Synthesis of a glandular secretion of the civet cat, (2S,6S)-(6- methyltetrahydropyran-2-yl)acetic acid and its enantiomer, by using the yeast-reduction product and recovered substrate from yeast reduction

Article abstract of DOI:10.1271/bbb.70.712

A glandular secretion of the civet cat, (2S,6S)-(6-methyltetrahydropyran-2- yl)acetic acid 1 and its enantiomer, were synthesized from the yeast-reduction product and recovered substrate from yeast reduction.

Full text of DOI:10.1271/bbb.70.712

Biosci. Biotechnol. Biochem., 70 (3), 712–717, 2006
Synthesis of a Glandular Secretion of the Civet Cat, (2S,6S)-
(6-Methyltetrahydropyran-2-yl)acetic Acid and Its Enantiomer,
by Using the Yeast-Reduction Product and Recovered
Substrate from Yeast Reduction
y
Shunji MORI, Shoko IWAMOTO, and Satoshi YAMAUCHI
Faculty of Agriculture, Ehime University, 3-5-7 Tarumi, Matsuyama, Ehime 790-8566, Japan
Received October 25, 2005; Accepted November 4, 2005
A glandular secretion of the civet cat, (2S,6S)-(6-
methyltetrahydropyran-2-yl)acetic acid 1 and its enan-
tiomer, were synthesized from the yeast-reduction
product and recovered substrate from yeast reduction.
substrate 35) from the yeast reduction via ketone 4
(Scheme 1).
Results and Discussion
Key words: yeast reduction; glandular secretion; civet
cat; (2S,6S)-(6-methyltetrahydropyran-2-
yl)acetic acid
The starting materials, (R)-5 and (S)-5, were respec-
tively prepared from 2 and 3 to more than 99% ee
(Scheme 1).4,5) After hydrolyzing (R)-5 (97% yield),
resulting carboxylic acid 6 was treated with pivaloyl
chloride, triethylamine, and the lithium salt of (R)-4-
benzyl-2-oxazolidinone to introduce Evans’s chiral
auxiliary in 95% yield (Scheme 2). Stereoselective ꢀ-
hydroxylation6) to 7 by MoOPH7) gave ꢀ-hydroxy
compound 8 as a single stereoisomer in 53% yield.
Acyl oxazolidinone 7 was recovered (26%) in this
hydroxylation reaction. Removal of the chiral auxiliary
by LiBH4 reduction gave glycol 9 in 89% yield. The
undesired 2S isomer of 9 was not produced. This
undesired 2S isomer of 9 was prepared from carboxylic
acid 6 by employing (S)-4-benzyl-2-oxazolidinone. The
NMR spectra of 9 were different from those of the 2S
isomer of 9. After reducing to 10 via the tosylate (76%
yield, 2 steps), the hydroxy group was protected as an
acetate in the pyridine-acetic anhydride system in 99%
(2S,6S)-(6-Methyltetrahydropyran-2-yl)acetic acid 1
is a glandular secretion of the civet cat.1) Two syntheses
of 1 using an enzyme-catalyzed reaction have been
reported. One of them employed porcine pancreatic
lipase to give a synthetic intermediate of 58% ee,2) and
the another used Thermoanaerobium brockii alcohol
dehydrogenase to obtain a synthetic intermediate of
98% ee.3) In this study, compound (R)-5, which has been
derived from yeast-reduction product 2 in more than
99% ee,4) was selected as the starting material. This
report describes a new synthetic route to (2S,6S)-1 by
using a biological transformation material to give higher
optical purity than that with the previous enzymatic
transformation. The synthesis of (2R,6R)-1 from (S)-5 is
also described. (S)-5 was prepared from recovered
O
ref.4
OH
OTBDPS
MeO
CO2H
CO2Me
O
OMOM
1
2
(R)-5
1) LiAlH4/ether
2) TBDPSCl, Et3N
4-DMAP/CH2Cl2
O
ref. 4
O
O
OTBDPS
MeO
CO2Me
OTBDPS
3) PCC/CH2Cl2
73%
OMOM
(S)-5
3
4
Scheme 1.
y
To whom correspondence should be addressed. Fax: +81-89-977-4364; E-mail: syamauch@agr.ehime-u.ac.jp

Synthesis of a Glandular Secretion of the Civet Cat
713
O
O
O
OTBDPS
OTBDPS
RO
d
b
N
O
OMOM
5: R = Me
6: R = H
R
OMOM
Bn
7: R = H
a
c
8: R = OH
OTBDPS
h
R1
R
O
OR2
OR3
9: R1 = OH, R2 = H, R3 = MOM
10: R1 = H, R2 = H, R3 = MOM
11: R1 = H, R2 = Ac, R3 = MOM
12: R1 = H, R2 = Ac, R3 = H
13: R = CH2OTBDPS
14: R = CH2OH
1: R = CO2H
e
i
j
f
g
Scheme 2. Synthesis of 1.
(a) 6 M aq. KOH–EtOH (1/1), 0 ꢀC, 1 h (97%); (b) Et3N, PivCl, lithium salt of (R)-4-benzyl-2-oxazolidinone, 0 ꢀC, 1 h; (c) KHMDS, MoOPH,
THF, ꢁ70 ꢀC, 2 h (53%); (d) LiBH4, MeOH, THF, 0 ꢀC, 2 h (89%); (e) (1) p-TsCl, pyridine, CH2Cl2, 0 ꢀC, 5 h (85%); (2) LiAlH4, THF, r.t., 1 h
(89%); (f) Ac2O–pyridine (1/1), 4-DMAP, r.t., 1 h (99%); (g) TMSBr, CH2Cl2, ꢁ10 ꢀC, 2 h (88%); (h) (1) MsCl, Et3N, CH2Cl2, r.t., 1 h; (2)
K2CO3, MeOH, r.t., 16 h; (3) K2CO3, DMF, 100 ꢀC, 12 h (57%, 3 steps); (i) (n-Bu)4NF, THF, r.t., 2 h (80%); (j) Jones reagent, acetone, 0 ꢀC, 2 h
(84%).
yield. Selective removal of the methoxymethyl group
was achieved by treating with trimethylsilyl bromide8) to
give alcohol 12 in 88% yield. Removal of methoxy-
methyl group under the protic acid condition was
accompanied by desilylation. Cyclization to tetrahydro-
pyran derivative 13 was achieved by successive mesy-
lation, methanolysis and treatment with K2CO3 in
heated DMF in 57% yield through 3 steps. Partial
cyclization was observed during this methanolysis.
Desilylation by using tetrabutylammonium fluoride gave
(2S,6S)-alcohol 14. The NMR datum agreed with that of
the literature.2) Desilylation under the acidic condition
gave a small amount of unknown by-products. (2R,6R)-
Alcohol 14 was also obtained from 3 by employing same
process. To determine the optical purity, (2S,6S)- and
(2R,6R)-14 were each treated with (S)-Mosher’s reagent.
An HPLC analysis of the resulting products with a chiral
column determined the optical purity of (2S,6S)- and
(2R,6R)-14 to be more than 99% ee, respectively. This
alcohol 14 was oxidized2,9–11) to 1 in 67% yield. The
NMR datum agreed with that of the literature.12)
The synthetic process involving biological transfor-
mation can be carried out under mild conditions, and the
stereoselectivity is sometimes high. However, only two
reports have been presented for the synthesis of
glandular secretion (2S,6S)-1 of the civet cat. In this
experiment, compound (2S,6S)-1 and its enantiomer
were synthesized by using the yeast-reduction product
and its recovered substrate from yeast reduction. This
new synthetic method employing enzyme-catalyzed
product gave higher optical purity than previously
reported enzymatic transformation. The use of recovered
substrate 3 was also demonstrated.
Experimental
NMR data were measured by a JNM-EX400 spec-
trometer, IR spectra were determined with a Shimadzu
FTIR-8100 spectrophotometer, and optical rotation
values were evaluated with a HORIBA SEPA-200
instrument. The silica gel used was Wakogel C-300
(Wako, 200–300 mesh). HPLC analyses were performed
with Shimadzu LC-6AD and SPD-6AV instruments.
(S)-2-[2-(tert-Butyldiphenylsilyloxy)ethyl]cyclohexa-
none (4). To an ice-cooled suspension of LiAlH4 (5.35 g,
0.14 mol) in ether (200 ml) was added a solution of (S)-
ketoester 35) (26.3 g, 0.15 mol) in ether (150 ml). The
resulting reaction mixture was stirred at room temper-
ature for 1 h before additions of sat. aq. MgSO4 and
K2CO3. After stirring at room temperature for 30 min,
the mixture was filtered. The filtrate was concentrated to
give crude diol. To an ice-cooled solution of the crude
diol, Et3N (25.1 ml, 18.2 g, 0.18 mol), and 4-DMAP
(0.73 g, 0.006 mol) in CH2Cl2 (50 ml) was added tert-
BuPh2SiCl (39.0 ml, 41.2 g, 0.15 mol). After the result-
ing reaction mixture was stirred at room temperature for
1 h, H2O and CH2Cl2 were added. The organic solution
was separated, washed with brine, and dried (Na2SO4).
Concentration gave a crude silyloxy alcohol. A reaction
mixture of the crude silyloxy alcohol and PCC (36.6 g,
0.17 mol), and MS 4A (0.5 g) in CH2Cl2 (250 ml) was

714
S. MORI et al.
stirred at room temperature for 16 h before addition of
ether. After filtration, the filtrate was concentrated. The
residue was applied to silica gel column chromatography
(2% EtOAc/hexane) to give ketone 4 (41.9 g, 0.11 mol,
(CHCl3): 2932, 1782, 1701, 1387, 1246, 1111, 1036,
909 cmꢁ1. Anal. Found: C, 70.33; H, 8.05; N, 2.20.
Calcd. for C36H47O6NSi: C, 69.97; H, 7.67; N, 2.27%.
20
(S)-[(S)]-7, ½ꢀꢂ
¼ þ27 (c 2.9, CHCl3).
D
73%) as a colorless oil. NMR spectra were agreed
20
with that of literature.4) ½ꢀꢂ
¼ þ0:8 (c 2.4, CHCl3),
(R)-4-Benzyl-3-[(2R,6R)-8-(tert-butyldiphenylsilyloxy)-
2-hydroxy-6-(methoxymethoxy)octanoyl]-2-oxazolidinone
(8). To a solution of KHMDS (72.6 ml, 0.5 M in toluene,
36.3 mmol) in THF (150 ml) was added a solution of
acyl oxazolidinone 7 (15.0 g, 24.2 mmol) in THF
(100 ml). After the mixture was stirred at ꢁ75 ꢀC for
30 min, MoOPH (15.8 g, 36.4 mmol) was added. The
reaction mixture was stirred at ꢁ75 ꢀC for 2 h, and then
sat. aq. Na2SO3 solution and EtOAc were added. The
organic solution was separated, washed with 1 M aq. HCl
solution, sat. aq. NaHCO3 solution, and brine, and dried
(Na2SO4). Concentration followed by silica gel column
chromatography (EtOAc/toluene ¼ 1=9) gave alcohol 8
(8.11 g, 12.8 mmol, 53%) as a colorless oil. Acyl
D
20
½ꢀꢂ
¼ ꢁ0:9 (c 3.3, CHCl3) in the literature.4)
D
(R)-8-(tert-Butyldiphenylsilyloxy)-6-(methoxymethoxy)-
octanoic acid (6). A reaction solution of ester 5 (23.3 g,
49.3 mmol) in EtOH (200 ml) and 6 M aq. KOH solution
(200 ml) was stirred at 0 ꢀC for 1 h before addition of
CHCl3. After acidification with 6 M aq. HCl solution, the
organic solution was separated, washed with brine, and
dried (Na2SO4). Concentration followed by silica gel
column chromatography (EtOAc/hexane ¼ 1=2) gave
carboxylic acid 6 (22.0 g, 48.0 mmol, 97%) as a color-
20
less oil. ½ꢀꢂ
¼ ꢁ1:6 (c 1.9, CHCl3). NMR ꢁH
D
(CDCl3): 1.05 (9H, s, tert-Bu), 1.39 (2H, m), 1.51
(2H, m), 1.63 (2H, m), 1.73 (2H, m), 2.34 (2H, t, J
7.3 Hz, 2-H2), 3.31 (3H, s, OCH2OCH3), 3.73–3.77 (3H,
m, 6-H, 8-H2), 4.58 (1H, d, J 6.8 Hz, OCHHOMe), 4.61
(1H, d, J 6.8 Hz, OCHHOMe), 7.36–7.42 (6H, m, ArH),
7.64–7.67 (4H, m, ArH). NMR ꢁC (CDCl3): 19.2, 24.7,
24.8, 26.9, 33.9, 34.4, 37.3, 55.5, 60.6, 74.7, 95.7, 127.6,
129.6, 133.9, 135.6, 179.0. IR ꢂmax (CHCl3): 2934,
1709, 1111, 1036, 909 cmꢁ1. Anal. Found: C, 68.18; H,
oxazolidinone 7 (3.74 g, 6.05 mmol, 26%) was recov-
20
ered. ½ꢀꢂ
¼ ꢁ31 (c 1.8, CHCl3). NMR ꢁH (CDCl3):
D
1.05 (9H, s, tert-Bu), 1.49–1.62 (5H, m), 1.72–1.85 (3H,
m), 2.84 (1H, dd, J 13.4, 9.5 Hz, ArCHH), 3.30 (1H, dd,
J 13.4, 3.4 Hz, ArCHH), 3.31 (3H, s, OCH2OCH3), 3.46
(1H, d, J 7.8 Hz, OH), 3.70–3.80 (3H, m, CHOMOM,
CH2OTBDPS), 4.23–4.27 (2H, m, 5-H2), 4.58 (1H, d, J
6.8 Hz, OCHHOMe), 4.61 (1H, d, J 6.8 Hz, OCH-
HOMe), 4.65 (1H, m, 4-H), 4.97 (1H, m, CHOH), 7.18–
7.21 (3H, m, ArH), 7.25–7.41 (8H, m, ArH), 7.64–7.67
(4H, m, ArH). NMR ꢁC (CDCl3): 19.2, 21.0, 26.9, 34.2,
34.4, 37.4, 37.5, 55.48, 55.50, 60.6, 66.9, 70.7, 74.7,
95.8, 127.50, 127.61, 129.0, 129.4, 129.6, 133.9, 134.8,
135.5, 153.2, 174.9. IR ꢂmax (CHCl3): 3530, 1788, 1694,
1389, 1352, 1298, 1113, 1036, 911 cmꢁ1. Anal. Found:
87.54. Calcd. for C26H38O5Si: C, 68.09; H, 8.35%. (S)-6,
20
½ꢀꢂ
¼ þ1:6 (c 1.2, CHCl3).
D
(R)-4-Benzyl-3-[(R)-8-(tert-butyldiphenylsilyloxy)-6-
(methoxymethoxy)octanoyl]-2-oxazolidinone (7). To a
solution of carboxylic acid 6 (10.2 g, 22.2 mmol) in THF
(200 ml) was added Et3N (3.25 ml, 2.36 g, 23.3 mmol)
and PivCl (2.87 ml, 2.81 g, 23.3 mmol) at ꢁ75 ꢀC, and
then the resulting mixture was stirred at 0 ꢀC for 1 h
before cooling to ꢁ75 ꢀC. To the resulting mixture was
added a solution of lithium salt of (R)-4-benzyl-2-
oxazolidinone (4.13 g, 23.3 mmol) in THF (100 ml) at
ꢁ75 ꢀC. After the resulting reaction mixture was stirred
at 0 ꢀC for 1 h, sat. aq. NH4Cl solution was added. The
organic solution was separated, washed with brine, and
dried (Na2SO4). Concentration followed by silica gel
column chromatography (EtOAc/hexane ¼ 1=4) gave
C, 68.46; H, 7.95; N, 2.21. Calcd. for C36H47O7NSi: C,
20
68.22; H, 7.47; N, 2.21%. (S)-[(2S,6S)]-8, ½ꢀꢂ
¼ þ31
D
(c 1.2, CHCl3).
(2R,6R)-8-(tert-Butyldiphenylsilyloxy)-6-(methoxyme-
thoxy)-1,2-octanediol (9). To an ice-cooled solution of
acyl oxazolidinone 8 (7.04 g, 11.1 mmol) and MeOH
(1.80 ml, 44.4 mmol) in THF (50 ml) was added LiBH4
(1.21 g, 55.6 mmol). The reaction solution was stirred at
0 ꢀC for 2 h before additions of sat. aq. NH4Cl solution
and EtOAc. The organic solution was separated, washed
with brine, and dried (Na2SO4). Concentration followed
by silica gel column chromatography (EtOAc/hexane ¼
acyl oxazolidinone 7 (13.0 g, 21.0 mmol, 95%) as a
20
colorless oil. ½ꢀꢂ
¼ ꢁ27 (c 1.9, CHCl3). NMR ꢁH
D
(CDCl3): 1.05 (9H, s, tert-Bu), 1.41–1.47 (2H, m), 1.55
(2H, m), 1.65–1.77 (2H, m), 1.74 (2H, m), 2.76 (1H, dd,
J 13.4, 9.5 Hz, ArCHH), 2.86–3.02 (2H, m, CH2C=O),
3.30 (1H, dd, J 13.4, 2.9 Hz, ArCHH), 3.31 (3H, s,
OCH2OCH3), 3.73–3.81 (3H, m, CHOMOM,
CH2OTBDPS), 4.11–4.21 (2H, m, 5-H2), 4.59 (1H, d,
J 6.8 Hz, OCHHOMe), 4.62 (1H, d, J 6.8 Hz, OCH-
HOMe), 4.67 (1H, m, 4-H), 7.19–7.21 (3H, m, ArH),
7.25–7.43 (8H, m, ArH), 7.65–7.68 (4H, m, ArH). NMR
ꢁC (CDCl3): 19.1, 24.4, 24.8, 26.8, 34.5, 35.5, 37.4, 37.9,
55.1, 55.5, 60.6, 66.1, 74.7, 95.7, 127.3, 127.6, 128.9,
129.4, 129.6, 133.9, 135.3, 135.5, 153.4, 173.1. IR ꢂmax
2=1) gave glycol 9 (4.57 g, 9.92 mmol, 89%) as a
20
colorless oil. ½ꢀꢂ
¼ þ2:8 (c 1.8, CHCl3). NMR ꢁH
D
(CDCl3): 1.05 (9H, s, tert-Bu), 1.42–1.52 (6H, m), 1.73
(2H, m), 2.22 (1H, br. s, OH), 2.41 (1H, br. s, OH), 3.31
(3H, s, OCH2OCH3), 3.42 (1H, dd, J 10.7, 7.8 Hz, 1-
HH), 3.66 (1H, dd, J 10.7, 11.2 Hz, 1-HH), 3.70 (1H, m,
2-H), 3.71–3.79 (3H, m, 6-H, 8-H2), 4.59 (1H, d, J
6.6 Hz, OCHHOMe), 4.62 (1H, d, J 6.6 Hz, OCH-
HOMe), 7.36–7.44 (6H, m, ArH), 7.64–7.67 (4H, m,
ArH). NMR ꢁC (CDCl3): 19.2, 21.2, 26.8, 33.1, 34.6,
37.4, 55.5, 60.5, 66.8, 72.0, 74.9, 95.8, 127.6, 129.6,

Synthesis of a Glandular Secretion of the Civet Cat
715
133.83, 133.85, 135.5. IR ꢂmax (CHCl3): 3425, 2934,
1111, 1092, 1036 cmꢁ1. Anal. Found: C, 67.69; H, 8.80.
Calcd. for C26H40O5Si: C, 67.79; H, 8.75%. (2S,6S)-9:
1.41–1.60 (2H, m), 1.49 (2H, m), 1.73 (2H, m), 2.02
(3H, s, Ac), 3.31 (3H, s, OCH2OCH3), 3.70–3.79 (3H,
m, 6-H, 8-H2), 4.58 (1H, d, J 6.8 Hz, CHHOMe), 4.61
(1H, d, J 6.8 Hz, CHHOMe), 4.88 (1H, m, 2-H), 7.35–
7.43 (6H, m, ArH), 7.64–7.67 (4H, m, ArH). NMR ꢁC
(CDCl3): 19.2, 19.9, 21.1, 21.4, 26.8, 34.5, 36.0, 37.3,
55.5, 60.6, 70.9, 74.6, 95.7, 127.6, 129.6, 133.9, 135.5,
170.7. IR ꢂmax (CHCl3): 2934, 1727, 1375, 1258, 1111,
20
½ꢀꢂ
¼ ꢁ2:7 (c 2.1, CHCl3). (2S,6R)-9: NMR ꢁH
D
(CDCl3): 1.05 (9H, s), 1.35–1.60 (5H, m), 1.69–1.77
(3H, m), 2.07 (1H, br. s), 2.22 (1H, br. s), 3.32 (3H, s),
3.43 (1H, m), 3.62–3.73 (3H, m), 3.73–3.78 (2H, m),
4.59 (1H, d, J 6.8 Hz), 4.62 (1H, d, J 6.8 Hz), 7.35–7.42
(6H, m), 7.63–7.66 (4H, m). NMR ꢁC (CDCl3): 19.1,
20.9, 26.7, 33.0, 34.4, 37.2, 55.3, 60.4, 66.6, 71.9, 74.7,
95.7, 127.5, 129.4, 133.69, 133.71, 135.4.
1036 cmꢁ1. Anal. Found: C, 69.38; H, 8.70. Calcd. for
20
C28H42O5Si: C, 69.10; H, 8.70%. (2R,6S)-11, ½ꢀꢂ
þ4:5 (c 1.4, CHCl3).
¼
D
(2S,6R)-8-(tert-Butyldiphenylsilyloxy)-6-(methoxyme-
thoxy)-2-octanol (10). To an ice-cooled solution of
glycol 9 (4.77 g, 10.4 mmol) and pyridine (1.68 ml,
1.65 g, 20.8 mmol) in CH2Cl2 (5 ml) was added p-TsCl
(1.97 g, 10.3 mmol). The reaction solution was stirred at
0 ꢀC for 5 h before additions of H2O and CH2Cl2. The
organic solution was separated, washed with 1 M aq. HCl
solution, sat. aq. NaHCO3 solution, and brine, and dried
(Na2SO4). Concentration followed by silica gel column
chromatography (EtOAc/hexane ¼ 1=2) gave unstable
tosylate (5.44 g, 8.85 mmol, 85%) as a colorless oil. To
an ice-cooled suspension of LiAlH4 (0.64 g, 16.9 mmol)
in THF (20 ml) was added a solution of tosylate (5.44 g,
8.85 mmol) in THF (10 ml). The reaction mixture was
stirred at room temperature for 1 h before additions of
sat. aq. MgSO4 solution and K2CO3. The mixture was
stirred for 30 min, and then filtered. After the filtrate was
concentrated, the residue was applied to silica gel
column chromatography (EtOAc/hexane ¼ 1=5) to give
(2S,6R)-8-(tert-Butyldiphenylsilyloxy)-6-hydroxyoct-
2-yl acetate (12). To a solution of MOM ether 11
(4.23 g, 8.69 mmol) in CH2Cl2 (85 ml) was added
TMSBr (1.14 ml, 1.32 g, 8.64 mmol) at ꢁ10 ꢀC, and
then the reaction solution was stirred at ꢁ10 ꢀC for 2 h.
After addition of sat. aq. NaHCO3 solution, the organic
solution was separated, washed with brine, and dried
(Na2SO4). Concentration followed by silica gel column
chromatography (EtOAc/hexane ¼ 1=5) gave hydroxy
acetate 12 (3.38 g, 7.64 mmol, 88%) as a colorless oil.
20
½ꢀꢂ
¼ þ3:8 (c 1.9, CHCl3). NMR ꢁH (CDCl3): 1.05
D
(9H, s, tert-Bu), 1.21 (3H, d, J 6.4 Hz, 1-H3), 1.33–1.55
(4H, m), 1.56–1.76 (4H, m), 2.02 (3H, s, Ac), 3.28 (1H,
br. s, OH), 3.82–3.89 (3H, m, 6-H, 8-H2), 4.90 (1H, m,
2-H), 7.38–7.46 (6H, m, ArH), 7.66–7.68 (4H, m, ArH).
NMR ꢁC (CDCl3): 19.0, 19.9, 21.4, 21.5, 26.8, 35.9,
37.3, 38.4, 63.6, 71.0, 71.7, 127.8, 129.83, 129.84,
132.9, 133.0, 135.5, 170.8, IR ꢂmax (CHCl3): 3524,
2934, 1725, 1375, 1258, 1113, 1082 cmꢁ1. Anal. Found:
alcohol 10 (3.52 g, 7.92 mmol, 89%) as a colorless oil.
C, 70.63; H, 8.77. Calcd. for C26H38O4Si: C, 70.55; H,
20
20
½ꢀꢂ
¼ þ3:8 (c 2.4, CHCl3). NMR ꢁH (CDCl3): 1.05
8.65%. (2S,6S)-12, ½ꢀꢂ
¼ ꢁ3:7 (c 1.4, CHCl3).
D
D
(9H, s, tert-Bu), 1.18 (3H, d, J 6.2 Hz, 1-H3), 1.20–1.58
(6H, m), 1.74 (2H, m), 3.32 (3H, s, OCH2OCH3), 3.74–
3.80 (4H, m, 2-H, 6-H, 8-H2), 4.59 (1H, d, J 6.8 Hz,
OCHHOMe), 4.62 (1H, d, J 6.8 Hz, OCHHOMe), 7.36–
7.42 (6H, m, ArH), 7.64–7.67 (4H, m, ArH). NMR ꢁC
(CDCl3): 19.2, 21.4, 23.5, 26.8, 34.6, 37.4, 39.3, 55.5,
60.6, 67.9, 74.9, 95.7, 127.6, 129.6, 133.87, 133.89,
135.5. IR ꢂmax (CHCl3): 3505, 2934, 1111, 1094,
(2S,6S)-2-(tert-Butyldiphenylsilyloxyethyl)-6-methyl-
tetrahydropyran (13). To an ice-cooled solution of
hydroxy acetate 12 (3.38 g, 7.64 mmol) and Et3N
(1.17 ml, 0.85 g, 8.39 mmol) in CH2Cl2 (3.5 ml) was
added MsCl (0.65 ml, 0.96 g, 8.40 mmol). The reaction
mixture was stirred at room temperature for 1 h before
additions of sat. aq. NaHCO3 solution and CH2Cl2. The
organic solution was separated, washed with brine, and
dried (Na2SO4). After concentration, a mixture of the
residue and K2CO3 (1.06 g, 7.67 mmol) in MeOH
(10 ml) was stirred at room temperature for 16 h before
concentration. The residue was dissolved in H2O and
EtOAc. The organic solution was separated, washed
with brine, and dried (Na2SO4). After concentration, a
mixture of the residue and K2CO3 (1.06 g, 7.67 mmol) in
DMF (3.5 ml) was stirred at 100 ꢀC for 12 h before
additions of H2O and EtOAc. The organic solution was
separated, washed with brine, and dried (Na2SO4).
Concentration followed by silica gel column chroma-
tography (2% EtOAc in hexane) gave tetrahydropyran
1036 cmꢁ1. Anal. Found: C, 70.20; H, 9.06. Calcd. for
20
C26H40O4Si: C, 70.23; H, 9.07%. (2R,6S)-10, ½ꢀꢂ
¼
D
ꢁ3:7 (c 1.2, CHCl3).
(2S,6R)-8-(tert-Butyldiphenylsilyloxy)-6-(methoxyme-
thoxy)oct-2-yl acetate (11). A reaction solution of
alcohol 10 (3.45 g, 7.76 mmol) and 4-DMAP (10 mg,
0.082 mmol) in pyridine (3.5 ml) and acetic anhydride
(3.5 ml) was stirred at room temperature for 1 h before
addition of ice. The mixture was extracted with EtOAc.
The extract was washed with 1 M aq. HCl solution
and sat. aq. NaHCO3 solution, and brine, and dried
(Na2SO4). Concentration followed by silica gel column
chromatography (EtOAc/hexane ¼ 1=9) gave acetate
derivative 13 (1.68 g, 4.39 mmol, 57%) as a colorless oil.
20
20
11 (3.74 g, 7.68 mmol, 99%) as a colorless oil. ½ꢀꢂ
¼
½ꢀꢂ
¼ þ16 (c 1.4, CHCl3). NMR ꢁH (CDCl3): 1.04
D
D
ꢁ4:7 (c 1.7, CHCl3). NMR ꢁH (CDCl3): 1.05 (9H, s,
tert-Bu), 1.20 (3H, d, J 5.9 Hz, 1-H3), 1.36 (2H, m),
(9H, s, tert-Bu), 1.15 (3H, d, J 5.9 Hz, CH3), 1.44–1.57
(5H, m), 1.65–1.81 (3H, m), 3.41 (1H, m, 6-H), 3.53

716
S. MORI et al.
(1H, m, 2-H), 3.72 (1H, m, CHHOTBDPS), 3.85 (1H, m,
CHHOTBDPS), 7.35–7.43 (6H, m, ArH), 7.66–7.73
(4H, m, ArH). NMR ꢁC (CDCl3): 19.2, 22.2, 23.8, 26.8,
31.5, 33.4, 39.4, 60.3, 73.7, 74.3, 127.53, 127.55, 129.4,
134.1, 135.5. IR ꢂmax (CHCl3): 3023, 1215, 1111,
mixture was stirred in ice-bath for 2 h, H2O and CH2Cl2
were added. The organic solution was separated, washed
with brine, and dried (Na2SO4). Concentration followed
by silica gel column chromatography (50% ether in
petroleum ether) gave carboxylic acid 1 (0.25 g, 1.58
20
1082 cmꢁ1. Anal. Found C, 75.48; H, 9.04. Calcd. for
mmol, 84%) as a colorless oil. ½ꢀꢂ
¼ þ20:2 (c 1.8,
D
20
31
C24H34O2Si: C, 75.34; H, 8.97%. (2R,6R)-13, ½ꢀꢂ
¼
CHCl3). ½ꢀꢂ
¼ þ20:5 (c 1.23, CHCl3) in the lit.12)
D
D
ꢁ16 (c 1.1, CHCl3).
The NMR data agreed with those in the literature.12)
20
(2R,6R)-1, ½ꢀꢂ
¼ ꢁ20:0 (c 1.5, CHCl3).
D
2-[(2S,6S)-(6-Methyltetrahydropyran-2-yl)]ethanol
(14). To an ice-cooled solution of silyl ether 13 (1.30 g,
3.40 mmol) in THF (2 ml) was added (n-Bu)4NF
(3.73 ml, 1 M in THF, 3.73 mmol). After the reaction
solution was stirred at room temperature for 1 h, sat. aq.
NH4Cl solution and EtOAc were added. The organic
solution was separated, washed with brine, dried
(Na2SO4), and concentrated. The residue was applied
to silica gel column chromatography (ether/petroleum
Acknowledgment
We measured the 400 MHz NMR data at INCS,
Ehime University. We are grateful to Marutomo Co. for
financial support.
References
ether = 1/1) to give alcohol 14 (0.39 g, 2.70 mmol,
20
1) Maurer, B., Grieder, A., and Thommen, W., (cis-6-
Methyltetrahydropyran-2-yl)acetic acid, a novel com-
pound from civet (Viverra civetta). Helv. Chim. Acta, 62,
44–47 (1979).
2) Jones, J. B., and Hinks, R. S., Enzymes in organic
synthesis 36. Synthesis of optically active civet constit-
uent from an enzyme-generated chiral synthon. Can. J.
Chem., 65, 704–707 (1987).
3) Keinan, E., Seth, K. K., and Lamed, R., Organic
synthesis with enzymes 3. TBDADH-catalyzed reduc-
tion of chloro ketones. Total synthesis of (+)-(S,S)-(cis-
6-methyltetrahydropyran-2-yl)acetic acid: a civet con-
stituent. J. Am.Chem. Soc., 108, 3474–3480 (1986).
4) Yamauchi, S., Mori, S., Hirai, Y., and Kinoshita, Y.,
Syntheses of (+)- and (ꢁ)-dihydropinidine and (+)- and
(ꢁ)-epidihydropinidine by using yeast reduction of
methyl (2-oxocyclohexyl)acetate. Biosci. Biotechnol.
Biochem., 68, 676–684 (2004).
5) Ganaha, M., Funabiki, Y., Motoki, M., Yamauchi, S.,
and Kinoshita, Y., Reduction of alkyl (2-oxocyclohex-
yl)acetates by baker’s yeast. Biosci. Biotechnol. Bio-
chem., 62, 181–184 (1998).
6) Evans, D. A., Morrisey, M. M., and Dorow, R. L.,
Asymmetric oxygenation of chiral imide enolates. A
general approach to the synthesis of enantiomerically
pure ꢀ-hydroxy carboxylic acid synthons. J. Am. Chem.
Soc., 107, 4346–4348 (1985).
80%) as a colorless oil. ½ꢀꢂ
¼ þ24:2 (c 1.8, CHCl3),
D
20
½ꢀꢂ
¼ þ24:6 in the literature.11) The NMR data
D
agreed with those of the literature.2) (2R,6R)-14,
20
½ꢀꢂ
¼ ꢁ24:1 (c 0.5, CHCl3).
D
Determination of the optical purity. To an ice-cooled
solution of (2S,6S)-alcohol 14 (24 mg, 0.17 mmol) and
4-DMAP (1 mg) in pyridine (0.5 ml) was added (S)-
Mosher’s acid chloride (37 ml, 51 mg, 0.20 mmol). The
resulting reaction mixture was stirred at room temper-
ature for 16 h before additions of CH2Cl2 and H2O. The
organic solution was separated, washed with 1 M aq. HCl
solution, sat. aq. NaHCO3 solution and brine, and dried
(Na2SO4). After concentration, the residue was applied
to a short silica gel column (EtOAc/hexane = 1/5) to
give the (S)-Mosher ester of (2S,6S)-alcohol 14 in
quantitative yield. NMR ꢁH (CDCl3): 1.10–1.20 (2H, m),
1.14 (3H, d, J 6.4 Hz), 1.42–1.57 (3H, m), 1.75–1.88
(3H, m), 3.26–3.38 (2H, m), 3.55 (3H, s), 4.39 (1H, m),
4.48 (1H, m), 7.40–7.42 (3H, m), 7.51–7.53 (2H, m).
NMR ꢁC (CDCl3): 22.0, 23.5, 31.2, 33.1, 35.0, 55.3,
63.4, 73.80, 73.83, 127.2, 127.3, 128.3, 128.4, 129.5,
129.6, 166.5. The HPLC analysis with an OD-H chiral
column (0.2% 2-propanol/hexane, 1 ml/min, detected at
260 nm) gave a retention time of 7.8 min. (S)-Mosher
ester of (2R,6R)-alcohol 14: NMR ꢁH (CDCl3): 1.10–
1.22 (2H, m), 1.15 (3H, d, J 6.4 Hz), 1.38–1.60 (3H, m),
1.75–1.86 (3H, m), 3.29–3.39 (2H, m), 3.56 (3H, s),
4.39–4.49 (2H, m), 7.39–7.41 (3H, m), 7.50–7.55 (2H,
m); NMR ꢁC (CDCl3): 22.0, 23.5, 31.2, 33.1, 34.9, 55.3,
63.3, 73.7, 73.8, 127.2, 128.3, 129.5, 132.4, 166.5. An
HPLC analysis with an OD-H chiral column (0.2% 2-
propanol/hexane, 1 ml/min, detected at 260 nm) gave a
retention time of 7.4 min.
7) Vedejs, E., and Larsen, S., Hydroxylation of enolates
with oxodiperoxymolybdenum(pyridine) (hexamethyl-
. .
phosphoric triamide), MoO5 Py HMPA (MoOPH): 3-
hydroxy-1,7,7-trimethylbicyclo[2.2.1]heptan-2-one. Org.
Synth. Coll. Vol. VII, 277–282 (1990).
8) Hanessian, S., Delorme, D., and Dufresne, Y., Mild
cleavage of methoxymethyl (MOM) ethers with trimeth-
ylsilyl bromide. Tetrahedron Lett., 25, 2515–2518
(1984).
9) Mandai, T., Ueda, M., Kashiwagi, K., Kawada, M.,
and Tsuji, J., A highly steroselective synthetic method
for cis-2-hydroxy-6-alkyltetrahydrofurans. Tetrahedron
Lett., 34, 111–114 (1993).
(2S,6S)-(6-Methyltetrahydropyran-2-yl)acetic acid
(1). To an ice-cooled solution of alcohol 14 (0.27 g,
1.87 mmol) in acetone (2 ml) was added Jones reagent
until the color turned to orange. After the reaction
10) Ishihara, K., Mori, A., and Yamamoto, H., Stereo-
selective reduction of acetals. A method for reductive
generation of heterocyclic ring systems. Tetrahedron,

Synthesis of a Glandular Secretion of the Civet Cat
717
46, 4595–4612 (1990).
lective oxygen to carbon rearrangements of anomerically
linked enol ethers and the total synthesis of (+)-(S,S)-
(cis-6-methyltetrahydropyran-2-yl)acetic acid, a compo-
nent of civet. J. Chem. Soc., Perkin Trans. 1, 2385–2394
(2000).
11) Masaki, Y., Serizawa, Y., Nagata, K., and Kaji, K.,
Enantiospecific synthesis of natural (+)-(S,S)-(cis-6-
methyltetrahydropyran-2-yl)acetic acid, a constituent of
civet. Chem. Lett., 1601–1602 (1983).
12) Dixon, D. J., Ley, S. V., and Tate, E. W., Diastereose-