Asymmetric addition of nucleophiles to C-1 position of isoquinolines using (S)-alanine derivatives as chiral auxiliaries

Article abstract of DOI:10.1016/S0040-4020(01)00881-X

5,8-Dibromoisoquinoline derivatives were allowed to react with a nucleophile (silyl enol ether or allyltributyltin) in the presence of an acyl chloride derived from (S)-alanine to afford the 1,2-addition products in good chemical yields and high stereoselectivity. The bromo groups were readily removed by a reduction process in which the double bond at C3-C4 was also reduced. Thus the reaction system provided a general method to synthesize asymmetric 1-substituted tetrahydroisoquinolines. In order to determine the absolute configuration of the reaction product, (-)-homolaudanosine was synthesized in an enantiopure form. The stereoselectivity was rationally understood from the conformation of intermediary N-acylated isoquinolinium salts.

Full text of DOI:10.1016/S0040-4020(01)00881-X

TETRAHEDRON
Pergamon
Tetrahedron 57 ,2001) 8827±8839
Asymmetric addition of nucleophiles to C-1 position of
isoquinolines using ꢀS)-alanine derivatives as chiral auxiliaries
Takashi Itoh, Kazuhiro Nagata, Michiko Miyazaki, Keiko Kameoka and Akio Ohsawap
School of Pharmaceutical Sciences, Showa University, 1-5-8 Hatanodai, Shinagawa-ku, Tokyo 142-8555, Japan
Received 13 July 2001; accepted 31 August 2001
AbstractÐ5,8-Dibromoisoquinoline derivatives were allowed to react with a nucleophile ,silyl enol ether or allyltributyltin) in the presence
of an acylchloride derived from , S)-alanine to afford the 1,2-addition products in good chemical yields and high stereoselectivity. The bromo
groups were readily removed by a reduction process in which the double bond at C3±C4 was also reduced. Thus the reaction system provided
a general method to synthesize asymmetric 1-substituted tetrahydroisoquinolines. In order to determine the absolute con®guration of the
reaction product, ,2)-homolaudanosine was synthesized in an enantiopure form. The stereoselectivity was rationally understood from the
conformation of intermediary N-acylated isoquinolinium salts. q 2001 Elsevier Science Ltd. All rights reserved.
Tetrahydroisoquinoline alkaloids are among major con-
stituents of naturalproducts, and there have been many
reports concerning the totalsyntheses of these compounds. 1
Most of these have a chiralcenter at their C-1 position, and
various enantioselective techniques have been applied to the
syntheses. Generalprocedures for obtaining tetrahydroiso-
quinoline ring systems involve asymmetric Pictet±Spengler
ring-closing reaction,2 and Bischler±Napieralski reaction
followed by enantioselective reduction,3 both of which
often require electron-donating group,s) on benzene ring
for the ring-closing processes. Recently, 1-substituted ,and
5,6,7,8-unsubstituted) tetrahydroisoquinolines have been
found to be relevant to pathogenesis of Parkinson's disease4
and have received attention from the ®eld of medicinal
chemistry,5 thus the modi®cation of these methods would
be necessary. On the other hand, direct introduction of
substituents on the isoquinoline ring in a stereoselective
manner was seldom reported. A standard procedure has
been developed by Meyers et al.6 in which a 2-substituted
1,2,3,4-tetrahydroisoquinoline was used as a starting
material. A similar procedure has been reported by Gawley
et al.7 Other possible substrates are 1-unsubstituted 3,4-
dihydro and aromatic isoquinolines. Since catalytic asym-
metric addition to imines have been developed recently
using various catalysts,8 3,4-dihydroisoquinoline deriva-
tives, which have an imine moiety, seem to be good starting
materials. These catalytic methods were, however, mostly
applied to imines having an aromatic substituent on
nitrogen, thus these methods would not be applicable to
3,4-dihydroisoquinolines. Thus, there is an only study that
reported the asymmetric addition to the compounds using a
stoichiometric amount of allylzinc reagent.9 In the cases of
isoquinoline rings, Comins et al. showed that 6,7-
dimethoxyisoquinoline was attacked by methylmagnesium
iodide in the presence of ,2)-8-phenylmenthyl chloro-
formate, and the reaction product was converted by several
steps to ,1)-carnegine in 62% ee.10 Although this system
was carried out by simple procedures, the obtained ee was
insuf®cient.
In the course of our study for the reactivity of N-acyl-
azolium and azinium salts,11 we reported the asymmetric
addition of allyltributyltin to 4-bromoisoquinoline using
MTPA chloride as an acylating agent.12 To make the reac-
tion system usefulfor practicalasymmetric synthesis, we
investigated the reaction using naturally occurring
carboxylic acids as chiral auxiliaries, and found that simple
ones derived from amino acids were good auxiliaries for the
asymmetric induction. And it was also revealed that intro-
duction of bromo group,s) to isoquinoline ring improved
both chemical yields and diastereoselectivity considerably.
This paper describes these results.13
Amino acids were adopted as chiralauxiliaries because they
are inexpensive, readily available, and have various types of
substituents. Fortunately, ,S)-alanine, the simplest and most
inexpensive chiralamino acid, was found to give moderate
to high diastereoselectivity ,Eq. ,1)).14
ꢀ1†
Keywords: isoquinoline; asymmetric addition; 5,8-dibromoisoquinoline;
allyltributyltin; silyl enol ether; chiral auxiliary; alanine; homolaudanosine.
Corresponding author. Tel.: 181-03-3784-8183; fax: 181-03-3784-
5982; e-mail: ohsawa@pharm.showa-u.ac.jp
p
0040±4020/01/$ - see front matter q 2001 Elsevier Science Ltd. All rights reserved.
PII: S0040-4020,01)00881-X

8828
T. Itoh et al. / Tetrahedron 57 )2001) 8827±8839
Table 1. Asymmetric addition reaction of 4-bromoisoquinoline ,1) with benzyl trimethylsilyl ketene acetal ,2) in the presence of an acylchloride derived from
,S)-alanine
Entry
R
Solvent
Product
Yield of 3 ,%)
de ,%)a
1
2
3
4
5
6
7
8
9
Benzyloxycarbonylamino
Benzoylamino
CH2Cl2
CH2Cl2
CH2Cl2
Toluene
DMF
CH2Cl2
toluene
CH2Cl2
CH2Cl2
±
±
0
0
67
88
Quant.
70
70
56
68
±
±
61
30
9
Phenylsulfonylamino
Phenylsulfonylamino
Phenylsulfonylamino
1-Naphthylsulfonylamino
p-Nitophenylsulfonylamino
p-Nitophenylsulfonylamino
Phthalimidob
3a
3a
3a
3b
3c
3c
3d
7
51
82
86
a
The diastereomeric excess was determined by 1H NMR.
,RS)-N-Phthaloylalanyl chloride was used.
b
Table 1 shows the results of the reaction using 4-bromoiso-
quinoline ,1), benzyltrimethylsilyl ketene acetal ,2), and
acylcholride derived from , S)-alanine. All the reactions
were carried out at 2788C for 1 h to compare the data
under the same conditions, thus the yields are not optimized.
Severalprotecting groups were used for the amino group of
alanine. Although the reaction did not proceed by use of a
standard protecting group such as benzyloxycarbonyl or
benzoylgroup ,entries 1 and 2), the use of more eelctron-
withdrawing phenylsulfonyl group resulted in a moderate
chemical yield and de in dichloromethane ,entry 3). Other
solvents gave lower selectivity despite high chemical yields
,entries 4 and 5). Further experiments showed that p-nitro-
phenylsulfonyl and phthaloyl groups were better protecting
groups ,entries 8 and 9).
Next, other nucleophiles were applied to the reaction using
parent isoquinoline ,4), 1, and 5,8-dibromoisoquinoline
,5),15 and the results are summarized in Table 2 ,Scheme 1).
Isoquinoline ,4) afforded moderate chemicaland stereo-
chemicalyidesl using
N-phthaloylalanyl chloride ,6)
,entries 1 and 8), but the selectivity did not reach a practical
level. Introduction of a bromo group slightly improved the
diastereoselectivity ,entry 7 and Table 1), and 5,8-dibromo
isoquinoline ,5) gave the best results in every case ,entries
Table 2. Asymmetric addition of isoquinoline derivatives with silyl enol ethers or allyltributyltin in the presence of the acyl chloride 6 or 7
a
Entry
Substrate
Acylchol ride
Nucleophile
Product
Yield ,%)
deb ,%)
1
2
3
4
5
6
7
8
9
4
4
5
5
5
5
1
4
5
62
7
62
7
68
69
610
610
610
11a
2
11c
2
11e
11f
12a
12b
12c
89
57
77
75
98
99
69
67
75
77
59
92
72
86
81
59
76
95
11b
11d
a
The acylchol ride 6 was used as a racemic form except entry 6.
The diastereomeric excess was determined by 1H NMR.
b
Scheme 1.

T. Itoh et al. / Tetrahedron 57 )2001) 8827±8839
Table 3. Reduction of bromo groups and a double bond of compound 11 or 12
8829
Entry
Compound
R
Solvent
Product
R0
Yield ,%)
1
2
3
11c
12c
11f
CH2COOBn
CH2CHvCH2
CH2COPh
MeOH/AcOEt
MeOH
MeOH/AcOEt
13a
13b
13c
CH2COOMe
CH2CH2CH3
CH2CH2Ph
76
91
82
3±6 and 9). For acyl chlorides, the phthaloyl derivative 6
showed good reactivity and selectivity, although N-,p-nitro-
phenylsulfonyl)alanyl chloride ,7) had similar selectivity in
some cases.
With these precedents in hand, we next investigated reaction
using 6,7-dimethoxyisoquinoline ,16), which is the most
ubiquitous nucleus in isoquinoline alkaloids, and the results
are shown in Table 4 ,Scheme 3).
The above results indicated that parent isoquinoline itself
was not a suitable substrate for the asymmetric addition, and
introduction of bromo group,s) was crucialfor the good
diastereoselectivity. Compound 5 was readily synthesized
from 4, bromine and AlCl3 in a good yield,15 and the
bromo groups of 5 were found to be eliminated by reduction
by which the C3±C4 double bond was hydrogenated
concurrently ,Eq. ,2) and Table 3).
Although the compound 16 itself afforded low chemical
yields ,entries 1 and 2), corresponding 5,8-dibromo deriva-
tive 17, which was readily obtained from 16, was found to
give high chemical yields and stereoselectivities. In these
cases, the chiralauxiilaries 6 and 7 afforded comparable
results, and 7 was superior to 6 in the addition of silyl
enolethers ,entries 3 and 4), whereas 6 showed better
selectivity in the case of allyltributyltin ,entries 8 and 9).
The diastereoselectivity was seldom altered by the bulkiness
of nucleophiles ,entries 6 vs 7), thus it was suggested that a
stable conformation of N-acylquaternary satls formed in
situ controlled the selectivity without in¯uence of the
nucleophile.
The obtained products 20 were converted to corresponding
tetrahydro derivatives 22 by the reduction with Pd/C±
HCO2NH4 ,Eq. ,3) and Table 5). In these cases, the use of
Pd/C±H2 afforded a mixture of some reduced products.
ꢀ2†
ꢀ3†
Thus, the double bond and bromo groups at C-5 and C-8
were reduced simultaneously to give tetrahydro derivatives
13 under catalytic hydrogenation conditions. Since other
reducible functional groups were also converted under the
conditions, suitable transformation or protection of these
groups is needed before the reduction. It was suggested,
however, that 5,8-dibromo derivative 5 is a potential
substitute for parent 4 in our reaction system.
Compound 13c thus obtained was recrystallized once to
give an optically pure form, and readily transformed by
reduction with LiAlH4 to give an optically pure tetrahydro
compound 14,16 whose con®guration was supposed to be R
by derivatization to 15 using MTPA chloride ,modi®ed
Mosher method)17 ,Scheme 2).
Thus the process was proved to be a good alternative for the
direct addition to 6,7-dimethoxyisoquinoline ,16). There-
fore, the data shown above revealed that brominated iso-
quinoline derivatives are good substrates for asymmetric
1,2-addition, and subsequent transformation completes a
versatile method for chiral tetrahydroisoquinoline synthesis.
Scheme 2.

8830
T. Itoh et al. / Tetrahedron 57 )2001) 8827±8839
Table 4. Asymmetric addition of 6,7-dimethoxyisoquinoline ,16) or 5,8-dibromo derivative ,17) with silyl enol ether or allyltributyltin in the presence of the
acylchol ride derive from , S)-alanine
a
Entry
Substrate
Acylchol ride
Nucleophile
Product
Yield ,%)
deb ,%)
1
2
3
4
5
6
7
8
9
166
167
17
17
17
17
17
17
17
2
20a
38
20
100
86
93
85
65
83
73
74
67
84
96
93
83
94
91
69
2
62
7
20b
20c
2
18
9
19
20d
20e
20f
20g
7
7
7
610
7
21a
10
21b
a
Compound 6 was used as a racemic form.
The diastereomeric excess was determined by 1H NMR.
b
Scheme 3.
Table 5. Reduction of 20 with HCO2NH4±Pd/C
Entry
Compound
R
Solvent
Product
R0
CH2COOH
CH2CO-3,4-di,MeO)Ph
CH2CH,OH)±Ph
Yield ,%)
1
2
3
20d
20e
20f
CH2COOBn
CH2CO-3,4-di,MeO)Ph
CH2COPh
MeOH/THF
MeOH/THF
MeOH
22a
22b
22c
98
65
62a
a
The reaction was run at 708C.
Scheme 4.

T. Itoh et al. / Tetrahedron 57 )2001) 8827±8839
8831
Scheme 5.
We next carried out the con®rmation of the absolute con-
®guration using the synthesis of ,2)-homolaudanosine,18
and the procedure is shown in Scheme 4. Compound 20e
obtained in 93% de was recrystallized from hexane/AcOEt
to give a single diastereomer, and converted to 22b by the
reduction with Pd/C±HCO2NH4. Compound 22b was
treated with H2±Pd/C in TFA/AcOH to reduce the keto
carbonylgroup to give 23. Reduction of 23 with LiAlH4
eliminated the chiral auxiliary to give compound 24,
which was methylated by HCHO±NaBH3CN to form homo-
laudanosine ,25) in an optically pure form. The measure-
ment of the speci®c rotation indicated that the absolute
con®guration of 25 was R. The overall yield from 17 was
32% with a single enantiomer.
used for the reaction of compound 17 and O-benzyl
trimethylsilyl ketene acetal ,2) ,Scheme 5).
Isopropylgroup affected the de in a negative manner in the
case of p-nitrophenylsulfonyl group ,19% de), but in a posi-
tive manner for phthalimide group ,95% de). Thus, stable
conformations of N-acylated isoquinolinium salts were
calculated by the PM3 method, and the results are shown
in Figs. 1 and 2.
As shown in Fig. 1, the isopropylgroup rendered the
p-nitrophenylsulfonyl group lower toward the Re side
because of the steric repulsion between these two groups.
That results in the block of both sides of the reaction site,
and the stereoselectivity might be lowered accompanied by
decrease of the chemicalyield. On the contrary, exchange of
methylgroup to isopropylgroup had no in¯uence on confor-
mation of the quaternary salts in the cases of phthalimido
groups ,Fig. 2). This is probably due to the rather restricted
conformation of phthaloyl group than that of p-nitrophenyl-
sulfonyl group. Thus the bulkiness of the alkyl group
effectively shielded the Si face of the reaction site to afford
the high selectivity, especially in the case of isopropyl group.
The data shown in Tables 2 and 4 suggested that the stereo-
selectivity was regulated by a conformation of the quatern-
ary salts of isoquinolines without the participation of
nucleophiles, and the results shown in Schemes 2 and 4
indicated that p-nitrophenylsulfonyl and phthaloyl groups
on ,S)-alanyl moiety both showed the R selectivity. In
order to obtain further information for the selectivity, chiral
auxiliaries derived from ,S)-valine were synthesized and
Figure 1. Calculated PM3 structures of N-,p-nitrophenylsulfonly)alanyl- and N-,p-nitrophenylsulfonyl) valinyl-5,8-dibromo-6,7-dimethoxyisoquinolinium
salts.

8832
T. Itoh et al. / Tetrahedron 57 )2001) 8827±8839
Figure 2. Calculated PM3 structures of N-phthaloylalanyl- and N-phthaloylvalinyl-5,8-dibromo-6,7-dimethoxyisoquinolinium salts.
In this paper, we disclosed a general method by which
asymmetric 1-substituted tetrahydroisoquinolines was
synthesized from corresponding aromatics. Introduction of
bromo groups on the substrate effectively increased both
chemicalyiedls and stereoseelctivity to give a practical
level of asymmetric adducts. Application of the reaction
system toward synthesis of isoquinoline alkaloids such as
emetine and pronuciferine,19 and other derivatives that
might have bioactivity towards Parkinson's disease is now
under investigation.20
synthesized according to the literatures shown below:
N-phenylsulfonyl-,S)-alanine;22 N-,p-nitrophenylsulfonyl)-
,S)-alanine;22 N-phthaloyl-,S)-alanine;23 N-,1-naphthyl-
sulfonyl)-,S)-alanine;24
N-,p-nitrophenylsulfonyl)-,S)-
valine;25 N-phthaloyl-,S)-valine.26 Since racemic N-phthal-
oylalanine is commercially available ,Tokyo Chemical
Industry Co.), it was used for the estimation of diastereo-
selectivity of the addition reaction.
1.4. Preparation of silyl enol ethers
Two silyl enol ethers which are not commercially available
were synthesized according to the reported methods: benzyl
trimethylsilyl ketene acetal;27 1-,3,4-dimethoxyphenyl)-1-
,trimethylsilyloxy)ethylene.18b
1. Experimental
1.1. General remarks
Melting points are uncorrected. 1H- and 13C NMR spectra of
CDCl3 and CD3OD solutions were recorded at 500 and
125 MHz, respectively, with tetramethylsilane ,TMS) as
an internalstandard. High-resoultion mass spectra ,FAB-
HRMS) were measured using p-nitrobenzylacloholas a
matrix.
1.5. Reaction of 4-bromoisoquinoline with silyl enol
ethers in the presence of an acyl chloride derived from
ꢀS)-alanine
To a benzene solution ,3 ml) of N-protected ,S)-alanine ,or
racemic N-phthaloylalanine) ,0.23 mmol) was added
thionylcholride ,SOCl 2) ,0.3 ml), and the mixture was
allowed to react at 608C for 1 h. Then the solvent and excess
SOCl2 were evaporated off in vacuo to leave viscous oil.
Methylene chloride ,2 ml) and 4-bromoisoquinoline were
successively added to the oil and the mixture was cooled
to 2788C under Ar. To the solution was added a cooled
CH2Cl2 solution ,1 ml) of benzyl trimethylsilyl ketene
acetal ,0.23 mmol). The mixture was allowed to react for
1 h at 2788C under Ar, then brought to room temperature.
The solvent was evaporated off to leave a residue, which
was chromatographed on silica gel ,CH2Cl2/Et2Oˆ10:1) to
give the product. The de was estimated from 1H NMR data
of the crude sample before the column chromatography. The
melting points and spectral data were obtained from the
samples after puri®cation.
1.2. Preparation of substrates
5,8-Dibromoisoquinoline ,5)15 and 6,7-dimethoxyisoquino-
line ,16)21 were prepared according to the literatures. 5,8-
Dibromo-6,7-dimethoxyisoquinoline ,17) was synthesized
using the same method as 5.
1.2.1. 5,8-Dibromo-6,7-dimethoxyisoquinoline ꢀ17). y
81%; Pale yellow needles from ethanol; mp 124.0±
1
124.68C. H NMR ,CDCl3) d 4.02 ,3H, s), 4.05 ,3H, s),
7.97 ,1H, d, Jˆ5.4 Hz), 8.64 ,1H, d, Jˆ5.4 Hz), 9.56 ,1H,
s). 13C NMR ,CDCl3) d 61.2, 61.3, 114.5, 118.7, 124.8,
133.8, 144.1, 149.9, 151.2, 154.0. HRMS ,FAB): Calcd
for C11H9Br2NO2 ,M1H)1: 345.9078. Found 345.9102.
1.3. Preparation of chiral auxiliaries
1.5.1. Benzyl 4-bromo-1,2-dihydro-2-[N-phenylsulfonyl-
ꢀS)-alanyl]isoquinolin-1-ylacetate ꢀ3a). y 67%; Yellow
powder from hexane; mp 110.6±112.18C ,55% de). The
Chiralacids derived from , S)-alanine and ,S)-valine were

T. Itoh et al. / Tetrahedron 57 )2001) 8827±8839
8833
1
NMR spectra of the major isomer are shown; H NMR
,CDCl3) d 1.33 ,3H, d, Jˆ6.8 Hz), 2.43 ,1H, dd, Jˆ14.0,
6.0 Hz), 2.51 ,1H, dd, Jˆ13.6, 8.0 Hz), 4.23 ,1H, dq,
Jˆ10.0, 7.2 Hz), 4.92 ,1H, d, Jˆ12.0 Hz), 4.99 ,1H, d,
Jˆ12.0 Hz), 5.55 ,1H, t, Jˆ7.2 Hz), 5.65 ,1H, d,
Jˆ9.6 Hz), 6.72 ,1H, d, Jˆ1.2 Hz), 6.83±7.90 ,14H, m).
13C NMR ,CDCl3) d 19.3, 39.1, 48.6, 50.1, 66.8, 108.7,
122.3, 125.5, 126.2, 126.9, 128.3, 128.40, 128.43, 128.46,
128.6, 129.0, 129.2, 131.9, 132.5, 135.2, 138.5, 169.1,
169.5. Anal. Calcd for C27H25BrN2O5S: C, 56.95; H, 4.42;
N, 4.92. Found C, 57.20; H, 4.24; N, 4.75.
to these reactions. In the case of the reactions using allyl-
tributyltin, sat. KF solution ,4 ml) was added to the mixture
after the reaction went to completion, and the mixture was
allowed to stand for 1 h with stirring. Then Et2O ,15 ml)
was added, and the precipitate thus formed was ®ltered. The
®ltrate was evaporated off to leave a residue, which was
chromatographed on silica gel to give the product. The de
1
was estimated from H NMR data of the crude sample
before the column chromatography. The melting points
and spectraldata were obtained from the sampels after
puri®cation.
1.5.2. Benzyl 4-bromo-1,2-dihydro-2-{N-[1-naphthylsul-
fonyl-ꢀS)-alanyl]}isoquinolin-1-ylacetate ꢀ3b). y 70%;
Yellow powder from CH2Cl2/Et2O; mp 70±718C ,31%
1.6.1. Benzyl 1,2-dihydro-2-[N-phthaloylalanyl]iso-
quinolin-1-ylacetateꢀ11a). y 89%; Colorless needles from
CH2Cl2/hexane; mp 183.4±184.88C ,100% de, a racemic
1
1
de). The NMR spectra of the major isomer are shown; H
mixture). H NMR ,CDCl3) d 1.63 ,3H, d, Jˆ7.0 Hz),
NMR ,CDCl3) d 1.28 ,3H, d, Jˆ6.8 Hz), 2.28 ,1H, dd,
Jˆ13.6, 6.4 Hz), 2.32 ,1H, dd, Jˆ12.0, 8.8 Hz), 4.15 ,1H,
dq, Jˆ10.0, 6.8 Hz), 4.85 ,1H, d, Jˆ12.0 Hz), 4.90 ,1H, d,
Jˆ12.0 Hz), 5.73±5.79 ,2H, m), 6.52 ,1H, s), 6.73±8.67
,16H, m). 13C NMR ,CDCl3) d 19.4, 39.2, 48.6, 49.9,
66.8, 107.7, 108.1, 122.3, 123.5, 124.1, 124.4, 125.5,
126.3, 126.7, 128.4, 128.5, 128.6, 128.7, 129.0, 129.1,
129.6, 131.6, 133.2, 133.6, 134.3, 134.6, 135.2, 169.0,
169.1. Anal. Calcd for C31H27BrN2O5S: C, 60.07; H, 4.40;
N, 4.52. Found C, 60.35; H, 4.35; N, 4.41.
2.61 ,1H, dd, Jˆ13.4, 6.9 Hz), 2.68 ,1H, dd, Jˆ13.4,
6.9 Hz), 5.01 ,1H, d, Jˆ12.3 Hz), 5.12 ,1H, q, Jˆ7.0 Hz),
5.75 ,1H, d, Jˆ7.6 Hz), 6.06 ,1H, t, Jˆ6.9 Hz), 6.42 ,1H, d,
Jˆ7.6 Hz), 6.88 ,1H, d, Jˆ6.8 Hz), 7.09±7.14 ,3H, m),
7.30±7.38 ,5H, m), 7.68 ,2H, dd, Jˆ5.5, 3.1 Hz), 7.77
,2H, dd, Jˆ5.5, 3.1 Hz). 13C NMR ,CDCl3) d 15.4, 39.4,
46.6, 51.6, 66.7, 110.8, 122.8, 123.5, 124.8, 126.4, 127.6,
127.9, 128.2, 128.5, 129.1, 131.4, 132,1, 134.2, 135.6,
166.8, 166.9, 169.7. Anal. Calcd for C29H24N2O5: C,
72.49; H, 5.03; N, 5.83. Found: C, 72.45; H, 4.77; N, 5.81.
1.5.3. Benzyl 4-bromo-1,2-dihydro-2-[N-ꢀp-nitrophenyl)-
sulfonyl-ꢀS)-alanyl]isoquinolin-1-ylacetate ꢀ3c). y 56%;
Yellow needles from hexane; mp 77.7±78.18C ,77% de).
The NMR spectra of the major isomer are shown; 1H
NMR ,CDCl3) d 1.39 ,3H, d, Jˆ7.0 Hz), 2.41 ,1H, dd,
Jˆ13.8, 5.8 Hz), 2.51 ,1H, dd, Jˆ13.8, 8.4 Hz), 4.28 ,1H,
dq, Jˆ10.1, 7.0 Hz), 4.92 ,1H, d, Jˆ12.1 Hz), 5.00 ,1H, d,
Jˆ12.1 Hz), 5.54 ,1H, dd, Jˆ8.4, 5.8 Hz), 5.61 ,1H, d,
Jˆ10.1 Hz), 6.72 ,1H, d, Jˆ1.5 Hz), 6.90 ,1H, d,
Jˆ7.0 Hz), 7.26±7.31 ,3H, m), 7.32±7.37 ,3H, m), 7.41
,1H, td, Jˆ7.7, 1.3 Hz), 7.54 ,1H, dd, Jˆ7.7, 1.1 Hz),
7.76 ,4H, s). 13C NMR ,CDCl3) d 19.2, 38.9, 48.6, 50.0,
66.8, 109.4, 121.6, 123.5, 124.2, 125.4, 127.6, 127.7, 128.0,
128.2, 128.3, 128.9, 129.9, 131.3, 134.9, 144.4, 149.3,
168.7, 168.8. Anal. Calcd for C27H24BrN3O7S: C, 52.78;
H, 3.94; N, 6.84. Found: C, 53.11; H, 3,90; N, 6.84.
1.6.2. Benzyl 1,2-dihydro-2-[N-ꢀp-nitrophenyl)sulfonyl-
ꢀS)-alanyl]isoquinolin-1-ylacetate ꢀ11b). y 57%; Yellow
needles from hexane; mp 68.1±70.58C ,64% de). The
1
NMR spectra of the major isomer are shown; H NMR
,CDCl3) d 1.39 ,3H, d, Jˆ7.0 Hz), 2.38 ,1H, dd, Jˆ13.7,
5.9 Hz), 2.48 ,1H, dd, Jˆ13.7, 8.6 Hz), 4.32 ,1H, dq,
Jˆ10.1, 7.0 Hz), 4.91 ,1H, d, Jˆ12.1 Hz), 5.00 ,1H, d,
Jˆ12.1 Hz), 5.50 ,1H, dd, Jˆ8.6, 5.9 Hz), 5.65 ,1H, d,
Jˆ10.1 Hz), 6.14 ,1H, d, Jˆ7.7 Hz), 6.37 ,1H, d,
Jˆ7.7 Hz), 6.89 ,1H, d, Jˆ7.7 Hz), 7.08±7.24 ,3H, m),
7.26±7.38 ,5H, m), 7.73 ,2H, d, Jˆ9.3 Hz), 7.76 ,2H, d,
Jˆ9.3 Hz). 13C NMR ,CDCl3) d 19.2, 38.9, 48.7, 50.0, 66.8,
114.3, 121.2, 123.8, 125.4, 125.8, 128.2, 128.3, 128.39,
128.46, 128.53, 128.8, 128.9, 131.4, 135.3, 144.5, 149.7,
169.3, 169.7. Anal. Calcd for C27H25N3O7S: C, 60.55; H,
4.70; N, 7.85. Found: C, 60.44; H, 4.61; N, 7.50.
1.5.4. Benzyl 4-bromo-1,2-dihydro-2-[N-phthaloyl-
alanyl]isoquinolin-1-ylacetate ꢀ3d). y 68%; Colorless
powder; mp 65±668C ,100% de, a racemic mixture). H
1.6.3. Benzyl 5,8-dibromo-1,2-dihydro-2-[N-phthaloyl-
alanyl]isoquinolin-1-ylacetate ꢀ11c). y 77%; Colorless
needles from CH2Cl2/hexane; mp 152.6±152.98C ,100%
1
1
NMR ,CDCl3) d 1.62 ,3H, d, Jˆ7.2 Hz), 2.63 ,1H, dd,
Jˆ13.6, 6.8 Hz), 2.69 ,1H, dd, Jˆ13.6, 6.8 Hz), 5.00±
5.12 ,3H, m), 6.05 ,1H, t, Jˆ7.2 Hz), 6.78 ,1H, s), 7.08±
7.22 ,4H, m), 7.33±7.37 ,5H, m), 7.69 ,2H, dd, Jˆ5.6,
3.2 Hz), 7.76 ,2H, dd, Jˆ5.6, 3.2 Hz). 13C NMR ,CDCl3)
d 15.4, 39.6, 46.7, 51.7, 66.8, 106.5, 123.3, 123.5, 124.1,
125.0, 126.2, 128.2, 128.3, 128.5, 129.0, 131.3, 132.5,
134.1, 134.3, 135.5, 166.6, 166.7, 169.4. Anal. Calcd for
C29H23N2O5Br: C, 62.24; H, 4.15; N, 5.01. Found C,
62.22; H, 4.25; N, 4.87.
de, a racemic mixture). H NMR ,CDCl3) d 1.62 ,3H, d,
Jˆ7.0 Hz), 2.55 ,1H, dd, Jˆ12.7, 3.8 Hz), 2.63 ,1H, dd,
Jˆ12.7, 9.2 Hz), 5.03±5.10 ,3H, m), 6.05 ,1H, d,
Jˆ7.6 Hz), 6.41 ,1H, dd, Jˆ9.2, 3.8 Hz), 6.55 ,1H, d,
Jˆ7.6 Hz), 7.21 ,1H, d, Jˆ8.7 Hz), 7.23 ,1H, d,
Jˆ8.7 Hz), 7.33±7.39 ,5H, m), 7.70 ,2H, dd, Jˆ5.3,
3.1 Hz), 7.78 ,2H, dd, Jˆ5.3, 3.8 Hz). 13C NMR ,CDCl3)
d 15.4, 36.5, 46.8, 51.8, 67.1, 109.4, 119.4, 120.5, 123.6,
125.9, 128.2, 128.4, 128.5, 131.2, 131.3, 133.0, 133.1,
134.3, 135.6, 166.9, 167.3, 169.5. Anal. Calcd for
C29H22Br2N2O5: C, 54.57; H, 3.47; N, 4.39. Found: C,
54.27; H, 3.13; N, 4.31.
1.6. Reaction of isoquinolines ꢀ1, 4 and 5) with various
silyl enol ethers or allyltributyltin in the presence of an
acyl chloride derived from ꢀS)-alanine
1.6.4. Benzyl 5,8-dibromo-1,2-dihydro-2-[N-ꢀp-nitro-
phenyl)sulfonyl-ꢀS)-alanyl]isoquinolin-1-ylacetate ꢀ11d).
y 75%; Pale yellow needles from CH2Cl2/hexane; mp
The same reaction procedure mentioned above was applied

8834
T. Itoh et al. / Tetrahedron 57 )2001) 8827±8839
165.6±167.88C ,100% de); [a]25 ˆ2303.9 ,100% ee) ,c
The NMR spectra of the major isomer are shown; 1H
NMR ,CDCl3) d 1.68 ,3H, d, Jˆ7.0 Hz), 2.40 ,2H, t,
Jˆ7.1 Hz), 4.92 ,1H, dd, Jˆ17.0, 1.9 Hz), 4.98 ,1H, dd,
Jˆ10.0, 1.9 Hz), 5.19 ,1H, q, Jˆ7.0 Hz), 5.66 ,1H, t,
Jˆ7.1 Hz), 5.73 ,1H, d, Jˆ7.7 Hz), 5.75 ,1H, ddt,
Jˆ17.0, 10.0, 7.1 Hz), 6.43 ,1H, dd, Jˆ7.7, 1.0 Hz),
6.87±6.90 ,1H, m), 7.03±7.06 ,1H, m), 7.09±7.16 ,2H,
m), 7.68 ,2H, dd, Jˆ5.5, 3.1 Hz), 7.78 ,2H, dd, Jˆ5.5,
3.1 Hz). 13C NMR ,CDCl3) d 15.5, 39.7, 46.7, 54.3,
111.0, 117.7, 123.1, 123.5, 124.7, 126.4, 127.1, 127.4,
129.3, 131.4, 133.3, 134.0, 134.1, 166.8, 167.0. Anal.
Calcd for C23H20N2O3: C, 74.18; H, 5.41; N, 7.52. Found:
C, 74.06; H, 5.42; N, 7.58.
D
1.02, CHCl3). 1H NMR ,CDCl3)
d
1.38 ,3H, d,
Jˆ7.0 Hz), 2.34 ,1H, dd, Jˆ13.2, 3.8 Hz), 2.46 ,1H, dd,
Jˆ13.2, 10.3 Hz), 4.28±4.35 ,1H, m), 4.91 ,1H, d,
Jˆ12.3 Hz), 5.00 ,1H, d, Jˆ12.3 Hz), 5.75 ,1H, d,
Jˆ10.3 Hz), 5.86±5.89 ,1H, m), 6.44 ,1H, dd, Jˆ7.7,
2.0 Hz), 6.50±6.54 ,1H, m), 7.26±7.38 ,6H, m), 7.42 ,1H,
dd, Jˆ8.6, 1.8 Hz), 7.79 ,2H, d, Jˆ8.8 Hz), 7.85 ,2H, d,
Jˆ8.8 Hz). 13C NMR ,CDCl3) d 19.1, 35.8, 48.7, 49.9,
67.0, 112.4, 119.8, 120.1, 123.5, 124.0, 128.1, 128.2,
128.3, 128.4, 130.2, 132.0, 133.1, 133.6, 135.1, 144.3,
149.3, 168.7, 169.7. Anal. Calcd for C27H23Br2N3O7S: C,
46.77; H, 3.34; N, 6.06. Found: C, 46.63; H, 3.01; N, 6.04.
1.6.9. 1-Allyl-5,8-dibromo-1,2-dihydro-2-[N-phthaloyl-
alanyl]isoquinoline ꢀ12c). y 75%; Colorless powder from
CH2Cl2/hexane; mp 170.9±171.58C ,100% de, a racemic
1.6.5. Phenyl 5,8-dibromo-1,2-dihydro-2-[N-phthaloyl-
alanyl]isoquinolin-1-ylacetate ꢀ11e). y 98%; Colorless
needles from CHCl3/hexane; mp 1908C ,100% de, a racemic
mixture). 1H NMR ,CDCl3) d 1.66 ,3H, d, Jˆ7.2 Hz), 2.72
,1H, dd, Jˆ12.4, 8.8 Hz), 2.80 ,1H, dd, Jˆ12.4, 8.8 Hz),
5.20,1H, q, Jˆ8.0 Hz), 6.16 ,1H, d, Jˆ8.0 Hz), 6.56,1H,
dd, Jˆ8.0, 4.0 Hz), 6.66 ,1H, d, Jˆ8.0 Hz), 7.18±7.28
,5H, m), 7.39 ,1H, d, Jˆ8.4 Hz), 7.41 ,1H, d, Jˆ7.6 Hz),
7.72 ,2H, dd, Jˆ5.6, 3.2 Hz), 7.80 ,2H, dd, Jˆ5.6, 3.2 Hz).
13C NMR ,CDCl3) d 15.5, 36.8, 46.8, 51.7, 109.6, 119.4,
120.5, 121.5, 123.5, 125.7, 125.8, 129.2, 131.1, 131.2,
132.3, 132.9, 133.1, 134.2, 150.5, 166.7, 167.4, 167.9.
Anal. Calcd for C28H20Br2N2O5: C, 53.84; H, 3.24; N,
4.49. Found: C, 53.55; H, 2.95; N, 4.54.
1
mixture). H NMR ,CDCl3) d 1.71 ,3H, d, Jˆ7.0 Hz),
2.40 ,2H, t, Jˆ7.2 Hz), 4.96 ,1H, d, Jˆ17.2 Hz), 5.01 ,H,
d, Jˆ10.0 Hz), 5.20 ,1H, q, Jˆ7.0 Hz), 5.84 ,2H, ddt,
Jˆ17.2, 10.0, 7.2 Hz), 6.08 ,1H, d, Jˆ7.8 Hz), 6.12 ,1H,
t, Jˆ7.2 Hz), 6.59 ,1H, d, Jˆ7.8 Hz), 7.19 ,1H, d,
Jˆ8.5 Hz), 7.21 ,1H, d, Jˆ8.5 Hz), 7.70 ,2H, dd, Jˆ5.3,
2.9 Hz), 7.78 ,2H, dd, Jˆ5.3, 2.9 Hz). 13C NMR ,CDCl3) d
15.5, 37.0, 46.8, 53.3, 109.7, 117.7, 119.2, 120.4, 123.4,
125.7, 131.0, 131.2, 132.1, 132.4, 133.6, 134.1, 134.4,
166.9, 167.1. Anal. Calcd for C23H18Br2N2O3: C, 52.10;
H, 3.42; N, 5.28. Found: C, 51.97; H, 3.07; N, 5.24.
1.6.6. 5,8-Dibromo-1,2-dihydro-1-phenacyl-2-[N-phthal-
oyl-ꢀS)-alanyl]isoquinoline ꢀ11f). y 99%; Colorless powder
from AcOEt/hexane; mp 193±1948C ,100% de);
1.7. Reduction of bromo groups and a double bond at
C3±C4 of compound 11 or 12
[a]25 ˆ2513.3 ,100% ee) ,c 1.02, CHCl3); 1H NMR
D
To a solution of compound 11c ,0.32 mmol) in MeOH
,25 ml)/AcOEt ,10 ml), 10% Pd/C ,200 mg) was added
and the mixture was allowed to react under H2 atmosphere
at room temperature for 3 h. Then the mixture was ®ltered
through a plug of Celite, and the ®ltrate was evaporated to
dryness under reduced pressure. The residue was puri®ed by
silica gel chromatography ,AcOEt) to give the product.
,CDCl3) d 1.57 ,3H, d, Jˆ6.8 Hz), 3.02 ,1H, dd, Jˆ12.4,
9.6 Hz), 3.29 ,1H, dd, Jˆ12.4, 4.4 Hz), 5.08 ,1H, q,
Jˆ6.8 Hz), 6.09 ,1H, d, Jˆ7.6 Hz), 6.44 ,1H, dd, Jˆ8.8,
3.6 Hz), 6.58 ,1H, d, Jˆ8.4 Hz), 7.25 ,2H, s), 7.46 ,2H, t,
Jˆ7.6 Hz), 7.57 ,1H, t, Jˆ7.2 Hz), 7.69 ,2H, dd, Jˆ5.2,
2.8 Hz), 7.77 ,2H, dd, Jˆ5.2, 3.2 Hz), 7.98 ,2H, d,
Jˆ7.2 Hz). 13C NMR ,CDCl3) d 15.4, 39.7, 46.7, 52.4,
109.5, 119.6, 120.5, 123.6, 126.1, 128.5, 128.6, 131.4,
131.5, 132.2, 133.0, 133.2, 133.4, 134.3, 137.2, 166.9,
167.1, 196.9. Anal. Calcd for C28H20Br2N2O4: C, 55.29;
H, 3.31; N, 4.61. Found: C, 54.87; H, 2.88; N, 4.50.
1.7.1. Methyl 1,2,3,4-tetrahydro-2-[N-phthaloylalanyl]-
isoquinolin-1-ylacetate ꢀ13a). y 76%; Colorless needles
from Et2O/hexane; mp 143.5±144.58C ,100% de, a racemic
mixture). The product was obtained as a mixture of two
conformationalisomers ,2:1). The NMR spectra of the
1
1.6.7. 1-Allyl-4-bromo-1,2-dihydro-2-[N-phthaloylalanyl]-
isoquinoline ꢀ12a). y 69%; Colorless powder from hexane;
mp 61.6±63.38C ,56% de, a racemic mixture). The NMR
spectra of the major isomer are shown; 1H NMR ,CDCl3) d
1.68 ,3H, d, Jˆ6.9 Hz), 2.39 ,2H, t, Jˆ7.3 Hz), 4.95 ,1H, d,
Jˆ17.0 Hz), 5.00 ,1H, d, Jˆ10.0 Hz), 5.15 ,1H, q,
Jˆ6.9 Hz), 5.65 ,1H, t, Jˆ7.3 Hz), 5.72 ,1H, ddt, Jˆ17.0,
10.0, 7.3 Hz), 6.80 ,1H, d, Jˆ0.7 Hz), 7.03±7.09 ,1H, m),
7.68 ,2H, dd, Jˆ5.5, 3.0 Hz), 7.75 ,2H, dd, Jˆ5.5, 3.0 Hz).
13C NMR ,CDCl3) d 15.6, 39.7, 46.8, 54.5, 106.6, 118.0,
123.3, 124.0, 124.6, 126.2, 127.5, 128.2, 128.3, 131.1,
133.2, 133.4, 134.0, 166.3, 166.5. Anal. Calcd for
C23H19BrN2O3: C, 61.21; H, 4.24; N, 6.21. Found: C,
61.43; H, 4.17; N, 5.94.
major isomer are shown; H NMR ,CDCl3) d 1.77 ,3H, d,
Jˆ6.0 Hz), 2.72±2.93 ,6H, m), 3.61±3,77 ,2H, m), 3.69
,3H, s), 5.23 ,1H, q, Jˆ5.9 Hz), 5.93 ,1H, dd, Jˆ6.6,
4.4 Hz), 7.04 ,1H, d, Jˆ5.9 Hz), 7.13±7.18 ,3H, m), 7.71
,2H, dd, Jˆ4.4, 2.4 Hz), 7.82 ,2H, dd, Jˆ4.4, 2.4 Hz). 13C
NMR ,CDCl3) d 15.4, 29.1, 40.2, 41.2, 47.4, 50.9, 52.0,
123.5, 126.8, 127.1, 127.2, 128.6, 131.7, 133.3, 134.2,
135.8, 167.7, 168.3, 170.9. Anal. Calcd for C23H22N2O5:
C, 67.97; H, 5.46; N, 6.89. Found: C, 68.03; H, 5.37; N,
6.89.
1.7.2. 1,2,3,4-Tetrahydro-2-[N-phthaloylalanyl]-1-pro-
pylisoquinoline ꢀ13b). y 91%; Colorless powder from
AcOEt/hexane; mp 114.4±115.38C ,100% de, a racemic
mixture). The product was obtained as a mixture of two
conformationalisomers ,2.5:1). The NMR spectra of the
1.6.8.
1-Allyl-1,2-dihydro-2-[N-phthaloylalanyl]iso-
1
quinoline ꢀ12b). y 67%; Yellow powder from CH2Cl2/
hexane; mp 166.0±167.88C ,83% de, racemic mixture).
major isomer are shown; H NMR ,CDCl3) d 0.95 ,3H, t,
Jˆ7.2 Hz), 1.31±1.51 ,2H, m), 1.66±1.89 ,2H, m), 1.83

T. Itoh et al. / Tetrahedron 57 )2001) 8827±8839
8835
,3H, d, Jˆ7.2 Hz), 2.75±2.89 ,2H, m), 3.60 ,1H, ddd,
Jˆ13.6, 9.6, 5.2 Hz), 3.75 ,1H, dt, Jˆ13.6, 4.4 Hz), 5.27
,1H, q, Jˆ7.2 Hz), 5.55 ,1H, dd, Jˆ8.8, 5.6 Hz), 7.00±7.21
,4H, m), 7.68 ,2H, dd, Jˆ5.6, 3.2 Hz), 7.80 ,2H, dd, Jˆ5.6,
3.2 Hz). 13C NMR ,CDCl3) d 13.9, 15.5, 19.5, 29.0, 38.9,
39.8, 47.5, 53.2, 123.3, 126.1, 126.3, 127.4, 128.3, 131.6,
132.9, 134.0, 137.6, 167.7, 168.1. Anal. Calcd for
C23H4N2O3: C, 73.38; H, 6.43; N, 7.44. Found: C, 73.18;
H, 6.66; N, 7.41.
Colorless oil. The product was obtained as a mixture of
two conformers ,4:1). In the H NMR, the existence of
1
two conformers was shown only at the peak of OMe
group ,d 3.84 and 3.23); H NMR ,CDCl3) d 1.49 ,1H,
1
ddd, Jˆ16.5, 11.0, 5.5 Hz), 2.12±2.18 ,3H, m), 2.71±2.88
,2H, m), 3.39 ,1H, ddd, Jˆ14.1, 11.7, 4.6 Hz), 3.84 ,3.23 for
the minor isomer) ,3H, q, Jˆ1.5 Hz), 4.11 ,1H, ddd,
Jˆ13.9, 5.2, 1.3 Hz), 5.82 ,1H, dd, Jˆ8.4, 5.0 Hz), 6.84
,1H, d, Jˆ7.5 Hz), 7.06±7.54 ,13H, m). In the 13C NMR,
almost all the peaks showed the existence of the isomers,
thus the NMR spectra of the major isomer are shown; 13C
NMR ,CDCl3) d 26.7, 33.2, 38.2, 38.9, 40.6, 53.1, 55.8,
126.0, 126.1, 126.6, 126.7, 127.1, 127.5, 128.2, 128.3,
128.4, 128.5, 129.3, 132.9, 133.9, 136.5, 141.5, 164.6.
HRMS ,FAB): Calcd for C27H27F3NO2 ,M1H)1:
454.1994. Found 454.1963.
1.7.3. 1,2,3,4-Tetrahydro-1-phenethyl-2-[N-phthaloyl-ꢀS)-
alanyl]isoquinoline ꢀ13c). y 82%; Colorless powder from
CH2Cl2/AcOEt; mp 140±1418C ,100% de); [a]25 ˆ264.9
D
,100% ee) ,c 1.02, CHCl3). The product was obtained as a
mixture of two conformationalisomers ,2.5:1). The NMR
spectra of the major isomer are shown; 1H NMR ,CDCl3) d
1.83 ,3H, d, Jˆ6.0 Hz), 2.02±2.93 ,2H, m), 2.61±2.86 ,4H,
m), 3.61 ,1H, ddd, Jˆ10.4, 7.2, 4.2 Hz), 3.77 ,1H, dt, Jˆ11.0,
3.7 Hz), 5.24 ,1H, q, Jˆ5.9 Hz), 5.67 ,1H, dd, Jˆ4.4,
2.9 Hz), 7.01±7.27 ,9H, m), 7.69 ,2H, dd, Jˆ4.4, 2.4 Hz),
7.81 ,2H, dd, Jˆ4.4, 2.4 Hz). 13C NMR ,CDCl3) d 15.6, 29.1,
32.7, 38.3, 40.0, 47.5, 53.5, 123.4, 125.8, 126.4, 126.6, 127.5,
128.27, 128.34, 128.5, 131.7, 134.0, 134.1, 137.3, 141.7,
167.8, 168.7. Anal. Calcd for C28H26N2O3: C, 76.69; H,
5.98; N, 6.39. Found: C, 76.34; H, 6.05; N, 6.36.
The proton on C-1 position of 15 showed a double doublet
signalat d 5.82. A corresponding diastereomeric mixture
was synthesized using racemic 14 and ,R)-MTPA chloride,
and the mixture showed the signalof C-1 proton at 5.71 ,t,
Jˆ7.2 Hz) and 5.82 ,dd, Jˆ8.4, 5.0 Hz) at a ratio of 1 to 1.
In Ref. 17b, Hoye and Renner extended modi®ed Mosher
method to secondary amines which have a chiralcenter at
a-position. They suggested that positive Dd ,,the d value of
,S)-MTPA amide)2,the d value of ,R)-MTPA amide))
indicates the absolute con®guration as ,R). Thus the con-
®guration of compound 14 was indicated as ,R) using the
above data ,Ddˆ10.11).
1.8. Synthesis of 1,2,3,4-tetrahydro-1-phenethyliso-
quinoline ꢀ14)
To a THF solution ,14 ml) of compound 13c ,1.0 mmol),
LiAlH4 ,2.5 mmol) was added and the mixture was allowed
to react for 1 h at room temperature. Then water was added
and the mixture was extracted with AcOEt. The organic
layer was dried over MgSO4, and evaporated off to leave
a residue, which was chromatographed on silica gel ,CHCl3/
MeOHˆ20) to give the product.
1.10. Reaction of 6,7-dimethoxyisoquinolines ꢀ16 or 17)
with silyl enol ethers or allyltributyltin in the presence of
an acyl chloride derived from ꢀS)-alanine
The same procedure as in the case of isoquinoline ,1, 4 and
5) was applied to these reactions.
1.8.1. 1,2,3,4-Tetrahydro-1-ꢀ2-phenethyl)isoquinoline ꢀ14).
1.10.1. Benzyl 1,2-dihydro-6,7-dimethoxy-2-[N-phthal-
oyl-ꢀS)-alanyl]isoquinolin-1-yl-acetate ꢀ20a).
y 85%; Pale brown oil; [a]25 ˆ123.2 ,100% ee) ,c 1.02,
y 38%;
D
CHCl3); 1H NMR ,CDCl3) d 1.99±2.18 ,3H, m), 2.68±2.86
,4H, m), 2.99 ,1H, ddd, Jˆ12.4, 7.6, 5.2 Hz), 3.23 ,1H, dt,
Jˆ12.4, 5.6 Hz), 3.99 ,1H, dd, Jˆ9.2, 3.6 Hz), 7.05±7.29
,9H, m). 13C NMR ,CDCl3) d 29.9, 32.4, 38.1, 40.9, 55.3,
125.8, 125.9, 126.1, 128.4, 129.3, 135.2, 139.3, 142.3.
HRMS ,FAB): Calcd for C17H20N ,M1H)1: 238.1595.
Found 238.1619.
Pale yellow powder from AcOEt/Hexane; mp 173.5±
174.28C ,83% de). The NMR spectra of the major isomer
are shown; 1H NMR ,CDCl3) d 1.62 ,3H, d, Jˆ7.2 Hz), 2.62
,1H, dd, Jˆ13.6, 7.0 Hz), 2.68 ,1H, dd, Jˆ13.6, 6.8 Hz),
3.75 ,3H, s), 3.77 ,3H, s), 5.03 ,1H, d, Jˆ12.4 Hz), 5.10
,1H, d, Jˆ12.4 Hz), 5.11 ,1H, q, Jˆ6.4 Hz), 5.69 ,1H, d,
Jˆ8.0 Hz), 6.02 ,1H, t, Jˆ6.8 Hz), 6.34 ,1H, d, Jˆ8.0 Hz),
6.40 ,1H, s), 6.69 ,1H, s), 7.31±7.38 ,5H, m), 7.69 ,2H, dd,
Jˆ5.6, 3.2 Hz), 7.78 ,2H, dd, Jˆ5.6, 3.2 Hz). 13C NMR
,CDCl3) d 15.5, 39.3, 46.5, 51.2, 55.7, 55.8, 66.5, 107.9,
109.7, 110.7, 120.9, 121.8, 123.3, 124.7, 127.9, 128.0,
128.3, 131.1, 133.9, 135.4, 148.06, 148.10, 166.5, 166.6,
169.6. Anal. Calcd for C31H28N2O7: C, 68.88; H, 5.22; N,
5.18. Found C, 68.67; H, 5.11; N, 5.18.
1.9. Conversion of compound 14 to the MTPA derivative
15
Triethylamine ,0.3 ml) and a THF solution ,2 ml) of ,R)-
methoxy,tri¯uoromethyl)phenylacetyl chloride ,,R)-MTPA
chloride) ,0.4 mmol) were successively added to a CH2Cl2
solution ,2 ml) of compound 14 ,0.11 mmol), and the
mixture was allowed to react for 8 h at room temperature.
After addition of AcOEt ,15 ml), the mixture was washed
with sat. NaHCO3 ,10 ml£3), and the organic layer was
dried over MgSO4, and evaporated. The residue was puri®ed
with alumina column chromatography ,CH2Cl2/hexaneˆ1)
to give the product.
1.10.2. Benzyl 1,2-dihydro-6,7-dimethoxy-2-[N-ꢀp-nitro-
phenyl)sulfonyl-ꢀS)-alanyl]isoquinolin-1-ylacetate ꢀ20b).
y 20%; Yellow needles from hexane; mp 77.9±79.08C ,61%
1
de). The NMR spectra of the major isomer are shown; H
NMR ,CDCl3) d 1.37 ,3H, d, Jˆ7.0 Hz), 2.39 ,1H, dd,
Jˆ13.7, 6.0 Hz), 2.45 ,1H, dd, Jˆ13.7, 8.1 Hz), 3.82 ,3H,
s), 3.93 ,3H, s), 4.35 ,1H, bs), 4.91 ,1H, d, Jˆ12.2 Hz), 4.98
,1H, d, Jˆ12.2 Hz), 5.43 ,1H, dd, Jˆ8.1, 6.0 Hz), 5.85±
5.88 ,1H, m), 6.06 ,1H, d, Jˆ7.5 Hz), 6.30 ,1H, d,
1.9.1. 1,2,3,4-tetrahydro-2-[methoxyꢀtri¯uoromethyl)-
phenylacetyl]-1-ꢀ2-phenethyl)isoquinoline ꢀ15). y 56%;

8836
T. Itoh et al. / Tetrahedron 57 )2001) 8827±8839
Jˆ7.5 Hz), 6.47 ,1H, s), 6.65 ,1H, s), 7.24±7.28 ,2H, m),
7.30±7.36 ,3H, m), 7.79 ,2H, d, Jˆ9.3 Hz), 7.82 ,2H, d,
Jˆ9.3 Hz). 13C NMR ,CDCl3) d 19.2, 39.1, 48.7, 49.8, 55.9,
56.1, 66.7, 108.5, 108.6, 114.0, 119.0, 120.9, 123.6, 123.9,
128.10, 128.12, 128.17, 128.3, 135.1, 144.2, 148.8, 149.2,
149.3, 169.2, 169.3. HRMS ,FAB): Calcd for C29H30N3O9S
,M1H)1: 596.1703. Found 596.1702.
4.01 ,3H, s), 4.04 ,3H, s), 4.22 ,1H, dq, Jˆ10.4, 7.0 Hz),
5.57 ,1H, d, Jˆ10.4 Hz), 5.87 ,1H, dd, Jˆ10.8, 3.6 Hz),
6.48 ,1H, d, Jˆ1.2 Hz), 6.49 ,1H, d, Jˆ1.2 Hz), 7.44 ,2H,
t, Jˆ7.2 Hz), 7.57 ,1H, t, Jˆ7.6 Hz), 7.77 ,2H, d,
Jˆ9.2 Hz), 7.85 ,2H, d, Jˆ9.2 Hz), 7.89 ,2H, d,
Jˆ8.0 Hz). 13C NMR ,CDCl3) d 19.3, 39.6, 49.0, 50.6,
61.2, 61.4, 112.5, 116.4, 116.8, 123.8, 124.3, 126.5, 128.6,
128.9, 129.0, 133.8, 136.6, 144.5, 149.7, 151.2, 151.4,
170.1, 196.3. Anal. Calcd for C28H25Br2N3O8S: C, 46.49;
H, 3.48; N, 5.81. Found: C, 46.78; H, 3.19; N, 5.75.
1.10.3. Benzyl 5,8-dibromo-1,2-dihydro-6,7-dimethoxy-
2-[N-phthaloylalanyl]isoquinolin-1-ylacetate ꢀ20c).
100%; Colorless powder from AcOEt/hexane; mp 68.5±
y
1
69.88C ,100% de, a racemic mixture). H NMR ,CDCl3) d
1.10.7. 1-Acetonyl-5,8-dibromo-1,2-dihydro-6,7-dimethoxy-
2-[N-ꢀp-nitrophenyl)sulfonyl-ꢀS)-alanyl]isoquinoline
ꢀ20g). y 65%; Colorless powder from AcOEt/hexane; mp
1.62 ,3H, d, Jˆ7.2 Hz), 2.55 ,1H, dd, Jˆ12.8, 4.0 Hz), 2.62
,1H, dd, Jˆ12.8, 9.2 Hz), 3.83 ,3H, s), 3.86 ,3H, s), 5.02±
5.11 ,1H, m), 6.10 ,1H, d, Jˆ7.6 Hz), 6.44 ,1H, dd, Jˆ8.4,
3.2 Hz), 6.51 ,1H, d, Jˆ7.6 Hz), 7.28±7.39 ,5H, m), 7.71
,2H, dd, Jˆ5.6, 2.8 Hz), 7.78 ,2H, dd, Jˆ5.2, 3.2 Hz). 13C
NMR ,CDCl3) d 15.4, 36.5, 46.8, 51.6, 60.7, 60.9, 67.1,
109.6, 115.5, 116.8, 123.5, 124.8, 127.2, 128.2, 128.4,
128.5, 128.9, 131.4, 134.2, 134.3, 135.7, 150.3, 167.0,
167.3, 169.7. HRMS ,FAB): Calcd for C31H27Br2N2O7
,M1H)1: 697.0185. Found 697.0253.
207±2098C ,100% de); [a]25 ˆ2276.8 ,100% ee) ,c 0.21,
D
1
CHCl3). H NMR ,CDCl3) d 1.43 ,3H, d, Jˆ8.0 Hz), 2.21
,3H, s), 2.31 ,1H, t, Jˆ11.2 Hz), 2.46 ,1H, dd, Jˆ12.0,
2.8 Hz), 4.00 ,3H, s), 4.02 ,3H, s), 4.26 ,1H, dq, Jˆ10.4,
6.8 Hz), 5.60 ,1H, d, Jˆ8.0 Hz), 5.82 ,1H, ddd, Jˆ11.6, 2.4,
1.2 Hz), 6.44 ,1H, dd, Jˆ7.6, 0.8 Hz), 6.49 ,1H, d,
Jˆ7.6 Hz), 7.82 ,2H, d, Jˆ9.2 Hz), 7.90 ,2H, d,
Jˆ8.8 Hz). 13C NMR ,CDCl3) d 19.1, 29.7, 44.7, 48.8,
49.7, 60.9, 61.1, 112.3, 116.1, 116.6, 122.4, 123.7, 126.0,
128.0, 128.7, 144.4, 149.5, 151.1, 151.2, 170.2, 204.8. Anal.
Calcd for C23H23Br2N3O8S: C, 41.77; H, 3.51; N, 6.35.
Found: C, 42.02; H, 3.23; N, 6.32.
1.10.4. Benzyl 5,8-dibromo-1,2-dihydro-6,7-dimethoxy-
2-[N-ꢀp-nitrophenyl)sulfonyl-ꢀS)-alanyl]isoquinolin-1-
ylacetate ꢀ20d). y 86%; Colorless powder from AcOEt/
hexane; mp 1398C ,100% de); [a]25 ˆ2209.3 ,100% ee)
D
,c 1.09, CHCl3). 1H NMR ,CDCl3) d 1.38 ,3H, d,
Jˆ7.0 Hz), 2.35 ,1H, dd, Jˆ13.0, 3.7 Hz), 2.42 ,1H, dd,
Jˆ13.0, 9.0 Hz), 3.98 ,3H, s), 3.99 ,3H, s), 4.27,1H, dq,
Jˆ10.1, 7.0 Hz), 5.75 ,1H, d, Jˆ10.1 Hz), 5.87 ,1H, dd,
Jˆ9.5, 3.7 Hz), 6.44 ,2H, s), 7.29±7.36 ,5H, m), 7.83
,2H, d, Jˆ8.8 Hz), 7.90 ,2H, d, Jˆ8.8 Hz). 13C NMR
,CDCl3) d 19.1, 36.2, 48.8, 50.1, 60.8, 61.0, 67.0, 112.2,
116.3, 116.4, 122.7, 123.6, 126.1, 127.7, 128.2, 128.3,
128.5, 128.6, 135.3, 144.3, 149.5, 151.0, 151.2, 169.0,
169.8. Anal. Calcd. for C29H27Br2N3O9S: C, 46.20; H,
3.62; N, 5.58. Found: C, 46.47; H, 3.37; N, 5.58.
1.10.8. 1-Allyl-5,8-dibromo-1,2-dihydro-6,7-dimethoxy-
2-[N-phthaloylalanyl]isoquinoline ꢀ21a). y 83%; Yellow
powder from AcOEt/hexane; mp 125±1268C ,100% de, a
racemic mixture). 1H NMR ,CDCl3) d 1.70 ,3H, d,
Jˆ6.8 Hz), 2.38 ,2H, t, Jˆ6.8 Hz), 3.85 ,3H, s), 3.88 ,3H,
s), 4.96 ,1H, dd, Jˆ16.8, 1.6 Hz), 5.01 ,1H, dd, Jˆ10.4,
1.6 Hz), 5.16 ,1H, q, Jˆ6.8 Hz), 5.79±5.90 ,1H, m),
6.09±6.16 ,2H, m), 6.50 ,1H, dd, Jˆ6.8, 1.6 Hz), 7.71
,2H, dd, Jˆ5.6, 3.2 Hz), 7.79 ,2H, dd, Jˆ5.6, 3.2 Hz). 13C
NMR ,CDCl3) d 15.5, 37.1, 53.3, 60.7, 60.9, 110.1, 116.0,
116.8, 117.7, 123.5, 124.6, 127.1, 130.6, 131.4, 133.9,
134.2, 150.1, 150.3, 167.1, 167.2. HRMS ,FAB): Calcd
for C25H23N2O5Br2 ,M1H)1: 588.9973. Found 588.9968.
1.10.5. 5,8-Dibromo-1-ꢀ3,4-dimethoxyphenacyl)-1,2-di-
hydro-6,7-dimethoxy-2-[N-ꢀp-nitrophenyl)sulfonyl-ꢀS)-
alanyl]isoquinoline ꢀ20e). y 93%; Colorless powder from
1.10.9. 1-Allyl-5,8-dibromo-1,2-dihydro-6,7-dimethoxy-
2-[N-ꢀp-nitrophenyl)sulfonyl-ꢀS)-alanyl]isoquinoline ꢀ21b).
y 73%; Yellow granules from AcOEt/hexane; mp 176±
1778C ,75% de). The NMR spectra of the major isomer
AcOEt/Hexane; mp 213±2148C ,100% de); [a]25 ˆ2284.9
D
,100% ee) ,c 0.46, CHCl3). 1H NMR ,CDCl3) d 1.40 ,3H, d,
Jˆ7.0 Hz), 2.63 ,1H, dd, Jˆ12.3, 11.2 Hz), 3.13 ,1H, dd,
Jˆ12.6, 3.7 Hz), 3.90 ,3H, s), 3.94 ,3H, s), 4.01 ,3H, s),
4.04 ,3H, s), 4.23 ,2H, dq, Jˆ10.3, 7.0 Hz), 5.54 ,1H, d,
Jˆ10.3 Hz), 5.87 ,1H, dd, Jˆ10.7, 3.3 Hz), 6.50 ,2H, s),
6.88 ,1H, d, Jˆ8.4 Hz), 7.36 ,1H, d, Jˆ1.8 Hz), 7.62 ,1H,
1
are shown; H NMR ,CDCl3) d 1.40 ,3H, d, Jˆ6.8 Hz),
2.13±2.26 ,2H, m), 4.00 ,6H, s), 4.30 ,1H, dq, Jˆ10.0,
6.8 Hz), 4.86 ,1H, dd, Jˆ16.8, 1.6 Hz), 4.91 ,1H, dd,
Jˆ10.4, 1.6 Hz), 5.53±5.65 ,2H, m), 5.80 ,1H, d,
Jˆ8.4 Hz), 6.39 ,1H, dd, Jˆ7.6, 1.2 Hz), 6.44 ,1H, d,
Jˆ7.6 Hz), 7.84 ,2H, d, Jˆ8.8 Hz), 7.90 ,2H, d,
Jˆ9.2 Hz). 13C NMR ,CDCl3) d 19.6, 37.1, 48.7, 51.8,
60.8, 61.0, 112.4, 116.1, 116.3, 118.0, 122.5, 123.6, 125.9,
128.6, 129.4, 133.4, 144.3, 149.5, 150.7, 150.8, 169.8.
HRMS ,FAB): Calcd for C23H24Br2N3O7S ,M1H)1:
643.9701. Found 643.9750.
dd, Jˆ8.4, 1.8 Hz), 7.77 ,2H, d, Jˆ9.0 Hz), 7.85 ,2H, d,
13
Jˆ8.8 Hz).
C NMR ,CDCl3) d 19.1, 29.7, 39.0, 48.8,
50.6, 56.0, 56.1, 60.8, 61.1, 110.0, 110.6, 112.1, 116.1,
116.6, 122.9, 123.3, 123.6, 126.2, 128.3, 128.7, 129.7,
144.2, 149.1, 149.4, 150.9, 151.1, 153.7, 169.8, 194.4.
Anal. Calcd for C30H29 Br2N3O10S: C, 45.99; H, 3.73; N,
5.36. Found: C, 46.19; H, 3.50; N, 5.38.
1.10.6. 5,8-Dibromo-1,2-dihydro-6,7-dimethoxy-2-[N-ꢀp-
nitrophenyl)sulfonyl-ꢀS)-alanyl]-1-phenacylisoquinoline
ꢀ20f). y 85%; Yellow prisms from AcOEt/hexane; mp 219±
1.11. Reduction of compounds 20 to tetrahydro
derivatives 22
2208C ,100% de); [a]25 ˆ2222.4 ,100% ee) ,c 0.41,
To a MeOH solution ,2 ml) of compound 20 ,0.2 mmol)
were added sat. HCO2NH4 ,2 ml) and 10% Pd/
C,0.4 equiv.), and the mixture was allowed to react for 6 h
D
1
CHCl3). H NMR ,CDCl3) d 1.37 ,3H, d, Jˆ6.8 Hz), 2.69
,1H, dd, Jˆ12.4, 10.8 Hz), 3.17 ,1H, dd, Jˆ12.8, 3.6 Hz),

T. Itoh et al. / Tetrahedron 57 )2001) 8827±8839
8837
at room temperature. Then the mixture was ®ltered through
a plug of Celite, and the ®ltrate was evaporated in vacuo. To
the residue was added AcOEt ,60 ml), and the solution was
washed with two portions of water ,10 ml) and brine ,5 ml).
The organic layer was dried over MgSO4, and evaporated to
leave a residue, which was chromatographed on silica gel to
give compound 22.
,30 ml)/THF ,12 ml) solvent. Then sat. HCO2NH4 ,10 ml)
and 10% Pd/C ,325 mg) was added to the solution, and the
mixture was allowed to react for 17 h at room temperature.
The mixture was ®ltered through a plug of Celite, and the
®ltrate was concentrated in vacuo. To the residue was added
10 mlof water, and the mixture was extracted with three
portions of AcOEt ,20 ml). The organic layer was washed
with brine ,5 ml), dried over MgSO4, and evaporated to give
compound 22b ,426 mg). The compound 22b ,387 mg) was
dissolved in a mixed solvent of AcOH ,20 ml) and tri¯uoro-
acetic acid ,2 ml), and 10% Pd/C ,510 mg) was added
successively. The mixture was allowed to stir for 21 h
under H2 atmosphere at room temperature, then was ®ltered
to give a ®ltrate, to which AcOEt ,100 ml) was added. The
mixture was washed with aq. 20% K2CO3 ,20 ml£3), and
the aqueous layer was extracted with AcOEt ,20 ml£2). The
organic layers were combined, washed with brine ,15 ml),
dried over MgSO4, and evaporated off to leave 23 ,278 mg)
as colorless oil. Compound 23 was used for the next pro-
cedure without further puri®cation. To a THF solution
,10 ml) of compound 23 ,182 mg) was added LiAlH4
,60 mg), and the mixture was allowed to react at 08C for
1 h. After addition of 20 mlof water, the mixture was
extracted with AcOEt ,20 ml£4). The organic layer was
washed with brine, dried over MgSO4, and evaporated off.
The residue was puri®ed by silica gel chromatography
,AcOEt) to give compound 24 ,65 mg).
1.11.1. 2-[N-ꢀp-Aminophenyl)sulfonyl-ꢀS)-alanyl]-1,2,3,
4-tetrahydro-6,7-dimethoxyisoquinolin-1-ylacetic acid
ꢀ22a). y 98%; Colorless powder from AcOEt/hexane; mp
128±1308C ,100% de); [a]25 ˆ117.8 ,100% ee) ,c 0.087,
D
1
CHCl3). H NMR ,CD3OD) d 1.28 ,3H, d, Jˆ7.1 Hz),
2.55±2.83 ,4H, m), 3.47 ,1H, m), 3.75 ,1H, m), 3.85 ,3H,
s), 3.88 ,3H, s), 4.25 ,1H, dq, Jˆ10.1, 7.1 Hz), 5.57 ,1H, d,
Jˆ10.1 Hz), 6.22 ,2H, d, Jˆ8.6 Hz), 6.63 ,1H, s), 6.65 ,1H,
m), 7.42 ,2H, d, Jˆ8.6 Hz). 13C NMR ,CD3OD) d 19.3,
28.1, 39.1, 41.4, 49.2, 50.3, 56.0, 56.2, 109.8, 111.2,
113.7, 119.1, 124.8, 127.0, 129.0, 147.9, 148.3, 150.5,
171.6, 173.9. Anal. Calcd for C22H29N3O8S ,monohydrate):
C, 53.32; H, 5.90; N, 8.48. Found: C, 53.36; H, 5.48; N,
8.01.
1.11.2. 2-[N-ꢀp-Aminophenyl)sulfonyl-ꢀS)-alanyl]1,2,3,4-
tetrahydro-6,7-dimethoxy-1-ꢀ3,4-dimethoxyphenacyl)-
isoquinoline ꢀ22b). y 65%; Colorless powder ,isolated with
preparative TLC); mp 135±1378C ,100% de);
[a]25 ˆ236.2 ,100% ee) ,c 0.31, CHCl3). 1H NMR
D
,CDCl3) d 1.21 ,3H, d, Jˆ6.8 Hz), 2.56±2.77 ,2H, m),
3.16 ,1H, dd, Jˆ14.0, 6.8 Hz), 3.29 ,1H, dd, Jˆ14.0,
6.8 Hz), 3.53±3.56 ,2H, m), 3.78 ,3H, s), 3.87 ,3H, s),
3.92 ,3H, s), 3.94 ,3H, s), 4.09 ,1H, dq, Jˆ9.2, 7.2 Hz),
5.62 ,1H, d, Jˆ8.8 Hz), 5.64 ,1H, d, Jˆ6.8 Hz), 6.26 ,2H,
1.12.1. 2-[N-ꢀp-Aminophenyl)sulfonyl-ꢀS)-alanyl]-6,7-di-
methoxy-1,2,3,4-tetrahydro-1-ꢀ3,4-dimethoxyphenethyl)-
isoquinoline ꢀ23). The product was obtained as a mixture of
two conformers ,7:1). The NMR spectra of the major isomer
1
are shown; H NMR ,CDCl3) d 1.38 ,3H, d, Jˆ7.0 Hz),
d, Jˆ8.8 Hz), 6.54 ,1H, s), 6.60 ,1H, s), 7.43 ,2H, d,
1.90±2.05 ,2H, m), 2.40±2.45 ,1H, m), 2.55±2.66 ,4H,
m), 3.43±3.50 ,1H, m), 3.834 ,3H, s), 3.836 ,3H, s), 3.85
,3H, s), 3.88 ,3H, s), 4.18 ,1H, dq, Jˆ9.2, 7.0 Hz), 5.24 ,1H,
dd, Jˆ9.9, 5.3 Hz), 5.74 ,1H, d, Jˆ9.2 Hz), 6.23 ,2H, d,
Jˆ8.8 Hz), 6.48 ,1H, s), 6.58 ,1H, s), 6.65±6.67 ,2H, m),
6.77 ,1H, d, Jˆ8.8 Hz), 7.44 ,2H, d, Jˆ8.8 Hz). 13C NMR
,CDCl3) d 20.4, 28.1, 32.0, 37.9, 38.9, 49.1, 52.3, 55.85,
55.91, 55.98, 56.02, 56.2, 110.1, 111.2, 111.6, 113.7, 119.9,
124.5, 127.4, 129.02, 129.08, 129.14, 133.9, 147.3, 147.4,
147.8, 148.8, 150.3, 170.8.
13
Jˆ8.8 Hz), 7.52 ,1H, s), 7.55 ,1H, s), 7.57 ,1H, s).
C
NMR ,CDCl3) d 19.9, 28.2, 40.2, 44.7, 49.1, 50.5, 56.0,
56.08, 56.12, 56.2, 110.0, 110.1, 110.2, 111.1, 113.5,
122.9, 124.9, 127.6, 127.8, 129.0, 130.0, 147.4, 147.9,
149.0, 150.2, 153.3, 170.4, 195.4. HRMS ,FAB): Calcd
for C30H36N3O8S ,M1H)1: 598.2223. Found 598.2272.
1.11.3. 2-[N-ꢀp-Aminophenyl)sulfonyl-ꢀS)-alanyl]-1,2,3,
4-tetrahydro-1-ꢀ2-hydroxyphenethyl)isoquinoline ꢀ22c).
y 62%; Colorless powder ,isolated with preparative TLC);
mp 164±1668C. The product was obtained as a mixture of
diastereomers and conformers ,ratio unknown). The NMR
1.12.2. 1,2,3,4-Tetrahydro-6,7-dimethoxy-1-ꢀ3,4-dimethoxy-
phenethyl)isoquinoline ꢀ24). y 50% from 20e. Colorless
1
oil; [a]25 ˆ14.3 ,100% ee) ,c 0.32, EtOH). 1H NMR
spectra of a major isomer are shown; H NMR ,CDCl3) d
D
1.48 ,3H, d, Jˆ6.8 Hz), 1.97±2.01 ,2H, m), 2.61±3.06 ,3H,
m), 3.71±3.75 ,2H, m), 3.90 ,3H, s), 3.92 ,3H, m), 4.42 ,1H,
dq, Jˆ10.4, 6.8 Hz), 5.44 ,1H, d, Jˆ10.4 Hz), 5.59 ,1H, d,
Jˆ10.0 Hz), 6.00 ,2H, d, Jˆ8.4 Hz), 6.63 ,1H, s), 6.69 ,1H,
s), 7.12±7.33 ,5H, m), 7.37 ,2H, d, Jˆ8.8 Hz). 13C NMR
,CDCl3) d 20.2, 28.0, 39.1, 45.9, 49.2, 50.1, 53.4, 56.0, 69.4,
109.7, 111.0, 113.6, 113.9, 125.4, 127.2, 128.3, 128.4,
129.0, 129.1, 129.2, 142.9, 147.7, 147.8, 150.5. Anal.
Calcd for C28H35N3O7S ,monohydrate): C, 60.31; H, 6.33;
N, 7.54. Found: C, 60.22; H, 5.88; N, 7.18.
,CDCl3) d 1.26 ,1H, brs), 2.04±2.14 ,2H, m), 2.67±2.73
,2H, m), 2.78±2.85,2H, m), 3.04 ,1H, ddd, Jˆ10.0, 5.9,
4.2 Hz), 3.29 ,1H, dt, Jˆ10.0, 4.4 Hz), 3.83 ,3H, s), 3.852
,3H, s), 3.856 ,3H, s), 3.862 ,3H, s), 4.04 ,1H, dd, Jˆ7.0,
2.4 Hz), 6.57 ,1H, s), 6.58 ,1H, s), 6.76±6.81 ,3H, m). 13C
NMR ,CDCl3) d 28.8, 29.7, 31.9, 38.2, 40.9, 55.0, 55.8,
55.9, 56.1, 109.2, 111.3, 111.7, 111.8, 120.2, 126.8, 130.1,
134.6, 147.3, 147.4, 147.6, 148.9. HRMS ,FAB): Calcd for
C21H27NO4 ,M1H)1: 358.2019. Found 358.2060.
1.12.3. Synthesis of homolaudanosine ꢀ25). To a CH3CN
solution ,0.3 ml) of compound 24 ,0.07 mmol) was added
37% aq. HCHO solution ,30 mg) and NaBH3CN ,8 mg),
and the mixture was allowed to react for 40 min at room
temperature. After quenching with AcOH, 10% aq. NaOH
,4 ml) was added and the mixture was extracted with AcOEt
1.12. Transformation of compound 20e to 24 via three
steps of reduction
Compound 20e ,493 mg), which was puri®ed to optically
pure form by recrystallization, was dissolved in MeOH

8838
T. Itoh et al. / Tetrahedron 57 )2001) 8827±8839
,6 ml£3). The organic layer was extracted with 10% aq.
HCl,4 ml £3), which was made basic with 20% aq.
NaOH. The basic aqueous layer was extracted with
AcOEt ,8 ml£3), and the organic layers thus obtained
were combined, dried over MgSO4 and evaporated off to
leave crude homolaudanosine ,25). Preparative TLC ,silica
gel5717, CHCl 3/MeOHˆ20) was employed for further
,1H, m), 3.82 ,3H, s), 3.85 ,3H, s), 4.67 ,1H, d, Jˆ9.2 Hz),
5.05 ,1H, d, Jˆ12.5 Hz), 5.09 ,1H, d, Jˆ11.9 Hz), 6.07 ,1H,
d, Jˆ7.9 Hz), 6.48 ,1H, dd, Jˆ8.6, 4.0 Hz), 6.66 ,1H, d,
Jˆ7.9 Hz), 7.32±7.42 ,5H, m), 7.71 ,2H, dd, Jˆ5.5,
3.1 Hz), 7.79 ,2H, dd, Jˆ5.5, 3.1 Hz). 13C NMR ,CDCl3)
d 18.6, 20.7, 27.9, 36.6, 51.7, 56.2, 60.7, 61.0, 67.1, 109.2,
115.5, 116.9, 123.7, 125.1, 127.4, 128.2, 128.4, 128.5,
128.9, 131.1, 134.4, 135.7, 150.2, 150.8, 165.9, 167.3,
169.7. HRMS ,FAB): Calcd for C33H31Br2N2O7 ,M1H)1:
725.0498. Found 725.0553.
puri®cation. y 71%. Colorless oil. [a]20 ˆ111.7 ,100%
D
1
ee) ,c 0.75, EtOH). H NMR ,CDCl3) d 2.01±2.07 ,2H,
m), 2.48 ,3H, s), 2.50±2.56 ,1H, m), 2.66±2.81 ,4H, m),
3.12±3.18 ,1H, m), 3.43 ,1H, t, Jˆ5.4 Hz), 3.83 ,3H, s),
3.85 ,3H, s), 3.856 ,3H, s), 3.858 ,3H, s), 6.54 ,1H, s), 6.58
,1H, s), 6.71±6.74 ,2H, m), 6.79 ,1H, d, Jˆ8.1 Hz). These
References
18
data are identicalwith the reported ones.
1. ,a) Herbert, R. B. In The Chemistry and Biology of Isoquino-
line Alkaloids; Philipson, J. D., Roberts, M. F., Zenk, M. H.,
Eds.; Springer: Berlin, 1985; p. 213. ,b) Rozwadowska, M. D.
Heterocycles 1994, 39, 903 and references cited therein.
2. ,a) Brossi, A.; Focella, A.; Teitel, S. Helv. Chim. Acta 1972,
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,d) Lee, A. W. M.; Chan, W. H.; Lee, Y. Tetrahedron Lett.
1991, 32, 6861.
1.13. Molecular orbital calculations
The molecular orbital calculations were carried out using
the PM3 procedure28 with the standard parameters, as
implemented in the MOPAC2000 program.
1.14. Synthesis of the 1,2-addition products using chiral
auxiliaries derived from ꢀS)-valine
3. ,a) Noyori, R.; Ohta, M.; Hsiao, Y.; Kimura, M.; Ohta, T.;
Takaya, H. J. Am. Chem. Soc. 1986, 108, 7117. ,b) Kitamura,
M.; Hsiao, Y.; Ohta, M.; Tsukamoto, M.; Ohta, T.; Takaya,
H.; Noyori, R. J. Org. Chem. 1994, 59, 297. ,c) Uematsu, N.;
Fujii, A.; Hashiguchi, S.; Ikariya, T.; Noyori, R. J. Am. Chem.
Soc. 1996, 118, 4916. ,d) Morimoto, T.; Suzuki, N.; Achiwa,
K. Tetrahedron: Asymmetry 1998, 9, 183.
The same procedure as in the case of 16 or 17 was applied to
these reactions. The de was estimated from 1H NMR data of
the crude sample before the column chromatography. The
melting points and spectral data were obtained from the
samples after puri®cation.
1.14.1. Benzyl 5,8-dibromo-1,2-dihydro-6,7-dimethoxy-
2-[N-ꢀp-nitrophenyl)sulfonyl-ꢀS)-valinyl]isoquinolin-1-
ylacetate ꢀ26). y 68%; Colorless powder from CHCl3/
4. ,a) Kohno, M.; Ohta, S.; Hirobe, M. Biochem. Biophys. Res.
Commun. 1986, 140, 448. ,b) Yamakawa, T.; Ohta, S.
Biochem. Biophys. Res. Commun. 1997, 236, 676.
5. ,a) Thull, U.; KneubuÈhler, S.; Gaillar, D. P.; Carrupt, P.-A.;
Testa, B.; Altomare, C.; Carotti, A.; Jenner, P.; McNaught,
K. S. P. Biochem. Pharmacol. 1995, 50, 869. ,b) Taniyama,
D.; Hasegawa, M.; Tomioka, K. Tetrahedron: Asymmetry
1999, 10, 221.
hexane; mp 205±2088C ,100% de); [a]25 ˆ2217.5
D
1
,100% ee) ,c 0.30, CHCl3); H NMR ,CDCl3) d 0.94 ,3H,
d, Jˆ6.7 Hz), 1.13 ,3H, d, Jˆ6.7 Hz), 1.96±2.02 ,1H, m),
2.33 ,1H, dd, Jˆ13.4, 3.7 Hz), 2.42 ,1H, dd, Jˆ13.1,
9.5 Hz), 3.95 ,1H, dd, Jˆ10.4, 4.0 Hz), 3.98 ,3H, s), 4.00
,3H, s), 4.90 ,1H, d, Jˆ12.2 Hz), 4.98 ,1H, d, Jˆ12.2 Hz),
5.55 ,1H, d, Jˆ10.4 Hz), 5.85 ,1H, dd, Jˆ9.5, 3.4 Hz), 6.39
,1H, d, Jˆ7.9 Hz), 6.41 ,1H, d, Jˆ7.6 Hz), 7.23±7.38 ,5H,
6. ,a) Meyers, A. I.; Dickman, D. A.; Boes, M. Tetrahedron
1987, 43, 5095. ,b) Gottlieb, L.; Meyers, A. I. J. Org.
Chem. 1990, 55, 5659. ,c) Meyers, A. I.; Sielecki, T. M.
J. Am. Chem. Soc. 1991, 113, 2789.
1
m), 7.81 ,2H, d, Jˆ8.9 Hz), 7.85 ,2H, d, Jˆ8.9 Hz). H
NMR ,CDCl3) ,for the minor isomer) d 0.72 ,3H, d,
Jˆ6.7 Hz), 1.05 ,3H, d, Jˆ6.7 Hz), 1.96±2.02 ,1H, m),
2.19 ,1H, dd, Jˆ12.8, 4.0 Hz), 2.44 ,1H, dd, Jˆ12.8,
7.6 Hz), 3.85 ,3H, s), 3.86 ,3H, s), 4.29 ,1H, dd, Jˆ9.2,
3.4 Hz), 4.80 ,1H, d, Jˆ12.2 Hz), 4.83 ,1H, d,
Jˆ12.2 Hz), 5.66 ,1H, d, Jˆ8.9 Hz), 6.17 ,1H, dd, Jˆ7.6,
4.0 Hz), 6.34 ,1H, d, Jˆ7.6 Hz), 6.51 ,1H, d, Jˆ7.9 Hz),
7.23±7.38 ,5H, m), 8.03 ,2H, d, Jˆ8.9 Hz), 8.33 ,2H, d,
Jˆ8.5 Hz). 13C NMR ,CDCl3) ,for the major isomer) d
16.1, 19.8, 30.5, 36.7, 50.2, 57.7, 60.8, 61.0, 66.9, 112.1,
116.3, 116.4, 122.8, 123.5, 126.0, 127.7, 128.2, 128.3,
128.5, 128.6, 135.4, 144.3, 149.4, 151.0, 151.2, 168.7,
169.0. Anal. Calcd for C31H31Br2N3O9S ,for the major
isomer): C, 47.65; H, 4.00; N, 5.38. Found: C, 47.95; H,
3.73; N, 5.35.
7. ,a) Gawley, R. E. J. Am. Chem. Soc. 1987, 109, 1265. ,b) Rein,
K. S.; Goicoechea-Pappas, M.; Anklekar, T. V.; Hart, G. C.;
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1564. ,d) Zhang, P.; Gawley, R. E. Tetrahedron Lett. 1992, 33,
2945.
8. Denmark, S. E.; Nicaise, O. J.-C. Comprehensive Asymmetric
Catalysis; Jacobsen, E. N., Pfaltz, A., Yamamoto, H., Eds.;
Springer: Berlin, 1999; Vol. 2, p. 923.
9. Nakamura, M.; Hirai, A.; Nakamura, E. J. Am. Chem. Soc.
1996, 118, 8489.
10. Comins, D. L.; Badawi, M. M. Heterocycles 1991, 32, 29.
11. ,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. ,c) Itoh,
T.; Miyazaki, M.; Hasegawa, H.; Nagata, K.; Ohsawa, A.
Chem. Commun. 1996, 1217. ,d) Itoh, T.; Miyazaki, M.;
Nagata, K.; Ohsawa, A. Tetrahedron 2000, 56, 4383.
12. Itoh, T.; Miyazaki, M.; Nagata, K.; Hasegawa, H.; Ohsawa,
A.; Nakamura, K. T. Heterocycles 1998, 47, 125.
1.14.2. Benzyl 5,8-dibromo-1,2-dihydro-6,7-dimethoxy-
2-[N-phthaloyl-ꢀS)-valinyl]isoquinolin-1-ylacetate ꢀ27).
1
y 98%. Colorless oil ,95% de). H NMR ,CDCl3) d 0.84
,3H, d, Jˆ7.0 Hz), 1.11 ,3H, d, Jˆ6.7 Hz), 2.54 ,1H, dd,
Jˆ12.5, 4.3 Hz), 2.58 ,1H, dd, Jˆ12.5, 9.2 Hz), 2.88±2.93

T. Itoh et al. / Tetrahedron 57 )2001) 8827±8839
8839
13. A preliminary communication; Itoh, T.; Nagata, K.; Miyazaki,
M.; Ohsawa, A. Synlett 1999, 1154.
was accord with the mechanism shown in this paper. These
results will be reported in near future.
14. The other amino acids such as leucine, isoleucine, valine,
phenylalanine, and proline were investigated as chiral
auxiliaries. The stereoselectivities, however, were lower
than that of alanine.
20. We reported the asymmetric synthesis of 1-allyl-1,2,3,4-tetra-
hydro-b-carboline derivatives using ,S)-proline derivatives as
chiralauxiliaries; see, ,a) Itoh, T.; Matsuya, Y.; Enomoto, Y.;
Nagata, K.; Miyazaki, M.; Ohsawa, A. Synlett 1999, 1799.
,b) Matsuya, Y.; Itoh, T.; Enomoto, Y.; Ohsawa, A. Hetero-
cycles 2000, 53, 2357. ,c) Itoh, T.; Matsuya, Y.; Enomoto, Y.;
Ohsawa, A. Tetrahedron 2001, 57, 7277.
15. Gordon, M.; Pearson, D. E. J. Org. Chem. 1964, 29, 329.
16. Meyers et al. reported the synthesis of the compound 14 using
chiral formamidines as auxiliaries, and estimated the absolute
con®guration as ,S) on the basis of stereoselectivity of their
21. Birch, A. J.; Jackson, A. H.; Shannon, P. V. R. J. Chem. Soc.,
Perkin Trans. 1 1974, 2185.
reaction system. The reported [a]25 ˆ223.5, which is accord
D
with our data ,[a]25 ˆ123.2 for the ,R) isomer); see, Meyers,
22. Wiley, R. H.; Davis, R. P. J. Am. Chem. Soc. 1954, 76, 3496.
23. Beckett, A. H.; Casy, A. F. J. Chem. Soc. 1955, 900.
24. Dobashi, A.; Hamada, M. Electrophoresis 1999, 20, 2761.
25. Kiyooka, S.; Kaneko, Y.; Kume, K. Tetrahedron Lett. 1992,
33, 4927.
D
A. I.; Dickman, D. A.; Boes, M. Tetrahedron 1987, 43, 5095.
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26. Hoffmann, E.; Schiff-Shenhav, H. J. Org. Chem. 1962, 27,
4686.
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27. ,a) Kita, Y.; Shibata, N.; Miki, T.; Takemura, Y.; Tamura, O.
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19. We have recently synthesized two isoquinoline alkaloids ,S)-
2,3,9,10,11-pentamethoxyhomoprotoberberine
methylkreysigine, and a precursor of ,R)-pronuciferine using
and
O-
28. Stewart, J. J. P. J. Comput. Chem. 1989, 10, 221.
our method. The absolute con®guration of these compounds