Total synthesis of angustine and angustoline

Article abstract of DOI:10.1016/j.tetlet.2020.151757

A short total synthesis of the indolopyridine alkaloids angustine (1) and angustoline (2) has been achieved in five and six steps, respectively. Two key steps for assembly of the pentacyclic core included a Bischler-Napieralski cyclization and a cobalt-catalyzed carbonylative lactamization. A late-stage Mukaiyama hydration allowed the first successful transformation of angustine (1) to angustoline (2).

Full text of DOI:10.1016/j.tetlet.2020.151757

Tetrahedron Letters xxx (xxxx) xxx
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Total synthesis of angustine and angustoline
⇑
⇑
Xin Peng, Min Fu, Jingdan Ou, Ruidi Cao, Hao Song , Xiao-Yu Liu, Yong Qin
Key Laboratory of Drug-Targeting and Drug Delivery System of the Education Ministry, Sichuan Engineering Laboratory for Plant-Sourced Drug and Sichuan Research Center for
Drug Precision Industrial Technology, West China School of Pharmacy, Sichuan University, Chengdu 610041, China
a r t i c l e i n f o
a b s t r a c t
Article history:
A short total synthesis of the indolopyridine alkaloids angustine (1) and angustoline (2) has been
achieved in five and six steps, respectively. Two key steps for assembly of the pentacyclic core included
a Bischler-Napieralski cyclization and a cobalt-catalyzed carbonylative lactamization. A late-stage
Mukaiyama hydration allowed the first successful transformation of angustine (1) to angustoline (2).
Ó 2020 Published by Elsevier Ltd.
Received 4 February 2020
Accepted 19 February 2020
Available online xxxx
Keywords:
Natural product
Alkaloid
Angustine
Angustoline
Total synthesis
Indolopyridine alkaloids, a group of natural products belonging
to the Vallesiachotaman class of monoterpenoid indole alkaloids,
have exhibited a wide range of interesting biological activities such
as anti-inflammatory, renin inhibitory, antimalarial, anti-prolifera-
tive, and antiviral activities [1–5]. Two representative members of
this structural type, angustine (1, Fig. 1) and (19R)-angustoline
[(À)-2] were first isolated from Strychnos angustiflora Benth., a
medicinal plant indigenous to South China, by Cheung and co-
workers in 1973 [6]. Since then, more angustine-type alkaloids
(e.g., 1–5) were found from various species of the genera Strychnos,
Mitragyna, Nauclea, Uncaria, and Vinca [7]. Of note, (19S)-angusto-
line [(+)-2] was also identified as a natural product by Liu, Luo, and
their colleagues [8]. Architecturally, angustine-type alkaloids fea-
ture a non-typical corynanthe framework with substituted pyri-
dine rings embedded in the pentacyclic or hexacyclic cores. From
a biogenesis point of view, these molecules were derived from
tryptamine and secologanin closely related to gentianine, with
the pyridine units formed by insertion of the nitrogen atom at a
late stage [6].
As the most representative angustine-type indolopyridine alka-
loids, structurally, angustine (1) and angustoline (2) share a com-
mon pentacyclic backbone and only differ in the side chains at
C20. The former possesses a terminal C18–C19 alkene, while the
latter contains a secondary hydroxyl group at the C19 position.
Due to the complex structures and intriguing bioactivities, angu-
stine (1) and angustoline (2) attracted the attention of synthetic
chemists since their isolation (Scheme 1A). In 1975, Kametani
et al reported the synthesis of angustine (1) using a condensation
(6 and 7 to 8) and an acidic cyclization (8 to 1) as key steps
[9,10]. Later, Repke group employed an organometallic addition
of lithium 10 to iminium salt 9 to yield the pentacyclic 11 and real-
ized an efficient synthesis of 1 [11,12]. Lavilla, Bosch, and col-
leagues disclosed the synthesis of angustine (1) harnessing a
nucleophilic addition (12 to 13) to establish the D ring, followed
by a palladium-catalyzed cross coupling to install the C20 terminal
alkene [13,14]. Of note, in an earlier study, Ninomiya and co-work-
ers documented a unified synthesis of angustine (1), angustoline
(2), and naucletine (3) relying on a photocyclization of enamide
14 as the key strategy [15,16]. Additionally, reduction of the ketone
carbonyl group in 3 provided 2, while further dehydration of 2
afforded 1. The aforementioned previous syntheses suffered from
several disadvantages including low-yielding transformations or
lack of regiospecificity with regard to the pyridine nitrogen atom
in D ring formation steps. Moreover, attempts to convert angustine
(1) into angustoline (2) by oxidation were unsuccessful [14],
although in reverse transformation of 2 to 1 worked with prece-
dents. Bearing in mind to address the above questions, and as
our continuous interest in the total synthesis indole alkaloids
[17,18], here we present a new synthetic approach to angustine
(1) and angustoline (2).
Our retrosynthetic analysis of angustine (1) and angustoline (2)
is depicted in Scheme 1B. We envisioned that angustoline (2) could
be accessed via a Mukaiyama hydration of the C18–C19 alkene in 1.
Generation of the pyridino-indolo-quinolizidinone pentacyclic
skeleton would rely on a carbonylation process of the advanced
intermediate 15. In turn, compound 15 could be synthesized from
amide 16 through a Bischler-Napieralski cyclization to assemble C
⇑
Corresponding authors.
E-mail addresses: songhao@scu.edu.cn (H. Song), yongqin@scu.edu.cn (Y. Qin).
https://doi.org/10.1016/j.tetlet.2020.151757
0040-4039/Ó 2020 Published by Elsevier Ltd.
Please cite this article as: X. Peng, M. Fu, J. Ou et al., Total synthesis of angustine and angustoline, Tetrahedron Letters, https://doi.org/10.1016/j.
tetlet.2020.151757

2
X. Peng et al. / Tetrahedron Letters xxx (xxxx) xxx
Fig. 1. Representative indolopyridine alkaloids.
ring. Finally, 16 could be traced back to tryptamine (6) and ester
17.
According to the retrosynthetic analysis, our synthetic endeav-
ors commenced with the preparation of amide 16. As shown in
Scheme 2, Suzuki coupling of the commercially available
3,5-dibromo-4-methylpyridine (18) with potassium vinyltrifluo-
roborate (19) occurred in the presence of Pd(dppf)2Cl2 in a mixture
of TEA and EtOH at 90 °C, which resulted in the generation of
alkene 20 (66% yield). Compound 20 was treated with dimethyl
carbonate and LHMDS to give ester 17 with a moderate 40% yield.
Next, condensation of 17 with tryptamine (6) under the conditions
of 1,5,7-triazabicyclo-[4.4.0]dec-5-ene (TBD) [19,20] in toluene at
80 °C allowed the formation of the desired amide 16 (46% yield).
Despite the success in a three-step preparation of the intermediate
16, the overall efficiency (12% yield from 18) was not satisfactory.
We suspected that the presence of a vinyl group on the pyridine
ring might cause the low yield of the homologation (20 to 17)
and amide formation (17 to 16) steps. In this context, a slightly
modified three-step approach was performed from dibromide 18.
The synthetic sequence included 1) esterification at the methyl
Scheme 2. Total synthesis of angustine (1) and angustoline (2).
group in 18 to afford 21, 2) aminolysis of ester 21 with tryptamine
(6) to yield 22, and 3) selective vinylation of 22 via Suzuki coupling,
leading to the key precursor 16 with improved overall yield (51%,
Scheme 1. A) Representative previous approaches to angustine (1) and angustoline (2) and B) retrosynthetic analysis in this work.
Please cite this article as: X. Peng, M. Fu, J. Ou et al., Total synthesis of angustine and angustoline, Tetrahedron Letters, https://doi.org/10.1016/j.
tetlet.2020.151757

X. Peng et al. / Tetrahedron Letters xxx (xxxx) xxx
3
Table 1
Moreover, to the best of our knowledge, we accomplished the con-
version of angustine (1) to angustoline (2) through a Mukaiyama
hydration for the first time. Further evaluation of the bioactivity
of associated compounds is currently underway in our laboratory.
Anti-ZIKV(BHK) activity data of (À)-angustoline and (+)-angustoline.
Compound
IC50[lM]
(À)-angustoline
(+)-angustoline
NITD008a
68.67
17.91
1.00
Declaration of Competing Interest
a
NITD008, a potent and selective flaviviruse inhibitor, was used as a positive
The authors declare that they have no known competing finan-
cial interests or personal relationships that could have appeared
to influence the work reported in this paper.
control here.
three steps). Subsequently, amide 16 was subjected to the condi-
tions of POCl3 at 80 °C and underwent the anticipated Bischler-
Napieralski reaction to furnish 15 as a pair of inseparable and
air-sensitive isomers (15a and 15b, 1:5 in d6-DMSO, 1:2 in CDCl3)
with 62% overall yield. While 15a and 15b existed in an equilib-
rium, we believed that both isomers could be carried forward in
subsequent synthesis. Thus, our next attention was focused on
the construction of the critical D ring of the target molecules
through carbonylation. Initial attempts by using methyl chlorofor-
mate or dimethyl carbonate in the presence of n-butyl lithium to
access angustine (1) were unsuccessful, as these conditions led to
either decomposition of precursor 15 or no reaction. Further
screening of the palladium-catalyzed conditions under CO failed
to construct the D-ring as well. Therefore, we turned to the cobalt
catalysts which were commonly used in the carbonylation of
enamide substrates. To our delight, when Co2(CO)8 was used as
the catalyst [21], carbonylation of 15a and 15b occurred with ethyl
chloroacetate under the conditions of potassium carbonate in
MeOH at 60 °C, efficiently providing angustine (1) in 78% yield with
the requisite carbonyl group installed. In this reaction, the alkyl-
cobalt complex of Co2(CO)8 and ClCH2COC2H5 acted as the true cat-
alyst [21], so that the product 1 could barely be detected in the
absence of ethyl chloroacetate. With a five-step synthesis of angu-
stine (1) established, we then investigated the transformation of
angustine (1) to angustoline (2). Based on the previous literature
reports, the vinyl side chain in 1 was unable to be modified by a
variety of agents such as m-chloroperbenzoic acid, hydrogen per-
oxide, and thallium trinitrate [14]. Pleasingly, we found that con-
version of angustine (1) to ( )-angustoline (2) was successful
with 84% yield under the Mukaiyama hydration conditions: [Mn
(dpm)3, PhSiH3, O2, EtOH, room temperature]. In order to further
explore the biological profiles of angustoline 2, both enantiomers
[i.e., (+)-(19S)-angustoline and (À)-(19R)-angustoline] were
obtained by resolution of the racemic material through preparative
HPLC. Preliminary in vitro activity screening revealed that (À)-
angustoline and (+)-angustoline exhibited weak inhibitory activity
against Zika virus (Table 1), which might be of value for further
investigations.
Acknowledgements
We are grateful for the financial support from National Natural
Science Foundation of China (21732005) and National Science and
Technology Major Projects for ‘‘Major New Drugs Innovation and
Development” (2018ZX09101003-005-004).
Appendix A. Supplementary data
Supplementary data to this article can be found online at
https://doi.org/10.1016/j.tetlet.2020.151757.
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In conclusion, we have developed a concise synthetic approach
to angustine (1) and angustoline (2). Key steps of this synthesis
include a Bischler-Napieralski cyclization to form the C ring and
a late-stage cobalt-catalyzed carbonylation to forge the D ring.
Please cite this article as: X. Peng, M. Fu, J. Ou et al., Total synthesis of angustine and angustoline, Tetrahedron Letters, https://doi.org/10.1016/j.
tetlet.2020.151757