Increasing Structural Diversity of Natural Products by Michael Addition with ortho-Quinone Methide as the Acceptor

Article abstract of DOI:10.1021/acs.joc.9b02971

The active form of clavatol, ortho-quinone methide, can be generated from hydroxyclavatol in an aqueous system and used as a highly reactive intermediate for coupling with diverse natural products under very mild conditions. These include flavonoids, hydr

Full text of DOI:10.1021/acs.joc.9b02971

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Increasing structural diversity of natural products by
Michael addition with ortho-quinone methide as the acceptor
Ge Liao, Jie Fan, Lena Ludwig-Radtke, Katja Backhaus, and Shu-Ming Li
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.9b02971 • Publication Date (Web): 20 Dec 2019
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The Journal of Organic Chemistry
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Increasing structural diversity of natural products by Michael
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addition with ortho-quinone methide as the acceptor
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†
†
Ge Liao, Jie Fan, Lena Ludwig-Radtke, Katja Backhaus, and Shu-Ming Li*
Institut für Pharmazeutische Biologie und Biotechnologie, Philipps-Universität Marburg, Robert-Koch Straße 4, Marburg
35037, Germany
*E-mail: shuming.li@staff.uni-marburg.de
Supporting Information Placeholder
O
R
R
O
O
O
O
R
O
coumarins
ABSTRACT: The active form of clavatol, ortho-quinone methide, can
be generated from hydroxyclavatol in an aqueous system and used as a
highly reactive intermediate for coupling with diverse natural products
under very mild conditions. These include flavonoids,
xanthones
hydroxynaphthalenes
R
R
O
O
anthraquinones
OH
flavonoids
O
O
OH
O
OH
OH -H2
OH +H2O
O
OH
O
R
NH2
tyrosine analogues
HO
OH
hydroxynaphthalenes,
coumarins,
xanthones,
anthraquinones,
hydroxyclavatol
ortho-quinone methide
phloroglucinol derivatives
O
phloroglucinols, phenolic acids, indole derivatives, tyrosine analogues,
and quinolines. The clavatol moiety was mainly attached via C-C bonds
to ortho- or para-position of phenolic hydroxyl/amino groups and the
C2-position of the indole ring.
O
R
OH
N
R
NH
quinolines
N
H
HN
phenolic acids
N
H
indole derivatives
O
cyclic dipeptides
mild reaction conditions
broad substrate scope
diverse product formation
Ortho-quinone methides (o-QMs), as transient intermediates
i
O
OH
O
OH
O
OH
with remarkable reactivity, have been utilized as useful
ClaD
OH
OH
-H2O
H2O
1
-5
reactants in chemical synthesis. A wide range of strategies,
+
6
,7
OH
e.g.
thermally
driven,
photolytically
induced
O
8
,9
10,11
tautomerization, and benzylic oxidation
were developed
clavatol
hydroxyclavatol
o-quinone methide
to generate o-QMs. However, o-QMs can also be formed by
ii
O
O
spontaneous elimination of a stable molecule with concomitant
O
1
2,13
dearomatization.
HO
OH
O
O
O
OH
O
Recently, we reported the formation of penilactones A and B
by two-step non-enzymatic Michael additions between a -
butyrolactone and two o-QM molecules. The key precursor
hydroxyclavatol was the oxidation product of clavatol by the
O
3
4
O
O
O
O
OH
HO
OH
R
II
penilactone A, R = CH , 3S,4R
non-heme Fe /2-oxoglutarate dependent oxygenase ClaD and
3
O
penilactone B, R = CH2COOH, 3R,4S
undergoes spontaneous water elimination, resulting in the
clavatol-flavanone adduct
O
12
active o-QM intermediate (Figure 1i).
In addition to penilactones A and B from Penicillium
N
H
OH
O
OH
O
OH
O
1
4
crustosum, a number of natural products containing a clavatol
14-20
unit are found in fungi, especially in Penicillium species.
These include a clavatol-flavanone adduct from Penicillium
N
H
O HO
communol A
HO
1
6
griseoroseum, coupling products of clavatol with -pyrone
(communol A) and indole (communol B) from Penicillium
communol B
FIGURE 1. The formation of hydroxyclavatol and its equilibration
with the o-QM intermediate (i). Representative examples of
clavatol-containing natural products (ii). See Figure S1 for more
examples.
1
7
commune (Figure 1ii). More coupling products of clavatol
with diverse lactones, phenols, and quinones are listed in Figure
S1 (see Supporting Information (SI)).
The occurrence of these natural products implies the
involvement of clavatol, very likely via the o-QM intermediate,
in their formation. Inspired by the post-biosynthetic non-
enzymatic event in the formation of penilactones A and B, we
wondered whether these clavatol-containing compounds are
also pseudo-natural products.
This hypothesis triggered our interest to prove the reactivity
of the o-QM intermediate derived from hydroxyclavatol with
diverse natural products. Encouraged by accumulation of the
clavatol-flavanone adduct in P. griseoroseum, we synthesized
hydroxyclavatol chemically (Scheme S1)
16
6,21
and screened its
reactivity with 16 flavonoids (1a – 16a) under mild conditions
Figures S2 – S4). Both hydroxyclavatol and reactants at a final
(
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O were incubated at 25 °C
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concentration of 0.4 mM in 50 L H
2
i flavonoids
R2
R3
R5
R2
R3
R4
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
for 16 h without pH adjustment. LC-MS analysis of the
O
OH
8
HO
O
O
HO
O
O
incubation mixtures showed that, with the exception for 10a,
7
6
+
OH
95 °C, 30 min
H2O
R1
[M+H] ions being 178 Da larger than the corresponding
R1
+
5
OH
OH
reactants were detected. These proved the formation of the
coupling products of flavonoids with clavatol. Masses of
products harboring two clavatol units were also detected when
using 4a, 5a, 8a, 9a, and 12a – 15a as reactants.
OH
2
b R1 = R2 = R3 = H, R4 = clavatyl, R5 = H, 38%
6b R1 = R2 = R3 = OH, R4 = clavatyl, R5 = H, 21%
6c R1 = R2 = R3 = OH, R4 = H, R5 = clavatyl, 19%
2a R1 = R2 = R3 = H
a R1 = R2 = R3 = OH
6
OH
OH
OH
R1
O
OH
8
HO
O
Subsequent assays of hydroxyclavatol with other phenolic
substances, including hydroxynaphthalenes (17a – 27a),
coumarins (28a – 32a), xanthones (33a – 38a), anthraquinones
HO
O
OH
OH
7
6
+
25 °C, 16 h
H2O
OH
R2
OH
5
OH
OH
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
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0
1
2
3
4
5
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9
0
1
2
3
4
5
6
7
8
9
0
14a
OH
(39a – 42a), phloroglucinol derivatives (43a – 51a), and
14b R1 = clavatyl, R2 = H, 23%
4c R1 = H, R2 = clavatyl, 5%
1
phenolic acids (52a – 60a) were carried out in a similar way as
mentioned above. Products were detected in incubation
mixtures of hydroxyclavatol with nine of eleven tested
hydroxynaphthalenes. This proved hydroxynaphthalenes as
suitable reactants for coupling with the o-QM (Figure S2 – S4).
Coumarins with 29a as an exception, xanthones, and
anthraquinones were relatively poor reaction partners for the o-
QM and gave no product or only trace amount of products in
their reaction mixtures (Figures S2 – S5). Among all the tested
phenolic substances, phloroglucinol derivatives were found to
be the most favorable Michael donors for the o-QM
intermediate, with 10 % to 55 % conversion (Figures S2, S5 and
S6). In addition, coupling products of benzoic acids (52a – 54a)
were also observed by LC-MS analysis, while products from
hydroxyphenyl acetic acid (55a), propionic acids (56a and 57a),
and acrylic acids (58a – 60a) were not detectable (Figures S2 –
S4).
ii hydroxynaphthalenes
O
OH
OH
1
OH
R3
OH
25 °C, 16 h
H2O
3
+
OH
R
R2
R1
17a R = H
17b R1 = clavatyl, R2 = H, R3 = H, 14%
7c R1 = clavatyl, R2 = H, R3 = clavatyl, 7%
8b R1 = clavatyl, R2 = OH, R3 = H, 36%
18a R = OH
1
1
iii coumarin
O
OH
OH
O
OH
OH
O
OH
95 °C, 30 min
2
+
H O
OH
O
O
O
OH
29a
29b, 65%
iv xanthone
O
OH
O
OH
O
OH
1
OH
9
5 °C, 30 min
We speculated that the formation of the clavatol-indole
+
3
H2O
O
HO
OH
OH
1
7
O
OH
adduct communol B from P. commune was also a non-
enzymatic event and therefore investigated the reaction activity
of hydroxyclavatol with indole derivatives (61a – 72a). The
incubation mixture of L-tryptophan (61a) with hydroxyclavatol
showed a coupling product with a conversion of 20 %, while
replacement of the nitrogen of the indole ring by sulfur (62a)
and methylation at N1 position (63a) significantly reduced the
activity. Other indole derivatives carrying different side chains
at C3 coupled with clavatol with up to 49 % conversion (Figures
S2, S3, and S7).
O
35a
35b, 34%
OH
v anthraquinone
O
OH
O
O
OH
OH
O
O
OH
OH O
OH
5 °C, 30 min
OH
9
+
OH
H2O
OH OH
OH
41a
41b, 86%
vi phloroglucinol derivatives
Subsequently, cyclic dipeptides (73a – 82a) were tested by
co-incubation with hydroxyclavatol. All tryptophan-containing
cyclic dipeptides (73a – 80a) showed UV detectable product
formation with 9 % to 29 % conversion. No product formation
was detected for the incubation mixtures of cyclo-L-Tyr-L-Tyr
(81a) and cyclo-L-Ser-L-Tyr (82a) (Figures S2 – 4, S7, and S8).
In contrast to the easy coupling of L-tryptophan with the o-QM,
L-tyrosine and its analogues (83a – 87a) were generally poorly
converted to their clavatol adducts. 88a – 90a with an amino
group at the benzene ring showed UV detectable product
formation (Figures S2 and S3). All selected quinolines (91a –
O
OH
O
OH
OH
OH
R
OH
R
25 °C, 16 h
H2O
+
HO
OH
OH
OH
OH OH
45b R = COOH, 34%
47b R = COCH2CH(CH3)2, 22%
4
4
5a R = COOH
7a R = COCH2CH(CH3)2
50a R = COCH CH (p-OH)Ph
2
2
50b R = COCH CH (p-OH)Ph, 26%
2
2
OH
OH
44a R =
44b R =
, 17%
OH
OH
OH
O
clavatyl =
HO
9
9a) served as Michael donors to couple with the o-QM,
especially 92a, 94a, 95a, and 98a with obvious product peaks
in UV chromatograms (Figures S2, S3, and S8).
In summary, we demonstrated in a previous study that
Michael additions between the o-QM and γ-butyrolactones took
place easily under neutral or acidic conditions. Therefore,
hydroxyclavatol was incubated in this study with 101 natural
products or natural product-like compounds at 25 °C and a
nearly neutral pH value, which led to the detection of coupling
products in 85 cases. Product formation with 10 to 55 %
conversion was detected for 49 reactants (Schemes 1 and 2,
Figures S5 – S10). To facilitate the isolation of the products for
structural elucidation, we changed the reaction temperature for
In addition, clear product formation was also detected for the
o-QM with other nitrogen-containing reactants, including 2-
aminobenzyl alcohol (100a), 2-aminobenzoic acid (101a), and
even tris(hydroxymethyl)aminomethane (Tris, 102a) prepared
as Tris-HCl buffer (pH 7.5) (Figures S2 and S8).
12
SCHEME 1. The reactions of hydroxyclavatol with nitrogen
free reactants.
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all the incubations to 95 °C for 30 min to improve the product
yields. As shown in Figures S5 – S10, the majority of the
reactions was promoted by increased temperature, leading to
generally two to ten-fold higher accumulation of the coupling
products. Taking purpurin (41a) as an example, its coupling
with clavatol was improved dramatically from trace amount to
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
SCHEME 2. The reactions of hydroxyclavatol with nitrogen
containing reactants.
vii indole derivatives
8
6 %. In total, product formation with 30 to 99 % conversion
R1
R2
R1
R2
O
OH
was achieved for 58 reactants at 95 °C for 30 min. However, in
a few cases, no significant change was observed for reactions
performed at 25 °C and 95 °C (Figures S5 – S10). Therefore,
large scaled reactions of hydroxyclavatol with 23 reactants of
different structural skeletons were carried out at either 25 °C or
95 °C, resulting in the isolation of 32 products, which were
further subjected to HR-ESI-MS and NMR analyses (Figures
S12 – S86).
OH
3
2
5 °C, 16 h
H2O
+
2
R3
OH
N
R4
N1
H
61a R1 = COOH, R2 =
65a R1 = COOH, R2 = NHCOCH3
2a R1 = CH2COOH, R2 = H
61b R1 = COOH, R2
NH , R3 = clavatyl, R4 = H, 20%
NH2
=
2
65b R1 = COOH, R2 = NHCOCH , R = clavatyl, R4 = H, 27%
3
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
3
7
65c R1 = COOH, R2 = NHCOCH , R3 = H, R4 = clavatyl, 10%
3
2b R1 = CH2COOH, R2 = H, R3 = clavatyl, R4 = H, 49%
7
viii tryptophan containing cyclic dipeptides
R
H
R
HN
Structural elucidation of the coupling products of phenolic
reactants confirmed the attachment of the clavatol unit to the
ortho- or para-position of the hydroxyl group at the benzene
ring. Herein, the o-QM formed from hydroxyclavatol in an
aqueous system was proposed to act as the Michael acceptor for
the phenolic substances (Figures S11i and ii). The formation of
O
N
H
N
O
R2
O
OH
H
O
N
N
H
O
OH
OH
N
H
O
+
3
25 °C, 16 h
O
+
N
O
OH
R1
2
H2O
NH
HO
H
NH
1
NH
7
7
6a R = CH(CH3)2
7a R = phenyl
76b R = CH(CH3)2, 10%
77b R = phenyl, 9%
79c R1 = clavatyl, R2 = H, 2%
79d R1 = R2 = clavatyl, 2%
H
N
H
N
1
7b and 98b represents examples for the attachment of a
clavatol moiety onto the para-position of hydroxyl group
Schemes 1 and 2, Figures S5 and S8). For flavonoids with a
,7-dihydroxyl feature (2a, 6a, and 14a), C8-adducts (2b, 6b,
and 14b) were identified as main products and the C6-adduct
14c) as a byproduct (Scheme 1, Figure S5). The clavatol-
79a R =
79b R =
, 21%
(
5
H
N
H
N
O
O
O
H
O
N
O
OH
N
H
O
OH
OH
9
5 °C, 30 min
+
N
OH
N
H
O
2
H O
NH
HO
HO
O
(
+
H
OH
NH
containing flavanone from P. griseoroseum (Figure 1) was
O
NH
80a
80b, 38%
80c, 7%
identified by feeding 5,7,3´,4´,5´-pentamethoxyflavanone into
1
6
the culture. The incorporation of clavatol unit into the
exogenous flavanone might be also a non-enzymatic product. In
analogy, 18b and 35b were identified as products of
hydroxyclavatol with 1,3-dihydroxynaphthalene (18a) and 1,3-
dihydroxyxanthone (35a) (Scheme 1, Figures S5 and S6).
Additionally, formation of 29b by the linkage between the
clavatol unit and the -pyrone moiety of 29a suggests that
communol A from P. commune could be formed in similar way
ix quinolines
OH
OH O
O
OH
OH
N
95 °C, 30 min
H2O
OH
+
OH
NH2
N
NH2
OH
95a
95b
, 71%
O
OH
OH
OH
OH
25 °C, 16 h
H2O
+
OH
N
N
O
OH
(Scheme 1, Figure S5). Phloroglucinol derivatives harboring
98a
98b, 29%
three hydroxyl groups at the benzene ring conjugated with a
clavatol also via C-C bonds (44b, 45b, 47b, and 50b) (Scheme
1, Figure S6).
OH
x anthranilic acid
O
OH
O
O
R1
OH
OH
OH
R2
The indole ring in tryptophanyl moiety contributes greatly to
structural complexity by enzymatic modifications and
95 °C, 30 min
H2O
+
OH
NH2
01a
N
H
1
2
2,23
spontaneous rearrangement.
Communol B mentioned above
01b R1 = clavatyl, R2 = H, 60%
1
101c R1 = H, R2 = clavatyl, 3%
101d R1 = R2 = clavatyl, 4%
represents a coupling example of clavatol moiety with indole
1
7
skeleton. Accordingly, incubation of L-tryptophan (61a) with
hydroxyclavatol enabled us to obtain the product (61b) with
similar structure to communol B (Scheme 2, Figure S7).
Subsequent isolation of clavatol adducts with different indole
derivatives ((±)-65b and 72b) confirmed the spontaneous
addition of the indole moiety via C2 to the o-QM (Scheme 2,
Figure S7). Furthermore, a number of coupling products of
clavatol with tryptophan-containing cyclic dipeptides were also
identified. Among them, C2-adducts were obtained as main
products (76b, 77b, 79b, and 80b) and C3-adducts (79c and 80c)
as byproducts (Scheme 2, Figures S7 and S8). In addition, a
cyclo-L-Trp-L-Trp derivative carrying two clavatol units (79d)
was also identified (Scheme 2, Figure S7). The conjugation
between the clavatol unit and indole skeleton indicates that the
electron transfer in the indole ring enabled the Michael addition
from C2 to the electrophilic methylene group of the o-QM
xi Tris
OH OH
O
OH
O
OH
NH2
2
5 °C, 16 h
N
OH
HO
O
OH
H
+
OH
H2O
OH
102b, 35%
OH
OH
02a
1
OH
clavatyl =
HO
Steinmetz et al24 reported C-N coupling compounds as
Michael addition products of different nucleophiles via their
amino groups to the p-quinone methide, i.e. elansolid A3.
However, only a few coupling products were obtained via C-N
bond formation in this study. Examples are (±)-65c as a
byproduct from the incubation of hydroxyclavatol with N-
acetyl-DL-tryptophan ((±)-65a), 101c and 101d from 2-
(Figure S11iii).
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aminobenzoic acid (101a), and 102b from Tris (102a) (Scheme that more clavatol-coupling natural products will be discovered
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
2, Figures S7, S8 and S11iv). It can be concluded that the cross-
coupling between the nucleophiles tested above and the o-QM
from hydroxyclavatol occurs preferentially via C-C bond
formation. In addition, the C-N bond in 101d seems instable and
can be easily hydrolyzed, which was observed by inspection of
in the near future.
EXPERIMENTAL SECTION
Chemicals. 35a – 38a, 46a – 48a, 73a, 75a, 79a, 80a were
28-34
chemically synthesized as previously reported.
chemicals used in this study were purchased from Bachem
Bubendorf, Switzerland), ABCR (Karlsruhe, Germany), TCI
Other
1
the H NMR spectrum of 101d (Figure S83) and comparison of
the impurity signals with those of 101b (Figure S79).
(
After structure elucidation, the obtained clavatol-containing
Europe (Zwijndrecht, Belgium), Alfa Aesar (Kandel, Germany),
Carl Roth (Karlsruhe, Germany), Sigma-Aldrich (St. Louis,
USA), or Acros (Merelbeke, Belgium).
products
were
screened
for
their
antibacterial,
acetylcholinesterase, and -glucosidase inhibition activities.
Detailed evaluation of the -glucosidase inhibitory activity
revealed the clavatol-coupling products 2b, 17b, 18b, 35b, 72b,
and 95b showed clear inhibition with IC50 values ranging from
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
Reaction conditions of hydroxyclavatol with the tested
aromatic compounds. Stock solutions of the tested compounds
were prepared at 20 mM in DMSO or DMSO/H O (v/v, 1:1).
2
4
3.8 ± 1.0 to 231.0 ± 7.5 M, while their precursors showed no
Reactions were initiated by adding hydroxyclavatol (0.4 mM)
activity. These concentrations are significantly lower than that
of the control substance acarbose with an IC50 at 766.2 ± 37.8
and reactants (0.4 mM) into 50 L distilled H O without pH
2
adjustion. As a result, the reactions generally took place in the

M (Table 1), indicating that conjugation of low-molecular
pH environment of 5.0 – 7.5. After incubation at 25 °C for 16
h, 50 L ACN were added into the reaction mixture. 5 L of
supernatant were injected into LC-MS for analysis after
centrifuging at 13,000 rpm for 30 min. Conversions were
calculated from peak areas of products and reactants with UV
detection. Two independent experiments were performed. In
addition, reactions of all reactants were also carried out at 95 °C
for 30 min.
compounds with clavatol has the potential to increase the
biological activity.
Table 1. Inhibitory effects of the selected compounds
against -glucosidase.
reactants
IC50 (M)
products
IC50 (M)
2
1
1
a
n.i.
2b
60.1 ± 0.6
167.8 ± 2.3
231.0 ± 7.5
43.8 ± 1.0
140.1 ± 1.3
52.0 ± 2.4
LC-MS analysis of reaction mixtures. LC-MS analysis was
performed on a microTOF-Q III spectrometer (Bruker, Bremen,
Germany) with an Agilent 1260 HPLC system (Agilent
Technologies, Böblingen, Germany), using the Multospher 120
RP18-5 column (250 × 2 mm, 5 m) (CS-Chromatographie
7a
8a
n.i.
17b
18b
35b
72b
95b
n.i.
35a
72a
n.i.
n.i.
2
Service GmbH). H O (A) and ACN (B), both with 0.1 % (v/v)
9
5a
n.i.
HCOOH, were used as solvents at flow rate of 0.25 mL/min.
The substances were eluted with a linear gradient from 5 –
100 % (v/v) B in 15 min. The column was then washed with 100
% (v/v) solvent B for 5 min and equilibrated with 5 % (v/v)
solvent B for 5 min. Detection was carried out on a photodiode
array detector and UV absorptions at 280 nm are illustrated in
this study. Electrospray ionization at positive or negative mode
was set for the determination of the accuracy masses. HCOONa
was used in each run for mass calibration. The capillary voltage
was set to 4.5 kV and a collision energy of 8.0 eV. Data were
evaluated with the Compass DataAnalysis 4.2 software (Bruker
Daltonik, Bremen, Germany). The masses were scanned in the
range of m/z 100 – 1500.
acarbose a
766.2 ± 37.8
apositive control. n.i.: no inhibition. The IC50 data with standard
deviation are mean values of three independent experiments.
In summary, our extended study on the utility of
hydroxyclavatol proved that the o-QM generated from
hydroxyclavatol can be considered as an excellent Michael
acceptor for a variety of substances. The coupling reactions
occurred under very mild condition, i.e. overnight incubation at
2
5 °C in water. Increasing the reaction temperature can
accelerate the reaction rate and promote the product
accumulation. Diverse clavatol-containing products were
identified in this study by incorporation of a clavatol unit onto
the ortho- or para-position of the hydroxyl group of different
phenolic compounds as well as connection between the
methylene group of clavatol unit and C2 of indole skeletons.
Additional C-N bond formation of clavatol coupling products
was also observed in a few cases.
Isolation and identification of the reaction products. To
isolate the reaction products for structural elucidation, reactions
were carried out in large scaled incubations (40 or 200 mL)
containing hydroxyclavatol (0.4 mM), different reactants (0.4 –
0.8 mM), and up to 2 % (v/v) DMSO. After incubation at 25 °C
for 16 h or heating at 95 °C for 30 min, the reaction mixtures
were extracted with double volume of EtOAc for three times.
The organic phases were combined and concentrated under
vacuum. The resulted residues were dissolved in MeOH and
centrifuged at 13,000 rpm for 20 min. The products were then
purified by silica gel column chromatography with stepwise
gradient of petroleum ether/EtOAc, or on Sephadex LH20
column with MeOH as elution solvent. A semi-preparative
HPLC equipped with an Agilent ZORBAX Eclipse XDB-C18
HPLC column (250 × 9.4 mm, 5 m) was also applied for
Despite of the wide application of QMs in chemical
1-5
synthesis, QMs have also been reported to be involved in the
assembly of natural products in recent years. For example,
elansolid A3 acts as a key intermediate in the biosynthesis of
2
5,26
elansolids.
intermediate was suggested for the formation of leprins.
Another QM-like intermediate is likely responsible for the
dimerization of benzofluorene-containing angucyclines. In
analogy, it is plausible that the clavatol-containing natural
products listed in Figures 1 and S1 are formed by non-
enzymatic Michael addition with involvement of the o-QM
derived from hydroxyclavatol. Furthermore, it can be expected
Spontaneous Diels-Alder addition via an o-QM
2
7
1
3
2
purification by using isocratic elution with H O and ACN
containing 0.1 % trifluoroacetic acid (TFA). NMR spectra were
recorded on a JEOL ECA-500 MHz spectrometer (JEOL,
ACS Paragon Plus Environment

Page 5 of 10
The Journal of Organic Chemistry
1
Tokyo, Japan). The spectra were processed with MestReNova
S81). In the H NMR spectrum of 101c, the coupling pattern
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
6.1.0 (Metrelab). Chemical shifts are referenced to those of the
solvent signals.
consisting of four protons at the benzene ring and a downfield
shift of the methylene group from 3.95 to 4.51 ppm (Figure S82)
indicated clavatol attachment to the amino group of 101a.
Similarly, one clavatol at para-position of the amino group and
one at the amino group can be concluded for the structure of
Structural elucidation. Characteristic signals of the clavatol
1
moiety were observed in H NMR spectra of all the isolated
products as a set of signals for an aromatic proton at
approximately 7.5 ppm, a singlet between 12 – 14 ppm, a
methylene group mostly between 3 – 4 ppm, and two methyl
groups at around 2.5 and 2.1 ppm. The clavatol-coupling
products generally belong to two major groups. The majority is
with clavatol unit attached to the ortho- or para-position of a
phenolic hydroxyl group at the benzene ring and other products
carrying clavatol moieties attached to C2 or C3 of the indole
skeleton.
1
01d (Figure S83). 102b is another clavatol coupling derivative
via C-N linkage, which was supported by the slightly downfield
1
shifts of the methylene group at 4.49 ppm in the H NMR
spectrum and confirmed by HMBC correlations (Figure S84 –
S86).
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
Characterization
data.
8-(3-acetyl-2,6-dihydroxy-5-
methylbenzyl)-5,7-dihydroxy-2-phenyl-4H-chromen-4-one (2b).
The title compound was prepared using 2a (0.106 mmol, 32.0
mg) and hydroxyclavatol (0.102 mmol, 20.0 mg) as reactants.
The product was isolated in 39 % yield (17.3 mg) as yellow
In the cases of 17b and 98b, the linkage between the methylene
group of the clavatol unit and the para-position of the hydroxy
group was proved by HMBC correlations (Figures S27 – S30
and S76 – S78). In analogy, correlations of the methylene group
to different aromatic carbons in the HMBC spectra supported
the linkage between the clavatol part and meta-dihydroxylated
benzene ring, such as 2b (Figures S12–S14), 6b (Figures S15 –
S17), 6c (Figures S18 – S20), 14b (Figures S21 – S25), 18b
1
amorphous solid. Eluent: petroleum ether/EtOAc (5 : 1, v/v). H
NMR (500 MHz, DMSO-d
6
) δ 13.00 (s, 1H), 8.00 (dd, J = 8.4,
.5 Hz, 2H), 7.59 (tt, J = 7.5, 1.5 Hz, 1H), 7.54 – 7.49 (m, 2H),
.52 (s, 1H), 6.91 (s, 1H), 6.25 (s, 1H), 4.10 (s, 2H), 2.49 (s,
1
7
3
1
1
1
1
3
1
6
H), 2.11 (s, 3H). C{ H} NMR (125 MHz, DMSO-d ) δ 203.2,
82.2, 163.4, 162.2, 160.9, 160.9, 159.1, 155.0, 131.8, 131.1,
30.8, 128.9, 128.9, 126.5, 126.5, 115.8, 113.1, 112.1, 105.5,
04.8, 103.8, 98.4, 26.1, 16.6, 16.2. HRMS (ESI-TOF) m/z: [M
(Figures S32 – S34), 35b (Figures S38 – S40), and 41b (Figures
S41 – S43). 14c obtained as the byproduct from the reaction
mixture of (+)-catechin (14a) with hydroxyclavatol is an
analogue of isopilosanols A – C. Its structure was confirmed by
+
+
H] Calcd for C25
H
21
O
7
433.1282; Found 433.1272.
8-(3-acetyl-2,6-dihydroxy-5-methylbenzyl)-2-(2,4-
1
comparison of H NMR spectra with those of reported data
dihydroxyphenyl)-3,5,7-trihydroxy-4H-chromen-4-one (6b).
The title compound was prepared using 6a (0.108 mmol, 32.9
mg) and hydroxyclavatol (0.066 mmol, 12.9 mg) as reactants.
The product was isolated in 17 % yield (5.5 mg) as yellow
35,36
(Figure S26).
Since 44b, 45b, 47b, and 50b are formed via
coupling of clavatol unit with phloroglucinol derivatives, the
attachment of clavatol to the phloroglucinol moiety in 44b and
47b was proved by HMBC correlations as examples (Figures
S44 – S46 and S48 – S50). The structures of 45b and 50b are
amorphous solid. Eluent: ACN/H
0.1 % TFA. H NMR (500 MHz, DMSO-d ) δ 12.82 (s, 1H),
2
O (55 : 45, v/v) supplied with
1
6
1
deduced according to their molecular weight and H NMR data
12.64 (s, 1H), 9.74 (s, 1H), 7.48 (s, 1H), 7.09 (d, J = 8.5 Hz,
1H), 6.37 (d, J = 2.3 Hz, 1H), 6.30 (dd, J = 8.5, 2.3 Hz, 1H),
(
Figures S47 and S51). 29b and 95b showed two sets of signals
1
13
1
in their H NMR, one set for clavatol subunit, and one set of
four coupling aromatic protons for ortho-disubstituted benzene
ring, suggesting the attachment of clavatol unit to the -pyrone
ring in 29b (Figures S35 – S37) and to the pyridine ring in 95b
6.20 (s, 1H), 3.95 (s, 2H), 2.49 (s, 3H), 2.07 (s, 3H). C{ H}
NMR (125 MHz, DMSO-d ) δ 202.8, 176.3, 160.9, 160.9, 160.4,
6
160.4, 158.4, 156.5, 154.5, 148.7, 135.4, 131.1, 130.5, 115.6,
113.1, 112.0, 109.5, 107.0, 104.7, 103.4, 102.9, 97.5, 26.1, 16.2,
+
(Figures S73 – S75).
16.2. HRMS (ESI-TOF) m/z: [M + H] Calcd for C25
H
21
O
10
4
81.1129; Found 481.1151.
6
1b, (±)-65b, and 72b are indole derivatives with clavatol unit
linked at C2 position and differ only at the side chain of C3
position. Therefore, their structures were determined by
comparison of the NMR data (Figures S52 – S54, and S60) with
2-(5-(3-acetyl-2,6-dihydroxy-5-methylbenzyl)-2,4-dihydrox-
phenyl)-3,5,7-trihydroxy-4H-chromen-4-one (6c). The title
compound was prepared using 6a (0.108 mmol, 32.9 mg) and
hydroxyclavatol (0.066 mmol, 12.9 mg) as reactants. The
product was isolated in 21% yield (6.7 mg) as yellow
17
the known compound communol B. (±)-65c is an example of
C-N bond formation between clavatol moiety and the indole
skeleton, which was confirmed by HMBC correlations (Figures
S55 – S59). 76b, 77b, 79b, 79c, 79d, 80b, and 80c are coupling
products of clavatol with tryptophan-containing cyclic
dipeptides (Figures S61 – S72). The structures of 79b and 80b
amorphous solid. Eluent: ACN/H
0
1
2
O (55 : 45, v/v) supplied with
.1 % TFA. H NMR (500 MHz, DMSO-d ) δ 12.95 (s, 1H),
0.66 (s, 1H), 7.58 (s, 1H), 6.79 (s, 1H), 6.50 (s, 1H), 6.18 (d, J
2.2 Hz, 1H), 6.14 (d, J = 2.2 Hz, 1H), 3.78 (s, 2H), 2.52 (s,
1
6
=
1
3
1
1
13
6
3H), 2.15 (s, 3H). C{ H} NMR (125 MHz, DMSO-d ) δ 203.2,
were unequivocally confirmed by H and C NMR data, as well
as HMBC correlations (Figures S63 – S66 and S69 – S71).
Other products are analogues of 79b and their structures were
determined according to the C2- and C3-substitution patterns of
1
1
1
76.0, 163.6, 160.9, 160.7, 160.6, 157.4, 156.7, 154.4, 148.9,
36.0, 131.1, 129.9, 117.6, 116.0, 113.2, 112.3, 109.0, 103.4,
02.6, 98.0, 93.1, 26.1, 21.1, 16.1. HRMS (ESI-TOF) m/z: [M
+
3
7
25 21 10
+ H] Calcd for C H O 481.1129; Found 481.1147.
the indole ring as reported before.
1
-(3-(((2R,3S)-2-(3,4-dihydroxyphenyl)-3,5,7-
In the cases of 101b – 101d obtained from 2-aminobenzoic acid
1
trihydroxychroman-8-yl)methyl)-2,4-dihydroxy-5-
(
101a), detailed inspection of the H NMR revealed that 101b
methylphenyl)ethan-1-one (14b). The title compound was
prepared using 14a (0.106 mmol, 30.8 mg) and hydroxyclavatol
(0.066 mmol, 12.9 mg) as reactants. The product was isolated
and 101c are products with one clavatol moiety and 101d
harboring two clavatol units. The presence of one set of
1
characteristic signals for an ABX system in the H NMR
in 28 % yield (8.6 mg) as brown oil. Eluent: ACN/H
2
O (55 : 45,
v/v) supplied with 0.1 % TFA. H NMR (500 MHz, acetone-d
δ 14.26 (s, 1H), 7.59 (s, 1H), 6.99 (d, J = 1.2 Hz, 1H), 6.86 (s,
spectrum of 101b revealed a para-substitution of the amino
group at the benzene ring. The structure of 101b was further
1
6
)
1
3
confirmed by C NMR and HMBC analyses (Figures S79 –
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 6 of 10
1
H), 6.86 (s, 1H), 6.11 (s, 1H), 4.81 (d, J = 7.8 Hz, 1H), 4.15 1H), 7.50 (dd, J = 8.4, 6.8 Hz, 1H), 7.47 (dd, J = 8.4, 6.8 Hz,
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
(ddd, J =8.5, 7.8, 5.5 Hz, 1H), 3.81 (d, J = 15.6 Hz, 1H), 3.77
(d, J = 15.6 Hz, 1H), 2.97 (dd, J = 16.3, 5.5 Hz, 1H), 2.61 (dd,
J = 16.3, 8.5 Hz, 1H), 2.53 (s, 3H), 2.09 (s, 3H). H NMR (500
1H), 7.00 (s, 1H), 4.30 (s, 2H), 3.98 (s, 2H), 2.63 (s, 3H), 2.55
(s, 3H), 2.24 (s, 3H), 2.15 (s, 3H). HRMS (ESI-TOF) m/z: [M -
1
-
H] Calcd for C30
H
27
O
7
499.1762; Found 499.1773.
MHz, pyridine-d
6
) δ 7.62 (d, J = 2.1 Hz, 1H), 7.47 (s, 1H), 7.30
1-(3-((2,4-dihydroxynaphthalen-1-yl)methyl)-2,4-dihydroxy-5-
meth-ylphenyl)ethan-1-one (18b). The title compound was
prepared using 18a (0.161 mmol, 25.9 mg) and hydroxyclavatol
(d, J = 8.1 Hz, 1H), 7.25 (dd, J = 8.1, 2.1 Hz, 1H), 6.67 (s, 1H),
5
4
.31 (d, J = 7.7 Hz, 1H), 4.57 (ddd, J = 8.4, 7.7, 5.4 Hz, 1H),
.47 (d, J = 15.1 Hz, 1H), 4.35 (d, J = 15.1 Hz, 1H), 3.63 (dd, J
(
0.089 mmol, 17.4 mg) as reactants. The product was isolated
=
16.1, 5.4 Hz, 1H), 3.31 (dd, J = 16.1, 8.4 Hz, 1H), 2.46 (s,
in 24 % yield (7.3 mg) as white amorphous solid. Eluent:
1
3
H), 2.20 (s, 3H). H NMR (500 MHz, DMSO-d
6
) δ 12.90 (s,
1
ACN/H
2
O (65 : 35, v/v) supplied with 0.1 % TFA. H NMR
500 MHz, DMSO-d ) δ 13.66 (s, 1H), 10.11 (s, 1H), 8.32 (d, J
8.9 Hz, 1H), 8.00 (d, J = 8.9 Hz, 1H), 7.55 (s, 1H), 7.37 (dd,
1
H), 9.67 (s, 1H), 9.11 (s, 1H), 8.95 (s, 1H), 7.48 (s, 1H), 6.66
(
=
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
(d, J = 2.0 Hz, 1H), 6.60 (d, J = 8.1 Hz, 1H), 6.46 (dd, J = 8.1,
2.0 Hz, 1H), 6.03 (s, 1H), 4.54 (d, J = 7.1 Hz, 1H), 3.82 – 3.78
(m, 1H), 3.76 (d, J = 14.8 Hz, 1H), 3.68 (d, J = 14.8 Hz, 1H),
2.62 (dd, J = 16.2, 5.3 Hz, 1H), 2.49 (s, 3H), 2.37 (dd, J = 16.2,
J = 8.9, 6.7 Hz, 1H), 7.19 (dd, J = 8.9, 6.7 Hz, 1H), 6.71 (s, 1H),
13
1
4
.18 (s, 2H), 2.54 (s, 3H), 2.04 (s, 3H). C{ H} NMR (125
MHz, DMSO-d ) δ 203.4, 160.9, 159.9, 153.1, 150.9, 134.1,
6
1
3
1
7
.7 Hz, 1H), 2.04 (s, 3H). C{ H} NMR (125 MHz, DMSO-d
6
)
131.0, 126.6, 123.5, 122.2, 121.5, 120.8, 116.1, 113.3, 112.1,
δ 202.6, 160.6, 160.4, 154.0, 153.0, 152.8, 144.6, 144.5, 130.3,
-
107.9, 99.6, 26.2, 17.1, 15.7. HRMS (ESI-TOF) m/z: [M - H]
1
9
30.2, 117.9, 115.6, 114.9, 114.4, 113.5, 112.2, 103.2, 99.8,
4.8, 81.2, 66.0, 30.6, 27.7, 26.2, 15.8. [α]20 D = +25 (c 0.1,
17 5
Calcd for C20H O 337.1081; Found 337.1097.
3-(3-acetyl-2,6-dihydroxy-5-methylbenzyl)-4-hydroxy-2H-
chromen-2-one (29b). The title compound was prepared using
29a (0.173 mmol, 28.1 mg) and hydroxyclavatol (0.076 mmol,
+
MeOH); HRMS (ESI-TOF) m/z: [M + H] Calcd for C25
H
25
O
9
4
69.1493; Found 469.1493.
1
-(3-(((2R,3S)-2-(3,4-dihydroxyphenyl)-3,5,7-
1
(
1
4.9 mg) as reactants. The product was isolated in 43 % yield
11.2 mg) as white amorphous solid. Eluent: ACN/H O (90 :
0, v/v) supplied with 0.1 % TFA. H NMR (500 MHz, CDCl
trihydroxychroman-6-yl)methyl)-2,4-dihydroxy-5-
methylphenyl)ethan-1-one (14c). The title compound was
prepared using 14a (0.106 mmol, 30.8 mg) and hydroxyclavatol
2
1
3
)
δ 14.70 (s, 1H), 10.28 (s, 1H), 10.23 (s, 1H), 7.93 (dd, J = 8.5,
(
0.066 mmol, 12.9 mg) as reactants. The product was isolated
in 6 % yield (1.8 mg) as brown oil. Eluent: ACN/H O (55 : 45,
v/v) supplied with 0.1 % TFA. H NMR (500 MHz, acetone-d
δ 14.5 (s, 1H), 7.67 (s, 1H), 6.85 (d, J = 2.0 Hz, 1H), 6.77 (d, J
8.1 Hz, 1H), 6.71 (dd, J = 8.1, 2.0 Hz, 1H), 6.10 (s, 1H), 4.57
d, J = 7.5 Hz, 1H), 3.98 (ddd, J = 8.5, 7.5, 5.3 Hz, 1H), 3.86 (s,
1
7
1
.6 Hz, 1H), 7.56 (ddd, J = 8.5, 7.0, 1.6 Hz, 1H), 7.43 (s, 1H),
.35 (dd, J = 8.4, 1.6 Hz, 1H), 7.33 (ddd, J = 8.5, 7.0, 1.6 Hz,
2
1
6
)
13
1
H), 3.87 (s, 2H), 2.58 (s, 3H), 2.21 (s, 3H). C{ H} NMR (125
) δ 203.6, 168.4, 163.4, 162.0, 158.9, 152.3, 132.6,
MHz, CDCl
3
=
(
131.1, 124.8, 123.9, 119.8, 116.7, 116.3, 112.6, 112.3, 103.5,
+
26.0, 18.2, 16.2. HRMS (ESI-TOF) m/z: [M + H] Calcd for
2
1
H), 2.87 (dd, J = 16.2, 5.3 Hz, 1H), 2.60 (s, 3H), 2.54 (dd, J =
6.2, 8.5 Hz, 1H), 2.15 (s, 3H). [α]20 D = +23 (c 0.1, MeOH);
19 17 6
C H O 341.1020; Found 341.1013.
4-(3-acetyl-2,6-dihydroxy-5-methylbenzyl)-1,3-dihydroxy-9H-
xanthen-9-one (35b). The title compound was prepared using
35a (0.122 mmol, 27.9 mg) and hydroxyclavatol (0.071 mmol,
+
HRMS (ESI-TOF) m/z: [M + H] Calcd for C25
Found 469.1496.
H
25
O
9
469.1493;
1
-(2,4-dihydroxy-3-((4-hydroxynaphthalen-1-yl)methyl)-5-
1
(
3.9 mg) as reactants. The product was isolated in 31 % yield
9.1 mg) as white amorphous solid. Eluent: ACN/H O (80 : 20,
v/v) supplied with 0.1 % TFA. H NMR (500 MHz, DMSO-d
δ 13.04 (s, 1H), 12.76 (s, 1H), 8.08 (dd, J = 8.0, 1.6 Hz, 1H),
methylph-enyl)ethan-1-one (17b). The title compound was
prepared using 17a (0.179 mmol, 25.9 mg) and hydroxyclavatol
2
1
6
)
(0.076 mmol, 14.9 mg) as reactants. The product was isolated
in 21 % yield (5.0 mg) as yellow amorphous solid. Eluent:
ACN/H O (70 : 30, v/v). H NMR (500 MHz, acetone-d ) δ
2 6
13.09 (s, 1H), 8.28 (dd, J = 8.6, 1.5, Hz, 1H), 8.23 (dd, J = 8.6,
1.5, Hz, 1H), 7.71 (s, 1H), 7.56 (ddd, J = 8.6, 7.0, 1.5 Hz, 1H),
7
8
1
.83 (ddd, J = 8.0, 7.2, 1.6 Hz, 1H), 7.52 (s, 1H), 7.42 (ddd, J =
1
.0, 7.2, 1.6 Hz, 1H), 7.39 (dd, J = 8.0, 1.6 Hz, 1H), 6.28 (s,
13
1
H), 4.06 (s, 2H), 2.50 (s, 3H), 2.16 (s, 3H). C{ H} NMR (125
) δ 203.1, 179.9, 161.0, 161.0, 160.3, 160.3,
MHz, DMSO-d
6
7
4
.48 (ddd, J = 8.6, 7.0, 1.5 Hz, 1H), 6.71 (s, 1H), 6.71 (s, 1H),
.38 (s, 2H), 2.60 (s, 3H), 2.25 (s, 3H). H NMR (500 MHz,
155.3, 154.8, 135.5, 130.7, 125.1, 124.1, 119.4, 117.3, 115.7,
1
113.4, 112.0, 105.5, 102.1, 97.5, 26.1, 16.3, 16.2. HRMS (ESI-
DMSO-d
8.5 Hz, 1H), 8.16 (d, J = 8.5 Hz, 1H), 7.66 (s, 1H), 7.55 (dd,
J = 8.5, 6.8 Hz, 1H), 7.46 (dd, J = 8.5, 6.8 Hz, 1H), 6.67 (d, J =
6
) δ 12.95 (s, 1H), 9.78 (s, 1H), 9.54 (s, 1H), 8.22 (d, J
+
TOF) m/z: [M + H] Calcd for C23
H
19
O
7
407.1125; Found
=
4
07.1116.
2-(3-acetyl-2,6-dihydroxy-5-methylbenzyl)-1,3,4-trihydroxy
anthracene-9,10-dione (41b). The title compound was prepared
using 41a (0.094 mmol, 24.1 mg) and hydroxyclavatol (0.058
mmol, 11.4 mg) as reactants. The product was isolated in 33%
8
2
1
.0 Hz, 1H), 6. 63 (d, J = 8.0 Hz, 1H), 4.26 (s, 2H), 2.57 (s, 3H),
.19 (s, 3H). C{ H} NMR (125 MHz, DMSO-d
61.1, 160.9, 151.4, 132.8, 131.3, 125.8, 125.6, 124.8, 124.1,
13
1
6
) δ 203.2,
124.0, 123. 6, 122.4, 116.0, 113.1, 112.3, 107.3, 26.2, 24.3, 16.2.
HRMS (ESI-TOF) m/z: [M - H] Calcd for C20H O 321.1132;
17 4
Found 321.1159.
yield (8.3 mg) as red amorphous solid. Eluent: ACN/H
2
O (75 :
5, v/v) supplied with 0.1 % TFA. H NMR (500 MHz, DMSO-
) δ 14.24 (s, 1H), 13.46 (s, 1H), 12.95 (s, 1H), 8.27 (dd, J =
-
1
2
d
7
7
3
6
1,1'-(((4-hydroxynaphthalene-1,3-diyl)bis(methylene))bis(2,4-
dihyd-roxy-5-methyl-3,1-phenylene))bis(ethan-1-one) (17c).
The title compound was prepared using 17a (0.179 mmol, 25.9
mg) and hydroxyclavatol (0.076 mmol, 14.9 mg) as reactants.
.6, 1.3 Hz, 1H), 8.26 (dd, J = 7.6, 1.3 Hz, 1H), 7.93 (td, J =
.6, 1.3 Hz, 1H), 7.89 (td, J = 7.6, 1.3 Hz, 1H), 7.51 (s, 1H),
.97 (s, 2H), 2.50 (s, 3H), 2.11 (s, 3H). C{ H} NMR (125
) δ 202.9, 184.8, 181.8, 161.2, 160.9, 160.9,
13
1
MHz, DMSO-d
6
The product was isolated in 6 % yield (1.5 mg) as yellow
155.8, 134.7, 133.7, 133.6, 132.4, 130.7, 126.3, 126.2, 123.2,
1
amorphous solid. Eluent: ACN/H
500 MHz, acetone-d
8.4 Hz, 1H), 8.16 (d, J = 8.4 Hz, 1H), 7.69 (s, 1H), 7.54 (s,
2
O (70 : 30, v/v). H NMR
115.8, 112.5, 112.2, 112.0, 109.8, 26.2, 17.5, 16.2. HRMS (ESI-
(
=
6
) δ 13.11 (s, 1H), 13.00 (s, 1H), 8.27 (d, J
+
TOF) m/z: [M + H] Calcd for C24
H
19
O
8
435.1074; Found
4
35.1069.
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1
-(2,4-dihydroxy-5-methyl-3-((2,3',4,5',6-pentahydroxy-[1,1'-
HRMS (ESI-TOF) m/z: [M + H]+ Calcd for C21
H N O
23 2 5
383.1601; Found 383.1609.
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
biphenyl]-3-yl)methyl)phenyl)ethan-1-one (44b). The title
compound was prepared using 44a (0.128 mmol, 30.0 mg) and
hydroxyclavatol (0.076 mmol, 14.9 mg) as reactants. The
product was isolated in 28 % yield (8.9 mg) as brown oil. Eluent:
ACN/H
2
1
-acetamido-3-(2-(3-acetyl-2,6-dihydroxy-5-methylbenzyl)-
H-indol-3-yl)propanoic acid ((±)-65b). The title compound
was prepared using (±)-65a (0.178 mmol, 44.0 mg) and
hydroxyclavatol (0.069 mmol, 13.5 mg) as reactants. The
1
2
O (60 : 40, v/v) supplied with 0.1 % TFA. H NMR
(500 MHz, DMSO-d
6
) δ 13.96 (s, 1H), 13.89 (s, 1H), 8.90 (s,
product was isolated in 29 % yield (8.6 mg) as brown oil. Eluent:
1
3
H), 8.87 (s, 1H), 7.64 (s, 1H), 6.10 (s, 1H), 6.06 – 6.04 (m,
1
ACN/H
2
O (55 : 45, v/v) supplied with 0.1 % TFA. H NMR
1
3
1
H), 3.73 (s, 2H), 2.56 (s, 3H), 2.12 (s, 3H). C{ H} NMR (125
) δ 203.8, 160.6, 158.7, 157.4, 157.4, 154.2,
52.9, 152.8, 136.3, 131.1, 117.2, 113.2, 112.2, 110.1, 109.4,
09.4, 103.4, 100.5, 94.9, 48.6, 26.1, 15.7. HRMS (ESI-TOF)
(500 MHz, acetone-d
6
) δ 13.26 (s, 1H), 7.66 (s, 1H), 7.53 (d, J
MHz, DMSO-d
1
1
6
=
7.4 Hz, 1H), 7.23 (d, J = 7.4 Hz, 1H), 6.96 (t, J = 7.4 Hz, 1H),
6
4
.92 (t, J = 7.4 Hz, 1H), 4.81 (ddd, J = 8.2, 7.7, 6.0 Hz, 1H),
.21 (d, J = 15.0 Hz, 1H), 4.18 (d, J = 15.0 Hz, 1H), 3.45 (dd, J
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
+
m/z: [M + H] Calcd for C22
21 8
H O 413.1231; Found 413.1242.
=
14.7, 6.0 Hz, 1H), 3.33 (dd, J = 14.7, 7.7 Hz, 1H), 2.57 (s,
3
-(3-acetyl-2,6-dihydroxy-5-methylbenzyl)-2,4,6-
3H), 2.26 (s, 3H), 1.85 (s, 3H). HRMS (ESI-TOF) m/z: [M +
+
trihydroxybenzoic acid (45b). The title compound was prepared
using 45a (0.024 mmol, 4.2 mg) and hydroxyclavatol (0.016
mmol, 3.1 mg) as reactants. The product was isolated in 44 %
yield (2.5 mg) as white amorphous solid. Eluent: ACN/H
:
23 25 2 6
H] Calcd for C H N O 425.1707; Found 425.1713.
a
N -acetyl-1-(3-acetyl-2,6-dihydroxy-5-
methylbenzyl)tryptophan ((±)-65c). The title compound was
prepared using (±)-65a (0.178 mmol, 44.0 mg) and
hydroxyclavatol (0.069 mmol, 13.5 mg) as reactants. The
2
O (60
1
40, v/v) supplied with 0.1 % TFA. H NMR (500 MHz,
6
acetone-d ) δ 14.42 (s, 1H), 7.64 (s, 1H), 6.04 (s, 1H), 3.82 (s,
product was isolated in 14 % yield (4.3 mg) as brown oil. Eluent:
2
H), 2.59 (s, 3H), 2.13 (s, 3H). HRMS (ESI-TOF) m/z: [M +
1
ACN/H
2
O (55 : 45, v/v) supplied with 0.1 % TFA. H NMR
+
H] Calcd for C17
17 8
H O 349.0918; Found 349.0925.
(500 MHz, acetone-d
6
) δ 13.31 (s, 1H), 7.71 (s, 1H), 7.70 (d, J
1
-(3-(3-acetyl-2,6-dihydroxy-5-methylbenzyl)-2,4,6-trihydroxy
= 8.2 Hz, 1H), 7.51 (d, J = 8.2 Hz, 1H), 7.29 (s, 1H), 7.09 (dd,
J = 8.2, 7.0 Hz, 1H), 6.97 (dd, J = 8.2, 7.0 Hz, 1H), 5.33 (s, 2H),
phenyl)-3-methylbutan-1-one (47b). The title compound was
prepared using 29a (0.142 mmol, 30.0 mg) and hydroxyclavatol
4
1
1
8
7
1
9
1
.68 (ddd, J = 8.2, 7.5, 5.6 Hz, 1H), 3.27 (dd, J = 14.7, 5.6 Hz,
(0.076 mmol, 14.9 mg) as reactants. The product was isolated
H), 3.10 (dd, J = 14.7, 7.5 Hz, 3H), 2.56 (s, 3H), 2.27 (s, 3H),
in 31 % yield (9.1 mg) as yellow amorphous solid. Eluent:
ACN/H
1
.83 (s, 3H). H NMR (500 MHz, DMSO-d
6
) δ 13.19 (s, 1H),
1
2
O (90 : 10, v/v) supplied with 0.1 % TFA. H NMR
) δ 13.09 (s, 1H), 10.69 (s, 1H), 7.51 (s,
.06 (d, J = 8.4 Hz, 1H), 7.69 (s, 1H), 7.65 (d, J = 8.2 Hz, 1H),
.48 (d, J = 8.2 Hz, 1H), 7.15 (s, 1H), 7.10 (dd, J = 8.2, 7.0 Hz,
H), 6.98 (dd, J = 8.2, 7.0 Hz, 1H), 5.25 (s, 2H), 4.38 (td, J =
.2, 5.1 Hz, 1H), 3.11 (dd, J = 15.0, 5.1 Hz, 1H), 2.90 (dd, J =
5.0, 9.2 Hz, 1H), 2.54 (s, 3H), 2.17 (s, 3H), 1.75 (s, 3H).
(500 MHz, DMSO-d
6
1H), 5.96 (s, 1H), 3.74 (s, 2H), 2.87 (d, J = 6.7 Hz, 1H), 2.51 (s,
3H), 2.14 (m, 1H), 2.08 (s, 3H), 0.90 (d, J = 6.7 Hz, 3H), 0.90
1
3
1
(d, J = 6.7 Hz, 3H). C{ H} NMR (125 MHz, DMSO-d
6
) δ
05.1, 203.0, 163.4, 162.3, 160.8, 160.7, 160.3, 130.4, 115.7,
13.3, 112.0, 104.4, 103.7, 94.4, 51.8, 48.6, 26.1, 24.8, 22.6,
2.6, 15.9. HRMS (ESI-TOF) m/z: [M + H] Calcd for C21H O
25 7
89.1595; Found 389.1597.
2
1
2
3
13
1
C{ H} NMR (125 MHz, DMSO-d
6
) δ 203.4, 173.4, 169.0,
161.0, 161.0, 136.0, 133.1, 127.3, 127.2, 120.8, 118.3, 118.1,
+
1
1
16.1, 112.4, 111.1, 110.2, 109.1, 52.8, 37.5, 26.9, 26.2, 22.2,
6.2. HRMS (ESI-TOF) m/z: [M + H] Calcd for C23H N O
25 2 6
+
1
-(3-(3-acetyl-2,6-dihydroxy-5-methylbenzyl)-2,4,6-trihydroxy
425.1707; Found 425.1708.
-(2-(3-acetyl-2,6-dihydroxy-5-methylbenzyl)-1H-indol-3-
yl)butanoic acid (72b). The title compound was prepared using
phenyl)-3-(4-hydroxyphenyl)propan-1-one (50b). The title
compound was prepared using 50a (0.028 mmol, 7.9 mg) and
hydroxyclavatol (0.024 mmol, 4.7 mg) as reactants. The
product was isolated in 19 % yield (2.0 mg) as white amorphous
4
7
2a (0.008 mmol, 1.6 mg) and hydroxyclavatol (0.008 mmol,
1
.6 mg) as reactants. The product was isolated in 46 % yield
solid. Eluent: ACN/H
2
O (80 : 20, v/v) supplied with 0.1 % TFA.
(
1.4 mg) as brown oil. Eluent: ACN/H
2
O (65 : 35, v/v) supplied
with 0.1 % TFA. H NMR (500 MHz, CDCl ) δ 13.30 (s, 1H),
.57 (s, 1H), 7.49 (d, J = 8.0 Hz, 1H), 7.40 (s, 1H), 7.24 (d, J =
1
H NMR (500 MHz, acetone-d ) δ 14.53 (s, 1H), 7.66 (s, 1H),
6
1
3
7.10 (d, J = 8.6 Hz, 2H), 6.75 (d, J = 8.6 Hz, 2H), 6.08 (s, 1H),
3.85 (s, 2H), 3.39 (t, J = 7.5 Hz, 2H), 2.90 (t, J = 7.5 Hz, 2H),
2.59 (s, 3H), 2.14 (s, 3H). HRMS (ESI-TOF) m/z: [M + H]
8
8
7
.0 Hz, 1H), 7.08 (dd, J = 8.0, 7.0 Hz, 1H), 7.03 (dd, J = 8.0,
.0 Hz, 1H), 4.14 (s, 2H), 2.95 (t, J = 7.0 Hz, 2H), 2.57 (s, 3H),
+
25 8
Calcd for C25H O 453.1544; Found 453.1561.
2.50 (t, J = 7.0 Hz, 2H), 2.18 (s, 3H), 2.07 – 2.01 (m, 2H).
+
(S)-3-(2-(3-acetyl-2,6-dihydroxy-5-methylbenzyl)-1H-indol-3-
yl)-2-aminopropanoic acid (61b). The title compound was
prepared using 61a (0.160 mmol, 44.0 mg) and hydroxyclavatol
HRMS (ESI-TOF) m/z: [M + H] Calcd for C22H24NO
5
382.1649; Found 382.1662.
(3S,6S)-3-((2-(3-acetyl-2,6-dihydroxy-5-methylbenzyl)-1H-
(0.102 mmol, 20.0 mg) as reactants. The product was isolated
indol-3-yl)methyl)-6-isobutylpiperazine-2,5-dione (76b). The
title compound was prepared using 76a (0.016 mmol, 4.8 mg)
and hydroxyclavatol (0.016 mmol, 3.2 mg) as reactants. The
in 27 % yield (10.4 mg) as yellow amorphous solid. Eluent:
CH
1
2
Cl
2 6
. H NMR (500 MHz, DMSO-d ) δ 10.19 (s, 1H), 7.56
(
(
(
s, 1H), 7.51 (d, J = 8.0 Hz, 1H), 7.26 (d, J = 8.0 Hz, 1H), 6.94
dd, J = 8.0, 6.8 Hz, 1H), 6.90 (dd, J = 8.0, 6.8 Hz, 1H), 4.14
d, J = 15.2 Hz, 1H), 4.07 (d, J = 15.2 Hz, 1H), 3.41 (dd, J =
product was isolated in 13 % yield (1.0 mg) as white amorphous
1
solid. Eluent: ACN/H
CDCl
7
1
4
1
2
O (60 : 40, v/v). H NMR (500 MHz,
3
) δ 13.40 (s, 1H), 8.77 (s, 1H), 7.51 (d, J = 8.0 Hz, 1H),
.46 (s, 1H), 7.25 (d, J = 8.0 Hz, 1H), 7.12 (dd, J = 8.0, 7.1 Hz,
H), 7.07 (dd, J = 8.0, 7.1 Hz, 1H), 6.39 (s, 1H), 5.99 (s, 1H),
.40 (d, J = 8.9 Hz, 1H), 4.16 (d, J = 15.0 Hz, 1H), 4.13 (d, J =
5.0 Hz, 1H), 3.94 (d, J = 10.0 Hz, 1H), 3.65 (dd, J = 14.8, 3.2
6
.8, 5.8, 1H), 3.18 (dd, J = 14.7, 5.8 Hz, 1H), 3.03 (dd, J = 14.7,
1
3
1
6.8 Hz, 1H), 2.52 (s, 3H), 2.11 (s, 3H). C{ H} NMR (125
MHz, DMSO-d ) δ 202.1, 171.2, 161.5, 136.1, 134.9, 130.8,
128.4, 119.8, 118.2, 118.0, 117.2, 111.9, 111.4, 110.9, 105.1,
5.0, 26.1, 25.9, 20.0, 16.5. [α]20 D = -6 (c 0.2, acetone);
6
5
Hz, 1H), 3.28 (dd, J = 14.8, 8.9 Hz, 1H), 2.60 (s, 3H), 2.23 (s,
3H), 1.68 – 1.60 (m, 1H), 1.61 – 1.56 (m, 1H), 1.17 (ddd, 13.7,
ACS Paragon Plus Environment

The Journal of Organic Chemistry
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1
0.0, 4.5 Hz, 1H), 0.86 (d, J = 6.2 Hz, 1H), 0.85 (d, J = 6.2 Hz,
1H). [α]20 D = -41 (c 0.1, CHCl ); HRMS (ESI-TOF) m/z: [M
478.2336; Found 478.2339.
3S,6S)-3-((2-(3-acetyl-2,6-dihydroxy-5-methylbenzyl)-1H-
(dd, J = 8.0, 7.0 Hz, 1H), 6.72 (d, J = 8.0 Hz, 1H), 5.60 (s, 1H),
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
5.47 (s, 1H), 4.29 (d, J = 11.0 Hz, 1H), 3.92 (dd, J = 11.3, 5.8
Hz, 1H), 3.69 (dd, J = 15.0, 3.5 Hz, 1H), 3.21 (d, J = 14.0 Hz,
1H), 2.97 (d, J = 14.0 Hz, 1H), 2.90 (dd, J = 15.0, 11.0 Hz, 1H),
3
+
32 3 5
+ H] Calcd for C27H N O
(
2
1
.74 (dd, J = 13.2, 5.8 Hz, 1H), 2.57 (s, 3H), 2.37 (dd, J = 13.2,
1.3 Hz, 1H), 2.18 (s, 3H). [α]20 D = -58 (c 0.06, CHCl );
indol-3-yl)methyl)-6-benzylpiperazine-2,5-dione (77b). The
title compound was prepared using 77a (0.032 mmol, 10.7 mg)
and hydroxyclavatol (0.016 mmol, 3.1 mg) as reactants. The
product was isolated in 24 % yield (2.0 mg) as white amorphous
solid. Eluent: ACN/H
DMSO-d
3
+
HRMS (ESI-TOF) m/z: [M + H] Calcd for C32
51.2289; Found 551.2314.
(3S,5aS,10bS,11aS)-10b-(3-acetyl-2,6-dihydroxy-5-
31 4 5
H N O
5
1
2
O (55 : 45, v/v). H NMR (500 MHz,
6
) δ 13.04 (s, 1H), 9.96 (s, 1H), 9.63 (s, 1H), 7.94 (d, J
3.0 Hz, 1H), 7.64 (d, J = 3.3 Hz, 1H), 7.62 (s, 1H), 7.43 (d, J
7.6 Hz, 1H), 7.22 (d, J = 7.6 Hz, 1H), 7.16 – 7.10 (m, 3H),
methylbenzyl)-3-((2-(3-acetyl-2,6-dihydroxy-5-methylbenzyl)-
1H-indol-3-yl)methyl)-2,3,6,10b,11,11a-hexahydro-4H-
pyrazino[1',2':1,5]pyrrolo[2,3-b] indole-1,4(5aH)-dione (79d).
The title compound was prepared using 79a (0.040 mmol, 14.9
mg) and hydroxyclavatol (0.033 mmol, 6.5 mg) as reactants.
=
=
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
6.95 (dd, J = 7.6, 6.5 Hz, 1H), 6.92 (dd, J = 7.6, 6.5 Hz, 1H),
6.62 (dd, J = 7.5, 2.3 Hz, 2H), 4.05 (d, J = 15.7 Hz, 1H), 4.07 –
4.04 (m, 1H), 4.01 (d, J = 15.7 Hz, 1H), 3.80 – 3.76 (m, 1H),
The product was isolated in 4 % yield (1.0 mg) as white
1
3.05 (dd, J = 14.7, 4.7 Hz, 1H), 2.98 (dd, J = 14.7, 5.4 Hz, 1H),
2.55 (s, 3H), 2.47 (m, 1H), 2.18 (s, 3H), 1.61 (dd, J = 13.7, 7.9
Hz, 1H). [α]20 D = -49 (c 0.2, MeOH); HRMS (ESI-TOF) m/z:
amorphous solid. Eluent: ACN/H
(500 MHz, CDCl
2
O (65 : 35, v/v). H NMR
3
) δ 12.98 (s, 1H), 12.92 (s, 1H), 8.18 (s, 1H),
7.59 (d, J = 8.0 Hz, 1H), 7.42 (s, 1H), 7.40 (d, J = 8.0 Hz, 1H),
7.24 – 7.21 (m, 1H), 7.19 (t, J = 7.5, 1H), 7.12 (dd, J = 8.0, 7.0
Hz, 1H) 7.12 (s, 1H), 6.89 (d, J = 7.5 Hz, 1H), 6.79 (d, J = 7.5
Hz, 1H), 6.71 (t, J = 7.5 Hz, 1H), 5.69 (s, 1H), 5.52 (s, 1H), 4.76
+
[M + H] Calcd for C30
H
30
N
3
O
5
512.2180; Found 512.2200.
3-((1H-indol-3-yl)methyl)-6-((2-(3-acetyl-2,6-dihydroxy-5-
methylbenzyl)-1H-indol-3-yl)methyl)piperazine-2,5-dione
(d, J = 15.2 Hz, 1H), 4.54 (d, J = 15.2 Hz, 1H), 4.46 (dd, J =
(
1
79b). The title compound was prepared using 79a (0.040 mmol,
4.9 mg) and hydroxyclavatol (0.033 mmol, 6.5 mg) as
reactants. The product was isolated in 30 % yield (5.4 mg) as
1
1
0.0, 3.4 Hz, 1H), 3.99 (dd, J = 11.9, 5.5 Hz, 1H), 3.70 (dd, J =
5.0, 3.4 Hz, 1H), 3.12 (dd, J = 15.0, 10.0 Hz, 1H), 2.78 (s, 2H),
1
2.69 (dd, J = 13.0, 5.5 Hz, 1H), 2.55 (s, 3H), 2.51 (s, 3H), 2.28
s, 3H), 2.04 (dd, J = 13.0, 11.9 Hz, 1H), 1.99 (s, 3H). [α]20 D
white amorphous solid. Eluent: ACN/H
NMR (500 MHz, CDCl ) δ 13.40 (s, 1H), 8.74 (s, 1H), 8.01 (s,
H), 7.48 (s, 1H), 7.47 (d, J = 8.0, 1H), 7.46 (d, J = 8.2, 1H),
2
O (65 : 35, v/v). H
(
3
+
= -63 (c 0.1, CHCl
3
); HRMS (ESI-TOF) m/z: [M + H] Calcd
1
7
8
41 4 8
for C42H N O
729.2919; Found 729.2932.
.34 (d, J = 8.2 Hz, 1H), 7.24 (d, J = 8.0 Hz, 1H), 7.17 (dd, J =
.2, 7.2 Hz, 1H), 7.11 (dd, J = 8.2, 7.2 Hz, 1H), 7.08 (dd, J =
(R)-3-((2-(3-acetyl-2,6-dihydroxy-5-methylbenzyl)-1H-indol-
3-yl)methyl)-3,4-dihydro-1H-benzo[e][1,4]diazepine-2,5-
dione (80b). The title compound was prepared using 80a (0.080
mmol, 24.5 mg) and hydroxyclavatol (0.051 mmol, 10.0 mg) as
8.0, 7.1 Hz, 1H), 7.05 (dd, J = 8.0, 7.1 Hz, 1H), 6.58 (s, 1H),
6.48 (s, 1H), 5.84 (s, 1H), 4.36 (d, J = 7.7 Hz, 1H), 4.20 (d, J =
10.1 Hz, 1H), 4.08 (d, J = 15.1 Hz, 1H), 4.04 (d, J = 15.1 Hz,
1
1
H), 3.45 (dd, J = 14.7, 3.2 Hz, 1H), 3.30 (dd, J = 14.5, 3.2 Hz,
H), 3.08 (dd, J = 14.5, 7.7 Hz, 1H), 2.61 (s, 3H), 2.27 – 2.24
reactants. The product was isolated in 21 % yield (5.3 mg) as
1
white amorphous solid. Eluent: ACN/H
NMR (500 MHz, acetone-d
2
O (55 : 45, v/v). H
1
(m, 1H), 2.23 (s, 3H). H NMR (500 MHz, DMSO-d
6
) δ 13.04
6
) δ 13.30 (s, 1H), 9.71 (s, 1H), 9.52
(s, 1H), 10.75 (d, J = 1.9 Hz, 1H), 9.92 (s, 1H), 9.61 (s, 1H),
(s, 1H), 7.71 (d, J = 8.0 Hz, 1H), 7.62 (s, 1H), 7.52 (dd, J = 8.0,
7.2 Hz, 1H), 7.45 (d, J = 8.0 Hz, 1H), 7.23 (d, J = 8.0 Hz, 1H),
7.21 (d, J = 8.0 Hz, 1H), 7.20 (dd, J = 8.0, 7.2 Hz, 1H), 6.93
(dd, J = 8.0, 7.0 Hz, 1H), 6.84 (dd, J = 8.0, 7.0 Hz, 1H), 4.28
(d, J = 15.0 Hz, 1H), 4.25 (dd, J = 9.0, 5.9 Hz, 1H), 4.22 (d, J =
15.0 Hz, 1H), 3.51 (dd, J = 15.0, 5.9 Hz, 1H), 3.34 (dd, J = 15.0,
7.85 (d, J = 2.5 Hz, 1H), 7.62 (s, 1H), 7.60 (d, J = 2.7 Hz, 1H),
7.30 (d, J = 8.0 Hz, 1H), 7.27 (d, J = 8.2 Hz, 1H), 7.25 (d, J =
8.2 Hz, 1H), 7.21 (d, J = 8.0 Hz, 1H), 6.98 (dd, J = 8.0, 7.0 Hz,
1H), 6.93 (dd, J = 8.0, 7.0 Hz, 1H), 6.90 (dd, J = 8.0, 7.0 Hz,
1H), 6.88 (dd, J = 8.0, 7.0 Hz, 1H), 6.37 (d, J = 2.1 Hz, 1H),
4.02 (dd, J = 8.1, 3.8 Hz, 1H), 3.97 (d, J = 15.4 Hz, 1H), 3.91
(d, J = 15.4 Hz, 1H), 3.81 – 3.76 (m, 1H), 2.99 (dd, J = 14.4,
1
3
1
9.0 Hz, 1H), 2.56 (s, 3H), 2.24 (s, 3H). C{ H} NMR (125
MHz, acetone-d ) δ 203.9, 172.7, 168.5, 161.4, 161.4, 137.5,
6
4
3
.6 Hz, 1H), 2.88 (dd, J = 14.4, 5.4 Hz, 1H), 2.71 (dd, J = 14.4,
.8 Hz, 1H), 2.55 (s, 3H), 2.17 (s, 3H), 1.85 (dd, J = 14.4, 8.1
136.6, 136.5, 133.3, 132.4, 131.8, 128.9, 127.1, 125.1, 121.9,
121.6, 119.5, 118.5, 117.0, 114.2, 113.8, 111.7, 106.3, 53.2,
1
3
1
Hz, 1H). C{ H} NMR (125 MHz, DMSO-d
6
) δ 203.1, 167.0,
26.4, 24.4, 20.2, 16.3. [α]20 D = -52 (c 0.1, acetone); HRMS
+
1
1
1
1
66.5, 160.7, 160.6, 136.1, 136.1, 135.2, 131.4, 128.4, 127.0,
24.2, 120.7, 119.8, 119.4, 118.2, 118.1, 118.0, 115.9, 112.5,
12.5, 111.1, 110.8, 108.8, 104.9, 55.9, 55.3, 30.6, 30.6, 26.2,
(ESI-TOF) m/z: [M + H] Calcd for C28
H
26
N
3
O
5
484.1867;
Found 484.1870.
(5aS,13aR,14aS)-14a-(3-acetyl-2,6-dihydroxy-5-
9.3, 16.2. [α]20 D = -38 (c 0.1, CHCl
3
); HRMS (ESI-TOF) m/z:
551.2289; Found 551.2313.
3S,5aS,10bS,11aS)-3-((1H-indol-3-yl)methyl)-10b-(3-acetyl-
methylbenzyl)-5a,13a,14,14a-
+
31 4 5
[M + H] Calcd for C32H N O
tetrahydrobenzo[5',6'][1,4]diazepino[1',2':1,5]pyrrolo[2,3-
b]indole-7,13(5H,12H)-dione (80c). The title compound was
prepared using 80a (0.080 mmol, 24.5 mg) and hydroxyclavatol
(0.051 mmol, 10.0 mg) as reactants. The product was isolated
(
2
4
,6-dihydroxy-5-methylbenzyl)-2,3,6,10b,11,11a-hexahydro-
H-pyrazino[1',2':1,5]pyrrolo[2,3-b]indole-1,4(5aH)-dione
(79c). The title compound was prepared using 79a (0.040 mmol,
14.9 mg) and hydroxyclavatol (0.033 mmol, 6.5 mg) as
reactants. The product was isolated in 3 % yield (0.6 mg) as
white amorphous solid. Eluent: ACN/H
NMR (500 MHz, CDCl
in 4 % yield (1.0 mg) as white amorphous solid. Eluent:
1
ACN/H
2
O (55 : 45, v/v). H NMR (500 MHz, acetone-d
6
) δ
13.14 (s, 1H), 9.54 (s, 1H), 8.63 (s, 1H), 7.76 (d, J = 8.0 Hz,
1H), 7.64 (s, 1H), 7.48 (dd, J = 8.0, 7.3 Hz, 1H), 7.20 (dd, J =
8.0, 7.3 Hz, 1H), 7.16 (dd, J = 8.2 Hz, 1H), 7.12 (d, J = 8.0 Hz,
1H), 6.97 (dd, J = 8.2, 7.7 Hz, 1H), 6.67 (d, J = 8.2 Hz, 1H),
6.61 (dd, J = 8.2, 7.7 Hz, 1H), 6.31 (s, 1H), 5.65 (s, 1H), 4.01
(dd, J = 8.2, 7.0 Hz, 1H), 3.22 (d, J = 14.0 Hz, 1H), 3.17 (d, J =
1
2
O (65 : 35, v/v). H
3
) δ 13.01 (s, 1H), 8.11 (s, 1H), 7.51 (d,
J = 8.0 Hz, 1H), 7.44 (s, 1H), 7.38 (d, J = 8.0 Hz, 1H), 7.21 (dd,
J = 8.0, 7.0 Hz, 1H), 7.15 (dd, J = 8.0, 7.0 Hz, 1H), 7.11 (d, J =
8
.0 Hz, 1H), 7.10 (dd, J = 8.0, 7.0 Hz, 1H), 7.06 (s, 1H), 6.82
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6
4.0 Hz, 1H), 3.17 (dd, J = 14.0, 7.0 Hz, 1H), 2.56 (s, 3H), 2.47 ) δ 13.21 (s, 1H), 13.06 (s, 1H),
1H NMR (500 MHz, acetone-d
1
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
(dd, J = 14.0, 8.2 Hz, 1H), 2.25 (s, 1H). [α]20 D = -47 (c 0.1,
acetone); HRMS (ESI-TOF) m/z: [M + H] Calcd for
7.89 (d, J = 2.1 Hz, 1H), 7.64 (s, 1H), 7.59 (s, 1H), 7.32 (dd, J
= 8.6, 2.1 Hz, 1H), 6.92 (d, J = 8.6 Hz, 1H), 4.49 (s, 2H), 3.91
+
C
28
H
26
N
3
O
5
484.1867; Found 484.1874.
(s, 2H), 2.55 (s, 3H), 2.54 (s, 3H), 2.22 (s, 3H), 2.17 (s, 3H).
+
HRMS (ESI-TOF) m/z: [M + H] Calcd for C27
H
28NO
8
1-(3-((2-amino-4-hydroxyquinolin-3-yl)methyl)-2,4-dihydroxy-
5-methylphenyl)ethan-1-one (95b). The title compound was
prepared using 95a (0.128 mmol, 20.6 mg) and hydroxyclavatol
4
94.1809; Found 494.1823.
1-(3-(((1,3-dihydroxy-2-(hydroxymethyl)propan-2-
yl)amino)methyl)-2,4-dihydroxy-5-methylphenyl)ethan-1-one
(0.058 mmol, 11.3 mg) as reactants. The product was isolated
in 46 % yield (9.0 mg) as brown amorphous solid. Eluent:
(102b). The title compound was prepared by using 102a (1.0
mmol, 122.0 mg, prepared as Tris-HCl buffer, pH7.5) and
hydroxyclavatol (0.066 mmol, 12.9 mg) as reactants. The
1
ACN/H
(
=
2
O (75 : 25, v/v) supplied with 0.1 % TFA. H NMR
500 MHz, DMSO-d ) δ 13.93 (s, 1H), 11.52 (s, 1H), 8.05 (d, J
8.2 Hz, 1H), 7.56 (s, 1H), 7.55 (dd, J = 8.2, 7.1, 1H), 7.36 (d,
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
product was isolated in 16 % yield (3.2 mg) as brown oil. Eluent:
1
J = 8.2 Hz, 1H), 7.25 (dd, J = 8.2, 7.1 Hz, 1H), 6.67 (s, 2H),
ACN/H
(500 MHz, CD
2.56 (s, 3H), 2.22 (s, 3H). C{ H} NMR (125 MHz, CD
2
O (70 : 30, v/v) supplied with 0.1 % TFA. H NMR
13
1
3
.70 (s, 2H), 2.53 (s, 3H), 2.08 (s, 3H). C{ H} NMR (125
3
OD) δ 7.72 (s, 1H), 4.49 (s, 2H), 3.82 (s, 6H),
13
1
MHz, DMSO-d ) δ 202.9, 174.0, 164.1, 159.4, 153.0, 136.9,
6
3
OD) δ
130.9, 130.8, 124.4, 122.3, 120.6, 117.7, 116.3, 113.1, 111.0,
204.9, 162.5, 162.4, 135.5, 117.3, 114.4, 107.3, 67.5, 59.7, 59.7,
+
+
101.0, 25.8, 17.6, 15.9. HRMS (ESI-TOF) m/z: [M + H] Calcd
59.7, 36.5, 26.3, 16.1. HRMS (ESI-TOF) m/z: [M + H] Calcd
for C19
H
19
N
2
O
4
339.1339; Found 339.1357.
6
for C14H22NO 300.1442; Found 300.1445.
1-(2,4-dihydroxy-3-((5-hydroxyquinolin-8-yl)methyl)-5-methyl
phenyl)ethan-1-one (98b). The title compound was prepared
using 98a (0.157 mmol, 22.9 mg) and hydroxyclavatol (0.059
mmol, 11.5 mg) as reactants. The product was isolated in 38 %
-Glucosidase inhibition assay. The -glucosidase inhibition
activity was evaluated by modified procedures reported
3
8,39
previously.
The assays contained 100 mM phosphate buffer
(pH 6.8), -glucosidase (1.3 U/mL) (Sigma-Aldrich, St. Louis,
USA), 10 L of 2 mM DMSO solution of compounds to be
tested. After pre-incubation at 37 °C for 15 min, the assays were
initiated by addition of 40 L of 2.5 mM p-nitrophenyl--D-
glucopyranoside solution (Sigma-Aldrich, St. Louis, USA) to a
final volume of 150 L. After incubating at 37 °C for further 15
min, the absorbance at 405 nm was recorded on a microplate
reader (BMG Labtech, Offenburg, Germany). DMSO was used
as negative control and acarbose (TCI Europe, Zwijndrecht,
Belgium) as positive control. All assays were performed in
triplicate. The IC50 value was determined by regression
yield (7.1 mg) as yellow amorphous solid Eluent: ACN/H
2
O (80
1
:
20, v/v) supplied with 0.1 % TFA. H NMR (500 MHz,
6
DMSO-d ) δ 13.19 (s, 1H), 10.59 (s, 1H), 9.01 (dd, J = 4.5, 1.7
Hz, 1H), 8.69 (dd, J = 8.4, 1.7 Hz, 1H), 7.75 (d, J = 8.0 Hz, 1H),
7
1
.63 (dd, J = 8.4, 4.5 Hz, 1H), 7.55 (s, 1H), 6.96 (d, J = 8.0 Hz,
13
1
H), 4.23 (s, 2H), 2.51 (s, 3H), 2.12 (s, 3H). C{ H} NMR (125
) δ 203.1, 161.2, 160.9, 152.0, 148.6, 144.4,
MHz, DMSO-d
6
133.7, 132.1, 130.7, 126.9, 120.2, 120.1, 117.3, 114.1, 112.0,
+
109.0, 26.1, 24.5, 15.9. HRMS (ESI-TOF) m/z: [M + H] Calcd
4
for C19H18NO 324.1230; Found 324.1235.
4
0,41
5-(3-acetyl-2,6-dihydroxy-5-methylbenzyl)-2-aminobenzoic
acid (101b). The title compound was prepared using 101a
(0.167 mmol, 23.0 mg) and hydroxyclavatol (0.066 mmol, 12.9
mg) as reactants. The product was isolated in 23 % yield (4.7
analysis.
ASSOCIATED CONTENT
Supporting Information
mg) as brown amorphous solid. Eluent: ACN/H
2
O (65 : 35, v/v)
supplied with 0.1 % TFA. H NMR (500 MHz, acetone-d ) δ
3.08 (s, 1H), 7.72 (d, J = 2.1 Hz, 1H), 7.62 (s, 1H), 7.37 (dd, J
1
The Supporting Information is available free of charge on the ACS
Publications website.
Chemical synthesis of hydroxyclavatol, structural overview of all
reactants, LC-MS chromatograms of selected reactions, NMR
spectra of coupling products (PDF).
6
1
=
(
8.4, 2.1 Hz, 1H), 6.68 (d, J = 8.4 Hz, 1H), 3.95 (s, 2H), 2.56
s, 3H), 2.24 (s, 3H). 13C{ H} NMR (125 MHz, acetone-d
1
6
) δ
2
1
04.0, 163.7, 162.0, 161.6, 146.0, 136.8, 132.2, 132.1, 129.8,
16.4, 115.5, 114.0, 114.0, 112.6, 27.9, 26.4, 16.3. HRMS (ESI-
AUTHOR INFORMATION
Corresponding Author
+
TOF) m/z: [M + H] Calcd for C17
H
18NO
5
316.1179; Found
316.1169.
2
-((3-acetyl-2,6-dihydroxy-5-methylbenzyl)amino)benzoic acid
*
E-mail: shuming.li@staff.uni-marburg.de.
(101c). The title compound was prepared using 101a (0.167
mmol, 23.0 mg) and hydroxyclavatol (0.066 mmol, 12.9 mg) as
reactants. The product was isolated in 6 % yield (1.2 mg) as
ORCID
Shu-Ming Li: 0000-0003-4583-2655
brown amorphous solid. Eluent: ACN/H
2
O (65 : 35, v/v)
supplied with 0.1 % TFA. H NMR (500 MHz, acetone-d ) δ
3.23 (s, 1H), 7.89 (d, J = 8.0 Hz, 1H), 7.68 (s, 1H), 7.37 (dd, J
1
Author Contributions
6
1
†
These authors contributed equally to this work.
=
8.0, 7.1 Hz, 1H), 7.05 (d, J = 8.0 Hz, 1H), 6.59 (dd, J = 8.0,
Notes
7
.1 Hz, 1H), 4.51 (s, 2H), 2.56 (s, 3H), 2.21 (s, 3H). HRMS
+
5
(ESI-TOF) m/z: [M + H] Calcd for C17H18NO 316.1179;
The authors declare no competing financial interest.
Found 316.1181.
ACKNOWLEDGMENT
5
-(3-acetyl-2,6-dihydroxy-5-methylbenzyl)-2-((3-acetyl-2,6-
dihydroxy-5-methylbenzyl)amino)benzoic acid (101d). The title
compound was prepared using 101a (0.167 mmol, 12.9 mg) and
hydroxyclavatol (0.066 mmol, 13.0 mg) as reactants. The
product was isolated in 3 % yield (0.9 mg) as yellow amorphous
We thank Rixa Kraut, Stefan Newel (University of Marburg) for
taking MS and NMR spectra, respectively. S.M.L. acknowledges
the DFG for funding the Bruker microTOF QIII mass spectrometer
(INST 160/620-1). Ge Liao (201607565014) and Jie Fan
2
solid. Eluent: ACN/H O (65 : 35, v/v) supplied with 0.1% TFA.
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(
201507565006) are scholarship recipients from the China
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1
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1
1
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2
2
2
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Scholarship Council.
2
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