Asymmetric Formal Synthesis of (+)-Catharanthine via Desymmetrization of Isoquinuclidine

Article abstract of DOI:10.1021/acs.orglett.9b01198

Although (+)-catharanthine is an attractive alkaloid for both clinical research and organic synthetic chemistry, only a limited number of approaches for its catalytic asymmetric synthesis exist. Herein, we describe a novel strategy for synthesizing a chir

Full text of DOI:10.1021/acs.orglett.9b01198

Letter
pubs.acs.org/OrgLett
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
Asymmetric Formal Synthesis of (+)-Catharanthine via
Desymmetrization of Isoquinuclidine
Masato Kono,† Shingo Harada,*,† Tomoyuki Nozaki,† Yoshinori Hashimoto,† Shun-ichi Murata,†
‡
Harald Groger, Yusuke Kuroda,§ Ken-ichi Yamada,∥ Kiyosei Takasu,§ Yasumasa Hamada,†
̈
and Tetsuhiro Nemoto*,†,⊥
†Graduate School of Pharmaceutical Sciences, Chiba University, 1-8-1, Inohana, Chuo-ku, Chiba 260-8675, Japan
‡
̈
Chair of Organic Chemistry I, Faculty of Chemistry, Bielefeld University, Universitatsstraße 25, 33615 Bielefeld, Germany
§Graduate School of Pharmaceutical Sciences, Kyoto University, Yoshida, Sakyo-ku, Kyoto 606-8501, Japan
∥Graduate School of Pharmaceutical Sciences, Tokushima University, Shomachi, Tokushima 770-8505, Japan
⊥Molecular Chirality Research Center, Chiba University, 1-33, Yayoi-cho, Inage-ku, Chiba 263-8522, Japan
S
* Supporting Information
ABSTRACT: Although (+)-catharanthine is an attractive
alkaloid for both clinical research and organic synthetic
chemistry, only a limited number of approaches for its catalytic
asymmetric synthesis exist. Herein, we describe a novel strategy
for synthesizing a chiral intermediate of (+)-catharanthine via
phosphoric acid-catalyzed asymmetric desymmetrization of a
meso-isoquinuclidine possessing a 1,3-diol unit that was
synthesized by a formal amide insertion reaction.
he two-azabicyclo[2.2.2]octane ring system, isoquinucli-
dine, is a privileged chemical structure found in bioactive
used in the treatment of several human cancers.9 The supply of
(+)-catharanthine, however, has long relied on its extraction
from the leaves of Madagascan periwinkle (Catharanthus roseus
L. Don).10 The low natural abundance (approximately
0.0003% of dried leaf mass) and unique functionalized
isoquinuclidine with a seven-membered ring-fused indole
ring system has motivated the development of a new synthetic
route to catharanthine. Although syntheses of ( )-cathar-
anthine in a racemic format have been investigated well,11 only
one asymmetric total synthesis was achieved by Oguri,12 using
a chiral auxiliary. Asymmetric formal synthesis of catharanthine
based on a chiral pool method,13 catalytic enantioselective
Diels−Alder reaction using chiral amines5b,14 or a chiral
Brønsted acid,6 and an enantioselective Pictet−Spengler-type
reaction15 have been reported to date. Given its biological
importance and limited synthetic methodology, new synthetic
approaches to the catalytic asymmetric construction of
isoquinuclidines for synthesizing (+)-catharanthine are in
high demand.
T
alkaloids and pharmaceuticals (Figure 1).1,2 Novel natural
Figure 1. Indole alkaloids possessing an isoquinuclidine framework.
products with an isoquinuclidine core, notably a family of
monoterpenoid indoles, continue to be isolated.3 The
molecular architecture is an advantageous scaffold for
synthesizing other natural products through functionalization
of the framework.4 The development of synthetic methods,
especially asymmetric syntheses, for isoquinuclidine, is there-
fore in high demand.5,6
(+)-Catharanthine is an important member of the Iboga
class of alkaloids.7 It is a representative indole alkaloid and has
attracted the attention of clinical researchers because it can be
converted into some (pseudo)natural products4b and vinblas-
tine in one step,8 which has strong anticancer activity and is
We recently developed a formal amide insertion of metal-
carbene16 followed by a diastereoselective reduction sequence
for the synthesis of meso-isoquinuclidine 5 with a 1,3-diol unit
from easily available diazo compounds 3 (Scheme 1).17 This
meso compound could be a versatile synthetic scaffold for a
chiral 2-azabicyclo[2.2.2]octane ring system with four chiral
stereocenters if an asymmetric desymmetrization of 5 is
Received: April 5, 2019
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.9b01198
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
Scheme 1. Synthetic Strategy for Chiral Isoquinuclidine
Based on an Amide Insertion-Asymmetric
Desymmetrization Sequence
Scheme 3. Acylation Reaction without the Use of a Catalyst
a
furnished the corresponding monoester 13 in an enantioen-
riched form, although a prolonged reaction time and a higher
temperature were required [89:11 er (entry 1, Table 1)].
Table 1. Optimization of the Reaction Conditions for
Asymmetric Desymmetrization
a
PMB is p-methoxybenzyl.
achieved. Methods for the desymmetrization of meso-1,3-diol,
however, are quite limited18 compared with that of meso-1,2-
diol,19 for which reactions using structurally simple 1,3-diols
were developed. Takasu and Yamada developed an asymmetric
acylation of cyclic secondary alcohols20 to separate the
enantiomeric constituents from a racemic mixture21 using a
chiral phosphoric acid.22 The acid catalyst enhanced the
electrophilicity of an acylation reagent and activated one
enantiomer of the secondary alcohol under a chiral environ-
ment. This background led us to hypothesize that desymmet-
rization of 5 would be realized using a chiral phosphoric acid
under the appropriate conditions. The application allowed us
to overcome the fundamental limitations of the yield (≤50%)
in our previous method based on kinetic resolution and
enantioselective synthesis of the isoquinuclidine architecture.
Herein, we report an amide insertion-asymmetric desym-
metrization strategy for the synthesis chiral isoquinuclidine,
leading to the formal asymmetric synthesis of (+)-cathar-
anthine.
entry
catalyst
solvent
CHCl3
1,4-dioxane
benzene
PhCF3
toluene
toluene
toluene
toluene
toluene
toluene
yield (%)
er
a
1
8a
8a
8a
8a
8a
8b
8c
8f
40
35
55
36
51
68
55
49
60
74
89:11
66:34
86:14
91:9
2
3
4
5
6
7
8
9
92:8
78:22
77:23
80:20
96:4
8d
8e
10
97:3
a
Reaction was performed under reflux.
Our synthesis commenced by the synthesis of 5 via a formal
amide insertion reaction, and then asymmetric acylation of the
meso-1,3-diol was examined using chiral phosphoric acid
catalyst 8a (Scheme 2).23 At first, the asymmetric acylation
Subsequent solvent screening to optimize the reaction
conditions revealed that a polar solvent was not suitable for
this reaction, giving 13 with decreased enantioselectivity (1,4-
dioxane, 66:34 er, entry 2). Nonpolar solvents, such as
benzene, PhCF3, and toluene, afforded 13 with good
enantioselectivity, although the product yields were still low
(36−55% yield, entries 3−5, respectively). Next, electronic
tuning and steric tuning of the Brønsted acid catalyst were
performed. The use of catalyst 8b, 8c, or 8f possessing a 3,5-
(CF3)2-C6H3, 4-Mes-C6H3, or Ph3Si group, respectively, at the
3,3′-positions of the BINOL core was not effective (77:23−
80:20 er, entries 6−8). Meanwhile, introduction of a nitro
group at the 6,6′-positions of the BINOL backbone was
beneficial for improving both the yield and the enantiose-
lectivity (8d, 60% yield, 96:4 er, entry 9).20,25 Isopropyl groups
on catalyst 8e were replaced with cyclohexyl groups to further
increase the reaction efficiency, producing 13 in 74% yield and
97:3 er (entry 10).26,27
Having successfully constructed chiral isoquinuclidine 13,
we moved on to the formal synthesis of (+)-catharanthine
(Scheme 4). First, 13 was converted into 14 via cost-friendly
Albright−Goldman oxidation28 using Ac2O in DMSO in 89%
yield. After recrystallization of 14 to increase the optical purity,
triflation using KHMDS and PhNTf2 proceeded in good yield.
Triflate 15 was next exposed to reductive conditions with
PdCl2(PPh3)2/HCOOH, affording disubstituted olefin 16 in
Scheme 2. Initial Trial of Desymmetrization
was applied to 5 in CHCl3 at room temperature, but that
resulted in low yield with no enantiomeric excess. This is
presumably due to a basic nitrogen functionality of the
substrate, which would cause a background reaction promoted
by intramolecular hydrogen bonding and/or deactivation of
the acid catalyst. Actually, the reaction of 5 without a catalyst
proceeded even at low temperatures (Scheme 3). To suppress
the nonselective reaction, we prepared N-Boc-protected
substrate 9 and tried desymmetrization, which afforded 10
with a 53:47 er. The reaction of 12 with an N-Ns group24 as a
more powerful electron-withdrawing substituent using 8a
B
DOI: 10.1021/acs.orglett.9b01198
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
Scheme 4. Asymmetric Formal Synthesis of
(+)-Catharanthine
ASSOCIATED CONTENT
■
a
S
* Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.9b01198.
Experimental details and characterization data (PDF)
AUTHOR INFORMATION
■
Corresponding Authors
*E-mail: sharada@chiba-u.jp.
*E-mail: tnemoto@faculty.chiba-u.jp.
ORCID
̈
Harald Groger: 0000-0001-8582-2107
Kiyosei Takasu: 0000-0002-1798-7919
Tetsuhiro Nemoto: 0000-0001-8858-161X
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
This work was supported by The Uehara Memorial
Foundation, a Grant-in-Aid from the Tokyo Biochemical
Research Foundation, Ube industries foundation, The Inohana
Foundation (Chiba University), the Nagai Memorial Research
Scholarship from the Pharmaceutical Society of Japan, and
JSPS KAKENHI Grants JP18K05098 and 18H02550.
a
EDCI is 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide.
REFERENCES
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under Albright−Goldman oxidation conditions, and its crude
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in our laboratory.
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(23) See the Supporting Information for details.
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(26) The electronic and steric effect of the N-Ns group in 12 seems
to enhance the enantioselectivity; however, the detailed reaction
mechanism is still unclear. Computational and experimental studies of
the mechanism of this asymmetric desymmetrization are the focus of
further investigations and will be reported in due course.
(27) We also performed a preliminary enzyme screening for the
desymmetrization. During the initial screening process, however, we
could find successful organocatalytic conditions. Therefore, the
enzyme approach has not been pursued further.
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E
DOI: 10.1021/acs.orglett.9b01198
Org. Lett. XXXX, XXX, XXX−XXX