Syntheses of (+)- and (-)-dihydropinidine and (+)- and (-)- epidihydropinidine by using yeast reduction of methyl (2-oxocyclohexyl)acetate

Article abstract of DOI:10.1271/bbb.68.676

(+) and (-)-Dihydropinidine and (+)- and (-)-epidihydropinidine were synthesized from hydroxy esters 1 and 2 which had been prepared by yeast reduction of methyl (2-oxocyclohexyl)acetate. The enantiomeric excess at the C-1 positions of 1 and 2 were both d

Full text of DOI:10.1271/bbb.68.676

This article was downloaded by: [Oakland University]
On: 25 November 2014, At: 12:31
Publisher: Taylor & Francis
Informa Ltd Registered in England and Wales Registered Number: 1072954 Registered office: Mortimer
House, 37-41 Mortimer Street, London W1T 3JH, UK
Bioscience, Biotechnology, and Biochemistry
Publication details, including instructions for authors and subscription information:
http://www.tandfonline.com/loi/tbbb20
Syntheses of (+)- and (-)-Dihydropinidine and (+)-
and (-)-Epidihydropinidine by Using Yeast Reduction
of Methyl (2-oxocyclohexyl)acetate
Satoshi YAMAUCHIa, Shunji MORIa, Yoshio HIRAIa & Yoshiro KINOSHITAa
a Faculty of Agriculture, Ehime University
Published online: 22 May 2014.
To cite this article: Satoshi YAMAUCHI, Shunji MORI, Yoshio HIRAI & Yoshiro KINOSHITA (2004) Syntheses of (+)- and
(-)-Dihydropinidine and (+)- and (-)-Epidihydropinidine by Using Yeast Reduction of Methyl (2-oxocyclohexyl)acetate,
Bioscience, Biotechnology, and Biochemistry, 68:3, 676-684, DOI: 10.1271/bbb.68.676
To link to this article: http://dx.doi.org/10.1271/bbb.68.676
PLEASE SCROLL DOWN FOR ARTICLE
Taylor & Francis makes every effort to ensure the accuracy of all the information (the “Content”) contained
in the publications on our platform. However, Taylor & Francis, our agents, and our licensors make no
representations or warranties whatsoever as to the accuracy, completeness, or suitability for any purpose of
the Content. Any opinions and views expressed in this publication are the opinions and views of the authors,
and are not the views of or endorsed by Taylor & Francis. The accuracy of the Content should not be relied
upon and should be independently verified with primary sources of information. Taylor and Francis shall
not be liable for any losses, actions, claims, proceedings, demands, costs, expenses, damages, and other
liabilities whatsoever or howsoever caused arising directly or indirectly in connection with, in relation to or
arising out of the use of the Content.
This article may be used for research, teaching, and private study purposes. Any substantial or systematic
reproduction, redistribution, reselling, loan, sub-licensing, systematic supply, or distribution in any
form to anyone is expressly forbidden. Terms & Conditions of access and use can be found at http://
www.tandfonline.com/page/terms-and-conditions

Biosci. Biotechnol. Biochem., 68 (3), 676–684, 2004
Syntheses of (+)- and (À)-Dihydropinidine and (+)- and (À)-Epidihydropinidine
by Using Yeast Reduction of Methyl (2-oxocyclohexyl)acetate
Satoshi YAMAUCHI,y Shunji MORI, Yoshio HIRAI, and Yoshiro KINOSHITA
Faculty of Agriculture, Ehime University, 3-5-7 Tarumi, Matsuyama, Ehime 790-8566, Japan
Received October 16, 2003; Accepted November 20, 2003
(+) and (À)-Dihydropinidine and (+)- and (À)-
epidihydropinidine were synthesized from hydroxy
esters 1 and 2 which had been prepared by yeast
reduction of methyl (2-oxocyclohexyl)acetate. The enan-
tiomeric excess at the C-1 positions of 1 and 2 were both
determined as more than 99% ee.
dropinidine, only two synthetic pathways to (+)-epidi-
hydropinidine have been reported.7,8) However, these
seems to have been no synthetic research of (ꢀ)-
epidihydropinidine. This article describes the syntheses
of (+)- and (ꢀ)-dihydropinidine and (+)- and (ꢀ)-
epidihydropinidine by using yeast reduction of methyl
(2-oxocyclohexyl)acetate. This is a first approach to get
both the (+) and (ꢀ) isomers of dihydropinidine and
epidihydropinidine from one racemic compound by
employing baker’s yeast. This is also the first synthetic
report on (ꢀ)-epidihydropinidine.
Key words: dihydropinidine; epidihydropinidine; yeast
reduction
Yeast reduction of methyl (2-oxocyclohexyl)acetate,
which gives hydroxy ester 1 (98% ee) and 2 (97%ee),
has been previously reported (Fig. 1).1) The purpose of
this work is to recheck the enantiomeric excess at the C-
1 positions of 1 and 2 and to apply these yeast-mediated
reduction products to the syntheses of natural products.
Ring opening of 1 and 2 would give useful chiral
synthons.
The synthetic plan is shown in Scheme 1. The
piperidine ring of (ꢀ)-3 and (+)-4 would be formed by
SN2 cyclization of 5 and 7, respectively. Compounds 6
and 8 could be respectively transformed to 5 and 7 via
stereoselective ꢀ-hydroxylation followed by SN2 con-
version to an amino group. Both compounds 6 and 8
would be obtained from lactone 9 by ring opening and
C–C bond elongation. Lactone 9 could be obtained from
yeast-mediated reduction product 1, and (+)-dihydropi-
nidine (3) and (ꢀ)-epidihydropinidine (4) could be
synthesized from yeast-mediated reductive product 2.
The C-1 positions of 1 and 2 would be respectively
converted to the C-6 positions of 3 and 4. This means
that the values for the enantiomeric excess at the C-6
positions of 3 and 4 would depend on that at the C-1
positions of 1 and 2. The chiral center at the C-2
positions of 3 and 4 would be introduced by using
Evans’s chiral auxiliaries.9)
(+)- and (ꢀ)-Dihydropinidine (3) and (+)- and (ꢀ)-
epidihydropinidine (4) were selected as the target
compounds. Dihydropinidine was isolated from the
Mexican bean beetle, Epilachna varivestis,2) and epi-
dihydropinidine was isolated from Pinus engelmannii.3)
Many reports of syntheses of (+)- and (ꢀ)-dihydropi-
nidine have been published, due to biological activity
(necrotoxic, hemolytic, phytotoxic, insecticidal, anti-
bacterial, and antifungal)4) of 2,6-disubstituted piperi-
dine. Two of these employed the enzymatic pathway.5,6)
T. Momose et al. have obtained enantiomerically pure
starting materials to (+)- and (ꢀ)-dihydropinidine.5) R.
ˆ
Chenevert et al. have obtained only (+)-dihydropinidine
Results and Discussion
from the enantiomerically pure starting material.6) In
both these reports, lipase has been employed to produce
enantiomerically pure material. In the case of epidihy-
Hydroxy ester 1 was subjected to LiAlH4 reduction
followed by protection of the resulting primary hydroxy
Fig. 1.
y
To whom correspondence should be addressed. Fax: +81-89-977-4364; E-mail: syamauch@agr.ehime-u.ac.jp

(+)- and (ꢀ)-Dihydropinidine and (+)- and (ꢀ)-Epidihydropinidine
677
Scheme 1. Retrosynthetic Analyses of Optically Active Dihydropinidine and Epidihydropinidine.
group as a TBDPS ether by using TBDPSCl and
imidazole (53% yield, 2 steps). After PCC oxidation
of cyclohexanol derivative 10 (95% yield), resulting
ketone 11 was converted to lactone 12 by Baeyer-
Villiger oxidation, employing MCPBA in a phosphate
buffer at pH 8 and CHCl3,10) in 98% yield.
The enantiomeric excess was determined after meth-
anolysis of this lactone 12. (R)-Hydroxy ester 13 was
reacted with (ꢀ)-menthyl chloroformate, and the prod-
uct was determined as being of more than 99% de by an
HPLC analysis. On the other hand, corresponding (S)-
hydroxy ester 13, which had been transformed from
yeast-mediated reduction product 2 by the same process,
was also determined as being of more than 99% de. It
became clear that the enantiomeric excess at the C-1
positions of yeast-mediated reduction products 1 and 2
were more than 99% ee, and that Baeyer-Villiger
oxidation had proceeded with complete retention of
the configuration.
After protecting of the secondary hydroxy group as an
MOM ether by using MOMCl and N,N-diisopropyl-
ethylamine in 95% yield, the silyl group was removed
by (n-Bu)4NF to give alcohol 15 in 94% yield. After
conversion to a tosylate (95% yield), C–C bond
elongation was accomplished by employing Me2CuLi,
giving 16 in 78% yield. Hydrolysis of 16 (98% yield)
followed by introduction of the S or R Evans’s chiral
auxiliary11) gave 18 in 93% yield and 25 in 97% yield,
respectively. The ꢀ-hydroxylation of 18 and 25 by using
MoOPH12) stereoselectively proceeded to give 19 (43%
yield, 17% recovered) and 26 (45% yield, 18%
recovered), respectively. In both reactions, 18 and 25
were recovered. The auxiliaries were reductively re-
moved by using LiBH4 to give glycols 20 (79% yield)
and 27 (84% yield), respectively. These glycols were
converted to monotosylates by using TsCl and pyridine,
which were subsequently treated with LiAlH4 to give 21
(66% yield, 2 steps) and 28 (73% yield, 2 steps),
respectively. After the secondary hydroxy groups had
been converted to mesylates by using MsCl and Et3N,
the resulting mesylates were treated with NaN3 to give
azides 22 (85% yield, 2 steps) and 29 (91% yield, 2
steps), respectively. To remove the MOM ethers, 22 and
29 were each treated with a diluted aqueous HCl
solution, giving alcohol 23 (95% yield) and 30 (95%
yield), respectively. After their conversion to mesylates,
SN2 cyclization was performed by treatment with Ph3P
in heated aqueous THF. The crude products were
respectively transformed to Cbz-form 24 (42% yield, 3
steps) and 31 (44% yield, 3 steps) by using CbzCl in an
aqueous K2CO3 solution and THF for purification.
Finally, removal of the Cbz groups by H2 and Pd(OH)2/
C followed by treatment with an aqueous HCl solution
gave (ꢀ)-3 (78% yield) and (+)-4 (98% yield),
respectively. By the same synthetic process, (+)-3 and
(ꢀ)-4 were respectively synthesized from yeast-medi-
ated reduction product 2 (Scheme 2).
The enantiomeric excess at the C-1 positions of yeast-
mediated reduction products 1 and 2 were determined as
more than 99% ee. (+)- and (ꢀ)-Dihydropinidine (3)
and (+)- and (ꢀ)-epidihydropinidine (4) were synthe-
sized from 1 and 2, (ꢀ)-epidihydropinidine being
synthesized for the first time. It was found that all four
optically active compounds (+)-3, (ꢀ)-3, (+)-4 and (ꢀ)-

678
S. YAMAUCHI et al.
Scheme 2. Syntheses of (ꢀ)-3 and (+)-4.
(a) (1) LiAlH4, ether, 0ꢁC, 1 h; (2) TBDPSCl, imidazole, r.t., 2 h (53%, 2 steps). (b) PCC, MS 4A, CH2Cl2, r.t., 15 h (95%). (c) MCPBA,
phosphate buffer pH 8, CHCl3, r.t., 14 h (98%). (d) K2CO3, MeOH, r.t., 1 h (98%). (e) MOMCl, N,N-(iso-Pr)2NEt, CH2Cl2, r.t., 15 h (95%). (f)
(n-Bu)4NF, THF, r.t., 2 h (94%). (g) (1) p-TsCl, pyridine, CH2Cl2, r.t., 12 h (95%); (2) Me2CuLi, ether, ꢀ40ꢁC, 2.5 h (78%). (h) 6 M aq. KOH,
EtOH, r.t., 2 h (98%). (i) Et3N, PivCl, lithium salt of (S)-4-benzyl-2-oxazolidinone, 0ꢁC, 30 min (93%). (j) Et3N, PivCl, lithium salt of (R)-4-
benzyl-2-oxazolidinone, 0ꢁC, 30 min (97%). (k) LDA, MoOPH, THF, ꢀ70ꢁC, 2 h (19: 43%, 26: 45%). (l) LiBH4, MeOH, THF, 0ꢁC, 2 h (20:
79%, 27: 84%). (m) (1) p-TsCl, pyridine, CH2Cl2, 0ꢁC, 5 h; (2) LiAlH4, THF, r.t., 2 h (21: 66%, 2 steps, 28: 73%, 2 steps). (n) (1) MsCl, Et3N,
CH2Cl2, r.t., 1.5 h; (2) NaN3, DMF, 100ꢁC, 1 h (22: 85%, 2 steps, 29: 91%, 2 steps). (o) 6 M aq. HCl solution, THF, r.t., 2 h (23: 95%, 30: 95%).
(p) (1) MsCl, Et3N, CH2Cl2, r.t., 1.5 h; (2) Ph3P, aq. THF, 50ꢁC, 60 h, and then 1 M aq. HCl solution; (3) CbzCl, 2 M aq. K2CO3 solution, THF,
r.t., 15 h (24: 42%, 3 steps, 31: 44%, 3 steps). (q) H2, 20% Pd(OH)2/C, EtOAc, ambient temperature, 1.5 h, and then 1 M aq. HCl solution ((ꢀ)-3:
78%, (+)-4: 98%).
4 could be synthesized from one racemic methyl (2-
oxocyclohexyl)acetate by using yeast reduction. The
utilization of yeast-mediated reduction products 1 and 2
is shown for the first time.
concentrated to give crude diol. A reaction solution of
crude diol, tert-butyldiphenylsilyl chloride (15.3 ml,
0.059 mol) and imidazole (8.01 g, 0.12 mol) in DMF
(2 ml) was stirred at room temperature for 2 h before
additions of sat. aq. NaHCO3 solution and ethyl acetate.
The organic solution was separated, washed with brine,
and dried (Na2SO4). After the organic solution was
concentrated, the residue was applied to silica gel
column chromatography (5% EtOAc in hexane) to give
Experimental
Melting point (mp) data are uncorrected. NMR data
were measured by a JNM-EX400 spectrometer, IR
spectra were determined with a Shimadzu FTIR-8100
spectrophotometer, FABMS data were measured with a
JMS-MS700V spectrometer, 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.
silyl ether 10 (11.7 g, 0.031 mol, 53%) as a colorless
20
oil, ½ꢀꢂ
¼ þ21 (c 0.5, CHCl3); ꢁmax (CHCl3)/cmꢀ1
D
3388, 2932, 1429, 1113, 1078, 1009; ꢂH (CDCl3) 0.90–
1.06 (2H, m), 1.06 (9H, s, tert-Bu), 1.10–1.28 (3H, m),
1.35 (1H, m), 1.50 (1H, m), 1.55–1.67 (1H, m), 1.70–
1.84 (2H, m), 2.01 (1H, m), 3.26 (1H, m, 1-H), 3.45 (1H,
s, OH), 3.68–3.79 (2H, m, CH2OTBDPS), 7.37–7.45
(6H, m, ArH), 7.67–7.69 (4H, m, ArH); ꢂC (CDCl3)
19.1, 24.9, 25.7, 26.8, 32.2, 35.1, 37.3, 44.3, 63.3, 74.7,
127.7, 129.7, 133.2, 135.6. Anal. Found: C, 75.09; H,
9.05. Calcd. for C24H34O2Si: C, 75.34; H, 8.96%.
(1S,2R)-2-[2-(tert-Butyldiphenylsilyloxy)ethyl]cyclo-
hexanol (10). To an ice-cooled suspension of LiAlH4
(2.04 g, 0.054 mol) in ether (20 ml) was added a solution
of trans-hydroxy ester 1 (10.1 g, 0.059 mol) in ether
(50 ml). After stirring at 0ꢁC for 1 h, sat. aq. MgSO4
solution and K2CO3 were added. The mixture was
stirred for 30 min before filtration. The filtrate was
(1S,2S)-2-[2-(tert-Butyldiphenylsilyloxy)ethyl]cyclo-
hexanol (1S,2S)-(10). By the same method as that
described for the preparation of (1S,2R)-10, the title

(+)- and (ꢀ)-Dihydropinidine and (+)- and (ꢀ)-Epidihydropinidine
679
compound was obtained from cis-hydroxy ester 2 as a
20
(R)-Methyl 8-tert-butyldiphenylsilyloxy-6-hydroxyoc-
tanoate (13). A reaction mixture of (R)-lactone 12
(22.7 g, 0.057 mol) and K2CO3 (7.91 g, 0.057 mol) in
MeOH (150 ml) was stirred at room temperature for 1 h
before concentration. The residue was dissolved in
EtOAc and H2O. The organic solution was separated,
washed with brine, and dried (Na2SO4). After the
organic solution was evaporated, the residue was applied
to silica gel column chromatography (EtOAc/hexane =
colorless oil in 80% yield. ½ꢀꢂ
¼ þ6:1 (c 1.6,
D
CHCl3). IR ꢁmax (CHCl3): 3400, 2934, 1429, 1111,
1075, 909, 824 cmꢀ1. NMR ꢂH (CDCl3): 1.05 (9H, s,
tert-Bu), 1.20–1.30 (1H, m), 1.32–1.47 (3H, m), 1.48–
1.57 (2H, m), 1.58–1.74 (4H, m), 1.75–1.82 (1H, m),
2.21 (1H, s, OH), 3.68 (1H, m, CHHOTBDPS), 3.74
(1H, m, CHHOTBDPS), 3.89 (1H, m, 1-H), 7.37–7.45
(6H, m, ArH), 7.66–7.68 (4H, m, ArH). NMR ꢂC
(CDCl3): 19.1, 20.7, 25.1, 26.8, 27.1, 32.7, 34.8, 39.0,
62.4, 69.1, 127.7, 129.7, 133.5, 133.6, 135.56, 135.59.
Anal. Found C, 75.13; H, 9.26. Calcd. for C24H34O2Si:
C, 75.34; H, 8.96%.
1/5) to give (R)-methyl ester 13 (23.8 g, 0.056 mol,
20
98%) as a colorless oil, ½ꢀꢂ
¼ þ7:2 (c 2.3, CHCl3).
D
IR ꢁmax (CHCl3): 3500, 2934. 1732, 1429, 1113,
1078 cmꢀ1. NMR ꢂH (CDCl3): 1.05 (9H, s, tert-Bu),
1.34–1.55 (4H, m), 1.60–1.75 (4H, m), 2.33 (2H, t, J
7.6 Hz, 2-H2), 3.26 (1H, s, OH), 3.66 (3H, s, OCH3),
3.80–3.92 (3H, m, 6-H, 8-H2), 7.38–7.46 (6H, m, ArH),
7.66–7.68 (4H, m, ArH). NMR ꢂC (CDCl3): 19.0, 25.0,
25.2, 26.8, 34.1, 37.1, 38.3, 51.5, 63.6, 71.6, 127.8,
129.8, 132.9, 133.0, 135.5, 135.6, 174.2. Anal. Found:
(R)-2-[2-(tert-Butyldiphenylsilyloxy)ethyl]cyclohexa-
none (11). A reaction mixture of alcohol 10 (23.5 g,
0.061 mol), PCC (14.6 g, 0.068 mol), and MS 4A (0.5 g)
in CH2Cl2 (300 ml) was stirred at room temperature for
15 h before addition of ether. After filtration, the filtrate
was concentrated. The residue was applied to silica gel
column chromatography (2% EtOAc in hexane) to give
C, 70.28; H, 8.76. Calcd. for C25H36O4Si: C, 70.05; H,
20
8.47%. (S)-13, ½ꢀꢂ
¼ ꢀ7:2 (c 1.8, CHCl3).
D
cyclohexanone derivative 11 (22.1 g, 0.058 mol, 95%) as
20
a colorless oil, ½ꢀꢂ
¼ þ1:0 (c 1.0, CHCl3). IR ꢁmax
Determination of the optical purity of the (R)- and
(S)-methyl esters (13). To an ice-cooled solution of (R)-
13 (28 mg, 0.065 mmol) in pyridine (50 ꢃl) was added
(ꢀ)-menthyl chloroformate (20.9 ꢃl, 0.098 mmol). After
the reaction mixture was stirred at room temperature for
1 h, H2O and EtOAc were added. The organic solution
was separated, washed with 0.5 M aq. HCl solution and
sat. aq. NaHCO3 solution, and brine, and dried
(Na2SO4). The organic solution was concentrated. The
residue was applied to HPLC (Merck, LiChrospher Si
60, 2% EtOAc in hexane, 2.0 ml/min, detected at 270
nm), retention time: 22 min, more than 99% de. Reaction
product of (S)-13 with (ꢀ)-menthyl chloroformate:
19 min, more than 99% de.
D
(CHCl3): 3021, 2934, 1705, 1429, 1217, 1113 cmꢀ1
.
NMR ꢂH (CDCl3): 1.04 (9H, s, tert-Bu), 1.25–1.43 (2H,
m), 1.60–1.68 (2H, m), 1.81 (1H, m), 1.98–2.10 (2H, m),
2.14 (1H, m), 2.26 (1H, m, 6-HH), 2.36 (1H, m, 6-HH),
2.52 (1H, m, 2-H), 3.70 (2H, t, J 6.1, Hz, CH2OTBDPS),
7.35–7.43 (6H, m, ArH), 7.63–7.66 (4H, m, ArH). NMR
ꢂC (CDCl3): 19.2, 25.1, 26.9, 28.1, 32.1, 34.0, 42.1, 47.1,
61.7, 127.6, 129.6, 133.9, 134.0, 135.5, 213.1. Anal.
Found: C, 75.71; H, 8.84. Calcd. for C24H32O2Si: C,
20
75.74; H, 8.48%. (S)-11, ½ꢀꢂ
¼ ꢀ0:9 (c 3.3, CHCl3).
D
(R)-8-(tert-Butyldiphenylsilyloxy)octan-6-olide (12).
A reaction mixture of (R)-ketone 11 (20.4 g, 0.054
mol) and MCPBA (16.4 g, 70%, 0.067 mol) in CHCl3
(200 ml) and phosphate buffer pH 8 (200 ml) was stirred
at room temperature for 14 h. After filtration, the filtrate
was washed with sat. aq. sodium thiosulfate solution,
sat. aq. NaHCO3 solution, and brine, and dried
(Na2SO4). The organic solution was evaporated, and
then the residue was applied to silica gel column
chromatography (5% EtOAc/hexane) to give lactone 12
(R)-Methyl 8-tert-butyldiphenylsilyloxy-6-methoxy-
methoxyoctanoate (14). A reaction mixture of (R)-
alcohol 13 (23.8 g, 0.056 mol), (iso-Pr)2EtN (38.7 ml,
0.22 mol), and MOMCl (8.43 ml, 0.11 mol) in CH2Cl2
(50 ml) was stirred at room temperature for 15 h before
additions of MeOH and H2O. The organic solution was
separated, washed with 1 M aq. HCl solution, sat. aq.
NaHCO3 solution, and brine, and dried (Na2SO4). The
organic solution was evaporated, and then the residue
was applied to silica gel column chromatography
(21.0 g, 0.053 mol, 98%) as colorless crystals, mp 60–
20
61ꢁC (petroleum ether), ½ꢀꢂ
¼ ꢀ40 (c 0.9, CHCl3).
D
IR ꢁmax (CHCl3): 3000, 2934, 1721, 1429, 1329, 1287,
1258, 1177, 1148, 1113, 1082, 1014 cmꢀ1. NMR ꢂH
(CDCl3): 1.05 (9H, s, tert-Bu), 1.52–1.68 (3H, m), 1.77
(1H, m), 1.87–1.98 (4H, m), 2.54 (1H, m, 2-HH), 2.65
(1H, m, 2-HH), 3.75 (1H, ddd, J 10.5, 4.9, 4.9 Hz, 8-
HH), 3.87 (1H, ddd, J 10.5, 8.6, 4.4 Hz, 8-HH), 4.54
(1H, m, 6-H), 7.36–7.44 (6H, m, ArH), 7.63–7.65 (4H,
m, ArH). NMR ꢂC (CDCl3): 19.2, 23.0, 26.9, 28.3, 34.5,
34.8, 39.0, 59.8, 77.0, 127.69, 127.72, 129.7, 133.5,
133.7, 135.5, 175.6. Anal. Found C, 73.02; H, 8.29.
(EtOAc/hexane = 1/7) to give (R)-MOM ether 14
20
(25.1 g, 0.053 mol, 95%) as a colorless oil, ½ꢀꢂ
¼
D
þ1:7 (c 1.2, CHCl3). IR ꢁmax (CHCl3): 3021, 1732,
1429, 1217, 1111, 1036 cmꢀ1. NMR ꢂH (CDCl3): 1.05
(9H, s, tert-Bu), 1.29–1.42 (2H, m), 1.48–1.53 (2H, m),
1.55–1.66 (2H, m), 1.70–1.75 (2H, m), 2.30 (2H, t, J
7.6 Hz, 2-H2), 3.31 (3H, s, OCH3), 3.66 (3H, s, OCH3),
3.71–3.79 (3H, m, 6-H, 8-H2), 4.58 (1H, d, J 6.8 Hz,
OCHHOCH3), 4.61 (1H, d, J 6.8 Hz, OCHHOCH3),
7.36–7.44 (6H, m, ArH), 7.64–7.67 (4H, m, ArH). NMR
ꢂC (CDCl3): 19.2, 24.8, 25.1, 26.9, 34.0, 34.4, 37.3, 51.4,
Calcd. for C24H32O3Si: C, 72.68; H, 8.13%. (S)-(12),
20
½ꢀꢂ
¼ þ40 (c 1.1, CHCl3).
D

680
S. YAMAUCHI et al.
55.5, 60.6, 74.7, 95.7, 127.6, 129.6, 133.9, 135.6, 174.1.
Anal. Found: C, 68.62; H, 8.42. Calcd. for C27H40O5Si:
Anal. Found: C, 61.80; H, 10.47. Calcd. for C12H24O4:
20
C, 62.04; H, 10.41%. (R)-16, ½ꢀꢂ
¼ þ4:9 (c 1.6,
D
20
C, 68.61; H, 8.53%. (S)-14, ½ꢀꢂ
¼ ꢀ1:6 (c 2.0,
CHCl3).
D
CHCl3).
(S)-6-Methoxymethoxynonanoic acid (17). A reaction
solution of (S)-ester 16 (10.1 g, 0.043 mol) in 6 M aq.
KOH solution (100 ml) and EtOH (100 ml) was stirred at
room temperature for 2 h before additions of CHCl3 and
6 M aq. HCl solution. The organic solution was sepa-
rated, washed with brine, and dried (Na2SO4). After the
organic solution was evaporated, the residue was applied
to silica gel column chromatography (EtOAc/hexane =
(R)-Methyl 8-hydroxy-6-methoxymethoxyoctanoate
(15). To an ice-cooled solution of silyl ether 14 (24.0
g, 0.051 mol) in THF (150 ml) was added (n-Bu)4NF
(0.056 ml, 1 M in THF, 0.056 mol). The reaction solution
was stirred at room temperature for 2 h before additions
of sat. aq. NH4Cl solution and EtOAc. The organic
solution was separated, washed with brine, and dried
(Na2SO4). After the mixture was concentrated, the
residue was applied to silica gel column chromatography
1/2) to give carboxylic acid 17 (9.17 g, 0.042 mol, 98%)
20
as a colorless oil; ½ꢀꢂ
¼ ꢀ3:9 (c 1.0, CHCl3). IR ꢁmax
D
(10% EtOAc in hexane) to give alcohol 15 (11.3 g,
20
(CHCl3): 3613, 2936, 1709, 1146, 1100, 1038. NMR ꢂH
(CDCl3): 0.92 (3H, t, J 7.3 Hz, 9-H3), 1.35–1.54 (8H,
m), 1.61–1.69 (2H, m), 2.36 (2H, t, J 7.3 Hz, 2-H2), 3.38
(3H, s, OCH3), 3.54 (1H, m, 6-H), 4.65 (2H, s,
OCH2OCH3). NMR ꢂC (CDCl3): 14.2, 18.5, 24.7,
24.8, 33.9, 36.5, 55.5, 77.1, 95.4, 179.4. FABMS m=z:
217 (Mþꢀ1, 10), 157 (100), 137 (70). HRMS (FAB)
0.048 mol, 94%) as a colorless oil; ½ꢀꢂ
¼ ꢀ50 (c 1.6,
D
CHCl3). IR ꢁmax (CHCl3): 3500, 2950, 1732, 1439,
1208, 1150, 1100, 1071, 1032 cmꢀ1. NMR ꢂH (CDCl3):
1.31–1.41 (2H, m), 1.49–1.72 (4H, m), 1.65–1.74 (2H,
m), 2.32 (2H, t, J 7.3 Hz, 2-H2), 2.43 (1H, br. s, OH),
3.40 (3H, s, OCH3), 3.67 (3H, s, OCH3), 3.71–3.79 (3H,
m, 6-H, 8-H2), 4.65 (1H, d, J 6.8 Hz, OCHHOCH3),
4.68 (1H, d, J 6.8 Hz, OCHHOCH3). NMR ꢂC (CDCl3):
24.7, 25.0, 33.9, 34.3, 36.6, 51.5, 55.7, 59.8, 76.2, 95.9,
m=z (Mþꢀ1): Calcd. for C11H21O4, 217.1439; found,
20
217.1441. (R)-17, ½ꢀꢂ
¼ þ3:8 (c 1.9, CHCl3).
D
174.0. Anal. Found: C, 56.06; H, 9.47. Calcd. for
20
(4S)-4-Benzyl-3-[(S)-6-methoxymethoxynonanoyl]-2-
oxazolidinone (18). To a solution of (S)-carboxylic acid
17 (6.57 g, 0.030 mol) and Et3N (4.41 ml, 0.032 mol) in
THF (150 ml) was added PivCl (3.89 ml, 0.032 mol) at
ꢀ70ꢁC. The mixture was stirred at 0ꢁC for 1 h before
cooling to ꢀ70ꢁC. To this mixture was added lithium
salt of (S)-4-benzyl-2-oxazolidinone, which was pre-
pared with (S)-4-benzyl-2-oxazolidinone (5.60 g, 0.032
mol) and n-BuLi (20.1 ml, 1.6 M in hexane, 0.032 mol) in
THF (150 ml) at ꢀ70ꢁC for 30 min. After the resulting
reaction mixture was stirred at 0ꢁC for 30 min, sat. aq.
NH4Cl solution was added. The organic solution was
separated, washed with brine, and dried (Na2SO4). The
organic solution was evaporated, and then the residue
was applied to silica gel column chromatography (10%
EtOAc in hexane) to give acyl oxazolidinone 18 (10.7 g,
C11H22O5: C, 56.39; H, 9.46%. (S)-15, ½ꢀꢂ
¼ þ50 (c
D
2.6, CHCl3).
(S)-Methyl 6-methoxymethoxynonanoate (16). A re-
action mixture of (R)-alcohol 15 (4.55 g, 0.019 mol), p-
TsCl (3.70 g, 0.019 mol) and pyridine (3.14 ml, 0.039
mol) in CH2Cl2 (8 ml) was stirred at room temperature
for 12 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). The organic solution was evaporated, and
then the residue was applied to silica gel column
chromatography (10% EtOAc in hexane) to give
unstable tosylate (7.15 g, 0.018 mol, 95%) as a colorless
oil. To a suspension of CuI (14.0 g, 0.074 mol) in ether
(15 ml) was added MeLi (66.9 ml, 2.2 M in ether,
0.15 mol) at ꢀ40ꢁC. After the mixture was stirred at
ꢀ40ꢁC for 2 h, tosylate (7.15 g, 0.018 mol) in ether
(20 ml) was added. The reaction mixture was stirred at
ꢀ40ꢁC for 2.5 h, and then sat. aq. NH4Cl solution and
ether were added. The organic solution was separated,
washed with brine, and dried (Na2SO4). After concen-
tration, the residue was purified with silica gel column
chromatography (10% EtOAc in hexane) to recover
0.028 mol, 93%) as colorless crystals, mp 60–61ꢁC (iso-
20
Pr2O); ½ꢀꢂ
¼ þ35 (c 1.0, CHCl3). IR ꢁmax (CHCl3):
D
2934, 1782, 1700, 1385, 1352, 1210, 1200, 1150, 1098,
1038 cmꢀ1. NMR ꢂH (CDCl3): 0.92 (3H, s, J 7.1 Hz,
CH3), 1.30–1.58 (8H, m), 1.62–1.74 (2H, m), 2.77 (1H,
dd, J 13.4, 9.5 Hz, PhCHH), 2.85–3.00 (2H, m,
O=CCH2), 3.34 (1H, dd, J 13.4, 3.1 Hz, PhCHH),
3.38 (3H, s, OCH3), 3.55 (1H, m, CHOMOM), 4.16 (1H,
dd, J 8.8, 3.4 Hz, 5-HH), 4.20 (1H, dd, J 8.8, 8.8 Hz, 5-
HH), 4.65 (2H, s, OCH2OCH3), 4.64–4.70 (1H, m, 4-H),
7.20–7.21 (2H, m, ArH), 7.27–7.29 (1H, m, ArH), 7.31–
7.35 (2H, m, ArH). NMR ꢂC (CDCl3): 14.3, 18.5, 24.4,
24.8, 34.1, 35.5, 36.6, 37.9, 55.5, 66.2, 77.1, 77.2, 95.4,
127.3, 128.9, 129.4, 135.3, 153.4, 173.2. Anal. Found:
tosylate (1.56 g, 0.0040 mol, 22%) and give (S)-16
20
(3.21 g, 0.014 mol, 78%) as a colorless oil; ½ꢀꢂ
¼
D
ꢀ4:9 (c 1.0, CHCl3). IR ꢁmax (CHCl3): 2936, 1732,
1466, 1458, 1439, 1213, 1169, 1148, 1100, 1038. NMR
ꢂH (CDCl3): 0.92 (3H, t, J 7.1 Hz, 9-H3), 1.30–1.53 (8H,
m), 1.60–1.68 (2H, m), 2.32 (2H, t, J 7.3 Hz, 2-H2), 3.37
(3H, s, OCH3), 3.53 (1H, m, 6-H), 3.67 (3H, s, OCH3),
4.64 (2H, s, OCH2OCH3). NMR ꢂC (CDCl3): 14.2, 18.5,
24.8, 25.1, 33.9, 34.0, 36.5, 51.4, 55.5, 77.1, 95.4, 174.1.
C, 66.75; H, 8.19; N, 3.44. Calcd. for C21H31O5N: C,
20
66.82; H, 8.28; N, 3.71%. (4R)-[(R)]-(18), ½ꢀꢂ
¼ ꢀ35
D
(c 1.9, CHCl3).

(+)- and (ꢀ)-Dihydropinidine and (+)- and (ꢀ)-Epidihydropinidine
681
(4S)-4-Benzyl-3-[(2S,6S)-2-hydroxy-6-methoxymeth-
oxynonanoyl]-2-oxazolidinone (19). To a solution of
(4S)-[(S)]-18 (10.7 g, 0.028 mol) in THF (300 ml) was
added KHMDS (84.9 ml, 0.5 M in toluene, 0.042 mol) at
ꢀ70ꢁC. After stirring at ꢀ70ꢁC for 30 min, MoOPH
(18.5 g, 0.043 mol) was added. The reaction mixture was
stirred at ꢀ70ꢁC for 2 h, and then sat. aq. Na2SO3
solution was added. The organic solution was separated,
washed with 1 M aq. HCl solution, sat. aq. NaHCO3
solution, and brine, and dried (Na2SO4). After evapo-
ration, the residue was applied to silica gel column
chromatography (10% EtOAc in hexane) to give (4S)-
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). After
evaporation, the residue was applied to silica gel column
chromatography (5% EtOAc in toluene) to give unstable
tosylate (1.62 g, 4.33 mmol, 71%) as a colorless oil. To
an ice-cooled suspension of LiAlH4 (0.32 g, 8.43 mmol)
in THF (10 ml) was added tosylate (1.60 g, 4.27 mmol)
in THF (20 ml). The reaction mixture was stirred at
room temperature for 2 h before additions of sat. aq.
MgSO4 and K2CO3. After filtration, the filtrate was
concentrated. The residue was applied to silica gel
column chromatography (10% EtOAc in hexane) to give
[(2S,6S)]-19 (4.72 g, 0.012 mol, 43%) as a colorless oil;
20
½ꢀꢂ
¼ þ32 (c 1.1, CHCl3). IR ꢁmax (CHCl3)/cmꢀ1
(2R,6S)-21 (0.81 g, 3.96 mmol, 93%) as a colorless oil;
20
D
3500, 2934, 1788, 1694, 1385, 1352, 1298, 1213, 1198,
1150, 1111, 1098, 1038, 912 cmꢀ1. NMR ꢂH (CDCl3):
0.92 (3H, t, J 7.3 Hz, CH3), 1.30–1.70 (9H, m), 1.82
(1H, m), 2.84 (1H, dd, J 13.7, 9.3 Hz, PhCHH), 3.31
(1H, dd, J 13.7, 3.2 Hz, PhCHH), 3.38 (3H, s, OCH3),
3.47 (1H, d, J 8.3 Hz, OH), 3.55 (1H, m, CHOMOM),
4.25 (1H, dd, J 9.3, 2.9 Hz, 5-HH), 4.28 (1H, dd, J 9.3,
9.3 Hz, 5-HH), 4.65 (2H, s, OCH2OCH3), 4.65–4.69
(1H, m, 4-H), 5.00 (1H, m, O=CCHOH), 7.20–7.22
(2H, m, ArH), 7.29–7.31 (1H, m, ArH), 7.33–7.36 (2H,
m, ArH). NMR ꢂC (CDCl3): 14.2, 18.5, 21.1, 33.9, 34.3,
36.6, 37.5, 55.5, 66.9, 70.6, 70.8, 77.2, 95.5, 127.5,
129.0, 129.4, 134.8, 153.2, 174.9. Anal. Found: C,
½ꢀꢂ
¼ ꢀ8:1 (c 0.7, CHCl3). IR ꢁmax (CHCl3): 3500,
D
2936, 1458, 1379, 1142, 1098, 1038. NMR ꢂH (CDCl3):
0.92 (3H, t, J 7.3 Hz, 9-H3), 1.19 (3H, d, J 5.9 Hz, 1-H3),
1.26–1.56 (10H, m), 1.60–1.79 (1H, br., OH), 3.38 (3H,
s, OCH3), 3.55 (1H, m, 6-H), 3.81 (1H, m, 2-H), 4.65
(2H, s, OCH2OCH3). NMR ꢂC (CDCl3): 14.2, 18.5,
21.3, 23.5, 34.2, 36.5, 39.4, 55.5, 68.0, 77.3, 95.4.
FABMS m=z: 205 (Mþ+1, 100), 198 (50). HRMS
(FAB) m=z (Mþ+1): Calcd. for C11H25O3, 205.1804;
20
found, 205.1801. (2S,6R)-21, ½ꢀꢂ
¼ þ8:0 (c 1.4,
D
CHCl3).
(2S,6S)-2-Azido-6-methoxymethoxynonane (22). To a
solution of (2R,6S)-alcohol 21 (0.81 g, 3.96 mmol) and
Et3N (0.61 ml, 4.38 mmol) in CH2Cl2 (5 ml) was added
MsCl (0.34 ml, 4.39 mmol). The reaction mixture was
stirred at room temperature for 1.5 h before additions of
H2O and CH2Cl2. The organic solution was separated,
washed with brine, and dried (Na2SO4). After concen-
tration, the residue was purified with silica gel column
chromatography (EtOAc/hexane = 1/4) to give unsta-
ble mesylate (1.00 g, 3.54 mmol, 89%) as a colorless oil.
A reaction solution of mesylate (1.00 g, 3.54 mmol) and
NaN3 (0.46 g, 7.08 mmol) in DMF (1 ml) was stirred at
100ꢁC for 1 h before additions of H2O and EtOAc. The
organic solution was separated, washed with brine, and
dried (Na2SO4). The solvent was evaporated. The
residue was applied to silica gel column chromatography
64.04; H, 7.91; N, 3.63. Calcd. for C21H31O6N: C,
20
64.10; H, 7.94; N, 3.56%. (4R)-[(2R,6R)]-19, ½ꢀꢂ
¼
D
ꢀ32 (c 1.5, CHCl3).
(2S,6S)-6-Methoxymethoxynonane-1,2-diol (20). To
an ice-cooled solution of (4S)-[(2S,6S)]-acyl oxazolidi-
none 19 (3.01 g, 7.65 mmol) and MeOH (1.24 ml,
30.6 mmol) in THF (80 ml) was added LiBH4 (0.83 g,
38.1 mmol). The resulting mixture was stirred at 0ꢁC for
2 h before addition of sat. aq. NH4Cl solution. The
organic solution was separated, washed with brine, and
dried (Na2SO4). After concentration of the solvent, the
residue was applied to silica gel column chromatography
(EtOAc/toluene = 1/4) to give (2S,6S)-glycol 20 (1.34
20
g, 6.08 mmol, 79%) as a colorless oil; ½ꢀꢂ
¼ þ6:8 (c
D
1.1, CHCl3). IR ꢁmax (CHCl3): 3500, 2936, 1460, 1148,
1134, 1096, 1038 cmꢀ1. NMR ꢂH (CDCl3): 0.92 (3H, t, J
7.3 Hz, 9-H3), 1.25–1.56 (10H, m), 2.36 (1H, br. s, OH),
2.49 (1H, br. s, OH), 3.38 (3H, s, OCH3), 3.44 (1H, dd, J
10.7, 7.3 Hz, 1-HH), 3.55 (1H, m, 6-H), 3.65 (1H, dd, J
10.7, 2.9 Hz, 1-HH), 3.70 (1H, m, 2-H), 4.65 (2H, s,
OCH2OCH3). NMR ꢂC (CDCl3): 14.2, 18.5, 21.1, 33.2,
34.2, 36.6, 55.5, 66.7, 72.1, 95.5. Anal. Found: C, 59.69;
(5% EtOAc in hexane) to give (2S,6S)-azide 22 (0.78 g,
20
3.40 mmol, 96%) as a colorless oil; ½ꢀꢂ
¼ þ30 (c 1.0,
D
CHCl3). IR ꢁmax (CHCl3): 2936, 2103, 1458, 1381,
1262, 1238, 1144, 1096, 1038 cmꢀ1. NMR ꢂH (CDCl3):
0.92 (3H, t, J 6.8 Hz, 9-H3), 1.25 (3H, d, J 6.3 Hz, 1-H3),
1.26–1.60 (10H, m), 3.38 (3H, s, OCH3), 3.42 (1H, m, 2-
H), 3.52 (1H, m, 6-H), 4.65 (2H, s, OCH2OCH3). NMR
ꢂC (CDCl3): 14.2, 18.5, 19.4, 21.9, 34.1, 36.4, 36.6, 55.5,
58.0, 77.1, 95.5. Anal. Found: C, 57.65; H, 10.12; N,
H, 11.01. Calcd. for C11H24O4: C, 59.97; H, 10.98%.
20
(2R,6R)-20, ½ꢀꢂ
¼ ꢀ6:9 (c 1.9, CHCl3).
18.21. Calcd. for C11H23O2N3: C, 57.61; H, 10.11; N,
20
D
18.32%. (2R,6R)-22, ½ꢀꢂ
¼ ꢀ30 (c 1.7, CHCl3).
D
(2R,6S)-6-Methoxymethoxy-2-nonanol (21). To an
ice-cooled solution of (2S,6S)-glycol 20 (1.34 g, 6.08
mmol) and pyridine (0.98 ml, 12.1 mmol) in CH2Cl2
(1 ml) was added p-TsCl (1.16 g, 6.08 mmol). The
reaction mixture was stirred at 0ꢁC for 5 h before
(4S,8S)-8-Azido-4-nonanol (23). To a solution of
(2S,6S)-22 (0.78 g, 3.40 mmol) in THF (17 ml) was
added 6 M aq. HCl solution (17 ml). The reaction
solution was stirred at room temperature for 2 h before

682
S. YAMAUCHI et al.
additions of H2O and EtOAc. The organic solution was
separated, washed with NaHCO3 and brine, and dried
(Na2SO4). After the solvent was concentrated, the
residue was purified with silica gel column chromatog-
tion mixture of (2S,6R)-24 (0.34 g, 1.23 mmol) and 20%
Pd(OH)2/C (350 mg) in EtOAc (10 ml) was stirred
under H2 gas at the ambient temperature for 1.5 h before
filtration. To the filtrate was added 1 M aq. HCl solution
and ether. The acidic aqueous solution was separated
and concentrated to give (2S,6R)-3 (0.17 g, 0.96 mmol,
raphy (5% EtOAc in hexane) to give (4S,8S)-alcohol 23
20
(0.60 g, 3.24 mmol, 95%) as a colorless oil; ½ꢀꢂ
¼
D
þ39 (c 0.8, CHCl3). IR ꢁmax (CHCl3): 3125, 2934, 2105,
1458, 1381, 1329, 1262, 1238, 1119, 1021 cmꢀ1. NMR
ꢂH (CDCl3): 0.93 (3H, t, J 7.1 Hz, 1-H3), 1.26 (3H, d, J
6.4 Hz, 9-H3), 1.30–1.58 (10H, m), 1.60 (1H, s, OH),
3.44 (1H, m, 8-H), 3.61 (1H, m, 4-H). NMR ꢂC (CDCl3):
14.1, 18.8, 19.4, 22.3, 36.2, 37.1, 39.7, 58.0, 71.5. Anal.
Found: C, 58.30; H, 10.40; N, 22.58. Calcd. for
78%) as colorless crystals, mp 239–240ꢁC (EtOH-
20
EtOAc); ½ꢀꢂ
¼ ꢀ13 (c 0.075, EtOH), lit,13) mp
D
20
245ꢁC, ½ꢀꢂ
¼ ꢀ12:71 (c 1.14, EtOH). NMR data
D
20
was agreed with that of literature. (2R,6S)-3, ½ꢀꢂ
¼
D
20
þ13 (c 1.12, EtOH) [lit,9) ½ꢀꢂ
¼ þ14:2 (c 1.05,
D
EtOH)].
C9H19ON3: C, 58.35; H, 10.34; N, 22.68%. (4R,8R)-
20
(R)-4-Benzyl-3-[(S)-6-methoxymethoxynonanoyl]-2-
20
23, ½ꢀꢂ
¼ ꢀ39 (c 1.7, CHCl3).
oxazolidinone (25). 97% yield. ½ꢀꢂ
¼ ꢀ49 (c 1.5,
D
D
CHCl3). IR ꢁmax (CHCl3): 2905, 1782, 1701, 1385,
1352, 1233, 1198, 1098, 1038 cmꢀ1. NMR ꢂH (CDCl3):
0.92 (3H, t, J 7.1 Hz, CH3), 1.31–1.58 (8H, m), 1.68–
1.76 (2H, m), 2.77 (1H, dd, J 13.2, 9.5 Hz, PhCHH),
2.91 (1H, ddd, J 16.6, 8.3, 6.4 Hz, O=CCHH), 2.99 (1H,
ddd, J 16.6, 8.3, 6.4 Hz, O=CCHH), 3.30 (1H, dd, J
13.2, 3.4 Hz, PhCHH), 3.38 (3H, s, OCH3), 3.56 (1H, m,
CHOMOM), 4.16 (1H, dd, J 9.3, 2.9 Hz, 5-HH), 4.20
(1H, dd, J 9.3, 9.3 Hz, 5-HH), 4.65 (2H, s, OCH2OCH3),
4.64–4.70 (1H, m, 4-H), 7.20–7.21 (2H, m, ArH), 7.25–
7.29 (1H, m, ArH), 7.32–7.35 (2H, m, ArH). NMR ꢂC
(CDCl3) 14.2, 18.5, 24.4, 24.8, 34.1, 35.5, 36.6, 37.9,
55.1, 55.5, 66.1, 77.1, 95.4, 127.3, 128.9, 129.4, 135.3,
153.4, 173.2. Anal. Found: C, 66.91; H, 8.12; N, 3.66.
(2S,6R)-1-Benzyloxycarbonyl-2-methyl-6-propylpipe-
ridine (24). To an ice-cooled solution of (4S,8S)-alcohol
23 (0.60 g, 3.24 mmol) and Et3N (0.50 ml, 3.59 mmol) in
CH2Cl2 (2 ml) was added MsCl (0.28 ml, 3.62 mmol).
After the reaction mixture was stirred at room temper-
ature for 1.5 h, H2O and CH2Cl2 were added. The
organic solution was separated, washed with brine, and
dried (Na2SO4). After concentration, the residue was
applied to silica gel column chromatography (EtOAc/
hexane = 1/7) to give unstable mesylate (0.82 g,
3.11 mmol, 96%) as a colorless oil. A reaction solution
of mesylate (0.82 g, 3.11 mmol), Ph3P (0.90 g,
3.43 mmol), and H2O (0.4 ml) in THF (40 ml) was
stirred at 50ꢁC for 60 h before additions of 1 M aq. HCl
solution and ether. To the aqueous solution was added
3 M aq. NaOH solution. The resulting alkaline aqueous
solution was extracted with ether, and then the ether
solution was treated with 1 M aq. HCl solution. The
acidic aqueous solution was concentrated. To an ice-
cooled mixture of the residue in THF (5 ml) and 2 M aq.
K2CO3 solution (4 ml) was added CbzCl (0.57 ml,
3.99 mmol). The reaction mixture was stirred at room
temperature for 15 h before additions of 10% aq.
NaHSO4 solution and EtOAc. The organic solution
was separated, washed with sat. aq. NaHCO3 solution
and brine, and dried (Na2SO4). After concentration, the
residue was purified with silica gel column chromatog-
raphy (2% EtOAc in hexane) to give (2S,6R)-24 (0.38 g,
Calcd. for C21H31O5N: C, 66.82; H, 8.28; N, 3.71%. (S)-
20
[(R)]-25, ½ꢀꢂ
¼ þ49 (c 1.2, CHCl3).
D
(R)-4-Benzyl-3-[(2R,6S)-2-hydroxy-6-methoxymeth-
oxynonanoyl]-2-oxazolidinone (26). 45% yield.
20
½ꢀꢂ
¼ ꢀ40 (c 1.1, CHCl3). IR ꢁmax (CHCl3): 3546,
D
2947, 1788, 1696, 1387, 1352, 1111, 1038, 909 cmꢀ1
.
NMR ꢂH (CDCl3): 0.92 (3H, t, J 7.1 Hz, CH3), 1.30–
1.65 (9H, m), 1.81 (1H, m), 2.84 (1H, dd, J 13.7, 9.3 Hz,
PhCHH), 3.31 (1H, dd, J 13.7, 3.2 Hz, PhCHH), 3.38
(3H, s, OCH3), 3.48 (1H, d, J 7.8 Hz, OH), 3.55 (1H, m,
CHOMOM), 4.25 (1H, dd, J 9.3, 2.9 Hz, 5-HH), 4.28
(1H, dd, J 9.3, 9.3 Hz, 5-HH), 4.65 (2H, s, OCH2OCH3),
4.60–4.69 (1H, m, 4-H), 4.99 (1H, m, CHOH), 7.20–
7.22 (2H, m, ArH), 7.28–7.29 (1H, m, ArH), 7.31–7.36
(2H, m, ArH). NMR ꢂC (CDCl3): 14.2, 18.5, 21.0, 33.8,
34.2, 36.6, 37.5, 55.47, 55.50, 66.9, 70.7, 77.1, 95.4,
127.5, 129.0, 129.4, 134.8, 153.2, 174.9. Anal. Found:
1.38 mmol, 44% yield from mesylate) as a colorless oil;
20
½ꢀꢂ
¼ þ11 (c 0.1, CHCl3). IR ꢁmax (CHCl3): 2941,
D
1678, 1416, 1343, 1314, 1275, 1103, 909 cmꢀ1. NMR ꢂH
(CDCl3): 0.89 (3H, t, J 7.3 Hz, (CH2)2CH3), 1.20 (3H, d,
J 6.8 Hz, CH3), 1.20–1.38 (3H, m), 1.40–1.75 (7H, m),
4.16 (1H, m, 2-H), 4.39 (1H, m, 6-H), 5.13 (2H, s,
PhCH2O), 7.29–7.36 (5H, m, ArH). NMR ꢂC (CDCl3):
14.1, 20.6, 27.4, 30.3, 37.3, 46.1, 50.5, 66.8, 127.8,
128.4, 137.2, 155.9. FABMS m=z: 276 (Mþ+1, 100),
232 (50). HRMS (FAB) m=z (Mþ+1): Calcd. for
C, 63.92; H, 8.23; N, 3.40. Calcd. for C21H31O6N: C,
20
64.10; H, 7.94; N, 3.56%. (S)-[(2S,6R)]-26, ½ꢀꢂ
¼
D
þ40 (c 1.6, CHCl3).
(2R,6S)-6-Methoxymethoxynonane-1,2-diol (27). 84%
20
yield. ½ꢀꢂ
¼ þ4:8 (c 1.7, CHCl3). IR ꢁmax (CHCl3):
D
3450, 2936, 1462, 1238, 1150, 1096, 1038, 911 cmꢀ1
.
C17H26O2N, 276.1962; found, 276.1964. (2R,6S)-24,
20
NMR ꢂH (CDCl3): 0.92 (3H, t, J 7.1 Hz, CH3), 1.30–
1.57 (10H, m), 2.62 (1H, br. s, OH), 2.77 (1H, br. s,
OH), 3.38 (3H, s, OCH3), 3.43 (1H, dd, J 11.2, 7.8 Hz,
1-HH), 3.54 (1H, m, 6-H), 3.63 (1H, dd, J 11.2, 2.9 Hz,
½ꢀꢂ
¼ ꢀ11 (c 1.5, CHCl3).
D
(2S,6R)-Dihydropinidine hydrochloride (3). A reac-

(+)- and (ꢀ)-Dihydropinidine and (+)- and (ꢀ)-Epidihydropinidine
683
1-HH), 3.70 (1H, m, 2-H), 4.65 (2H, s, OCH2OCH3).
NMR ꢂC (CDCl3): 14.2, 18.5, 21.2, 33.1, 34.2, 36.6,
55.5, 66.7, 72.0, 77.3, 95.4. FABMS m=z: 221 (Mþ+1,
13), 207 (15), 189 (13), 171 (12), 159 (23), 147 (38).
(2R,6R)-Epidihydropinidine (4). 98% yield, mp 162–
20
163ꢁC (2-propanol-EtOAc); ½ꢀꢂ
¼ þ5:1 (c 0.4,
D
20
EtOH), lit7) mp 164.5–165.5ꢁC, ½ꢀꢂ
¼ þ4:7 (EtOH).
D
The NMR data agreed with those of the literature.
20
HRMS (FAB) m=z (Mþ+1): Calcd. for C11H25O4,
(2S,6S)-4, ½ꢀꢂ
¼ ꢀ5:1 (c 1.14, EtOH).
D
20
221.1752; found, 221.1749. (2S,6R)-27, ½ꢀꢂ
¼ ꢀ4:7
D
(c 1.7, CHCl3)
Acknowledgment
(2S,6S)-6-Methoxymethoxy-2-nonanol (28). 73%
20
We measured the 400 MHz NMR data at INCS,
Ehime University. We thank the staff of this center for
the FAB measurements. We are grateful to Marutomo
Co. for financial support.
yield (2 steps). ½ꢀꢂ
¼ þ5:9 (c 1.0, CHCl3). IR ꢁmax
D
(CHCl3): 3500, 2949, 1460, 1379, 1240, 1144, 1096,
1038, 912 cmꢀ1. NMR ꢂH (CDCl3): 0.92 (3H, t, J
6.8 Hz, 9-CH3), 1.19 (3H, d, J 5.9 Hz, 1-CH3), 1.28–1.58
(10H, m), 3.38 (3H, s, OCH3), 3.54 (1H, m, 6-H), 3.80
(1H, m, 2-H), 4.65 (2H, s, OCH2OCH3). NMR ꢂC
(CDCl3): 14.2, 18.5, 21.5, 23.5, 34.2, 36.6, 39.4, 55.5,
67.9, 77.2, 95.4. FABMS m=z: 205 (Mþ+1, 35), 154
(98), 143 (95), 136 (100). HRMS (FAB) m=z (Mþ+1):
References
1) 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).
2) Attygalle, A. B., Xu, S. C., McCormick, K. D.,
Meinwald, J., Blankespoor, C. L., and Eisner, T.,
Alkaloids of the Mexican bean beetle, Epilachna
varivestis (Coccinellidae). Tetrahedron, 49, 9333–9342
(1993).
Calcd. for C11H25O3, 205.1804; found, 205.1807.
20
(2R,6R)-28, ½ꢀꢂ
¼ ꢀ5:8 (c 1.6, CHCl3).
D
(2R,6S)-2-Azido-6-methoxymethoxynonane (29). 91%
20
yield (2 steps). ½ꢀꢂ
¼ ꢀ27 (c 1.4, CHCl3). IR ꢁmax
D
(CHCl3): 2936, 2103, 1466, 1381, 1242, 1144, 1096,
1038, 912 cmꢀ1. NMR ꢂH (CDCl3): 0.92 (3H, t, J
7.1 Hz, 9-CH3), 1.25 (3H, d, J 6.3 Hz, 1-CH3), 1.32–1.56
(10H, m), 3.38 (3H, s, OCH3), 3.44 (1H, m, 2-H), 3.54
(1H, m, 6-H), 4.65 (2H, m, OCH2OCH3). NMR ꢂC
(CDCl3) 14.2, 18.5, 19.4, 21.8, 34.0, 36.3, 36.5, 55.5,
57.9, 77.1, 95.4. Anal. Found: C, 57.62; H,9.77; N,
3) Schneider, M. J., Montali, J. A., Hazen, D., and Stanton,
C. E., Alkaloids of Pidea. J. Nat. Prod., 54, 905–909
(1991).
4) Numata, A., and Ibuka, I., Alkaloids from ants and other
insects. In ‘‘The Alkaloids’’ Vol. 43, ed. Brossi, A.,
Academic Press, New York, pp. 185–298 (1993).
5) Momose, T., Toyooka, N., and Jin, M., Asymmetric
twin-ring differentiation by lipase-catalyzed enantioto-
poselective reaction of the ring-crossed meso glycol:
asymmetric synthesis of a highly functionalized pipe-
ridine from the conjoined twin piperidine system.
Tetrahedron Lett., 33, 5389–5390 (1992).
18.40. Calcd. for C11H23O2N3: C, 57.61; H, 10.11; N,
20
18.32%. (2S,6R)-29, ½ꢀꢂ
¼ þ27 (c 1.6, CHCl3)
D
20
(4S,8R)-8-Azido-4-nonanol (30). 95% yield. ½ꢀꢂ
¼
D
ꢀ30 (c 1.1, CHCl3). IR ꢁmax (CHCl3): 3500, 2934, 2105,
1458, 1381, 1244 cmꢀ1. NMR ꢂH (CDCl3): 0.93 (3H, t, J
6.8 Hz, 1-CH3), 1.26 (3H, d, J 6.8 Hz, 9-CH3), 1.30–1.64
(10H, m), 3.44 (1H, m, 8-H), 3.61 (1H, m, 4-H). NMR
ꢂC (CDCl3): 14.1, 18.8, 19.4, 22.2, 36.2, 37.1, 39.7, 57.9,
71.4. Anal. Found: C, 58.24; H, 10.47; N, 22.69. Calcd.
ˆ
6) Chenevert, R., and Dickman, M., Enzymatic route to
chiral, nonracemic cis-2,6- and cis, cis-2,4,6-substituted
piperidines. Synthesis of (+)-dihydropinidine and den-
drobate alkaloid (+)-241D. J. Org. Chem., 61, 3332–
3341 (1996).
7) Takahata, H., Kubota, M., Takahashi, S., and Momose,
T., A new asymmetric entry to 2-substituted piperidines.
A concise synthesis of (+)-coniine, (ꢀ)-pelletierine,
(+)-ꢂ-coniceine, and (+)-epidihydropinidine. Tetrahe-
dron: Asymmetry, 7, 3047–3054 (1996).
8) Takahata, H., Yotsui, Y., and Momose, T., A general
asymmetric route to trans- or cis-2,6-disubstituted
piperidine. First total synthesis of (+)-9-epi-6-epipinidi-
nol and (ꢀ)-pinidinol. Tetrahedron, 54, 13505–13516
(1998).
9) Gage, J. R., and Evans, D. A., (S)-4-(Phenylmethyl)-2-
oxazolodinone. Org. Synth. Coll. Vol. VIII, 528–531
(1993).
10) Delay, F., and Ohloff, G., Synthesis of (R)- and (S)-p-
mentha-1,8-dien-4-ols from (R)-limonene. Helv. Chim.
Acta, 62, 2168–2173 (1979).
for C9H19ON3: C, 58.35; H, 10.34; N, 22.68%. (4R,8S)-
20
30, ½ꢀꢂ
¼ þ30 (c 1.5, CHCl3).
D
(2R,6R)-1-Benzyloxycarbonyl-2-methyl-6-propylpipe-
20
ridine (31). 44% yield (3 steps). ½ꢀꢂ
¼ ꢀ34 (c 1.3,
D
CHCl3). IR ꢁmax (CHCl3): 2959, 1680, 1412, 1320,
1100 cmꢀ1. NMR ꢂH (CDCl3): 0.89 (3H, t, J 7.3 Hz,
(CH2)2CH3), 1.27 (3H, d, J 6.8 Hz, CH3), 1.30–1.37
(1H, m), 1.43–1.57 (3H, m), 1.60–1.69 (4H, m), 1.76–
1.90 (2H, m), 3.90 (1H, m, 2-H), 3.98 (1H, m, 6-H), 5.10
(1H, d, J 12.5 Hz, PhCHH), 5.16 (1H, d, J 12.5 Hz,
PhCHH), 7.29–7.36 (5H, m, ArH). NMR ꢂC (CDCl3):
13.9, 14.0, 20.1, 20.8, 23.4, 27.0, 36.3, 47.4, 51.9, 66.5,
127.7, 127.8, 128.4, 137.2, 155.8. FABMS m=z: 276
(Mþ+1, 63), 91 (100). HRMS (FAB) m=z (Mþ+1):
11) 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).
Calcd. for C17H26O2N, 276.1964; found: 276.1965.
20
(2S,6S)-31, ½ꢀꢂ
= +34 (c 1.8, CHCl3).
D

684
S. YAMAUCHI et al.
12) Vedejs, E., and Larsen, S., Hydroxylation of enolates
with oxodiperoxymolybdenum(pyridine)(hexamethyl-
phosphoric triamide), MoO5ꢃPyꢃHMPA (MoOPH): 3-
hydroxy-1,7,7-trimethylbicyclo[2.2.1]heptan-2-one.
Org. Synth. Coll. Vol. VII, 277–282 (1990).
H., and Ohmiya, S., Asymmetric synthesis of (+)- and
(ꢀ)-dihydropinidines: diastereoselective addition to chi-
ral imine or 1,3-oxazolidine derived from (R)-phenyl-
glycinol as a single starting material with organometallic
reagents. J. Chem. Soc. Perkin Trans. I, 2791–2794
(1999).
13) Yamauchi, T., Fujikura, H., Higashiyama, K., Takahashi,