Stereoselective synthesis of (+)-spectaline

Article abstract of DOI:10.1016/S0957-4166(02)00794-2

Our synthesis of (+)-spectaline revealed that the methodology involving diastereoselective palladium(0)-catalyzed oxazoline formation and intramolecular reductive amination by catalytic hydrogenation of an oxazoline is an effective method for the asymmetric synthesis of natural products possessing complex functionalized piperidine cores.

Full text of DOI:10.1016/S0957-4166(02)00794-2

TETRAHEDRON:
ASYMMETRY
Pergamon
Tetrahedron: Asymmetry 14 (2003) 87–93
Stereoselective synthesis of (+)-spectaline
Yiu-Suk Lee,a Yong-Ho Shin,a Yong-Hyun Kim,a Kee-Young Lee,a Chang-Young Oh,a
Sung-Jae Pyun,a Hyun-Ju Park,a Jin-Hyun Jeongb and Won-Hun Hama,*
aCollege of Pharmacy, SungKyunKwan University, Suwon 440-746, Korea
bCollege of Pharmacy, Kyung Hee University, Seoul 130-701, Korea
Received 7 October 2002; accepted 21 November 2002
Abstract—Our synthesis of (+)-spectaline revealed that the methodology involving diastereoselective palladium(0)-catalyzed
oxazoline formation and intramolecular reductive amination by catalytic hydrogenation of an oxazoline is an effective method for
the asymmetric synthesis of natural products possessing complex functionalized piperidine cores. © 2003 Elsevier Science Ltd. All
rights reserved.
1. Introduction
oxazoline 4 by the sequential unmasking of the oxazo-
line and intramolecular reductive amination under
hydrogenolysis conditions.
Piperidine alkaloids are widespread in nature and many
compounds of this family exhibit interesting biological
activity.1 All cis-2,6-disubstituted 3-piperidinols such as
cassine 12 and spectaline 23 are members of this family
that have been the subjects of synthetic studies. Over
the past several years, we have been investigating the
stereocontrolled synthesis of the trans-oxazoline ring
via the highly stereoselective intramolecular cyclization
of acyclic allylic and homoallylic amides having a ben-
zoyl substituent as an N-protecting group in the pres-
ence of tetrakis(triphenylphosphine) palladium(0) and
base (K2CO3).4 More recently, the trans-oxazoline has
been applied successfully to the synthesis of (+)-
preussin 3,5 a potent antifungal agent possessing a
pyrrolidine skeleton. We have now explored this strat-
egy as an efficient route to the cis-2,6-disubstituted
piperidin-3-ol skeleton, a core found in a number of
biologically active compounds. Herein, we report the
stereoselective synthesis of (+)-spectaline 2, a potent
antifungal agent possessing a piperidinol skeleton (Fig.
1).
2. Results and discussion
The synthesis of oxazoline 6 began with
L-N-benzoyl
serinol 7 as shown in Scheme 2. Oxidation of alcohol 7
with Dess–Martin periodinane4b,6 gave the correspond-
ing aldehyde without racemization,4b,6b which was
reacted with vinylmagnesium bromide in THF at 0°C
to afford the corresponding allyl alcohol 8 as a ca. 1.1:1
mixture of syn/anti isomer (1H NMR) in 75% yield.7
Acetylation of the hydroxyl group yielded the sec-
Our approach to the piperidinol skeleton, shown ret-
rosynthetically in Scheme 1, is focused on the utiliza-
tion of oxazoline 6 as a building block to generate the
vicinal amino alcohol stereochemistry of the spectaline
and the stereoselective intramolecular cyclization of
* Corresponding author. Tel.: +82 331 290 7706; fax: +82 331 292
8800; e-mail: whham@speed.skku.ac.kr
Figure 1.
0957-4166/03/$ - see front matter © 2003 Elsevier Science Ltd. All rights reserved.
PII: S0957-4166(02)00794-2

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Y.-S. Lee et al. / Tetrahedron: Asymmetry 14 (2003) 87–93
Scheme 1. Retrosynthesis of (+)-spectaline.
Scheme 2. Reagents and conditions: (a) Dess–Martin periodinane, CH2Cl2, rt; (b) vinylmagnesium bromide, THF, 0°C, 75% for
two steps; (c) Ac2O, Pyri, DMAP, CH2Cl2, rt, 99%; (d) Pd(Ph3P)4, K2CO3, CH3CN, reflux, 75%.
ondary allylic acetate 9. The standard oxazoline ring
formation reaction (Pd(PPh3)4, K2CO3, in CH3CN) of
secondary allylic acetate 9 gave the desired trans-oxazo-
line 6 in good yield (75%) as a single isomer.
resulting ketone 4 could be directly converted to (+)-
spectaline 2 as a single isomer by means of a one-pot
procedure for a multi-reaction. Thus, unmasking of the
oxazoline followed by intramolecular reductive
amination11 of the resulting amine and deprotection of
terminal ketone occurred consecutively by simple treat-
ment of 20% Pd(OH)2 in AcOH/MeOH (1:9) under H2
atmosphere (70 psi) for 24 h in 70% yield (Scheme 4).
The trans-oxazoline 6 was converted into the a,b-unsat-
urated methyl ester 10 in 86% yield in two steps via
ozonolysis and subsequent Horner–Wardworth–
Emmons reaction. 1,4-Reduction8 of 10 with copper
bromide, Red-Al and 2-butanol gave the saturated
methyl ester 11 in 82% yield. Hydrolysis of 11 with
LiOH gave the corresponding acid which was converted
to its Weinreb amide9 5 via DCC-mediated condensa-
tion with N,O-dimethylhydroxylamine in 76% yield
over two steps (Scheme 3).
Not even a trace of the C-2 epimer could be detected.
The stereochemistry may be attributed to the steric
hindrance by which the catalytic hydrogenation occurs
from the less hindered site (a-face) of intermediate A
and B (Fig. 2). The physicochemical properties of (+)-
spectaline obtained from the present synthesis were in
complete agreement with those reported in the litera-
ture. ([h]2D5 +8.8 (c 1.3, CHCl3) [lit.3c [h]2D6 +9.0 (c 1.3,
CHCl3)]).
The conversion of 5 to 12 was accomplished by a three
step sequence: Removal of the TBDMS group with
tetrabutylammonium fluoride (TBAF) followed by iodi-
nation and subsequent reduction of the resulting iodide
with tri-n-butyltin hydride gave the corresponding
amide 12 in 74% overall yield in three steps. Treatment
of 12 with Grignard reagent, which was prepared from
13,10 provided ketone 4 in 70% yield. Fortunately, the
3. Conclusion
In summary, we report a new asymmetric synthetic
method for (+)-spectaline from oxazoline. This synthe-

Y.-S. Lee et al. / Tetrahedron: Asymmetry 14 (2003) 87–93
89
Scheme 3. Reagents and conditions: (a) O3, MeOH, −78°C then DMS; (b) (MeO)2POCH2CO2Me, LiCl, DBU, CH3CN, 86% for
two steps; (c) CuBr, Red-Al, 2-butanol, THF, 82%; (d) LiOH, THF/H2O, rt; (e) NH(CH3)OCH3·HCl, DCC, HOBT, Et3N,
CH2Cl2, 76% for two steps.
Scheme 4. Reagents and conditions: (a) TBAF, THF, 0°C; (b) PPh3, I2, Imidazole, CH3CN/Et2O; (c) Bu3SnH, AIBN,
PhH/MeOH, reflux 74% for three steps; (d) 13, Mg, THF, 0°C, 70%; (e) 20% Pd(OH)2/C, 70 psi H2, MeOH/AcOH (9:1), 70%.
sis revealed that the methodology involving diastereose-
lective palladium(0)-catalyzed oxazoline formation and
piperidine formation by catalytic hydrogenation of oxa-
zoline is effective for the asymmetric synthesis of natu-
ral products possessing complex functionalized
piperidine subunits.
values in ppm relative to CHCl3 (7.26) in CDCl3. IR
spectra were measured on an Nicolet 205 FT-IR spec-
trometer. The high resolution mass spectra were
recorded at 70 eV ionizing voltage; ammonia was used
for chemical ionization (CI). Flash chromatography
was executed with Merck Kiesegel 60 (230–400 mesh).
Tetrahydrofuran (THF) and diethylether (Et2O) were
distilled over sodium and benzophenone (indicator).
Methylene chloride (CH2Cl2) was shaken with concen-
trated sulfuric acid, dried over potassium carbonate,
and distilled. Commercially available compounds were
used without further purification.
4. Experimental
4.1. General methods
Melting points were determined with a capillary
apparatus and are uncorrected. Optical rotations were
measured on a JASCO DIP 1020 digital polarimeter.
1H NMR spectra were recorded at 400 or 500 MHz in
CDCl3 unless specified otherwise. 13C NMR spectra
were recorded at 100 or 125 MHz in CDCl3 unless
specified otherwise. Chemical shifts are reported as l
4.2. (−)-N-[(1S,2S)-2-Hydroxy-1-(tert-butyldimethyl
silanyloxymethyl)-3-butenyl]-benzamide, 8
To a stirred solution of 7 (3.10 g, 10.02 mmol) in
CH2Cl2 (20 mL) at 0°C under argon was added Dess–
Martin periodinane (6.32 g, 15.03 mmol), and stirring

90
Y.-S. Lee et al. / Tetrahedron: Asymmetry 14 (2003) 87–93
Figure 2.
was allowed to continue for 2 h at 25°C, after which
time TLC analysis indicated complete reaction. The
reaction mixture was diluted with Et2O (100 mL) and
poured into saturated aqueous NaHCO3 solution (200
mL) containing Na2S2O3 (16.6 g, 105.1 mmol, 10.5
equiv.). The mixture was stirred to dissolve the solid,
and the layers were separated. The ethereal layer was
washed with saturated NaHCO3 (100 mL) and with
water (100 mL), dried with MgSO4. The filtrate was
concentrated in vacuo to give crude aldehyde. This
aldehyde was immediately employed in the next step
without further purification. To a stirred solution of
crude aldehyde (1.0 mmol) in THF (50 mL) at −78°C,
was added a solution of vinylmagnesium bromide (1.0
M in THF, 50.1 mL). After being stirred for 1 h, the
reaction mixture was washed with saturated aqueous
NH4Cl (20 mL×2), brine (20 mL×2), dried with Na2SO4
and evaporated in vacuo. Purification by silica gel
chromatography (ethyl acetate/hexane=1/10) gave 8
(2.52 g, 96%); colorless oil; [h]2D4 +8.3 (c 1.0, CHCl3); IR
(neat) 3427, 2930, 2857, 1643 cm−1; 1H NMR (500
MHz) l 0.064–0.10 (d, 6H), 0.91 (s, 9H), 3.62 (s, 1H),
3.99–4.01 (dd, J=2.5, 4.0 Hz, 2H), 4.16 (m, 1H), 4.64
(m, 1H), 5.21 (dt, J=1.5, 11.0 Hz, 1H), 5.39 (dt,
J=1.5, 15.5 Hz, 1H), 5.88 (ddd, J=6.0, 11.0, 15.5 Hz,
1H), 6.79 (d, J=7.5 Hz, 1H), 7.43–7.52 (m, 3H), 7.76–
7.78 (m, 2H); 13C NMR (125 MHz) l −5.33, 18.37,
26.04, 53.74, 65.36, 73.83, 116.47, 127.15, 128.86,
131.84, 134.60, 137.54, 167.91; HRMS (EI, 70 eV) calcd
for C18H29NO3Si 335.1917, found 335.1917.
2), dried with Na2SO4, and evaporated in vacuo. Purifi-
cation by silica gel chromatography (ethyl
acetate/hexane=1/15) gave 9 (389 mg, 99%); colorless
oil; [h]2D4 +8.4 (c 1.0, CHCl3); IR (neat) 3322, 2931,
1
2857, 1745, 1646 cm−1; H NMR (500 MHz) l 0.036–
0.060 (d, 6H), 0.91 (s, 9H), 1.58 (s, 3H), 3.69 (dd,
J=3.0, 10.0 Hz, 1H), 3.82 (dd, J=5.5, 10.0 Hz, 1H),
4.39 (m, 1H), 5.31 (dt, J=1.0, 11.0 Hz, 1H), 5.37 (dt,
J=1.0, 17.5 Hz, 1H), 5.67 (m, 1H), 5.88 (ddd, J=6.5,
11.0, 17.5 Hz, 1H), 6.49 (d, J=9.5 Hz, 1H), 7.43–7.52
(m, 3H), 7.74–7.75 (m, 2H); 13C NMR (125 MHz) l
−5.35, 18.42, 21.34, 26.03, 53.55, 62.00, 73.86, 119.41,
127.07, 128.93, 131.85, 133.71, 134.61, 167.25, 170.63;
HRMS (EI, 70 eV) calcd for C20H31NO4Si 377.2022,
found 377.2027.
4.4. (4S,trans)-4,5-Dihydro-4-(tert-butyl-dimethylsilanyl-
oxymethyl)-2-phenyloxazoline, 6
To a stirred solution of 9 (400 mg, 1.06 mmol) and
K2CO3 (439 mg, 3.178 mmol) in CH3CN (20 mL) was
added Pd(PPh3)4 (6.12 mg, 0.053 mmol) under N2. The
resulting mixture was heated under reflux for 24 h,
whereupon it was allowed to cool to rt and was filtered
through a pad of silica, which was then evaporated
under reduced pressure to give crude product. Purifica-
tion by silica gel chromatography (ethyl acetate/hex-
ane=1/20) gave 6 (252 mg, 75%); colorless oil; [h]D25
−3.7 (c 1.0, CHCl3); IR (neat) 2930, 2857, 1650 cm−1;
1H NMR (500 MHz) l 0.04–0.076 (d, 6H), 0.86 (s, 9H),
3.69 (dd, J=7.0, 10.0 Hz, 1H), 3.94 (dd, J=4.0, 10.0
Hz, 1H), 4.06 (ddd, J=4.0, 5.5, 7.0 Hz, 1H), 5.02 (dd,
J=5.5, 6.5 Hz, 1H), 5.21 (dt, J=1.5, 10.5 Hz, 1H),
5.36–5.40 (dt, J=1.5, 17.0 Hz, 1H), 5.96 (ddd, J=6.5,
10.5, 17.0 Hz, 1H), 7.39–7.48 (m, 3H), 7.95–7.97 (m,
2H); 13C NMR (125 MHz) l −5.08, 26.04, 64.95, 74.33,
83.31, 116.62, 128.02, 128.54, 131.59, 137.00, 164.11;
HRMS m/e calcd for C18H27NO2Si 318.1889, found
318.1880.
4.3. (−)-N-((1S,2S)-2-Acetoxy-1-(tert-butyldimethyl-
silanyloxymethyl)-3-butenyl)-benzamide, 9
To a stirred solution of 8 (350 mg, 1.04 mmol) in
CH2Cl2 (4 mL) were added acetic anhydride (0.11 mL,
1.42 mmol), pyridine (0.093 mL, 1.42 mmol), and stir-
ring was allowed to continue for 12 h. The reaction
mixture was washed with 1N HCl (20 mL×2), saturated
aqueous NaHCO3 solution (20 mL×2), brine (20 mL×

Y.-S. Lee et al. / Tetrahedron: Asymmetry 14 (2003) 87–93
91
4.5. (2E)-3-((4S,trans)-4,5-Dihydro-4-(tert-butyl-
dimethylsilanyloxymethyl)-2-phenyloxazol-5-yl)-acrylic
acid methyl ester, 10
4.7. 3-((4S,trans)-4,5-Dihydro-4-(tert-butyl-dimethyl-
silanyloxymethyl)-2-phenyloxazol-5-yl)-N-methoxy-N-
methyl-propionamide, 5
Oxazoline 6 (2.0 g, 6.30 mmol) was dissolved in dry
methanol (50 mL) and cooled to −78°C. Pass ozonied
oxygen until the reaction is complete. The reaction
mixture was quenched with (CH3)2S (0.93 mL, 12.6
mmol) and allowed to warm to rt. The solvents were
evaporated under reduced pressure. The crude alde-
hyde was immediately employed in the next step
without further purification. To a stirred solution of
LiCl (320 mg, 7.56 mmol) in CH3CN (80 mL) were
added trimethylphosphonoacetate (1.09 mL, 7.56
mmol), 8-diazabicyclo[5,4,0]undec-7-ene (DBU) (0.942
mL, 6.30 mmol) and stirring was allowed to continue
for 1 h. The crude aldehyde in CH3CN (20 mL) was
added and the reaction mixture was stirred for 2 h.
The reaction mixture was poured into H2O (30 mL),
extracted with EtOAc (100 mL). The organic extract
was washed with brine, dried with Na2SO4 and evap-
orated in vacuo. Purification by silica gel chromatog-
raphy (ethyl acetate/hexane=1/6) gave 10 (2.03 g,
85.8%); colorless oil; [h]2D4 +53.9 (c 1.0, CHCl3); IR
(neat) 2954, 2857, 1729, 1653 cm−1; 1H NMR (500
MHz) l 0.04–0.08 (d, 6H), 0.87 (s, 9H), 3.68 (dd,
J=7.0, 10.0 Hz, 1H), 3.75 (s, 3H), 3.97 (dd, J=4.0,
10.0 Hz, 1H), 4.14 (dt, J=4.0, 6.5 Hz, 1H), 5.19 (dd,
J=1.5, 6.5 Hz, 1H), 6.10 (dt, J=1.5, 15.5 Hz, 1H),
7.00 (dd, J=5.0, 15.5 Hz, 1H), 7.41–7.51 (m, 3H),
7.95–7.96 (m, 2H); 13C NMR (125 MHz) l −5.10,
18.44, 26.00, 52.04, 64.85, 74.35, 80.94, 120.84,
127.48, 128.57, 128.67, 131.91, 145.92, 164.03, 166.67;
HRMS m/e calcd for C20H29NO4Si 376.1944, found
376.1953.
To a stirred solution of 11 (600 mg, 1.59 mmol) in
THF/H2O (2.5:1, 10 mL) was added LiOH (333 mg,
7.94 mmol), and stirring was allowed to continue for 2
h. The reaction mixture was diluted with EtOAc and
washed with brine, dried with MgSO4, and evaporated
in vacuo. The crude acid was immediately employed in
the next step without further purification. The crude
acid (570 mg), N,O-dimethylhydroxylamine hydrochlo-
ride (167.8 mg, 1.72 mmol), and triethylamine (0.24
mL, 1.72 mmol) were dissolved in CH2Cl2 (20 mL) and
cooled to 0°C. N-Hydroxybenzotriazole (HOBt) (232
mg, 1.72 mmol), DCC (324 mg, 1.57 mmol) were added
and the reaction mixture was stirred for 12 h. The
reaction mixture was filtered to remove dicyclohexyl-
urea and concentrated. The resulting slurry was diluted
with EtOAc and washed with 1N HCl, saturated
aqueous NaHCO3 solution, brine, dried with Na2SO4,
and evaporated in vacuo. Purification by silica gel
chromatography (ethyl acetate/hexane=2/1) gave 5
(491 mg, 76%); colorless oil; [h]2D4 −32.2 (c 1.0, CHCl3);
1
IR (neat) 2931, 2857, 1669 cm−1; H NMR (500 MHz)
l 0.027–0.076 (d, 6H), 0.86 (s, 9H), 2.03 (m, 2H), 2.63
(brs, 2H), 3.18 (s, 3H), 3.61 (dd, J=7.0, 10.0 Hz, 1H),
3.90 (s, 3H), 3.92 (dd, J=4.0, 10.0 Hz, 1H), 3.97 (ddd,
J=4.0, 6.0, 7.0 Hz, 1H), 4.64 (dd, J=6.0, 7.0 Hz, 1H),
7.38–7.47 (m, 3H), 7.92–7.94 (m, 2H); 13C NMR (125
MHz) l −5.11, 18.46, 26.05, 27.86, 30.52, 61.44, 65.24,
73.46, 82.42, 128.19, 128.40, 128.48, 131.51, 164.12;
HRMS m/e calcd for C21H34N2O4Si 407.2366, found
407.2362.
4.8. 3-((4S,trans)-4,5-Dihydro-4-methyl-2-phenyloxazol-
5-yl)-N-methoxy-N-methyl propionamide, 12
4.6. 3-((4S,trans)-4,5-Dihydro-4-(tert-butyl-dimethyl-
silanyloxymethyl)-2-phenyloxazol-5-yl)-propionic acid
methyl ester, 11
To a stirred solution of 5 (1.0 g, 2.46 mmol) in THF (10
mL) at 0°C was added Bun NF (1.0 M solution in
4
THF, 2.71 mL, 2.71 mmol). The reaction mixture was
stirred at rt for 1 h. The reaction was quenched with
saturated aqueous NH4Cl, extracted with Et2O fol-
lowed by washing with brine, dried with MgSO4 and
evaporated in vacuo. Purification by silica gel chro-
matography (ethyl acetate/hexane=3/1) gave primary
alcohol (680 mg, 94%); white solid; [h]2D3 −83.5 (c 1.0,
CHCl3); mp 111ꢀ112°C; IR (KBr) 3214, 2917, 2866,
To a stirred solution of cuprous bromide (1.53 g,
10.65 mmol) and Red-Al (6.39 mL, 21.30 mmol) in
THF (30 mL) at −78°C, was added 2-butanol (4.4
mL, 47.93 mmol) all at once, followed by a solution
of 10 (1.0 g, 2.66 mmol) in THF (10 mL). After 10
min at −78°C, the reaction mixture was stirred at
−20°C for 4 h. The reaction mixture was quenched
with 1N HCl (20 mL), extracted with Et2O. The
organic extract was washed with brine, dried with
Na2SO4, and evaporated in vacuo. Purification by sil-
ica gel chromatography (ethyl acetate/hexane=1/6)
gave 11 (828 mg, 82.4%); colorless oil; [h]2D4 −15.7 (c
1.0, CHCl3); IR (neat) 2953, 2857, 1741, 1649 cm−1;
1H NMR (500 MHz) l 0.034–0.079 (d, 6H), 0.86 (s,
9H), 2.02 (m, 2H), 2.53 (m, 2H), 3.58 (dd, J=7.0,
10.0 Hz, 1H), 3.68 (s, 3H), 3.91 (dd, J=4.0, 10.0 Hz,
1H), 3.94 (m, 1H), 4.61 (dd, J=6.0, 12.5 Hz, 1H),
7.39–7.48 (m, 3H), 7.91–7.93 (m, 2H); 13C NMR (125
MHz) l −5.13, 18.47, 26.06, 30.08, 30.85, 51.94,
65.30, 73.51, 82.24, 128.04, 128.48, 128.53, 131.60,
164.12, 173.61; HRMS m/e calcd for C20H31NO4Si
378.2101, found 378.2094.
1
1651 cm−1; H NMR (500 MHz) l 2.09 (m, 2H), 2.67
(m, 2H), 3.20 (s, 3H), 3.71 (s, 3H), 3.88 (m, 2H), 4.03
(ddd, J=4.0, 5.0, 7.0 Hz, 1H), 4.62 (ddd, J=5.0, 8.0,
12.0 Hz, 1H), 7.40–7.49 (m, 3H), 7.93–7.95 (m, 2H); 13
C
NMR (125 MHz) l 27.82, 30.16, 32.48, 61.53, 64.78,
73.63, 81.76, 127.83, 128.55, 128.58, 131.79; HRMS m/e
calcd for C15H20N2O4 293.1501, found 293.1527.
To a stirred solution of primary alcohol (600 mg, 2.05
mmol) in CH3CN/Et2O (3:5, 5.7 mL) were added
triphenylphosphine (1.4 g, 5.34 mmol), imidazole (381
mg, 5.60 mmol) followed by portionwise of iodine (1.49
g, 5.88 mmol) at 0°C. The reaction mixture was stirred
at rt for 4 h. Dilution with Et2O followed by washing
with saturated aqueous Na2S2O3 (20 mL), saturated

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Y.-S. Lee et al. / Tetrahedron: Asymmetry 14 (2003) 87–93
aqueous CuSO4 (20 mL), brine, dried with MgSO4 and
evaporated in vacuo. Purification by silica gel chro-
matography (ethyl acetate/hexane=1/1) gave iodide
(743 mg, 90%); yellow oil; IR (neat) 2962, 1777, 1646
gel chromatography (ethyl acetate/hexane=1/3) gave 4
(162 mg, 70%); colorless oil; [h]2D3 −21.0 (c 1.0, CHCl3);
1
IR (neat) 2927, 2852, 1709, 1649 cm−1; H NMR (400
MHz) l 1.26–1.40 (br m, 22H), 1.56–1.65 (m, 2H), 1.90
(m, 1H), 2.01 (m, 1H), 2.43 (t, J=9.6 Hz, 2H), 2.61 (t,
J=9.8 Hz, 2H), 3.92 (m, 5H), 4.21 (ddd, J=4.0, 7.0,
8.0 Hz, 1H), 7.38–7.47 (m, 3H), 7.91–7.94 (m, 2H); 13C
NMR (125 MHz) l 21.59, 23.92, 24.31, 28.83, 29.37,
29.42, 29.59, 29.66, 29.75, 29.78, 29.80, 29.81, 30.04,
38.30, 39.45, 43.20, 43.99, 64.79, 67.45, 86.00, 128.18,
128.36, 128.49, 131.46, 162.72, 210.25; HRMS m/e
calcd for C29H45NO4 472.3427, found 472.3436.
1
cm−1; H NMR (500 MHz) l 2.04 (m, 2H), 2.68 (m,
2H), 3.19 (s, 3H), 3.20 (dd, J=7.0, 10.0 Hz, 1H), 3.48
(dd, J=4.0, 10.0 Hz, 1H), 3.71 (s, 3H), 4.09 (ddd,
J=3.5, 4.0, 5.5 Hz, 1H), 4.51 (ddd, J=5.5, 8.5, 10.0
Hz, 1H), 7.41–7.51 (m, 3H), 7.94–7.95 (m, 2H); 13C
NMR (125 MHz) l 10.72, 27.77, 29.94, 30.52, 61.53,
72.35, 80.88, 127.76, 128.64, 128.66, 131.98, 164.59;
HRMS m/e calcd for C15H19N2O3 403.0519, found
403.0511.
4.11. (+)-Spectaline, 2
To a stirred solution of iodide (945 mg, 2.35 mmol) and
azobis (isobutyronitrile) (386 mg, 2.35 mmol) in ben-
zene/MeOH (5:1, 8.8 mL) was added tri-n-butyltin
hydride (1.26 mL, 4.7 mmol), and the reaction mixture
was heated under reflux for 1 h. The solvents were
removed under reduced pressure. Purification by silica
gel chromatography (ethyl acetate/hexane=1/1) gave
12 (390 mg, 87.5%); white–yellow oil; [h]2D5 −53.9 (c 1.0,
CHCl3); IR (neat) 2965, 2929, 1648 cm−1; 1H NMR
(400 MHz) l 1.36 (d, J=6.5 Hz, 3H), 1.97 (m, 1H),
2.08 (m, 1H), 2.65 (m, 2H), 3.20 (s, 3H), 3.82 (s, 3H),
3.95 (dd, J=6.5, 7.0 Hz, 1H), 4.28 (ddd, J=4.0, 7.0, 8.5
Hz, 1H), 7.46–7.56 (m, 3H), 7.92–7.95 (m, 2H); 13C
NMR(125 MHz) l 21.60, 27.93. 29.84, 61.50, 67.53,
86.18, 128.32, 128.40, 128.52, 131.45, 162.82; HRMS
m/e calcd for C15H20N2O3 277.1552, found 277.1567.
A solution of 4 (366 mg, 0.78 mmol) in AcOH/MeOH
(1:9, 10 mL), to which was added 366 mg of 20%
Pd(OH)2, was vigorously shaken under 75 psi H2 for 24
h at ambient temperature. The mixture was then filtered
through a pad of silica and concentrated in vacuo.
Purification by column chromatography over silica gel
(CHCl3/ EtOH=100:1) gave (+)-spectaline, 2 (158 mg,
70%); white solid; [h]2D6 +8.8 (c 1.3, CHCl3); mp 59ꢀ
1
61°C; IR (KBr) 3283, 2916, 2848, 1706 cm−1; H NMR
(500 MHz) l 1.12 (d, J=6.5 Hz, 3H), 1.25–1.39 (br,
21H), 1.47–1.57 (br m, 4H), 1.90 (br m, OH, NH), 2.13
(s, 3H), 2.41 (t, J=7.5 Hz, 2H), 2.50–2.54 (m, 1H), 2.79
(qd, J=7.0, 1.0 Hz, 1H), 3.56 (br s, 1H); 13C NMR
(125 MHz) l 18.54, 24.10, 25.84, 26.01, 29.41, 29.63,
29.68, 29.81, 29.83, 29.87, 29.93, 29.98, 30.08, 32.15,
36.75, 44.05, 56.15, 57.53, 68.03, 209.64; HRMS m/e
calcd for C20H39NO2 326.3059, found 326.3070.
4.9. 2-(12-Bromododecyl)-2-methyl-1,3-dioxolane, 13
To a stirred solution of 1,10-dibromodecane (1.54 g,
5.13 mmol) in THF (3 mL) at rt was added dropwise
dilithium tetrachlorocuprate solution (15.4 mL, 0.1 M).
Grignard reagent 20.5 mL, which was prepared from
2-(2-bromoethyl)-2-methyl-1,3-dioxolane and magne-
sium turning, was added dropwise and the reaction
mixture was stirred for 2 h. The reaction mixture was
washed with saturated aqueous NH4Cl, brine, dried
with MgSO4 and evaporated in vacuo. Purification by
silica gel chromatography (ethyl acetate/hexane=1/30)
Acknowledgements
This study was supported by a grant of the Korea
Health 21 R&D Project, Ministry of Health and Wel-
fare, Republic of Korea (01-PJ1-PG1-01CH13-0002).
References
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