SPECIAL TOPIC
Asymmetric Synthesis of Tetrahydro- and Dihydroisoquinoline Derivatives
1717
tives by the efficient chiral phase-transfer catalysis of
(S,S)-3,4,5-F3-Ph-NAS-Br. This also paved the way for
the catalytic asymmetric synthesis of quaternary isoquin-
oline derivatives, which are expected to produce polypep-
tides with even more constrained conformations.
Figure 2 Structures of some 1,2,3,4-tetrahydroisoquinoline-3-car-
boxylic Acid Derivatives
tert-Butyl (3R)-3-Methyl-1,2,3,4-tetrahydroquinoline-3-
carboxylate (9a); Typical Procedure
To a mixture of 8a (134 mg, 0.5 mmol), chiral catalyst (S,S)-3,4,5-
F3-Ph-NAS-Br (4.6 mg, 0.005 mmol) and , ’-dibromo-o-xylene
(5; 145 mg, 0.55 mmol) in toluene (2 mL) was added CsOH H2O
(420 mg, 2.5 mmol; commercially available from Aldrich Chemical
Co., Inc., and used without further treatment) at 0 °C, and the reac-
tion mixture was stirred vigorously for 0.5 h. Then H2O was added
and the extraction was performed with Et2O. Solvents were evapo-
rated and the residue was dissolved in THF (2 mL). After the addi-
tion of 0.5 M citric acid (5 mL), the mixture was stirred at r.t. for 1
h. The aqueous phase was separated and washed with hexane to re-
move organic-soluble materials. It was then basified by the addition
of solid NaHCO3 and extracted with Et2O. The organic extracts
were dried (Na2SO4) and concentrated. Purification of the residual
oil by column chromatography on silica gel (EtOAc–hexane, 2:1 as
eluent) gave the alkylation product 9a (79 mg, 64%) as a colorless
oil. 1H NMR (400 MHz, CDCl3) 7.00–7.13 (4H, m, Ar), 4.14 (1H,
d, J = 16.0 Hz, CHN), 4.02 (1H, d, J = 16.0 Hz, CHN), 3.18 (1H, d,
J = 16.0 Hz, CHCCO), 2.75 (1H, d, J = 16.0 Hz, CHCCO), 1.67
(1H, br s, NH), 1.40 (3H, s, Me), 1.36 (9H, s, t-Bu).
tives. When a p-chlorobenzaldehyde Schiff base of DL-
alanine tert-butyl ester (8a) was treated with 5,
CsOH H2O (5 equiv) and a catalytic amount of (S,S)-
3,4,5-F3-Ph-NAS-Br (1 mol%) in toluene at 0 °C for 0.5
hours, the transient monoalkylation product was rapidly
produced, which was transformed into the desired 9a
(64%, 88% ee) by similar workup procedure (Scheme 2).
The efficiency of this alkylation-cyclization sequence
seemed to be scarcely affected by the substituent of the
starting -amino acid as demonstrated by the reactions
with DL-leucine- and DL-phenylalanine-derived Schiff
bases 8b and 8c. Moreover, catalytic asymmetric phase-
transfer alkylation of 8a with 10 (1.1 equiv) under similar
conditions followed by the sequential treatment with 1 N
HCl and then excess NaHCO3 furnished the correspond-
ing dihydroisoquinoline derivative 11a in 87% yield with
94% ee. The sensitivity of the present system involving
intramolecular imine formation to the steric demand of the
-substituent of the parent amino acid was implied by the
decreased chemical yield and enantioselectivity observed
in the reaction of 8c.
IR (liquid film) 3340, 2976, 1724, 1458, 1369, 1257, 1163, 1113,
849, 745 cm–1.
MS: m/z 248 ([M + H]+), 246, 192, 190, 146 (100%), 144.
HRMS Calcd for C15H21NO2: 247,1572 (M+). Found: 247,1555
M+).
In conclusion, we have presented a facile asymmetric syn-
thesis of tetrahydroisoquinoline-3-carboxylic acid deriva-
The enantiomeric excess was determined by chiral HPLC analysis
of the corresponding N-benzoate [DAICEL CHIRALPAK AD,
hexane–propan-2-ol, 10:1, flow rate 0.5 mL/min, retention time
13.5 min (S) and 15.5 min (R)].
O
p-Cl-Ph
N
OBut
Acknowledgement
R"
8a (R" = Me)
8b (R" = i-Bu)
8c (R" = Bn)
This work was partially supported by a Grant-in-Aid for Scientific
Research from the Ministry of Education, Culture, Sports, Science
and Technology, Japan.
Br
Br
Br
O
5
10
O
References
(S,S)-3,4,5-F3-Ph-NAS-Br
(1 mol%)
(1) (a) Bently, K. W. The Isoquinoline Alkaloids; Harwood
Academic: Singapore, 1998. (b) Biagani, S. C. G.; North,
M. In Amino Acids, Peptides and Proteins Specialist
Periodicals Reports, Vol. 27; Davies, J. S., Ed.; The Royal
Society of Chemistry: London, 1996, Chap. 3. (c) Gante, J.
Angew. Chem. Int. Ed. Engl. 1994, 33, 1699. (d) Giannis,
A.; Kolter, T. Angew. Chem. Int. Ed. Engl. 1993, 32, 1244.
(e) Grethe, G. In The Chemistry of Heterocyclic Compounds,
Vol. 38, Part 1; Wiley: New York, 1981. (f)Kametani,T. In
The Total Synthesis of Natural Products, Vol. 3; Apsimon,
J., Ed.; Wiley: New York, 1977.
toluene, 0 °C, 0.5–1 h
1) 0.5 M citric acid/THF
2) excess NaHCO3
1) 1 N HCl/THF
2) excess NaHCO3
R"
R"
CO2But
CO2But
NH
9
N
11
64%, 88% ee (9a, R" = Me)
56%, 84% ee (9b, R" = i-Bu)
60%, 84% ee (9c, R" = Bn)
87%, 94% ee (11a, R" = Me)
53%, 87% ee (11c, R" = Bn)
[–10 °C, 3 h]
(2) (a) Grunewald, G. L.; Caldwell, T. M.; Li, Q.; Criscione, K.
R. Bioorg. Med. Chem. 1999, 7, 869. (b) Steinbaugh, B. A.;
Hamilton, H. V.; Patt, W. C.; Rapundalo, S. T.; Batley, B. L.;
Scheme 2
Synthesis 2001, No. 11, 1716–1718 ISSN 0039-7881 © Thieme Stuttgart · New York