Concise Total Synthesis of Dioncophylline E through an ortho-Arylation Strategy

Article abstract of DOI:10.1002/anie.201701136

The first total synthesis of the potent antimalarial 7,3′-linked naphthylisoquinoline alkaloid dioncophylline E (1) has been completed. The synthesis proceeds in 12 steps (longest linear sequence) and in 15 % overall yield. Key transformations include an ortho-arylation of a naphthol with an aryllead triacetate to construct the sterically hindered biaryl bond, and a three-step sequence to stereoselectively generate the trans-1,3-dimethyl-1,2,3,4-tetrahydroisoquinoline moiety.

Full text of DOI:10.1002/anie.201701136

Angewandte
Communications
Chemie
International Edition: DOI: 10.1002/anie.201701136
German Edition: DOI: 10.1002/ange.201701136
Total Synthesis
Concise Total Synthesis of Dioncophylline E through an ortho-
Arylation Strategy
Hamish D. Toop, Jason S. Brusnahan, and Jonathan C. Morris*
Abstract: The first total synthesis of the potent antimalarial
7,3’-linked naphthylisoquinoline alkaloid dioncophylline E
(1) has been completed. The synthesis proceeds in 12 steps
(longest linear sequence) and in 15% overall yield. Key
transformations include an ortho-arylation of a naphthol with
an aryllead triacetate to construct the sterically hindered biaryl
bond, and a three-step sequence to stereoselectively generate
the trans-1,3-dimethyl-1,2,3,4-tetrahydroisoquinoline moiety.
M
alaria is an infectious disease caused by protozoan
parasites of the genus Plasmodium, in particular Plasmodium
falciparum (P. falciparum), and is spread by mosquitoes.[1,2]
Approximately 212 million people were infected with malaria
in 2015, resulting in an estimated 429 thousand deaths.[1]
While antimalarial drug regimens have been effective, strains
of P. falciparum are increasingly becoming resistant to the
frontline therapeutics and this presents as a major threat to
controlling the disease.[3,4] It has been recognized that the
discovery and development of new therapeutic agents is
vital.[3]
Figure 1. Structures of dioncophylline E (1), ancistrocladidine (2), and
ancistrotanzanine A (3).
yield.[11] There have been no reports of syntheses of the 5,3’-
linked members. Thus, there is room for improvement in the
synthesis of these valuable scaffolds.
Dioncophylline E (1) is a 7,3’-linked naphthylisoquinoline
alkaloid that was isolated from the roots of the rare tropical
liana Dioncophyllum thollonii by Bringmann and co-work-
ers.[12] In contrast to most naphthylisoquinoline alkaloids, the
biaryl axis of dioncophylline E (1) is configurationally semi-
stable, slowly interconverting at room temperature. The
potency of 1 against both chloroquine-sensitive (NF54; IC50
The naphthylisoquinoline alkaloids have attracted a great
deal of interest in this context owing to their potent
antimalarial activity, favorable pharmacological profile, and
low cytotoxicity.[5,6] However, as noted by Bringmann,[7a] the
plants that produce the naphthylisoquinoline alkaloids are
rare and difficult to cultivate,[7] which has stymied efforts to
utilize these scaffolds. This means that total synthesis must be
used to generate these valuable molecules. While there has
been impressive progress in accessing these intriguing natural
products through synthesis[8,9] there has been limited success
in accessing the 7,3’- and 5,3’-linked naphthylisoquinoline
alkaloids (Figure 1), since these contain the most sterically
congested biaryl bonds in the series.
The first synthesis of a 7,3’-linked alkaloid was that of
ancistrocladidine (2) by our group, but the long endgame of
this synthesis limits the utility for further work on analogue
production.[10] Bringmann and co-workers recently developed
an atropselective synthesis of 2 by making an advancement in
his impressive “lactone method”, but the key biaryl-bond-
forming step in this sequence could only be achieved in 32%
22 ngmLꢀ1) and chloroquine-resistant (KI; IC50 21 ngmLꢀ1
)
strains of P. falciparum makes it an intriguing target for
synthesis. Herein we present a direct, modular approach that
allows 1 to be synthesized in 12 steps, and will allow a full
SAR study to be undertaken.
Our retrosynthetic analysis is depicted in Scheme 1. We
chose to investigate a trans-selective reduction of 1,3-
dimethyl-3,4-dihydroisoquinoline 4, using conditions de-
scribed by Bringmann and co-workers.[13] 1,3-Dimethyl-3,4-
dihydroisoquinoline 4 could be generated using a two-step
[*] Dr. H. D. Toop, Prof. J. C. Morris
School of Chemistry, UNSW, Sydney, NSW, 2052 (Australia)
E-mail: jonathan.morris@unsw.edu.au
Dr. J. S. Brusnahan
School of Chemistry and Physics, The University of Adelaide
Adelaide, SA, 5005 (Australia)
Supporting information and the ORCID identification number(s) for
the author(s) of this article can be found under:
https://doi.org/10.1002/anie.201701136.
Scheme 1. Retrosynthetic analysis of dioncophylline E (1).
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sulfinimine addition/cyclisation method developed by Davis
and co-workers.[14] This would require o-tolylnitrile 5, which
serves to direct cyclisation to the desired 1-position.
protection of the naphthol as the benzyl ether, deprotonation
using LDA, followed by addition of t-butylsulfinimine 11[23] in
THF at ꢀ788C, afforded sulfinamide 12 in 72% yield as
a 50:50 mixture of atropisomers with > 97:3 diastereoselec-
tivity at C3.[24] While 1 has a semistable biaryl axis, the benzyl-
protecting groups ortho to the biaryl axis clearly restrict
rotation and lead to the formation of atropisomers. Since
these benzyl groups would eventually be removed, no attempt
was made to separate the atropisomers. The core 1,3-
dimethyl-3,4-dihydroisoquinoline 4 was completed in 71%
yield by treating sulfinamide 12 with MeLi in THF followed
by acidic work-up. However, reduction of this substrate using
Bringmannꢀs method to synthesise the trans stereoisomer
(AlMe3, LiAlH4, THF, ꢀ788C!08C)[13] resulted in a 50:50
mixture of the cis and trans stereoisomers. This was compli-
cated further since there was still a 50:50 mixture of
atropisomers, and a pure sample of dioncophylline E could
not be isolated.
Access to 5 would be accomplished using the Pinhey–
Barton ortho-arylation method developed in our synthesis of
ancistrocladidine (2).[10] This reaction would require access to
aryllead triacetate 6, which could be coupled to naphthol 7.[15]
While there has been some application of simple aryllead
triacetate reagents in synthesis, there are few applications in
more complex systems.[10b,16,17] This strategy is advantageous
since it only requires functionalization of one coupling
ꢀ
partner and therefore can be thought of as a C H activation
strategy.
Our synthesis commenced with phenol 8, which was
generated from commercially available o-tolylnitrile.[18]
Regioselective ortho-bromination (NBS, HNiPr2, CH2Cl2)
and protection of the phenol as the benzyl ether afforded
bromide 9 in 92% yield overall. The aryllead triacetate 6 was
prepared through transmetalation from a boronic acid since
these have been reported to be superior in regard to
functional-group tolerance and reactivity.[19,17c] Halogen–lith-
ium exchange of 9, using tBuLi, followed by quenching with
B(OiPr)3, afforded the boronic acid 10 in 84% yield. Trans-
metalation using freshly dried Pb(OAc)4 and 10 mol% Hg-
To circumvent this issue, we investigated nucleophilic
addition of the C1 methyl group stereoselectively to 3-methyl-
3,4-dihydroisoquinoline 13.[9g] Access to 13 was achieved from
sulfinamide 12 in 65% yield through treatment with DIBAL-
H in PhMe followed by 2m aqueous HCl solution in THF
(Scheme 3). Screening of a number of methyl nucleophiles led
[20]
(OTFA)2 in CH2Cl2 successfully generated aryllead triace-
tate 6,[21] which was immediately reacted with naphthol 7 and
pyridine in 1,2-dichloroethane. Pleasingly, this afforded
arylated naphthol 5 in 77% yield over the two steps
(Scheme 2).[22]
With the ortho-arylated naphthol 5 in hand, our attention
turned to construction of the isoquinoline moiety. After
Scheme 3. Reagents and conditions: a) DIBAL-H, PhMe, 08C!RT
then 2m aq. HCl, THF, RT, 65%; b) MeLi, CeCl3, THF, ꢀ78!08C,
75%; c) BCl3, C6HMe5, CH2Cl2, ꢀ788C, then TFA, CH2Cl2, 82%.
DIBAL-H=diisobutylaluminium hydride.
us to the methylcerium reagent, prepared from MeLi and
freshly dried CeCl3 in THF at ꢀ788C.[25,26] This resulted in
formation of the trans-1,3-dimethyl-1,2,3,4-tetrahydroisoqui-
noline 14 in 75% yield with complete stereocontrol at C1.[24]
The synthesis was completed by global deprotection of the
benzyl-protecting groups using BCl3 with pentamethylben-
zene in CH2Cl2 at ꢀ788C. Since Bringmann and co-workers
isolated 1 as the TFA salt, our sample was treated with TFA,
resulting in the isolation of dioncophylline E (1) as its TFA
salt in 82% yield for the two steps.[27] The spectroscopic data
obtained from this material matched that reported for the
natural product.[12,27]
Scheme 2. Reagents and conditions: a) NBS, HNiPr2, CH2Cl2, RT,
95%; b) BnBr, K2CO3, DMF, RT, 97%; c) tBuLi, THF then B(OiPr)3,
ꢀ95!08C, 84%; d) Pb(OAc)4, 10 mol% Hg(OTFA)2, CH2Cl2, RT; e) 7,
py, 1,2-DCE, RT, 77% (2 steps); f) NaH, DMF then BnBr, RT, 87%;
g) LDA, THF, ꢀ788C then 11, THF, ꢀ788C, 72%; h) MeLi, THF,
ꢀ788C!RT, then 2m aq. HCl, 71%; i) LiAlH4, AlMe3, THF, ꢀ78!
ꢀ42!ꢀ23!08C. NBS=N-bromosuccinimide, DMF=N,N-dimethyl-
formamide, THF=tetrahydrofuran, TFA=trifluoroacetic acid,
DCE=1,2-dichloroethane, LDA=lithium diisopropylamide.
In summary, the first total synthesis of dioncophylline E
(1) has been completed in 15% overall yield with a longest
linear sequence of 12 steps. It is envisaged that the strategy
2
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2004, 69, 4152 – 4158; f) G. Bringmann, A. Hamm, M. Schraut,
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thylisoquinoline alkaloid family that have eluded synthetic
efforts, as well as facilitating SAR investigations.
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b) C. J. Bungard, J. C. Morris, J. Org. Chem. 2006, 71, 7354 –
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Acknowledgements
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The authors would like to acknowledge funding from UNSW
Sydney and the University of Adelaide, Australian Postgrad-
uate Awards to H.D.T. and J.S.B as well as the NMR facility
within the Mark Wainwright Analytical Centre at UNSW
Sydney for NMR support.
[12] G. Bringmann, K. Messer, K. Wolf, J. Mꢅhlbacher, M. Grꢅne, R.
Brun, A. M. Louis, Phytochemistry 2002, 60, 389 – 397.
[13] G. Bringmann, R. Weirich, J. R. Reuscher, J. R. Jansen, L.
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[14] F. A. Davis, P. K. Mohanty, D. M. Burns, Y. W. Andemichael,
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[15] a) M. Watanabe, S. Hisamatsu, H. Hotokezaka, S. Furukawa,
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[16] Demetallation of aryllead triacetates by nitrogen containing
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[18] Phenol 7 was prepared in 2 steps from o-tolylnitrile using
a procedure reported in W. Li, P. Sun, J. Org. Chem. 2012, 77,
8362 – 8366, followed by deprotection of the methyl ether (see
the Supporting Information for details).
[19] J. Morgan, J. T. Pinhey, J. Chem. Soc. Perkin Trans. 1 1990, 715 –
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[20] a) J. T. Pinhey, Aust. J. Chem. 1991, 44, 1353 – 1382; b) G. I.
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[21] Since aryllead triacetate 6 is sensitive to purification, it was
immediately used in the arylation reaction. The 1H NMR
spectrum of the crude reaction mixture confirmed the gener-
ation of the lead species, with the diagnostic broad singlet at d =
2.1 ppm (9H) and the presence of the H-Pb coupling for the 4-
Me group (t, JH-Pb = 8.4 Hz).
[22] The tri-n-butylstannyl substrate was also investigated, but
transmetallation of the stannane was slow and stoichiometric
quantities of the mercury salt were required to obtain any
arylated naphthol 5.
Conflict of interest
The authors declare no conflict of interest.
Keywords: alkaloids · aryllead triacetate · biaryls ·
dioncophylline E · total synthesis
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1
[24] Determined by analysis of the H NMR spectrum of the crude
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[25] The use of MeMgBr resulted in an incomplete reaction, while
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[26] H. J. Liu, K. S. Shia, X. Shang, B. Y. Zhu, Tetrahedron 1999, 55,
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[27] The atropisomeric ratio at 258C was 60:40 (measured by
1H NMR) and changed to 55:45 when measured at 308C.
Manuscript received: February 1, 2017
Final Article published: && &&, &&&&
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ꢀ 2017 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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Angewandte
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Communications
Total Synthesis
Access granted: Total synthesis of the
potent antimalarial 7,3’-linked naphthyl-
isoquinoline alkaloid dioncophylline E
was achieved. The synthesis proceeds in
12 steps (longest linear sequence) and
15% overall yield. Key transformations
include an ortho-arylation of a naphthol
with an aryllead triacetate to give the
sterically hindered biaryl bond, and
a three-step sequence to stereoselectively
generate the trans-1,3-dimethyl-1,2,3,4-
tetrahydroisoquinoline moiety.
H. D. Toop, J. S. Brusnahan,
J. C. Morris*
&&&& — &&&&
Concise Total Synthesis of
Dioncophylline E through an ortho-
Arylation Strategy
4
www.angewandte.org
ꢀ 2017 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Angew. Chem. Int. Ed. 2017, 56, 1 – 4
These are not the final page numbers!