Synthesis of the 1-phenethyltetrahydroisoquinoline alkaloids (+)-dysoxyline, (+)-colchiethanamine, and (+)-colchiethine

Article abstract of DOI:10.1021/jo302157e

Asymmetric total syntheses of the 1-phenethyl-1,2,3,4- tetrahydroisoquinoline alkaloids (+)-dysoxyline (1), (+)-colchiethanamine (2), and (+)-colchiethine (3) are described. In the synthetic routes, coupling of a key, enatiomerically pure 1-(sulfonylmethyl)tetrahydroisoquinoline with aromatic aldehydes, performed by using the Julia-Kocienski reaction, afforded the corresponding 1-(β-styryl)-substituted tetrahydroisoquinolines with complete retention of the absolute configuration at the C1 carbon atom. Functionalization of the products generated in these processes by using four-or five-step sequences gave the target alkaloids 1-3.

Full text of DOI:10.1021/jo302157e

Article
pubs.acs.org/joc
Synthesis of the 1‑Phenethyltetrahydroisoquinoline Alkaloids
(+)-Dysoxyline, (+)-Colchiethanamine, and (+)-Colchiethine
Raju Jannapu Reddy, Nobuyuki Kawai, and Jun’ichi Uenishi*
Kyoto Pharmaceutical University, Misasagi, Yamashina, Kyoto 607-8412, Japan
S
* Supporting Information
ABSTRACT: Asymmetric total syntheses of the 1-phenethyl-1,2,3,4-tetrahydroisoquinoline alkaloids (+)-dysoxyline (1),
(+)-colchiethanamine (2), and (+)-colchiethine (3) are described. In the synthetic routes, coupling of a key, enatiomerically pure
1-(sulfonylmethyl)tetrahydroisoquinoline with aromatic aldehydes, performed by using the Julia−Kocienski reaction, afforded
the corresponding 1-(β-styryl)-substituted tetrahydroisoquinolines with complete retention of the absolute configuration at the
C1 carbon atom. Functionalization of the products generated in these processes by using four- or five-step sequences gave the
target alkaloids 1−3.
INTRODUCTION
■
Alkaloids possessing the 1,2,3,4-tetrahydroisoquinoline
(THIQ) ring system are of great interest because of their
unique and wide-ranging biological activities.1 Numerous 1-
substituted tetrahydroisoquinolines and related alkaloids are
found in nature, as exemplified by 1-phenethyltetrahydroiso-
quinoline, which serves as a precursor of the homoaporphine,
homoproaporphine, and homomorphinandione alkaloids2
involved in the biosynthesis of colchicine.3 Importantly, an
intramolecular oxidative coupling reaction of 1-phenethylte-
trahydroisoquinoline has been proposed to be the pivotal
process in the colchicine biosynthetic pathway.
It is interesting that alkaloids conatining both (S)- and (R)-
configurations at the C-1 positions of 1-substituted tetrahy-
droisoquinoline moieties are found in nature. For example,
(+)-dysoxyline (1),4 (+)-colchiethanamine (2),5 (+)-colchie-
Figure 1. Structures of 1-phenethyltetrahydroisoquinoline natural
thine (3),5 and (+)-homolaudanosine (4)4 have an (S)-
products.
configuration at their C-1 centers, while (−)-autumnaline6
and (−)-isoautumnaline7 have the (R)-configuration at their C-
(+)-colchiethanamine (2), and (+)-colchiethine (3) that rely
on key Julia−Kocienski olefination processes.
1 positions (Figure 1). As a consequence of this feature,
strategies to construct C-1-substituted members of the THIQ
alkaloid family must pay attention to the control of the absolute
stereochemistry at the C-1 center.2 Although a number of
synthetic methods have been developed to control the
stereochemistry of the C-1 center in the 1-substituted
THIQ,8 only the synthesis of optically pure (+)-homolauda-
nosine has been reported thus far9,10 for the synthesis of 1-
phenethyl-THIQ alkaloids. In the studies described below, we
have developed routes for the synthesis of (+)-dysoxyline (1),
RESULTS AND DISCUSSION
■
We have recently described the employment of a Bi(OTf)3-
catalyzed dehydrative cyclization, which takes place with 1,3-
chirality transfer,11 to the preparation of the (S)- and (R)-
Received: October 6, 2012
Published: November 25, 2012
© 2012 American Chemical Society
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Scheme 1. Synthesis of (+)-Dysoxyline Using a Wittig Reaction Protocol
enantiomers of the 1-alkenyl-substituted THIQ 5 and its
application to the synthesis of selected pyrrolotetrahydroiso-
quinoline alkaloids,12 exemplified by the preparation of
(+)-dysoxyline (1) (Scheme 1).
obtained from the following experiments (Scheme 2).
Specifically, the ozonide intermediate produced by treatment
of 5 with ozone was reduced by the addition of
triphenylphosphine and immediately treated with NaBH4 in
methanol at room temperature to form alcohol 12 (78% yield).
Analysis of the alcohol product 12 showed that it was
comprised of a 74:26 mixture of enantiomers. In contrast,
The route employed to prepare 1 began with ozonolysis of 5
followed by reduction of the ozonide with triphenylphosphine
to give aldehyde 6, which was immediately subjected to Wittig
olefination, using the ylide generated from (benzo[d][1,3]-
dioxol-5-ylmethyl)triphenylphosphonium bromide with
NaHMDS, to afford alkenyl product 7 in 54% yield (two
steps). Pd-catalyzed hydrogenation of the alkene moiety in 7
gave 8 in 95% yield. Replacement of the C-6 O-pivaloyl ester in
8 by an O-methyl ether was performed in two steps, involving
sequential reaction with NaOMe and diazotrimethylsilyl-
methane to generate 10 in 84% yield (two steps). Removal
of the N-Boc group in 10 with trifluoroacetic acid gave 11
(90%), which upon reductive methylation with formaldehyde
and NaB(CN)H3 in the presence of ZnCl2 afforded
(+)-dysoxyline 1 in 90% yield. Unfortunately, the specific
rotation of the synthetic dysoxyline {[α]2D5 = +5.2 (c 0.4,
EtOH)} was found to be considerably lower than that of the
reported natural (+)-dysoxyline {[α]2D5 = +22 (c 0.34, EtOH)}.4
Moreover, chiral HPLC analysis of the synthetic dysoxyline
showed that it had a low 74:26 ratio of enantiomers (48% ee).
Because the starting tetrahydroisoquinoline (+)-5 had a high
enantiomeric ratio of 93:7 (86% ee), we speculated that partial
racemization at the C-1 center occurred during the conversion
of 5 to aldehyde 6 and/or during the ensuing Wittig olefination
reaction.13 This expectation was confirmed by the results
Scheme 2. Ozonolysis and Reduction
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when the ozonide was directly reduced by addition of NaBH4 at
−78 °C, alcohol 12 was generated in an high 93:7 enantiomeric
ratio (86% ee, determined by using chiral HPLC).14
competitive retro-Michael type C−N bond cleavage of the
anion intermediate (Scheme 4). Conversion of 7 to
Because the aldehyde 6 undergoes ready racemization, the
synthetic route was modified by using the Julia−Kocienski
reaction15 instead of the Wittig reaction to prepare alkene 7
(Scheme 3). We believed that the alternative approach would
Scheme 4. Possible Retro-Michael Cleavage of
Sulfonylmethyl Anion of 14
Scheme 3. Synthesis of (+)-Dysoxyline by Using the Julia−
Kocienski Reaction Based Route
(+)-dysoxyline (1) was then achieved by utilizing the same
five-step route outlined in Scheme 3. Importantly, the specific
rotation of 1 generated by using the modified procedure was
found to be +16.2, corresponding to a 94:6 enantiomer ratio
(88% ee) by using chiral HPLC analysis.
The general strategy used to carry out the synthesis of
(+)-dysoxyline was employed to prepare the enantiomerically
enriched 6,7-dioxytetrahydroisoquinoline alkaloids (+)-colchie-
thanamine (2) and (+)-colchiethine (3) (Scheme 5). Julia−
Kocienski olefination of 14 with the 4-(pivaloyloxy)-
benzaldehyde in the presence of LiHMDS provided the desired
15a as a single E-isomer in 79% yield. Hydrogenation of 15a
provided 16a (94%), which was then subjected to sequential
deprotection of the N-Boc group with TMSOTf in CH2Cl2 and
reductive methylation to form 18a in 70% overall yield in two
steps. Finally, removal of the pivaloyl groups in 18a by using
NaOMe afforded (+)-colchiethanamine (2) in a 93:7
enantiomeric ratio (chiral HPLC analysis), the spectroscopic
data of which matched those reported in the literature.5
(+)-Colchiethine (3) was also synthesized in a similar manner
starting with 14 by using anisaldehyde instead of 4-
(pivaloyloxy)benzaldehyde in the Julia−Kocienski coupling
step (five steps, 53% yield, Scheme 5).
In the study described above, we have demonstrated that the
chiral tetrahydroisoquinoline (S)-5 can be employed as a
common starting material for the synthesis of enantiomerically
enriched 1-phenethyltetrahydroisoquinoline alkaloids. Specifi-
cally, a strategy leading to the first asymmetric total syntheses of
(+)-dysoxyline (1), (+)-colchiethanamine (2), and (+)-colchie-
thine (3) has been developed that relies on Julia−Kocienski
olefination reactions as key steps. The sulfone 14 used in these
approaches should serve as a versatile intermediate in the routes
for the synthesis of other phenethyltetrahydroisoquinoline and
related alkaloids.2,3
EXPERIMENTAL SECTION16
avoid racemization at the C-1 center. The sulfone precursor,
required for the Julia−Kocienski reaction, was prepared by
using a two-step procedure starting with alcohol 12 (86% ee).
Sulfenylation of 12 with 5-mercapto-1-phenyltetrazole under
Mitsunobu reaction conditions gave the desired sulfide 13,
which was then oxidized by treatment with 30% hydrogen
peroxide in the presence of catalytic (NH4)6Mo7O24·4H2O to
give sulfone 14 in 82% yield (two steps). The anion of 14
generated by treatment with LiHMDS in THF was reacted with
piperonal in THF at −35 °C to produce alkene 7 in 85% yield
as a single (E)-isomer. Although concerned by the possibility,
the Julia−Kocienski reaction was not complicated by
■
(S)-1-(2-(Benzo[d][1,3]dioxol-5-yl)ethenyl)-N-tert-butoxycar-
bonyl-7-methoxy-6-(pivaloyloxy)-3,4-dihydro-2(1H)-isoquino-
line (7) Using a Wittig Olefination Strategy. To a stirred solution
of 5 (50 mg, 0.12 mmol) in CH2Cl2 (3 mL) was bubbled a stream of
ozone at −78 °C until TLC analysis indicated complete consumption
of the starting material (ca. 1 min). Argon gas was passed through the
solution for an additional 1 min and then Ph3P (84 mg, 0.32 mmol)
was added. The mixture was stirred at 0 °C for 15 min and
concentrated in vacuo, giving a residue that was dissolved in THF (1.5
mL). The solution was added immediately to a solution of Wittig
reagent generated from (piperonyl)triphenylphosphonium bromide
(190 mg, 0.4 mmol) and NaHMDS (1.9 M solution in THF, 0.17 mL,
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Scheme 5. Syntheses of (+)-Colchiethanamine (2) and (+)-Colchiethine (3)
0.32 mmol) in THF (1.5 mL) at 0 °C. After stirring for 30 min,
saturated ammonium chloride was added and the aqueous layer was
extracted with ethyl acetate. The organic layer was washed with water
and brine, dried over MgSO4, and concentrated in vacuo. The residual
product was purified by silica gel column chromatography (5% and
then 10% EtOAc in hexane) to provide the alkene 7 (30 mg) as a
colorless oil in 49% yield. [α]2D2 = +25.4 (c 0.1, CHCl3). IR (CHCl3,
C21H31NO6: C, 64.10; H, 7.94; N, 3.56. Found: C, 63.81; H, 7.84;
N, 3.42. The enantiomeric ratio of the alcohol 12 was found to be
74:26 (48% ee) determined by chiral HPLC analysis (Chiralcel OD-H,
5% 2-propanol in hexane, flow rate = 0.5 mL/min, T = 20 °C, 254
nm): ts = 13.8 (major; S-isomer), ts = 18.3 (minor; R-isomer).
Preparation of 12 by Ozonolysis of 5 and Direct Reduction
of the Ozonide. To a stirred solution of 5 (400 mg, 1 mmol) in
CH2Cl2 (20 mL) cooled at −78 °C was bubbled a stream of ozone
until TLC analysis indicated complete consumption of the starting
material. An excess of ozone was removed by bubbling of Ar through
the solution at the same temperature. Dilution of the solution with
MeOH (10 mL) at −78 °C was followed by addition of sodium
borohydride (190 mg, 5 mmol) in one portion at the same
temperature. Following stirring at room temperature for 30 min, the
mixture was diluted by slow addition of saturated ammonium chloride
and extracted with CH2Cl2. The organic layer was washed with brine,
dried over MgSO4, and concentrated in vacuo. The residual product
was purified by flash column chromatography (50% EtOAc in hexane)
to provide the alcohol (334 mg, 85%) as a white amorphous powder.
Rf = 0.5 (50% EtOAc in hexane). Mp: 57−59 °C. [α]2D0 = +53.9 (c
0.77, CHCl3). The enantiomeric ratio (er: 93:7; 86% ee) was
determined by chiral HPLC analysis under the conditions described in
the proceeding experiment.
(R)-N-tert-Butoxycarbonyl-1-[(1-phenyl-1H-tetrazol-5-yl)-
thiomethyl]-7-methoxy-6-(pivaloyloxy)-3,4-dihydro-2(1H)-iso-
quinoline (13). To a stirred solution of 12 (200 mg, 0.5 mmol),
phenyl-1H-tetrazole-5-thiol (107 mg, 0.6 mmol), and triphenylphos-
phine (157 mg, 0.6 mmol) in THF (10 mL) was added diisopropyl
azodicarboxylate (2.2 M solution in hexane, 280 μL, 0.6 mmol)
dropwise at 0 °C. The solution was allowed to stir at room
temperature for an additional 30 min and concentrated in vacuo. The
residual product was purified by flash column chromatography (20%−
30% EtOAc in hexane) to give 13 (250 mg, 90%) as a colorless viscous
liquid. Rf = 0.35 (30% EtOAc in hexane). [α]2D0 = +82.5 (c 1.65,
CHCl3). IR (CHCl3, cm−1): 1752, 1692. 1H NMR (500 MHz,
CDCl3): the compound exists as a 1.5:1 mixture of carbamate
rotamers; signals correspond to both rotamers; δ 7.62 (d, J = 7.0 Hz,
2H), 7.58−7.50 (m, 3H), 7.06 (s, 0.6H), 6.97 (s, 0.4H), 6.78 (s, 1H),
5.66 (apparent d, J = 10.0 Hz, 0.6H), 5.55 (apparent d, J = 10.0 Hz,
0.4H), 4.30 (apparent d, J = 14.0 Hz, 0.8H), 4.00 (apparent d, J = 14.0
Hz, 1.2H), 3.86 (s, 1.8H), 3.82 (s, 1.2H), 3.55 (apparent t, J = 12.0 Hz,
0.4H), 3.43 (apparent t, J = 12.0 Hz, 0.6H), 3.23 (apparent t, J = 12.0
1
cm−1): 1752, 1691. H NMR (500 MHz, CDCl3): δ 6.88 (s, 1H),
6.86−6.66 (m, 4H), 6.32 (d, J = 15.0 Hz, 1H), 6.12 (d, J = 15.0 Hz,
1H), 5.93 (s, 2H), 5.65 (apparent bs, 1H), 4.20 (apparent bs, 1H),
3.75 (s, 3H), 3.15 (apparent bs, 1H), 2.85 (t, J = 15.0 Hz, 1H), 2.64
(d, J = 15.0 Hz, 1H), 1.49 (s, 9H), 1.36 (s, 9H). 13C NMR (125 MHz,
CDCl3): δ 176.8, 154.5, 149.5, 148.0, 147.2, 138.9, 131.2, 131.0, 127.3,
127.1, 122.7, 121.1, 111.8, 108.3, 108.2, 105.7, 101.0, 79.9, 56.0, 39.0,
29.6, 28.5, 27.8, 27.1. MS (EI): m/z 509 (M+). HRMS (EI): calcd for
C29H35NO7 m/z 509.2413, found 509.2405.
(R)-N-tert-Butoxycarbonyl-1-(hydroxymethyl)-7-methoxy-6-
(pivaloyloxy)-3,4-dihydro-2(1H)-isoquinoline (12). Stepwise
Preparation by Ozonolysis of Alkene 5 and Reduction of
Aldehyde 6. To a stirred solution of 5 (20 mg, 0.05 mmol) in
CH2Cl2 (1 mL) was bubbled a stream of ozone at −78 °C (ca. 60 s).
An argon gas was then passed through the solution for an additional 1
min and Ph3P (26 mg, 0.1 mmol) was added. The mixture was stirred
at 0 °C for 15 min and concentrated in vacuo at 0 °C, giving a residue
that was dissolved in MeOH (2 mL). Then, to the MeOH solution
was added sodium borohydride (9.6 mg, 0.25 mmol) at 0 °C. The
resulting mixture was stirred at room temperature for 15 min.
Saturated ammonium chloride was slowly added to give a mixture that
was extracted with dichloromethane. The organic extract was washed
with brine, dried over MgSO4, and concentrated in vacuo. The residual
product was purified by silica gel column chromatography (50%
EtOAc in hexane) to provide alcohol 12 (15.2 mg) in 78% yield. [α]D22
1
= +40.4 (c 0.1, CHCl3). IR (CHCl3, cm−1): 3434, 1749, 1680. H
NMR (500 MHz, CDCl3): the compound exists as a 1.78:1 mixture of
carbamate rotamers; δ 6.79 (s, 1H), 6.75 (s, 1H), 5.25 (apparent bs,
0.64H), 5.10 (apparent bs, 0.36H), 3.94−3.70 (m, 6H), 3.40 (apparent
bs, 0.64H), 3.24 (apparent bs, 0.36H), 2.86−2.62 (m, 2H), 1.49 (s,
9H), 1.35 (s, 9H). 13C NMR (125 MHz, CDCl3): signals correspond
to both rotamers; δ 176.8, 157.0, 154.0, 149.6, 139.1, 131.5, 127.6,
127.3, 123.0, 122.6, 111.3, 80.5, 67.3, 66.0, 56.9, 56.6, 56.1, 39.6, 39.0,
37.7, 28.4, 27.7, 27.2. MS (EI): m/z 393 (M+). HRMS (EI): calcd for
C21H31NO6 m/z 393.2151, found 393.2147. Anal. Calcd for
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Hz, 0.4H), 3.04 (apparent t, J = 12.0 Hz, 0.6H), 3.00−2.78 (m, 1H),
2.64−2.58 (m, 1H), 1.39 (s, 3H), 1.35 (s, 9H), 1.20 (s, 6H). 13C NMR
(125 MHz, CDCl3): signals correspond to both rotamers; δ 176.7,
154.5, 154.2, 149.8, 139.4, 133.6, 132.9, 130.0, 129.9, 129.8, 129.5,
126.5, 124.1, 123.3, 123.0, 122.8, 111.2, 80.3, 79.9, 56.1, 52.5, 39.0,
38.1, 36.1, 28.1, 27.2, 27.1. MS (EI): m/z 553 (M+). HRMS (EI):
calcd for C28H35N5O5S m/z 553.2358, found 553.2366.
rotamers; δ 6.79−6.60 (m, 5H), 5.91 (s, 2H), 5.20 (apparent bs,
0.47H), 5.05 (apparent bs, 0.53H), 4.23 (apparent d, J = 12.0 Hz,
0.53H), 3.97 (apparent d, J = 12.0 Hz, 0.47H), 3.76 (apparent d, J =
12.0 Hz, 3H), 3.26−3.12 (m, 1H), 2.90−2.70 (m, 1H), 2.69−2.58 (m,
3H), 2.14−1.94 (m, 2H), 1.48 (s, 9H), 1.35 (s, 9H). 13C NMR (125
MHz, CDCl3): signals correspond to both rotamers; δ 176.8, 155.0,
154.8, 149.3, 147.5, 147.4, 145.6, 145.4, 138.7, 138.6, 136.1, 135.8,
135.6, 135.5, 126.6, 126.2, 122.8, 122.6, 121.0, 120.9, 111.2, 110.9,
108.8, 108.7, 108.1, 100.7, 80.0, 79.6, 56.0, 54.6, 53.8, 39.0, 38.6, 38.1,
36.6, 32.6, 32.5, 28.4, 27.6, 27.4, 27.1. MS (EI): m/z 511 (M+). HRMS
(EI): calcd for C29H37NO7 m/z 511.2570, found 511.2562. Anal.
Calcd for C29H37NO7: C, 68.08; H, 7.29; N, 2.74. Found: C, 67.68; H,
6.97; N, 2.75.
(R)-N-tert-Butoxycarbonyl-1-[(1-phenyl-1H-tetrazol-5-
sulfonyl)methyl]-7-methoxy-6-(pivaloyloxy)-3,4-dihydro-
2(1H)-isoquinoline (14). To a stirred solution of sulfide 13 (250 mg,
0.45 mmol) in ethanol (10 mL) were added ammonium para-
molybdate tetrahydrate (111 mg, 0.09 mmol) and 30% hydrogen
peroxide (0.5 mL, 5.4 mmol) at 0 °C. The mixture was stirred at room
temperature for 12 h, poured into saturated aqueous sodium
thiosulfate, and extracted with ethyl acetate three times. The combined
organic layers were washed with water and brine and dried over
MgSO4. The solvent was removed in vacuo and the residual product
was purified by flash chromatography (30% EtOAc in hexane) to give
14 (240 mg, 91%) as a white amorphous solid. Rf = 0.38 (30% EtOAc
in hexane). Mp: 70−71 °C. [α]2D0 = +73.8 (c 0.3, CHCl3). IR (CHCl3,
(S)-1-(2-(Benzo[d][1,3]dioxol-5-yl)ethyl)-N-tert-butoxycar-
bonyl-6-hydroxy-7-methoxy-3,4-dihydro-2(1H)-isoquinoline
(9). A mixture of 8 (66 mg, 0.13 mmol) and NaOMe (70.0 mg, 1.3
mmol) in MeOH (4 mL) was stirred for 4 h at room temperature. The
mixture was quenched with dilute HCl and extracted with ethyl
acetate. The extract was dried over MgSO4, and concentrated in vacuo,
giving a residue that was subjected to silica gel column
chromatography (30% EtOAc in hexane) to give 9 (50 mg, 90%) as
a colorless solid. Rf = 0.31 (30% EtOAc in hexane). Mp: 129−131 °C.
1
cm−1): 1750, 1691, 1352, 1116. H NMR (500 MHz, CDCl3): the
compound exists as a 2:1 mixture of carbamate rotamers; δ 7.72 (d, J =
7.0 Hz, 2H), 7.66−7.54 (m, 3H), 6.88 (s, 0.33H), 6.84 (s, 0.67H), 6.80
(s, 0.33H), 6.77 (s, 0.67H), 5.99 (apparent t, J = 6.0 Hz, 0.33H), 5.84
(apparent d, J = 6.0 Hz, 0.67H), 4.24−4.10 (m, 2H), 4.5 (m, 0.67H),
3.96 (m, 0.33H), 3.80 (m, 3H), 3.26 (m, 0.67H), 3.15 (m, 0.33H),
2.86 (m, 0.33H), 2.78 (m, 0.67H), 2.69−2.60 (m, 1H), 1.35 (s, 9H),
1.32 (s, 9H). 13C NMR (125 MHz, CDCl3): signals correspond to
both rotamers; δ 176.6, 154.2, 153.8, 153.5, 153.2, 150.1, 149.9, 139.8,
139.7, 133.1, 132.8, 131.8, 131.4, 131.3, 131.2, 129.7, 129.3, 127.2,
126.7, 125.5, 124.8, 123.4, 123.1, 110.7, 110.5, 81.0, 80.6, 60.3, 59.8,
56.1, 49.6, 49.3, 39.0, 38.4, 36.7, 28.2, 28.0, 27.1. MS (EI): m/z 585
(M+). HRMS (EI): calcd for C28H35N5O7S m/z 585.2257, found
585.2251. Anal. Calcd for C28H35N5O7S: C, 57.42; H, 6.02; N, 11.96.
Found: C, 57.63; H, 6.10; N, 11.69.
[α]2D2 = +51.4 (c 0.24, CHCl3). IR (CHCl3, cm−1): 3365, 1683. H
1
NMR (500 MHz, CDCl3): the compound exists as a 1:1 mixture of
carbamate rotamers; δ 6.76−6.64 (m, 4H), 6.53 (s, 1H), 5.90 (s, 2H),
5.52 (s, 1H), 5.13 (apparent bs, 0.5H), 4.99 (apparent bs, 0.5H), 4.18
(apparent d, J = 10.0 Hz, 0.5H), 3.94 (apparent d, J = 10.0 Hz, 0.5H),
3.85 (apparent d, J = 10.0 Hz, 3H), 3.28−3.15 (m, 1H), 2.84−2.70 (m,
1H), 2.68−2.56 (m, 3H), 2.10−1.92 (m, 2H), 1.48 (s, 9H). 13C NMR
(125 MHz, CDCl3): signals correspond to both rotamers; δ 155.0,
154.8, 147.5, 147.4, 145.6, 145.4, 144.9, 144.2, 144.1, 136.0, 135.7,
129.4, 128.9, 127.1, 126.7, 120.9, 120.8, 114.4, 114.2, 109.5, 109.1,
108.8, 108.7, 108.1, 108.0 100.7, 79.9, 79.5, 56.0, 54.5, 53.7, 39.2, 38.8,
38.4, 36.9, 32.6, 32.5, 28.4, 27.8, 27.6. MS (EI): m/z 427 (M+). HRMS
(EI): calcd for C24H29NO6 m/z 427.1995, found 427.1989. Anal.
Calcd for C24H29NO6: C, 67.43; H, 6.84; N, 3.28. Found: C, 67.11; H,
6.51; N, 3.22.
(S)-1-(2-(Benzo[d][1,3]dioxol-5-yl)ethenyl)-N-tert-butoxycar-
bonyl-7-methoxy-6-(pivaloyloxy)-3,4-dihydro-2(1H)-isoquino-
line (7). To a stirred solution of 14 (117 mg, 0.2 mmol) and piperonal
(164 mg, 1 mmol) in THF (5 mL) was added lithium bis-
(trimethylsilyl)amide (1.30 M in THF, 0.46 mL, 0.6 mmol) dropwise
at −35 °C. The resulting pale-yellow solution was stirred vigorously
for an additional 1 h and diluted with the sat. ammonium chloride, and
the mixture was extracted with ethyl acetate. The organic extract was
washed with water and brine and dried over MgSO4. The solvent was
evaporated and the residual product was purified by silica gel column
chromatography (5% and then 10% EtOAc in hexane) to provide 7 in
85% yield (86 mg) as a colorless solid. Rf = 0.40 (20% EtOAc in
hexane). [α]2D0 = +37.3 (c 0.28, CHCl3). Mp: 61−62 °C. IR (CHCl3,
(S)-1-(2-(Benzo[d][1,3]dioxol-5-yl)ethyl)-N-tert-butoxycar-
bonyl-6,7-dimethoxy-3,4-dihydro-2(1H)-isoquinoline (10). To a
solution of 9 (43 mg, 0.1 mmol) in MeOH (4 mL) was added
TMSCHN2 (0.6 M solution in hexane, 1.66 mL, 1 mmol) and the
mixture was stirred at room temperature for 4 h. Water was added and
the reaction mixture was extracted with ethyl acetate. The extract was
dried over MgSO4 and concentrated in vacuo, giving a residue that was
subjected to silica gel column chromatography (30% EtOAc in
hexane) to give 10 (41 mg, 93%) as a pale yellow liquid. Rf = 0.3 (30%
EtOAc in hexane). [α]D22 = +56.2 (c 0.95, CHCl3). IR (CHCl3, cm−1):
1
1749, 1684. H NMR (500 MHz, CDCl3): the compound exists as a
1
cm−1): 1752, 1691. H NMR (500 MHz, CDCl3): δ 6.88 (s, 1H),
1.13:1 mixture of carbamate rotamers; δ 6.75−6.57 (m, 3H), 6.56−
6.50 (m, 2H), 5.90 (s, 2H), 5.15 (apparent bs, 0.47H), 5.00 (apparent
bs, 0.53H), 4.25 (apparent d, J = 12.0 Hz, 0.53H), 4.00 (apparent d, J
= 12.0 Hz, 0.47H), 3.84 (s, 6H), 3.22−3.10 (m, 1H), 2.90−2.63 (m,
1H), 2.62−2.58 (m, 3H), 2.10−1.94 (m, 2H), 1.49 (s, 9H). 13C NMR
(125 MHz, CDCl3): signals correspond to both rotamers; δ 155.0,
154.8, 147.6, 147.5, 147.3, 145.6, 145.4, 144.9, 136.0, 135.7, 130.0,
129.5, 126.3, 125.9, 120.8, 111.5, 111.4, 110.1, 109.8, 108.7, 108.1,
100.7, 79.9, 79.5, 56.0, 55.8, 54.4, 53.1, 39.1, 38.7, 38.2, 36.8, 32.7,
32.6, 28.4, 28.0, 27.9. MS (EI): m/z 441 (M+). HRMS (EI): calcd for
C25H31NO6 m/z 441.2151, found 441.2157.
6.86−6.66 (m, 4H), 6.32 (d, J = 15.0 Hz, 1H), 6.12 (d, J = 15.0 Hz,
1H), 5.93 (s, 2H), 5.65 (apparent bs, 1H), 4.20 (apparent bs, 1H),
3.75 (s, 3H), 3.15 (apparent bs, 1H), 2.85 (t, J = 15.0 Hz, 1H), 2.64
(d, J = 15.0 Hz, 1H), 1.49 (s, 9H), 1.36 (s, 9H). 13C NMR (125 MHz,
CDCl3): δ 176.8, 154.5, 149.5, 148.0, 147.2, 138.9, 131.2, 131.0, 127.3,
127.1, 122.7, 121.1, 111.8, 108.3, 108.2, 105.7, 101.0, 79.9, 56.0, 39.0,
29.6, 28.5, 27.8, 27.1. MS (EI): m/z 509 (M+). HRMS (EI): calcd for
C29H35NO7 m/z 509.2413, found 509.2405. Anal. Calcd for
C29H35NO7: C, 68.35; H, 6.92; N, 2.75. Found: C, 68.05; H, 6.66;
N, 2.99.
(S)-1-(2-(Benzo[d][1,3]dioxol-5-yl)ethyl)-6,7-dimethoxy-
1,2,3,4-tetrahydroisoquinoline (11). A solution of 10 (38 mg,
0.086 mmol) and trifluoroacetic acid (0.32 mL, 4.3 mmol) in CH2Cl2
(4 mL) was stirred at room temperature for 30 min. The reaction
mixture was carefully poured into aq NaHCO3 and extracted with
CH2Cl2 three times. The combined extracts were dried over MgSO4
and concentrated in vacuo. The residual product was purified by silica
gel column chromatography (10% MeOH in CHCl3) to provide 11
(26 mg, 90%) as a pale yellow liquid. Rf = 0.36 (10% MeOH in
(S)-1-(2-(Benzo[d][1,3]dioxol-5-yl)ethyl)-N-tert-butoxycar-
bonyl-7-methoxy-6-(pivaloyloxy)-3,4-dihydro-2(1H)-isoquino-
line (8). A mixture of 7 (76 mg, 0.15 mmol) and 5% Pd−charcoal (20
mg) was stirred in MeOH (5 mL) under a H2 gas atmosphere at room
temperature for 24 h. The mixture was diluted with CHCl3 and filtered
through a Celite pad. The filtrate was concentrated in vacuo, giving a
residue that was subjected to silica gel column chromatography (20%
EtOAc in hexane) to give 8 in 95% yield (73 mg) as a colorless solid.
Rf = 0.42 (20% EtOAc in hexane). Mp: 50−52 °C. [α]2D2 = +41.1 (c
1
1
0.3, CHCl3). IR (CHCl3, cm−1): 1749, 1684. H NMR (500 MHz,
CHCl3). [α]2D0 = −2.7 (c 0.56, CHCl3). IR (CHCl3, cm−1): 3346. H
CDCl3): the compound exits as a 1.13:1 mixture of carbamate
NMR (500 MHz, CDCl3): δ 6.73 (d, J = 8.0 Hz, 2H), 6.67 (d, J = 8.0
11105
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Hz, 1H), 6.57 (s, 1H), 6.55 (s, 1H), 5.91 (s, 2H), 4.00 (d, J = 6.0 Hz,
1H), 3.84 (s, 3H), 3.83 (s, 3H), 3.28 (m, 1H), 3.04 (m, 1H), 2.85−
2.60 (m, 4H), 2.41 (bs, 1H), 2.14−1.98 (m, 2H). 13C NMR (125
MHz, CDCl3): δ 147.6, 147.5, 147.3, 145.6, 135.8, 130.1, 126.7, 121.0,
111.7, 109.1, 108.8, 108.2, 100.7, 56.0, 55.8, 54.8, 40.8, 38.2, 32.0, 28.8.
MS (EI): m/z 341 (M+). HRMS (EI): calcd for C20H23NO4 m/z
341.1627, found 341.1636.
16a. Rf = 0.32 (20% EtOAc in hexane); colorless solid. Mp: 68−70
°C. [α]2D0 = +42.1 (c 0.5, CHCl3). IR (CHCl3 film, cm−1): 1752, 1691,
1508. H NMR (500 MHz, CDCl3): the compound exists as a 1.13:1
1
mixture of carbamate rotamers; δ 7.19 (d, J = 7.0 Hz, 2H), 6.96 (d, J =
7.0 Hz, 2H), 6.75 (s, 0.53H), 6.74 (s, 0.47H), 6.62 (s, 1H), 5.21
(apparent bs, 0.47H), 5.07 (apparent bs, 0.53H), 4.23 (apparent d, J =
8.4 Hz, 0.53H), 3.97 (apparent d, J = 5.5 Hz, 0.47H), 3.76 (apparent d,
J = 10.5 Hz, 3H), 3.28−3.12 (m, 1H), 2.90−2.56 (m, 4H), 2.14−1.98
(m, 2H), 1.49 (s, 9H), 1.35 (s, 9H), 1.34 (s, 9H). 13C NMR (125
MHz, CDCl3): signals correspond to both rotamers; δ 177.1, 176.8,
155.0, 154.8, 149.4, 149.2, 139.2, 139.0, 138.7, 138.6, 136.0, 135.6,
129.0, 126.6, 126.2, 122.8, 122.6, 121.3, 121.2, 111.2, 110.9, 80.0, 79.6,
56.1, 54.7, 53.8, 39.02, 39.00, 38.6, 38.2, 36.7, 32.3, 32.2, 28.4, 27.6,
27.4, 27.18, 27.12. MS (EI): m/z 567 (M+). HRMS (EI): calcd for
C33H45NO7 m/z 567.3196, found 567.3193. Anal. Calcd for
C33H45NO7: C, 69.82; H, 7.99; N, 2.47. Found: C, 69.53; H, 7.80;
N, 2.42.
(+)-Dysoxyline (1). A mixture of 11 (24 mg, 0.07 mmol) and
paraformaldehyde (6.3 mg, 0.21 mmol) in MeOH (1 mL) was added
to a stirred solution of ZnCl2 (4.7 mg, 0.035 mmol) and NaBH3CN
(4.8 mg, 0.077 mmol) in MeOH (3 mL) at room temperature and the
mixture was stirred for 15 min. Water was added and the mixture was
extracted with ethyl acetate. The extract was dried over MgSO4,
filtered, and condensed. The residual product was purified by silica gel
column chromatography (10% MeOH in CHCl3) to provide
(+)-dysoxyline 1 (26 mg, 90%) as a pale yellow liquid. Rf = 0.38
(10% MeOH in CHCl3). [α]2D0 = +16.2 (c 0.35, EtOH); lit.4 [α]D25
=
+22 (c 0.34, MeOH). IR (CHCl3, cm−1): 2933, 1608, 1515, 1440,
1372, 1246, 1104, 1038, 928, 808, 755. 1H NMR (500 MHz, CDCl3):
δ 6.71 (d, J = 8.0 Hz, 1H), 6.67 (s, 1H), 6.62 (d, J = 8.0 Hz, 1H), 6.56
(s, 1H), 6.53 (s, 1H), 5.90 (s, 2H), 3.85 (s, 3H), 3.83 (s, 3H), 3.40 (t, J
= 4.0 Hz, 1H), 3.15 (m, 1H), 2.82−2.60 (m, 4H), 2.49 (m, 1H), 2.46
(s, 3H), 2.06−1.94 (s, 2H). 13C NMR (125 MHz, CDCl3): δ 147.4,
147.27, 147.22, 145.3, 136.8, 129.7, 126.7, 121.0, 111.2, 110.0, 108.9,
108.0, 100.6, 62.6, 55.9, 55.7, 48.1, 42.6, 37.1, 31.3, 25.4. MS (EI): m/z
355 (M+). HRMS (EI): calcd for C21H25NO4 m/z 355.1783, found
355.1792. The enantiomeric ratio (er: 94:6; 88% ee) was determined
by chiral HPLC analysis (Sumichiral OA-4700, hexane:2-propanol:T-
FA = 90:10:0.2, flow rate = 1.0 mL/min, T = 20 °C, 254 nm): ts = 20.0
(minor; R-isomer), ts = 20.8 (major; S-isomer).
Synthesis of 15a and 15b from 14. A stirred solution of sulfone
14 (117 mg, 0.2 mmol) and 4-(pivaloyloxy)benzaldehyde (206 mg, 1
mmol) or 4-methoxybenzaldehyde (136 mg, 1 mmol) was cooled to
−35 °C in THF (5 mL). To this mixture was added dropwise a
solution of lithium bis(trimethylsilyl)amide (1.30 M in THF, 0.46 mL,
0.6 mmol) at the same temperature. After following the experimental
procedure described for the synthesis of 7, compounds 15a and 15b
were obtained in 79% and 86% yields, respectively.
16b. Rf = 0.42 (20% EtOAc in hexane); colorless solid. Mp: 118−
120 °C. [α]2D4 = +45.5 (c 1.0, CHCl3). IR (CHCl3 film, cm−1): 1752,
1
1688, 1614. H NMR (500 MHz, CDCl3): the compound exists as a
1.13:1 mixture of carbamate rotamers; δ 7.10 (d, J = 8.0 Hz, 2H), 6.81
(d, J = 8.0 Hz, 2H), 6.78−6.72 (apparent m, 1H), 6.62 (s, 1H), 5.20
(apparent bs, 0.47H), 5.06 (apparent bs, 0.53H), 4.23 (apparent d, J =
14.5 Hz, 0.53H), 3.97 (apparent d, J = 14.5 Hz, 0.47H), 3.80−3.72 (m,
6H), 3.30−3.12 (m, 1H), 2.90−2.78 (m, 1H), 2.74−2.55 (m, 3H),
2.12−1.92 (m, 2H), 1.49 (s, 9H), 1.35 (s, 9H). 13C NMR (125 MHz,
CDCl3): signals correspond to both rotamers; δ 176.8, 157.8, 157.7,
155.0, 154.8, 149.4, 138.7, 138.5, 135.7, 134.1, 129.1, 126.7, 126.2,
122.8, 122.6, 114.7, 113.8, 111.3, 111.0, 80.0, 79.5, 56.1, 55.2, 54.7,
53.9, 39.0, 38.6, 38.2, 36.7, 32.0. 31.8, 28.5, 27.7, 27.4, 27.2. MS (EI):
m/z 497 (M+). HRMS (EI): calcd for C29H39NO6 m/z 497.2777,
found 497.2779. Anal. Calcd for C29H39NO6: C, 69.99; H, 7.90; N,
2.81. Found: C, 69.70; H, 7.98; N, 2.66.
Synthesis of 17a and 17b from 16a and 16b. Into a stirred
solution of 16 (0.12 mmol) in CH2Cl2 (4 mL) was dropped TMSOTf
(83 μL, 0.36 mmol) at 0 °C and the reaction mixture was stirred at
room temperature for 15 min. The mixture was poured into aq
NaHCO3, stirred for 10 min, and diluted with water. It was extracted
with CH2Cl2, dried over MgSO4, filtered, and then concentrated in
vacuo. The residual product was purified by silica gel column
chromatography (10% MeOH in CHCl3) to provide the desired
compound 17a in 86% yield and 17b in 90% yield, respectively.
15a. Rf = 0.30 (20% EtOAc in hexane); colorless solid. Mp: 82−84
°C. [α]2D0 = +54.9 (c 0.24, CHCl3). IR (CHCl3 film, cm−1): 1751,
1
1696. H NMR (500 MHz, CDCl3): δ 7.34 (d, J = 8.0 Hz, 2H), 6.99
(d, J = 8.0 Hz, 2H), 6.81 (s, 1H), 6.71 (s, 1H), 6.40 (apparent d, J =
14.0 Hz, 1H), 6.25 (apparent d, J = 14.0 Hz, 1H), 5.63 (apparent bs,
1H), 4.16 (apparent bs, 1H), 3.75 (s, 3H), 3.20 (apparent bs, 1H),
2.86 (apparent t, J = 13.5 Hz, 1H), 2.65 (apparent d, J = 13.5 Hz, 1H),
1.49 (s, 9H), 1.36 (s, 9H), 1.34 (s, 9H). 13C NMR (125 MHz,
CDCl3): δ 176.9, 176.8, 154.5, 150.5, 149.5, 139.0, 134.1, 132.9, 130.6,
129.1, 127.3, 127.1, 122.7, 121.5, 111.7, 80.0, 56.6, 56.0, 39.0, 37.5,
28.4, 27.8, 27.1, 27.0. MS (EI): m/z 565 (M+). HRMS (EI): calcd for
C33H43NO7 m/z 565.3039, found 565.3047. Anal. Calcd for
C33H43NO7: C, 70.06; H, 7.66; N, 2.48. Found: C, 69.89; H, 7.39;
N, 2.35.
17a. Rf = 0.40 (10% MeOH in CHCl3); pale-yellow liquid. [α]D201
=
−15.4 (c 0.5, CHCl3). IR (CHCl3 film, cm−1): 3420, 1749, 1508. H
NMR (500 MHz, CDCl3): δ 7.22 (d, J = 8.5 Hz, 2H), 6.97 (d, J = 8.5
Hz, 2H), 6.72 (s, 1H), 6.62 (s, 1H), 3.97 (dd, J = 3.0 and 6.0 Hz, 1H),
3.74 (s, 3H), 3.22 (m, 1H), 2.99 (m, 1H), 2.83 (m, 1H), 2.80−2.60
(m, 3H), 2.20−1.98 (m, 2H), 1.35 (s, 9H), 1.34 (s, 9H). 13C NMR
(125 MHz, CDCl3): δ 177.2, 176.8, 149.2, 149.1, 139.4, 138.4, 137.0,
129.2, 127.4, 122.9, 121.3, 110.1, 56.1, 55.1, 40.6, 39.0, 38.0, 31.7, 29.6,
28.8, 27.2, 27.1. MS (EI): m/z 467 (M+). HRMS (EI): calcd for
C28H37NO5 m/z 467.2671, found 467.2663.
15b. Rf = 0.40 (20% EtOAc in hexane); colorless solid. Mp: 49−51
17b. Rf = 0.40 (10% MeOH in CHCl3); pale-yellow liquid. [α]D24
=
°C. [α]2D4 = +73.9 (c 0.5, CHCl3). IR (CHCl3 film, cm−1): 1752, 1691,
−14.2 (c 0.75, CHCl3). IR (CHCl3 film, cm−1): 3584, 1751. 1H NMR
(500 MHz, CDCl3): δ 7.14 (d, J = 9.5 Hz, 2H), 6.83 (d, J = 9.5 Hz,
2H), 6.71 (s, 1H), 6.60 (s, 1H), 4.02 (m, 1H), 3.78 (s, 3H), 3.73 (s,
3H), 3.24 (m, 1H), 3.03 (m, 1H), 2.95 (bs, 1H), 2.86−2.73 (m, 2H),
2.72−2.64 (m, 2H), 2.14−1.95 (m, 2H), 1.35 (s, 9H). 13C NMR (125
MHz, CDCl3): δ 176.8, 157.8, 149.4, 138.6, 136.1, 133.8, 129.3, 126.8,
122.9, 113.9, 110.2, 56.1, 55.2, 55.0, 40.4, 39.0, 37.9, 31.3, 28.2, 27.2.
MS (EI): m/z 397 (M+). HRMS (EI): calcd for C24H31NO4 m/z
397.2253, found 397.2259.
Synthesis of 18a and 18b from 17a and 17b. A mixture of
compound 17 (0.1 mmol) and paraformaldehyde (9 mg, 0.3 mmol) in
MeOH (1 mL) was added to a stirred solution of ZnCl2 (6.8 mg, 0.05
mmol) and NaCNBH3 (6.9 mg, 0.11 mmol) in MeOH (4 mL). The
resulting mixture was stirred at room temperature for 20 min.
Following a similar procedure, 18a and 18b were obtained in 83% and
87% yields, respectively.
1
1606. H NMR (500 MHz, CDCl3): δ 7.28 (d, J = 8.5 Hz, 2H), 6.83
(d, J = 8.5 Hz, 2H), 6.80 (s, 1H), 6.71 (s, 1H), 6.36 (apparent d, J =
16.0 Hz, 1H), 6.17 (apparent d, J = 16.0 Hz, 1H), 5.75 (apparent bs,
1H), 4.16 (apparent bs, 1H), 3.79 (s, 3H), 3.75 (s, 3H), 3.20
(apparent bs, 1H), 2.85 (m, 1H), 2.63 (m, 1H), 1.49 (s, 9H), 1.36 (s,
9H). 13C NMR (125 MHz, CDCl3): δ 176.8, 159.3, 154.6, 149.5,
139.0, 133.3, 131.1, 129.4, 127.7, 127.2, 126.9, 122.8, 114.0, 111.9,
79.9, 56.6, 56.1, 55.3, 39.0, 37.9, 29.7, 28.5, 27.9, 27.2. MS (EI): m/z
495 (M+). HRMS (EI): calcd for C29H37NO6 m/z 495.2621, found
495.2612. Anal. Calcd for C29H37NO6: C, 70.28; H, 7.52; N, 2.83.
Found: C, 70.48; H, 7.22; N, 3.01.
Synthesis of 16a and 16b from 15a and 15b. Compounds 15a
and 15b (0.15 mmol) were hydrogenated in MeOH (5 mL) under the
same conditions described for the synthesis of 8 to provide 16a or 16b
in 94% and 95% yields, respectively.
11106
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18a. Rf = 0.5 (10% MeOH in CHCl3); pale-yellow liquid. [α]D20
=
ACKNOWLEDGMENTS
■
−2.2 (c 0.5, CHCl3). IR (CHCl3 film, cm−1): 1750. H NMR (500
MHz, CDCl3): δ 7.17 (d, J = 8.5 Hz, 2H), 6.95 (d, J = 8.5 Hz, 2H),
6.73 (s, 1H), 6.59 (s, 1H), 3.74 (s, 3H), 3.44 (t, J = 5.5 Hz, 1H), 3.12
(m, 1H), 2.84−2.61 (m, 4H), 2.56 (m, 1H), 2.45 (s, 3H), 2.08−1.96
(m, 2H), 1.35 (s, 9H), 1.34 (s, 9H). 13C NMR (125 MHz, CDCl3): δ
177.2, 176.9, 149.3, 149.0, 140.0, 138.3, 135.9, 129.2, 126.9, 122.5,
121.1, 111.1, 62.7, 56.1, 47.5, 42.5, 39.02, 39.01, 36.9, 30.9, 27.2, 27.1,
24.6. MS (EI): m/z 481 (M+). HRMS (EI): calcd for C29H39NO5 m/z
481.2828, found 481.2833.
1
This work was supported by a Grant-in-Aid for Scientific
Research from the Japan Society for the Promotion of Science.
R.J.R. acknowledges postdoctoral fellowship support provided
to foreign researchers by the Japan Society for the Promotion
of Science.
REFERENCES
■
18b. Rf = 0.42 (10% MeOH in CHCl3); pale-yellow liquid. [α]D24
=
(1) (a) Scott, J. D.; Williams, R. M. Chem. Rev. 2002, 102, 1669−
1730. (b) Ozturk, T. In The Alkaloids; Cordell, G. A., Ed.; Academic
1
+0.42 (c 0.22, CHCl3). IR (CHCl3 film, cm−1): 1748. H NMR (400
MHz, CDCl3): δ 7.10 (d, J = 8.4 Hz, 2H), 6.82 (d, J = 8.4 Hz, 2H),
6.72 (s, 1H), 6.58 (s, 1H), 3.77 (s, 3H), 3.74 (s, 3H), 3.44 (t, J = 5.6
Hz, 1H), 3.14 (m, 1H), 2.80−2.59 (m, 4H), 2.54 (m, 1H), 2.46 (s,
3H), 2.08−1.96 (m, 2H), 1.35 (s, 9H). 13C NMR (100 MHz, CDCl3):
δ 176.8, 157.6, 149.2, 138.3, 136.0, 134.7, 129.3, 126.8, 122.4, 113.7,
111.1, 62.7, 56.0, 55.2, 47.4, 42.4, 39.0, 37.1, 30.8, 27.2, 24.6. MS (EI):
m/z 411 (M+). HRMS (EI): calcd for C25H33NO4 m/z 411.2409,
found 411.2406.
Press: San Diego, 2000; Vol. 53, pp 119−238. (c) Lundstrom, J. In
̈
The Alkaloids; Brossi, A., Ed.; Academic Press: New York, 1983; Vol.
21, pp 255−327. (d) Bentley, K. W. Nat. Prod. Rep. 2005, 22, 249−
268.
(2) (a) Kametani, T.; Koizumi, M. In The Alkaloids; Brossi, A., Ed.;
Academic Press: New York, 1973; Vol. 14, pp 265−323. (b) Kametani,
T.; Koizumi, M. In The Alkaloids; Brossi, A., Ed.; Academic Press: New
York, 1989; Vol. 36, pp 171−223. (c) Umezawa, B.; Hoshino, O.
Heterocycles 1975, 3, 1005−1033. (d) Tojo, E. J. Nat. Prod. 1989, 52,
909−921. (e) Blasko, G.; Cordell, G. A. Heterocycles 1988, 27, 1269−
1300.
Synthesis of Compounds 2 and 3. Methanolysis of O-pivaloates
18a and 18b was carried out by the same method described for the
methanolysis of 8.
(+)-Colchiethanamine 2. Compound 2 was obtained from 18a in
85% yield as a pale-yellow liquid using 20% MeOH in CHCl3 as an
eluent for column chromatography. Rf = 0.5 (20% MeOH in CHCl3).
[α]2D0 = +4.8 (c 0.3, MeOH). IR (CHCl3, cm−1): 3566, 3460, 3024,
2360, 1508, 1456. 1H NMR (500 MHz, CDCl3): δ 7.00 (d, J = 8.5 Hz,
2H), 6.72 (d, J = 8.5 Hz, 2H), 6.63 (s, 1H), 6.47 (s, 1H), 3.82 (s, 3H),
3.49 (t, J = 6.0 Hz, 1H), 3.20 (m, 1H), 2.84−2.73 (m, 2H), 2.72−2.62
(m, 2H), 2.55 (m, 1H), 2.48 (s, 3H), 2.11 (m, 1H), 1.97 (m, 1H). 13C
NMR (125 MHz, CDCl3): δ 154.1, 145.0, 144.0, 134,0, 129.4, 128.3,
126.4, 115.3, 114.2, 109.4, 62.6, 56.0, 47.1, 42.0, 37.2, 30.9, 29.6. MS
(EI): m/z 313 (M+). HRMS (EI): calcd for C19H23NO3 m/z 313.1678,
found 313.1669. The enantiomeric ratio (er: 93:7; 86% ee) was
determined by chiral HPLC analysis (Sumichiral OA-4700, hexane:2-
propanol:TFA = 85:15:0.2, flow rate = 1.0 mL/min, T = 20 °C, 254
nm): ts = 24.0 (minor; R-isomer), ts = 25.2 (major; S-isomer).
(+)-Colchiethine 3. Compound 3 was obtained from 18b in 83%
yield as a yellow viscous liquid using 15% MeOH in CHCl3 as an
eluent for column chromatography. Rf = 0.38 (10% MeOH in CHCl3).
[α]2D4 = +1.9 (c 0.4, MeOH). IR (CHCl3, cm−1): 3544, 3018, 2936,
2360, 1611, 1509, 1464, 1371, 1339, 1245, 1215, 1178, 1105, 1034,
754, 668. 1H NMR (400 MHz, CDCl3): δ 7.12 (dd, J = 2.0 and 8.5 Hz,
2H), 6.83 (dd, J = 2.0 and 8.5 Hz, 2H), 6.65 (s, 1H), 6.50 (s, 1H), 3.84
(s, 3H), 3.79 (s, 3H), 3.47 (t, J = 6.4 Hz, 1H), 3.19 (m, 1H), 2.80−
2.64 (m, 4H), 2.57 (m, 1H), 2.50 (s, 3H), 2.14−1.95 (m, 2H). 13C
NMR (100 MHz, CDCl3): δ 157.6, 145.0, 143.8, 134.6, 129.3, 114.1,
113.7, 109.3, 62.7, 56.0, 55.2, 47.5, 42.3, 37.1, 30.8, 24.7. MS (EI): m/z
327 (M+). HRMS (EI): calcd for C20H25NO3 m/z 327.1834, found
327.1837. The enantiomeric ratio (er: 93.5:6.5; 87% ee) was
determined by chiral HPLC analysis (Sumichiral OA-4700,
hexane:2-propanol:TFA = 85:15:0.2, flow rate = 0.5 mL/min, T =
24 °C, 254 nm): ts = 28.1 (minor; R-isomer), ts = 29.1 (major; S-
isomer).
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ASSOCIATED CONTENT
■
S
* Supporting Information
HPLC chromatograms of 12 and 1−3 and NMR spectra for all
new compounds. This material is available free of charge via the
Internet at http://pubs.acs.org
AUTHOR INFORMATION
■
(10) Some syntheses of racemic compounds: (a) Nimgirawath, S.
Aust. J. Chem. 1994, 47, 957−962. (b) Zhang, A.; Leitch, D. C.; Lu, M.;
Patrick, B. O.; Schafer, L. L. Chem.Eur. J. 2007, 13, 2012−2022.
(c) Singh, K. N.; Singh, P.; Kaur, P.; Singh, P. Synlett 2012, 23, 760−
764.
Corresponding Author
*E-mail: juenishi@mb.kyoto-phu.ac.jp
Notes
The authors declare no competing financial interest.
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The Journal of Organic Chemistry
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(16) Low- and high-resolution mass spectra were measured by a
double-focusing mass spectrometer.
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