Enzymatic resolution of (±)-5-acetoxy-4-aryl-(2E)-pentenoate derivatives

Article abstract of DOI:10.1248/cpb.53.565

Enzymatic resolution of six (±)-5-acetoxy-4-aryl-(2E)-pentenoate derivatives, compounds 9, 11, 13, 15, 17, and 19 bearing a different aromatic substitution pattern, using lipase OF-360 from Candida rugosa was carried out. The absolute configurations of al

Full text of DOI:10.1248/cpb.53.565

May 2005
Notes
Chem. Pharm. Bull. 53(5) 565—569 (2005)
565
Enzymatic Resolution of (ꢀ)-5-Acetoxy-4-aryl-(2E)-pentenoate
Derivatives
Shin TANIKAWA, Machiko ONO, and Hiroyuki AKITA*
School of Pharmaceutical Sciences, Toho University; 2–2–1 Miyama, Funabashi, Chiba 274–8510, Japan.
Received September 17, 2004; accepted February 13, 2005
Enzymatic resolution of six (ꢀ)-5-acetoxy-4-aryl-(2E)-pentenoate derivatives, compounds 9, 11, 13, 15, 17,
and 19 bearing a different aromatic substitution pattern, using lipase OF-360 from Candida rugosa was carried
out. The absolute configurations of all hydrolyzed products and all unchanged acetates were found to be S and R,
respectively. Moreover, the enantiomeric excess of the enzymatic resolution products from 9, 11, and 13 with the
ortho-methoxyl group in the aromatic ring was higher than that of the substrates with no methoxyl group at the
ortho-position in the aromatic ring.
Key words bisabolane sesquiterpene; enzymatic resolution; lipase
Phenolic sesquiterpenes of the bisabolane family have acetylation from the reported racemic alcohols 8, 10, 12, 14,
been isolated from many different natural sources.1) In the 16, and 18,15) respectively. In the present case, lipase OF-360
preceding paper, we reported the total synthesis of (S)- and from Candida rugosa was applied for the enzymatic resolu-
(R)-curcuphenols (1)2,3) and (S)- and (R)-elvirols (2).4) The tions and the results are shown in Table 1.
(S)-curcuphenol (1), isolated from the marine sponge Epipo-
Initially, 9 was subjected to enzymatic resolution in water-
lasis sp., strongly inhibits the activity of gastric H, K-AT- saturated diisopropyl ether, and the alcohol (S)-8 [(16%,
Pase,5—7) while the (R)-(ꢀ)-curcuphenol (1), isolated from 81%, enantiomeric excess (ee)] and unchanged (R)-9 (79%,
the Caribbean gorgonians Pseudopterogorgia rigida and 22% ee) were obtained (entry 1). The ee of all enzymatic res-
Lasianthaea podocephala, exhibits antibacterial activities olution products mentioned below was obtained based on
against Staphylococcus aureus and Vibrio anguillarum.8) Ac- HPLC analysis using a chiral column, and the detailed proce-
cordingly, the establishment of an efficient and general syn- dure is described in the Experimental section. The ee of (R)-
thetic route to both enantiomers of these sesquiterpenoids is 9 was obtained by means of HPLC analysis of the deacylated
of significance. In the chiral synthesis of (S)- and (R)-1, and compound (R)-8. Determination of the absolute structure of
(S)- and (R)-2, enzymatic resolutions of an acetate (ꢁ)-5 all enzymatic resolution products are described below. The
with lipase MY-30 from Candida rugosa and an acetate (ꢁ)- substrates 11, 13, 15, 17, and 19 were subjected to enzymatic
7 with lipase OF-360 from Candida rugosa, respectively, are resolution in water-saturated isopropyl ether, and the results
found to be the crucial step in their total synthesis. Although are shown in Table 1 (entries 2—4, 7, 8). To improve the ee
racemic syntheses of bisabolane sesquiterpenes have been of (S)-14, the 40% ee of (S)-14 was subjected to enzymatic
developed,9—11) useful asymmetric synthesis bearing a ben- acetylation in the presence of isopropenyl acetate in diiso-
zylic asymmetric center has not been reported except for a propyl ether to provide (S)-14 (77%, 34% ee) and (S)-15
few examples.12—14) We report here enzymatic resolutions of (19%, 67% ee) (entry 5), and the 67% ee of (S)-15 was again
(ꢁ)-4-aryl-5-acetoxy-(2E)-pentenoate derivatives 9, 11, 13, subjected to enzymatic resolution in water-saturated iso-
15, 17, and 19 bearing a different aromatic substitution pat- propyl ether to give the alcohol (S)-14 (60%, 79% ee) and
tern for the sake of the other chiral synthesis of bisabolane unchanged (S)-15 (23%, 36% ee) (entry 6). From these enzy-
sesquiterpens such as (S)- and (R)-curcuhydroquinones (3).
matic resolution experiments, it became apparent that the ee
Enzymatic Resolutions Six racemic acetates 9, 11, 13, values of the enzymatic resolution products from 9, 11, and
15, 17, and 19 were obtained in good yield by the usual 13 with the ortho-methoxyl group in the aromatic ring were
higher than those of the substrates with no methoxyl group
(entries 1—3).
Determination of the Absolute Structure of Enzymatic
Products To determine the absolute configuration of the
product (ꢂ)-8, it was successfully converted to the reported
a-ketoester (S)-22.4) Treatment of (ꢂ)-8 (81% ee) with
p-tosyl chloride (p-TsCl) followed by the consecutive cat-
alytic hydrogenation and NaBH4 reduction provided 4-aryl-
substituted pentanoate 21 in 44% overall yield from (ꢂ)-8.
Oxidative cleavage of the aromatic ring of 21 with NaIO4 in
the presence of a catalytic amount of RuCl3·3H2O followed
by esterification with CH2N2 gave (ꢂ)-22 {16% yield, [a]D26
ꢂ3.4° (cꢃ1.57, CHCl3), corresponding to 81% ee}. The
physical data ([a]D, 1H-NMR) of (ꢂ)-22 derived from (ꢂ)-8
Chrat 1
were consistent with those {[a]D27 ꢂ3.2° (cꢃ1.35, CHCl3),
∗ To whom correspondence should be addressed. e-mail: akita@phar.toho-u.ac.jp
© 2005 Pharmaceutical Society of Japan

566
Vol. 53, No. 5
Table 1. Enzymatic Resolution of (ꢁ)-5-Acetoxy-4-aryl-(2E)-pentenoate Derivatives
Entry
Substrate (g)
Time (h)
Product (%, ee)
(R)-9 (79%, 22% ee)
1
2
3
(ꢁ)-9 (0.5 gꢄ4)
8
24
48
24
24
72
8
(S)-8 (16%, 81% ee)
(S)-10 (61%, 52% ee)
(S)-12 (61%, 43% ee)
(S)-14 (13%, 40% ee)
(S)-14 (77%, 34% ee)
(S)-14 (60%, 79% ee)
(S)-16 (34%, 25% ee)
(S)-18 (77%, 7% ee)
(ꢁ)-11 (0.095 g)
(ꢁ)-13 (0.096 g)
(ꢁ)-15 (6.75 gꢄ2)
(ꢁ)-14 (1.5 g, 40% ee)
(ꢁ)-15 (0.34 g, 67% ee)
(ꢁ)-17 (0.1 g)
(R)-11 (29%, 84% ee)
(R)-13 (31%, 80% ee)
(R)-15 (80%, 15% ee)
(S)-15 (19%, 67% ee)
(S)-15 (23%, 36% ee)
(R)-17 (61%, 20% ee)
(R)-19 (18%, 29% ee)
4
5a)
6
7
8
(ꢁ)-19 (0.098 g)
24
a) Enzymatic acetylation with isopropenyl acetate was carried out.
corresponding to 76% ee} of the authentic (S)-(ꢂ)-224) and
thence the absolute configurations of (ꢂ)-8 was determined
to be S. The absolute configuration of the (ꢀ)-14 was also
determined in the same way as that from (ꢂ)-8. Thus treat-
ment of (ꢀ)-14 (79% ee) with p-TsCl gave the tosylate (ꢂ)-
23 {[a]D21 ꢂ4.3° (cꢃ1.56, CHCl3)} in 89% yield, which was
subjected to consecutive catalytic hydrogenation and NaBH4
reduction to provide the 4-aryl-substituted pentanoate 24 in
56% overall yield from (ꢂ)-23. Oxidative cleavage of the
aromatic ring of 23 with NaIO4 in the presence of a catalytic
amount of RuCl3·3H2O followed by esterification with
CH2N2 gave (ꢂ)-25 {33% yield, [a]D21 ꢂ13.9° (cꢃ0.78,
CHCl3), corresponding to 79% ee}. The physical data ([a]D,
1H-NMR) of (ꢂ)-25 derived from (ꢀ)-14 were consistent
with those {[a]D25 ꢂ15.8° (cꢃ0.72, CHCl3), corresponding to
90% ee} of the reported dimethyl 2-methylglutarate (S)-(ꢂ)-
254) and thus the absolute configurations of (ꢀ)-14 was de-
termined to be S.
By applying the reported procedure,15) the four (S)-4-aryl-
5-hydroxy-(2E)-pentenoate derivatives 10, 12, 18, and 16
were obtained by the reaction of (4S)-(4,5)-epoxy-(2E)-pen-
tenoate 2616) and substituted benzene derivatives in the pres-
ence of BF3·Et2O. The reaction of (S)-26 (93% ee) and 1,3-
dimethoxybenzene in the presence of BF3·Et2O gave (S)-10
{38%, [a]D29 ꢀ15.2° (cꢃ0.50, CHCl3), corresponding to 93%
ee}. The reaction of (S)-26 (93% ee) and anisole in the pres-
Chart 2
ence of BF3·Et2O afforded (S)-12 {10%, [a]D21 ꢀ17.9° Discussion
(cꢃ0.51, CHCl3), corresponding to 93% ee} and (S)-18
Although lipases are widely used as enantioselective hy-
{42%, [a]D22 ꢀ2.2° (cꢃ0.51, CHCl3), corresponding to 93% drolysis or transesterification catalysts, the structural basis
ee}. The reaction of (S)-26 (93% ee) and 3,4-dimethoxy- for this enantioselectivity was unknown so far. The speci-
toluene in the presence of BF3·Et2O provided (S)-16 {46%, ficity of lipase from Candida rugosa has established a simple
[a]D29 ꢂ22.7° (cꢃ0.33, CHCl3), corresponding to 93% ee}. empirical rule that predicts its enantiopreference for sec-
The absolute configurations of the hydrolyzed products (ꢀ)- ondary alcohols. On the other hand, the explanation concern-
10, (ꢀ)-12, (ꢀ)-18, and (ꢂ)-16 were confirmed by a direct ing the molecular recognition of primary alcohols has been
comparison of the retention time of the synthesized authentic more difficult. Most lipases show low enantioselectivity to-
samples (S)-10, (S)-12, (S)-18, and (S)-16, respectively. The ward primary alcohols. Only lipase from Pseudomonas cepa-
detailed data are shown in the Experimental section.
cia (PCL) and lipase from porcine pancreas (PPL) show
moderate to high enantioselectivity toward a wide range of
primary alcohols, but even for these the enantioselectivity is

May 2005
567
for (ꢁ)-9 to give a crude oil, which was chromatographed on silica gel (60 g,
n-hexane : AcOEtꢃ5 : 1) to give a colorless oil (ꢁ)-11 (2.566 g, 84%). (ꢁ)-
11: IR (neat): 1725 cmꢀ1. NMR: 2.02 (3H, s), 3.72 (3H, s), 3.79 (3H, s),
3.81 (3H, s), 4.11—4.18 (1H, m), 4.29 (1H, dd, Jꢃ6, 11 Hz), 4.37 (1H, dd,
Jꢃ8, 11 Hz), 5.85 (1H, dd, Jꢃ2, 16 Hz), 6.43 (1H, d, Jꢃ8 Hz), 6.46 (1H, s),
7.01 (1H, d, Jꢃ8 Hz), 7.14 (1H, dd, Jꢃ7, 16 Hz). Anal. Calcd for C16H20O6:
C, 62.33; H, 6.54. Found: C, 62.40; H, 6.43. EI-MS m/z: 308 (Mꢂ).
Methyl (ꢀ)-5-Acetoxy-4-(2-methoxyphenyl)-(2E)-pentenoate (13)
A
solution of (ꢁ)-12 (0.331 g, 1.4 mmol) in pyridine (2 ml) was treated with
Ac2O (0.28 g, 2.7 mmol), and the reaction mixture was stirred for 24 h at
room temperature. The reaction mixture was worked up in the same way as
for (ꢁ)-9 to give a crude oil, which was chromatographed on silica gel (30 g,
n-hexane : AcOEtꢃ6 : 1) to give a colorless oil (ꢁ)-13 (0.323 g, 83%). (ꢁ)-
13: IR (neat): 1740 cmꢀ1. NMR: 2.02 (3H, s), 3.72 (3H, s), 3.82 (3H, s),
4.23 (1H, br q, Jꢃ7 Hz), 4.33 (1H, dd, Jꢃ5, 11 Hz), 4.40 (1H, dd, Jꢃ9,
11 Hz), 5.87 (1H, dd, Jꢃ2, 16 Hz), 6.88 (1H, dd, Jꢃ2, 8 Hz), 6.92 (1H, dt,
Jꢃ2, 8 Hz), 7.11 (1H, dd, Jꢃ2, 8 Hz), 7.16 (1H, dd, Jꢃ7, 16 Hz), 7.25 (1H,
dt, Jꢃ2, 8 Hz). Anal. Calcd for C15H18O5: C, 64.74; H, 6.52. Found: C,
64.60; H, 6.50. FAB-MS m/z: 279 (Mꢂꢂ1).
Fig.
1
usually lower than that toward secondary alcohols. The em-
pirical rule summarizes the enantiopreference of PCL for pri-
mary alcohol or its acylated derivative, as shown in Fig.
1.17,18) When the hydroxyl methyl (–CH2OH) or acyloxy
methyl (–CH2OCOR) group exists in the plane of the page,
the favored enantiomer bears a large substituent (L) on the
right, and a medium substituent (M) on the left. The enantio-
Methyl (ꢀ)-5-Acetoxy-4-(4-methoxy-2-methylphenyl)-(2E)-pentenoate
(15) A solution of (ꢁ)-14 (11.63 g, 46.5 mmol) in pyridine (30 ml) was
treated with Ac2O (5.3 g, 52.3 mmol), and the reaction mixture was stirred
for 24 h at room temperature. The reaction mixture was worked up in the
preference toward primary alcohols or their acetates using li- same way as for (ꢁ)-9 to give a crude oil, which was chromatographed on
silica gel (100 g, n-hexane : AcOEtꢃ9 : 1) to give a colorless oil (ꢁ)-15
pase OF-360 from Candida rugosa might be explained by
the present empirical rule.
(13.46 g, 99%). (ꢁ)-15: IR (neat): 1739 cmꢀ1. NMR: 2.03 (3H, s), 2.32 (3H,
s), 3.72 (3H, s), 3.78 (3H, s), 3.99—4.05 (1H, m), 4.29 (1H, dd, Jꢃ6,
11 Hz), 4.31 (1H, dd, Jꢃ6, 11 Hz), 5.81 (1H, dd, Jꢃ2, 16 Hz), 6.73 (1H, dd,
Jꢃ2, 8 Hz), 6.74 (1H, d, Jꢃ2 Hz), 7.03 (1H, dd, Jꢃ2, 8 Hz), 7.08 (1H, dd,
Jꢃ7, 16 Hz). Anal. Calcd for C16H20O5: C, 65.74; H, 6.90. Found: C, 65.66;
H, 7.03. FAB-MS m/z: 293 (Mꢂꢂ1).
Conclusion
Enzymatic resolution of the six (ꢁ)-5-acetoxy-4-aryl-
(2E)-pentenoate derivatives 9, 11, 13, 15, 17, and 19 bearing
a different aromatic substitution pattern, using lipase OF-360
from Candida rugosa was carried out. The absolute configu-
rations of all hydrolyzed products and all unchanged acetates
were found to be S and R, respectively. Moreover, the ee of
the enzymatic resolution products from (ꢁ)-9, (ꢁ)-11, and
(ꢁ)-13 with the ortho-methoxyl group in the aromatic ring
was higher than that of the substrates with no methoxyl
group at this position.
Methyl
(ꢀ)-5-Acetoxy-4-(4,5-dimethoxy-2-methylphenyl)-(2E)-pen-
tenoate (17) A solution of (ꢁ)-16 (4.683 g, 16.7 mmol) in pyridine (10 ml)
was treated with Ac2O (1.53 g, 15.0 mmol), and the reaction mixture was
stirred for 24 h at room temperature. The reaction mixture was worked up in
the same way as for (ꢁ)-9 to give a crude oil, which was chromatographed
on silica gel (60 g, n-hexane : AcOEtꢃ6 : 1) to give a colorless oil (ꢁ)-17
(4.656 g, 86%). (ꢁ)-17: IR (neat): 1710 cmꢀ1. NMR: 2.04 (3H, s), 2.28 (3H,
s), 3.73 (3H, s), 3.84 (3H, s), 3.86 (3H, s), 3.97—4.03 (1H, m), 4.32 (1H, dd,
Jꢃ5, 11 Hz), 4.34 (1H, dd, Jꢃ9, 11 Hz), 5.83 (1H, dd, Jꢃ2, 16 Hz), 6.61
(1H, s), 6.70 (1H, s), 7.08 (1H, dd, Jꢃ7, 16 Hz). EI-MS (HR-MS) m/z:
Calcd for C17H22O6: 322.1416 (Mꢂ). Found: 322.1440.
Experimental
Methyl (ꢀ)-5-Acetoxy-4-(4-methoxyphenyl)-(2E)-pentenoate (19)
A
All melting points were measured on a Yanaco MP-3S micromelting point
apparatus and are uncorrected. H-NMR (400-MHz) spectra were recorded
solution of (ꢁ)-18 (2.15 g, 9.1 mmol) in pyridine (5 ml) was treated with
Ac2O (2.02 g, 19.7 mmol), and the reaction mixture was stirred for 24 h at
room temperature. The reaction mixture was worked up in the same way as
for (ꢁ)-9 to give a crude oil, which was chromatographed on silica gel (60 g,
n-hexane : AcOEtꢃ6 : 1) to give a colorless oil (ꢁ)-19 (2.19 g, 86%). (ꢁ)-
19: IR (neat): 1740 cmꢀ1. NMR: 2.02 (3H, s), 3.73 (3H, s), 3.78 (1H, br q,
Jꢃ7 Hz), 3.79 (3H, s), 4.28—4.35 (2H, m), 5.86 (1H, dd, Jꢃ2, 16 Hz), 6.88
(2H, d, Jꢃ9 Hz), 7.09 (1H, dd, Jꢃ7, 16 Hz), 7.12 (2H, d, Jꢃ9 Hz). Anal.
Calcd for C15H18O5: C, 64.74; H, 6.52. Found: C, 64.34; H, 6.49. FAB-MS
m/z: 279 (Mꢂꢂ1).
Enzymatic Resolution of (ꢀ)-9, (ꢀ)-11, (ꢀ)-13, (ꢀ)-15, (ꢀ)-17, and
(ꢀ)-19 i) Table 1, Entry 1: A suspension of (ꢁ)-9 (0.53 g) and lipase
OF-360 (0.2 g) in H2O-saturated-diisopropyl ether (60 ml) was incubated at
33 °C for 8 h. This scale experiment was simultaneously carried out four
times (total amount of (ꢁ)-9 was 2.12 g). After the reaction mixture was fil-
tered, the precipitate was washed with diisopropyl ether. The combined or-
ganic layer was dried over MgSO4 and evaporated. The residue was chro-
matographed on silica gel (50 g) to give (R)-9 [1.675 g, 79%, 22% ee of the
corresponding acetate (R)-9, Chiralcel OD, eluent, n-hexane : EtOH : iso-
PrOHꢃ60 : 1 : 1, tRꢃ16.9 min (61%), tRꢃ19.0 min (39%)] from n-
hexane : AcOEtꢃ7 : 1 eluate and (S)-8 {0.295 g, 16%, [a]D25 ꢂ0.32°
(cꢃ1.19, CHCl3), corresponding to 81% ee, Chiralcel OD, eluent, n-
hexane : EtOH : iso-PrOHꢃ60 : 1 : 1, tRꢃ16.9 min (9.5%), tRꢃ19.0 min
(90.5%)} as a homogeneous oil from n-hexane : AcOEtꢃ3 : 1 eluate. The
NMR data of (S)-8 were identical with those of the reported (ꢁ)-8.15)
ii) Table 1, Entry 2: A suspension of (ꢁ)-11 (0.095 g) and lipase OF-
360 (0.1 g) in H2O-saturated-diisopropyl ether (20 ml) was incubated at
33 °C for 24 h. The reaction mixture was worked up in the same way as (ꢁ)-
9 to give a crude oil, which was chromatographed on silica gel (15 g) to give
(R)-11 {0.027 g, 29%, [a]D29 ꢂ13.6° (cꢃ0.39, CHCl3), corresponding to
84% ee, Chiralpac AD, eluent, n-hexane : EtOHꢃ10 : 1, tRꢃ11.7 min (92%),
1
by a JEOL EX 400 spectrometer (Tokyo, Japan). Spectra were recorded with
5—10% (w/v) solution in CDCl3 with Me4Si as an internal reference. High-
resolution mass spectra (HR-MS) and fast-atom bombardment mass spectra
(FAB-MS) were obtained with a JEOL JMS-DX 303 (matrix; glycerol, m-ni-
trobenzyl alcohol) spectrometer. IR spectra were recorded on a JASCO
FT/IR-300 spectrometer. The HPLC system was composed of a detector
(UV detector SSC-5200, Senshu), pump (SSC-3210, Senshu), and integrator
(chromatocorder SIC 21). HPLC analysis conditions were: column, Chiral-
cel OD and Chiralpac AD and AS; detection, UV at 254 nm, and flow rate,
1 ml/min. All evaporations were performed under reduced pressure. For col-
umn chromatography, silica gel (Kieselgel 60) was employed.
Syntheses of Substrates. Methyl (ꢀ)-5-Acetoxy-4-(2,5-dimethoxy-4-
methylphenyl)-(2E)-pentenoate (9)
A solution of (ꢁ)-8 (4.018 g,
14.4 mmol) in pyridine (10 ml) was treated with Ac2O (2.14 g, 21.0 mmol),
and the reaction mixture was stirred for 24 h at room temperature. The reac-
tion mixture was diluted with H2O and extracted with ether. The ether layer
was washed with 2 M aqueous HCl, 7% aqueous NaHCO3, and saturated
brine and dried over MgSO4. Evaporation of the organic layer gave a crude
residue, which was chromatographed on silica gel (60 g, n-hexane : AcOEtꢃ
7 : 1) to give a colorless oil (ꢁ)-9 (3.897 g, 84%). (ꢁ)-9: IR (neat):
1710 cmꢀ1. NMR: 2.02 (3H, s), 2.21 (3H, s), 3.72 (3H, s), 3.76 (3H, s), 3.77
(3H, s), 4.12—4.19 (1H, m), 4.31 (1H, dd, Jꢃ6, 11 Hz), 4.40 (1H, dd, Jꢃ6,
11 Hz), 5.86 (1H, dd, Jꢃ2, 16 Hz), 6.59 (1H, s), 6.71 (1H, s), 7.16 (1H, dd,
Jꢃ7, 16 Hz). FAB-MS (HR-MS) m/z: Calcd for C17H22O6: 322.1416 (Mꢂ).
Found: 322.1447.
Methyl (ꢀ)-5-Acetoxy-4-(2,4-dimethoxyphenyl)-(2E)-pentenoate (11)
A solution of (ꢁ)-10 (2.629 g, 9.9 mmol) in pyridine (5 ml) was treated with
Ac2O (1.51 g, 15.4 mmol), and the reaction mixture was stirred for 24 h at
room temperature. The reaction mixture was worked up in the same way as

568
Vol. 53, No. 5
tRꢃ13.3 min (8%)} from n-hexane : AcOEtꢃ8 : 1 eluate and (S)-10 (10 ml) was hydrogenated over 20% Pd-C (50 mg) at room temperature
{(0.050 g, 61%, [a]D29 ꢀ8.5° (cꢃ0.42, CHCl3), corresponding to 52% ee,
Chiralcel OD, eluent, n-hexane : EtOH : iso-PrOHꢃ60 : 1 : 1, tRꢃ38.0 min
under atmospheric pressure of hydrogen. After removal of the catalyst by fil-
tration, the filtrate was evaporated quantitatively to give crude (S)-20, which
(24%), tRꢃ65.0 min (76%)} as
a homogeneous oil from n-hexane : was used for the next reaction without further purification. The NMR data of
AcOEtꢃ3 : 1 eluate. The NMR data of (S)-10 were identical with those of
(S)-20 were identical with those of the reported (ꢁ)-20.11) A solution of the
crude (S)-20 and NaBH4 (0.31 g, 8.2 mmol) in DMSO (10 ml) was warmed
for 3 h at 80 °C, then allowed to cool. Small amounts of acetone, ether, and
the reported (ꢁ)-10.15)
iii) Table 1, Entry 3: A suspension of (ꢁ)-13 (0.096 g) and lipase OF-
360 (0.1 g) in H2O-saturated-diisopropyl ether (20 ml) was incubated at 7% aqueous NaHCO3 were added to the reaction mixture and the organic
33 °C for 48 h. The reaction mixture was worked up in the same way as (ꢁ)-
9 to give a crude oil, which was chromatographed on silica gel (15 g) to give
(R)-13 {0.030 g, 31%, [a]D24 ꢂ7.1° (cꢃ0.34, CHCl3), corresponding to 80%
ee, Chiralcel OD, eluent, n-hexane : EtOHꢃ1000 : 2, tRꢃ83.6 min (10%),
tRꢃ97.2 min (90%)} from n-hexane : AcOEtꢃ8 : 1 eluate and (S)-12
{0.050 g, 61%, [a]D25 ꢀ7.6° (cꢃ0.49, CHCl3), corresponding to 43% ee,
layer was washed with saturated brine and dried over MgSO4. The organic
layer was evaporated to give a residue, which was chromatographed on silica
gel (20 g, n-hexane : AcOEtꢃ30 : 1) to afford (S)-21 [(0.260 g, 44% overall
yield from (S)-8]. The NMR data of (S)-21 were identical with those of the
reported (ꢁ)-21.11) ii) To a solution of (ꢂ)-21 (0.260 g, 0.97 mmol) in
MeCN (1 ml) was added NaIO4 (4.19 g, 19.6 mmol) and H2O (1.5 ml) at
Chiralpac AD, eluent, n-hexane : EtOHꢃ10 : 1, tRꢃ13.3 min (72%), tRꢃ 0 °C. A mixture of RuCl3·3H2O (20 mg) in CCl4 (1 ml) was added to the
15.1 min (29%)} as a homogeneous oil from n-hexane : AcOEtꢃ3:1 eluate. above reaction mixture, and the whole mixture was vigorously stirred at
The NMR data of (S)-12 were identical with those of the reported
room temperature for 6 h and allowed to stand for 12 h. The reaction mixture
was filtered with the aid of Celite, and the precipitate was washed with
MeCN. The filtrate and washing were combined and concentrated to give a
residue, which was acidified with 2 M aqueous HCl. The acidic layer was ex-
tracted with ether, and the organic layer was washed with saturated brine and
dried over MgSO4. Evaporation of the organic layer gave a residue, which
was treated with an excess of CH2N2-ether solution to afford a crude oil. It
was chromatographed on silica gel (10 g, n-hexane : AcOEtꢃ20 : 1) to afford
(ꢂ)-22 (0.031 g, 16%) as a homogeneous oil. (ꢂ)-22: [a]D26 ꢂ3.4° (cꢃ1.57,
(ꢁ)-12.15)
iv) Table 1, Entry 4: A suspension of (ꢁ)-15 (6.75 g) and lipase OF-360
(0.6 g) in H2O-saturated-diisopropyl ether (600 ml) was incubated at 33 °C
for 48 h. This scale experiment was simultaneously carried out two times
(total amount of (ꢁ)-15 was 13.5 g). The reaction mixture was worked up in
the same way as (ꢁ)-9 to give a crude oil, which was chromatographed on
silica gel (200 g) to give (R)-15 [(10.8 g, 80%, 15% ee, Chiralcel OD, eluent,
n-hexane : EtOH : iso-PrOHꢃ60 : 1 : 1, tRꢃ8.6 min (42.5%), tRꢃ9.9 min
(57.5%)] from n-hexane : AcOEtꢃ10 : 1 eluate and (S)-14 [(1.734 g, 13 %, CHCl3), corresponding to 81% ee. The NMR data of (ꢂ)-22 were identical
40% ee, Chiralcel OD, eluent, n-hexane : EtOH : iso-PrOHꢃ60 : 1 : 1, tRꢃ with those of the reported (S)-22 {[a]D27 ꢂ3.2° (cꢃ1.35, CHCl3) correspond-
27.2 min (30%), tRꢃ34.4 min (70%)] as a homogeneous oil from n- ing to 76% ee}.4)
hexane : AcOEtꢃ3 : 1 eluate. The NMR data of (S)-14 were identical with
Synthesis of Methyl (4S)-(4-Methoxy-2-methylphenyl)pentanoate (24)
and Degradation of the Phenyl Part i) A solution of (S)-14 (79% ee,
1.247 g, 5.0 mmol) and p-TsCl (1.42 g, 7.4 mmol) in pyridine (20 ml) was al-
lowed to stand for 12 h at room temperature. The reaction mixture was di-
luted with ether. The organic layer was washed with 2 M aqueous HCl, 7%
aqueous NaHCO3, and saturated brine and dried over MgSO4. The organic
layer was evaporated to give a residue, which was chromatographed on silica
gel (50 g, n-hexane : AcOEtꢃ8 : 1) to afford (S)-23 (1.801 g, 89%). (S)-23:
[a]D21 ꢂ4.3° (cꢃ1.56, CHCl3). NMR: 2.04 (3H, s), 2.44 (3H, s), 3.71 (3H, s),
3.76 (3H, s), 3.98—4.05 (1H, m), 4.18—4.24 (2H, m), 5.75 (1H, dd, Jꢃ2,
those of the reported (ꢁ)-14.15)
v) Table 1, Entry 5: A suspension of (S)-14 (1.5 g, 40% ee) and lipase
OF-360 (0.6 g) and isopropenyl acetate (3.06 g, 30.5 mmol) in diisopropyl
ether (200 ml) was incubated at 33 °C for 24 h. The reaction mixture was
worked up in the same way as (ꢁ)-9 to give a crude oil, which was chro-
matographed on silica gel (50 g) to give (S)-15 (0.333 g, 19%, 67% ee) from
n-hexane : AcOEtꢃ10 : 1 eluate and (S)-14 (1.155 g, 77%, 34% ee) as a
homogeneous oil from n-hexane : AcOEtꢃ3 : 1 eluate.
vi) Table 1, Entry 6: A suspension of (S)-15 (0.333 g, 67% ee) and li-
pase OF-360 (0.1 g) in H2O-saturated-diisopropyl ether (40 ml) was incu- 16 Hz), 6.65 (1H, dd, Jꢃ3, 9 Hz), 6.69 (1H, d, Jꢃ3 Hz), 6.86 (1H, d,
bated at 33 °C for 72 h. The reaction mixture was worked up in the same way
as (ꢁ)-9 to give a crude oil, which was chromatographed on silica gel (10 g)
to give (S)-15 (0.077 g, 23%, 36% ee) from n-hexane : AcOEtꢃ10 : 1 eluate
and (S)-14 {0.171 g, 60 %, [a]D27 ꢀ4.5° (cꢃ1.08, CHCl3), corresponding to
79% ee)} as a homogeneous oil from n-hexane : AcOEtꢃ3 : 1 eluate.
vii) Table 1, Entry 7: A suspension of (ꢁ)-17 (0.106 g) and lipase OF-
Jꢃ9 Hz), 6.95 (1H, dd, Jꢃ7, 16 Hz), 7.31 (2H, d, Jꢃ9 Hz), 7.71 (2H, d,
Jꢃ9 Hz). HR-MS-(EI) m/z: Calcd for C21H24O6S: 404.1294 (Mꢂ), Found:
404.1321. ii) A solution of (S)-23 (1.801 g, 4.5 mmol) in AcOEt (20 ml) was
hydrogenated over 20% Pd–C (50 mg) at room temperature under atmos-
pheric pressure of hydrogen. After removal of the catalyst by filtration, the
filtrate was evaporated to give a crude tosylate, which was used for the next
360 (0.1 g) in H2O-saturated-diisopropyl ether (20 ml) was incubated at reaction without further purification. A solution of the tosylate and NaBH4
33 °C for 8 h. The reaction mixture was worked up in the same way as (ꢁ)-9
to give a crude oil, which was chromatographed on silica gel (15 g) to give
(0.80 g, 21.1 mmol) in DMSO (20 ml) was warmed for 3 h at 80 °C and then
allowed to cool. Small amounts of acetone, ether, and 7% aqueous NaHCO3
(R)-17 [(0.065 g, 61%, 20% ee, Chiralcel OD, eluent, n-hexane : EtOH : were added to the reaction mixture, and the organic layer was washed with
iso-PrOHꢃ60 : 1 : 1, tRꢃ14.5 min (40%), tRꢃ23.1 min (60%)] from n- saturated brine and dried over MgSO4. The organic layer was evaporated to
hexane : AcOEtꢃ8 : 1 eluate and (S)-16 {0.031 g, 34%, [a]D28 7.10° (cꢃ give a residue, which was chromatographed on silica gel (20 g, n-
0.31, CHCl3), corresponding to 25% ee, Chiralcel OD, eluent, n- hexane : AcOEtꢃ30 : 1) to afford (S)-24 [0.589 g, 56% overall yield from
hexane : EtOH : iso-PrOHꢃ60 : 1 : 1, tRꢃ47.7 min (62.5%), tRꢃ60.0 min
(S)-23]. (S)-24: [a]D25 ꢂ12.7° (cꢃ1.97, CHCl3). IR (CHCl3): 1735 cmꢀ1
.
(37.5%)} as a homogeneous oil from n-hexane : AcOEtꢃ3 : 1 eluate. The NMR: 1.19 (3H, d, Jꢃ7 Hz), 1.86—1.92 (1H, m), 2.19—2.23 (2H, m), 2.28
NMR data of (S)-16 were identical with those of the reported (ꢁ)-16.15)
viii) Table 1, Entry 8: A suspension of (ꢁ)-19 (0.095 g) and lipase OF-
(3H, s), 2.94 (1H, sextet, Jꢃ7 Hz), 3.62 (3H, s), 3.76 (3H, s), 6.68 (1H, d,
Jꢃ3 Hz), 6.73 (1H, dd, Jꢃ3, 9 Hz), 7.08 (1H, d, J=9 Hz). HR-MS-(EI) m/z:
360 (0.1 g) in H2O-saturated-diisopropyl ether (20 ml) was incubated at Calcd for C14H20O3: 236.1412 (Mꢂ), Found: 236.1401. iii) To a solution of
33 °C for 24 h. The reaction mixture was worked up in the same way as
(ꢁ)-9 to give a crude oil, which was chromatographed on silica gel
(15 g) to give (R)-19 [(0.018 g, 18%, 29% ee, Chiralpac AD, eluent,
n-hexane : EtOHꢃ50 : 1, tRꢃ34.5 min (35.5%), tRꢃ39.0 min (64.5%)] from
n-hexane : AcOEtꢃ8 : 1 eluate and (S)-18 [(0.064 g, 77%, 7% ee, Chiralpac
AS, eluent, n-hexane : EtOHꢃ10 : 1, tRꢃ13.2 min (53.5%), tRꢃ16.1 min
(46.5%)] as a homogeneous oil from n-hexane : AcOEtꢃ3 : 1 eluate. The
NMR data of (S)-18 were identical with those of the reported (ꢁ)-18.15)
(ꢂ)-24 (0.317 g, 1.34 mmol) in MeCN (2 ml) was added NaIO4 (5.75 g,
26.9 mmol) and H2O (3 ml) at 0 °C. A mixture of RuCl3·3H2O (20 mg) in
CCl4 (2 ml) was added to the above reaction mixture, and the whole mixture
was vigorously stirred at room temperature for 6 h and allowed to stand for
12 h. The reaction mixture was filtered with the aid of Celite, and the precip-
itate was washed with MeCN. The filtrate and washing were combined and
concentrated to give a residue, which was acidified with 2 M aqueous HCl.
The acidic layer was extracted with ether, and the organic layer was washed
Structure Elucidation. Synthesis of Methyl (4S)-(2,5-Dimethoxy-4- with saturated brine and dried over MgSO4. Evaporation of the organic layer
methylphenyl)pentanoate (21) and Degradation of the Phenyl Part i) A
solution of (S)-8 (81% ee, 0.613 g, 2.2 mmol) and p-TsCl (0.63 g, 3.3 mmol)
gave a residue, which was treated with an excess of CH2N2-ether solution to
afford a crude oil. It was chromatographed on silica gel (10 g, n-
in pyridine (10 ml) was allowed to stand for 12 h at room temperature. The hexane : AcOEtꢃ40 : 1) to afford (ꢂ)-25 (0.078 g, 33%) as a homogeneous
reaction mixture was diluted with ether. The organic layer was washed with oil. (ꢂ)-25: [a]D21 ꢂ13.9° (cꢃ0.78, CHCl3), corresponding to 79% ee. The
2 M aqueous HCl, 7% aqueous NaHCO3, and saturated brine and dried over
MgSO4. The organic layer was evaporated to give a residue that was chro- ꢂ15.8° (cꢃ0.72, CHCl3), corresponding to 90% ee}.4)
NMR data of (ꢂ)-25 were identical with those of the reported (S)-25 {[a]D25
matographed on silica gel (25 g, n-hexane : AcOEtꢃ8 : 1) to afford the corre-
sponding tosylate (0.704 g, 74%). A solution of the tosylate in AcOEt
Synthesis of Authentic Samples (S)-10, (S)-12, (S)-16, and (S)-18 i)
To a solution of (S)-26 (93% ee, 0.5 g, 3.9 mmol)16) and 1,3-dimethoxyben-

May 2005
569
zene (1.08 g, 7.8 mmol) in CH2Cl2 (10 ml) was added BF3·Et2O (0.55 g,
3.9 mmol) at ꢀ78 °C, and the whole mixture was stirred for 1 h at the same
temperature. The reaction mixture was diluted with brine and extracted with
AcOEt. The organic layer was dried over MgSO4 and evaporated to give a
crude oil, which was chromatographed on silica gel (28 g, n-
hexane : AcOEtꢃ4 : 1) to afford (S)-10 (0.39 g, 38%) as a colorless oil. The
NMR data of (S)-10 were identical with those of the reported (ꢁ)-10.15) (S)-
10: [a]D29 ꢀ15.2° (cꢃ0.50, CHCl3), corresponding to 93% ee, Chiralcel OD,
References
1) ApSimon J. (ed.), “The Total Synthesis of Natural Products,” Vol. V,
John Wiley & Sons, New York, 1983, p. 3545.
2) Ono M., Ogura Y., Hatogai K., Akita H., Tetrahedron: Asymmetry, 6,
1829—1832 (1995).
3) Ono M., Ogura Y., Hatogai K., Akita H., Chem. Pharm. Bull., 49,
1581—1585 (2001).
4) Ono M., Suzuki K., Tanikawa S., Akita H., Tetrahedron: Asymmetry,
12, 2597—2604 (2001).
eluent,
n-hexane : EtOH : iso-PrOHꢃ60 : 1 : 1,
tRꢃ38.0 min
(3.5%),
tRꢃ65.0 min (96.5%). ii) To a solution of (S)-26 (93% ee, 0.727 g,
5.7 mmol)16) and anisole (1.23 g, 11.4 mmol) in CH2Cl2 (10 ml) was added
BF3·Et2O (0.85 g, 6 mmol) at ꢀ78 °C, and the whole mixture was stirred for
1 h at the same temperature. The reaction mixture was diluted with brine and
extracted with AcOEt. The organic layer was dried over MgSO4 and evapo-
rated to give a crude oil, which was chromatographed on silica gel (30 g) to
afford (S)-12 (0.139 g, 10%) as a colorless oil from n-hexane : AcOEtꢃ3 : 1
5) Fusetani N., Sugano M., Matsunaga S., Hashimoto K., Experientia,
43, 1234—1235 (1987).
6) Wright A. E., Pomponi S. A., McConnell O. J., Kohmoto S., McCarthy
P., J. Nat. Prod., 50, 976—978 (1987).
7) Ghisalberti E. L., Jefferies P. R., Stuart A. D., Aust. J. Chem., 32,
1627—1630 (1979).
8) McEnroe F. J., Fenical W., Tetrahedron, 34, 1661—1664 (1978).
9) Tanaka J., Nobutani K., Adachi K., Nippon Kagakukaishi, 1988,
1065—1073 (1988).
eluate and (S)-18 (0.564 g, 42%) as
a
colorless oil from n-
hexane : AcOEtꢃ2 : 1 eluate. The NMR data of (S)-12 and (S)-18 were iden-
tical with those of the reported (ꢁ)-12 and (ꢁ)-18, respectively.15) (S)-12: 10) Shama M. L., Chand T., Indian J. Chem., 36B, 553—556 (1997).
[a]D21 ꢀ17.9° (cꢃ0.51, CHCl3), corresponding to 93% ee, Chiralpac AD,
eluent, n-hexane : EtOHꢃ10 : 1, tRꢃ13.3 min (96.5%), tRꢃ15.1 min (3.5%).
(S)-18: [a]D22 ꢀ2.2° (cꢃ0.51, CHCl3), corresponding to 93% ee, Chiralpac
AS, eluent, n-hexane : EtOHꢃ10 : 1, tRꢃ13.2 min (96.5%), tRꢃ16.1 min
11) Ono M., Yamamoto Y., Akita H., Chem. Pharm. Bull., 43, 553—558
(1995).
12) Sugawara T., Ogasawara K., Tetrahedron: Asymmetry, 9, 2215—2217
(1998).
(3.5%). iii) To a solution of (S)-26 (93% ee, 1.23 g, 9.6 mmol)16) and 3,4- 13) Fuganti C., Serra S., Synlett, 1998, 1252—1254 (1998).
dimethoxytoluene (2.19 g, 14.4 mmol) in CH2Cl2 (10 ml) was added 14) Fuganti C., Serra S., J. Chem. Soc. Perkin Trans. I, 2000, 3758—3764
BF3·Et2O (1.36 g, 9.6 mmol) at ꢀ78 °C, and the whole mixture was stirred
(2000).
for 1 h at the same temperature. The reaction mixture was diluted with brine 15) Ono M., Todoriki R., Yamamoto Y., Akita H., Chem. Pharm. Bull., 42,
and extracted with AcOEt. The organic layer was dried over MgSO4 and
evaporated to give a crude oil, which was chromatographed on silica gel
(20 g, n-hexane : AcOEtꢃ2 : 1) to afford (S)-16 (1.237 g, 46%) as a colorless
1590—1595 (1994).
16) Ono M., Tanikawa S., Suzuki K., Akita H., Tetrahedron, 60, 10187—
10195 (2004).
oil. The NMR data of (S)-16 were identical with those of the reported (ꢁ)- 17) Weissfloch A. N. E., Kazalauskas R. J., J. Org. Chem., 60, 6959—6969
16.15) (S)-16: [a]D29 ꢂ22.7° (cꢃ0.33, CHCl3), corresponding to 93% ee, Chi-
(1995).
ralcel OD, eluent, n-hexane : EtOH : iso-PrOHꢃ60 : 1 : 1, tRꢃ47.7 min 18) Tuomi W. V., Kazalauskas R. J., J. Org. Chem., 64, 2638—2647
(96.5%), tRꢃ60.0 min (3.5%).
(1999).
Acknowledgment The authors are grateful to Meito Sangyo Co., Ltd.,
Japan, for providing the lipase OF-360.