An Enantioselective Access to 1-Alkyl-1,2-Dihydroisoquinolines and 1-Alkyl-, 3-Alkyl-, and 1,3-Dialkyl-1,2,3,4-tetrahydroisoquinolines

Article abstract of DOI:10.1021/jo970768a

New chiral isoquinolinium salt derivatives 1, 2 or 3 have been treated with Grignard reagents to give as major products, 1-substituted 1,2-dihydroisoquinolines 4a-f, oxazolidine derivatives 10a-f or 21, respectively, in good yield and in moderate to good diastereoisomeric excess. The stereochemistry of these new derivatives has been elucidated, in particular, by X-ray crystallographic studies of 1,2-dihydroisoquinoline 4b and the minor oxazolidine lib. Reduction of all these intermediates gave chiral 1-substituted 1,2,3,4-tetrahydroisoquinolines such as base 8. The enantioselective synthesis of the natural alkaloid (-)-salsonidine in three steps and 38% overall yield from salt 3 is described as an application. Reduction of salt 2 gave a new oxazolidine derivative 15 which is a practical intermediate for the synthesis of 3-alkyl 1,2,3,4-tetrahydroisoquinolines 17a,b, while oxazolidines such as 10 are convenient precursors of 1,3-disubstituted tetrahydroisoquinolines, as illustrated by a synthesis of 1,3-dimethyl tetrahydroisoquinoline 20.

Full text of DOI:10.1021/jo970768a

J . Org. Chem. 1998, 63, 1767-1772
1767
An En a n tioselective Access to 1-Alk yl-1,2-Dih yd r oisoqu in olin es
a n d 1-Alk yl-, 3-Alk yl-, a n d
1,3-Dia lk yl-1,2,3,4-tetr a h yd r oisoqu in olin es
Denis Barbier, Christian Marazano,* Claude Riche, Bhupesh C. Das,* and Pierre Potier
Institut de Chimie des Substances Naturelles, C.N.R.S., 91198 Gif-sur-Yvette Cedex, France
Received April 30, 1997
New chiral isoquinolinium salt derivatives 1, 2 or 3 have been treated with Grignard reagents to
give as major products, 1-substituted 1,2-dihydroisoquinolines 4a -f, oxazolidine derivatives 10a -f
or 21, respectively, in good yield and in moderate to good diastereoisomeric excess. The
stereochemistry of these new derivatives has been elucidated, in particular, by X-ray crystallographic
studies of 1,2-dihydroisoquinoline 4b and the minor oxazolidine 11b. Reduction of all these
intermediates gave chiral 1-substituted 1,2,3,4-tetrahydroisoquinolines such as base 8. The
enantioselective synthesis of the natural alkaloid (-)-salsonidine in three steps and 38% overall
yield from salt 3 is described as an application. Reduction of salt 2 gave a new oxazolidine derivative
15 which is a practical intermediate for the synthesis of 3-alkyl 1,2,3,4-tetrahydroisoquinolines
17a ,b, while oxazolidines such as 10 are convenient precursors of 1,3-disubstituted tetrahydroiso-
quinolines, as illustrated by a synthesis of 1,3-dimethyl tetrahydroisoquinoline 20.
Previously, it was demonstrated1 that the Zincke
Sch em e 1
reaction between chiral primary amines2 and N-(2,4-
dinitrophenyl)isoquinolinium salts provided a practical
entry to new chiral isoquinolinium salt derivatives such
as 1, 2, or 3. The lipophilic sulfate counteranion ensured
solubilization of these salts in organic solvents, particu-
larly in toluene or THF, thus allowing further studies of
their reactions with Grignard reagents.3 We now report
the results of these studies4 and the first applications of
this strategy to the enantioselective syntheses of 1-sub-
stituted 1,2-dihydroisoquinolines, 1- or 3-substituted
1,2,3,4-tetrahydroisoquinolines, and 1,3-disubstituted
1,2,3,4-tetrahydroisoquinolines.
droisoquinolines, few procedures are available at present
for the synthesis of polysubstituted tetrahydroisoquino-
lines.6
The present approach complements the existing meth-
ods reported for the stereoselective synthesis of 1-sub-
stituted 1,2,3,4-tetrahydroisoquinolines, an area of re-
search which has generated much interest in the past
few years.5 In addition, it gives an access to chiral 1,2-
dihydroisoquinoline derivatives and 1,3-disubstituted
tetrahydroisoquinolines which are difficult to obtain
otherwise. Indeed, while several methods would now
allow synthesis of various 1-substituted chiral tetrahy-
Our attention was first directed to reactions of salt 1
with different Grignard reagents (Scheme 1) in THF
under the conditions found appropriate in the corre-
sponding pyridinium series.3 The results are sum-
marized in Table 1. The yields of rather unstable 1-sub-
stituted dihydroisoquinolines 4a -f and 5a -f were prac-
tically quantitative, but in most instances the diastere-
oisomeric excess (de), estimated by the integration of
relevant signals in the 1H NMR spectra of the crude
(1) Barbier, D.; Marazano, C.; Das, B. C.; Potier, P. J . Org. Chem.
1996, 61, 9596-9598.
(2) Ge´nisson, Y.; Marazano, C.; Mehmandoust, M.; Gnecco, D.; Das,
B. C. Synlett 1992, 431.
(3) For previous results in pyridinium series, see: Ge´nisson, Y.;
Marazano, C.; Das, B. C. J . Org. Chem. 1993, 58, 2052.
(4) For other examples of the reaction of chiral isoquinolinium salts
with Grignard reagents, see: Comins, D. L.; Badawi, M. M. Hetero-
cycles 1991, 32, 1869.
(5) For a recent review, see: Rozwadowska, M. D. Heterocycles 1994,
39, 903.
(6) Previous enantiospecific accesses to 1,3-disubstituted tetrahydro-
isoquinolines: (a) Coote, S. J .; Davies, S. G.; Sutton, K. H. J . Chem.
Soc., Perkin Trans. 1 1988, 1481. (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) Bringmann, G.; Weirich, R.; Reuscher, H.; J ansen, J .
R.; Kisinger, L.; Ortmann, T. Liebigs Ann. Chem. 1993, 877. (d) Tietze,
L. F.; Burkhardt, O. Synthesis 1994, 1331. (e) Gosmann, G.; Guillaume,
D.; Husson, H.-P. Tetrahedron Lett. 1996, 37, 4369.
S0022-3263(97)00768-8 CCC: $15.00 © 1998 American Chemical Society
Published on Web 02/24/1998

1768 J . Org. Chem., Vol. 63, No. 6, 1998
Barbier et al.
Ta ble 2. Alk yla tion of Sa lt 2 w ith Som e Gr ign a r d
Ta ble 1. Alk yla tion of Sa lt 1 w ith Som e Gr ign a r d
Rea gen ts
Rea gen ts
a
Ratio calculated from 1H NMR of the crude mixture at
equilibrium. Calculated from 1H NMR of the crude mixture after
NaBH4 reduction. c Crude mixture obtained immediately after
extraction.
b
a
b
Ratio calculated from 1H NMR of the crude mixture. Calcu-
lated from 1H NMR of the crude mixture of adducts 6 and 7. c Not
separated. Yield from 4b isolated after crystallization.
d
1,2-dihydroisoquinolines 9a -f cyclized spontaneously
upon hydrolysis, in the same way as previously reported
for the analogous 1,2-dihydropyridine derivatives,8 to give
Sch em e 2
9
as major products oxazolidines 10a -f and 11a -f ac-
companied with small amounts (see Table 2) of 1,2-
dihydroisoquinolines 12a -f (stereochemistry not deter-
mined). Since these intermediates were too unstable to
be separated, the de of the reactions were estimated from
1
the H NMR analysis of the mixture of diastereoisomers
obtained after sodium borohydride reduction, in the
presence of acetic acid, of the crude mixture of the
Grignard reaction.
A comparison between Table 1 and Table 2 showed
that the diastereoselectivities of Grignard addition prod-
ucts were significantly increased in passing from salt 1
having a phenylethyl auxiliary to salt 2 having a phe-
nylethanol auxiliary. This can be readily interpreted if
one considers that the alcohol function in salt 2 reacts
first to give an organomagnesium complex (see A in
Scheme 2) which can then direct the alkylation from the
face opposite to the phenyl ring. Again, the lowest de
were observed with benzylic Grignard reagents.10
The stereochemistry at the C10a center of oxazolidines
10a -f and 11a -f was easily determined from the 1H
NMR chemical shift of the corresponding proton which
is deshielded in 10a -f (δ near 5.4 ppm) and shielded in
11a -f (δ near 4.5 ppm). These different chemical shifts
can result from a deshielding effect due to the syn
relationship between the nitrogen doublet and the proton
at C10a in 10a -f compared to the anti arrangement in
11a -f. The predominance of oxazolidines 10a -f over
oxazolidines 11a -f can be possibly explained by desta-
bilizing steric interactions between the phenyl group of
the oxazolidine ring and the substituents R at C5. Strong
support for these hypotheses as well as confirmation of
the stereochemistry at C10a was obtained from an X-ray
analysis of the minor oxazolidine 11b which crystallized
out when the crude Grignard reaction mixture was
dissolved in Et2O. We checked by 1H NMR spectroscopy
that crystals of oxazolidine 11b equilibrated very rapidly
reaction mixture, was modest. Particularly with benzylic
Grignard reagents, the observed de’s were significantly
lower than those observed in the corresponding 3,4-
disubstituted pyridinium series (de>80%).3 Neverthe-
less, reduction of the crude mixture of unseparable
intermediates 4a -f and 5a -f with sodium borohydride
in the presence of acetic acid afforded tetrahydroiso-
quinolines 6a -f and 7a -f which were in general sepa-
rable by chromatography and thus could be obtained in
a few steps, by using simple protocols and inexpensive
reagents.
The preparation of base (+)-8 turned out to be par-
ticularly easy since the intermediate 4b was obtained in
good de (74%) and could be isolated after crystallization
from dichloromethane-ethanol in 72% yield. The X-ray
crystallographic structure of 4b secured the attribution
of the absolute configuration of base (+)-8 as 1S (in a
recent paper7 this configuration was erroneously reported
as 1R and should therefore be corrected accordingly). The
stereochemical preferences in favor of adducts 4a -f are
identical to those observed in the corresponding pyri-
dinium series and can be interpreted in a similar way3.
The reactions of salt 2, having a chiral phenylethanol
auxiliary on the nitrogen, with Grignard reagents were
investigated next. The results are depicted in Scheme 2
and Table 2. In this particular case, the intermediate
(8) Ge´nisson, Y.; Mehmandoust, M.; Marazano, C.; Das, B. C.
Heterocycles 1994, 39, 811.
(9) For the use of other oxazolidine intermediates in the enantiose-
lective syntheses of 1-alkyl 1,2,3,4-tetrahydroisoquinoline series see
(7) Yamato, M.; Hashigaki, K.; Qais, N.; Ishikawa, S. Tetrahedron
1990, 46, 5909.
references 6e, 7,
Heterocycles 1993, 36, 1763.
8 and Carbonelle, A. C.; Gott, V.; Roussi, G.

Enantiosynthesis of Dihydro- and Tetrahydroisoquinolines
J . Org. Chem., Vol. 63, No. 6, 1998 1769
Sch em e 3
Sch em e 4
four diastereoisomers 17c, 18c, and 19 (two epimers at
C3 in 8:3 ratio) was obtained in 70:17:13 ratio and in a
total yield of 95%. Compared to the alkylation of oxazo-
lidine 15 and 16 in THF, the reaction was brought to
completion in a single step in toluene. The role of toluene
proved to be crucial since the reaction was found to be
incomplete when THF was used as solvent.
Finally the utility of this approach was also illustrated
by an enantioselective synthesis of the natural alkaloid
(-)-salsolidine7,12 according to Scheme 4. Thus, treat-
ment of salt 3 with methylmagnesium iodide gave a
mixture of adducts 21, 22, and the corresponding dihy-
droisoquinoline (undefined stereochemistry) in 40:20:20
ratio and 79% total yield. Reduction of this mixture with
sodium borohydride in the presence of acetic acid afforded
two diastereoisomers allowing determination of the se-
lectivity (60% de) of the attack by methylmagnesium
when dissolved in deuteriochloroform to give back isomer
10b as the major component.
Reduction of salt 2 (Scheme 3) with sodium borohy-
dride in an alkaline medium gave the unstable 1,2-
dihydroisoquinoline 14 which could not be isolated since
it cyclized spontaneously to oxazolidines 15 and 16 in 4:1
ratio (accompanied with a small amount, ca. 5%, of
uncyclized 14). This result was similar to that obtained
in the corresponding 1,2-dihydropyridine series.8 Thus,
in the absence of a substituent at position 1, the 1,2-
dihydroisoquinoline 14 prefers to cyclize, as expected, to
give the major oxazolidine 15 having a cis relationship
between the C10a-O and the C3-phenyl bonds, while, for
steric reasons, the trans relationship is preferred in the
presence of a substituent at C1 to give as major products
the trans oxazolidines 10a -f.
The oxazolidine derivatives 15 and 16 are intermedi-
ates of interest11 toward a rapid access to chiral 3-sub-
stituted tetrahydroisoquinolines. Thus, for example, they
gave adducts 17a ,b (64% and 50% de) and 18a ,b when
treated with the appropriate Grignard reagents. These
reactions were difficult to bring to completion, significant
quantities of starting material being recovered, even
when a large excess of the Grignard reagent was used.
This was presumably due to the Grignard acting also as
a base which deprotonated the starting oxazolidines
giving rise to the corresponding dihydroisoquinoline
whose hydrolysis gave back the starting oxazolidines 15
and 16. For these reasons, the reaction was repeated
twice in order to give satisfactory yields of the desired
alkylated products. Finally, according to this procedure,
the major adducts 17a or 17b were recovered in about
40-50% yield after chromatography. The enantioselec-
tive approach to 1,3-disubstituted tetrahydroisoquino-
lines starting from chiral isoquinolinium salt derivatives,
is illustrated by one example. When the crude mixture
of adducts 10a , 11a , and 12a was treated with an excess
of methylmagnesium chloride in toluene, a mixture of
1
iodide by H NMR spectroscopy. The major isomer 23,
isolated in 45% yield after chromatography over alumina,
was hydrogenated in acidic medium to give (-)-salsoni-
dine in 38% overall yield from 3.
In conclusion, we believe that these new chiral iso-
quinolinium salts, readily available by the Zincke pro-
cedure starting from isoquinolines and chiral primary
amines, can be considered as good synthons for the
enantioselective syntheses of a number of substituted 1,2-
dihydro- or 1,2,3,4-tetrahydroisoquinolines.
Exp er im en ta l Section
Alk yla tion of Sa lt 1 w ith Gr ign a r d Rea gen ts: P r ep a -
r a tion of Ba se (+)-8 a s a Typ ica l P r oced u r e. To a solution
of salt 11 (7 g, 18.1 mmol) in THF (150 mL) was added
dropwise, at 0 °C under an inert atmosphere, an excess of 1
M phenylmagnesium iodide in THF (38.2 mL, 38.2 mmol).
After 1 h at 0 °C, the resulting mixture was poured into a 32%
NH4OH solution with strirring and then extracted with cold
Et2O. Removal of solvent left a mixture (5.34 g, 17.16 mmol,
95%) of enamines 4b and 5b as an oil in 87:13 ratio. The major
isomer (1S,1R)-(+)-1-p h en yl-2-(1-p h en ylet h yl)-1,2-d ih y-
d r oisoqu in olin e (4b) was isolated by crystallization from
CH2Cl2-EtOH (4.05 g, 13.02 mmol, 72%): mp 122-124 °C;
[R]D +563 (c 1, CH2Cl2); 1H NMR (300 MHz, CDCl3) δ 1.46 (d,
J ) 7.1 Hz, 3H), 4.24 (q, J ) 7.1 Hz, 1H), 5.35 (d, J ) 7.6 Hz,
1H), 5.40 (s,1H), 6.64 (ld, J ) 7.4 Hz, 1H), 6.70 (d, J ) 7.6 Hz,
1H), 6.81 (ddd, J ) 1.4, 7.4, 7.4 Hz, 1H), 6.88 (dd, J ) 1.4, 7.5
Hz, 1H), 7.01 (ddd, J ) 1.4, 7.4, 7.5 Hz, 1H),7.2-7.4 (m, 10H);
13C NMR (75.47 MHz, CDCl3) δ 21.5, 58.9, 64.5, 96.7, 131.9,
122.8, 124.4, 127.0, 127.3, 126.6-128.7 (10C), 132.7, 134.5,
143.8, 144.8; MS (EI) m/z (rel intensity) 311 (M+•, 100), 234
(99), 208 (19), 206 (99), 130 (100), 105 (64), 77 (38). Anal. Calcd
for C23H21N-0.2 H2O: C, 87.69; H, 6.84; N, 4.44. Found C,
87.59; H, 6.94; N, 4.31. NMR studies of the mother liquors
(10) Improved selectivities for the alkylation of related 3,4-dihy-
droisoquinoline equivalents were observed using benzylic titanium
reagents: Hashigaki, K.; Kan, K.; Qais, N.; Takeuchi, Y.; Yamato, M.
Chem. Pharm. Bull. 1991, 39, 1126.
(11) For a recent review see: Meyers, A. I.; Brengel G. P. Chem.
Commun. 1997, 1.
(12) Battersby, A. R.; Edwards, T. P. J . Chem. Soc. 1960, 1214.

1770 J . Org. Chem., Vol. 63, No. 6, 1998
Barbier et al.
allowed characterization of the minor isomer (1R,1R)-1-
p h en yl-2-(1-p h en ylet h yl)-1,2-d ih yd r oisoq u in olin e (5b):
1H NMR (300 MHz, CDCl3) δ 1.48 (d, J ) 7 Hz, 3H), 4.34 (q,
J ) 7 Hz, 1H), 5.22 (d, J ) 7.4 Hz, 1H), 5.66 (s, 1H), 6.16 (d,
J ) 7.4 Hz, 1H), 6.6-7.4 (m, 14H); 13C NMR (75.47 MHz,
CDCl3) characteristic signals at δ 18.2, 59.3, 63.9, 96.8, 134.5.
To a solution of the major isomer 4b (1.5 g, 4.82 mmol) in THF
(50 mL) was added NaBH4 (1.87 g) with stirring. After 0.25
h, a solution of 25% acetic acid in THF (25 mL) was added
dropwise with vigorous stirring. After an additional 0.5 h, the
resulting mixture was basified with 2 N NaOH and the product
extracted with Et2O to give crude base 6b. The corresponding
hydrochloride 6b,HCl was dissolved in a minimum of MeOH
and precipitated with acetone. Filtration gave a white powder
which was extracted in alkaline medium to give (1S,1R)-(+)-
1-p h en yl-2-(1-p h en ylet h yl)-1,2,3,4-t et r a h yd r oisoq u in o-
lin e (6b) (1.5 g, 100%): [R]D +185 (c 2.5, CHCl3); 1H NMR
(300 MHz, CDCl3) δ 1.37 (d, J ) 6.9 Hz, 3H), 2.39 (ddd, J ) 4,
8.3, 12 Hz, 1H), 2.80 (ddd, J ) 4, 5.2, 16.2 Hz, 1H), 2.95 (ddd,
J ) 5.2, 8.3, 16.2 Hz, 1H), 3.23 (ddd, J ) 5.2, 5.2, 12 Hz, 1H),
3.82 (q, J ) 6.9 Hz, 1H), 4.79 (s, 1H), 6.74 (ld, J ) 7.6 Hz,
1H), 6.94 (ddd, J ) 2.5, 6, 7.6 Hz, 1H), 7.01-7.10 (m, 2H),
7.18-7.38 (m, 10H); 13C NMR (75.47 MHz, CDCl3) δ 20.6, 29.0,
41.3, 53.7, 64.6, 125.6, 125.8, 128.7, 129.1, 127.0-129.5 (10C),
135.2, 138.4, 142.3-145.3 (2C); MS (EI) m/z (rel intensity) 313
(M+•, 74), 298 (78), 236 (100), 208 (35), 206 (8), 132 (98), 130
(23), 105 (98), 77 (44); ΗRΜS (EI): calcd for C23H23N m/z
313.1830, obsd m/z 313.1836. Base 6b (1.2 g, 3.83 mmol) was
dissolved in EtOAc (5 mL) and EtOH (15 mL) to which an
aqueous solution of 2.4 N HCl (2 mL) was added, and the
resulting solution was hydrogenated over 10% Pd/C for 15 h
with stirring. Filtration over Celite followed by evaporation
of solvents left a residue which was dissolved in water and
extracted with Et2O. The aqueous phase was evaporated to
give crude salt 8‚HCl which was dissolved in a minimum of
MeOH and precipitated with acetone. The precipitate was
filtered and dissolved in water to which an excess of sodium
bicarbonate was added. Extraction with CH2Cl2 gave pure
(1S)-(+)-1-ph en yl-1,2,3,4-tetr ah ydr oisoqu in olin e (+)-8 (580
mg, 2.76 mmol, 72%) as a colorless oil: [R]D +13.5 (c 1.15,
CHCl3); 1H NMR (300 MHz, CDCl3) δ 2.00 (bs, 1H, NH), 2.78-
2.88 (m, 1H), 3.01-2.88 (m, 2H), 3.23-3.31 (m, 1H), 5.1 (s,
1H), 6.75 (d, J ) 7.6 Hz, 1H), 7.05 (m, 1H), 7.15 (m, 2H), 7.2-
7.36 (m, 5H); 13C NMR (75.47 MHz, CDCl3) δ 29.9, 42.3, 62.2,
125.8, 126.4, 127.5, 128.2, 128.5, 129.1, 135.5, 138.3, 144.9;
MS (EI) m/z (rel intensity) 209 (M+•, 52), 208 (56), 132 (100),
130 (13), 77 (5); ΗRΜS (EI): calcd for C15H15N m/z 209.1204,
obsd m/z 209.1209.
4.89; found: C, 84.17; H, 6.55: N, 4.11; O, 4.61. The crude
mixture of dihydroisoquinolines 10b, 11b, and 12b (680 mg,
2.08 mmol) was reduced with NaBH4 following the procedure
used for the preparation of 6b to give tetrahydroisoquinoline
13b accompanied with a small amount of the corresponding
1R isomer in 95:5 ratio. (1S,2R)-(+)-1-P h en yl-2-(1-p h en yl-
2-h ydr oxyeth yl)-1,2,3,4-tetr ah ydr oisoqu in olin e (13b) (396
mg, 1.2 mmol, 58%) was isolated by chromatography on silica
gel using EtOAc-pentane as eluent: [R]D +40.9 (c 1.08, EtOH);
1H NMR (300 MHz, CDCl3) δ 2.02 (s, 1H, -OH), 2.78 (ddd, J
) 4.9, 5.3, 16.7 Hz, 1H), 2.97 (ddd, J ) 5.1, 8.7, 16.7 Hz, 1H),
2.97-3.08 (m, 1H), 3.17 (ddd, J ) 4.9, 8.7, 14.5 Hz, 1H), 3.88
(dd, J ) 4.7, 6.2 Hz, 1H), 3.97 (dd, J ) 4.7, 10.8 Hz, 1H), 4.0
(dd, J ) 6.2, 10.8 Hz, 1H), 4.90 (ls, 1H), 6.71 (d, J ) 7.3 Hz,
1H), 6.98-7.08 (m, 1H), 7.10-7.40 (m, 12H); 13C NMR (62.89
MHz, CDCl3) δ 26.5, 41.7, 62.6, 63.6, 64.8, 125.8, 126.3, 127.0,
127.6, 128.2, 128.5, 128.6, 128.8, 129.3, 134.9, 136.7, 140.4,
144.7; MS (IC) m/z (rel intensity) 330 (MH+, 100), 328 (19),
312 (9), 298 (9), 210 (42), 208 (22), 206 (4); ΗRΜS (IC): calcd
for C23H24NO m/z 330.1858, obsd m/z 330.1859. Minor 1R
isomer (19 mg): [R]D -157.6 (c 0.36, EtOH); 1H NMR (300
MHz, CDCl3), 2.38 (ddd, J ) 3, 11.3, 11.4 Hz, 1H), 2.80 (ddd,
J ) 2.4, 3, 15.9 Hz, 1H), 3.21 (dddd, J ) 1.5, 4.9, 11.4, 15.9
Hz, 1H), 3.38 (ddd, J ) 2.4, 4.9, 11.3 Hz, 1H), 3.46 (dd, J )
4.7, 10.2 Hz, 1H), 3.94 (dd, J ) 4.7, 10.8 Hz, 1H), 4.08 (dd, J
) 10.2, 10.8 Hz, 1H), 4.58 (d, J ) 1.5 Hz, 1H), 6.62 (d, J ) 7.3
Hz, 1H), 6.92 (ddd, J ) 2.1, 6.7, 7.3 Hz, 1H), 6.98-7.09 (m,
2H), 7.20-7.45 (m, 10H); 13C NMR (62.89 MHz, CDCl3) δ 30.4,
42.1, 60.3, 62.8, 65.6, 125.9, 127.8, 128.2, 128.4, 129.0, 129.1,
129.5, 129.7, 134.3, 134.9, 138.9, 144.4; MS (IC) m/z (rel
intensity) 330 (MH+, 100), 328 (6), 312 (6), 298 (8), 210 (44),
208 (14), 206 (4). Tetrahydroisoquinoline 13b (120 mg, 0.36
mmol) was hydrogenated under the conditions used for the
hydrogenolysis of tetrahydroisoquinoline 6b to give base (+)-8
(54 mg, 0.36 mmol, 67%): [R]D +14.8 (c 1.7, CHCl3); 1H NMR,
13C NMR and MS spectra were identical with those of base
(+)-8 obtained from tetrahydroisoquinoline 6b.
(3R,10a R)-3-P h en yl-2,3,5,10-tetr a h yd r o-10a H-oxa zolo-
[2,3-b]isoqu in olin e (15). Salt 21 (1.08 g, 2 mmol), dissolved
in MeOH (4 mL), was added dropwise with vigorous stirring
to a two-phase system consisting of 5 N NaOH (2 mL) and
Et2O (10 mL) containing NaBH4 (100 mg, 2.5 mmol). After
0.6 h, the organic phase was collected and filtered over alumina
(30 g) with Et2O as solvent. Removal of solvent under reduced
pressure left a pale yellow oil composed of oxazolidine 15
accompanied with isomers 16 and 14 in a 77:18:5 ratio (490
mg, 1.95 mmol, 93%): MS (EI) m/z (rel intensity) 251 (M+•
,
78), 250 (27), 220 (36), 130 (21), 104 (100); ΗRΜS (EI): calcd
for C17H17NO m/z 251.1310, obsd m/z 251.1304. Major oxazo-
lidine 15: 1H NMR (300 MHz, CDCl3) δ 3.00-3.23 (m, 2H),
3.46 (d, J ) 14.5 Hz, 1H), 3.71 (dd, J ) 7.6, 7.6 Hz, 1H), 3.83
(dd, J ) 7.6, 7.6 Hz, 1H), 3.95 (d, J ) 14.5 Hz, 1H), 4.25 (dd,
J ) 4, 4 Hz, 1H), 4.32 (dd, J ) 7.6 Hz, 1H), 6.90-7.25 (m,
4H), 7.25-7.60 (m, 5H); 13C NMR (75.47 MHz, CDCl3) δ 35.8,
52.0, 68.0, 74.0, 92.2, 126.2-129.9, 127.9-128.9 (5C), 132.9,
134.1, 138.5; MS (EI) m/z (rel intensity) 251 (M+•, 78), 250 (27),
220 (36), 174 (1), 130 (21), 104 (100). Minor oxazolidine 16:
1H NMR (300 MHz, CDCl3) δ 2.8-3.15 (m, 2H), 3.55 (m, 1H),
3.6 (m, 1H), 3.71 (dd, J ) 7.6, 7.6 Hz, 1H), 3.8 (d, J ) 13 Hz,
1H), 4.16 (m, 1H), 5.18 (dd, J ) 4.7, 4.7 Hz, 1H); 13C NMR
(75.47 MHz, CDCl3) characteristic signals at δ 34.3, 50.9, 67.9,
72.6, 91.0. Dihydroisoquinoline 14: 1H NMR (300 MHz,
CDCl3) characteristic signals at δ 2.43 (m, 2H), 2.82-3.03 (m,
2H), 4.06 (d, J ) 12.5 Hz, 2H), 4.19-4.22 (m, 1H), 5.33 (d, J
) 7.5 Hz, 1H).
(3R ,2R )-(-)-3-P h e n yl-2-(1-p h e n yl-2-h yd r oxye t h yl)-
1,2,3,4-tetr a h yd r oisoqu in olin e (17b). To a solution of
oxazolidine 15, accompanied with isomers 16 and 14 in a77:
18:5 ratio (220 mg, 0.88 mmol), in Et2O (25 mL) was added
dropwise at 0 °C with stirring a 0.8 M solution of phenylmag-
nesium iodide in Et2O (3.2 mL, 2.56 mmol). The resulting
mixture was stirred for 1 h at 0 °C, followed by 2 h at 20 °C,
and then poured into a 32% solution of NH4OH saturated with
NaCl. Extraction with Et2O left a mixture of the starting
materials and adducts 17b and 18b. This mixture was again
Alk yla tion of Sa lt 2 w ith Gr ign a r d Rea gen ts: P r ep a -
r a tion of Ba se (+)-8 a s a Typ ica l P r oced u r e. Salt 21 (1.6
g, 3.11 mmol) was treated with an excess of phenylmagnesium
iodide under the conditions used for the preparation of
enamine 4b to give a mixture (0.82 g, 2.51 mmol, 81%) of
oxazolidines 10b and 11b accompanied with a small amount
of enamine 12b in a 69:29:7 ratio at equilibrium. (3R,5S,10aS)-
3,5-Dip h en yl-2,3,5,10-tetr a h yd r o-10aH-oxa zolo[2,3-b]iso-
qu in olin e (10b): 1H NMR (300 MHz, CDCl3) characteristic
signals at δ 2.69 (dd, J ) 4.8, 15.8 Hz, 1H), 2.89 (dd, J ) 2.3,
15.8 Hz, 1H), 3.59 (dd, J ) 8.5, 8.5 Hz, 1H), 4.01 (dd, J ) 6.4,
8.5 Hz, 1H), 4.11 (dd, J ) 6.4, 8.5 Hz, 1H), 4.84 (s, 1H), 5.39
(dd, J ) 2.3, 4.8 Hz, 1H); 13C NMR (75.47 MHz, CDCl3)
characteristic signals at δ 33.4, 63.2, 68.1, 72.7, 90.9. Crystals
of the minor oxazolidine (3R,5S,10a R)-3,5-d ip h en yl-2,3,5,-
10-tetr a h yd r o-10a H-oxa zolo[2,3-b] isoqu in olin e (11b),
suitable for X-ray analysis, were obtained from Et2O: mp 126-
1
130 °C; H NMR (300 MHz, CDCl3) δ 3.25 (dd, J ) 4.1, 14.7
Hz, 1H), 3.37 (dd, J ) 9.1, 14.7 Hz, 1H), 3.76 (dd, J ) 6.2, 8.2
Hz, 1H), 3.87 (dd, J ) 6.2, 8.2 Hz, 1H), 4.32 (dd, J ) 8.2, 8.2
Hz, 1H), 4.45 (dd, J ) 4.1, 9.1 Hz, 1Ha), 4.71 (s, 1H), 6.60-
7.60 (m, 9 H); 13C NMR (75.47 MHz, CDCl3) δ 35.9, 67.6, 70.4,
75.11, 92.6, 126.1-141.3; MS (IC) m/z (rel intensity) 328 (MH+,
100), 206 (28); MS (EI) m/z (rel intensity) 327 (M+•, 53), 326
(18), 296 (4), 250 (21), 206 (8), 180 (100), 130 (15), 103 (8), 77
(9). Anal. Calcd for C23H21NO: C, 84.37; H, 6.46: N, 4.28; O,

Enantiosynthesis of Dihydro- and Tetrahydroisoquinolines
J . Org. Chem., Vol. 63, No. 6, 1998 1771
treated with an excess of phenylmagnesium iodide using the
above conditions. Finally, base 17b and the corresponding 3S
isomer 18b were obtained in 75:25 ratio (210 mg, 0.64 mmol).
Chromatographic separation on silica gel (50 g) using EtOAc-
pentane as eluent (from 0:100 to 30:70) gave major isomer 17b
as a pale yellow oil (130 mg, 0.4 mmol, 45%): [R]D -20.3 (c
corresponding dihydroisoquinoline, in a 40:20:20 ratio at
equilibrium, as a pale yellow oil: MS (EI) m/z (rel intensity)
325 (M+•, 30), 310 (100), 190 (73), 178 (100), 163 (15); ΗRΜS
(EI): calcd for C20H23NO3 m/z 325.1678, obsd m/z 325.1662.
(3R,5S,10a S)-7,8-Dim eth oxy-5-m eth yl-3-p h en yl-2,3,5,10-
tetr ah ydr o-10aH-oxazolo[2,3-b]isoqu in olin e (21): 1H NMR
(250 MHz, CDCl3) δ 1.33 (d, J ) 6.9 Hz, 3H), 2.92 (dd, J )
4.3, 16 Hz, 1H), 3.10 (dd, J ) 4.9, 16 Hz, 1H), 3.51 (dd, J )
8.1, 9 Hz, 1H), 3.74 (q, J ) 6.9 Hz, 1H), 3.84 (s, 3H), 3.87 (s,
3H), 4.04 (dd, J ) 6.7, 9 Hz, 1H), 4.18 (dd, J ) 6.7, 8.1 Hz,
1H), 5.27 (dd, J ) 4.3, 4.9 Hz, 1H), 6.62 (s, 1H), 6.65 (s, 1H);
13C NMR (62.89 MHz, CDCl3) δ 21.6, 32.8, 55.3, 55.9, 56.0,
68.0, 73.0, 90.2, 108.9, 112.1. (3R,5S,10a R)-7,8-Dim eth oxy-
5-m eth yl-3-p h en yl-2,3,5,10-tetr a h yd r o-10a H-oxa zolo[2,3-
b]isoqu in olin e (22): 1H NMR (250 MHz, CDCl3) δ 1.06 (d, J
) 6.5 Hz, 3H), 3.07-3.18 (m, 2H), 3.75-3.9 (m, 1H), 3.84 (s,
3H), 3.87 (s, 3H), 3.75-3.95 (m, 1H), 3.80-4.00 (m, 1H), 4.27
(dd, J ) 4.4, 8.7 Hz, 1H), 4.33 (dd, J ) 6.2, 6.2 Hz, 1H), 6.62
(s, 1H), 6.75 (s, 1H), 7.20-7.50 (m, 5H); 13C NMR (62.89 MHz,
CDCl3) δ 22.0, 35.6, 55.9, 56.0, 59.5, 67.0, 72.2, 92.4, 109.7,
1
1.83, EtOH); H NMR (250 MHz, CDCl3) δ 2.05 (s, OH), 2.95
(dd, J ) 4.4, 16.7 Hz, 1H), 3.16 (dd, J ) 6.1, 16.7 Hz, 1 H),
3.79 (d, J ) 16 Hz, 1H); 3.87-3.95 (m, 3H), 3.92 (d, J ) 16
Hz, 1H), 3.98 (dd, J ) 7.3, 11.8 Hz, 1H), 4.29 (dd, J ) 4.4, 6.1
Hz, 1H), 6.85-7.55 (m, 14H); 13C NMR (62.89 MHz, CDCl3) δ
32.9, 47.8, 58.5, 62.5, 65.3, 126.0, 126.4, 126.6, 127.3, 127.6,
127.9, 128.5, 134.3, 135.3, 139.9, 143.0; MS (IC) m/z (rel
intensity) 330 (MH+, 44), 328 (100), 312 (4), 298 (4), 210 (24),
208 (74), 144 (56); ΗRΜS (IC): calcd for C23H24NO m/z
330.1857 (MH+), obsd m/z 330.1849. Isomer 18b (43 mg, 0.13
mmol, 15%) was isolated as an oil: [R]D -63.3 (c 1.03, EtOH);
1H NMR (250 MHz, CDCl3) δ 1.28 (s, 1H, -OH), 3.0 (dd, J )
5.2, 16.6 Hz, 1H), 3.11 (dd, J ) 8.7, 16.6 Hz, 1H), 3.58 (dd, J
) 3.6, 9.2 Hz, 1H), 3.59 (d, J ) 15 Hz, 1), 3.87 (dd, J ) 5.2, 8.7
Hz, 1H), 3.98 (d, J ) 15 Hz, 1H), 4.12 (dd, J ) 9.2, 10.2 Hz,
1H), 4.19 (dd, J ) 3.6, 10.2 Hz, 1H), 7.00-7.50 (m, 14H); 13C
NMR (62.89 MHz, CDCl3) δ 39.5, 47.5, 60.6, 62.0, 62.6, 125.9,
126.3, 126.5, 127.7, 127.9, 128.0, 128.3, 128.6, 129.0, 129.3,
134.2, 134.7, 135.5, 142.8; MS (IC) m/z (rel intensity) 330
(MH+, 100), 328 (43), 312 (5), 298 (5), 210 (22), 208 (26), 144
(13).
112.0.
(2R)-6,7-Dim et h oxy-1-m et h yl-2-(1-p h en yl-2-h y-
d r oxyeth yl)-1,2-d ih yd r oisoqu in olin e: 1H NMR (250 MHz,
CDCl3) δ 1.17 (d, J ) 6.5 Hz, 3H), 1.6 (ls, 1H, -OH), 2.87-
2.91 (m, 1H), 2.93-2.97 (m, 1H), 3.84 (s, 3H), 3.87 (s, 3H), 4.53
(dq, J ) 1.5, 6.5 Hz, 1H), 4.75 (dd, J ) 4, 8.9 Hz, 1H), 5.37 (d,
J ) 7.4 Hz, 1H), 6.18 (dd, J ) 1.5, 7.4 Hz, 1H), 6.45 (s, 1H),
6.51 (s, 1H); 13C NMR (62.89 MHz, CDCl3) δ 21.0, 55.9, 56.0,
57.3, 73.8, 85.1, 98.2, 109.3, 110.2, 130.4) The crude mixture
of oxazolidines 21 and 22 and the corresponding dihydroiso-
quinoline (200 mg, 0.62 mmol) was reduced with NaBH4
according to the procedure used for the preparation of 6b to
give tetrahydroisoquinoline 23 accompanied with the corre-
sponding 1R isomer in 80:20 ratio. Chromatography over
alumina using EtOAc-pentane as eluent gave (1S,2R)-(-)-
6,7-d im e t h oxy-1-m e t h yl-2-(1-p h e n yl-2-h yd r oxye t h yl)-
1,2,3,4-tetr a h yd r oisoqu in olin e (23) as an oil (135 mg, 0.41
mmol, 66%): [R]D -5.8 (c 1.28, EtOH); 1H NMR (250 MHz,
CDCl3) δ 1.31 (d, J ) 6.8 Hz, 3H), 2.23 (ls, 1H, -OH), 2.49
(ddd, J ) 1.8, 3.9, 16 Hz, 1H), 2.90 (ddd, J ) 6.2, 11.8, 16 Hz,
1H), 3.04 (ddd, J ) 1.8, 6.2, 13.1 Hz, 1H), 3.12 (ddd, J ) 3.9,
11.8, 13.1 Hz, 1H), 3.81 (s, 3H), 3.83 (dd, J ) 4, 12 Hz, 1H),
3.84 (s, 3H), 3.84 (dd, J ) 4, 6.9 Hz, 1H), 3.93 (dd, J ) 6.9, 12
Hz, 1H), 3.95 (q, J ) 6.8 Hz, 1H), 6.43 (s, 1H), 6.56 (s, 1H),
7.25-7.40 (m, 5H); 13C NMR (62.89 MHz, CDCl3) δ 20.1, 26.2,
39.8, 54.2, 55.9, 56.0, 63.8, 66.2, 110.5, 111.5, 125.9, 127.6-
128.6, 132.2, 141.2, 147.3, 147.5.MS (IC) m/z (rel intensity)
328 (MH+, 100), 326 (35), 312 (5), 310 (8), 296 (5), 208 (42),
206 (56), 204 (59), 194 (3), 192 (14), 190 (28), 121 (10); ΗRΜS
(IC): calcd for C20H26NO3 m/z 372.1964, obsd m/z 372.1954.
Minor 1R isomer was obtained as an oil (25 mg, 0.08 mmol,
(1S,2R,3S)-(+)-1,3-Dim eth yl-2-(1-p h en yl-2-h yd r oxyeth -
yl)-1,2,3,4-tetr a h yd r oisoqu in olin e (20). A crude mixture
(860 mg, 3.24 mmol) of oxazolidines 10a , 11a and dihydroiso-
quinoline 12a , resulting from the treatment of salt 2 with
methylmagnesium chloride, was dissolved in toluene (50 mL).
To this solution was added dropwise at 0 °C with stirring a
0.9 M solution of methylmagnesium chloride in toluene (11
mL, 9.8 mmol). After stirring for 1 h at 0 °C, the resulting
mixture was poured into a 32% solution of NH4OH saturated
with NH4Cl. Extraction with Et2O left a gum (849 mg)
containing adducts 17c, 18c, and 19 (two epimers at C3 in 8:3
1
ratio) in a 76:11:13 ratio as shown by H NMR spectroscopy.
Chromatography over silica gel using EtOAc-pentane gave
major isomer 17c as a colorless oil (560 mg, 2 mmol, 65%):
[R]D +48.3 (c 4, CHCl3); 1H NMR (250 MHz, CDCl3) δ 1.43 (d,
J ) 6.8 Hz, 3H); 1.51 (d, J ) 6.9 Hz, 3H), 2.33 (dd, J ) 11.1,
16.8 Hz, 1H), 2.45 (dd, J ) 4.8, 16.8 Hz, 1H), 3.50 (dd, J )
5.3, 10.5 Hz, 1H), 3.71 (ddq, J ) 4.8, 6.8, 11.1 Hz, 1H), 3.92
(dd, J ) 10.5, 10.5 Hz, 1H), 4.23 (dd, J ) 5.3, 10.5 Hz, 1H),
4.45 (qdd, J ) 6.9 Hz, 1H), 6.62 (d, J ) 7.6 Hz, 1H), 6.80-
7.25 (m, 8H); 13C NMR (62.89 MHz, CDCl3) δ 20.1, 24.8, 34.0,
47.0, 51.1, 60.2, 61.5, 125.4, 125.5, 126.5, 127.4, 127.6, 128.5,
128.9, 134.6, 139.5, 139.9; MS (IC) m/z (rel intensity) 282
(MH+, 100), 280 (19), 264 (20), 250 (4), 162 (4), 160 (15); ΗRΜS
(IC): calcd for C19H24NO m/z 282.1858, obsd m/z 282.1849.
Minor isomer 18c: 1H NMR (250 MHz, CDCl3) δ 1.05 (d, J )
6.6 Hz, 3H), 1.50 (d, J ) 6.8 Hz, 3H), 2.32-2.43 (m, 2H), 3.43
(m, 1H), 3.72 (dd, J ) 5.4, 10.5 Hz, 1H), 3.95 (dd, J ) 8.3,
10.5 Hz, 1H), 4.09 (dd, J ) 5.4, 8.3 Hz, 1H), 4.10 (q, J ) 6.8
Hz, 1H), 6.95-7.35 (m, 9H); 13C NMR (62.89 MHz, CDCl3) δ
23.2, 23.7, 35.0, 47.2, 54.4, 61.5, 66.6. Tetrahydroisoquinoline
17c (150 mg, 0.53 mmol) was hydrogenated under the condi-
tions used for the hydrogenolysis of tetrahydroisoquinoline
13b. The resulting salt 20‚HCl was isolated by crystallization
from acetone (78 mg, 0.4 mmol, 74): mp 232-240 °C; [R]D
1
13%): [R]D -38 (c 0.8, EtOH); H NMR (250 MHz, CDCl3) δ
1.58 (d, J ) 6.4 Hz, 3H), 2.40 (ddd, J ) 4, 8.1, 11.7 Hz, 1H),
2.63 (ddd, J ) 4, 5.7, 15.8 Hz, 1H), 2.76 (ddd, J ) 4.5, 8.1,
15.8 Hz, 1H), 3.12 (ddd, J ) 4.5, 5.7, 11.7 Hz, 1H), 3.78 (dd, J
) 5.1, 10.5 Hz, 1H), 3.82 (s, 3H), 3.83 (s, 3H), 3.97 (q, J ) 6.4
Hz, 1H), 3.98 (dd, J ) 8.3, 10.5 Hz, 1H), 4.12 (dd, J ) 5.1, 8.3
Hz, 1H), 6.43 (s, 1H), 6.56 (s, 1H), 7.25-7.4 (m, 5H); 13C NMR
(62.89 MHz, CDCl3) δ 22.3, 28.9, 41.0, 53.9, 56.0, 56. 1, 61.3,
64.1, 110.4, 111.3, 126.9, 128.0-129.2, 132.0, 137.2, 147.4,
147.5. Tetrahydroisoquinoline 23 (80 mg, 0.24 mmol) was
hydrogenated under the conditions used for the hydrogenolysis
of tetrahydroisoquinoline 6b to give (-)-salsolidine base (37
mg, 0.18 mmol, 73%): [R]D -57.4 (c 1.4, EtOH) [lit.11 [R]D:
-59.5 (c 4.39, EtOH)]; 1H NMR (250 MHz, CDCl3) δ 1.44 (d, J
) 6.7 Hz, 3H), 1.67 (ls, 1H, N-H), 2.64 (ddd, J ) 4.7, 4.7, 16
Hz, 1H), 2.79 (ddd, J ) 5.4, 8.6, 16 Hz, 1H), 3 (ddd, J ) 4.7,
8.6, 12.6 Hz, 1H), 3.25 (ddd, J ) 4.7, 5.4, 12.6 Hz, 1H), 3.85
(s, 3H), 3.86 (s, 3H), 4.04 (qd, J ) 1, 6.7 Hz, 1H), 6.57 (s, 1H),
6.63 (s, 1H); 13C NMR (62.89 MHz, CDCl3) δ 23.0, 29.7, 42.0,
51.3, 55.9-56.1, 109.2, 111.9, 127.0, 132.7, 147.3, 147.4; MS
(EI) m/z (rel intensity) 207 (M+•, 12), 206 (11), 205 (10), 204
(4), 192 (100), 190 (8); ΗRΜS (IC): calcd for C12H18NO2 m/z
208.1337 (MH+), obsd m/z 208.1357.
1
+25.1 (c 0.8, MeOH); H NMR (250 MHz, CDCl3) δ 1.48 (d, J
) 6.4 Hz, 3H), 1.69 (d, J ) 6.9 Hz, 3H), 2.88 (dd, J ) 10.2,
17.4 Hz, 1H), 3.29 (dd, J ) 4.8, 17.4 Hz, 1H), 3.83 (ddq, J )
4.8, 6.4, 10.2 Hz, 1H), 4.7 (q, J ) 6.9 Hz, 1H), 7.27-7.32 (m,
4H); 13C NMR (62.89 MHz, CDCl3) δ 18.6, 20.8, 34.2, 46.2, 51.8,
127.6, 128.3, 129.1, 130.2, 131.9, 134.3; ΗRΜS (IC): calcd for
C
11H16N m/z 162.1283, obsd m/z 162.1278.
Syn th esis of (-)-Sa lson id in e: To a solution of salt 31 (560
mg, 0.97 mmol) in THF (20 mL) was added dropwise with
stirring at -78 °C a 1 M solution of methylmagnesium chloride
in THF (5 mL, 5 mmol). Applying the procedure utilized for
the preparation of enamine 4b gave an unseparable mixture
(250 mg, 3.4 mmol, 79%) of oxazolidines 21, 22 and the

1772 J . Org. Chem., Vol. 63, No. 6, 1998
Barbier et al.
Su p p or tin g In for m a tion Ava ila ble: X-ray data for in-
termediates 4b and 11b, copies of 1H and 13C NMR spectra of
compounds 4b, 6b, 6e-f, 7e-f, 8, 10b, 13a ,b, 13e,f, 17b,c,
18b, 20‚HCl, 23, (-)-salsolidine, and mixtures of 4a -5a , 10a -
12a , 10b-11b, 15 and 16 with attribution of signals (59
pages). This material is contained in libraries on microfiche,
immediately follows this article in the microfilm version of the
journal, and can be ordered from the ACS; see any current
masthead page for ordering information.
J O970768A