Catalytic asymmetric synthesis of (R)-(-)-calycotomine, (S)-(-)-salsolidine and (S)-(-)-carnegine

Article abstract of DOI:10.1055/s-2006-941586

A simple and efficient procedure for a synthesis of isoquinoline alkaloids is described. The key step of the synthesis was a hydrocyanation of 6,7-dimethoxy-3,4-dihydroisoqunoline giving the corresponding 1-cyano-1,2,3,4-tetrahydroisoquinoline. The asymme

Full text of DOI:10.1055/s-2006-941586

LETTER
1595
Catalytic Asymmetric Synthesis of (R)-(–)-Calycotomine, (S)-(–)-Salsolidine
and (S)-(–)-Carnegine
Synthesis of
(
R
)
a
-(–)-Calyc
k
otomine,
(
S
)-
u
(
–)-Salsolidi
y
ne and
(
S
)-(–
a
)-Carnegine Kanemitsu, Yuki Yamashita, Kazuhiro Nagata, Takashi Itoh*
School of Pharmaceutical Sciences, Showa University, 1-5-8 Hatanodai, Shinagawa-ku, Tokyo 142-8555, Japan
Fax +81(3)37845982; E-mail: itoh-t@pharm.showa-u.ac.jp
Received 15 March 2006
In the synthetic study of isoquinoline alkaloids, we have
Abstract: A simple and efficient procedure for a synthesis of iso-
quinoline alkaloids is described. The key step of the synthesis was
a hydrocyanation of 6,7-dimethoxy-3,4-dihydroisoqunoline giving
the corresponding 1-cyano-1,2,3,4-tetrahydroisoquinoline. The
been interested in synthesis of optically active structure
using catalytic process, and found that the enantioselec-
tive allylation of 6,7-dimethoxy-3,4-dihydroisoquinoline
asymmetric Strecker reaction was accomplished in high yield and (1) at C-1 position proceeded smoothly by the Cu(I)-tol-
high enantiomeric excess using Jacobsen’s thiourea-containing
BNAP catalyst, and applied the reaction to the total syn-
thesis of (–)-emetine.9 In the process, it was thought that
catalyst. The 1-cyanoisoquinoline thus obtained was transformed
to natural products, (R)-(–)-calycotomine, (S)-(–)-salsolidine and
the introduction of an electrophilic carbon unit at C-1 po-
(S)-(–)-carnegine.
sition would be of immense use due to its applicability as
a reaction site of nucleophiles. Thus, we studied catalytic
Key words: isoquinoline alkaloid, asymmetric synthesis, Strecker
reaction, Jacobsen’s catalyst, calycotomine
addition of a carbon unit at C-1, and Jacobsen’s thiourea-
containing catalyst10 was found to be efficient for asym-
metric Strecker reaction to the substrate 1. The adduct
Tetrahydroisoquinoline alkaloids are often selected as
thus obtained was readily converted to three simple iso-
synthetic targets due to their various physiological activi-
quinoline alkaloids. This paper describes these results.
ties and structural properties,1 and some of them are rele-
vant to Parkinson’s and other neurotic diseases.2 Although
MeO
MeO
a
b
many of the most interesting isoquinolines have chiral 1-
substituted tetrahydroisoquinoline nuclei, there are no
general synthetic methods to obtain optically active deriv-
atives. The Pictet–Spengler3 and Bischler–Napieralski4
condensation are useful methods for the formation of iso-
quinoline ring systems, but there are only a few papers
that present a synthesis of 1-substituted tetrahydroiso-
quinoline in a highly enantioselective manner, and these
studies adopted chiral auxiliaries for constructing the
chiral structures.
N
CF3
N
MeO
MeO
CN
O
1
3
MeO
MeO
MeO
MeO
c
NH
NH
MeO
O
HO
O
4
5
Me
S
N
Me
N
N
Only recently, Ukaji and Inomata have succeeded in an
enantioselective addition of carbon unit into the C-1 posi-
tion of 6,7-dimethoxy-3,4-dihydroisoquinoline N-oxide
using external chiral auxiliary.5 In addition, there are a
few papers that mentioned catalytic asymmetric addition
of a carbon unit into the C-1 position. Firstly, Jørgensen et
al. reported aluminum–BINOL-complex-catalyzed enan-
tioselective 1,3-dipolar cycloaddition reaction of cyclic
nitrones with alkyl vinyl ethers, giving 1,2,3,4-tetra-
hydroisoquinolines.6 Then, Murahashi et al. revealed the
synthetic method of 1,2,3,4-tetrahydro-1-isoquinoline-
acetic acid derivatives by enantioselective addition reac-
tion of ketene silyl acetals to cyclic nitrones catalyzed by
titanium–BINOL complex.7 Recently, Chrzanowska et al.
showed a method of catalytic enantioselective addition of
organometallic compounds to the C-1 position of 6,7-
dimethoxy-3,4-dihydroisoquinoline.8
H
H
O
N
HO
O
O
Jacobsen's catalyst 2
Scheme 1 Reagents and conditions: (a) HCN (1.5 equiv), Jacob-
sen’s catalyst 2 (0.05 equiv), toluene, –70 °C, 40 h, then TFAA (4.0
equiv), –60 °C, 2 h, 86%, 95% ee; (b) H2SO4–H2O (1:1), r.t., 40 h;
(c) H2SO4–MeOH (1:5), reflux, 4 h, 72% (2 steps).
Recently, Jacobsen and co-workers described an asym-
metric Strecker reaction catalyzed by thiourea-containing
catalyst.10 Since the reaction was supposed to proceed via
syn-imines isomerized from corresponding anti-isomers
in the reaction mixture, cyclic imine 1 is thought to be a
good substrate for the reaction.
The substrate 1 was obtained from 2-(3,4-dimethoxy-
phenyl)ethylamine and hexamethylenetetramine accord-
ing to a literature procedure.11 The catalyst 2 was
synthesized according to Jacobsen’s procedure.10d Hydro-
SYNLETT 2006, No. 10, pp 1595–1597
Advanced online publication: 12.06.2006
DOI: 10.1055/s-2006-941586; Art ID: U02806ST
© Georg Thieme Verlag Stuttgart · New York
2
1
.0
6
.2
0
0
6

1596
T. Kanemitsu et al.
LETTER
MeO
MeO
cyanation of 6,7-dimethoxy-3,4-dihydroisoquinoline (1)
by adding of HCN solution slowly in the presence of 5
mol% of the thiourea-containing catalyst 2 followed by
protection by trifluoroacetyl group gave 1-cyano-6,7-
dimethoxy-2-trifluoroacetyl-1,2,3,4-tetrahydroisoquino-
line (3) in high yield (86%) and enantiomeric excess (95%
ee).12 Hydrolysis of the cyano group under acidic condi-
tions and subsequent esterification afforded methyl ester
5 (Scheme 1).
MeO
MeO
a
N
O
N
O
O
O
TsO
HO
9
7
MeO
MeO
MeO
MeO
c
b
NH
Me
N
O
O
Me
10
(S)-(–)-salsolidine (11)
The compound 5 was protected with Boc group, and the
ester group was reduced by lithium aluminum hydride to
give an alcohol 7 in high yield. The 1-hydoxymethyl iso-
quinoline 7 was treated with acidic conditions for depro-
tection of Boc group to obtain (R)-(–)-calycotomine (8,
Scheme 2). The absolute configuration of the product was
confirmed as R by comparison of the specific rotation
([a]D21 –37.9) with a reported value.13
MeO
MeO
d
NMe
Me
(S)-(–)-carnegine (12)
Scheme 3 Reagents and conditions: (a) TsCl (1.5 equiv), pyridine,
r.t., 10 h, 81%; (b) LiAlH4 (4 equiv), THF, 60 °C, 5 h, 56%; (c)
TMSOTf (2 equiv), CH2Cl2, r.t., 30 min, 86%; (d) HCHO aq (5
equiv), NaBH3CN (1.6 equiv), MeCN, r.t., 2 h, 87%.
MeO
MeO
MeO
b
N
O
O
a
NH
O
MeO
O
MeO
MeO
5
6
References and Notes
MeO
MeO
MeO
MeO
(1) (a) Rozwadowska, M. D. Heterocycles 1994, 39, 903.
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2004, 104, 3341. (c) Kaufman, T. S. Tetrahedron:
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D. Biochem. Pharmacol. 1998, 56, 921. (e) Sano, T. J.
Synth. Org. Chem. Jpn. 1999, 57, 136.
c
N
O
NH
O
HO
HO
7
(R)-(–)-calycotomine (8)
Scheme 2 Reagents and conditions: (a) (Boc)2O (2 equiv), CH2Cl2,
r.t., 30 min, 99%; (b) LiAlH4 (1 equiv), THF, r.t., 3 h, 99%; (c) TMS-
OTf (2 equiv), CH2Cl2, r.t., 30 min, 81%.
In order to synthesize (S)-(–)-salsolidine and (S)-(–)-car-
negine, compound 7 was tosylated to give compound 9,
which was treated with lithium aluminum hydride to give
the precursor of salsolidine. The compound 10 was de-
protected in acidic conditions to obtain (S)-(–)-salsolidine
(11).14 (S)-(–)-Salsolidine (11) was transformed to (S)-
(–)-carnegine (12) by N-methylation using formaldehyde
and NaBH3CN (Scheme 3).15
(3) (a) Chan, W. H.; Lee, A. W. M.; Jiang, L. Tetrahedron Lett.
1995, 36, 715. (b) Bravo, P.; Crucianelli, M.; Farina, A.;
Meille, S. V.; Volonterio, A.; Zanda, M. Eur. J. Org. Chem.
1998, 435. (c) Gremmen, C.; Wanner, M. J.; Koomen, G.-J.
Tetrahedron Lett. 2001, 42, 8885.
In this paper, we have presented an efficient enantioselec-
tive synthesis of three isoquinoline alkaloids. The key step
of the synthesis of (R)-(–)-calycotomine, (S)-(–)-sal-
solidine and (S)-(–)-carnegine is construction of an
optically active 1-cyano-6,7-dimethoxy-1,2,3,4-tetra-
hydroisoquinoline using Jacobsen’s thiourea-containing
catalyst. The product was readily transformed to these
alkaloids, which were identical with natural compounds in
terms of 1H NMR and 13C NMR spectral data.16 In addi-
tion, it is thought that the 1-cyano group is an electrophilic
site at which various nucleophiles are able to attack, and
the products thus obtained are good starting material for
other alkaloid syntheses. The application of the addition
product 3 to the synthesis of other isoquinoline alkaloids
is now in progress in our laboratory.
(4) (a) Polniaszek, R. P.; Kaufman, C. R. J. Am. Chem. Soc.
1989, 111, 4859. (b) Suzuki, H.; Aoyagi, S.; Kibayashi, C.
Tetrahedron Lett. 1995, 36, 6709. (c) Ziółkowski, M.;
Czarnocki, Z. Tetrahedron Lett. 2000, 41, 1963.
(5) (a) Ukaji, Y.; Shimizu, Y.; Kenmoku, Y.; Ahmed, A.;
Inomata, K. Chem. Lett. 1997, 59. (b) Ukaji, Y.; Shimizu,
Y.; Kenmoku, Y.; Ahmed, A.; Inomata, K. Bull. Chem. Soc.
Jpn. 2000, 73, 447. (c) Ukaji, Y.; Inomata, K. Synlett 2003,
1075.
(6) Jensen, K. B.; Roberson, M.; Jørgensen, K. N. J. Org. Chem.
2000, 65, 9080.
(7) Murahashi, S.-I.; Imada, Y.; Kawakami, T.; Harada, K.;
Yonemushi, Y.; Tomita, N. J. Am. Chem. Soc. 2002, 124,
2888.
(8) Chrzanowska, M. Tetrahedron: Asymmetry 2002, 13, 2497.
(9) Itoh, T.; Miyazaki, M.; Fukuoka, H.; Nagata, K.; Ohsawa, A.
Org. Lett. 2006, 8, 1295.
Synlett 2006, No. 10, 1595–1597 © Thieme Stuttgart · New York

LETTER
Synthesis of (R)-(–)-Calycotomine, (S)-(–)-Salsolidine and (S)-(–)-Carnegine
(13) Analytical Data for (R)-(–)-Calycotomine (8).
1597
(10) (a) Sigman, M. S.; Jacobsen, E. N. J. Am. Chem. Soc. 1998,
120, 4901. (b) Sigman, M. S.; Vachal, P.; Jacobsen, E. N.
Angew. Chem. Int. Ed. 2000, 39, 1279. (c) Vachal, P.;
Jacobsen, E. N. Org. Lett. 2000, 2, 867. (d) Vachal, P.;
Jacobsen, E. N. J. Am. Chem. Soc. 2002, 124, 10012.
(e) Wenzel, A. G.; Lalonde, M. P.; Jacobsen, E. N. Synlett
2003, 1919. (f) Gröger, H. Chem. Rev. 2003, 103, 2795.
(g) Takemoto, Y. Org. Biomol. Chem. 2005, 3, 4299.
(h) Taylor, M. S.; Jacobsen, E. N. Angew. Chem. Int. Ed.
2006, 45, 1520.
Colorless solid; mp 138 °C; [a]D21 –37.9 (c 0.13, H2O); lit.17
[a]D29 +33.7 (c 1.05, H2O); lit.18 [a]D25 +37.9 (c 0.2, H2O),
both of these values referred to the S enantiomer. 1H NMR
(CDCl3): d = 6.59 (s, 1 H), 6.58 (s, 1 H), 4.00 (dd, 1 H,
J = 4.1, 9.3 Hz), 3.850 (s, 3 H), 3.846 (s, 3 H), 3.77 (dd, 1 H,
J = 4.1, 10.7 Hz), 3.63 (dd, 1 H, J = 9.5, 10.7 Hz), 3.13–3.02
(m, 2 H), 2.76–2.63 (m, 2 H). 13C NMR (CDCl3): d = 147.82,
147.49, 127.49, 126.77, 111.96, 109.13, 63.98, 56.00, 55.97,
55.86, 38.70, 28.95. HRMS–FAB: m/z calcd for C12H18NO3:
224.1287 [M + H]+; found: 224.1294.
(11) Ivanov, I.; Venkov, A. Heterocycles 2001, 55, 1569.
(12) Synthesis of (R)-(+)-1-Cyano-6,7-dimethoxy-1,2,3,4-
tetrahydroisoquinoline (3).
(14) Analytical Data for (S)-(–)-Salsolidine (11).
Colorless oil; [a]D20 –57.9 (c 0.11, EtOH); lit.18 [a]D25 +59.5
(c 0.9, EtOH); lit.19 [a]D25 +54.0 (c 0.63, EtOH), both of
these values referred to the R enantiomer. 1H NMR (CDCl3):
d = 6.62 (s, 1 H), 6.58 (s, 1 H), 4.13 (q, 1 H, J = 6.8 Hz), 3.86
(s, 3 H), 3.85 (s, 3 H), 3.33–3.27 (m, 1 H), 3.06 (ddd, 1 H,
J = 4.9, 8.3, 13.2 Hz), 2.89–2.82 (m, 1 H), 2.75–2.68 (m, 1
H), 1.51 (d, 3 H, J = 6.8 Hz). 13C NMR (CDCl3): d = 148.16,
147.88, 127.53, 124.40, 111.38, 108.74, 55.94, 55.79, 50.32,
39.40, 26.34, 20.52. HRMS–FAB: m/z calcd for C12H18NO2:
208.1338 [M + H]+; found: 208.1359.
A 50 mL round-bottom flask equipped with a stir bar was
charged with 6,7-dimethoxy-3,4-dihydroisoquinoline (1,
190 mg, 0.994 mmol), the catalyst 2 (28 mg, 0.049 mmol,
0.05 equiv), and toluene (15 mL). The reaction was cooled
to –70 °C by means of a constant-temperature bath. In
another 30 mL flask equipped with a stir bar, 10 mL of
toluene and 200 mL of TMSCN (1.5 mmol, 1.5 equiv) were
combined. This solution was cooled to 0 °C and 60 mL of
MeOH (1.5 mmol, 1.5 equiv) were added. The solution was
allowed to stir for 2 h at 0 °C and then added to the reaction
flask by syringe addition over 20 h at –70 °C. The reaction
was allowed to stir for 40 h at –70 °C. To the reaction
mixture, an excess of TFAA (560 mL, 4.0 mmol, 4 equiv)
was added and the mixture was stirred for 2 h at –60 °C. The
reaction mixture was concentrated in vacuo. The residue was
purified by column chromatography with 40% EtOAc in
hexanes to afford 3 (269 mg, 86%) as colorless needles, mp
96 °C; [a]D18 +127.1 (c 1.05, CHCl3). HPLC: tR (S) = 16.7
min; tR (R) = 19.5 min [Chiralpak OD (0.46 cm × 25 cm,
Daicel Chemical Ind., Ltd.), hexane–i-PrOH, 90:10, 1.0 mL/
min] 95% ee. 1H NMR (CDCl3): d = 6.82 (s, 1 H), 6.67 (s, 1
H), 6.28 (s, 1 H), 4.24–4.20 (m, 1 H), 3.90 (s, 3 H), 3.88 (s,
3 H), 3.81–3.73 (m, 1 H), 3.07–2.99 (m, 1 H), 2.91–2.87 (m,
1 H). 13C NMR (CDCl3): d = 156.96 (q, J = 37.2 Hz), 149.85,
148.79, 125.18, 118.17, 116.47, 111.33, 109.17, 56.05,
55.92, 44.60, 41.72, 41.69, 27.79. Anal. Calcd for
C14H13F3N2O3: C, 53.51; H, 4.17; N, 8.91. Found: C, 53.62;
H, 3.96; N, 8.63.
(15) (S)-(–)-Carnegine (12).
Colorless oil. [a]D20 –47.8 (c 0.10, EtOH); lit.20 [a]D25 –51.5
(c 1.70, EtOH). 1H NMR (CDCl3): d = 6.59 (s, 1 H), 6.57 (s,
1 H), 3.848 (s, 3 H), 3.845 (s, 3 H), 3.57 (q, 1 H, J = 6.6 Hz),
3.04 (ddd, 1 H, J = 4.9, 6.6, 11.7 Hz), 2.85–2.72 (m, 2 H),
2.65 (ddd, 1 H, J = 4.9, 7.1, 12.0 Hz). 2.49 (s, 3 H), 1.39 (d,
3 H, J = 6.6 Hz). 13C NMR (CDCl3): d = 147.28, 147.23,
131.38, 125.77, 111.17, 109.86, 58.66, 55.94, 55.78, 48.80,
42.80, 27.37, 19.73. HRMS–FAB: m/z calcd for C13H20NO2:
222.1494 [M + H]+; found: 222.1502.
(16) Menachery, M. D.; Lavanier, G. L.; Wetherly, M. L.;
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Synlett 2006, No. 10, 1595–1597 © Thieme Stuttgart · New York