Stereoselective Total Synthesis of KAE609 via Direct Catalytic Asymmetric Alkynylation to Ketimine

Article abstract of DOI:10.1021/acs.orglett.5b02300

A direct catalytic asymmetric alkynylation protocol is applied to provide the requisite enantioenriched propargylic α-tertiary amine, allowing for the stereoselective total synthesis of KAE609 (formerly NITD609 or cipargamin).

Full text of DOI:10.1021/acs.orglett.5b02300

Letter
pubs.acs.org/OrgLett
Stereoselective Total Synthesis of KAE609 via Direct Catalytic
Asymmetric Alkynylation to Ketimine
Hisashi Takada,† Naoya Kumagai,*,† and Masakatsu Shibasaki*,†,‡
†Institute of Microbial Chemistry (BIKAKEN), Tokyo, 3-14-23 Kamiosaki, Shinagawa-ku, Tokyo 141-0021, Japan
‡JST, ACT-C, 3-14-23 Kamiosaki, Shinagawa-ku, Tokyo 141-0021, Japan
S
* Supporting Information
ABSTRACT: A direct catalytic asymmetric alkynylation
protocol is applied to provide the requisite enantioenriched
propargylic α-tertiary amine, allowing for the stereoselective
total synthesis of KAE609 (formerly NITD609 or cipargamin).
alaria is a life-threatening infectious disease that remains
a persistent global health concern. In 2013 alone,
the most active compound (Figure 1).5 The Pictet−Spengler
M
reaction of 5-chloroisatin (1) and α- methyltryptamine (2)
preferentially afforded the desired diastereomer,8,9 and a more
efficient synthetic approach via enantioenriched (S)-2 was
extensively studied using engineered enzymes for large scale
production of KAE609.10 The amine-containing tetrasubsti-
tuted stereogenic center of KAE609 and its favorable promise
as a novel treatment for malaria led us to examine the potential
of our asymmetric catalysts to furnish this fascinating molecule.
We anticipated that direct catalytic asymmetric alkynylation of
ketimines,11,12 which was recently developed in our group,13
would be feasible for use with a functionalized terminal alkyne
to construct the requisite tetrasubstituted stereogenic center
(Scheme 1). The halogenated o-alkynylaniline moiety of the
resulting adduct is a direct precursor of an indole unit, and
malaria caused ∼584,000 deaths, mostly among African
children.1 Malaria is caused by protozoan parasites, Plasmodium
falciparum and Plasmodium vivax, causing acute flu-like
symptoms. Currently, the primary treatment of malaria
infection is artemisinin-containing combination therapies, but
the recent emergence of artemisinin-resistant strains has led to
an urgent demand for new antimalarial drug candidates.2−4 The
Novartis Institute of Tropical Diseases discovered a new
spiroindolone entity by high-throughput screening, KAE609
(formerly NITD609 or cipargamin), that exhibits novel and
potent antimalarial activity (Figure 1).5−7 Under the growing
Scheme 1. Retrosynthetic Analysis of KAE609
Figure 1. Structure of KAE609 and its synthetic approach.
threat of artemisinin resistance, clinical development of
KAE609 is now underway (phase II) with promising prospects.
KAE609 is characterized by a tetrasubstituted stereogenic spiro
carbon at the junction of an oxindole unit and an indole-fused
piperidine unit with an additional chiral center. The three
halogen atoms present necessitate prefunctionalization of the
synthetic units. All four stereoisomers were synthesized and
separated by HPLC (Figure 1a), and KAE609 was identified as
Received: August 8, 2015
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.5b02300
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Organic Letters
Letter
Table 1. Direct Catalytic Asymmetric Alkynylation Functionalized Terminal Alkyne 3 to N-(Diphenylthiophosphinoyl)ketimine
a
4
alkyne 3
product
b
c
entry
R =
ligand
solvent
config
temp (°C)
time (h)
yield (%)
ee (%)
1
2
3
4
5
H
3a
3b
3c
3d
3e
3e
(S,S)-Ph-BPE
(S,S)-Ph-BPE
(S,S)-Ph-BPE
(S,S)-Ph-BPE
(S,S)-Ph-BPE
THF
THF
THF
THF
THF
DMF
5a
5b
5c
5d
5e
5e
−78
−78
−78
−78
−78
18
21
18
24
18
24
79

38
98
87
97
73

81
40
87
96
CF3CO
Cbz
Fmoc
Boc
R
S
d
6
Boc
(R,R)-Ph-BPE
−30
d
a
b
c
3: 0.075 mmol. 4a: 0.05 mmol. Isolated yield. Determined by chiral-stationary-phase HPLC. 3.1 g of 4a was used. 1.2 equiv of 3e was used.
subsequent introduction of an acetonyl group at C3 of the
indole followed by intramolecular reductive amination would
afford KAE609.
The synthesis of KAE609 was initiated by direct catalytic
asymmetric alkynylation of functionalized terminal alkyne 3 to
N-(diphenylthiophosphinoyl(thioDpp))ketimine 4a derived
from 5-chloroisatin (Table 1).14,15 Based on our previous
communication documenting the alkynylation of N-thioDpp-
ketimines derived from aryl alkyl ketones (e.g., acetophenones),
we applied a catalyst comprising mesitylcopper/(S,S)-Ph-BPE
for the alkynylation using terminal alkyne 3a with the requisite
halogen substituents and a free amino group (entry 1). In
contrast to the reaction using N-thioDpp-ketimines derived
from normal ketones, 4a exhibited much higher reactivity and
the reaction proceeded even at −78 °C, affording 5a in 79%
yield with 73% ee. Mesitylcopper ligated with Ph-BPE initially
generated a Cu-alkynylide from a terminal alkyne that was
sufficiently nucleophilic toward 4a, which was also activated by
a Cu/Ph-BPE complex through a soft−soft interaction. The
thus-generated intermediate 6 deprotonated 3 and drove the
following catalytic cycle with concomitant liberation of product
5a. A protecting group on the nitrogen modulated the reaction
profile. Whereas alkyne 3b with a trifluoroacetyl protecting
group gave a complicated mixture (entry 2), N-Cbz, -Fmoc, and
-Boc protected alkynes 3c−e afforded the desired products
(entries 3−5). 3d exhibited superior reactivity (entry 4), but
based on enantioselectivity, 3e (Boc) was selected as the best
substrate (entry 5). Unexpectedly, the absolute configuration of
the alkynylated product 5e was the undesired R. Based on a
previous observation that alkynes approached from the upper
prochiral face of ketimines derived from aryl alkyl ketones (e.g.,
acetophenone 4b) using (S,S)-Ph-BPE (Figure 2a), we
anticipated that ketimine 4a would react in a similar manner
in an essentially identical catalytic system. In contrast to our
expectation, however, the manner of approach for 4a was the
opposite; 3e approached from the lower prochiral face of 4a
(Figure 2b), presumably due to the different orientation of the
thioDpp group, which would determine the stereochemical
Figure 2. (a) Structures of stable conformers of ketimines 4b and 4c
and stereochemical course of asymmetric alkynylation using (S,S)-Ph-
BPE. (b) Crystal structure of 4a. White, hydrogen; gray, carbon; blue,
nitrogen; red, oxygen; orange, phosphorus; yellow, sulfur; green,
chlorine.
course in the present Cu(I) catalysis. The optimized structures
were computed for 4b and simplified isatin-derived ketimine 4c
using the 6-31G+(d,p) basis set at the B3LYP level of theory
(Figure 2a).16 Whereas the thioDpp group was located on the
side opposite that of the aromatic group of 4b, it occupied the
same side relative to the aromatic ring of 4c, likely due to
electronic repulsion with the neighboring carbonyl. Indeed, X-
ray crystallographic analysis of 4a revealed the expected
geometry (Figure 2b). The different orientation might be
responsible for the opposite stereochemical course. Use of
B
DOI: 10.1021/acs.orglett.5b02300
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Organic Letters
Letter
Scheme 2. Synthesis of KAE609
DMF as a solvent improved the enantioselectivity, and the
desired (S)-5e was obtained on a greater than 3-g scale in 97%
yield with 96% ee using (R,R)-Ph-BPE (entry 6).
14 with the requisite spiroindole core. Final removal of the N-
PMB group on the oxindole of isolated diastereomer 14 was
achieved by TfOH, affording KAE609, whose spectroscopic
data were consistent with previously reported data.
Synthesis of KAE609 from key intermediate (S)-5e is
illustrated in Scheme 2. After removing the Boc group of
(S)-5e by TFA, Cu(I) catalyzed intramolecular hydroamination
of the alkyne furnished the requisite indole unit to give 8 in
93% yield.17 Racemic ( )-8 was preferentially recrystallized
from EtOAc/n-hexane, and the mother liquor was enriched to
afford enantiomerically pure 8, from which we removed the N-
thioDpp group. Acidic conditions are generally applied to
remove the protecting group, but acidic treatment of 8 gave a
mixture of unidentified compounds. Alternatively, the thio-
phosphinoyl group was desulfurinated by Raney-Ni and the
thus-generated trivalent aminophosphine was hydrolyzed under
the mild acidic conditions of AcOH to give 9. Before
manipulation of the indole ring, the free amine was protected
by a Cbz group, and various conditions were evaluated to
directly provide 13 bearing an acetonyl unit at the 3-position of
indole, which were unsuccessful. Therefore, a stepwise
approach to 13 was adopted and the C1-unit was initially
introduced by a Vilsmeier−Haack reaction to deliver 3-
formylated indole 11.18 A nitroaldol/β-elimination sequence
with nitroethane gave nitroolefin 12, and subsequent reduction
of the nitro group mediated by Zn followed by acidic hydrolysis
gave 13, which was a key substrate for the crucial
diastereoselective intramolecular reductive amination. The
Cbz group was resistant to removal under conventional
conditions, and only specific conditions of Et3SiH/Pd(OAc)2
were effective in giving a transient triethylsilyl carbamate.19
Addition of TFA triggered the decomposition of the silyl
carbamate to expose a free amine, affording a cyclic ketimine
intermediate. Because the attempts to isolate the cyclic
ketimine led to undesired benzylic oxidation, the ketimine
was directly subjected to reducing conditions using BH3·
picoline,20 which preferentially furnished desired diastereomer
In conclusion, KAE609 (formerly NITD609 or cipargamin),
a potent antimalaria drug under Phase II clinical trials by
Novartis, was synthesized in an optically pure form. Direct
catalytic asymmetric alkynylation of ketimine was applied as a
key step to generate the requisite tetrasubstituted stereogenic
center. Asymmetric alkynylation to ketimines using a catalytic
amount of metal remains challenging, and the synthesis
presented here showcases the synthetic utility of this elusive
reaction.
ASSOCIATED CONTENT
* Supporting Information
■
S
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.5b02300.
Experimental procedures and characterization of new
compounds (PDF)
X-ray data for 4a (CIF)
AUTHOR INFORMATION
Corresponding Authors
■
*E-mail: nkumagai@bikaken.or.jp.
*E-mail: mshibasa@bikaken.or.jp.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
This work was financially supported by JST, ACT-C, and JSPS
KAKENHI Grant Number 25713002. N.K. thanks The
Mochida Memorial Foundation for Medical and Pharmaceutical
C
DOI: 10.1021/acs.orglett.5b02300
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Letter
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Research for financial support. Dr. Tomoyuki Kimura at the
Institute of Microbial Chemistry is gratefully acknowledged for
technical assistance with the X-ray crystallographic analysis of
4a.
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