Concise Synthesis of the Antiplasmodial Isocyanoterpene 7,20-Diisocyanoadociane

Article abstract of DOI:10.1002/anie.201906834

The flagship member of the antiplasmodial isocyanoterpenes, 7,20-diisocyanoadociane (DICA), was synthesized from dehydrocryptone in 10 steps, and in 13 steps from commercially available material. Our previous formal synthesis was reengineered, leveraging

Full text of DOI:10.1002/anie.201906834

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Accepted Article
Title: Concise Synthesis of the Antiplasmodial Isocyanoterpene 7,20-
Diisocyanoadociane
Authors: Alexander S Karns, Bryan D Ellis, Philipp C Roosen, Zeinab
Chahine, Karine G Le Roch, and Christopher D. Vanderwal
This manuscript has been accepted after peer review and appears as an
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To be cited as: Angew. Chem. Int. Ed. 10.1002/anie.201906834
Angew. Chem. 10.1002/ange.201906834
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10.1002/anie.201906834
Angewandte Chemie International Edition
COMMUNICATION
Concise Synthesis of the Antiplasmodial Isocyanoterpene 7,20-
Diisocyanoadociane
Alexander S. Karnsa$, Bryan D. Ellisa$, Philipp C. Roosena, Zeinab Chahineb, Karine G. Le Rochb, and
Christopher D. Vanderwala*
a.
NC
Abstract: The flagship member of the antiplasmodial
isocyanoterpenes, 7,20-diisocyanoadociane (DICA), was
NC
H
H
H
H
H
H
synthesized from dehydrocryptone in 10 steps, and 13 from
commercially available material. Our previous formal synthesis was
reengineered, leveraging only productive transformations to deliver
DICA in fewer than half the number of steps of our original effort.
Important contributions, in addition to the particularly concise
strategy, include a solution to the problem of axial nucleophilic
methylation of a late-stage cyclohexanone, and the first selective
synthesis and antiplasmodial evaluation of the DICA stereoisomer
with both isonitriles equatorial.
H
O
CN
HO
H
NC
H
H
1: 7,20-diisocyanoadociane
(DICA)
[isocycloamphilectane]
W2: 13 nM
Cl
2: kalihinol B
[kalihinane]
Dd2: 5 nM
NC
H
NC
H
H
H
H
H
H
H
Sponge-derived
isocyanoterpene
(ICT)
secondary
metabolites are striking for their isonitrile functional groups—
rarely found in natural products—and their potent antiplasmodial
activity, which appear correlated.1 This family includes a range
of complex polycyclic architectures (Figure 1a) that has inspired
our group to develop a unified strategy toward seemingly
topologically disparate ICT diterpenes. Among them, 7,20-
diisocyanoadociane (DICA, 1) stands out as arguably the most
stereochemically complex.1 DICA was described in 1976,2 but it
wasn’t until studies by König and colleagues two decades later3
that DICA’s potent antiplasmodial activity was revealed. The
compelling combination of its structure and activity originated
our interest in DICA and, by extension, the rest of the ICT
family.4-7
3: [amphilectane]
W2: 31 nM
4: [isoneoamphilectane]
W2: 100 nM
b.
Conjugate addition/enolate trapping strategy to ICTs
O
O
NC
H
H
H
6
H
5
R
R
R
Figure 1. a. Select ICTs including 7,20-diisocyanoadociane and their
antiplasmodial activities. W2 and Dd2 are drug-resistant strains of
the malaria-causing parasite Plasmodium falciparum; the
concentrations given are IC50 values. These data are taken from refs
3c and 4. b. A general strategy to access various ICT architectures.
Upon initiation of our efforts in this area, we identified 2-
isocyanodecalin fragment 6 (Figure 1b) as a common motif in
many potent ICT diterpenes and developed a general strategy
around retron 5.8 An intermolecular conjugate addition/enolate
trapping strategy was devised with the goal of maximizing
convergency and overall efficiency; this approach appeared to
offer the flexibility to be generalizable to many ICTs.9 Indeed,
this strategy was central to our synthesis of kalihinol B (2),4
many simplified yet active kalihinol analogues,5 and our previous
formal synthesis of DICA (1).6a
activation by trifluoroacetylation and treatment with TMSCN and
TiCl4 led to stereochemically uncontrolled formation of 1 and its
three stereoisomers. Several subsequent formal syntheses were
based on the formation of the Corey dione, and thus inherited its
troublesome endgame. These achievements include a Diels–
Alder approach strategically similar to Corey’s from the Miyaoka
group,11 an oxidative enolate coupling/ring-closing metathesis
approach from Robinson and Thomson12 and our own conjugate
addition/enolate trapping strategy.6a Two total syntheses sought
to solve the stereocontrol conundrum at the C7 and C20
isonitrile-bearing carbons: Fairweather and Mander’s approach
used stereospecific Curtius rearrangements to install tertiary
carbinolamines as isonitrile precursors,13 and the Shenvi group’s
synthesis14 featured their method for invertive displacement of
tertiary trifluoroacetates (TMSCN, Sc(OTf)3) on the bis-
trifluoroacetate derived from 8, which provided a stereoselective
counterpoint to the endgame from 7.15
In 1987, Corey and Magriotis described the first synthesis of
DICA via a logical, Diels–Alder based strategy that generated
tetracyclic diketone (Corey dione) 7 in about two dozen steps
(Scheme 1).10 Double equatorial nucleophilic methylation,
[a]
[b]
A. S. Karns, B. D. Ellis, P. C. Roosen, and Prof. C. D. Vanderwal
1102 Natural Sciences II, Department of Chemistry
University of California
Irvine, CA, 92697-2025, USA
E-mail: cdv@uci.edu
Z. Chahine and Prof. K. G. Le Roch
Institute for Integrative Genome Biology
Center for Infectious Disease and Vector Research
900 University Avenue, Department of Molecular, Cell, and Systems
Biology
Our previous formal synthesis was problematic because it
required over two dozen steps to arrive at the Corey dione, from
which no satisfactory stereocontrolled endgame could be
envisaged. Improving on this earlier work required addressing its
critical problems: (1) underfunctionalized early intermediate 9
required late-stage introduction of the C17 and C19 methyl
groups; (2) the THF ring in 9, introduced as a protecting group
for the corresponding 1,4-diol, proved challenging to open, and
required a half dozen steps to appropriately elaborate; and (3)
the end-game from the Corey dione to DICA would be
University of California, Riverside
Riverside, CA 92521, USA
$These authors contributed equally. Supporting information for this
article is given via a link at the end of the document.
This article is protected by copyright. All rights reserved.

10.1002/anie.201906834
Angewandte Chemie International Edition
COMMUNICATION
unselective. The reconciliation of these problems has led to the
total synthesis of DICA itself described herein, which was
completed in fewer than half the number of operations and
captures the spirit of our general ICT strategy.
Meinwald
rearrangement/Friedel–Crafts
cyclodehydration
affords tetracyclic styrene 13.18
Although dihydronapthalene 13 appears to be only
moderately related to DICA, it is readily elaborated to the
target’s perhydropyrene core in only four carefully orchestrated
transformations, with which five stereogenic centers are installed
by reduction, each with greater than 10:1 diastereoselectivity.
Birch reduction of 13 proceeds with the addition of six molar
equivalents of electrons, reducing the styrene, the electron-rich
aromatic ring, and—critically—the lactone. After hydrolysis of the
initial reduction product, 14 is obtained with high control at C1
and C3 (C15 is easily epimerizable in a subsequent step, and
the acetal center is irrelevant). Heterogeneous hydrogenation of
the enone is completely selective for the trans-ring juncture, and
provides the ketone that serves as the pronucleophile for an
aldol condensation with the acetal carbon. Controlling the
reduction to deliver a lactol ensured the correct oxidation state
for the subsequent proline-mediated aldol condensation, which
H
O
H
O
O
H
H
H
refined strategy
described here
H
H
MeO
H
MeO
H
H
19
10: key properly
functionalized
intermediate
NC
7
9: underfunctionalized
H
intermediate
8
H
H
16
11
13
12
CN
part of a ca. 25-step
formal synthesis
(intersects 7)
part of a 13-step
total synthesis
(via 8)
4
20
H
H
1
18
17
3
15
H
1: DICA
O
H
OH
H
H
H
H
H
H
H
unselective
selective
O
HO
1. MeLi·CeCl3
2. TFAA
3. TMSCN, TiCl4
1. TFAA
2. TMSCN
Sc(OTf)3
H
H
H
H
directly provided 15.
A
second heterogeneous enone
hydrogenation—performed in basic methanol—introduces the
C11 stereogenic center with high efficiency and selectivity, and
equilibrates the C15 center such that the methyl group resides
equatorially, delivering 16 as a single diastereomer.
7: Corey dione
8: Shenvi diol
Scheme 1. Our previous synthesis via intermediate 9 enabled a lengthy formal
synthesis by producing the Corey dione (7), for which stereocontrolled
conversion to DICA is not straightforward. Our improved synthesis proceeds
via 10, permitting a concise and stereocontrolled synthesis. TFAA:
trifluoroacetic anhydride.
Given our focus on brevity to this point, we were compelled
to find a way to directly introduce the C16 methyl group in an
axial orientation. The Shenvi group reported that their efforts to
do so were unsuccessful, opting instead for a multi-step but
highly diastereoselective sequence of Peterson olefination and
oxymercuration/reduction.14 Presented with this opportunity for
discovery, we embarked upon a screen of combinations of
different methyl organometallic reagents, Lewis acids additives,
solvents, and co-solvents, while simultaneously studying
classical literature on carbonyl additions. In this way, and with
guidance from the critical studies of Ashby and co-workers,20 we
found that an excess of trimethylaluminum in solvents of low
polarity tended to favor the generation of the desired axially
methylated adduct 8.
Scheme 2 reveals how dehydrocryptone (11) is converted to
DICA in 10 steps (13 steps from its chiral pool precursor
perillaldehyde16). Conjugate arylation and in situ enolate
trapping with ethyl bromoacetate provides the three-component
coupling product in high yield with complete stereochemical
control. Selective nucleophilic methylation of the ketone leads to
lactone 12.17 Equatorial methyl addition to the C7 ketone
delivers an axial C–O bond that will later—upon displacement
with TMSCN—result in the C7 equatorial isonitrile found in the
natural product. Notably, the conversion of 11 to 12 introduces
all of the skeletal carbon atoms of DICA except for the C16
methyl group. Sequential epoxidation and Lewis-acid-induced
MeO
O
O
O
1. ArMgBr, CuI•2LiCl, then
HMPA, BrCH2CO2Et (61%)
2. MeMgBr (99%)
Li, NH3, s-BuOH
dioxane, –40 °C;
aq. HCl, MeOH
O
O
O
DMDO;
BF3·OEt2
7
H
H
H
H
H
O
(85%)
formal
dehydrogenative
coupling
stereotetrad
>10:1 dr
(70%)
MeO
MeO
H
H
H
>10:1 dr at
C1 & C3
3
1
H
H
H
3:1 dr
H
H
14
H
H
11:
dehydrocryptone
12: all skeletal carbons
but one, and
3 new stereocenters
13
1. H2, Rh/Al2O3 (97%)
2. proline (xs), (CO2H)2
H2O/DMSO, 100 °C
(55–63%)
5 new stereocenters
by reduction
over 4 steps
>10:1 dr
at C12
NC
OH
7
OH
OH
H
H
H
H
H
H2, Pd/C
K2CO3, MeOH
1. TFAA
2. TMSCN, Sc(OTf)3
AlMe3, PhMe
–78 to 20 ºC
H
H
H
H
H
H
H
H
H
H
11
O
O
CN
HO
(59%, 2 steps)
5:1 dr of crude
(63% of 8)
(95%)
>10:1 dr at
C11 & C15
12
20
H
H
H
H
H
H
2.5:1 dr at C20
axial
methylation
15
H
H
1: DICA
8
16
15
· nine of ten stereogenic centers (all except C20) controlled with high selectivity
· DICA prepared in 10 steps from dehydrocryptone
Scheme 2. A short synthesis of DICA from dehydrocryptone. HMPA: hexamethylphosphoramide; DMDO: dimethyldioxirane; DMSO: dimethyl sulfoxide.
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10.1002/anie.201906834
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COMMUNICATION
To date, we have managed selectivities of 2–2.5:1, but the trivial
separation of the resulting diastereomers, the avoidance of
stoichiometric mercury reagents, and the identical yield to
Shenvi’s multi-step solution makes this an attractive alternative.
Conversion of 8 to 1 by application of Shenvi’s invertive
isocyanation protocol afforded the natural product exactly as
described.14,15 At this stage, we have made over 30 mg of DICA
via this sequence, without any particular efforts to scale up the
chemistry; indeed, all indications to date suggest that significant
quantities of the natural product should be available when
needed.
Our achievement provides
a
reminder that efficient
syntheses need not necessarily rely on the development of new
chemical methods. Indeed, with the wealth of chemical tools
currently at our disposal, strategic advances will continue to be
major contributors to efficiency.
Acknowledgements
Early studies were supported by the National Science
Foundation (CHE-1564340). This work is currently funded by the
National Institutes of Health (AI-138139).
Keywords: terpenoids • antimalarial • Birch reduction • total
While DICA itself has been tested many times, the activities
of its isonitrile-bearing-carbon stereoisomers have not been
reported. The general preference for equatorial methylation of
cyclohexanones renders 16 particularly well suited to making the
unnatural epimer of DICA with both isonitriles equatorial (C20-
epi-DICA, 17, Figure 2). Treatment of 16 with methylmagnesium
chloride was diastereoselective for equatorial methylation, and
further processing afforded 17.20 The potent activity of DICA is
largely retained in its stereoisomer 17, with only a five-fold
decrease in potency toward a drug-resistant (Dd2) strain of
Plasmodium falciparum and a 25-fold decrease against a drug-
sensitive (3D7) strain. This outcome is consistent with the model
put forth by Wright, Tilley and co-workers pertaining to the
antiplasmodial activity of many polycyclic ICTs;21 their modeling
analysis suggests that the C7 equatorial isonitrile correlates with
significant antiplasmodial activity, and that C20 axial substitution
provides a supportive role in slightly improving potency. The
model appears to embrace either electron-poor or alkyl groups
axial at C20, which is further supported by 17’s only modest loss
in activity. Given this outcome, evaluation of the antiplasmodial
activity of the other C7/C20 diastereomers of DICA is
warranted—especially given the pseudo-symmetry of these
compounds—and will be reported in due course.
synthesis • stereocontrol
[1]
[2]
[3]
M. J. Schnermann, R. A. Shenvi, Nat. Prod. Rep. 2015, 32, 543–577.
J. T. Baker, R. J. Wells, J. Am. Chem. Soc. 1976, 98, 4010–4012.
(a) C. K. Angerhofer, J. M. Pezzuto, G. M. König, A. M. Wright, O.
Sticher, J. Nat. Prod. 1992, 55, 1787–1789; (b) G. M König, A. D.
Wright, C. K. Angerhofer, J. Org. Chem. 1996, 61, 3259–3267; For a
review, see: (c) A. D. Wright, G. M. König, C. K. Angerhofer, P.
Greenidge, A. Linden, R. Desqueyroux-Faúndez, J. Nat. Prod. 1996, 59,
710–716.
[4]
[5]
[6]
Kalihinol B: M. E. Daub, J. Prudhomme, K. Le Roch, C. D. Vanderwal, J.
Am. Chem. Soc. 2015, 137, 4912–4915.
Kalihinol analogues: M. E. Daub, J. Prudhomme, C. Ben Mamoun, K. G.
Le Roch, C. D. Vanderwal, ACS Med. Chem. Lett. 2017, 8, 355–360.
DICA: (a) P. C. Roosen, C. D. Vanderwal, Angew. Chem. Int. Ed. 2016,
55, 7180–7183; Angew. Chem. 2016, 128, 7296–7299; (b) Earlier
routes were unsuccessful: P. C. Roosen, C. D. Vanderwal, Org. Lett.
2014, 16, 4368–4371.
[7]
[8]
A. M. White, K. Dao, D. Vrubliauskas, Z. A. Könst, G. K. Pierens, A.
Mándi, K. T. Andrews, T. S. Skinner-Adams, M. E. Clarke, P. Narbutas,
D. C.-M. Sim, K. L. Cheney, T. Kurtán, M. J. Garson, C. D. Vanderwal,
J. Org. Chem. 2017, 82, 13313–13323.
Such substructures played intermediary roles in other ICT syntheses,
most notably in the Wood and Miyaoka groups’ kalihinol work, wherein
they were generated by intramolecular Diels–Alder reactions. See (a) R.
D. White, G. F. Keaney, C. D. Slown, J. L. Wood, Org. Lett. 2004, 6,
1123–1126. (b) H. Miyaoka, H. Shida, N. Yamada, H. Mitome, Y.
Yamada, Tetrahedron Lett. 2002, 43, 2227–2230. (c) H. Miyaoka, Y.
Abe, N. Sekiya, H. Mitome, E. Kawashima, Chem. Commun. 2012, 48,
901–903. (d) H. Miyaoka, Y. Abe, E. Kawashima, Chem. Pharm. Bull.
2012, 60, 1224–1226.
NC
NC
NC
20
CN
17: C20-epi-DICA
1: DICA
IC50 Dd2: 15 nM
IC50 3D7: 2 nM
78 nM
51 nM
[9]
For a review of recurring themes in ICT synthesis strategies, see: M. E.
Daub, P. C. Roosen, C. D. Vanderwal, J. Org. Chem. 2017, 82, 4533–
4541.
Figure 2. The antiplasmodial activity of DICA and C20-epi-DICA
[10] E. J. Corey, P. A. Magriotis, J. Am. Chem. Soc. 1987, 109, 287–288.
[11] H. Miyaoka, Y. Okubo, M. Muroi, H. Mitome, E. Kawashima, Chem. Lett.
2011, 40, 246–247.
In conclusion, we have developed a particularly concise
synthesis of DICA—based on our general strategy—that
features a rapid buildup of much of its carbon scaffold, followed
by efficient introduction of key stereogenic centers by reduction.
We have thereby reduced the problem posed by DICA to a
sequence of ten chemical steps from simple, known starting
materials, obviating all of the unproductive steps that plagued
our previous effort. This synthesis further showcases the power
of the conjugate addition/enolate trapping strategy as a valuable
means of accessing ICT natural products. We have capitalized
on this short, stereoselective synthesis to produce C20-epi-DICA,
which was tested for antiplasmodial activity for the first time, the
results of which support the current working hypothesis on the
activity of polycyclic ICTs.
[12] E. R. Robinson, R. J. Thomson, J. Am. Chem. Soc. 2018, 140, 1956–
1965.
[13] K. A. Fairweather, L. N. A. Mander, Org. Lett. 2006, 8, 3395–3398.
[14] H.-H Lu, S. V. Pronin, Y. Antonova-Koch, S. Meister, E. A. Winzeler, R.
A. Shenvi, J. Am. Chem. Soc. 2016, 138, 7268–7271.
[15] (a) S. V. Pronin, R. A. Shenvi, J. Am. Chem. Soc. 2012, 134, 19604–
19606. (b) S. V. Pronin, C. A. Reiher, R. A. Shenvi, Nature 2013, 501,
195–199.
[16] We use a slightly modified version of the procedure of Razdan and co-
workers to make dehydrocryptone, in which the three-step sequence is
performed with a single purification by distillation of 11: C. Siegel, P. M.
Gordon, D. B. Uliss, G. R. Handrick, H. C. Dalzell, R. K. Razdan, J. Org.
Chem. 1991, 56, 6865–6872. See ref. 6a for details.
[17] The two reactions can also be combined itno a one-pot four-component
coupling process, albeit with diminished yields (ca. 30%).
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10.1002/anie.201906834
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COMMUNICATION
[18] (a) J. Meinwald, S. S. Labana, M. S. Chadha, J. Am. Chem. Soc. 1963,
85, 582–585. For a recent application, see: (b) X. Liao, L. M. Stanley, J.
F. Hartwig, J. Am. Chem. Soc. 2011, 133, 2088–2091.
[20] See supporting information for details.
[21] A. D. Wright, H. Wang, M. Gurrath, G. M. König, G. M.; G. Kocak, G.
Neumann, P. Loria, M. Foley, L. Tilley, J. Med. Chem. 2001, 44, 873–
885.
[19] (a) E. C. Ashby, S. H. Yu, P. V. Roling, J. Org. Chem. 1972, 37, 1918–
1925. (b) J. Laemmle, E. C. Ashby, P. V. Roling, J. Org. Chem. 1973,
38, 2526–2534.
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10.1002/anie.201906834
Angewandte Chemie International Edition
COMMUNICATION
Layout 1:
COMMUNICATION
Br
NC
The flagship antimalarial
isocyanoterpene,
diisocyanoadociane, was
constructed in ten steps from
simple starting materials.
O
H
A. S. Karns, B. D. Ellis, P. C.
Roosen, Z. Chahine, K. G. Le
Roch, and C. D. Vanderwal*
H
O
10 steps
H
H
H
OEt
CN
H
H
MeO
MgBr
Page No. – Page No.
7,20-diisocyanoadociane
A Concise Synthesis of the
Antiplasmodial
simple starting materials
Isocyanoterpene 7,20-
Diisocyanoadociane
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