
at room temperature for 10 min and concentrated in vacuo to
one-fifth of the original volume. The residue was extracted with
CH2Cl2, and the organic layer was concentrated in vacuo to
(R)-(1-Hyr oxym eth yl-7-m eth oxyin d a n -1-yl)m eth yl 4-
Br om oben zoa te (3Ag). A colorless oil: 86% ee; [R]D28 ) -1.7
(c ) 1.1, CHCl3). 1H NMR (CDCl3): δ 2.04-2.21 (3H, m), 2.96
(2H, t, J ) 7.5 Hz), 3.69 (1H, d, J ) 10.5 Hz), 3.73 (1H, d, J )
10.5 Hz), 3.79 (3H, s), 4.45 (1H, d, J ) 11.0 Hz), 4.49 (1H, d,
J ) 11.0 Hz), 6.72-6.90 (2H, m), 7.21-7.26 (1H, m), 7.60 (2H,
d, J ) 8.5 Hz), 7.89 (2H, d, J ) 8.5 Hz). IR (CHCl3): 3700-
3200, 1730, 1580 cm-1. HRMS. Calcd C19H1981BrO4 (M+):
392.0422. Found: 392.0446.
[1-(H yd r oxym et h yl)b en z[e]in d a n -1-yl]m et h yl 4-Br o-
m oben zoa te (3Bg). A colorless oil: 81% ee; [R]D23 ) -31.2 (c
1.3, CHCl3). 1H NMR (CDCl3): δ 2.33-2.47 (2H, m), 3.12 (2H,
t, J ) 7.5 Hz), 4.07-4.15 (1H, m), 4.12 (1H, d, J ) 11.5 Hz),
4.29 (1H, d, J ) 11.5 Hz), 4.69 (1H, d, J ) 11.0 Hz), 4.94 (1H,
d, J ) 11.0 Hz), 7.39-7.48 (3H, m), 7.52 (2H, d, J ) 8.5 Hz),
7.71-7.77 (1H, m), 7.73 (2H, d, J ) 8.5 Hz), 7.87 (1H, dd, J )
2.0. 8.0 Hz), 8.15 (1H, d, J ) 8.0 Hz). IR (KBr): 3750-3250,
1742 cm-1. HRMS. Calcd for C22H1981BrO3 (M+): 412.0471.
Found: 412.0497.
1
give (R)-6b (34 mg, quant.). A colorless oil. H NMR (CDCl3):
δ 0.88 (3H, t, J ) 7.5 Hz), 2.04-2.24 (2H, m), 4.78 (1H, d, J )
11.0 Hz), 4.86 (1H, d, J ) 11.0 Hz), 6.46 (1H, dd, J ) 2.0, 3.5
Hz), 7.06 (1H, br d, J ) 3.5 Hz), 7.25-7.42 (5H, m), 7.57 (1H,
dd, J ) 1.0, 2.0 Hz). IR (CHCl3): 3400-2500, 1723 cm-1
.
NaOMe (35 mg, 0.88 mmol) was added to (R)-6b (34 mg,
0.12 mmol) in MeOH (2.0 mL) at 0 °C. The mixture was stirred
at room temperature for 1 h and concentrated in vacuo. The
residue was purified by column chromatography (CH2-
Cl2-MeOH ) 5:1) to give (R)-7b (20 mg, 89%). A colorless oil:
[R]D ) +14.3 (c ) 0.8, CHCl3) [lit.3c [R]D ) -16.5 (c ) 1.0,
22
20
1
CHCl3) for 97% ee of the (S)-form]. H NMR (CDCl3): δ 0.94
(3H, t, J ) 7.5 Hz), 2.17 (2H, q, J ) 7.5 Hz), 3.92 (1H, d, J )
12 Hz), 3.99 (1H, d, J ) 12 Hz), 4.50-6.50 (2H, m), 7.20-7.50
(5H, m). IR (CHCl3): 3400-3100, 1713 cm-1
.
Con ver sion of (R)-3Ab to (S)-8. (i) Meth od A. Under a
nitrogen atmosphere, pyridine (6.6 mL, 82 mmol) and (t-Bu)-
Me2SiCl (2.2 g, 15 mmol) were added to an ice-cooled solution
of (R)-3Ab (96% ee, 1.8 g, 5.8 mmol) in anhydrous dimethyl-
formamide (DMF) (4 mL). The reaction mixture was stirred
at room temperature for 2 h, to which were added water and
Et2O. The organic layer was separated, and the aqueous layer
was extracted with Et2O. The combined organic layer was
washed with water, dried (Na2SO4), and concentrated in vacuo.
The residue was purified by flash column chromatography
(CH2Cl2) to give (S)-[1-(tert-butyldimethylsiloxy)methyl-7-
methoxyindan-1-yl]methyl 2-furoate (2.4 g, quant.). Colorless
[(6-Ch lor o-1-(h yd r oxym eth yl)in d a n -1-yl]m eth yl 4-Br o-
23
m oben zoa t e (3Cg). A colorless oil: 71% ee; [R]D ) +7.7
(c ) 1.4, CHCl3). 1H NMR (CDCl3): δ 2.01-2.21 (3H, m), 2.95
(2H, t, J ) 7.5 Hz), 3.70 (1H, d, J ) 12.5 Hz), 3.74 (1H, d, J )
12.5 Hz), 4.46 (1H, d, J ) 12.5 Hz), 4.50 (1H, d, J ) 12.5 Hz),
7.16-7.23 (2H, m), 7.33 (1H, d, J ) 2.0 Hz), 7.61 (2H, d, J )
8.5 Hz), 7.88 (2H, d, J ) 8.5 Hz). IR (KBr): 3700-3200, 1725
cm-1. HRMS. Calcd for C18H1681BrClO3 (M+): 395.9969.
Found: 359.9951.
crystals: Mp 50-51 °C. [R]D ) +15.9 (c ) 2.2, CHCl3). 1H
27
Typ ica l P r oced u r e for th e Kin etic Resolu tion of (()-
3Aa , 3Ab, 3Ag Usin g 1a , 1b, 1g. To a solution of 1b (46 mg,
NMR (CDCl3): δ -0.08, (3H, s), -0.01, (3H, s), 0.82 (9H, s),

Desymmetrization of Disubstituted 1,3-Propanediols
J . Org. Chem., Vol. 67, No. 2, 2002 419
2.14-2.32 (2H, m), 2.94 (2H, t, J ) 7.5 Hz), 3.75 (3H, s), 3.80
(1H, d, J ) 9.5 Hz), 4.04 (1H, d, J ) 9.5 Hz), 4.68 (2H, s), 6.44
(1H, dd, J ) 2.0, 3.5 Hz), 6.64 (1H, d, J ) 7.5 Hz), 6.81 (1H,
dd, J ) 1.0, 7.5 Hz), 6.95 (1H, dd, J ) 1.0, 3.5 Hz), 7.15 (1H,
t, J ) 7.5 Hz), 7.53 (1H, dd, J ) 1.0, 2.0 Hz). IR (CHCl3): 1734,
1590 cm-1. Anal. Calcd for C23H32O5Si: C, 66.31; H, 7.74.
Found: C, 66.43; H, 7.68.
(110 mg, 55%, 82% ee). The optical purity of the product was
determined by HPLC using CHIRALCEL OD. A colorless oil:
[R]D ) -1.9 (c ) 1.1, CHCl3). 1H NMR (CDCl3): δ 1.59-2.15
19
(7H, m), 4.26-4.31 (1H, m), 5.16-5.22 (1H, m), 6.52 (1H, dd,
J ) 2.0, 3.5 Hz), 7.21 (1H, dd, J ) 1.0, 3.5 Hz), 7.58 (1H, dd,
J ) 1.0, 2.0 Hz). IR (CHCl3): 3560, 1717 cm-1. Anal. Calcd
for C10H12O4: C, 61.22; H, 6.16. Found: C, 61.06; H, 6.22.
Acetyla tion of (1R,2S)-10Ab. Under a nitrogen atmo-
sphere, to an ice-cooled solution of (1R,2S)-10Ab (97% ee, 11
mg, 0.052 mmol) in pyridine (0.20 mL) was added Ac2O (0.010
mL, 0.11 mmol). The reaction mixture was stirred at room
temperature for 2 h, and water and Et2O were added to it.
The mixture was extracted with ether. The organic layer was
successively washed with water and brine, dried over MgSO4,
and concentrated in vacuo. The residue was purified by column
chromatography (Et2O-pentane ) 1:1) to give (1R,2S)-11A
Under a nitrogen atmosphere, K2CO3 (20 mg, 0.15 mmol)
was added to an ice-cooled solution of the above compound (50
mg, 0.12 mmol) in anhydrous MeOH (1 mL). The reaction
mixture was stirred at 0 °C for 30 min and then at room
temperature for 3 h and filtered. The filtrate was concentrated
in vacuo, and the residue was purified by flash column
chromatography (benzene) to give (S)-8 (37 mg, 95%). The
optical purity was determined to be 96% ee by HPLC using
28
CHIRALPAK AD. A colorless oil: [R]D ) +15.9 (c ) 2.2,
1
23
CHCl3). H NMR (CDCl3): δ -0.01 (3H, s), 0.04 (3H, s), 0.87
(13.4 mg, quant). A colorless oil: [R]D ) -45.5 (c ) 0.67,
1
(9H, s), 2.06-2.24 (2H, m), 2.87-2.93 (2H, m), 3.20 (1H, dd,
J ) 3.0, 9.0 Hz), 3.63 (1H, d, J ) 9.5 Hz), 3.74 (1H, dd, J )
9.0, 10.5 Hz), 3.81 (3H, s), 4.11 (1H, dd, J ) 3.0, 10.5 Hz),
4.15 (1H, d, J ) 9.5 Hz), 6.68 (1H, d, J ) 7.5 Hz), 6.84 (1H, d,
J ) 7.5 Hz), 7.16 (1H, t, J ) 7.5 Hz). IR (KBr): 3500-3400,
1590 cm-1. Anal. Calcd for C19H30O3Si: C, 67.03; H, 9.38.
Found: C, 66.93; H, 9.26.
CHCl3). H NMR (CDCl3): δ 1.38-2.15 (8H, m), 2.05 (3H, s),
5.02-5.12 (1H, m), 5.25-5.29 (1H, m), 6.51 (1H, dd, J ) 1.5,
3.5 Hz), 7.17 (1H, dd, J ) 1.0, 3.5 Hz), 7.59 (1H, dd, J ) 1.0,
1.5 Hz). IR (CHCl3): 1717 cm-1. HRMS. Calcd for C13H16O5
(M+): 252.0998. Found: 252.0996.
Acetyla tion of (1R,2S)-10Bb. Similarly to the acetylation
of (1R,2S)-10Ab, (1R,2S)-10Bb (18.1 mg, 0.092 mmol) was
converted to (1R,2S)-11B (22.0 mg, quant). A colorless oil:
(ii) Meth od B. Under a nitrogen atmosphere, to a solution
of the silyl ether (10.3 mg, 0.025 mmol), obtained by the above
method, in anhydrous CH2Cl2 (0.25 mL) was added (i-Bu)2AlH
(0.95 M solution in hexane, 0.80 mL, 0.76 mmol) over a period
of 5 min at -60 °C. The reaction mixture was stirred for 1.5
h at -60 °C and concentrated in vacuo. The residue was
purified by column chromatography (benzene) to give (S)-8 (7.1
mg, 88%).
19
1
[R]D ) -35.0 (c ) 1.13, CHCl3). H NMR (CDCl3): δ 1.63-
2.12 (6H, m), 2.03 (3H, s), 5.23 (1H, dt, J ) 4.5, 6.0 Hz), 5.36
(1H, dt, J ) 4.5, 6.0 Hz), 6.51 (1H, dd, J ) 2.0, 3.5 Hz), 7.15
(1H, dd, J ) 1.0, 3.5 Hz), 7.58 (1H, dd, J ) 1.0, 2.0 Hz). IR
(CHCl3): 1717 cm-1. Anal. Calcd for C12H14O5: C, 60.50; H,
5.92. Found: C, 60.73; H, 6.00.
F u r oyla tion of 12A. Under a nitrogen atmosphere, a
mixture of DCC (62 mg, 0.30 mmol), DMAP (3.0 mg, 0.02
mmol), and 2-furoic acid (34 mg, 0.30 mmol) in CH2Cl2 (2.0
mL) was stirred at 0 °C for 30 min, and a solution of 12A
(29 mg, 0.18 mmol), prepared by the reported method,10b in
CH2Cl2 (1.0 mL) was added to it. The reaction mixture was
stirred at room temperature for 4 h and filtered through a
Celite pad. The filtrate was concentrated in vacuo, and the
residue was purified by column chromatography (hexanes-
ethyl acetate ) 5:1) to give (1S,2R)-11A (26 mg, 56%). A
Con ver sion of (R)-3Aa , (R)-3Ag to (S)-8. According to the
method B, (R)-3Aa (71% ee, 10 mg, 0.032 mmol) was converted
to (S)-8 (8.8 mg, 85%, 70% ee), and (R)-3Ag (86% ee, 12 mg,
1
0.031 mmol), to (S)-8 (7.9 mg, 80%, 85% ee). IR and H NMR
data of these compounds were in accord with those of the
products obtained from (R)-3Ab.
En zym a tic Desym m etr iza tion of th e Meso 1,2-Diols 9.
A Typ ica l P r oced u r e. To a mixture of 1b (196 mg, 1.08
mmol) and 9A (50 mg, 0.43 mmol) in t-BuOMe (10 mL) was
added CHIRAZYME L9 (450 mg). The reaction mixture was
stirred at 45 °C for 2 days and filtered through a Celite pad.
The filtrate was concentrated in vacuo, and the residue was
purified by column chromatography (hexanes-ethyl acetate
) 5:1) to give (1R,2S)-10Ab (70 mg, 77%, 97% ee). The optical
purity of the product was determined by HPLC using CHIRAL-
CEL OJ .
20
colorless oil: [R]D ) +45.1 (c ) 0.67, CHCl3).
F u r oyla tion of 12B. Similarly to the furoylation of 12A,
12B (21 mg, 0.15 mmol), prepared by the reported method,10b
was converted to (1S,2R)-11B (9.3 mg, 28%). A colorless oil:
20
[R]D ) +18.0 (c ) 0.46, CHCl3).
Ack n ow led gm en t. This work was supported by
Grants-in-Aid for Scientific Research (Nos. 11672102
and 13672214) from the Ministry of Education, Science,
Sports, and Culture, J apan and the Takeda Science
Foundation, J apan. The Meito Sangyo Co., Ltd., J apan,
and Roche Diagnostics K. K., J apan, are thanked for
their generous gifts of the lipases.
(1R,2S)-2-Hyd r oxycycloh exyl 2-F u r oa te (10Ab). A col-
22
1
orless oil: [R]D ) -2.5 (c ) 1.0, CHCl3). H NMR (CDCl3): δ
1.20-2.10 (9H, m), 3.97 (1H, br d, J ) 8.0 Hz), 5.16 (1H, dt,
J ) 3.0, 8.0 Hz), 6.51 (1H, dd, J ) 1.5, 3.0 Hz), 7.17 (1H, dd,
J ) 1.0, 3.0 Hz), 7.59 (1H, dd, J ) 1.0, 1.5 Hz); IR (CHCl3):
3560, 1717 cm-1. Anal. Calcd for C11H14O4: C, 62.83; H, 6.72.
Found: C, 62.57; H, 6.68.
(1R,2S)-2-Hyd r oxycyclop en tyl 2-F u r oa te (10Bb). Com-
pound 9B (104 mg, 1.02 mmol) was converted to (1R,2S)-10Bb
J O010587F