Synthesis of (±)-phthalascidin 622

Article abstract of DOI:10.1007/s11426-010-4075-z

A synthesis of functionalized phenolic α-amino-alcohols (±)-8 and (±)-16 as synthetic precursors of the catechol tetrahydroisoquinoline structure of phthalascidin 650 was disclosed. (±)-8 was prepared in 5 steps from the commercially available sesamol. Starting from 3-methyl catechol 5, 8 steps gave rise to the synthesis of phenolic α-amino-alcohol (±)-16 in 27% overall yield. This synthetic strategy involved the elaboration of fully functionalized aromatic aldehyde 13 and its transformation into a phenolic α-amino-alcohol (±)-16, through a Knoevenagel condensation, simultaneous reduction of nitroketene and ester functions, and hydrogenolysis of the benzyl protecting group. The pentacycle (±)-4 was obtained after 4 additional steps. The Pictet-Spengler cyclisation between the phenolic α-amino-alcohol (±)-16 and the N-protected α-amino-aldehyde 4 allowed to obtain (1,3′)-bis- tetrahydroisoquinoline 17 with N-methylated and N-Fmoc removed. The last step was a Swern oxidation allowing the expected intramolecular condensation.

Full text of DOI:10.1007/s11426-010-4075-z

SCIENCE CHINA
Chemistry
September 2010 Vol.53 No.9: 1888–1898
doi: 10.1007/s11426-010-4075-z
• ARTICLES •
Synthesis of (±)-phthalascidin 622
CHRISTIAN R. Razafindrabe1,2, SYLVAIN Aubry2, BENJAMIN Bourdon2,
MARTA Andriantsiferana1, STEPHANE Pellet-Rostaing2,3* & MARC Lemaire2*
1Laboratoire de Chimie des Produits Naturels et Biotechnologie (LPNB), Université d’Antananarivo,
17 Cité Mahatazana-Ampandrianomby, 101 Antananarivo, Madagascar, France
2ICBMS, 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
3ICSM, 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
Received June 20, 2010; accepted July 21, 2010
A synthesis of functionalized phenolic-amino-alcohols (±)-8 and (±)-16 as synthetic precursors of the catechol tetrahydroi-
soquinoline structure of phthalascidin 650 was disclosed. (±)-8 was prepared in 5 steps from the commercially available
sesamol. Starting from 3-methyl catechol 5, 8 steps gave rise to the synthesis of phenolic-amino-alcohol (±)-16 in 27% over-
all yield. This synthetic strategy involved the elaboration of fully functionalized aromatic aldehyde 13 and its transformation
into a phenolic -amino-alcohol (±)-16, through a Knoevenagel condensation, simultaneous reduction of nitroketene and ester
functions, and hydrogenolysis of the benzyl protecting group. The pentacycle (±)-4 was obtained after 4 additional steps. The
Pictet-Spengler cyclisation between the phenolic-amino-alcohol (±)-16 and the N-protected -amino-aldehyde 4 allowed to
obtain (1,3′)-bis-tetrahydroisoquinoline 17 with N-methylated and N-Fmoc removed. The last step was a Swern oxidation al-
lowing the expected intramolecular condensation.
phthalascidin, ecteinascidin, (1,3′)-bis-tetrahydroisoquinoline, Pictet-Spengler, Bishler-Napieralsky
sis [8–12]. With regard to the structural complexity of Et
1 Introduction
743 and its relative unstability in solution, synthetic phtha-
lascidins analogues were envisaged. Thus, the synthesis and
biological evaluation of Pt 650 2 was first reported by
Corey et al. [13–16] and exhibited similar biological activ-
ity to the natural product. A semi-synthetic route was
achieved by Cuevas et al. [17, 18] through fermentation of
the bacteria Pseudomonas fluorescens to produce cyanosa-
fracin B (3) [19], an antibiotic of bacterial origin. However,
since the discovery of Pt 650, several research groups were
involved in the research of potentially more active struc-
tures, bearing a piperazine system [20–35]. The most im-
pressive results were reported by Myers, with the discovery
of a quinaldic acid derivative (QAD, 3), exhibiting excellent
antitumoral activity against a range of cancer cell lines in
vitro [20, 22]. This group also described the synthesis of a
The interest for the tetrahydroisoquinoline alkaloids is es-
sentially aroused from their natural architectural complexity
and their noteworthy biological properties as antitumor an-
tibiotics [1]. The most active member of this family, Ec-
teinascidin 743 (1, Et 743), was isolated from the Caribbean
tunicate Ecteinascidia turbinate [2–6] (Figure 1) and dis-
played highly potent cytotoxic activity against a variety of
tumor cancer cells in vitro [7] and is approved for the teat-
ment of soft tissue sarcoma under the brand name of Yon-
delis. The natural scarcity and potent medical use of Et 743
have attracted several groups to embark on its total synthe-
*Corresponding author (email: stephane.pellet-rostaing@cea.fr; marc.kmaire@univ-lyon.fr)
© Science China Press and Springer-Verlag Berlin Heidelberg 2010
chem.scichina.com
www.springerlink.com

CHRISTIAN R. Razafindrabe, et al. Sci China Chem September (2010) Vol.53 No.9
1889
Figure 1 Ecteinascidin 743 (1), Phthalascidin 650 (2) and Cyanosafracin B (3).
wide range of synthetic analogues using the solid supported
chemistry [20, 21]. Spencer [23], Ong [24], Williams [25,
26], Liu [27, 28], Avendaño [29, 30], Echavarren [31],
Kubo [32, 33] and Griecoer et al. [34] were also involved in
the synthesis and biological evaluation of simpler Et 743
synthetic analogues and obtained promising results.
In our previous communications, our ongoing project
concerning the synthesis and biological evaluation of Pt 650
synthetic analogues [36–38], encouraged us toward the
synthesis of the iminobenzazocine pentacyclic system con-
tained in the Pt 650 starting from 3-methylcatechol 5 and
sesamol 6.
efficiency has already been evaluated by Corey et al. [9].
2 Experimental
Starting materials were obtained from commercial suppliers
and used without further purification. Solvents were distilled
prior to use. Flash chromatographic purification was carried
out on 230–400 mesh silica gel 60. NMR spectra were re-
corded on DRX 300 and 500 Brücker FT spectrometers.
Abbreviation was used as: s (singlet), d (doublet), dd (di-
vided doublet), t (triplet), q (quadruplet), m (multiplet).
Herein, we report an efficient synthesis of the tetrahy-
droisoquinoline alkaloid (±)-phthalascidin 622 4 (Figure 2)
by Pictet-Spengler condensation involving N-protected
-amino-alcohol 12 and aminoalcohol 16. After suitable
modifications (nitrogen methylation and Fmoc deprotection,
Swern oxidation), an intramolecular Strecker cyclisation
from the 1,3′-bistetrahydroisoquinoline 17 could give rise to
the formation of a (±)-Pt 650 analogue containing a meth-
oxy group in place of the classical acetoxy group. As far as
we know, the synthesis of this 16-[(1,3-dihydro-1,3-dioxo-
2H-isoindol-2-yl)methyl]-6,6a,7,13,14,16-hexahydro-8-hyd
roxy-5,9-dimethoxy-4,10,17-trimethyl-7,13-Imino-12H-1,3-
dioxolo[7,8]isoquino[3,2-b][3]benzazocine (phthalascidin 622
(4)) was never described in literature, although its antitumor
5-Methoxybenzo[d][1,3]dioxole-5-carbaldehyde (7) [39]
To a stirring solution of sesamol 5 (25 g, 181 mmol) in ace-
tone (400 mL) under Ar, was added K2CO3 (87.5 g, 633.5
mmol) and MeI dropwise (51.3 g, 362 mmol). The mixture
was then stirred at room temperature for 24 h. The reaction
mixture was filtered off and the solid washed with Et2O (3×
100 mL). The organic layer was washed successively with 1.5
N HCl (50 mL) and 1 N NaOH (50 mL), dried over MgSO4
and evapored. To a solution of 5.32 g of the pure
5-methoxybenzo[d][1,3]dioxole (35.11 mmol) in dry THF
(21 mL), 2.5 M n-BuLi (35 mL, 86 mmol) in hexane was
added at 20 °C. The mixture was stirred for 1 h, and then
MeI (14.8 g, 105.34 mmol) in THF (21 mL) was added
Figure 2 Retrosynthetic analysis of Phthalascidin 622.

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CHRISTIAN R. Razafindrabe, et al. Sci China Chem September (2010) Vol.53 No.9
dropwise. After stirring for an additional time of 1 h, H2O
(100 mL) was added. The mixture was then extracted with
ether (3 × 100 mL). The organic layers were washed with 1
N NaOH (150 mL), dried over MgSO4 and evapored. The
crude residue was purified by flash column chromatography
(silica gel, cyclohexane) to give the 5-methoxybenzo[d][1,3]
dioxole intermediate (5.17 g, 89%). This compound (5 g,
30.1 mL) was dissolved in DMF and added to a solution of
POCl3 (4.2 mL, 45.2 mmol) preliminary added dropwise at
0 °C to a stirred anhydrous DMF (10 mL). The mixture was
stirred at 100 °C for 3 h. Then a saturated NaHCO3 aqueous
solution (100 mL) was added at 0 °C and the aqueous layer
was extracted with CH2Cl2 (3 × 50 mL). The organic layers
were dried over MgSO4 and evaporated. The residue was
recrystallized from n-heptane to give 7 as colourless crystals
(5.78 g, 85%). Mp 95–96 °C; 1H NMR (300 MHz, CDCl3) 
10.19 (s, 1H, CHO), 7.11 (s, 1H, ArH), 6.03 (s, 2H,
OCH2O), 3.84 (s, 3H, OCH3), 2.19 (s, 3H, CH3). 13C NMR
(125 MHz, CDCl3)  188.9, (CHO), 160.4, 153.0, 144.5,
123.5, 103.5 (ArC), 114.0 (ArCH), 102.5 (CH2), 64.6
(OCH3), 9.1 (CH3). ESI-MS: m/z (%) = 194 [M]+ (100), 163
[M−CH3OH]+ (21), 148 [M−OCH3-CH2]+ (54). Anal. calcd
for C10H10O4: C 61.85; 5.19%, found C 62.00; 5.25%.
179 [M–H3NCHCH2OH]+ (68). Anal. calcd for C12H17O4N
C 60.24;H 7.16; 5.85%, found C 60.11; H 6.98; N 5.73%.
(9-((1,3-Dioxoisoindolin-2-yl)methyl)-3-(6-methoxy-4-methyl-
6,7-dihydro-[1,3]dioxolo[4,5-h]isoquinolin-7-yl)methyl-2-(1,3-
dioxoisoindolin-2-yl)acetate (9)
To a stirring solution of 8 (0,58 g, 2.43 mmol) in CH2Cl2
(42 mL) was added Et3N (0.49 g, 4.85 mmol) and phthalyl-
glydyl chloride (1.30 g, 5.82 mmol) at 0 °C. The mixture
was stirred 3 h at room temperature. The solution was then
washed with 1.5 N HCl (10 mL), aqueous Na2CO3 (30 mL),
brine, dried over Na2SO4, evaporated and purified by flash
column chromatography (silica gel, cyclohexane/EtOAc,
94%). To the pure 2-(2-((1,3-dioxoisoindolin-2-yl)acetamido)-
3-(6-methoxy-7-methylbenzo[d][1,3]dioxol-5-yl)propyl-2-
(1,3-dioxoisoindolin-2-yl)acetate (1.30 g, 2.12 mmol) in
CH3CN (2.62 mL) was added dropwise POCl3 (0.975 g,
6.36 mmol) at 0 °C and stirred and heated at 90 °C for 3 h.
The reaction mixture was neutralized with a saturated
Na2CO3 aqueous solution (15 mL) at 0 °C and the aqueous
layer was extracted with CH2Cl2. The organic layer was
dried over Na2SO4, evaporated and purified by flash chro-
matography (silica gel, cyclohexane/AcOEt=50:50 to 0:100)
to yield 9 as a white solid (1.19 g, 95%). Mp 110–112 °C.
1H NMR (500 MHz, CDCl3)  7.92 (m, 2H, J =5.4, 3.0 Hz,
2ArH), 7.89 (m, 2H, J = 5.4, 3.0 Hz, 2ArH), 7.76 (m, 4
ArH), 6.07 (d, 2H, J = 16.2 Hz, OCH2O), 5.13 (dd, 1H, J =
17.6, 2.8 Hz, NCCH2N), 4.78 (d, 1H, J=17.7 Hz, NCCH2N),
4.42 (d, 1H, J = 17.7 Hz, OCOCH2N), 4.35 (d, 1H, J =17.4
Hz, OCOCH2N), 4.29 (m, 1H, J = 10.7, 4.7 Hz, CH2OCO),
4.12 (m, 1H, J = 10.7, 8.0 Hz, CH2OCO), 3.67 (s, 3H, CH3),
3.57 (m, 1H, CHN), 2.93 (d, 1H, J = 15.8 Hz, CH2CHN),
2.28 (m, 1H, CH2CHN), 2.23 (s, 3H, CH3). 13C NMR (125
MHz, CDCl3)  168.9 (CO), 167.7 (NCO), 167.3 (CN),
150.4, 146.2, 141.8, 132.8, 132.4, 121.0, 115.9 (ArC), 134.6,
134.2, 124.0, 123.7 (ArCH), 102.0 (OCH2O), 68.9 (CH2),
61.2 (OCH3), 55.5 (CH), 43.5 (CH2), 39.1 (CH2), 22.7
(CH2), 9.9 (CH3). ESI-MS: m/z (%) = 596 [M + H]+ (100).
HRMS (ESI) calcd for C32H26O9N3 [M + H]+ 596.1669,
found 596.1670.
(±)-2-Amino-3-(6-methoxy-7-methylbenzo[d][4,5]dioxol-5-yl)
propan-1-ol (8) [40]
To a srirring solution of TiCl4 (2.93 g, 15.46 mmol) in THF
(10 mL), 7 (0.5 g, 2.58 mmol) in THF (4.5 mL) was added
dropwise at 5 °C. After stirring at room temperature for 1h,
ethyl nitroacetate (0.595 g, 5.66 mmol) was added at 5 °C.
Then, the mixture was stirred for an additional time of 1 h
and i-Pr2NEt (2.98 g, 23.17 mmol) was added. The mixture
was then stirred at room temperature for 24 h and H2O (20
mL) was added. The residue was extracted with CH2Cl2 (3 ×
50 mL). The organic layer was washed with brine, dried
over MgSO4, evaporated and purified by flash chromatography
(silica gel, cyclohexane/AcOEt) to yield a 50:50 mixture of
(E):(Z) of the corresponding olefine as a yellow oil (0.79 g,
99%). Then, olefin intermediate (0.5 g, 1.618 mmol) was
reduced with LiAlH4 (614.2 mg, 16.18 mmol) in Et2O (30
mL), under Ar. After stirring at room temperature for 4 h,
CH2Cl2 (50 mL), H2O (0.62 mL), 2N NaOH (0.62 mL) and
H2O (1.86 mL) were added at 0 °C until a white solid ap-
peared. The mixture was then filtered and the solid washed
with CH2Cl2, dried over MgSO4, and evaporated to yield 8
(1,3-Dioxo-1,3-dihydro-isoindol-2-yl)acetic acid 9-(1,3-
dioxo-1,3-dihydroisoindol-2-yl-methyl)-5-methoxy-4-methyl-
6,7,8,9-tetrahydro-[1,3]dioxolo[4,5-h]isoquinolin-7-yl-methyl
ester (10)
1
as a pale yellow oil (352 mg, 91%). H NMR (500 MHz,
A mixture of 9 (1 g, 1.68 mmol) and 10% Pd/C (0.358 mg,
0.337 mmol) in MeOH/CH2Cl2 (1:1.5 mL) was stirred for
24 h at room temperature under H2 atmosphere (10 bars).
Then, the residue was filtered through Celite, and dried over
Na2SO4, evaporated and purified by flash chromatography
(silica gel, cyclohexane/AcOEt 7:3) to yield 10 as a colour-
less solid (0.812 g, 81%). Mp 180 °C. 1H NMR (500 MHz,
CDCl3)  7.91 (m, 4H, 4ArH), 7.78 (dd, 2H, J=5.5, 3.0 Hz,
2ArH), 7.75 (dd, 2H, J = 5.5, 3.0 Hz, 2ArH), 5.92 (s, 1H,
CDCl3)  6.47 (s, 1H, ArH), 5.87 (s, 2H, OCH2O), 4.55 (s,
1H, OH), 3.63 (s, 3H, OCH3), 3.49 (dd, 1H, J=11.0, 4.1 Hz,
CH2O), 3.33 (dd, 1H, J = 11.0, 6.0 Hz, CH2O), 2.99 (s, 1H,
CHN), 2.64 (m, 1H, CH2CHN), 2.50 (m, 1H, CH2CHN), 2.7
(br s, 2H, NH2), 2.13 (s, 3H, CH3). 13C NMR (125 MHz,
CDCl3)  151.7, 145.4, 143.1, 123.5, 113.5, 107.0 (ArC),
101.1 (CH2), 66.05 (CH2), 61.01 (OCH3), 53.98 (CH), 34.75
(CH2), 9.47 (CH3). ESI-MS: m/z (%) = 240 [M + H]+ (100),

CHRISTIAN R. Razafindrabe, et al. Sci China Chem September (2010) Vol.53 No.9
1891
OCH2O), 5.88 (s, 1H, OCH2O), 4.60 (m, 1H, CHCH2N),
3-(Benzyloxy)-4-methoxy-5-methylbenzaldehyde (13)
4.52 (s, 1H, OCOCH2N), 4.51 (s, 1H, OCOCH2N), 4.45 (dd,
1H, J=14.0, 4.3 Hz, CHCH2N), 4.23 (m, 2H, CH2OCOCH2),
3.86 (dd, 1H, J = 14.0, 8.9 Hz, CHCH2N), 3.77 (s, 3H,
OCH3), 2.87 (dd, 1H, J = 15.6, 2.8 Hz, CH2CHN), 2.35 (m,
1H, CH2CHN), 2.17 (s, 3H, CH3). 13C NMR (125 MHz,
CDCl3)  169.2 (CO), 167.8, 167.6 (NCO), 151.3, 144.9,
140.0, 132.5, 132.4, 121.4, 115.4, 112.6 (ArC), 134.7, 134.6,
124.0, 123.0 (ArCH), 101.2 (OCH2O), 69.4, 42.7, 39.3, 27.1
(CH2), 60.9 (OCH3), 52.6, 51.7 (CH), 9.5 (CH3). ESI-MS:
m/z (%) = 598 [M + H]+ (100). HRMS (ESI) calcd for
C32H27O9N3 [M + H]+ 598.1826, found 598.1825.
To a solution of 5 (3.8 g, 15.74 mmol) in DMF/acetone 2/1
(50 mL) were added K2CO3 (6.55 g, 47.34 mmol) and BnBr
(3 g, 17.52 mmol). After stirring at room temperature for 2 h,
the reaction mixture was filtered and the solid washed with
Et2O (400 mL). The organic layer was washed with a 1.5 N
HCl solution (100 mL). Then, the residue was extracted
with Et2O (3 × 150 mL), dried over MgSO4, evaporated and
purified by flash column chromatography (silica gel, cyclo-
hexane/ethyl acetate = 8:2) to yield the corresponding
4-hydroxy-3-benzyloxy-5-methylphenol as an orange oil
(5.5 g, 90%). This intermediate (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 (3 × 50 mL). The organic
layers were dried over MgSO4, evaporated and purified by
flash column chromatography (silica gel, cyclohexane) to
give the corresponding 3-(benzyloxy)-4-hydroxy-5-methyl-
benzaldehyde in 90% yield (4.97 g), Rf = 0.3 (cyclohexane/
AcOEt = 9:1. To a solution of pure 3-(benzyloxy)-4-hydroxy-
5-methylbenzaldehyde (38.1 g, 0.196 mmol) in acetone (212
mL) were added K2CO3 (81.4 g, 0.589 mmol) and Me2SO4
(49.5 g, 0.393 mmol). After stirring at room temperature for
4 h, the reaction mixture was filtered and the solid washed
with Et2O. The organic 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 chromatography
(silica gel, cyclohexane/AcOEt = 100:2→95:5) to yield 13
as a pale yellow oil (35.8 g, 88%). Rf = 0.6 (cyclohexane/
(±)-N-Fmoc-(1,3-dioxo-1,3-dihydro-isoindol-2-yl)acetic acid
9-(1,3-dioxo-1,3-dihydroisoindol-2-yl-methyl)-5-methoxy-4-
methyl-6,7,8,9-tetrahydro-[1,3]dioxolo[4,5-h]isoquinolin-7-
yl-carbaldehyde (12)
A 15% by weight solution of Dess-Martin periodinane (670
mg, 0.237 mmol) in CH2Cl2 was added to a solution of the
N-Fmoc -amino-alcohol preliminary obtained from (±)-11
(100 mg, 0.158 mmol) in CH2Cl2 (1 mL) at 0 °C. After stir-
ring for 30 min at room temperature, the mixture was diluted
with Et2O (10 mL), and saturated solutions of Na2S2O3
(5 mL) and NaHCO3 (5 mL) were added. The resulting bi-
phasic mixture was then stirred for 30 min, by which time
both layers had become clear and colourless. After 20 min
under stirring, the mixture was diluted with Et2O (10 mL),
and the organic layer separated, washed successively with
NaHCO3 (10 mL), H2O (10 mL) and brine (10 mL), dried
over Na2SO4, filtered, evaporated and purified by flash
column chromatography (SiO2, cyclohexane/AcOEt = 80/20)
to yield (±)-12 as a white solid (79.7 mg, 80%). Mp 114 °C.
1
ACOEt = 9:1). H NMR (CDCl3, 300 MHz)  9.75 (s, 1H,
1
Rf = 0.6 (cyclohexane/AcOEt = 50/50). H NMR (500 MHz,
CHO), 7.20 (s, 1H, ArH), 7.19 (s, 1H, ArH), 4.56 (sept, 1H,
J = 6.0 Hz, CH(CH3)2), 3.82 (s, 3H, OCH3), 2.22 (s, 3H,
CH3), 1.31 (d, 6H, J = 6.0 Hz, CH (CH3)2). 13C NMR
(CDCl3, 75 MHz)  191.8 (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 (CH(CH3)2), 16.4
(CH3). EI-MS: m/z (%) = 208 [M]+ (36), 166 [M−C3H6]+
(100), 165 [M−C3H7]+ (56), 151 [M−CH3−C3H6]+ (30), 123
DMSO-d6, 80 °C)  9.57 (s, 1H, CHO), 7.84 (s, 6H, 6ArH),
7.60 (br s, 1H, 1ArH), 7.51 (d, 1H, J = 7.6 Hz, 1ArH),
7.41–7.37 (m, 2H, 2ArH), 7.31–7.27 (m, 2H, 2ArH), 5.91 (s,
1H, OCHAHBO), 5.64 (t, 1H, J = 7. 2 Hz, CHCH2N), 5.44 (s,
1H, OCHAHBO), 4.24 (m, 2H, OCHAHBCH and OCHAHBCH),
4.16 (m, 1H, OCH2CH), 4.05 (m, 1H, CHCHO), 3.93 (m,
1H, CHCHAHBN), 3.87 (m, 1H, CHCHAHBN), 3.66 (s, 3H,
OCH3), 3.14 (m, 1H, J = 5.6, 15.4 Hz, CHAHBCHN), 2.86
(dd, 1H, J = 11.7, 15.4 Hz, CHAHBCHN), 2.09 (s, 3H, CH3).
13C NMR (125 MHz, DMSO-d6, 80 °C)  199.5 (CHO),
167.0 (3C, 3NCO), 155.3 (ArCO), 149.9 (ArCO), 144.2
(ArCO), 143.2 (ArC), 140.3 (2ArC), 138.7 (ArC), 134.1
(2ArCH), 131.1 (2ArC), 127.3 (2ArCH), 126.7 (2ArCH),
124.4 (2ArCH), 122.6 (2ArCH), 119.6 (2ArCH), 117.0
(ArC), 112.5 (ArC), 112.1 (ArC), 100.9 (OCH2O), 66.2
(CH2), 60.4 (CH and OCH3), 48.1 (CH), 46.3 (CH), 41.5
(CH2), 20.7 (CH2), 8.5 (CH3). ESI-MS: m/z (%) = 653
[M+Na]+ (33), 631 [M + H]+ (69), 453 [M + H−C13H9CH2]+
(41), 409 [M + H−C13H9CH2−CO2]+ (100), 391 [M + H−
C13H9CH2−CO2−H2O]+ (100). HRMS (ESI) calcd for C37H30
N2NaO8 [M+Na]+ 653.1900, found 653.1901.
[M−C3H6−CH3−CO]+ (22). Anal. calcd for C12H16O3
C
69.21; H 7.74 %, found C 69.03; H 7.93 %.
2-Amino-3-(3-(benzyloxy)-4-methoxy-5-methylphenyl)propan-
1-ol (15)
To a stirring solution of TiCl4 (2.66 g, 14.04 mmol) in THF
(9 mL) was added dropwise at 5 °C 13 (0.6 g, 2.34 mmol)
contained in THF (4.1 mL). After stirring at room tempera-
ture for 30 min, ethyl nitroacetate (0.685 g, 5.15 mmol) was
added at 5°C. Then, the mixture was stirred for an addi-
tional time of 30 min nd 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 (3 × 50 mL). The organic layers

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CHRISTIAN R. Razafindrabe, et al. Sci China Chem September (2010) Vol.53 No.9
were washed with brine, dried over MgSO4, evaporated and
purified by flash column chromatography (SiO2, cyclohexane/
AcOEt = 100:090:10) to yield a 40:60 mixture of 14 as a
yellow oil (0.64 g, 74 %). Nitroesters 14 (0.2 g, 0.539 mmol)
was then reduced with LiAlH4 (0.205 g, 5.39 mmol) in a
stirring 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), 2N 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
(3 × 30 mL). The filtrate was dried over Na2SO4, evaporated
(±)-5-(2-amino-3-hydroxypropyl)-2-methoxy-3-methylphen
ol 16 (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 (3 × 100 mL). The organic layers were dried
over Na2SO4, evaporated and purified by flash column chro-
matography (silica gel, cyclohexane/AcOEt = 90:1040:60)
to yield the regioisomers 17 and 18, bis-1,3′-tetrahydroiso-
quinolines as a brown oil. 17 (210 mg, 33%), Rf = 0.3, 18
1
(130mg, 18%), Rf = 0.2 (cyclohexane/AcOEt = 50/50). H
1
to yield 15 as a pale yellow oil (151 mg, 93%). H NMR
NMR (CDCl3, 300 MHz)  7.80 (m, 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 (s br, 2H, OH and NH), 5.56 (s, 1H,
ArOH), 5.11 (m, 1H, CHCH2O) 4.57 (d, 1H, J = 6.4 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).
(300 MHz, CDCl3)  7.48 (d, 2H, J = 7.23 Hz, ArH), 7.42
(m, 2H, ArH), 7.35 (m, 1H, J = 7.3 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, J = 10.8, 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, J = 13.6, 5.1 Hz, CHCHD), 2.43 (m, 1H,
CHAHB), 2.29 (s, 3H, CH3 ), 2.26 (br s, 21H, NH2). 13C
NMR (125 MHz, CDCl3)  152.0 (ArCO), 147.0 (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 (%) = 302 [M + H]+
(100), 272 [M + H−CH3OH]+ (21), 241 [M + H−
H3NCHCH2OH]+ (13). HRMS (ESI) calcd for C18H23NO3Na
[M+Na]+ 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%.
(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-dimethyl-1,2,3,4-tetrahydroisoquinolin-1-yl)-5-methoxy-
4-methyl-6,7-dihydro-[1,3]dioxolo[4,5-h]isoquinoline-8(9H)-
carboxylate (19)
17 (110 mg, 0.13mmol) was dissolved in 8:9 mixture of
CH2O/HCO2H (1.7 mL) and stirred under atmosphere of
argon at 70 °C. After 23 h the reaction mixture was basified
with NaHCO3 (100 mL) aqueous solution at 0 °C, extracted
with DCM. The combined organic layers were dried over
Na2SO4, filtered, evaporated and purified by flash column
chromatography (SiO2, cyclohexane/80:2050:50) to give
rise the protected amine 19 (95 mg, 62%). Rf = 0.6 (cyclo-
(±)-5-(2-Amino-3-hydroxypropyl)-2-methoxy-3-methylphenol
(16) [41]
A mixture of 15 (0.16 g, 0.532 mmol) and 10% Pd/C (64
mg), in 1:1 mixture of MeOH/CH2Cl2 (9 mL), was stirred
overnight at room temperature under 5 bars of H2 atmosphere.
After the catalyst was filtered and washed with MeOH, the
filtrate was dried over Na2SO4 and evaporated to give 16 as
1
hexane/ACOEt = 5:5). H NMR (CDCl3, 300 MHz)  7.80
1
a colourless oil (110 mg, 98%). H NMR (CD3OD, 500
(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 (s br, 1H, ArOH), 4.65 (s br, 1H, OH), 4.45 (m, 1H,
CHCHCN) 4.42 (m, 1H, CHCH2O), 4.19 (m, 1H,
OCHAHBCH) 4.13 (m, 1H, OCHAHBCH), 4.08 (d, 1H, J =
6.4 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):  167.6 (NCO), 157.2 (NCO),
150.4 (ArC), 150.0 (ArC), 146.8 (ArC), 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),
MHz)  6.65 (d, 1H, J=1.9 Hz, ArH), 6.6 (d, 1H, J=1.0 Hz,
ArH), 4.93 (s, 4H, NH2, ArCOH, OH), 3.77 (s, 3H, OCH3),
3.71 (m, 1H, OCHAHB), 3.53 (dd, 1H, J = 11.7, 1.3 Hz,
OCHAHB), 3.39 (br, 1H, CH), 2.79 (d, 2H, J = 7.5 Hz,
CH2CHN), 2.25 (s, 3H, CH3). 13C NMR (MeOH, 125 MHz)
 150.4 (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 (%) =212
[M + H]+ (100), 151 [M + H−H3NCHCH2OH]+ (40). HRMS
(EI) calcd for C11H17O3N [M]+ 211.1208, found 212.1207.
(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-dimethyl-1,2,3,4-tetrahydroisoquinolin-1-yl)-5-methoxy-6,7-
dihydro-[1,3] dioxolo[4,5-h]isoquinoline-8(9H)-carboxylate (17)
A mixture of aldehyde 12 (550 mg, 0.873 mmol) and

CHRISTIAN R. Razafindrabe, et al. Sci China Chem September (2010) Vol.53 No.9
1893
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 (%)=
838 [M + H]+ (100), 837 [M + 2H]+ (51).
After stirring overnight at room temperature, the reaction
mixture was washed with water (3 × 50 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 phenol 4 as a brown solid
1
(40 mg, 27%). Rf = 0.3 (DCM/MeOH = 86:14). H NMR
(CDCl3 , 500 MHz)  7.73 (m, 2H, 2ArH), 7.68 (m, 2H,
2ArH), 6.41 (s, 1H, ArH15), 5.75 (s, 1H, ArOH), 5.54 (s, 1H,
OCHAHBO), 5.04 (s, 1H, OCHAHBO), 4.23 (s, 1H, H12),
4.19(d, 1H, J = 8.2 Hz, H1), 4.11 (s, 1H, H11), 3.74 (s, 3H,
OMe17), 3,71 (s, 3H, OMe5), 3.60 (m, 2H, H22 and H22′),
3.36 (d, 1H, J = 7.5 Hz, H13), 3.21 (m, 2H, H3 and H4′), 3.07
(dd, 1H, J = 7.6, 18.1 Hz, H14′), 2.62 (d, 1H, J = 19.9 Hz,
H14), 2.31 (s, 3H, NMe), 2.24 (s, 3H, Me16) 2.08 (s, 3H,
Me6), 1.84 (m, 1H, H4). 13C NMR (125 MHz, CDCl3): 
168.4 (2NCO), 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 (%) =623 [M +H]+ (100), 624
[M + 2H]+ (33). HRMS (EI) calcd for C35H35O7N4 [M]+
623.2506, found. 623.2510.
2-(((7S,9R)-7-((1R,3S)-8-Hydroxy-3-(hydroxymethyl)-7-met-
hoxy-2,6-dimethyl-1,2,3,4-tetrahydroisoquinolin-1-yl)-5-met-
hoxy-4-methyl-6,7,8,9-tetrahydro-[1,3]dioxolo[4,5-h]isoqui-
nolin-9-yl)methyl)isoindoline-1,3-dione (20)
To a solution of 19 (210 mg, 0.25 mmol) in DCM (0.84 mL)
was added DBU (49 L) under atmosphere of argon. After
stirring at room temperature for 30 min, the reaction mix-
ture was dissolved in DCM (20 mL) and washed respec-
tively 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 20 as a brown solid (150 mg, 97%). Rf =
1
0.5 (DCM/MeOH = 90:10). H NMR (CDCl3 , 500 MHz) 
7.84 (dd, 1H, J = 5.4, 3.0 Hz, ArH), 7.74 (dd, 1H, J = 5.5,
3.0 Hz, ArH), 7.70 (dd, 1H, J = 5.4, 3.0 Hz, ArH), 7.68 (dd,
1H, J=5.4, 3.1 Hz, ArH), 7.26 (s, 1H, ArH), 6.65 (d, 1H, J=
9.3 Hz, OCHAHBO), 5.83 (d, 1H, J = 16.6 Hz, OCHAHBO),
5.82 (s, 1H, ArOH), 4.59 (m, 1H, CHCH2N), 4.51 (s br, 1H,
OH), 4.4 (m, 1H, CHCHAHBN), 4.0 (s br, 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,
J = 10.9, 2.5 Hz, CHAHBOH), 3.41 (s, 3H, OCH3), 3.15 (m,
1H, CH), 3.07 (dd, J = 16.4, 3.4Hz, CHAHBCHN), 2.52 (dd,
J = 15.3, 4.1Hz, 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): 
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 (%) = 616 [M + H]+ (100),
617 [M + 2H]+ (35). HRMS (EI) calcd for C34H38O8N3 [M]+
616.2659, found 616.2659.
3 Results and discussion
N-protected -amino-alcohol 13 was obtained from the
aminoalcohol 8. Starting from the commercially available
sesamol 6, methylation of the hydroxyl group with MeI in a
suspension of K2CO3 in acetone as a base followed by a
selective ortho-lithiation in THF using n-BuLi at 20 °C,
and methylation with MeI, allowed the formation of the
corresponding methylated intermediate in 86% yield over
two steps. The Vilsmeier-Haack formylation of this derivative
with POCl3 in DMF at 100 °C gave rise to aldehyde 7,
which was purified by recrystallisation in 99% yield [42].
Aldehyde 7 was then engaged in a Knoevenagel condensa-
tion with ethyl nitroacetate in THF, in the presence of TiCl4
and i-Pr2NEt, to afford the corresponding nitroalkene in
99% yield as a 1:1 mixture of E/Z isomers [43–45]. Then,
the simultaneous reduction of the carbon-carbon double
bond, ester and nitro functions was accomplished by LiAlH4
in Et2O in 91% yield, giving the racemic-amino-alcohol 8
used in the next step without further purification. Com-
pound 8 was obtained in 77% overall yield after five syn-
thetic steps, with only two silica gel chromatography puri-
fication.
Phthalascidin 622 (4)
DMSO (571 mg, 7.32 mmol) was added to the stirring solu-
tion of (COCl)2 (929 mg, 7.32 mmol) in DCM (20 mL), at
60 °C. After stirring for 30 min, the amine 20 (150 mg,
0.244 mL) dissolved in DCM (6 mL) was added at 60 °C.
Then the reaction mixture was stirred for an additional time
of 30 min at 60 °C and i-Pr2NEt (1.6 g, 12.19 mmol) was
added. The mixture was stirred for 1h at room temperature
and TMSCN (474 mg, 4.78 mmol) was added dropwise.
Acylation of both alcohol and amine reactive sites of 8 with
phthaloyl glycine chloride [46, 47] in CH2Cl2, in the pres-
ence of NEt3, provided the corresponding diprotected inter-
mediate. The latter was then converted into the corresponding

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CHRISTIAN R. Razafindrabe, et al. Sci China Chem September (2010) Vol.53 No.9
Scheme 1 Synthesis of -amino-alcool 8.
tetrahydroisoquinoline 10 through a Bischler-Napieralski
reaction with POCl3 in DMF which proceeded in 95% yield
[48, 49], followed by a highly diastereoselective hydrogenation
of the dihydroisoquinoline 9. Indeed, reduction of the imine
function by H2 in the presence of 20% Pd/C in a 1:1 mixture
of MeOH/CH2Cl2 proceeded smoothly, to give racemic
-amino-ester cis-10 in 81% yield with a diastereoisomeric
9-fluorenylmethyl pentafluorophenyl carbonate in DMF,
affording the corresponding N-protected -amino-alcohol in
89% yield. Subsequent oxidation of the hydroxyl group of
this derivative in the presence of Dess-Martin periodinane
reagent [50, 51] in CH2Cl2 gave rise to the formation of the
chemically stable aldehyde (±)-12 in 80% yield [38].
Then, we focused on the synthesis of a phenolic -amino-
alcohol synthetic precursor 16 (Scheme 3) which could be
readily accessible and compatible for the stereoselectivity
and regioselectivity of the Pictet-Spengler cyclization [25,
52, 53]. The synthesis of phenolic -amino-alcohol 16 has
been conducted in 6 steps of classical chemical transformations
with an overall yield of 57%. Regioselective benzylation of
the less hindered hydroxyl group of the commercially
available 3-methylcatechol 5, followed by Duff formylation
1
excess of 96%, determined by H NMR of the crude reaction
mixture. The -amino-ester cis-10 was then transesterified
in a 1:1 mixture of MeOH/CH2Cl2 in the presence of Me-
ONa, providing the -amino-alcohol cis-11 in 63% yield.
The cis-configuration of 11 was determined on the basis of
the 500 MHz NOESY spectrum analysis from the correla-
tion analysis of the cross peak protons between H-1 and H-3.
The amino group of (±)-11 was consequently protected with
Scheme 2 Synthesis of N-protected -amino-aldehyde 12.
Scheme 3 Synthesis of phenolic -amino-alcohol 16.

CHRISTIAN R. Razafindrabe, et al. Sci China Chem September (2010) Vol.53 No.9
1895
[54, 55] and O-methylation of the residual hydroxy group
gave 13 in a 85% global yield. Knoevenagel condensation
[43] of 13 with ethyl nitroacetate gave 14 in a 1:1 mixture
of E/Z nitroketene derivative. Compound 14 was then reduced
with LiAlH4 to afford the corresponding racemic -amino-
alcohol 15 in 93% yield. Finally, hydrogenolysis of the
benzyl group of 15 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 16 in 98% yield.
The iminobenzazocine pentacyclic system 21 was finally
obtained in four steps from the preliminary Pictet-Spengler
condensation of the diastereoisomer 12 with the racemic
amino-alcohol 16 (Scheme 4). Cyclisation was performed at
80 °C in a 85:15 mixture of toluene/TFA [56, 57] to give a
mixture of (1, 3′)-bistetrahydroisoquinolines as two regioisom-
ers 17 and 18, respectively in 33% and 18% yields. The
regisomer 17 arised from cyclization otho- to the 3-phenolic
group of 16, and 18 from cyclization para- to the same
3-phenolic group. The complete stereochemical assignments
of (1,3′)-bistetrahydroisoquinolines was achieved by NMR.
Structural elucidation of 17 and 18 was made by 2D NMR
(HSQC, COSY, HMBC and NOESY techniques). Moreover,
17 and 18 were obtained as mixtures of two diastereoisomers.
The cis configuration of diastereoisomers 17 and 18 was
determined on the basis of the 500 MHz NOESY spectrum
analysis from a correlation analysis of the cross-peak pro-
tons between H-1 and H-3′. After methylation of the secon-
dary amine of 17 in the Escweiler Clarke conditions
(HCO2H/HCOH, 2:1.7), the cleavage of the N-Fmoc group
of 19 occurred by treatment with DBU affording the amine
20 in 67% yield. Finally, 4 was obtained in 72% yield by an
intramolecular Stecker reaction based on the Swern oxida-
tion of the primary alcohol of 20 followed the treatment of
the corresponding hemiaminal formed in situ with TMSCN.
High-resolution EIMS of ()-phtalascidin 622 4 demon-
strated a molecular composition of C35H35O7N4 (M +H)+ by
observation of the peak at a m/z 623.2510 (0.4 mmu).
The lack of published data for 4 frustrated our attempts to
identify our sample by simple comparison of NMR data.
Therefore, extensive analyses of spectral data were neces-
sary to confirm the structure. All protons and carbons were
assigned by NMR experiments including COSY, HSQC,
HMBC and NOESY techniques (Figures 3 and 4).
More especially, the resonance signal of the residual
aromatic proton H15 was located at 6.41 ppm based on the
cross peaking correlation with H14, H14′ and Me16 resonance
signals identified from the COSY and NOESY spectra and
located at 2.24 ppm, 2.62 ppm and 3.07 ppm respectively.
From these hypotheses, OMe17 was characterized by a
singlet at 3.74 ppm which was confirmed by a NOESY
cross peaking correlation with the OH group at 5.75 ppm.
COSY experiment allowed us to assign all of the resonance
signals to the corresponding protons and the proposed
stereochemistry of 4 was confirmed by NOESY experiment,
especially for the cis position of H4, H3 and H11 as well as
the anti position of H12 towards H1 and H13 which is also in
anti 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.
Scheme 4 Synthesis of (±)-Pt 622 4.

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CHRISTIAN R. Razafindrabe, et al. Sci China Chem September (2010) Vol.53 No.9
Figure 3 1H NMR spectrum of 4 (CDCl3).
Figure 4 2D COSY and NOESY spectra of 4 (CDCl3).
the synthetic precursors (±)-12 and (±)-16, Pt 622 4 was
finally obtained in an overall yield of 5.6%.
4 Conclusion
To conclude, a practical synthesis of fully functionalized
phenolic -amino-alcohol (±)-16 which constitutes the
catechol aromatic fragment of the tetrahydroisoquinoline of
(±)-Pt 622, has been synthesized in six steps from 3-methyl
catechol 5 with an overall yield of 57%. After four addi-
tional steps involving a Pictet-Spengler condensation from
The authors wish to thank the ‘AUF Antananarivo, Région Rhône-Alpes
and EGIDE Lyon’ for the grant to C.R.R.'s Ph.D.
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