Total synthesis of malagashanine: a chloroquine potentiating indole alkaloid with unusual stereochemistry

Article abstract of DOI:10.1039/c6sc03578g

The first total synthesis of malagashanine, a chloroquine potentiating indole alkaloid, is presented. A highly stereoselective cascade annulation reaction was developed to generate the tetracyclic core of the Malagasy alkaloids. This chemistry is likely to be broadly applicable to the synthesis of other members of this stereochemically unique family of natural products.

Full text of DOI:10.1039/c6sc03578g

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Total synthesis of malagashanine: a chloroquine
potentiating indole alkaloid with unusual
stereochemistry†
Cite this: DOI: 10.1039/c6sc03578g
*
A. Kong, D. E. Mancheno, N. Boudet, R. Delgado, E. S. Andreansky and S. B. Blakey
Received 10th August 2016
Accepted 11th September 2016
The first total synthesis of malagashanine, a chloroquine potentiating indole alkaloid, is presented. A highly
stereoselective cascade annulation reaction was developed to generate the tetracyclic core of the Malagasy
alkaloids. This chemistry is likely to be broadly applicable to the synthesis of other members of this
stereochemically unique family of natural products.
DOI: 10.1039/c6sc03578g
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sharing this unusual stereochemical arrangement have been
identied from Strychnos species in both Africa and South
America.4 These unprecedented structural features, combined
with the potential utility of these natural products to further our
understanding of malarial drug resistance highlight the Mala-
gasy alkaloids as important targets to be addressed by total
synthesis.
Prior to our studies, attempts to synthesize malagashanine
by manipulation of strychnobrasiline had failed, as the trans-CD
ring fusion could not be established.4 More recently, a synthesis
of 16-epi-11-demethoxymyrtoidine was reported.5 These studies
highlight the challenge presented by the seven consecutive
stereocenters found in the natural product.
Introduction
Malagashanine (1, Fig. 1) is a structurally unusual alkaloid that
was isolated from the stem bark of the Madagascan shrub
Strychnos myrtoides in the early 1990s.1 It was isolated during an
ethnobotanical study investigating local approaches to malaria
treatment, and was found to potentiate chloroquine against
otherwise resistant Plasmodium falciparum.2 To date, the
mechanism of action for this observed activity has not been
established, although it was noted that malagashanine impacts
chloroquine accumulation in the food vacuole of the malaria
parasite.2c Although initially incorrectly assigned, the structure
of malagashanine was unambiguously determined by X-ray
crystallography.3 The pentacyclic alkaloid contains seven
consecutive stereocenters, and most strikingly, a trans-ring
fusion between the C and D rings. To the best of our knowledge,
this represents the rst report of a trans-ring fusion in
a Strychnos alkaloid and as a result, this core structure had not
been the focus of any synthetic studies. Subsequent to the
discovery of malagashanine, several other alkaloids (2–4)
Results and discussion
Strategically we chose to construct the tetracyclic core of the
Malagasy alkaloids (5, Fig. 2) in a cascade annulation reaction,
initiated by Lewis-acid induced decomposition of a simple
linear aminol substrate (6) with subsequent indole attack on the
resulting iminium ion, and nally, an appropriately positioned
allylsilane would complete the sequence and close the D-ring of
the natural product. This approach was inspired by Corey's
elegant synthesis of aspidophytine.6 However, implementation
in the context of the Malagasy alkaloid framework posed
a number of signicant challenges not addressed in the cascade
established for aspidophytine, and thus offered an opportunity
to further explore and dene the generality of the strategy.
Specically, we would need to establish iminium ion geometry
in an acyclic context, and translate this geometry into the
correct C3–C7 relative stereochemistry required for malaga-
shanine. Attack of the indole onto the iminium ion would need
to outpace migration of the b,g-unsaturation into conjugation,
and a trisubstituted allylsilane would need to close stereo-
selectively onto the resulting indolium ion, without the help of
a Thorpe–Ingold preorganization, prior to alkyl migration
leading to competing Pictet–Spengler product.
Fig. 1 The Malagasy alkaloids.
Department of Chemistry, Emory University, 1515 Dickey Drive, Atlanta, GA 30322,
USA. E-mail: sblakey@emory.edu
† Electronic supplementary information (ESI) available: Experimental details and
spectral data are provided. CCDC 1489617. For ESI and crystallographic data in
CIF or other electronic format see DOI: 10.1039/c6sc03578g
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N-Tosyl amidation was accomplished via the intermediacy of
a mixed pivaloyl anhydride of acid 9. In a modication of Kim's
procedure,11 amide 13 was converted to the N-tosyl-O-TMS-
aminol by DIBAL-H reduction and TMS-imidazole quench. We
note that the addition of 20 mol% imidazole to the reaction
accelerates the transmetallation from the aluminate to the
silylether, and led to reproducibly high yields in the reaction.
Finally, treatment of the aminol with BF3$OEt2 resulted in
cascade cyclization to produce tetracycle 14 as a single diaste-
reomer (70% yield). However extensive COSY and nOe NMR
experiments revealed that the C16 stereocenter had the oppo-
site relative conguration to that which is required for the
synthesis of malagashanine, suggesting that the nal cycliza-
tion had in fact proceeded through a boat transition state (8,
Fig. 2). This analysis suggested that the E-olen 15 would be
required to complete the synthesis (Scheme 2).
Fig. 2 Synthetic strategy for malagashanine.
This was accomplished in a straightforward manner, with
Ready's directed hydrozirconation methodology delivering vinyl
iodide 16 as a single geometric isomer from homopropargyl
alcohol 17 in 61% yield.12 An additional 12% of iodide
regioisomer was also isolated. Elaboration of alcohol 16 to
carboxylic acid 18 and subsequent conversion to amide 19
proceeded smoothly using the reaction conditions established
for the Z-isomer. Reduction to give the TMS-aminol and cycli-
zation with BF3$OEt2 gave tetracycle 20 containing four of the
seven stereocenters as a single diastereomer in excellent yield
(77% over 2 steps). This high delity in translating allylsilane
geometry into the C16 stereochemistry is consistent with
a highly ordered boat transition state. The preference for boat
transition state 8 over the chair 7 appears to be dictated by the
spirocyclic motif linking the indolium ion and allylsilane. This
motif splays the reactive terminals apart in a chair conforma-
tion, but allows good overlap between the allysilane p-system
and the indolium ion p* orbital in the boat conformation.
Having established a robust synthesis of the core structure of
the Malagasy alkaloids, our attention turned to installation of
In a preliminary study we had established the importance of
utilizing an N-tosyl iminium ion to selectively form the tetra-
cyclic cascade product in preference to the Pictet–Spengler
product, and that iminium-ion geometry control produced the
required trans-ring fusion.7 However the delicate balance of the
reaction suggested that extension to trisubstituted allylsilanes
might not be straightforward. We initiated our study with the
assumption that closure of the allylsilane onto the indolium ion
would proceed through a chair transition state (7), and thus
embarked on a synthesis of the Z-allylsilane 9 (Scheme 1).
The olen geometry was established by Red-Al reduction of
propargyl alcohol 10.8 Quenching of the organoaluminate
intermediate with NIS delivered the Z-vinyl iodide 11 in 83%
yield. Alcohol protection and PMB removal provided alcohol 12
(92% yield). Subsequent oxidation to the carboxylic acid,9 and
Negishi cross coupling delivered the required allylsilane 9 in
78% yield.10
Scheme 1 Synthesis and cyclization of Z-allylsilane precursor 13 gives Scheme 2 Allylsilane geometry controls C16 stereochemistry. Selec-
the 16-epi-malagashanine core.
tive synthesis of the malagashanine tetracyclic core 20.
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the tetrahydropyran E-ring. A hydroboration-Knochel trans-
metallation protocol enabled a formal hydroacylation of the
exocyclic olen of 20 (Scheme 3).13
This protocol was moderately selective providing a 4 : 1
mixture of separable diastereomers with the major diaste-
reomer 21 isolated in 50% yield. Hydrogenolysis efficiently
removed the benzyl protecting groups from both the indoline
nitrogen and the 1ꢀ alcohol, and the crude reaction mixture was
immediately subjected to acid catalyzed dehydration to deliver
dihydropyran 22 in 88% yield. Installation of the acetamide
found in the natural product proceeded smoothly (23, 96%
yield). Introduction of the C20 ester functionality proved diffi-
cult, and acylation of the enol ether with trichloroacetic anhy-
dride under a range of conditions delivered disappointing
yields of the trichloroketone. Ultimately we found that acylation
with the more reactive triuoroacetic anhydride in the presence
of pyridine was more effective, and gave reproducibly excellent
yields (94%) of triuoroketone 24.14 Hydrolysis of the tri-
uoroketone was accomplished with potassium hydroxide in
a reuxing water/benzene mixture, and treatment of the
resulting carboxylic acid with TMS-diazomethane gave the
methyl ester 25 in 79% yield (over 2 steps).
Scheme 4 Ionic reduction of dihydropyran 25 leads to 20-epi-
malagashanine.
olen 25 did not result in any hydrogenation reaction. Addi-
tionally, a selection of common heterogeneous catalysts were
also investigated under a variety of forcing conditions, but none
were effective.17 Ionic reduction with triethylsilane in triuoro-
acetic acid gave the reduced compound 26 (Scheme 4).18
However, the trans-reduction product, in which both the C20
methyl ester and the C19 methyl substituent of the tetrahy-
dropyran occupy equatorial positions, was obtained.
The stereochemical outcome of the reaction was unambig-
uously conrmed by X-ray crystallography, and although the
product was epimeric to the natural product at C20, this
structure served to conrm that the previously established
stereocenters were correctly congured. Reduction product 26
was converted to 20-epi-malagashanine (27) utilizing standard
conditions (2 steps, 60% yield).
At this stage we attempted to hydrogenate the tetrasub-
stituted olen from the convex face, to complete the synthesis of
the tetrahydropyran and set the remaining two stereocenters in
the natural product. Although reductions of tetrasubstituted
olens are relatively rare, good results have been reported with
a
Rh/Josiphos combination,15 and with Pfaltz's iridium
complexes.16 Unfortunately application of these conditions to
In order to synthesize the correctly congured natural
product, we discovered that removal of the tosyl protecting
group of 25 under dissolving metal conditions and reductive
amination of the resulting amine provided substrate 28 that
could be successfully hydrogenated using Raney nickel as the
catalyst (110 bar, 5 days) providing malagashanine (1) in 97%
yield (Scheme 5).
Scheme 3 Core homologation and installation of the malagashanine
E-ring.
Scheme 5 Completion of the total synthesis of malagashanine.
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4 M. T. Martin, P. Rasoanaivo, G. Palazzino, C. Galeffi,
M. Nicoletti, F. Trigalo and F. Frappier, Phytochemistry,
1999, 51, 479.
5 J. Zhu, Y. J. Cheng, X. K. Kuang, L. Wang, Z. B. Zheng and
Y. Tang, Angew. Chem., Int. Ed., 2016, 55, 9224.
6 F. He, Y. X. Bo, J. D. Altom and E. J. Corey, J. Am. Chem. Soc.,
1999, 121, 6771.
7 R. Delgado and S. B. Blakey, Eur. J. Org. Chem., 2009, 1506.
8 (a) E. J. Corey, J. A. Katzenellenbogen and G. H. Posner, J. Am.
Chem. Soc., 1967, 89, 4245; (b) S. E. Denmark and T. K. Jones,
J. Org. Chem., 1982, 47, 4595.
Conclusions
In summary, we report a stereoselective synthesis of the chlo-
roquine potentiating natural product malagashanine. A novel
cascade annulation protocol efficiently constructs the C and D
rings and installs four of the ve consecutive D-ring stereo-
centers, including the critical trans-CD ring fusion. This repre-
sents the rst total synthesis of a member of the Malagasy
alkaloid family of natural products and provides a foundation
for an exploration of the interesting biological activity presented
by these compounds.
9 (a) D. B. Dess and J. C. Martin, J. Org. Chem., 1983, 48, 4155;
(b) B. S. Bal, W. E. Childers and H. W. Pinnick, Tetrahedron,
1981, 37, 2091.
10 A. Duchene, M. Abarbri, J. L. Parrain, M. Kitamura and
R. Noyori, Synlett, 1994, 524.
11 Y. G. Suh, D. Y. Shin, J. K. Jung and S. H. Kim, Chem.
Commun., 2002, 1064.
12 D. H. Zhang and J. M. Ready, J. Am. Chem. Soc., 2007, 129,
12088.
Acknowledgements
This research was supported by the NSF (CHE-1362502). We
gratefully acknowledge Dr John Bacsa and Dr Kenneth Hard-
castle (Emory X-Ray Center) for assistance with X-ray structural
analysis.
13 (a) E. Hupe, M. I. Calaza and P. Knochel, Tetrahedron Lett.,
2001, 42, 8829; (b) E. Hupe, M. I. Calaza and P. Knochel,
Chem.–Eur. J., 2003, 9, 2789.
14 J. W. Harbuck and H. Rapoport, J. Org. Chem., 1972, 37, 3618.
15 (a) J. R. Calvin, M. O. Frederick, D. L. Laird, J. R. Remacle and
S. A. May, Org. Lett., 2012, 14, 1038; (b) J. H. Frederich and
P. G. Harran, J. Am. Chem. Soc., 2013, 135, 3788.
16 B. Wuestenberg and A. Pfaltz, Adv. Synth. Catal., 2008, 350,
174.
Notes and references
1 P. Rasoanaivo, S. Ratsimamanga-Urverg, R. Milijaona,
H. Rafatro, A. Rakoto-Ratsimamanga, C. Galeffi and
M. Nicoletti, Planta Med., 1994, 60, 13.
2 (a) D. Ramanitrahasimbola, S. Ratsimamanga-Urverg,
P. Rasoanaivo and A. Rakoto-Ratsimamanga, Phytomedicine,
1999, 6, 331; (b) H. Rafatro, D. Ramanitrahasimbola,
P. Rasoanaivo, S. Ratsimamanga-Urverg, A. Rakoto-
Ratsimamanga and F. Frappier, Biochem. Pharmacol., 2000,
59, 1053; (c) D. Ramanitrahasimbola, P. Rasoanaivo,
S. Ratsimamanga and H. Vial, Mol. Biochem. Parasitol., 2006,
146, 58.
17 See ESI for details.†
18 Z. G. Song, A. O. King, M. S. Waters, F. G. Lang, D. Zewge,
M. Bio, J. L. Leazer, G. Javadi, A. Kassim, D. M. Tschaen,
R. A. Reamer, T. Rosner, J. R. Chilenski, D. J. Mathre,
R. P. Volante and R. Tillyer, Proc. Natl. Acad. Sci. U. S. A.,
2004, 101, 5776.
3 M. R. Caira and P. Rasoanaivo, J. Chem. Crystallogr., 1995, 25,
725.
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