Total Synthesis of (+)-Fusarisetin A Driven by a One-Pot Four-Reaction Process

Article abstract of DOI:10.1021/acs.orglett.6b00036

A concise, asymmetric total synthesis of (+)-fusarisetin A, a hybrid natural product, has been achieved. A one-pot four-reaction process efficiently delivered the tetracycle 2 which served as a key intermediate for the synthesis of the title natural product and its analogues through amino acid incorporation.

Full text of DOI:10.1021/acs.orglett.6b00036

Letter
pubs.acs.org/OrgLett
Total Synthesis of (+)-Fusarisetin A Driven by a One-Pot Four-
Reaction Process
Chenguang Liu, Zhixiong Zeng, Renzhi Chen, Xunjin Jiang, Yinglu Wang, and Yandong Zhang*
Department of Chemistry and Fujian Provincial Key Laboratory of Chemical Biology, College of Chemistry and Chemical
Engineering, Xiamen University, Xiamen, Fujian 361005, China
*
S Supporting Information
ABSTRACT: A concise, asymmetric total synthesis of
+)-fusarisetin A, a hybrid natural product, has been achieved.
(
A one-pot four-reaction process efficiently delivered the
tetracycle 2 which served as a key intermediate for the
synthesis of the title natural product and its analogues through
amino acid incorporation.
1
ybrid natural products are composed of two or more
molecule, a couple of novel strategies have been developed and
some analogues have been prepared.
9
H
metabolic units with different biosynthetic origins and
usually exhibit unique biological properties, thus providing
many opportunities for developing new therapeutic agents.
Inspired by nature, chemists artificially combine natural or
unnatural molecules through covalent bonds, which plays an
With the goal of reducing time, cost, and waste production,
10
one-pot reactions have developed greatly in the past two
decades. Herein, we describe a concise, asymmetric total
synthesis of (+)-fusarisetin A driven by a one-pot four-reaction
process. Furthermore, our convergent synthetic route and late-
stage incorporation of amino acid units would greatly facilitate
2
important role in modern pharmaceutical chemistry.
As the essential biosynthetic building blocks for peptides and
3
11
proteins, as well as alkaloids, amino acid units have also been
the diverted total synthesis of the analogues.
widely found in other bioactive natural products (Figure 1).
Our modular strategy originates from the hypothesis that
fusarisetin A could be viewed as a hybrid molecule of an amino
acid and a polyketide-like compound. As outlined in Scheme 1,
we anticipated that 1 could be assembled from tetracyclic
12
polyketide-like compound 2 and the serine unit 3. Then
rupture of the three indicated C−C bonds within 2, through an
intramolecular Diels−Alder reaction (IMDA)/Mukaiyama
aldol/desilylation/oxidation sequence, revealed triene 4 as a
Scheme 1. Retrosynthetic Analysis of (+)-Fusarisetin A (1)
Figure 1. Hybrid natural products containing amino acids.
(
+)-Fusarisetin A (1, Figure 1), isolated from the soil fungus
Fusarium sp. FN080326, exhibited potent inhibition of
metastasis in MDA-MB-231 breast cancer cells without
4
significant cytotoxicity. Structurally, fusarisetin A features a
pentacyclic ring system comprising 10 continuous stereo-
centers, in particular, a complicated 5,5,5-angular tricycle motif
containing a masked N-methyl serine. Its fascinating structure
and promising therapeutic value have attracted considerable
synthetic interest, thus culminating in several elegant total
5
6
synthesis of 1 by the groups of Li in 2011, Theodorakis and
Received: January 6, 2016
7
8
Gao in 2012, and Yang in 2013. In the pursuit of this
©
XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.6b00036
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
1
8
possible precursor. To simplify the synthesis, we would practice
these conversions in a one-pot manner, although the
compatibility of reaction conditions and functional groups in
each step is challenging. The retrosynthetic scission of the C8−
C9 bond of precursor 4 led to vinyl borate 5 and iodide 6 as
two similarly sized fragments, which could be connected
through a Suzuki coupling. Finally, 5 and 6 could be prepared
Sc(OTf) ) investigated, 1.0 equiv of BF ·OEt in CH Cl at 0
3 3 2 2 2
°C gave the cycloadduct 10 in the highest yield of 60% (7:1
endo/exo). In spite of the failure of the intramolecular aldol
addition with LDA or KHMDS as base, 10 was successfully
converted to 12 probably via intermediate 11 under a
Mukaiyama aldol condition (TMSOTf and DIPEA) in 80%
yield as a mixture of diastereomers (5:1 dr). However, the
incompatibility between BF ·OEt and TMSOTf impeded the
19
13
respectively from known lactone 7 and (R)-(+)-citronellal 8.
The stereoselective synthesis of trienaldehyde 4 commenced
with the synthesis of two chiral building blocks 5 and 6 and
3
2
further exploration of the one-pot mechanics of these two steps.
Although TMSOTf is a poor activator for the dienophiles
bearing α,β-unsaturated carbonyls in intermolecular Diels−
14
proceeded as summarized in Scheme 2. Takai olefination of
20
Alder reactions, we reexamined the above-mentioned IMDA
Scheme 2. Synthesis of Intermediate 4
reaction with this Lewis acid. Rewardingly, subjection of 4 to
5
.0 equiv of TMSOTf in CH Cl at −78 °C afforded 10 in 70%
2
2
yield (9:1 endo/exo) if we quenched the reaction at this stage.
To our great delight, the subsequent intramolecular aldol
reaction proceeded smoothly only with the addition of 5.0
equiv of DIPEA to the preceding reaction mixture after
warming to rt, thereby providing tetracycle 12 in a one-pot
reaction manner. Encouraged by this success, we next explored
the possibility of running the desilylation and oxidation in the
same flask. After extensive screening of reaction conditions, the
tetracyclic lactone 2 (as a pure β-keto lactone form) was
obtained in 43% overall yield by sequential treatments with HF·
21
Py at 0 °C and PCC at rt. Its structure was unambiguously
confirmed by single crystal X-ray diffraction (Scheme 3). In this
one-pot IMDA/Mukaiyama aldol/desilylation/oxidation se-
quence, three rings together with five stereogenic centers
were built up. Of particular note was that the efficient one-pot
four-reaction process only required sequential addition of the
reagents at the corresponding reaction temperature.
(
R)-(+)-citronellal 8 afforded a vinyl iodide intermediate as an
15
inseparable mixture of E/Z isomers in 70% yield, which was
converted to α,β-unsaturated aldehyde 6 by a regioselective
allylic oxidation. Fragment 5 was obtained via a Ru-catalyzed
olefin cross metathesis (Hoveyda−Grubbs’ second generation
catalyst) between lactone 7 and pinacol vinylborate 9 in 70%
yield as a mixture of E/Z isomers (ca. 10:1). To our delight, the
Suzuki cross-coupling of the vinyl borate 5 and vinyl iodide 6 in
With polyketide-like compound 2 in hand, our efforts were
then focused on the incorporation of N-methyl serine unit 3
16
(
Scheme 4). Direct aminolysis of five-membered lactone in 2
Scheme 4. Completion of Total Synthesis
17
the presence of Pd(PPh ) and Ag O smoothly delivered
3
4
2
(
E,E,E)-triene 4 in 75% yield.
With 4 in hand, we then focused on the key one-pot reaction
sequence (Scheme 3). We first examined the intramolecular
Diels−Alder reaction. Among the thermal conditions (ben-
zene/150 °C/sealed tube, xylene/150 °C/microwave) and
Lewis acidic conditions (e.g., Et AlCl, BF ·OEt , BBr , and
2
3
2
3
Scheme 3. One-Pot Reaction for the Synthesis of Tetracycle
2
22
with 3 in the presence of the various additives (e.g., DMAP,
Sn(OAc) , 2-hydroxypyridine, and AlMe ) did not produce any
2
3
desired product, probably due to a combination of unfavorable
entropic and enthalpic factors. However, this challenge was
smoothly overcome by another one-pot two-step operation: 2
2
3
was first treated with MeOH/Et N (1:1) in the presence of
3
24
MgSO4 at rt, and the resulting C5 alcohol was instantly
protected as a TMS ether in the same flask (79% yield). NMR
NOE studies indicated the inversion of the C1 stereocenter (S
→
R) which was probably a major driving force for the
transesterification. By treatment with the aminoester 3 and
DMAP, 13 was converted to amide 14 as a pair of inseparable
C1 epimers (1:1). Finally, when it was subjected to NaOMe in
B
DOI: 10.1021/acs.orglett.6b00036
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
MeOH at 0 °C, similar to Yang’s observation, (+)-fusarisetin A
Letter
8
Science (BNLMS). We also thank Ms. Fuling Liu of Xiamen
University for solving the X-ray structure.
(
1) and (+)-C3-epi-fusarisetin A were obtained in a 1.25/1.0
25
ratio in a combined yield of 50% in two steps. The
spectroscopic data ( H and C NMR, HRMS, and optical
rotation) for the synthetic sample (1) and its C3-epimer
1
13
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■
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fully coincided with those reported.
After the successful synthesis of fusarisetin A, we examined
the feasibility of our modular synthetic strategy in the diverted
total synthesis of the analogues guided by a “hybridization”
concept. Through the late-stage incorporation of amino acid
units, as examples, two pentacyclic compounds 16 and 18 were
synthesized respectively in 60% and 55% yield (1:2 dr at C3′)
from the advanced intermediate 13 (Scheme 5). It is
noteworthy to mention that the epimerization at C3′ seems
(
4
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synthetic strategy for the asymmetric total synthesis of
+)-fusarisetin A, featuring a Suzuki coupling and a novel
one-pot four-reaction sequence (IMDA/Mukaiyama aldol/
desilylation/oxidation). Our method is also viable for the
diverted total synthesis of the analogues. We anticipated that
this approach would provide a diverse array of analogues for
further biological studies of tumor metastasis.
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ASSOCIATED CONTENT
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Corresponding Author
*E-mail: ydzhang@xmu.edu.cn.
(15) A two-step synthesis of pure E-vinyl iodide 6 was also reported
Notes
in the Supporting Information.
The authors declare no competing financial interest.
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ACKNOWLEDGMENTS
We gratefully acknowledge the Natural Science Foundation of
China for financial support of this work by grants (Nos.
1142007, 21272194, 21572187, and U1405228). We thank
the support from SRF for ROCS of SEM, FRFCU (Nos.
0720150145 and 20720160025), PCSIRT, and the opening
foundation from Beijing National Laboratory for Molecular
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24) The promotion of the transesterification by MgSO4 was
fortuitously found by the use of methanol dried over MgSO , in which
4
a tiny amount of MgSO was dissolved.
4
(
25) This enatiospecific synthesis required eight steps from (R)-
+)-citronellal and seven steps from known lactone 7 which could be
prepared in large scale by procedures reported in ref 13.
26) The stereochemistry of C3-epi-fusarisetin A was also confirmed
by NMR NOE studies.
(
(
D
DOI: 10.1021/acs.orglett.6b00036
Org. Lett. XXXX, XXX, XXX−XXX