Structural revision of kynapcin-12 by total synthesis, and inhibitory activities against prolyl oligopeptidase and cancer cells

Article abstract of DOI:10.1016/j.bmcl.2014.05.091

Kynapcin-12 is a prolyl oligopeptidase (POP) inhibitor isolated from Polyozellus multiplex, and its structure was assigned as 1 having a p-hydroquinone moiety by spectroscopic analyses and chemical means. This Letter describes the total syntheses of the proposed structure 1 for kynapcin-12 and 2′,3′-diacetoxy-1,5′,6′,4″-tetrahydroxy-p- terphenyl 2 isolated from Boletopsis grisea, revising the structure of kynapcin-12 to the latter. These syntheses involved double Suzuki-Miyaura coupling, CAN oxidation, and LTA oxidation as key steps. The inhibitory activities of synthetic compounds against POP and cancer cells were also evaluated.

Full text of DOI:10.1016/j.bmcl.2014.05.091

Accepted Manuscript
Structural Revision of Kynapcin-12 by Total Synthesis, and Inhibitory Activities
against Prolyl Oligopeptidase and Cancer Cells
Shunya Takahashi, Ayaka Yoshida, Shota Uesugi, Yayoi Hongo, Ken-ichi
Kimura, Koji Matsuoka, Hiroyuki Koshino
PII:
S0960-894X(14)00600-3
DOI:
http://dx.doi.org/10.1016/j.bmcl.2014.05.091
BMCL 21705
Reference:
Bioorganic & Medicinal Chemistry Letters
To appear in:
Received Date:
Revised Date:
Accepted Date:
30 April 2014
23 May 2014
26 May 2014
Please cite this article as: Takahashi, S., Yoshida, A., Uesugi, S., Hongo, Y., Kimura, K-i., Matsuoka, K., Koshino,
H., Structural Revision of Kynapcin-12 by Total Synthesis, and Inhibitory Activities against Prolyl Oligopeptidase
and Cancer Cells, Bioorganic & Medicinal Chemistry Letters (2014), doi: http://dx.doi.org/10.1016/j.bmcl.
2014.05.091
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Structural Revision of Kynapcin-12 by Total Synthesis, Leave this area blank for abstract info.
and Inhibitory Activities against Prolyl Oligopeptidase
and Cancer cells
Shunya Takahashi,* Ayaka Yoshida, Shota Uesugi, Yayoi Hongo, Ken-ichi Kimura, Koji Matsuoka, and
Hiroyuki Koshino*

Bioorganic & Medicinal Chemistry Letters
jo u rn al h ome p ag e : w ww .e lse vie r .c om
Structural Revision of Kynapcin-12 by Total Synthesis, and Inhibitory Activities
against Prolyl Oligopeptidase and Cancer Cells
Shunya Takahashia∗, Ayaka Yoshidaa,b, Shota Uesugic, Yayoi Hongoa, Ken-ichi Kimurac, Koji Matsuokab,
and Hiroyuki Koshino*a
aRIKEN, Wako-shi, Saitama, 351-0198, Japan
bDivision of Material Science, Graduate School of Science and Engineering, Saitama University, Saitama 338-8570, Japan
cThe United Graduate School of Agricultural Sciences, Iwate University, Morioka, Iwate 020-8550, Japan
ARTICLE INFO
ABSTRACT
Article history:
Received
Kynapcin-12 is a prolyl oligopeptidase (POP) inhibitor isolated from Polyozellus multiplex, and
its structure was assigned as 1 having a p-hydroquinone moiety by spectroscopic analyses and
chemical means. This paper describes the total syntheses of the proposed structure 1 for
kynapcin-12 and 2’,3’-diacetoxy-1,5’,6’,4”-tetrahydroxy-p-terphenyl 2 isolated from Boletopsis
grisea, revising the structure of kynapcin-12 to the latter. These syntheses involved double
Suzuki-Miyaura coupling, CAN oxidation, and LTA oxidation as key steps. The inhibitory
activities of synthetic compounds against POP and cancer cells were also evaluated.
Revised
Accepted
Available online
Keywords:
p-terphenyl
2009 Elsevier Ltd. All rights reserved.
Prolyl oligopeptidase inhibitor
Kynapcin-12
Terphenyls are aromatic hydrocarbons consisting of a chain
of three benzene rings.1 Structurally, these compounds can be
classified into three types in which the terminal rings are ortho
(o)-, meta (m)-, or para (p)-substituents of the central aromatic
ring. Most natural terphenyls belong to p-terphenyl derivatives,
and some of them have been reported to exhibit significant
biological activities such as potent immunosuppressants,
neuroprotective, and cytotoxic activities. In 2000, Song et al.
isolated a new p-terphenyl from the methanolic extract of
Polyozellus multiplex and named it kynapcin-12.2 The structure
was determined to be 1 by spectroscopic and chemical means;
the position of two acyl groups was deduced by the experimental
results that the natural product did not form the corresponding
phenylboronate and that its colourimetric test3 for detecting a
catechol function was negative. This structure seemed to be of
interest because natural p-terphenyls with diacyl groups at the
central ring have been isolated so far as a regioisomeric mixture
except the corresponding catechol derivatives.4,5 The natural
product exhibits an inhibitory activity (IC50 = 1.25 µM) against
prolyl oligopeptidase (POP, EC3.4.21.26).6 POP is a serine
protease and it cleaves the carboxyl side of proline in peptides
that are <30 amino acids in length such as oxytocin, vasopressin
and neurotensin, etc.7 Recent studies have revealed that the
enzyme participates in several functions of the central nervous
diseases such as Alzheimer’s and Parkinson’s diseases.8,9 It has
also been reported that POP inhibition suppressed the growth of
human neuroblastoma cell line, NB-1 and human gastric cancer
cell line, KATO III, respectively.10,11 Therefore, POP inhibitors
are expected to be a promising tool for the prevention and
treatment of neurodegenerative diseases and cancer. Recently,
we have been engaged in synthetic studies on natural p-
terphenyls, resulting in the total synthesis of vialinins A,12 B,13
and telephantin G.4 As part of our continuing studies in this
field, we describe herein total synthesis of kynapcin-12 which
dictates revision of the formula to 2. The inhibitory activities of
synthetic compounds against POP and cancer cells were also
evaluated.
Figure 1. The original structure for kynapcin-12 (1) and its revised form
2.
system and that it was a target in memory and neurodegenerative
———
∗ Corresponding authors. Fax: +81-48-462-4627 (Takahashi); fax: +81-48-462-1640 (Koshino). E-mail: shunyat@riken.jp (S.T.): koshino@riken.jp (H.K.).

Table 1. 1H-NMR data (δ) for natural kynapcin-12, 1, 2, and 12 in MeOH–
d4.
position
2 (6)
Kynapcin-12a,b
6.83 d (8.4)
7.16 d (8.4)
7.16 d (8.4)
6.83 d (8.4)
1.90 s
1b,c
12b,c
2b,d
6.82 d (8.7)
7.14 d (8.7)
7.14 d (8.7)
6.82 d (8.7)
1.94 s
6.78 d (8.7)
7.03 d (8.7)
7.25 d (8.3)
6.85 d (8.3)
1.92 s
6.82 d (8.8)
7.15 d (8.8)
7.15 d (8.8)
6.82 d (8.8)
1.92 s
3 (5)
2” (6”)
3” (5”)
CH3
aRef. 2 (400 MHz). bNumbers in parentheses are J values. c600 MHz. d500 MHz
Table 2. 13C-NMR data (δ) for natural kynapcin-12, 1, 2, and 12 in MeOH–
d4.
position
1
Kynapcin-12a,b
158.1
116.0
132.6
125.0
123.8
134.8
142.5
123.8
134.8
142.5
125.0
132.6
116.0
158.1
170.6
20.1
1c
12c
2d,e
158.2
116.0
132.6
125.0
123.8
134.9
142.5
123.8
134.9
142.5
125.0
132.6
116.0
158.2
170.6
20.1
158.1
115.9
132.6
125.3
125.2
140.9
136.7
125.2
140.9
136.7
125.3
132.6
115.9
158.1
171.0
20.5
158.2
115.8
132.0
125.3
129.7
131.0
146.1
119.5
146.1
131.0
125.3
133.3
116.1
157.9
171.4
20.5
2 (6)
3 (5)
4
1’
2’
3’
4’
5’
6’
1”
2” (6”)
3” (5”)
4”
C=O
CH3
aRef. 2 (100 MHz). bThe original data for 2’,5’ and 3’, 6’ denoted in ref 2 were opposite.
c150 MHz. d125 MHz. eThe carbon-numbering system was conveniently according to
one shown in Figure 1.
labile toward the CAN oxidation. Prolonged reaction time
caused over-oxidation, resulting in a formation of de-BOM
quinone. Thus, the CAN oxidation of 7 was carefully performed
by monitoring the progress of the reaction by TLC, affording 9
in good yield. Reduction of 9 followed by acetylation led to a p-
hydroquinone derivative 11. Hydrogenolysis of 11 with Pd(OH)2
afforded an inseparable mixture of 1 and 12 (1/12 = ca.3:4)
again, and the pure p-hydroquinone 1 could not be isolated.
Extensive NMR analysis, however, revealed the structure of
each isomer unambiguously (Table 1 and 2). The NMR data of 1
were inconsistent with those of kynapcin-12 reported, showing
that the proposed structure 1 was incorrect. In addition, the
reported data also did not match with those of 12. We also
observed that 1 was unstable toward air oxidation and that
Synthesis of the proposed structure 1 for kynapcin-12 and its isomer 12.
Reagents and conditions: (a) Pd(OAc)2, 5, K3PO4, aq. THF, 70 °C, 81% for
7; (b) CAN, aq. THF, rt, 72% for 9; (c) Na2S2O4, aq. THF, rt; (d) LHMDS,
THF, -78 °C, and then AcCl, -78 -> 0 °C 91% for 10 from 8, 60% for 11
from 9; (e) TFA-H2O (15:1), rt, 88% for 1+12 (1/12 = 7/2) from 10; (f) H2,
Pd(OH)2/C, THF, MeOH, rt, 35% for 1+12 (1/12 = 3/4) from 11.
Synthesis of 1 started from sodium dithionite reduction of p-
quinone 814 obtained by ceric ammonium nitrate (CAN)
oxidation of 6 (Scheme 1). The resulting hydroquinone was
treated with n-BuLi in THF at -78 °C and then the addition of
acetyl chloride gave diacetate 1015 in high yield. Brief treatment
of this with degassed TFA-H2O (15:1) furnished a single product
as judged by TLC analysis. However, 1H-NMR (d4-MeOH)
analyses showed it to be an inseparable mixture of 1 and its m-
isomer 12 (1:12 = ca.3:1) which attained equilibrium (1:12 = ca.
1:3) after 12h. The migration of an acetyl group to adjacent
hydroxyls under acidic conditions is well documented.16 In order
to suppress the acyl migration at the final stage, we next
1
gradually changed to the corresponding p-quinone 13 by H-
NMR analyses (Fig. 2). When used as a non-degassed solvent,
this oxidation was fast in d6-acetone and slow in d4-MeOH. In
implemented
a
second approach that employed the
benzyloxymethyl (BOM) group as a hydroxyl protection. The
double Suzuki-Miyaura coupling17 of 3 and 4 was accomplished
by the action of Pd(OAc)2 and K3PO4 in the presence of the
Buchwald ligand 5,18,19 giving 7 in good yield. Different from
the case of oxidation of 6, the BOM group in 9 was found to be
Figure 2. The structure of an oxidised product of 1.
the literature,2 kynapcin-12 could be obtained as a single isomer
and the comment with regard to the oxidised product was not

denoted. Re-examining the NMR data of the natural product, we
found that the data of the carbon signals derived from terminal
aromatic rings of natural kynapcin-12 were similar to those of 1
rather than 12. This finding suggests that the real structure of
kynapcin-12 would be a C2 symmetry compound such as 2. Such
consideration prompted us to prepare 2. The known o-quinone
1412 was transformed into diacetate 15 according to the method
described above. Lead tetraacetate (LTA) oxidation of 15
proceeded without trouble to give triacetate 16 in a quantitative
yield. Final deprotection20 was performed by brief treatment of
16 with HF·pyridine followed by the action of TBAF, affording
2. The NMR data of synthetic 2 were consistent with those of
the natural product reported (Table 1 and 2).2
activities against POP and HL60 cells. These results are not only
useful for designing new anti-amnesic drugs, but also for anti-
cancer agents.
Table 3. Inhibitory activity of synthetic samples 1+12,
2, 6-8, 10, and 13-16, toward POP and HL60
IC50 (µM)
Compound
POP
HL60
1+12
2
2.5
15.2
10.5
>20.0
14.4
>20.0
6.5
6
>50.0
>50.0
11.5
7
8
10
13
14
15
>50.0
14.9
19.1
>20.0
2.8
15.1
17.7
2.9
16
propeptina,b
3.5
1.4
4.2
-
a Ref. 25. bThis compound was used as a positive control.
Total synthesis of the proposed structure 1 for kynapcin-12
and its o-isomer 2, and the detailed NMR analyses revealed that
the real structure of kynapcin-12 should be revised to be 2. A
fully O-protected form of 2 such as 16 was shown to have potent
inhibitory activities against POP and HL60 cells.
Acknowledgments
We are grateful to Prof. K.-S. Song in Kyungpook National
University for proving us copies of the original spectra of
natural kynapcin-12. This work was supported by JSPS
KAKENHI Grant Number 24580168.
References and notes
Synthesis of the revised structure 2 for kynapcin-12. Reagents and
conditions: (a) Na2S2O4, aq. THF, rt; (b) LHMDS, THF, -78 °C, and then
AcCl, -78 -> 0 °C 70% from 14; (c) LTA, benzene, 80 °C, 99%; (d) HF·Pyr,
CH2Cl2, rt, and then TBAF, CH2Cl2, rt, 69%.
1.
2.
Liu, J.-K. Chem. Rev. 2006, 106, 2209-2223.
Lee, H-J.; Rhee, I-K.; Lee, K-B.; Yoo, I-D.; Song, K-S. J.
Antibiotics 2000, 53, 714-719.
Prakasa, S.; Reddy, C. S.; Reddy, B. S. Ind. J. Pharmaceut. Sci.
1982, 52-57.
3.
4.
5.
6.
Ye, Y-Q.; Koshino, H.; Onose, J.; Negishi, C.; Yoshikawa, K.;
Abe, N.; Takahashi, S. J. Org. Chem., 2009, 74, 4642-4645.
Hu, L.; Gao, J.-M.; Liu, J.-K. Helv. Chim. Acta. 2001, 84, 3342-
3349.
After completion of the total synthesis of 2, we found that
such a compound has already been isolated from Boletopsis
grisea21 as a natural product by the CAS database. However, no
report of synthetic studies on the natural product has suggested
the necessity of structural confirmation by chemical synthesis.22
Our synthetic work confirms the structure of p-terphenyl 2
derived from Boletopsis grisea as well as the revision of the
structure of kynapcin-12.
Prolyl oligopeptidase has been assigned different names such as
post-proline cleaving enzyme (PPCE) and prolyl endopeptidase
(PEP).
7.
8.
9.
Yoshimoto, T.; Walter, R.; Tsuru, D. J. Biol. Chem. 1980, 225,
4786-4792.
Yoshimoto, T.; Kado, K.; Matsubara, F.;Koriyama, N.; Kaneto,
H.; Tsuru, D. J. Pharmacobiodyn. 1987, 10, 730-735.
Lawandi, J.; Gerber-Lemaire, S.; Juillerat-Jeanneret, L.;
Moitessier, N. J. Med. Chem., 2010, 53, 3423-3438.
We next examined the effect of synthetic compounds on the
inhibition activity of POP and the cytotoxicity against human
acute promyelocytic leukemia cell line, HL60, according to the
modified method of Yoshimoto et al.7,23 or Kimura et al.24 Since
separation of 1 was impossible, the bioassay could be performed
for the mixture 1 and 12 (ca. 2:3). We could not gain reliable
data of 9 and 11 due to the low solubility in DMSO and/or in the
assay buffer. As shown in Table 3, compounds synthesised in
Scheme 2 rather than in Scheme 1 showed relatively strong
inhibitory activity. Compounds 1+12 and 16 exhibited a potent
POP inhibition activity. The reason why our synthetic sample 2
showed a slightly weak inhibitory activity compared to that in
the literature2 is not clear. For cytotoxicity against HL60 cells,
compounds 8, 14, 15, and 16 were observed to be strong. It is
interesting that an orthoester 16 showed both potent inhibition
10. Sakaguchi, M.; Matsuda, T.; Matsumura, E.; Yoshimoto, T.;
Takaoka, M. Biochem. Biophys. Res. Commun. 2011, 409, 693-
698.
11. Suzuki, K.: Sakaguchi, M.; Tanaka, S.; Yoshimoto, T.; Takaoka,
M. Biochem. Biophys. Res. Commun. 2014, 443, 91-96.
12. Ye, Y-Q.; Koshino, H.; Onose, J.; Yoshikawa, K.; Abe, N.;
Takahashi, S. Org. Lett. 2007, 9, 4131-4134.
13. Ye, Y-Q.; Koshino, H.; Onose, J.; Yoshikawa, K.; Abe, N.;
Takahashi, S. Org. Lett., 2009, 11, 5074-5077.
14. Ye, Y-Q.; Koshino, H.; Abe, N.; Nakamura, T.; Hashizume, D.;
Takahashi, S. Biosci. Biotech. Biochem., 2010, 74, 2342-2344.
15. Spectral data of new compounds:
1
Compound 7: H-NMR (500 MHz, CDCl3): δ 7.45 (4H, d, J = 8.8
Hz), 7.42 (4H, brd, J = 7.5 Hz), 7.36-7.25 (18H, m), 7.11 (8H,
brd, J = 7.5 Hz), 7.00 (4H, d, J = 8.8 Hz), 5.04 (4H, s), 4.96 (8H,
s), 4.11 (8H, s); 13C-NMR (125 MHz, CDCl3): δ 158.0, 144.4,

137.6, 136.9, 132.6, 130.5, 128.6, 128.2, 127.9, 127.7, 127.5,
127.4, 126.5, 114.2, 96.5, 70.5, 69.9; HRMS (ESI+) calcd for
C64H58O10Na [M+Na]+ 1009.3928, found 1009.3932.
MeOH): δ 170.6, 158.2, 142.5, 134.9, 132.6, 125.0, 123.8, 116.0,
20.1; HRMS (ESI+) calcd for C22H18O8Na [M+Na]+ 433.0899,
found 433.0901.
Compound 9: 1H-NMR (500 MHz, CDCl3): δ 7.43 (4H, brd, J =
7.4 H), 7.40-7.30 (14H, m), 7.07-7.03 (10H, m), 5.24 (4H, s),
5.10 (4H, s), 4.24 (4H, s); 13C-NMR (125 MHz, CDCl3): δ 183.7,
159.2, 152.1, 136.7, 136.6, 132.3, 130.4, 128.6, 128.3, 128.1,
128.0, 127.9, 127.4, 122.0, 114.4, 96.1, 71.0, 70.0; HRMS (ESI+)
calcd for C48H40O8Na [M+Na]+ 767.2621 , found 767.2620.
Compound 10: 1H-NMR (500 MHz, CDCl3): δ 7.23 (4H, d, J =
8.8 Hz), 6.87 (4H, d, J = 8.8 Hz), 4.63 (4H, s), 3.04 (6H, s), 2.01
(6H, s), 0.99 (18H, s), 0.20 (12H, s); 13C-NMR (125 MHz,
CDCl3): δ 168.5, 155.3, 143.6, 140.2, 131.4, 130.1, 125.6, 119.9,
98.9, 56.9, 25.7, 20.4, 18.3, -4.4; HRMS (ESI+) calcd for
C38H54O10NaSi2 [M+Na]+ 749.3153, found 749.3148.
16. Haines, A. H. Adv. Carb. Chem. Biochem. 1976, 33, 101–107.
17. Miyaura, N.; Suzuki, A. Chem. Rev., 1995, 95, 2457.
18. Barder, T. E.; Walker, S. D.; Martinelli, J. R.; Buchwald, S. L. J.
Am. Chem. Soc. 2005, 127, 4685-4696.
19. A combination of Pd(OAc)2-Ph3P frequently gave a considerable
amount of a de-brominated biphenyl derivative as a by-product
while the use of the Buchwald ligand 5 improved the yield and
reproducibility.
20. Only the use of HF·pyridine or TBAF required a long duration
for the global deprotection, resulting in a low yield of the desired
final product. In contrast, acid treatment of 16 caused de-
acetylation of the catechol moiety although such a condition was
successfully employed at the final step in the total synthesis12 of
vialinin A.
Compound 11: 1H-NMR (500 MHz, CDCl3): δ 7.43 (4H, d, J =
8.0 Hz), 7.39-7.25 (16H, m), 7.13 (4H, brd, J = 7.5 Hz), 6.98
(4H, brd, J = 7.5 Hz), 5.06 (4H, s), 4.77 (4H, s), 4.24 (4H, s),
1.99 (6H, s); 13C-NMR (125 MHz, CDCl3): δ 168.6, 158.4, 143.7,
140.3, 137.3, 136.8, 131.5, 129.9, 128.6, 128.3, 128.0, 127.6,
127.6, 127.5, 125.1, 114.6, 96.8, 70.7, 70.0, 20.4; HRMS (ESI+)
calcd for C52H46O10Na [M+Na]+ 853.2989, found 853.2971.
21. Hu, L.; Don, Z-J.; Liu, J.-K. Chinese Chem. Lett. 2001, 12, 335-
336.
22. Although natural p-terphenyls have a relatively simple structure,
their structural analyses are not so easy because such compounds
contain many quaternary carbon atoms and they frequently lack
hydrogens suitable for HMBC experiments on 2D-NMR spectra.
Several groups have reported structural revisions and confirmed
p-terphenyls by total synthesis.4, 12, 26-29
1
Compound 13: H-NMR (500 MHz, d6-acetone): δ 7.25 (4H, d, J
= 8.7 Hz), 6.93 (4H, d, J = 8.7 Hz), 2.22 (6H, s); 13C-NMR (150
MHz, d6-acetone): δ 180.7, 168.9, 159.7, 148.0, 134.0, 132.6,
120.3, 115.9, 20.2; HRMS (ESI-) calcd for C22H15O8 [M-H]+
407.0767, found 407.0769.
23. Kimura, K.; Kawaguchi, N.; Yoshihama, M.; Kawanishi, G.
Agric. Biol. Chem. 1990, 54, 3021-3022.
24. Kimura, K.; Sakamoto, Y.; Fujisawa, N.; Uesugi, S.; Aburai, N.;
Kawada, M.; Ohba, S.; Yamori, T.; Tsuchiya, E.; Koshino, H.
Bioorg. Med. Chem., 2012, 20, 3887-3897.
Compound 15: 1H-NMR (500 MHz, CDCl3): δ 7.36 (4H, d, J =
8.5 Hz), 6.87 (4H, d, J = 8.5 Hz), 6.00 (2H, s), 2.05 (6H, s), 1.00
(18H, s), 0.22 (12H, s); 13C-NMR (125 MHz, CDCl3): δ 168.6,
155.6, 142.9, 134.9, 130.7, 123.8, 119.9, 116.8, 101.6, 25.6, 20.3,
18.2, -4.4; HRMS (ESI+) calcd for C37H48O10NaSi2 [M+Na]+
731.2684, found 731.2668.
25. Kimura, K.; Kanou, F.; Takahashi, H.; Esumi, Y.; Uramoto, M.;
Yoshihama, M. J. Antibiot. 1997, 50, 373-378
26. Lin, D. W.; Masuda, T.; Biskup, M. B.; Nelson, J. D.; Baran, P.
S. J. Org. Chem. 2011, 76, 1013-1030.
1
Compound 16: H-NMR (500 MHz, CDCl3): δ 7.75 (1H, s), 7.37
27. Nakazaki, A.; Huang, W.-Y.; Koga, K.; Yingyongnarongkul, B.-
e.; Boonsombat, J.; Sawayama, Y.; Tsujimoto, T.; Nishikawa, T.
Biosci. Biotech. Biochem., 2013, 77, 1529-1532.
(4H, d, J = 8.8 Hz), 6.89 (4H, d, J = 8.8 Hz), 2.11 (3H, s), 2.07
(6H, s), 1.00 (18H, s), 0.24 (12H, s); 13C-NMR (125 MHz,
CDCl3): δ 168.7, 168.4, 155.9, 140.3, 135.7, 130.7, 123.2, 120.0,
117.5, 113.0, 25.7, 21.1, 20.3, 18.2, -4.4; HRMS (ESI+) calcd for
C35H46O8NaSi2 [M+Na]+ 673.2629, found 673.2634.
Compound 2: mp 228-230 °C (lit.2 184-185 °C, lit.21 229-230
°C); UV λmax (MeOH) nm (logε): 225.5 (4.32), 263.0 (4.27); 1H-
NMR (500 MHz, d4-MeOH): δ 7.15 (4H, d, J = 8.8 Hz), 6.82
(4H, d, J = 8.8 Hz), 1.92 (6H, s); 13C-NMR (125 MHz, d4-
28. Usui, I.; Lin, D. W.; Masuda, T.; Baran, P. S. Org. Lett. 2013, 15,
2080-2083.
29. Norikura, T.; Fujiwara, K.; Narita, T.; Yamaguchi, S.; Morinaga,
Y.; Iwai, K.; Matsue, H. J. Agric. Food Chem. 2011, 59, 6974−
6979.