Synthesis of (±)-phthalascidin 650 analogue: New synthetic route to (±)-phthalascidin 622

Article abstract of DOI:10.1016/j.tet.2010.08.053

A synthesis of functionalized phenolic α-amino-alcohol (±)-13 as synthetic precursor of the catechol tetrahydroisoquinoline structure of phthalascidin 650 is disclosed. Starting from 3-methylcatechol 5, eight steps of synthesis give rise to the synthesis of phenolic α-amino-alcohol (±)-13 in 27% overall yield. This synthetic strategy involves the elaboration of fully functionalized aromatic aldehyde 8 and its transformation into a phenolic α-amino-alcohol (±)-13, through a Knoevenagel condensation, simultaneous reduction of nitroketene and ester functions and hydrogenolysis of the benzyl protecting group. The pentacycle (±)-18 was obtained after four additional steps. The Pictet-Spengler cyclisation between the phenolic α-amino-alcohol (±)-13 and N-protected α-amino-aldehyde 4 allowed to obtain (1,3′)-bis- tetrahydroisoquinoline 14 with N-methylated and N-Fmoc removed. The last step was a Swern oxidation for allowing an intramolecular condensation.

Full text of DOI:10.1016/j.tet.2010.08.053

Tetrahedron 66 (2010) 9061e9066
Contents lists available at ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Synthesis of (ꢀ)-phthalascidin 650 analogue: new synthetic route to
(ꢀ)-phthalascidin 622
,
Christian R. Razafindrabe a b, Sylvain Aubry b, Benjamin Bourdon b, Marta Andriantsiferana a,
,
c
,
b,
*
Stéphane Pellet-Rostaing b , Marc Lemaire
*
a Laboratoire de Chimie des Produits Naturels et Biotechnologie (LPNB), Université d’Antananarivo, 17 Cité Mahatazana, Ampandrianomby, 101 Antananarivo, Madagascar
b ICBMS, Institut de Chimie et Biochimie Moléculaires et Supramoléculaires, CNRS, UMR5246, Laboratoire de Catalyse et Synthèse Organique,
43 boulevard du 11 novembre 1918, Villeurbanne F-69622, France
c ICSM, institut de Chimie Séparative de Marcoule, CNRS/CEA/UM2/ENSCM, UMR 5257, Laboratoire de Tri Ionique par des Systèmes Moléculaires auto-assemblés, Bat 426,
route de Marcoule, 30207 Bagnols sur Cèze, France
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 9 July 2010
Received in revised form 17 August 2010
Accepted 20 August 2010
Available online 25 August 2010
A synthesis of functionalized phenolic
a
-amino-alcohol (ꢀ)-13 as synthetic precursor of the catechol
tetrahydroisoquinoline structure of phthalascidin 650 is disclosed. Starting from 3-methylcatechol 5,
eight steps of synthesis give rise to the synthesis of phenolic
-amino-alcohol (ꢀ)-13 in 27% overall yield.
This synthetic strategy involves the elaboration of fully functionalized aromatic aldehyde 8 and its
transformation into a phenolic
a
a
-amino-alcohol (ꢀ)-13, through a Knoevenagel condensation, simulta-
neous reduction of nitroketene and ester functions and hydrogenolysis of the benzyl protecting group.
The pentacycle (ꢀ)-18 was obtained after four additional steps. The PicteteSpengler cyclisation between
the phenolic
a
-amino-alcohol (ꢀ)-13 and N-protected
a
-amino-aldehyde 4 allowed to obtain (1,30)-bis-
tetrahydroisoquinoline 14 with N-methylated and N-Fmoc removed. The last step was a Swern oxidation
for allowing an intramolecular condensation.
Ó 2010 Elsevier Ltd. All rights reserved.
1. Introduction
tumour cancer cells in vitro3 and is approved for the treatment of
soft tissue sarcoma under the brand name of Yondelis. The natural
The interest for the tetrahydroisoquinoline alkaloids is essen-
tially aroused from their natural architectural complexity and their
noteworthy biological properties as antitumour antibiotics.1 The
most active member of this family, Ecteinascidin 743 (1, Et 743) was
isolated from the Caribbean tunicate Ecteinascidia turbinate2 (Fig. 1)
and displayed highly potent cytotoxic activity against a variety of
scarcity and potent medical use of Et 743 have attracted several
groups to embark on its total synthesis.4 With regard to the
structural complexity of Et 743 and its relative unstability in solu-
tion, synthetic phthalascidins analogues were envisaged. Thus, the
synthesis and biological evaluation of Pt 650 2 were first reported
by Corey4b,5 and exhibited similar biological activity to the natural
OMe
OMe
HO
H
Me
HO
H
HO
Me
OAc
O
O
OMe
NH
HO
H
H
Me
O
MeO
Me
Me
Me
N
Me
N
Me
O
OAc
H
H
S
N
O
N
H
MeO
H
N
H
H
O
N
Me
O
CN
OH
NH
N
H
O
O
O
H
OH
O
O
Me
1
2
3
Fig. 1. Ecteinascidin 743 (1), Phthalascidin 650 (2) and Cyanosafracin B (3).
* Corresponding authors. E-mail address: stephane.pellet-rostaing@cea.fr
(S. Pellet-Rostaing).
0040-4020/$ e see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2010.08.053

9062
C.R. Razafindrabe et al. / Tetrahedron 66 (2010) 9061e9066
product. A semi-synthetic route was achieved by Cuevas6 through
fermentation of the bacteria Pseudomonas fluorescens to produce
cyanosafracin B (3),7 an antibiotic of bacterial origin.
In our previous communications, we reported the synthesis of
a functionalized N-protected a-amino-aldehyde bearing a phthali-
midomethyl function constituting the sesamol tetrahy-
droisoquinoline scaffold of phthalascidin 650 by a new synthetic
approach involving a BischlereNapieralski reaction.8 Our ongoing
project concerning the synthesis and biological evaluation of Pt 650
synthetic analogues,9 encouraged us towards the synthesis of the
iminobenzazocine pentacyclic system contained in the Pt 650
starting from 3-methylcatechol 5.
compatible for the stereoselectivity and regioselectivity of the
PicteteSpengler cyclization.4d,10
We started our synthesis with the commercially available 3-
methylcatechol 5 by a regioselective isopropylation of the less hin-
dered hydroxyl group in presence of i-PrBr and K2CO3 in a 2:1
mixture of DMF/acetone to give 6a in 69% yield as previously de-
scribed (Scheme 1).11 The resulting compound 6a was then for-
mylated in the Duff conditions with HMTA in AcOH at 100 ꢁC to give
7a in 85% yield12 and subsequent methylation of the free hydroxyl
group in acetone by Me2SO4 in the presence of K2CO3 took place,
giving the aldehyde 8 in 88% yield. The isopropyl group of 8 was then
cleaved with AlCl3 allowing to 9 in 83% yield and the resultant hy-
droxyl group protected by BnBr in DMF to produce 10 in 94% yield.
An alternative route for the preparation of 10 was also performed
based on the direct regioselective benzylation of 5 with BnBr, fol-
lowed by Duff formylation. Then, O-methylation of the residual
hydroxyl group gave 10 in a global yield of 85% in three steps.
By a Knoevenagel condensation a 1:1 mixture of E/Z nitroketene
11 was obtained in 74% yield.13 The lower yield in comparison to
those obtained for the Knoevenagel condensation with sesamol
derivative8 could be explained by a partial cleavage of the benzyl
protecting group by TiCl4 and confirmed by lowering the TiCl4
stoichiometry. Compound 11 was then reduced with LiAlH4 to af-
Herein, we report an efficient synthesis of a functionalized phenol
a
-amino-alcohol as precursor for the building block of the tetrahy-
droisoquinoline alkaloid (ꢀ)-phthalascidin 650 by PicteteSpengler
condensation with N-protected -amino-aldehyde 4. Then, we could
a
considered after suitable functionalization (nitrogen methylation and
Fmoc deprotection), anintramolecularStreckercyclisationtogiverise
tothe formation ofa (ꢀ)-Pt650 analogue containinga methoxygroup
in place of the classical acetoxy group (Fig. 2). This 16-[(1,3-dihydro-
1,3-dioxo-2H-isoindol-2-yl)methyl]-6,6a,7,13,14,16-hexahydro-8-hy-
droxy-5,9-dimethoxy-4,10,17-trimethyl-7,13-Imino-12H-1,3-dioxolo
[7,8]isoquino[3,2-b]3-benzazocine (phthalascidin 622 18) was al-
ready obtained and evaluated by Corey.5a
ford the corresponding racemic
a
-amino-alcohol 12 in 93% yield.
OMe
O
H
Me
MeO
Me
H
OMe
H
NFmoc
HO
HO
H
Me
O
O
H
Strecker
intramolecular
cyclisation
OMe
OMe
O
H
Pictet-Spengler
Condensation
N
H
Me
Me
Me
N
MeN
H
O
H
H
NH
N
( )-4
H
O
O
O
H
O
+
O
CN
O
N
O
Me
MeO
N
OH
O
O
NH2
OH
( )-13
OMe analogue of
Pt 650
(1,3')-bis-tetrahydroisoquinoline
Fig. 2. Retrosynthetic analysis of Phthalascidin 650.
From 7a
1) Me2SO4, acetone, r.t. (8:88%)
2) AlCl3, CH2Cl2, r.t. (9: 83%)
3) BnBr, DMF, r.t.(10: 94%)
i-PrBr or BnBr, K2CO3,
DMF/acetone (2 : 1),
t.a., 15h
Me
Me
HO
Me
HO
CHO
HMTA, AcOH,
100°C, 96h
HO
OH
5
From 7b
OR
OR
Me2SO4, acetone, r.t. (10: 99%)
6a: R = i-Pr (69%)
6b: R = Bn (90%)
7a: R = i-Pr (85%)
7b: R = Bn (95%)
1) LiAlH4, Et2O, r.t., 4h
TiCl4, THF, -5°C
and
Me
Me
CHO
Me
CO2Et
NO2
OH
(( )-12: 93%)
NH2
MeO
MeO
MeO
O2NCH2CO2Et
et i-Pr2NEt
74%
2) H2 (5 bars), Pd/C,
MeOH/CH2Cl2, 18h, r.t.
(( )-13: 98%)
OH
OBn
10
OBn
(Z)/(E) = 1:1
Scheme 1. Synthesis of phenolic
11
( )-13
a
-amino-alcohol 13.
2. Results and discussion
Finally, hydrogenolysis of the benzyl group of 12 was realized in
presence of Pd/C under 5 bar of H2 in a 1:1 mixture of MeOH/
CH2Cl2, to obtain the corresponding phenol 13 in 98% yield.13 The
At first, we focused on the synthesis of a phenolic
a-amino-al-
cohol synthetic precursor, which could be readily accessible and
synthesis of phenolic a-amino-alcohol 13 has been conducted in six

C.R. Razafindrabe et al. / Tetrahedron 66 (2010) 9061e9066
9063
steps of classical chemical transformation with an overall yield of
57% through a Knoevenagel condensation.
cross peaking correlation with the OH group at 5.75 ppm. COSY ex-
periment allowed us to assign all of the resonance signals to the
corresponding protons and the proposed stereochemistry of 18 was
confirmed by NOESYexperiment, especially for the cis position of H4,
The iminobenzazocine pentacyclic system 18 was finally
obtained in four steps from the preliminary PicteteSpengler con-
densation of the diastereoisomer 4 with the racemic amino-alcohol
13 (Scheme 2). Cyclisation was performed at 80 ꢁC in a 85:15
mixture of toluene/TFA14,15 to give a mixture of (1, 30)-bistétrahy-
droisoquinolines as two regioisomers 14 and 15, respectively, in
33% and 18% yields. Isomers 14 arised from cyclization ortho- to the
3-phenolic group of 13, and 15 from cyclization para- to the same
3-phenolic group. The complete stereochemical assignments of
(1,30)-bistetrahydroisoquinolines was achieved by NMR. Structural
elucidation of 14 and 15 was determined by 2D NMR (HSQC, COSY,
HMBC and NOESY techniques). Moreover, 14 and 15 were obtained
as mixtures of two diastereoisomers. The syn configuration of di-
astereoisomers 14 and 15 was determined on the basis of the
500 MHz NOESY spectrum analysis from a correlation analysis of
the cross-peak protons between H-1 and H-30. After methylation of
the secondary amine of 14 in the Eschweiler Clarke conditions
(HCO2H/HCOH, 2:1.7),16 the cleavage of the N-Fmoc group of 16
occurred by treatment with DBU affording the amine 17 in 67%
yield. Finally, 18 was obtained in 72% yield by an intramolecular
Stecker reaction based on the Swern oxidation of the primary al-
cohol of 17 followed the treatment of the corresponding hemi-
aminal formed in situ with TMSCN.
H3 and H11 as well as the anti position of H21 towards H1 and H13
,
0
which is also in trans with H14 . HSQC experiment allowed us to
attribute all of the primary, secondary and tertiary carbons. Finally,
resonance signals of the quaternary carbons were deduced from the
HMBC experiment.
To conclude, a practical synthesis of fully functionalized phe-
nolic
a
-amino-alcohol (ꢀ)-13, which constitutes the catechol aro-
matic fragment of the tetrahydroisoquinoline of (ꢀ)-Pt 622, has
been synthesized in six steps from 3-methylcatechol 5 with an
overall yield of 57%. Four additional steps involving a PicteteSpen-
gler condensation from the synthetic precursors (ꢀ)-4 and (ꢀ)-13,
Pt 622 18 was finally obtained in an overall yield of 5.6%.
3. Experimental section
3.1. General
Starting materials were obtained from commercial suppliers and
used without further purification. Solvents were distilled prior to use.
Flashchromatographicpurificationwascarriedouton230e400mesh
silica gel 60. NMR spectrawere recorded on DRX 300 and 500 Brücker
MeO
HO
MeO
Me
Me
MeO
Me
OH
OH
NH2
OMe
O
H
H
H
OMe
OMe
Me
H
H
OH
H
3'
HN
Me
Me
H
1
HN
NFmoc
O
+
( )-13
H
H
O
NFmoc
NFmoc
OH
OH
O
O
O
N
Toluene/TFA (85:15)
80°C, 6h
O
O
O
O
N
N
O
O
O
( )-4
HCO2H/HCOH, 70°C
(62%)
( )-14 (33%)
( )-15 (18%)
MeO
HO
MeO
HO
OMe
Me
Me
Me
HO
H
Me
1) Swern
OMe
H
H
OMe
OMe
2) TMSCN,
AcOH, CH2Cl2
r.t., 2h
H
H
H
Me
DBU, DCM
r.t., 30 min.
Me
Me
N
H
MeN
MeN
NH
N
H
H
N
OH
OH
O
H
O
O
Fmoc
O
CN
O
O
(72%)
(67%)
O
O
O
N
N
N
O
O
O
( )-18
( )-16
( )-17
Scheme 2. Synthesis of (ꢀ)-Pt 622 18.
High-resolution EI-MS of (ꢀ)-phtalascidin 622 18 demonstrated
a molecular composition of C35H35O7N4 (MþH)þ by observation of
FTspectrometers. Abbreviationwasusedas:s(singlet),d(doublet),dd
(divided doublet), t (triplet), q (quadruplet), m (multiplet).
the peak at a m/z 623.2510 (
D
ꢂ0.4 mmu). The lack of published
data for 18 frustrated our attempts to identify our sample by simple
comparison of NMR data. Therefore, extensive analyses of spectral
data were necessary to confirm the structure. All protons and car-
bons were assigned by NMR experiments including COSY, HSQC,
HMBC and NOESY techniques (Figs. 3 and 4).
3.1.1. 4-Hydroxy-3-isopropoxy-5-methylbenzaldehyde 7a. A solu-
tion of 6a (5 g, 30.12 mmol) in AcOH (150 mL) and HMTA (10.54 g,
75.3 mmol) was stirred at 100 ꢁC for 96 h. After this period, the
solution was cooled and a saturated solution of NaHCO3 was added.
The aqueous layer was extracted with CH2Cl2 (3ꢃ50 mL). The organic
layer was dried over MgSO4, evaporated and purified by flash col-
umn chromatography (silica gel, cyclohexane) to give 7a in 85% yield
(4.97 g), Rf¼0.3 (cyclohexane/AcOEt¼9:1). 1H NMR (CDCl3, 300 MHz)
More especially, the resonance signal of the residual aromatic
proton H15 was located at 6.41 ppm based on the cross peaking
0
correlationwith H14, H14 and Me16 resonance signals identified from
the COSYand NOESY spectra and located at 2.24 ppm, 2.62 ppm and
3.07 ppm, respectively. From these hypotheses, OMe17 was charac-
terized by a singlet at 3.74 ppm, which was confirmed by a NOESY
d
¼9.77 (s, 1H, CHO), 7.26 (s, 1H, ArH), 7.25 (s, 1H, ArH), 6.32 (s, 1H,
OH), 4.68 (sept,1H, J¼6.0 Hz, CH(CH3)2), 2.31 (s, 3H, CH3),1.38 (d, 6H,
J¼6.0 Hz, CH(CH3)2). 13C NMR (CDCl3, 75 MHz)
¼191.6 (CHO), 151.0
d

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C.R. Razafindrabe et al. / Tetrahedron 66 (2010) 9061e9066
OMe17
OMe17
17
H
21H11
OMe5
HO
H11
Me16
Me16
Me6
H4
3
18
16
19 15
20
H4'
OMe5
H1
H3+H4'
H22
+
H3
NMe
H15
Me6
11
4
1
Me
5
N
13
6
7
14
10
9
H22'
H4
H14
8
H14'
21
H14
N
H3
H14
'
O
H13
H
21 CN
O
H1
H22
'
CDCl3
22
H22
O
N
3' 1'
O
8'
9'
4'
7'
6'
H15
OH
ArHpth
5'
OCH2O
( )-18
8.0
7.5
7.0
6.5
6.0
5.5
5.0
(ppm)
4.5
4.0
3.5
3.0
2.5
2.0
Fig. 3. 1H NMR spectrum of 18 (CDCl3).
Fig. 4. 2D COSY and NOESY spectra of 18 (CDCl3).
(ArC),145.1 (ArC),129.1 (ArCH),128.8 (ArCH),124.5 (ArC), 109.3 (ArC),
72.3 (CH(CH3)2), 22.4 (CH(CH3)2), 15.8 (CH3). ESI-MS: m/z (%)¼194
[M]þ (27), 152 [MꢂC3H6]þ (82), 151 [MꢂC3H7]þ (100). Anal. Calcd for
C11H14O3 C 68.02; H 7.27%, found C 68.07; H 7.37%.
layer was washed with a 1.5 N HCl solution (180 mL) and 1 N NaOH
solution (200 mL). Then, the residue was extracted with Et2O, dried
over MgSO4, evaporated and purified by flash column chromatog-
raphy (silica gel, cyclohexane/AcOEt¼100:2/95:5) to yield 8 as
a pale yellow oil (35.8 g, 88%), Rf¼0.6 (cyclohexane/ACOEt¼9:1). 1H
3.1.2. 3-Isopropoxy-4-methoxy-5-methylbenzaldehyde 8. To a solu-
tion of 7a (38.1 g, 0.196 mmol) was added K2CO3 (81.4 g,
0.589 mmol) in acetone (212 mL) and Me2SO4 (49.5 g, 0.393 mmol)
dropwise. After stirring at room temperature for 4 h, the reaction
mixture was filtered and the solid washed with Et2O. The organic
NMR (CDCl3, 300 MHz)
d
¼9.75 (s, 1H, CHO), 7.20 (s, 1H, ArH), 7.19 (s,
1H, ArH), 4.56 (sept, 1H, J¼6.0 Hz, CH(CH3)2), 3.82 (s, 3H, OCH3),
2.22 (s, 3H, CH3), 1.31 (d, 6H, J¼6.0 Hz, CH (CH3)2). 13C NMR (CDCl3,
75 MHz)
d
¼191.8 (CHO), 154.2 (ArC), 151.5 (ArC), 133.0 (ArCH), 132.3
(ArCH), 127.1 (ArC), 112.1 (ArC), 71.2 (CH(CH3)2), 60.5 (OCH3), 22.4

C.R. Razafindrabe et al. / Tetrahedron 66 (2010) 9061e9066
9065
(CH(CH3)2), 16.4 (CH3). EI-MS: m/z (%)¼208 [M]þ (36), 166
[MꢂC3H6]þ (100), 165 [MꢂC3H7]þ (56), 151 [MꢂCH3ꢂC3H6]þ (30),
123 [MꢂC3H6eCH3eCO]þ (22). Anal. Calcd for C12H16O3 C 69.21; H
7.74%, found C 69.03; H 7.93%.
(ArCO), 137.6 (ArC), 134.3 (ArC), 132.5 (ArC), 128.9 (2C, ArCH), 128.3
(ArCH), 127.7 (2C, ArCH), 124.3 (ArCH), 113.5 (ArCH), 71.1 (CH2), 66.7
(CH2), 60.6 (OCH3), 54.5 (CH), 40.9 (CH2), 16.3 (CH3). ESI-MS: m/z
(%)¼302 [MþH]þ (100), 272 [MþHꢂCH3OH]þ (21), 241
[MþHꢂH3NCHCH2OH]þ (13). HRMS (ESI) calcd for C18H23NO3Na
[MþNa]þ 324.1576, found 324.1577. Anal. Calcd for C18H23NO3: C
71.73, H 7.69, N 4.65%, found C 71.54, H 7.80, N 4.52%.
3.1.3. 3-Hydroxy-4-methoxy-5-methylbenzaldehyde 9. To a stirring
solution of 8 (1 g, 4.81 mmol) in CH2Cl2 (18.4 mL) was added AlCl3
(1.85 g, 13.94 mmol) at room temperature. After stirring for 90 min,
the reaction mixture was hydrolyzed with NH4Cl (50 ml) and the
aqueous layer extracted with CH2Cl2 (3ꢃ50 mL). Then, the organic
layers weres dried with MgSO4, evaporated and purified by flash
column chromatography (silica gel, cyclohexane/AcOEt¼
90:10/80:20) to yield 9 as pale yellow oil (0.666 g, 83%), Rf¼0.4
3.1.6. (ꢀ)-5-(2-Amino-3-hydroxypropyl)-2-methoxy-3-methyl-
phenol 1317. A mixture of 12 (0.16 g, 0.532 mmol) and 10% Pd/C
(64 mg), in 1:1 mixture of MeOH/CH2Cl2 (9 mL), was stirred over-
night at room temperature under 5 bar of H2 atmosphere. After the
catalyst was filtered, washed with MeOH and dried over Na2SO4
and evaporated to give 13 as a colourless oil (110 mg, 98%). 1H NMR
(cyclohexane/AcOEt¼8:2). 1H NMR (300 MHz, CDCl3)
¼9.76 (s, 1H,
d
CHO), 7.25 (d, 1H, J¼2.0 Hz, ArH), 7.20 (m, 1H, J¼2.0 Hz ArH), 6.10 (s,
(MeOD, 500 MHz)
d
¼6.65 (d,1H, J¼1.9 Hz, ArH), 6.6 (d, 1H, J¼1.0 Hz,
1H, OH), 3.80 (s, 3H, OCH3), 2.29 (s, 3H, CH3). 13C NMR (75 MHz,
ArH), 4.93 (s, 4H, NH2, ArCOH, OH), 3.77 (s, 3H, OCH3), 3.71 (m, 1H,
OCHAHB), 3.53 (dd, 1H, J¼11.7, 1.3 Hz, OCHAHB), 3.39 (br, 1H, CH),
2.79 (d, 2H, J¼7.5 Hz, CH2CHN), 2.25 (s, 3H, CH3). 13C NMR (MeOH,
CDCl3)
d
¼192.13 (CHO), 151.29 (ArC), 149.99 (ArC), 133.23 (ArC),
132.11 (ArC), 125.68 (ArCH), 114.31 (ArCH), 61.09 (OCH3), 16.48
(CH3). EI-MS: m/z (%)¼166 [M]þ (100), 151 [MꢂCH3]þ (21), 123
[MꢂCH3CO]þ (60). Anal. Calcd for C9H10O3 C, 65.05; H, 6.07%, found
C, 65.00; H, 6.15%.
125 MHz)
d
¼150.4 (ArCO), 145.5 (ArCO), 132.1 (ArC), 132.0 (ArC),
122.5 (ArH), 115.0 (ArH), 60.9 (OCH2), 59.4 (OCH3), 54.8 (CH), 35.3
(CH2CHN), 15.0 (CH3). ESI-MS: m/z (%)¼212 [MþH]þ (100), 151
[MþHꢂH3NCHCH2OH]þ (40). HRMS (EI) calcd for C11H17O3N [M]þ
211.1208, found 212.1207.
3.1.4. 3-(Benzyloxy)-4-methoxy-5-methylbenzaldehyde 10. To a so-
lution of 9 (600 mg, 3.61 mmol) was added K2CO3 (1.5 g,
10.84 mmol) in DMF (12 mL) and BnBr (680 mg, 3.97 mmol). After
stirring at room temperature for 2 h, the reaction mixture was fil-
tered and the solid washed with Et2O (100 mL). The organic layer
was washed with a 1.5 N HCl solution (20 mL). Then, the residue
was extracted with Et2O (3ꢃ50 mL), dried over MgSO4, evaporated
and purified by flash column chromatography (silica gel, cyclo-
hexane/ethyl acetate¼8:2) to yield 10 as an orange oil (870 mg,
3.1.7. (7S,9R)-(9H-Fluoren-9-yl)methyl 9-((1,3-dioxoisoindolin-2-yl)
methyl)-7-((1R,3S)-8-hydroxy-3-(hydroxymethyl)-7-methoxy-2,6-di-
methyl-1,2,3,4-tetrahydroisoquinolin-1-yl)-5-methoxy-6,7-dihydro-
[1,3] dioxolo[4,5-h]isoquinoline-8(9H)-carboxylate 14. A mixture of
aldehyde 4 (550 mg, 0.873 mmol) and (ꢀ)-5-(2-amino-3-hydrox-
ypropyl)-2-methoxy-3-methylphenol 13 (368 mg, 1.74 mmol) in
7:3 mixture of toluene/TFA (4.7 mL) was stirred overnight at 80 ꢁC.
Then, the reaction mixture was neutralized with a saturated
Na2CO3 aqueous solution (15 mL) at 0 ꢁC and the aqueous layer was
extracted with CH2Cl2 (3ꢃ100 mL). The organic layer was dried over
Na2SO4, evaporated and purified by flash column chromatography
(silica gel, cyclohexane/AcOEt¼90:10/40:60) to yield the
regioisomers 14 and 15, bis-1,30-tetrahydroisoquinolines as
a brown oil 14 (210 mg, 33%), Rf¼0.3, 15 (130 g, 18%), Rf¼0.2 (cy-
94%). 1H NMR (CDCl3, 300 MHz)
d
¼9.75 (s, 1H, CHO), 7.45 (m, 5H,
ArH), 7.33 (m, 2H, ArH), 5.16 (s, 2H, CH2), 3.93 (s, 3H, OCH3), 2.34 (s,
3H, CH3). 13C NMR (CDCl3, 75 MHz)
d
¼191.8 (CHO), 153.7 (ArCO),
152.7 (ArCO), 136.8 (2C, ArC), 133.0 (ArC), 132.4 (ArCH), 129.0
(ArCH), 128.5 (ArCH), 127.8 (ArCH), 127.7 (ArCH), 111.0 (ArCH), 71.1
(CH2), 60.8 (OCH3), 16.5 (CH3). EI-MS: m/z (%)¼256 [M]þ (5), 228
[MꢂCO]þ (4), 165 [MꢂCH2C6H5]þ (3), [C6H5CH2]þ (100). Anal. Calcd
for C16H16O3: C 74.98, H 6.29%, found C 75.45, H 6.36%.
clohexane/AcOEt¼50/50). 1H NMR (CDCl3, 300 MHz)
¼7.80 (m,
d
2H, 2ArH), 7.7 (m, 4H, 4ArH), 7.53 (m, 1H, 1ArH), 7.35 (m, 3H, 3ArH),
7.26 (s, 2H, 2ArH), 6.50 (s, 1H, ArH), 6.35 (m, 1H, CHCH2N), 6.22 (s,
1H, OCHAHBO), 5.96 (m, 1H, CHCHCN), 5.84(s, 1H, OCHAHBO), 5.65
(br s, 2H, OH and NH), 5.56 (s, 1H, ArOH), 5.11 (m,1H, CHCH2O), 4.57
(d, 1H, J¼6.4 Hz, CHCHCN), 4.22 (m, 2H, OCHAHBCH and
OCHAHBCH), 4.04 (m, 2H, CHCH2N), 3.76 (s, 6H, 2OCH3), 3.73 (m, 2H,
OCHAHB and OCHAHB), 3.57 (m, 1H, CH), 3.46 (m, 2H, CH2CHN), 2.54
(m, 1H, CHAHBCHN), 2.26 (s, 3H, CH3), 2.21 (m, 1H, CHAHBCHN), 2.08
(s, 3H, CH3).
3.1.5. 2-Amino-3-(3-(benzyloxy)-4-methoxy-5-methylphenyl)
propan-1-ol 12. To a stirred solution of TiCl4 (2.66 g, 14.04 mmol) in
THF (9 mL) was added dropwise at ꢂ5 ꢁC 10 (0.6 g, 2.34 mmol)
contained in THF (4.1 mL). After stirring at room temperature for
30 min, ethyl nitroacetate (0.685 g, 5.15 mmol) was added at ꢂ5 ꢁC.
Then, the mixture was stirred for an additional time of 30 min and
i-Pr2NEt (2.76 g, 21.09 mmol) was added. The mixture was then
stirred at room temperature stirring for 24 h and H2O (20 mL) was
added. The residue was extracted with CH2Cl2 (3ꢃ50 mL). The or-
ganic layer was washed with brine, dried over MgSO4, evaporated
and purified by flash column chromatography (SiO2, cyclohexane/
AcOEt¼100:0/90:10) to yield a 40:60 mixture of 11 as a yellow oil
(0.64 g, 74%). Nitroesters 11 (0.2 g, 0.539 mmol) was then reduced
with LiAlH4 (0.205 g, 5.39 mmol) in a stirred solution of Et2O
(12 mL), under an atmosphere of argon. After stirring at room
temperature for 4 h, CH2Cl2 (25 mL), H2O (0.2 mL), 2 N NaOH
(0.2 mL) and H2O (0.6 mL) were added at 0 ꢁC until a white solid
appears. The mixture was then filtered and the solid washed with
CH2Cl2 (3ꢃ30 mL), dried over Na2SO4, evaporated to yield 12 as
3.1.8. (7S,9R)-(9H-Fluoren-9-yl)methyl 9-((1,3-dioxoisoindolin-2-yl)
methyl)-7-((1R,3S)-8-hydroxy-3-(hydroxymethyl)-7-methoxy-2,6-di-
methyl-1,2,3,4-tetrahydroisoquinolin-1-yl)-5-methoxy-4-methyl-6,7-
dihydro-[1,3]dioxolo[4,5-h]isoquinoline-8(9H)-carboxylate
16. Compound 14 (110 mg, 0.13 mmol) was dissolved in 8:9 mix-
ture of CH2O/HCO2H (1.7 mL) and stirred under atmosphere of ar-
gon at 70 ꢁC. After 23 h the reaction mixture was made alkaline
with NaHCO3 (100 mL) aqueous solution at 0 ꢁC, extracted with
DCM. The combinated organic layers was dried over Na2SO4, fil-
tered, evaporated and purified by flash column chromatography
(SiO2, cyclohexane/80:20/50:50) to give rise the protected amine
16. Rf¼0.6 (cyclohexane/ACOEt¼5:5). 1H NMR (CDCl3, 300 MHz)
a pale yellow oil (151 mg, 93%). 1H NMR (300 MHz, CDCl3)
d¼7.48
(d, 2H, J¼7.23 Hz, ArH), 7.42 (m, 2H, ArH), 7.35 (m, 1H, J¼7.3 Hz,
ArH), 6.66 (s, 1H, ArH), 6.65 (s, 1H, ArH), 5.14 (s, 2H, CH2), 3.87 (s,
3H, CH3), 3.61 (dd, 1H, J¼10.8, 3.8 Hz, CHAHB), 3.38 (dd, 1H, 10.8,
7.0 Hz, CHAHB), 3.08 (m, 1H, CH), 2.94 (m, 1H, OH), 2.7 (dd, 1H,
J¼13.6, 5.1 Hz, CHCHD), 2.43 (m, 1H, CHAHB), 2.29 (s, 3H, CH3), 2.26
d
¼7.80 (m, 4H, 4ArH), 7.70 (m, 2H, 2ArH), 7.58 (m, 1H, ArH), 7.49 (m,
2H, ArH), 7.41 (m, 2H, ArH), 7.26 (s, 1H, ArH), 6.55 (s, 1H, ArH), 6.06
(m, 1H, CHCH2N), 5.66 (s, 1H, OCHAHBO), 5.46 (s, 3H, NCH3), 4.90 (s,
1H, OCHAHBO), 4.70 (br s,1H, ArOH), 4.65 (br s,1H, OH), 4.45 (m,1H,
CHCHCN), 4.42 (m, 1H, CHCH2O), 4.19 (m, 1H, OCHAHBCH), 4.13 (m,
(br s, 21H, NH2). 13C NMR (125 MHz, CDCl3)
d¼152.0 (ArCO), 147.0

9066
C.R. Razafindrabe et al. / Tetrahedron 66 (2010) 9061e9066
1H, OCHAHBCH), 4.08 (d, 1H, J¼6.4 Hz, CHCHCN), 3.98 (m, 2H,
CHCH2N), 3.82 (s, 3H, OCH3), 3.57 (s, 3H, OCH3), 3.45 (m, 2H,
OCHAHB and OCHAHB), 3.23 (m, 1H, CH), 2.90 (m, 1H, CHAHBN), 2.60
(m, 1H, CHAHBCHN), 2.35 (m, 1H, CHCHDCHN), 2.27 (s, 3H, CH3), 2.17
(m, 1H, CHCHDCHN), 2.01 (s, 3H, CH3). 13C NMR (75 MHz, CDCl3)
OCHAHBO), 5.04 (s, 1H, OCHAHBO), 4.23 (s, 1H, H12), 4.19(d, 1H,
J¼8.2 Hz, H1), 4.11 (s, 1H, H11), 3.74 (s, 3H, OMe17), 3.71 (s, 3H,
0
OMe5), 3.60 (m, 2H, H22 and H22 ), 3.36 (d, 1H, J¼7.5 Hz, H13), 3.21
0
0
(m, 2H, H3 and H4 ), 3.07 (dd, 1H, J¼7.6, 18.1 Hz, H14 ), 2.62 (d, 1H,
J¼19.9 Hz, H14), 2.31 (s, 3H, NMe), 2.24 (s, 3H, Me16) 2.08 (s, 3H,
d
167.6 (NCO), 157.2 (NCO), 150.4 (ArC), 150.0 (ArC), 146.8 (ArC),
Me6), 1.84 (m, 1H, H4). 13C NMR (125 MHz, CDCl3)
d 168.4 (2 NCO),
144.7 (ArC), 143.6 (ArC), 141.4 (ArC), 141.2 (ArC), 139.3 (ArC), 137.6
(ArC), 133.9 (ArCH), 132.4 (ArCH), 131.8 (ArCH), 131.3 (ArC), 130.5
(ArC), 130.0 (ArCH), 128.2 (2ArCH), 128.1 (2ArCH), 127.8 (ArC), 127.7
(ArCH), 127.2 (ArC), 125.5 (ArC), 123.2 (ArCH), 120.3 (ArC), 120.0
(ArCH), 119.9 (ArCH), 114.2 (ArCH), 113.1 (ArC), 112.8 (ArC), 100.9
(OCH2O), 69.0 (CH), 63.8 (OCH2), 63.7 (CH2), 61.1 (OCH3), 59.9
(NCH3, OCH3), 47.8 (2CH), 47.1 (CH), 39.8 (CH2), 31.8 (CH2), 26.8
(CH2), 15.8 (CH3), 9.0 (CH3). ESI-MS: m/z (%)¼838 [MþH]þ (100),
837 [Mþ2H]þ (51).
150.4(ArCOMe1), 146.9 (ArCOH), 144.5 (ArCO), 142.9 (ArCOMe2),
139.8 (ArCO), 134.1 (2ArCH), 132.3 (2ArC), 131.3 (ArC), 128.9 (ArC),
123.5 (2ArCH), 121.3 (ArC), 121.2 (ArCH), 118.7 (CN), 116.9 (ArC),
113.9 (ArC) 112.6 (ArC), 101.2 (OCH2O), 61.4 (OMe), 61.1 (OMe), 61.0
(CH), 58.1 (CH), 57.0 (CH2), 55.9 (CH3), 55.6 (CH), 42.9 (CH2), 42.2
(NMe), 26.5 (CH2), 25.9 (CH2), 16.4 (Me), 9.7 (Me). ESI-MS: m/z (%)¼
623 [MþH]þ (100), 624 [Mþ2H]þ (33). HRMS (EI) calcd for
C35H35O7N4 [M]þ 623.2506, found. 623.2510.
Acknowledgements
3.1.9. 2-(((7S,9R)-7-((1R,3S)-8-Hydroxy-3-(hydroxymethyl)-7-me-
thoxy-2,6-dimethyl-1,2,3,4-tetrahydroisoquinolin-1-yl)-5-methoxy-
4-methyl-6,7,8,9-tetrahydro-[1,3]dioxolo[4,5-h]isoquinolin-9-yl)
methyl)isoindoline-1,3-dione 17. To a solution of 16 (210 mg,
The authors wish to thank the ‘AUF Antananarivo, Région
Rhône-Alpes and EGIDE Lyon’ for the grant to C.R.R.’s Ph.D.
0.25 mmol) in DCM (0.84 mL) was added DBU (49 mL) under at-
References and notes
mosphere of argon. After stirring at room temperature for 30 min,
the reaction mixture was dissolved in DCM (20 mL) and washed,
respectively, with water and brine. The organic layer was then dried
over Na2SO4, filtered, evaporated and purified by flash column
chromatography (SiO2, DCM/MeOH 100:00/90:10) to give 17 as
a brown solid (150 mg, 97%), Rf¼0.5 (DCM/MeOH¼90:10). 1H NMR
1. (a) Scott, J.; Williams, R. M. Chem. Rev. 2002, 102, 1669; (b) Siengalewicz, P.;
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G. R.; Shield, L. S. Pure Appl. Chem. 1990, 62, 1277; (b) Wright, A. E.; Forleo, D. A.;
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1996, 118, 9017.
3. Aune, G. J.; Furuta, T.; Pommier, Y. Anti-Cancer Drugs 2002, 13, 545.
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Martinez, E. J.; Corey, E. J. Org. Lett. 2000, 2, 993; (c) Endo, A.; Yanagisawa, A.;
Abe, M.; Tohma, S.; Kan, T.; Fukuyama, T. J. Am. Chem. Soc. 2002, 124, 6552; (d)
Chen, J.; Chen, X.; Bois-Choussy, M.; Zhu, J. J. Am. Chem. Soc. 2006, 128, 87; (e)
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S. J. Angew. Chem., Int. Ed. 2006, 45, 1754.
5. (a) Martinez, E. J.; Owa, T.; Schreiber, S. L.; Corey, E. J. Proc. Natl. Acad. Sci. U.S.A.
1999, 96, 3496; (b) Martinez, E. J.; Corey, E. J.; Owa, T. Chem. Biol. 2001, 8, 1151;
(c) Gonzáles, J. F.; Salazar, L.; de la Cuesta, E.; Avendaño, C. Tetrahedron 2005, 61,
7447; (d) Ortìn, I.; Gonzáles, J. F.; de la Cuesta, E.; Manguan-Garcia, C.; Perona,
R.; Avendaño, C. Bioorg. Med. Chem. 2008, 16, 9065; (e) Ortìn, I.; Gonzáles, J. F.;
de la Cuesta, E.; Perona, R.; Avendaño, C. Tetrahedron 2009, 65, 2201.
6. (a) Cuevas, C.; Pérez, M.; Martín, M. J.; Chicharro, J. L.; Fernández-Rivas, C.;
Flores, M.; Francesch, A.; Gallego, P.; Zarzuelo, M.; de la Calle, F.; García, J.;
Polanco, C.; Rodríguez, I.; Manzanares, I. Org. Lett. 2000, 2, 2545; (b) Menchaca,
R.; Martínez, V.; Rodríguez, A.; Rodríguez, N.; Flores, M.; Gallego, P.; Man-
zanares, I.; Cuevas, C. J. Org. Chem. 2003, 68, 8859.
(CDCl3, 500 MHz)
d
¼7.84 (dd, 1H, J¼5.4, 3.0 Hz, ArH), 7.74 (dd, 1H,
J¼5.5, 3.0 Hz, ArH), 7.70 (dd, 1H, J¼5.4, 3.0 Hz, ArH), 7.68 (dd, 1H,
J¼5.4, 3.1 Hz, ArH), 7.26 (s, 1H, ArH), 6.65 (d, 1H, J¼9.3 Hz,
OCHAHBO), 5.83 (d, 1H, J¼16.6 Hz, OCHAHBO), 5.82 (s, 1H, ArOH),
4.59 (m, 1H, CHCH2N), 4.51 (br s, 1H, OH), 4.4 (m, 1H, CHCHAHBN),
4.0 (br s, 1H, NH), 3.95 (m, 1H, CHCHAHBN), 3.79 (m, 1H, CHAHBOH),
3.71 (m, 1H, CH), 3.57 (s, 1H, CH), 3.55 (s, 3H, OCH3), 3.44 (dd, 1H,
J¼10.9, 2.5 Hz, CHAHBOH), 3.41 (s, 3H, OCH3), 3.15 (m, 1H, CH), 3.07
(dd, J¼16.4, 3.4 Hz, CHAHBCHN), 2.52 (dd, J¼15.3, 4.1 Hz,
CHAHBCHN), 2.46 (s, 3H, NCH3), 2.43 (m,1H, CHAHBCHN), 2.2 (m,1H,
CHAHBCHN), 2.14 (s, 3H, CH3), 2.08 (s, 3H, CH3). 13C NMR (125 MHz,
CDCl3)
d 168.8 (NCO), 168.0 (NCO), 151.0 (ArC), 150.8 (ArC), 145.9
(ArC), 143.6 (ArC), 139.4 (2ArC), 139.3 (ArC), 133.9 (ArCH), 133.5
(ArCH), 131.9 (2ArC), 123.3 (ArCH), 123.1 (ArCH), 120.9 (ArCH), 120.8
(ArC), 120.7 (ArC), 112.2 (ArC), 112.1 (ArC), 101.0 (OCH2O), 64.2 (CH),
63.6 (OCH2), 60.1 (OCH3), 59.9 (NCH3, OCH3), 52.5 (CH), 49.0 (CH),
45.7 (CH), 39.6 (CH2), 31.7 (CH2), 26.6 (CH2), 15.6 (CH3), 8.9 (CH3).
ESI-MS: m/z (%)¼616 [MþH]þ (100), 617 [Mþ2H]þ (35). HRMS (EI)
calcd for C34H38O8N3 [M]þ 616.2659, found 616.2659.
7. Ikeda, Y.; Idemeto, H.; Hirayama, F.; Yamamoto, K.; Iwao, K.; Asao, T.; Munakata,
T. J. Antibiot. 1983, 36, 1279.
8. Aubry, S.; Bourdon, B.; Razafindrabe, R. C.; Pellet-Rostaing, S.; Lemaire, M.
Tetrahedron Lett. 2007, 48, 9163.
3.1.10. Phthalascidin 622 18. DMSO (571 mg, 7.32 mmol) was added
to the stirred solution of (COCl)2 (929 mg, 7.32 mmol) in DCM
(20 mL), at ꢂ60 ꢁC. After stirring for 30 min, the amine 17 (150 mg,
0.244 mL) dissolved in DCM (6 mL) was added at ꢂ60 ꢁC. Then the
reaction mixture was stirred for an additional time of 30 min at
ꢂ60 ꢁC and i-Pr2NEt (1.6 g, 12.19 mmol) was added. The mixture
was stirred for 1 h at room temperature and the TMSCN (474 mg,
4.78 mmol) was added dropwise, kept overnight at room temper-
ature, washed with water (3ꢃ50 mL) and brine, dried over Na2SO4,
filtered, evaporated and purified by flash column chromatography
(SiO2, cyclohexane/AcOEt 100:00/00:100 then MeOH) to yield the
9. (a) Aubry, S.; Pellet-Rostaing, S.; Fenet, R.; Lemaire, M. Tetrahedron Lett. 2006,
47, 1319; (b) Aubry, S.; Pellet-Rostaing, S.; Fenet, R.; Lemaire, M. Bioorg. Med.
Chem. Lett. 2007, 17, 2598.
10. (a) Lane, J. W.; Chen, Y.; Williams, R. M. J. Am. Chem. Soc. 2005, 127, 12684; (b)
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13. (a) Knoevenagel, E. Chem. Ber. 1896, 29, 172; (b) Lehnert, W. Tetrahedron 1972,
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59, 8245.
15. Chang, Y. A.; Sun, T. H.; Chiang, M. Y.; Lu, P. J.; Yi-Ting Huang, Y. T.; Liang, L. C.;
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phenol 18 as
a
brown solid (40 mg, 27%). Rf¼0.3 (DCM/
16. Cundasawmy, N. E.; Maclean, D. B. Can. J. Chem. 1972, 50, 3026.
17. (a) Chen, X.; Chen, J.; Paolis, M.; Zhu, J. J. Org. Chem. 2005, 70, 4397; (b) Chen, R.;
Zhu, D.; Hu, Z.; Chen, X. Tetrahedron: Asymmetry 2010, 21, 39.
MeOH¼86:14). 1H NMR (CDCl3, 500 MHz)
¼7.73 (m, 2H, 2ArH),
d
7.68 (m, 2H, 2ArH), 6.41 (s,1H, ArH15), 5.75 (s,1H, ArOH), 5.54 (s,1H,