An approach to the synthesis of tetrahydroisoquinoline alkaloids by alkene hydroamination: Synthesis of coralydine

Article abstract of DOI:10.1055/s-0033-1339375

The protoberberine alkaloid coralydine was synthesized in a short sequence by a strategy including an intramolecular alkene hydroamination as the key step, followed by a Pictet-Spengler cyclization. Georg Thieme Verlag Stuttgart · New York.

Full text of DOI:10.1055/s-0033-1339375

LETTER
▌1805
lAettner Approach to the Synthesis of Tetrahydroisoquinoline Alkaloids by Alkene
Hydroamination: Synthesis of Coralydine
Synthesis of Coralydine
Annie Pouilhès, Jean-Pierre Baltaze, Cyrille Kouklovsky*
Institut de Chimie Moléculaire et des Matériaux d’Orsay (UMR CNRS n°8182), Bâtiment 410, Université de Paris-Sud, 91405 Orsay, France
Fax +33(1)69154679; E-mail: cyrille.kouklovsky@u-psud.fr
Received: 11.06.2013; Accepted after revision: 15.06.2013
Dedicated to the memory of Professor Jean-Louis Namy
struction of nitrogen heterocycles.5 Although the reaction
Abstract: The protoberberine alkaloid coralydine was synthesized
may be performed under a variety of condition (neutral,
in a short sequence by a strategy including an intramolecular alkene
cationic, anionic or radical), recent advances have focused
hydroamination as the key step, followed by a Pictet–Spengler
on metal-mediated hydroamination reactions (alkali met-
als,6 transition metals7 or lanthanides8). Moreover, the de-
velopment of enantioselective methods has allowed the
access to enantioenriched nitrogen heterocycles. Indeed,
the intramolecular alkene hydroamination may provide an
alternative approach to the synthesis of tetrahydroisoquin-
oline framework starting from o-alkenyl catecholamines
(Scheme 1).
cyclization.
Key words: alkaloids, total synthesis, nitrogen, heterocycles
The tetrahydroisoquinoline motif is one of the most im-
portant frameworks in natural products. Indeed, tetra-
hydroisoquinoline alkaloids are a very important family
of compounds which display various biological proper-
ties, and are precursors to other families of alkaloids.1 A
particular subclass of this family is the protoberberine al-
kaloids:2 representative natural products of this family are
berberine (1), the tetrahydroprotoberberine alkaloid cor-
alydine (2)3 and its epimer O-methylcorytenchirine (3;
Figure 1).
MeO
MeO
NH2
NH2
MeO
MeO
OMe
OMe
CHO
OMe
OMe
H+
NH
Pictet–Spengler
MeO
hydroamination
R
tetrahydroisoquinoline
MeO
MeO
O
O
NH
MeO
R2
R1
N
N
OMe
OMe
H
OMe
OMe
OMe
coralydine (2)
OMe
coralydine (2) R1 = Me, R2 = H
O-methylcorytenchirine (3) R1 = H, R2 = Me.
berberine (1)
Scheme 1 Strategies for the synthesis of tetrahydroisoquinoline al-
kaloids
Figure 1 Tetrahydroisoquinoline framework and representative pro-
toberberine alkaloids
The hydroamination approach to tetrahydroisoquinolines
has been already investigated9 and has culminated in the
recent enantioselective synthesis of the tetrahydroisoquin-
oline alkaloid laudanosine 6 by n-butyllithium-mediated
asymmetric hydroamination in the presence of a bisoxa-
zoline ligand 510 (Scheme 2).
Due to the high importance of tetrahydroisoquinoline al-
kaloids, numerous methods for their synthesis have been
reported, including the biogenetically inspired Pictet–
Spengler cyclization.4 These strategies are also adapted to
the synthesis of various protoberberine alkaloids.
In our ongoing studies concerning the hydroamination re-
action and its synthetic applications,11 we evaluated the
possibility of accessing berberine alkaloids such as cor-
alydine (2).12 This strategy involves an intramolecular hy-
droamination with a primary amine followed by a Pictet–
Spengler reaction.
In the recent years, the intramolecular alkene hydroamina-
tion reaction has emerged as a powerful tool for the con-
SYNLETT 2013, 24, 1805–1808
Advanced online publication: 01.08.2013
0
9
3
6
-
5
2
1
4
1
4
3
7
-
2
1
0
X
DOI: 10.1055/s-0033-1339375; Art ID: ST-2013-D0541-L
© Georg Thieme Verlag Stuttgart · New York

1806
A. Pouilhès et al.
LETTER
formed with secondary amines bearing either alkyl or
electron-withdrawing substituents. In fact, the formation
of six-membered rings by hydroamination from primary
amines remains a challenge.5
BuLi, i-Pr2NH
O
O
N
N
The results are presented in Table 1. Standard conditions
(n-BuLi, THF) failed to give the tetrahydroisoquinoline
13, with the starting material being recovered. Changing
to a less polar solvent such as benzene and raising the tem-
perature to 120 °C (sealed tube) afforded the target prod-
uct, albeit in a low yield (Table 1, entry 2). Surprisingly,
the addition of the chiral bisoxazoline 5 (Box) completely
inhibited the reaction.13
MeO
MeO
5
NHMe
OMe
toluene, –30 °C
96%
OMe
MeO
4
NMe
MeO
Better results were obtained using lithium bistrimethylsi-
lylamide (LiHMDS) as the base, provided that an additive
such as TMEDA was added. Indeed, the best results were
obtained adding two aliquots of base (0.5 equiv each) and
of TMEDA (1 equiv each) at 120 °C in benzene; under
these conditions an appreciable yield of 52% was ob-
tained. In contrast with the BuLi-mediated reaction, the
addition of a bisoxazoline ligand did not inhibit the reac-
tion but a racemic product was obtained, thus demonstrat-
ing that no coordination between the lithium salt and the
chiral ligand was involved.
OMe
OMe
6
76% ee
Scheme 2 Asymmetric synthesis of laudanosine (6) by intramolecu-
lar alkene hydroamination10
The hydroamination precursor 12 was prepared according
to Scheme 3. Heck reaction between 2-bromo-4,5-dime-
thoxybenzaldehyde (9) and 3,4-dimethoxystyrene (8)
[obtained from commercially available 3,4-dimethoxy-
benzaldehyde (7)] gave the stilbene derivative 10. The
aminoethyl chain was installed by Henry reaction fol-
lowed by reduction to give 12.
These results proved that the behavior of primary amines
in the lithium base promoted hydroamination is complete-
ly different from that of the secondary amines such as N-
methyl or N-benzyl derivatives; the reaction is more slug-
gish, higher temperatures are required and no chiral in-
duction was observed using traditional bisoxazoline
ligands.
With the precursor 12 in hand, the key hydroamination re-
action was investigated. Generally, the nature of nitrogen
substituents has a lot of influence on the course of the re-
action; indeed most of hydroamination reactions are per-
MeO
CHO
Br
MeO
MeO
MeO
CHO
9
O
Pd(OAc)2
K3PO4, DMAC
Ph3P=CH2
H2O–dioxane
OMe
OMe
OMe
H
10
73%
OMe
OMe
74%
OMe
8
7
MeO
NO2
MeO
MeO
MeNO2
NH4OAc
LiAlH4
Et2O
NH2
MeO
99%
OMe
82%
OMe
OMe
11
12
OMe
MeO
MeO
MeO
MeCH(OMe)2
H3PO4, 4 Å MS
toluene, 70 %
N
Me
N
Me
NH
MeO
H
see Table 1
MeO
MeO
+
H
OMe
61%
13
2
3
OMe
OMe
OMe
OMe
OMe
2/3 = 1:1
Scheme 3 Synthesis of coralydine (2) and its epimer O-methylcorytenchirine (3)
Synlett 2013, 24, 1805–1808
© Georg Thieme Verlag Stuttgart · New York

LETTER
Synthesis of Coralydine
1807
Table 1 Hydroamination of Compound 12
Entry Conditions
Temp
Time
Yield
no reaction
1
2
3
4
5
BuLi (0.2 equiv), THF
r.t.
15 h
BuLi (0.5 equiv), C6H6
120 °C
120 °C
120 °C
120 °C
48 h
28%
BuLi (0.5 equiv), Box (0.5 equiv), C6H6
LiHMDS (0.5 equiv), C6H6
24 h
no reaction
no reaction
24 h
LiHMDS (0.5 equiv + 0.5 equiv), TMEDA (1 equiv + 1 equiv), C6H6
1 h + 4 h
52%
(68% brsm)
6
LiHMDS (0.5 equiv + 0.5 equiv), TMEDA (1 equiv + 1 equiv), Box (0.5 equiv), C6H6
120 °C
1 h + 3 h
51%a
a Racemic product was obtained.
(5) For recent reviews, see: (a) Majumdar, K. C.; Debnath, P.;
De , N.; Roy, B. Curr. Org. Chem. 2011, 15, 1760.
(b) Chemler, S. R. Org. Biomol. Chem. 2009, 7, 3009.
(c) Müller, T. E.; Hultzsch, K. C.; Yus, M.; Foubelo, F.;
Tada, M. Chem. Rev. 2008, 108, 3795. (d) Aillaud, I.; Collin,
J.; Hannedouche, J.; Schulz, E. Dalton Trans. 2007, 5105.
(e) See also: Smith, A. R.; Lovick, H. M.; Livinghouse, T.
Tetrahedron Lett. 2012, 53, 6358; and references cited
therein.
(6) (a) Deschamp, J.; Collin, J.; Hannedouche, J.; Schulz, E.
Eur. J. Org. Chem. 2011, 3329. (b) Martinez, P. H.;
Hultzsch, K. C.; Hampel, F. Chem. Commun. 2006, 2221.
(7) Hesp, K. D.; Stradiotto, M. ChemCatChem 2010, 2, 1192.
(8) Zi, G. Dalton Trans. 2009, 9191.
The final step in the synthesis of coralydine is the Pictet–
Spengler reaction; although the use of acetaldehyde under
acidic conditions led to low yields and conversions, better
results were obtained using acetaldehyde dimethyl acetal
in the presence of orthophosphoric acid in toluene to give
synthetic coralydine (2) together with its epimer O-meth-
ylcorytenchirine (3; 61% combined yield) in a 1:1 ratio.
The diastereomers could be easily separated and assigned
1
by H NMR. The spectroscopic data were in full agree-
ment with those reported in literature.3,12 Coralydine (2)
was thus synthesized in six steps from commercially
available starting material in 14% overall yield.14
(9) (a) Henderson, L.; Knight, D. W.; Williams, A. C.
Tetrahedron Lett. 2012, 53, 4657. (b) Tsuchida, S.;
Kanegishe, A.; Ogata, T.; Baba, H.; Yamamoto, Y.;
Tomioka, K. Org. Lett. 2008, 10, 3635. (c) Otterlo, W. A. L.;
Pathak, R.; Koning, C. B.; Fernandes, M. A. Tetrahedron
Lett. 2004, 45, 9561.
(10) Ogata, T.; Kimachi, T.; Yamada, K.-I.; Yamamoto, Y.;
Tomioka, K. Heterocycles 2012, 86, 469.
(11) Queffelec, C.; Boeda, F.; Pouilhès, A.; Meddour, A.;
Kouklovsky, C.; Hannedouche, J.; Collin, J.; Schulz, E.
ChemCatChem 2011, 3, 122.
In conclusion, we have shown that the hydroamination re-
action provides an efficient alternative access to protober-
berine alkaloids via tetrahydroisoquinoline intermediates.
Although the hydroamination of primary amines still
needs to be optimized, it may be used for the synthesis of
various alkaloid families. Further applications of hy-
droamination reactions as well as the investigation of pri-
mary amines behavior in hydroamination reactions are
currently underway in our laboratory.
(12) For the synthesis of coralydine, see: (a) Chaumontet, M.;
Piccardi, R.; Baudoin, O. Angew. Chem. Int. Ed. 2009, 48,
179. (b) Szawkalo, J.; Czarnocki, Z. Monatsh. Chem. 2005,
136, 1619. (c) Orito, K.; Miyazawa, M.; Kanbayashi, R.;
Tatsuzawa, T.; Tokuda, M.; Suginome, H. J. Org. Chem.
2000, 65, 7495. (d) Sotomayor, N.; Dominguez, E.; Lete, E.
J. Org. Chem. 1996, 61, 4062. (e) Czarnocki, Z.; McLean,
D. B.; Szarek, W. A. Bull. Soc. Chim. Belg. 1986, 95, 749.
(13) The use of other chiral bisoxazoline ligands gave similar
results.
Acknowledgment
This research was supported by CNRS and the Université de Paris-
Sud. We are grateful to Drs. E. Schulz and J. Hannedouche (Univer-
sité de Paris-Sud, France) for helpful discussions.
Supporting Information for this article is available online at
http://www.thieme-connect.com/ejournals/toc/synlett.SnoIufproig
m
iotSrat
ungIifoop
r
t
(14) Synthesis of Coralydine (2) and O-Methylcorytenchirine
(3): To a solution of compound 13 (52 mg, 0.15 mmol) in
toluene (3 mL) were added at r.t. 4 Å molecular sieves (200
mg) and orthophosphoric acid (50 mg). The solution was
stirred for 5 min at r.t. and 1,1-dimethoxyethane was added
(0.2 mL). After 4 h at 70 °C, the solution was cooled, filtered
and evaporated to dryness. The residue was dissolved in
CH2Cl2 (20 mL) and neutralized with an aq 10% Na2CO3
solution (20 mL). The organic layer was dried (Na2SO4),
filtered and concentrated in vacuo. The residue was purified
by chromatography (20% EtOAc–Et2O) to give 2 (17 mg)
and 3 (17 mg) as colorless oils that solidify on standing
(combined yield: 61%). Data for coralydine (2; natural
product numbering): Rf 0.55 (20% EtOAc–Et2O). 1H NMR
References and Notes
(1) Bentley, K. W. Nat. Prod. Rep. 2006, 23, 444.
(2) Da-Cunha, E. V. L.; Fechine, I. M.; Guedes, D. N.; Barbosa-
Filho, J. M.; Da Silva, M. S. Alkaloids Chem. Biol. 2005, 62,
1.
(3) For isolation and structure determination, see: (a) Bruderer,
H.; Metzeger, J.; Brossi, A.; Daly, J. J. Helv. Chim. Acta
1976, 59, 2793. (b) Lu, S.-T.; Su, T.-L.; Kametani, T.; Ujiie,
A.; Ihara, M.; Kukumoto, K. Heterocycles 1975, 3, 459.
(4) Chrzanowska, M.; Rozwadowska, M. D. Chem. Rev. 2004,
104, 3341.
© Georg Thieme Verlag Stuttgart · New York
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1808
A. Pouilhès et al.
LETTER
(400 MHz, CDCl3): δ = 1.51 (d, J= 6.3 Hz, 3 H, C19-H),
2.40–2.46 (m, 1 H, C6-Ha), 2.66–2.70 (m, 1 H, C5-Ha), 2.84
(m, 1 H, C13-Hb), 3.09 (dd, J1,13a= 16 Hz, J13a,13b= 2.5 Hz, 1
H, C13-Ha), 3.11 (m, 1 H, C5-Hb), 3.35 (m, 1 H, C6-Hb),
3.66–3.69 (m, 2 H, C8-H, C18-H), 3.83 (s, 3 H, OMe), 3.84
(s, 6 H, 2 × OMe), 3.85 (s, 3 H, OMe), 6.60 (s, 1 H, C4-H),
6.63 (s, 1 H, C12-H), 6.66 (s, 1 H, C9-H), 6.73 (s, 1 H, C1-
H). 13C NMR (100 MHz, CDCl3): δ = 22.2 (C19), 29.9 (C5),
36.8 (C13), 47.3 (C6), 56.0 (OMe), 56.3 (OMe), 59.2, 59.5
(C8, C18), 109.1 (C1), 109.8 (C9), 111.3, 111.5 (C4, C12),
127.0, 127.2 (C15, C20), 130.7 (C14), 131.6 (C21), 147.6,
147.7 (C2, C3, C10, C11). HRMS (ESI+): m/z [M + H]+
+
calcd for [C22H28NO4 ]: 370.2013; found: 370.2016. Data
for O-methylcorytenchirine (3): see Supporting Information.
Synlett 2013, 24, 1805–1808
© Georg Thieme Verlag Stuttgart · New York