Asymmetric total synthesis and revision of absolute configurations of azaphilone derivative felinone A

Article abstract of DOI:10.1016/j.tetlet.2017.09.090

The first total synthesis of the azaphilone derivative, felinone A, was accomplished. The absolute configuration of natural felinone A was revised to be 3S, 6S, and 7R.

Full text of DOI:10.1016/j.tetlet.2017.09.090

Accepted Manuscript
Asymmetric total synthesis and revision of absolute configurations of azaphi-
lone derivative felinone A
Hideki Abe, Haruhito Tango, Toyoharu Kobayashi, Hisanaka Ito
PII:
S0040-4039(17)31249-2
https://doi.org/10.1016/j.tetlet.2017.09.090
TETL 49360
DOI:
Reference:
Tetrahedron Letters
To appear in:
Received Date:
Revised Date:
Accepted Date:
23 August 2017
25 September 2017
29 September 2017
Please cite this article as: Abe, H., Tango, H., Kobayashi, T., Ito, H., Asymmetric total synthesis and revision of
absolute configurations of azaphilone derivative felinone A, Tetrahedron Letters (2017), doi: https://doi.org/
10.1016/j.tetlet.2017.09.090
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Asymmetric total synthesis and revision of
absolute configurations of azaphilone
derivative felinone A
Leave this area blank for abstract info.
Hideki Abe,∗ Haruhito Tango, Toyoharu Kobayashi, and Hisanaka Ito∗

1
Tetrahedron Letters
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Asymmetric total synthesis and revision of absolute configurations of azaphilone
derivative felinone A
Hideki Abea,b,∗ Haruhito Tangoa, Toyoharu Kobayashia, and Hisanaka Itoa∗
aSchool of Life Sciences, Tokyo University of Pharmacy and Life Sciences, 1432-1 Horinouchi, Hachioji, Tokyo 192-0392, Japan.
bDepartment of Chemical and Biological Sciences, Faculty of Science, Japan Women’s University, 2-8-1 Mejirodai, Bunkyo-ku, Tokyo 112-8681, Japan.
ARTICLE INFO
ABSTRACT
Article history:
Received
The first total synthesis of the azaphilone derivative, felinone A, was accomplished. The
absolute configuration of natural felinone A was revised to be 3S, 6S, and 7R.
Received in revised form
Accepted
2009 Elsevier Ltd. All rights reserved.
Available online
Keywords:
Felinone A
Asymmetric total synthesis
Revision of absolute configurations
Intramolecular oxymercuration/demercuration
Shi epoxidation
Introduction
Azaphilones belong to a family of polyketide metabolites that
possess highly oxygenated isochromene skeletons.1 Recent
reports demonstrated that many azaphilone derivatives possess
biological activities, such as inhibition of p53–MDM2 protein–
protein interactions,2 inhibition of gp120–CD4 binding,3
cytotoxicity, antimicrobial action, and anti-inflammatory
actions.4 Four similar azaphilone derivatives (Figure 1) have been
reported recently. Felinone A (1)5 was isolated by bioassay-
guided fractionation of a culture extract of the marine-derived
entomopathogenic fungus Beauveria felina EN-135 in 2014. The
relative configurations of felinone A were determined using 1D
and 2D NMR spectral data. Although the use of Mosher’s
method to determine the absolute configurations of 1 failed, its
absolute configuration was tentatively assigned by comparison of
Fig. 1. Structures of azaphilone derivatives.
CD
spectral
data
with
that
of
(S)-2-acetyl-3,6-
dihydroxycyclohex-2-enone6 to be 3R, 6R, and 7S.
which is a diastereoisomer at the C3 position of felinone A (1),
was not determined. The relative stereochemistry of
hypoillexidiol was assigned only using NOESY analysis.
In the following year, two azaphilone derivatives,
fusaraisochromenone (2)7 and hypoillexidiol (3),8 which are
diastereoisomers of felinone A, were isolated from the broth
extracts of the endophytic fungus Fusarium sp. PDB51F5 and
Hypoxylon sp. BCRC 12F 0687, respectively. Although the
stereochemistry at the C3 position of fusaraisochromenone (2)
was unclear, the absolute stereochemistry of 2 regarding a cis-
diol moiety was assigned by the same method as that used for
felinone A (1). The absolute configuration of hypoillexidiol (3),
———
In 2016, Rukachaisirikul and co-workers reported the isolation
and structural determination of a new azaphilone derivative 4,
named xylariphilone, from the seagrass-derived fungus
Xylariales sp. PSU-ES163.9 The relative configuration of
xylariphilone (4) was assigned from coupling constants and
selected NOEDIFF results. In addition, the absolute
configuration of xylariphilone (4) was determined through
∗ Corresponding author. Tel.: +0-3-5981-3660; fax: +0-3-5981-3660; e-mail: abehi@fc.jwu.ac.jp
∗ Corresponding author. Tel.: +0-42-676-7293; fax: +0-42-676-7282; e-mail: itohisa@toyaku.ac.jp

2
Tetrahedron
analysis of CD spectral data as 3S, 6R and 7S. The relative
recrystallization, transformation of enantiomerically pure 11
(99% ee) to the highly oxygenated bicyclic lactone gave 7 in four
steps with high diastereoselectivity.
stereochemistry of xylariphilone (4) is identical with that of
hypoillexidiol (3), but the sign of optical rotation is opposite
[hypoillexidiol (3): [α]D +231 (c 0.09, MeOH),8 and
xylariphilone (4): [α]D –25.1 (c 0.50, CHCl3)9]. Thus,
hypoillexidiol is an enantiomer of xylariphilone, and the absolute
configuration of hypoillexidion is 3R, 6S and 7R.
Construction of the conjugated diene on bicyclic lactone 7 was
achieved in two steps: reduction of carbonyl group of 7 with
DIBALH at –78 °C to hemiacetal 12, followed by Wittig reaction
of the resulting crude product 12 using a combination of ethyl
Very recently, we reported that the synthesis of polyketide
having a dihydroxy-methylcyclohexenone nucleus was similar to
that of felinone A (1).10,11 Our previous study11 based on Shi
asymmetric epoxidation, regioselective epoxide ring opening,
and diastereoselective dihydroxylation, was achieved via
triphenylphosphonium
bromide
and
lithium
hexamethyldisilazane in THF to afford alcohol 6 in 89% yield as
a 1:1.3 mixture of E/Z isomers. Although many different reaction
conditions for Wittig olefination (e.g., bases, phosphonium
reagents, solvents, temperatures) and for Julia olefinations were
used, all attempts gave a 1:1 to 1:3 mixture of E/Z isomers.
enantioselective
construction
of
the
dihydroxy-
methylcyclohexenone skeleton of these azaphilone derivatives.
The present report describes the asymmetric synthesis of felinone
A using the previously reported methodology, leading to revision
of its absolute configuration.
Results and discussion
The synthetic plan is outlined in Scheme 1. Target molecule 1
would be synthesized from compound 5 by cleaving protective
groups and transforming allyl alcohol to a conjugated enone part
by oxidation. The bicyclic skeleton of hexahydroisochromene
derivative
5
would be constructed by intramolecular
oxymercuration/demercuration of the dienyl alcohol 6, derived
from the optically active bicyclic lactone 7 in two steps,
reduction of the lactone ring to a cyclic hemiacetal moiety,
followed by Wittig reaction. The optically pure (99% ee) bicyclic
lactone 7 could be derived easily from propargyl alcohol (8) in
eight steps using a previously reported method.10,11
Scheme 2. Asymmetric synthesis of the oxymercuration
precursor 6.
After synthesis of alcohol 6 containing a conjugated diene, our
efforts were focused on the synthesis of felinone A (1) via
construction of
a hexahydroisochromene skeleton through
intramolecular oxymercuration, followed by demercuration.
After separation of the E/Z isomers using HPLC, intramolecular
oxymercuration of E- and Z-6 were conducted as shown in
Scheme 3. Intramolecular oxymercuration of Z-6 with
mercury(II) trifluoroacetate in methanol, followed by
demercuration with 3 M NaOH and sodium borohydride gave the
undesirable hexahydroisobenzofuran derivative 13 produced by
5-exo type cyclization as a 5:1 diastereomixture in 85% yield. In
contrast, treatment of E-6 with the same protocol afford the
desired hexahydroisochromene derivative 5 in 54% yield with
7:1 diastereoselectivity and 5:1 regioselectivity. Although the
relative configuration of 5 could not be confirmed, even after
extensive spectroscopic analysis including NOESY experiments,
the relative configurations of three asymmetric carbons were
determined by X-ray crystallography of final compound 1.15
Although no details exist about the difference in oxymercuration
reactions between Z-6 and E-6, cyclization of E-6 was thought to
occur via cyclic mercurium ion to afford the desired product as a
major cyclized product. However, reaction of Z-6 occurred by
cyclization via allyl cation species, because the hydroxyl group
Scheme 1. Synthetic plan for felinone A (1).
The synthesis began with installation of a conjugated diene
moiety to the known bicyclic lactone 7, prepared in an optically
pure form from propargyl alcohol over eight steps, including
chemo- and enantioselective epoxidation (Scheme 2). The
bicyclic lactone 9, which was a precursor of enantioselective
epoxidation, was derived from propargyl alcohol (8) as a starting
material in three steps using a previously reported method.
Chemo- and enantioselective epoxidation of 9 with Oxone® and
Shi catalyst 10 prepared from D-fructose gave the epoxide 11 in
98% yield with an 87% enantiomeric excess.12-14 The absolute
stereochemistry of the newly formed asymmetric carbon at C6
position was confirmed to be the R configuration using a
modified Mosher’s method.11 After purification by

3
and reaction point of the cyclic mercurium ion could not
approach with the conformation of the transition state.
absolute configuration of natural felinone A (1) was revised to
be 3S, 6S and 7R.
Treatment of 5 with trifluoroacetic acid (TFA) in CH2Cl2–H2O
for 1 h selectively cleaved the acetonide group to afford 14 in
80% yield. After Ley oxidation16,17 of the diol 14 to 15,
treatment of the resulting ketone 15 with tetra-n-butylammonium
fluoride (TBAF) provided the target compound 1 in 69% yield.
Both 1H- and 13C-NMR spectral data were identical with data
In conclusion, the first total synthesis of azaphilone derivative
felinone A was accomplished. The synthesis featured Shi
asymmetric epoxidation of a bicyclic lactone, and intramolecular
oxymercuration/demercuration for construction of the
dihydropyrane ring. The absolute configuration of felinone A
was revised to be 3S, 6S, and 7R.
Acknowledgments
This work was supported by the Platform for Drug Discovery,
Informatics, and Structural Life Science from the Ministry of
Education, Culture, Sports, Science and Technology, Japan.
References and notes
1. Gao, J.-M.; Yang, S.-X.; Qin, J.-C. Chem. Rev. 2013, 113, 4755–
4811.
2. Clark, R. C.; Lee, S. Y.; Searcey, M.; Boger, D. L. Nat. Prod. Rep.
2009, 26, 465–477.
3. Matsuzaki, K.; Tahara, H.; Inokoshi, J.; Tanaka, H. J. Antibiot.
1998, 51, 1004–1011.
4. Hsu, W.-H.; Pan, T.-M. Appl. Microbiol. Biotechnol. 2012, 93,
1831–1842.
5. Du, F.-Y.; Li, X.-M.; Zhang, P.; Li, C.-S.; Wang, B.-G. Mar.
Drugs 2014, 12, 2816–2826.
6. Zaitsev, V. G.; Mikhal’chuk, A. L. Chirality 2001, 13, 488–492.
7. Boonyaketgoson, S.; Trisuwan, K.; Bussaban, B.; Rukachaisirikul,
V.; Phongpaichit, S. Tetrahedron Lett. 2015, 56, 5076–5078.
8. Chen, Y.-S.; Cheng, M.-J.; Hsiao, Y.; Chan, H.-Y.; Hsieh, S.-Y.;
Chang, C.-W.; Liu, T.-W.; Chang, H.-S. Chen, I.-S. Helv. Chim.
Acta 2015, 98, 1167–1176.
9. Arunpanichlert, J.; Rukachaisirikul, V.; Phongpaichit, S.;
Supaphon, O.; Sakayaroj, J. Nat. Prod. Res. 2016, 30, 46–51.
10. Abe, H.; Itaya, S.; Sasaki, K.; Kobayashi, T.; Ito, H. Chem.
Commun. 2015, 51, 3586–3589.
11. Abe, H.; Itaya, S.; Sasaki, K.; Kobayashi, T.; Ito, H. Chem.
Pharm. Bull. 2016, 64, 772–777.
12. Wang, Z.-X.; Tu, Y.; Frohn, M.; Zhang, J.-R.; Shi, Y. J. Am.
Chem. Soc. 1997, 119, 11224–11235.
13. Shi, Y. Acc. Chem. Res. 2004, 37, 488–496.
14. Wong, O. A.; Shi, Y. Chem. Rev. 2008, 108, 3958–3987.
15. CCDC 1526954 contains the supplemental crystallographic data
of 1 for this paper.
16. Griffith, W. P.; Ley, S. V.; Whitcombe, G. P.; White, A. D. J.
Chem. Soc., Chem. Commun. 1987, 1625–1627.
17. Ley, S. V.; Norman, J.; Griffith, W. P.; Marsden, S. P. Synthesis
1994, 639–666.
18. The detailed experimental results are described in the Supporting
Information.
Scheme 3. Synthesis of felinone A (1).
Supplementary Material
reported for 1.5 The optical rotation of synthetic 3R,6R,7S-1 [[α]D
–167.0 (c 0.55, MeOH)] was opposite to that of natural felinone
A [[α]D +104.8 (c 0.21, MeOH)]. In addition, the circular
dichroism spectra for synthetic 1 indicated a positive cotton
effect at 215 nm and a negative effect at 247 nm, which were
opposite of those for a natural sample5 [negative effect at 219
nm, and positive effect at 248 nm]. To confirm the absolute
configuration of synthetic 1, a modified Mosher’s method of 1
was carried out.18 From the analysis of 1H NMR spectra of
MTPA esters derived from 1 with (R)- or (S)-MTPACl, the
absolute stereochemistry of the asymmetric carbon at C6 position
was reconfirmed to be the R configuration. Therefore, the
Supplementary material that may be helpful in the review
process should be prepared and provided as a separate electronic
file. That file can then be transformed into PDF format and
submitted along with the manuscript and graphic files to the
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4
Tetrahedron
Highlights
•
•
•
Asymmetric total synthesis of azaphilone
derivative felinone A was accomplished.
The absolute configuration of felinone A was
revised.
Construction of the dihydropyrane ring by
intramolecular oxymercuration/demercuration.