Total synthesis of (+)-blennolide C and (+)-gonytolide C via spirochromanone

Article abstract of DOI:10.1016/j.tetlet.2017.10.038

We report the asymmetric total synthesis of (+)-blennolide C and (+)-gonytolide C isolated from endophytic fungi. The synthesis involved construction of a spirochromanone with a chiral quaternary carbon by the aldol reaction of o-hydroxyacetophenones and

Full text of DOI:10.1016/j.tetlet.2017.10.038

Accepted Manuscript
Total synthesis of (+)-blennolide C and (+)-gonytolide C via spirochromanone
Kanna Adachi, Sho Hasegawa, Kazuaki Katakawa, Takuya Kumamoto
PII:
S0040-4039(17)31318-7
https://doi.org/10.1016/j.tetlet.2017.10.038
TETL 49400
DOI:
Reference:
Tetrahedron Letters
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12 October 2017
16 October 2017
Please cite this article as: Adachi, K., Hasegawa, S., Katakawa, K., Kumamoto, T., Total synthesis of (+)-blennolide
C and (+)-gonytolide C via spirochromanone, Tetrahedron Letters (2017), doi: https://doi.org/10.1016/j.tetlet.
2017.10.038
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Total synthesis of (+)-blennolide C and (+)-
gonytolide C via spirochromanone
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Kanna Adachi, Sho Hasegawa, Kazuaki Katakawa, Takuya Kumamoto

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Tetrahedron Letters
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Total synthesis of (+)-blennolide C and (+)-gonytolide C via spirochromanone
Kanna Adachi,a Sho Hasegawa,a Kazuaki Katakawa,a Takuya Kumamotob *
a Department of Synthetic Organic Chemistry, Research Institute of Pharmaceutical Sciences, Musashino University, 1-1-20 Shinmachi, Nishitokyo 202-8585,
Japan.
b Department of Synthetic Organic Chemistry, Graduate School of Biomedical & Health Sciences, Hiroshima University, 1-2-3 Kasumi, Minami-ku, Hiroshima,
732-8553, Japan
This article is dedicated to the late Professor István E Markó, Université catholique de Louvain, deceased on July 31, 2017.
ARTICLE INFO
ABSTRACT
Article history:
Received
We report the asymmetric total synthesis of (+)-blennolide C and (+)-gonytolide C isolated from
endophytic fungi. The synthesis involved construction of a spirochromanone with a chiral
quaternary carbon by the aldol reaction of o-hydroxyacetophenones and optically active α-
oxygenated cyclohexenone, followed by cyclization under acidic conditions. Oxidative cleavage
of the alkene moiety of the spirochromanone furnished the chromanone diester. Through treating
the diester with a Lewis acid, the first total synthesis of (+)-blennolide C was achieved by
deprotecting the oxygen functionality of the diester and simultaneous Dieckmann condensation.
Total synthesis of (+)-gonytolide C was also achieved by lactone formation from the deprotected
diester.
Received in revised form
Accepted
Available online
Keywords:
total synthesis
xanthones
spirochromanones
asymmetric synthesis
enzymatic resolution
2009 Elsevier Ltd. All rights reserved.
Naturally occurring xanthones1 and their biogenetically
related chromanones with γ-butyrolactones have been isolated
from a wide range of plants, bacteria, fungi, and lichens as
monomeric and dimeric structures. Some of these compounds
exhibit antibacterial, antifungal, and antialgal activities.
Monomeric xanthones (+)-blennolides A (1) and C (2) were
isolated with dimeric (+)-secalonic acid B (1)2 from the fungus
Blennoria sp., an endophytic fungus from Carpobrotus edulis.3
Synthetic studies towards these xanthones and related
chromanones have been performed, and the total syntheses of
some of monomeric5 and dimeric derivatives6 have been
reported. Asymmetric total syntheses of natural (+)-gonytolide C
(4) was reported,7 however synthesis of natural (+)-blennolide C
(2) has not been reported yet. Moreover, these syntheses are
target-oriented using γ-lactone derivatives and development of
more flexible synthetic methods is expected toward synthesis of
natural products as well as their derivatives.
Biogenetically related (+)-gonytolide
C
(4), monomeric
chromanone with γ-lactone moiety was isolated from the fungus
Gonytrichum sp. with dimeric (+)-gonytolide A (5) which shows
innate immune promoter activity4 (Figure 1).
In our ongoing synthetic studies of biologically active natural
products,8 we planned to develop a new methodology for
asymmetric total synthesis of (+)-blennolide
C (2), (+)-
gonytolide C (4) and their derivatives with other ring sizes. We
assumed that optically active α-oxygenated cyclohexenone 6 (n =
1) derived from cyclohexanone or cyclohexene oxide can be used
as the source of cyclohexene and γ-lactone in 2 and 4. Aldol
reaction with o-hydroxyacetophenone 7 and cyclization of the
aldol adducts 8 should give spirochromanones 9 with a chiral
quaternary center.9 Target natural products 2 and 4 could be
obtained by oxidative cleavage of the alkene moiety in 9
followed by cyclization. Derivatives with other sizes of
cycloalkene or lactone in 2 and 4 can be accessed using another
ring sizes of cycloalkenones 6 (n = 0, 2, 3,…). Based on this
analysis, we examined the total synthesis of (+)-blennolide C (2)
and (+)-gonytolide C (4) via spirochromanone using optically
active α-oxygenated cyclohexenone and o-hydroxyacetophenone
(Scheme 1).
A model synthetic study using simple o-hydroxyacetophenone
(11) and α-oxygenated cyclohexenone 12 was performed. 12
Figure 1. Representative xanthones 1–3 and chromanones 4–5
from endophytic fungi.

2
Tetrahedron Letters
chromanone of gonytolide C (4) with γ-lactone moiety. The
Dieckmann condensation reaction of 23 under basic conditions
(NaH or LDA) gave complex mixtures. No reaction occurred
when 23 was treated with TiCl4 in the presence of Et3N in
refluxed CH2Cl2.14 Reaction in the absence of Et3N gave desired
24, the model xanthone of blennolide C (2), in 17% yield with
the recovery of 23 in 33% yield. The yield of 24 was improved to
89% when 1,2-dichloroethane was used instead of CH2Cl2
(Scheme 3).
Scheme 1. Retrosynthesis for blennolide C (2) and gonytolide C
(4) via spirochromanone intermediates 9. P: protecting groups.
(36% ee with R configuration as the major isomer) was prepared
by acetoxylation of cyclohexenone (13) with Mn(OAc)3 followed
by enzymatic hydrolysis of acetate ( )-14.10 After the benzylation
of 12, cyclohexenone 1511 was subjected to an aldol reaction with
11 in the presence of 2 equivalents of LDA12 to give the aldol
adducts 16 and 17 as a mixture of diastereomers. Less polar 16
was obtained as a major isomer. After separation, 16 was
cyclized under acidic conditions (HCl in CH3OH, reflux, 33 h)13
to afford diastereomeric spirochromanones 18 (12%) and 19
(27%) and dehydrated dienone 20. Less polar 19 was obtained as
the major isomer in this reaction. The relative stereochemistry of
16 and 18 was determined as cis for the two oxygen
functionalities on cyclohexene ring by NOE experiments, which
showed a correlation between the methylene protons derived
from 11 and the proton of the methyne bearing the benzyloxy
group (Scheme 2).
Scheme 3. Synthesis of model chromanone 23 and xanthone 24.
Next, we performed the asymmetric total synthesis of (+)-
blennolide C (2) and (+)-gonytolide C (4) with functionalized
acetophenone 7 and optically active cyclohexenone (S)-15 with
correct
stereochemistry
(Scheme
4).
(1S,2S)-1,2-
Cyclohexanediol monobenzyl ether (25, 97% ee) prepared by
PLE-catalyzed resolution of ( )-25 using vinyl acetate15 was used
as a key synthetic intermediate. Swern oxidation of (1S,2S)-25,
regioselective conversion of the resultant ketone 26 to silyl enol
ether 27 using magnesium amide,16 followed by palladium-
catalyzed oxidation of 27 mediated by oxygen (O2),17 afforded
optically active enone (S)-15. The optical purity of (S)-15 was
estimated as 97% ee. The aldol reaction of mono-MOM-
protected acetophenone 28, derived from dihydroxyacetophenone
7,5b and enone (S)-15, gave adducts 29 and 30.18 After isolation,
treatment of major isomer 29 with HCl in CH3OH gave
spirochromanones 31 and less polar 32 in 37% and 39% yields,
respectively. When the crude product of the aldol reaction of 28
and (S)-15 was subjected directly to the cyclization conditions,
31 and 32 were obtained in 42% and 34% yields in 2 steps,
respectively. Sufficient information for the relative configuration
of 31 and 32 was not obtained by the NOE experiment.
Therefore, the relative stereochemistry of 31 and 32 were
deduced by correlation of the 1H NMR data and the polarity of 18
and 19. The chemical shifts of the protons around the
stereocenters in more polar 18 and 31 generally showed a greater
upfield shift than those of less polar 19 and 32. The ∆δ values of
the two benzylic protons (Hd and He) were similar between those
of 18 and 31, and 19 and 32, respectively (Table 1). Based on
these data, the absolute configurations of 31 and 32 were
deduced as (1R,2S) and (1S,2S), respectively. Optical purity was
estimated for 31 and 32 as 96% ee, which shows that these
compounds were obtained without any loss of optical purity
during the reaction course.19 After the diastereomers were
separated by column chromatography, 32 with the desired
configuration was subjected to similar treatment to 19 to give
diester 33. Trial for the catalytic hydrogenation of 33 recovered
the starting material. Treatment of 33 with TiCl4 and Et3N gave
(+)-blennolide C (2), xanthone with methyl enol ether 34, and
deprotected alcohol 35.4a The NOESY spectrum of 34 showed
the cis relationship between the proton at the ring juncture and
C5-H. Enol ether 34 can be converted to blennolide C (2) under
acidic conditions. Alcohol 35 was treated with p-TsOH under
Scheme 2. Synthesis of model spirochromanones 18 and 19.
Lemieux-Johnson oxidation of the alkene in 19 with the
desired relative stereochemistry, followed by Jones oxidation and
esterification, gave diester 21. Trial for Claisen condensation of
21 using TiCl4/Et3N system14 gave deprotected alcohol 22, which
was treated with p-TsOH gave γ-lactone 23, the model
reflux
in
toluene
to
give
(+)-

3
Scheme 4. Total synthesis of (+)-blennolide C (2) and (+)-gonytolide C (4).
Table 1. Comparison of 1H NMR data and polarity of 18, 19, 31, and 32 (unit: ppm).a
18 (more polar)
19 (less polar)
31 (more polar)
32 (less polar)
Ha, Hb
2.59, 3.15 (0.56)
2.77, 3.28 (0.51)
2.49, 3.23 (0.74)
2.73, 3.27 (0.54)
Hc
Hd, He
3.50
4.49, 4.66 (0.17)
3.90
4.55, 4.63 (0.08)
3.48
4.49, 4.73 (0.24)
3.87
4.55, 4.64 (0.09)
a∆δ of the two protons is shown in parentheses.
gonytolide C (4). The spectral data for synthesized (+)-blennolide
C (2) and (+)-gonytolide C (4) were identical to those of the
natural products. The optical rotations of synthesized blennolide
References and notes
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22.6
C (2) and gonytolide C (4) were estimated as [α]D +180.7 (c
0.07, CHCl3) and [α]D
23.7
+25.6 (c 0.18, CHCl3), which were
25
identical with the natural products [lit. 2: [α]D +181.7 (c 0.06,
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In summary, first total syntheses of (+)-blennolide C (2) and
synthesis of (+)-gonytolide
C (4) were achieved. Key
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Ueda, K.; Kurata, S.; Katou, Y.; Oshima, Y. Org. Lett. 2011, 13,
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2016, 79, 1259-1266.
spirochromanone 31 was obtained by the aldol reaction of o-
hydroxyacetophenone and optically active α-oxygenated
cyclohexenone and cyclization in acidic condition. Oxidative
cleavage of the alkene moiety in the spirochromanone gave
diester 32, which was subjected to Dieckmann condensation
resulted in the total synthesis of (+)-blennolide C (2). Lactone
formation of hydroxyester 34 derived from diester 32 furnished
(+)-gonytolide C (4). Extension of this methodology to the
synthesis of other natural products and the derivatives are
currently being examined using a variety of acetophenones and
α-oxygenated cycloalkenones with another substituents and ring
sizes.
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T.; Johnson, R. P.; Porco Jr, J. A. J. Am. Chem. Soc. 2011, 133,
1714-1717. Asymmetric syntheses of the enantiomers of 1, 2 and
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F.; Jackenkroll, S.; Hierold, J.; Ma, L.; Waldecker, B. Chem. Eur.
J. 2014, 20, 8628-8635. Synthesis of epimers of 2: (e) Meister, A.
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M.; Bräse, S. Eur. J. Org. Chem. 2014, 4861-4875.
6. For the enantioselective total synthesis of secalonic acids A and B:
(a) Qin, T.; Porco Jr, J. A. Angew. Chem. Int. Ed. 2014, 53, 3107-
3110. (b) E (enantiomer of B): Ganapathy, D.; Reiner, J. R.;
Löffler, L. E.; Ma, L.; Gnanaprakasam, B.; Niepötter, B.; Koehne,
I.; Tietze, L. F. Chem. Eur. J. 2015, 21, 16807-16810. Examples
of the dimerization of related xanthones: (c) Qin, T.; Skraba-
Joiner, S. L.; Khalil, Z. G.; Johnson, R. P.; Capon, R. J.; Porco Jr,
Acknowledgments
This work was partially supported by GAKUIN
TOKUBETSU KENKYUHI Grant (Musashino University).

4
Tetrahedron
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M. L. Tetrahedron Lett. 2002, 43, 5805-5808.
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18. The diastereoselectivity was improved when toluene was used as a
solvent with adding HMPA to give ca. 5 : 1 of 29 and 30 (52%
and 11%, respectively).
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2006, 17, 3004-3009. Even though (S)-12 is the desired
enantiomer for asymmetric total synthesis of natural (+)-2 and (+)-
4, trials with (R)-12 with the opposite configuration in low optical
purity was examined in this stage because trials for the hydrolysis
of acetate 14 gave 12 in low yields (up to 24%) under acidic (p-
TsOH, HCl, Sc(OTf)3, Hf(OTf)4) and basic (K2CO3, NaOH)
conditions. Using Sc(OTf)3 for the hydrolysis of α-
19. The undesired chromanone 31 can be isomerized to desired 32
when 31 was heated in toluene in a sealed tube under microwave
irradiation at 150 ºC in the presence of pyrrolidine to give a 1 : 1
mixture of 31 and 32.
Supplementary Material
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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acetoxyketones, see: Kajiro, H.; Mitamura, S.; Mori, A.; Hiyama,
T. Bull. Chem. Soc. Jpn. 1999, 72, 1553-1560.
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glucal, see Momose, T.; Setoguchi, M.; Fujita, T.; Tamura, H.;
Chida, N. Chem. Commun. 2000, 2237-2238.
12. Reaction of cyclohexenone and O-protected 11 using 1 equivalent
of LDA gave the corresponding aldol adduct in low yield. The
detail will be reported elsewhere.
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5
Highlights
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ꢀ
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First total synthesis of natural (+)-blennolide C
was achieved.
Synthesis of (+)-gonytolide C was also
achieved via spirochromanone.
Adduct of acetophenone and cyclohexenone is
a good substrate for spirochromanone.
Xanthones were constructed via alkene
cleavage in spirochromanone and cyclization.