Synthetic studies on saframycin anibiotics: an improved synthesis of tricyclic lactam intermediate and construction of the core ring system of saframycin A

Article abstract of DOI:10.3987/COM-14-S(K)24

An improved synthesis of the tricyclic lactam intermediate of saframycin antibiotics and the construction of the core ring system having a cyano group at C-21 position were presented.1 The stereochemistry of several key intermediates was determined by X-r

Full text of DOI:10.3987/COM-14-S(K)24

HETEROCYCLES, Vol. 90, No. 1, 2015
327
HETEROCYCLES, Vol. 90, No. 1, 2015, pp. 327 - 343. © 2015 The Japan Institute of Heterocyclic Chemistry
Received, 2nd May, 2014, Accepted, 13th June, 2014, Published online, 24th June, 2014
DOI: 10.3987/COM-14-S(K)24
SYNTHETIC STUDIES ON SAFRAMYCIN ANIBIOTICS: AN
IMPROVED SYNTHESIS OF TRICYCLIC LACTAM INTERMEDIATE
AND CONSTRUCTION OF THE CORE RING SYSTEM OF
SAFRAMYCIN A
Shinya Kimura, Shintaro Kawai, Masayuki Azuma, Yoshifumi Umehara,
Yu-ichi Koizumi, Masashi Yokoya, and Naoki Saito*
Graduate School of Pharmaceutical Sciences, Meiji Pharmaceutical University,
2-522-1 Noshio, Kiyose, Tokyo 204-8588, Japan
E-mail: naoki@my-pharm.ac.jp
This paper is dedicated to Professor Dr. Isao Kuwajima (Professor Emeritus,
Tokyo Institute of Technology) on the occasion of his 77th birthday.
Abstract – An improved synthesis of the tricyclic lactam intermediate of
saframycin antibiotics and the construction of the core ring system having a cyano
group at C-21 position were presented.1 The stereochemistry of several key
intermediates was determined by X-ray crystallographic analysis.
INTRODUCTION
Natural products belonging to the bistetrahydroisoquinolinequinone family and their reduced forms,
including saframycins,2 renieramycins,3 and the most notable example, ecteinascidin 743,4 have received
considerable attention due to their potent biological activities and structural diversity, as well as their
meager availability in nature (Figure 1).5 Among them, saframycin A is the most representative
compound because of its remarkable antitumor activity.6 To date, one racemic and three asymmetric total
syntheses of saframycin A have been accomplished by the groups of Fukuyama,7 Corey,8 Myers,9 and
Liu.10
In the course of our research on new metabolites, which involves the isolation and characterization of
biologically active compounds and the synthesis of their respective analogues, we have developed the
total syntheses of (±)-saframycins B11 and C,12 and (-)-N-acetylsaframycin Mx 2.13 Furthermore, we
have reported the total syntheses of (±)-renieramycin G14 and (±)-cribrostatin 4.15 However, none of

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those compounds exhibited biological activities, the reason being that a cyano or a hydroxyl group at
C-21 position is essential to producing the desired biological activities, and the elimination of those
functional groups under physiological conditions results in the formation of a reactive iminium species
that is responsible for covalent bond formation with its target compound.16
OMe
OMe
HO
O
H
Me
O
O
H
Me
O
N
O
O
O
E
H
MeO
OMe
H
N
H
N
4
Me
D
Me
O
HO
H
Me
N
Me
N
Me
A
B
C
14
AcO
S
H
MeO
H
MeO
H
21
O
1
Me
H
H
N
Me
O
X
X Y
Me
NH
O
N
H
O
O
O
H
O
H
X
O
Me
Me
ecteinascidins
743: X = OH
770: X = CN
saframycins
A: X = CN
B: X = H
renieramycins
E: X = OH, Y = H
G: X, Y = O
S: X = OH
M: X = CN, Y = H
Figure 1. Structures of bistetrahydroisoquinoline natural products
We have already reported the preparation of the key tricyclic lactam intermediate of saframycin A.17 In
this paper, we describe new developments in the total synthesis of saframycin A, including an improved
synthesis of the tricyclic lactam intermediate of saframycin A and the construction of the core ring system
having a cyano group at C-21 position.
RESULTS AND DISCUSSION
Our strategy for the synthesis of saframycin A was based on retrosynthetic analysis using tricyclic lactam
(1) as the key intermediate. Reduction of the double bond of 217 by catalytic hydrogenation (2.7 MPa) in
the presence of 20% Pd(OH)2/C in ethanol at 80 oC for 22 h occurred cleanly from the -face to give 1 in
94% yield (Scheme 1). With key intermediate 1 in hand, we looked into ways to establish a practical
conversion of 318 into 10 with reduction of the number of steps from seven (26.5% overall yield) to four
(Scheme 2). Treatment of 3 with isopropyl chloroformate gave imide 11 in 96% yield. Condensation of
11 with 2,4,5-trimethoxy-3-methylbenzaldehyde in the presence of a base afforded 12 in 78% yield.
Chemoselective reduction of the carbonyl group at C-2 of 12 with lithium tri-tert-butoxyaluminum
hydride, followed by treatment with formic acid at 60 oC for 1 h gave 13 in 64% yield. Deprotection of 13
o
with TFA and H2SO4 at 25 C for 5 h gave (Z)-lactam 10 in 91% yield. Thus, we were able to devise a
four-step transformation of 3 into 10 in 43.6% overall yield.

HETEROCYCLES, Vol. 90, No. 1, 2015
329
O
O
OMe
OMe
MeO
MeO
O
OMe
OMe
MeO
MeO
O
O
OMe
OMe
R
OMe
Me
Me
Ac
OMe
Me
Me
R
OMe
N
N
d
N
b
N
N
N
Ac
MeO
R
MeO
Me
PMB
O
3: R = H
5: R = H
7: R = H
8: R = CO2 Pr
a
c
e
4: R = Ac
6: R = PMB
i
MeO
OMe
OMe
Me
OMe
OMe
MeO
H
Me
10
MeO
H
Me
MeO
H
Me
MeO
MeO
MeO
MeO
7
2a
H
H
g
1'
f
Me
OMe
i
OMe
Me
OMe
1
4
CO2Pri
N
5
Me
N
N
R
2
6
N
N
N
6'
MeO
H
H
MeO
H
H
PMB
O
O
MeO
O
1
9
10: R = H
h
217: R = Me
Scheme 1. a) Ac2O, 110 oC, 4 h, 83%; b) 2,4,5-trimethoxy-3-methylbenzaldehyde, KOtBu, tBuOH, DMF, 25 oC, 24 h, 81%; c)
NaH, DMF, PMBCl, 25 oC, 2 h,100%; d) NH2NH2-H2O, DMF, 25 oC, 1 h, 86%; e) ClCO2 Pr, CH2Cl2, Et3N, DMAP, 25 oC, 1 h,
i
91%; f) LiAl(OBut)3H, THF, 0 oC, 1 h, and then MsCl, CH2Cl2, TEA, reflux, 20 h, 70%; g) H2SO4, TFA = 1 : 20, 25 oC, 72%;
h) 37% HCHO-HCO2H, 70 oC, 1 h, 80%; i) H2 (2.7 MPa), 20% Pd(OH)2/C, EtOH, 80 oC, 22 h, 94%.
OMe
MeO
H
Me
O
O
OMe
OMe
OMe
OMe
O
2
OMe
OMe
OMe
OMe
i
CO2 Pr
R
OMe
Me
Me
OMe
Me
Me
OMe
N
N
N
R
b
c
N
N
N
Ac
MeO
H
MeO
H
H
O
O
i
3 : R = H
13: R = CO2 Pr
10: R = H
12
a
d
i
11: R = CO2 Pr
Scheme 2. a) ClCO2 Pr, CH2Cl2, Et3N, DMAP, 25 oC, 2 h, 96%; b) 2,4,5-trimethoxy-3-methylbenzaldehyde,
KOBut, tBuOH, DMF, 25 oC, 1.5 h, 78%; c) LiAl(OtBu)3H, THF, 0 oC, 4.5 h, and then HCO2H, 60 oC, 1 h, 64%;
d) H2SO4, TFA (1 : 20), 25 oC, 5 h, 91%.
i
Then, we investigated the conversion of lactam 1 into -aminonitrile 14 (Scheme 3). LiAlH4 reduction of
1 followed by KCN and acetic acid gave desired product 14 in only 18% yield together with secondary
amine 15 (50%) and recovered 1 (18%). After numerous attempts under a variety of conditions, a
sequence of reactions via cyclic imine 16 was achieved. Reaction of 1 with Cp2ZrHCl (Schwartz’s
reagent)19 gave 16, and the subsequent treatment of 16 with trimethylsilyl cyanide (TMSCN) produced 14

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in a one-pot operation, stereoselectively (95% yield). X-Ray crystallographic analysis revealed that the
cyano group had -axial orientation (Figure 2).
OMe
OMe
MeO
Me
MeO
Me
MeO
MeO
H
H
MeO
MeO
H
H
Me
OMe
a
OMe
Me
N
Me
N
Me
1
1
N
N
MeO
H
H
MeO
H
H
CN
b
15
14
OMe
MeO
Me
MeO
H
H
c
Me
OMe
N
Me
14
N
MeO
H
MeO
16
Figure 2. ORTEP Drawing of Compound 14
Scheme 3. a) LiAlH4 (8 equiv.), THF, 0 oC 2 h and 25 oC, 3 h, and then KCN, AcOH-H2O, 25 oC, 17 h, 14 (18%), 15 (50%), 1 (18%);
b) Cp2ZrHCl (3 equiv.), THF, -17 oC, 1 h and 25 oC, 1 h; c) TMSCN (1.4 equiv.), THF, 25 oC, 1 h, 95% (2 steps).
We next investigated the construction of the core ring system having a cyano group at C-21 position from
14. We anticipated obtaining thermodynamically stable compound 17a in order to avoid the steric
repulsion between the side chain and the cyano group (Chart 1).

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According to the results of our recent model conversion,20 treatment of 14 with 2,2-diethoxyethyl
benzoate21 (8 equiv.) and TMSOTf (2 equiv.) in (CH2Cl)2 at 25 oC for 100 h gave 17b in 46% yield, and
27% of starting material 14 was recovered (Scheme 4). After performing several experiments to verify the
optimum reaction conditions, the following procedure was found to be best in terms of product yield and
reproducibility of the reaction. Treatment of 14 with a large excess of benzoyloxyacetaldehyde21 in
o
TFA-AcOH (4:1) at 25 C for 4 h afforded 17b in 97% yield according to the procedure of Ong et al.22
However, the stereochemistry of 17b could not be determined at this stage. Numerous efforts to
hydrolyze the benzoyl ester at C-1 position of 17b under basic or acidic condition failed to bear fruit.
o
However, treatment of 17b with hydrazine hydrate in methanol at 60 C for 6 h gave oxazolidine 18 in
high yield. The formation of the oxazolidine ring was proven by the emergence of the characteristic
N,O-acetal carbon signal at  95.8 ppm and the analysis of the heteronuclear multiple-bond correlation
(HMBC) NMR spectrum. The stereochemical structure of 18 was finally confirmed by X-ray
crystallographic analysis (Figure 3). Another approach involved the hydride reduction of 17b with
o
diisobutylaluminum hydride (DIBAL-H) in THF at -78 C for 15 h to generate alcohol 19 in 61% yield.
However, this compound was easily transformed into 18 during purification by silica gel column
chromatograpy.23
In summary, we succeeded in reducing the number of steps for the synthesis of intermediate 10 from 3,
i.e., from the original seven steps (26.5% overall yield) to four, in 43.6% overall yield. Stereoselective
cyclization of -aminonitrile 14 generated 17b in high yield, but its C-1 configuration was the opposite of

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HETEROCYCLES, Vol. 90, No. 1, 2015
that of saframycin A. Investigations of the isomerization at C-1 position of the core ring system and its
application to the total synthesis of saframycin A and renieramycin M are under way.24
EXPERIMENTAL
All melting points were determined with a Yanagimoto micro melting point apparatus and are
uncorrected. IR spectra were obtained with a Shimadzu Prestige-21/IR Affinity-1 Fourier Transform
1
Infrared (FT-IR) spectrometer. H- and 13C-NMR spectra were recorded on a JEOL ECA-500 NMR
spectrometer at 500 MHz for 1H and 125 MHz for 13C, on a JEOL ECS-400 spectrometer at 400 MHz for
1H and 100 MHz for 13C, on a JEOL AL-400 spectrometer at 400 MHz for 1H and 100 MHz for 13C, and
on a JEOL AL-300 spectrometer at 300 MHz for 1H. NMR spectra were measured in CDCl3, DMSO-d6,
or MeOD and the chemical shifts were recorded inH values relative to (CH3)4Si (TMS) as the internal
standard. Mass spectra were recorded on a JMS-700 instrument with a direct inlet system operating at 70
eV. Elemental analyses were conducted on a YANACO MT-6 CHN CORDER elemental analyzer.
(1R*,2S*,5S*)-7,9,10-Trimethoxy-8,11-dimethyl-4-oxo-2-[(2,4,5-trimethoxy-3-methylphenyl)methyl]-
1,2,3,4,5,6-hexahydro-1,5-imino-3-benzazocine (1)
A suspension of 2 (996 mg, 2.00 mmol) in EtOH (40 mL) was hydrogenated over 20% Pd(OH)2 on
o
carbon (280 mg, 0.40 mmol) at 80 C for 22 h under 2.7 MPa hydrogen. The catalyst was removed by
filtration and the residue trapped by the filter paper was washed with CHCl3 and MeOH. The combined
filtrates were concentrated in vacuo to give a residue, the recrystallization of which from hexane-EtOAc
afforded 1 (857 mg, 85.7%) as colorless prisms. The mother liquid (148 mg) was subjected to column
chromatography on SiO2 (15 g) with CHCl3-MeOH (90:1-80:1) to afford a solid, the recrystallization of
which from hexane-EtOAc gave an additional amount of 1 (79 mg, 7.9%; total amount: 936 mg, 93.6%),
mp 165-167 oC.
max (KBr) 3433, 3385, 2940, 2905, 1676, 1489, 1464, 1408, 1339, 1242, 1113, 1009, 999 cm-1. H (400
MHz) 2.02 (1H, dd, J = 14.0, 11.3 Hz, 2a-H), 2.18 (3H, s, 3’-OCH3), 2.23 (3H, s, 8-OCH3), 2.53 (3H, s,
NCH3), 2.97 (1H, d, J = 17.9 Hz, 6H-), 3.10 (1H, dd, J = 17.9, 7.3 Hz, 6H-), 3.29 (1H, dd, J = 14.0, 2.4
Hz, 2a-H), 3.56 (3H, s, 2’-OCH3), 3.59 (1H, d, J = 7.3 Hz, 5-H), 3.72 (3H, s, 7-OCH3), 3.77 (3H, s,
4’-OCH3 or 10-OCH3), 3.80 (3H, s, 5’-OCH3), 3.82 (3H, s, 9-OCH3), 3.85 (3H, s, 4’-OCH3 or 10-OCH3),
4.25-4.31 (2H, overlapped, 1-H and 2-H), 5.55 (1H, s, NH), 6.45 (1H, s, 6’-H). C (100 MHz) 9.4 (8-CH3),
9.6 (3’-CH3), 23.8 (C-6), 32.2 (C-2a), 40.4 (NCH3), 54.6 (C-1), 55.5 (C-2), 55.9 (C-5’), 58.2 (C-5), 59.8
(7-OCH3), 60.0 (C-9), 60.2 (C-4’ and C-10), 110.8 (C-6’), 122.3 (C-6a), 122.6 (C-10a), 124.7 (C-1’ and
C-8), 126.2 (C-3’), 146.9 (C-4’), 147.2 (C-10), 149.3 (C-5’), 149.8 (C-9), 151.1 (C-2’), 152.4 (C-7),

HETEROCYCLES, Vol. 90, No. 1, 2015
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171.9 (CO). EIMS m/z (%): 500 (M+, 15), 250 (9), 249 (29), 248 (100), 218 (11). Anal. Calcd for
C27H36N2O3: C 64.78, H 7.25, N 5.60. Found: C 64.51, H 7.15, N 5.24.
1-Acetyl-3-[(2,4,5-trimethoxy-3-methylphenyl)methyl]-4-isopropoxycarbonylpiperazine-2,5-dione (11)
Isopropyl chloroformate (10.9 mL, 96.0 mmol) was added to a mixture of 3 (8.38 g, 23.9 mmol), Et3N
(7.0 mL, 48.0 mmol), and DMAP (5.86 g, 48.0 mmol) in CH2Cl2 (400 mL) over 10 min at 0 oC, and the
mixture was stirred at 25 oC for 2 h. The reaction mixture was diluted with H2O (600 mL) and extracted
with CHCl3 (3 x 600 mL). The combined extracts were washed with 1 M aqueous HCl solution (600 mL)
and then with 5% aqueous NaHCO3 solution (600 mL), dried, and concentrated in vacuo. The residue
(12.01 g) was subjected to column chromatography on SiO2 (200 g) with hexane-EtOAc (4:1) to give 11
(9.99 g, 95.7%) as a colorless syrup.
max (CHCl3) 3021, 1782, 1721, 1487, 1369, 1304, 1261, 1233, 1202, 1103, 1088 cm-1. H (400 MHz)
1.31 (3H, d, J = 6.3 Hz, CH(CH3)2), 1.34 (3H, d, J = 6.3 Hz, CH(CH3)2), 2.15 (3H, s, 3’-CH3), 2.55 (3H, s,
COCH3), 3.10 (1H, d, J = 18.8 Hz, 6-H), 3.21 (1H, dd, J = 13.7, 5.4 Hz, 3a-H), 3.31 (1H, dd, J = 13.7, 6.3
Hz, 3a-H), 3.63 (3H, s, 2’-OCH3), 3.76 (3H, s, 5’-OCH3), 3.78 (3H, s, 4’-OCH3), 4.64 (1H, d, J = 18.8 Hz,
6-H), 5.06 (1H, sept, J = 6.3 Hz, CH(CH3)2), 5.13 (1H, dd, J = 6.3, 5.4 Hz, 3-H), 6.45 (1H, s, 6’-H). C
(100 MHz) 9.7 (3-CH3), 21.6 (CH(CH3)2), 21.7 (CH(CH3)2), 26.9 (COCH3), 33.4 (C-3a), 46.6 (C-6), 56.0
(5’-OCH3), 60.4 (4’-OCH3), 60.6 (1’-OCH3), 61.2 (C-3), 72.3 (CH(CH3)2), 111.6 (C-6’), 121.6 (C-1’),
i
125.9 (C-3’), 147.9 (C-4’), 149.2 (C-5’), 150.9 (CO2 Pr), 151.2 (C-2’), 163.1 (C-5), 167.3 (C-2), 171.0 (s,
COCH3). EIMS m/z (%): 436 (M+, 16), 196 (11), 195 (100), 165 (6). HREIMS m/z 436.1845 (M+, calcd
for C21H28N2O8, 436.1846).
(Z)-1-Isopropoxycarbonyl-6-[(2,4,5-trimethoxy-3-methylphenyl)methyl]-3-[(2,4,5-trimethoxy-3-methyl-
phenyl)methylene]-piperazine-2,5-dione (12).
A solution of tert-BuOK in tert-BuOH (1 M, 3.4 mL, 3.38 mmol) was added to a solution of 11 (1.23 g,
2.81 mmol) and 2,4,5-trimethoxy-3-methylbenzaldehyde (591 mg, 2.81 mmol) in CH2Cl2 (10 mL) over
o
o
30 min at 0 C, and the mixture was stirred at 0 C for 40 min, and then at 25 oC for 1.5 h. The reaction
mixture was diluted with H2O (100 mL) and extracted with CH2Cl2 (3 x 100 mL). The combined extracts
were washed with brine (100 mL), dried, and concentrated in vacuo. The residue (1.48 g) was subjected
to column chromatography on SiO2 (50 g) with hexane-EtOAc (2:1) to give 12 (1.28 g, 77.7 %) as a pale
yellow amorphous powder.

max (KBr) 1701, 1489, 1466, 1456, 1422, 1377, 1341, 1281, 1238, 1180, 1123, 1105, 1088, 1009 cm-1. H
(400 MHz) 1.37 (3H, d, J = 6.3 Hz, CH(CH3)2), 1.40 (3H, d, J = 6.3 Hz, CH(CH3)2), 2.01 (3H, s, 3”-CH3),

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HETEROCYCLES, Vol. 90, No. 1, 2015
2.20 (3H, s, 3’-CH3), 3.07 (1H, dd, J= 13.7, 3.6 Hz, 6a-H), 3.39 (3H, s, 5”-OCH3), 3.42 (1H, dd, J = 13.7,
5.7 Hz, 6a-H), 3.50 (3H, s, 4’-OCH3), 3.58 (3H, s, 2”-OCH3), 3.72 (3H, s, 4”-OCH3), 3.83 (3H, s,
2’-OCH3), 3.95 (3H, s, 5’-OCH3), 5.10 (1H, dd, J = 5.7, 3.6 Hz, 6-H), 5.16 (1H, sep, J = 6.3 Hz,
CH(CH3)2), 6.26 (1H, s, 6”-H), 6.42 (1H, s, 3a-H), 6.50 (1H, s, 6’-H), 9.05 (1H, br-s, NH). C (100 MHz)
9.5 (3’-CH3 or 3”-CH3), 9.6 (3’-CH3 or 3”-CH3), 21.8 and 21.8 (CH(CH3)2), 33.3 (C-6a), 55.1 (5”-OCH3),
55.6 (5’-OCH3), 59.9 (4”-OCH3), 60.2 (C-6), 60.3 (2’-OCH3), 60.3 (2”-OCH3), 61.2 (4’-OCH3), 71.7
(CH(CH3)2), 111.8 (C-6”), 112.0 (C-6’), 115.8 (C-3a), 121.0 (C-1’), 121.8 (C-1”), 125.2 (C-3), 125.5
(C-3’), 125.7 (C-3’), 147.6 (C-4”), 148.4 (C-4’), 148.5 (C-2’), 148.9 (C-5”), 149.2 (C-5’), 151.7 (C-2”),
i
152.0 (CO2 Pr), 158.6 (C-2), 165.5 (C-5). EIMS m/z (%): 586 (M+, 45), 570 (8), 196 (12), 195 (100), 165
(5). HREIMS m/z 586.2528 (M+, calcd for C30H38N2O10, 586.2526).
Isopropyl (Z)-(1R*,5S*)-7,9,10-Trimethoxy-8-methyl-4-oxo-2-[(2,4,5-trimethoxy-3-methylphenyl-
methylene)-1,2,3,4,5,6-hexahydro-1,5-imino-3-benzazocine-11-carboxylate (13)
Li(tert-BuO)3AlH (1.27 g, 5.00 mmol) was added to a solution of 12 (586 mg, 1.00 mmol) in THF (33
o
mL) at 0 C over 20 min, and the reaction mixture was stirred at the same temperature for 4.5 h.
Anhydrous Na2SO4 (4.2 g) was added and the reaction was quenched by the addition of water (2.8 mL).
The reaction mixture was filtered through Celite pad, and the residue was washed with CHCl3 (150 mL).
The combined filtrates were diluted with brine (150 mL) and extracted with CHCl3 (3 x 100 mL). The
combined extracts were washed with brine (100 mL), dried, and concentrated in vacuo to give a residue in
the form of a pale yellow amorphous powder, and this was used in the next step without further
purification. A solution of the above product (684 mg) in formic acid (16.5 mL) was heated at 60 oC for 1
h. After the reaction mixture was concentrated in vacuo, the residue was diluted with 5% aqueous
NaHCO3 solution (100 mL) and extracted with CHCl3 (100 mL x 3). The combined extracts were washed
with brine (100 mL), dried, and concentrated in vacuo to give a residue (600 mg), which was subjected to
column chromatography on SiO2 (25 g) with hexane-EtOAc (7:3) to afford 13 (367 mg, 63.8%) as a
colorless amorphous powder. Further elution with hexane-EtOAc (3:1) gave 12 (61 mg, 10.4% recovery).
max (KBr) 1694, 1489, 1466, 1423, 1408, 1342, 1298, 1265, 1244, 1111, 1088, 1069, 1000 cm-1. H
(DMSO-d6, 140 oC, 400 MHz) 1.15 (3H, d, J = 6.2 Hz, CH(CH3)2), 1.17 (3H, d, J = 6.2 Hz, CH(CH3)2),
2.02 (3H, s, 3’-CH3), 2.14 (3H, s, 8-CH3), 2.95-2.96 (2H, overlapped, 6-H2), 3.34 (3H, s, 2’-OCH3), 3.56
(3H, s, 7-OCH3), 3.641 (3H, s, 4’-OCH3 or 9-OCH3), 3.74 (3H, s, 4’-OCH3 or 9-OCH3), 3.78 (3H, s,
5’-OCH3), 3.93 (3H, s, 10-OCH3), 4.77-4.88 (1H, overlapped, 5-H), 4.80 (1H, sep, J = 6.2 Hz, CH(CH3)2),
5.82 (1H, s, 1-H), 5.84 (1H, s, 2a-H), 6.62 (1H, s, 6’-H), 8.50 (1H, br s, NH). C (DMSO-d6, 140 oC, 100
MHz) 8.4 (3’-CH3 or 8-CH3) 8.5 (3’-CH3 or 8-CH3), 21.0 (CH(CH3)2), 25.8 (C-6), 49.3 (C-1), 51.4 (C-5),

HETEROCYCLES, Vol. 90, No. 1, 2015
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55.8 (5’-OCH3), 58.8, 58.9, and 59.0 (4’-OCH3, 7-OCH3, and 9-OCH3), 59.2 (2’-OCH3), 59.3 (10-OCH3),
68.6 (CH(CH3)2), 102.0 (C-2a), 111.9 (C-6’), 119.8 (C-6a or C-10a), 121.2 (C-1’), 123.6 (C-8), 123.9
(C-3’), 124.3 (C-6a or C-10a), 132.4 (C-2), 144.9 (C-10), 146.7 (C-4’), 148.0 (C-5’), 148.7 (C-2’), 149.1
i
(C-9), 151.4 (C-7), 152.2 (CO2 Pr), 166.8 (C-4). EIMS m/z (%): 570 (M+, 100), 469 (5), 279 (5), 278 (10),
234 (20), 206 (6), 204 (7). HREIMS m/z 570.2572 (M+, calcd C30H38N2O9, 570.2577).
(Z)-(1R*,5S*)-7,9,10-Trimethoxy-8-methyl-4-oxo-2-[(2,4,5-trimethoxy-3-methylphenyl)methylene]-
1,2,3,4,5,6-hexahydro-1,5-imino-3-benzazocine (10)
Concentrated H2SO4 (2.0 mL) was added to a stirred solution of 13 (1.14 g, 2.00 mmol) in TFA (40 mL)
o
o
over 5 min at 0 C, and the mixture was stirred at 25 C for 5 h. The reaction mixture was diluted with
water (130 mL) at 0 oC, made alkaline with concentrated NH4OH (90 mL), and extracted with CHCl3 (3 x
130 mL). The combined extracts were washed with brine (130 mL), dried, and concentrated in vacuo to
give a residue. The residue (1.17 g) was subjected to column chromatography on SiO2 (36 g) with
CHCl3-MeOH (200:1) to give a fraction (1.07 g) containing 10, the recrystallization of which from
hexane-EtOAc afforded 10 (861 mg, 88.9%) as colorless prisms. The mother liquid (91 mg) was
subjected to column chromatography on SiO2 (8.4 g) with CHCl3-MeOH (350:1) to give a solid, the
recrystallization of which from hexane-EtOAc afforded an additional amount of 10 (19 mg, 2.0%; total
amount: 880 mg, 90.9%), mp 126-127 oC (lit.,17 mp 125.5-127 oC).
H (300 MHz) 2.17 (3H, s, Ar-CH3), 2.19 (3H, s, Ar-CH3), 3.09 (1H, dd, J = 17.3, 6.5 Hz, 6-Hα), 3.18
(1H, dd, J = 17.3, 1.5 Hz, 6-Hβ), 3.40 (3H, s, OCH3), 3.69 (3H, s, OCH3), 3.72 (3H, s, OCH3), 3.78 (3H, s,
OCH3), 3.83 (3H, s, OCH3), 3.91 (3H, s, OCH3), 4.03 (1H, dd, J = 6.5, 1.5 Hz, 5-H), 4.98 (1H, s, 1-H),
5.87 (1H, s, 2a-H), 6.57 (1H, s, ArH), 8.40 (1H,br s, NH).
Compound 10 was identical with an authentic sample on direct comparison of spectroscopic data
(1H-NMR, 13C-NMR, IR, MS) and TLC behavior.
Preparation of compound 14.
Method A: A solution of LiAlH4 in THF (1.0 M, 400 L, 400 mol) was added to a stirred solution of 1
(25.0 mg, 50.0 mol) in THF (2 mL) at 0 oC, and the reaction mixture was stirred at the same temperature
for 2 h and then at 25 oC for 3 h. Aqueous KCN solution (4.5 M, 67 L, 300 mol) and AcOH (400 L)
were added, and stirring was continued at 25 oC for 17 h. The reaction mixture was diluted with saturated
aqueous NaHCO3 solution (20 mL) and extracted with CHCl3 (3 x 20 mL). The combined extracts were
washed with brine (20 mL), dried, and concentrated in vacuo to give a residue (33.4 mg), which was
subjected to column chromatography on SiO2 (10 g) with CHCl3-MeOH (200:1) to furnish 14 (4.7 mg,

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18.4%). Further elution with CHCl3-MeOH (99:1) gave 1 (4.5 mg, 18.0% recovery), and elution with
CHCl3-MeOH (20:1) afforded 15 (12.1 mg, 49.8%) as a pale yellow amorphous powder.
(1R*,2S*,4R*,5S*)-7,9,10-Trimethoxy-8,11-dimethyl-2-[(2,4,5-trimethoxy-3-methylphenyl)methyl]-
1,2,3,4,5,6-hexahydro-1,5-imino-3-benzazocine-4-carbonitrile (14)
An analytical sample was obtained by recrystallization from hexane-EtOAc as colorless prisms, mp
168-169 oC. max (CHCl3) 3021, 2938, 2359, 1487, 1464, 1408, 1194, 1136, 1111, 1076, 1043, 1013, 995,
976, 962 cm-1. H (500 MHz) 2.15 (3H, s, 3’-CH3), 2.19 (1H, dd, J = 14.9, 11.4 Hz, 2a-H), 2.22 (3H, s,
8-CH3), 2.36 (3H, s, NCH3), 2.45 (1H, d, J = 18.2 Hz, 6-Hβ), 2.997 (1H, dd, J = 14.9, 2.7 Hz, 2a-Hα),
3.004 (1H, dd, J = 18.2, 7.5 Hz, 6-Hα), 3.29 (1H, br d, J = 7.5 Hz, 5-H), 3.49 (3H, s, 2’-OCH3), 3.70 (3H,
s, 7-OCH3), 3.77 (3H, s, 4’-OCH3), 3.81 (3H, s, 10-OCH3), 3.82 (3H, s, 5’-OCH3 or 9-OCH3), 3.81-3.84
(1H, overlapped with OCH3 signals, 2-H), 3.84 (3H, s, 5’-OCH3 or 9-OCH3), 3.91 (1H, d, J = 2.4 Hz,
4-H), 4.08 (1H, d, J = 2.1 Hz, 1-H), 6.61 (1H, s, 6’-H). C (125 MHz) 9.4 (8-CH3), 9.6 (3’-CH3), 21.4
(C-6), 31.2 (C-2a), 42.1 (NCH3), 53.9 (C-4), 54.4 (d, C-5), 56.0 (5’-OCH3 or 9-OCH3), 56.3 (C-2), 57.3
(C-1), 59.6 (7-OCH3), 60.0 (5’-OCH3 or 9-OCH3), 60.2 (4’-OCH3), 60.3 (10-OCH3), 60.4 (2’-OCH3),
109.5 (C-6’), 120.0 (s, CN), 123.1 (C-10a), 123.5 (C-8), 123.7 (C-6a), 125.6 (C-3’), 125.8 (C-1’), 146.3
(C-4’), 147.6 (C-10), 149.4 (C-5’ or C-9), 149.5 (C-5’ or C-9), 151.2 (C-2’), 151.2 (C-7). FABMS m/z
512 [M + H]+. HRFABMS m/z 512.2764 ([M + H]+, calcd for C28H38N3O6, 512.2761). Anal. Calcd for
C28H38N3O6: C 65.73, H 7.29, N 8.21. Found: C 65.80, H 7.20, N 8.20.
(1R*,2S*,5S*)-7,9,10-Trimethoxy-8,11-dimethyl-2-[(2,4,5-trimethoxy-3-methylphenyl)methyl]-1,2,3,4,
5,6-hexahydro-1,5-imino-3-benzazocine (15).
This sample was identical with an authentic sample11b on direct comparison of spectroscopic data
(1H-NMR, 13C-NMR, IR, MS) and TLC behavior.H (300 MHz) 2.02 (1H, dd, J = 14.4, 11.2 Hz, 2a-H),
2.15 (3H, s, ArCH3), 2.23 (3H, s, ArCH3), 2.33 (3H, s, NCH3), 2.51 (1H, d, J = 17.2 Hz, 6-Hβ), 2.89 (1H,
dd, J = 12.2, 1.4 Hz, 4-H), 2.97 (1H, dd, J = 14.4, 2.7 Hz, 2a-Hα), 2.99 (1H, dd, J = 17.2, 7.7 Hz, 6-Hα),
3.04 (1H, m, 5-H), 3.14 (1H, dd, J = 12.2, 2.4 Hz, 4-H), 3.48 (1H, ddd, J = 11.2, 2.7, 2.7 Hz, 2-H), 3.51
(3H, s, OCH3), 3.73 (3H, s, OCH3), 3.74 (3H, s, OCH3), 3.78 (3H, s, OCH3), 3.79 (3H, s, OCH3), 3.81
(3H, s, OCH3), 4.06 (1H, d, J = 2.7 Hz, 1-H), 6.62 (1H, s, ArH).
Method B: A suspension of Cp2ZrHCl (2.01 g, 7.80 mmol) in dry THF (45 mL) was added to a stirred
o
solution of 1 (1.30 g, 2.60 mmol) in THF (20 mL) at -20 C, and this mixture was stirred at the same
o
temperature for 1 h and then at 25 C for 2 h to generate imine intermediate 16. TMSCN (458 µL, 3.64
mmol) was added to the reaction mixture over 5 min, and the stirring was continued for 1 h at 25 oC. The
reaction mixture was diluted with saturated aqueous NaHCO3 solution (1 L) and extracted with CHCl3 (3
x 1 L). The combined extracts were washed with brine (1 L), dried, and concentrated in vacuo to give a

HETEROCYCLES, Vol. 90, No. 1, 2015
337
residue (1.62 g), which was subjected to column chromatography on SiO2 (80 g) with CHCl3 to furnish
14 (1.26 g, 94.7%) as a colorless amorphous powder.
(1R*,2S*,5S*)-7,9,10-Trimethoxy-8,11-dimethyl-2-[(2,4,5-trimethoxy-3-methylphenyl)methyl]-1,2,5,6-
tetrahydro-1,5-imino-3-benzazocine (16).
An analytical sample of 16 was obtained as a pale yellow amorphous powder by filtration (hexane) of the
reaction mixture treated with Cp2ZrHCl, concentration in vacuo, and column chromatography (elution
with CHCl3-MeOH).
max (CHCl3) 3015, 2938, 2832, 1663, 1487, 1463, 1408, 1337, 1227, 1111, 1086, 1013, 1001 cm-1. H
(400 MHz) 7.80 (1H, t, J = 2.9 Hz, 4-H), 6.70 (1H, s, 6’-H), 4.32 (1H, br d, J = 11.9 Hz, 2-H), 4.19 (1H,
d, J = 4.9 Hz, 1-H), 3.78 (6H, s, 9-OCH3 and 10-OCH3), 3.77 (3H, s, 5’-OCH3), 3.72 (3H, s, 4’-OCH3),
3.68 (3H, s, 8-OCH3), 3.58 (3H, s, 2’-OCH3), 3.58 (1H, br d, J = 6.2 Hz, 5-H), 3.35 (1H, dd, J = 14.6, 2.9
Hz, 2a-Hα), 2.85 (1H, dd, J = 17.7, 6.2 Hz, 6-Hα), 2.67 (1H, d, J = 17.7 Hz, 6-Hβ), 2.40 (3H, s, NCH3),
2.18 (3H, s, 8-CH3), 2.16 (3H, s, 3’-CH3), 1.98 (1H, dd, J = 14.6, 11.9 Hz, 2a-Hβ). C (100 MHz) 9.4
(8-CH3), 9.6 (3’-CH3), 20.8 (C-6), 31.8 (C-2a), 40.2 (NCH3), 54.4 (C-5), 55.8 (C-1), 55.8 (5’-OCH3), 59.7
(7-OCH3), 60.0 (9-OCH3 or 10-OCH3), 60.1 (9-OCH3 or 10-OCH3), 60.1 (4’-OCH3), 60.3 (2’-OCH3),
61.0 (C-2), 111.1 (C-6’), 121.3 (C-6a or C-10a), 123.8 (C-8), 124.7 (C-6a or C-10a), 125.0 (C-3’), 128.5
(C-1’), 145.8 (C-4’), 147.6 (C-10), 148.9 (C-4’), 150.0 (C-9), 150.8 (C-2’), 152.6 (C-7), 162.5 (C-4).
EIMS m/z (%): 484 (M+, 100), 453 (27), 289 (15), 262 (12), 261 (28), 250 (14), 249 (33), 248 (81), 246
(12), 218 (17). HREIMS m/z calcd for C27H36N2O6, 484.2573. Found: 484.2574.
X-Ray Structure Determination of Compound 14.
Crystals of 14 (C28H38N3O6) belong to triclinic space group P-1 (#2) with a = 9.0438(2) Å, b = 11.1268(2)
Å, c = 13.8750(2) Å, V = 1353.13(5) Å3, Z = 2, and Dcalcd = 1.256 g/cm3. X-Ray intensities were
measured with a Rigaku R-AXIS RAPID diffractometer in the graphite-monochromatic CuK radiation
mode (= 1.54187 Å). The final cycle of the full-matrix least-squares refinement was based on 4883
unique reflections (2θ < 136.5o) and 348 variable parameters, and converged with unweighted and
weighted agreement factors of R = 0.0441, Rw = 0.1102, and R1 = 0.0394 for I > 2.0 (I) data. The
drawing of the molecule was made by ORTEP as shown here. CCDC-No. (999806) contains the
supplementary crystallographic data for this paper. These data can be obtained free of charge via
www.ccdc.cam.ac.uk/data_request/cif.
Preparation of C2 unit.
According to the published protocol,21 we prepared 2,2-diethoxyethyl benzoate (ii) and

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benzoyloxyacetaldehyde (iii). Both compounds were much easier to handle after purification by vacuum
distillation. Compound ii (68% yield, pale yellow oil, bp 125-130 oC (2 mmHg)) H (300 MHz) 1.17 (6H,
t, J = 7.0 Hz, 2 x CH2CH3), 3.55 (2H, dq, J = 9.4, 7.1 Hz, CH2CH3), 3.69 (2H, dq, J = 9.4, 7.0 Hz,
CH2CH3), 4.27 (2H, d, J = 5.4 Hz, 2-H), 4.76 (1H, t, J = 5.4 Hz, CH), 7.37 (2H, t, J = 7.3 Hz, 3’-H), 7.50
(1 H, t, J = 7.3 Hz, 4’-H), 7.99 (2H, d, J = 7.1 Hz, 2’-H).
Compound iii (69% yield, pale yellow oil, bp 100 oC (3-4 mmHg)) H (300 MHz) 4.90 (2H, s, 2-H), 7.48
(2H, t, J = 7.6 Hz, 3’-H), 7.62 (1H, dt, J = 7.6, 7.3 Hz, 4’-H), 8.11 (2H, d, J = 7.3 Hz, 2’-H), 9.73 (1H, s,
CHO).
EtO
EtO
HCO2H-H2O (4 : 1)
25 oC, 3 h
PhCO2Na
DMF, reflux
EtO
EtO
O
Br
O
O
H
69%
58%
O
O
ii
iii
i
((6S*,7R*,9S*,14aS*,15R*)-7-Cyano-1,2,4,10,11,13-hexamethoxy-3,12,16-trimethyl-6,7,9,14,14a,15-
hexahydro-5H-6,15-epiminobenzo[4,5]azocino[1,2-b]isoquinolin-9-yl)methylbenzoate (17b)
Method A: TMSOTf (18.1 mL, 0.10 mmol) was added to a stirred solution of 14 (25.5 mg, 0.05 mmol)
and 2,2-diethoxyethyl benzoate21 (95.2 mg, 0.40 mmol) in (CH2Cl)2 (0.2 mL), and the mixture was stirred
o
at 25 C for 100 h. The reaction mixture was diluted with saturated aqueous NaHCO3 solution (20 mL)
and extracted with CHCl3 (3 x 20 mL). The combined extracts were washed with brine (20 mL), dried,
and concentrated in vacuo to give a residue (65.9 mg), which was subjected to column chromatography
on SiO2 (12 g) with hexane-EtOAc (3:1) to furnish 17b (10.7 mg, 46.0%) as a pale yellow amorphous
powder. Further elution with the same solvent system afforded 14 (6.9 mg, 27% recovery).
Method B: TFA (3.2 mL) was added to a stirred solution of 14 (67.0 mg, 0.131 mmol) and
benzoyloxyacetaldehyde21 (219.0 mg, 1.31 mmol) in acetic acid (0.8 mL), and the mixture was stirred at
o
25 C for 4 h. The reaction mixture was diluted with saturated aqueous NaHCO3 solution (120 mL) and
extracted with CHCl3 (3 x 120 mL). The combined extracts were washed with brine (120 mL), dried, and
concentrated in vacuo to give a residue (277.0 mg), which was subjected to column chromatography on
SiO2 (11 g) with hexane-EtOAc (3:1) to afford 17b (83.5 mg, 96.9%) as a pale yellow amorphous
powder.
max (CHCl3) 2938, 2228, 1719, 1464, 1452, 1410, 1273, 1252, 1113, 1096, 1072, 1026 cm-1. H (400
MHz) 1.98 (3H, s, 3-CH3), 2.00 (3H, s, 12-CH3), 2.23 (3H, s, NCH3), 2.40 (1H, d, J = 17.8 Hz, 5-H),
2.88 (1H, dd, J = 17.2, 9.0 Hz, 14-Hβ), 2.93 (1H, dd, J = 17.8, 7.6 Hz, 5-Hα), 3.27 (1H, dd, J = 7.6, 2.4

HETEROCYCLES, Vol. 90, No. 1, 2015
339
Hz, 6-H), 3.30 (1H, dd, J = 17.2, 3.4 Hz, 14-Hα), 3.50 (3H, s, 13-OCH3), 3.55 (3H, s, 4-OCH3), 3.61 (3H,
s, 2-OCH3), 3.64 (3H, s, 11-OCH3), 3.69 (3H, s, 10-OCH3), 3.75 (3H, s, 1-OCH3), 3.99 (1H, d, J = 2.4 Hz,
15-H), 4.19-4.22 (1H, overlapped, 14a-H), 4.21 (1H, d, J = 2.4 Hz, 7-H), 4.39 (1H, t, J = 4.7 Hz, 9-H),
4.48 (1H, dd, J = 11.6, 4.7 Hz, 17-H), 4.53 (1H, dd, J = 11.6, 4.7 Hz, 17-H), 7.42 (2H, t, J = 7.5 Hz, 3'-H),
7.53 (1H, t, J = 7.5 Hz, 4'-H), 8.04 (2H, d, J = 7.5 Hz, 2'-H). C (100 MHz) 9.1 (3-CH3), 9.2 (12-CH3),
21.6 (C-5), 22.8 (C-14), 42.0 (NCH3), 53.4 (C-14a), 55.5 (C-6), 56.6 (C-9), 57.5 (C-15), 59.5 (13-OCH3),
59.5 (4-OCH3), 59.7 (2-OCH3), 59.8 (11-OCH3), 60.2 (10-OCH3), 60.3 (1-OCH3), 60.7 (C-7), 66.3
(C-17), 119.8 (CN), 122.2 (C-13a), 122.5 (C-4a), 123.1 (C-12), 123.4 (C-15a), 126.0 (C-9a), 128.3 (C-3’),
129.7 (C-2’), 130.2 (C-1’), 132.8 (C-4’), 144.1 (C-10), 147.7 (C-1), 148.5 (C-2), 148.9 (C-11), 151.2
(C-4), 151.5 (C-13), 166.3 (PhCO). EIMS m/z (%): 657 (M+, 7), 523 (8), 522 (22), 495 (22), 289 (10),
288 (59), 249 (37), 248 (100), 234 (10), 218 (14), 105 (11). HREIMS m/z calcd for C37H43N3O8,
657.3050. Found: 657.3043.
(4bS*,6aS*,7S*,13R*,13aS*)-1,3,4,9,11,12-Hexamethoxy-2,10,15-trimethyl-4b,5,6a,7,8,13,13a,14-octa-
hydro-6-oxa-14a1,15-diaza-7,13-methanobenzo[g]benzo[5,6]cycloocta[1,2,3-cd]indene (18)
Hydrazine monohydrate (2.0 mL, 40 mmol) was added to a solution of 17b (262.8 mg, 0.40 mmol) in
EtOH (10 mL) at 25 oC, and the reaction mixture was stirred at 60 oC for 3 h. As the starting material still
remained at this stage, additional hydrazine monohydrate (0.5 mL, 10 mmol) was introduced to the
o
reaction mixture and the whole was heated at 60 C for 3 h. The reaction mixture was diluted with 1 M
HCl (50 mL) and extracted with CHCl3 (3 x 50 mL). The combined extracts were washed with brine (50
mL), dried, and concentrated in vacuo to give a residue (246.9 mg), which was subjected to column
chromatography on SiO2 (10 g) with CHCl3-MeOH (98:2) to furnish 18 (198.1 mg, 94.2%) as a colorless
amorphous powder. An analytical sample was obtained by recrystallization from hexane-EtOAc as
colorless prisms, mp 105-107 oC.

max (CHCl3) 3019, 2995, 2938, 2833, 1464, 1410, 1207, 1113, 1072, 1009 cm-1. H (400 MHz) 2.15 (3H,
s, 2-CH3), 2.18 (1H, dd, J = 16.3, 12.1 Hz, 14-Hβ), 2.19 (3H, s, 10-CH3), 2.46 (3H, s, NCH3), 2.58 (1H, d,
J = 18.2 Hz, 8-Hβ), 3.08 (1H, dd, J = 16.3, 2.6 Hz, 14-Hα), 3.11 (1H, dd, J = 18.2, 8.4 Hz, 8-Hα), 3.22
(1H, ddd, J = 12.1, 2.6, 2.6 Hz, 13a-H), 3.59 (1H, dd, J = 8.4, 1.5 Hz, 7-H), 3.62 (3H, s, 1-OCH3), 3.71
(1H, dd, J = 8.7, 7.2 Hz, 5-H), 3.713 (3H, s, 9-OCH3), 3.75 (3H, s, 3-OCH3), 3.77 (3H, s, 4-OCH3), 3.78
(3H, s, 11-OCH3), 3.86 (3H, s, 12-OCH3), 4.03 (1H, d, J = 2.6 Hz, 13-H), 4.23 (1H, dd, J = 8.7, 7.2 Hz,
5-H), 4.37 (1H, t, J = 8.7 Hz, 4a-H), 4.56 (1H, d, J = 1.5 Hz, 6a-H). C (100 MHz) 9.2 (3-CH3), 9.4
(10-CH3), 21.0 (C-8), 27.2 (C-14), 41.1 (NCH3), 52.7 (C-13a), 53.3 (C-7), 55.9 (C-13), 59.5 (9-OCH3),
59.6 (1-OCH3), 59.8, 59.9, and 60.0 (3-OCH3, 4-OCH3 and 11-OCH3), 59.9 (C-4a), 60.2 (12-OCH3), 67.8

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(C-5), 95.4 (C-6a), 123.1 (C-8a), 123.1 (C-12a), 123.6 (C-2 or C-10), 123.9 (C-10 or C-2), 124.4 (C-14a),
125.8 (C-4a), 146.3 (C-4), 147.5 (C-12), 149.3 (C-3), 149.5 (C-11), 151.8 (C-9), 152.1 (C-1). EIMS m/z
(%): 526 (M+, 28), 496 (15), 278 (47), 262 (21), 249 (21), 248 (100). HREIMS m/z calcd for C29H38N2O7,
526.2679. Found: 526.2674. Anal. Calcd for C29H38N2O7: C 66.14, H 7.27, N 5.32. Found: C 66.15, H
7.19, N 5.17.
X-Ray Structure Determination of Compound 18.
Crystals of 18 (C29H38N2O7) belong to triclinic space group P-1 (#2) with a = 11.0963(2) Å, b =
11.2124(2) Å, c = 11.4822(2) Å, V = 1313.71(5) Å3, Z = 2, and Dcalcd = 1.331 g/cm3. X-Ray intensities
were measured with a Rigaku R-AXIS RAPID diffractometer in the graphite-monochromatic CuK
radiation mode (= 1.54187 Å). The final cycle of the full-matrix least-squares refinement was based on
4739 unique reflections (2θ < 136.5o) and 352 variable parameters, and converged with unweighted and
weighted agreement factors of R = 0.0455, Rw = 0.1100, and R1 = 0.0399 for I > 2.0 (I) data. The
drawing of the molecule was made by ORTEP as shown in Figure 2. CCDC-No.999807 contains the
supplementary crystallographic data for this paper. These data can be obtained free of charge via
www.ccdc.cam.ac.uk/data_request/cif.
(6S*,7R*,9S*,14aS*,15R*)-9-(Hydroxymethyl)-1,2,4,10,11,13-hexamethoxy-3,12,16-trimethyl-6,7,9,14,
14a,15-hexahydro-5H-6,15-epiminobenzo[4,5]azocino[1,2-b]isoquinoline-7-carbonitrile (19)
A solution of DIBAL-H in toluene (1.0 M, 400 L, 400 mol) was added to a stirred solution of 17b
(32.9 mg, 0.05 mmol) in THF (2 mL) at - 78 oC over 15 min, and the reaction mixture was stirred at the
same temperature for 11 h. Anhydrous Na2SO4 (4.2 g) was added and the reaction was quenched by the
addition of water (2.0 mL). The reaction mixture was filtered through Celite pad and the residue was
washed with CHCl3 (150 mL). The combined filtrates were diluted with brine (20 mL) and extracted with
CHCl3 (3 x 30 mL). The combined extracts were washed with brine (30 mL), dried, and concentrated in
vacuo to give a residue (33.4 mg), which was subjected to column chromatography on SiO2 (4 g) with
hexane-AcOEt (1:2) to furnish 19 (16.9 mg, 61.0%). Further elution with AcOEt gave 18 (5.1 mg,
19.0%).
max (KBr) 3502, 2935, 2892, 2831, 2223, 1463, 1409, 1340, 1215, 1112, 1072, 1004, 962 cm-1. H (400
MHz) 2.00 (6H, s, 12-CH3 and 3-CH3), 2.24 (3H, s, NCH3), 2.58 (1H, d, J = 18.5 Hz, 5-Hβ), 2.87 (1H, dd,
J = 17.5, 8.6 Hz, 14-Hβ), 2.94 (1H, dd, J = 18.5, 8.1 Hz, 5-Hα), 3.26 (1H, dd, J = 17.5, 3.3 Hz, 14-Hα),
3.26 (1H, br d, J = 6.6 Hz, 6-H), 3.56 (3H, s, 13-OCH3), 3.59 (3H, s, 4-OCH3), 3.61 (3H, s, 11-OCH3),
3.65 (3H, s, 10-OCH3), 3.66 (3H, s, 2-OCH3), 3.73 (3H, s, 1-OCH3), 3.79 (2H, d, J = 4.3 Hz, 17-H), 3.96

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(1H, br d, J = 2.3 Hz, 15-H), 4.09 (1H, t, J = 4.3 Hz, 9-H), 4.16 (1H, dt, J = 8.6, 3.3 Hz, 14a-H), 4.24 (1H,
d, J = 2.5 Hz, 7-H). C (100 MHz) 9.1 (12-CH3), 9.2 (3-CH3), 21.6 (C-5), 23.3 (C-14), 42.0 (NCH3), 53.6
(C-14a), 55.2 (C-6), 57.3 (C-15), 59.3 (C-9), 59.5 (4-OCH3 and 13-OCH3), 59.8, 60.2, and 60.2 (2-OCH3,
10-OCH3 and 11-OCH3), 60.2 (1-OCH3), 60.4 (C-7), 64.8 (C-17), 120.6 (CN), 122.3 (C-4a), 122.3
(C-15a), 123.1 (C-3 or C-12), 123.2 (C-3 or C-12), 123.7 (C-13a), 126.7 (C-9a), 144.0 (C-10), 147.8
(C-1), 148.6 (C-11), 148.9 (C-2), 151.2 (C-4), 151.5 (C-13). FABMS m/z (%): 554 [M + H]+. HRFABMS
m/z calcd for C30H40N3O7, 554,2866. Found: 554.2858.
Transformation of 19 into 18.
o
A mixture of 19 (8.5 mg) with silica gel (10.0 mg) in CHCl3 (2.9 mL) was stirred at 25 C for several
hours. The reaction mixture was diluted with water (10 mL) and extracted with CHCl3 (3 x 10 mL). The
combined extracts were washed with brine (10 mL), dried, and concentrated in vacuo. The residue was
subjected to silica gel column chromatography with CHCl3-MeOH (50:1) to give 18 (7.6 mg, 92% yield).
ACKNOWLEDGEMENTS
This work was supported by a Grant-in-Aid (No. 23590019) for Scientific Research from the Ministry of
Education, Culture, Sports, Science and Technology (MEXT) of Japan. We would like to thank Dr.
Kazuhiko Takatori of Meiji Pharmaceutical University for the X-ray crystallographic analysis of 14 and
18. We are also grateful to Dr. Takuo Tsukuda (Chugai Pharmaceutical Company, Kamakura Research
Center) for conducting the cytotoxicity assay.
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o
23. Treatment of 18 with boron trifluoride and TMSCN in (CH2Cl)2 at -30 C for 20 min generated 19,
but 18 was recovered during purification.
24. Four synthetic compounds (14, 16, 17b, 18) were tested for in vitro antitumor activity against

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HCT116 human colon carcinoma, QG56 human lung carcinoma, and DU145 human prostate
carcinoma cell lines. None of the compounds showed antitumor activity. Benzoyl ester 17b showed
very low cytotoxic activity against HCT116 (IC50 = 0.86 M).