Synthetic investigations of (1,3′)-bistetrahydroisoquinolines: Towards pentacyclic analogues of piperazine core alkaloids

Article abstract of DOI:10.1016/j.tetlet.2005.12.056

Synthetic investigations of (1,3′)-bistetrahydroisoquinolines are reported as the key intermediates for the synthesis of ecteinascidin and phthalascidin pentacyclic structure analogues through successive Pictet-Spengler cyclization and intramolecular peptide coupling. The direct Pictet-Spengler reaction between a derivative of l-DOPA and N-protected-α-aminoaldehyde was first extended to the synthesis of cis-(1,3′)- bistetrahydroisoquinoline. After introduction of the required amino acid moiety, an efficient six-membered ring intramolecular peptide coupling gave rise to piperazine derivative structures. Complete structural assignments were corroborated by NMR and X-ray spectroscopic methods. Nevertheless, the optical integrity of the N-protected-α-aminoaldehyde seems to be sensitive to the reaction conditions. Pentacylic structures, having an anti C3-C11 backbone stereochemistry, were obtained from cyclization para- and ortho- to the 3-OH group of the l-DOPA derivative.

Full text of DOI:10.1016/j.tetlet.2005.12.056

Tetrahedron
Letters
Tetrahedron Letters 47 (2006) 1319–1323
Synthetic investigations of (1,30)-bistetrahydroisoquinolines:
towards pentacyclic analogues of piperazine core alkaloids
a
a
b
a,
*
´
Sylvain Aubry, Stephane Pellet-Rostaing, Bernard Fenet and Marc Lemaire
a
`
´
Laboratoire de Catalyse et Synthese Organique, Universite Claude Bernard Lyon 1, 69622 Villeurbanne cedex, France
ˆ
Centre de Re´sonance Magne´tique Nucle´aire, UCB-CPE, Bat. 308, 43 Bd. du 11 Novembre 1918, 69622 Villeurbanne cedex, France
b
Received 21 November 2005; revised 8 December 2005; accepted 12 December 2005
Available online 28 December 2005
Abstract—Synthetic investigations of (1,30)-bistetrahydroisoquinolines are reported as the key intermediates for the synthesis of
ecteinascidin and phthalascidin pentacyclic structure analogues through successive Pictet–Spengler cyclization and intramolecular
peptide coupling. The direct Pictet–Spengler reaction between a derivative of L-DOPA and N-protected-a-aminoaldehyde was first
extended to the synthesis of cis-(1,30)-bistetrahydroisoquinoline. After introduction of the required amino acid moiety, an efficient
six-membered ring intramolecular peptide coupling gave rise to piperazine derivative structures. Complete structural assignments
were corroborated by NMR and X-ray spectroscopic methods. Nevertheless, the optical integrity of the N-protected-a-aminoalde-
hyde seems to be sensitive to the reaction conditions. Pentacylic structures, having an anti C3–C11 backbone stereochemistry, were
obtained from cyclization para- and ortho- to the 3-OH group of the L-DOPA derivative.
Ó 2005 Elsevier Ltd. All rights reserved.
OMe
The synthesis of tetrahydroisoquinoline alkaloids has
received particular attention in the field of medicinal
chemistry due to their biological activity.1 The most bio-
active member of this family, ecteinascidin 743 (1, Et
743), was isolated from Caribbean tunicate Ecteinascidia
turbinate2 (Fig. 1) and revealed potent antitumour activ-
ity under phase II/III clinical trials for various human
cancer cell lines.3
HO
HO
H
Me
OMe
NH
HO
OAc
O
MeO
H
Me Me
O
OAc
N
Me
S
H
H
H
N
N
O
O
Me
H
O
N
Me
CN
H
O
N
O
H
OH
1
O
2
So far, two successful total syntheses, performed by
Corey4 and Fukuyama,5 respectively, and a semi-synthe-
sis achieved by Cuevas6 have been reported. However, a
synthetic analogue, phthalascidin 650 (2, Pt 650),7 which
exhibits a similar biological activity to the natural prod-
uct, has also been prepared (Fig. 1). Their antiprolifera-
tive activity on tumour cells was essentially due to DNA
minor groove alkylation8 as previously demonstrated
for saframycin S (3), the most active compound of this
alkaloid series.9 More recently, the construction of these
alkaloid architectures10–16 was improved by several
groups, and the closing of the 10-membered sulfur-
containing lactone in Et 743 construction was
investigated.11c,17
OMe
O
Me
H
O
O
H
N
O
Me
N
Me
H
O
MeO
H
OH
NH
O
Me
3
Figure 1. Tetrahydroisoquinoline alkaloids.
Several groups have reported an intermolecular peptide-
coupling connecting both subunits by amide bond
formation to a secondary amine.4,11b,13 Nevertheless,
*
Corresponding author. E-mail: pellet@univ-lyon1.fr
0040-4039/$ - see front matter Ó 2005 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2005.12.056

1320
S. Aubry et al. / Tetrahedron Letters 47 (2006) 1319–1323
the direct synthesis of tetrahydroisoquinolines incorpo-
rating heterocyclic structures received little atten-
tion.18,19 As far as we know, the direct synthesis of
(1,30)-bistetrahydroisoquinolines was not done using
the Pictet–Spengler condensation. According to the
study here, we propose a new and short methodology
dedicated to the synthesis of piperazine pentacyclic
structure analogues. Based on the use of the direct
Pictet–Spengler phenolic cyclization,20 condensation
between N-Boc-1,2,3,4-tetrahydroisoquinoline-3-carbox-
aldehyde 7 and L-3,4-dihydroxyphenylalanine methyl
ester hydrochloride 4 afforded (1,30)-bistetrahydroiso-
quinolines as synthetic intermediates of the desired pen-
tacyclic structures 17 and 19 (vide infra).
O
1) Boc2O, CH2Cl2, 1 h
OH
91% (6 : 99% ee)
H
NH
2) Dess-Martin periodinane,
CH2Cl2, 1 h
NBoc
5
79% (94% ee)
7
HO
COOMe
HO
HO
HO
COOMe
NH2.HCl
H
NH
H
4
+
EtOH, NEt3, 24 h
NBoc
8 : 49%
HO
Starting from the commercially available (S)-(ꢀ)-
1,2,3,4-tetrahydroisoquinolinemethanol 5, protection
of the amino group with Boc2O provided 6 in 91% yield
and 99% ee.21 Oxidation of 6 with Dess–Martin period-
inane reagent22 in CH2Cl2 afforded the N-Boc-a-amino-
aldehyde 723 in 79% yield and up to 94% ee after silica
gel column chromatography (Scheme 1). The optical
purity24 of 6 and 7 was assessed by HPLC analyses (Chi-
ralcel OD) of the racemic mixture. As established by
Kametani and co-workers,25 condensation of 7 with L-
3,4-dihydroxyphenylalanine methyl ester hydrochloride
4 under the non-acidic conditions of the Pictet–Spengler
reaction (EtOH, NEt3, rt) led to the formation of three
(1,30)-bistetrahydroisoquinolines, 8, 9 and 10, obtained
as a mixture of three isomers with a complete cis-stereo-
selectivity. Isomers 8 and 9 arised from cyclization para-
to the 3-phenolic group of 4, and 10 from cyclization
ortho- to the same 3-phenolic group.
COOMe
COOMe
HO
HO
NH
H
H
NH
+
HO
H
H
NBoc
NBoc
9+10 : 29%
Scheme 1. Synthesis of (1,30)-bistetrahydroisoquinolines 8, 9 and 10.
6.65 ppm (J = 8 Hz) corresponding to the adjacent aro-
matic protons. Nevertheless, epimerization of the alde-
hyde stereocenter occurred during the cyclization step
affording 8 and 10, and was confirmed at a later stage
of this synthetic sequence by single-crystal X-ray analy-
sis of 12 and 19.26 This event occurred at the aldehyde
stereocenter, which can be configurationally unstable
in solution.24 Successively, three synthetic steps of func-
tionalization were conducted to introduce the required
amino acid moiety of the (1,30)-bistetrahydroisoquino-
lines. Thus, the trimethylation of 8 with an excess of
Me2SO4 and K2CO3 in DMF at room temperature
afforded the amino ester 11 in 85% yield (Scheme 2).
Hydrolysis of the ester 11 with LiOH in a mixture of
MeOH/H2O (3/1) was performed to give 14 in 95%
yield. The direct deprotection/cyclization of 11 as de-
scribed by Liu13 with CF3CO2H in CH2Cl2 did not pro-
duce the corresponding pentacyclic structure, with any
reaction conditions tried (TMSOTf,27 K2CO3/MeOH).
Purification by chromatography afforded pure 8 in 49%
yield and an inseparable mixture of 9 and 10 in a 50/50
ratio (29% yield). Two rotamers were characterized for
each compound 8, 9 and 10. Configurational elucidation
of 8 was determined by 2D NMR experiments (includ-
1
ing HSQC, COSY and NOESY techniques). H NMR
experiment in DMSO-d6 at 80 °C, confirmed the compo-
sition of the mixture of 9 and 10. The structure of 10 was
established by two doublets at 6.45 ppm (J = 8 Hz) and
MeO
COOR
Me2SO4,
K2CO3,
MeO
1) CF3CO2H, 30 min. 99%
H
N
H
8
DMF, 16 h
85%
2) DMF/DMSO (4/1),
FDPP, DIEA, 60 ºC, 16 h
64%
Me
NBoc
11 (R=Me)
14 (R=H)
LiOH, MeOH,
H2O, 16 h 95%
OMe
OMe
OMe
OMe
18
H
18
H
15
15
H
DIBAL-H, THF,
-78 ºC, 1 h, then
H
11
N
Me
11
N
Me
3
3
N
TMSCN, AcOH,
CH2Cl2, 2 h
N
H
H
O
CN
17
72%
18
Scheme 2. Synthetic procedure for the pentacyclic system 18.

S. Aubry et al. / Tetrahedron Letters 47 (2006) 1319–1323
1321
This could be explained by the relatively low nucleophi-
licity of the secondary amine intermediate. The N-Boc
linkage was then cleaved by CF3CO2H and the corre-
sponding amino acid intermediate was engaged in the
next step without further purification. Usual activation
agents of the carboxyl groups with DCC and DMAP,28a
EDC and HOBt28b–d or PyBoPÒ28e were inefficient
(Table 1, entries 1–4), affording 17 in poor yields. Finally,
after investigation of reaction conditions (Table 1), the
six-membered intramolecular peptide coupling29 effi-
ciently takes place with pentafluorophenyl diph-
enylphosphinate (FDPP)30 as coupling agent allowing
the increase of the peptide coupling yield from 24% to
32% in CH2Cl2 (entry 5) or DMF (entries 6–8). The best
conditions of those investigated of the six-membered
intramolecular peptide coupling were obtained in a mix-
ture of DMF/DMSO (entries 9–12) and provided the
pentacyclic compound 17 exclusively in 64% yield (entry
12). At starting material concentrations higher than
0.15 mol/L, oligomerization increased dramatically.
methylsilyl cyanide, to amino nitrile 18 in 72% yield.
The structure of 18 was determined on the basis of the
500 MHz NOESY spectrum by measurement of the
interproton distances from the ratio analysis of the cross
and diagonal peak intensities.31 According to this study,
this compound exhibited the opposite C3–C11 backbone
stereochemistry recurrent in this alkaloid family.
To complete the synthetic sequence from 9 and 10, an
N- and O-methylation step was also done affording the
trimethylated compounds 12 and 13 (Scheme 3). Struc-
tural elucidation of 12 was established by single-crystal
X-ray analysis.26 Surprisingly, after hydrolysis of ester
12 and deprotection of the N-Boc linkage of the corre-
sponding acid, the final cyclization step failed. Due to
the steric hindrance imposed by the activated acid inter-
mediate, the intramolecular peptide coupling was ineffi-
cient. However, hydrolysis of ester 13 and cleavage of
the N-Boc linkage provided the corresponding amino
acid derivative, which was immediately cyclized under
the best conditions of peptide coupling (entry 12: FDPP,
DIEA, DMF/DMSO: 4/1, 0.15 mol/L) affording the
pentacyclic compound 19 in 61% yield.
Taking into account the reasons for the antiproliferative
activities of this alkaloid family, the reduction of the lac-
tam ring of 17 was explored with DIBAL-H in THF at
ꢀ78 °C, achieving the corresponding carbinolamine
which was converted, under acidic conditions with tri-
Complete structural characterization of 19 was
achieved by NMR and X-ray spectroscopic methods.
Table 1. Intramolecular peptide coupling optimization
Entry
Coupling agent
Solvent
Base (equiv)
Concentration (mol/L)
Temperature (°C)
Time (h)
Yield 17 (%)
1
2
4
5
6
7
8
9
DCC/DMAP
EDC/HOBt
PyBopÒ
FDPP
FDPP
FDPP
FDPP
FDPP
FDPP
FDPP
FDPP
CH2Cl2
DMF
DMF
CH2Cl2
DMF
DMF
DMF
DMF/DMSO (4/1)
DMF/DMSO (4/1)
DMF/DMSO (4/1)
DMF/DMSO (4/1)
Net3 (3)
Net3 (3)
Net3 (3)
0.05
0.05
0.05
0.05
0.06
0.01
0.06
0.06
0.06
0.10
0.15
rt
rt
rt
rt
24
24
24
24
24
24
24
16
16
16
16
15
20
18
24
28
19
32
32
36
41
64
DIEA (5)
DIEA (5)
DIEA (5)
DIEA (5)
DIEA (5)
DIEA (5)
DIEA (5)
DIEA (5)
rt
60
60
rt
60
60
60
10
11
12
MeO
COOR
MeO
COOR
N
Me2SO4,
K2CO3,
MeO
H
9
+
10
N
H
MeO
+
DMF, 16 h
Me
Me
H
H
NBoc
NBoc
13 : 38% (R=Me)
16 : 94% (R=H)
12 : 39% (R=Me, X-ray)
15 : 95% (R=H)
LiOH, MeOH,
H2O, 16 h
LiOH, MeOH,
H2O, 16 h
1) CF3CO2H,
30 min.
2) DMF/DMSO (4/1),
FDPP, DIEA,
OMe
99%
MeO
16
H
H
15
60 ºC, 16 h 61%
11
N
Me
3
N
H
O
19 (X-ray)
Scheme 3. Separation of 12 and 13 and synthesis of pentacycle 19.

1322
S. Aubry et al. / Tetrahedron Letters 47 (2006) 1319–1323
1
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Interpretation of the room temperature H NMR spec-
trum revealed that the typical doublets corresponding to
the AB system of the catechol protons of intermediates
13 and 16 collapsed to a singlet at 6.86 ppm for com-
pound 19. This phenomenon results from a degenerated
spin coupling effect of H-15 and H-16 resonance signals
which possess the same chemical shift. Moreover,
HSQC experiment confirmed this hypothesis, exhibiting
two cross-peaks between the proton resonance signal at
6.86 ppm and the carbon peaks at 112.4 and 124.4 ppm.
Nevertheless, the X-ray diffraction analysis of 1926
revealed an anti C3–C11 backbone stereochemical
relationship according to the epimerization of the N-
protected-a-aminoaldehyde 7 during the Pictet–Spengler
cyclization step. As previously observed by several
groups, the epimerization at C3 occurred through the
phenolic cyclization step.11d,12d
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`
The authors wish to thank the ‘Ministere de l’Enseigne-
ment Superieur et de la Recherche’, for the Grant to
S.A.’s Ph.D. and wish to thank Dr. Christine Clozel-
Fox and Dr. Igor Kazmierski, for correcting the
manuscript.
´
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