Asymmetric Total Synthesis of Kopsiyunnanine K, a Monoterpenoid Indole Alkaloid with a Rearranged Skeleton

Article abstract of DOI:10.1021/acs.orglett.6b01704

A new monoterpenoid indole alkaloid, kopsiyunnanine K, was isolated from Kopsia arborea. Its intriguing rearranged structure and absolute configuration, which were inferred from spectral data and a possible biosynthetic pathway, were determined on the bas

Full text of DOI:10.1021/acs.orglett.6b01704

Letter
pubs.acs.org/OrgLett
Asymmetric Total Synthesis of Kopsiyunnanine K, a Monoterpenoid
Indole Alkaloid with a Rearranged Skeleton
Ryoko Tokuda, Yoshiki Okamoto, Tetsuya Koyama, Noriyuki Kogure, Mariko Kitajima,
and Hiromitsu Takayama*
Graduate School of Pharmaceutical Sciences, Chiba University, 1-8-1 Inohana, Chuo-ku, Chiba 260-8675, Japan
*
S Supporting Information
ABSTRACT: A new monoterpenoid indole alkaloid, kopsiyunna-
nine K, was isolated from Kopsia arborea. Its intriguing rearranged
structure and absolute configuration, which were inferred from
spectral data and a possible biosynthetic pathway, were determined
on the basis of a 13-step asymmetric total synthesis.
he genus Kopsia, which belongs to family Apocynaceae, is a
T
rich source of monoterpenoid indole alkaloids possessing
1
structural diversity and a wide range of biological activities. As a
result of our continuing chemical studies on novel bioactive
2
alkaloids, we were able to accomplish the structure elucidation
of several unique monoterpenoid indole alkaloids from Kopsia
3
arborea, which is native to the Yunnan Province in China
(Figure 1). Further investigations have led to the isolation of an
Figure 2. Structure and key COSY and HMBC correlations of
kopsiyunnanine K (1).
{
[α] 24 −60.0 (c 0.02, MeOH)}, named kopsiyunnanine K, was
D
found to have the molecular formula C H N O from HRESI-
MS [m/z 327.20725 (M + H) ]. The UV spectrum was
20
26
2
2
+
characteristic of an indole chromophore with absorption maxima
1
13
at 290.0, 280.0, and 224.0 nm. H and C NMR measurements
revealed a nonsubstituted A ring of an indole system, a methyl
ester, an ethyl group, and one methine group and two methylene
1
1
groups attached to a nitrogen (Table 1). H− H COSY (Figure
2
) suggested the existence of three consecutive methylene
groups (C-3−C-14−C-15). HMBC correlations (Figure 2)
indicated connections among C-3, C-5, and C-16 through a
nitrogen atom and among C-15, C-17, the ethyl group, and the
methyl ester through the C-20 quaternary carbon. Moreover,
correlations of H-16 with C-7 and H-6 with C-2 and C-8
suggested that C-16 was connected to C-2 of the indole moiety.
From these data, compound 1 was proposed to be a
monoterpenoid indole alkaloid bearing the azepine-fused
tetrahydro-β-carboline ring system, which has never been
discovered in monoterpenoid indole alkaloids. The absolute
Figure 1. Structures of kopsiyunnanines A, B, and E.
intriguing new alkaloid named kopsiyunnanine K (1), which has
an unprecedented azepine-fused tetrahydro-β-carboline ring
skeleton (Figure 2). We herein describe the structure elucidation
of the alkaloid based on spectroscopic analysis and biogenetic
consideration and the asymmetric total synthesis consisting of 13
steps.
The crude base obtained from the aerial part of K. arborea was
purified by repeated chromatography to afford new indole
alkaloid 1 (0.0015% yield based on the crude base). Compound 1
Received: June 13, 2016
©
XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.6b01704
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Letter
1
13
Table 1. H NMR (600 MHz) and C NMR (150 MHz)
Spectral Data of Kopsiyunnanine K (1) (in CDCl3)
Scheme 1. Possible Biogenetic Route of Kopsiyunnanine K
(1)
kopsiyunnanine K (1)
position
δH (multi, J, Hz)
δC
2
136.6
60.6
3
5
6
3.12 (ddd, 12.1, 6.5, 1.5)
2
.55−2.63 (overlapped)
3.03 (ddd, 11.5, 4.1, 4.1)
.55−2.63 (overlapped)
2.90 (dddd, 14.9, 9.5, 4.1, 1.9)
.74 (dddd, 14.9, 4.1, 4.1, 1.6)
52.2
21.7
2
2
7
8
9
1
1
1
1
1
1
107.9
126.9
118.0
119.0
121.2
110.7
136.2
24.2
7.47 (d, 7.6)
0
1
2
3
4
5
7.07 (ddd, 7.6, 7.6, 1.1)
7.13 (ddd, 7.6, 7.6, 1.1)
7.36 (d, 7.6)
1.77−1.94 (2H, overlapped)
2.13 (ddd, 13.1, 10.4, 1.2)
esterification of the aldehyde function in B, followed by the
formation of an aldehyde group at C-16 from the hemiaminal
function in B, a possible biogenetic precursor C of
kopsiyunnanine K (1) is generated. Next, 1 would be formed
by Pictet−Spengler reaction of C. This hypothesis allowed us to
suggest that 1 has the rearranged skeleton with C-20R
configuration.
To clarify the structure and the absolute configuration at C-16
and C-20 of 1, asymmetric total synthesis was performed
(Scheme 2). We initially prepared ester derivative 4 from δ-
36.7
1
.77−1.94 (overlapped)
1
1
6
7
3.64 (d, 6.1)
56.4
41.0
2.55−2.63 (overlapped)
1
.77−1.94 (overlapped)
1
1
8
9
0.78 (3H, t, 7.6)
9.2
1.69 (m)
33.8
1
.63 (m)
2
2
0
1
49.9
179.2
52.1
CO CH3
3.79 (3H, s)
8.52 (s)
Scheme 2. Synthesis of Chiral Ester 9
2
NH
configurations at C-16 and C-20 were deduced as follows. The
CD spectrum of 1 showed a Cotton effect opposite to that of
decarbomethoxydihydrogambirtannine (2), a yohimbane-type
alkaloid possessing 3S configuration, which led us to propose that
the configuration at C-16 in 1 was R (Figure 3). The
Figure 3. CD spectra of 1 and 2.
valerolactone (5) via a five-step operation: alkylation of 5 with
EtI, methanolysis, MEM protection of the primary alcohol,
alkaline hydrolysis of 6, and condensation of the resultant
configuration at C-20 was deduced from a biogenetic point of
view. Biogenetically, 1 could be generated from (−)-eburnamine
4
(
3), which coexists in K. arborea, as shown in Scheme 1. The
carboxylic acid with chiral alcohol 6. Asymmetric Ireland−
bond cleavage between C-2 and C-21 positions in 3 occurs by
initial protonation at the C-2 position of the indole moiety to give
the C/E ring-opening intermediate A. Next, hydrolysis of an
iminium function in A gives aldehyde B. By oxidation and
Claisen rearrangement of MEM-protected allyl alcohol derivative
5
4 was performed under the optimum conditions using KHMDS
and TMSCl in toluene. Methylation of the resultant carboxylic
acid 7 gave ester 9 in 90% yield with 92% ee in two steps. An
B
DOI: 10.1021/acs.orglett.6b01704
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efficient chirality transfer process of the Ireland−Claisen
rearrangement can be explained by using a transition state
depicted in Scheme 2. In the chairlike transition state, the phenyl
group takes the pseudoequatrial position. Furthermore, in the
ketene acetal moiety, the side chain with a MEM group favors the
equatorial position with the aid of the chelate effect. Actually,
when a MOM group or a TBS group was used for the protection
of the primary alcohol in place of the MEM group in 4, the
enantiomeric excesses of the products formed by the Ireland−
Claisen rearrangement decreased (MOM, 81% ee; TBS, 0.3%
ee).
Therefore, the structure and the absolute configuration of
kopsiyunnanine K were established, as shown in formula 1.
In conclusion, we have succeeded in the asymmetric total
synthesis of kopsiyunnanine K (1), an indole alkaloid that was
newly isolated from Kopsia arborea, via an asymmetric Ireland−
Claisen rearrangement and an intramolecular diastereoselective
Pictet−Spengler reaction, and proved its unique rearranged
skeleton and absolute configuration. Its biological activity is
currently being evaluated.
ASSOCIATED CONTENT
Supporting Information
■
Next, an amine function was introduced to 9 by deprotection
of the MEM group followed by the Mitsunobu reaction with
*
S
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.orglett.6b01704.
NsNH to afford amide 10 (Scheme 3). After ozonolysis of 10,
2
Experimental procedures for the isolation of kopsiyunna-
nine K (1), preparation of compounds 4−6, 9−12, and
synthetic 1, and copies of NMR spectral data for natural 1,
compounds 4−6, 9−12, and synthetic 1 (PDF)
X-ray data of compound 1 (CIF)
Scheme 3. Synthesis of Kopsiyunnanine K (1)
AUTHOR INFORMATION
Corresponding Author
■
*
E-mail: takayamah@faculty.chiba-u.jp.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
This work was supported by JSPS KAKENHI Grant Nos.
6293023 and 16H05094, and The Uehara Memorial
■
2
Foundation.
REFERENCES
■
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DOI: 10.1021/acs.orglett.6b01704
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