Total Synthesis of (-)-Melanthioidine by Copper-Mediated Cyclodimerization

Article abstract of DOI:10.1021/acs.orglett.6b01496

An efficient asymmetric total synthesis of the dimeric macrocyclic diaryl ether phenethyltetrahydroisoquinoline alkaloid (-)-melanthiodine is reported. Key steps of the synthesis include an efficient Noyori asymmetric transfer hydrogenation to access the enantioenriched phenethyltetrahydroisoquinoline monomeric subunit and a copper-mediated cyclodimerization to form the two diaryl ether linkages with concomitant macrocyclization.

Full text of DOI:10.1021/acs.orglett.6b01496

Letter
pubs.acs.org/OrgLett
Total Synthesis of (−)-Melanthioidine by Copper-Mediated
Cyclodimerization
Jianjun Wang and Gwilherm Evano*
Laboratoire de Chimie Organique, Service de Chimie et PhysicoChimie Organiques, Universite
D. Roosevelt 50, CP160/06, 1050 Brussels, Belgium
́
libre de Bruxelles (ULB), Avenue F.
S
* Supporting Information
ABSTRACT: An efficient asymmetric total synthesis of the dimeric macrocyclic diaryl ether
phenethyltetrahydroisoquinoline alkaloid (−)-melanthiodine is reported. Key steps of the
synthesis include an efficient Noyori asymmetric transfer hydrogenation to access the
enantioenriched phenethyltetrahydroisoquinoline monomeric subunit and a copper-
mediated cyclodimerization to form the two diaryl ether linkages with concomitant
macrocyclization.
Scheme 1. Retrosynthetic Analysis of (−)-Melanthioidine
imeric macrocyclic diaryl ether tetrahydroisoquinoline
Dalkaloids, whose general structure can be depicted such as
1 (head-to-tail dimers) or 2 (head-to-head dimers) (Figure 1),
represent a large family of natural products that have been
isolated from the leaves, roots, barks, and corms of a variety of
plants throughout the world. From a structural point of view,
they can be classified according to the nature of the monomeric
tetrahydroisoquinoline subunit, which is in most cases a benzyl
(1 and 2, n = 1) and, more rarely, a phenethyl (1, n = 2)
derivative, and to the symmetry of the macrocycle which can be
composed of two identical tetrahydroisoquinolines or not.1,2 In
addition to their interesting structures, they have been shown to
possess a range of biological activities including antitumor,3 anti-
inflammatory,4 antihypertensive,5 antiplasmodial,6 antimalarial,7
and antileishmanial2a,8 properties, just to mention a few, and
were also shown to be potent molecules for the treatment of
major diseases such as HIV9 and Ebola.10
this was taken into consideration, mostly by using a double
Ullmann condensation reaction, the synthesis was hampered by
the preparation of the enantio-enriched tetrahydroisoquinoline
monomer which was usually based on a resolution step.12
Based on our long-standing interest in the use of copper-
mediated cyclization reactions in natural product synthesis,13,14
we became interested in this family of natural products and chose
(−)-melanthioidine 3 (Figure 1) as a target. The bisphenethyl-
The interesting topology of these natural products coupled
with their biological activities prompted immediate interest from
the synthetic community, especially in the symmetrical dimeric
series. However, most syntheses reported to date did not profit
from the symmetrical nature of the target, which resulted in
lengthy routes as well as reduced overall efficiencies.11 Whenever
tetrahydroisoquinoline alkaloid was isolated in 1962 by the
15
̌
Santavy group from the leaves and corms of Androcymbium
́
melanthioides, a perennial flowering plant which grows in
Southern and Eastern Africa that is extensively used in folk
medicine for the treatment of many diseases. Its structure was
12a
̌
elucidated in 1967 by the Santavy and Battersby groups. To
́
date, two syntheses of this natural product were reported, both
based on a copper-catalyzed dimerization of a suitably function-
alized phenethyltetrahydroisoquinoline possessing both a phenol
and an aromatic bromide, the macrocyclization performing with
little (4%)12b or moderate (30%)12a efficiency. While demon-
strating the feasibility of this strategy, the efficiency of these
Figure 1. General structure of dimeric macrocyclic diaryl ether
tetrahydroisoquinoline alkaloids 1 (head-to-tail) and 2 (head-to-head)
and structure of melanthioidine 3.
Received: May 24, 2016
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.6b01496
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
enriched phenethyltetrahydroisoquinoline 4 possessing an
aromatic bromide and a free phenol required for such a step in
which both the macrocycle and the two diaryl ethers17 of the
target molecule would be formed in a single operation (Scheme
1). As for the tetrahydroisoquinoline 4, it could be obtained in a
straightforward and stereocontrolled manner using a Bieschler−
Napieralski/Noyori asymmetric hydrogenation18 sequence
starting from suitably functionalized amide 5.
Scheme 2. Synthesis of the Starting Dihydroisoquinoline/
Dihydroisoquinolinium
Our synthesis started with the preparation of amide 5 in order
to test the Bieschler−Napieralski/Noyori asymmetric hydro-
genation sequence. This amide was readily prepared by an EDC/
HOBt-mediated coupling of homobenzylic amine 7 and acid 9,
these substrates being prepared from vanillin19 and 3-(4-
hydroxyphenyl)propionic acid,12b respectively, using basic
modifications of previously reported procedures (Scheme 2).
Upon treatment with phosphorus oxychloride in refluxing
toluene, a smooth Bieschler−Napieralski cyclization occurred,
affording the desired sensitive dihydroisoquinoline 10 which,
after further reaction with iodomethane, was converted to the
corresponding dihydroisoquinolinium iodide 11, both com-
pounds being potential substrates for the asymmetric transfer
hydrogenation reaction.20
Having in hand an efficient synthesis of dihydroisoquinoline
derivatives 10 and 11, this indeed set the stage for the study of
their asymmetric transfer hydrogenation (Table 1). We initially
focused our efforts on the reduction of cyclic iminium ion 11: its
reduction under standard conditions using 3 mol % of catalyst
[Ru*]-a and a mixture of formic acid and triethylamine as the
reducing agent being totally inefficient (Table 1, entry 1), we
then switched to the use of sodium formate as the reductant in
water in combination with cetyltrimethylammonium bromide
(CTAB) as the surfactant at room temperature.20a While we were
pleased to note that the desired phenethyltetrahydroisoquinoline
syntheses was however limited by either the resolution of the
phenethyltetrahydroisoquinoline12a or the tedious separation of
the diastereoisomeric macrocycles when such a step was not
performed.12b
We therefore wondered if an efficient asymmetric total
synthesis of (−)-melanthioidine could be designed based on a
copper-mediated cyclodimerization16 starting from enantio-
Table 1. Optimization of the Asymmetric Transfer Hydrogenation Reaction of Dihydroisoquinoline 10/Dihydroisoquinolinium
Ion 11
entry
substrate
[Ru*]cat.
conditions
product
yield (%)
ee (%)
1
11
11
11
11
11
11
11
11
11
11
11
10
10
10
[Ru*]-a (3 mol %)
[Ru*]-a (3 mol %)
[Ru*]-a (3 mol %)
[Ru*]-a (3 mol %)
[Ru*]-a (15 mol %)
[Ru*]-b (15 mol %)
[Ru*]-c (15 mol %)
[Ru*]-d (15 mol %)
[Ru*]-a (15 mol %)
[Ru*]-b (15 mol %)
[Ru*]-c (15 mol %)
[Ru*]-a (15 mol %)
[Ru*]-a (15 mol %)
[Ru*]-a (15 mol %)
HCO2H/Et3N (5:2), CH3CN, rt, 24 h
HCO2Na, CTAB, H2O, rt, 24 h
13
13
13
13
13
13
13
13
13
13
13
12
12
12
−
−
2
54
54
50
61
40
51
10
78
84
97
−
40
45
70
63
87
71
0
3
HCO2Na, CTAB, AgSbF6 (4 mol %), H2O, rt, 24 h
HCO2Na, CTAB, H2O, 0 °C, 24 h
HCO2Na, CTAB, H2O, 0 °C, 7 h
HCO2Na, CTAB, H2O, 0 °C, 7 h
HCO2Na, CTAB, H2O, 0 °C, 7 h
HCO2Na, CTAB, H2O, 0 °C, 30 h
HCO2Na, CTAB, H2O, 40 °C, 7 h
HCO2Na, CTAB, H2O, 40 °C, 7 h
HCO2Na, CTAB, H2O, 40 °C, 7 h
HCO2H/Et3N (5:2), CH3CN, rt, 24 h
HCO2H/Et3N (5:2), CH2Cl2, rt, 24 h
HCO2H/Et3N (5:2), DMF, rt, 24 h
4
5
6
7
b20b
8
9
0
10
11
12
13
14
0
0
−
−
91
−
95
a
b
Isolated as its hydrochloride after treatment with anhydrous HCl in diethyl ether. In situ generated from [RuCl2(p-cymeme)]2 and the
corresponding chiral ligand.
B
DOI: 10.1021/acs.orglett.6b01496
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
Further methylation by reductive amination of 12 and
subsequent cleavage of the acetate provided the properly
substituted phenethyltetrahydroisoquinoline 4 possessing both
the aromatic bromide and the phenol required for the
cyclodimerization step (Table 2).
Table 2. Optimization of the Copper-Mediated
Cyclodimerization and Completion of the Synthesis
With an efficient enantioselective synthesis of monomeric
precursor 4 in hand, we next moved to the crucial copper-
mediated cyclodimerization step. Among all systems available for
the formation of diaryl ethers mediated by copper complexes,27
we first focused our efforts on catalytic systems (Table 2, entries
1−4). While we could detect minor amounts (8%) of the desired
macrocyclic dimer 14 using the combination of Cu(OTf)2·C6H6
and cesium carbonate in pyridine used in Cuny’s total synthesis
of verbanachalcone,22 all other catalytic systems tested based on
the use of a copper(I) halide in combination with picolinic acid,23
N-benzyl-N′-(5-methyl-[1,1′-biphenyl]-2-yl)oxalamide,24 or
2,2,6,6-tetramethylheptane-3,5-dione (TMHD)25 failed to pro-
mote the cyclodimerization or only afforded a byproduct
resulting from the reduction of the starting aromatic bromide.
Switching to stoichiometric amounts of the copper complex
turned out to be much more efficient, the concentration of the
reaction mixture being crucial for the reaction to occur. Indeed,
while the use of 1 equiv of copper(I) chloride in combination
with 2 equiv of TMHD in pyridine at 0.16 M afforded the target
macrocycle, although in a low yield (10%, Table 2, entry 5),
diluting the reaction mixture to 0.02 M to avoid problems
associated with oligomerization completely inhibited the
reaction (Table 2, entry 6).
yield
14
entry
1
conditions
(%)
Cu(OTf)2·C6H6 (0.1 equiv), Cs2CO3 (1.1 equiv), pyridine
8
(0.16 M), 110 °C, 24 h22
2
3
CuBr (0.1 equiv), picolinic acid (0.2 equiv), Cs2CO3
−
−
(2.0 equiv), DMSO (0.16 M), 90 °C, 24 h23
CuI (0.1 equiv), N-benzyl-N′-(5-methyl-[1,1′-biphenyl]-2-yl)
oxalamide (0.2 equiv), K3PO4 (1.5 equiv), DMSO (0.16 M),
120 °C, 48 h24
4
CuCl (0.2 equiv), TMHD (0.4 equiv), Cs2CO3 (1 equiv),
−
pyridine (0.16 M), 150 °C, 24 h25
A brief screening of other copper complexes revealed that the
5
CuCl (1 equiv), TMHD (2 equiv), Cs2CO3 (3 equiv), pyridine
10
−
12a
(0.16 M), 120 °C, 24 h
̌
system used in the Santavy and Battersby synthesis was far
́
6
CuCl (1 equiv), TMHD (2 equiv), Cs2CO3 (3 equiv), pyridine
(0.02 M), 120 °C, 24 h
from optimal and only gave 15% of O,O-dibenzylmelanthioidine
14 (Table 2, entry 7), which is in sharp contrast with the yield
initially reported by the authors. A slightly superior result was
obtained when switching to copper(II) oxide in pyridine, a
system used for the synthesis of a variety of naturally occurring
diaryl ethers26 which gave 14 in 20% yield (Table 2, entry 8). A
significant increase in the yield (30%) could be obtained by
combining a more soluble copper salt, CuBr·SMe2, and the more
reactive cesium phenoxide generated from cesium carbonate in
pyridine, acting as both a ligand for copper salts and the solvent
(Table 2, entry 9). Finally, the desired macrocycle 14 could be
obtained in 35% yield by decreasing the amount of both the
copper complex and the base while increasing the reaction time
(Table 2, entry 10). This yield compares rather well with the ones
typically obtained for cyclodimerization reactions16 and is
actually more than acceptable when considering that a 20-
membered ring macrocycle and two sterically hindered diaryl
ethers are formed in a single operation and given the difficulties
associated with the formation of macrocyclic ethers in general.
Simple deprotection of the two benzyl ethers in 14 by
treatment with hydrochloric acid in refluxing methanol followed
by purification on silica gel finally afforded the desired synthetic
melanthioidine 3 (23 mg). The IR, NMR data and melting point
for the synthetic compound were identical to the ones reported
in the literature,12 and a negative optical rotation was recorded.
No O.R.D. was measured in the present study.
7
Cu (3 equiv), K2CO3 (1.1 equiv), pyridine (0.16 M), 150 °C,
15
20
30
35
24 h12a
8
CuO (3 equiv), K2CO3 (1.1 equiv), pyridine (0.16 M), 120 °C,
24 h26
9
CuBr·SMe2 (3 equiv), Cs2CO3 (9 equiv), pyridine (0.16 M),
150 °C, 10 h
CuBr·SMe2 (1 equiv), Cs2CO3 (3 equiv), pyridine (0.16 M),
150 °C, 48 h
10
13 was formed in 54% yield, the enantioselectivity was found to
be rather poor and the addition of silver hexafluoroantimony
only gave a minor improvement of enantioselectivity. Cooling
the reaction to 0 °C resulted in a significant improvement of the
ee (70%) which was however still too low to be of any synthetic
usefulness. At this stage, the yield could be improved to 61% by
increasing the amount of the catalyst, and a brief screening of
different ruthenium catalysts (Table 1, entries 5−8) revealed that
both the yield and enantioselectivity could not be simultaneously
improved. In addition, performing the reaction at 40 °C enabled
a clean reaction with excellent conversion but was detrimental for
the enantioselectivity, the phenethyltetrahydroisoquinoline 13
formed at this temperature being racemic, regardless of the
nature of the ruthenium catalyst used (Table 1, entries 9−11).
With the little success met for the asymmetric reduction of
iminium 11, we switched the substrate to dihydroisoquinoline
10, which turned out to have an unexpected and unpredictable
dramatically different behavior. In this case, the outcome of the
asymmetric transfer hydrogenation was found to strongly
depend on the nature of the solvent (Table 1, entries 12−14).
To our delight, performing the reaction in DMF at rt afforded the
anticipated phenethyltetrahydroisoquinoline 12 which could be
isolated as its hydrochloride salt in 95% yield and 91% ee.21
In conclusion, we have developed the first enantioselective
total synthesis of the dimeric macrocyclic diaryl ether phenethyl-
tetrahydroisoquinoline alkaloid (−)-melanthiodine. Key steps of
the synthesis include an efficient Noyori asymmetric hydro-
genation to access the enantioenriched phenethyltetrahydro-
isoquinoline monomeric subunit and a highly challenging
copper-mediated cyclodimerization. Both the two diaryl ether
C
DOI: 10.1021/acs.orglett.6b01496
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
(11) For examples, see: (a) Tomita, M.; Fujitani, K.; Aoyagi, Y.
Tetrahedron Lett. 1966, 7, 4243. (b) Tomita, M.; Fujitani, K.; Aoyagi, Y.
Chem. Pharm. Bull. 1968, 16, 62.
linkages and the macrocycle are installed in a single operation
using this strategy which highlights the efficiency of copper-
mediated transformations in the synthesis of natural products
and the impact of copper catalysis in the synthesis of complex
molecules and macrocyclic ethers. Further applications of
copper-mediated cyclodimerization reactions are under study
and will be reported in due course.
̌
(12) (a) Battersby, A. R.; Herbert, R. B.; Mo, L.; Santavy, F. J. Chem.
́
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(d) Toumi, M.; Couty, F.; Marrot, J.; Evano, G. Org. Lett. 2008, 10,
ASSOCIATED CONTENT
■
́
5027. (e) Coste, A.; Toumi, M.; Wright, K.; Razafimahaleo, V.; Couty,
S
* Supporting Information
F.; Marrot, J.; Evano, G. Org. Lett. 2008, 10, 3841. (f) Toumi, M.;
Rincheval, V.; Young, A.; Gergeres, D.; Turos, E.; Couty, F.; Mignotte,
B.; Evano, G. Eur. J. Org. Chem. 2009, 2009, 3368. (g) Evano, G.; Toumi,
M.; Coste, A. Chem. Commun. 2009, 4166.
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.orglett.6b01496.
Detailed experimental procedures and full characterization
for all new compounds (PDF)
(14) For general references on the use of copper catalysis in natural
product synthesis, see: (a) Evano, G.; Blanchard, N.; Toumi, M. Chem.
Rev. 2008, 108, 3054. (b) Evano, G.; Theunissen, C.; Pradal, A. Nat.
Prod. Rep. 2013, 30, 1467. (c) Lee, J.; Panek, J. S. In Copper Mediated
Cross-Coupling Reactions; Evano, G., Blanchard, N., Eds.; Wiley:
Hoboken, NJ, 2013; pp 589−641. (d) Pappo, D. In Copper Mediated
Cross-Coupling Reactions; Evano, G., Blanchard, N., Eds.; Wiley:
Hoboken, NJ, 2013; pp 643−682.
AUTHOR INFORMATION
■
Corresponding Author
*E-mail: gevano@ulb.ac.be.
Notes
̌
(15) Hrbek, J., Jr.; Santavy, F. Collect. Czech. Chem. Commun. 1962, 27,
255.
́
The authors declare no competing financial interest.
(16) For selected syntheses of natural products based on a metal-
mediated cyclodimerization step, see: (a) Corey, E. J.; Nicolaou, K. C.;
Melvin, L. S., Jr. J. Am. Chem. Soc. 1975, 97, 653. (b) Paterson, I.;
Lombart, H.-G.; Allerton, C. Org. Lett. 1999, 1, 19. (c) Smith, A. B., III;
Adams, C. M.; Kozmin, S. A.; Paone, D. V. J. Am. Chem. Soc. 2001, 123,
5925.
ACKNOWLEDGMENTS
■
Our work was supported by the Universite
(ULB). J.W. acknowledges the Chinese Scholarship Council for a
graduate fellowship.
́
libre de Bruxelles
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(18) Uematsu, N.; Fujii, A.; Hashiguchi, S.; Ikariya, T.; Noyori, R. J.
Am. Chem. Soc. 1996, 118, 4916.
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DOI: 10.1021/acs.orglett.6b01496
Org. Lett. XXXX, XXX, XXX−XXX