Chemistry of renieramycins. Part 12: An improved total synthesis of (±)-renieramycin G

Article abstract of DOI:10.1016/j.tet.2012.03.105

An improved total synthesis of (±)-renieramycin G (1g) from readily available 2-hydroxy-3-methyl-4,5-dimethoxybenzaldehyde (7) in 21 steps (6.3% overall yield) is described. The synthesis features the concise construction of a pentacyclic framework using the stereoselective Pictet-Spengler type cyclization reaction of lactam (25) with ethyl diethoxyacetate, followed by the base-catalyzed epimerization of the C-1 stereo center of aldehyde (30a). The results of cytotoxicity studies are also presented.

Full text of DOI:10.1016/j.tet.2012.03.105

Tetrahedron 68 (2012) 4166e4181
Contents lists available at SciVerse ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Chemistry of renieramycins. Part 12: An improved total synthesis of
(ꢀ)-renieramycin G
*
Masashi Yokoya, Kimiko Shinada-Fujino, Saiko Yoshida, Masahiro Mimura, Hiroki Takada, Naoki Saito
Graduate School of Pharmaceutical Sciences, Meiji Pharmaceutical University, 2-522-1 Noshio, Kiyose, Tokyo 204-8588, Japan
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 6 March 2012
Received in revised form 24 March 2012
Accepted 26 March 2012
Available online 30 March 2012
An improved total synthesis of (ꢀ)-renieramycin G (1g) from readily available 2-hydroxy-3-methyl-4,5-
dimethoxybenzaldehyde (7) in 21 steps (6.3% overall yield) is described. The synthesis features the
concise construction of a pentacyclic framework using the stereoselective PicteteSpengler type cycli-
zation reaction of lactam (25) with ethyl diethoxyacetate, followed by the base-catalyzed epimerization
of the C-1 stereo center of aldehyde (30a). The results of cytotoxicity studies are also presented.
Ó 2012 Elsevier Ltd. All rights reserved.
Keywords:
Total synthesis
Marine natural product
Isoquinoline
Renieramycin G
Cytotoxicity
1. Introduction
with potassium cyanide.14,15 We have prepared a variety of
renieramycin derivatives from 1m for the investigation of SARs.16,17
Natural
products
belonging
to
the
tetrahy-
Furthermore, we were able to find three new minor renieramycins
T, U,18 and V.19 We focused on renieramycins C, D, and G along with
cribrostatin 4 (¼renieramycin H: 1h) having a lactam carbonyl at C-
21 position (see 1e, 1m, 2a, 2s, 3a, 3c, 4a, and 4c), because these
compounds retained their cytotoxicity despite the lack of such es-
sential functional groups as hemiaminal or aminonitrile at that
position. To date, four total syntheses of 1g20e23 and four total
syntheses of 1h24e27 have been reported. Recently, we completed
a 25-step stereocontrolled total synthesis of (ꢀ)-1g in 1.0% overall
yield.28 In this paper, we present a full account of our total synthesis
of (ꢀ)-1g along with our improved 21-step version. The results of
cytotoxicity studies are also presented.
Our retrosynthetic analysis of 1g was based on the pathway that
we had established for saframycin B,29 N-acetylsaframycin Mx 2,30
and renieramycin derivatives,31 which involved the key trans-
formations outlined in Scheme 1: (1) regioselective synthesis of the
highly substituted piperazine-2,5-dione (III) having a masked para
quinone equivalent at both benzene rings; (2) the PicteteSpengler
type cyclization reaction of the non-basic nitrogen of the secondary
amide (II) with ethyl diethoxyacetate to construct the pentacyclic
framework, with reference to the encouraging results of our model
study;32 (3) and epimerization of the pentacyclic compound (I) at
C-1 position33 and subsequent transformation to generate 1g.
Our strategy was expected to yield a 1-epi-pentacyclic com-
pound. A serendipitous discovery afforded an unnatural analog as
droisoquinolinequinone family and their reduced forms, such as
renieramycin marine natural products (1), together with saframycin
(2) and safracin (3) antibiotics, have attracted considerable interest
over the past 30 years due to their unique structures and meager
availability in nature, and for their potent antitumor activity
(Fig. 1).1,2 The most bioactive member of this family, ecteinascidin
743 (4a: YondelisÔ, trabectedin), has a unique mechanism of action,
that is, based on its binding to the minor groove of DNA to interfere
with cell division, activated transcription, and DNA repair.3,4 Fol-
lowing the first discovery of renieramycins by Frincke and Faulkner
from the Mexican blue sponge Reniera sp. in 1982,5 more than 10
marine natural renieramycins,6e9 along with jorumycin10 and jor-
unnamycins,11 were isolated from several kinds of marine organ-
isms. Renieramycins are expected to be one of the candidates for
new anticancer drugs. However, the structureeactivity relation-
ships (SARs) of renieramycins are little explored12,13 because these
marine natural products are available in very minute quantities.
As part of our search for new metabolites via the isolation and
characterization of biologically active compounds from Thai marine
animals, we successfully isolated renieramycin M (1m) in gram
scale from the Thai blue sponge Xestospongia sp. by pretreatment
* Corresponding author. Tel./fax: þ81 42 495 8794; e-mail address: naoki@
my-pharm.ac.jp (N. Saito).
0040-4020/$ e see front matter Ó 2012 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2012.03.105

M. Yokoya et al. / Tetrahedron 68 (2012) 4166e4181
4167
OMe
OMe
OMe
O
H
Me
O
O
H
Me
O
HO
H
Me
OH
O
E
O
O
O
O
H
3
H
Me
D
Me
Me
N
Me
N
Me
N
Me
A
B
C
N
O
O
N
O
N
X
H
MeO
21
1
H
H
MeO
MeO
H
H
H
X
O
O
O
22
Me
Me
O
Me
O
H
O
H
O
H
Me
Me
Me
renieramycins
renieramycins
renieramycin H (1h)
E (1e): X = OH
M (1m): X = CN
C (1c): X = OH
D (1d): X = OEt
G (1g): X = H
(= cribrostatin 4)
OMe
OMe
HO
O
Me
O
HO
Me
N
H
O
O
H
O
O
MeO
H
OMe
H
N
H
O
Me
Me
MeO
HO
Me
N
O
Me
N
Me
H
H
AcO
S
N
H
O
H
H
MeO
Me
H
H
N
Me
X
X
NH
NH
N
H
NH2
O
O
O
X
O
H
Me
Me
saframycins
ecteinascidins
safracins
A (2a): X = CN
B (2b): X = H
S (2s): X = OH
743 (4a): X = OH
745 (4b): X = H
770 (4c): X = CN
A (3a): X = H
B (3b): X = OH
3c: X = CN
Fig. 1. Structures of bis-1,2,3,4-tetrahydroisoquinolinequinones and their related natural products.
OMe
OMe
OMe
O
H
Me
O
MeO
Me
OH
MeO
Me
OH
O
H
HO
H
H
HO
H
H
Me
Me
N
Me
Me
N
Me
N
Me
21
1
N
O
N
O
H
MeO
N
O
H
MeO
H
H
MeO
H
H
O
O
R
MeO
Me
MeO
O
H
Me
I
II
1g
i
CO2Pr
N
TsO
O
OMe
OMe
O
TsO
O
Me
OMe
OMe
Me
Ac
N
Me
H
N
+
+
H
N
O
R
Me
OMOM
MeO
Ac
MeO
O
MeO
O
OMOM
MeO
5a
III
5b
6
Scheme 1. Retrosynthesis of renieramycin G base on our total synthesis of 2b.

4168
M. Yokoya et al. / Tetrahedron 68 (2012) 4166e4181
part of a comprehensive study of this family of biologically active
compounds.
lactam 17a and (E)-lactam 17b in 64% and 1.5% yields,
respectively.
Phenol 734 was protected with a methoxymethyl (MOM) group
to afford 5a (Scheme 2), the condensation of which with diacetate
635,36 in the presence of a base gave (Z)-arylidenepiperazinedione
8 in 73% yield. Catalytic hydrogenation of 8 over 5% RheC in 2-
propanol at 25 ꢁC for 14 h gave 9, which was subsequently
treated with acetic anhydride to provide diacetate 10 in 88%
overall yield. Condensation of 10 with 5b37 and a base gave (Z)-
isomer 11a and (E)-isomer 11b in 89% and 3% yields, respectively.
The transformation of 11a into carbamate 14 in three steps was
achieved with the method disclosed in our synthetic approach to
saframycin A38 (2a) in 87% overall yield. Regioselective hydride
reduction at C-2 carbonyl to generate unstable alcohol 15 and
sequential dehydration/cyclization of 15 afforded (E)-1,5-imino-3-
benzazocine 16 in 89% yield. Deprotection of 16 with trifluoro-
acetic acid (TFA) and H2SO4 (20/1) at 25 ꢁC for 20 h gave (Z)-
With key intermediate 17a in hand, we looked into ways to
establish a practical conversion of 9 into 17a with a reduction of
the number of steps from nine to six (Scheme 3). The piper-
azinedione ring of 9 was activated by the introduction of a 2-
propyloxycarbonyl group to give imide 18 in 96% yield. Conden-
sation of 18 with 5b and a base gave 19 in 70% yield. Chemo-
selective reduction of 19 in the usual manner afforded
a diastereomeric mixture of alcohol 20, which on treatment with
formic acid at 60 ꢁC for 2.5 h afforded 21a (73%) along with 21b
(17%). Deprotection of 21a with TFA and H2SO4 at 25 ꢁC for 6 h
gave (Z)-lactam 17a and (E)-lactam 17b in 69% and 8% yields, re-
spectively. Deprotection of 21b in the same manner afforded 17a
and 17b in 73% and 9% yields, respectively. Reductive N-methyla-
tion of 17a and 17b gave 22a and 22b in 93% and 91% yields, re-
spectively. Detailed 2-D NMR studies were performed to confirm
O
TsO
O
Ac
N
Me
H
OMe
N
O
O
OMe
Ac
O
O
OMe
MeO
OMe
H
6
OMe
Me
R
O
b
OMe
Me
5b
MeO
e
N
N
H
a
c
Me
N
N
Ac
Ac
O
OR
OMOM
OMOM
7
: R = H
9
: R = H
8
d
5a: R = MOM
10: R = Ac
TsO
O
O
OMe
OH
N
TsO
O
O
OMe
Ac
Me
OMe
Me
i
CO2Pr
Ar'
N
Me
R
OMe
Me
Ar
N
N
i
f
N
MeO
H
N
MeO
MeO
OMOM
O
MeO
OMOM
11a
:
Z
-form
11b
:
E
-form
12: R = Ac
13: R = H
MeO
g
MeO
15
h
i
14: R = CO2Pr
MeO
Me
TsO
OMe
MeO
MeO
Me
TsO
OMe
MeO
OMe
OMe
OMe
Me
OH
MeO
H
Me
OH
Me
OH
H
TsO
j
H
k
Me
MeO
N
i
CO2Pr
N
H
N
H
+
N
N
O
H
N
H
H
H
H
O
MeO
O
16
17a
17b
MeO
t
Scheme 2. (a) NaH, DMF, then MOMCl, 25 ꢁC, 2 h, 100%; (b) BuOK, tBuOH, CH2Cl2, 25 ꢁC, 1 h, 73%; (c) H2, 5% RheC, 25 ꢁC, 2-propanol, 14 h; (d) Ac2O, pyridine, DMAP, 25 ꢁC, 2.5 h,
88% (two steps); (e) tBuOK, tBuOH, THF, 5.5 h, 11a (89%) and 11b (3%) (two steps); (f) NaH, DMF, 25 ꢁC, 0.5 h, then 4-MeOC6H4CH2Cl, 25 ꢁC, 14 h; (g) 5% NaHCO3eH2O, EtOH, reflux,
2.5 h, 87% (two steps); (h) ClCOi2Pr, TEA, DMAP, CH2Cl2, 25 ꢁC, 23 h, 100%; (i) Li(tBuO)3AlH, THF, 0 ꢁC, 4.5 h; (j) HCO2H, 60 ꢁC,1 h, 89% (two steps); (k) H2SO4eTFA (1/20), 25 ꢁC, 20 h,
17a (64%) and 17b (1.5%).

M. Yokoya et al. / Tetrahedron 68 (2012) 4166e4181
4169
OMe
O
O
OMe
MeO
H
Me
OH
5b
TsO
X
R
+
OMe
Me
i
CO2Pr
N
Me
TsO
N
d
b
N
Me
Ac
N
N
i
MeO
H
CO2Pr
OMOM
N
O
MeO
O
OMOM
Me
MeO
H
H
MeO
MeO
9
: R = H
19: X = O
21a
: -form
Z
OMe
a
c
21b
:
E
-form
i
20: X = H, OH
18: R = CO2Pr
starting
material
products (%)
17a
e
17b
+
21a
21b
69%
8%
9%
17a
+
17b
73%
OMe
MeO
Me
OH
TsO
H
Me
c-f
f-1
N
Me
N
17a
22a (83%) + 22b (9%)
19
MeO
H
H
MeO
O
22a
MeO
Me
TsO
OMe
MeO
OMe
OMe
MeO
Me
OH
Me
OH
TsO
H
H
f-2
H
Me
g
N
Me
17b
N
22a
Me
N
O
MeO
H
H
N
H
H
MeO
O
23
22b
Scheme 3. (a) ClCO2i Pr, TEA, DMAP, CH2Cl2, 25 ꢁC, 2 h, 96%; (b) tBuOK, tBuOH, CH2Cl2, 25 ꢁC, 40 min, 70%; (c) Li(tBuO)3AlH, THF, 0 ꢁC, 4.5 h; (d) HCO2H, 60 ꢁC, 2.5 h, 21a (73%) and 21b
(17%) (two steps); (e) H2SO4, TFA, 25 ꢁC, 6 h (for yields, see table); (f-1) 37% HCHOeH2O, HCO2H, 70 ꢁC, 1 h, 93%; (f-2) 37% HCHOeH2O, HCO2H, 70 ꢁC, 2 h, 91%; (g) H2 (2.8 MPa), 20%
Pd(OH)2eC, EtOH, 80 ꢁC, 41 h, 93%.
the structures of 22a and 22b. The NMR spectrum of 22a displayed
H-14 and H-15 proton signals at 5.93 and 4.60, respectively,
whereas the NMR spectrum of 22b had H-14 and H-15 proton
signals appearing at 5.48 and 4.97, respectively. An observable
according to the procedure of Ong et al.39e41 The stereochemistry of
d
d
24 was readily identified on the basis of the chemical shifts of H-4
b
(d
2.20) and H-3 (d 3.89), along with the coupling between H-4
b
d
d
NOE revealed the relative stereochemistries of the exo-double
bonds of both 22a and 22b (Fig. 2).
MeO
Me
OMe
H
OTs
Me
Accordingly, the sequence of transformations of 19 into 22
without any purification of the intermediates was found to be the
best choice in terms of overall yield (22a in 83% yield and 22b in 9%
yield). We were also able to devise a six-step transformation of 9
into 22a in 56% overall yield. Reduction of the double bond of 22a
through the action of hydrogen (28 atm) on 20% Pd(OH)2eC in
H
H
H
MeO
MeO
14
N
Me
14
H
15
TsO
N
Me
15
O
N
H
H
H
N
H
H
O
ethanol at 80 ꢁC for 41 h occurred from the less hindered
a-face to
afford 22a in 93% yield.
22a
22b
Treatment of 23 with a large excess of paraformaldehyde in
acetic acideTFA (4/1) at 80 ꢁC for 15 h provided 24 in 66% yield,
Fig. 2. Key NOE correlations of 22a and 22b.

4170
M. Yokoya et al. / Tetrahedron 68 (2012) 4166e4181
and H-3 (J¼12.2 Hz), as noted previously for related systems
(Scheme 4).42
Then, we examined several routes for the construction of
a pentacyclic framework having a hydroxymethyl substituent at
C-1 using the modified PicteteSpengler reaction via the O-trime-
thylsilyllactim intermediate with ethyl diethoxyacetate. Attempts
made under a variety of conditions that were based on the results
of our recent model conversion32 were fruitless (Scheme 5).43 We
OMe
MeO
Me
OH
TsO
H
H
a
Me
N
Me
23
N
O
MeO
H
MeO
24
ORTEP drawing of the ester 26.
OMe
OMe
MeO
Me
OR
MeO
Me
RO
H
HO
H
H
H
b
c
Me
Me
OH
Me
e
N
Me
N
1
N
N
MeO
MeO
H
H
H
H
O
MeO
O
O
MeO
O
26: R = H
d
25
Me
27: R = Bn
OMe
OMe
OMe
MeO
Me
MeO
Me
MeO
Me
BnO
H
BnO
H
BnO
MeO
H
H
H
N
H
H
N
H
Me
OBn
Me
Me
MeO
OBn
Me
Me
MeO
OBn
g
h
N
N
N
Me
N
O
30a
+
MeO
H
H
H
H
H
O
H
O
MeO
f
R
MeO
O
O
28: R = CO2H
30b
30a
29a: R = CH2OH
OMe
OMe
MeO
Me
OR
O
H
Me
O
RO
Me
H
O
O
H
H
k
i
Me
N
Me
N
Me
30b
N
N
MeO
H
H
MeO
H
H
MeO
O
O
OH
OH
32
29b: R = Bn
31: R = H
l
j
m
OMe
MeO
Me
OR
RO
H
H
Me
MeO
renieramycin G
1g
n
N
Me
N
O
H
H
MeO
O
Me
O
H
33
Me
Scheme 4. (a) (HCHO)n, AcOHeTFA (4/1), 80 ꢁC, 15 h, 66%; (b) NH2NH2eH2O, MeOH, reflux, 73 h, 80%; (c) (EtO)2CHCO2Et (4 equiv), TMSOTf (1.04 equiv), (CH2Cl)2, 120 ꢁC, 13 h, 77%;
(d) BnBr, K2CO3, acetone, reflux, 12 h, 88%; (e) 0.1 M LiOHeH2O, THFeMeOH (3/1), 25 ꢁC, 8 days; (f) ClCO2Et, TEA, THF, ꢂ7 ꢁC, 3 h; and then NaBH4, H2O, 0 ꢁC, 2 h, 81% (three steps);
(g) (COCl)2, DMSO, CH2Cl2, ꢂ78 ꢁC, then TEA at ꢂ40 ꢁC, 92%; (h) DBU (1 equiv), THF, 24 h, 30a (85%) and 30b (4%) (three times); (i) NaBH3CN, THF, AcOH, 25 ꢁC, 3.5 h, 65%; (j) H2, 20%
Pd(OH)2eC, MeOH, 25 ꢁC, 2 h, 100%; (k) CAN, MeCNeH2O, 0 ꢁC, 15 min; (l) (Z)-MeCH]C(Me)COCl, CH2Cl2, 25 ꢁC, 25 h, 36% (two steps); (m) (Z)-MeCH]C(Me)COCl, CH2Cl2, 25 ꢁC,
2 h, 93%; (n) CAN, MeCNeH2O, 0 ꢁC, 15 min, 80%.

M. Yokoya et al. / Tetrahedron 68 (2012) 4166e4181
4171
values of 0.5 and 1.0
m
g/mL, respectively.7 Williams and co-
(EtO)2CHCO2Et (4 eq)
TMSOTf (8 eq)
ClCH2CH2Cl
OMe
workers also reported that synthetic (ꢂ)-1g and the correspond-
ing epimer, 3-epi-renieramycin G had minimal inhibitory effects
on both human colon (HCT116) and human lung (A549) cancer cell
lines.12 Thus, the compounds synthesized above, including natural
(ꢂ)-renieramycin M (1m), were tested in vitro for cytotoxicity
using three representative human solid tumor cell lines (HCT116
human colon carcinoma, QG56 human lung carcinoma, and DU145
MeO
Me
OH
TsO
H
H
100oC, 42 h
Me
N
Me
23
N
MeO
H
46%
MeO
O
CO2Et
26a
prostate
carcinoma)
following
the
standard
3-[4,5-
dimethylthiazol-2-yl]-2,5-diphenyltetrazolium bromide (MTT)
method (Table 1). Synthetic (ꢀ)-1g displayed very weak micro-
molar inhibitory effects and all of the pentacyclic analogs did not
show any cytotoxicity.
Scheme 5. Preparation of 26a from 23.
then tried to increase the reactivity of the A-ring, such as phenol 25,
which was easily prepared from 23 in 80% yield. The reaction of 23
with ethyl diethoxyacetate in the presence of trimethylsilyl tri-
fluoromethanesulfonate (TMSOTf) in dichloroethane at 120 ꢁC for
13 h gave cyclized ester 26 in 77% yield. X-ray crystallographic
analysis of 26 revealed that the stereochemistry at C-1 was epi-
meric to that of natural renieramycins.
Table 1
Cytotoxicities of racemic renieramycin G (1g) and related compounds to various
human cancer cell lines (IC50 mM)
Compound
HCT116
QG56
DU145
26
>2
>2
>2
27
>2
>2
>2
29a
29b
30a
30b
31
32
33
>2
>2
>2
>2
>2
>2
>2
1.1
>2
>2
>2
>2
>2
1.7
>2
1.3
>2
>2
>2
>2
>2
>2
>2
1.3
The remaining problem was the isomerization at C-1 of 26. As 26
was not sufficiently soluble in any solvent, we thought it would be
better to convert 26 into 27 before starting our study of the isom-
erization at C-1. Thus, benzylation of 26 with benzyl bromide and
a base gave 27 in 88% yield. Another problem was that obtained
ester 27 should be oriented in the a-axial direction because the b-
(ꢀ)-1g (renieramycin G)
equatorial space was hindered by both the methoxyl group at the
peri position and the lactam carbonyl at C-21. Indeed, voluminous
effort to epimerize 27 under basic conditions was unsuccessful.
Nevertheless, this problem was solved by selecting the smallest
carbonyl functional group at C-1. Treatment of ester 27 with
aqueous LiOH in THFeMeOH (3/1) at 25 ꢁC for 8 days gave corre-
sponding carboxylic acid 28, which was subsequently subjected to
hydride reduction via the mixed anhydride to afford alcohol 29a in
81% overall yield. The Swern oxidation of 29a afforded aldehyde
30a in 92% yield. Treatment of 30a with 1.0 equiv of 1,8-
diazabicyclo[5.4.0]undec-7-ene (DBU)44e46 in THF at 25 ꢁC for
24 h afforded 30b in 62% yield, and 33% of starting material 30a was
recovered.47 Isomerization of recovered 30a by repeating twice
gave finally 30b and 30a in 85% and 4%, respectively. The 1H NMR
spectrum of 30b displayed an H-1 signal that appeared as a singlet
(ꢂ)-1m (renieramycin M)
5.2ꢃ10ꢂ3
17.0ꢃ10ꢂ3
1.7ꢃ10ꢂ3
In summary, we have succeeded in reducing the number of steps
of our total synthesis of (ꢀ)-renieramycin G from 25 steps in 1.0%
overall yield to 21 steps in 6.3% overall yield. We have embarked on
a more general SAR study to gain a more detailed understanding of
this family of compounds. Ways to utilize this approach for the
synthesis of other members of the renieramycin family, including
renieramycins E (1e) and M (1m), together with the corresponding
C-1 epimers, are under study in our laboratories.
2. Experimental section
2.1. General
at
d
6.06 and an H-3 signal at
d
3.92, whereas the 1H NMR spectrum
6.27 and an H-3 signal at 4.18.
of 30a showed an H-1 signal at
d
d
IR spectra were obtained with a Shimadzu Prestige 21/IRA
Affinity-1 FT-IR spectrometer. 1H and 13C NMR spectra were
recorded on a JEOL JNM-ECA 500 FT NMR spectrometer at 500 MHz
for 1H and 125 MHz for 13C; a JEOL JNM-AL 400 NMR spectrometer
at 400 MHz for 1H and 100 MHz for 13C; and a JEOL JNM-AL 300
NMR spectrometer at 300 MHz for 1H and 75 MHz for 13C (parts per
million, J in hertz with TMS as internal standard). All proton and
carbon signals were assigned by extensive NMR measurements
using COSY, HMBC, and HMQC techniques. Mass spectra were
recorded on a JEOL 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.
The remarkable difference in the chemical shifts of the methine
protons must be due to the steric interactions between the side
chains at C-1 and C-3.48 Reduction of 30b with sodium cyanobor-
ohydride (NaBH3CN) in THF in the presence of a catalytic amount of
AcOH gave 29b in 65% yield.49,50
Debenzylation of 29b gave 31 in a quantitative yield. Oxidative
demethylation of 31 with ceric ammonium nitrate (CAN) in aque-
ous acetonitrile afforded 32, which was
a Magnus 1g in-
termediate.20 The final step of our total synthesis involved the
treatment of 32 with angeloyl chloride in CH2Cl2 to give
(ꢀ)-renieramycin G (1g) in 36% overall yield according to the pro-
cedure of Magnus.20 The yield of the two-step process from 31 to 1g
via 32 was disappointingly low. This low yield plus the exceedingly
troublesome procedure prompted us to examine another approach
that involved the conversion 31 into 1g via 33. Treatment of 31 with
angeloyl chloride in CH2Cl2 at 25 ꢁC for 2 h afforded 33 in 93% yield.
Oxidative demethylation of 33 with CAN in aqueous acetonitrile at
0 ꢁC for 15 min gave 1g in 80% yield. Synthetic 1g was identical with
the natural one on comparison of their spectroscopic data along
with data of the racemic compound by Magnus.
2.1.1. 2-Hydroxy-4,5-dimethoxy-3-methylbenzaldehyde (7).36,51
2.1.1.1. 3,4-Dimethoxy-2-methylphenol.52,53 Sodium hydride (60%
oil dispersion, washed with dry hexane three times, 9.36 g,
390 mmol) was added to a stirred solution of 2,3-dimethoxyphenol
(30.0 g, 195 mmol) in DMF (170 mL), and the resulting mixture was
stirred at 0 ꢁC for 30 min. Then, MOMCl (29.6 mL, 390 mmol) was
added over 30 min and the reaction mixture was stirred at 0 ꢁC for
2 h. Thereafter, the reaction mixture was diluted with water
(750 mL) and extracted with ether (3ꢃ750 mL). The combined ex-
tracts were washed with water (300 mL), dried, and concentrated
in vacuo to give (3,4-dimethoxy-2-methylphenoxy)methyl methyl
Despite having a lactam carbonyl group at C-21, Davidson
reported that natural (ꢂ)-renieramycin G (1g) showed moderate
cytotoxicity to two human cancer cell lines, KB and LoVo, with MIC

4172
M. Yokoya et al. / Tetrahedron 68 (2012) 4166e4181
ether as a dark oil, which was used in the next step without further
purification. 1H NMR (CDCl3, 300 MHz)
3.49 (3H, s, CH2OCH3),
3.84 (3H, s, OCH3), 3.86 (3H, s, OCH3), 5.12 (2H, s, OCH2O), 6.59 (1H,
dd, J¼8.6, 2.8 Hz, 6-H), 6.63 (1H, d, J¼2.8 Hz, 2-H), 6.76 (1H, d,
J¼8.6 Hz, 5-H).
was added to a stirred solution of 7 (19.6 g, 100 mmol) and trie-
thylamine (20.9 mL, 150 mmol) in CH2Cl2 (200 mL) at 0 ꢁC over
10 min, and stirring was continued at 25 ꢁC for 3 h. The reaction
mixture was diluted with brine (500 mL) and extracted with CH2Cl2
(3ꢃ1000 mL). The combined extracts were washed with water
(800 mL), dried, and concentrated in vacuo to give a solid, the re-
crystallization of which from benzene gave 7b (33.3 g, 95%) as pale
d
A solution of n-BuLi (1.65 mmol hexane solution, 296 mL,
488 mmol) was added to a solution of the above residue in THF
(280 mL) at ꢂ17 ꢁC for 2 h, and the reaction mixture was stirred at
the same temperature for 1 h. A solution of iodomethane (36.4 mL,
585 mmol) in THF (115 mL) was added over 1 h and the resulting
mixture was stirred for 2 h at 0 ꢁC. Thereafter, the reaction mixture
was diluted with water (500 mL) and extracted with ether
(3ꢃ500 mL). The combined extracts were washed with brine
(500 mL), dried, and concentrated in vacuo to give a residue, which
was also used in the next step without further purification. 1H NMR
red prisms, mp 147e148 ꢁC. IR (KBr) 2940, 1686, 1591 cmꢂ1
;
1H
NMR (CDCl3, 300 MHz)
d
2.06 (3H, s, 3-CH3), 2.49 (3H, s, 40-CH3),
3.88 (3H, s, OCH3), 3.90 (3H, s, OCH3), 7.29 (1H, s, 6-H), 7.37 (2H, d,
J¼8.3 Hz, 2ꢃArH), 7.76 (2H, d, J¼8.3 Hz, 2ꢃArH), 9.78 (1H, s, CHO);
EIMS m/z (%) 350 (Mþ, 27), 195 (100). HREIMS m/z 350.0825 (Mþ,
calcd for C17H18O6S, 350.0824). Anal. Calcd for C17H18O6S: C, 58.27;
H, 5.18. Found: C, 58.44; H, 5.17.
(CDCl3, 300 MHz)
(3H, s, OCH3), 3.82 (3H, s, OCH3), 5.12 (2H, s, OCH2O), 6.67 (1H, d,
J¼9.0 Hz, 6-H), 6.77 (1H, d, J¼9.0 Hz, 5-H).
d
2.18 (3H, s, 2-CH3), 3.49 (3H, s, CH2OCH3), 3.79
2.1.4. (3Z)-1-Acetyl-3-[[4,5-dimethoxy-2-(methoxymethoxy)-3-
methylphenyl]methylene]piperazine-2,5-dione (8). A solution of po-
tassium tert-butoxide (13.5 g, 120 mmol) in tert-butyl alcohol
(120 mL) was added to a stirred solution of 5a (24.0 g, 100 mmol)
and 1,4-diacetylpiperazine-2,5-dione 635,36 (19.8 g, 100 mmol) in
CH2Cl2 (400 mL) at 0 ꢁC over 1 h, and stirring was continued at 25 ꢁC
for 1 h. The reaction mixture was poured into saturated aqueous
NH4Cl solution (2.0 L) and extracted with CH2Cl2 (3ꢃ800 mL). The
combined extracts were washed with brine (1.0 L), dried, and con-
centrated in vacuo to give a solid, the recrystallization of which from
hexaneeethyl acetate gave 8 (27.6 g, 73.0%) as pale yellow prisms,
mp 133e134 ꢁC. IR (KBr) 3279,1678,1642,1386,1332,1064 cmꢂ1; 1H
Concentrated hydrochloric acid (0.9 mL) was added to a stirred
solution of the above residue in ethanol (900 mL) and this mixture
was heated under reflux for 1.5 h. The reaction mixture was con-
centrated in vacuo and the residue was diluted with 5% aqueous
NaHCO3 solution (600 mL) and then extracted with chloroform
(3ꢃ600 mL). The combined extracts were washed with water
(600 mL), dried, and concentrated in vacuo to produce a solid, the
recrystallization of which from ether gave 3,4-dimethoxy-2-
methylphenol (10.0 g, 85.0%) as pale yellow needles, mp
99.5e101.0 ꢁC. 1H NMR (CDCl3, 300 MHz)
d
2.18 (3H, s, 2-CH3), 3.80
NMR (CDCl3, 300 MHz) d
2.27 (3H, s, 30-CH3), 2.65 (3H, s, COCH3),
(3H, s, OCH3), 3.81 (3H, s, OCH3), 6.51 (1H, d, J¼8.8 Hz, 6-H), 6.64
3.54 (3H, s, CH2OCH3), 3.84 (6H, s, 2ꢃOCH3), 4.47 (2H, s, 6-H2), 4.85
(1H, d, J¼8.8 Hz, 5-H). The OH signal could not be detected.
(2H, s, OCH2O), 6.66 (1H, s, 60-H), 7.09 (1H, s, 3a-H), 8.84 (1H, br s,
NH); 13C NMR (CDCl3, 67.5 MHz) 10.3 (30-CH3), 27.1 (COCH3), 46.2
d
2.1.1.2. 2-Hydroxy-4,5-dimethoxy-3-methylbenzaldehyde (7). A
solution of the above phenol (10.0 g, 59.5 mmol) and hexamethy-
lenetetramine (25.0 g, 178 mmol) in acetic acid (500 mL) was
heated at 125 ꢁC for 1 h. The reaction mixture was diluted with
water (500 mL) and extracted with chloroform (3ꢃ600 mL). The
combined extracts were washed with saturated aqueous NaHCO3
(600 mL), dried, and concentrated in vacuo to give a solid, the re-
crystallization of which from ether gave 7 (9.35 g, 80.0%) as color-
less needles, mp 76.0e76.5 ꢁC. IR (KBr) 3015, 2924, 1854, 1649,
(C-6), 56.0 (OCH3), 58.2 (OCH3), 60.4 (OCH3), 100.4 (OCH2O), 111.1
(C60), 117.7 (C3a), 121.7, 125.4, 127.2, 146.9, 149.4, 149.9, 160.4 (CO),
162.5 (CO), 172.5 (CO); EIMS m/z (%) 378 (Mþ, 76), 346 (100), 304
(77), 291 (61), 206 (30). Anal. Calcd for C18H22N2O7: C, 57.09; H, 5.86;
N, 7.40. Found: C, 57.09; H, 5.95; N, 7.33.
2.1.5. 1,4-Diacetyl-3-[(4,5-dimethoxy-2-methoxymethoxy-3-
methylphenyl)methyl]piperazine-2,5-dione (10).
2.1.5.1. 1-Acetyl-3-[(4,5-dimethoxy-2-methoxymethoxy-3-
1624, 1485, 1328, 1087 cmꢂ1; 1H NMR (CDCl3, 300 MHz)
d
2.17 (3H,
methylphenyl)methyl]piperazine-2,5-dione (9). A solution of 8
s, 3-CH3), 3.86 (3H, s, OCH3), 3.91 (3H, s, OCH3), 6.86 (1H, s, 6-H),
9.75 (1H, s, CHO), 11.29 (1H, s, OH); EIMS m/z (%) 196 (Mþ, 100), 181
(51), 153 (13). HREIMS m/z 196.0739 (Mþ, calcd for C10H12O4,
196.0736). Anal. Calcd for C10H12O4: C, 61.22; H, 6.16. Found: C,
61.46; H, 6.17.
(5.0 g, 6.16 mmol) in 2-propanol (200 mL) was hydrogenated over
5% RheC (2.6 g, 1.28 mmol) at 25 ꢁC for 14 h. The catalyst was re-
moved by filtration and washed with 2-propanol (200 mL) and
then CHCl3 (200 mL). The combined filtrate was concentrated in
vacuo. Crude solid 9 (5.33 g) was used in the following step without
further purification. An analytical sample of 9 was obtained by
recrystallization from hexaneeethyl acetate as colorless prisms, mp
2.1.2. 4,5-Dimethoxy-2-(methoxymethoxy)-3-methylbenzaldehyde
(5a). Sodium hydride (60% oil dispersion, washed with dry hexane
three times, 7.20 g, 300 mmol) was added to a stirred solution of 7
(19.6 g, 100 mmol) in DMF (500 mL), and the reaction mixture was
stirred at 0 ꢁC for 30 min. Then, MOMCl (22.8 mL, 300 mmol) was
added over 10 min and the reaction mixture was stirred at 25 ꢁC for
2 h. The reaction mixture was diluted with water (800 mL) and
extracted with ether (3ꢃ800 mL). The combined extracts were
washed with water (800 mL), dried, and concentrated in vacuo to
give 5a (24.0 g, 100%), the recrystallization of which from ether
gave colorless needles, mp 43.5e44 ꢁC. IR (KBr) 2940, 1686,
116e117 ꢁC. IR (KBr) 3100, 1720, 1700, 1455, 1270, 1245 cmꢂ1
;
1H
NMR (CDCl3, 300 MHz)
d
2.18 (3H, s, 30-CH3), 2.60 (3H, s, COCH3),
3.08 (1H, dd, J¼14.1, 8.3 Hz, 3a-H), 3.44 (1H, dd, J¼14.1, 4.1 Hz, 3a-
H), 3.59 (3H, s, CH2OCH3), 3.80 (3H, s, OCH3), 3.81 (3H, s, OCH3), 4.10
(1H, d, J¼17.8 Hz, 6-H), 4.30 (1H, d, J¼17.8 Hz, 6-H), 4.37 (1H, ddd,
J¼8.3, 4.1, 1.7 Hz, 3-H), 4.94 (2H, s, OCH2O), 6.50 (1H, br s, NH) 6.57
(1H, s, 60-H); EIMS m/z (%) 380 (Mþ, 34), 348 (41), 225 (30), 220 (13),
195 (13), 193 (11), 182 (16), 181 (100), 180 (29), 165 (14), 45 (32).
Anal. Calcd for C18H24N2O7$1/10H2O: C, 56.57; H, 6.38; N, 7.33.
Found: C, 57.07; H, 6.40; N, 6.86.
1591 cmꢂ1 1H NMR (CDCl3, 300 MHz)
; d 2.23 (3H, s, 3-CH3), 3.59
(3H, s, CH2OCH3), 3.88 (3H, s, OCH3), 3.89 (3H, s, OCH3), 5.02 (2H, s,
OCH2O), 7.24 (1H, s, 6-H), 10.25 (1H, s, CHO); EIMS m/z (%) 240 (Mþ,
82), 195 (54), 194 (100), 45 (63). Anal. Calcd for C12H16O5: C, 59.99;
H, 6.71. Found: C, 60.02; H, 6.70.
2.1.5.2. Diacetate (10). A solution of the above residue (9:
5.33 g) and DMAP (323 mg, 2.6 mmol) in pyridine (80 mL) was
cooled with ice water and acetic anhydride (1.5 mL, 16 mmol) was
added dropwise over 10 min. The reaction mixture was stirred at
25 ꢁC for 1 h. The solvent was removed in vacuo and then, the
residue was taken up in water (500 mL) and extracted with ethyl
acetate (3ꢃ500 mL). The combined extracts were washed with
2.1.3. 4,5-Dimethoxy-3-methyl-2-[(4-methylphenylsulfonyl)oxy]-
benzaldehyde (5b). 4-Toluenesulfonyl chloride (28.6 g, 150 mmol)

M. Yokoya et al. / Tetrahedron 68 (2012) 4166e4181
4173
brine (500 mL), dried, and concentrated in vacuo to give a solid, the
recrystallization of which from hexaneeethyl acetate afforded 10
(4.90 g, 88%, two steps) as colorless prisms, mp 105 ꢁC. IR (KBr)
128.3 (2ꢃCH), 129.9 (2ꢃCH), 133.8, 140.6, 145.6, 147.7, 148.4, 149.4,
149.8, 150.5, 158.9 (CO), 166.8 (CO), 172.1 (CO); EIMS m/z (%) 712
(Mþ, 86), 557 (49), 377 (64), 181 (100); HREIMS m/z 712.2305 (Mþ,
calcd for C35H40N2O12S, 712.2302).
1708, 1238, 1219, 1062 cmꢂ1; 1H NMR (CDCl3, 300 MHz)
d 2.13 (3H,
s, 30-CH3), 2.55 (3H, s, COCH3), 2.56 (3H, s, COCH3), 2.93 (1H, d,
J¼19.0 Hz, 6-H), 3.22 (1H, dd, J¼13.9, 4.6 Hz, 3a-H), 3.37 (1H, dd,
J¼13.9, 6.4 Hz, 3a-H), 3.53 (3H, s, CH2OCH3), 3.75 (3H, s, OCH3), 3.78
(3H, s, OCH3), 4.56 (1H, d, J¼19.0 Hz, 6-H), 4.81 (2H, s, OCH2O), 5.39
(1H, dd, J¼6.4, 4.6 Hz, 3-H), 6.43 (1H, s, 60-H); EIMS m/z (%) 422 (Mþ,
62), 225 (100), 195 (30), 181 (47), 45 (31). Anal. Calcd for
C20H26N2O8: C, 56.86; H, 6.20; N, 6.63. Found: C, 57.01; H, 6.35; N,
6.56.
2.1. 8. (3Z)-6-[4, 5-Dimethoxy-2-(methoxymethoxy)-3-
methylphenylmethyl]-3-[4,5-dimethoxy-3-methyl-2-[(4-methylphenyl)
sulfoxyphenyl]methylene]-4-(4-methoxyphenylmethyl)-piperazine-
2,5-dione (13). Sodium hydride (60% oil dispersion, washed with
dry hexane three times, 360 mg, 15.0 mmol) was added to a stirred
solution of 11a (10.7 g, 15.0 mmol) in DMF (300 mL) at 0 ꢁC, and the
reaction mixture was stirred at 25 ꢁC for 30 min. Then, 4-
methoxybenzyl chloride (2.35 g, 16.5 mmol) was added over
20 min and the resulting mixture was stirred at 25 ꢁC for 14 h. The
reaction mixture was diluted with water (1 L) and extracted with
ethyl acetate (3ꢃ1 L). The combined extracts were washed with
brine (1 L), dried, and concentrated in vacuo. Obtained crude solid
12 (14.5 g) was used in the following step without further purifi-
cation. An analytical sample was obtained by recrystallization from
ethereethyl acetate as colorless prisms, mp 159e160 ꢁC. IR (KBr)
2.1.6. (3Z)-1-Acetyl-6-[4,5-dimethoxy-2-(methoxymethoxy)-3-
methylphenylmethyl]-3-[4,5-dimethoxy-3-methyl-2-[(4-
methylphenylsulfoxy) phenyl]methylene]piperazine-2,5-dione
(11a). A solution of potassium tert-butoxide (4.48 g, 40.0 mmol)
in tert-butyl alcohol (80 mL) was added to a stirred solution of 10
(16.9 g, 40.0 mmol) and 5b (14.0 g, 140.0 mmol) in THF (80 mL) at
0 ꢁC over 20 min, and stirring was continued at 25 ꢁC for 5.5 h. The
reaction mixture was poured into brine (2.0 L) and extracted with
ethyl acetate (3ꢃ2.0 L). The combined extracts were washed with
brine (2.0 L), dried, and concentrated in vacuo to give a solid, the
recrystallization of which from ethereethyl acetate gave 11a
(25.1 g, 88.0%) as pale yellow prisms, mp 169e170 ꢁC. IR (KBr) 1701,
1672, 1620 cmꢂ1 1H NMR (CDCl3, 300 MHz)
; d 1.91 (3H, s, ArCH3),
2.04 (3H, s, ArCH3), 2.46 (3H, s, ArCH3), 2.51 (3H, s, COCH3), 3.20
(1H, dd, J¼14.0, 7.0 Hz, 6a-H), 3.28 (1H, dd, J¼14.0, 5.6 Hz, 6a-H),
3.50 (3H, s, OCH3), 3.54 (3H, s, OCH3), 3.72 (3H, s, OCH3), 3.76 (3H, s,
OCH3), 3.85 (3H, s, OCH3), 3.97 (3H, s, OCH3), 4.15 (1H, d, J¼14.1 Hz,
NCH), 4.77 (1H, d, J¼5.7 Hz, OCHO), 4.81 (1H, d, J¼5.7 Hz, OCHO),
5.01 (1H, d, J¼14.1 Hz, NCH), 5.44 (1H, dd, J¼7.0, 5.6 Hz, 6-H), 6.41
(1H, s, 3a-H), 6.72 (2H, d, J¼8.8 Hz, 2ꢃArH), 6.90 (1H, s, ArH), 7.07
(1H, s, ArH), 7.09 (2H, d, J¼8.8 Hz, 2ꢃAr), 7.32 (2H, d, J¼8.2 Hz,
2ꢃArH), 7.85 (2H, d, J¼8.2 Hz, 2ꢃArH); EIMS m/z (%) 832 (Mþ, 4),
661 (17), 660 (17), 616 (16), 394 (12), 393 (47),121 (100). Anal. Calcd
for C43H48N2O13S: C, 62.01; H, 5.81; N, 3.36. Found: C, 61.78; H,
5.82; N, 2.96.
1489, 1375, 1228, 1070 cmꢂ1; 1H NMR (CDCl3, 300 MHz)
d 2.01 (3H,
s, ArCH3), 2.18 (3H, s, ArCH3), 2.39 (3H, s, ArCH3), 2.60 (3H, s,
COCH3), 3.06 (1H, dd, J¼13.8, 2.8 Hz, 6a-H), 3.35 (1H, dd, J¼13.8,
5.5 Hz, 6a-H), 3.44 (3H, s, OCH3), 3.54 (3H, s, OCH3), 3.63 (3H, s,
OCH3), 3.84 (3H, s, OCH3), 4.00 (3H, s, OCH3), 4.75 (1H, d, J¼6.0 Hz,
OCHO), 4.77 (1H, d, J¼6.0 Hz, OCHO), 5.31 (1H, dd, J¼5.5, 2.8 Hz, 6-
H), 6.16 (1H, s, 3a-H), 6.21 (1H, s, ArH), 6.53 (1H, s, ArH), 7.24 (2H, d,
J¼8.1 Hz, 2ꢃArH), 7.39 (1H, s, NH), 7.65 (2H, d, J¼8.1 Hz, 2ꢃArH);
13C NMR (CDCl3, 67.5 Hz)
d
10.3 (ArCH3), 11.2 (ArCH3), 21.7 (ArCH3),
A solution of the above residue (12: 14.5 g) in ethanol (500 mL)
and aqueous 5% NaHCO3 solution (100 mL) was heated under reflux
for 2.5 h. The reaction mixture was concentrated in vacuo and then,
the residue was diluted with water (1 L) and extracted with ethyl
acetate (3ꢃ1 L). The combined extracts were washed with brine
(1 L) and concentrated in vacuo to give a solid, the recrystallization
of which from ether gave 13 (10.3 g, 87.0%, two steps) as colorless
prisms, mp 152e153 ꢁC. IR (KBr) 3250, 1688, 1636, 1487, 1375, 1244,
27.2 (COCH3), 33.0 (C6a), 55.5 (OCH3), 56.0 (OCH3), 57.3 (C6), 57.7
(OCH3), 60.1 (OCH3), 60.4 (OCH3), 99.9 (OCH2O), 110.4 (CH), 112.3
(CH), 114.1 (C3a), 122.3, 122.7, 125.3, 126.1, 128.3 (2ꢃCH), 128.5,
129.7 (2ꢃCH), 133.2, 139.4, 145.5, 148.1, 148.7, 149.5, 149.6, 151.6,
159.0 (CO), 165.5 (CO), 172.4 (CO); EIMS m/z (%) 712 (Mþ, 100), 558
(20), 557 (42), 377 (58), 335 (36), 317 (20), 246 (25), 235 (45), 225
(45), 192 (23), 181 (88); HREIMS m/z 712.2299 (Mþ, calcd for
C35H40N2O12S, 712.2302). Anal. Calcd for C35H40N2O12S: C, 58.98; H,
5.66; N, 3.99. Found: C, 58.98; H, 5.72; N, 3.89.
After collecting the crystals of 11a described above, the filtrate
was concentrated in vacuo to give a residue, which showed two
major spots on TLC. Chromatography on a silica gel column with
hexaneeethyl acetate (3/2) as the eluent gave an additional amount
of 11a (330.4 mg, 1.0%) as colorless prisms. Further elution with
hexaneeethyl acetate (1/1) afforded 11b (940.0 mg, 3.0%) as a pale
yellow amorphous powder.
1176 cmꢂ1 1H NMR (CDCl3, 400 MHz)
; d 1.99 (3H, s, ArCH3), 2.21
(3H, s, ArCH3), 2.40 (3H, s, ArCH3), 3.05 (1H, dd, J¼14.0, 4.9 Hz, 6a-
H), 3.51 (1H, dd, J¼14.0, 4.2 Hz, 6a-H), 3.59 (3H, s, OCH3), 3.72 (3H, s,
OCH3), 3.76 (3H, s, OCH3), 3.78 (3H, s, OCH3), 3.81 (3H, s, OCH3),
3.83 (3H, s, OCH3), 4.13 (1H, d, J¼15.0 Hz, NCH), 4.43 (1H, dd, J¼9.3,
4.2 Hz, 6-H), 4.88 (1H, d, J¼15.0 Hz, NCH), 4.95 (1H, d, J¼6.0 Hz,
OCHO), 4.97 (1H, d, J¼6.0 Hz, OCHO), 6.25 (1H, br s, NH), 6.59 (1H, s,
ArH), 6.65 (1H, s, ArH), 6.76 (2H, d, J¼8.8 Hz, 2ꢃArH), 6.82 (2H, d,
J¼8.8 Hz, 2ꢃArH), 6.89 (1H, s, 3a-H), 7.28 (2H, d, J¼8.5 Hz, 2ꢃArH),
7.76 (2H, d, J¼8.5 Hz, 2ꢃArH); 13C NMR (CDCl3, 100 Hz)
d 10.5
2.1.7. (3E)-1-Acetyl-6-[4,5-dimethoxy-2-(methoxymethoxy)-3-
methylphenylmethyl]-3-[4,5-dimethoxy-3-methyl-2-[(4-
methylphenyl)sulfoxyphenyl]methylene]piperazine-2,5-dione
(11b). IR (KBr) 1697, 1489, 1384, 1238, 1068 cmꢂ1; 1H NMR (CDCl3,
(ArCH3), 10.8 (ArCH3), 21.6 (ArCH3), 32.3 (C6a), 47.8 (NCH2), 55.1
(OCH3), 55.4 (OCH3), 55.9 (C6), 55.9 (OCH3), 57.5 (OCH3), 60.1
(OCH3), 60.4 (OCH3), 99.8 (OCH2O), 110.2 (CH), 111.7 (CH), 113.5
(2ꢃCH), 117.0 (C3a), 124.2, 124.4, 125.8, 127.4, 128.2 (2ꢃCH), 128.5,
128.5 (2ꢃCH), 129.7 (2ꢃCH), 131.1, 133.3, 140.1, 145.3, 147.2, 148.3,
148.7, 149.6, 150.9, 158.6, 163.9 (CO), 167.3 (CO); EIMS m/z (%) 790
(Mþ, 5), 619 (17), 618 (24), 394 (18), 393 (63), 272 (11), 181 (10);
HREIMS m/z 790.2772 (Mþ, calcd for C41H46N2O12S, 790.2781).
Anal. Calcd for C41H46N2O12S$1/2(CH3CH2)2O: C, 62.38; H, 6.21; N,
3.38. Found: C, 62.44; H, 6.22; N, 3.36.
300 MHz)
d 1.94 (3H, s, ArCH3), 2.07 (3H, s, ArCH3), 2.42 (3H, s,
COCH3), 2.46 (3H, s, ArCH3), 3.15 (1H, dd, J¼14.0, 4.9 Hz, 6a-H), 3.42
(1H, dd, J¼14.0, 5.9 Hz, 6a-H), 3.56 (3H, s, OCH3), 3.62 (3H, s, OCH3),
3.73 (3H, s, OCH3), 3.80 (3H, s, OCH3), 3.89 (3H, s, OCH3), 4.84 (1H, d,
J¼6.3 Hz, OCHO), 4.85 (1H, d, J¼6.3 Hz, OCHO), 5.39 (1H, dd, J¼5.9,
4.9 Hz, 6-H), 6.02 (1H, s, 3a-H), 6.50 (1H, s, ArH), 6.72 (1H, s, ArH),
7.30 (2H, d, J¼8.3 Hz, 2ꢃArH), 7.72 (2H, d, J¼8.3 Hz, 2ꢃArH), 8.29
(1H, s, NH); 13C NMR (CDCl3, 67.5 Hz)
d
10.5 (ArCH3), 10.8 (ArCH3),
2.1.9. (3Z)-1-Isopropyloxycarbonyl-6-[4,5-dimethoxy-2-(methoxy-
methoxy)-3-methylphenylmethyl]-3-[4,5-dimethoxy-3-methyl-2-[(4-
methylphenyl)sulfoxyphenyl]methylene]-4-(4-methoxyphenylmethyl)
piperazine-2,5-dione (14). A solution of 13 (12.7 g, 16.1 mmol), TEA
21.7 (ArCH3), 27.3 (COCH3), 33.6 (C6a), 56.0 (OCH3), 56.3 (OCH3),
57.0 (C6), 57.7 (OCH3), 60.1 (OCH3), 60.4 (OCH3), 100.0 (OCH2O),
112.0 (CH), 112.4 (CH), 119.3 (C3a), 123.0, 123.4, 125.4, 125.7, 126.5,

4174
M. Yokoya et al. / Tetrahedron 68 (2012) 4166e4181
(8.9 mL, 64.2 mmol), and DMAP (7.84 g, 64.2 mmol) in dichloro-
methane (1 L) was cooled with ice water and isopropyl chlor-
oformate (3.22 mL, 28.0 mmol) was added dropwise over 10 min.
The reaction mixture was stirred at 25 ꢁC for 23 h. The organic layer
was washed with 1 M aqueous HCl (50 mL) and then water (50 mL),
dried, and concentrated in vacuo to give a residue (15.7 g). Chro-
matography on a silica gel (110 g) column with hexaneeethyl ace-
tate (1/1) as the eluent gave 14 (14.1 g, 100%) as a pale yellow
amorphous powder. IR (KBr) 1772, 1722, 1693, 1487, 1244, 1176,
126.9 (2ꢃCH), 127.7, 128.9 (2ꢃCH), 133.4, 136.6, 139.7, 142.4, 144.3,
146.3, 148.0, 148.6, 149.8, 152.0, 157.6, 166.5 (C4); FABMS m/z 817
[MþH]þ; HRFABMS m/z 817.2999 (Mþþ1, calcd for C43H48N2O12S,
817.3006). Anal. Calcd for C43H48N2O12S: C, 63.22; H, 5.92; N, 3.38.
Found: C, 63.21; H, 6.15; N, 3.30.
2.1.11. (Z)-(1R
*
,5S )-1,2,3,4,5,6-Hexahydro-7-hydroxy-2-[3,4-
*
dimethoxy-3-methyl-2-[(4-methylphenyl)sulfoxyphenyl]methylene]-
9,10-dimethoxy-8-methyl-4-oxo-1,5-imino-3-benzazocine
(17a). Concentrated H2SO4 (7.2 mL) was added to a stirred solution
of 16 (6.0 g, 7.35 mmol) in TFA (144.0 mL) at 0 ꢁC over 5 min, and
the reaction mixture was stirred at 25 ꢁC for 20 h. The reaction
mixture was poured into water (800 mL) at 0 ꢁC, basified with
concentrated NH4OH (200 mL), and then extracted with chloro-
form (3ꢃ1 L). The combined extracts were washed with brine (1 L),
dried, and concentrated in vacuo to give a residue (5.86 g). Chro-
matography of this residue on a silica gel (30 g) column with
chloroformemethanol (50/1) gave 17a (2.88 g, 64.0%) as a solid, the
recrystallization of which from methanoledichloromethane affor-
ded 17a as colorless needles, mp 230e232 ꢁC. IR (KBr) 3310, 3194,
1070 cmꢂ1
;
1H NMR (CDCl3, 400 MHz)
d
1.16 (3H, d, J¼6.3 Hz,
OCHCH3), 1.26 (3H, d, J¼6.3 Hz, OCHCH3), 2.01 (3H, s, ArCH3), 2.13
(3H, s, ArCH3), 2.46 (3H, s, ArCH3), 3.19 (1H, dd, J¼13.8, 7.3 Hz, 6a-
H), 3.35 (1H, dd, J¼13.8, 6.3 Hz, 6a-H), 3.52 (3H, s, OCH3), 3.62 (3H,
s, OCH3), 3.72 (3H, s, OCH3), 3.77 (3H, s, OCH3), 3.86 (3H, s, OCH3),
3.93 (3H, s, OCH3), 4.15 (1H, d, J¼15.0 Hz, NCH), 4.83 (1H, d,
J¼6.0 Hz, OCHO), 4.87 (1H, d, J¼6.0 Hz, OCHO), 4.94 (1H, sept,
J¼6.3 Hz, OCH), 4.96 (1H, d, J¼15.0 Hz, NCH), 5.19 (1H, dd, J¼7.3,
6.3 Hz, 6-H), 6.45 (1H, s, ArH), 6.73 (2H, d, J¼8.7 Hz, 2ꢃArH), 6.85
(1H, s, ArH), 7.09 (2H, d, J¼8.7 Hz, 2ꢃArH), 7.16 (1H, s, 3a-H), 7.34
(2H, d, J¼8.2 Hz, 2ꢃArH), 7.90 (2H, d, J¼8.2 Hz, 2ꢃArH); 13C NMR
(CDCl3, 100 Hz)
d
10.5 (ArCH3), 11.0 (ArCH3), 21.6 (OCHCH3), 21.8
2945, 1668, 1361, 1332, 1283, 1250, 1221, 1069 cmꢂ1
(CDCl3, 500 MHz)
1.91 (3H, s, 30-CH3), 2.17 (3H, s, 8-CH3), 2.48 (3H,
s, TsCH3), 3.02 (1H, dd, J¼17.4, 1.3 Hz, 6-H ), 3.08 (1H, dd, J¼17.4,
7.0 Hz, 6-H ), 3.77 (3H, s, OCH3), 3.79 (3H, s, 9-OCH3), 3.82 (3H, s,
;
1H NMR
(OCHCH3), 21.9 (ArCH3), 33.1 (C6a), 49.7 (NCH2), 55.2 (OCH3), 56.0
(OCH3), 56.1 (OCH3), 57.6 (OCH3), 59.9 (C6), 60.0 (OCH3), 60.6
(OCH3), 71.7 (OCH), 100.0 (OCH2O), 110.0 (CH), 111.8 (CH), 113.7
(2ꢃCH), 119.7 (C3a), 123.1, 123.4, 125.5, 127.8, 128.4 (2ꢃCH), 128.4,
129.4 (2ꢃCH), 129.9 (2ꢃCH), 130.0, 132.8, 140.5, 145.4, 147.2, 148.7,
149.0, 149.2, 151.0, 151.0, 158.8, 161.5 (CO), 166.7 (CO); FABMS m/z
877 [MþH]þ; HRFABMS m/z 877.3210 (Mþþ1, calcd for
C45H53N2O14S, 877.3218).
d
b
a
OCH3), 3.90 (3H, s, 10-OCH3), 3.96 (3H, br s, OH, 2ꢃNH), 4.08 (1H,
dd, J¼7.0, 1.3 Hz, 5-H), 4.95 (1H, br s, 1-H), 5.93 (1H, s, 2a-H), 6.59
(1H, s, 60-H), 7.36 (2H, d, J¼8.1 Hz, 2ꢃArH), 7.73 (2H, d, J¼8.1 Hz,
2ꢃArH); 13C NMR (CDCl3, 125 Hz)
d
8.6 (30-CH3), 10.4 (8-CH3), 21.2
(TsCH3), 26.6 (C6), 48.0 (C1), 51.5 (C5), 55.7 (50-OCH3), 59.8 (9-
OCH3), 60.0 (40-OCH3), 60.0 (10-OCH3), 102.4 (C2a), 110.1 (C60),
114.6 (C6a), 118.9 (C8), 124.0 (C10), 124.2 (C10a), 127.4 (C30), 127.9
(2ꢃCH), 129.6 (2ꢃCH), 133.6 (C100), 135.6 (C2), 139.5 (C20), 143.3
(C10), 145.4 (C400), 146.9 (C40), 148.4 (C7), 149.6 (C9), 151.2 (C50),
171.0 (C4); EIMS m/z 610 (Mþ, 14), 456 (32), 455 (100), 221 (12), 220
(50); HREIMS m/z 610.1985 (Mþ, calcd for C31H34N2O9S, 610.1982).
Anal. Calcd for C31H34N2O9S: C, 60.97; H, 5.61; N, 4.59. Found: C,
60.95; H, 5.74; N, 4.36.
2.1.10. Isopropyl
(E)-(1R
*
,5S )-1,2,3,4,5,6-hexahydro-7-hydroxy-3-
*
(4-methoxyphenylmethyl)-2-[3,4-dimethoxy-3-methyl-2-[(4-
methylphenyl)sulfoxyphenyl]methylene]-9,10-dimethoxy-8-methyl-
4-oxo-1,5-imino-3-benzazocine-11-carboxylate (16). A stirred solu-
tion of 14 (13.6 g, 15.5 mmol) in THF (480 mL) was cooled with ice
water and lithium tri-tert-butoxyaluminohydride (15.8 g,
62.1 mmol) was added over 10 min. After continued stirring at 0 ꢁC
for 4.5 h, anhydrous Na2SO4 (10.0 g) was added and the reaction
mixture was quenched with water (20 mL). The reaction mixture
was filtered through Celite pad and then, the filtrate was diluted
with brine (1 L) and extracted with chloroform (3ꢃ1 L). The com-
bined extracts were washed with brine (1 L), dried, and concen-
trated in vacuo to give 15, which was used in the next step without
further purification. A solution of crude 15 in formic acid (240 mL)
was heated at 60 ꢁC for 1 h. After the reaction mixture was con-
centrated in vacuo, the residue was diluted with 5% aqueous
NaHCO3 solution (500 mL) and extracted with chloroform (3ꢃ1 L).
The combined extracts were washed with water (500 mL), dried,
and concentrated in vacuo to give a residue, the recrystallization of
which from ether gave 16 (11.1 g, 89.0%) as colorless prisms, mp
128e130 ꢁC. IR (KBr) 3412, 2978, 2933, 1701, 1631, 1514, 1458, 1410,
Further elution with chloroformemethanol (10/1) gave 17b
(65.2 mg, 1.5%) as a colorless amorphous powder.
2.1.12. (E)-(1R
*
,5S )-1,2,3,4,5,6-Hexahydro-7-hydroxy-2-[3,4-
*
dimethoxy-3-methyl-2-[(4-methylphenyl)sulfoxyphenyl]methylene]-
9,10-dimethoxy-8-methyl-4-oxo-1,5-imino-3-benzazocine (17b). IR
(KBr) 3539, 3442, 1674, 1460, 1354, 1192, 1172, 1072, 866 cmꢂ1 1H
;
NMR (CDCl3, 400 MHz)
2.42 (3H, s, TsCH3), 2.89 (1H, d, J¼15.3 Hz, 6-H
), 3.59 (3H, s, 9-OCH3),
d
2.05 (3H, s, 30-CH3), 2.08 (3H, s, 8-CH3),
), 2.98 (3H, s, 10-
b
OCH3), 3.11 (1H, dd, J¼15.3, 7.3 Hz, 6-H
a
3.78 (1H, d, J¼7.3 Hz, 5-H), 3.82 (3H, s, 40-OCH3), 3.85 (3H, s, 50-
OCH3), 4.82 (1H, br s, 1-H), 5.15 (1H, br s, OH), 5.39 (1H, s, 2a-H),
6.69 (1H, s, 60-H), 7.30 (2H, d, J¼8.5 Hz, 2ꢃArH), 7.76 (2H, d,
J¼8.5 Hz, 2ꢃArH), 8.30 (1H, br d, NH); 13C NMR (CDCl3, 125.7 Hz)
1348, 1296, 1247, 1174, 1117, 1074 cmꢂ1
400 MHz at 140 ꢁC)
1.20 (3H, d, J¼6.1 Hz, OCHCH3), 1.25 (3H, d,
J¼6.1 Hz, OCHCH3), 2.06 (3H, s, ArCH3), 2.16 (3H, s, ArCH3), 2.42 (3H,
s, ArCH3), 2.87 (1H, dd, J¼17.0, 6.1 Hz, 6-H ), 2.92 (3H, s, OCH3), 3.05
(1H, dd, J¼17.0, 1.7 Hz, 6-H ), 3.54 (3H, s, OCH3), 3.67 (3H, s, OCH3),
;
1H NMR (DMSO-d6,
d
8.9 (30-CH3), 11.0 (8-CH3), 21.8 (TsCH3), 27.7 (C6), 45.4 (C1), 52.5
d
(C5), 56.0 (10-OCH3), 59.0 (9-OCH3), 59.9 (40-OCH3), 60.5 (50-OCH3),
102.7 (C2a), 112.0 (C60), 115.1 (C6a), 117.4 (C8), 125.1 (C10), 126.5
(C10a), 126.5 (C30), 128.0 (2ꢃCH), 129.7 (2ꢃCH), 134.1 (C100), 138.5
(C2), 139.6 (C20), 143.4 (C10), 145.3 (C400), 146.4 (C40), 147.6 (C7),
149.1 (C9), 150.8 (C50), 171.9 (C4); EIMS m/z 610 (Mþ, 13), 456 (35),
455 (100), 221 (16), 220 (60), 205 (11); HREIMS m/z 610.1985 (Mþ,
calcd for C31H34N2O9S, 610.1992).
a
b
3.78 (3H, s, OCH3), 3.87 (3H, s, OCH3), 4.43 (1H, d, J¼16.1 Hz, 3-CH),
4.75 (1H, d, J¼16.1 Hz, 3-CH), 4.85 (1H, dd, J¼6.1, 1.7 Hz, 5-H), 4.87
(1H, sept, J¼6.1 Hz, OCH), 5.93 (1H, br s,1-H), 6.13 (1H, s, 2a-H), 6.60
(2H, d, J¼8.8 Hz, 2ꢃArH), 6.69 (2H, d, J¼8.8 Hz, 2ꢃArH), 7.07 (1H, s,
60-H), 7.35 (2H, d, J¼8.5 Hz, 2ꢃArH), 7.69 (2H, d, J¼8.5 Hz, 2ꢃArH),
2.2. Improved synthesis of 17a
7.76 (1H, s, OH); 13C NMR (DMSO-d6, 100 Hz, 140 ꢁC)
d 8.4 (ArCH3),
10.1 (ArCH3), 20.2 (ArCH3), 20.9 (OCHCH3), 21.0 (OCHCH3), 26.6
(C6), 43.2 (NCH2), 45.5 (C1), 52.5 (C5), 54.4 (OCH3), 55.7 (OCH3),
58.1 (OCH3), 58.6 (OCH3), 59.1 (OCH3), 68.6 (OCH), 105.1 (C2a), 112.6
(CH), 113.0 (2ꢃCH), 115.2, 118.3, 122.9, 124.9, 125.3, 126.6 (2ꢃCH),
2.2.1. 1-Acetyl-4-isopropyloxycarbonyl-3-(4,5-dimethoxy-2-
methoxymethoxy-3-methylphenyl)methyl]piperazine-2,5-dione
(18). A solution of
9 (380.0 mg, 1.0 mmol), TEA (0.28 mL,
2.0 mmol), and DMAP (244.0 mg, 2.0 mmol) in dichloromethane

M. Yokoya et al. / Tetrahedron 68 (2012) 4166e4181
4175
(30 mL) was cooled with ice water, and isopropyl chloroformate
(0.46 mL, 4.0 mmol) was added dropwise over 20 min. The reaction
mixture was stirred at 25 ꢁC for 2 h. The organic layer was washed
with 1 M aqueous HCl (50 mL) and then water (50 mL), dried, and
concentrated in vacuo to give a residue. Chromatography on a silica
gel (20 g) column with hexaneeethyl acetate (3/1) as the eluent
gave 18 (447 mg, 96.0%) as a pale yellow amorphous powder. IR
used in the next step without further purification. A solution of
crude 20 in formic acid (13 mL) was heated at 60 ꢁC for 2.5 h. After
the reaction mixture was concentrated in vacuo, the residue was
diluted with 5% aqueous NaHCO3 solution (70 mL) and extracted
with chloroform (3ꢃ70 mL). The combined extracts were washed
with water (70 mL), dried, and concentrated in vacuo to give
a residue. Chromatography on a silica gel (20 g) column with hex-
aneeethyl acetate (2/1) as the eluent gave 21a (413.3 mg, 73.0%) as
a pale yellow amorphous powder. IR (KBr) 3429, 3389, 2980, 2938,
1682,1460,1422,1375,1348, 1300,1273,1246,1219,1192,1177,1113,
(CHCl3) 3022, 2940, 1780, 1717, 1261, 1205 cmꢂ1
300 MHz)
;
1H NMR (CDCl3,
d
1.28 (3H, d, J¼6.2 Hz, OCHCH3), 1.32 (3H, d, J¼6.2 Hz,
OCHCH3), 2.14 (3H, s, 30-CH3), 2.56 (3H, s, COCH3), 3.24 (1H, dd,
J¼13.8, 6.2 Hz, 3a-H), 3.25 (1H, d, J¼18.8 Hz, 6-H), 3.38 (1H, dd,
J¼13.8, 6.2 Hz, 3a-H), 3.55 (3H, s, CH2OCH3), 3.78 (6H, s, 2ꢃOCH3),
4.70 (1H, d, J¼18.8 Hz, 6-H), 4.84 (1H, d, J¼5.6 Hz, OCHO), 4.86 (1H,
d, J¼5.6 Hz, OCHO), 5.03 (1H, sept, J¼6.2 Hz, OCH), 5.15 (1H, t,
1069 cmꢂ1 1H NMR (DMSO-d6, 400 MHz at 100 ꢁC)
; d 1.24 (3H, d,
J¼6.2 Hz, OCHCH3), 1.26 (3H, d, J¼6.2 Hz, OCHCH3), 1.97 (3H, s,
ArCH3), 2.08 (3H, s, ArCH3), 2.44 (3H, s, ArCH3), 2.92 (2H, d,
J¼5.6 Hz, 6-H2), 3.71 (3H, s, OCH3), 3.73 (3H, s, OCH3), 3.78 (3H, s,
OCH3), 3.80 (3H, s, OCH3), 4.81 (1H, d, J¼5.6 Hz, 5-H), 4.89 (1H, sept,
J¼6.1 Hz, OCH), 5.76 (1H, br s, 1-H or 2a-H), 5.77 (1H, s, 1-H or 2a-
H), 6.67 (1H, s, 60-H), 7.44 (2H, d, J¼8.5 Hz, 2ꢃArH), 7.72 (2H, d,
J¼8.5 Hz, 2ꢃArH), 8.01 (1H, s, OH); 13C NMR (DMSO-d6, 100 Hz,
J¼6.2 Hz, 3-H), 6.47 (1H, s, 60-H); 13C NMR (CDCl3, 100 MHz)
d 10.4
(30-CH3), 21.7 (CHCH3), 21.8 (CHCH3), 27.0 (COCH3), 33.7 (C3a), 46.7
(C6), 56.0 (OCH3), 57.7 (OCH3), 60.5 (OCH3), 61.2 (C3), 72.4
(OCHCH3), 99.9 (OCH2O), 111.7 (C60), 122.4 (C3a), 126.0, 147.8, 149.1,
149.5, 151.0 (NCO2), 163.5 (C2), 167.3 (C5), 171.1 (COCH3); EIMS m/z
(%) 466 (Mþ, 50), 348 (31), 225 (100), 195 (26), 181 (65), 180 (26), 45
(30). HREIMS m/z 466.1951 (Mþ, calcd for C22H30N2O9, 466.1953).
100 ꢁC)
d 8.8 (ArCH3), 10.3 (ArCH3), 20.6 (ArCH3), 21.3 (OCHCH3),
21.3 (OCHCH3), 26.0 (C6), 48.9 (C1), 51.6 (C5), 55.6 (OCH3), 59.2
(OCH3), 59.2 (OCH3), 59.5 (OCH3), 68.7 (OCH), 101.1 (C2a), 111.6
(CH), 114.6, 118.3, 123.7, 123.8, 125.8, 127.1 (2ꢃCH), 129.2 (2ꢃCH),
132.4, 133.8, 138.3, 142.4, 144.7, 146.1, 148.0, 148.8, 150.1, 152.2
(NCO2), 167.3 (C4); EIMS m/z 696 (Mþ, 24), 542 (50), 541 (100), 456
(22), 455 (83), 220 (53). HREIMS m/z 696.2353 (Mþ, calcd for
C35H40N2O11S, 696.2350).
2.2.2. (Z)-1-Isopropyloxycarbonyl-6-[4,5-dimethoxy-2-(methoxy-
methoxy)-3-methylphenylmethyl]-3-[4,5-dimethoxy-3-methyl-2-[(4-
methylphenyl)sulfoxyphenyl]methylene]-4-(4-methoxyphenylmethyl)
piperazine-2,5-dione (19). A solution of potassium tert-butoxide
(1.65 g, 14.7 mmol) in tert-butyl alcohol (14.7 mL) was added to
a stirred solution of 5b (4.3 g, 12.3 mmol) and 18 (5.7 g, 12.3 mmol)
in dichloromethane (50 mL) at 0 ꢁC over 60 min, and stirring was
continued at 25 ꢁC for 40 min. The reaction mixture was poured
into brine (500 mL) and extracted with ethyl acetate (3ꢃ500 mL).
The combined extracts were washed with brine (500 mL), dried,
and concentrated in vacuo to give a residue. Chromatography on
a silica gel (60 g) column with hexaneeethyl acetate (2/1) as the
eluent gave 19 (6.5 g, 70.0%) as a colorless amorphous powder. IR
(KBr) 2940, 2982, 1772, 1692, 1489, 1375, 1279, 1244, 1224, 1177,
Further elution with chloroform gave 21b (94.1 mg, 17.0%) as
a pale yellow amorphous powder.
2.2.4. Isopropyl
(E)-(1R
*
,5S )-1,2,3,4,5,6-hexahydro-7-hydroxy-2-
*
[3,4-dimethoxy-3-methyl-2-[(4-methylphenyl)-sulfoxyphenyl]methy-
lene]-9,10-dimethoxy-8-methyl-4-oxo-1,5-imino-3-benzazocine-11-
carboxylate (21b). IR (KBr) 3447, 1674, 1458, 1423, 1346, 1300, 1248,
1173, 1113, 1070 cmꢂ1 1H NMR (DMSO-d6, 400 MHz at 100 ꢁC)
;
d
1.18 (3H, d, J¼6.2 Hz, OCHCH3), 1.24 (3H, d, J¼6.2 Hz, OCHCH3),
2.02 (3H, s, ArCH3), 2.18 (3H, s, ArCH3), 2.38 (3H, s, ArCH3), 2.81 (1H,
), 3.04 (3H, s,
1072 cmꢂ1
;
1H NMR (CDCl3, 400 MHz)
d
1.39 (3H, d, J¼6.3 Hz,
dd, J¼17.2, 5.6 Hz, 6-H
a
), 2.91 (1H, d, J¼17.2 Hz, 6-H
b
OCHCH3), 1.41 (3H, d, J¼6.3 Hz, OCHCH3), 1.96 (3H, s, ArCH3), 2.26
(3H, s, ArCH3), 2.38 (3H, s, ArCH3), 3.18 (1H, dd, J¼13.9, 3.9 Hz, 6a-
H), 3.36 (1H, dd, J¼13.9, 6.0 Hz, 6a-H), 3.55 (3H, s, CH2OCH3), 3.59
(3H, s, OCH3), 3.63 (3H, s, OCH3), 3.85 (3H, s, OCH3), 3.96 (3H, s,
OCH3), 4.77 (1H, d, J¼6.0 Hz, OCHO), 4.84 (1H, d, J¼6.0 Hz, OCHO),
5.03 (1H, dd, J¼16.0, 3.9 Hz, 6-H), 5.15 (1H, sept, J¼6.3 Hz, OCH),
6.18 (1H, s, C3a), 6.28 (1H, s, ArH), 6.47 (1H, s, 60-H), 6.55 (1H, s,
OCH3), 3.58 (3H, s, OCH3), 3.79 (3H, s, OCH3), 3.89 (3H, s, OCH3),
4.66 (1H, br d, J¼5.6 Hz, 5-H), 4.83 (1H, sept, J¼6.1 Hz, OCH), 5.68
(1H, br s,1-H), 7.14 (1H, s), 7.26 (2H, d, J¼8.1 Hz, 2ꢃArH), 7.72 (2H, d,
J¼8.1 Hz, 2ꢃArH), 7.94 (1H, s), 8.20 (1H, s, OH), 9.50 (1H, s, NH); 13C
NMR (DMSO-d6, 100 Hz, 100 ꢁC)
d 8.7 (ArCH3), 10.3 (ArCH3), 20.6
(ArCH3), 21.2 (OCHCH3), 21.3 (OCHCH3), 25.9 (C6), 43.9 (C1), 51.6
(C5), 55.8 (OCH3), 58.5 (OCH3), 58.9 (OCH3), 59.3 (OCH3), 68.6
(OCH), 102.4 (C2a), 111.6 (CH), 114.9, 118.1, 123.5, 125.3, 125.5, 126.9
(2ꢃCH), 128.8 (2ꢃCH), 133.0, 135.6, 139.4, 142.1, 144.2, 145.8, 148.0,
148.4, 149.9, 152.1 (NCO2), 166.9 (C4); EIMS m/z 696 (Mþ, 25), 542
(44), 541 (100), 456 (21), 455 (79), 221 (11), 220 (47). HREIMS m/z
696.2353 (Mþ, calcd for C35H40N2O11S, 696.2352).
ArH); 13C NMR (CDCl3, 100 MHz)
d 10.5 (ArCH3), 11.6 (ArCH3), 21.8
(ArCH3), 21.9 (CHCH3), 22.0 (CHCH3), 33.7 (C6a), 55.8 (OCH3), 56.1
(OCH3), 57.7 (CH2OCH3), 59.8 (C6), 60.2 (OCH3), 60.5 (OCH3), 72.0
(OCHCH3), 99.8 (OCH2O), 109.9 (CH), 112.7 (CH), 114.0 (C3a), 122.1,
122.3, 125.1, 125.8, 128.2 (2ꢃCH), 128.8, 129.8 (2ꢃCH), 132.5, 139.6,
145.4, 147.8, 148.6, 149.2, 149.2, 151.3, 151.9 (NCO2), 157.1 (C2), 165.0
(C5); EIMS m/z (%) 756 (Mþ, 100), 584 (25), 483 (35), 303 (43), 235
(39), 225 (32), 220 (34), 181 (65). HREIMS m/z 756.2564 (Mþ, calcd
for C37H44N2O13S, 756.2562).
2.2.5. (Z)-(1R
*
,5S )-1,2,3,4,5,6-Hexahydro-7-hydroxy-2-[3,4-
*
dimethoxy-3-methyl-2-[(4-methylphenyl)sulfoxyphenyl]methylene]-
9,10-dimethoxy-8-methyl-4-oxo-1,5-imino-3-benzazocine
(17a). Concentrated H2SO4 (0.4 mL) was added to a stirred solution
of 21a (298.0 mg, 0.43 mmol) in TFA (8 mL) at 0 ꢁC over 5 min, and
the reaction mixture was stirred at 25 ꢁC for 6 h. The reaction
mixture was poured into water (800 mL) at 0 ꢁC, basified with
concentrated NH4OH (10 mL), and then extracted with chloroform
(3ꢃ50 mL). The combined extracts were washed with brine
(50 mL), dried, and concentrated in vacuo to give a residue. Chro-
matography of this residue on a silica gel (30 g) column with
chloroformemethanol (50/1) gave 17a (179.0 g, 69.0%) as a solid,
the recrystallization of which from methanoledichloromethane
afforded 17a as colorless needles, mp 230e232 ꢁC. Its spectra were
identical with those of an authentic sample described above. Fur-
ther elution with chloroformemethanol (20/1) gave 17b (21.0 mg,
2.2.3. Isopropyl
(Z)-(1R
*
*
5S )-1,2,3,4,5,6-hexahydro-7-hydroxy-2-
[3,4-dimethoxy-3-methyl-2-[(4-methylphenyl)sulfoxyphenyl]methy-
lene]-9,10-dimethoxy-8-methyl-4-oxo-1,5-imino-3-benzazocine-11-
carboxylate (21a). A stirred solution of 19 (611.0 mg, 0.81 mmol) in
THF (30 mL) was cooled with ice water and lithium tri-tert-butoxy-
aluminohydride (1.0 g, 4.0 mmol) was added over 5 min. After
continued stirring at 0 ꢁC for 4.5 h, anhydrous Na2SO4 (1.0 g) was
added and the reaction mixture was quenched with water (2.0 mL).
The reaction mixture was filtered through Celite pad and then, the
filtrate was diluted with brine (100 mL) and extracted with chlo-
roform (3ꢃ50 mL). The combined extracts were washed with brine
(50 mL), dried, and concentrated in vacuo to give 20, which was

4176
M. Yokoya et al. / Tetrahedron 68 (2012) 4166e4181
8.0%) as a pale yellow amorphous powder, the spectra of which
were also identical with those of an authentic sample described
above.
469 (100), 235 (12), 234 (39); HREIMS m/z 624.2142 (Mþ, calcd for
C32H36N2O9S, 624.2137).
Almost the same results were obtained when the reaction was
initiated from 21b (30.0 mg, 43.1 mmol) to give 17a (19.3 mg,
73.0%) and 17b (2.4 mg, 9.0%).
2.3. Practical synthesis of 22a from 19
A stirred solution of 19 (3.01 g, 3.98 mmol) in THF (130 mL) was
cooled with ice water and lithium tri-tert-butoxyaluminohydride
(5.04 g, 19.8 mmol) was added over 10 min. After continued stirring
at 25 ꢁC for 24 h, anhydrous Na2SO4 (10.0 g) was added and the re-
action mixture was quenched with water (20 mL). The reaction
mixture was filtered through Celite pad and then, the filtrate was
diluted with brine (200 mL) and extracted with chloroform
(3ꢃ200 mL). The combined extracts were washed with brine
(200 mL), dried, and concentrated invacuotogive 20, which wasused
in the next step without further purification. A solution of crude 20 in
formic acid (40 mL) was heated at 60 ꢁC for 1 h. After the reaction
mixture was concentrated in vacuo, the residue was diluted with 5%
aqueous NaHCO3 solution (200 mL) and extracted with chloroform
(3ꢃ200 mL). The combined extracts were washed with water
(200 mL), dried, and concentrated in vacuo to give 21a along with
21b, which was used in the next step without further purification.
Concentrated H2SO4 (4.0 mL) was added to a stirred solution of
the above products in TFA (80 mL) at 0 ꢁC over 5 min, and the re-
action mixture was stirred at 25 ꢁC for 7.5 h. The reaction mixture
was poured into water (600 mL) at 0 ꢁC, basified with concentrated
NH4OH (100 mL), and then extracted with chloroform (3ꢃ500 mL).
The combined extracts were washed with brine (500 mL), dried,
and concentrated in vacuo to give 17a along with 17b, which was
used in the next step without further purification.
A 37% aqueous solution of formaldehyde (40.5 mL) was added to
a stirred solution of the above mixture of products 17a and 17b in
formic acid (46.5 mL) at 50 ꢁC, and the reaction mixture was heated
at 70 ꢁC for 2 h. After being concentrated in vacuo, the reaction
mixture was diluted with 5% aqueous NaHCO3 solution (300 L) and
extracted with chloroform (3ꢃ300 L). The combined extracts were
washed with brine (300 L), dried, and concentrated in vacuo to give
a residue. Chromatography of this residue on a silica gel (80 g)
column with chloroformemethanol (100/1) gave a solid, the re-
crystallization of which from ethyl acetateeether afforded 22a
(2.06 g, 82.9%, four steps) as colorless prisms. Further elution with
chloroformemethanol (50/1) gave 22b (230.0 mg, 9.3%) as colorless
prisms.
2.2.6. (Z)-(1R
*
,5S )-1,2,3,4,5,6-Hexahydro-7-hydroxy-2-[3,4-
*
dimethoxy-3-methyl-2-[(4-methylphenyl)sulfoxyphenyl]methylene]-
9,10-dimethoxy-8,11-dimethyl-4-oxo-1,5-imino-3-benzazocine
(22a). A 37% aqueous solution of formaldehyde (86 mL) was added
to a stirred solution of 17a (5.26 g, 8.6 mmol) in formic acid
(103 mL) at 50 ꢁC, and the reaction mixture was heated at 70 ꢁC for
1 h. After being concentrated in vacuo, the reaction mixture was
diluted with 5% aqueous NaHCO3 solution (1 L) and extracted with
chloroform (3ꢃ1 L). The combined extracts were washed with
brine (1 L), dried, and concentrated in vacuo to give a residue.
Chromatography of this residue on a silica gel (80 g) column with
chloroformemethanol (50/1) gave a solid, the recrystallization of
which from ethyl acetateeether afforded 22a (5.01 g, 93.0%) as
colorless prisms, mp 218e220 ꢁC. IR (KBr) 3385, 3267, 2937, 1674,
1483, 1460, 1418, 1404, 1368, 1348, 1281, 1244, 1219, 1175, 1111,
1067 cmꢂ1
(3H, s, 8-CH3), 2.45 (3H, s, TsCH3), 2.57 (3H, s, NCH3), 2.92 (1H, dd,
), 3.64 (1H, dd,
; d
1H NMR (CDCl3, 500 MHz) 1.89 (3H, s, 30-CH3), 2.15
J¼17.1,1.0 Hz, 6-H
b
), 3.06 (1H, dd, J¼17.1, 7.3 Hz, 6-H
a
J¼7.3, 1.0 Hz, 5-H), 3.76 (3H, s, 40-OCH3), 3.77 (3H, s, 50-OCH3), 3.78
(3H, s, 9-OCH3), 3.88 (3H, s, 10-OCH3), 4.60 (1H, s, 1-H), 5.30 (1H, br
s, OH), 5.93 (1H, s, 2a-H), 6.49 (1H, s, 60-H), 7.30 (2H, d, J¼8.2 Hz,
2ꢃArH), 7.71 (2H, d, J¼8.2 Hz, 2ꢃArH); 13C NMR (CDCl3, 125 Hz)
d
8.8 (30-CH3),10.8 (8-CH3), 21.7 (TsCH3), 26.7 (C6), 41.5 (NCH3), 55.6
(C1), 56.1 (9-OCH3), 59.1 (C5), 60.1 (40-OCH3), 60.3 (50-OCH3), 60.3
(10-OCH3), 104.2 (C2a), 110.1 (C60), 114.2 (C6a), 117.6 (C8), 124.8
(C10), 125.9 (C10a), 128.0 (C30), 128.3 (2ꢃCH), 129.8 (2ꢃCH), 133.9
(C100), 134.7 (C2), 139.6 (C20), 143.9 (C10), 145.3 (C400), 147.2þ(C40),
147.8 (C7), 149.8 (C9), 151.4 (C50), 170.2 (C4); EIMS m/z 624 (M , 13),
470 (30), 469 (100), 235 (12), 234 (39); HREIMS m/z 624.2142 (Mþ,
calcd for C32H36N2O9S, 624.2137). Anal. Calcd for C32H36N2O9S: C,
61.52; H, 5.81; N, 4.48. Found: C, 61.25; H, 5.90; N, 4.40.
2.2.7. (E)-(1R
*
,5S )-1,2,3,4,5,6-Hexahydro-7-hydroxy-2-[3,4-
*
dimethoxy-3-methyl-2-[(4-methylphenyl)sulfoxyphenyl]methylene]-
9,10-dimethoxy-8,11-dimethyl-4-oxo-1,5-imino-3-benzazocine
(22b). A 37% aqueous solution of formaldehyde (1.0 mL) was added
to a stirred solution of 17b (61.0 mg, 0.1 mmol) in formic acid
(1.2 mL) at 50 ꢁC, and the reaction mixture was heated at 70 ꢁC for
2 h. The reaction mixture was diluted with 5% aqueous NaHCO3
solution (20 mL) and extracted with chloroform (3ꢃ20 mL). The
combined extracts were washed with brine (20 mL), dried, and
concentrated in vacuo to give a residue. Chromatography of this
residue on a silica gel (15 g) column with chloroformemethanol
(60/1) gave a solid, the recrystallization of which from chlor-
oformehexane afforded 22b (57.0 mg, 91.3%) as colorless prisms,
mp 224e225 ꢁC. IR (KBr) 3370, 2938, 1670, 1460, 1418, 1346, 1173,
2.3.1. (1R
*
,2S
*
,5S )-1,2,3,4,5,6-Hexahydro-7-hydroxy-2-[3,4-
*
dimethoxy-3-methyl-2-[(4-methylphenyl)sulfoxy]-phenyl]methyl]-
9,10-dimethoxy-8,11-dimethyl-4-oxo-1,5-imino-3-benzazocine
(23). A solution of 22a (998.4 mg, 1.60 mmol) in ethanol (40 mL)
was hydrogenated over 20% Pd(OH)2 (448.0 mg) at 80 ꢁC for 41 h
under 2.8 MPa hydrogen. The catalyst was removed by filtration
and washed with ethanol (200 mL) and then CHCl3 (200 mL). The
combined filtrate was concentrated in vacuo to give a residue.
Chromatography of this residue on a silica gel (80 g) column with
chloroformemethanol (50/1) gave a solid, the recrystallization of
which from ethyl acetateeether afforded 23 (928.0 mg, 93.0%) as
colorless prisms, mp 200.5e202 ꢁC. IR (KBr) 3375, 3267, 2940, 1665,
1115, 1067 cmꢂ1
2.23 (3H, s, 30-CH3), 2.36 (3H, s, TsCH3), 2.60 (3H, s, NCH3), 2.95 (1H,
), 3.11 (3H,
; d 2.11 (3H, s, 8-CH3),
1H NMR (CDCl3, 500 MHz)
dd, J¼17.1, 2.0 Hz, 6-H
b
), 3.01 (1H, dd, J¼17.1, 6.3 Hz, 6-H
a
1459, 1418, 1368, 1346, 1244, 1219, 1175, 1111, 1065 cmꢂ1
(CDCl3, 500 MHz)
1.92 (3H, s, 30-CH3), 2.19 (3H, s, 8-CH3), 2.20 (1H,
dd, J¼14.7, 11.6 Hz, 2a-H ), 2.45 (3H, s, TsCH3), 2.46 (3H, s, NCH3),
2.85 (1H, d, J¼17.4 Hz, 6-H ), 2.98 (1H, dd, J¼17.4, 7.3 Hz, 6-H ),
), 3.75
;
1H NMR
s, 10-OCH3), 3.63 (1H, dd, J¼6.3, 2.0 Hz, 5-H), 3.65 (3H, s, 9-OCH3),
3.84 (3H, s, 40-OCH3), 3.87 (3H, s, 50-OCH3), 4.97 (1H, s, 1-H), 5.48
(1H, s, 2a-H), 6.83 (1H, s, 60-H), 7.02 (2H, d, J¼8.5 Hz, 2ꢃArH), 7.73
d
b
b
a
(2H, d, J¼8.5 Hz, 2ꢃArH); 13C NMR (CDCl3, 125 Hz)
d
8.9 (3-CH3),
3.62 (1H, d, J¼7.3 Hz, 5-H), 3.66 (1H, dd, J¼14.7, 2.1 Hz, 2a-H
a
11.2 (12-CH3), 21.6 (TsCH3), 26.4 (C6), 41.3 (NCH3), 51.1 (C1), 55.9
(50-OCH3), 59.2 (C5), 59.3 (10-OCH3), 59.9 (9-OCH3), 60.5 (40-OCH3),
106.6 (C2a), 110.4 (C60), 114.26 (C6a), 117.7 (C8), 124.7 (C10a), 126.0
(C10), 127.7 (C30), 128.3 (2ꢃCH), 129.4 (2ꢃCH), 134.3 (C100), 135.4
(C2), 141.2 (C20), 144.1 (C10), 145.3 (C400), 146.8 (C40), 147.8 (C7),
149.4 (C9), 150.8 (C50), 170.4 (C4); EIMS m/z 624 (Mþ, 13), 470 (30),
(3H, s, 40-OCH3), 3.81 (3H, s, 50-OCH3 or 9-OCH3), 3.82 (3H, s, 50-
OCH3 or 9-OCH3), 3.84 (3H, s, 10-OCH3), 4.21 (1H, d, J¼1.8 Hz, 1-H),
4.31 (1H, ddd, J¼11.6, 2.1, 1.8 Hz, 2-H), 5.36 (1H, s, NH), 6.25 (1H, s,
OH), 6.54 (1H, s, 60-H), 7.33 (2H, d, J¼8.2 Hz, 2ꢃArH), 7.70 (2H, d,
J¼8.2 Hz, 2ꢃArH); 13C NMR (CDCl3, 125 Hz)
d
9.0 (30-CH3), 10.9
(8-CH3), 21.7 (TsCH3), 23.1 (C6), 33.6 (C2a), 40.0 (NCH3), 54.5 (C1),

M. Yokoya et al. / Tetrahedron 68 (2012) 4166e4181
4177
55.7 (C2), 55.9 (OCH3), 58.0 (C5), 60.2 (OCH3), 60.2 (OCH3), 60.4
(OCH3), 111.5 (C60), 114.8 (C6a), 118.3 (C8), 121.1 (C10a), 126.9 (C10),
127.7 (C30), 127.9 (2ꢃCH), 129.8 (2ꢃCH), 133.9 (C100), 140.6 (C20),
144.8 (C10), 145.3 (C400), 146.9 (Cþ40), 148.2 (C7), 149.8 (C9), 151.5
(C50), 172.2 (C4); EIMS m/z 626 (M , 11), 472 (9), 471 (16), 235 (29),
234 (100); HREIMS m/z 626.2298 (Mþ, calcd for C32H38N2O9S,
626.2297). Anal. Calcd for C32H38N2O9S: C, 61.33; H, 6.11; N, 4.47.
Found: C, 61.21; H, 6.21; N, 4.50.
172.4 (C4); EIMS m/z 472 (Mþ, 47), 457 (12), 234 (100); HREIMS m/z
472.2210 (Mþ, calcd for C25H32N2O7, 472.2208).
2.3.4. Ethyl (6S
dihydroxy-1,2,10,11-tetramethoxy-3,12,16-trimethyl-6,15-imino-5H-
isoquino[3,2-b][3]benzazocin-7-one-9-carboxylate (26). TMSOTf
*
,9S
*
,14aS
*
,15R
*
)-6,7,9,14,14a,15-Hexahydro-4,13-
(0.33 mL, 1.85 mmol) was added to a suspended solution of 25
(209.0 mg, 0.443 mmol) and ethyl diethoxyacetate (83.0 mL,
0.46 mmol) in dichloroethane (15 mL), and the reaction mixture
was heated at 120 ꢁC for 13 h. The reaction mixture was diluted
with saturated NaHCO3 (200 mL) and extracted with chloroform
(3ꢃ200 mL). The combined extracts were washed with brine
(200 mL), dried, and concentrated in vacuo to give a residue
(246 mg). Chromatography of this residue on a silica gel (120 g)
column with dichloromethaneemethanol (50/1) gave 26
(190.0 mg, 77.1%) as a pale yellow amorphous powder, the re-
crystallization of which from ethyl acetateeether afforded 26 as
colorless prisms, mp 253e254 ꢁC. IR (KBr) 3399, 2940, 1732, 1639,
2.3.2. (6S
*
,14aS
*
,15R )-6,7,9,14,14a,15-Hexahydro-4-hydroxy-
*
1,2,10,11-tetramethoxy-3,12,16-trimethyl-13-[(4-methylphenyl)sul-
foxy]-6,15-imino-5H-isoquino[3,2-b][3]benzazocin-7-one
(24). Paraformaldehyde (15 mg, 0.5 mmol) was added to a stirred
solution of 23 (31.3 mg, 0.05 mmol) in acetic acideTFA (4/1; 4.0 mL)
at 25 ꢁC, and the reaction mixture was heated at 80 ꢁC for 15 h. The
reaction mixture was diluted with 5% aqueous NaHCO3 solution
(20 mL) and extracted with chloroform (3ꢃ20 mL). The combined
extracts were washed with brine (20 mL), dried, and concentrated
in vacuo to give a residue. Chromatography of this residue on
a silica gel (15 g) column with dichloromethaneemethanol (50/1)
gave a solid, the recrystallization of which from ethyl acetateeether
gave 24 (21.1 mg, 66.0%) as colorless prisms, mp 198e200 ꢁC. IR
(KBr) 3300, 1628, 1412, 1300, 1178 cmꢂ1; 1H NMR (CDCl3, 500 MHz)
1460, 1422, 1350, 1281, 1192, 1117, 1067 cmꢂ1
500 MHz)
1.28 (3H, t, J¼7.0 Hz, OCH2CH3), 2.06 (3H, s, 12-CH3),
2.11 (3H, s, 3-CH3), 2.30 (1H, dd, J¼16.8, 10.4 Hz, 14-H ), 2.54 (3H, s,
NCH3), 2.77 (1H, d, J¼17.7 Hz, 5-H ), 2.94 (1H, dd, J¼16.8, 5.5 Hz,14-
), 2.95 (1H, dd, J¼17.7, 8.1 Hz, 5-H ), 3.72 (3H, s, 2-OCH3), 3.77
;
1H NMR (CDCl3,
d
b
b
Ha
a
(3H, s, 10-OCH3), 3.79 (3H, s, 11-OCH3), 3.82 (1H, d, J¼8.1 Hz, 6-H),
3.86 (3H, s, 1-OCH3), 4.18 (1H, dq, J¼10.7, 7.0 Hz, OCHCH3), 4.25 (1H,
dq, J¼10.7, 7.0 Hz, OCHCH3), 4.36 (1H, dd, J¼5.5, 1.5 Hz, 15-H), 4.51
(1H, dt, J¼10.4, 5.5 Hz, 14a-H), 4.80 (1H, br s, OH), 6.46 (1H, s, 9-H);
d
1.82 (3H, s, 12-CH3), 2.20 (1H, dd, J¼16.5, 12.2 Hz, 14-H
s, 3-CH3), 2.47 (3H, s, TsCH3), 2.49 (3H, s, NCH3), 2.92 (1H, d,
J¼17.2 Hz, 5-H ), 2.99 (1H, dd, J¼17.2, 6.7 Hz, 5-H ), 3.58 (1H, dd,
J¼16.3, 2.6 Hz, 14-H ), 3.73 (3H, s, OCH3), 3.77e3.79 (1H, m, 6-H),
b), 2.16 (3H,
b
a
a
13C NMR (CDCl3, 125 Hz)
d 8.7 (3 or 12-CH3), 8.8 (3 or 12-CH3), 14.2
3.80 (3H, s, OCH3), 3.84 (3H, s, OCH3), 3.87e3.91 (1H, overlapped,
14a-H), 3.89 (3H, s, OCH3), 4.30 (1H, d, J¼4.3 Hz, 15-H), 4.55 (1H, d,
(OCH2CH3), 23.5 (C5), 24.8 (C14), 40.3 (NCH3), 50.6 (C9), 52.3
(C14a), 54.6 (C15), 58.5 (C6), 60.1 (2-OCH3), 60.2 (10 or 11-OCH3),
60.3 (10 or 11-OCH3), 60.7 (1-OCH3), 61.7 (OCH2CH3), 114.7 (C4a),
115.3 (C9a), 117.5 (C3 or C12), 117.7 (C3 or C12), 121.8 (C13a), 122.9
(C15a), 143.8 (C10), 144.4 (C1), 146.9 (C13), 148.3 (C4), 149.3 (C2),
149.6 (C11),169.9 (C7),171.3 (C16); EIMS m/z 556 (Mþ, 20), 484 (10),
234 (100); HREIMS m/z 556.2421 (Mþ, calcd for C29H36N2O9,
556.2421). Anal. Calcd for C29H36N2O9: C, 62.58; H, 6.52; N, 5.03.
Found: C, 62.79; H, 6.68; N, 4.98.
J¼18.6 Hz, 9-H
b
), 4.66 (1H, d, J¼18.6 Hz, 9-H
a), 5.94 (1H, s, OH),
7.40 (2H, d, J¼8.1 Hz, 2ꢃArH), 7.92 (2H, d, J¼8.1 Hz, 2ꢃArH); 13C
NMR (CDCl3, 125 Hz)
d
8.9 (30-CH3), 10.4 (8-CH3), 21.7 (TsCH3), 22.7
(C5), 27.5 (C14), 39.9 (NCH3), 40.4 (C9), 54.6 (C15), 56.3 (C14a), 58.6
(C6), 60.1 (OCH3), 60.1 (OCH3), 60.4 (OCH3), 60.7 (OCH3), 114.6
(C4a), 118.2 (C3), 121.4 (C15a), 124.2 (C9a), 125.3 (C13a), 126.0 (C13),
128.4 (2ꢃCH), 129.8 (2ꢃCH), 133.7 (C10), 140.5 (C12), 145.0 (C1),
145.4 (C40), 148.3 (C2), 148.3 (C4), 149.7 (C11), 149.9 (C10), 170.6
(C7); EIMS m/z 638 (Mþ, 11), 484 (10), 483 (24), 235 (39), 234 (100);
Anal. Calcd for C33H38N2O9S: C, 62.05; H, 6.00; N, 4.39. Found: C,
61.79; H, 6.13; N, 4.28.
2.4. X-ray structure determination of compound 2654
All measurements were performed on a Rigaku AFC7S diffrac-
tometer with graphic-monochromated Cu
K
a
radiation
ꢀ
2.3.3. (1R
*
,2S
*
,5S )-1,2,3,4,5,6-Hexahydro-7-hydroxy-2-[(2-hydroxy-
*
(
l
¼1.54178 A). The single crystal of 26 (C29H36N2O6) belongs to the
ꢀ
3,4-dimethoxy-3-methylphenyl)methyl]-9,10-dimethoxy-8,11-
dimethyl-4-oxo-1,5-imino-3-benzazocine (25). Hydrazine mono-
hydrate (200 mL) was added to a stirred solution of 23 (2.57 g,
4.10 mmol) in methanol (240 mL) at 25 ꢁC, and the reaction mix-
ture was heated under reflux for 73 h. The reaction mixture was
diluted with brine (1.2 L) and extracted with 5% methanol in
chloroform (4ꢃ1.2 L). The combined extracts were washed with 5%
aqueous NaHCO3 solution (1.2 L), dried, and concentrated in vacuo
to give a residue. Chromatography of this residue on a silica gel
(15 g) column with dichloromethaneemethanol (40/1) gave 25
(1.54 g, 80.0%) as a pale yellow amorphous powder. IR (KBr) 3372,
2938, 1651, 1489, 1456, 1417, 1344, 1314, 1244, 1209, 1116,
triclinic space group P-1 (#2) with cell constants a¼8.807 (5) A,
ꢀ
ꢀ
b¼9.357 (4) A, c¼18.741 (6) A,
a
¼88.05 (3)ꢁ,
b
3
¼86.28 (3)ꢁ,
¼66.65
g
3
ꢀ
ꢁ
(4) , V¼1415 (1) A , Z¼2, and Dc¼1.306 g/cm . The data were col-
lected at a temperature of ꢂ160.0 ꢁC to a maximum 2
q value of
136.1ꢁ. A total of 5467 reflections were collected. The linear ab-
sorption coefficient,
m, for Cu Ka
radiation was 8.097 cmꢂ1. The
structure was solved by direct methods (SIR92)55 and expanded
using the Fourier technique. Non-hydrogen atoms were refined
anisotropically. Hydrogen atoms were included, but their positions
were not refined: isotropic B values were refined. The final cycle of
the full-matrix least-squares refinement was based on 5108 ob-
served reflections [I>2.00s (I)] and 398 variable parameters and
1076 cmꢂ1
2.09e2.14 (1H, m, 2a-H
2.85 (1H, dd, J¼17.6, 1.5 Hz, 6-H
;
1H NMR (CDCl3, 400 MHz)
), 2.14 (3H, s, 8-CH3), 2.47 (3H, s, NCH3),
), 2.93 (1H, dd, J¼17.6, 6.6 Hz, 6-
d
2.09 (3H, s, 30-CH3),
converged with unweighted and weighted agreement factors of
R¼0.078, R1¼0.075, and Rw¼0.212. Neutral atom scattering factors
were taken from Cromer and Waber.56 Anomalous dispersion ef-
b
b
fects were included in Fcalc; D D
57 the values for f0 and f00 were those
Ha
), 3.24 (1H, dd, J¼14.1, 2.0 Hz, 2a-H ), 3.54 (1H, br d, J¼6.6 Hz,
a
5-H), 3.75 (3H, s, 40-OCH3), 3.77 (6H, s, 50-OCH3 and 9-OCH3), 3.81
of Creagh and McAuley.58 The values for the mass attenuation co-
efficients were those of Creagh and Hubbell.59 All calculations were
performed using the CrystalStructure60,61 crystallographic software
package. The drawing of the molecule was made by ORTEP.
(3H, s, 10-OCH3), 4.23e4.27 (2H, m, 1-H and 2-H), 5.94 (1H, s, NH),
6.46 (1H, s, 60-H); 13C NMR (CDCl3, 100 Hz)
d
9.3 (30-CH3), 9.3 (8-
CH3), 23.6 (C6), 32.6 (C2a), 40.2 (NCH3), 54.4 (C1), 56.1 (C2), 56.4
(OCH3), 57.9 (C5), 60.3 (OCH3), 60.4 (OCH3), 60.5 (OCH3), 112.2 (C60),
115.5 (C6a), 118.7 (C10), 118.8 (C8), 119.1 (C30), 121.5 (C10a), 144.5
(C10), 146.3 (C20), 146.8 (C50), 146.9 (C40), 148.1 (C7), 149.5 (C9),
2.4.1. Ethyl (6S
*
,9S
*
,14aS
*
,15R
*
)-6,7,9,14,14a,15-Hexahydro-4,13-[(4-
methylphenyl)sulfoxy]-1,2,10,11-tetramethoxy-3,12,16-trimethyl-

4178
M. Yokoya et al. / Tetrahedron 68 (2012) 4166e4181
6,15-imino-5H-isoquino[3,2-b][3]benzazocin-7-one-9-carboxylate
(26a). TMSOTf (55.2 L, 305 mol) was added to a suspension of 23
(31.8 mg, 50.8 mol) and ethyl diethoxyacetate (27.3 L, 152 mol)
diphenylmethoxy-6,15-imino-5H-isoquino[3,2-b][3]benzazocin-7-
one (29a). Aqueous LiOH monohydrate (0.1 M, 15.8 mL, 1.58 mmol)
was added to a stirred solution of 27 (529.0 mg, 0.72 mmol) in THF
(48 mL) and methanol (16 mL), and the reaction mixture was stir-
red at 25 ꢁC for 8 days. The reaction mixture was poured into sat-
urated aqueous NH4Cl solution (250 mL) and extracted with
chloroform (3ꢃ500 mL). The combined extracts were washed with
brine (500 mL), dried, and concentrated in vacuo to give corre-
sponding carboxylic acid 28 as a solid, which was used in the next
step without further purification. 1H NMR (CD3COD, 300 MHz)
m
m
m
m
m
in dichloroethane (2 mL), and the reaction mixture was heated at
100 ꢁC for 21.5 h. As a large amount of starting material still
remained at this stage, TMSOTf (18.2
mL, 102 mmol) and ethyl
diethoxyacetate (9.1 L, 50.8 mol) were added to the reaction
m
m
mixture and the whole was heated at 100 ꢁC for 20.5 h. The reaction
mixture was diluted with saturated NaHCO3 (10 mL) and extracted
with chloroform (3ꢃ30 mL). The combined extracts were washed
with brine (30 mL), dried, and concentrated in vacuo to give a resi-
due (60 mg). Chromatography of this residue on a silica gel (10 g)
columnwith chloroformemethanol (100/1) gave 26a (16.1 mg, 46%)
as a pale yellow oil. IR (KBr) 3375, 2927, 2854,1734,1645,1460,1178,
d
2.13 (1H, m, 14-H
(1H, d, J¼18.3 Hz, 5-H
(1H, dd, J¼11.4, 3.3 Hz, 14-H
b
), 2.17 (6H, s, 3ꢃArCH3), 2.55 (3H, s, NCH3), 2.82
), 3.07 (1H, dd, J¼18.3, 7.7 Hz, 5-H ), 3.36
), 3.49 (3H, s, OCH3), 3.73 (3H, s,
b
a
a
OCH3), 3.75 (1H, d, J¼7.5 Hz, 6-H), 3.83 (3H, s, OCH3), 3.85 (3H, s,
OCH3), 4.40e4.51 (1H, m, 14a-H), 4.51 (1H, br s, 15-H), 4.60e4.80
(4H, m, 2ꢃOCH2Ar), 6.21 (1H, s, 9-H), 7.22e7.55 (10H, m, 10ꢃArH);
EIMS m/z 708 (Mþ, 0.6), 631 (100), 325 (65).
1058 cmꢂ1
OCH2CH3), 1.86 (3H, s, 12-CH3), 2.11 (3H, s, 3-CH3), 2.26 (1H, dd,
J¼17.1, 10.7 Hz, 14-H ), 2.50 (3H, s, TsCH3), 2.55 (3H, s, NCH3), 2.78
(1H, d, J¼17.4 Hz, 5-H ), 2.97 (1H, dd, J¼17.4, 7.6 Hz, 5-H ), 3.26 (1H,
dd, J¼17.1, 4.2 Hz,14-H ), 3.69 (3H, s, 2-OCH3), 3.74 (3H, s,11-OCH3),
;
1H NMR (CDCl3, 500 MHz)
d
1.289 (3H, t, J¼7.2 Hz,
b
b
a
Ethyl chloroformate (83 mL, 0.86 mmol) was added to a stirred
a
solution of the above residue (28: 510.0 mg) and TEA (0.12 mL,
0.83 mmol) in THF (75 mL) at ꢂ7 ꢁC, and the resulting mixture was
stirred at the same temperature for 3 h. The precipitates were re-
moved by filtration and the filter cake was carefully washed with
THF (50 mL). The combined filtrates were stirred at 0 ꢁC and so-
dium cyanoborohydride (60.6 mg, 1.60 mmol) was added. Then, the
reaction mixture was stirred at 0 ꢁC for 2 h, diluted with saturated
aqueous NH4Cl solution (500 mL), and extracted with chloroform
(3ꢃ500 mL). The combined extracts were washed with brine
(500 mL), dried, and concentrated in vacuo to give a residue
(520 mg). Chromatography of this residue on a silica gel (20 g)
column with dichloromethaneemethanol (100/1) gave 29a
(402.2 mg, 80.7%) as a colorless amorphous powder. IR (KBr) 3441,
3.83 (3H, s, 10-OCH3), 3.87 (3H, s, 1-OCH3), 3.86e3.90 (1H, over-
lapped, 6-H), 4.23 (2H, q, J¼7.0 Hz, OCH2CH3), 4.24e4.29 (1H, m,14a-
H), 4.31 (1H, br s,15-H), 4.70 (1H, br s, OH), 6.34 (1H, s, 9-H), 7.38 (2H,
d, J¼8.2 Hz, 2ꢃ20-H), 7.86 (2H, d, J¼8.2 Hz, 2ꢃ30-H); 13C NMR (CDCl3,
125 Hz)
d 8.7 (3-CH3), 10.8 (12-CH3), 14.2 (OCH2CH3), 21.4 (TsCH3),
23.6 (C5), 26.5 (C14), 40.4 (NCH3), 51.2 (C9), 52.4 (C14a), 54.2 (C15),
58.6 (C6), 59.9 (10-OCH3), 60.0 (2-OCH3), 60.3 (1-OCH3), 60.6 (11-
OCH3), 61.7 (OCH2CH3), 114.3 (C4a), 117.3 (C3), 122.4 (C9a), 123.0
(C15a), 125.0 (C13a), 127.1 (C12), 128.6 (2ꢃCH), 129.7 (2ꢃCH), 133.6
(C10),141.0 (C13),144.7 (C1),145.3 (C40),147.8 (C4),148.9 (C10),149.3
(C2), 149.6 (C11), 169.8 (C7), 171.4 (C16); FABMS m/z 711 [Mþ1]þ;
HRFABMS m/z 711.2585 (Mþþ1, calcd for C36H43N2O11S, 711.2588).
1645, 1457, 1416, 1371, 1339, 1115, 1067 cmꢂ1
500 MHz)
2.17 (6H, s, 2ꢃArCH3), 2.20 (1H, dd, J¼17.1, 12.2 Hz, 14-
), 2.57 (3H, s, NCH3), 2.96 (1H, d, J¼18.2 Hz, 5-H ), 3.09 (1H, dd,
J¼18.2, 7.9 Hz, 5-H ), 3.35 (1H, dd, J¼17.1, 4.0 Hz, 14-H ), 3.49 (3H,
;
1H NMR (CDCl3,
2.4.2. Ethyl (6S
*
,9S
*
,14aS
*
,15R
*
)-6,7,9,14,14a,15-Hexahydro-1,2,10,11-
d
tetramethoxy-3,12,16-trimethyl-4,13-diphenylmethoxy-6,15-imino-
5H-isoquino[3,2-b][3]benzazocin-7-one-9-carboxylate (27). Benzyl
bromide (0.114 mL. 0.955 mmol) was added to a suspension of 26
(177.0 mg, 0.318 mmol) and anhydrous K2CO3 (308.0 mg,
2.23 mmol) in acetone (20 mL), and the reaction mixturewas heated
under reflux for 12 h. The inorganic materials were removed by fil-
tration and washed with chloroform (50 mL). The combined filtrates
were concentrated in vacuo to give a residue. Chromatography of
Hb
b
a
a
s, OCH3), 3.77 (1H, overlapped, 6-H), 3.78 (3H, s, OCH3), 3.83 (3H, s,
OCH3), 3.84 (1H, overlapped, 9-CH), 3.87 (3H, s, OCH3), 4.06 (1H, dd,
J¼11.6, 3.7 Hz, 9-CH), 4.46 (1H, br d, J¼4.3 Hz, 15-H), 4.55 (1H, m,
14a-H), 4.60 (1H, d, J¼10.6 Hz, OCHAr), 4.73 (1H, d, J¼11.3 Hz,
OCHAr), 4.78 (1H, d, J¼10.6 Hz, OCHAr), 4.79 (1H, d, J¼11.3 Hz,
OCHAr), 5.98 (1H, dd, J¼7.6, 3.7 Hz, 9-H), 7.29e7.54 (10H, m,
this residue on
a
silica gel (20 g) column with dichlor-
10ꢃArH); 13C NMR (CDCl3, 125 Hz)
d 9.5 (ArCH3), 9.7 (ArCH3), 23.6
omethaneemethanol (100/1) gave 27 (205.5 mg, 87.7%) as a color-
less oil. IR (KBr) 3443, 2838, 1732, 1663, 1456, 1418, 1371, 1341, 1281,
(C5), 25.9 (C14), 40.2 (NCH3), 50.6 (C9), 52.0 (C14a), 54.4 (C15), 58.6
(C6), 60.0 (OCH3), 60.0 (OCH3), 60.1 (OCH3), 60.4 (OCH3), 65.7
(9CH2), 73.9 (OCH2Ar), 73.9 (OCH2Ar), 122.0 (C9a), 122.2 (C4a),
123.0 (C13a), 123.2 (C15a), 124.7 (C3), 125.3 (C12), 127.7 (C400), 127.8
(C40), 128.0 (C300), 128.1 (C30), 128.4 (C200), 128.5 (C20), 137.2 (C10),
137.3 (C100), 146.0 (C10), 147.6 (C1), 149.8 (C11), 149.8 (C2), 150.2
(C13), 151.2 (C4), 171.7 (C7); FABMS m/z 695 [Mþ1]þ; HRFABMS m/z
695.3334 (Mþþ1, calcd for C41H47N2O8, 695.3332).
1267, 1251, 1211, 1115, 1069 cmꢂ1; 1H NMR (CDCl3, 400 MHz)
d
1.30
(3H, t, J¼7.0 Hz, OCH2CH3), 2.16 (3H, s, 12-CH3), 2.17 (3H, s, 3-CH3),
2.22 (1H, dd, J¼14.7, 10.8 Hz, 14-H ), 2.56 (3H, s, NCH3), 2.95 (1H, d,
J¼18.1 Hz, 5-H ), 3.11 (1H, dd, J¼18.1, 7.5 Hz, 5-H ), 3.32 (1H, dd,
J¼14.7, 3.1 Hz,14-H ), 3.49 (3H, s, OCH3), 3.75 (3H, s, OCH3), 3.77 (1H,
b
b
a
a
d, J¼7.5 Hz, 6-H), 3.82 (3H, s, OCH3), 3.84 (3H, s, OCH3), 4.17e4.29
(2H, m, OCHCH3), 4.42 (1H, br s, 15-H), 4.40e4.47 (1H, m, 14a-H),
4.62 (1H, d, J¼11.0 Hz, OCHAr), 4.72 (1H, d, J¼11.0 Hz, OCHAr), 4.76
(1H, d, J¼11.0 Hz, OCHAr), 4.78 (1H, d, J¼11.0 Hz, OCHAr), 6.39 (1H, s,
2.4.4. (6S
*
,9S
*
,14aS
*
,15R )-6,7,9,14,14a,15-Hexahydro-1,2,10,11-
*
tetramethoxy-3,12,16-trimethyl-4,13-diphenylmethoxy-6,15-imino-
5H-isoquino[3,2-b][3]benzazocin-7-one-9-carbaldehyde
(30a). Oxalyl chloride (0.53 mL, 6.18 mmol) was added to a stirred
solution of DMSO (0.878 mL, 12.4 mmol) at ꢂ78 ꢁC over 10 min and
the resulting mixture was stirred at the same temperature for
9-H), 7.30e7.54 (10H, m, 10ꢃArH); 13C NMR (CDCl3, 125 Hz)
d 9.7 (3
or 12-CH3), 9.7 (3 or 12-CH3), 14.3 (OCH2CH3), 24.5 (C5), 26.0 (C14),
40.6 (NCH3), 51.3 (C9), 52.2 (C14a), 54.4 (C15), 58.8 (C6), 59.9 (OCH3),
59.9 (OCH3), 60.0 (OCH3), 60.1 (OCH3), 61.6 (OCH2CH3), 73.9
(OCH2Ar), 74.0 (OCH2Ar),121.6 (C9a),122.2 (C4a),123.0 (C13a),123.8
(C15a), 125.1 (C3), 125.2 (C12), 127.6 (C400), 127.7 (C40), 127.9 (C300),
128.0 (C30), 128.3 (C200), 128.4 (C20), 137.2 (C10), 137.3 (C100), 146.7
(C10),147.2 (C1),149.4 (C11),149.7 (C2),149.9 (C13),151.1 (C4),170.2
(C16), 171.2 (C7); EIMS m/z 736 (Mþ, 1.4), 645 (100), 324 (38);
HREIMS m/z 736.3360 (Mþ, calcd for C43H48N2O9, 736.3361).
10 min. Then,
a solution of 29a (536.0 mg, 0.772 mmol) in
dichloromethane (30 mL) was added dropwise to the above mix-
ture over 5 min. After being kept at the same temperature for 2 h,
the temperature was increased to ꢂ60 ꢁC and kept there for 2 h.
TEA (2.2 mL, 15.4 mmol) was added to the reaction mixture and
stirring was continued at ꢂ40 ꢁC for 1 h, and then at 25 ꢁC for 1.5 h.
The reaction mixture was concentrated in vacuo and the residue
was diluted with saturated aqueous NaHCO3 solution (500 mL) and
extracted with dichloromethane (3ꢃ500 mL). The combined
2.4.3. (6S
*
,9S
*
,14aS
*
,15R )-6,7,9,14,14a,15-Hexahydro-9-
*
hydroxymethyl-1,2,10,11-tetramethoxy-3,12,16-trimethyl-4,13-

M. Yokoya et al. / Tetrahedron 68 (2012) 4166e4181
4179
extracts were washed with brine (500 mL), dried, and concentrated
in vacuo to give a residue. The residue (671.0 mg) was subjected to
chromatography on a silica gel (20 g) column with ethyl acetatee
hexane (2/1) to give 30a (489.3 mg, 91.5%) as a colorless amorphous
powder. IR (KBr) 3435, 2936, 1734, 1654, 1456, 1418, 1371, 1341,
(CHO); FABMS m/z 693 [Mþ1]þ; HRFABMS m/z 693.3182 (Mþþ1,
calcd for C41H45N2O8, 693.3176).
2.6. Reduction of 30b to generate 29b
1271, 1115, 1067 cmꢂ1
;
1H NMR (CDCl3, 500 MHz)
d
2.18 (3H, s,
ArCH3), 2.20 (3H, s, ArCH3), 2.21 (1H, dd, J¼16.8, 12.6 Hz, 14-H ),
2.72 (3H, s, NCH3), 3.00 (1H, d, J¼18.0 Hz, 5-H ), 3.17 (1H, dd,
J¼18.0, 8.0 Hz, 5-H ), 3.37 (1H, dd, J¼16.8, 3.7 Hz, 14-H ), 3.54 (3H,
Method A: Sodium cyanoborohydride (1.0 M THF solution,
b
88.0
58.0
m
L, 88.0
mmol) was added to a stirred solution of 30b (40.2 mg,
b
mmol) and acetic acid (0.43 mL, 7.2 mmol) in THF (8.0 mL) at
a
a
0 ꢁC over 5 min, and the resulting mixture was stirred at 25 ꢁC for
3.5 h. The reaction mixture was diluted with saturated aqueous
NaHCO3 solution (100 mL) and extracted with chloroform
(3ꢃ100 mL). The combined extracts were washed with brine
(100 mL), dried, and concentrated in vacuo to give a residue.
Chromatography of this residue on a silica gel (10 g) column with
chloroformwchloroformemethanol (50/1) gave 29b (26.0 mg,
64.6%) as a colorless amorphous powder.
s, OCH3), 3.80 (3H, s, OCH3), 3.82 (1H, d, J¼8.0 Hz, 6-H), 3.84 (3H, s,
OCH3), 3.90 (3H, s, OCH3), 4.18 (1H, ddd, J¼12.6, 4.6, 3.7 Hz, 14a-H),
4.39 (1H, br d, J¼4.6 Hz, 15-H), 4.58 (1H, d, J¼11.0 Hz, OCHAr), 4.73
(1H, d, J¼11.3 Hz, OCHAr), 4.77 (1H, d, J¼11.3 Hz, OCHAr), 4.78 (1H,
d, J¼11.0 Hz, OCHAr), 6.27 (1H, s, 9-H), 7.30e7.55 (10H, m, 10ꢃArH),
9.72 (1H, s, CHO); 13C NMR (CDCl3, 125 Hz)
d 9.6 (ArCH3), 9.7
(ArCH3), 25.1 (C5), 25.7 (C14), 40.8 (NCH3), 52.7 (C14a), 54.6 (C15),
58.6 (C6), 58.7 (C9), 60.0 (OCH3), 60.0 (OCH3), 60.1 (OCH3), 60.1
(OCH3), 73.8 (OCH2Ar), 74.0 (OCH2Ar), 118.5 (C9a), 122.4 (C4a),
123.2 (C13a), 125.2 (C3), 125.7 (C12), 127.6 (C15a), 127.6 (C400), 127.8
(C40), 128.0 (C300), 128.2 (C30), 128.5 (C200), 128.5 (C20), 137.1 (C10),
137.3 (C100), 145.8 (C10), 147.2 (C1), 149.8 (C11), 149.9 (C2), 150.6
(C4), 151.3 (C13), 172.0 (C7), 196.1 (CHO); FABMS m/z 693 [Mþ1]þ;
HRFABMS m/z 693.3179 (Mþþ1, calcd for C41H45N2O8, 693.3176).
2.6.1. (6S
*
,9R
*
,14aS
*
,15R )-6,7,9,14,14a,15-Hexahydro-9-
*
hydroxymethyl-1,2,10,11-tetramethoxy-3,12,16-tri-methyl-4,13-
diphenylmethoxy-6,15-imino-5H-isoquino[3,2-b][3]benzazocin-7-
one (29b). IR (KBr) 3431, 2935, 1645, 1630, 1456, 1416, 1371, 1337,
1279, 1250, 1115, 1070 cmꢂ1; 1H NMR (CDCl3, 500 MHz)
d
2.08 (1H,
), 2.22 (3H, s, ArCH3), 2.25 (3H, s, ArCH3),
2.44 (3H, s, NCH3), 3.04 (1H, d, J¼17.8 Hz, 5-H ), 3.12 (1H, dd, J¼17.8,
6.5 Hz, 5-H
), 3.27 (1H, dd, J¼9.9, 6.5 Hz, 9-CH), 3.46 (1H, dd, J¼9.9,
4.6 Hz, 9-CH), 3.51 (1H, dd, J¼15.3, 2.2 Hz, 14-H ), 3.72 (1H, d,
dd, J¼15.3, 12.4 Hz, 14-H
b
b
2.5. Transformation of 30a into 30b (epimerization of C9
position)
a
a
J¼6.5 Hz, 6-H), 3.76 (3H, s, OCH3), 3.80 (3H, s, OCH3), 3.82 (3H, s,
OCH3), 3.85 (1H, ddd, J¼12.4, 3.1, 2.2 Hz, 14a-H), 3.89 (3H, s, OCH3),
4.13 (1H, d, J¼3.1 Hz, 15-H), 4.68 (1H, d, J¼10.5 Hz, OCHAr), 4.73
(1H, d, J¼10.5 Hz, OCHAr), 4.76 (1H, d, J¼11.0 Hz, OCHAr), 4.79 (1H,
d, J¼11.0 Hz, OCHAr), 5.79 (1H, dd, J¼6.5, 4.6 Hz, 9-H), 7.39e7.56
DBU (0.207 mL, 1.39 mmol) was added to a stirred solution of
30a (930.0 mg, 1.39 mmol) in THF (250 mL), and the reaction
mixture was stirred at 25 ꢁC for 24 h. The reaction mixture was
diluted with saturated aqueous NaHCO3 solution (1 L) and extrac-
ted with chloroform (3ꢃ1 L). The combined extracts were washed
with brine (1 L), dried, and concentrated in vacuo to give a residue.
Chromatography of this residue on a silica gel (50 g) column with
ethyl acetateehexane (2/1) gave 30a (290.4 mg, 31% recovery).
Further elution with ethyl acetateehexane (2/1)wethyl acetate
gave 30b (571.8 mg, 62.0%).
(10H, m, 10ꢃArH); 13C NMR (CDCl3, 125 Hz)
d 9.7 (ArCH3), 9.8
(ArCH3), 25.0 (C5), 25.8 (C14), 40.2 (NCH3), 52.5 (C9), 55.5 (C15),
58.3 (C14a), 59.6 (C6), 60.0 (OCH3), 60.1 (OCH3), 60.2 (OCH3), 60.6
(OCH3), 69.1 (9CH2), 74.4 (OCH2Ar), 75.4 (OCH2Ar), 122.5 (C4a),
122.6 (C15a), 124.9 (C3), 125.1 (C13a), 125.2 (C9a), 125.3 (C12), 127.8
(C200), 128.0 (C400), 128.4 (C40), 128.4 (C20), 128.5 (C300), 128.6 (C30),
137.0 (C10), 137.3 (C100), 146.3 (C10), 147.3 (C1), 149.6 (C13), 150.0
(C2), 150.2 (C11), 151.4 (C4), 173.2 (C7); FABMS m/z 695 [Mþ1]þ;
HRFABMS m/z 695.3327 (Mþþ1, calcd for C41H47N2O8, 695.3332).
Method B: A 0.5 M THF solution of NaBH(HFIP)3 (0.258 mL,
0.129 mmol) was added to a stirred solution of 30b (14.9 mg,
Recovered 30a (290.4 mg) was treated again with DBU (62.8 mL,
0.42 mmol) in THF (100 mL) at 25 ꢁC for 1 h to give 30b (158.9 mg)
and 30a (99.0 mg). Furthermore, recovered 30a (99.0 mg) was
treated with DBU (21.4 mL, 0.14 mmol) at 25 ꢁC for 24 h, and per-
forming the same work-up and separation described above affor-
ded 30b (60.0 mg) and 30a (37.1%). Thus, 790.7 mg of 30b (85.0%)
could be obtained along with recovered 30a (37.1 mg, 4.0%).
21.5 m
mol) in dichloromethane (3.7 mL) at 0 ꢁC over 5 min, and the
resulting mixture was stirred at 25 ꢁC for 32 h. The reaction mixture
was diluted with saturated aqueous NH4Cl solution (40 mL) and
extracted with chloroform (3ꢃ40 mL). The combined extracts were
washed with brine (40 mL), dried, and concentrated in vacuo to
give a residue. Chromatography of this residue on a silica gel (7 g)
column with chloroform gave 29b (4.0 mg, 26.8%) as a colorless
solid. Further elution with chloroformemethanol (20/1) gave 29a
(10.6 mg, 71.1%) as a colorless solid.
2.5.1. (6S
*
,9R
*
,14aS
*
,15R )-6,7,9,14,14a,15-Hexahydro-1,2,10,11-
*
tetramethoxy-3,12,16-trimethyl-4,13-diphenylmethoxy-6,15-imino-
5H-isoquino[3,2-b][3]benzazocin-7-one-9-carbaldehyde
(30b). Colorless amorphous powder. IR (KBr) 3447, 2936, 1736,
1651, 1456, 1418, 1371, 1354, 1338, 1273, 1115, 1069 cmꢂ1
;
1H NMR
), 2.20 (3H, s,
ArCH3), 2.23 (3H, s, ArCH3), 2.50 (3H, s, NCH3), 3.04 (1H, d,
J¼17.8 Hz, 5-H ), 3.14 (1H, dd, J¼17.8, 6.2 Hz, 5-H ), 3.59 (1H, dd,
J¼15.4, 2.1 Hz, 14-H ), 3.69 (3H, s, OCH3), 3.79 (1H, d, J¼6.2 Hz, 6-
(CDCl3, 500 MHz)
d
1.94 (1H, dd, J¼15.4, 12.2 Hz, 14-H
b
b
a
2.6.2. (6S
*
,9R
*
,14aS
*
,15R )-6,7,9,14,14a,15-Hexahydro-4,13-
*
a
dihydroxy-9-hydroxymethyl-1,2,10,11-tetramethoxy-3,12,16-
trimethyl-6,15-imino-5H-isoquino[3,2-b][3]benzazocin-7-one (31). A
solution of 29b (103.0 mg, 0.148 mmol) in methanol (35 mL) was
hydrogenated over 20% Pd(OH)2eC (31.2 mg) at 25 ꢁC for 2 h. The
catalyst was removed by filtration and washed with methanol
(50 mL) and then chloroform (50 mL). The combined filtrates were
concentrated in vacuo to give a residue. Chromatography of this
residue on a silica gel (6 g) column with chloroformemethanol (50/
1) gave 31 (76.5 mg, 100%) as a colorless amorphous powder. IR
(KBr) 3418, 2940, 1628, 1462, 1420, 1352, 1277, 1254, 1117,
H), 3.81 (3H, s, OCH3), 3.83 (3H, s, OCH3), 3.92 (1H, dt, J¼12.2,
2.1 Hz, 14a-H), 3.93 (3H, s, OCH3), 4.28 (1H, br s, 15-H), 4.61 (1H, d,
J¼10.7 Hz, OCHAr), 4.69 (1H, d, J¼10.7 Hz, OCHAr), 4.80 (1H, d,
J¼11.0 Hz, OCHAr), 4.83 (1H, d, J¼11.0 Hz, OCHAr), 6.06 (1H, s, 9-H),
7.32e7.55 (10H, m, 10ꢃArH), 9.30 (1H, s, CHO); 13C NMR (CDCl3,
125 Hz)
d 9.7 (ArCH3), 9.7 (ArCH3), 24.3 (C5), 25.79 (C14), 40.2
(NCH3), 55.0 (C15), 56.9 (C14a), 58.6 (C6), 58.8 (C9), 60.1 (OCH3),
60.1 (OCH3), 60.2 (OCH3), 60.7 (OCH3), 74.5 (OCH2Ar), 75.2
(OCH2Ar), 119.1 (C9a), 122.5 (C4a), 125.3 (C3), 125.4 (C13a), 126.3
(C12), 128.0 (C15a), 128.0 (C300), 128.0 (C20), 128.2 (C400), 128.4 (C40),
128.5 (C30), 128.6 (C200), 136.1 (C10), 137.4 (C100), 146.7 (C10), 147.3
(C1), 149.9 (C11), 150.0 (C2), 150.2 (C13), 151.5 (C4), 170.4 (C7), 193.5
1070 cmꢂ1
12.8 Hz, 14-H
d, J¼17.9 Hz, 5-H
;
1H NMR (CDCl3, 500 MHz)
), 2.13 (6H, s, 2ꢃArCH3), 2.44 (3H, s, NCH3), 2.85 (1H,
), 3.05 (1H, dd, J¼17.9, 6.8 Hz, 5-H ), 3.13 (1H, dd,
d
2.03 (1H, dd, J¼15.6,
b
b
a

4180
M. Yokoya et al. / Tetrahedron 68 (2012) 4166e4181
J¼10.7, 6.5 Hz, 9-CH), 3.34 (1H, dd, J¼10.7, 4.5 Hz, 9-CH), 3.51 (1H,
7.2 Hz, 5-H
J¼16.5, 3.2 Hz, 14-H
a
), 2.87 (1H, dd, J¼20.7, 0.6 Hz, 5-H
b
), 3.10 (1H, dd,
dd, J¼15.6, 2.5 Hz, 14-H
a
), 3.70 (1H, br d, J¼6.8 Hz, 6-H), 3.74 (3H, s,
a
), 3.38 (1H, dt, J¼12.2, 3.2 Hz, 14a-H), 3.49
OCH3), 3.80 (3H, s, OCH3), 3.80 (3H, s, OCH3), 3.82 (3H, s, OCH3),
(1H, d, J¼7.2 Hz, 6-H), 3.63 (3H, s, 2-OCH3), 3.79 (3H, s, 11-OCH3),
3.83 (1H, d, J¼3.2 Hz, 15-H), 4.52 (1H, dd, J¼11.6, 2.2 Hz, 9-CH),
4.92 (1H, dd, J¼11.6, 2.2 Hz, 9-CH), 5.35 (1H, qq, J¼7.4, 1.4 Hz,
C¼CHCH3), 5.56 (1H, q, J¼2.2 Hz, 9-H); 13C NMR (CDCl3, 125 Hz)
3.83 (1H, overlapped, 14a-H), 4.27 (1H, d, J¼3.4 Hz, 15-H), 5.59 (1H,
dd, J¼6.5, 4.5 Hz, 9-H); 13C NMR (CDCl3, 125 Hz)
d 9.5 (ArCH3), 9.6
(ArCH3), 25.5 (C5), 26.7 (C14), 40.1 (NCH3), 52.7 (C9), 56.7 (C15),
59.8 (C14a), 60.4 (OCH3), 60.6 (C6), 60.8 (OCH3), 61.0 (OCH3), 61.1
(OCH3), 65.7 (9CH2), 117.1 (C4a), 120.1 (C3), 120.5 (C12), 121.8
(C13a),122.6 (C15a),125.8 (C9a),145.2 (C10),145.9 (C1),148.6 (C13),
150.1 (C4), 151.1 (C2), 151.9 (C11), 173.2 (C7); FABMS m/z 515
[Mþ1]þ; HRFABMS m/z 515.2397 (Mþþ1, calcd for C27H35N2O8,
515.2393).
d
8.6 (QuCH3), 8.6 (QuCH3), 15.3 (C 40), 20.3 (20-CH3), 23.6 (C5),
26.0 (C14), 39.3 (NCH3), 50.8 (C9), 53.3 (C15), 56.0 (C14a), 59.2
(C6), 60.5 (2-OCH3), 60.9 (11-OCH3), 62.9 (9CH2), 126.9 (C20), 127.5
(C12), 128.8 (C3), 135.1 (C15a), 136.3 (C9a), 139.1 (C30), 141.1 (C13a),
142.2 (C4a), 155.5 (C2), 156.4 (C11), 166.8 (C10), 170.0 (C7), 180.4
(C10), 182.7 (C1), 185.0 (C13), 185.9 (C4); FABMS m/z 565 [Mþ1]þ;
HRFABMS m/z 565.2183 (Mþþ1, calcd for C30H33N2O9, 565.2186).
2.6.3. (6S
*
,9R
*
,14aS
*
15R )-6,7,9,14,14a,15-Hexahydro-9-
*
hydroxymethyl-2,11-dimethoxy-3,12,16-trimethyl-1,4,7,10,13-
pentaoxo-6,15-imino-4H-isoquino[3,2-b][3]benzazocin (32). A solu-
2.8. Preparation of angelate 33 from 31
tion of CAN (27.7 mg, 50.6
mL) was added to a stirred solution of 31
(5.2 mg, 10.1
m
mol) in acetonitrile at 0 ꢁC within 1 min, and the
Oxalyl chloride (17.0 mL, 0.20 mmol) and DMF (1.5 mL, 19.8 mmol)
resulting mixture was stirred at the same temperature for 15 min.
The reaction mixture was diluted with 5% aqueous NaHCO3 solution
(20 mL) and extracted with dichloromethane (3ꢃ10 mL). The
combined extracts were washed with brine (20 mL), dried, and
concentrated in vacuo to give a residue. Chromatography of this
residue on a silica gel (3 g) column with ethyl acetateehexane (1/5)
gave 32 (76.5 mg, 100%) as a colorless amorphous powder. IR (KBr)
3431, 2936, 1657, 1616, 1445, 1431, 1373, 1352, 1308, 1277, 1233,
were added to a stirred solution of commercially available angelic
acid (20.2 mg, 0.20 mmol) in ether (1.0 mL) at 0 ꢁC, and the
resulting mixture was stirred at 25 ꢁC for 2 h. A dichloromethane
(0.5 mL) solution of 31 (5.0 mg, 9.7 mmol) was added to the above
mixture over 5 min, the resulting mixture was concentrated in
vacuo with a stream of argon gas to give a residue. Dichloroethane
(1.0 mL) was added to the residue and the resulting mixture was
heated at 80 ꢁC for 3 h. After being concentrated, the crude product
was subjected to chromatography [silica gel 4 g; elution with
chloroformemethanol (30/1)] to give 33 (5.4 mg, 93%) as a colorless
amorphous powder.
1150, 1117 cmꢂ1; 1H NMR (CDCl3, 500 MHz)
12.2, 1.2 Hz, 14-H ), 1.94 (3H, s, QuCH3), 1.95 (3H, s, QuCH3), 2.38
(3H, s, NCH3), 2.68 (1H, d, J¼20.7 Hz, 5-H ), 2.89 (1H, dd, J¼20.7,
6.6 Hz, 5-H ), 3.44 (1H, dd,
d
1.68 (1H, ddd, J¼16.5,
b
b
a
), 3.06 (1H, dd, J¼16.5, 2.7 Hz, 14-H
a
J¼11.3, 4.3 Hz, 9-CH), 3.69 (1H, br d, J¼6.6 Hz, 6-H), 3.74 (1H, dd,
J¼11.3, 3.4 Hz, 9-CH), 3.90 (1H, br d, J¼12.2 Hz, 14a-H), 3.98 (3H, s,
OCH3), 3.99 (3H, s, OCH3), 4.14 (1H, br s, 15-H), 5.30 (1H, ddd, J¼4.3,
2.8.1. (6S
*
,9R
*
,14aS
*
15R )-6,7,9,14,14a,15-Hexahydro-4,13-
*
dihydroxy-9-hydroxymethyl-1,2,10,11-tetramethoxy-3,12,16-
trimethyl-6,15-imino-5H-isoquino[3,2-b][3]benzazocin-7-one ange-
late (33). IR (KBr) 3414, 2930, 1719, 1636, 1458, 1420, 1351, 1296,
3.4, 1.2 Hz, 9-H); 13C NMR (CDCl3, 125 Hz)
d 8.9 (QuCH3), 8.9
(QuCH3), 24.3 (C5), 25.8 (C14), 39.9 (NCH3), 52.5 (C9), 53.4 (C15),
57.0 (C14a), 59.2 (C6), 61.4 (OCH3), 61.4 (OCH3), 65.7 (9CH2), 129.2
(C3), 129.7 (C12), 135.2 (C15a), 137.1 (C9a), 142.2 (C4a), 142.3 (C13a),
156.0 (C2), 156.0 (C11), 171.2 (C7), 181.2 (C10), 182.7 (C1), 185.7
(C13), 186.8 (C4); FABMS m/z 483 [Mþ1]þ; HRFABMS m/z 483.1768
(Mþþ1, calcd for C25H27N2O8, 483.1767).
1279, 1148, 1117, 1070 cmꢂ1
;
1H NMR (CDCl3, 500 MHz)
d
1.37 (3H,
quint, J¼1.4 Hz, C¼CHCH3),1.59 (3H, dq, J¼7.1, 1.4 Hz, C¼CCH3), 2.04
(1H, dd, J¼15.3, 11.5 Hz, 14-H ), 2.14 (3H, s, 12-CH3), 2.15 (3H, s, 3-
CH3), 2.43 (3H, s, NCH3), 2.81 (1H, d, J¼17.3 Hz, 5-H ), 3.01 (1H, dd,
J¼17.3, 7.4 Hz, 5-H ), 3.25 (1H, dd, J¼15.3, 2.6 Hz, 14-H ), 3.76 (3H,
b
b
a
a
s, 2-OCH3), 3.80 (1H, d, J¼7.4 Hz, 6-H), 3.81 (3H, s, 11-OCH3), 3.83
(3H, s, 10-OCH3), 3.84 (3H, s, 1-OCH3), 3.92 (1H, ddd, J¼11.5, 2.8,
2.6 Hz, 14a-H), 4.14 (1H, dd, J¼11.3, 2.9 Hz, 9-CH), 4.19 (1H, d,
J¼2.8 Hz, 15-H), 4.49 (1H, dd, J¼11.3, 3.9 Hz, 9-CH), 5.70 (1H, dd,
J¼3.9, 2.9 Hz, 9-H), 5.73 (1H, qq, J¼7.1, 1.4 Hz, CH]CCH3); 13C NMR
2.7. Two-stepsynthesis of( )-renieramycin G (1g)from 31 via 32
An aqueous (0.24 mL) solution of CAN (27.7 mg, 50.6
mL) was
added to a stirred solution of 31 (5.2 mg, 10.1 mol) in acetonitrile
m
(CDCl3, 125 Hz) d
8.9 (ArCH3), 8.9 (ArCH3), 15.1 (C40), 20.1 (20-CH3),
at 0 ꢁC within 1 min, and the resulting mixture was stirred at the
same temperature for 15 min. The reaction mixture was diluted
with 5% aqueous NaHCO3 solution (20 mL) and extracted with
dichloromethane (3ꢃ10 mL). The combined extracts were washed
with brine (20 mL), dried, and concentrated in vacuo to give 32
(4.9 mg), which was used in the following step without further
purification.
23.3 (C5), 25.5 (C14), 40.0 (NCH3), 49.8 (C9), 55.4 (C15), 58.1 (C14a),
59.3 (C6), 60.1 (OCH3), 60.3 (OCH3), 60.6 (OCH3), 60.7 (OCH3), 64.7
(9CH2), 114.9 (C4a), 117.0 (C12), 117.7 (C3), 118.7 (C13a), 124.2 (C9a),
127.5 (C20), 128.1 (C15a), 137.1 (C30), 143.7 (C10), 144.6 (C1), 146.1
(C13),148.1 (C4),149.5 (C11),149.7 (C2),167.0 (C10), 171.0 (C7); EIMS
m/z 596 (Mþ, 16), 234 (100); HREIMS m/z 596.2736 (Mþ, calcd for
C32H40N2O9, 596.2734).
Angeloyl chloride (24.0 mg, 0.20 mmol) was added to a stirred
solution of crude 32 described above in dichloromethane (1.0 mL),
and the resulting mixture was stirred at 25 ꢁC for 25 h. The re-
action mixture was diluted with 5% aqueous NaHCO3 solution
(15 mL) and extracted with dichloromethane (3ꢃ15 mL). The
combined extracts were washed with brine (15 mL), dried, and
concentrated in vacuo to give a residue (17.2 mg). Chromatography
of this residue on a silica gel (4 g) column with ethyl aceta-
teehexane (2/1) gave 1g (2.1 mg, 36% in two steps) as a dark
brown amorphous powder. IR (KBr) 2945, 1717, 1655, 1616, 1449,
2.9. Preparation of ( )-renieramycin G (1g) from 33
An aqueous (0.53 mL) solution of CAN (43.7 mg, 79.7
mL) was
added to a stirred solution of 33 (9.5 mg, 15.9 mol) in acetonitrile
m
at 0 ꢁC in one portion, and the resulting mixture was stirred at the
same temperature for 15 min. The reaction mixture was diluted
with 5% aqueous NaHCO3 solution (20 mL) and extracted with
dichloromethane (3ꢃ10 mL). The combined extracts were washed
with brine (20 mL), dried, and concentrated in vacuo to give a res-
idue. Chromatography of this residue on a silica gel (6 g) column
with ethyl acetateehexane (2/1) gave 1g (7.2 mg, 80.0%) as a col-
orless amorphous powder.
1422, 1373, 1352, 1307, 1231, 1150 cmꢂ1 1H NMR (C6D6, 500 MHz)
;
d
1.37 (3H, quint, J¼1.4 Hz, C]CCH3), 1.51 (1H, ddd, J¼16.5, 12.2,
2.2 Hz, 14-H
b
), 1.55 (3H, dq, J¼7.4, 1.4 Hz, C]CHCH3), 1.81 (3H, s,
NCH3), 1.87 (3H, s, 3-CH3), 1.90 (3H, s, 12-CH3), 2.61 (1H, dd, J¼21.0,

M. Yokoya et al. / Tetrahedron 68 (2012) 4166e4181
4181
25. Vincent, G.; Williams, R. M. Angew. Chem., Int. Ed. 2007, 46, 1517e1520; Corri-
gendum: Vincent, G.; Williams, R. M. Angew. Chem., Int. Ed. 2011, 50, 8458.
26. Chen, X.; Zhu, J. Angew. Chem., Int. Ed. 2007, 46, 3962e3965.
27. Yokoya, M.; Ito, H.; Saito, N. Tetrahedron 2011, 67, 9185e9192.
28. Yokoya, M.; Shinada-Fujino, K.; Saito, N. Tetrahedron Lett. 2011, 52, 2446e2449.
29. Kubo, A.; Saito, N.; Yamato, H.; Masubuchi, K.; Nakamura, M. J. Org. Chem. 1988,
53, 4295e4310.
2.10. Cell growth inhibition assay (IC50
)
A single-cell suspension (2ꢃ103 cells/well) was added to serially
diluted test compounds in a microplate. The cells were then cul-
tured for 4 days. Cells were enumerated with a cell counting kit
(DOJINDO, Osaka, Japan). IC50 was expressed as the concentration
at which cell growth was inhibited by 50% compared with the
untreated control.
30. Saito, N.; Harada, S.; Inouye, I.; Yamaguchi, K.; Kubo, A. Tetrahedron 1995, 51,
8231e8246.
31. Saito, N.; Yamauchi, R.; Kubo, A. Heterocycles 1991, 32, 1203e1214.
32. Yokoya, M.; Kawachi, O.; Saito, N. Heterocycles 2008, 76, 1497e1509.
33. For simplicity, natural product numbering was used in this manuscript, but
IUPAC names and numbers were used in the Experimental.
34. Our starting material for the E-ring portion of 1g was the commercially
available 3,4-dimethoxyphenol, the phenolic OH protection of which followed
by three steps (a: n-BuLi, MeI, THF, 0 ꢁC; b: HCleEtOH; c: HMTA, AcOH) gave 7
in 68% overall yield: see Experimental.
35. Sasaki, T. Chem. Ber. 1921, 54, 163e168.
36. Kubo, A.; Saito, N.; Yamato, H.; Kawakami, Y. Chem. Pharm. Bull. 1987, 35,
2525e2532.
37. Aldehyde 5b was prepared from 7 in 95% yield: see Experimental.
38. Saito, N.; Yamauchi, R.; Nishioka, H.; Ida, S.; Kubo, A. J. Org. Chem. 1989, 54,
5391e5395.
39. Chang, Y.-A.; Sun, T.-H.; Chiang, M. Y.; Lu, F.-J.; Huang, Y.-T.; Liang, L.-C.; Ong, C.
W. Tetrahedron 2007, 63, 8781e8787.
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, Japan. This work was also partially sup-
ported by the Japan Society for the Promotion of Science (JSPS) Asia
and Africa Science Platform Program (2010e2012), and a grant from
the High-Tech Research Center Project, the Ministry of Education,
Culture, Sports, Science and Technology (MEXT), Japan (No.
S0801043). We are grateful to Dr. Takuo Tsukuda (Chugai Pharma-
ceutical Company, Kamakura Research Center) for conducting the
cytotoxicity assay.
40. Ong, C. W.; Chang, Y. A.; Wu, J.-Y.; Cheng, C.-C. Tetrahedron 2003, 59,
8245e8249.
41. Ong, C. W.; Lee, H. C. Aust. J. Chem. 1990, 43, 773e775.
42. Saito, N.; Seki, R.; Kameyama, N.; Sugimoto, R.; Kubo, A. Chem. Pharm. Bull.
2003, 51, 821e831.
43. Treatment of 23 with trimethylsilyl chloride (TMSCl) and TEA in dichloroethane
at 25 ꢁC for 2 h, followed by treatment with ethyl diethoxyacetate in the presence
of TMSOTf at the same temperature for 17 h, and finally refluxing for 42 h gave an
inseparable mixture of many products. In contrast, the reaction of 23 with ethyl
diethoxyacetate in the presence of TMSOTf in dichloroethane at 120 ꢁC for 42 h
gave 26a in 46% yield (see Experimental), but the product yield and re-
producibility of this transformation were surprisingly low.
44. Isomerization of 1,3-disubstituted 1,2,3,4-tetrahydroisoquinoline derivatives by
DBU was reported in the synthetic studies on ecteinascidin 743 (4a).45,46
45. Herberich, B.; Kinugawa, M.; Vazquez, A.; Williams, R. M. Tetrahedron Lett. 2001,
42, 543e546.
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