Total Synthesis of Scholarisine K and Alstolactine A

Article abstract of DOI:10.1021/acs.orglett.7b00722

The first asymmetric total syntheses of scholarisine K and alstolactine A have been accomplished. Our syntheses feature (1) ring closure metathesis and an intramolecular Heck reaction to construct the 1,3-bridged [3,3,1] bicycle (C-D ring), (2) intramolec

Full text of DOI:10.1021/acs.orglett.7b00722

Letter
pubs.acs.org/OrgLett
Total Synthesis of Scholarisine K and Alstolactine A
Dan Wang, Min Hou, Yue Ji, and Shuanhu Gao*
Shanghai Key Laboratory of Green Chemistry and Chemical Processes, School of Chemistry and Molecular Engineering, East China
Normal University, 3663 N Zhongshan Road, Shanghai 200062, China
*
S Supporting Information
ABSTRACT: The first asymmetric total syntheses of scholar-
isine K and alstolactine A have been accomplished. Our
syntheses feature (1) ring closure metathesis and an
intramolecular Heck reaction to construct the 1,3-bridged
[
3,3,1] bicycle (C−D ring), (2) intramolecular alkylation
followed by Fischer indolization to form the basic skeleton of
akuammilines, and (3) bioinspired, acid-promoted epoxide
opening/lactonization to generate the second lactone ring of
alstolactine A. These results provide evidence of a biogenetic relationship between scholarisine K and alstolactine A, which
should facilitate the preparation of other akuammiline-type natural products and their derivatives for functional studies.
kuammiline alkaloids are a family of biogenetically related
A
indole monoterpenoids isolated mainly from Alstonia
1
scholaris. The intriguing structures of these natural molecules
and their broad spectrum of biological activities have made
them the focus of many synthetic studies. Several strategies and
methodologies have been developed to generate the challeng-
ing cage-like structures, starting with the first total synthesis of
2
vincorine (3) by Qin and co-workers. Since then, the total
syntheses of several members of this family of natural alkaloids
3
4
5
have been reported by the groups of Ma, MacMillan, Smith,
6
7
8
9
10
11
12
Snyder, Garg, Zhu, Li, Zu, Yang, Fujii and Ohno,
1
3
14
Gaich, and Zhai. Most akuammiline alkaloids share indole-
containing polycyclic rings (A-B ring), a 1,3-bridged [3,3,1]
bicycle (C−D ring), and an all-carbon quaternary stereocenter
on C-7. Structural and functional diversity within this family of
alkaloids is due to the oxidation state and connectivity at C-5.
In rhazimal (1), C-5 in the core methanoquinolizine can be
oxidized, disconnected from N-4, and reconnected with either
C-2 or C-20, thereby generating vincorine (3) or scholarisine A
1
5
1
6
(
4). The resulting fused furanoindoline skeleton with altered
oxidation state on C-5 also appears in the structures of
1
7
18
18
aspidophylline A (5), scholarisine C (6), E (7), picrinine
(
1
9
20
21
8), scholarisine K (9), and alstolactine A (10). We also
Figure 1. Akuammiline alkaloids.
noticed that the C19−C20 double bond can be epoxidized,
such as in compounds 7 and 9 (Figure 1). Since our research
group is devoted to the synthesis of bioactive natural products,
we initiated a research program to explore the chemical
synthesis of this family of natural alkaloids as well as divergent
preparation of its analogues and derivatives for medicinal
studies. Here we report the total synthesis of scholarisine K (9)
and biogenetic transformation of 9 into alstolactine A (10).
Scholarisine K (9) and alstolactine A (10) were isolated by
Liu, Luo and co-workers from Alstonia scholaris leaves that had
Based on the retrosynthetic analysis shown in Scheme 1, we
planned to install the epoxide on C19−C20 via late-stage
oxidation of intermediate 11, which already contains the basic
skeleton of akuammiline alkaloids. When the fused lactone of
1
1 is reduced to a hemiacetal, subsequent acid-promoted C5−
N4 bond formation transforms 11 to picrinine (8). Base-
promoted ring opening of cyclic anhydride 13 followed by
recyclization via 12 can generate the lactone fragment of 11.
20,21
been stored for 7 years.
The remarkable, highly oxidized
skeleton bearing a two-lactone framework in 10 can be
biogenetically derived from 9 via acid-promoted lactonization.
Received: March 10, 2017
21
©
XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.7b00722
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
Scheme 1. Retrosynthetic Analysis of the Scholarisine K and
Alstolactine A
Scheme 2. Synthesis of the Chiral C−D Ring
We also planned to develop a reliable approach for synthesis of
1
3 from easily available building blocks such as 14−18. In these
reactions, the chirality of the amino group on C-3 is generated
through use of the chiral amino acid L-2-allylglycine (14).
Our synthesis commenced with asymmetric construction of
the C ring of the scholarisine family of alkaloids. This ring
contains a chiral amino group at C-3. This source of chirality
was the commercially available amino acid L-2-allylglycine
Scheme 3. Attempts to Prepare Heteroanhydrides 28 and 30
(
>98% ee), which was transformed into aldehyde 19 (see
details in Supporting Information) without loss of ee via a
22
modified three-step sequence on a large scale. In-mediated
Barbier reaction between 19 and methyl 2-(bromomethyl)
acrylate 17 gave rise to the desired amino alcohol 20 as a
mixture of two diastereomers (dr 1.7:1) in 72% yield. The two
isomers of 20 were carefully isolated with 98.9% and 96.7% ee.
Ring-closing metathesis (RCM) of 20 using Grubbs II
catalyst afforded the cyclized product 21 in 82% yield.
Trifluoroacetic acid-mediated removal of Boc followed by 2-
nitrobenzenesulfonyl protection of the free amino group
furnished 22 in a one-pot operation. Subsequently, alkylation
23
We also attempted to construct the C6−C7 bond prior to
indolization by using heteroanhydride 30 for the intramolecular
alkylation. Therefore, we hydrolyzed ester 26 to produce acid
29 without isomerization, which unfortunately proved inert in
the reaction with 2-bromoacetyl bromide. We hypothesized
that inductive effects by the bromide group rendered substrates
such as 28 and 30 extremely unstable under basic conditions,
causing them to hydrolyze rapidly to form the corresponding
acids.
24
of 22 with allyl bromide 18 yielded 23, which served as the
precursor for the formation of the D ring. Pd(0)-catalyzed
25
intramolecular Heck reaction of 23 connected the C15−C20
bond, and the o-nitrobenzenesulfonyl protecting group was
replaced with Cbz to provide α,β-unsaturated ester 24 in 77%
yield. Since direct hydrogenation of the unsaturated ester of 24
turned out to be surprisingly difficult, 24 was oxidized to
conjugated keto-ester 25 (>98.4% ee) with Dess−Martin
reagent. The conjugated double bond was then reduced via
Therefore, we revised our strategy for generating a stable side
chain, opting for formation of the C6−C7 carbon bond
(Scheme 4). We discovered that SmI reduced the conjugated
2
SmI -mediated reduction to afford 26 as a mixture of two
ketoester 25 to alcohol 32 in the presence of water (100 equiv)
in 72% yield, together with the isomer 31 (11% yield). We
readily protected 32 as the TES ether using TESCl/imidazole/
DMAP in dichloromethane. Then the ester group of 33 was
2
diastereomers at C-16 (dr 5.7:1) in 83% yield (Scheme 2).
With chiral ketone 26 in hand, we started to prepare
heteroanhydride 28 for the formation of cyclic anhydride 13
based on the retrosynthetic analysis (Scheme 1). We
anticipated that intramolecular alkylation of 28 would construct
the C6−C7 bond of akuammilines. Fischer indolization of
ketoester 26 with phenylhydrazine followed by hydrolysis with
lithium hydroxide produced acid 27 (Scheme 3). We found that
the carboxyl acid group at C-16 was completely epimerized to
the α-configuration. We also tested classical conditions to
prepare anhydride 28, in expectation that the ester could be
isomerized again. However, mixing 27 with 2-bromoacetyl
bromide resulted only in starting material with none of the
desired heteroanhydride 28. We obtained similar results when
we treated the acyl chloride of 27 with 2-bromoacetic acid
under basic conditions (see details in Supporting Information).
reduced using lithium aluminum hydride (LiAlH ) in 98%
4
yield. The resulting primary alcohol was treated with vinyl ethyl
ether and NIS, and then the TES group was deprotected using
concentrated HCl/MeOH to give iodide 34 in a one-pot
operation. This two-carbon synthon has been used by Li and
co-workers in their elegant syntheses of the aspidophylline
9
alkaloids aspidodasycarpine and lonicerine. The compound 34
was oxidized to ketone 35 in 75% yield in a modified Swern
reaction, in which reaction temperature and time were strictly
controlled in order to prevent side reactions (see details in
Supporting Information). With ketone 35 in hand, we screened
a variety of bases, solvents, and additives to achieve the
intramolecular S 2 reaction to form the C6−C7 bond. Under
N
B
DOI: 10.1021/acs.orglett.7b00722
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
Scheme 4. Total Synthesis of Scholarisine K
harsh conditions involving heating at 105 °C in toluene for 27
Scheme 5. Total Synthesis of Alstolactine A
min, cyclization occurred with KHMDS as the base, producing
3
6 in 57% yield (71% brsm). Hydrolysis of acetal 36 afforded
the crude hemiacetal, which was oxidized to lactone 37 in the
26
presence of Ac O/DMSO. Lactone 37 was transformed via
2
Fischer indolization to indolenine 38, which bears an all-carbon
quaternary stereocenter on C-7. The structure and relative
configuration of 38 was confirmed by X-ray crystallographic
analysis. Subsequently, base-promoted (LiOH) lactone opening
and recyclization generated hydro-indol 39 in 61% yield over
two steps. Our approach echoes the interrupted Fischer
indolization used in Garg’s original synthesis of akuammiline
7
alkaloids. To construct the epoxide group of scholarisine K
(9), we first attempted without success to directly epoxidate the
double bond of 39 using m-CPBA, H O , and oxone. We
2
2
hypothesized that the exposed amino group of the hydro-iodole
might be participating in the oxidation, giving rise to side
reactions. Therefore, we designed a two-step oxidation
sequence in which we oxidized the primary alcohol of 39 to
the corresponding carboxylic acid, and then we performed
iodolactonization in the presence of KI/I /NaHCO3 to
2
9
,27
produce iodide 40 in 54% yield over three steps.
Transesterification and epoxide formation under basic con-
ditions in MeOH generated epoxide 41 in 80% yield. Removal
conditions. Intramolecular lactonization generates 42 (path A,
Scheme 5), and a second dehydration affords conjugated diene
43 (path B, Scheme 5). Based on the similar transformations,
we generated alstolactine A (10) in 79% yield by replacing the
Cbz with a methyl group.
of N-Cbz under Pd(OH) /C and reductive amination in 79%
2
1
yield over two steps achieved scholarisine K (9), which gave H
NMR, 13C NMR, high-resolution mass spectrometric, and
optical rotation results identical to those of the natural
compound.
In summary, the first asymmetric total syntheses of two
akuammiline natural products, scholarisine K and alstolactine A,
have been accomplished. Schlorisine K was synthesized in 25
linear steps from commercial materials. In these syntheses,
commercially available L-2-allylglycine was used to introduce
the chiral amino group at C-3. Intramolecular alkylation
followed by Fischer indolization was developed to construct
the basic akuammiline skeleton. The bioinspired synthesis of
alstolactine A was achieved through acid-promoted epoxide
ring opening and lactonization. These results imply a biogenetic
relationship between scholarisine K and alstolactine A. The
syntheses described here may provide a new approach to other
akuammilines and derivatives for medicinal studies.
We envisioned that alstolactine A (10), which contains an
additional lactone framework, could be biogenetically derived
from 9 via acid-promoted lactonization. Unfortunately,
exposing scholarisine K (9) to acidic conditions led to its
decomposition. Further experiments showed that epoxide 41
could be used to construct the second lactone. Treatment of 41
with 3 M H SO in acetone produced 42 in 31% yield and
2
4
elimination product 43 in 42% yield (Scheme 5). We propose
that the epoxide is first activated by protonic acid, followed by
intermolecular S 2 addition by water to produce intermediate
N
4
5, which gives the cationic intermediate 46 under acidic
C
DOI: 10.1021/acs.orglett.7b00722
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
(
9) Li, Y.; Zhu, S.; Li, J.; Li, A. J. Am. Chem. Soc. 2016, 138, 3982−
ASSOCIATED CONTENT
Supporting Information
■
3
985.
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The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.7b00722.
10483−10486.
(11) Jiang, S.; Zeng, X.; Liang, X.; Lei, T.; Wei, K.; Yang, Y. Angew.
Chem., Int. Ed. 2016, 55, 4044−4048.
(12) Nishiyama, D.; Ohara, A.; Chiba, H.; Kumagai, H.; Oishi, S.;
Experimental procedures, characterization data, and
NMR spectra (PDF)
Fujii, N.; Ohno, H. Org. Lett. 2016, 18, 1670−1673.
(13) (a) Eckermann, R.; Breunig, M.; Gaich, T. Chem. Commun.
X-ray data for compound 38 (CIF)
2016, 52, 11363−11365. (b) Eckermann, R.; Breunig, M.; Gaich, T.
Chem. - Eur. J. 2017, 23, 3938−3949.
(14) Wang, T. M.; Duan, X. G.; Zhao, H.; Zhai, S. X.; Tao, C.; Wang,
AUTHOR INFORMATION
Corresponding Author
■
*
H. F.; Li, Y.; Cheng, B.; Zhai, H. Org. Lett. 2017, DOI: 10.1021/
acs.orglett.7b00448.
(
15) Ahmad, Y.; Fatima, K.; Le Quesne, P. W.; Atta-Ur-Rahman.
Phytochemistry 1983, 22, 1017−1019.
16) Cai, X.-H.; Tan, Q.-G.; Liu, Y.-P.; Feng, T.; Du, Z.-Z.; Li, W.-Q.;
Luo, X.- D. Org. Lett. 2008, 10, 577−580.
17) Subramaniam, G.; Hiraku, O.; Hayashi, M.; Koyano, T.;
E-mail: shgao@chem.ecnu.edu.cn.
ORCID
(
Shuanhu Gao: 0000-0001-6919-4577
Notes
(
Komiyama, K.; Kam, T.-S. J. Nat. Prod. 2007, 70, 1783−1789.
(18) Feng, T.; Cai, X.-H.; Zhao, P.-J.; Du, Z.-Z.; Li, W.-Q.; Luo, X.-D.
Planta Med. 2009, 75, 1537−1541.
The authors declare no competing financial interest.
(19) Chatterjee, A.; Mukherjee, B.; Ray, A. B.; Das, B. Tetrahedron
ACKNOWLEDGMENTS
We thank the National Natural Science Foundation of China
21422203), National Young Top-notch Talent Support
Program, and Program for Changjiang Scholars and Innovative
Research Team in University (PCSIRT) for generous financial
support. We thank Kui Liao and Renyi Zhu (ECNU) for HPLC
analysis.
■
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DOI: 10.1021/acs.orglett.7b00722
Org. Lett. XXXX, XXX, XXX−XXX