Diastereoselective addition of metalated isoindolin-1-ones to aldehydes. Stereoselective preparation of (E)-3-arylideneisoindolin-1-ones

Article abstract of DOI:10.1016/S0040-4039(02)00236-8

Lithiated isoindolinones react with aromatic aldehydes to afford 3-hydroxybenzyl derivatives with high diastereoselectivity. Dehydration of erythro and threo adducts through an E1cb mechanism gives rise indiscriminately to the (E)-arylideneisoindolinones.

Full text of DOI:10.1016/S0040-4039(02)00236-8

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 43 (2002) 2207–2210
Diastereoselective addition of metalated isoindolin-1-ones to
aldehydes. Stereoselective preparation of
(E)-3-arylideneisoindolin-1-ones
Axel Couture,* Eric Deniau, Pierre Grandclaudon, Christophe Hoarau and Ve´ronique Rys
Laboratoire de Chimie Organique Physique, UPRESA 8009, Universite´ des Sciences et Technologies de Lille,
F-59655 Villeneuve d’Ascq Cedex, France
Received 18 December 2001; accepted 30 January 2002
Abstract—Lithiated isoindolinones react with aromatic aldehydes to afford 3-hydroxybenzyl derivatives with high diastereoselec-
tivity. Dehydration of erythro and threo adducts through an E1cb mechanism gives rise indiscriminately to the (E)-arylideneisoin-
dolinones. © 2002 Elsevier Science Ltd. All rights reserved.
II 1, velutinam 2 and eupolauramine 3. It also represents
the main structural subunit of architecturally sophisti-
cated alkaloids like aristoyagonine 4 and fumaridine 5.
On the other hand, some phenolic derivatives 6 have been
shown to possess inhibitory activity for thromboxan A2
analogue (U-46619)-induced vasoconstriction.2
The 3-ylideneisoindolin-1-one ring system has featured in
recent years as a desirable synthetic target in view of its
presence in both natural products and synthetic pharma-
ceuticals with biological activity. This highly conjugated
system is indeed present in a group of natural products
as exemplified by aristolactam alkaloids1 enterocarpam
O
R2
1
2
3
R1 = R3 = R5 = H; R2 = OH; R4 = OMe; X = C-OMe Enterocarpam II
N R1
X
R1 = R3 = R5 = H; R4 = OH; R2 = OMe; X = C-OMe
Velutinam
R5
R1 = Me; R2 = R3 = R4 = H; R5 = OMe; X = N
Eupolauramine
R3
R4
OMe
O
MeO
N H
O
O
O
N H
N Me
MeO
OH (o, m, p)
O
O
MeO
MeO
N
5 Fumaridine
4
Aristoyagonine
6
Me
Me
Keywords: metalation; diastereoselection; stereochemistry; enamides.
* Corresponding author. Fax: +33 (0)3 20 33 63 09; e-mail: axel.couture@univ-lille1.fr
0040-4039/02/$ - see front matter © 2002 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(02)00236-8

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A. Couture et al. / Tetrahedron Letters 43 (2002) 2207–2210
As a part of a program aimed at the synthesis of 1–53,4
we were interested in the development of a stereoselec-
tive method for the preparation of (Z)- and (E)-3-aryli-
deneisoindolin-1-ones in order to facilitate access to the
above-mentioned natural products and synthetic bioac-
tive compounds. In previous papers3–5 we have
observed that the configuration of the exocyclic double
bond in models elaborated under the agency of the
Horner process (Retrosynthetic Scheme 1, path a) was
precisely governed by the presence of bulky substituent
connected to the lactam nitrogen. In all cases variable
mixtures of (E) and (Z) isomers were obtained. We
then anticipated that isoindolinone benzylic deprotona-
tion of O-substituted alcohol derivatives (Scheme 1,
path b) through an E1cb mechanism could ensure the
stereoselective formation of (E) and (Z) isomers. Con-
sequently we embarked on a program aimed at the
stereoselective synthesis of the parent erythro (u) and
threo (l) alcohols6 (Scheme 1, R2=H). Synthetic
methodology for CꢀC bond formation at the isoindoli-
none benzylic position has been dominated by proce-
dures based on the nucleophilic interception of iminium
ions,7 while radical and carbanionic approaches have
received far less attention.8 We recently reported on the
synthesis of a variety of 3-substituted isoindolinones by
quenching with alkyl halides isoindolinones regioselec-
tively metalated by weak nucleophilic metalating
reagent sparing the lactam unit.9 We therefore decided
to adopt the same strategy for the installation of the
hydroxybenzyl appendage.
reaction with a range of aromatic aldehydes 11–15
(Scheme 2, Table 1). All reactions were carried out in
THF at −78°C. Dropwise addition of the base gave a
deep orange solution of benzylic anions deriving from
7–10, the colour of which was discharged on addition
of the appropriate aromatic aldehydes 11–15. A series
of compounds which have been prepared by this
method are presented in Table 1, where it may be seen
that this simple procedure affords good yields of the
hydroxybenzyl adducts 16–25. It is worth noting that
the reaction performed with sodium and potassium
amidic bases gave invariably a mixture of erythro and
threo isomers. The major diastereomer was shown to
possess an (u)-configuration based on the 1H NMR
observed vicinal coupling constant J3-1%=2.7 Hz (value
given for 16),10–12 whereas J3-1%=4.2 Hz for the minor
diastereomer with (l)-configuration. Furthermore, the
relative configuration of the major isomers was
determined unequivocally by X-ray crystallography.13
The highest diastereoselectivity was obtained with
lithiated base LHMDS (Table 1). Interestingly it has
been shown that addition of aromatic aldehydes to
related metalated species such as lithiated tet-
rahydroisoquinoline pivalamide11 and isoquinolylox-
azoline12 gave a mixture of both erythro and threo
isomers, whereas the majority formation of the erythro
isomer required transmetalation with magnesium bro-
mide prior to addition. We did not find the same trend
with lithiated isoindolinones since whatever the struc-
ture of the parent models and the aromatic carboxalde-
hyde derivatives, the erythro adducts were always
predominant by a large margin. These were easily
obtained in pure form (>99%) by simple recrystalliza-
tion from ethanol. Replacement of the N-methyl
For this purpose we examined the metalation of a
variety of isoindolin-1-ones 7–10 with amidic bases
differing by the metal counterion, and their subsequent
O
O
O
N R1
path a
N R1
N R1
path b
H
H
OR2
P O
Ph
Ar
Ph
Ar
+
ArCHO
erythro and threo
Scheme 1.
Scheme 2.

A. Couture et al. / Tetrahedron Letters 43 (2002) 2207–2210
2209
Table 1. Ratio of diastereomers produced by reaction of metalated 7–10 with 11–15
Entry
Compounds 7–10
Aldehydes 11–15 (ArCHO)
Diastereomeric ratio erythro:threo (yield %)
R1
R2
R3
X
Ar
KHMDSa
NaHMDSb
50:50 (80)
LHMDSc
1
2
3
4
5
6
7
8
9
7
¦
¦
PMBd
¦
¦
¦
¦
Me
¦
¦
¦
¦
H
¦
¦
¦
OMe
H
¦
¦
¦
H
¦
¦
¦
OMe
H
¦
¦
¦
CH
¦
¦
¦
COMe
CH
¦
¦
¦
N
11
12
13
14
11
11
12
14
15
11
C6H5
1-Naphthyl
3,4,5-Trimethoxy-C6H2
2,3,4-Trimethoxy-C6H2
C6H5
16
17
18
19
20
21
22
23
24
25
55:45 (88)
55:45 (83)
80:20 (91)
45:55 (76)
75:25 (88)
50:50 (92)
50:50 (89)
80:20 (81)
55:45 (90)
95:5 (87)
90:10 (82)
85:15 (78)
85:15 (74)
65:35 (71)
65:35 (78)
90:10 (90)
90:10 (82)
95:5 (75)
¦
8
9
¦
¦
¦
¦
65:35 (83)
60:40 (80)
1-Naphthyl
2,3,4-Trimethoxy-C6H2
2-Iodo-C6H4
C6H5
90:10 (88)
\95:5 (86)
10
10
¦
¦
a KHMDS: potassium bis(trimethylsilyl)amide.
b NaHMDS: sodium bis(trimethylsilyl)amide.
c LHMDS: lithium bis(trimethylsilyl)amide.
d PMB: para-methoxybenzyl.
group by the larger benzyl group had no effect, as
shown in entries 1–5. A slight decrease of stereoselec-
tivity was, however, observed with the trimethoxy
parent compound (entry 5), but results obtained with
trimethoxybenzaldehydes (entries 3 and 4) suggest
that steric effects predominate over electronic effects.
The high degree of diastereoselectivity observed with
LHMDS may be tentatively rationalized by sta-
bilization of the alkoxide by chelation of the lithium
counterion embedded in a five-membered heteroring
system in the primary adduct 26. p-Donor–acceptor
interactions may also account for the highest
diastereoselectivity observed with the p-deficient pyri-
dine model 10.
Scheme 3.

2210
A. Couture et al. / Tetrahedron Letters 43 (2002) 2207–2210
The stereoselective preparation of the erythro hydroxy-
benzyl derivatives (u)-16–25 allowed us to envisage the
development of a stereoselective method for the prepa-
ration of the 3-arylidene derivatives (E)-31–34. For this
purpose we opted to perform the hydroxyalkylation
and elimination reactions a single one-pot reaction.
Metalation of the parent isoindolinones 7–10 and
stereoselective connection of the hydroxyalkyl
appendage was then carried out as described above
(Scheme 3, path a). O-Silylation in situ of the transient
oxanion 27 with TMSCl and subsequent treatment with
LHMDS in the sequel ensured completion of the elimi-
nation reaction and gratifyingly this protocol delivered
the (E)-isomers 31–34 in yields ranging from 73 to 87%.
The stereochemistry of the exocyclic double bond of
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(E)-31–34 follows unambiguously from the H NMR
data14 and has also been related by characteristic chem-
ical shift data to known arylideneisoindolinones.15 We
were also surprised to note that the same geometrical
isomers were obtained exclusively by applying the same
reaction sequence to a mixture of erythro (u) and threo
(l) isomers 28 obtained by making use of KHMDS as
the base (Scheme 3, path b). It is then likely that
deprotonation of the O-silylated derivatives 28 (l+u)
leads to the metalated species 29 which can adopt the
o-quinodimethane structure 30 owing to electronic
delocalization. Consequently once formed 29 and 30
collapse to (E)-31–34 stereospecifically through the
E1cb mechanism.16 Interestingly such a phenomenon
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In the course of this work we have then shown that
lithiated isoindolinones react with aromatic aldehydes
at the C-3 position of the lactam ring to afford hydrox-
yalkyl derivatives in good yields and with high
diastereoselectivity. We have further demonstrated that
the dehydration leading solely to the (E)-isomer could
be indiscriminately performed on erythro and threo
adducts.