Synthesis of enantiomerically pure cycloalkenols via combination strategy of enzyme-catalyzed reaction and RCM reaction

Article abstract of DOI:10.1016/j.tetasy.2007.10.005

The preparation of three types of cyclic alkenols, (S)-2-cyclohexenol, (R)-2,5-dihydrobenzo[b]oxepin-5-ol, and (R)-5,6-dihydro-2H-benzo[b]oxocin-6-ol, has been accomplished in enantiomerically pure forms as model compounds using a combination of a lipase-catalyzed reaction and a ring closing olefin metathesis (RCM) reaction.

Full text of DOI:10.1016/j.tetasy.2007.10.005

Available online at www.sciencedirect.com
Tetrahedron: Asymmetry 18 (2007) 2484–2490
Synthesis of enantiomerically pure cycloalkenols via combination
strategy of enzyme-catalyzed reaction and RCM reaction
Han Shi-Hui, Takuya Hirakawa, Takaaki Fukuba, Shuichi Hayase,
Motoi Kawatsura and Toshiyuki Itoh*
Department of Material Sciences, Faculty of Engineering, Tottori University, Tottori 680-8552, Japan
Received 4 September 2007; accepted 2 October 2007
Abstract—The preparation of three types of cyclic alkenols, (S)-2-cyclohexenol, (R)-2,5-dihydrobenzo[b]oxepin-5-ol, and (R)-5,6-dihydro-
2H-benzo[b]oxocin-6-ol, has been accomplished in enantiomerically pure forms as model compounds using a combination of a
lipase-catalyzed reaction and a ring closing olefin metathesis (RCM) reaction.
Ó 2007 Elsevier Ltd. All rights reserved.
1. Introduction
Grubbs et al. reported the synthesis of chiral cycloalkenols
using the kinetic resolution of acyclic racemic dienes by
asymmetric RCM, though the recorded highest ee of these
compounds was 84%.7 Kamei et al. reported successful
examples of cyclic compounds via a RCM reaction starting
from optically active monoacetate that was prepared by a
lipase-catalyzed reaction.8 With these results in mind, we
The chemo-enzymatic reaction protocol is now well recog-
nized as a very useful means to prepare optically active
compounds.1 Lipases are important tools for organic syn-
thesis, particularly for the preparation of optically active
secondary alcohols. Although lipases generally have a wide
applicability for various types of substrate, poorly enantio-
selective reactions are sometimes obtained for some com-
pounds, in particular, cyclic alcohols. For example, both
lipase PS from Burkholderia cepacia and Novozym 435
from Candida antarctica lipase, that are well respected
and the most widely used enzymes for organic synthesis,1
showed poor reactivity with 2-cyclohexen-1-ol 1 exhibiting
low enantioselectivity.2,3 We also attempted to resolve se-
ven-membered cyclic alkenol 2 and eight-membered cyclic
alkenol 3 using lipases, however, no enzyme which was able
to react with these compounds was found among the seven
types of typical commercial lipases tested.4 On the other
hand, we established that lipase works as an excellent cat-
alyst for the transesterification of acyclic allylic alcohols.5
For example, excellent enantioselectivity was recorded for
the Novozym 435-catalyzed transesterification of octane-
1,7-diene-3-ol ( )-5 using vinyl acetate as an acyl donor;
since 5 has two vinyl groups at either terminal of the mol-
ecule, we anticipated that it will create 2-cyclohexen-1-ol 1
via a ring closing metathesis (RCM) reaction.6
OH
OH
OH
O
O
1
2
3
RCM
RCM
O
O
O
R
R
O
n
O
4
6a: n=0
6b: n=1
Lipase
Acyldonor
OH
OH
n
O
5
7
*
Figure 1. Combination protocol for the preparation of enantiomerically
Corresponding author. Tel./fax: +81 857 31 5259; e-mail: titoh@chem.
pure cycloalkenol using chemo-enzymatic reaction.
tottori-u.ac.jp
0957-4166/$ - see front matter Ó 2007 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetasy.2007.10.005

H. Shi-Hui et al. / Tetrahedron: Asymmetry 18 (2007) 2484–2490
2485
planned to prepare optically pure cycloalkenols via a
combination of a chemo-enzymatic reaction and a RCM
reaction (Fig. 1). Herein we report the synthesis of three
types of enantiomerically pure cyclic alkenols using this
methodology.
[bmim][PF6] as a reaction medium under ambient pressure,
although it is difficult to use the enzyme repeatedly (see
Section 4).
It should be emphasized that the system allowed the
recyclable use of the enzyme with five repetitions, while
maintaining perfect reactivity. The RCM reaction of phen-
oxy acetate (S)-4a (R = CH2OPh) proceeded smoothly in
the presence of 5 mol % of the first generation Ru cata-
lyst6,15 in an ionic liquid, [bmim][PF6], at 80 °C for 48 h
to give the cyclohexenol derivative (S)-8 in 90%. One of
the most important benefits for using an ionic liquid as a
solvent in organic synthesis is that the system allows the
repeated use of the catalyst; it was confirmed that the Ru
catalyst was indeed recyclable with three repetitions after
the usual work-up process and still retained perfect
reactivity. Subsequent alkaline hydrolysis of it into (S)-8
converted (S)-2-cyclohexen-1-ol 116 in 93% yield. Synthesis
of cyclohexen-1-ol has thus been accomplished through our
methodology.
2. Results and discussion
2.1. Synthesis of (S)-2-cyclohexenol
As a touchstone of our synthetic protocol, we initially
undertook the preparation of enantiomerically pure (S)-
2-cyclohexen-1-ol 1 (Scheme 1).
O
O
OPh
OPh
+
MeO
O
OH
Novozym 435
(R)-5
[bmim][PF6]
39% ee
Y= 67%
( )-5
Vinyl acetate
(S)-4a
400Torr, 35 °C,
0.5 h
2.2. Synthesis of (R)-2,5-dihydrobenzo[b]oxepin-5-ol and
(R)-5,6-dihydro-2H-benzo[b]oxocin-6-ol derivatives
[α]25D = -11.9
Novozym 435
(c 1.2, CHCl3)
c 0.28, E>200
E>200
99.6%ee
Y= 27%
The RCM reaction is well recognized as a useful means of
preparing medium sized ring compounds.17 We therefore
next attempted to synthesize seven- or eight-membered cyc-
lic alkenols using our methodology. The optical resolution
of two types of cyclic alcohols using lipase technology was
conducted using traditional reaction conditions with diiso-
propyl ether instead of an ionic liquid solvent system (Eq.
1). Racemic 1-(2-(allyloxy)phenyl)prop-2-en-1-ol 7a was
subjected to a Novozym 435-catalyzed transesterification
using vinyl acetate (1.5 equiv vs substrate) as an acyl
donor; (R)-(ꢀ)-1-(2-(allyloxy)phenyl)allyl acetate 6a
(n = 0) and (S)-(ꢀ)-1-(2-(allyloxy)phenyl)prop-2-en-1-ol
7a (n = 0) were obtained with perfect enantioselectivity in
46% and 50% yields, respectively (Table 1, entry 1). The
absolute configuration of unreacted (ꢀ)-7a was determined
to be (S) by comparison of the specific rotation value with
that of (S)-1-phenylprop-2-en-1-ol.18 Lipase PS also gave
the desired (R)-6a in 21% yield with >99% ee (entry 2),
though the reaction rate was less satisfactory than that with
Novozym 435.
OAc
PCy3
Ru
+
(R)-5
[bmim][PF6],
Cl
Cl
(S)-4b
97% ee
80°C, 48 h,
Y= 90%
Ph
PCy3
5 mol%
1) RCM
2) LiOH
O
OPh
OH
O
LiOH
THF-H2O
(3:1), rt 12 h
(S)-1
[α]23D = -69.9
(c 1.5, CHCl3)
(S)-8
[α]25D = -56.9
(c 0.9, CHCl3)
Y= 93%
Scheme 1. Synthesis of enantiomerically pure (S)-2-cyclohexen-1-ol (1)
using chemo-enzymatic reaction.
Ionic liquids are widely recognized as green solvents, suit-
able for use in both organic reactions and enzymatic reac-
tions.9–12 We recently established an efficient lipase-
catalyzed transesterification under reduced pressure condi-
tions in an ionic liquid solvent system;12 the system was, in
fact, very useful for preparing enantiomerically pure (S)-
octa-1,7-dien-3-yl 2-phenoxyacetate 4a.
Lipase
OH
OAc
Vinyl acetate
i-Pr2O, 35°C
(
(
S
)-7a
)-7b
n
n
+
S
ð1Þ
O
O
( )-7a: n=0
( )-7b: n=1
(
(
R
R
)-6a: n=0
)-6b: n=1
Racemic octa-1,7-diene-3-ol ( )-513 was reacted with
methyl phenoxyacetate in the presence of Novozym 435
(C. antarctica lipase) in 1-butyl-3-methylimidazolium hexa-
fluorophosphate ([bmim][PF6]) at 400 Torr at 35 °C for
0.5 h; after the reaction, ester (S)-4a (99.6% ee) was pro-
duced in 27% yield while the unreacted alcohol (R)-5
(39% ee) was obtained in 67% yield after silica gel flash col-
umn chromatography; the E-value14 was calculated as
being over 200. Since the enantioselectivity of C. antarctica
lipase to ( )-5 is very high, we can use diisopropyl ether or
In contrast, we encountered a problem when racemic 1-(2-
(allyloxy)phenyl)but-3-en-1-ol ( )-7b,19 n = 1 was used as a
substrate for the enzymatic reaction: the reaction was too
slow to obtain the product practically, though sufficient
enantioselectivity was obtained. It required 192 h to obtain
(R)-(ꢀ)-1-(2-(allyloxy)phenyl)but-3-enyl acetate 6b in 13%
yield with 90% ee; the E-value was calculated as 22 for
the Novozym 435-catalyzed reaction (entry 3). The desired
(R)-5c was also obtained using lipase PS, but the yield was
only 3% with 94% ee after 240 h reaction (entry 4).

2486
H. Shi-Hui et al. / Tetrahedron: Asymmetry 18 (2007) 2484–2490
Table 1. Resolution of acyclic alkenol ( )-4 via lipase-catalyzed reaction
Entry
Compound (n)
Lipasea
Reaction time (h)
Yield of 6b (% ee)c
Yield of 7b (% ee)c
Conv.d (c)
E valued
1
2
3
4
5
7a (0)
7a (0)
7b (1)
7b (1)
7b (1)
Novozym 435
Lipase PS
Novozym 435
Lipase PS
IL1-PS20
4
48
192
240
23
46 (>99)
21 (>99)
13 (90)
3 (94)
15 (>99)
50 (>99)
52 (53)
77 (19)
78 (3)
0.50
0.35
0.18
0.03
0.24
>200
>200
22
>200
>200
70 (32)
a Novozym 435 (Novo): Candida antarctica. Lipase PS (Amano): Burkholderia cepacia. IL1-PS: Burkholderia cepacia, see Ref. 17.
b Isolated yield.
c Determined by HPLC: for 6a (AD, hexane/2-propanol = 100:1, 35 °C, 0.5 mL/min); for 6b (AD, hexane/2-propanol = 9:1, 35 °C, 0.5 mL/ min); for 7a
(OD-H, hexane/2-propanol = 40:1, 35 °C, 0.5 mL/min); for 7b (AD, hexane/2-propanol = 9:1, 35 °C, 0.5 mL/min).
d Calculated by % ee of (R)-6 (eep) and % ee of (S)-7 (ees). E = ln[(1 ꢀ c)(1 + eep)]/ln[(1 ꢀ c)(1 ꢀ eep)], here c means conv. which was calculated by the
following formula: c = eep/(eep + ees). See Ref. 14.
This difficulty was solved by the ionic liquid mediated acti-
vation of enzyme that we recently developed:20,21 PEG-
alkyl sulfate imidazolium salt ionic liquid (IL1) coated
lipase PS (IL1-PS) worked better than that of lipase PS
or Novozym 435 and the desired acetate (R)-(ꢀ)-6b was
obtained in 15% yield with over 99% ee after 23 h of reac-
tion (entry 5). The absolute configuration of the acetates
produced, (ꢀ)-6b, was determined to be (R) by the
Kusumi–Ohtani method (see Section 4).22
3. Conclusion
In conclusion, we have developed a useful strategy for pre-
paring optically active cycloalkenol via a combination pro-
cess of lipase-catalyzed reaction and RCM reaction. Three
model compounds were synthesized in enantiomerically
pure form through our protocol. Since RCM reaction has
good tolerance to the substrates and lipase-catalyzed reac-
tion proceeds with excellent enantioselectivity for various
types of acyclic allylic alcohols, further investigation of
the scope and limitation of the present methodology will
make it even more beneficial.
We had two substrates for RCM reaction at hand, the
RCM reaction of (R)-6a was next investigated; the reaction
proceeded very smoothly in the presence of 5 mol % of the
first generation Ru catalyst in CH2Cl2 at rt and the desired
seven-membered cyclic ether (R)-2a was obtained in 89%
yield after silica gel flash column chromatography (Eq. 2).
4. Experimental
4.1. General procedures
PCy3
Cl
Ru
OAc
Cl
Ph
Reagents and solvents were purchased from common com-
mercial sources and were used as received or purified by
distillation over appropriate drying agents. Both first gen-
eration Ru catalyst and second generation Ru catalyst were
PCy3
(10 mol%)
ð2Þ
(R)-6a
CH2Cl2, reflux,
24 h
O
1
(R)-2a
purchased from Aldrich. H NMR spectra and 13C NMR
Y = 89%
spectra were recorded on a JEOL JNM MH-500 or JNM
MH-400 MHz spectrometer. Chemical shifts are expressed
in ppm downfield from tetramethylsilane (TMS) in CDCl3
as an internal reference. IR spectra were obtained on SHI-
MADZU FT-IR 8000 spectrometers. Optical rotation was
measured with a JASCO DIP-370 digital polarimeter.
Conversely, as anticipated, the RCM reaction of the eight-
membered compound was difficult, and the desired (R)-3a
was obtained in only 41% yield with 43% of (R)-6b unre-
acted (Eq. 3). An ionic liquid solvent system for the
RCM reaction of (R)-6b, unfortunately, provided no
improvement in the result. Since the second generation
Ru catalyst23 exhibited higher thermal stability and wider
functional group tolerance than the first generation one,
we tested the reaction using the second generation catalyst
under highly diluted conditions. However, only a slight
improvement (45%) was obtained in the results even when
20 mol % catalyst was used. In fact, a significant amount of
polymeric compounds was produced due to intermolecular
reactions, when the amount of catalyst was increased.
Therefore, it was found that the best practical way to
obtain (R)-3a was under the conditions described in Eq. 3.
4.2. Novozym 435-catalyzed acylation of ( )-octa-1,7-dien-
3-ol 5 under reduced pressure conditions in [bmim][PF6]
To a mixture of ( )-513 (757 mg, 6.0 mmol) and methyl
phenoxyacetate (498 mg, 3 mmol) in [bmim][PF6]
(3.0 mL) was added Novozym 435 (378 mg, 50 wt %).
The mixture was stirred under a reduced pressure of
400 mmHg at 35 °C, and was monitored by capillary GC
analysis. After being stirred for 0.5 h, ether (3 mL) was
added to the reaction mixture to form the biphasic layer.
The produced ester and the remaining alcohol were
extracted from the ether layer and subsequently purified
by silica gel flash column chromatography to afford (S)-4a
(421 mg, 1.62 mmol, 27%) and (R)-5 (507 mg, 67%), respec-
tively. The enantioselectivity of these compounds was
determined by HPLC analysis on a chiral column: Chiral-
cel AD, hexane/2-propanol = 8:1, 35 °C, 0.5 mL/min;
OAc
Grubbs 1st
(10 mol%)
(R)-6b
ð3Þ
CH2Cl2 (0.02 M),
reflux, 24 h
O
(R)-3a
Y= 41%

H. Shi-Hui et al. / Tetrahedron: Asymmetry 18 (2007) 2484–2490
2487
rt = 4.2 min for (R)-4a; rt = 4.9 min for (S)-4a. The enan-
tiomeric excess of (R)-5 was determined as the correspond-
ing acetate 4b using capillary GC analysis using a chiral
evaporated. Silica gel flash column chromatography (hex-
ane/ethyl acetate = 100:1 ꢂ 40:1 ꢂ 10:1) gave acetate (S)-
4b (3.95 g, 23.5 mmol, 30%, 98% ee) and (R)-5 (5.34,
42.3 mmol, 54%, 64% ee): Conversion 0.39, E >200.
column (Chiraldex G-Ta: rt = 7.7 min for (R)-4b;
23
rt = 9.1 min for (S)-4b, 70 °C, He gas). (S)-4a: ½aꢁD
¼
ꢀ11:9 (c 1.0, CHCl3), 99.6% ee; Rf 0.8 (hexane/ethyl ace-
tate = 5:1); 1H NMR (500 MHz, ppm, CDCl3) d 1.24–
1.38 (2H, m), 1.52–1.64 (2H, m), 1.92–2.03 (2H, m),
4.62–4.65 (1H, m), 4.77 (2H, s), 4.86–5.26 (4H, m), 5.66–
5.77 (2H, m); 13C NMR (125 MHz, ppm, CDCl3) d
24.08, 33.20, 33.38, 65.36, 75.73, 114.56, 114.56, 114.85,
117.40, 121.60, 129.43, 129.43, 135.70, 138.03, 157.77,
168.23; IR (neat, cmꢀ1) 936, 2862, 1763, 1736, 1601,
1497, 1192, 1088, 914, 754, 691.
4.5. Synthesis of (S)-1 using RCM reaction
4.5.1. (S)-Cyclohex-2-enyl phenoxyacetate 8. To a mixture
of (S)-4a (210 mg, 0.79 mmol) in [bmim][PF6] (1.0 mL) was
added Grubbs catalyst (32 mg, 0.039 mmol) in one portion
at rt, after which the mixture was stirred at 80 °C for 10 h
under argon atmospheric conditions. After cooling to rt,
ether was added to the reaction mixture and then extracted
with ether ten times. Silica gel chromatography gave (S)-8
25
(169 mg, 0.73 mmol) in 90% yield: ½aꢁD ¼ ꢀ56:9 (c 0.9, CH-
23
(R)-5: ½aꢁD ¼ ꢀ2:2 (c 1.4, CHCl3), 39% ee; Rf 0.4 (hexane/
Cl3), >99% ee; Rf 0.6 (hexane/ethyl acetate = 5:1); bp
105 °C/6 Torr (Kugelrohor); 1H NMR (500 MHz, ppm,
CDCl3) d 1.24–1.38 (2H, m), 1.52–1.64 (2H, m), 1.92–
2.03 (2H, m), 4.62–4.65 (1H, m), 4.77 (2H, s), 4.86–5.26
(4H, m), 5.66–5.77 (2H, m); 13C NMR (125 MHz, ppm,
CDCl3) d 24.08, 33.20, 33.38, 65.36, 75.73, 114.56,
114.56, 114.85, 117.40, 121.60, 129.43, 129.43, 135.70,
138.03, 157.77, 168.23; IR (neat, cmꢀ1) 2936, 2862, 1763,
1736, 1601, 1497, 1192, 1088, 914, 754, 691; Anal. Calcd
for C14H16O3: C, 72.39; H, 6.94. Found: C, 72.27; H, 6.65.
1
ethyl acetate = 4:1); H NMR (500 MHz, ppm, CDCl3) d
1.32–1.48 (4H, m), 2.00 (2H, dt, J = 11.9, 6.0 Hz), 3.24
(OH, s), 3.94 (1H, dt, J = 12.4, 6.5 Hz), 4.85–5.13 (4H,
m), 5.69–5.81 (2H, m); 13C NMR (125 MHz, ppm, CDCl3)
d 24.49, 33.47, 36.28, 72.89, 114.42, 114.49, 138.49, 141.13;
IR (neat, cmꢀ1) 350, 3078, 2918, 2862, 1641, 1452, 993, 912,
636.
4.3. Resolution of ( )-octa-1,7-dien-3-ol 5 using vinyl acetate
as acyl donor under ambient pressure (in [bmim][PF6])
We tested the recyclable use of the first generation Ru cat-
alyst and confirmed that the catalyst had lost no activity
after three repetitions of the process.
To the mixture of ( )-513 (50 mg, 0.40 mmol) and vinyl
acetate (52 mg, 0.60 mmol) in [bmim][PF6] (1.0 mL) was
added Novozym 435 (25 mg, 50 wt %). The mixture was
stirred at 35 °C, and was monitored by capillary GC anal-
ysis. After being stirred for 2.5 h, ether (2 mL) was added
to the reaction mixture to form the biphasic layer. The ace-
tate and the remaining alcohol were extracted from the
ether layer (10 times) and subsequently purified by silica
gel flash column chromatography to afford acetate (S)-4b
The absolute configuration of the products of the lipase-
catalyzed reaction was determined by the comparison of
the [a]D value of (S)-1 which was derived from (S)-8 by
alkaline hydrolysis (LiOH/THF–H2O (3:1)) in 93% yield.
23
(S)-1: ½aꢁD ¼ ꢀ69:9 (c 1.5, CHCl3), lit.16a = ꢀ52.8 (S); Rf
0.24 (hexane/ethyl acetate = 5:1); 1H NMR (500 MHz,
ppm, CDCl3) d 1.26 (OH, br s), 1.59–1.62 (2H, m), 1.62–
1.80 (2H, m), 1.86–2.02 (2H, m), 4.18–4.20 (1H, m),
5.75–5.77 (1H, m), 5.82–5.83 (1H, m); 13C NMR
(125 MHz, ppm, CDCl3) d 18.89, 25.00, 31.95, 65.46,
129.82, 130.49; IR (neat, cmꢀ1) 3331, 3024, 2934, 2837,
1437, 1055, 961, 727.
(22 mg, 0.13 mmol, 33%) and (R)-5 (29 mg, 0.23 mmol,
23
58%): Conversion 0.48, E >200. (S)-4b: ½aꢁD ¼ ꢀ12:0
23
(c 1.12, CHCl3), 97% ee; (R)-5: ½aꢁ ¼ ꢀ4:2 (c 1.43, CHCl3),
92% ee; The enantiomeric excessDof (R)-5 was determined
as acetate 4b by capillary GC analysis using a chiral col-
umn (Chiraldex G-Ta, 70 °C, He).
23
(S)-Octa-1,7-dien-3-yl acetate 4b:13 ½aꢁD ¼ ꢀ12:0 (c 1.12,
4.6. Resolution of ( )-7a and ( )-7b using lipase technology
1
CHCl3), 97% ee; Rf 0.73 (hexane/ethyl acetate = 2:1); H
NMR (200 MHz, ppm, CDCl3) d 1.23–1.46 (2H, m), 1.48–
1.70 (2H, m), 2.00 (3H, s), 1.91–2.68 (2H, m), 4.82–5.01
(2H, m), 5.04–5.23 (3H, m), 5.58–5.83 (2H, m); 13C NMR
(50 MHz, ppm, CDCl3) d 21.1, 24.2, 33.3, 33.5, 74.5, 114.7,
116.5, 136.4, 138.1, 170.1; IR (neat, cmꢀ1) 079, 2939, 2863,
1740, 1643, 1433, 1371, 1240, 1021, 994, 963, 916.
4.6.1. ( )-1-(2-(Allyloxy)phenyl)prop-2-en-1-ol 7a. To a
solution of 2-(allyloxy)benzaldehyde24 (1.768 g, 10.9 mmol)
in THF (11 mL) and 41 mL of 0.658 M THF, a solution of
vinyl magnesium bromide (27 mmol) was added at 0 °C
and the resulting mixture was stirred for 1 h at the same
temperature. The reaction was quenched by the addition
of saturated aqueous ammonium chloride and acidified
completely by 2 M HCl, after which it was extracted with
ethyl acetate. The organic layer was washed with brine,
dried over anhydrous MgSO4 and evaporated. Silica gel
flash column chromatography gave ( )-7a (1.68 g,
8.45 mmol) in 77% yield: Rf 0.4 (hexane/ethyl ace-
tate = 4:1); bp 90 °C/7.0 Torr (Kugelrohr); 1H NMR
(400 MHz, ppm, CDCl3) d 2.78 (br s, OH), 4.57 (2H, dt,
J = 3.3, 1.8 Hz), 5.15 (1H, dt, J = 10.5, 1.4 Hz), 5.27–5.33
(2H, m), 5.38–5.43 (2H, m), 6.00–6.08 (1H, m), 6.12 (1H,
dq, J = 17.4, 5.3 Hz), 6.86 (1H, d, J = 8.2 Hz), 6.95 (1H,
4.4. Resolution of ( )-octa-1,7-dien-3-ol 4a using vinyl
acetate as an acyl donor under ambient pressure
(in i-Pr2O): large scale preparation
To a mixture of ( )-512 (10.0 g, 79 mmol) and vinyl acetate
(10.0 g, 118 mmol) in i-Pr2O (260 mL) was added Novozym
435 (200 mg, 2 wt %). The mixture was stirred at 35 °C, and
was monitored by capillary GC analysis. After being stirred
for 6 h, lipase was removed by filtration through a sintered
glass filter with a Celite pad, after which the filtrate was

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H. Shi-Hui et al. / Tetrahedron: Asymmetry 18 (2007) 2484–2490
dt, J = 7.3, 0.9 Hz), 7.21–7.24 (1H, m), 7.30 (1H, dd,
J = 7.6, 1.6 Hz); 13C NMR (125 MHz, ppm, CDCl3) d
68.90, 71.73, 111.96, 114.51, 117.68, 121.11, 127.49,
The enantiomeric excess of 6a was determined by HPLC
analysis using a chiral column: AD, hexane/2-propa-
nol = 100:1, 35 °C, 0.5 mL/min, rt = 12.1 min for (R)-6a;
rt = 13.0 min for (S)-6a. % ee of 7a was determined by
HPLC analysis using chiral column: OD-H, hexane/2-pro-
panol = 40:1, 35 °C, 0.5 mL/min, rt = 32.2 min for (S)-7a;
rt = 34.1 min for (R)-7a.
128.66, 131.06, 132.93, 139.47, 155.70; IR (neat, cmꢀ1
)
3408, 3080, 2984, 2869, 1601, 1489, 1452, 1236, 997, 924,
754; Anal. Calcd for C12H14O2: C, 75.76; H, 7.42. Found:
C, 75.57; H, 7.19.
4.8. Resolution of ( ) of 1-(2-(allyloxy)phenyl)but-3-en-1-ol
7b24
4.6.2. ( )-1-(2-(Allyloxy)phenyl)but-3-en-1-ol 7b.19,24 To
a solution of 3.0 mL of mixed solvent (THF/H2O = 1:1) of
2-(allyloxy)benzaldehyde22 (174 mg, 1.07 mmol) and allyl
bromide (194 mg, 1.61 mmol) was added indium powder
(123 mg, 1.07 mmol), and the resulting mixture was stirred
for 8 h at 30 °C. The reaction was monitored by capillary
GC analysis. The reaction was quenched by the addition
of 2 M HCl and extracted by ethyl acetate. The organic
layer was washed with aqueous sodium hydrogen carbon-
ate (NaHCO3) and brine, dried over anhydrous MgSO4
and evaporated. Silica gel flash column chromatography
gave ( )-7b (208 mg) in 95% yield: Rf 0.29 (hexane/ethyl
4.8.1. (R)-1-(2-(Allyloxy)phenyl)but-3-enyl acetate 6b. To
a solution of ( )-7b (50 mg, 0.24 mmol) and vinyl acetate
(32.7 mg, 0.37 mmol, 1.5 equiv) in i-Pr2O (2 mL) was
added IL1-PS20 (11 mg) and the mixture was stirred at
35 °C. The reaction course was monitored by capillary
GC analysis and silica gel TLC. (R)-1-(2-(Allyl-
oxy)phenyl)but-3-enyl acetate 6b (9.0 mg) and (S)-7b
(35 mg) were obtained by TLC. The enantioselectivity of
6b was determined by HPLC analysis on a chiral column
(AD, hexane/2-propanol = 9:1), 35 °C, 0.5 mL/min;
rt = 12.1 min for (R)-6b; rt = 3.6 min for (S)-6b.
1
acetate = 5:1); H NMR (500 MHz, ppm, CDCl3) d 1.5
(br s, OH), 2.45 (1H, m), 2.56 (1H, m), 4.52 (2H, d,
J = 5.0 Hz), 4.93 (1H, t, J = 5.0 Hz), 5.03–5.09 (2H, m),
5.23 (1H, ddt, J = 10.5, 2.8, 1.5 Hz), 5.35 (1H, ddt,
J = 17.5, 3.2, 1.9 Hz), 5.74–5.84 (1H, m), 5.96–6.04 (1H,
m), 6.80 (1H, d, J = 8.3 Hz), 6.89 (1H, dd, J = 7.3,
0.9 Hz), 7.15 (1H, dd, J = 9.6, 1.8 Hz), 7.28 (1H, d,
J = 7.7 Hz); 13C NMR (125 MHz, ppm, CDCl3) d 41.9,
68.6, 69.6, 111.5, 117.3, 117.5, 120.9, 126.8, 128.1, 132.0,
133.0, 135.1, 155.2; IR (neat, cmꢀ1) 3398, 3074, 2978,
2868, 1638, 1601, 1491, 1452, 1234, 997, 754.
22
(R)-6b: Rf 0.47 (hexane/ethyl acetate = 5:1); ½aꢁD ¼ þ39:4
(c 1.0, CHCl3), >99% ee; Rf 0.47 (hexane/ethyl ace-
tate = 5:1); bp 110 °C/6.0 Torr (Kugelrohr); 1H NMR
(500 MHz, ppm, CDCl3) d 2.09 (3H, s), 2.53–2.65 (2H,
m), 4.57 (2H, ddd, J = 4.7, 2.7, 1.0 Hz), 5.01–5.07 (2H,
m), 5.28 (1H, dddd, J = 10.5, 4.5, 3.0, 1.6 Hz), 5.44 (1H,
ddt, J = 17.8, 3.5, 2.1 Hz), 5.73–5.79 (1H, m), 6.01–6.07
(1H, m), 6.27 (1H, t, J = 5.1 Hz), 6.85 (1H, d,
J = 8.2 Hz), 6.95 (1H, dd, J = 6.9, 0.5 Hz), 7.21 (1H, dd,
J = 9.1, 1.9 Hz), 7.32 (1H, d, J = 7.7 Hz); 13C NMR
(125 MHz, ppm, CDCl3) d 21.2, 39.6, 68.8, 69.9, 111.8,
117.0, 117.4, 120.6, 126.4, 128.5, 129.1, 133.2, 133.9,
155.1, 170.1; IR (neat, cmꢀ1) 3078, 1740, 1491, 1452,
1373, 1236, 1022, 920, 754; Anal. Calcd for C15H18O3: C,
73.15; H, 7.37. Found: C, 72.49; H, 7.21.
4.7. Resolution of ( )-1-(2-(allyloxy)phenyl)prop-2-en-1-ol
7a
4.7.1. (R)-1-(2-(Allyloxy)phenyl)allyl acetate 6a. To a
solution of ( )-7a (200 mg, 1.05 mmol) and vinyl acetate
(141 mg, 1.64 mmol, 1.5 equiv) in i-Pr2O (8.0 mL) was
added Novozym 435 (100 mg) and the mixture was stirred
at 35 °C for 4 h. The reaction mixture was filtered through
a sintered glass filter to remove enzyme and the filtrate was
evaporated. Purification by silica gel TLC gave (R)-6a
(90.6 mg, 0.39 mmol, 37%) and (S)-7a (100 mg, 0.52 mmol,
50%).
23
(S)-7b: Rf 0.29 (hexane/ethyl acetate = 5:1); ½aꢁD ¼ ꢀ4:5 (c
1.0, CHCl3), 32% ee; The enantioselectivity of 7b was deter-
mined by HPLC analysis on a chiral column (OD-H, hex-
ane/2-propanol = 20:1), 35 °C, 0.5 mL/min; rt = 23.2 min
for (S)-7b; rt = 25.7 min for (R)-7b (Table 2).
4.9. Determination of the absolute configuration of (+)-6b
and (ꢀ)-7b
22
(R)-6a: Rf 0.47 (hexane/ethyl acetate = 5:1); ½aꢁD ¼ þ41:4
(c 1.0, CHCl3), >99% ee; bp 90–95 °C/6.0 Torr (Kugelrohr);
1H NMR (500 MHz, ppm, CDCl3) d 2.04 (3H, s), 4.51 (2H,
dt, J = 3.3, 1.7 Hz), 5.11–5.14 (1H, m), 5.17–5.21 (2H, m),
5.35 (1H, dq, J = 17.2, 1.6 Hz), 5.93–6.01 (2H, m), 6.63
(1H, d, J = 6.0 Hz), 6.80 (1H, d, J = 8.2 Hz), 6.89 (1H, t,
J = 7.6 Hz), 7.17–7.20 (1H, m), 7.28 (1H, dd, J = 7.6,
1.6 Hz); 13C NMR (125 MHz, ppm, CDCl3) d 21.2, 68.9,
70.8, 112.0, 116.0, 117.2, 120.8, 127.3, 127.7, 129.0, 133.1,
135.8, 155.5, 169.8; IR (neat, cmꢀ1) 2868, 1742, 1491,
1232, 1020, 932, 754; Anal. Calcd for C14H16O3: C, 72.39;
H, 6.94. Found: C, 71.59; H, 6.85.
22
Ester (+)-6b {½aꢁD ¼ þ53:2 (c 1.0, CHCl3), >99% ee} was
hydrolyzed to (+)-7b (>99% ee) using K2CO3 in MeOH;
(+)-7b was then converted to the corresponding (S)-
Mosher ester and (R)-Mosher ester and the absolute con-
figuration of the produced acetate, (+)-6b, was determined
to be (R) by the Kusumi–Ohtani method (Fig. 2).
4.10. Synthesis of (R,Z)-2,5-dihydrobenzo[b]oxepin-5-yl
acetate 2a by the RCM reaction
To a solution of the first generation Grubbs catalyst
(6.7 mg, 0.008 mmol, 10 mol %) in CH2Cl2 (8.1 mL) was
added (R)-6a (18.7 mg, 0.0805 mmol). The mixture was
stirred at 60 °C for 24 h under an argon atmosphere, then
22
(S)-7a: ½aꢁD ¼ ꢀ18:6 (c 1.0, CHCl3), >99% ee. (S)-1-phen-
rt
ylprop-2-en-1-ol: [a]D = ꢀ8.4 (c 2.87, benzene),18a ½aꢁD ¼
ꢀ5:2 (neat).18b

H. Shi-Hui et al. / Tetrahedron: Asymmetry 18 (2007) 2484–2490
2489
Table 2. Chemical shift of (S)-MTPA and (R)-MTPA ester of (+)-6b (400 MHz 1H NMR, CDCl3)
Chemical shift (ppm)
dS ꢀ dR
(S)-MTPA ester of 9 (from (+)-6b)
(R)-MTPA ester of 9 (from (+)-6b)
2.66
3.57
4.57
5.08
5.10
5.28
5.42
5.80
6.05
6.46
6.83
6.84
7.00
7.01
7.30
7.46
2H, t, J = 6.4 Hz
3H, OMe, s
2H, m
2.64
3.5
t (dd), J = 6.4 Hz
OMe, s
0.02
0.07
4.58
4.84
4.98
5.27
5.45
5.67
6.05
6.54
6.87
6.87
6.93
6.93
7.34
7.49
dd, J = 5.2, 1.2 Hz
d, J = 11.2 Hz
dd, J = 16.4, 11.2 Hz
dd, J = 10.8, 1.6 Hz
dd, J = 17.6, 1.2 Hz
m
ꢀ0.01
1H, dd, J = 10.3, 1.6 Hz
0.24
1H, dd, J = 15.6, 1.6 Hz
1H, dd, J = 10.8, 1.6 Hz
1H, dd, J = 17.1, 1.6 Hz
1H, m
0.12
0.01
ꢀ0.03
0.13
1H, m
m
0
1H, t, J = 6.8 Hz
2H, t, J = 7.6 Hz
1H, d, J = 8.4 Hz
1H, d, J = 8.0 Hz
1H, d, J = 8.0 Hz
2H, m (7.19–7.41)
2H, d, J = 7.2 Hz
t, J = 6.0 Hz
d, J = 8.4 Hz
d, J = 8.4 Hz
d, J = 8.0 Hz
d, J = 8.0 Hz
m (7.23–7.45)
d, J = 6.8 Hz
ꢀ0.08
ꢀ0.04
ꢀ0.03
0.07
0.08
(ꢀ0.04)
ꢀ0.03
1043, 1024, 795, 758, 737, 679, 584; Anal. Calcd for
C12H12O3: C, 70.57; H, 5.92. Found: C, 70.36; H, 5.75.
OMe
MTPA
CF3
O
O
C
H
HC
HX
4.11. Synthesis of (R,Z)-5,6-dihydro-2H-benzo[b]oxocin-6-yl
acetate 3a by the RCM reaction
2 δ<0
2 δ>0
HY
HZ
HB
HA
To a solution of the first generation Grubbs catalyst
(2.5 mg, 0.003 mmol, 0.05 equiv) in CH2Cl2 was added
(R)-6b (15 mg, 0.061 mmol), and the mixture was stirred
at 60 °C for 24 h under an argon atmosphere. The reaction
course was verified by capillary GC analysis, after which it
was evaporated and purified by TLC (hexane/ethyl ace-
tate = 5:1) to give product (R)-3a (11 mg) in 41% yield.
The Kusumi-Ohtani's rule
Δδ<0
Δδ>0
OCH3
CF3
O
23
-0.03
(R)-3a: ½aꢁD ¼ ꢀ7:5 (c 1.0, CHCl3); Rf 0.5 (hexane/ethyl
H
+0.13
H
O
acetate = 5:1); bp 60 °C/6 Torr (Kugelrohr); 1H NMR
(500 MHz, ppm, CDCl3) d 2.83–2.86 (2H, m), 4.55 (2H,
dd, J = 6.0, 4.1 Hz), 5.40 (1H, t, J = 2.7 Hz), 5.75 (1H,
dt, J = 20.1, 0.9 Hz), 6.12–6.14 (1H, m), 7.07 (1H, d,
J = 7.8 Hz), 7.13 (1H, dd, J = 7.3, 0.9 Hz), 7.28–7.34
(2H, m); 13C NMR (125 MHz, ppm, CDCl3) d 170.4,
157.0, 131.8, 130.9, 130.0, 128.5, 128.1, 127.6, 124.8,
123.2, 74.5, 73.6, 32.6, 21.3; IR (neat, cmꢀ1) 2926, 1736,
1491, 1371, 1236, 1203, 1113, 1018, 758; Anal. Calcd for
C13H14O3: C, 71.54; H, 6.47. Found: C, 71.42; H, 6.20.
4
+0.24
a
H
-0.03
-0.04
2
H
3
1
H
0
H
H
H
H
+0.12
b
+0.02
O
-0.04
H
H
1'
H
a
b
+0.01
-0.03
3'
-0.01
H
2'
H
-0.03
H
9
(+)-(R)-6b (Product)
Figure 2. Dd = (dS ꢀ dR) values analysis of the Mosher esters.
Acknowledgement
The present work was supported by a Grant-in-Aid for Sci-
entific Research in a Priority Area, ‘Science of Ionic Liq-
uids’, from the Ministry of Education, Culture, Sports,
Science and Technology of Japan.
the mixture was evaporated and purified by TLC (hexane/
ethyl acetate = 5:1) to give product (R)-2a (14.6 mg,
25
0.0716 mmol) in 89% yield: ½aꢁD ¼ þ3:4 (c 1.0, CHCl3);
Rf 0.49 (hexane/ethyl acetate = 5:1); bp 60 °C/6 Torr (Ku-
gelrohr); 1H NMR (500 MHz, CDCl3) d 2.18 (3H, s), 4.51–
4.68 (2H, m) 5.59 (1H, dq, J = 11.9, 2.4 Hz), 5.83–5.87
(1H, m) 6.68 (1H, dd, J = 4.1, 2.1 Hz), 7.10–7.13 (2H, m)
7.27–7.29 (2H, m); 13C NMR (125 MHz, CDCl3) d 21.2,
70.5, 70.6, 121.9, 124.3, 125.97, 127.84, 129.3, 129.4,
134.9, 156.6, 170.1; IR (neat, cmꢀ1) 3855, 3753, 3676,
3395, 2924, 2853, 1742, 1585, 1489, 1458, 1369, 1232,
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