A novel synthesis of chiral tetrahydroisoquinolines employing silyl enol ethers in the presence of chiral acyl chlorides

Article abstract of DOI:10.1055/s-1999-3160

6,7-Dimethoxyisoquinoline derivatives reacted with silyl enol ethers in a highly diastereoselective manner in the presence of an acyl chloride derived from L-alanine. (-)-Homolaudanosine was synthesized in an enantiopure form from 6,7-dimethoxyisoquinoline via six steps using this method.

Full text of DOI:10.1055/s-1999-3160

1154
LETTER
A Novel Synthesis of Chiral Tetrahydroisoquinolines Employing Silyl Enol
Ethers in the Presence of Chiral Acyl Chlorides
Takashi Itoh, Kazuhiro Nagata, Michiko Miyazaki, Akio Ohsawa*
School of Pharmaceutical Sciences, Showa University, 1-5-8 Hatanodai, Shinagawa-ku, Tokyo 142-8555, Japan
Fax +81-3-3784-5982; E-mail: ohsawa@pharm.showa-u.ac.jp
Received 13 April 1999
aged us to investigate a practical reaction system using
Abstract: 6,7-Dimethoxyisoquinoline derivatives reacted with silyl
6,7-dimethoxyisoquinoline, which is the ubiquitous par-
enol ethers in a highly diastereoselective manner in the presence of
ent nucleus of various isoquinoline alkaloids, as a sub-
an acyl chloride derived from L-alanine. (-)-Homolaudanosine was
strate. It was found that simple acyl chlorides derived
from L-alanine gave a good diastereoselectivity toward N-
acylated isoquinolines, and that dibromination of the sub-
strate not only accelerates the addition reaction but also
enhances the diastereoselectivity. In addition, the diaste-
reoselective adduct was readily converted to homo-
laudanosine to determine the absolute configuration. This
paper describes these results.
synthesized in an enantiopure form from 6,7-dimethoxyisoquino-
line via six steps using this method.
Key words: 6,7-dimethoxyisoquinoline, silyl enol ether, asymmet-
ric addition, chiral acyl chloride, homolaudanosine
1-Substituted tetrahydroisoquinoline alkaloids have been
intensive targets for organic synthesis because of their
ubiquitous occurrence in nature and diverse physiological
and pharmacological actions.1 In recent years, the enan-
tioselective procedures have been applied to these
studies.2 There has been a sole example,3 however, that
used the isoquinoline derivatives as the starting material
in spite of their ready availability. In the case, Comins et
al. showed that 6,7-dimethoxyisoquinoline was attacked
by methylmagnesium iodide in the presence of (-)-8-phe-
nylmenthyl chloroformate, and the reaction product was
converted by several steps to (+)-carnegine in 62% ee.4
Although this system was carried out by simple proce-
dures, the ee was insufficient.
Our attempts on the asymmetric synthesis commenced
with the selection of an effective chiral auxiliary. We re-
stricted our research area in the field of amino acids since
they are readily available, and fortunately, L-alanine, the
simplest and most inexpensive chiral amino acid, was re-
vealed to afford high de.7 Table 1 (and Scheme 2) shows
the results of the reaction using 4-bromoisoquinoline and
benzyltrimethylsilyl ketene acetal.8 The reaction was car-
ried out at -78 °C for 1h to compare the data systematical-
ly, and the de was estimated by NMR.
Br
Br
In the course of our studies on the reaction of N-acylated
azaaromatics, we found that a trace amount of N-acylated
azaaromatic was trapped efficiently by organotin
reagents5 and silyl enol ethers,6 both of which did not react
with parent azaaromatics and acylating reagents (Scheme
1).
H
H
OTMS
OBn
O
N
NHR
N
O
C
NHR
H
Me
H
Cl
C
H
Me
-78°C, 1 h
O
BnO
1
2
Scheme 2
RCOCl
Nu-
Nu
Although the addition did not occur in the cases of using
standard protecting groups such as benzyloxycarbonyl or
benzoyl group (entries 1 and 2), the more electron-with-
drawing phenylsulfonyl group afforded moderate de in
dichloromethane (entry 3). Sterically hindered naphthyl-
sulfonyl group gave a low de, but the more electron-at-
tractive p-nitrophenylsulfonyl group afforded higher de in
spite of rather slow reaction (entry 8). According to these
results, N-(p-nitrophenyl)sulfonyl-L-alanyl chloride was
selected as an activator for further investigation.9
N
N
N
H
COR
N-acylated
azaaromatics
COR
trapping in situ by silyl
enol ethers
Scheme 1
In the cases of isoquinolines, the nucleophiles attacked
exclusively at C-1 position, thus it was supposed that a
chiral acylating agent at N-2 position would induce asym-
metric addition of the nucleophile at C-1. In the previous
paper, we disclosed the possibility of asymmetric addition
of allyltributyltin to 4-bromoisoquinoline using MTPA
chloride as an acylating agent.6d This precedent encour-
Next, 6,7-dimethoxyisoquinoline and its derivatives, and
the ketene silyl acetal derived from benzyl acetate were
allowed to react in the presence of N-(p-nitrophenyl)sul-
Synlett 1999, No. 07, 1154–1156 ISSN 0936-5214 © Thieme Stuttgart · New York

LETTER
A Novel Synthesis of Chiral Tetrahydroisoquinolines Employing Silyl Enol Ethers
1155
stituent(s) increased not only the chemical yields, but also
the de, and it was up to 96% when two bromo groups were
introduced (entry 4). Compound 3d was found to show
high diastereoselectivity toward other silyl enol ethers
(entries 5-7).
Compound 3d was readily obtained from 3a by dibromi-
nation with Br2 and AlCl3 in 81% yield, and was reduced
to 3a by HCO2NH4-Pd/C in a quantitative yield. There-
fore, compound 3d was thought to be the active alterna-
tive for compound 3a, which is a ubiquitous nucleus for
many isoquinoline alkaloids (Scheme 4).
Br
MeO
MeO
MeO
MeO
Br2, AlCl3 81%
N
N
HCO2NH4-Pd/C y.q.
fonyl-L-alanyl chloride (Scheme 3 and Table 2, entries 1-
4).
Br
3a
3d
Scheme 4
X
H
H
OTMS
R
MeO
MeO
In order to determine the absolute configuration, the
above system was applied to the total synthesis of homo-
laudanosine, whose scheme is shown below (Scheme 5).
Compound 5 obtained in 93% yield (93% de) was treated
with HCO2NH4-Pd/C to eliminate the bromo groups, and
to reduce the double bond at C3-C4, and the nitro group
simultaneously to afford compound 6. This was treated
with H2/Pd-C according to Wanner’s procedure10 to re-
duce the keto carbonyl group. Reduction with LiAlH4 to
remove the chiral auxiliary and N-methylation afforded
(-)-homolaudanosine (8) in an optically pure form. The
overall yield from 3d was 32%.
N
O
C
NHR'
Cl
C
-78°C, 1 h
Y
H
Me
3
R'= p-nitrophenylsulfonyl
X
MeO
O
N
NHR'
MeO
Y
H
Me
H
O
R
In this paper, we described a new method for the asym-
metric addition of silyl enol ethers to N-acylated isoquin-
olinium salts and the concise total synthesis of (-)-
homolaudanosine from 6,7-dimethoxyisoquinoline. In the
crucial step, the unstable N-acylated derivative13 of the
key compound 3d was found to afford high diastereose-
lectivity toward the addition of silyl enol ethers. Although
there are examples of asymmetric addition to N-acylimin-
ium salts,14 they were prepared by elimination reaction of
neutral N-acyl compounds whose chiral centers exist in
other parts than acyl group, and few methods were report-
ed that the salts was formed by the direct attack of chiral
acyl halides.3, 10 Thus, our method might be of practical
use because the chiral auxiliary is readily exchanged and
removed. Application of this method to the total synthesis
of other isoquinoline alkaloids is now under investigation.
4
Scheme 3
References and Notes
(1) Herbert, R. B. in The Chemistry and Biology of Isoquinoline
Alkaloids, Philipson, J. D.; Roberts, M. F.; Zenk, M. H. Ed.
Springer Verlag, Berlin, 1985, p 213.
(2) Rozwadowska, M. D. Heterocycles 1994, 39, 903, and
references cited therein.
Although the moderate ee was observed in the parent one
(X=Y=H), the chemical yield was too low for practical
use (entry 1). In order to increase the reactivity, a electron-
withdrawing group was introduced to the substrate (en-
tries 2-4). The results showed that the introduction of sub-
(3) Comins, D. L.; Badawi, M. M. Heterocycles 1991, 32, 1869.
Synlett 1999, No. 07, 1154–1156 ISSN 0936-5214 © Thieme Stuttgart · New York

1156
T. Itoh et al.
LETTER
OTMS
Br
Br
Br
Br
MeO
MeO
R
MeO
MeO
O
(R=3,4-dimethoxyphenyl)
N
NHSO2
NO2
N
H
H
O
Me
NHSO2
NO2
O
3d
5 y. 93% (de 93%)11
Cl
C
C
H
Me
R
MeO
MeO
MeO
MeO
HCO2NH4-Pd/C
THF/MeOH
1) H2-Pd/C
AcOH/TFA
O
N
NH
NHSO2
NH2
2) LiAlH4, THF
H
H
H
Me
O
R
R
7 y. 50% from 5
6
MeO
MeO
20
NaBH3CN
N
Me
[α]D = -11.7° (c 0.75, EtOH)
HCHO 71%
H
25
lit.12 [α]D = +11.0° (c 0.21, EtOH)
MeO
for (+)-homolaudanosine
8
MeO
Scheme 5
(4) The overall yield of (+)-carnegine was not shown in ref. 3.
(5) a) Itoh, T.; Hasegawa, H.; Nagata, K.; Ohsawa, A. J. Org.
Chem. 1994, 59, 1319. b) Itoh, T.; Hasegawa, H.; Nagata, K.;
Okada, M.; Ohsawa, A. Tetrahedron 1994, 50, 13089.
(6) a) Itoh, T.; Miyazaki, M.; Hasegawa, H.; Nagata, K.; Ohsawa,
A. Chem. Commun. 1996, 1217. b) Itoh, T.; Matsuya, Y.;
Hasegawa, H.; Nagata, K.; Okada, M.; Ohsawa, A. J. Chem.
Soc., Perkin Trans. 1 1996, 2511. c) Itoh, T.; Miyazaki, M.;
Nagata, K.; Ohsawa, A. Heterocycles 1997, 46, 83. d) Itoh, T.;
Miyazaki, M.; Nagata, K.; Hasegawa, H.; Ohsawa, A.;
Nakamura, K. T. Heterocycles 1998, 47, 125.
(9) It is possible that p-(nitrophenyl)sulfonyl-L-alanyl group is
labile enough to racemize under these conditions. However,
no racemization was observed in our reaction processes,
which was confirmed by chiral HPLC.
(10) Wanner, K. T.; Praschak, I. Heterocycles 1989, 29, 29.
(11) Compound 5 was recrystallized with hexane/AcOEt to give a
single diastereomer.
(12) Aladesanmi, A. J.; Kelley, C. J.; Leary, J. D. J. Nat. Prod.
1983, 46, 127.
(13) In the reaction mixture, the N-acylated quaternary salt was not
detected by NMR due to its low concentration.
(7) Other amino acids were also investigated. L-Phenylalanine
and L-proline derived acyl chlorides afforded comparable
yields and diastereoselectivities to those obtained with the
alanine derivatives. The details will be disclosed in a separate
paper.
(14) de Koning, H.; Speckamp, W. N. in Stereoselective Synthesis;
Helmchen, G.; Hoffmann, R. W.; Mulzer, J.; Schaumann, E.
Ed.; Houben-Weyl: Stuttgart, 1996, Vol. 3, pp 1953-2009.
(8) In ref. 6d, 4-bromoisoquinoline was shown to be more
reactive to silyl enol ethers than parent isoquinoline.
Article Identifier:
1437-2096,E;1999,0,07,1154,1156,ftx,en;Y08499ST.pdf
Synlett 1999, No. 07, 1154–1156 ISSN 0936-5214 © Thieme Stuttgart · New York