Lipase-catalyzed transesterification of 2-hydroxy-2- (pentafluorophenyl)acetonitrile leading to (1R,2R)-and (1S,2S)-bis (pentafluorophenyl)ethane-1,2-diol

Article abstract of DOI:10.1021/jo9918551

Optically pure (IR,2R)- and (1S,2S)-1,2-bis(pentafluorophenyl)ethane- 1,2-diol (1) were synthesized from key intermediates (R)- and (S)-2-hydroxy- 2-(pentafluorophenyl)acetonitrile (2), both of which were prepared by the lipase LIP-catalyzed transesterification (E - 465). The absolute configuration of (S)-2 was determined by X-ray structural analysis after transformation into (S)-a-cyano-2,3,4,5,6-pentafluorobenzyl (S)-6-methoxy-a- methyl-2-naphthaleneacetate (S,S)-9. In addition, the crystal structure of (S,S)-9 has an interesting well-ordered packing pattern which shows face-to- face stacking interactions and end-to-end parallel contacts between the pentafluorophenyl and 6-methoxynaphthyl groups of the adjacent molecules.

Full text of DOI:10.1021/jo9918551

2740
J . Org. Chem. 2000, 65, 2740-2747
Lip a se-Ca ta lyzed Tr a n sester ifica tion of
2-Hyd r oxy-2-(p en ta flu or op h en yl)a ceton itr ile Lea d in g to (1R,2R)-
a n d (1S,2S)-Bis(p en ta flu or op h en yl)eth a n e-1,2-d iol
Takashi Sakai,* Yasushi Miki, Masashi Tsuboi, Hiroaki Takeuchi, Tadashi Ema,
Kenji Uneyama, and Masanori Utaka
Department of Applied Chemistry, Faculty of Engineering, Okayama University, Tsushima-naka,
Okayama 700-8530, J apan
Received December 2, 1999
Optically pure (1R,2R)- and (1S,2S)-1,2-bis(pentafluorophenyl)ethane-1,2-diol (1) were synthesized
from key intermediates (R)- and (S)-2-hydroxy-2-(pentafluorophenyl)acetonitrile (2), both of which
were prepared by the lipase LIP-catalyzed transesterification (E ) 465). The absolute configuration
of (S)-2 was determined by X-ray structural analysis after transformation into (S)-R-cyano-2,3,4,5,6-
pentafluorobenzyl (S)-6-methoxy-R-methyl-2-naphthaleneacetate (S,S)-9. In addition, the crystal
structure of (S,S)-9 has an interesting well-ordered packing pattern which shows face-to-face
stacking interactions and end-to-end parallel contacts between the pentafluorophenyl and 6-meth-
oxynaphthyl groups of the adjacent molecules.
In tr od u ction
Optically active 1,2-diphenylethane-1,2-diol and its
derivatives have attracted much attention owing to the
versatile utilities as chiral ligands1 and chiral auxiliaries1a,2
in asymmetric syntheses. The stereoselectivity of the
reactions with these compounds are generally controlled
by the steric interaction of phenyl groups. On the other
hand, perfluorophenyl group is known to construct the
face-to-face stacking arrangement with phenyl group3 due
to the favorable electrostatic interaction between the
aromatic rings (Figure 1a).4-7 Recently, such stacking
interactions have been utilized in the stereocontrolled
photochemical reactions in the crystalline state,8 in
F igu r e 1. Features of the perfluorophenyl group. (a) Stacking
ability with phenyl group. (b) Electron-withdrawing property.
* To whom correspondence should be addressed. Phone:
(+81)-86-251-8091. Fax: (+81)-86-251-8092. E-mail: tsakai@
cc.okayama-u.ac.jp.
supramolecular systems,9,10 and in the design of fluori-
nated drugs.11 Moreover, the electron-withdrawing prop-
erty of perfluorophenyl group (Figure 1b) has been
utilized for enhancing the Lewis acidity of boranes12-15
(1) (a) Wang, Z.-M.; Sharpless, K. B. J . Org. Chem. 1994, 59, 8302-
8303 and references therein. (b) Frost, C. G.; Williams, M. J . Synlett
1994, 551-552. (c) Bruin, M. E.; Ku¨ndig, E. P. Chem. Commun. 1998,
2635-2636. (d) Ku¨ndig, E. P.; Saudan, C. M.; Bernardinelli, G. Angew.
Chem., Int. Ed. 1999, 38, 1219-1223. (e) Shindo, M.; Koga, K.;
Tomioka, K. J . Org. Chem. 1998, 63, 9351-9357 and references
therein. (f) For lipase-catalyzed desymmetrization of the meso-1,2-
diphenylethane-1,2-diol: Nicolosi, G.; Patti, A.; Piattelli, M.; Sanfilippo,
C. Tetrahedron: Asymmetry 1994, 5, 283-288.
(7) Recently, an example for charge-transfer interaction between
hexafluorobenzene and metallocene has been reported: Aspley, C. J .;
Boxwell, C.; Buil, M. L.; Higgitt, C. L.; Long, C.; Perutz, R. N. Chem.
Commun. 1999, 1027-1028.
(2) (a) Stolle, A.; Becker, H.; Salau¨n, J .; Meijere, A. Tetrahedron Lett.
1994, 35, 3521-3524. (b) Marshall, J . A.; Xie, S. J . Org. Chem. 1995,
60, 7230-7237. (c) Fujioka, H.; Kitagawa, H.; Nagatomi, Y.; Kita, Y.
Tetrahedron: Asymmetry 1995, 6, 2113-2116. (d) Fujioka, H.; Matsu-
naga, N.; Kitagawa, H.; Nagatomi, Y.; Kondo, M.; Kita, Y. Tetrahedron:
Asymmetry 1995, 6, 2117-2120. (e) Cossy, J .; Bouzbouz, S. Tetrahedron
Lett. 1996, 37, 5091-5094. (f) Akhoon, K. M.; Myles, D. C. J . Org.
Chem. 1997, 62, 6041-6045. (g) Tunge, J . A.; Gately, D. A.; Norton, J .
R. J . Am. Chem. Soc. 1999, 121, 4520-4521.
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A.; Grubbs, R. H. Angew. Chem., Int. Ed. Engl. 1997, 36, 248-251. (b)
Coates, G. W.; Dunn, A. R.; Henling, L. M.; Ziller, J . W.; Lobkovsky,
E. B.; Grubbs, R. H. J . Am. Chem. Soc. 1998, 120, 3641-3649.
(9) Fujita, M.; Nagao, S.; Iida, M.; Ogata, K.; Ogura, K. J . Am. Chem.
Soc. 1993, 115, 1574-1576.
(10) (a) Gillard, R. E.; Stoddart, J . F.; White, A. J . P.; Williams, B.
J .; Williams, D. J . J . Org. Chem. 1996, 61, 4504-4505. (b) Li, Z.-T.;
Becher, J . Synlett 1997, 557-560. (c) Ballardini, R.; Balzani, V.; Credi,
A.; Brown, C. L.; Gillard, R. E.; Montalti, M. Philp, D.; Stoddart, J . F.;
Venturi, M.; White, A. J . P.; Williams, B. J .; Williams, D. J . J . Am.
Chem. Soc. 1997, 119, 12503-12513.
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10.1021/jo9918551 CCC: $19.00 © 2000 American Chemical Society
Published on Web 03/31/2000

Transesterification of 2-Substituted Acetonitrile
J . Org. Chem., Vol. 65, No. 9, 2000 2741
and for promoting Diels-Alder16 and Baylis-Hillman17
reactions. Despite their useful properties, only a few
examples of perfluorophenyl-containing chiral com-
pounds1c,d,18 have been reported so far.
Sch em e 1
In this paper, we report the synthesis of both enanti-
omers of (1R,2R)- and (1S,2S)-1,2-bis(pentafluorophenyl)-
ethane-1,2-diol, (1R,2R)- and (1S,2S)-1, as new entries
of pentafluorophenyl-containing optically active com-
pounds through key intermediates of (R)- and (S)-2-
hydroxy-2-(pentafluorophenyl)acetonitrile, (R)- and (S)-
2, respectively. We expected that introduction of penta-
fluorophenyl groups into chiral 1,2-diols will endow new
potentialities in asymmetric syntheses and lead to in-
teresting advanced materials reflecting the stacking
interaction and the electron-withdrawing property.
In our preceding papers,19 enantiomerically pure
(1R,2S)- and (1S,2R)-2-amino-1,2-bis(pentafluorophenyl)-
ethanol19a were synthesized from racemic (()-2-(tert-bu-
tyldimethylsilyloxy)-2-(pentafluorophenyl)acetonitrile (3)
through chemical resolutions with D-camphorsulfonic
acid. Quite recently, we have reported the synthesis of
optically pure (S)-319c by the lipase-catalyzed enantiose-
lective hydrolysis of racemic propanoate of 2 followed by
TBS protection. In this paper, we successfully prepared
both (R)- and (S)-2 by the lipase-catalyzed transesteri-
fication with improved yields and optical purities. The
absolute configuration of (S)-2 was determined by X-ray
structural analysis of its naproxen ester. Noteworthy is
a well-ordered packing structure of the naproxen ester,
where the pentafluorophenyl and the 6-methoxynaphthyl
groups construct face-to-face stacking interactions and
end-to-end parallel contacts.
pentafluorobenzene-n-BuLi in ether, -78 °C) gave imine
(()-4. Subsequent hydrolysis with 5% aqueous HCl-
EtOH furnished the TBS ether of ketone (()-5 (53%
yield). Attempts of chromatographic purification of (()-4
rather contaminated it with unidentified compounds.
Reduction of (()-5 with NaBH4 in ethanol followed by
desilylation with tetra-n-butylammonium fluoride (TBAF)
in THF gave (()-threo-1 together with a small amount
of erythro-1 [threo/erythro ) 95:5 (85% yield)], which
were easily separated chromatographically.
The relative stereochemistry of (()-threo-1 was deter-
mined by 1H NMR analysis after transformation (SOCl2-
Et3N) into the corresponding cyclic sulfite 6. The 1H NMR
spectrum for trans-6 showed two doublets at δ 5.96 and
6.49 (J vic ) 10.2 Hz) assignable to chemically nonequiva-
lent vicinal methine protons (Ha and Hb). On the other
hand, cis-6 similarly prepared from erythro-1 exhibits one
singlet at δ 6.52 assignable to the equivalence of Ha and
Hb.
Resu lts a n d Discu ssion
Dia ster eoselective Syn th esis of Ra cem ic 1,2-Diol
(()-1. Prior to the synthesis of optically active diols
(1R,2R)-1 and (1S,2S)-1, we first established the diaste-
reoselective pathway for the racemic (()-threo-1, which
was prepared from racemic tert-butyldimethylsilyl (TBS)
ether of cyanohydrin (()-3 as a key intermediate in three
steps (Scheme 1). Thus, the reaction of (()-3 with 1.6
equiv of (pentafluorophenyl)lithium (prepared from bromo-
(16) (a) Kan, T.; Ohfune, Y. Tetrahedron Lett. 1995, 36, 943-946.
(b) J acques, F.; Dupeyroux, H.; J oly, J .-P.; Chapleur, Y. Tetrahedron
Lett. 1997, 38, 73-76.
(17) Ramachandran, P. V.; Reddy, M. V. R.; Rudd, M. T.; de Alaniz,
J . R. Tetrahedron Lett. 1998, 39, 8791-8794.
(18) (a) Ojima, I.; Kwon, H. B. J . Am. Chem. Soc. 1988, 110, 5617-
5621. (b) Ku¨ndig, E. P.; Dupre´, C.; Bourdin, B.; Cunningham, A., J r.;
Pons, D. Helv. Chem. Acta 1994, 77, 421-428. (c) Matsukawa, S.;
Mikami, K. Tetrahedron: Asymmetry 1995, 6, 2571-2574.
(19) (a) Sakai, T.; Kubo, K.; Kashino, S.; Uneyama, K. Tetrahedron:
Asymmetry 1996, 7, 1883-1886. (b) Sakai, T.; Takayama, T.; Ohkawa,
T.; Yoshio, O.; Ema, T.; Utaka, M. Tetrahedron Lett. 1997, 38, 1987-
1991. (c) Sakai, T.; Miki, Y.; Nakatani, M.; Ema, T.; Uneyama, K.;
Utaka, M. Tetrahedron Lett. 1998, 39, 5233-5236.
The diastereoselectivity in NaBH4 reduction of (()-5
can be rationalized by the Felkin-Anh model20 (Scheme
(20) Lodge, E. P.; Heathcock, C. H. J . Am. Chem. Soc. 1987, 109,
3353-3361.

2742 J . Org. Chem., Vol. 65, No. 9, 2000
Sakai et al.
Ta ble 1. Scr een in g of Lip a ses for th e En a n tioselective
Sch em e 2
Tr a n sester ifica tion of (()-2a
time conversionb
(S)-7
(R)-2
lipase
(h)
26
72
6.5
1.5
(%)
(% eec) (% eed) E valuee
lipase AKf
lipase PSg
lipase PSh
lipase LIPi
32
8
35
44
61
20
85
96
48
20
47
79
6
>227
18
113
a
Conditions: lipase (100 mg), (()-2 (50 mg, 0.224 mmol), vinyl
2). The silyloxy (OTBS) group seems to be bulkier than
the pentafluorophenyl group. Consequently, the OTBS
group locates in the least sterically hindered site and
hydride attacks the carbonyl group from a direction
antiperiplanar to the OTBS group.
acetate (0.448 mmol), dry diisopropyl ether (2.5 mL), 30 °C.
Determined by GC analysis. c Determined by 1H NMR spectra
b
(200 MHz) in the presence of Eu(hfc)3. Determined by 1H NMR
d
spectra (200 MHz) after transformation into MTPA ester. e Cal-
culated from E ) ln [1 - c[1 + 7(ee)]]/ln[1 - c[1 - 7(ee)]], c )
2(ee)/[7(ee) + 2(ee)] according to ref 24. f Pseudomonas fluorescens
Lip a se-Ca ta lyzed Tr a n sester ifica tion of Cya n o-
h yd r in (()-2. If optically active TBS ethers (R)- and (S)-3
are available, both enantiomers of optically active diols
(1R,2R)- and (1S,2S)-1 would be prepared. For this
purpose, we now prepared racemic cyanohydrin precursor
(()-2, a new compound itself, and then subjected it to
the lipase-catalyzed transesterification in an organic
solvent. Cyanohydrin (()-2 could be prepared by two new
methods (Scheme 3) via its acetate (()-7 (method A) or
its trimethylsilyl (TMS) ether (()-8 (method B),21 both
of which were readily prepared from pentafluorobenzal-
dehyde.22 In method A, hydrolysis of acetate (()-7 was
successfully carried out only by using lipase A6-catalyzed
reaction in a phosphate buffer (pH 5.6)-acetone system
(75% yield), although both LiAlH4 reduction and alkaline
saponification of (()-7 resulted in decomposed com-
pounds. In the case of method B, hydrolysis of TMS ether
(()-8 was achieved by using 3% aqueous HCl, giving
(()-2 (98% yield).
The lipase-catalyzed transesterifications of (()-2 were
carried out with vinyl acetate in dry diisopropyl ether at
30 °C (Scheme 4). Several commercially available lipases
were examined as shown in Table 1. Among them, lipase
PS showed the highest enantioselectivity (E > 227), while
the reaction rate was slow (72 h for 8% conversion). In
contrast, lipase PS immobilized on Toyonite-DM23 re-
markably accelerated the reaction rate (6.5 h for 35%
conversion) while the enantioselectivity (E ) 18) was
decreased. The best choice was lipase LIP, which gave a
good enantioselectivity (E ) 113) with enhanced reaction
rate (1.5 h for 44% conversion). We have previously
reported the suitability of lipase LIP for the resolution
of pentafluorophenyl-containing compounds such as the
propanoate of (()-2 (E ) 211) in hydrolysis19c and
3-hydroxy-3-(pentafluorophenyl)propionitrile (E > 1057)
in transesterification.19b
g
h
lipase. Pseudomonas cepacia lipase. Pseudomonas cepacia li-
pase immobilized on Toyonite-DM. Pseudomonas aeruginosa
i
lipase immobilized on Hyflo Super-Cel.
F igu r e 2. Correlation between the ln E in the lipase LIP-cata-
lyzed transesterifications of (()-2 and 1/T. Conditions: lipase
LIP (100 mg), (()-2 (50 mg), vinyl acetate (2 equiv), in dry
i-Pr2O (2.5 mL). Reaction temperature (E value, reaction time,
conversion): (a) 45 °C (53, 1.0 h, 47%), (b) 30 °C (113, 1.5 h,
48%), (c) 15 °C (197, 2.3 h, 44%), (d) 0 °C (>427, 4.0 h, 44%).
transesterification (Figure 2) showed the linear correla-
tion by changing the reaction temperature from 45 to 0
°C.25
By using the optimized conditions, transesterification
on a preparative scale [(()-2 (2 g), lipase LIP (2 g), vinyl
acetate (4 equiv) in dry diisopropyl ether, 0 °C, 23 h] gave
optically active (S)-7 (50% yield, 98% ee) and its antipodal
alcohol (R)-2 (46% yield, 96% ee) with high enantiose-
lectivity (E ) 465). Moreover, lipase LIP was reusable
to give both enantiomers with retention of the enanti-
oselectivity [(S)-7: 50% yield, 98% ee; (R)-2: 47% yield,
94% ee, E ) 356]. The optical purity of (R)-2 was
increased up to >99% ee by one recrystallization from
petroleum ether-CH2Cl2.
Further optimization of the enantioselectivity (E >
427) was attained by lowering the reaction temperature
to 0 °C. The plot of ln E vs 1/T in the lipase LIP-catalyzed
Absolu te Con figu r a tion of Cya n oh yd r in 2 Ob-
ta in ed in th e Tr a n sester ifica tion . We have reported
the determination of the absolute configuration of (S)-2
by X-ray structural analysis after conversion to its
naproxen ester 9 (Figure 3).19c The optically active (S)-2
has been prepared by the hydrolytic resolution of acetate
(()-7. In the present transesterification of (()-2, the
remaining enantiomer of 2 was assigned to be (R) by
(21) Gassman, P. G.; Talley, J . J . Tetrahedron Lett. 1978, 25, 3773-
3776.
(22) Conventional method for nonfluorinated analogue using ace-
tonecyanohydrin was not applicable for (()-2. Inagaki, M.; Hatanaka,
A.; Mimura, M.; Hiratake, J .; Nishioka, T.; Oda, J . Bull. Chem. Soc.
J pn. 1992, 65, 111-120.
(23) Toyonite-DM, a new type of the spherical ceramics support
having 155 ( 5 µm average diameter, was supplied by Toyo Denka
Kogyo Co., Ltd., Kochi, J apan. The porous ceramics is prepared from
kaolin minerals and the average pore size is nearly 100 nm. The pores
have cross linkages consisting of methacryloxy groups at the end of
methylene chains for binding lipases. The immobilized lipases on this
support usually greatly accelerate the reaction rate. Yamashita, Y.;
Kamori, M.; Takeneka, H.; Takahashi, J . J pn Kokai Tokkyo Koho 09
313 179, 1997; Chem. Abstr. 1998, 128, 72373.
(25) We have reported the low-temperature effect for enhancement
of enantioselectivity in lipase-catalyzed transesterifications of both
primary and secondary alcohols: (a) Sakai, T.; Kawabata, I.; Kishimoto,
T.; Ema, T.; Utaka, M. J . Org. Chem. 1997, 62, 4906-4907. (b) Sakai,
T.; Kishimoto, T.; Tanaka, Y.; Ema, T.; Utaka, M. Tetrahedron Lett.
1998, 39, 7881-7884.
(24) Chen, C.-S.; Fujimoto, Y.; Girdaukas, G.; Sih, C. J . J . Am. Chem.
Soc. 1982, 104, 7294-7299.

Transesterification of 2-Substituted Acetonitrile
J . Org. Chem., Vol. 65, No. 9, 2000 2743
Sch em e 3
Sch em e 4
The pentafluorophenyl and 6-methoxynaphthyl groups
of the adjacent molecule are stacked alternately in a face-
to-face fashion (Figure 4a). The interplate distance is
approximately 3.5 Å, which is often observed between
phenyl and perfluorophenyl groups. On the other hand,
a view along the axis perpendicular to the π-plane of the
pentafluorophenyl and the 6-methoxynaphthyl rings
(Figure 4b) shows intermolecular end-to-end parallel
contacts between each aromatic rings. The distances
between the fluorine and the hydrogen atoms (F‚‚‚H) are
3.07 and 3.70 Å, which are somewhat longer than the
sum of VDW radius (rF + rH ) 2.55 Å) of fluorine and
hydrogen atoms. These results suggest that there are
only weak interactions between the aromatic fluorine and
hydrogen.27
Syn th esis of Op tica lly Active 1,2-Diols (1R,2R)-
a n d (1S,2S)-1. Because cyanohydrin 2 was found to be
relatively optically and structurally unstable as compared
with the nonfluorinated one, we transformed it into TBS
ether immediately after the lipase-catalyzed resolution.
Protection of optically active (R)-2 (96% ee) with tert-
butyldimethylsilyl trifluoromethanesulfonate (TBSOTf)
and 4-(dimethylamino)pyridine (DMAP) at 0 °C gave
(R)-3 without racemization [94% yield (Scheme 5)]. The
conventional procedure28 for nonfluorinated analogue by
using TBSCl and imidazole in DMF gave only 17% yield
of (R)-3 together with considerable amounts of (R)-2
recovered, which is provably due to the decreased nu-
cleophilicity of the oxygen in the hydroxyl group. Trans-
formation of (R)-3 (96% ee) into diol (1R,2R)-1 was carried
out in a similar procedure to that of racemic diol (()-
threo-1 (Scheme 1). In the transformation (Scheme 5),
the obtained diol (1R,2R)-1 retained the optical purity
(94% ee), although there is a possibility of partial
racemization arising from imine-enamine tautomerism.
One recrystallization from petroleum ether-CH2Cl2 in-
creased the ee up to 99%.
comparison of the optical rotation with that of (S)-(-)-2
(Scheme 4). Therefore, produced acetate 7 was assigned
to be (S), which was confirmed by the acidic hydrolysis
to (S)-2 as shown below. These facts indicate that the
enantiopreference is in agreement with the empirical rule
proposed by Kazlauskas et al.26
P a ck in g P a tter n of (S,S)-9. X-ray crystal analysis
of (S,S)-9 communicated previously19c is discussed here
in detail. As shown in Figure 4, the crystal structure of
(S,S)-9 has an interesting well-ordered packing pattern.
The antipodal (1S,2S)-1 was also obtained from (S)-2,
which was prepared by deacetylation of (S)-7 (Scheme
6). Thus, (S)-7 (98% ee) was treated with 1 equiv of
(26) Kazlauskas, R. J .; Weissfloch, A. N. E.; Rappaport, A. T.; Cuccia,
L. A. J . Org. Chem. 1991, 56, 2656-2665.
(27) Recently, intermolecular F‚‚‚H interaction between perfluoro-
arene- and arene-containing molecules has been reported: (a) Thalladi,
V. R.; Weiss, H.-C.; Bla¨ser, D.; Boese, R.; Nangia, A.; Desiraju, G. R.
J . Am. Chem. Soc. 1998, 120, 8702-8710. (b) Renak, M. L.; Bartholo-
mew, G. P.; Wang, S.; Ricatto, P. J .; Lachicotte, R. J .; Bazan, G. C. J .
Am. Chem. Soc. 1999, 121, 7787-7799.
F igu r e 3. Synthesis and crystal structure of (S,S)-9 for
determining the absolute configuration of (S)-2.
(28) Brussee, J .; Roos, E. C.; van der Gen, A. Tetrahedron Lett. 1988,
29, 4485-4488.

2744 J . Org. Chem., Vol. 65, No. 9, 2000
Sakai et al.
F igu r e 4. Packing pattern of naproxen ester (S,S)-9. (a) View along the horizontal axis. (b) View along the perpendicular axis
for the π-plane of the pentafluorophenyl and 6-methoxynaphthayl groups.
Sch em e 5a
were prepared by the lipase-catalyzed transesterifica-
tions. The conditions of the transformations were opti-
mized by searching the lipases and by the low-temper-
ature method. The X-ray crystal structure of compound
(S,S)-9 has an interesting well-ordered packing pattern
which shows face-to-face stacking interaction and end-
to-end parallel contacts between the pentafluorophenyl
and the 6-methoxynaphthyl groups of the adjacent
molecules.
Exp er im en ta l Section
Gen er a l Meth od s. All reactions were carried out under a
nitrogen atmosphere with dry and freshly distilled solvents
under anhydrous conditions, unless otherwise noted. Benzene,
diethyl ether (ether), diisopropyl ether, and tetrahydrofuran
(THF) were distilled from sodium, and methylene chloride
(CH2Cl2) was distilled from calcium hydride. Anhydrous ace-
tonitrile was purchased from Wako Pure Chemical Industries
Co., Ltd. and used without any purification. Lipase LIP was
provided by TOYOBO Co., Ltd., and lipase AK, AH, and PS
were provided by Amano Pharmaceutical Co., Ltd. and used
without any purification. Lipase PS immobilized on Toyonite-
DM was provided by Toyo Denka Kogyo Co., Ltd. Reactions
were monitored by thin-layer chromatography with precoated
silica gel plates (Merck 60 F254, plate length 40 mm). As a usual
workup procedure, the reaction mixture was extracted with
ethyl acetate (EtOAc). The organic layer was dried over
MgSO4, filtrated with suction, and concentrated in vacuo.
Preparative column chromatography were carried out by using
silica gel (Fuji Silysia BW-127 ZH, 100-270 mesh). Boiling
points were oven temperatures at the bulb-to-bulb distillation
a
Reagents and condition: (a) TBSOTf, DMAP in CH2Cl2, 0 °C,
2.5 h, 94%; (b) recrystallization from petroleum ether-CH2Cl2.
Sch em e 6a
1
and are incorrected. H NMR spectra were measured at 200
a
Reagents and condition: (a) TsOH in EtOH, rt, 2 days, 92%;
or 500 MHz and 13C NMR spectra at 50 MHz, respectively,
and chemical shifts are given relative to tetramethylsilane
(TMS). 19F NMR spectra were measured at 188 MHz and
chemical shifts are given relative to C6F6.
(b) TBSOTf, DMAP in CH2Cl2, 0 °C, 2.0 h, 92%; (c) recrystallization
from petroleum ether-CH2Cl2.
(()-2-(ter t-Bu tyldim eth ylsiloxy)-2-(pen taflu or oph en yl)-
a ceton itr ile ((()-3). A mixture of sodium cyanide (980 mg,
20.0 mmol), zinc bromide (113 mg, 0.5 mmol), molecular sieves
4A (250 mg), and acetonitrile (20 mL) was placed in a 100 mL
round-bottomed flask. To this were added pentafluorobenzal-
dehyde (1.96 g, 10.0 mmol, distilled before use) and tert-
butyldimethylchlorosilane (TBSCl, 1.81 g, 12.0 mmol) dissolved
in acetonitrile (8 mL) successively at room temperature
through syringe. After the mixture was stirred for 12 h at room
temperature, saturated aqueous NaHCO3 was added to make
the mixture basic (pH 9). The resulting mixture was treated
in the usual manner to give a viscous brown oil, which was
distilled (bp 150 °C, 15 Torr) to remove high-boiling com-
pounds. Further purification by column chromatography (SiO2,
hexane-EtOAc, 50:1) gave (()-3 (2.95 g, 87% yield) as a
p-tolueneslufonic acid (TsOH) to give (S)-2 with a slightly
decreased optical purity (94% ee, 92% yield). Other
methods for deacetylation of (S)-7, such as basic saponi-
fication, lipase-catalyzed hydrolysis, and reductive deg-
radation by NaBH4, failed to give (S)-2. Desired (1S,2S)-1
with 91% ee was obtained by the method similar to that
described for (1R,2R)-1. Two recrystallization from pe-
troleum ether-CH2Cl2 increased the ee up to >99%.
Con clu sion
We have synthesized optically pure 1,2-bis(pentafluo-
rophenyl)ethane-1,2-diols (1R,2R)- and (1S,2S)-1 via
cyanohydrin intermediates (R)- and (S)-2, both of which
1
colorless oil: Rf ) 0.58 (SiO2, hexane-EtOAc, 4:1); H NMR

Transesterification of 2-Substituted Acetonitrile
J . Org. Chem., Vol. 65, No. 9, 2000 2745
(200 MHz, CDCl3) δ 0.13 (s, 3H), 0.26 (s, 3H), 0.90 (s, 9H),
5.77 (s, 1H); 13C NMR (CDCl3) δ -5.4, -5.3, 18.1, 25.4, 54.1,
111.2 (m), 116.6, 135.2 (m), 140.4 (m), 142.4 (m), 147.5 (m);
19F NMR (CDCl3) δ 1.7-2.1 (m, 2F), 11.6 (t, J ) 20.3 Hz, 1F),
IR (KBr) 3476 (OH), 2955, 1529, 1504, 982 cm-1. Anal. Calcd
for C14H4F10O2: C, 42.66; H, 1.02. Found: C, 42.69; H, 1.07.
For erythro-1: white crystals; mp 185-187 °C (petroleum
1
ether-THF); Rf ) 0.35 (SiO2, hexane-EtOAc, 4:1); H NMR
20.0-20.2 (m, 2F); IR (neat) 2958, 2934, 2862, 1513, 1003 cm-1
.
(200 MHz, CDCl3) δ 2.45-2.60 (m, 2H), 5.32-5.45 (m, 2H);
13C NMR (acetone-d6) δ 68.2, 117.5 (m), 135.9 (m), 139.1 (m),
140.9 (m), 144.1 (m), 149.1 (m); 19F NMR (CDCl3) δ 0.6-1.0
(m, 4F), 9.1 (t, J ) 21.1 Hz, 2F), 18.8-19.2 (m, 4F); IR (KBr)
3462 (OH), 2955, 1532, 1504, 989 cm-1. Anal. Calcd for
Anal. Calcd for C14H16F5NOSi: C, 49.84; H, 4.78; N, 4.15.
Found: C, 49.47; H, 4.47; N, 4.49.
TBS Eth er (R)-3: TBS P r otection of Op tica lly Active
Cyan oh ydr in (R)-2. tert-Buthyldimethylsilyl trifluoromethane-
sulfonate (TBSOTf, 1.3 mL, 5.7 mmol) was slowly added to a
solution of cyanohydrin (R)-2 (848 mg, 3.80 mmol, 96% ee)
obtained by the lipase LIP-catalyzed transesterification of
cyanohydrin (()-2 (as shown below) and 4-(dimethylamino)-
pyridine (DMAP, 928 mg, 7.60 mmol) in CH2Cl2 (9.5 mL) in
an ice bath. After being stirred for 2.5 h in an ice bath, the
mixture was acidified (pH 4) by addition of 3% aqueous HCl.
The resulting mixture was treated in the usual manner. The
residual mixture was purified by column chromatography
(SiO2, hexane-EtOAc, 50:1) to give (R)-3 (1.21 g, 94% yield,
96% ee) as a colorless oil; >99% ee on the basis of HPLC
analysis: retention time ) 10.7 and 11.5 min for (S)- and (R)-
3, respectively. The condition of HPLC is as follows: Daicel
CHIRALCEL OD-H, 4.6 mm × 25 cm, hexane-i-PrOH (300:
C
14H4F10O2: C, 42.66; H, 1.02. Found: C, 42.72; H, 0.91.
1,2-Diol (1R,2R)-1. This compound was synthesized from
optically active TBS ether (R)-3 (1.02 g, 3.0 mmol, 96% ee)
obtained by the lipase LIP-catalyzed resolution (as shown
below) in a similar procedure to that for (()-threo-1: 35% yield
(420 mg) from (R)-3 after column chromatography; white
crystals; mp 150-152 °C (petroleum ether-CH2Cl2); 99% ee
on the basis of HPLC analysis: retention times ) 11.5 and
14.2 min for (1R,2R)- and (1S,2S)-1, respectively. The condi-
tions of HPLC are as follows: column; Daicel CHIRALCEL
OD-H, 4.6 mm × 25 cm, hexane-i-PrOH (9:1), 0.5 mL min-1
,
UV 254 nm; [R]27 ) +40.0 (c 0.54, EtOH).
D
1,2-Diol (1S,2S)-1. This compound was synthesized from
optically active TBS ether (S)-3 (266 mg, 0.8 mmol, 94% ee)
obtained by the lipase LIP-catalyzed resolution and acidic
alcoholysis of acetate (S)-7 (as shown below) in a similar
procedure to that for (()-threo-1: 34% yield (104 mg) from
(S)-3 after column chromatography: white crystals; mp 151-
1), 0.5 mL min-1, UV 254 nm; [R]28 ) +30.1 (c 0.87, CHCl3).
D
(()-2-(ter t-Bu t yld im et h ylsiloxy)-1,2-b is(p en t a flu or o-
p h en yl)eth a n -1-on e (5). To a solution of bromopentafluo-
robenzene (1.58 g, 6.40 mmol) in ether (10.7 mL) was added
dropwise n-BuLi (1.54 M in hexane, 4.2 mL, 6.4 mmol) over
10 min at -78 °C. The solution was stirred for 1 h at the
temperature. The resultant pale white mixture was further
cooled to -85 °C, and a solution of TBS ether (()-3 (1.35 g,
4.00 mmol) in ether (6.7 mL) was added dropwise over 5 min.
After being stirred for additional 1 h at the temperature, the
mixture was quickly acidified by addition of 5% aqueous HCl-
EtOH (4 + 8 mL) solution, and the combined mixture was
stirred for 1.5 h in an ice bath. The resulting mixture was
treated in the usual manner. The residual oil was purified by
column chromatography (SiO2, hexane-EtOAc, 100:1) to give
(()-5 (1.06 g, 53% yield) as a light yellow oil: bp 160 °C (14
Torr); Rf ) 0.65 (SiO2, hexane-EtOAc, 4:1); 1H NMR (200
MHz, CDCl3) δ -0.16 (s, 3H), 0.10 (s, 3H), 0.71 (s, 9H), 5.75
(s, 1H); 13C NMR (CDCl3) δ -5.8, -5.3, 17.9, 25.3, 71.7, 113.2
(m), 135.2 (m), 139.6 (m), 140.4 (m), 141.5 (m), 142.8 (m), 144.7
(m), 145.6 (m), 146.6 (m), 147.8 (m), 193.0; 19F NMR (CDCl3)
δ 1.0-1.3 (m, 2F), 1.6-1.9 (m, 2F), 10.5 (t, J ) 20.7 Hz, 1F),
13.0 (t, J ) 19.8 Hz, 1F), 20.9 (d, J ) 18.2 Hz), 21.9 (d, J )
18.2 Hz, 2F); IR (neat) 2958, 2934, 2862, 1734 (CdO), 1523,
1498, 984 cm-1. Anal. Calcd for C20H16F10O2Si: C, 47.44; H,
3.18. Found: C, 47.21; H, 3.02.
153 °C (petroleum ether-CH2Cl2); >99% ee; [R]29 ) -40.8 (c
D
0.52, EtOH).
(()-tr a n s-2-Oxo-4,5-bis(p en ta flu or op h en yl)-1,3-d ioxa -
2-th ia cyclop en ta n e ((()-tr a n s-6). Thionyl chloride (15 µL,
0.20 mmol, distilled before use) was slowly added to a solution
of (()-threo-1 (39.4 mg, 0.10 mmol) and triethylamine (56 µL,
0.40 mmol) in CH2Cl2 (1.0 mL) in an ice bath. After being
stirred for 2 h in an ice bath, the mixture was acidified (pH 4)
by addition of 3% aqueous HCl. The resulting mixture was
treated in the usual manner. The residual oil was purified by
column chromatography (SiO2, hexane-EtOAc, 40:1) to give
(()-trans-6 (41.0 mg, 87% yield) as white crystals: mp 96-97
°C (petroleum ether); Rf ) 0.65 (SiO2, hexane-EtOAc, 4:1);
1H NMR (200 MHz, CDCl3) δ 5.96 (d, J ) 10.2 Hz, 1H, CHa),
6.49 (d, J ) 10.2 Hz, 1H, CHb); 13C NMR (CDCl3) δ, 72.7, 76.8,
105.3 (m), 135.7 (m), 140.7 (m), 143.5 (m), 145.8 (m), 148.6
(m); 19F NMR (CDCl3) δ 2.4-3.2 (m, 4F), 13.7 (t, J ) 20.7 Hz,
1F), 14.1 (t, J ) 20.9 Hz, 1F), 21.4-21.9 (m, 4F); IR (KBr)
2963, 2939, 1531, 1505, 1223 (SdO), 1010, 986 cm-1. Anal.
Calcd for C14H2F10O3S: C, 38.20; H, 0.46. Found: C, 37.92;
H, 0.37.
(()-th r eo-1,2-Bis(p en t a flu or op h en yl)et h a n e-1,2-d iol
((()-1). To a solution of ketone (()-5 (1.05 g, 2.08 mmol) in
EtOH (5.2 mL) was added sodium borohydride (79.0 mg, 2.08
mmol) suspended in EtOH (7.0 mL) in an ice bath under
atmospheric conditions. After being stirred for 1.5 h in an ice
bath, the mixture was acidified (pH 4) by addition of 3%
aqueous HCl. The resulting mixture was treated in the usual
manner. The obtained alcohol of (()-5 (1.05 g, pale yellow solid)
Su lfite cis-6. This compound was synthesized from eryth-
ro-1 (39.4 mg, 0.10 mmol) in a procedure similar to that for
(()-trans-6: 70% yield (33.0 mg) after column chromatography;
white crystals; mp 137-138 °C (petroleum ether); Rf ) 0.63
(SiO2, hexane-EtOAc, 4:1); 1H NMR (200 MHz, CDCl3) δ 6.52
(s, 2H); 13C NMR (CDCl3) δ 76.3, 106.6 (m), 135.2 (m), 140.0
(m), 142.3 (m), 144.6 (m), 147.4 (m); 19F NMR (CDCl3) δ 2.3-
2.7 (m, 4F), 12.9 (t, J ) 21.2 Hz, 2F), 21.3-21.8 (m, 4F); IR
(KBr) 2982, 1530, 1500, 1223 (SdO), 975 cm-1. Anal. Calcd
for C14H2F10O3S: C, 38.20; H, 0.46. Found: C, 37.98; H, 0.48.
1
had a satisfactory purity according to the H NMR spectrum
[(200 MHz, CDCl3) δ -0.09 (s, 3H), 0.08 (s, 3H), 0.89 (s, 9H),
5.37 (s, 2H)] and was used in the following reaction without
any purification. The alcohol of (()-5 (1.01 g, 1.99 mmol) was
dissolved in THF (10.0 mL) and was allowed to react with
tetra-n-butylammonium fluoride (TBAF, 1 M in THF, 2.0 mL,
2.0 mmol) for 30 min in an ice bath under atmospheric
conditions. The resulting solution was concentrated in vacuo,
and the residual viscous oil was purified by column chroma-
tography (SiO2, hexane-EtOAc, 4:1 then 1:1) to give (()-
threo-1 (560 mg, 72% yield) and erythro-1 (31.3 mg, 4.0% yield).
(()-2-Acetoxy-2-(p en ta flu or op h en yl)a ceton itr ile ((()-
7). Pentafluorobenzaldehyde (3.33 g, 17.0 mmol, distilled
before use) and acetyl chloride (2.4 mL, 34.0 mmol) were added
successively to a mixture of sodium cyanide (1.72 g, 34.0
mmol), zinc bromide (3.8 mg, 0.017 mmol), and acetonitrile
(15 mL) at room temperature. After the mixture was stirred
for 40 h at room temperature, saturated aqueous NaHCO3 was
added to make the mixture basic (pH 9). The resulting mixture
was treated in the usual manner. The residual viscous brown
oil (5.56 g) was found to contain about 25% (5.5 mmol) of
For (()-threo-1: white crystals; mp 155-156 °C (petroleum
1
ether-THF); Rf ) 0.16 (SiO2, hexane-EtOAc, 4:1); H NMR
1
cyanohydrin 2 by H NMR analysis. For complete conversion
(200 MHz, CDCl3) δ 3.05-3.15 (m, 2H), 5.45-5.50 (m, 2H);
13C NMR (acetone-d6) δ 68.7, 115.0 (m), 135.8 (m), 139.3 (m),
140.8 (m), 143.4 (m), 144.2 (m), 148.4 (m); 19F NMR (CDCl3) δ
1.2-1.6 (m, 4F), 10.1 (t, J ) 21.1 Hz, 2F), 20.1-20.4 (m, 4F);
to acetate 7, the mixture was allowed to react again with acetyl
chloride (1.20 mL, 16.5 mmol) and pyridine (2.90 mL, 27.5
mmol) in acetonitrile (20 mL) for 19 h at room temperature.29

2746 J . Org. Chem., Vol. 65, No. 9, 2000
Sakai et al.
After being acidified (pH 4) by addition of 3% aqueous HCl,
the resulting mixture was treated in the usual manner to give
a viscous brown oil, which was distilled (bp 170 °C, 35 Torr)
to remove high-boiling compounds. Further purification by
column chromatography (SiO2, hexane-EtOAc, 10:1) gave
(()-7 (4.18 g, 92% yield) as a colorless oil: Rf ) 0.55 (SiO2,
hexane-EtOAc, 3:1); 1H NMR (200 MHz, CDCl3) δ 2.18 (s, 3H),
6.66 (s, 1H);13C NMR (CDCl3) δ 20.1, 52.2, 106.7 (m), 113.5,
135.5 (m), 140.6 (m), 142.9 (m), 145.9 (m), 148.0 (m), 168.4;
19F NMR (CDCl3) δ 2.4-2.8 (m, 2F), 13.9 (t, J ) 21.6 Hz, 1F),
22.5-22.9 (m, 2F); IR (neat) 2962, 1771, 1760 (CdO), 1515,
1029, 1005 cm-1. Anal. Calcd for C10H4F5NO2: C, 45.30; H,
1.52; N, 5.28. Found: C, 45.37; H, 1.32; N, 5.45.
mixture was stirred for 10 min at the indicated temperature,
fleshly distilled vinyl acetate (38.8 mg, 0.448 mmol) was added.
The reaction progress was monitored by gas chromatogra-
phy: retention times ) 4.5 and 11.9 min for cyanohydrin (R)-2
and antipodal acetate (S)-7, respectively. The conditions of gas
chromatography are as follows: 5% PEG-20M (60-80 mesh),
2.9 mm × 3.0 m, 80-190 °C (7.5 °C min-1), nitrogen (12 mL
min-1). When the conversion was reached at 40-50%, the
mixture was filtered through Celite pad with suction, and the
filtrate was concentrated in vacuo.
Deter m in a tion of Op tica l P u r ity of Cya n oh yd r in (R)-2
a n d Aceta te (S)-7. Cyanohydrin (R)-2 as a mixture with (S)-7
was allowed to react with (R)-2-methoxy-2-(trifluoromethyl)-
phenylacetyl (MTPA) chloride (2 equiv) in the usual manner,30
giving a mixture of the corresponding MTPA ester and
remaining (S)-7. 1H NMR spectrum (200 MHz) of the mixture
showed two signals due to the methoxy protones at δ 3.48 and
3.60 for the MTPA esters of (S)- and (R)-2, respectively. On
Aceta te (S)-7. This compound was obtained by the lipase
LIP-catalyzed resolution of cyanohydrin (()-2 as shown be-
low: colorless oil; 98% ee; [R]28 ) +1.1 (c 2.20, CHCl3).
D
(()-2-Hyd r oxy-2-(p en ta flu or op h en yl)a ceton itr ile ((()-
2) (Meth od A). A mixture of acetate (()-7 (200 mg, 0.754
mmol), lipase A6 (600 mg), acetone (0.5 mL), and 67 mM
phosphate buffer (pH 5.6, 5.0 mL) was placed in a test tube
and stirred for 12 h at 40 °C under atmospheric conditions.
The resulting mixture was treated in the usual manner. The
residual viscous oil was purified by column chromatography
(SiO2, hexane-EtOAc, 10:1 then 4:1) to give (()-2 (126 mg,
75% yield) as a white solid: mp 54-56 °C (petroleum ether-
CH2Cl2).
1
the other hand, Eu(hfc)3 (1 equiv)-induced H NMR spectrum
(200 MHz) of the mixture showed two signals at δ 2.2-2.4 and
2.3-2.5 due to acetates (S)- and (R)-7, respectively.
P r ep a r a tive-Sca le Lip a se LIP -Ca ta lyzed Tr a n sester i-
fica tion of (()-2. This reaction was carried out by using (()-2
(2.00 g, 8.96 mmol), lipase LIP (2.00 g), dry diisopropyl ether
(50 mL), and vinyl acetate (3.4 mL, 35.6 mmol) for 21 h at 0
°C in a manner similar to that described above. The residual
oil was purified by column chromatography (SiO2, hexane-
EtOAc, 10:1 then 1:1) to give acetate (S)-7 (1.20 g, 50% yield,
98% ee) and remaining alcohol (R)-2 (0.91 g, 46% yield, 96%
ee). Optically active (R)-2 could be stored in a refrigerator for
a few weeks without decomposition and racemization.
Cya n oh yd r in (()-2: Acid ic Hyd r olysis of TMS Eth er
8 (Meth od B). Pentafluorobenzaldehyde (5.93 g, 30.2 mmol)
and trimethylsilyl cyanide (5.20 mL, 39.0 mmol) were added
to a mixture of zinc bromide (203 mg, 0.900 mmol) and CH3-
CN (30 mL) at room temperature, and the mixture was stirred
for 40 h at room temperature. After being cooled in an ice bath,
the mixture was acidified by addition of 3% aqueous HCl (5
mL) and was stirred for additional 1 h in an ice bath, and then
the organic layer was extracted with EtOAc. The extract was
washed with 67 mM phosphate buffer (pH 8.0, 20 mL) and
treated in a usual manner. The residual oil was purified by
column chromatography (SiO2, hexane-EtOAc, 4:1) to give
(()-2 (6.60 g, 98% yield) as white crystals: mp 54-56 °C
(petroleum ether-CH2Cl2); Rf ) 0.37 (SiO2, hexane-EtOAc,
(S)-r-Cya n o-2,3,4,5,6-pen ta flu or oben zyl (S)-6-Meth oxy-
r-m eth yl-2-n a p h th a len ea ceta te (Na p r oxen Ester , (S,S)-
9). Pyridine (0.30 mL, 3.6 mmol) was added to a solution of
(S)-2 (80.3 mg, 0.360 mmol, 94% ee) obtained by the lipase
LIP-catalyzed hydrolysis of (()-719c and (S)-6-methoxy-R-
methyl-2-naphthaleneacetyl chloride (naproxen chloride, 180
mg, 0.720 mmol)31 in benzene (5 mL) in an ice bath. The
mixture was stirred for 2 h in an ice bath and then stirred for
additional 18 h at room temperature. After being acidified (pH
4) by addition of 3% aqueous HCl, the resulting mixture was
treated in the usual manner. The residual oil was purified by
column chromatography (SiO2, hexane-EtOAc, 5:1) and then
recrystallized from petroleum ether to give (S,S)-9 (82 mg, 56%
1
3:1); H NMR (200 MHz, CDCl3) δ 3.49 (d, J ) 7.6 Hz, 1H),
5.84 (d, J ) 6.8 Hz, 1H); 13C NMR (CDCl3) δ 52.9, 109.7 (m),
116.4, 135.5 (m), 140.4 (m), 142.6 (m), 145.5 (m), 147.7 (m);
19F NMR (CDCl3) δ 2.2-2.7 (m, 2F), 12.7 (t, J ) 20.0 Hz, 1F),
19.9-20.2 (m, 2F); IR (KBr) 3490 (OH), 2952, 1513, 1002, 982
cm-1. Anal. Calcd for C8H2F5NO: C, 43.07; H, 0.90; N, 6.28.
Found: C, 42.89; H, 0.76; N, 6.33.
yield) as white crystals: mp 104-105 °C; >99% ee; [R]27
)
D
-26.4 (c 1.91, CHCl3); Rf ) 0.53 (SiO2, hexane-EtOAc, 3:1);
1H NMR (500 MHz, CDCl3) δ 1.61 (d, J ) 7.0 Hz, 3H), 3.92 (s,
3H), 3.94 (q, J ) 7.0 Hz, 1H), 6.64 (s, 1H), 7.12 (d, J ) 2.5 Hz,
1H), 7.16 (dd, J ) 9.0, 2.5 Hz, 1H), 7.35 (dd, J ) 8.5, 2.0 Hz,
1H), 7.65 (d, J ) 2.0 Hz, 1H), 7.70 (d, J ) 9.5 Hz, 1H), 7.72 (d,
J ) 8.5 Hz, 1H); 13C NMR (CDCl3) δ 18.2, 45.0, 52.7, 55.5,
105.8, 106.9 (m), 113.3, 119.5, 125.8, 126.3, 127.7, 129.0, 129.4,
133.5, 134.1, 135.5 (m), 140.5 (m), 142.8 (m), 146.0 (m), 147.9
(m), 158.1, 172.2; 19F NMR (CDCl3) δ 2.3-2.8 (m, 2F), 13.9 (t,
J ) 17.3 Hz, 1F), 22.7 (d, J ) 17.3 Hz, 2F); IR (KBr) 2946,
1756 (CdO), 1604, 1392, 1123, 997, 863, 823 cm-1. Anal. Calcd
for C22H14F5NO3: C, 60.70; H, 3.24; N, 3.22. Found: C, 60.45;
H, 3.12; N, 3.18.
Cya n oh yd r in (R)-2. This compound was prepared by the
lipase LIP-catalyzed resolution (as shown below) and subse-
quent recrystallization from petroleum ether-CH2Cl2: white
crystals; mp 71-73 °C; >99% ee determined by HPLC after
transformation into TBS ether (R)-3; [R]28 ) +33.7 (c 1.14,
D
CHCl3).
Cya n oh yd r in (S)-2: Acid ic Alcoh olysis of Aceta te (S)-
7. p-Toluenesulfonic acid (TsOH) monohydride (380 mg, 2.00
mmol) was added to a solution of acetate (S)-7 (530 mg, 2.00
mmol, 98% ee) obtained by lipase LIP-catalyzed transesteri-
fication of (()-2 (as shown below) in EtOH (10 mL) at room
temperature under an atmosphere. After being stirred for 2
days at room temperature, the solution was concentrated in
vacuo. The residual viscous oil was purified by column chro-
matography (SiO2, hexane-EtOAc, 4:1) to give (S)-2 (413 mg,
92% yield) as white crystals: mp 71-73 °C (petroleum ether-
CH2Cl2); 94% ee determined by HPLC after transformation
X-r a y cr ysta l d a ta for (S,S)-9: C22H14F5NO3, M ) 435.35,
monoclinic, space group P21, a ) 9.602(6) Å, b ) 15.545(8) Å,
c ) 9.449(1) Å, â ) 135.030(6)°, V ) 996.89(0) Å3, Z ) 2, Dcalc
) 1.45(0) g cm-3, R ) 0.080 for 1273 observed reflections [I >
3.00σ(I)] and 280 variable parameters. All measurements were
made on a Rigaku RAXIS-IV imaging plate area detector with
Mo KR radiation.
into TBS ether (S)-3; [R]27 ) -30.4 (c 1.17, CHCl3) [lit.19c
D
>99% ee; [R]26 ) -30.5 (c 1.10, CHCl3)].
D
Gen er a l P r oced u r e for th e Lip a se-Ca ta lyzed Tr a n s-
ester ifica tion . A mixture of cyanohydrin (()-2 (50.0 mg, 0.224
mmol), lipase (100 mg), and dry diisopropyl ether (2.5 mL) was
placed in a test tube and stirred at the temperature indicated
(45, 30, 15, and 0 °C) under atmospheric conditions. After the
Ack n ow led gm en t. This work was partially sup-
ported by a Grant-in-Aid for Scientific Research from
the Ministry of Education, Science and Culture of
(30) Dale, J . A.; Mosher, H. S. J . Am. Chem. Soc. 1973, 95, 512-
(29) Addition of excess acetyl chloride directly to residual cyanohy-
drin 2 was unsuccessful, and thus one repetition procedure was usually
required.
519.
(31) Bu¨yu¨ktimkin, N.; Buschauer, A. J . Chromatogr. 1988, 450,
281-283.

Transesterification of 2-Substituted Acetonitrile
J . Org. Chem., Vol. 65, No. 9, 2000 2747
1
Su p p or tin g In for m a tion Ava ila ble: Copies of H NMR
J apan. We are grateful to Amano Pharmaceutical Co.,
Ltd., Toyobo Co., Ltd., Sumitomo Chemical Co., Ltd.,
and Toyo Denka Kogyo Co., Ltd. for kind supply of the
lipases and/or their support Toyonite. We also thank the
SC-NMR laboratory for 1H, 13C, 19F NMR and the
Venture Business Laboratory of Okayama University
for X-ray analysis.
spectra for compounds (()-trans-/cis-6 and 13C NMR spectra
for compounds (()-threo-/erythro-1, (()-2, (()-3, (()-5, (()-
trans-/cis-6, (()-7, and (S,S)-9; X-ray crystallographic data for
(S,S)-9. This material is available free of charge via the
Internet at http.//pubs.acs.org.
J O9918551