Asymmetric Intramolecular Allylic Amination: Straightforward Approach to Chiral C1-Substituted Tetrahydroisoquinolines

Article abstract of DOI:10.1055/s-2003-41502

Newly introduced Pd-catalyzed asymmetric intramolecular allylic amination provides an easy access to pharmaceutically important 1-substituted tetrahydroisoquinolines. With this amination as the key step, (R)-carnegine was synthesized in an enantioselectiv

Full text of DOI:10.1055/s-2003-41502

LETTER
1809
Asymmetric Intramolecular Allylic Amination: Straightforward Approach to
Chiral C1-Substituted Tetrahydroisoquinolines
A
symmetric Intra
m
a
olecular
A
t
llylic
A
s
minationuji Ito,*a Suemi Akashi,a Bunnai Saito,b Tsutomu Katsuki*b
a
Department of Chemistry, Fukuoka University of Education, CREST,Japan Science and Technology (JST), Akama, Munakata, Fukuoka,
811-4192, Japan
Fax +81(940)351711; E-mail: itokat@fukuoka-edu.ac.jp
b
Department of Chemistry, Faculty of Science, Graduate School, Kyushu University 33, CREST, Japan Science and Technology (JST),
Hakozaki, Higashi-ku, Fukuoka 812-8581, Japan
Received 6 June 2003
fully used for this purpose in terms of enantioselectivity
are limited to the following three reactions: i) asymmetric
reduction of 1-alkylidenetetrahydroisoquinolines7 ii)
alkylation of 3,4-dihydroisoquinolines prepared by the
Bischler–Napieralski cyclization8 and iii) Sharpless
asymmetric dihydroxylation that was followed by Pomer-
anz–Fritsch cyclization.9 In the syntheses using such
asymmetric reactions, the chirality introduction and the
hetero-cyclization have been carried out separately. We
expected that the synthesis would become more efficient;
if the chirality introduction and the hetero-cyclization are
carried out in a single step and that asymmetric intra-
molecular allylic amination would be a good candidate for
that purpose (Scheme 1). The resulting vinyl substituent
at C1 is amenable to further functionalization to give
various optically active 1-substituted tetrahydroisoquino-
lines.
Abstract: Newly introduced Pd-catalyzed asymmetric intra-
molecular allylic amination provides an easy access to pharmaceu-
tically important 1-substituted tetrahydroisoquinolines. With this
amination as the key step, (R)-carnegine was synthesized in an
enantioselective manner.
Key words: asymmetric allylic amination, tetrahydroisoquinoline,
asymmetric catalysis, palladium, chiral P-N ligand
Alkaloids possessing 1-substituted tetrahydroiso-
quinoline skeleton include many pharmacologically
active compounds such as (S)-laudanosine, (S)-sinactine,
(S)-carnegine, and (S)-calycotomine (Figure 1).1 Thus,
construction of this class of compounds in optically active
forms has drawn much attention of synthetic organic
chemists and many efficient methodologies have been
reported.2 However, most of them use chiral building
blocks or rely on diastereoselective reactions for
introducing the chirality at C13–6 and, therefore, these
syntheses are condemned to use stoichiometric amount of
chiral sources.
*
*
L
L
L
L
MeO
MeO
Pd
Pd
NHR
O
NHR
O
MeO
MeO
R'
1
MeO
MeO
MeO
MeO
NMe
N
MeO
MeO
OMe
OMe
O
O
NR
*
(S)-Laudanosine
(S)-Sinactine
Scheme 1
MeO
MeO
MeO
Although many asymmetric allylic amination reactions
have been reported, most of them are intermolecular
ones10 and intramolecular version is limited to a few
examples that provide pyrrolidine or piperidine
derivatives with high enantioselectivity.11 We have
reported that chiral 2-(phosphinophenyl)pyridine ligands
bearing 7-substituted dihydropyrindine unit are efficient
chiral auxiliaries for palladium-catalyzed allylic alkyla-
tion of both acyclic and cyclic alkenyl substrates12 We
expected that palladium-mediated intramolecular allylic
amination of allyl carboxylate 1 giving 1-vinyltetrahy-
droisoquinoline derivatives would be realized in a highly
NMe
NH
OH
MeO
(S)-Carnegine
(S)-Calycotomine
Figure 1
With the development of asymmetric reactions, much
effort has been directed toward the synthesis using cata-
lytic enantioselective reaction as the key step for chirality
introduction at C1, but the asymmetric reactions success-
SYNLETT 2003, No. 12, pp 1809–1812
2
9
.0
9
.2
0
0
3
Advanced online publication: 19.09.2003
DOI: 10.1055/s-2003-41502; Art ID: U10703st.pdf
© Georg Thieme Verlag Stuttgart · New York

1810
K. Ito et al.
LETTER
Pd2(dba)3•CHCl3
(1.5 mol%)
enantioselective manner by using chiral 2-(phosphinophe-
nyl)pyridine as the chiral auxiliary. Here, we wish to re-
port a new approach toward chiral 1-substituted
MeO
MeO
1a
N
chiral ligand
(3.0 mol%)
Cs2CO3
COCF3
*
tetrahydroisoquinolines using
a palladium-mediated
asymmetric allylic amination as the key step.
Scheme 3
Table 1 Asymmetric Intramolecular Allylic Amination of 1a
The requisite substrates 1a,b13 for the present study were
prepared in a conventional manner, starting from
commercial 3,4-dimethoxyphenethylamine as described
in Scheme 2.
En- Ligand Solvent
try
Temp
Time Yield Eea
(%)
Configu-
rationb
1) (CF3CO)2O
MeO
MeO
NHCOCF3
MeO
MeO
NH2
1
2
2
2
3
3
4
4
5
5
CH2Cl2
DMF
r.t.
4 h
–
90
–
39
–
R
–
NEt3
2) HIO3, I2
66%
I
2
r.t.
3c
4
DMF
60 °C
r.t.
18 d
3 d
52
58
42
83
82
76
51
67
12
23
53
23
24
32
R
R
R
S
OH
MeO
MeO
NHCOCF3
H2/P2-Ni
CH2Cl2
DMF
(PPh3)2PdCl2, CuI
HNEt2
quant.
5c
6
60 °C
r.t.
13 d
4 d
quant.
OH
CH2Cl2
DMF
NHCOCF3
NHCOCF3
O
MeO
MeO
MeO
7
60 °C
r.t.
18 h
4 d
R
R
R
MeO
R'
OH
O
8
CH2Cl2
DMF
1a: R'= Me quant.
1b: R'= t-Bu 95%
Ac2O, NEt3 for 1a
pivaloyl chloride, pyridine for 1b
9c
60 °C
24 d
Scheme 2
a Enantiomeric excess was determined by HPLC analysis using chiral
stationary phase column (Daicel Chiralcel OJ-H; hexane:i-
PrOH = 90:10).
We first examined the intramolecular allylic amination of
1a using cesium carbonate as a base in dichloromethane in
the presence of a catalytic amount of Pd(0) complex of 2-
(phosphinophenyl)pyridine 2 (Table 1). The reaction pro-
ceeded smoothly at room temperature but enantioselectiv-
ity was low (entry 1). On the other hand, use of
dimethylformamide (DMF) as the solvent inhibited the re-
action: no reaction occurred at room temperature, but the
reaction proceeded slowly at 60 °C in the absence of the
base and showed moderate enantioselectivity of 67% ee
(entries 2 and 3). The reaction was also examined with 2-
(phosphinophenyl)oxazoline 3 that have been proved ex-
cellent chiral auxiliary for intermolecular and some
intramolecular allylic substitutions,14 but only modest
enantioselectivity was observed (entries 4 and 5). In con-
trast, the reaction using BINAP (4) in dichloromethane
showed moderate enantioselectivity of 53% ee, while the
use of DMF as the solvent reduced enantioselectivity and
reversed the sense of asymmetric induction (entries 6 and
7). We also examined the reaction using the bulkier tol-
BINAP (5) but both the enantioselectivities of the re-
actions in dichloromethane and in DMF were modest
(entries 8 and 9, Figure 2 and Scheme 3).
b Configuration was determined by comparison with the published
value after converted to the 6,7-dimethoxy-1-ethyl-1,2,3,4-tetrahy-
droisoquinoline (ref.7h).
c Reaction was performed in the absence of cesium carbonate.
It is known that the nature of the leaving group of the
alkenyl substrate often affects enantioselectivity and/or
reactivity in allylic substitution.12 Thus, we examined the
cyclization of 1b bearing bulky pivaloyloxy group as the
leaving group, by using Pd-2 complex as the catalyst
(Table 2, Scheme 4). Fortunately, the reaction in
dichloromethane proceeded with good enantioselectivity
of 75% ee as well as good chemical yield (entry 1).
Lowering the reaction temperature diminished the
enantioselectivity and the reaction rate (entry 2). On the
other hand, the reaction in DMF at 60 °C showed a slight-
ly better enantioselectivity of 82% ee, though the reaction
was slow (entry 6). Further raising the reaction
temperature accelerated the cyclization, but the enantiose-
lectivity was somewhat reduced (entries 7 and 8). We next
examined the effect of the base in the reaction in dichloro-
methane: the reaction rate became slow in the order of
Cs2CO3>K2CO3>Na2CO3>Li2CO3, but the maximum
enantioselectivity of 88% ee was observed when K2CO3
or Na2CO3 was used as the base (entries 3 and 4).15 The re-
action using BINAP (4) was also examined, but the
reaction was slow and the enantioselectivity was low (en-
try 9).
O
PR2
N
PPh2
N
PPh2
PR2
The cyclization product 616 was converted into alcohol 7a
by the sequence: i) deprotection of trifluoroacetyl group
by LAH reduction, ii) ethoxycarbonylation of the
R= Ph: BINAP (4)
R= p-toluyl: tol-BINAP (5)
2
3
Figure 2
Synlett 2003, No. 12, 1809–1812 © Thieme Stuttgart · New York

LETTER
Asymmetric Intramolecular Allylic Amination
1811
from hexane–dichloromethane twice, iii) alcoholysis of
7b (K2CO3–EtOH). Enantiomerically enriched 7a17 thus
obtained was then converted to (R)-(+)-carnegine (8), the
enantiomeric form of natural (S)-(–)-carnegine, according
to the reported procedure with some modifications:3d i) to-
sylation using a combination of tosyl chloride and N,N-
dimethylaminopyridine in dichloromethane and ii) LAH
reduction in diethyl ether. The spectroscopic data were
identical with those reported by Szarek et al.3d The specif-
ic rotation of 8 was +25.7° (c 0.042, EtOH) {Lit.6a [for
(R)-carnegine] +23.4° (c 1.5, EtOH)}.
Scheme 4
Table 2 Asymmetric Intramolecular Allylic Amination of 1b
Entry Ligand Solvent Base
Temp
Time Yield Eea
(%)
1
2
2
2
2
2
2
2
2
4
CH2Cl2 Cs2CO3 r.t.
CH2Cl2 Cs2CO3 0 °C
CH2Cl2 K2CO3 r.t.
CH2Cl2 Na2CO3 r.t.
21 h 92
5 d 89
75
40
88
88
–
In conclusion, we were able to develop new intra-
molecular allylic amination and to demonstrate its utility
for enantioselective synthesis of C1-substituted isoquino-
line alkaloids. Further study on the mechanism of asym-
metric induction is in progress in our laboratory.
2
3
12 d 89
23 d 49
4
5
CH2Cl2 Li2CO3
r.t.
–
–
References
6b
7b
8b
9c
DMF
DMF
DMF
–
–
–
60 °C
80 °C
100 °C
23 d 58
3 h 76
3 h 78
36 d 63
82
79
77
33
(1) (a) Herbert, R. B. In The Chemistry and Biology of
Isoquinoline Alkaloids; Philipson, J. D.; Roberts, M. F.;
Zenk, M. H., Eds.; Springer Verlag: Berlin, Heidelberg, New
York, Tokyo, 1985, 213. (b) Bentley, K. W. In The
Isoquinoline Alkaloids; Harwood Academic Publishers:
Amsterdam, 1998.
CH2Cl2 Cs2CO3 r.t.
(2) For a review, see: Rozwadowska, M. D. Heterocycles 1994,
39, 903.
a Enantiomeric excess was determined by HPLC analysis using chiral
stationary phase column (Daicel Chiralcel OJ-H; hexane:i-
PrOH = 90:10).
(3) (a) Brossi, A.; Focella, A.; Teitel, S. Helv. Chim. Acta 1972,
55, 15. (b) Konda, M.; Shioiri, T.; Yamada, S. Chem.
Pharm. Bull. 1975, 23, 1025. (c) Piper, I. M.; MacLean, D.
B.; Kvarnstrom, I.; Szarek, W. Can. J. Chem. 1983, 61,
2721. (d) Czarnocki, Z.; MacLean, D. B.; Szarek, W. Can. J.
Chem. 1986, 64, 2205. (e) Comins, D. L.; Badawi, M.
Tetrahedron Lett. 1991, 32, 2995. (f) Kawate, T.; Yamada,
H.; Matsumizu, M.; Nishida, A.; Nakagawa, M. Synlett
1997, 761. (g) Ziólkowski, M.; Czarnocki, Z. Tetrahedron
Lett. 2000, 41, 1963.
(4) (a) Meyers, A. I.; Dickman, D. A. J. Am. Chem. Soc. 1987,
109, 1263. (b) Pyne, S. G.; Dikic, S. J. Org. Chem. 1990, 55,
1932. (c) Hashigaki, K.; Kan, K.; Qais, N.; Takeuchi, Y.;
Yamato, M. Chem. Pharm. Bull. 1991, 39, 1126.
(d) Meyers, A. I.; Warmus, J. S.; Gonzalez, M. A.; Guiles, J.;
Akahane, A. Tetrahedron Lett. 1991, 32, 5509. (e) Meyers,
A. I. Tetrahedron 1992, 48, 2589. (f) Nakamura, M.; Hirai,
A.; Nakamura, E. J. Am. Chem. Soc. 1996, 118, 8489.
(g) Okamoto, S.; Teng, X.; Fujii, S.; Takayama, Y.; Sato, F.
J. Am. Chem. Soc. 2001, 123, 3462. (h) Adam, S.;
Pannecoucke, X.; Combret, J.-C.; Quirion, J.-C. J. Org.
Chem. 2001, 66, 8744.
b Reaction was performed in the absence of base.
c S-Isomer was obtained.
resulting secondary amine, and iii) oxidative cleavage of
double bond under modified Lemieux–Johnson condi-
tions and subsequent reduction with sodium borohydride
(Scheme 5). The exchange of the N-protecting group was
required, because the modified Lemieux–Johnson oxida-
tion of 6 gave messy product. Enantiomeric excess of 7a
was enhanced to 98% ee by the following step: i) 3,5-dini-
trobenzoylation of 7a to 7b, ii) recrystallization of 7b
MeO
MeO
MeO
MeO
1) LAH
N
N
COOEt
COCF3
2) ClCOOEt
pyridine
6
95%
(5) (a) Yamada, K.; Takeda, M.; Iwakuma, T. J. Chem. Soc.,
Perkin Trans. 1 1983, 265. (b) Polniaszek, R. P.; Kaufman,
C. R. J. Am. Chem. Soc. 1989, 111, 4859.
1) K2OsO4•2H2O
NaIO4
MeO
MeO
N
(6) (a) Pyne, S. G.; Bloem, P.; Chapman, S. L.; Dixon, C. E.;
Griffith, R. J. Org. Chem. 1990, 55, 1086. (b) Richter-
Addo, G. B.; Knight, D. A.; Dewey, M. A.; Arif, A. M.;
Gladysz, J. A. J. Am. Chem. Soc. 1993, 115, 11863.
(c) Chan, E.; Lee, A. W. M.; Jiang, L. Tetrahedron Lett.
1995, 36, 715. (d) Wirth, T.; Fragale, G. Synthesis 1998,
162. (e) Wünsch, B.; Nerdinger, S. Eur. J. Org. Chem. 1998,
711. (f) Itoh, T.; Nagata, K.; Miyazaki, M.; Ohsawa, A.
Synlett 1999, 1154. (g) Pedrosa, R.; Andrés, C.; Iglesias, J.
M. J. Org. Chem. 2001, 66, 243. (h) Alexakis, A.; Amiot, F.
Tetrahedron: Asymmetry 2002, 13, 2117.
COOEt
2) NaBH4
69%
OR
7a: R= H
7b: R= C(O)C6H3(3,5-NO2)
94%
90%
MeO
MeO
(R)-(+)-Carnegine (8)
1) p-TsCl, DMAP
N
Me
2) LAH
61%
Scheme 5
Synlett 2003, No. 12, 1809–1812 © Thieme Stuttgart · New York

1812
K. Ito et al.
LETTER
(14) (a) von Matt, P.; Pfaltz, A. Angew. Chem., Int. Ed. Engl.
(7) (a) Noyori, R.; Ohta, M.; Hsiao, Y.; Kimura, M.; Ohta, T.;
Takaya, H. J. Am. Chem. Soc. 1986, 108, 7117. (b)Kimura,
M.; Hsiao, Y.; Ohta, M.; Tsukamoto, M.; Ohta, T.; Takaya,
H.; Noyori, R. J. Org. Chem. 1994, 59, 297. (c) Morimoto,
T.; Achiwa, K. Tetrahedron: Asymmetry 1995, 6, 2661.
(d) Morimoto, T.; Suzuki, N.; Achiwa, K. Heterocycles
1996, 43, 2557. (e) Willoughby, C. A.; Buchwald, S. L. J.
Am. Chem. Soc. 1994, 116, 8952. (f) Willoughby, C. A.;
Buchwald, S. L. J. Am. Chem. Soc. 1994, 116, 11703.
(g) Uematsu, N.; Fujii, A.; Hashiguchi, S.; Ikariya, T.;
Noyori, R. J. Am. Chem. Soc. 1996, 118, 4916. (h) Kang, J.;
Kim, J. B.; Cho, K. H.; Cho, B. T. Tetrahedron: Asymmetry
1997, 8, 657. (i) Morimoto, T.; Suzuki, N.; Achiwa, K.
Tetrahedron: Asymmetry 1998, 9, 183. (j) Mao, J.; Baker,
D. C. Org. Lett. 1999, 1, 841.
1993, 32, 566. (b) Sprinz, J.; Helmchen, G. Tetrahedron
Lett. 1993, 34, 1769. (c) Dawson, G. J.; Frost, C. G.;
Williams, J. M. J. J. Tetrahedron Lett. 1993, 34, 3149.
(d) Loiseleur, O.; Meier, P.; Pfaltz, A. Angew. Chem., Int.
Ed. Engl. 1996, 35, 200.
(15) Typical Experimental Procedure for Allylic Amination:
Tris(dibenzylideacetone)dipalladium(0) chloroform adduct
(1.9 mg, 1.8 mmol) and ligand 2 (1.5 mg, 3.6 mmol) was
placed in a flask under nitrogen and CH2Cl2 (0.36 mL) was
added. After being stirred for 30 min at r.t., compound 1b
(50 mg, 0.12 mmol) in CH2Cl2 (0.24 mL) and K2CO3 (49.8
mg, 0.36 mmol) was added successively and the mixture was
stirred at the temperature for 12 d. The mixture was
quenched with H2O and extracted with CH2Cl2. The extract
was dried over anhyd MgSO4 and concentrated. Silica gel
chromatography of the residue (hexane–EtOAc = 9:1) gave
the desired product (33.7 mg, 89%) as an oil. [a]D23 –157.7
(c 0.38, CHCl3). 1H NMR analysis of the product at 24 °C
revealed that it existed as a 78:22 mixture of two rotamers
based on the amide function. 1H NMR (400 MHz): d = 6.64
(s, 0.22 H), 6.61 (s, 0.78 H), 6.60 (s, 0.78 H), 6.56 (s, 0.22
H), 6.06–5.93 (m, 1.78 H), 5.48–5.45 (m, 0.22 H), 5.33–5.29
(m, 1 H), 5.17–5.11 (m, 0.78 H), 5.05 (d, J = 17.2 Hz, 0.22
H), 4.55–4.48 (m, 0.22 H), 4.09–3.98 (m, 0.78 H), 3.87 (s, 3
H), 3.85 (s, 3 H), 3.56 (dt, J = 4.0 and 12.0 Hz, 0.78 H), 3.26
(dt, J = 4.8 and 12.4 Hz, 0.22 H), 3.02–2.92 (m, 1 H), 2.78–
2.71 (m, 1 H). Anal. Calcd for C15H16F3NO3: C, 57.14; H,
5.12; N, 4.44. Found: C, 57.02; H, 5.16; N, 4.42.
(8) Ukaji, Y.; Shimizu, Y.; Kenmoku, Y.; Ahmed, A.; Inomata,
K. Chem. Lett. 1997, 59.
(9) (a) Hirsenkorn, R. Tetrahedron Lett. 1990, 31, 7591.
(b) Hirsenkorn, R. Tetrahedron Lett. 1991, 32, 1775.
(10) For reviews see: (a) Hayashi, T. In Catalytic Asymmetric
Synthesis; Ojima, I., Ed.; VCH: Weinheim, 1993, 325.
(b) Trost, B. M.; van Vranken, D. L. Chem. Rev. 1996, 96,
395. (c) Johannsen, M.; Jørgensen, K. A. Chem. Rev. 1998,
98, 1689.
(11) Example of intramolecular allylic amination: (a) Trost, B.
M.; Krische, M. J.; Radinov, R.; Zanoni, G. J. Am. Chem.
Soc. 1996, 118, 6297. (b) Domino Heck-allylic amination:
Flubacher, D.; Helmchen, G. Tetrahedron Lett. 1999, 40,
3867.
(12) (a) Ito, K.; Kashiwagi, R.; Iwasaki, K.; Katsuki, T. Synlett
1999, 1563. (b) Ito, K.; Kashiwagi, R.; Hayashi, S.; Uchida,
T.; Katsuki, T. Synlett 2001, 284.
Enantiomeric excess of the product was determined to be
88% by HPLC using a chiral stationary phase column
(Daicel Chiralcel OJ-H; hexane:i-PrOH= 9:1).
(13) All the compounds in Scheme 2 gave satisfactory 1H NMR
(400 MHz) spectra. Compound 1a: d = 6.73 (dt, J = 1.2 and
11.2 Hz, 1 H), 6.65 (s, 1 H), 6.64 (s, 1 H), 5.81 (dt, J = 6.8
and 11.2 Hz, 1 H), 4.71 (dd, J = 1.2 and 6.8 Hz, 2 H), 3.87
(s, 6 H), 3.52 (dt, J = 6.8 and 6.8 Hz, 2 H), 2.87 (t, J = 6.8
Hz, 2 H), 2.03 (s, 3 H). Compound 1b: d = 6.95 (br s, 1 H),
6.74 (dt, J = 1.2 and 11.2 Hz, 1 H), 6.65 (s, 1 H), 6.62 (s, 1
H), 5.77 (dt, J = 6.8 and 11.2 Hz, 1 H), 4.73 (dd, J = 1.2 and
6.8 Hz, 2 H), 3.87 (s, 3 H), 3.86 (s, 3 H), 3.53–3.43 (m, 2 H),
2.89 (t, J = 6.8 Hz, 2 H), 1.13 (s, 9 H).
(16) A larger scale cyclization of 1b (0.64 mmol scale) afforded
6 with slightly reduced enantioselectivity (85% ee). This
compound 6 was used for the following reactions.
(17) The specific rotation of 7a (98% ee) was [a]D24 –91.0 (c 2.03,
CHCl3) {Lit. R-isomer3d [a]D23 +88.8 (c 2.08, CHCl3)}.
Since the enantiomer of 7a has been converted into the
enantiomers of (S)-calycotomine and (S)-N-methyl-
calycotomine respectively, the synthesis of 7a means that
formal total syntheses of those isoquinoline alkaloids have
been achieved.3d
Synlett 2003, No. 12, 1809–1812 © Thieme Stuttgart · New York