Enantioselective straightforward access to benzo[b]thiophene analogs of Azatoxin

Article abstract of DOI:10.1016/j.tetlet.2012.04.055

Horner-Wadsworth Emmons olefination followed by asymmetric hydrogenation allowed the first synthetic access to the chiral thiotryptophan with good enantiomeric excess. Oxazolidinone formation followed by a Pictet-Spengler condensation provided the benzothiophenic analog of Azatoxin.

Full text of DOI:10.1016/j.tetlet.2012.04.055

Tetrahedron Letters 53 (2012) 3165–3168
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Enantioselective straightforward access to benzo[b]thiophene analogs
of Azatoxin
⇑
Stéphanie Gracia, Cédric Marion, Jullien Rey, Florence Popowycz, Stéphane Pellet-Rostaing ,
Marc Lemaire
⇑
Institut de Chimie et Biochimie Moléculaires et Supramoléculaires, UMR-CNRS 5246, Equipe Catalyse Synthèse Environnement, Université de Lyon, Université Claude Bernard – Lyon 1,
Bâtiment Curien, 43 Bd du 11 Novembre 1918, F-69622 Villeurbanne, France
a r t i c l e i n f o
a b s t r a c t
Article history:
Horner-Wadsworth Emmons olefination followed by asymmetric hydrogenation allowed the first syn-
thetic access to the chiral thiotryptophan with good enantiomeric excess. Oxazolidinone formation fol-
lowed by a Pictet–Spengler condensation provided the benzothiophenic analog of Azatoxin.
Ó 2012 Elsevier Ltd. All rights reserved.
Received 7 March 2012
Revised 6 April 2012
Accepted 11 April 2012
Available online 20 April 2012
Keywords:
Azatoxin
Benzothiophene
Chiral thiotryptophan
Oxazolidininone
Pictet–Spengler Cylization
The development of new methods for the synthesis of sulfur-
containing heterocycles is of importance in medicinal chemistry.
Among these structures, benzothienopyridines were recently re-
ported to be highly efficient inhibitors of Eg5 kinesin and cell cycle
specific inducers of apoptosis in cancer cells.1 To our knowledge,
only few examples described the straightforward preparation of
1,2,3,4-tetrahydro-benzo[4,5]thieno[2,3-c]pyridine.2 The focus
onto this sulfur analog substrate is consistent with the large repre-
sentation of the indole nucleus in natural and synthetic molecules,
displaying thus a wide range of biological properties.
In a general point of view, the tetrahydro-b-carboline skeleton is
a major component of a wide range of alkaloids, among them Reser-
pin, Suaveoline and Azatoxin (Fig. 1). The latter compound is a hy-
brid of two anti-cancer agents: etoposide and ellipticine and
displays biological properties such as high cytotoxicity associated
with the inhibition of topoisomerase II3 and tubulin polymerization
inhibition.4 Azatoxin synthesis initially described by Leteurtre,3,4
followed the Tomioka procedure based on the Pictet–Spengler
methodology6 or in C-3 position via SNAr or Friedel–Crafts acyla-
tion.7 Herein, we propose a straightforward and enantioselective
strategy to access to benzo[b]thiophene analog of azatoxin (4)
(Fig. 1).
The sulfur analog (4) of azatoxin could be obtained by a Pictet–
Spengler condensation. The key step is the asymmetric hydrogena-
tion resulting in the control of the created stereogenic center. The
cheap and commercially available benzo[b]thiophene would be
OMe
OMe
O
H
N
O
OMe
N
H
H
MeO
H
OMe
Reserpin (1) MeO2C
H
N
H
O
NH
condensation between syringaldehyde dimethyl acetal and
L-tryp-
N
O
tophanol derived oxazolidinone.5
N
H
In the laboratory, the design of original benzo[b]thiophene has
been realized either in C-2 position through an arylation
X
OMe
Suaveoline (2)
OH
Azatoxin (3)
MeO
⇑
Corresponding authors. Tel.: +3 346 633 9308; fax: +3 346 679 7611 (S.P.-R.);
X = NH
tel.: +3 347 243 1409; fax: +3 347 243 1408. (M.L.)
E-mail addresses: stephane.pellet-rostaing@cea.fr (S. Pellet-Rostaing), marc.le-
maire@univ-lyon1.fr (M. Lemaire).
X = S Benzothiophene azatoxin analog (4)
Figure 1. Tetrahydro-b-carboline containing alkaloids.
0040-4039/$ - see front matter Ó 2012 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tetlet.2012.04.055

3166
S. Gracia et al. / Tetrahedron Letters 53 (2012) 3165–3168
CO2Me
NHCBz
O
H
Pictet
Spengler
O
N
H
O
N
O
S
S
S
OMe
OH
Asymmetric
hydrogenation
(4)
MeO
CO2Me
NHCBz
Horner-Wadsworth
Emmons
S
S
Scheme 1. Retrosynthetic strategy.
used as starting material and engaged, after formylation in Horner–
Wadsworth–Emmons (Scheme 1).
CHO
Cl2CHOMe (5 eq), TiCl4 (2.5 eq)
CHCl3, reflux, 4 h
Results and discussion
(5)
S
83%
S
Commercially available benzo[b]thiophene was submitted to
Rieche formylation in the presence of dichloromethyl methyl ether
and TiCl4 to provide 3-formyl benzo[b]thiophene (5) in 83% yield.8
Condensation of carboxaldehyde 5 with (benzyloxycarbonyl)-
O
(MeO)2P
CO2Me
(1.1 eq)
NHCbz
88%
TMG (1.1 eq), CH2Cl2
-30°C during 30 min
then, rt, 3 h
a
-phosphonoglycine trimethyl ester in the presence of N,N,N0,N0-
tetramethylguanidine in dichloromethane according to Obrecht
procedure afforded the desired Z-olefin 6 (Scheme 2).9
CO2Me
NHCbz
CO2Me
Typical procedure for asymmetric hydrogenation of alkenes
substituted by an ester group or other electron-withdrawing group
suggested the classical use of rhodium complexes associated either
with Duphos or Binap as ligands.10 First attempt of the reduction of
[Rh(COD)2]BF4 (10 mol%)
(R)-Binap (11 mol%)
NHCbz
H2 (20 bars), 70°C, 15 h
(7)
(6)
S
S
94%
compound 6 with [Rh(COD)(S,S)-Duphos]+CF3CO3 (10 mol%) at
ꢀ
ee=95%
50 °C under 10 bars H2 afforded (S)-7 in a moderate 41% yield
within 5 days. Excellent yield and enantioselectiꢀvity were reached
with the concomitant use of [Rh(COD)2]+BF4 (10 mol %) and
(R)-Binap at 70 °C under 20 bars H2. Enantioselectivity rate was
determined by chiral GC Supelco b-dex 225. In the latter conditions,
the rate of the reaction was significantly enhanced to reach 94%
yield and 95% enantioselectivity in 15 h (Scheme 2). (S)-Methyl-
(3-benzo[b]thiophen-3-yl)-2-(benzyloxycarbonylamino)propanoate
7,11 on its enantiomeric pure form, was obtained in a three-step se-
quence from commercially available benzo[b]thiophene in global
yield of 69%.
Reduction of ester 7 to alcohol was performed quantitatively in
the presence of lithium borohydride. The crude aminoalcohol 8
was directly submitted to cyclization conditions into oxazolidi-
none 9. Treatment of compound 8 with 5 equiv of thionyl chloride
in CH2Cl2 was successfully achieved in 70% yield (Scheme 3).
Among the different methods reported for the formation of the
1,2,3,4-tetrahydro-benzo[4,5]thieno[2,3-c]pyridine or the tetrahy-
dro-b-carboline nuclei, Pictet–Spengler reaction is one of the most
efficient routes, affording a library of potentially bioactive b-carb-
oline derivatives.12 This reaction was largely applied to the racemic
Scheme 2. Access to chiral thiotryptophan.
OH
CO2Me
LiBH4 (2.6 eq)
THF / MeOH (2/1)
rt, 5 h
NHCbz
NHCbz
quantitative
S
(7)
S
(8)
SOCl2 (5 eq)
CH2Cl2
70%
rt, 72 h
O
O
N
H
(9)
S
Scheme 3. Formation of the oxazolidinone.
CHO
O
O
1.05 eq
O
N
N
O
CF3
(9)
S
Na2SO4 (1 eq)
S
(10)
CF3
(11)
CF3
Scheme 4. Pictet–Spengler cyclization.

S. Gracia et al. / Tetrahedron Letters 53 (2012) 3165–3168
3167
Table 1
Table 2
Pictet–Spengler conditions to prepare compound 11
Extension to other aldehydes
Entry
Solvent
TFA
T (°C)
Time
Yield
Entry Compound Aldehyde
Isolated yield
(%)
Global yield
(%)
a
1
2
3
4
CH2Cl2
—
—
rt
96 h
48 h
24 h
96 h
—
—
a
Toluene
Toluene
Toluene
Reflux
Reflux
Reflux
F3C
CHO
CHO
1
2
11
12
42
76
20
1 equiv
10 equiv
34%
42%
a
No conversion was detected.
36
MeO
O2N
CHO
3
4
13
14
51
61
24
29
and diastereoselective synthesis of aryl and heteroaryl tetrahydro
isoquinolines.13
CHO
We investigated the potential of oxazolidinone to undergo Pic-
tet–Spengler cyclization in the presence of an aryl aldehyde. To
encourage the low nucleophilicity the oxazolidinone NH position,
the first attempt was performed on a para-electronwithdrawing
substituted benzaldehyde to enhance the electrophilic character
of the aldehyde (Scheme 4). Amine 9 was condensated with p-triflu-
orobenzaldehyde (1.05 equiv) in the presence of sodium sulfate as a
water scavenger to displace the equilibrium of imine formation.
The formation of the imine was followed by 1H NMR experi-
ments, but at room temperature in dichloromethane or toluene
(Table 1, entries 1 and 2), no trace of conversion was detected.
The electronic environment around the nitrogen of oxazolidinone
should be probably responsible of this lack of reactivity. The intro-
duction of an additive such as a strong Brönsted acid should help to
promote the complete conversion of the reaction. In our case, the
introduction of 1 equiv of TFA allowed the obtention of compound
11 but only in a 34% moderate yield (Table 1, entry 3). Similar con-
ditions requiring 10 equiv of trifluoroacetic acid in refluxing tolu-
ene during 3 days led to 100% conversion but only 42% of
isolated yield of 11. Conversion was followed by proton NMR with
the disappearance of the singlet at d = 10 ppm (aldehyde) and the
concomitant appearance of another singlet at 6.2 ppm, characteris-
tic of Ha proton of the tetracyclic skeleton.
MeO
HO
CHO
5
6
15
16
42
23
20
11
MeO
NC
CHO
The methodology was thus extended to the preparation of a
family of new benzo[b]thiophene derivatives 12–16 (Scheme 5, Ta-
ble 2). As already described above with p-trifluorobenzaldehyde,
Pictet–Spengler condensation systematically generated the ex-
pected compounds in trans configuration only. At this stage, the
compounds were produced with moderate to good yield ranging
from 42 to 76%. The low yield of 23% reported is the case of p-cya-
nobenzaldehyde (Table 2, entry 6) and is probably explained from
the reactivity of the nitrile function in competition with the car-
bonyl group of the aldehyde.
The benzothiophenic analog 15 of azatoxin was obtained in 42%
for the Pictet–Spengler condensation and in 20% in all the 6 steps
sequence from commercially available benzo[b]thiophene.
The relative configuration of the cyclized product was eluci-
dated by 2D-NOESY correlations. No correlation was observed be-
tween Ha proton assigned at 6.2 ppm and Hb proton (multiplet at
4.2 ppm). A significant correlation was observed between Ha and
aromatic protons, proving the trans diastereoselectivity of the Pic-
tet–Spengler (Fig. 2).
Conclusions
A new strategy to provide the sulfur analog of azatoxin was re-
ported from benzo[b]thiophene. Based on Horner–Wadsworth–
Emmons olefination, the key step reaction is the asymmetric
hydrogenation. This crucial step allows an excellent control of
the created stereogenic center with an enantiomeric excess mea-
sured at 95%. By this way, we report thus the first synthetic access
to chiral thiotryptophan in an efficient step of hydrogenation. Eas-
ily prepared corresponding oxazolidinone was engaged in a pivotal
Pictet–Spengler condensation affording the sulphur azatoxin ana-
log and derivatives with global yield for the sequence varying from
11% to 36% (6 steps).
NOE correlation
Hb
O
N
O
S
Ha
Acknowledgment
Harom
CF3
(11)
The Ministère de l’Enseignement Supérieur et de la Recherche is
gratefully acknowledged for a Grant to S.G.
Figure 2. Structure elucidation by 2D-NOESY correlations.
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