Collective Total Synthesis of (-)-Lundurines A-C

Article abstract of DOI:10.1021/acs.orglett.8b00210

A collective asymmetric total synthesis of lundurines A-C using l-pyroglutamic acid derived from the chiral pool is described. The key steps include a tandem reductive amination/lactamization sequence to introduce the pyrrolidinone ring, a palladium-catalyzed intramolecular direct C-H vinylation of indole to construct the crucial polyhydroazocine ring, and a Lewis acid promoted formal [3 + 2] cycloaddition/N₂ extrusion process to install the polysubstituted cyclopropyl ring.

Full text of DOI:10.1021/acs.orglett.8b00210

Letter
pubs.acs.org/OrgLett
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
Collective Total Synthesis of (−)-Lundurines A−C
Wei Xu,† Jianfei Zhao,† Cheng Tao,† Huifei Wang,‡ Yun Li,† Bin Cheng,*,† and Hongbin Zhai*,†,‡,⊥
†The State Key Laboratory of Applied Organic Chemistry, College of Chemistry and Chemical Engineering, Lanzhou University,
Lanzhou 730000, China
‡Key Laboratory of Chemical Genomics, School of Chemical Biology and Biotechnology, Shenzhen Graduate School of Peking
University, Shenzhen 518055, China
⊥Collaborative Innovation Center of Chemical Science and Engineering (Tianjin), Tianjin 300071, China
S
* Supporting Information
ABSTRACT: A collective asymmetric total synthesis of lundurines A−C using L-pyroglutamic acid derived from the chiral pool
is described. The key steps include a tandem reductive amination/lactamization sequence to introduce the pyrrolidinone ring, a
palladium-catalyzed intramolecular direct C−H vinylation of indole to construct the crucial polyhydroazocine ring, and a Lewis
acid promoted formal [3 + 2] cycloaddition/N2 extrusion process to install the polysubstituted cyclopropyl ring.
ccurring with molecular complexity and diversity, natural
Oproducts serve as an important basis for drug develop-
ment, which has been playing a crucial role in life science.1
Chemical total synthesis of natural products is the most
effective way to obtain these compounds because of their
pervasive scarcity in nature. The development of novel
strategies to collectively synthesize natural products with
similar scaffolds has resulted in greatly improved synthetic
efficiency.2 Over the past century, hundreds of Kopsia alkaloids
with complex structures have been isolated.3 Among them,
(−)-lundurines A−D (1−4), isolated from Kopsia tenuis by
Kam and co-workers in 1995−2004,4 share a unique hexacyclic
skeleton with a pentasubstituted cyclopropane being fused to
the indoline moiety, an aza cyclooctane, and a pyrrolidine ring.
In addition, several structurally and biogenetically related
Kopsia indole alkaloids,4b,5 such as lapidilectine B (5),5a
Figure 1. Lundurines (1−4) and related alkaloids.
grandilodines (6, 10, and 11),5e tenuisines (7−9),4b,5c,d
lapidilectinol (12), and epi-lapidilectinol (13),5b were isolated
from the plants of the same genus (Figure 1). Most of these
(2) in racemic form.6c,d In the same year, Qin’s group achieved
the first asymmetric synthesis of (−)-lundurine A (1) using an
intramolecular Simmons−Smith reaction to establish the
cyclopropyl ring and confirmed its absolute configuration.6f In
2016, Echavarren and co-workers achieved an elegant and
collective asymmetric synthesis of (−)-lundurines A−C (1−
3),6h utilizing a gold(I)-catalyzed alkyne hydroarylation to build
the crucial eight-membered ring.6a Having been continuously
interested in the synthesis of indole alkaloids7 and enamored by
structurally fascinating molecules possess important bioactiv-
ities. For example, lundurines B (2) and D (4) were found to
be cytotoxic against B16 melanoma cells in vitro and also
showed potential activity to reverse multidrug resistance in
vincristine-resistant KB cells.4b
Due to their intriguing structure and promising bioactivities,
lundurines have attracted considerable attention from synthetic
chemists after their isolation, and numerous synthetic
explorations have been implemented.6 A remarkable break-
through was made by Nishida and co-workers in 2014, as they
accomplished the first total synthesis of lundurines A (1) and B
Received: January 20, 2018
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.8b00210
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
these structurally unique compounds, we initiated a research
program to explore the synthesis of lundurine alkaloids. A novel
strategy, featuring a tandem reductive amination/lactamization
sequence and a palladium-catalyzed direct intramolecular C−H
vinylation8 of indole, was developed, leading to a collective total
synthesis of (−)-lundurines A−C.
Scheme 2. Synthesis of Vinyl Iodide 16
Our synthetic strategy for the synthesis of lundurines A−C
(1−3) is outlined in Scheme 1. A cyclopropanation9 could be
Scheme 1. Retrosynthetic Analysis of Lundurines A−C
was very unstable and used for the next step without further
purification. Gratifyingly, when a mixture of the aldehyde and
12a,c
amine 20 was treated with NaBH(OAc)3
and then reacted
for a prolonged period, the reductive amination and the
subsequent lactamization proceeded smoothly to give desired
iodide 16 in 78% yield from 20.
With the precursor 16 in hand, the crucial indole C−H
vinylation was then evaluated. As summarized in Table 1, the
achieved through a Lewis acid promoted formal [3 + 2]
cycloaddition of sulfonyl hydrazone 14, followed by extrusion
of nitrogen, a novel protocol developed by Echavarren.6h
Sulfonyl hydrazone 14, in turn, could be accessed from
tetrahydroazocine 15 via a series of functional group trans-
formations. We envisaged that the key tetracyclic intermediate
15 could be obtained from vinyl iodide 16 through a direct
ring-closing C−H bond vinylation of indole,8a−j which has
rarely been utilized in natural product synthesis. Disconnection
of the C−N bond led to two fragments, i.e., tryptophol
derivative 17 and bicyclic compound 18. The latter could be
prepared from commercially available L-pyroglutamic acid in
several steps, from which the first chiral quaternary carbon
center is established.10
Our synthesis commenced with the preparation of vinyl
iodide 16, the key precursor to perform the direct vinylation
(Scheme 2). Stork−Zhao−Wittig olefination11 of known
aldehyde 19, prepared from L-pyroglutamic acid according to
the procedure reported previously,10a led to the (Z)- iodide 18
as the major product (>15:1, Z/E) in 86% yield after isolation,
which underwent a ring-opening alcoholysis in acidic methanol
to give two thermodynamically equilibrative compounds, the
unstable linear amine 20 (53%), and the lactam 21(45%). The
latter could be partially converted into 20 in 58% yield (90%
brsm) under the same conditions. Methoxycarbonylation of the
nitrogen atom in 5-methoxyl tryptophol TBS ether 17,
followed by desilylation, afforded alcohol 22 in 90% yield
over two steps. Next, we turned our attention to the linkage of
C−N bond to obtain vinylation precursor 16. Extensive
attempts toward direct N-alkylation of pyrrolidone 21 proved
to be problematic. We then tried to explore a reductive
amination12/lactamization sequence with 20, a protocol
previously used by Echavarren and co-workers.6a Oxidation of
alcohol 22 with IBX led to the corresponding aldehyde, which
a
Table 1. Optimization of the Reaction Conditions
b
entry
Pd(II)
temp (°C)
time (min)
yield (%)
1
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(TFA)2
Pd(MeCN)2Cl2
Pd(dppf)Cl2
PdCl2
40
50
65
80
90
100
90
90
90
90
240
150
45
22
31
35
38
45
40
58
56
38
42
2
3
4
25
5
15
6
10
7
15
8
15
9
15
10
15
a
Reaction conditions: 16 (0.23 mmol), Pd(II) (0.1 equiv), AcOK (3.0
b
equiv), DMF (8 mL). Isolated yields.
reaction was initially carried out with 0.1 equiv of Pd(OAc)2 as
the catalyst and AcOK as the base in DMF at 65 °C (entry 3),
and the C−H vinylation proceeded smoothly to provide the
desired tetrahydroazocine 15, albeit in poor yield (35%).
Encouraged by the success, we then optimized the reaction
conditions. Entries 1 and 2 show that only lower yields were
obtained, even with a prolonged reaction time when the
temperature was lowered. We then elevated the reaction
temperature and observed an increase in yields (entries 4 and
5). Surprisingly, a slightly higher temperature (100 °C) led to a
B
DOI: 10.1021/acs.orglett.8b00210
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
decreased yield (entry 6). Consequently, the optimal temper-
ature turned out to be 90 °C. Furthermore, in order to confirm
the effect of catalyst, we substituted Pd(OAc)2 with Pd(TFA)2,
Pd(MeCN)2Cl2, Pd(dppf)Cl2, and PdCl2 (entries 7−10), to
perform the reaction, and we found that Pd(TFA)2 gave the
highest yield (58%), which was slightly superior to Pd(MeCN)
2Cl2. Several ligands and bases were also employed for further
screening; however, we failed to gain a higher yield.
Unexpectedly, we found that 16 remained unreacted in the
presence of catalytic phosphine ligands (such as PPh3), or
tertiary amines (such as Et3N) as bases.
to furnish (−)-lundurine C (3) in 89% (brsm) yield with a
small amount of lactam remaining. However, the optical
598
rotation ([αD
= −2.0°, CH2Cl2, c 1.0, 294 K]) of the
598
synthetic lundurine C (3) is close to Echavarren’s value ([αD
= −6.2 0.8°, CH2Cl2, c 0.3, 301 K]) but significantly different
598
from the one reported by Kam ([αD = −25°, CHCl3, c
0.067]).4 On the other hand, lithium enolate generated from 27
in the presence of LDA at −78 °C was oxidized with
Mukaiyama’s oxidant 28 (N-tert-butylbenzenesulfinimidoyl
chloride)14 to furnish (−)-lundurine A (1) in a single step.
Lundurine A (1) showed an optical rotation ([αD598 = −114.0°,
CHCl3, c 1.0, 297 K]) similar to the value of the natural
Having rapidly constructed the eight-membered ring, our
attention was shifted to the challenging cyclopropanation and
the completion of the total synthesis of lundurines A−C (1−3).
Thus, reduction of the α-amino carboxylic ester 15 with NaBH4
provided the corresponding alcohol in 96% yield, and
hydrogenolysis of the double bond delivered 23. Upon
exposure to a mixture of 10:1 (v/v) DMSO and Ac2O,13
compound 23 was oxidized to aldehyde 24 in 89% yield.
Aldehyde 25 was obtained in 56% overall yield via a two-step
homologation sequence. Condensation of compound 25 with
tosyl hydrazine in the presence of catalytic tosylic acid afforded
hydrazone 14, a scaffold poised for cyclopropanation (Scheme
3).
598
product ([αD
= −90°, CHCl3, c 0.09]). Finally, O-
methylation of the unsaturated lactam with Meerwein’s salt
(Me3O+BF4 ) and subsequent NaBH4 reduction of the
−
resulting iminium ion yielded (−)-lundurine B (2), with an
598
optical rotation ([αD = −27.9°, CHCl3, c 0.43, 296 K])
similar to that of the natural product ([αD598 = −34°, CHCl3, c
0.16]). The spectral data of synthetic lundurines A−C are
identical to those reported for natural products4 and previous
syntheses.6
In conclusion, we have accomplished a collective asymmetric
total synthesis of lunduines A−C (1−3) in 15, 16, and 15 steps,
respectively, from tryptophol derivative 17 and bicyclic
compound 18. Optically pure and readily available L-
pyroglutamic acid was employed as the chiral pool to establish
the first chiral quaternary carbon center. The pyrrolidone ring
was forged through a tandem reductive amination/lactamiza-
tion sequence. A palladium(II)-catalyzed direct C−H vinylation
of indole allowed us to rapidly construct the central eight-
memberd ring. Finally, the pentasubstituted cyclopropanyl ring
was installed by a late-stage Lewis acid promoted formal [3 + 2]
cycloaddition/N2 extrusion process.6h Further synthetic ex-
ploration of related indole alkaloids is ongoing in our
laboratory.
According to Echavarren’s protocol,6h exposure of hydrazone
14 to Et2O·BF3 at 80 °C yielded cyclopropane 27 via N2
extrusion of pyrazoline intermediate 26, which was not isolated
due to its instability (Scheme 3). At this point, further
elaboration of the lactam ring was required to complete the
synthesis. Reduction of 27 with Me2S·BH3 proceeded smoothly
Scheme 3. Total Synthesis of (−)-Lundurines A−C
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.8b00210.
Experimental procedures and characterization data
(PDF)
AUTHOR INFORMATION
Corresponding Authors
■
*E-mail: chengb@lzu.edu.cn.
*E-mail: zhaihb@pkusz.edu.cn.
ORCID
Yun Li: 0000-0003-2236-9880
Bin Cheng: 0000-0002-8276-6653
Hongbin Zhai: 0000-0003-2198-1357
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We are grateful to Prof. Zhiqiang Ma of South China University
of Technology for enlightening discussion. We thank the NSFC
(21732001; 21672017; 21472072; 21290183), the Shenzhen
Science and Technology Innovation Committee
C
DOI: 10.1021/acs.orglett.8b00210
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
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