Catalytic asymmetric allylation of 3,4-dihydroisoquinolines and its application to the synthesis of isoquinoline alkaloids

Article abstract of DOI:10.1021/jo101956m

A catalytic asymmetric allylation of 3,4-dihydroisoquinoline was carried out with allyltrimethoxylsilane-Cu as the nucleophile in the presence of DTBM-SEGPHOS as the chiral ligand to afford corresponding chiral 1-allyltetrahydroisoquinoline derivatives in good yield and stereoselectivity. The allyl adduct thus obtained was applied to the synthesis of several isoquinoline alkaloids such as crispine A and homolaudanosine. The reaction was further used for the synthesis of the isoquinoline moiety of schulzeine A.

Full text of DOI:10.1021/jo101956m

pubs.acs.org/joc
Catalytic Asymmetric Allylation of 3,4-Dihydroisoquinolines and Its
Application to the Synthesis of Isoquinoline Alkaloids
Michiko Miyazaki, Nami Ando, Keita Sugai, Yuki Seito, Hiromi Fukuoka,
Takuya Kanemitsu, Kazuhiro Nagata, Yuki Odanaka, Kazuo T. Nakamura, and
Takashi Itoh*
School of Pharmacy, Showa University, 1-5-8 Hatanodai, Shinagawa-ku, Tokyo 142-8555, Japan
itoh-t@pharm.showa-u.ac.jp
Received October 16, 2010
A catalytic asymmetric allylation of 3,4-dihydroisoquinoline was carried out with allyltrimethoxylsilane-
Cu as the nucleophile in the presence of DTBM-SEGPHOS as the chiral ligand to afford corresponding
chiral 1-allyltetrahydroisoquinoline derivatives in good yield and stereoselectivity. The allyl adduct thus
obtained was applied to the synthesis of several isoquinoline alkaloids such as crispine A and homo-
laudanosine. The reaction was further used for the synthesis of the isoquinoline moiety of schulzeine A.
Introduction
procedures for the synthesis of isoquinoline moieties. How-
ever, these methods require a stoichiometric amount of a
chiral source to introduce the chirality at C-1.5
A variety of isoquinoline alkaloids exist in nature, and
have various biological activities.1 A specific structural
feature of many of these alkaloids is a chiral center at C-1
(based on isoquinoline numbering),2 thus the construction
of a chiral carbon at C-1 is a key step for the asymmetric total
synthesis of these compounds. The Pictet-Spengler reac-
tion3 and Bischler-Napieralski reaction4 are representative
Recently, enantioselective syntheses of C-1 substituted
tetrahydroisoquinoline have been developed. Chong et al.
reported an allylation using a variety of cyclic imines,
including 3,4-dihydroisoquinoline, to give the corresponding
chiral C-1 allyl adducts with high enantioselectivity.6 In
this process, a stoichiometric amount of a chiral auxiliary
was used. Although few methods allow the synthesis of
chiral 1-substituted tetrahydroisoquinoline derivatives using
catalysts, one of the best methods for asymmetric catalytic
synthesis is the reduction of the imine in 3,4-dihydro-
isoquinoline using asymmetric Ru(II) catalyst, as reported
by Noyori.7 It is difficult, however, to apply this procedure
to compounds which have a functional group sensitive
to reduction. In part to address this limitation, Sodeoka
et al. reported a Pd(II)-catalyzed addition reaction of
malonate to dihydroisoquinoline to give 1-substituted
tetrahydroisoquinoline derivatives in a highly stereose-
lective manner.8
(1) (a) Shamma, M. Organic Chemistry,
A series of Monographs;
Academic Press, Inc.: New York; Vol. 25 (b) Rozwadowska, M. D. Hetero-
cycles 1994, 39, 903. (c) Chrzanowska, M.; Rozwadowska, M. D. Chem. Rev.
2004, 104, 3341.
(2) Bentley, K. W. The Isoquinoline Alkaloids; Harwood Academic
Publishers: Amsterdam, The Netherlands, 1998.
(3) (a) Brossi, A.; Focella, A.; Teitel, S. Helv. Chim. Acta 1972, 55, 15.
(b) Kawai, M.; Deng, Y.; Kimura, I.; Yamamura, H.; Araki, S.; Naoi, M.
Tetrahedron: Assymmetry 1997, 8, 1487. (c) Gremmen, C.; Wanner, M.;
^
Koomen, G.-J. Tetrahedron Lett. 2001, 42, 8885. (d) Pedrosa, R.; Andres, C.;
Iglesias, J. M. J. Org. Chem. 2001, 66, 243.
(4) (a) Polniaszek, R. P.; Kaufman, C. R. J. Am. Chem. Soc. 1989, 111,
4859. (b) Czarnocki, Z.; Suh, D.; MacLean, D. B.; Hultin, P. G.; Szarek,
W. A. Can. J. Chem. 1992, 70, 1555. (c) Miyatani, K.; Ohno, M.; Tatsunami,
K.; Ohishi, Y.; Kunitomo, J.; Kawasaki, I.; Yamashita, M.; Ohta, S.
Heterocycles 2001, 55, 589.
(5) Although several papers reported asymmetric catalytic Pictet-
Spengler reactions, the substrate was limited to indole derivatives. See:
Muratore, M. E.; Holloway. C. A.; Pilling, A. W.; Storer, R. I.; Trevitt,
G.; Dixon, D. J. J. Am. Chem. Soc. 2009, 131, 10796 and references cited
therein.
(6) Wu, T. R.; Chong, J. M. J. Am. Chem. Soc. 2006, 128, 9646.
(7) (a) Uematsu, N.; Fujii, A.; Hashiguchi, S.; Ikariya, T.; Noyori, R.
J. Am. Chem. Soc. 1996, 118, 4916. (b) Noyori, R.; Hashiguchi, S. Acc. Chem.
Res. 1997, 30, 97.
534 J. Org. Chem. 2011, 76, 534–542
Published on Web 12/28/2010
DOI: 10.1021/jo101956m
r
2010 American Chemical Society

Miyazaki et al.
JOCArticle
The allyl group is versatile due to its ready modification to
other functional groups.9 Thus, we investigated an asym-
metric allylation reaction at the C-1 position of the isoquino-
line nucleus. Shibasaki et al. reported catalytic allylation of a
carbonyl group using allyltrimethoxysilane, and in the pres-
ence of a chiral phosphine ligand, asymmetric induction was
observed.10 In a previous paper, we applied this reaction
system to 6,7-dimethoxy-3,4-dihydroisoquinoline as a cyclic
imine to obtain the corresponding C-1 allyl adduct with
moderate stereoselectivity, and after recrystallization in the
presence of dibenzoyltartaric acid, applied this adduct to the
total synthesis of (-)-emetine.11 To improve the stereoselec-
tivity of the 1-allyl adduct, we studied other chiral ligands
and found that DTBM-SEGPHOS gave better results. The
resulting allyl adduct was used for the synthesis of several
isoquinoline alkaloids described herein.
FIGURE 1
SCHEME 2
Results and Discussion
Asymmetric Allylation to the Cyclic Imine. We previously
reported11 that an asymmetric catalytic allylation of 6,7-
dimethoxy-3,4-dihydroisoquinoline (1) proceeded in a stereo-
selective manner to afford 1-allyl-6,7-dimethoxy-1,2,3,4-
tetrahydroisoquinoline (2), using allyltrimethylsilane-Cu
as the nucleophile in the presence of tol-BINAP as the
chiral ligand (Scheme 1). After recrystallization of allyl
adduct 2 with a chiral tartaric acid, compound 2 was
obtained in 78% yield (97% ee) from 1.
The results from using several other phosphine ligands for
the catalytic allylation of 3 (Scheme 3) are summarized in
Table 1. Higher reaction temperature improved the reac-
tion yield without significantly decreasing stereoselectivity
(Table 1, entries 5, 7 vs 6, 8), but the ee did not exceed 70%.13
Thus, other systems for the addition reaction were studied.
We found that the reaction conditions used by Shibasaki’s
group for asymmetric vinylation14 were effective. This reac-
tion system was applied to the allylation of compound 3 by
using allyltrimethoxysilane instead of trimethoxyvinylsilane.
The results are shown in Table 2.
SCHEME 1
First, a catalytic amount of a chiral phosphine ligand and
CuF2 in wet methanol was refluxed for 2 h. After removal of
the solvent in vacuo, tetrabutylammonium triphenyldifluor-
osilicate (TBAT), allyltrimethoxysilane, and substrate 3 were
added to the residue as THF solutions. In the case of Tol-
BINAP, the allyl adduct was obtained in poor yield and with
poor stereoselectivity (Table 2, entry 1). The use of SEG-
PHOS as a ligand improved both yield and selectivity. This
result prompted us to use the more bulky DTBM-SEGPHOS
as a ligand, and we observed that yield increased with
increasing reaction temperature without loss of stereoselec-
tivity. To minimize the amount of ligand required, the
reaction was carried out at various ratios of ligand and
CuF2 (entries 7-12). At a phosphine ligand:metal ratio of
2:1,14 20 mol % of DTBM-SEGPHOS was needed to obtain
satisfactory results. By increasing the relative amount of
CuF2, the reaction proceeded smoothly, and 9 mol % of
the ligand was sufficient at a ligand:metal ratio of 3:2. Thus, a
high chemical yield of 97% and 82% ee was accomplished by
using 9 mol % of DTBM-SEGPHOS and 6 mol % of CuF2
(Table 2, entry 11).
We next applied this reaction system to the synthesis of an
isoquinoline moiety of schulzeine A, a natural product from
the marine sponge Penares schulzei (Figure 1).12 Schulzeine
A is comprised of a tricyclic structure that includes a 6,8-
dihydroxyisoquinoline nucleus and a C28 fatty acid side
chain. To synthesize the tricyclic core in a stereoselective
manner, the present reaction system was applied to 6,8-
dimethoxy-3,4-dihydroisoquinoline, but the selectivity was
found to be moderate (62% ee; Scheme 2 and Table 1, entry 6),
and subsequent attempts to recrystallize 4 in the presence
of a chiral acid were unsuccessful.
This reaction condition was applied to 6,7-dimethoxy-3,4-
dihydroisoquinoline (1) and yielded improved results
(entries 13 and 14), demonstrating that a reaction system
with DTBM-SEGPHOS as a chiral source is a practical
(8) (a) Sasamoto, N.; Dubs, C.; Hamashima, Y.; Sodeoka, M. J. Am.
Chem. Soc. 2006, 128, 14010. (b) Dubs, C.; Hamashima, Y.; Sasamoto, N.;
Seidel, T. M.; Suzuki, S.; Hashizume, D.; Sodeoka, M. J. Org. Chem. 2008,
73, 5859.
(9) Denmark, S. E.; Fu, J. Chem. Rev. 2003, 103, 2763 and references cited
therein.
(12) Takeda, K.; Uehara, T.; Nakao, Y.; Matsunaga, S.; van Soest, R. W.;
Fusetani, N. J. Am. Chem. Soc. 2004, 126, 187.
(10) Yamasaki, S.; Fujii, K.; Wada, R.; Kanai, M.; Shibasaki, M. J. Am.
Chem. Soc. 2002, 124, 6536.
(13) Although several solvents other than THF were used as a reaction
solvent, the yields were lower in every case.
(11) Itoh, T.; Miyazaki, M.; Fukuoka, H.; Nagata, K.; Ohsawa, A. Org.
Lett. 2006, 8, 1295.
(14) Tomita, D.; Wada, R.; Kanai, M.; Shibasaki, M. J. Am. Chem. Soc.
2005, 127, 4138.
J. Org. Chem. Vol. 76, No. 2, 2011 535

Miyazaki et al.
JOCArticle
TABLE 1. Allylation of 3 in the Presence of a Chiral Ligand
entry
chiral ligand
X (mol %)
temp (°C)
time
yield (%)
ee (%)
1
2
3
4
5
6
7
8
(R)-QUINAPa
10
10
10
10
10
10
3
rt
rt
23 h
23 h
6 h
6 h
1 d
2.5 h
7 d
3 h
0
0
39
9
5
73
6
(S)-SEGPHOSb
(S)-SEGPHOS
70
50
rt
50
rt
28 (R)
0.3
64 (R)
62 (R)
69 (R)
51 (R)
(R)-DTBM-SEGPHOSc
(S)-Tol-BINAPd
(S)-Tol-BINAP
(S)-Tol-BINAP
(S)-Tol-BINAP
3
50
61
b
aQUINAP: 1-(2-diphenylphosphino-1-naphthyl)isoquinoline. SEGPHOS: 5,50-bis(diphenylphosphino)-4,40-bi-1,3-benzodioxole. cDTBM-SEG-
PHOS: 5,50-bis[di(3,5-di-tert-butyl-4-methoxyphenyl)phosphino]-4,40-bi-1,3-benzodioxole. dTol-BINAP: 2,20-bis(di-p-tolylphosphino)-1,10-bi-
naphthyl.
TABLE 2. Allylation of 1 or 3 with Allylsilane and Cu(II) in the Presence of a Chiral Ligand
entry
SM
chiral ligand (mol %)
CuF2 (mol %)
solvent
temp (°C)
time (h)
product
yield (%)
ee (%)
1
2
3
4
5
6
7
8
9
10
11
12
13
14
3
3
3
3
3
3
3
3
3
3
3
3
1
1
(S)-Tol-BINAP (20)
(S)-SEGPHOS (20)
10
10
10
10
10
10
1
5
7.5
4
THF
THF
THF
THF
THF
DMF
THF
THF
THF
THF
THF
THF
THF
THF
50
70
rt
6
4
4
4
4
4
4
4
4
4
4
4
4
4
2
2
17
61
50
31
quant
77
16
26
42
72
97
88
87
53 (R)
61 (R)
87 (S)
84 (S)
83 (S)
82 (S)
26 (S)
81 (S)
84 (S)
56 (S)
82 (S)
84 (S)
80 (S)
81 (S)
(R)-DTBM-SEGPHOS (20)
(R)-DTBM-SEGPHOS (20)
(R)-DTBM-SEGPHOS (20)
(R)-DTBM-SEGPHOS (20)
(R)-DTBM-SEGPHOS (2)
(R)-DTBM-SEGPHOS (10)
(R)-DTBM-SEGPHOS (15)
(R)-DTBM-SEGPHOS (6)
(R)-DTBM-SEGPHOS (9)
(R)-DTBM-SEGPHOS (15)
(R)-DTBM-SEGPHOS (20)
(R)-DTBM-SEGPHOS (20)
24
22
1.5
0.5
21
28
14
8
50
70
70
70
70
70
70
70
70
70
70
6
4.5
1.5
1
10
10
6
2.5
85
SCHEME 3
isolated in 2002 by Cheng’s group, and was found to
show cytotoxicity in vitro.15 Although several groups have
reported the total synthesis of crispine A,16 asymmetric
synthesis of the compound has published only recently.17,6
Thus, we carried out the asymmetric total synthesis of
crispine A using (R)-2.
After protecting the N-2 position of (R)-allyl adduct 2 with
(Boc)2O, product 6 was subjected to hydroboration-oxidation
to give primary alcohol 7 (Scheme 5, top). Deprotection of 7
gave amino alcohol 8 in moderate yield, and Mitsunobu
reaction with DEAD and PPh3 (Scheme 5, bottom) afforded
the ring-closing product, crispine A (9).
In this procedure, the yield of the last step was only 50%,
and the overall yield of crispine A (9) was 26.7% in 5 steps.
Therefore, other cyclization processes were investigated. As
a result, alcohol 7 was activated with TsCl, and subsequent
deprotection with TMSOTf in air resulted in spontaneous
cyclization to obtain 9 in 2 steps with 74% yield (5 steps, 54%
yield from 2). The specific rotation of 9 was identical with
that of crispine A, and the synthesis proceeded without
racemization.
method for the asymmetric catalytic allylation of cyclic
imines.
Determination of the Absolute Configuration of the Allyl
Adduct. The absolute configuration of the allyl adduct 4 was
determined as follows. First, racemic 4 was obtained quanti-
tatively by the reaction of 3 and allyl magnesium bromide.
The racemate was reacted with N-phthaloyl-(S)-alanine in
the presence of EDCI to give diastereomeric amides 5a and
5b (Scheme 4). The products were recrystallized from hexane-
dichloromethane, and 5a was obtained as a colorless
crystal. The structure of 5a was determined by X-ray crystal-
lographic analysis and showed that the absolute configura-
tion at the C-1 position is R (Scheme 4). Next, compound 4,
which was obtained from the reaction with use of (R)-
DTBM-SEGPHOS, was reacted with N-phthaloyl-(S)-
alanine to give 5b as the main product. The C-1 absolute con-
figuration of 5b was determined to be S, indicating that the
use of (R)-DTBM-SEGPHOS provides 4 in the S form. The
stereoselectivity was found to be consistent with those of
Shibasaki’s reaction.14
(15) Zhang, Q.; Tu, G.; Zhao, Y.; Cheng, T. Tetrahedron 2002, 58, 6795.
€
(16) (a) King, F. D. Tetrahedron 2007, 63, 2053. (b) Knolker, H.-J.;
Agawal, S. Tetrahedron Lett. 2005, 46, 1173. (c) Orito, K.; Matsuzaki, T.;
Suginome, H. Heterocycles 1988, 2403. (d) Schell, F. M.; Smith, A. M.
Tetrahedron Lett. 1983, 24, 1883.
(17) (a) First enantioselective synthesis of crispine A: Szawkalo, J.;
Zawadzka, A.; Wojtasiewicz, K.; Leniewski, A.; Drabowicz, J.; Czarnocki,
Z. Tetrahedron: Asymmetry 2005, 16, 3619. (b) Allin, S. M.; Gaskell, S. N.;
Towler, J. M. R.; Bulman Page, P. C.; Saha, B.; McKenzie, M. J.; Martin,
W. P. J. Org. Chem. 2007, 72, 8972. (c) Szawkalo, J.; Czarnocki, S. J.;
Zawadzka, A.; Wojtasiewicz, K.; Leniewski, A.; Maurin, J. K.; Czarnocki,
Z.; Drabowicz, J. Tetrahedron: Asymmetry 2007, 18, 406. (d) Hou, G.-H.;
Xie, J.-H.; Yan, P.-C.; Zhou, Q.-L. J. Am. Chem. Soc. 2009, 131, 1366.
(e) Amat, M.; Elias, V.; Llor, N.; Subrizi, F.; Molins, E.; Bosch, J. Eur. J. Org.
Chem. 2010, 4017. (f ) Deracemization of racemic crispine A: Bailey, K. R.;
Ellis, A. J.; Reiss, R.; Snape, T. J.; Turner, N. J. Chem. Commun. 2007, 3640.
Asymmetric Synthesis of Crispine A. To demonstrate the
usefulness of chiral allyl adducts 2 and 4, several isoquinoline
alkaloids were synthesized by using these as starting materi-
als. First, we selected crispine A, one of the simplest iso-
quinoline alkaloids, as the target molecule. Crispine A was
536 J. Org. Chem. Vol. 76, No. 2, 2011

Miyazaki et al.
JOCArticle
SCHEME 4
SCHEME 5
Synthesis of Homolaudanosine. Homolaudanosine (14), an
alkaloid identified in 1983 by Leary, has a chiral center at the
C-1 position.18 Several total syntheses have been reported,19
including our paper that described the asymmetric synthesis
of (R)-homolaudanosine using a chiral auxiliary derived
from an amino acid.20
To evaluate the synthetic value of chiral allyl adduct 2 as a
stating material, the synthesis of 14 was reinvestigated
(Scheme 6).
After protection of N-2 in 2 with ethyl chloroformate,
allyl adduct 11 was transformed to aldehyde 12 using
OsO4-NaIO4 oxidation. Compound 12 was subjected to
the Grignard reaction with 3,4-dimethoxyphenylmagne-
sium bromide to give secondary alcohol 13. The hydroxyl
group of 13 was converted to the Cl group with SOCl2 in
pyridine, and subsequent reduction with LiAlH4 afforded
(S)-homolaudanosine 14 in an overall yield of 29.1% from
compound 2.
Compound S-2 also could be transformed into (-)-
emetine21 according to the previously described strategy.11
Synthesis of Schulzeine A (Isoquinoline Framework).
Schulzeines (A, B, and C), which are alkaloids first isolated
by Fusetani et al. in 2003,12 have high R-glucosidase inhibi-
tion activity (Figure 1). Their intriguing structure and
bioactivity prompted four groups to attempt the synthesis
(18) Aladesanmi, A. J.; Kelly, C. J.; Leary, J. D. J. Nat. Prod. 1983,
46, 127.
(19) (a) Czarnocki, Z.; MacLean, D. B.; Szarek, W. A. J. Chem. Soc.,
Chem. Commun. 1987, 493. (b) Meyers, A. I.; Dickman, D. A.; Boes, M.
Tetrahedron 1987, 43, 5095. (c) Yamato, M.; Hashigaki, K.; Qais, N.;
Ishikawa, S. Tetrahedron 1990, 46, 5909. (d) Wanner, K. T.; Praschak, I.
Heterocycles 1991, 32, 1869. (e) Pedrosa, R.; Andres, C.; Iglesias, J. M.
J. Org. Chem. 2001, 66, 243. (f ) Taylor, A. M.; Schreiber, S. L. Org. Lett.
2006, 8, 143. (g) Zang, Z.; Leitch, D. C.; Lu, M.; Patrick, B. O.; Scafer, L. L.
Chem. Eur. J. 2007, 13, 2012.
;
(20) Itoh, T.; Nagata, K.; Miyazaki, M.; Ohsawa, A. Synlett 1999, 1154.
J. Org. Chem. Vol. 76, No. 2, 2011 537

Miyazaki et al.
JOCArticle
SCHEME 6
SCHEME 8
the original structure at C-200.22d The four reports used
similar approaches for the synthesis of the tricyclic iso-
quinoline derivative, that is, the chiral center at C-3 was
derived from glutaminic acid and the C-11b chiral center
was obtained by the diastereoselective Pictet-Spengler
reaction. The purity of C-11b was not always high, and the
separation of the diastereomer was crucial in every case.
Since satisfactory yields and stereoselectivity were not
obtained, allylation product 2 was applied to the synthesis
of the isoquinoline fragment in schulzeine A (Scheme 7).
R-Allyl adduct 4 obtained from the reaction of 6,8-
dimethoxy-3,4-dihydroisoquinoline (3) and (S)-DTBM-
SEGPHOS was protected by (Boc)2O, and oxidized with
OsO4-NaIO4 to aldehyde 16. Horner-Wadsworth-Emmons
olefination of aldehyde 16 with dimethylphosphate de-
rived from glycine gave dehydroamino acid 17 in high
yield.23
SCHEME 7
Asymmetric reduction of the olefin was needed to intro-
duce another chiral center in the heterotricyclic schulzeines.
The reaction was carried out by Feringa’s method, using
Rh-catalysis24 with the chiral ligand (R)-[4-N,N-dim-
ethylamino]dinaphtho[2,1-d:10,20-f][1,3,2]dioxaphosphepine
((R)-MONOPHOS), to obtain 18 (Scheme 8). Due to the
presence of complicated conformational isomers in 18, it was
difficult to determine the stereoselectivity of the reduction at
this point. Deprotection of the Boc group and successive
cyclization of 18 provided a diastereomeric mixture of 19a
and 19b. The mixture was successfully separated by column
chromatography.
To determine the ratio and enantiomeric excess of diaste-
reomer 19, reduction-cyclization was studied by using race-
mic and optically active (82% ee) 17.
To determine the configuration of 19a and 19b obtained
by the asymmetric reduction, the Cbz group was removed
under catalytic hydrogenation conditions to give amines 20a
and 20b (Scheme 9), respectively. NOEs showed a correla-
tion between H-3 and H-11b in 20b, whose 11b position has
of these compounds.22 Recently, Wardrop reported the
first total synthesis of schulzeine A, leading to revision of
(21) (a) Brossi, A.; Baumann, M.; Schnider, O. Helv. Chim. Acta 1959, 42,
1515. (b) Szantay, C.; Toke, L. Tetrahedron Lett. 1963, 1323. (c) Szantay, C.;
Toke, L.; Kolonis, P. J. Org. Chem. 1966, 31, 1447. (d) van Tamelen, E. E.;
Placeway, C.; Schiemenz, G. P.; Wright, I. G. J. Am. Chem. Soc. 1969, 91,
7359. (e) Takano, S.; Sasaki, M.; Kanno, H.; Shishido, K.; Ogasawara, K.
Heterocycles 1977, 7, 143. (f) Kametani, T.; Suzuki, Y.; Terasawa, H.; Ihara,
M.; Fukumoto, K. Heterocycles 1977, 8, 119. (g) Fujii, T.; Ohba, M.;
Akiyama, S. Heterocycles 1984, 22, 159. (h) Naito, T.; Kojima, N.; Miyata,
O.; Ninomiya, I. J. Chem. Soc., Chem. Commun. 1985, 22, 1611. (i) Ihara, M.;
Yasui, K.; Taniguchi, N.; Fukumoto, K. J. Chem. Soc., Perkin Trans. 1 1990,
1469. ( j) Gulles, J. W.; Meyers, A. I. J. Org. Chem. 1991, 56, 6873.
(k) Stearman, C. J.; Wilson, M.; Padwa, A. J. Org. Chem. 2009, 74, 3491.
(l) Tietze, L. F.; Rackelmann, N.; Sekar, G. Angew. Chem., Int. Ed. 2003, 42,
€
4254. (m) Tietze, L. F.; Rackelmann, N.; Muller, I. Chem. Eur. J. 2004, 10,
;
2722.
(22) (a) Kuntiyong, P.; Akkarasamiyo, S.; Eksinitkun, G. Chem. Lett.
2006, 35, 1008. (b) Gurjar, M. K.; Pramanik, C.; Bhattasali, D.; Ramana,
C. V.; Mohapatra, D. K. J. Org. Chem. 2007, 72, 6591. (c) Liu, G.; Romo, D.
Org. Lett. 2009, 11, 1143. (d) Wardrop, D. J.; Bowen, E. G. J. Am. Chem. Soc.
2009, 131, 6062.
(23) Endo, A.; Yanagisawa, A.; Abe, M.; Tohma, S.; Kan, N.; Fukuya-
ma, T. J. Am. Chem. Soc. 2002, 124, 6552.
(24) Van Den Berg, M.; Minnaard, A. J.; Schudde, E. P.; Van Esch, J.;
De Vries, A. H. M.; De Vries, J. G.; Feringa, B. L. J. Am. Chem. Soc. 2000,
122, 11539.
538 J. Org. Chem. Vol. 76, No. 2, 2011

Miyazaki et al.
JOCArticle
SCHEME 9
added H2O, and the mixture was basified with potassium
carbonate and then extracted with CH2Cl2. The combined organic
layer was dried over MgSO4 and then the solvent was removed in
vacuo. The residue was purified by column chromatography
(EtOAc/MeOH = 20 to 4) to give 3,4-dihydroisoquinolines 1 or
3 as a yellow solid in 90% (for 1) or 96% (for 3) yield, respectively.
6,7-Dimethoxy-3,4-dihydroisoquinoline (1):26 colorless oil; 1H
NMR (CDCl3) δ 2.68 (2H, t, J=7.9 Hz), 3.73 (2H, td, J=8.7,
1.8 Hz), 3.91 (3H, s), 3.93 (3H, s), 6.68 (1H, s), 6.81 (1H, s), 8.23
(1H, t, J=2.1 Hz); 13C NMR (CDCl3) δ 24.1, 46.8, 55.4, 55.5,
109.8, 109.9, 120.9, 129.2, 147.2, 150.6, 159.0. Anal. Calcd for
C11H13NO2: C, 69.09; H, 6.85; N, 7.32. Found: C, 68.97; H, 6.85;
N, 7.18. HR-FAB MS calcd for C11H14NO2 [M þ H]þ 192.1025,
found 192.1024.
6,8-Dimethoxy-3,4-dihydroisoquinoline (3):27 colorless oil;
1H NMR (CDCl3) δ 2.66 (2H, t, J=7.7 Hz), 3.67 (2H, td, J=
7.7, 1.9 Hz), 3.83 (3H, s), 3.85 (3H, s), 6.27 (1H, s), 6.31 (1H, s),
8.61 (1H, t, J=2.0 Hz); 13C NMR (CDCl3) δ 26.0, 46.6, 55.3,
55.4, 96.3, 103.8, 111.5, 139.9, 155.1, 158.5, 162.6. Anal. Calcd
for C11H13NO2: C, 69.09; H, 6.85; N, 7.32. Found: C, 68.77; H,
6.84; N, 7.21. HR-FAB MS calcd for C11H14NO2 [M þ H]þ
192.1025, found 192.1026.
TABLE 3
ee (%)
19a:19b 19a 19b
yield (%) yield (%)
of 18
ratio
substrate
of 19
racemic 17
17 (82% ee) (R:S = 91:9)
quant
99
93
96
53:47
82:18
78 80
98 62
Preparation of Chiral 1-Allyl-1,2,3,4-tetrahydroisoquinolines
2 or 4. After heating a mixture of CuF2 (1.2 mg, 0.012 mmol) and
DTBM-SEGPHOS (21.2 mg, 0.018 mmol) in MeOH (1 mL) and
H2O (100 μL) at 80 °C for 2 h, the solvent was removed in vacuo,
and subsequently azeotropically dehydrated by using toluene
twice (each 0.5 mL). To the residue dissolved in THF (1 mL) was
added tetra-n-butylammonium difluorotriphenylsilicate (10.8
mg, 0.02 mmol) and the reaction mixture was cooled to 0 °C.
To the cooled reaction mixture were added 3,4-dihydroisoquino-
line (1 or 3) (38.2 mmol, 0.2 mmol) and allyltrimethoxysilane
(68 μL, 0.4 mmol). Again the reaction mixture was warmed to
room temperature and t-BuOH (20 mL, 0.2 mol) was added to
the mixture. After stirring at 70 °C for 4.5 h under Ar, saturated
aqueous sodium bicarbonate solution (10 mL) was added to the
mixture, which was extracted with EtOAc, and the combined
organic layer was dried over MgSO4, filterd, and concentrated in
vacuo. The residue was purified by column chromatography
(EtOAc/MeOH=10 to 1) to give the allyl adduct (2 or 4) as a
colorless oil.
S-configuration, but no correlation in 20a, which has an
R-isomer at H-11b. The results indicated that asymmetric
reduction by Feringa’s method was accomplished in a highly
S-selective manner. The results summarized in Table 3 sug-
gested that the reduction process is stereospecific regardless
of the pre-existing chiral center at C-11b.
The asymmetric synthesis of 20a, an intermediate of
schulzeine A, was accomplished with an overall yield of
68.1% via 9 steps from 6,8-dimethoxy-3,4-dihydroisoquino-
line (3) and (S)-DTBM-SEGPHOS.
In this paper, we described the catalytic asymmetric
allylation of 3,4-dihydroisoquinolines, and its application
in the synthesis of several isoquinoline alkaloids. The results
show the usefulness of the allyl adduct as a starting material
for optically active isoquinoline alkaloid synthesis. Further
applications and the total synthesis of schulzeine A are now
in progress.
To determine the enantiomeric excesses, thus obtained allyl
adduct was subjected to N-trifluoroacetylation, and the ee was
subsequently detected by HPLC, using Daicel Chiralcel OD-H
(eluent was hexane/2-propanol=100). The compound 2a was
obtained in 97% yield, and the ee was determined as 82% by
using the HPLC method.
Experimental Section
General. The reagents were commercially available and used
without further purification. Thin-layer chromatography
(TLC) was conducted with silica gel, using UV light (254 nm),
an acetone solution of potassium permangarate, and iodine as
monitoring methods. Silica gel (spherical, neutral, 100-200 μm)
and NH silica gel (100-200 mesh) were used for column
chromatography. All the reaction temperatures shown are bath
temperatures. The nuclear magnetic resonance spectra (NMR)
were measured with 400 and 500 MHz spectrometers. Chemical
shifts for 1H NMR were reported downfield from tetramethyl-
silane (TMS) as the internal standard. The signal multiplicities
were shown as follows: s=singlet, d=doublet, t=triplet, q=
quartet, m=multiplet, and br=broad. The standard chemical
shifts for 13C NMR were derived from the used solvent.
1-Allyl-6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline (2): col-
orless oil; 1H NMR (CDCl3) δ 1.82 (1H, br s), 2.49 (1H, dtd, J=
15.3, 8.0, 1.0 Hz), 2.60-2.67 (1H, m), 2.67-2.79 (2H, m), 2.95
(1H, ddd, J=12.6, 7.8, 4.9 Hz), 3.22 (1H, dt, J=12.3, 5.3 Hz),
3.85 (6 H, s), 4.00 (1H, dd, J=8.7, 3.6 Hz), 5.13-5.21 (2H, m),
5.79-5.89 (1H, m), 6.58 (1H, s), 6.66 (1H, s); 13C NMR (CDCl3)
δ 29.5, 40.8, 41.1, 54.7, 55.8, 56.0, 109.1, 111.8, 117.9, 127.5,
130.5, 135.6, 147.2, 147.4. Anal. Calcd for C14H19NO2: C, 72.07;
H, 8.21; N, 6.00. Found: C, 71.81; H, 8.34; N, 5.94. HR-FAB
MS calcd for C14H20NO2 [M þ H]þ 234.1494, found 234.1480.
1-Allyl-6,8-dimethoxy-1,2,3,4-tetrahydroisoquinoline (4): col-
orless oil; (R)-4 (82% ee) [R]18D þ38.8 (c 0.30, CHCl3); 1H NMR
(CDCl3) δ 2.31 (1H, br s), 2.34 (1H, dt, J = 14.1, 9.2 Hz),
2.58-2.64 (1H, m), 2.66 (1H, dt, J=12.2, 4.0 Hz), 2.86 (1H, ddd,
J=16.3, 10.0, 6.0 Hz), 2.94 (1H, ddd, J=12.4, 5.9, 3.2 Hz), 3.16
(1H, ddd, J=12.5, 10.2, 4.4 Hz), 3.78 (3H, s), 3.79 (3H, s), 4.15
(1H, dd, J=9.5, 2.6 Hz), 5.09-5.13 (2H, m), 5.84-5.92 (1H, m),
Preparation of 3,4-Dihydroisoquinolines 1 or 3.25 Hexamethyl-
enetetramine (7.74 g, 55.2 mmol) was added to the mixture of
2-(dimethoxyphenyl)ethylamine (5 g, 27.6 mmol), AcOH (30 mL),
and trifluoroacetic acid (7.5 mL) under Ar, and the mixture was
allowed to stir at 90 °C for 30 min (for 3,4-dimethoxyphen-
ethylamine) or 3 h (for 3,5-dimethoxyphenethylamine), respec-
tively. To the reaction mixture cooled to room temperature was
(26) (a) Whalley, W. M.; Meadow, M. J. Chem. Soc. 1953, 23, 1067.
(b) Warrener, R. N.; Liu, L.; Russell, R. A. Tetrahedron 1998, 54, 7485.
(27) Gray, von R. W.; Dreiding, A. S. Helv. Chim. Acta 1980, 63, 315.
(25) Ivanov, I.; Venkov, A. Heterocycles 2001, 55, 1569.
J. Org. Chem. Vol. 76, No. 2, 2011 539

Miyazaki et al.
JOCArticle
6.23 (1H, d, J = 2.3 Hz), 6.29 (1H, d, J = 2.3 Hz); 13C NMR
(CDCl3) δ 29.5, 37.58, 37.62, 50.2, 55.17, 55.22, 96.4, 104.4,
117.2, 119.6, 136.57, 136.62, 157.2, 158.8; HR-FAB MS calcd
for C14H20NO2 [M þ H]þ 234.1494, found 234.1488.
1-(3-Hydroxypropyl)-6,7-dimethoxy-1,2,3,4-tetrahydroisoquino-
line (8):28 colorless powder; 1H NMR (CDCl3) δ 1.67-1.85
(2H, m), 1.91-2.04 (2H, m), 2,67 (1H, dt, J=16.4, 6.2 Hz), 2.77
(1H, dt, J=16.5, 5.8 Hz), 3.06 (1H, ddd, J=13.1, 6.1, 5.3 Hz),
3.20 (1H, ddd, J=12.9, 7.3, 5.4 Hz), 3.55 (1H, ddd, J=11.1, 8.1,
3.0 Hz), 3.66 (1H, ddd, J=17.3, 6.2, 3.2 Hz), 3.85 (3H, s), 3.85
(3H, s), 3.94 (1H, dd, J=7.8, 3.9 Hz), 6.57 (1H, s), 6.59 (1H, s);
13C NMR (CDCl3) δ 28.8, 30.7, 35.6, 39.7, 55.4, 55.8, 56.0, 62.8,
109.3, 111.6, 126.6, 130.3, 147.2, 147.4. Anal. Calcd for
The Purification of 2 (71% ee, R isomer), Using (-)-Dibenzoyl-
L-tartaric Acid. Compound 2 (123.7 mg, 0.53 mmol) and (-)-
dibenzoyl-L-tartaric acid (190 mg, 0.53 mmol) were recrys-
tallized from CH3CN/H2O (20), and the solid thus obtained
was filtrated, dissolved in EtOAc, and extracted with aq
Na2CO3. The organic layer was dried over MgSO4, and evapo-
rated off to leave optically more active 2 (97%ee, R) in 78%
yield (96.5 mg).
C14H21NO3 1/3H2O: C, 65.34; H, 8.49; N, 5.44. Found: C,
3
65.59, H, 8.59; N, 5.24. HR-FAB MS calcd for C14H22NO3[M
þ H]þ 252.1586, found 252.1600.
The Protection of N-2 Position of Compound 2 by the Use of the
Boc Group. To the solution of (Boc)2O (580.2 mg, 2.5 mmol) in
CH2Cl2 (8 mL) was added 1-allyl-6,7-dimethoxy-1,2,3,4-tetra-
hydroisoquinoline (2) (307.7 mg, 1.3 mmol) in CH2Cl2 (7 mL) at
room temperature, and the mixture was allowed to stir for 1 h.
Then the reaction was quenched by the addition of H2O, and the
mixture was extracted with CH2Cl2. The organic layer was dried
over MgSO4 and the solvent was removed in vacuo. The residue
was purified by column chromatography (CH2Cl2/EtOAc=20)
to give 6 (98%) as a colorless powder.
Crispine A (9). To a solution of 7 (124.0 mg, 0.38 mmol) in
ethyl acetate (1 mL) was added DABCO (92.7 mg, 0.83 mmol)
and p-toluenesulfonyl chloride (119.0 mg, 0.62 mmol) at 0 °C
under Ar, and the mixture was allowed to stir at room tempera-
ture for 4 h. The insoluble material was filtered through the
Celite pad and filtrate was evaporated in vacuo to give the crude
Ts-adduct 10 as a colorless oil. Compound 10 thus obtained was
dissolved in CH2Cl2 (5 mL), and trimethylsilyl trifluoromethane-
sulfonate (0.33 mL, 1.81 mmol) was added in air. After 3 h, the
reaction mixture was basified with saturated sodium bicarbon-
ate aqueous solution and extracted with CH2Cl2. The collected
organic layer was dried over MgSO4 and removed in vacuo. The
residue was purified with silica gel column chromatography
(EtOAc to MeOH) to give the ring closing product crispine A (9)
in 74% in two steps.
tert-Butyl 1-allyl-6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline-
2-carboxylate (6): colorless powder, mp 71-74 °C; (R)-6
D
1
(98.7% ee) [R]18 -105.3 (c 1.15, CHCl3); H NMR (DMSO-
d6, 100 °C) δ 1.44 (9H, s), 2.45-2.57 (2H, m), 2.65 (1H, dt, J=
16.2, 4.2 Hz), 2.72 (1H, ddd, J=16.2, 10.4, 5.8 Hz), 3.19 (1H,
ddd, J=13.1, 10.4, 4.3 Hz), 3.74 (3H, s), 3.75 (3H, s), 3.94 (1H,
dt, J=12.8, 4.5 Hz), 4.99-5.06 (3H, m), 5.82 (1H, ddt, J=17.1,
10.1, 7.1 Hz), 6.70 (1H, s), 6.77 (1H, s); 13C NMR (DMSO-d6,
100 °C) δ 27.2, 27.8, 37.2, 40.4, 53.2, 55.7, 55.9, 78.6, 111.5,
112.8, 116.2, 126.1, 129.1, 135.1, 147.4, 147.7, 153.8. Anal.
Calcd for C19H27NO4: C, 68.44; H, 8.16; N, 4.20. Found: C,
68.43; H, 8.37; N, 4.04. HR-FAB MS calcd for C19H28NO4
[M þ H]þ 334.2018, found 334.2029.
tert-Butyl 6,7-dimethoxy-1-[3-(toluene-4-sulfonyloxy)propyl]-
1,2,3,4-tetrahydroisoquinoline- 2-carboxylate (10): colorless oil;
(R)-10 (99.6% ee) [R]18 -69.8 (c 0.49, CHCl3); 1H NMR
D
(CDCl3, 60 °C) δ 1.44 (9H, s), 1.75-1.83 (4H, m), 2.43 (3H,
s), 2.57 (1H, dt, J=15.9, 3.7 Hz), 2.77-2.86 (1H, m), 3.11 (1H,
br s), 3.83 (3H, s), 3.84 (1H, s), 4.01-4.09 (2H, m), 4.16-4.22
(1H, m), 4.98 (1H, br s), 6.56 (1H, s), 6.57 (1H, s), 7.31 (2H, d, J=
8.5 Hz), 7.77 (2H, d, J=8.3 Hz); 13C NMR (CDCl3, 60 °C) δ
21.4, 26.0, 28.0 28.4, 32.5, 47.1, 53.4, 56.1, 56.3, 70.2, 79.8, 110.8,
112.2, 126.4, 127.8, 129.8, 130.4, 133.7, 144.6, 147.9, 148.1,
154.9. Anal. Calcd for C26H35NO7S: C, 61.76; H, 6.98; N,
2.77. Found: C, 61.34, H, 7.15; N; 2.72. HR-FAB MS calcd
for C26H36NO7S [M þ H]þ 506.2212, found 506.2205.
Hydroboration-Oxidation of the Compound 6. To the allyl
derivative 6 (427.1 mg, 1.28 mmol) dissolved in THF (5 mL)
solution was added BH3-THF (1 M solution, 3.9 mL, 3.9
mmol) at -25 °C under Ar, and the mixture was allowed to stir
for 3 h. After addition of H2O into the reaction mixture, 3 M
NaOH (1 mL) and H2O2 (30%, 1 mL) were added, and the
reaction was continued for 24 h at room temperature. Then
brine (15 mL) was added to the reaction mixture, which was
extracted with EtOAc. The collected organic layer was dried
with MgSO4 and removed in vacuo. The residue was purified
with silica gel column chromatography (EtOAc) to give the
primary alcohol product 7 in 89% yield.
Crispine A (9):15 colorless powder, mp 85-88 °C; (R)-9
(99.3% ee) [R]18D þ90.4 (c 0.79, CHCl3); 1H NMR (CDCl3,) δ
1.67-1.77 (1H, m), 1.81-2.00 (2H, m), 2,28-2.36 (1H), 2.55 (1
h, q, J=8.5 Hz), 2.63 (1H, td, J=10.7, 4.8 Hz), 2.73 (1H, dt, J=
16.3, 3.7 Hz), 2.94-3.04 (1H, m), 3.85 (3H, s), 6.57 (1H, s), 6.61
(1H, s); 13C NMR (CDCl3) δ 22.3, 28.2, 30.5, 48.2, 53.2, 55.9,
56.0, 63.0, 108.8, 111.3, 126.2, 131.0,. 147.1, 147.2; HR-FAB MS
calcd for C14H19NO2 [M þ H]þ 234.1479, found 234.1494.
N-Protection of Compound 2 with Ethyl Chloroformate. To a
solution of 2 (253.2 mg, 1.09 mmol) in CH2Cl2 (10 mL) was
added triethylamine (0.23 mL, 1.65 mmol) and ethyl chlorofor-
mate (0.16 mL, 1.67 mmol) at room temperature under Ar, and
the mixture was allowed to stir for 3 h. After addition of H2O (10
mL), the reaction mixture was extracted with CH2Cl2 and the
collected organic layer was dried over MgSO4 and removed in
vacuo. The residue was purified with column chromatography
(EtOAc) to give 11 as a colorless oil.
tert-Butyl 1-(3-hydroxypropyl)-6,7-dimethoxy-1,2,3,4-tetra-
hydroisoquinoline-2-carboxylate (7): colorless oil; (R)-7 (99.6%
ee) [R]18D -90.0 (c 0.28, CHCl3); 1H NMR (CDCl3, 60 °C) δ 1.48
(9H, s), 1.61-1.76 (2H, m), 1.78-1.86 (2H, m), 2.61 (1H, dt, J=
16.1, 3.9 Hz), 2.83 (1H, ddd, J=16.1, 10.5, 5.7 Hz), 3.21 (1H, br
s), 3.65-3.76 (2H, m), 3.83 (3H, s), 3.84 (3H, s), 4.06 (1H, br s),
5.06 (1H, br s), 6.58 (1H, s); 13C NMR (CDCl3, 60 °C) δ 25.5,
28.1, 28.5, 29.5, 33.4, 54.0, 56.1, 56.3, 62.7, 79.8, 110.9, 112.2,
126.4, 130.4, 147.8, 155.1. Anal. Calcd for C19H29NO5 1/4H2O:
3
C, 64.11; H, 8.35; N, 3.94. Found: C, 64.16; H, 8.35.37; N, 3.80.
HR-FAB MS calcd for C19H30NO5 [M þ H]þ 352.2131, found
352.2124.
Ethyl 1-allyl-6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline-2-
carboxylate (11): colorless oil; (S)-11 (97% ee) [R]16D þ123.6 (c
1
0.25, CHCl3); H NMR (CDCl3, 60 °C) δ 1.25 (3H, t, J =7.1
Deprotection of N-Boc to the Formation of an Aminoalcohol 8.
To compound 7 (177.5 mg, 0.51 mmol) in CH2Cl2 was added
TMSOTf (0.4 mL, 2.21 mmol) at room temperature under air,
and the mixture was allowed to stir for 1 h. The mixture was
basified with saturated sodium bicarbonate, and extracted with
CH2Cl2. The collected organic layer was dried over MgSO4 and
removed in vacuo to leave the residue, which was purified with
NH silica gel column chromatography (EtOAc/MeOH=5) to
give an aminoalcohol 8 (72%) as a colorless solid.
Hz), 2.53 (2H, t, J = 6.7 Hz), 2.62 (1H, dt, J = 15.9, 3.9 Hz),
2.79-2.87 (1H, m), 3.26 (1H, br s), 3.82 (6H, s), 4.07-4.17 (3H,
m), 5.00-5.04 (2H, m), 5.10 (1H, br s), 5.78-5.88 (1H, m), 6.57
(1H, s), 6.60 (1H, s); 13C NMR (CDCl3, 60 °C) δ 14.7, 28.1, 38.0,
41.3, 54.1, 56.1, 56.2, 61.2, 110.9, 112.2, 117.1, 126.4, 129.3,
(28) Lazar, L.; Fulop, F.; Bernath, G.; Mattinen, J. Org. Prep. Proced.
Int. 1993, 25, 91.
540 J. Org. Chem. Vol. 76, No. 2, 2011

Miyazaki et al.
JOCArticle
135.1, 147.8, 148.2, 155.7; HR-FAB MS calcd for C17H24NO4
[M þ H]þ 306.1705, found 306.1693.
product homolaudanosine as a colorless oil, which was further
purified with column chromatography (CH2Cl2/MeOH = 10)
(24.0 mg, 61%).
Transformation of the Allyl Adduct 11 to the Aldehyde 12. To a
solution of 11 (636.7 mg, 2.09 mmol) in acetone (10 mL) and
H2O (5 mL) was added OsO4 (1.9 mL, 4% aqueous solution,
0.31 mmol) and 4-methylmorpholine N-oxide (0.16 mL, 1.67 mmol)
at room temperature, and the mixture was allowed to stir for 2.3 h.
After addition of a 10% NaHSO3 aqueous solution (30 mL), the
reaction mixture was extracted with ethyl acetate and the
collected organic layer was dried over MgSO4 and the solvent
was removed in vacuo. Then NaIO4 (957 mg, 4.48 mmol) in H2O
(4 mL) was added into the residue dissolved in acetone (16 mL),
and the mixture was stirred for 2 h at room temperature.
Saturated NaCl aqueous solution (20 mL) was added into the
reaction mixture, which was extracted with ethyl acetate. The
collected organic layer was dried over MgSO4, and evaporated
off in vacuo. The resultant was purified by column chromatog-
raphy (EtOAc) to obtain 12 as a colorless solid (465.5 mg, 73%
in two steps).
Homolaudanosine (14):29 colorless oil; (S)-14 [R]18 þ10.5
D
(c 0.16, EtOH); 1H NMR (CDCl3, 60 °C) δ 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, J=5.4 Hz), 3.83 (3H, s), 3.851 (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, J=8.1 Hz); 13C NMR (CDCl3, 60 °C) δ 24.8,
31.1, 36.8, 42.4, 47.5, 55.71, 55.72, 55.81, 55.83, 62.4, 110.5,
111.2, 111.3, 111.8, 120.0, 126.3, 129.3, 135.2, 146.8, 147.21,
147.23, 148.7; HR-FAB MS calcd for C22H30NO4 [M þ H]þ
372.2175, found 372.2184.
The Protection of N-2 of Compound 4 with the Boc Group.
Compound 4 (997 mg, 4.3 mmol) and (Boc)2O (1.18 mL, 5.1
mmol) were dissolved in CH2Cl2 (30 mL) and the mixture was
stirred for 20 h under Ar at room temperature. The reaction was
quenched by addition of H2O (60 mL) and the aqueous solution
thus obtained was extracted with CH2Cl2 and the combined
organic layer was dried over MgSO4, filtered, and concentrated
in vacuo. The residue was purified by column chromatography
(hexane/EtOAc=4 to 2) to obtain the desired product 23 (1.39 g)
as a colorless oil in 97% yield.
tert-Butyl 1-allyl-6,8-dimethoxy-1,2,3,4-tetrahydroisoquino-
line-2-carboxylate (15): HPLC: CHIRALPAK IA, hexane:
CH2Cl2=10:1, 0.5 mL/min, retention times 23.9 and 25.2 min
(R)-15 (82% ee) [R]20D -53.8 (c 0.55, CHCl3); colorless oil; 1H
NMR (DMSO-d6, 100 °C) δ 1.40 (9H, s), 2.30-2.38 (1H, m),
2.45-2.52 (1H, m), 2.69-2.73 (2H, m), 3.21-3.28 (1H, m), 3.73
(3H, s), 3.79 (3H, s), 3.82-3.90 (1H, m), 4.91-5.01 (2H, m), 5.21
(1H, dd, J=8.9, 3.9 Hz), 5.72-5.82 (1H, m), 6.30 (1H, d, J=2.2
Hz), 6.40 (1H, d, J=2.2 Hz); 13C NMR (DMSO-d6, 100 °C) δ
27.4, 27.6, 37.9, 48.6, 54.7, 55.0, 78.1, 96.4, 104.7, 104.9, 115.3,
118.2, 135.2, 135.4, 153.5, 155.9, 158.5; HR-FAB MS calcd for
C19H28NO4 [M þ H]þ 334.2018, found 334.2034.
Ethyl 6,7-dimethoxy-1-(2-oxoethyl)-1,2,3,4-tetrahydroisoquin-
oline-2-carboxylate (12): colorless solid; (S)-12 (97% ee)
[R]18D þ55.3 (c 0.28, CHCl3); 1H NMR (CDCl3, 60 °C) δ 1.27
(3H, t, J=7.1 Hz), 2.67 (2H, dt, J=16.1, 4.0 Hz), 2.82-2.90
(3H, m), 3.28 (1H, br s), 3.83 (6H, s), 4.13-4.21 (3H, m), 5.63
(1H, br s), 6.62 (1H, s), 6.66 (1H, s), 9.83 (1H, t, J=2.6 Hz); 13
C
NMR (CDCl3, 60 °C) δ 14.4, 27.8, 38.2, 49.8, 51.0, 55.9, 56.0,
61.4, 110.1, 112.1, 126.3, 127.9, 148.1, 148.4, 155.2, 199.6; HR-
FAB MS calcd for C16H22NO5[M þ H]þ 308.1498, found
308.1501.
The Grignard Reaction to the Aldehyde 12. To Mg (145.9 mg, 6
mmol) in THF (2 mL) were added 4-bromoveratorole (0.87 mL,
6.05 mmol) and a small amout of I2 and the mixture was stirred
at 110 °C for 2 h under Ar. Thus prepared Grignard reagent
solution was cooled to 0 °C, the aldehyde 12 dissolved in THF
(2 mL) was added to the Grignard reagent solution, and the
mixture was allowed to stir for 18 h under Ar. Then 10% NH4Cl
aqueous solution was added to stop the reaction. The reaction
mixture was extracted with ethyl acetate, which was dried over
MgSO4, and removed in vacuo. The residue thus formed was
purified with column chromatography (CH2Cl2 to EtOAc) to
give the alcohol 13 (48.8 mg, 81%).
The Conversion of the Allyl Adduct 15 to the Aldehyde 16. To
the allyl adduct 15 (1.28 g, 3.8 mmol) dissolved in a mixture of
acetone (35 mL) and H2O (15 mL) were added NMO (50%
aqueous solution, 3.7 mL, 17.5 mmol) and OsO4 (4% aqueous
solution 1.1 mL, 0.18 mmol), and the mixture was allowed to stir
at room temperature for 1.5 h. Then the reaction was quenched
with 10% NaHSO3 aqueous solution (40 mL), and the resultant
solution was extracted with ethyl acetate. The combined organic
layer was dried over MgSO4, filtered, and concentrated in vacuo.
The residue thus obtained was dissolved in the mixture of acetone
(90 mL) and H2O (20 mL), and NaIO4 (1.9 g, 2.3 mmol) was
added at room temperature and the mixture was stirred for 12 h.
The reaction mixture was diluted with brine (100 mL) and
extracted with ethyl acetate. The combined organic layer was
dried over MgSO4, filterd, and concentrated in vacuo. The residue
thus formed was purified with column chromatography (EtOAc)
to give the aldehyde 16 as a yellow oil (1305 mg, quant).
Ethyl
1-[2-(3,4-dimethoxyphenyl)-2-hydroxyethyl]-6,7-di-
methoxy-1,2,3,4-tetrahydroisoquinoline-2-carboxylate (13): col-
orless oil; 1H NMR (CDCl3, 60 °C) δ 1,24-1,33 (4H, m),
2.08-2.13 (1H, m), 2.34 (1H, qui, J = 7.4 Hz), 2.66 (1H, dt,
J = 16.0, 4.4 Hz), 2.82-2.89 (1H, m), 3.28-3.34 (1H, m),
3.79-3.88 (12H, m), 4.09-4.27 (3H, m), 4.60-4.84 (1H, m),
5.21-5.41 (1H, m), 6.56-6.63 (2H, m), 6.78-7.00 (3H, m); 13
C
NMR (CDCl3, 60 °C) [those derived from a minor diastereomer
and/or a conformational isomer are shown in parentheses] δ
14.5 (14.6), 27.8 (28.0), 38.5 (38.3), 46.1 (46.5), 51.6 (51.3), 55.72
(55.66), 55.77 (55.82), 55.98 (56.0), 56.1 (56.2), 61.9 (61.4), 72.0
(69.2), 109.7 (110.3), 110.6 (110.7), 111.2 (111.4), 111.7 (112.0),
117.8 (118.0), 127.3 (125.5), 129.3 (129.7), 137.5 (136.7), 148.05
(147.8), 148.08 (148.11), 149.2 (149.3), 155.5 (155.9); HR-FAB
MS calcd for C24H32NO7 [M þ H]þ 446.2179, found 446.2170.
The Synthesis of Homolaudanosine (14). To compound 13
(47.0 mg, 0.11 mmol) dissolved in THF (3 mL) was added
pyridine (30 μL, 0.37 mmol) and thionyl chloride (25 μL, 0.34
mmol), and the mixture was stirred for 2.3 h at 0 °C under Ar.
Then LiAlH4 (63 mg, 1.66 mmol) was added, and the mixture
was warmed to 100 °C with stirring for 6.7 h. The reaction was
quenched with 10% HCl aqueous solution, and saturated aque-
ous sodium bicarbonate (20 mL) was added. Insoluble material
was filtered through a Celite pad, and the filtrate was extracted
with ethyl acetate. The Celite pad used was washed with hot
CHCl3, and the combined organic layers were dried over
MgSO4, filtered, and removed in vacuo to obtain the desired
tert-Butyl 6,8-dimethoxy-1-(2-oxoethyl)-1,2,3,4-tetrahydro-
isoquinoline-2-carboxylate (16): pale yellow oil; (R)-16 (82% ee)
[R]19D -68.0(c 1.03, CHCl3); 1H NMR(DMSO-d6, 100 °C) δ 1.41
(9H, s), 2.61 (1H, ddd, J=14.9, 8.5, 3.7 Hz), 2.67-2.80 (3H, m),
3.20-3.27 (1H, m), 3.74 (3H, s), 3.80 (3H, s), 3.88-3.91 (1H, m),
5.59 (1H, dd, J=8.4, 4.6 Hz), 6.34 (1H, d, J=2.2 Hz), 6.42 (1H, d,
J=2.2 Hz), 9.68 (1H, dd, J=2.7, 3.5 Hz); 13C NMR (DMSO-d6,
100 °C) δ 28.0, 28.1, 37.6, 45.6, 48.8, 55.4, 55.6, 79.5, 97.1, 105.7,
117.5, 136.1, 153.9, 156.2, 159.5, 200.3; HR-FAB MS calcd for
C18H26NO5 [M þ H]þ 336.1811, found 336.1818.
Horner-Wadsworth-Emmons Reaction of 16. To the alde-
hyde 16 (329.4 mg, 0.98 mmol) solution of acetonitrile (30 mL)
were added benzyloxycarbonyl-R-phosphonoglycine trimethyl
(29) Itoh, T.; Nagata, K.; Miyazaki, M.; Kameoka, K.; Ohsawa, A.
Tetrahedron 2001, 57, 8827.
J. Org. Chem. Vol. 76, No. 2, 2011 541

Miyazaki et al.
JOCArticle
ester (390 mg, 1.2 mmol) and tetramethylguanidine (185 μL,
1.5 mmol) at 10 °C. After stirring at room temperature for 2 h,
the reaction mixture was diluted with CH2Cl2, and washed by
10% citric acid aqueous solution, saturated aqueous sodium
bicarbonate solution, and brine, respectively. The resulting
organic layer was dried over MgSO4, filtered, and evaporated.
The residue was purified by column chromatography (hexane/
EtOAc=1) to obtain the dehydroamino acid 17 as a colorless
amorphous solid (501.2 mg, 95%).
hexane:i-PrOH=1:1, 0.5 mL/min, retention times 22.5 and 35.0
min (3S,11bR)-19a (98% ee) [R]20D þ198.6 (c 0.26, CHCl3); 1H
NMR (CDCl3) δ 1.26-1.38 (1H, m), 1.72-1.82 (1H, m), 2.36
(1H, br s), 2.47-2.54 (2H, m), 2.72-2.79 (1H, m), 2.88-2.91
(1H, m), 3.695 (3H, s), 3.702 (3H, s), 3.97-4.06 (1H, m),
4.62-4.64 (1H, m), 4.81-4.84 (1H, m), 5.03 (2H, d, J = 3.6
Hz), 5.81 (1H, br s), 6.17 (1H, s), 6.26 (1H, d, J = 2.4 Hz),
7.18-7.28 (5H, m); 13C NMR (CDCl3) δ 27.4, 27.8, 30.4, 39.4,
52.8, 55.1, 55.2, 55.9, 66.6, 97.1, 104.6, 117.6, 127.87, 127.92,
128.3, 136.4, 137.6, 156.5, 157.6, 159.0, 168.4; HR-FAB MS
calcd for C23H27N2O5 [M þ H]þ 411.1920, found 411.1942.
19b (yield 17%, 62% ee): mp. 55-59 °C; Rf 0.60 (silicagel,
EtOAc:hexane = 4:1); HPLC: CHIRALPAK AD-H, hexane:
i-PrOH = 1:1, 0.5 mL/min, retention times 20.9 and 25.2 min.
(3S,11bS)-19b (62% ee) [R]19D -117.0 (c 0.39, CHCl3); 1H NMR
(CDCl3) δ 1.19-1.38 (3H, m), 2.26-2.37 (1H, m), 2.50-2.74
(4H, m), 3.69 (3H, s), 3.72 (3H, s), 4.28-4.34 (1H, m), 4.57-4.64
(1H, m), 4.74 (1H, dd, J=11.0, 3.8 Hz), 5.04 (2H, d, J=5.2 Hz),
6.06 (1H, d, J=4.8 Hz), 6.20 (1H, d, J=2.0 Hz), 6.26 (1H, d, J=
2.4 Hz), 7.17-7.30 (5H, m); 13C NMR (CDCl3) δ 25.8, 28.5, 29.8,
39.1, 48.8, 50.4, 55.5, 55.6, 66.9, 97.2, 104.6, 116.9, 128.27, 128.31,
128.7, 136.8, 137.3, 156.3, 157.1, 159.7, 170.4; HR-FAB MS calcd
for C23H27N2O5 [M þ H]þ 411.1920, found 411.1895.
tert-Butyl 1-(3-benzyloxycarbonylamino-3-methoxycarbonylallyl)-
6,8-dimethoxy-3,4-dihydro-1H-isoquinoline-2-carboxylate (17):
colorless amorphous, mp 55-63 °C; (R)-17 (82% ee) [R]19
D
-42.2 (c 2.3, CHCl3); 1H NMR (DMSO-d6, 100 °C) δ 1.42 (9H,
s), 2.51-2.76 (4H, m), 3.17-3.20 (1H, m), 3.64 (3H, s), 3.75 (3H,
s), 3.77 (3H, s), 3.84 (1H, br s), 5.05 (2H, d, J = 2.9 Hz),
5.247-5.254 (1H, m), 6.33 (1H, d, J = 2.3 Hz), 6.41 (1H, d,
J=2.3 Hz), 6.52 (1H, t, J=6.9 Hz), 7.31-7.34 (5H, m), 8.23
(1H, br s); 13C NMR (DMSO-d6) [those derived from confor-
mational isomer are shown in parentheses] δ 27.4, 27.5, 31.9,
36.7, 48.0, 51.0, 54.8, 55.0, 65.3 (65.4), 78.62 (78.4 and 78.58),
96.4, 105.0, 117.6, 126.9, 127.1, 127.65, 127.72, 133.3, 135.5,
136.3, 153.7, 153.4, 155.9, 158.7, 164.1. Anal. Calcd for
C29H36N2O8: C, 64.43; H, 6.71; N, 5.18. Found: C, 64.15; H,
6.79; N, 5.19. HR-FAB MS calcd for C29H37N2O8 [M þ H]þ
541.2550, found 541.2595.
Elimination of the Cbz Group To Give the Isoquinoline Moiety
of Schulzeine. Compound 19a (207 mg, 0.5 mmol) and Pd-C (10
wt.% Pd/C, 79.5 mg, 0.075 mmol) were dissolved in MeOH (20
mL), then hydrogen gas was purged and the mixture was
allowed to stir at room temperature for 21 h. The reaction
mixture was filtered through a Celite pad and the filtrate was
concentrated in vacuo. The residue thus obtained was purified
by column chromatography (EtOAc/MeOH=10 to 2) to give
the desired amine 20a as a yellow oil (150.7 mg, quant). The same
procedure was applied to compound 19b (182 mg, 0.44 mmol) to
give amine 20b (129 mg, quant).
Reduction of 25 by the Use of MONOPHOS Ligand. Com-
pound 17 (161.8 mg, 0.33 mmol), (R)-MONOPHOS (23.5 mg,
0.073 mmol), and Rh(COD)2BF4 (12.2 mg, 0.033 mmol) were
dissolved in CH2Cl2 (7 mL). The reaction mixture was charged
with H2 gas at room temperature and stirred for 2 days. The
reaction mixture was adsorbed on the surface of silica gel and
sequentially purified by column chromatography (hexane/
EtOAc = 1) to give an amino acid derivative 18 as a colorless
amorphous solid (160.7 mg, 99%).
tert-Butyl 1-(3-benzyloxycarbonylamino-3-methoxycarbonyl-
propyl)-6,8-dimethoxy-1,2,3,4-tetrahydroisoquinoline-2-carbox-
ylate (18): colorless amorphous; 1H NMR (DMSO-d6, 100 °C) δ
1.41 (9H, s), 1.56-1.79 (4H, m), 2.63-2.77 (2H, m), 3.19-3.25
(1H, m), 3.62 (3H, s), 3.72 (3H, s), 3.74 (3H, d, J = 8.4 Hz),
3.80-3.90 (1H, m), 4.07-4.20 (1H, m), 5.03-5.04 (2H, m), 5.11
(1H, br s), 6.29 (1H, br s), 6.38 (1H, t, J=3.2 Hz), 7.25-7.34
(5H, m); 13C NMR (CDCl3) [those derived from a minor isomer
and/or a conformational isomer are shown in parentheses] δ
28.4, 28.7, 29.7 (29.4), 30.1 (30.3), 36.2 (36.1), 37.7 (37.5), 49.1,
49.7, 52.2, 54.6 (54.1), 55.3 (55.2), 66.9 (66.7), 79.6 (79.9), 96.4
(96.6), 104.2 (104.3), 119.4 (119.0), 128.1 (127.9), 128.5 (128.4),
135.7, 136.2 (136.7), 155.2 (154.8), 156.1 (155.8), 156.8 (156.6),
159.1, 173.0 (173.2); HR-FAB MS calcd for C29H39N2O8 [M þ
H]þ 543.2706, found 543.2706
The Ring Formation to Compound 19. To the solution of
compound 18 (1.34 g, 2.5 mmol) in CH2Cl2 (20 mL) was added
TMSOTf (0.45 mL, 2.5 mmol), and the mixture was allowed to
stand for 11 h under air. The reaction was quenched with MeOH (20
mL) and the solvent was removed in vacuo. The residue thus
obtained was dissolved in MeOH (20 mL), and 18-crown-6 (1.23
g, 4.7 mmol) and K2CO3 (0.34 g, 2.5 mmol) were added, then the
mixture was allowed to stir for 1 d under Ar. H2O (20 mL) and
saturated aqueous NaHCO3 solution (20 mL) were added to the
reaction mixture and the obtained aqueous solution was extracted
with CH2Cl2. After washed with brine, the organic layer was dried
over MgSO4, filtered, and concentrated in vacuo. The mixture of the
diastereomeric compounds was separated with column chromatog-
raphy (hexane/EtOAc=4 to 0.25) to obtain 19a (796 mg, 79%) and
19b (171.3 mg, 17%) as colorless amorphous solids, respectively.
Benzyl (9,11-dimethoxy-4-oxo-1,3,4,6,7,11b-hexahydro-2H-
pyrido[2,1-a]isoquinolin-3-yl)carbamate (19a, 19b): colorless
amorphous. 19a (yield 79%, 98% ee): mp 61-65 °C; Rf 0.49
(silica gel, EtOAc:hexane=4:1); HPLC: CHIRALPAK AD-H,
3-Amino-9,11-dimethoxy-1,2,3,6,7,11b-hexahydropyrido[2,1-a]-
isoquinolin-4-one (20a, 20b). 20a: 1H NMR (CD3OD) δ 1.43 (1H,
dddd, J=13.9, 12.5, 12.5, 2.6 Hz), 1.95 (1H, dddd, J=12.9, 12.9,
12.7, 2.5 Hz), 2.27-2.33 (1H, m), 2.62-2.69 (2H, m), 2.76-2.87
(1H, m), 3.03-3.09 (1H, m), 3.77 (3H, s), 3.74-3.83 (1H, m), 3.81
(3H, s), 4.78-4.85 (2H, m), 6.33 (1H, d, J=2.0 Hz), 6.43 (1H, d,
J = 2.0 Hz); 13C NMR (CD3OD) δ 27.0, 28.6, 31.1, 40.6, 52.2,
55.78, 55.80, 57.2, 98.2, 106.1, 117.9, 138.7, 159.0, 160.9, 168.3;
HR-FAB MS calcd for C15H21N2O3 [M þ H]þ 277.1552, found
277.1535.
20b: 1H NMR (CDCl3) δ 1.38-1.50 (1H, m), 1.66-1.77 (1H,
m), 2.38-2.49 (2H, m), 2.73-2.79 (3H, m), 3.78 (3H, s), 3.83
(3H, s), 4.04-4.09 (1H, m), 4.61-4.69 (1H, m), 4.86 (1H, dd, J=
3.2, 11.2 Hz), 6.37 (1H, d, J=2.0 Hz), 6.44 (1H, d, J=2.0); 13
C
NMR (CDCl3) δ 24.8, 28.8, 30.2, 40.1, 50.0, 50.8, 55.8, 55.9,
98.0, 105.8, 117.0, 138.3, 158.3, 161.1, 170.1; HR-FAB MS calcd
for C15H21N2O3 [M þ H]þ 277.1552, found 277.1574.
Acknowledgment. This work was supported by a “High-
Tech Research Center” Project for Private Universities:
matching fund subsidy from MEXT (Ministry of Education,
Culture, Sports, Science and Technology), and a Grant-in-
Aid for Scientific Research (C) from Japan Society for the
Promotion of Science. We thank Dr. Saito of Takasago
International Corporation for providing us with DTBM-
SEGPHOS and SEGPHOS, and Ms. K. Shiohara of Showa
University for measuring the HRMS spectra.
1
Supporting Information Available: H and 13C NMR spectra
for compounds 1-13, 15-16, and 18-20, and ORTEP drawing
of the X-ray crystal structure of compound 5a. This material is
available free of charge via the Internet at http://pubs.acs.org.
542 J. Org. Chem. Vol. 76, No. 2, 2011