Asymmetric total synthesis of (+)-fusarisetin A via the intramolecular Pauson-Khand reaction

Article abstract of DOI:10.1021/ol401831w

An asymmetic total synthesis of (+)-fusarisetin A has been achieved. The essential to our strategy was the application of the intramolecular Pauson-Khand reaction for the stereoselective construction of the trans-decalin subunit of (+)-fusarisetin A with a unique C16 quarternary chiral center. The developed chemistry offers an alternative to the IMDA reaction that has been used for fusarisetin A, and is applicable to analogue synthesis for biological evaluation.

Full text of DOI:10.1021/ol401831w

ORGANIC
LETTERS
2013
Vol. 15, No. 15
4018–4021
Asymmetric Total Synthesis of
(þ)-Fusarisetin A via the Intramolecular
PausonꢀKhand Reaction
Jun Huang,†,§ Lichao Fang,†,§ Rong Long,† Li-Li Shi,† Hong-Juan Shen,†
Chuang-chuang Li,*,† and Zhen Yang*,†,‡
Laboratory of Chemical Genomics, School of Chemical Biology and Biotechnology,
Peking University Shenzhen Graduate School, Shenzhen 518055, China, and Key
Laboratory of Bioorganic Chemistry and Molecular Engineering of Ministry of
Education and Beijing National Laboratory for Molecular Science (BNLMS), and
Peking-Tsinghua Center for Life Sciences, Peking University, Beijing 100871, China
licc@pkusz.edu.cn; zyang@pku.edu.cn
Received July 1, 2013
ABSTRACT
An asymmetic total synthesis of (þ)-fusarisetin A has been achieved. The essential to our strategy was the application of the intramolecular
PausonꢀKhand reaction for the stereoselective construction of the trans-decalin subunit of (þ)-fusarisetin A with a unique C16 quarternary chiral
center. The developed chemistry offers an alternative to the IMDA reaction that has been used for fusarisetin A, and is applicable to analogue
synthesis for biological evaluation.
(þ)-Fusarisetin A (1, Figure 1)1 represents an emerging
class of anticancer agents structurally related to the mem-
bers of the cytochalasin family of fungal metabolites.2 This
molecule has elicited considerable levels of biological
interest because it exerts a potent inhibitory effect on
metastasis in the MDA-MB-231 breast cancer cells, as well
as inhibiting acinar morphogenesis (77 μM), cell migration
(7.7 μM), and cell invasion (26 μM) in the same cell line
without any significant cytotoxicity.2 The structure of 1
was estblishedbyNMR and X-ray diffraction analyses,1 as
well as its total synthesis.3
Structurally, 1 is composed of 10 stereocenters and an
unprecedented carbon skeleton consisting of a pentacyclic
ring system comprising decalin (6/6) and tricyclic (5/5/5)
Figure 1. Structure of (þ)-fusarisetin A (1).
moieties that are both decorated with a variety of different
functionalities. The novel structural features of these fun-
† Peking University Shenzhen Graduate School.
‡ Peking University.
gal metabolites have led to the deployment of considerable
synthetic efforts that have culminated in several successful
total syntheses of 1 by the groups of Li in 20113 and
Theodorakis4 and Gao5 in 2012.
§ These authors contributed equally.
(1) Jang, J.-H.; Asami, Y.; Jiang, J.-P.; Kim, S.-O.; Shin, S.-S.;
Hashizume, D.; Muroi, M.; Saito, T.; Oh, H.; Kim, B. Y.; Osada, H.;
Ahn, J. S. J. Am. Chem. Soc. 2011, 133, 6865.
(2) Li, J. Y.; Strobel, G. A.; Harper, J. K.; Lobkovsky, E.; Clardy, J.
Org. Lett. 2000, 2, 767.
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Chem. Soc. 2012, 134, 5072. (b) Xu, J.; Caro-Diaz, J. E.; Lacoske, M. H.;
Hung, C.-I.; Jamora, C.; Theodorakis, E. A. Chem. Sci. 2012, 3, 3378.
(3) Deng, J.; Zhu, B.; Lu, Z.-Y.; Yu, H.-X.; Li, A. J. Am. Chem. Soc.
2012, 134, 920.
r
10.1021/ol401831w
Published on Web 07/19/2013
2013 American Chemical Society

During the course of the past two decades, the Pausonꢀ
Khand (PK) reaction6 has emerged as a powerful method
for the synthesis of cyclopentenones,7 and the reaction has
been successfully applied to the total syntheses of complex
natural products.8 Herein, we report our recent accom-
plishment of the total synthesis of (þ)-fusarisetin A by
using the PK reaction as a key step.
Retrosynthetically, (þ)-fusarisetin A (1) could be made
from amide 4 via the Dieckmann-type cyclization followed
by hemiacetalization via the published protocol (Figure 2).3
Amide 4 could in turn be generated via the aminolysis of
the β-keto ester 5 with aminoester 6.
reaction9 followed by the oxidation of the resulting β-hydroxy
ester. The epoxide ester 7 could be prepared by the
epoxidation of 8. Given that the Pd-catalyzed carbonylation
of enol triflates has been reported as an effective method for
the conversion of ketones to its corresponding R,β-unsatu-
rated esters,10 this approach was used for the construction
of the R,β-unsaturated ester in 8 in a regiocontrolled manner
from ketone 9, which was itself derived from 10 via a stereo-
selective 1,4-reduction. It was also expected that enyne 11,
which already included three necessary chiral centers
(C10, C12, and C15), could be stereoselectively transformed
into 10 via a transition metal catalyzed PK reaction. The
precursor enyne 11 could be constructed from epoxide 12,11
which could itself be prepared by the known precudure.12
Our synthesis started with the synthesis of enone 10. In the
event, addition of chloromethylithium, generated from chloro-
iodomethane and n-BuLi, to aldehyde 1311 at ꢀ78 °C gave
epoxide 12 in 72% yield,12 together with its diastereoisomer
12a in 12% yield (Scheme 1). Further reaction of epoxide 12
with lithium acetylide 1413 at ꢀ78 °C in THF in the presence
of BF3 Et2O gave the requisite enyne 11 in 60% yield.
3
Our attention then shifted to the intramolecular PK
reaction of enyne 11. To establish the optimal reaction
conditions, the effects of a variety of different parameters
(e.g., metal catalyst, additive, solvent, and temperature) on
the outcome of the reaction were investigated. Several
different transition metal complexes were tested, including
PdCl2 in the presence of tetramethyl thiourea (TMTU)14
and Co2(CO)8 under a variety of different conditions in the
presence of several different additives, including molecular
sieves,15 Me2S,16 water,17 ethane-1,2-diol,18 N-methyl-
morpholine-N-oxide (NMO),19 trimethylamine-N-oxide
(TMANO),20 and TMTU.14 The results indicated that the
Co2(CO)8-mediated PK reaction was the most efficient
method of those tested for the stereoselective construction
of the quaternary stereogenic center at the C16 position of
cyclopentenone 10. Of the different solvents tested, including
THF, benzene, toluene, and CH3CN, toluene was found to
provide the best results. The temperature for the reaction was
evaluated at temperatures ranging from 70 to 130 °C, with
120 °C giving the best result. Taken together, an 82% yield
Figure 2. Retrosynthetic analysis of (þ)-fusarisetin A (1).
It was envisaged that the ester 5 could be prepared from
the epoxide ester 7 via a reductive epoxide-ring-opening
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Org. Lett., Vol. 15, No. 15, 2013
4019

of product 10 with the desired quaternary chiral center
was remarkably obtained when a stoichiometric amount
of Co2(CO)8 was used at a reaction temperature of 120 °C
under argon.
The trans-configuration21 across the two newly generated
chiral centers at C6 anf C7 suggested that the ketone-
mediated epimerization22 occurred during the reaction.
To generate the desired stereochemistry at the C7 posi-
tion, the decision was taken to use mesylate as the protect-
ing group in consideration of the tendency of mesylate23 to
form a H-bonding network with ethanol (solvent) and the
C5 hydroxyl group. As a result, 16 would likely adopt its
conformation as 17a (see its 3D structure in Scheme 4).
Thus, the C5 methyl group would block the catalyst to
access the C6, C7 double bond from the top face, leading to
the formation of 16 predominately.
Scheme 1. Synthesis of Cyclopentanaphthalenone 10
To this end, 10 was reacted with MsCl in the presence of
Et3N/DMAP, followed by desilylation to afford 17 in 68%
yield over the two steps (Scheme 3). Thus, hydrogenation
of 17 under the same conditions as used before (i.e., PdꢀC,
EtOH, Et3N, and H2 under balloon pressure) effectively
saturated the double bond and afforded 18 in 70% yield as
the major product. The structure of 18 was confirmed by
X-ray crystallographic analysis.
We then investigated the stereoselective reduction of
enone 10 via hydrogenation. Initially, various conditions
were attempted; however, no hydrogenation was observed,
presumably because of the steric hindrance of the TBS group.
We then decided to remove this silyl group. In the event, the
hydroxyl group in 10 was first protected as its methoxy
methyl ether (MOM), and the resultant MOM ether was
Scheme 3. Synthesis of Compound 20
then subjected to desilylaytion with HF pyridine to afford
3
product 15 (Scheme 2). Thus, under the hydrogenation
conditions with Pd/C as a catalyst, 16 was obtained in 89%
yield as a single isomer. However, the stereochemistries at
the C6- and C7-positions in 16 were the opposite of what
we expected. The stereochemistry of 16 was established via a
2D-NMR study (see Supporting Information for details).
Scheme 2. Synthesis of Compound 16
To continue our planned strategy toward the total syn-
thesis of the target molecule, it was necessary to prepare the
R,β-unsaturated ester 20 via the Pd-catalyzed esterification
As a working hypothesis, it was assumed that an intramo-
lecular H-bonding existed between the C5 hydroxyl and C1
carbonyl groups (see 3D structure of 15a in Scheme 2), which
regulated the C5 methyl group down and could lead the
catalyst to approach the double bond from the top face,
resulting in the formation of product 16 as the sole product.
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4020
Org. Lett., Vol. 15, No. 15, 2013

process from the precursor enol triflate 19 (Scheme3). Tothis
end, the hydroxyl group in ketone 18 was first protected as the
corresponding TBS ether, and the resulting ketone was then
reacted with Comins’ reagent24 in the presence of KHMDS
as a base to give enol triflate 19 in 95% yield. Triflate 19 was
subsequently subjected to a Pd-catalyzed carbonylative ester-
ification reaction25 to give 20 in 65% yield. This sequence
conveniently established the R,β-unsaturated ester function-
ality necessary for the epoxidation to 21. It is worthwhile to
mention that the major side product observed in this reaction
occurred as a consequence of reductive demesylation.
We then proceeded to synthesize the key intermediate
amide 4 (Scheme 4). Although it was anticipated that
the R,β-unsaturated ester in 20 would provide facile access
to the corresponding epoxide in 21, the treatment of substrate
21 with a variety of different oxidative agents, such as tert-
butyl hydroperoxide (TBHP)/1,8-diazabicyclo[5.4.0]undec-
7-ene (DBU),26 m-chloroperbenzoic acid (m-CPBA),27 and
H2O2/NaOH,28 did not result in the formation of the desired
product.
Scheme 5. Completion of the Total Synthesis
No efforts were made at this stage to assign the stereo-
chemistry at the newly formed epoxide centers because
the stereochemistry at these positions would be eliminated
in the subsequent steps. Thus, epoxide 21 was demesylated
by treatment with DBU in refluxing toluene, followed
by reductive epoxide opening with SmI2, and the newly
generated hydroxyl group was oxidized with DMP to give
the corresponding β-keto ester 5 in 37% yield for three
steps. Thus, aminolysis proceeded smoothly when the β-keto
ester 5 was reacted with the aminoester 6, and amide 4 was
formed in 73% yield.
Scheme 4. Synthesis of Compound 4
To complete the total synthesis, amide 4 was first treated
with HF to remove the TBS groups, and the resulting ester
was then treated with NaOMe in MeOH to undergo the
planned transannulation process, and (þ)-fusarisetin A (1)
and (þ)-C3-epi-fusarisetin A (22) were formed in a ratio of
6/4 in a combined yield of 73% (Scheme 5). The spectro-
scopic data (1H and 13C NMR spectra, HRMS analyses,
and optical rotation) of the synthesized sample (1) were
fully consistent with the corresponding data for the natu-
rally occurring fusarisetin A.1 The structure of (þ)-C3-epi-
fusarisetin A (25) was deduced by the analysis of its NMR
spectra, as well as its epimerization tendency of the C3
position during the base-mediated Dieckmann cyclization.
In conclusion, we have developed a concise synthetic
strategy for the total synthesis of (þ)-fusarisetin A (1) in 16
steps from the commercially available aldehyde 13. Essen-
tial to our strategy was the application of the intramole-
cular PK reaction for the stereoselective construction of
the cyclopentenone 10 with a unique C16 quaternary chiral
center. The chemistry offers an alternative to the IMDA
reaction that has been used for fusarisetin A and is applic-
able to analogue synthesis for biological evaluation.
It was later established that epoxide 21 could be syn-
thesized in a 75% yield as a single diastereoisomer by reac-
tion of 20 with m-CPBA in the presence of NaHCO3,
presumably because NaHCO3 could scavenge the gener-
ated chlorobenzoic acid, which might cause the formed
product 21 decomposition.
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Acknowledgment. Financial support from the National
Science Foundation of China (91013004, 21072006, and
21072011) and National 863 Program (2013AA090203) is
acknowledged.
Supporting Information Available. Experimental proce-
dure and 1Hand13C NMR spectra. This material is available
free of charge via the Internet at http://pubs.acs.org.
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The authors declare no competing financial interest.
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