Synthetic studies toward ecteinascidin 743 (trabectedin)

Article abstract of DOI:10.1055/s-0032-1316579

An alternative synthetic route to an intermediate in the synthesis of ecteinascidin 743 has been established by using a Pictet-Spengler reaction and a Friedel-Crafts type reaction.

Full text of DOI:10.1055/s-0032-1316579

PAPER
▌2743
paper
Synthetic Studies toward Ecteinascidin 743 (Trabectedin)
Synthetic Studies toward Ecteinascidin 743
Takahiro Imai,1 Hiyoku Nakata, Satoshi Yokoshima, Tohru Fukuyama*
Graduate School of Pharmaceutical Sciences, University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-0033, Japan
Fax +81(3)58028694; E-mail: fukuyama@mol.f.u-tokyo.ac.jp
Received: 01.05.2012; Accepted after revision: 31.05.2012
eral other research groups.12 Despite considerable effort
toward the total synthesis of Et 743, its clinical supply re-
lies solely on a long semisynthetic route from cyanosafra-
cin B, produced by bacterial fermentation.13 A practical
and scalable synthesis of Et 743 is therefore eagerly
sought.
Abstract: An alternative synthetic route to an intermediate in the
synthesis of ecteinascidin 743 has been established by using a
Pictet–Spengler reaction and a Friedel–Crafts type reaction.
Key words: alkaloids, anticancer drugs, Pictet–Spengler reaction,
Friedel–Crafts reaction, total synthesis
Our previous synthesis of Et 743, featuring the Ugi four-
component condensation reaction, allowed easy access to
the diketopiperazine through an intramolecular Heck re-
action for the construction of the bicyclo [3.3.1] skeleton.
Phenol-aldehyde cyclization was employed to construct
the B ring, followed by the acid-induced ten-membered
sulfide formation (Scheme 1).7b Herein, we disclose an-
other synthetic approach to the key intermediate 7 via a
Pictet–Spengler reaction and a Friedel–Crafts type reac-
tion of an iminolactone.
Tetrahydroisoquinoline alkaloids show a broad range of
biological properties, including antitumor and antimicro-
bial activities.2 Ecteinascidin 743 (Et 743, 1; Figure 1,
also known as trabectedin or Yondelis®), isolated from the
Caribbean tunicate Ecteinascidia turbinate,3 has been
shown to display highly potent cytotoxicity against a va-
riety of tumor cell lines at very low concentrations. Be-
cause of the unique mechanism of action against the
tumor cell lines,4 Et 743 was considered as a potential an-
ticancer drug. Extensive clinical trials resulted in the ap-
proval of Et 743 in 2007 for the treatment of advanced soft
tissue sarcoma and, in 2009, for relapsed platinum-sensi-
tive ovarian cancer in combination with liposomal doxo-
rubicin. Et 743 is currently in clinical trials for the
treatment of breast, lung, pancreas, and prostate cancers.5
In our previous total synthesis, amine 2 was prepared by
the addition of phenol 10 to iminolactone 11 (Scheme 2).
Transformation of the resulting adduct 12 into amine 2,
however, required a rather tedious cleavage of the chiral
auxiliary, which was clearly problematic from a synthetic
perspective. As illustrated in Scheme 3, we envisioned
that the intermediate 7 could be constructed by incorporat-
ing the chiral auxiliary moiety in a synthetic intermediate
itself. In a retrosynthetic sense, cleavage of the oxazoli-
dine ring in 7 and manipulation of the diols at C4 and C22
would lead to lactone 14. The addition of an aryl group to
iminolactone 15 would occur from the less hindered face,
giving the desired trans product. The iminolactone 15
could be derived from aminoalcohol 16, which, in turn,
could be prepared via a Pictet–Spengler reaction between
aldehyde 17 and amine 18.
OMe
HO
OAc
H
N
Me
S
N
O
H
O
OH
O
O
MeO
HO
NH
Our synthesis commenced with the preparation of the
amine unit 18 (Scheme 4). After benzylation of the known
aldehyde 19,14 a Horner–Wadsworth–Emmons reaction of
20 was conducted with phosphonate 2115 using N,N,N′,N′-
tetramethylguanidine as a base to give dehydrophenylala-
nine 22 stereoselectively. Asymmetric hydrogenation of
22 through the use of {Rh[(cod)-(S,S)-Et-Du-
PHOS]OTf}16 under a hydrogen atmosphere (500 psi) at
50 °C proceeded uneventfully to give aminoester 23 in
85% yield with 95% enantiomeric excess. After switching
the Boc group to a Cbz group,17 the methyl ester was con-
verted into Weinreb amide 24 via a two-step sequence in-
volving basic hydrolysis followed by condensation of the
resulting carboxylic acid with N,O-dimethylhydroxyl-
Figure 1 Structure of ecteinascidin 743 (1; trabectedin)
The structural complexity and the limited availability of
Et 743 from nature have made it a very attractive synthetic
target. The first total synthesis of Et 743 was accom-
plished in 1996 by Corey and co-workers.6 Since then,
total syntheses have been reported from our own
laboratories7 and also by Zhu and co-workers.8 Three formal
total syntheses were reported by Williams,9 Danishefsky,10
and Takemoto11 along with synthetic approaches by sev-
SYNTHESIS 2012, 44, 2743–2753
Advanced online publication: 06.07.2012
0
0
3
9
-
7
8
8
1
1
4
3
7
-
2
1
0
X
DOI: 10.1055/s-0032-1316579; Art ID: SS-2012-H0408-OP
© Georg Thieme Verlag Stuttgart · New York

2744
T. Imai et al.
PAPER
OMe
Boc
OMe
OBn
I
OMOM
BnO
PMP
O
MeCHO
PMPNC
OH
NH
8 steps
+
I
NH2
HN
Ugi 4CC
O
BocHN
N
O
O
OTBDPS
OMe
CO2H
H
O
O
2
3
TBDPSO
4
OMe
OMe
OBn
I
BnO
BnO
OMs
OMs
OBn OTBS
H
10 steps
N
Boc
N
Boc
N
Troc
intramolecular
Heck reaction
N
N
N
O
O
O
H
H
O
O
O
O
H
O
O
TBDPSO
TBDPSO
5
6
7
OMe
OMe
BnO
HO
OBn
O
OH OH
H2
4 steps
12 steps
H
H
N
Pd/C
ecteinascidin 743 (1)
N
Troc
N
Troc
THF, r.t.
N
O
O
phenol-aldehyde
cyclization
H
H
AcO
O
O
CN
CN
AcO
8
9
Scheme 1
showed that the reaction proceeded with complete cis-se-
lectivity. Selective benzylation of the phenol in 28 and
protection of the secondary amine moiety as its 2-chloro-
ethyl carbamate furnished 29. Treatment of 29 with 2-
mercaptoethanol and 1,8-diazabicyclo[5.4.0]undec-7-ene
(DBU) caused concomitant cleavage of the p-nosyl group
and the acetonide to give 1,2-aminoalcohol 30 in 84%
yield.
N
Ph
OMOM
OMOM
HO
HO
O
O
O
H
N
Ph
11
O
TFA, CH2Cl2
–10 °C
O
O
O
O
10
12
89%
Scheme 2
We next focused on introducing the A ring unit via a
Friedel–Crafts type arylation of an iminolactone (Scheme
7).19 Aminoalcohol 30 was treated with phenyl bromoac-
etate (31) according to Harwood’s procedure20 to furnish
morpholinone 32, which was oxidized with N-bromosuc-
cinimide (NBS) to give iminolactone 33 in good yield.
Addition of phenol 34 to 33 proceeded smoothly in the
presence of a large excess of trifluoroacetic acid (TFA) at
0 °C, yielding 35 as a single product. The reaction oc-
curred from the less hindered face of the iminolactone to
produce the desired isomer. The product 35 was then con-
verted into the intermediate of our previous synthetic
route. Thus, conversion of the phenol into the correspond-
ing triflate, followed by methanolysis, afforded a hy-
droxyester, which was protected with a TBS group to give
36 in good yield. The ester moiety in 36 was reduced to
give alcohol 37.21 Upon treatment with BF3·OEt2, 37 un-
derwent cleavage of the dimethyl acetal moiety, which in-
duced formation of a bicyclo [3.3.1] skeleton and an
oxazolidine ring to furnish 38 in 73% yield. This result
confirmed that the crucial Pictet–Spengler reaction pro-
amine. Reduction of 24 with diisobutylaluminum hydride
(DIBAL-H) gave an aldehyde, which was protected as its
dimethyl acetal. Subsequent hydrogenolysis of the Cbz
and benzyl groups afforded 18.
The aldehyde unit was prepared in the following manner
(Scheme 5). A p-nosyl group was introduced to the amino
group of L-serine methyl ester (25). After formation of the
acetonide, the methyl ester moiety was reduced with
DIBAL-H to afford 27 in good yield.18
With the amine unit 18 and the aldehyde unit 27 in hand,
we next attempted the crucial Pictet–Spengler reaction
(Scheme 6). After extensive optimization, we found that
the reaction proceeded in dichloromethane by mixing 18
and 27 in the presence of formic acid and sodium sulfate
at ambient temperature, thereby providing the desired tet-
rahydroisoquinoline 28 as a single diastereomer. The
regio- and stereoselectivity of the reaction was secured by
a NOESY experiment as shown in Scheme 6, which
Synthesis 2012, 44, 2743–2753
© Georg Thieme Verlag Stuttgart · New York

PAPER
Synthetic Studies toward Ecteinascidin 743
2745
OMe
OMe
OMe
TBSO
22
BnO
OBn OTBS
HO
BnO
O
O
BnO
H
4
22
4
H
3
1
H
BnO
BnO
4
N
N
H
N
Troc
H
H
H
N
PG
H
H
3
PGN
N
1
O
O
H
H
O
O
O
H
O
O
MeO
OMe
MeO
OMe
22
7
13
14
OMe
OMe
OMe
O
O
BnO
H
HO BnO
H
HO
O
+
N
H2N
H
N
R
H
H
PGN
PGN
H2N
H
CHO
H
H
17
MeO
OMe
MeO
OMe
MeO
OMe
15
16
18
Scheme 3
ceeded with cis-selectivity. At this stage,22 a Pd-catalyzed
cross coupling between 38 and MeZnCl23 was performed
to give 39 in 76% yield. Finally, the protective group on
the secondary amine was converted into a 2,2,2-trichlo-
roethoxycarbonyl (Troc) group in three steps to afford the
desired synthetic intermediate 7, the spectral data of
which were consistent with those reported previously.
OH
O
O
c
a,b
HCl⋅H2N
N
N
Ns
Ns
H
H
CHO
27
CO2Me
CO2Me
25
26
Scheme 5 Reagents and conditions: (a) p-NsCl, Et3N, CH2Cl2, 0 °C
to r.t., 92%; (b) 2,2-dimethoxypropane, TsOH, benzene, reflux, 98%;
(c) DIBAL-H, –78 °C, toluene, quant.
OMe
OMe
HO
BnO
a
b
In summary, an alternative synthetic route to the late-
stage intermediate in our previous synthesis of ecteinasci-
din 743 has been developed. The approach features a
Pictet–Spengler reaction and a Friedel–Crafts type reac-
tion as key steps. Further investigations to establish a truly
practical synthesis of ecteinascidin 743 are underway in
our laboratories.
O
BocHN
MeO2C
P(OMe)2
CHO
CHO
19
20
21
OMe
OMe
BnO
BnO
c
d–g
All non-aqueous reactions were carried out in oven-dried glass
tubes under a slightly positive pressure of argon unless otherwise
noted. Dehydrated CH2Cl2, toluene, THF, Et2O, MeCN, DMF,
MeOH, and EtOH were purchased from Kanto Chemical Co., Inc.
and stored over 3 Å or 4 Å molecular sieves. Pyridine, Et3N and
N,N-diisopropylethylamine (DIPEA) were dried over KOH. All
other reagents were commercially available and used without fur-
ther purification. Preparative flash chromatography was performed
using Silica Gel 60 (spherical, 40–100 μm) purchased from Kanto
H
BocHN
BocHN
CO2Me
CO2Me
22
23
OMe
OMe
BnO
HO
h–j
1
Chemical Co., Inc. H and 13C NMR spectra were recorded with
H
H
JEOL LA-MHz and ECS-400 spectrometers. IR spectra were re-
corded with a JASCO FT/IR-5300 Fourier Transform Infrared
Spectrophotometer. Mass spectra (MS) were obtained with an Agi-
lent 6530 Q-TOF/MS (HRMS), Shimazu QP2010 (GC-MS) instru-
ment. Optical rotations were measured with a JASCO DIP-370
instrument. Melting points were measured with an Ishii melting
points apparatus.
CbzHN
H2N
OMe
O
N
MeO
OMe
Me
24
18
Scheme 4 Reagents and conditions: (a) BnBr, K2CO3, acetone, r.t.,
90%; (b) phosphonate 21, N,N,N′,N′-tetramethylguanidine, r.t., 89%;
(c) H2 (500 psi), {Rh[(cod)-(S,S)-Et-DuPHOS]OTf} (1.5 mol%),
EtOAc, 50 °C, 85%; (d) AcCl, MeOH, 0 °C to r.t.; (e) CbzCl, Et3N,
CH2Cl2, 0 °C to r.t., 75% (2 steps); (f) LiOH, H2O, 0 °C to r.t.; (g)
MeNHOMe·HCl, EDCI·HCl, HOBt, Et3N, 0 °C to r.t., 80% (2 steps);
(h) DIBAL-H, –78 °C; (i) HC(OMe)3, TsOH, MeOH, r.t.; (j) 10%
Pd/C, MeOH, 62% (3 steps).
(S)-Methyl 2,2-Dimethyl-3-[(4-nitrophenyl)sulfonyl]oxazoli-
dine-4-carboxylate (26)
To a mixture of L-serine methyl ester (25; 15.3 g, 98.3 mmol) and
Et3N (34.3 mL, 246 mmol, 2.50 equiv) in CH2Cl2 (300 mL) was
added p-nitrobenzenesulfonyl chloride (24.0 g, 108 mmol, 1.10
equiv) portionwise at 0 °C. The reaction mixture was allowed to
warm to r.t. and stirred for 16.5 h. The mixture was diluted with
EtOAc (300 mL) and poured into ice-cooled sat. aq NaHCO3
© Georg Thieme Verlag Stuttgart · New York
Synthesis 2012, 44, 2743–2753

2746
T. Imai et al.
PAPER
OMe
OMe
OMe
OMe
OMe
OMe
OMe
HO
HO
H
CH3
H
BnO
H
HO BnO
H
O
O
O
+
a
b,c
d
N
N
H2N
H
N
Ns
H
H
H
Ns
Ns
H2N
HN
H
PGN
H
PGN
H
CHO
H
H
NOESY:
MeO
MeO
28
OMe
MeO
MeO
27
18
29
(PG = ClCH2CH2OCO)
30
(PG = ClCH2CH2OCO)
Scheme 6 Reagents and conditions: (a) HCO2H, Na2SO4, CH2Cl2, 83%; (b) BnBr, K2CO3, acetone, 99%; (c) 2-chloroethyl chloroformate, pyr-
idine, CH2Cl2, 0 °C to r.t., 90%; (d) 2-mercaptoethanol, DBU, MeCN, 0 °C to r.t., 84%.
OMe
OMe
OMe
HO BnO
H
O
O
BnO
H
O
O
N
BnO
H
c
a
b
H2N
H
N
H
H
H
BnO
HO
Br
CO2Ph
PGN
PGN
H
PGN
H
31
H
O
MeO
OMe
MeO
OMe
MeO
OMe
O
30
(PG = ClCH2CH2OCO)
32
33
34
OMe
OMe
OMe
OMe
OMe
O
O
BnO
H
TBSO BnO
HO TBSO BnO
MeO2C
H
H
d–f
g
BnO
HO
BnO
TfO
BnO
TfO
N
H
N
H
N
H
H
H
H
H
H
H
PGN
H
PGN
H
PGN
O
O
O
O
H
O
O
MeO
MeO
MeO
OMe
OMe
35
36
37
OMe
OMe
BnO
BnO
BnO
H
H
H
H
H
N
H
N
h
i
j–l
BnO
BnO
BnO
TBSO
O
N
PG
TBSO
O
N
PG
TBSO
O
N
Troc
N
O
H
H
H
TfO
O
O
O
O
O
38
39
(PG = ClCH2CH2OCO)
7
Scheme 7 Reagents and conditions: (a) phenyl bromoacetate (31), i-Pr2NEt, MeCN, 0 °C to r.t., 90%; (b) NBS, Et3N, CH2Cl2, 0 °C to r.t., 89%;
(c) phenol 34, TFA, CH2Cl2, 0 °C, 81%; (d) Tf2O, pyridine, CH2Cl2, 0 °C, 80%; (e) Et3N, MeOH; (f) TBSCl, imidazole, DMF, 0 °C to r.t., 90%
(2 steps); (g) NaBH4, LiCl, THF–EtOH, 89%; (h) BF3·OEt2, CH2Cl2, 0 °C, 73%; (i) MeZnCl, [PdCl2(dppf)], THF, reflux, 76%; (j) NaI, DMF,
110 °C, 96%; (k) Zn, AcOH, THF, r.t.; (l) TrocCl, pyridine, CH2Cl2, 44% (2 steps).
(100 mL). The resulting mixture was extracted with EtOAc (3 × 20
mL), and the combined organic phase was sequentially washed with
brine (50 mL), 1 M aq HCl (50 mL), brine (50 mL), sat. aq NaHCO3
(50 mL), and brine (50 mL). The organic layer was dried over
Na2SO4 and concentrated under reduced pressure. The resulting sol-
id was washed with ice-cooled EtOAc (5 mL) to afford a p-nitro-
benzenesulfonamide.
13C NMR (100 MHz, CD3OD): δ = 171.2, 151.1, 147.9, 129.3,
124.9, 63.9, 59.5, 52.6.
HRMS (ESI): m/z [M – H]+ calcd for C10H11N2O7S: 303.0287;
found: 303.0295.
To a solution of the above p-nitrobenzenesulfonamide (1.11 g, 3.65
mmol) in benzene (15 mL) were added 2,2-dimethoxypropane (2.3
mL, 19 mmol, 5.0 equiv) and p-TsOH·H2O (36 mg, 0.19 mmol, 5.0
mol%). The reaction mixture was heated to reflux for 2.5 h. After
cooling, the mixture was diluted with EtOAc (15 mL), and
quenched with sat. aq NaHCO3 (15 mL). The organic layer was sep-
arated, and the aqueous phase was extracted with EtOAc (3 × 10
mL). The combined organic phase was washed with brine (10 mL),
dried over Na2SO4, and concentrated under reduced pressure. The
crude product was purified by flash column chromatography
(EtOAc–n-hexane, 33%) to afford 26.
Yield: 27.4 g (90.0 mmol, 92%); white solid; mp 160–162 °C
(dec.); [α]D25 –2.5 (c 0.59, MeOH).
IR (neat film): 2361, 2341, 1743, 1606, 1529, 1440, 1350, 1311,
1222, 1167, 1126, 1093, 854, 769, 738 cm–1.
1H NMR (400 MHz, CD3OD): δ = 8.36 (d, J = 8.7 Hz, 2 H), 8.07 (d,
J = 8.7 Hz, 2 H), 4.08 (dd, J = 5.0 Hz, 1 H), 3.77 (dd, J = 11.0,
5.0 Hz, 1 H), 3.68 (dd, J = 11.0, 5.0 Hz, 1 H), 3.48 (s, 3 H).
Synthesis 2012, 44, 2743–2753
© Georg Thieme Verlag Stuttgart · New York

PAPER
Synthetic Studies toward Ecteinascidin 743
2747
25
Yield: 1.23 g (3.57 mmol, 98%); orange solid; mp 75–77 °C; [α]D
–51 (c 0.56, CHCl3).
separated, and the aqueous phase was extracted with EtOAc (3 × 30
mL). The combined organic phase was washed with brine (30 mL),
dried over Na2SO4, and concentrated under reduced pressure. The
crude product was purified by flash column chromatography
(EtOAc–n-hexane, 10→30%) to afford 22.
IR (neat film): 2361, 2341, 1755, 1531, 1352, 1309, 1259, 1205,
1165, 1101, 1035, 856, 771, 738 cm–1.
1H NMR (400 MHz, CDCl3): δ = 8.35 (d, J = 9.0 Hz, 2 H), 8.09 (d,
J = 9.0 Hz, 2 H), 4.52 (dd, J = 6.8, 2.7 Hz, 1 H), 4.21 (dd, J = 9.6,
6.8 Hz, 1 H), 4.12 (dd, J = 9.6, 2.7 Hz, 1 H), 3.64 (s, 3 H), 1.70 (s,
3 H), 1.62 (s, 3 H).
Yield: 6.69 g (15.6 mmol, 89%); yellow solid; mp 95–97 °C.
IR (neat film): 3315, 3065, 2978, 2949, 2361, 2339, 1718, 1639,
1579, 1494, 1454, 1435, 1367, 1334, 1292, 1251, 1159, 1132, 1089,
1051, 1028, 1006, 912, 844, 773, 736, 698 cm–1.
1H NMR (400 MHz, CDCl3): δ = 7.30–7.46 (m, 4 H), 7.18 (br, 1 H),
7.09 and 7.10 (s, 1 H), 6.99 and 7.00 (s, 1 H), 6.11 (br, 1 H), 5.08 (s,
2 H), 3.85 (s, 3 H), 3.83 (s, 3 H), 2.25 (s, 3 H), 1.42 (br, 9 H).
13C NMR (100 MHz, CDCl3): δ = 165.9, 152.7, 151.2, 148.6, 136.6,
131.8, 130.7, 129.1, 128.4, 127.8, 127.1, 125.5, 123.2, 113.1, 80.8,
70.6, 60.2, 52.5, 28.2, 16.1.
13C NMR (100 MHz, CDCl3): δ = 169.9, 149.8, 146.1, 128.7, 123.9,
99.3, 67.2, 60.2, 52.8, 27.3, 26.1.
HRMS (ESI): m/z [M + H]+ calcd for C13H17N2O7S: 345.0756;
found: 345.0760.
(S)-2,2-Dimethyl-3-[(4-nitrophenyl)sulfonyl]oxazolidine-4-
carbaldehyde (27)
To a stirred solution of 26 (1.23 g, 3.57 mmol) in toluene (40 mL)
was added DIBAL-H (0.99 M in toluene, 5.5 mL, 5.5 mmol, 1.5
equiv) dropwise over 55 min at –78 °C under argon. After stirring
at –78 °C for 35 min, MeOH (4 mL) and 30% aq Rochelle’s salt
(10 mL) were added to the mixture. The mixture was then diluted
with EtOAc (10 mL), and stirred at r.t. for 1 h. The organic layer
was separated, and the aqueous phase was extracted with EtOAc
(3 × 5 mL). The combined organic phase was washed with brine (5
mL), dried over Na2SO4, and concentrated under reduced pressure.
The crude product was purified by flash column chromatography
(EtOAc–n-hexane, 33%) to afford 27.
HRMS (ESI): m/z [M + Na]+ calcd for C24H29NO6Na: 450.1893;
found: 450.1890.
(S)-Methyl 3-[3-(Benzyloxy)-4-methoxy-5-methylphenyl]-2-
[(tert-butoxycarbonyl)amino]propanoate (23)
A degassed solution of 22 (13.7 g, 31.9 mmol) and {Rh[(cod)-(S,S)-
Et-DuPHOS]OTf} (346 mg, 0.479 mmol, 1.50 mol%) in EtOAc
(130 mL) was placed in a high-pressure Parr reactor, which was
sealed under hydrogen (500 psi). After stirring at 50 °C for 3 d, the
solution was concentrated under reduced pressure, and the residue
was purified by flash column chromatography (EtOAc–CH2Cl2,
5%) to afford 23. The enantiomeric excess of the product was deter-
mined after conversion of the Boc group into a Cbz group.
22
Yield: 1.16 g (3.69 mmol, quant); orange solid; mp 77–78 °C; [α]D
–85 (c 0.21, CHCl3).
25
IR (neat film): 3107, 2989, 2939, 2866, 2363, 1736, 1606, 1531,
1479, 1402, 1352, 1311, 1228, 1209, 1165, 1099, 1035, 1010, 920,
856, 831, 738, 686 cm–1.
1H NMR (400 MHz, CDCl3): δ = 9.59 (d, J = 2.7 Hz, 1 H), 8.39
(ddd, J = 8.5, 2.4, 2.4 Hz, 2 H), 8.06 (ddd, J = 8.5, 2.4, 2.4 Hz, 2 H),
4.13–4.18 (m, 2 H), 4.05–4.09 (m, 1 H), 1.74 (s, 3 H), 1.55 (s, 3 H).
13C NMR (100 MHz, CDCl3): δ = 197.2, 150.0, 145.5, 128.6, 124.3,
99.3, 65.6, 64.4, 28.5, 25.1.
GC-MS (SCI): m/z = 315 [M + H]+.
Yield: 12.5 g (29.1 mmol, 91%); pale-yellow foam; [α]D 27 (c
0.31, CHCl3).
IR (neat film): 3362, 2976, 2930, 2361, 2341, 1745, 1714, 1589,
1498, 1437, 1390, 1365, 1284, 1230, 1167, 1076, 1012, 844, 738,
698 cm–1.
1H NMR (400 MHz, CDCl3): δ = 7.30–7.45 (m, 5 H), 6.57 and 6.57
(s, 1 H), 6.54 (s, 1 H), 5.06 (s, 2 H), 4.95 and 5.04 (d, J = 7.3 Hz,
1 H), 4.51–4.56 (m, 1 H), 3.81 and 3.82 (s, 3 H), 3.67 (s, 3 H), 2.91–
3.02 (m, 2 H), 2.23 and 2.24 (s, 3 H), 1.43 (br, 9 H).
13C NMR (100 MHz, CDCl3): δ = 172.1, 154.8, 151.4, 146.6, 136.9,
131.8, 131.1, 128.4, 127.7, 127.1, 124.0, 112.8, 79.9, 70.7, 60.2,
54.4, 52.2, 38.0, 28.4, 16.0.
3-(Benzyloxy)-4-methoxy-5-methylbenzaldehyde (20)
To a solution of 19 (3.24 g, 19.5 mmol) in acetone (50 mL) were
added benzyl bromide (12 mL, 100 mmol, 5.0 equiv) and K2CO3
(13.5 g, 97.7 mmol, 5.00 equiv) at r.t., and the mixture was stirred
at r.t. for 2 h. The reaction mixture was filtered through a pad of
Celite, and the filtrate was concentrated under reduced pressure.
The crude product was purified by flash column chromatography
(EtOAc–n-hexane, 10→30%) to afford 20.
HRMS (ESI): m/z [M + Na]+ calcd for C24H31NO6Na: 452.2049;
found: 452.2058.
(S)-Benzyl {3-[3-(Benzyloxy)-4-methoxy-5-methylphenyl]-1-
[methoxy(methyl)amino]-1-oxopropan-2-yl}carbamate (24)
To a solution of 23 (12.5 g, 29.1 mmol) in a mixture of MeOH (25
mL) and CH2Cl2 (12 mL) at 0 °C, was added a solution of ice-
cooled HCl in MeOH [prepared by mixing AcCl (21.0 mL, 295
mmol, 10.0 equiv) with MeOH (29 mL) at 0 °C], and the mixture
was allowed to warm to r.t. After stirring for 1.5 h, the reaction mix-
ture was concentrated under reduced pressure. To a solution of the
crude product in CH2Cl2 (25 mL) were added CbzCl (8.3 mL, 58
mmol, 2.0 equiv) and a solution of Et3N (12.2 mL, 87.9 mmol, 3.00
equiv) in CH2Cl2 (10 mL) at 0 °C, and the mixture was allowed to
warm to r.t. and stirred for 1 h. To the mixture was added Et3N (5.0
mL, 36 mmol, 1.2 equiv) and the mixture was stirred for an addi-
tional 2 h. The reaction mixture was diluted with EtOAc (35 mL),
and quenched with sat. aq NaHCO3 (30 mL). The organic layer was
separated, and the aqueous phase was extracted with EtOAc (3 × 10
mL). The combined organic phase was washed with brine (10 mL),
dried over Na2SO4, and concentrated under reduced pressure. The
crude product was purified by flash column chromatography
(EtOAc–n-hexane, 30%) to afford a Cbz-protected amino ester.
Yield: 4.51 g (17.6 mmol, 90%); colorless oil.
IR (neat film): 2935, 2829, 2735, 2361, 2341, 1689, 1583, 1489,
1437, 1381, 1329, 1294, 1234, 1138, 1086, 1003, 854, 736, 696,
669 cm–1.
1H NMR (400 MHz, CDCl3): δ = 9.83 (s, 1 H), 7.32–7.47 (m, 7 H),
5.15 (s, 2 H), 3.92 (s, 3 H), 2.33 (s, 3 H).
13C NMR (100 MHz, CDCl3): δ = 191.0, 153.0, 151.9, 136.2, 132.4,
131.7, 128.4, 127.9, 127.2, 127.1, 110.4, 70.7, 60.4, 16.1.
HRMS (ESI): m/z [M + H]+ calcd for C16H17O3: 257.1178; found:
257.1176.
(Z)-Methyl 3-[3-(Benzyloxy)-4-methoxy-5-methylphenyl]-2-
[(tert-butoxycarbonyl)amino]acrylate (22)
To a mixture of 20 (4.51 g, 17.6 mmol) and phosphonate 21 (8.0 g,
27 mmol, 1.5 equiv) in CH2Cl2 (100 mL) was added N,N,N′,N′-tet-
ramethylguanidine (3.3 mL, 26 mmol, 1.5 equiv) at r.t., and the
mixture was stirred at r.t. for 2 d. The reaction mixture was
quenched with 15% aq citric acid (30 mL). The organic layer was
25
Yield: 10.1 g (21.8 mmol, 75% over 2 steps); colorless oil; [α]D
34.2 (c 1.82, CHCl3); 95% ee {determined by HPLC (DAICEL-
© Georg Thieme Verlag Stuttgart · New York
Synthesis 2012, 44, 2743–2753

2748
T. Imai et al.
PAPER
CHIRALCEL-OD-H; hexane–i-PrOH, 90:10; flow rate 1.0
mL/min) tR = 23.3 (S), 28.5 (R) min}.
and concentrated under reduced pressure, then used without further
purification.
IR (neat film): 3342, 3032, 2951, 2361, 2339, 1722, 1589, 1498,
1439, 1377, 1346, 1282, 1215, 1149, 1060, 1010, 910, 842, 738,
696, 667 cm–1.
1H NMR (400 MHz, CDCl3): δ = 7.24–7.41 (m, 10 H), 6.54 (s, 1 H),
6.51 (s, 1 H), 5.05–5.20 (m, 3 H), 5.01 (s, 2 H), 4.60 (dd, J = 13.9,
5.9 Hz, 1 H), 3.80 (s, 3 H), 3.66 (s, 3 H), 2.97–3.00 (m, 2 H), 2.21
(s, 3 H).
13C NMR (100 MHz, CDCl3): δ = 171.7, 155.4, 151.4, 146.7, 136.8,
136.0, 131.9, 130.7, 128.3, 128.0, 127.9, 127.6, 127.0, 126.7, 123.9,
112.7, 70.6, 66.9, 60.1, 54.8, 52.2, 37.9, 16.0.
To a mixture of the crude product and trimethyl orthoformate (75.0
mL, 685 mmol, 39.1 equiv) in MeOH (220 mL) was added
TsOH·H2O (332 mg, 1.75 mmol, 10.0 mol%), and the resulting
mixture was stirred at r.t. for 1.5 h. To the reaction mixture was add-
ed NaH (100 mg, 2.50 mmol, 0.14 equiv) and the mixture was con-
centrated under reduced pressure. The crude product was purified
by flash column chromatography (MeOH–CHCl3, 1%) to afford a
dimethyl acetal.
25
Yield: 9.60 g; white solid; mp 100–101 °C; [α]D –25 (c 0.81,
CHCl3).
IR (neat film): 3317, 3065, 3036, 2932, 2829, 2361, 1689, 1589,
1548, 1498, 1442, 1385, 1340, 1286, 1265, 1230, 1186, 1149, 1130,
1072, 1008, 964, 912, 852, 773, 734, 696 cm–1.
1H NMR (400 MHz, CDCl3): δ = 7.27–7.44 (m, 10 H), 6.65 (s, 1 H),
6.61 (s, 1 H), 4.93–5.11 (m, 5 H), 4.13 (d, J = 3.2 Hz, 1 H), 3.99–
4.06 (m, 1 H), 3.81 (s, 3 H), 3.38 (s, 3 H), 3.35 (s, 3 H), 2.79 (dd,
J = 13.9, 6.3 Hz, 1 H), 2.70 (dd, J = 13.9, 7.6 Hz, 1 H), 2.23 (s,
3 H).
13C NMR (100 MHz, CDCl3): δ = 155.8, 151.3, 146.1, 137.0, 136.3,
132.9, 131.7, 128.3, 127.8, 127.7, 127.6, 127.0, 123.9, 112.7, 104.4,
70.5, 66.6, 60.2, 55.7, 55.7, 53.4, 35.9, 16.0.
HRMS (ESI): m/z [M + Na]+ calcd for C28H33NO6Na: 502.2206;
found: 502.2208.
HRMS (ESI): m/z [M + H]+ calcd for C27H30NO6: 464.2073; found:
464.2076.
To a solution of the above Cbz-protected amino ester (10.1 g, 21.8
mmol) in a mixture of MeOH (50 mL), H2O (12.5 mL), and THF
(12.5 mL) was added LiOH (1.90 g, 45.3 mmol, 2.00 equiv) at 0 °C.
The mixture was allowed to warm to r.t. and stirred for 55 min. The
reaction mixture was diluted with toluene (100 mL) and concentrat-
ed under reduced pressure. To the residue was added 10% aq citric
acid (30 mL), and the resulting suspension was extracted with EtO-
Ac (3 × 20 mL). The organic layer was washed with brine (20 mL),
dried over Na2SO4, and concentrated under reduced pressure to give
a carboxylic acid. To a mixture of the crude carboxylic acid and
N,O-dimethylhydroxylamine hydrochloride (3.20 g, 32.8 mmol,
1.50 equiv) in CH2Cl2 (100 mL) were added WSCD·HCl (5.80 g,
32.6 mmol, 1.50 equiv), HOBt (5.00 g, 32.7 mmol, 1.50 equiv) and
Et3N (9.2 mL, 66 mmol, 3.0 equiv) at 0 °C. The mixture was al-
lowed to warm to r.t. and stirred for 24 h. The reaction mixture was
diluted with EtOAc (100 mL), and washed with brine. The aqueous
phase was extracted three times with EtOAc (3 × 20 mL). The com-
bined organic phase was washed with brine (20 mL), dried over
Na2SO4, and concentrated under reduced pressure. The crude prod-
uct was purified by flash column chromatography (EtOAc–n-hex-
ane, 40%) to afford 24.
A mixture of the above dimethyl acetal (9.60 g, 37.5 mmol) and
10% Pd/C [10.0 g, AD-type (wet), 50% water; purchased from
Kawaken Fine Chemicals Co.] in MeOH (120 mL) was stirred un-
der 1 atm of hydrogen at r.t. for 2 d. The reaction mixture was fil-
tered through a pad of Celite, and the filtrate was concentrated under
reduced pressure. The crude product was purified by flash column
chromatography (MeOH–CHCl3, 10%) to afford 18.
Yield: 3.37 g (13.2 mmol, 62% over 3 steps); yellow oil; [α]D21 –23
(c 0.99, CHCl3).
25
Yield: 8.60 g (17.5 mmol, 80% over 2 steps); colorless oil; [α]D
IR (neat film): 3360, 3292, 2935, 2833, 1589, 1494, 1446, 1315,
1278, 1232, 1190, 1140, 1066, 1008, 970, 842 cm–1.
9.9 (c 1.5, CHCl3).
1H NMR (400 MHz, CDCl3): δ = 6.64 (d, J = 1.9 Hz, 1 H), 6.53 (d,
J = 1.9 Hz, 1 H), 4.14 (d, J = 5.8 Hz, 1 H), 3.77 (s, 3 H), 3.45 (s,
3 H), 3.44 (s, 3 H), 3.10 (ddd, J = 9.5, 3.9, 1.7 Hz, 1 H), 2.85 (dd,
J = 13.4, 3.9 Hz, 1 H), 2.39 (dd, J = 13.4, 9.5 Hz, 1 H), 2.25 (s,
3 H).
13C NMR (100 MHz, CDCl3): δ = 148.9, 144.0, 134.5, 130.8, 122.8,
114.2, 107.2, 60.3, 55.2, 55.0, 54.0, 37.7, 16.0.
IR (neat film): 3304, 3063, 3034, 2937, 2827, 2363, 2249, 1720,
1658, 1589, 1529, 1496, 1454, 1388, 1323, 1282, 1253, 1232, 1180,
1149, 1089, 1053, 1028, 1010, 910, 846, 773, 736, 698 cm–1.
1H NMR (400 MHz, CDCl3): δ = 7.23–7.42 (m, 10 H), 6.59 (s, 1 H),
6.56 (s, 1 H), 5.40 (br, 1 H), 5.02–5.11 (m, 4 H), 4.94 (br, 1 H), 3.79
(s, 3 H), 3.62 (s, 3 H), 3.13 and 3.39 (s, 3 H), 2.94 (br, 1 H), 2.80 (br,
1 H), 2.21 (s, 3 H).
13C NMR (100 MHz, CDCl3): δ = 171.9, 155.9, 151.6, 146.8, 137.2,
136.3, 132.0, 131.6, 128.6, 128.2, 128.0, 127.9, 127.3, 124.2, 113.1,
70.7, 66.9, 61.6, 60.3, 52.0, 38.3, 32.1, 16.0.
HRMS (ESI): m/z [M + H]+ calcd for C28H33N2O6: 493.2339; found:
493.2328.
HRMS (ESI): m/z [M + H]+ calcd for C13H22NO4: 256.1549; found:
256.1547.
(1R,3S)-3-(Dimethoxymethyl)-1-{(R)-2,2-dimethyl-3-[(4-nitro-
phenyl)sulfonyl]oxazolidin-4-yl}-7-methoxy-6-methyl-1,2,3,4-
tetrahydroisoquinolin-8-ol (28)
To a mixture of dried Na2SO4 (10.1 g), amine 18 (1.02 g, 4.00
mmol) and aldehyde 27 (1.39 g, 4.42 mmol, 1.10 equiv) in CH2Cl2
(30 mL) at 0 °C, was added HCO2H (0.76 mL, 20.1 mmol, 5.00
equiv), and the reaction mixture was allowed to warm to r.t. and
stirred for 24 h. The reaction mixture was diluted with EtOAc
(30 mL), and quenched with sat. aq NaHCO3 (30 mL). The organic
layer was separated, and the aqueous phase was extracted with
EtOAc (3 × 10 mL). The combined organic phase was washed with
brine (10 mL), dried over Na2SO4, and concentrated under reduced
pressure. The crude product was dissolved in a minimum amount of
EtOAc, and hexane was added to induce precipitation. The precipi-
tates were collected by filtration to afford 28.
(S)-5-(2-Amino-3,3-dimethoxypropyl)-2-methoxy-3-methyl-
phenol (18)
To a stirred solution of 24 (8.60 g, 17.5 mmol) in toluene (120 mL)
was added DIBAL-H (0.99 M in toluene, 27.0 mL, 26.7 mmol, 1.50
equiv) dropwise over 1 h at –78 °C under argon. To the mixture was
added additional DIBAL-H (0.99 M in toluene, 6.0 mL, 5.9 mmol,
0.3 equiv) dropwise over 15 min at –78 °C. After stirring at –78 °C
for an additional 15 min, MeOH (25 mL) and 30% aq Rochelle’s
salt (60 mL) were added to the mixture. The mixture was then dilut-
ed with EtOAc (30 mL), and stirred at r.t. for 1 h. The organic layer
was separated, and the aqueous phase was extracted with EtOAc
(3 × 10 mL). The combined organic phase was washed with sat. aq
NaCl (20 mL), dried over Na2SO4, and concentrated under reduced
pressure. The crude product was filtered through a pad of silica gel
23
Yield: 1.83 g (3.32 mmol, 83%); yellow solid; mp 96–98 °C; [α]D
–105 (c 0.63, CHCl3).
Synthesis 2012, 44, 2743–2753
© Georg Thieme Verlag Stuttgart · New York

PAPER
Synthetic Studies toward Ecteinascidin 743
2749
IR (neat film): 3458, 3107, 2988, 2941, 2893, 2835, 1668, 1606,
1581, 1531, 1500, 1458, 1417, 1350, 1309, 1290, 1232, 1203, 1165,
1147, 1084, 1064, 1032, 999, 958, 910, 856, 831, 736, 688 cm–1.
1H NMR (400 MHz, CDCl3): δ = 8.39 (ddd, J = 9.0, 2.2, 2.2 Hz,
2 H), 8.23 (ddd, J = 9.0, 2.2, 2.2 Hz, 2 H), 6.48 (s, 1 H), 6.02 (s,
1 H), 4.93 (br, 1 H), 4.72 (ddd, J = 7.3, 6.1, 2.9 Hz, 1 H), 4.26 (d,
J = 7.3 Hz, 1 H), 3.85 (dd, J = 8.5, 6.1 Hz, 1 H), 3.77 (s, 3 H), 3.53
(dd, J = 8.5, 7.3 Hz, 1 H), 3.44 (s, 3 H), 3.41 (s, 3 H), 2.95–3.00 (m,
1 H), 2.66 (dd, J = 15.1, 2.2 Hz, 1 H), 2.51 (dd, J = 15.1, 10.9 Hz,
1 H), 2.40 (br, 1 H), 2.25 (s, 3 H), 1.75 (s, 3 H), 1.53 (s, 3 H).
1H NMR (400 MHz, CDCl3): δ = 8.21 (d, J = 8.3 Hz, 2 H), 7.86 (d,
J = 8.3 Hz, 2 H), 7.56–7.62 (m, 2 H), 7.32–7.41 (m, 3 H), 6.76 (s,
1 H), 5.86–5.97 (m, 1 H), 5.14–5.22 (m, 1 H), 4.80–4.82 (m, 2 H),
4.56–4.59 (m, 2 H), 4.24 (br, 1 H), 4.08 (br, 2 H), 3.89–3.92 (m,
3 H), 3.64–3.70 (m, 2 H), 3.62 (s, 3 H), 3.52 (s, 3 H), 3.10–3.16 (m,
1 H), 2.95 (br, 1 H), 2.27 (s, 3 H), 1.61 (s, 3 H), 1.43 (br, 1 H), 1.23
(s, 3 H).
13C NMR (100 MHz, CDCl3): δ = 156.0, 155.3, 149.8, 149.4, 148.6,
147.7, 137.2, 136.8, 131.6, 130.5, 129.5, 128.6, 128.3, 128.1, 127.8,
124.9, 123.7, 105.7, 104.7, 99.2, 75.9, 75.6, 66.6, 65.7, 61.3, 60.5,
57.5, 57.4, 55.5, 54.9, 52.1, 42.7, 41.9, 29.4, 29.0, 24.9, 24.8, 16.0.
13C NMR (100 MHz, CDCl3): δ = 149.6, 145.6, 145.1, 143.1, 132.5,
128.9, 128.5, 123.9, 122.7, 118.6, 107.0, 99.3, 65.4, 60.9, 60.4,
54.0, 53.7, 52.7, 52.6, 32.4, 28.4, 25.4, 15.8.
HRMS (ESI): m/z [M – H]+ calcd for C35H41ClN3O11S: 746.2150;
found: 746.2156.
HRMS (ESI): m/z [M + H]+ calcd for C25H34N3O9S: 552.2016;
found: 552.2015.
(1R,3S)-2-Chloroethyl 1-[(R)-1-Amino-2-hydroxyethyl]-8-(ben-
zyloxy)-3-(dimethoxymethyl)-7-methoxy-6-methyl-3,4-dihy-
droisoquinoline-2(1H)-carboxylate (30)
(1R,3S)-2-Chloroethyl 8-(Benzyloxy)-3-(dimethoxymethyl)-1-
{(R)-2,2-dimethyl-3-[(4-nitrophenyl)sulfonyl]oxazolidin-4-yl}-
7-methoxy-6-methyl-3,4-dihydroisoquinoline-2(1H)-carboxyl-
ate (29)
To a solution of 29 (805 mg, 1.08 mmol) in MeCN (20 mL) at 0 °C
were added 2-mercaptoethanol (0.12 mL, 1.71 mmol, 1.50 equiv)
and DBU (0.25 mL, 1.7 mmol, 1.5 equiv), and the mixture was al-
lowed to warm to r.t. and stirred for 2 h. The reaction mixture was
diluted with EtOAc (20 mL), and quenched with sat. aq NaHCO3
(10 mL). The organic layer was separated, and the aqueous phase
was extracted with EtOAc (3 × 5 mL). The organic phase was se-
quentially washed with sat. aq NaHCO3 (5 mL) and brine (5 mL).
The organic layer was dried over Na2SO4, and concentrated under
reduced pressure. The crude product was purified by flash column
chromatography (MeOH–CHCl3, 5%) to afford 30.
To a solution of 28 (2.01 g, 3.65 mmol) in acetone (40 mL) at 0 °C,
were added benzyl bromide (0.53 mL, 4.46 mmol, 1.20 equiv) and
K2CO3 (606 mg, 4.38 mmol, 1.20 equiv), and the reaction mixture
was allowed to warm to r.t. and stirred for 24 h. To the mixture were
added benzyl bromide (3.80 mL, 31.9 mmol, 8.60 equiv) and
K2CO3 (4.50 g, 32.6 mmol, 8.90 equiv) at 0 °C, and the reaction
mixture was allowed to warm to r.t. and stirred for an additional
17.5 h. The reaction mixture was filtered through a pad of Celite,
and the filtrate was concentrated under reduced pressure. The crude
product was purified by flash column chromatography (EtOAc–
n-hexane, 0→20%) to afford a benzyl ether.
Yield: 471 mg (0.901 mmol, 83%); pale-yellow foam; [α]D23 13 (c
0.27, CHCl3).
IR (neat film): 2937, 2361, 2341, 1693, 1454, 1408, 1352, 1313,
1238, 1116, 1068, 999, 906, 808 cm–1.
Yield: 2.32 g (3.62 mmol, 99%); pale-yellow foam; [α]D23 –115 (c
0.57, CHCl3).
1H NMR (400 MHz, CDCl3): δ = 7.50–7.54 (m, 2 H), 7.31–7.42 (m,
3 H), 6.82 (s, 1 H), 5.46 and 5.56 (d, J = 10.7 Hz, 1 H), 5.14 and
5.24 (d, J = 10.7 Hz, 1 H), 4.80–4.87 (m, 2 H), 4.36–4.41 and 4.53–
4.58 (m, 1 H), 4.16–4.19 and 4.23–4.29 (m, 1 H), 3.92–3.99 (m,
1 H), 3.81 and 3.84 (s, 3 H), 3.59–3.79 (m, 4 H), 3.57 (s, 3 H), 3.51
and 3.53 (s, 3 H), 3.10 (dd, J = 15.3, 12.2 Hz, 1 H), 2.98–3.00 (m,
1 H), 2.80–2.89 (m, 1 H), 2.28 (s, 3 H).
13C NMR (100 MHz, CDCl3): δ = 156.5, 149.4, 147.8, 136.7, 131.5,
131.5, 130.0, 128.2, 127.8, 127.7, 127.5, 127.1, 125.4, 125.2, 105.2,
104.5, 74.7, 65.7, 65.3, 63.7, 63.4, 60.1, 57.4, 57.2, 55.7, 54.9, 54.8,
54.6, 53.2, 42.4, 41.9, 24.3, 24.0, 15.7.
IR (neat film): 3364, 3105, 2988, 2937, 2891, 2835, 2363, 1606,
1531, 1483, 1452, 1413, 1350, 1313, 1232, 1201, 1167, 1149, 1084,
1064, 1030, 1001, 964, 910, 856, 833, 738, 688 cm–1.
1H NMR (400 MHz, CDCl3): δ = 7.83 (ddd, J = 9.0, 2.2, 2.2 Hz,
2 H), 7.76 (ddd, J = 9.0, 2.2, 2.2 Hz, 2 H), 7.59–7.61 (m, 2 H),
7.36–7.44 (m, 3 H), 5.18 (d, J = 10.4 Hz, 1 H), 5.08 (br, 1 H), 4.92
(d, J = 10.4 Hz, 1 H), 4.61 (ddd, J = 6.8, 6.8, 3.1,Hz, 1 H), 4.26 (d,
J = 7.1 Hz, 1 H), 3.87 (s, 3 H), 3.72 (dd, J = 8.7, 6.8 Hz, 1 H), 3.47
(s, 3 H), 3.43 (s, 3 H), 3.40 (dd, J = 8.7, 6.8 Hz, 1 H), 3.00–3.05 (m,
1 H), 2.71 (dd, J = 15.3, 2.6 Hz, 1 H), 2.53 (dd, J = 15.3, 10.9 Hz,
1 H), 2.39 (br, 1 H), 2.26 (s, 3 H), 1.69 (s, 3 H), 1.37 (s, 3 H).
13C NMR (100 MHz, CDCl3): δ = 149.6, 149.2, 148.9, 146.0, 137.0,
132.1, 131.0, 128.8, 128.6, 128.5, 128.4, 126.8, 126.2, 123.7, 107.2,
98.7, 75.7, 65.2, 62.4, 60.8, 54.0, 54.0, 53.2, 52.6, 32.6, 28.2, 25.4,
15.8.
HRMS (ESI): m/z [M + H]+ calcd for C26H36ClN2O7: 523.2211;
found: 523.2217.
(1R,3S)-2-Chloroethyl 8-(Benzyloxy)-3-(dimethoxymethyl)-7-
methoxy-6-methyl-1-[(R)-6-oxomorpholin-3-yl]-3,4-dihydro-
isoquinoline-2(1H)-carboxylate (32)
HRMS (ESI): m/z [M + H]+ calcd for C32H40N3O9S: 642.2485;
found: 642.2485.
To a solution of 30 (606 mg, 1.16 mmol) in MeCN (12 mL) was
added a solution of phenyl bromoacetate (31; 277 mg, 1.29 mmol,
1.10 equiv) and DIPEA (0.23 mL, 1.3 mmol, 1.1 equiv) in MeCN
(12 mL) dropwise over 30 min at 0 °C. The mixture was allowed to
warm to r.t. and stirred for 23 h. The solution was concentrated un-
der reduced pressure and the residue was purified by column chro-
matography (neutral silica gel; EtOAc–hexane, 40%) to afford 32.
To a solution of the above benzyl ether (49.3 mg, 0.0768 mmol) in
CH2Cl2 (1.0 mL) at 0 °C were added pyridine (0.07 mL, 0.9 mmol,
10 equiv), and 2-chloroethyl chloroformate (0.08 mL, 0.8 mmol, 10
equiv), and the mixture was allowed to warm to r.t. and stirred for 1
h. The reaction mixture was diluted with EtOAc (5 mL), and
quenched with sat. aq NaHCO3 (5 mL). The organic layer was sep-
arated, and the aqueous phase was extracted with EtOAc (3 × 5
mL). The combined organic phase was washed with sat. aq NaCl (5
mL), dried over Na2SO4, and concentrated under reduced pressure.
The crude product was purified by flash column chromatography
(MeOH–CH2Cl2, 1%) to afford 29.
Yield: 589 g (1.05 mmol, 91%); pale-yellow foam; [α]D25 –17.3 (c
1.18, CHCl3).
IR (neat film): 3348, 2939, 2837, 2363, 1743, 1697, 1585, 1485,
1454, 1406, 1356, 1309, 1236, 1211, 1138, 1113, 1070, 1033, 999,
912, 812, 754, 702 cm–1.
1H NMR (400 MHz, CDCl3): δ = 7.32–7.54 (m, 5 H), 6.82 (s, 1 H),
5.54 and 5.66 (d, J = 10.5 Hz, 1 H), 5.10 and 5.19 (d, J = 10.5 Hz,
1 H), 4.90 and 4.96 (d, J = 10.1 Hz, 1 H), 4.81 and 4.85 (br, 1 H),
4.55 and 4.58 (d, J = 3.6 Hz, 1 H), 4.15–4.53 (m, 3 H), 3.98 (ddd,
J = 12.4, 6.9, 2.3 Hz, 1 H), 3.81 and 3.84 (s, 3 H), 3.52–3.77 (m,
23
Yield: 51.7 mg (0.0691 mmol, 90%); pale-yellow foam; [α]D
–32.7 (c 1.03, CHCl3).
IR (neat film): 3624, 2935, 2361, 2341, 1697, 1604, 1531, 1462,
1404, 1354, 1307, 1238, 1167, 1066, 912, 854, 733 cm–1.
© Georg Thieme Verlag Stuttgart · New York
Synthesis 2012, 44, 2743–2753

2750
T. Imai et al.
PAPER
3 H), 3.56 (s, 3 H), 3.52 and 3.54 (s, 3 H), 3.38–3.46 (m, 2 H), 3.07–
3.16 (m, 1 H), 2.84–2.92 (m, 1 H), 2.26 (s, 3 H).
3.78 and 3.79 (s, 3 H), 3.57 (s, 3 H), 3.49 and 3.52 (s, 3 H), 3.49–
3.75 (m, 3 H), 2.96–3.05 (m, 1 H), 2.81–2.90 (m, 1 H), 2.26 (s,
3 H).
13C NMR (100 MHz, CDCl3): δ = 168.8, 168.7, 155.7, 155.0, 149.4,
149.2, 148.1, 141.9, 141.8, 140.5, 137.0, 136.7, 135.7, 133.6, 132.0,
131.8, 130.4, 130.0, 128.6, 128.3, 128.1, 128.0, 128.0, 127.9, 127.8,
127.7, 126.2, 125.6, 125.5, 110.1, 110.0, 105.2, 104.8, 104.6, 101.5,
75.5, 75.1, 71.9, 70.5, 70.3, 65.6, 65.4, 60.1, 60.0, 57.4, 56.9, 56.8,
55.3, 55.0, 54.9, 54.8, 51.3, 51.1, 50.8, 50.4, 42.5, 41.9, 24.2, 24.0,
15.7.
13C NMR (100 MHz, CDCl3): δ = 169.0, 156.2, 155.4, 149.7, 149.5,
148.3, 137.6, 137.2, 132.6, 132.4, 130.3, 130.2, 128.7, 128.4, 128.2,
127.6, 127.1, 126.4, 125.9, 125.8, 105.6, 104.5, 75.3, 74.8, 73.4,
72.6, 65.9, 65.6, 60.3, 57.6, 57.4, 55.6, 55.1, 53.4, 51.7, 51.4, 47.0,
42.6, 42.l, 24.4, 24.2, 15.9.
HRMS (ESI): m/z [M + H]+ calcd for C28H36ClN2O8: 563.2160;
found: 563.2144.
HRMS (ESI): m/z [M + H]+ calcd for C42H46ClN2O12: 805.2739;
found: 805.2743.
(1R,3S)-2-Chloroethyl 8-(Benzyloxy)-3-(dimethoxymethyl)-7-
methoxy-6-methyl-1-[(R)-6-oxo-3,6-dihydro-2H-1,4-oxazin-3-
yl]-3,4-dihydroisoquinoline-2(1H)-carboxylate (33)
To a solution of 32 (566 mg, 1.01 mmol) in CH2Cl2 (12 mL) were
added Et3N (1.40 mL, 10.0 mmol, 10.0 equiv) and NBS (198 mg,
1.11 mmol, 1.10 equiv) at 0 °C. After stirring for 30 min, the reac-
tion mixture was diluted with EtOAc (12 mL), and quenched with
sat. aq NaHCO3 (10 mL). The organic layer was separated, and the
aqueous phase was extracted with EtOAc (3 × 5 mL). The com-
bined organic phase was washed with sat. aq NaCl (5 mL) , dried
over Na2SO4, and concentrated under reduced pressure. The residue
was purified by column chromatography (neutral silica gel; EtOAc–
hexane, 50%) to afford 33.
(1R,3S)-2-Chloroethyl 8-(Benzyloxy)-1-{(4R,6R)-4-[6-(benzyl-
oxy)-7-{[(trifluoromethyl)sulfonyl]oxy}benzo[d][1,3]dioxol-4-
yl]-9,9,10,10-tetramethyl-3-oxo-2,8-dioxa-5-aza-9-silaundecan-
6-yl}-3-(dimethoxymethyl)-7-methoxy-6-methyl-3,4-dihy-
droisoquinoline-2(1H)-carboxylate (36)
To a solution of 35 (537 mg, 0.667 mmol) in CH2Cl2 (10 mL) at
0 °C were added pyridine (0.08 mL, 1.0 mmol, 1.5 equiv) and Tf2O
(0.17 mL, 1.0 mmol, 1.5 equiv). After stirring for 0.5 h, the reaction
mixture was diluted with EtOAc (10 mL), and quenched with sat. aq
NaHCO3 (10 mL). The organic layer was separated, and the aque-
ous phase was extracted with EtOAc (3 × 5 mL). The combined or-
ganic phase was washed with brine (5 mL), dried over Na2SO4, and
concentrated under reduced pressure. The crude product was puri-
fied by flash column chromatography (EtOAc–hexane, 40%) to af-
ford the corresponding triflate.
Yield: 500 mg (0.891 mmol, 88%); pale-yellow foam; [α]D24 –51 (c
0.54, CHCl3).
IR (neat film): 2939, 2837, 2361, 2341, 1747, 1699, 1630, 1587,
1547, 1485, 1460, 1406, 1354, 1313, 1273, 1236, 1219, 1138, 1114,
1072, 1035, 999, 906, 868, 812, 771, 733, 698 cm–1.
23
Yield: 503 mg (0.537 mmol, 81%); colorless foam; [α]D –13 (c
1H NMR (400 MHz, CDCl3): δ = 7.60 and 7.65 (br, 1 H), 7.29–7.45
(m, 5 H), 6.84 (s, 1 H), 5.66 and 5.78 (d, J = 11.0 Hz, 1 H), 5.11 (s,
1 H), 5.03 and 5.13 (d, J = 11.0 Hz, 1 H), 4.84 and 4.89 (br, 1 H),
4.57–4.60 (m, 1 H), 4.13–4.53 (m, 5 H), 4.04–4.09 (m, 1 H), 3.79
and 3.80 (s, 3 H), 3.58 (s, 3 H), 3.57–3.73 (m, 1 H), 3.53 and 3.55
(s, 3 H), 3.16 and 3.19 (d, J = 12.4 Hz, 1 H), 2.91–2.99 (m, 1 H),
2.28 (s, 3 H).
13C NMR (100 MHz, CDCl3): δ = 156.1, 155.3, 154.6, 152.6, 152.4,
149.7, 149.5, 148.6, 148.3, 138.2, 137.9, 132.6, 132.5, 129.8, 128.5,
127.8, 127.8, 127.0, 126.5, 125.5, 125.4, 74.3, 74.0, 68.9, 68.5,
65.9, 65.5, 60.1, 58.6, 58.4, 57.7, 57.6, 57.3, 57.2, 55.5, 55.0, 51.2,
50.8, 42.6, 42.1, 24.4, 24.1, 16.0.
0.64, CHCl3).
IR (neat film): 3319, 2939, 2837, 2363, 1743, 1699, 1498, 1460,
1425, 1408, 1377, 1358, 1309, 1288, 1211, 1138, 1087, 1001, 956,
912, 831, 734, 698 cm–1.
1H NMR (400 MHz, CDCl3): δ = 7.52 and 7.58 (d, J = 7.1 Hz, 2 H),
7.33–7.43 (m, 8 H), 6.82 (s, 1 H), 5.85–6.08 (m, 3 H), 5.78 and 5.79
(br, 1 H), 4.85–5.18 (m, 4 H), 4.72 (s, 2 H), 4.45–4.69 (m, 3 H),
4.27–4.30 (m, 1 H), 3.99–4.04 (m, 1 H), 3.76 and 3.78 (s, 3 H),
3.68–3.74 (m, 2 H), 3.58 (s, 3 H), 3.50 and 3.52 (s, 3 H), 3.50–3.61
(m, 2 H), 2.97–3.06 (m, 1 H), 2.84–2.92 (m, 1 H), 2.26 (s, 3 H).
13C NMR (100 MHz, CDCl3): δ = 168.2, 168.0, 156.0, 155.2, 149.6,
149.4, 148.3, 146.2, 146.1, 140.6, 140.2, 137.0, 136.7, 135.3, 132.4,
132.2, 132.1, 130.2, 128.9, 128.6, 128.3, 128.2, 128.1, 128.0, 127.3,
126.9, 126.2, 125.9, 125.8, 124.0, 123.0, 122.5, 119.8, 119.0, 118.8,
116.6, 105.5, 105.4, 104.2, 103.0, 75.8, 75.5, 71.7, 70.4, 70.3, 60.2,
57.6, 57.0, 56.9, 55.5, 55.0, 54.8, 54.7, 51.7, 51.5, 50.9, 50.5, 42.7,
42.2, 24.4, 24.2, 15.9.
HRMS (ESI): m/z [M + Na]+ calcd for C28H33ClN2O8Na: 583.1823;
found: 583.1831.
(1R,3S)-2-Chloroethyl 8-(Benzyloxy)-1-{(3R,5R)-5-[6-(benzyl-
oxy)-7-hydroxybenzo[d][1,3]dioxol-4-yl]-6-oxomorpholin-3-
yl}-3-(dimethoxymethyl)-7-methoxy-6-methyl-3,4-dihydroiso-
quinoline-2(1H)-carboxylate (35)
HRMS (ESI): m/z [M + H]+ calcd for C43H45ClF3N2O14S: 937.2232;
To a solution of 33 (483 mg, 0.861 mmol) and phenol 34 (315 mg,
1.29 mmol, 1.50 equiv) in CH2Cl2 (10 mL) was added TFA (1.28
mL, 17.4 mmol, 20.0 equiv) dropwise. After stirring for 25 min, the
mixture was diluted with EtOAc (10 mL), and poured into sat. aq
NaHCO3 (10 mL). The resulting mixture was extracted with EtOAc
(3 × 5 mL). The combined organic phase was washed with brine (5
mL) , dried over Na2SO4, and concentrated under reduced pressure.
The crude product was purified by flash column chromatography
(EtOAc–hexane, 50%) to afford 35.
found: 937.2235.
To a solution of the above triflate (179 mg, 0.191 mmol) in MeOH
(8 mL) was added Et3N (0.06 mL, 0.4 mmol, 2 equiv) at r.t., and the
reaction was stirred for 1 h. The reaction mixture was concentrated
under reduced pressure. To a solution of the residue in DMF (8 mL)
at 0 °C were added TBSCl (44.0 mg, 0.29 mmol, 1.5 equiv) and im-
idazole (19.5 mg, 0.286 mmol, 1.50 equiv), and the mixture was al-
lowed to warm to r.t. and stirred for 1 h. TBSCl (22.0 mg, 0.146
mmol, 0.80 equiv) and imidazole (10.0 mg, 0.147 mmol, 0.80
equiv) were added at r.t. and the mixture was stirred for an addition-
al 1 h. The reaction mixture was diluted with EtOAc (15 mL), and
washed with brine (15 mL). The aqueous phase was extracted with
EtOAc (3 × 5 mL) and the combined organic phase was washed
with 20% aq NaCl (3 × 5 mL), dried over Na2SO4, and concentrated
under reduced pressure. The crude product was purified by flash
column chromatography (EtOAc–n-hexane, 20%) to afford 36.
23
Yield: 564 mg (0.700 mmol, 81%); colorless foam; [α]D –7.2 (c
0.84, CHCl3).
IR (neat film): 3630, 3331, 2939, 2361, 2253, 1743, 1697, 1498,
1458, 1406, 1356, 1309, 1234, 1207, 1113, 1070, 1035, 999, 947,
912, 814, 733, 700.
1H NMR (400 MHz, CDCl3): δ = 7.52 and 7.59 (d, J = 7.1 Hz, 2 H),
7.32–7.41 (m, 8 H), 6.80 and 6.84 (s, 1 H), 5.70–6.02 (m, 3 H), 5.66
(br, 1 H), 5.41 (br, 1 H), 4.91–5.19 (m, 3 H), 4.84 (m, 1 H), 4.70 (s,
2 H), 4.42–4.66 (m, 3 H), 4.23–4.28 (m, 1 H), 3.97–4.02 (m, 1 H),
Yield: 187 mg (0.173 mmol, 91% over 2 steps); colorless foam;
[α]D23 –16 (c 0.42, CHCl3).
Synthesis 2012, 44, 2743–2753
© Georg Thieme Verlag Stuttgart · New York

PAPER
Synthetic Studies toward Ecteinascidin 743
2751
IR (neat film): 2953, 2932, 2856, 2363, 2341, 1741, 1699, 1643,
1496, 1458, 1427, 1406, 1358, 1311, 1271, 1249, 1213, 1138, 1078,
1005, 956, 902, 835, 773, 736, 696 cm–1.
1H NMR (400 MHz, CDCl3): δ = 7.51–7.52 (m, 2 H), 7.29–7.38 (m,
8 H), 6.80 (s, 1 H), 6.42 (s, 1 H), 5.95 (s, 1 H), 5.86 and 5.86 (s,
1 H), 5.60 and 5.75 (d, J = 10.5 Hz, 1 H), 5.11–5.20 (m, 1 H), 5.02
and 5.05 (s, 1 H), 4.84–4.86 (m, 2 H), 4.68 and 4.76 (br, 1 H), 4.18–
4.23 (m, 2 H), 3.94–3.98 (m, 1 H), 3.39–3.79 (m, 6 H), 3.76 (s,
3 H), 3.53 (s, 3 H), 3.42 (s, 3 H), 3.14–3.21 (m, 2 H), 2.78–2.82 (m,
1 H), 2.26 (s, 3 H), 0.84 (s, 9 H), 0.01 (s, 6 H).
13C NMR (100 MHz, CDCl3): δ = 171.2, 155.6, 149.3, 148.0, 146.1,
140.7, 139.3, 137.9, 135.3, 132.4, 131.1, 130.5, 128.0, 127.9, 127.7,
127.2, 126.8, 124.9, 124.6, 121.9, 119.7, 119.0, 118.9, 116.5, 105.9,
104.8, 103.9, 102.5, 73.9, 71.4, 65.1, 65.0, 60.0, 57.4, 57.1, 56.9,
56.7, 55.3, 51.8, 51.3, 41.7, 25.8, 24.0, 18.3, 15.8, –5.4.
phase was extracted with EtOAc (3 × 5 mL). The combined organic
phase was washed with brine (5 mL), dried over Na2SO4, and con-
centrated under reduced pressure. The crude product was purified
by flash column chromatography (EtOAc–n-hexane, 25%) to afford
38.
23
Yield: 85.2 mg (0.0859 mmol, 73%); white foam; [α]D –31 (c
0.43, CHCl3).
IR (neat film): 2953, 2930, 2887, 2856, 2361, 2341, 1707, 1635,
1489, 1452, 1427, 1344, 1325, 1286, 1251, 1215, 1138, 1093, 1020,
906, 835, 773, 736, 698 cm–1.
1H NMR (400 MHz, CDCl3): δ = 7.57 (d, J = 7.1 Hz, 1 H), 7.53 (d,
J = 6.6 Hz, 1 H), 7.26–7.44 (m, 8 H), 6.75 and 6.77 (s, 1 H), 6.55 (s,
1 H), 5.98 (d, J = 1.2 Hz, 1 H), 5.87 and 5.88 (d, J = 1.2 Hz, 1 H),
5.46 and 5.48 (d, J = 2.2 Hz, 1 H), 5.37 and 5.41 (dd, J = 8.1,
4.2 Hz, 1 H), 5.20 and 5.25 (d, J = 10.5 Hz, 1 H), 4.73–4.91 (m,
4 H), 4.22–4.45 (m, 4 H), 4.11 (dd, J = 7.3, 1.0 Hz, 1 H), 3.86 and
3.87 (s, 3 H), 3.60–3.71 (m, 3 H), 3.18–3.26 (m, 2 H), 3.08 and 3.11
(d, J = 8.3 Hz, 1 H), 2.69 (d, J = 17.3 Hz, 1 H), 2.21 and 2.21 (s,
3 H), 0.63 and 0.65 (s, 9 H), –0.28 and –0.25 (s, 3 H), –0.36 and
–0.33 (s, 3 H).
13C NMR (100 MHz, CDCl3): δ = 154.0, 153.4, 149.2, 149.0, 147.7,
147.5, 145.3, 139.4, 139.4, 137.0, 136.9, 135.4, 131.2, 131.0, 129.8,
129.5, 128.2, 128.1, 127.8, 127.8, 127.7, 127.1, 125.2, 125.1, 124.8,
124.4, 123.6, 121.2, 119.7, 116.5, 103.1, 103.1, 102.5, 92.1, 75.3,
75.1, 71.0, 68.1, 68.0, 66.8, 66.7, 65.3, 64.9, 60.1, 60.0, 59.8, 59.6,
47.9, 47.4, 47.1, 46.1, 42.1, 41.8, 30.5, 30.2, 25.4, 17.8, 17.7, 15.7,
–5.9, –5.9, –6.0.
HRMS (ESI): m/z [M + H]+ calcd for C50H63ClF3N2O15SSi:
1083.3359; found: 1083.3356.
(1R,3S)-2-Chloroethyl 8-(Benzyloxy)-1-[(R)-1-({(R)-1-[6-(ben-
zyloxy)-7-{[(trifluoromethyl)sulfonyl]oxy}benzo[d][1,3]dioxol-
4-yl]-2-hydroxyethyl}amino)-2-{(tert-butyldimethylsi-
lyl)oxy}ethyl]-3-(dimethoxymethyl)-7-methoxy-6-methyl-3,4-
dihydroisoquinoline-2(1H)-carboxylate (37)
To a mixture of 36 (245 mg, 0.226 mmol) and LiCl (96.0 mg, 2.26
mmol, 10.0 equiv) in THF (3.75 mL) were added NaBH4 (86.0 mg,
2.27 mmol, 10.0 equiv) and EtOH (7.5 mL) at 0 °C, and the mixture
was allowed to warm to r.t. and stirred for 2 d. The reaction mixture
was diluted with EtOAc (10 mL), and quenched with 1 M aq HCl
(10 mL) at 0 °C, and the mixture was neutralized with sat. aq
NaHCO3 (10 mL). The organic layer was separated, and the aque-
ous phase was extracted with EtOAc (3 × 5 mL). The combined or-
ganic phase was washed with brine (5 mL), dried over Na2SO4, and
concentrated under reduced pressure. The crude product was puri-
fied by flash column chromatography (EtOAc–n-hexane, 30%) to
afford 37.
HRMS (ESI): m/z [M + H]+ calcd for C47H55ClF3N2O12SSi:
991.2886; found: 991.2887.
(3R,5R,6R,12S,12aS)-2-Chloroethyl 7-(benzyloxy)-3-[6-(benzyl-
oxy)-7-methylbenzo[d][1,3]dioxol-4-yl]-5-{[(tert-butyldi-
methylsilyl)oxy]methyl}-8-methoxy-9-methyl-3,5,6,11,12,12a-
hexahydro-2H-6,12-epiminobenzo[e]oxazolo[3,2-a]azocine-13-
carboxylate (39)
23
Yield: 217 mg (0.206 mmol, 91%); colorless foam; [α]D 9.7 (c
To a degassed solution of 38 (76.7 mg, 0.0774 mmol) in THF (3
mL) at 0 °C was added MeZnCl (2.0 M in THF, 0.15 mL, 0.30
mmol, 3.0 equiv), and the mixture was allowed to warm to r.t. To
the mixture was added [PdCl2(dppf)] (6.3 mg, 0.0086 mmol, 10
mol%), and the resulting mixture was heated to reflux. After stirring
for 1 h, [PdCl2(dppf)] (6.0 mg, 0.0082 mmol, 10 mol%) and MeZn-
Cl (2.0 M in THF, 0.60 mL, 1.2 mmol, 12 equiv) were added to the
mixture and heating was continued for an additional 2.5 h. The re-
action mixture was diluted with EtOAc (5 mL) and quenched with
sat. aq NaHCO3 (5 mL). The organic layer was separated, and the
aqueous phase was extracted with EtOAc (3 × 5 mL). The com-
bined organic phase was washed with brine (5 mL), dried over
Na2SO4, and concentrated under reduced pressure. The crude prod-
uct was purified by flash column chromatography (EtOAc–n-hex-
ane, 25%) to afford 39.
0.42, CHCl3).
IR (neat film): 3476, 2932, 2858, 2361, 2341, 1699, 1647, 1498,
1456, 1425, 1406, 1358, 1311, 1286, 1249, 1211, 1138, 1078, 1003,
951, 835, 773, 736, 698 cm–1.
1H NMR (400 MHz, CDCl3): δ = 7.52–7.57 (m, 2 H), 7.28–7.38 (m,
8 H), 6.84 (s, 1 H), 6.29 and 6.32 (br, 1 H), 5.83–5.91 (m, 2 H),
5.09–5.78 (m, 1 H), 4.70–4.95 (m, 4 H), 4.02–4.48 (m, 2 H), 3.83
(br, 3 H), 3.56 (s, 3 H), 3.06–3.77 (m, 12 H), 2.85–2.87 (m, 1 H),
2.28 (s, 3 H), 0.81 (s, 9 H), –0.01 (s, 3 H), –0.08 (br, 3 H).
13C NMR (100 MHz, CDCl3): δ = 149.7, 148.2, 146.3, 140.1, 139.5,
137.9, 137.7, 135.4, 131.2, 129.7, 129.2, 128.5, 128.2, 128.0, 127.6,
127.4, 126.9, 125.6, 121.9, 119.9, 116.7, 106.2, 105.0, 104.4, 104.2,
102.5, 71.7, 65.4, 63.5, 62.0, 61.0, 60.3, 58.8, 57.9, 57.7, 57.4, 57.2,
57.0, 56.0, 55.5, 51.6, 51.3, 42.8, 41.7, 25.9, 24.3, 18.5, 16.0, –5.4,
–5.7.
23
Yield: 50.3 mg (0.0587 mmol, 76%); colorless foam; [α]D –34.3
(c 1.57, CHCl3).
HRMS (ESI): m/z [M + H]+ calcd for C49H63ClF3N2O14SSi:
1055.3410; found: 1055.3413.
IR (neat film): 3065, 3032, 2953, 2930, 2885, 2856, 2361, 2251,
1950, 1707, 1610, 1581, 1485, 1427, 1379, 1342, 1325, 1284, 1257,
1224, 1195, 1114, 1072, 1020, 939, 908, 839, 775, 734, 698, 667
cm–1.
1H NMR (400 MHz, CDCl3): δ = 7.58 (d, J = 6.8 Hz, 1 H), 7.54 (d,
J = 7.1 Hz, 1 H), 7.29–7.48 (m, 8 H), 6.73 and 6.75 (s, 1 H), 6.40
and 6.41 (s, 1 H), 5.85 and 5.86 (s, 1 H), 5.77 and 5.77 (s, 1 H), 5.48
and 5.50 (d, J = 1.7 Hz, 1 H), 5.35 and 5.41 (dd, J = 7.3, 3.4 Hz,
1 H), 5.18 and 5.23 (d, J = 10.7 Hz, 1 H), 4.70–4.90 (m, 4 H), 4.22–
4.45 (m, 5 H), 3.85 and 3.87 (s, 3 H), 3.61–3.75 (m, 3 H), 3.14–3.25
(m, 3 H), 2.69 (d, J = 17.3 Hz, 1 H), 2.21 (s, 3 H), 2.08 (s, 3 H), 0.67
and 0.69 (s, 9 H), –0.24 and –0.27 (s, 3 H), –0.29 and –0.32 (s, 3 H).
(3R,5R,6R,12S,12aS)-2-chloroethyl 7-(benzyloxy)-3-[6-(benzyl-
oxy)-7-{[(trifluoromethyl)sulfonyl]oxy}benzo[d][1,3]dioxol-4-
yl]-5-{[(tert-butyldimethylsilyl)oxy]methyl}-8-methoxy-9-meth-
yl-3,5,6,11,12,12a-hexahydro-2H-6,12-epiminobenzo[e]oxazo-
lo[3,2-a]azocine-13-carboxylate (38)
To a solution of 37 (124 mg, 0.117 mmol) in CH2Cl2 (4 mL) was
added a solution of BF3·OEt2 (0.075 mL, 0.59 mmol, 5.0 equiv) in
CH2Cl2 (1 mL) at 0 °C, and the reaction was stirred for 1 h. To the
reaction mixture was added a solution of BF3·OEt2 (0.075 mL, 0.52
mmol, 5.0 equiv) in CH2Cl2 (1 mL) at 0 °C, and the mixture was
stirred for an additional 55 min. The reaction mixture was diluted
with EtOAc (10 mL), and quenched with sat. aq NaHCO3 (10 mL)
at 0 °C. The organic layer was separated at r.t., and the aqueous
13C NMR (100 MHz, CDCl3): δ = 154.0, 153.4, 151.4, 149.1, 148.9,
147.7, 147.4, 146.1, 137.8, 137.0, 130.9, 130.8, 130.1, 129.8, 128.2,
© Georg Thieme Verlag Stuttgart · New York
Synthesis 2012, 44, 2743–2753

2752
T. Imai et al.
PAPER
128.2, 128.0, 127.9, 127.7, 127.4, 127.1, 126.9, 125.2, 125.1, 125.0,
124.5, 120.5, 107.6, 101.7, 101.6, 100.4, 92.0, 91.9, 75.3, 75.1,
70.2, 68.1, 67.9, 66.6, 66.5, 65.2, 64.9, 60.2, 60.1, 60.1, 60.0, 59.8,
59.7, 48.1, 47.5, 47.1, 46.2, 42.1, 41.8, 30.5, 30.2, 25.5, 17.8, 17.8,
15.7, 8.7, –5.8, –5.8, –5.9, –5.9.
HRMS (ESI): m/z [M + H]+ calcd for C47H58ClN2O9Si: 857.3600;
found: 857.3588.
IR (neat film): 3726, 3626, 3586, 2928, 2883, 2854, 2361, 2341,
1720, 1485, 1427, 1377, 1342, 1323, 1282, 1259, 1222, 1195, 1116,
1072, 1022, 939, 906, 839, 775, 667 cm–1.
1H NMR (400 MHz, CDCl3): δ = 7.58 (d, J = 8.0 Hz, 1 H), 7.50 (d,
J = 6.8 Hz, 1 H), 7.26–7.49 (m, 8 H), 6.77 and 6.73 (s, 1 H), 6.41
and 6.40 (s, 1 H), 5.86 (s, 1 H), 5.77 (s, 1 H), 5.57 and 5.51 (s, 1 H),
5.41 (br, 1 H), 5.21 (dd, J = 10.4, 10.4 Hz, 1 H), 4.93 (dd, J = 7.2,
6.0 Hz, 1 H), 4.69–5.02 (m, 5 H), 4.20–4.35 (m, 3 H), 3.87 and 3.83
(s, 3 H), 3.74 (m, 1 H), 3.14–3.35 (m, 3 H), 2.73 (dd, J = 17.6,
6.0 Hz, 1 H), 2.21 (s, 3 H), 2.09 (s, 3 H), 0.71 and 0.69 (s, 9 H),
–0.21 and –0.26 (s, 3 H), –0.27 and –0.31 (s, 3 H).
13C NMR (100 MHz, CDCl3): δ = 153.1, 153.5, 151.8, 149.5, 149.4,
148.1, 147.6, 146.5, 138.2, 137.4, 137.3, 131.4, 131.2, 130.2, 129.9,
128.6, 128.5, 128.4, 128.3, 128.0, 127.9, 127.7, 127.7, 127.2, 127.2,
125.5, 125.0, 124.4, 120.7, 120.6, 107.9, 101.9, 101.7, 100.7, 100.6,
95.4, 62.1, 62.1, 75.5, 75.2, 75.0, 74.8, 70.3, 68.9, 68.3, 68.1, 66.7,
66.6, 60.5, 60.3, 60.2, 60.1, 60.0, 59.9, 48.5, 48.1, 47.5, 46.7, 30.7,
30.5, 25.6, 17.8, 15.7, 15.7, 8.7, –5.9, –5.9, –6.0, –6.0.
(3R,5R,6R,12S,12aS)-2,2,2-Trichloroethyl 7-(Benzyloxy)-3-[6-
(benzyloxy)-7-methylbenzo[d][1,3]dioxol-4-yl]-5-{[(tert-butyl-
dimethylsilyl)oxy]methyl}-8-methoxy-9-methyl-
3,5,6,11,12,12a-hexahydro-2H-6,12-epiminobenzo[e]oxazo-
lo[3,2-a]azocine-13-carboxylate (7)
To a solution of 39 (8.7 mg, 0.010 mmol) in DMF (1 mL) was added
NaI (30.0 mg, 0.200 mmol, 20.0 equiv) at r.t., and the resulting mix-
ture was heated at 110 °C with stirring for 18 h. The reaction mix-
ture was diluted with EtOAc (5 mL) at r.t., and quenched with H2O
(5 mL). The organic layer was separated, and the aqueous phase
was extracted with EtOAc (3 × 5 mL). The combined organic phase
was washed with 20% aqueous NaCl (3 × 5 mL), dried over
Na2SO4, and concentrated under reduced pressure. The crude prod-
uct was purified by flash column chromatography (EtOAc–n-hex-
ane, 25%) to afford the iodide.
HRMS (ESI): m/z [M + H]+ calcd for C47H56Cl3N2O9Si: 927.2791;
found: 927.2787.
Yield: 9.1 mg (0.0096 mmol, 96%); colorless oil; [α]D23 –32 (c 0.46,
CHCl3).
Acknowledgment
This work was financially supported by Grants-in-Aid for Scientific
Research (20002004, 22590002) from the Japan Society for the
Promotion of Science (JSPS), the Research Foundation for Phar-
maceutical Sciences, the Mochida Memorial Foundation for Medi-
cal and Pharmaceutical Research, and the Uehara Memorial
Foundation.
IR (neat film): 2951, 2928, 2883, 2856, 1707, 1608, 1548, 1485,
1425, 1379, 1342, 1323, 1284, 1259, 1222, 1195, 1111, 1068, 1012,
939, 906, 839, 773, 734, 698 cm–1.
1H NMR (400 MHz, CDCl3): δ = 7.57 (d, J = 6.8 Hz, 1 H), 7.53 (d,
J = 6.9 Hz, 1 H), 7.30–7.44 (m, 8 H), 6.73 and 6.74 (s, 1 H), 6.39
and 6.40 (s, 1 H), 5.85 and 5.86 (s, 1 H), 5.76 and 5.77 (s, 1 H), 5.46
and 5.48 (br, 1 H), 5.35 and 5.41 (dd, J = 7.4, 3.2 Hz, 1 H), 5.18 and
5.26 (d, J = 11.0 Hz, 1 H), 4.70–4.89 (m, 4 H), 4.22–4.44 (m, 5 H),
3.84 and 3.86 (s, 3 H), 3.69–3.74 (m, 1 H), 3.32 and 3.33 (d,
J = 6.8 Hz, 1 H), 3.13–3.27 (m, 4 H), 2.67 (d, J = 17.4 Hz, 1 H),
2.20 (s, 3 H), 2.08 (s, 3 H), 0.67 and 0.70 (s, 9 H), –0.21 and –0.27
(s, 3 H), –0.27 and –0.32 (s, 3 H).
Supporting Information for this article is available online at
http://www.thieme-connect.com/ejournals/toc/synthesis.SnoIufproi
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References
13C NMR (100 MHz, CDCl3): δ = 154.3, 153.7, 151.9, 149.5, 149.3,
148.2, 148.0, 146.5, 138.3, 137.6, 137.5, 137.4, 131.4, 131.2, 130.5,
130.2, 128.7, 128.6, 128.5, 128.2, 128.1, 127.8, 127.3, 125.6, 125.4,
124.9, 120.9, 107.9, 102.0, 101.9, 100.8, 92.3, 75.6, 75.4, 70.5,
68.4, 68.2, 66.9, 66.7, 65.8, 65.5, 60.4, 60.4, 60.2, 60.0, 60.0, 48.3,
47.7, 47.3, 46.4, 30.8, 30.4, 25.7, 25.7, 18.0, 17.9, 15.8, 8.8, 1.7,
–5.7, –5.8.
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To a solution of the above iodide (9.1 mg, 0.00959 mmol) in THF
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Yield: 3.9 mg (0.0042 mmol, 44% over 2 steps); colorless oil; [α]D
–32 (c 0.16, CHCl3).
Synthesis 2012, 44, 2743–2753
© Georg Thieme Verlag Stuttgart · New York

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© Georg Thieme Verlag Stuttgart · New York
Synthesis 2012, 44, 2743–2753