Highly diastereoselective conjugate addition of aryllithium to chiral β-nitrostyrene derivative: An application to the asymmetric synthesis of 4-aryl-1,2,3,4-tetrahydroisoquinoline

Article abstract of DOI:10.1246/cl.2007.64

Highly diastereoselective conjugate addition of aryllithium to β-nitrostyrene derivative, having chiral acetal moiety derived from (S,S)-1,2-bis(1-hydroxypropyl)benzene, was achieved. The adduct was transformed to 4-aryl-1,2,3,4-tetrahydroisoquinoline in

Full text of DOI:10.1246/cl.2007.64

64
Chemistry Letters Vol.36, No.1 (2007)
Highly Diastereoselective Conjugate Addition of Aryllithium to Chiral ꢀ-Nitrostyrene Derivative:
An Application to the Asymmetric Synthesis of 4-Aryl-1,2,3,4-tetrahydroisoquinoline
Masatoshi Asami,ꢀ Ayako Taketoshi, Keita Miyoshi, Hayato Hoshino, and Kazuhisa Sakakibara
Department of Advanced Materials Chemistry, Graduate School of Engineering, Yokohama National University,
79-5 Tokiwadai, Hodogaya-ku, Yokohama 240-8501
(Received November 2, 2006; CL-061292; E-mail: m-asami@ynu.ac.jp)
Highly diastereoselective conjugate addition of aryllithium
to ꢀ-nitrostyrene derivative, having chiral acetal moiety derived
from (S,S)-1,2-bis(1-hydroxypropyl)benzene, was achieved. The
adduct was transformed to 4-aryl-1,2,3,4-tetrahydroisoquinoline
in high enantiomeric excess (ee).
in five steps from o-bromobenzaldehyde by the conventional
methods as shown in Scheme 1. ꢀ-Nitrostyrene derivatives
5b–5d were also prepared from o-bromobenzaldehyde and
C2-symmetrical chiral diols, (S,S)-hydrobenzoine 1b, (2S,4S)-
2,4-pentanediol 1c, or (2S,3S)-2,3-dimethoxybutane-1,4-diol
1d, in the similar manner, respectively.
Then, the reaction of 5a and phenyllithium (1.5 equiv.) was
carried out in THF at ꢁ78 ꢂC for 30 min to give the desired
adduct 6a in 76% as a mixture of diastereomers. The ratio of
the diastereomers was estimated to be 96.5:3.5 [93% diastereo-
meric excess (de)] by 270 MHz 1H NMR. The de was improved
to 95% when the reaction was carried out at ꢁ100 ꢂC (83%).
When the reaction was carried out using 5b–5d, the de’s were
33, 5, and 65%, respectively. Thus, the effectiveness of (S,S)-
1,2-bis(1-hydroxypropyl)benzene 1a was realized. The results
are summarized in Table 1.
As the high selectivity was achieved by the conjugate
addition of phenyllithium to 5a, conjugate addition of various
aryllithiums, generated in situ from the corresponding arylbro-
mides and butyllithium, was conducted in THF at ꢁ100 ꢂC.
The products were obtained in good yields with high de’s in
every case as shown in Table 2.
Chiral acetals prepared from chiral diols are useful com-
pounds in asymmetric reactions as chiral synthetic equivalents
of carbonyl compounds1a,1b,2 as well as chiral protecting group
of carbonyl compounds having the reactive prochiral center in
the vicinity.1b,1c,3 C2-Symmetrical chiral diols are of attension
among various chiral diols as they can avoid the formation of
diastereoisomers.1 Previously, we reported a convenient method
for the preparation of C2-symmetrical chiral 1,4-diol, 1,2-bis-
(1-hydroxyalkyl)benzene,4 and an application of the chiral diol
to highly diastereoselective photochemical cyclization of an in-
dolylfulgide derivative.5 The result prompted us to examine
asymmetric reactions employing acetals derived from chiral
1,2-bis(1-hydroxypropyl)benzene 1a. Here, we wish to report
effectiveness of chiral acetal moiety derived from (S,S)-1,2-
bis(1-hydroxypropyl)benzene 1a in diastereoselective 1,4-addi-
tion of aryllithium to ꢀ-nitrostyrene derivative 5a, and transfor-
mation of the adduct to chiral 4-aryl-1,2,3,4-tetrahydroisoquino-
line framework which is involved in naturally occurring
alkaloids6 and several useful biologically active compounds.7
In the first place, ꢀ-nitrostyrene derivative 5a was prepared
Although the biological activity of 4-aryl-1,2,3,4-tetra-
hydroisoquinoline depends on the stereochemistry at the C-4
Table 1. 1,4-Addition of phenyllithium to ꢀ-nitrostyrenes having
chiral acetal with C2 axis of symmetry
O
O
PhLi (2.0 equiv.)
O
O
Et
O
Et
THF, –100 °C, 1 h
CHO
cat. PPTS
NO2
NO2
OH
OH
+
Ph
6a–6d
Toluene, reflux, 3.5 h
Br
O
5a–5d
Et
Et
Br
C2-Symmetrical diol
5
a
Yield/%
83a
de/%
2a
98%
1a
Et
Et
1) n-BuLi (1.5 equiv.)
THF, –78 °C, 15 min
MeNO2 (3.0 equiv.),
KOH aq. (1.5 equiv.)
OH
1a
95b (S)
OH
O
Et
2) DMF (3.0 equiv.)
rt, 1 h
MeOH–THF,
0 °C, 15 min
O
Et
Ph
Ph
OH
78
45
81
33c (R)
5c (S)
CHO
b
c
1b
1c
1d
OH
Et
O
3a
89%
Et
O
OH
OH
Ac2O (1.5 equiv.), DMAP
O
Et
O
Pyridine, 0 °C, 30 min
Et
NO2
MeO
MeO
OH
OH
65b (R)
NO2
OH
d
4a
5a
88%
86%
aReaction was carried out using 1.5 equiv. of PhLi for 30 min.
1
c
Scheme 1. Preparation of ꢀ-nitrostyrene 5a.
bDetermined by H NMR. Determined after conversion to 8.
Copyright Ó 2007 The Chemical Society of Japan

Chemistry Letters Vol.36, No.1 (2007)
65
Table 2. 1,4-Addition of various aryllithiums to ꢀ-nitrostyrene 5a
C
C
C
Et
Et
C
C
C
C
O
O
O
C
RLi (1.5 equiv.)
C
C
C
C
C
re face
C
O
O
C
THF, –100 °C, 30 min
C
O
C
Et
Et
C
C
O
N
NO2
NO2
O
C
Li
R
6a
Ar
C
si face
5a
Entry
R
Yield/%
dea/%
Figure 1. The most stable conformation of 5a. The hydrogen atoms
are omitted for clarity.
1
2
3
4
5
6
7
8
9
Ph
83
67
75
79
91
82
85
90
84
95
92
96
96
98
96
93
95
96
o-MeC6H4
m-MeC6H4
p-MeC6H4
p-ClC6H4
p-MeSC6H4
p-MeOC6H4
acetal moiety. Aryllithium approaches 5a from si face with the
aid of the coordination by one of oxgen atoms of the acetal
and adds to the double bond to afford 6a with high stereoselec-
tivity (Figure 1).
It should be noted that the conjugate addition of aryllithium
to ꢀ-nitrostyrene derivative having the chiral acetal moiety,
derived from (S,S)-1,2-bis(1-hydroxypropyl)benzene 1a, pro-
ceeded with high diastereoselectivity, and 4-aryl-1,2,3,4-tetra-
hydroisoquinoline was obtained conveniently in high ee. Other
applications of (S,S)-1,2-bis(1-hydroxypropyl)benzene 1a in
asymmetric reaction is now in progress.
3,4-MethylenedioxyC6H3
1-Naphthyl
aDetermined by H NMR.
1
position of the isoquinoline ring,7a,7c only a limited number of
methods have been reported so far on the enantioselective
synthesis of 4-aryl-1,2,3,4-tetrahydroisoquinoline.8 Thus, we
examined a transformation of the adduct 6a to chiral 4-phenyl-
1,2,3,4-tetrahydroisoquinoline 9. At first, the nitro group in 6a
was reduced to amino group in 87% by hydrogenation in the
presence of Raney Ni (MeOH, rt, 8 h). Then, the acetal moiety
of the resulting amine 7 was hydrolyzed (1 M aqueous HCl–ace-
tone, rt, 1 h) to aldehyde and 4-phenyl-3,4-dihydroisoquinoline 8
was obtained in 88% by the spontaneous intramolecular cycliza-
tion. The enantiomeric excess (ee) of the resulting 8 was 94% by
HPLC analysis which indicated that the stereochemistry at C-4
was maintained during the transformations. The chiral auxiliary,
(S,S)-1,2-bis(1-hydroxypropyl)benzene 1a, was recovered quan-
titatively by usual work up without the loss of ee. Then, 8 was
reduced to (S)-(–)-4-phenyl-1,2,3,4-tetrahydroisoquinoline 9
Dedicated to Prof. Teruaki Mukaiyama on the occasion of
his 80th birthday.
References and Notes
1
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(84%, ½ꢁꢃD ꢁ11:8 (c 1.01, MeOH)), (lit.;7c ½ꢁꢃD ꢁ11:1 (c
26
20
0.85, MeOH)) by NaBH4 (EtOH, rt, 4 h) (Scheme 2).
We assume the stereochemical course of the reaction of 5a
and aryllithium as follows; in the most stable conformation of 5a
obtained by conformational search carried out by the MM3 force
field with stochastic search algorithm,9 re face of the nitrosty-
rene moiety is blocked by one of the ethyl substituents in the
4
5
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Et
O
Et
O
6
7
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O
O
Et
NO2
Et
NH2
´
´
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Ph
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6a
7
87%
´
8
9
N. Philippe, V. Levacher, G. Dupas, G. Queguiner, J.
N
NH
1 M HCl aq.
NaBH4 (4.0 equiv.)
EtOH, rt, 4 h
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Acetone, rt, 1 h
Ph
Ph
8
9
84%
88%
10 Supporting Information is available electronically on the
CSJ-Journal Web site, http://www.csj.jp/journals/chem-lett/
index.html.
Scheme 2. Asymmetric synthesis of 4-phenyl-1,2,3,4-tetrahydro-
isoquinoline 9.
Published on the web (Advance View) December 23, 2006; doi:10.1246/cl.2007.64