2452
K. Tomooka et al.
LETTER
NMR (67.5 MHz): d = 164.8, 143.2, 141.0, 132.5, 128.6,
128.5, 128.3, 127.8, 127.6, 126.6, 126.1, 124.4, 74.1, 58.8,
40.8, 32.2, 31.6, 25.4, 22.8, 13.9.
n-Bu
n-Bu OLi
n-Bu OLi
O
R
R
1
Li
Li
R
4
3
(1S,1'R)-2
N
N
H
1'
5a: dr = 85:15. 1H NMR (300 MHz): d = 8.10 (d, J = 7.5 Hz,
1 H), 7.65–7.35 (m, 3.90 H), 7.20–7.15 (m, 2.58 H), 7.07–
7.04 (m, 1.71 H), 6.64 (br s, 0.85 H), 6.36 (br s, 0.15 H), 4.86
(s, 0.15 H), 4.64 (d, J = 4.5 Hz, 0.85 H), 2.31 (br s, 0.15 H),
2.05–1.97 (m, 1.85 H), 1.90 (br s, 0.85 H), 1.57–1.40 (m,
0.85 H), 1.57–1.07 (m, 3.15 H), 1.06–0.95 (m, 0.15 H), 0.86
(t, J = 7.5 Hz, 2.55 H), 0.68 (t, J = 7.5 Hz, 0.45 H). 13C NMR
(75 MHz): d = 166.43, 165.10, 143.89, 142.89, 136.73,
135.56, 132.72, 132.25, 128.74, 128.58, 128.51, 128.46,
128.00, 127.86, 127.70, 126.63, 125.40, 125.13, 74.54,
73.61, 65.78, 63.74, 41.66, 34.72, 29.70, 25.82, 24.88,
22.89, 14.06, 13.96.
NLi
R
Li
O
O
O
(1S,1'R)-v
vi
(3S,4S)-iii
O
n-Bu OLi
n-Bu OLi
1
Li
Li
R
n-Bu
N
(1R,1'R)-2
N
H
1'
NLi
R
Li
O
O
O
(1R,1'R)-v
epi-vi
(3S,4R)-iii
O
n-Bu OLi
5b: dr = >95:<5. 1H NMR (300 MHz): d = 8.10 (d, J = 7.5
Hz, 1 H), 7.57–7.50 (m, 2 H), 7.45–7.40 (m, 1 H), 7.30–7.26
(m, 3 H), 7.22–7.19 (m, 2 H), 6.40 (br s, 1 H), 4.61 (d, J = 3.3
Hz, 1 H), 2.08 (s, 1 H), 1.67 (s, 3 H). 13C NMR (75 MHz):
d = 65.17, 143.70, 136.58, 133.36, 128.83, 128.75, 128.70,
128.30, 128.11, 126.67, 124.14, 71.21, 65.50, 28.33.
5c: dr = >95:<5. 1H NMR (270 MHz, DMSO-d6): d = 8.22
(d, J = 3.1 Hz, 1 H), 7.98 (dd, J = 7.3, 1.8 Hz, 1 H), 7.54–
7.46 (m, 2 H), 7.26 (s, 5 H), 7.16–7.04 (m, 6 H), 6.14 (s, 1
H), 4.98 (d, J = 3.1 Hz, 1 H).
R
Li
H
n-Bu
N
R
NLi
Li
O
ent-vi
O
(3R,4R)-iii
Scheme 9
References and Notes
5d: dr = 58:42. 1H NMR (300 MHz): d = 7.97 (d, J = 7.2 Hz,
0.42 H), 7.69 (d, J = 7.2 Hz, 0.58 H), 7.53–7.30 (m, 5 H),
7.25–7.14 (m, 3 H), 6.51 (br s, 0.58 H), 6.25 (br s, 0.42 H),
4.88–4.74 (m, 2 H), 2.71 (br s, 0.58 H), 2.18 (br s, 0.42 H).
13C NMR (75 MHz): d = 166.02, 165.96, 139.24, 138.90,
138.51, 136.61, 132.99, 132.81, 128.98, 128.80, 128.58,
128.19, 128.04, 127.83, 127.41, 127.17, 127.07, 71.68,
69.24, 62.48, 60.33.
(1) (a) Chrzanowska, M.; Rozwadowska, M. D. Chem. Rev.
2004, 104, 3341. (b) Briet, N.; Brookes, M. H.; Davenport,
R. J.; Galvin, F. C. A.; Gilbert, P. J.; Mack, S. R.; Sabin, V.
Tetrahedron 2002, 58, 5761.
(2) For recent studies of the asymmetric synthesis of tetrahydro-
isoquinolones, see: (a) Vicario, J. L.; Badia, D.; Carrillo, L.;
Anakabe, E. Tetrahedron: Asymmetry 2003, 14, 347.
(b) Derdau, V.; Snieckus, V. J. Org. Chem. 2001, 66, 1992.
(c) Davis, F. A.; Mohanty, P. K.; Burns, D. M.;
(6) The diastereomeric ratio was determined by 1H NMR
analysis.
Andemichael, Y. W. Org. Lett. 2000, 2, 3901. (d) Davis, F.
A.; Andemichael, Y. W. J. Org. Chem. 1999, 64, 8627.
(e) Clark, R. D.; Souchet, M.; Kern, J. R. J. Chem. Soc.,
Chem. Commun. 1989, 930.
(7) Bisagni and co-workers reported a similar tetrahydroiso-
quinolone synthesis involving the dilithiated intermediate,
see: Delcey, M. C.; Huel, C.; Bisagni, E. Heterocycles 1995,
41, 1721.
(3) (a) Tomoyasu, T.; Tomooka, K. Synlett 2004, 1925.
(b) Tomoyasu, T.; Tomooka, K.; Nakai, T. Tetrahedron Lett.
2003, 44, 1239. (c) Tomoyasu, T.; Tomooka, K.; Nakai, T.
Tetrahedron Lett. 2000, 41, 345. (d) Tomoyasu, T.;
Tomooka, K.; Nakai, T. Synlett 1998, 1147.
(8) The exact origin of the observed high reactivity of MeLi
compared with that of n-BuLi is not clear at present, though
it might be considered as the result of a difference of their
aggregation states.
(9) Ring-Enlarging Reaction; Typical Procedure: To a
solution of hemiaminal 6b (61 mg, 0.24 mmol) in anhyd
THF (10 mL) was added MeLi (1.04 M solution in Et2O;
1.15 mL, 1.20 mmol) dropwise at –78 °C under an argon
atmosphere. The resulting mixture was stirred at –78 °C for
30 min and then the temperature was allowed to rise to 0 °C
over a period of 30 min. The reaction was quenched with a
sat. aq solution of NH4Cl. The aqueous layer was extracted
with EtOAc. Then, the combined organic layer was washed
with a sat. aq solution of NaCl, dried over Na2SO4, filtered,
and the solvent was removed under reduced pressure. Puri-
fication by silica gel chromatography (hexane–EtOAc, 3:1)
gave 56 mg (91%; dr 93%) of tetrahydroisoquinolone 5b.
(10) The relative stereochemistry of 5c was determined as syn by
X-ray crystallography of its dimethylated derivative 13
(Scheme 10). The stereochemistry of tetrahydroiso-
quinolones 5a, 5b, and 5d was speculated as syn based on its
similarity with 5c. Crystallographic data for 13 have been
deposited with the Cambridge Crystallographic Data Center
as supplementary publication no. CCDC 610566. Copies of
the data can be obtained free of charge on application to
CCDC, 12 Union Road, Cambridge CB21EZ, UK (deposit
@ccdc.cam.ac.uk).
(4) The ring-enlarging reaction of the phthalimide-derived
enolate is well established as the Gabriel–Colman rearrange-
ment; see: Allen, C. F. H. Chem. Rev. 1950, 47, 275.
(5) All the compounds were characterized by 1H and 13C NMR
analyses (recorded in CDCl3 unless specified otherwise).
Data for selected products follow.
(1R*,1¢R*)-2: 1H NMR (270 MHz): d = 7.71–7.67 (m, 1 H),
7.52–7.40 (m, 3 H), 7.25–7.09 (m, 5 H), 3.23 (dd, J = 9.2,
5.3 Hz, 1 H), 2.70–1.90 (m, 6 H), 1.61–0.79 (m, 34 H). 13
NMR (67.5 MHz): d = 166.8, 146.5, 141.9, 131.8, 131.6,
129.6, 128.3, 125.8, 123.0, 121.7, 92.8, 38.7, 35.8, 34.6,
29.3, 29.1, 27.6, 25.9, 22.6, 13.7, 11.4.
C
(1S*,1¢R*)-2: 1H NMR (270 MHz): d = 7.75–7.72 (m, 1 H),
7.52–7.45 (m, 3 H), 7.30–7.17 (m, 5 H), 3.43–3.35 (m, 1 H),
2.80–2.51 (m, 3 H), 2.18–1.90 (m, 3 H), 1.65–0.74 (m, 34
H). 13C NMR (67.5 MHz): d = 167.1, 146.2, 141.7, 131.7,
129.6, 128.3, 128.2, 125.9, 122.8, 121.6, 91.9, 39.1, 36.0,
34.7, 29.3, 29.1, 27.5, 26.1, 22.5, 13.6, 11.1.
3: 1H NMR (270 MHz): d = 8.03–7.99 (m, 1 H), 7.57–7.48
(m, 2 H), 7.42–7.34 (m, 1 H), 7.27–7.11 (m, 6 H), 6.83 (dd,
J = 14.3, 4.8 Hz, 1 H), 3.41 (td, J = 7.9, 2.8 Hz, 1 H), 2.84–
2.75 (m, 1 H), 2.66–2.55 (m, 1 H), 2.28 (s, 1 H), 2.18–2.07
(m, 1 H), 2.02–1.92 (m, 1 H), 1.87–1.75 (m, 1 H), 1.65–1.52
(m, 1 H), 1.39–1.04 (m, 4 H), 0.81 (t, J = 7.1 Hz, 3 H). 13
C
Synlett 2006, No. 15, 2449–2453 © Thieme Stuttgart · New York