pubs.acs.

org/joc Article

Talaromynoids A−E: Five New Fusicoccane Diterpenoids from the

Endophytic Fungus Talaromyces sp. DC-26
Peng Zhou,§ Xiaotian Zhang,§ Chong Dai, Shan Yan, Mengsha Wei, Wenya Feng, Qin Li, Junjun Liu,
Hucheng Zhu, Zhengxi Hu,* Chunmei Chen,* and Yonghui Zhang*
Cite This: J. Org. Chem. 2022, 87, 7333−7341 Read Online

ACCESS Metrics & More Article Recommendations *

sı Supporting Information
See https://pubs.acs.org/sharingguidelines for options on how to legitimately share published articles.

ABSTRACT: Talaromynoids A−E (1−5), five new fusicoccane

diterpenoids, were obtained from the endophytic fungus
Downloaded via UNIV FED DO AMAZONAS on July 18, 2022 at 20:44:26 (UTC).

Talaromyces sp. DC-26, which was isolated from a wild leech.

Talaromynoid A (1) represents the first fusicoccane diterpenoid
bearing an unexpected 5−7−5 tricyclic ring system, which is
possibly derived from normal 5−8−5 ones by ring contraction.
Talaromynoid E (5) is characterized by an unusual oxygen bridge
between C-1 and C-8 that establishes the eight-membered ring B
to be a 9-oxo-bicyclo[3.3.1]nonane. Structures of 1−5 with
absolute configurations were determined by extensive NMR
spectral analyses, electronic circular dichroism (ECD) calculations, X-ray diffraction analyses, and acid hydrolysis.

■ INTRODUCTION
The family of fusicoccane terpenoids are normally charac-
matory activity, and inhibitory activities toward xanthine
oxidase (XOD) and protein tyrosine phosphatase 1b.14−16
Pinophicin A, isolated from a plant endophytic fungus
terized by a 5−8−5 fused carbocyclic skeleton including five
Talaromyces pinophilus, showed antimicrobial activity,17 while
subclasses: fusicoccins, cotylenins, and brassicicenes as
roussoellol C, obtained from a marine-derived fungus
examples of diterpenes, and ophiobolins and ceroplastols as
Talaromyces purpurogenus, showed cytotoxic activity.18 Inspired
examples of sesterterpenes.1 In our previous investigations on
by these findings, the fungus Talaromyces sp. DC-26, which
fusicoccane diterpenoids, compounds with diverse carbocyclic was isolated from a wild leech, was investigated, leading to the
skeletons were found successively from Alternaria brassicicola isolation of five new fusicoccane diterpenoids (1−5, Figure 1)
and Talaromyces stipitatus;2−4 in addition, a series of and three known analogues including cotylenin E (6)19 and
fusicoccane dimers were isolated in further efforts on the dongtingnoids D and E (7 and 8).20 Compound 1 is
metabolites of A. brassicicola.5 Fusicoccanes are well known for characterized by an unexpected 5−7−5 (dicyclopenta[a,d]-
their phytohormone-like activities, and there are many cycloheptane) tricycle ring system, which represents a new
examples including stimulating the growth of cotyledons of subtype of the fusicoccane family. Talaromynoid E (5) is also
Chinese cabbage seedlings, radishes, and cucumbers6,7 and the first representative of fusicoccane diterpenoid with an
germinating seeds of Monochoria vaginalis and tubers of oxygen bridge between C-1 and C-8. Herein, we report the
Sagittaria trifolia.8,9 Actually, the bioactivities of fusicoccanes isolation, structural elucidation as well as the bioactivity
are not restricted to plant cells, as it was reported that evaluation for these metabolites.

■
cotylenin A showed differentiation-inducing and antitumor
activities against acute myeloid leukemia in both human and RESULTS AND DISCUSSION
mouse cells,10,11 and proliferation-inhibiting, apoptosis-induc-
Talaromynoid A (1) was isolated as a colorless oil. Its
ing, and PAX6 mRNA expression increasing activities in
molecular formula, C27H 42 O 7 , was deduced from the
retinoblastoma cell lines.12 Investigations revealed that
HRESIMS ion peak at m/z 501.2837 [M + Na]+ (calcd. for
fusicoccanes could interact with 14−3−3 proteins, which
C27H42O7Na+, 501.2823), corresponding to seven degrees of
may result in these bioactivities for both plant and animal
cells.13
Many metabolites with complex structures and good Received: March 7, 2022
bioactivities were reported from Talaromyces sp. in recent Published: May 19, 2022
years, such as polycyclic meroterpenoids, isocoumarin
derivatives, and nonadride and spirocyclic anhydride deriva-
tives; these compounds displayed an antiviral activity against
pseudorabies virus (PRV), antimigratory activity, anti-inflam-

© 2022 American Chemical Society https://doi.org/10.1021/acs.joc.2c00528

7333 J. Org. Chem. 2022, 87, 7333−7341
The Journal of Organic Chemistry pubs.acs.org/joc Article

Figure 1. Chemical structures of compounds 1−8.

Table 1. 1H NMR (400 MHz) Data for Compounds 1−5 (δ in ppm, J in Hz)
no. 1a 2a 3b 4a 5b
1 5.36 d (2.6) 5.74 d (2.3) 5.73 d (2.0) 5.44 d (1.7)
4 5.89 brs 1.97 m, 1.44 m 1.76 m, 1.69 m 5.89 brs 2.45 m, 2.40 m
5 2.67 dd (17.9, 9.0), 2.16 m 2.03 m, 1.40 m 1.83 m, 1.62 m 2.01 brd (17.7), 2.85 dd (17.7, 8.1) 1.61 m, 1.46 m
6 3.05 m 2.82 ddd (8.7, 6.3, 2.2) 2.64 m 3.17 m 2.95 m
7 2.29 m 2.01 m 2.11 m 1.93 m 1.77 m
8 3.45 m 4.05 dd (10.0, 4.4) 4.04 dd (9.8, 4.5) 4.07 m 4.03 s
9 3.61 m, 3.64 m 4.24 d (10.0) 4.18 d (9.8) 3.90 d (10.1) 4.13 s
12 1.71 m 2.51 d (18.3) 2.37 d (18.4), 1.81 dt (12.1, 6.1), 1.46 m
2.35 d (18.3) 2.29 d (18.4) 1.68 dt (12.1, 7.9) 1.26 m
13 2.19 m 2.24 dd (8.3, 6.0) 2.18 m, 2.00 dd (16.4, 9.3)
15 2.86 sept (6.8) 3.29 m 3.20 m 3.28 m 2.71 sept (6.9)
16 4.06 brs 3.42 d (9.9), 3.19 d (3.3) 4.05 m
3.25 d (9.9)
17 0.91 d (7.1) 0.94 d (7.1) 1.03 d (6.9) 0.82 d (7.0) 0.91 d (7.0)
18 1.19 s 1.49 s 1.45 s 1.23 s 1.25 s
19 1.00 d (6.8) 1.21 d (7.0) 1.22 d (6.9) 1.04 d (6.8) 0.85 d (6.8)
20 1.04 d (6.8) 1.28 d (6.8) 1.26 d (6.9) 1.09 d (6.6) 0.89 d (7.0)
1′ 4.79 d (3.6) 5.00 d (3.9) 5.07 d (3.5) 4.92 d (3.5)
2′ 3.41 m 3.48 dd (9.7, 3.9) 3.65 m 3.44 m
3′ 3.69 m 3.67 m 3.79 m 3.71 m
4′ 3.37 m 3.30 m 3.52 m 3.61 m
5′ 3.62 m 3.67 m 3.65 m 3.43 m
6′ 3.77 m 3.53 m 3.59 dd (10.1, 3.9) 3.73 m
3.43 dd (10.1, 4.2) 3.65 m
16-OMe 3.32 s 3.38 s 3.39 s 3.33 s 3.65 s
6′-OMe 3.31 s 3.35 s
a
Recorded in CD3OD. bRecorded in CDCl3.

unsaturation. Its 1H NMR (Table 1) along with HSQC carbon, nine sp3 methines (five oxygenated ones), six
spectrum displayed characteristic resonances for four methyl methylenes (three oxygenated ones), one methoxyl group,
groups [δH 0.91 (d, J = 7.1 Hz, H3-17), 1.19 (s, H3-18), 1.00 and four methyl groups. These data suggested 1 to be a
(d, J = 6.8 Hz, H3-19), and 1.04 (d, J = 6.8 Hz, H3-20)], a fusicoccane glucoside.20
methoxyl group [δH 3.32 (s, C-16-OMe)], and two olefinic The heteronuclear multiple bond correlation (HMBC)
protons at δH 5.36 (d, J = 2.6 Hz, H-1) and δH 5.89 (brs, H-4). correlations from H-1 to C-3 and C-6, H-4 to C-2, and H-7
In addition, the characteristic signal of an anomeric proton at to C-2 and C-6, as well as the 1H−1H correlation spectroscopy
δH 4.79 (d, J = 3.6 Hz, H-1′), along with a series of protons (COSY) cross-peaks of H-4/H2-5/H-6 established the five-
ranging from δH 3.37 to 3.77, revealed the presence of a sugar membered ring A. The location of the methoxy group at C-16
residue in the molecule. The 13C NMR (Table 2) and was determined according to the HMBC correlations from C-
distortionless enhancement by polarization transfer (DEPT) 16-OMe to C-16. Then, the other five-membered ring C was
spectra displayed 27 carbon signals, including six olefinic revealed based on the HMBC correlations from Me-18 to C-1,
carbons (two olefinic methines), one sp3 nonprotonated C-10, C-11, and C-12 and from H-15 to C-10, C-13, and C-14,
7334 https://doi.org/10.1021/acs.joc.2c00528
J. Org. Chem. 2022, 87, 7333−7341
The Journal of Organic Chemistry pubs.acs.org/joc Article

Table 2. 13C NMR (100 MHz) Data for Compounds 1−5 (δ The relative configuration of 1 was identified by analysis of
in ppm) its nuclear overhauser effect spectroscopy (NOESY) spectrum
(Figure 2). The NOESY correlations of Me-18 (δH 1.19)/H2-9
no. 1a 2a 3b 4a 5b
1 128.2 135.0 132.7 130.1 100.5
2 141.8 142.1 141.3 143.9 157.1
3 143.0 83.2 81.8 142.9 129.7
4 134.4 36.4 35.7 133.8 32.8
5 38.4 32.7 33.4 43.4 24.1
6 44.1 41.7 40.7 40.6 47.7
7 36.3 43.0 42.5 44.6 35.7
8 43.8 78.6 77.4 79.0 84.6
9 71.8 78.1 77.4 77.8 66.7
10 138.2 173.7 171.6 139.8 137.5
11 54.7 47.7 46.4 53.4 54.7
12 42.6 54.2 53.7 42.5 33.1
13 27.6 209.8 207.5 28.1 27.9
14 148.0 148.9 147.8 148.8 146.4
15 28.2 27.9 26.8 29.0 27.0
16 69.8 78.0 78.9 69.7 168.8
17 10.0 8.9 9.4 7.0 15.3
18 28.1 27.2 27.8 27.3 21.6
19 21.4 19.9 19.6 20.7 21.1
20 21.9 20.5 20.2 22.1 21.4 Figure 2. Key 1H−1H COSY, HMBC, and NOESY correlations of
1′ 100.8 103.7 101.6 103.2 compounds 1 and 5.
2′ 73.6 73.4 70.5 71.0
3′ 75.1 74.9 73.8 75.0
4′ 71.6 71.4 72.1 73.6 (δH 3.62) and Me-17 (δH 0.91)/H2-9 (δH 3.62) revealed their
5′ 73.8 73.5 71.6 73.7 being cofacial and were assigned to be β-oriented, and
6′ 62.4 73.1 72.5 61.9 accordingly, H-8 (δH 3.45) and H-7 (δH 2.29) should both
16-OMe 58.1 59.6 59.5 58.3 52.6 be α-oriented. Moreover, the NOESY correlation of H-6 (δH
6′-OMe 59.5 59.7 3.05)/H-8 (δH 3.45) indicated that H-6 also adopted an α-
a orientation. To determine the absolute configuration of the
Recorded in CD3OD. bRecorded in CDCl3.
diterpenoid part of compound 1, its Boltzmann-weighted
electronic circular dichroism (ECD) spectrum was calculated
along with the 1H−1H COSY correlation of H-12/H-13. using time-dependent density functional theory (TDDFT)
Moreover, the HMBC correlations from both Me-19 and Me- with the sugar-contained model. The experimental ECD curve
20 to C-15 and C-14 revealed the location of the isopropyl at was in good agreement with the calculated one (Figure 3),
C-14. The connection of both rings via C-1 was determined by indicating the absolute configuration of the aglycone of 1 as
HMBC correlations from H-1 to C-3, C-6, C-10, C-11, and C- 6S,7R,8R,11R.
12. Talaromynoid B (2) was isolated as colorless crystals
Then, the 1H−1H COSY correlations of H-6/H-7/Me-17 (MeOH). Its molecular formula, C28H44O10, with seven
and H-7/H-8/H-9 along with the HMBC correlations from degrees of unsaturation, was determined by the HRESIMS
Me-17 to C-6, C-7, and C-8, from H2-9 to C-7 and C-8, and ion peak at m/z 563.2830 [M + Na] + (calcd. for
from H-8 to C-10, C-11, and C-14 established the fragment of C28H44O10Na+, 563.2827). The 1H NMR (Table 1) and
C-6−C-9 as well as its connection between C-6 and C-10, HSQC data of 2 revealed the presence of four methyl groups
which finally constructed the 5−7−5 tricycle ring system of the [δH 0.94 (d, J = 7.1 Hz, H3-17), 1.49 (s, H3-18), 1.21 (d, J =
aglycon moiety. The sugar residue was possibly assigned as a 7.0 Hz, H3-19), and 1.28 (d, J = 6.8 Hz, H3-20)], two methoxyl
glucose by analyses of the 1H−1H COSY and HMBC spectra, groups [δH 3.38 (s, C-16-OMe) and 3.31 (s, C-6′-OMe)], and
and comparing the NMR data with those in the literature21 one olefinic proton signal at δH 5.74 (d, J = 2.3 Hz, H-1). In
and the relatively small coupling constant of H-1′ at δH 4.79 addition, the characteristic signal of an anomeric proton at δH
(d, J = 3.6 Hz, H-1′) suggested the sugar to be an α-glucose. 5.00 (d, J = 3.9 Hz, H-1′), along with signals for six protons
To determine the absolute configuration of the sugar moiety of resonating δH 3.30−3.67, suggested the presence of a sugar
compound 1, acid hydrolyses were performed for 1. Then, residue. The 13C NMR (Table 2) along with its DEPT
trimethylsilyl-L-cysteine derivatization was performed for the spectrum displayed 28 carbon signals, including one carbonyl,
sugar part of compound 1 as well as D- and L-glucose standards. four olefinic carbons (one olefinic methine), ten sp3 methines
The retention time of derivation of the sugar moiety of (seven oxygenated ones), two sp3 nonprotonated carbons, five
compound 1 in gas chromatography (GC) spectra was methylenes (two oxygenated ones), two methoxyl groups, and
identical to that of D-glucose, implying α-D-glucose for 1 (tR four methyl groups. In general, the NMR data of 2 resembles
for compound 1, D-, and L-glucose standards: 19.26, 19.21, and those of cotylenin E (6).19 The main differences between 2
19.69 min, respectively; Figures S48, S50, and S51). Finally, and 6 were the presence of a carbonyl group (δC 209.8) and
the location of the sugar residue at C-9 was established by the the absence of a methylene in 2. In the HMBC spectrum,
HMBC correlation from H2-9 to C-1′. Thus, the gross correlations from H-15 to C-10, C-13, and C-14 revealed the
structure of 1 was established. location of the carbonyl group (δC 209.8) at C-13. The planar
7335 https://doi.org/10.1021/acs.joc.2c00528
J. Org. Chem. 2022, 87, 7333−7341
The Journal of Organic Chemistry pubs.acs.org/joc Article

Figure 3. Calculated and experimental ECD curves of 1 and experimental ECD curves of 2 and 3.

Figure 4. ORTEP drawing of compounds 2 and 5 (displacement ellipsoids are drawn at 30% probability level).

structure of 2 was further confirmed by two-dimensional (2D) methyl-α-D-glucose by the almost identical retention time with
NMR experiments including HMBC and 1H−1H COSY that of compound 2 in the GC spectrum (tR for 2 and 3: 16.35
spectra (Figure S1). and 16.37 min, respectively; Figures S52 and S53).
The NOESY correlations of Me-18 (δH 1.49)/H-9 (δH Talaromynoid D (4) was isolated as a colorless oil. Its
4.24), H-9/Me-17 (δH 0.94), and Me-17/H-16 (δH 3.42) molecular formula was determined to be C27H42O8, as revealed
suggested that they were cofacial and were assigned β- by the HRESIMS ion peak at m/z 517.2794 [M + Na]+ (calcd.
orientation. In addition, the NOESY correlation observed for for C27H42O8Na+, 517.2772), implying seven degrees of
H-6 (δH 2.82)/H-8 (δH 4.05) suggested that they were on the unsaturation. The 1H and 13C NMR data (Tables 1 and 2)
opposite side and α-oriented (Figure S2). Finally, single-crystal along with DEPT spectrum displayed 27 carbon signals,
X-ray diffraction analysis of 2 (Figure 4, CCDC 2081359) including six olefinic carbons (two olefinic methines), ten sp3
using Cu Kα radiation was performed, and the structure of 2 methines (seven oxygenated ones), one sp3 nonprotonated
with absolute configuration was unequivocally confirmed as carbon, five methylenes (two oxygenated ones), one methoxyl
3R,6S,7R,8R,9R,11R with Flack parameters of 0.00(3). group, and four methyl groups. These data of compound 4
Simultaneously, the sugar unit of 2 was determined as 6-O- were almost the same as those of dongtingnoid E (8),20 except
methyl-α-D-glucose. for the absence of a methoxyl group in 4. Comprehensive
Talaromynoid C (3) has the same molecular formula as 2 analyses of the 2D NMR spectra including HMBC and 1H−1H
based on HRESIMS data. The 1H and 13C NMR data (Tables COSY spectra established the structure of 4 as shown in Figure
1 and 2) along with DEPT and HSQC displayed 28 carbon 1, whose aglycone was the same as that of 8 but the sugar
signals, including one carbonyl, four olefinic carbons (one residue was an α-glucose moiety, instead of a 6-O-methyl-α-D-
olefinic methine), ten sp3 methines (seven oxygenated ones), glucose unit in 8, which was further proved by acid hydrolyses.
two sp3 nonprotonated carbons, five methylenes (two The retention time of derivation of the sugar moiety of
oxygenated ones), two methoxyl groups, and four methyl compound 4 in GC spectra was identical to that of D-glucose,
groups. Further analyses of its HMBC and 1H−1H COSY implying α-D-glucose for 4 (tR for compound 4, D-, and L-
spectra revealed that compound 3 shares the same planar glucose standards: 19.28, 19.21, and 19.69 min, respectively;
structure as 2. The NOESY correlations of H2-16 (δH 3.19)/H- Figures S49−S51). The relative configuration of compound 4
5α (δH 1.83) and H-5β (δH 1.62)/Me-17 (δH 1.03) revealed was established as shown according to its NOESY data. Finally,
the α-orientation of CH2-16. According to the similarity of the similarity of the experimental ECD curves of compound 4
experimental ECD curves of compounds 3 and 2, the absolute and that of dongtingnoid E (8) revealed the same absolute
configuration of the diterpenoid fragment of 3 was determined configuration of the diterpenoid fragment of compound 4 as
to be 3S,6S,7R,8R,9R,11R (Figure 3), and compound 3 was that of 8, which should be 6S,7R,8R,9R,11R (Figure 5).
established as the C-3 epimer of 2. Moreover, we can conclude Talaromynoid E (5) was isolated as colorless crystals
that the effects of ECD of 2 and 3 are not associated with (MeOH). Its molecular formula was determined to be
configurations of C-3 in 2 and 3, similar to dontingnoids A and C21H30O5 according to the HRESIMS ion peak at m/z
B.20 Due to the lack of 6-O-methyl-D-glucose and 6-O-methyl- 385.2028 [M + Na]+ (calcd. for C21H30O5Na+, 385.1985),
L-glucose standards, compound 2 was used as a reference requiring an index of hydrogen deficiency of seven. In the 1H,
13
whose sugar moiety was determined as 6-O-methyl-D-glucose C NMR (Tables 1 and 2), and DEPT spectra, 21 carbon
by X-ray diffraction analysis. Acid hydrolysis and trimethylsilyl- resonances were observed, including one carbonyl (δC 168.8),
L-cysteine derivatization were also performed for compounds 2 four olefinic carbons (δC 129.7, 137.5, 146.4, and 157.1), two
and 3. The sugar moiety of 3 was determined to be 6-O- sp3 nonprotonated carbons (δC 54.7 and 100.5), five sp3
7336 https://doi.org/10.1021/acs.joc.2c00528
J. Org. Chem. 2022, 87, 7333−7341
The Journal of Organic Chemistry pubs.acs.org/joc Article

accordingly, the oxygen bridge should be β-oriented (Figure

2). Finally, a crystal of compound 5 was obtained from MeOH,
and X-ray diffraction analysis was performed with Cu Kα
radiation (Figure 4, CCDC 2081492). Thus, the overall
structure of 5 was unambiguously established, including the
absolute configuration (1R,6S,7R,8R,9S,11S) with the Flack
parameter 0.00(3). It is interesting that C-9-OH of 5 is β-
oriented, which is different from any other fusicoccane
regardless of whether aglycones or glycosides.
The discovery of 1 with an unusual 5−7−5 tricycle scaffold
prompted us to investigate its plausible biosynthetic pathway.
The biosynthesis route of the common 5−8−5 fusicoccane
diterpenoids had been clarified well in recent years.22−24
Concisely, the intermediate (+)-fusicocca-2,10(14)-diene
Figure 5. Experimental ECD curves of compound 4 and (FD) could be obtained from GGPP by a series of cyclization
dongtingnoid E (8). reactions, and further oxidation, hydroxylation, methoxylation,
and glycosylation led to intermediate i. Further protonation
and dehydration of 4 at C-8 could afford the carbocation
methines (two oxygenated ones), four methylenes, one intermediate ii, which underwent electronic migration from the
methoxyl group (δH 3.65 and δC 52.6), and four methyl
double bond between C-10 and C-14 to C-8, leading to the
groups (δH 0.91 and δC 15.3; δH 0.85 and δC 21.1; δH 0.89 and
formation of the key carbon−carbon bond between C-8 and C-
δC 21.4; δH 1.25 and δC 21.6). These data partially resemble
10 (iii). Then, with the activation of the proton, the cleavage
that of cotylenol,19 and their main differences include: the
of cyclopropane ring between C-9 and C-10 led to the
presence of one carbonyl (δ C 168.8) in 5; one sp 3
nonprotonated carbon with chemical shift sharply downfield formation of fusicoccane diterpenoid iv bearing a 5−7−5
shifted (δC 100.5) in 5 as compared with that of cotylenol (δC tricycle scaffold. Another key intermediate V could be afforded
84.0); and two tetrasubstituted double bonds in 5 instead of by oxidation−reduction reactions. Finally, the glycosidation
one tetrasubstituted double bond and one trisubstituted occurred at 9-OH yield 1 (Scheme 1).
double bond in cotylenol. Based on the HMBC correlations The inhibitory activities of compounds 1−8 against four
from H2-4 to C-2 and C-3, and H2-5 to C-2 and C-3, the enzymes (α-glucosidase, β-glycuronidase, acetylcholinesterase,
tetrasubstituted double bond was assigned between C-2 (δC and butyrylcholinesterase) were evaluated. However, none of
157.1) and C-3 (δC 129.7). Moreover, the HMBC correlations them exhibited any notable activities up to the concentration
from Me-18 (δH 1.25) to C-1 (δC 100.5), C-10 (δC 137.5), C- of 40 μM. These compounds were also evaluated for their
11 (δC 54.7), and C-12 (δC 33.1) revealed that the sp3 cytotoxicities against four cell lines (including HepG2, RKO,
nonprotonated carbon at δC 100.5 was located at C-1. The HL60, SUDHL-4) and neuroprotective activities against CoCl2
carbonyl, two double bonds, and three rings have occupied six and H2O2, induced SH-SY5Y cell injury, but all of these
unsaturation and the remaining one required an additional experiments did not provide any positive results.
ring. Based on the HMBC correlations from H-8 (δH 4.03) to In conclusion, compound 1 reported in this study represents
C-1 (δC 100.5), C-6 (δC 47.7), C-7 (δC 35.7), and C-9 (δC an unexpected scaffold with a tricycle 5−7−5 carbocyclic
66.7), an oxygen bridge was supposed to be formed between skeleton outstanding from the fusicoccane diterpenoids family.
C-1 and C-8. In addition, the carbonyl whose chemical shift The biosynthetic pathway of compound 1 was proposed and it
was significantly upfield shifted (δC 168.8) was determined as was supposed to be formed by ring contraction from the
an ester carbonyl located at C-16, as supported by the HMBC normal 5−8−5 ring system. Compounds 2 and 3 are epimers
correlation from C-16-OMe (δH 3.65) to C-16. of C-3 that are likely the products of a nonenzymatic water
In the NOESY spectrum, the correlations of H-6 (δH 2.95)/ addition on a precursor similar to 4. Compound 5 outstands
H-9 (δH 4.13) and H-7 (δH 1.77)/H-9 (δH 4.13) suggested from the fusicoccane diterpenoids family by the construction
that they were cofacial and set to be α-oriented, and of an unusual oxygen bridge between C-1 and C-8.

Scheme 1. Proposed Biosynthetic Pathways of Compound 1

7337 https://doi.org/10.1021/acs.joc.2c00528
J. Org. Chem. 2022, 87, 7333−7341
The Journal of Organic Chemistry pubs.acs.org/joc Article

Furthermore, 5 is also the first representative of the (MeCN-H2O, 45%, v = 3.0 mL/min) to give compounds 6 (3.5 mg,
fusicoccane family with the C-9-OH adopting a β orientation, tR 12.2 min) and 7 (10.8 mg, tR 15.5 min).
which may be formed from nonenzymatic reduction at C-9. Fr. 4.15 (448 mg) was subjected to silica gel CC eluted with
CH2Cl2-MeOH (30:1 to 10:1) to obtain eight fractions (Fr. 4.15.1−
These findings enriched the structure diversities of the
Fr. 4.15.8). Fr. 4.15.8 was purified to yield compound 4 (14.1 mg, tR
fusicoccane family. 18.8 min) using semipreparative HPLC (MeCN-H2O, 21%, v = 3.0

■ EXPERIMENTAL SECTION
General Experimental Procedures. One-dimensional (1D) and
mL/min). Fr. 4.16 was subjected to Sephadex LH-20 (MeOH) and
then separated using semipreparative HPLC (MeCN-H2O, 45%, v =
3.0 mL/min) to obtain compounds 1 (2.7 mg, tR 35.5 min) and 8
(50.5 mg, tR 46.0 min).
2D NMR spectra were performed on a Bruker AM-400 spectrometer Talaromynoid A (1). Colorless oil, [α]20D +59 (c 0.1, MeOH); UV
and tetramethylsilane (TMS) was used as the internal standard. The (MeOH) λmax nm (log ε): 204 (4.16), 242 (4.07) λ (200−400 nm);
chemical shifts (δ) were expressed in ppm with reference to the ECD (MeOH) λmax nm (Δε): 205 (+1.26), 214 (−4.30), 257 (+0.71)
solvent signals for CD3OD (δH 3.31 and δC 49.0) and CDCl3 (δH 7.26 λ (200−400 nm); IR (KBr) νmax: 3420, 2928, 1384, 1025 cm−1; 1H
and δC 77.7). UV spectra and optical rotations were recorded in NMR and 13C NMR data: Tables 1 and 2; HRESIMS m/z 501.2837
MeOH with a Lambda 35 instrument and a PerkinElmer 341 [M + Na]+ (calcd. for C27H42O7Na+, 501.2823).
spectropolarimeter, respectively. HRESIMS data were acquired with a Talaromynoid B (2). Colorless crystals (MeOH), [α]20 D +26 (c 0.1,
Bruker MicrOTOF II spectrometer. A Vertex 70 FT-IR spectropho- MeOH); UV (MeOH) λmax nm (log ε): 206 (3.94), 240 (3.97) λ
tometer was used to collect the IR spectra. A JASCO-810 (200−400 nm); ECD (MeOH) λmax nm (Δε): 204 (+1.08), 217
spectrometer was used to record the CD spectra in MeOH. Column (−3.32), 230 (+1.82), 257 (−2.52), λ (200−400 nm); IR (KBr) νmax:
chromatography was carried out on silica gel (200−300, 100−200, 3396, 2922, 2851, 1455, 1382, 1698, 1139, 1100, 1046 cm−1; 1H
and 80−120 mesh; Qingdao Marine Chemical Inc., Qingdao, China), NMR and 13C NMR data: Tables 1 and 2; HRESIMS m/z 563.2830
ODS (50 μm, YMC Co. Ltd., Tokyo, Japan), and Sephadex LH-20 [M + Na]+ (calcd. for C28H44O10Na+, 563.2827).
(Pharmacia Biotech AB, Uppsala, Sweden). Semipreparative HPLC Talaromynoid C (3). Colorless oil, [α]20D +68 (c 0.1, MeOH); UV
was performed on an Agilent HPLC system with a reversed-phase (MeOH) λmax nm (log ε): 202 (4.03), 242 (3.95) λ (200−400 nm);
(RP) Welch Ultimate XB-C18 column (10 × 250 mm, 5 μm). The ECD (MeOH) λmax nm (Δε): 206 (+6.37), 219 (−2.02), 232
components were detected by TLC and spots were visualized by (+3.78), 258 (−6.11) λ (200−400 nm); IR (KBr) νmax: 3418, 2930,
heating silica gel plates sprayed with 10% H2SO4 in EtOH. 1699, 1383, 1045 cm−1; 1H NMR and 13C NMR data: Tables 1 and 2;
Fungal Materials. The fungal strain Talaromyces sp. DC-26 was HRESIMS m/z 563.2817 [M + Na]+ (calcd. for C28H44O10Na+,
separated from a wild leech, collected from the coast of Jingshan 563.2827).
County, Jingmen District, Hubei Province, People’s Republic of Talaromynoid D (4). Colorless oil, [α]20D +36 (c 0.1, MeOH); UV
China. This strain was cultured on potato dextrose agar (PDA) at 28 (MeOH) λmax nm (log ε): 204 (4.02), 248 (4.05) λ (200−400 nm);
°C for a week in an incubator and then sent for identification. The ECD (MeOH) λmax nm (Δε): 202 (+4.27), 242 (−9.06), 269
strain was identified by the analysis of the ITS regions of its rDNA (−1.08) λ (200−400 nm); IR (KBr) νmax: 3396, 2928, 1454, 1383,
and morphological observation and its sequence data have been 1048, 1027 cm−1; 1H NMR and 13C NMR data: Tables 1 and 2;
submitted to the DDBJ/EMBL/GenBank (No. MZ233534). The HRESIMS m/z 517.2794 [M + Na]+ (calcd. for C27H42O8Na+,
fungal sample was preserved in the culture collection of Tongji 517.2772).
Medical College, Huazhong University of Science and Technology. Talaromynoid E (5). Colorless crystals, [α]20
D +14 (c 0.1, MeOH);
Fermentation and Isolation. The strain of Talaromyces sp. DC- UV (MeOH) λmax nm (log ε): 206 (4.12) λ (200−400 nm); ECD
26 was cultured on potato dextrose agar (PDA) at 28 °C for 7 days (MeOH) λmax nm (Δε): 208 (+5.94), 223 (−2.07), 232 (+2.65), 240
and then the agar was cut into pieces and inoculated in Erlenmeyer (−1.63) λ (200−400 nm); IR (KBr) νmax: 3408, 2923, 1691, 1640,
flasks containing 200 g of rice and 200 mL of distilled water, which 1438, 1384, 1099 cm−1; 1H NMR and 13C NMR data: Tables 1 and 2;
were previously sterilized by autoclaving (total fermentation: 50 kg of HRESIMS [M + Na]+ m/z 385.2028 (calcd. for C21H30O5Na+,
rice). After incubation at 28 °C for 28 days, fungal growth was 385.1985).
stopped by adding 200 mL of ethanol and then extracted with ethanol X-ray Crystal Structure Analysis. Crystals of compounds 2 and
5 times (4 × 20 L). The ethanol was removed under reduced pressure 5 were obtained in MeOH. Intensity data for compound 2 were
to yield a crude extract, which was partitioned between ethyl acetate collected at 100 K on a Bruker D8 QUEST diffractometer equipped
(EtOAc) and water to afford the EtOAc-soluble fraction (200.1 g). with a PHOTON II using Cu Kα radiation. Intensity data for
The EtOAc extract was chromatographed over silica gel by means of compound 5 were recorded on a XtaLAB PRO MM007HF using Cu
gradient elution using petroleum ether/EtOAc (50:1 to EtOAc neat, Kα radiation. Bruker SAINT was used for cell refinement and data
v/v) and EtOAc/MeOH (10:1 to MeOH, v/v) to obtain five fractions reduction. The structures were solved by direct methods using
(Fr. 1−Fr. 5). SHELXT-2014/7. SHELXL-2014/7 full-matrix least-squares were
Fr. 2 (16.1 g) was chromatographed over ODS (MeOH-H2O, 20− adopted for refinements, and anisotropic displacement parameters
100%) to yield nine fractions (Fr. 2.1−Fr. 2.9). Fr. 2.2 (75 mg) was were used for all of the nonhydrogen atoms. Hydrogen atoms were
purified by semipreparative HPLC (MeCN-H2O, 62%, v = 2.5 mL/ fixed at calculated positions. Crystallographic data for compounds 2
min) to obtain compound 5 (7.3 mg, tR 29.6 min) after removing part (CCDC 2081359) and 5 (CCDC 2081492) have been deposited in
of the impurities using Sephadex LH-20 (MeOH). the Cambridge Crystallographic Data Center.
Fr. 4 (10.0 g) was chromatographed over ODS (MeOH-H2O, 20− Crystallographic Data for Talaromynoid B (2). 2(C28H44O10)·
100%) to yield 21 fractions (Fr. 4.1−Fr. 4.21). Fr. 4.6 (231 mg) was H2O, M = 1099.27, a = 11.5160(3) Å, b = 15.7830(4) Å, c =
subjected to Sephadex LH-20 (MeOH) and then purified by 16.8575(5) Å, α = 103.4350(10)°, β = 95.6740(10)°, γ =
semipreparative HPLC (MeCN-H2O, 25%, v = 2.0 mL/min) to 95.6190(10)°, V = 2942.30(14) Å3, T = 100.(2) K, space group P1,
obtain compound 2 (44.6 mg, tR 20.0 min). Fr. 4.9 (890 mg) was Z = 2, μ(Cu Kα) = 0.780 mm−1, 107 312 reflections measured, and
subjected to Sephadex LH-20 (MeOH), then separated by silica gel 22 567 independent reflections (Rint = 0.0382). The final R1 values
CC eluted with CH2Cl2−MeOH (50:1 to 10:1) to obtain 12 fractions were 0.0470 (I > 2σ(I)). The final wR(F2) values were 0.1305 (I >
(Fr. 4.9.1−Fr. 4.9.12). Fr.4.9.10 afforded compound 3 (4.1 mg, tR 2σ(I)). The final R1 values were 0.0480 (all data). The final wR(F2)
50.5 min) using semipreparative HPLC (MeCN-H2O, 21%, v = 3.0 values were 0.1317 (all data). The goodness of fit on F2 was 1.044.
mL/min). After removing the impurities by Sephadex LH-20, Fr. 4.11 Flack parameter = 0.00(3).
(361 mg) was subjected to semipreparative HPLC (MeOH-H2O, Crystallographic Data for Talaromynoid E (5). C21H30O5, M =
65%, v = 2.0 mL/min) to obtain a mixed sample Fr. 4.11.1 (100 mg, 362.45, a = 9.459 Å, b = 10.494 Å, c = 19.31010(10) Å, α = 90°, β =
tR 36.1 min) that was then further purified by semipreparative HPLC 90°, γ = 90°, V = 1916.733(10) Å3, T = 293(2) K, space group

7338 https://doi.org/10.1021/acs.joc.2c00528
J. Org. Chem. 2022, 87, 7333−7341
The Journal of Organic Chemistry

■
pubs.acs.org/joc Article

P212121, Z = 4, wavelength 1.54178 Å, reflections collected 27 699; ASSOCIATED CONTENT

independent reflections 3841 (Rint = 0.0229); The final R1 values were
0.0265 (I > 2σ(I)). The final wR(F2) values were 0.0686 (I > 2σ(I)).
*
sı Supporting Information

The final R1 values were 0.0265 (all data). The final wR(F2) values The Supporting Information is available free of charge at
were 0.0687 (all data). The goodness of fit on F2 was 1.067. Flack https://pubs.acs.org/doi/10.1021/acs.joc.2c00528.
parameter = 0.00(3). Spectroscopic data including the NMR spectra, HRMS
ECD Calculations. All calculations were performed using (ESI), UV, and IR spectra of 1−5; GC analyses of 1−4
Gaussian 09W. The three-dimensional (3D) structure of 1 was
(PDF)
established based on the analysis of key NOESY correlations and used
as geometry input. The electronic circular dichroism (ECD) spectrum Accession Codes
was calculated for 1 using the TDDFT methodology at the B3LYP/6- CCDC 2081359 and 2081492 contain the supplementary
31G(d,p) level with MeOH as solvent by the IEFPCM solvation crystallographic data for this paper. These data can be obtained
model implemented in Gaussian 09 program[3].25 The ECD spectra
were simulated using a Gaussian function with a bandwidth σ of 0.3
free of charge via www.ccdc.cam.ac.uk/data_request/cif, or by
eV. The spectra were combined after Boltzmann weighting according emailing [email protected], or by contacting The
to their population contributions and UV correction was applied.26 Cambridge Crystallographic Data Centre, 12 Union Road,
Cambridge CB2 1EZ, UK; fax: +44 1223 336033.

■
Then, the calculated ECD spectrum of 1 was subsequently compared
with the experimental one. The ECD spectrum was simulated by
overlapping Gaussian functions for each transition according to AUTHOR INFORMATION
A
Corresponding Authors
Δε(E) =
1
×
1 2
∑ ΔEiR i e−[(E − Ei)/(2σ)] Zhengxi Hu − Hubei Key Laboratory of Natural Medicinal
2.297 × 10−39 2πσ i Chemistry and Resource Evaluation, Tongji Medical College,
Huazhong University of Science and Technology, Wuhan
where σ represents the width of the band at 1/e height, and ΔEi and 430030, People′s Republic of China; Email: hzx616@
Ri are the excitation energies and rotational strengths for transition i, 126.com
respectively. σ = 0.30 eV and Rvel had been used in this work. Chunmei Chen − Hubei Key Laboratory of Natural
Acid Hydrolysis and GC Analyses to Determine the Medicinal Chemistry and Resource Evaluation, Tongji
Absolute Configurations of Sugars. Compounds 1−4 (1.0 mg
of each) were hydrolyzed with 1 N CF3COOH (2.0 mL) at 100 °C Medical College, Huazhong University of Science and
for 3 h. After cooling to room temperature, the reaction mixture was Technology, Wuhan 430030, People′s Republic of China;
extracted with EtOAc (3 × 2.0 mL), and the aqueous layer was Email: [email protected]
concentrated to dryness under reduced pressure. The dried sugar Yonghui Zhang − Hubei Key Laboratory of Natural
residue was dissolved in dry pyridine (0.2 mL) containing (L)- Medicinal Chemistry and Resource Evaluation, Tongji
cysteine methyl ester hydrochloride (2 mg) and kept at 65 °C for 1.5 Medical College, Huazhong University of Science and
h, N-trimethylsilylimidazole (200 μL) was added and stirred at 65 °C Technology, Wuhan 430030, People′s Republic of China;
for another 1.5 h. Then, the reaction mixture was suspended in 1.0 orcid.org/0000-0002-7222-2142; Phone: 86-27-
mL H2O and extracted with n-hexane (3 × 1.0 mL). The n-hexane 83692892; Email: zhangyh@ mails.tjmu.edu.cn; Fax: 86-
fraction was concentrated to dryness under reduced pressure and 50
μL n-hexane was added to prepare the solution for GC analysis. GC
27-83692762
detection conditions: WM-1 capacity column, 0.25 mm (Ø), 30 m; Authors
flame ionization detector (FID); carrier gas, N2; constant flow, 1.0
Peng Zhou − Hubei Key Laboratory of Natural Medicinal
mL/min; injector temperature, 250 °C; injected volume, 1.0 μL; split
ratio, 1:10. The GC oven was set at 220 °C for 5 min and increased to Chemistry and Resource Evaluation, Tongji Medical College,
280 °C for 7 min at a rate of 2 °C/min. The N-trimethylsilylth- Huazhong University of Science and Technology, Wuhan
iazolidine derivatives of the standards D- and L-glucose were also 430030, People′s Republic of China; Journal Editorial
prepared and analyzed by GC. Department, Guangdong Pharmaceutical University,
Enzymes Inhibitory Activities Assay. The inhibitory activities Guangzhou 510006, People′s Republic of China
against four enzymes (α-glucosidase, β-glycuronidase, acetylcholines- Xiaotian Zhang − Hubei Key Laboratory of Natural
terase, butyrylcholinesterase) were evaluated. And the methods of Medicinal Chemistry and Resource Evaluation, Tongji
these tests against the four enzymes were similar and described below Medical College, Huazhong University of Science and
using α-glucosidase as an example. The α-glucosidase from Technology, Wuhan 430030, People′s Republic of China
Saccharomyces cerevisiae (Sigma-Aldrich) was dissolved in 0.1 M
Chong Dai − Hubei Key Laboratory of Natural Medicinal
phosphate buffer (pH 6.8). In the assay, compounds and α-
glucosidase (2 U/mL) were incubated for 10 min at room Chemistry and Resource Evaluation, Tongji Medical College,
temperature, then 5 mM pNPG was added, and incubated for an Huazhong University of Science and Technology, Wuhan
additional 15 min. The increase of absorbance at 405 nm due to the 430030, People′s Republic of China
release of p-nitrophenol from pNPG was measured using a microplate Shan Yan − Hubei Key Laboratory of Natural Medicinal
reader. The positive control was acarbose, and each treatment was Chemistry and Resource Evaluation, Tongji Medical College,
conducted in three replicates. Huazhong University of Science and Technology, Wuhan
Cytotoxicity Evaluation. The growth inhibitory effects of 430030, People′s Republic of China
compounds 1−8 were evaluated against human hepatocellular Mengsha Wei − Hubei Key Laboratory of Natural Medicinal
carcinoma cells (HepG2), human colon cancer cells (RKO), human Chemistry and Resource Evaluation, Tongji Medical College,
promyelocytic leukemia cells (HL60), and human diffuse large B-cell
Huazhong University of Science and Technology, Wuhan
lymphoma (DLBCL) cells (SUDHL-4) according to the previously
described method.18 430030, People′s Republic of China
Neuroprotection Activity Assay. Compounds 1−8 were Wenya Feng − Hubei Key Laboratory of Natural Medicinal
evaluated for their neuroprotective activities against CoCl2 and Chemistry and Resource Evaluation, Tongji Medical College,
H2O2-induced SH-SY5Y cell injury according to the previously Huazhong University of Science and Technology, Wuhan
described method.27 430030, People′s Republic of China
7339 https://doi.org/10.1021/acs.joc.2c00528
J. Org. Chem. 2022, 87, 7333−7341
The Journal of Organic Chemistry pubs.acs.org/joc Article

Qin Li − Hubei Key Laboratory of Natural Medicinal (6) Sassa, T.; Tojyo, T.; Munakata, K. Isolation of a new plant
Chemistry and Resource Evaluation, Tongji Medical College, growth substance with cytokinin-like activity. Nature 1970, 227, 379.
Huazhong University of Science and Technology, Wuhan (7) Sassa, T.; Takahama, A. Isolation and identification of cotylenins
430030, People′s Republic of China F and G. Agric. Biol. Chem. 1975, 39, 2213−2215.
(8) Takeuchi, Y.; Sassa, T.; Kawaguchi, S.; Ogasawara, M.;
Junjun Liu − Hubei Key Laboratory of Natural Medicinal
Yoneyama, K.; Konnai, M. Stimulation of germination of Monochoria
Chemistry and Resource Evaluation, Tongji Medical College, vaginalis seeds by seed coat puncture and cotylenins. J. Weed Sci.
Huazhong University of Science and Technology, Wuhan Technol. 1995, 40, 221−224.
430030, People′s Republic of China; orcid.org/0000- (9) Harada, J.; Tanaka, T.; Sassa, T. Sprouting of dormant tubers of
0001-9953-8633 Sagittaria trifolia, a perennial paddy weed, caused by cotylenin E, a
Hucheng Zhu − Hubei Key Laboratory of Natural Medicinal new plant growth regulator. J. Weed Sci. Technol. 1981, 26, 37−39.
Chemistry and Resource Evaluation, Tongji Medical College, (10) Asahi, K.-i.; Honma, Y.; Hazeki, K.; Sassa, T.; Kubohara, Y.;
Huazhong University of Science and Technology, Wuhan Sakurai, A.; Takahashi, N. Cotylenin A, a plant-growth regulator,
430030, People′s Republic of China induces the differentiation in murine and human myeloid leukemia
cells. Biochem. Biophys. Res. Commun. 1997, 238, 758−763.
Complete contact information is available at: (11) Yamamoto-Yamaguchi, Y.; Yamada, K.; Ishii, Y.; Asahi, K.-i.;
https://pubs.acs.org/10.1021/acs.joc.2c00528 Tomoyasu, S.; Honma, Y. Induction of the monocytic differentiation
of myeloid leukaemia cells by cotylenin A, a plant growth regulator.
Author Contributions Br. J. Haematol. 2001, 112, 697−705.
§
P.Z. and X.Z. contributed equally to this work. (12) Kashiwagi, Y.; Kato, N.; Sassa, T.; Nishitsuka, K.; Yamamoto,
T.; Takamura, H.; Yamashita, H. Cotylenin A inhibits cell
Notes
proliferation and induces apoptosis and PAX6 mRNA transcripts in
The authors declare no competing financial interest.

■
retinoblastoma cell lines. Mol. Vision 2010, 16, 970−982.
(13) de Boer, A. H.; de Vries-van Leeuwen, I. J. Fusicoccanes:
ACKNOWLEDGMENTS diterpenes with surprising biological functions. Trends Plant Sci. 2012,
This work was financially supported by the Program for 17, 360−368.
Changjiang Scholars of Ministry of Education of the People’s (14) Cao, X.; Shi, Y.; Wu, X.; Wang, K.; Huang, S.; Sun, H.;
Dickschat, J. S.; Wu, B. Talaromyolides A−D and talaromytin:
Republic of China (No. T2016088), the National Natural
polycyclic meroterpenoids from the fungus Talaromyces sp. CX11.
Science Foundation for Distinguished Young Scholars Org. Lett. 2019, 21, 6539−6542.
(81725021), the National Natural Science Foundation for (15) Yuan, W.-H.; Teng, M.-T.; Yun, Y.-F.; Jiang, N.; Ma, L.; Sun,
Excellent Young Scholars (81922065), the National Natural S.-S.; Yuan, B.; Tang, J.; Wu, Q.-Y.; Li, Q.; Zhang, P.; Morris-
Science Foundation of China (82173706 and 82104028), Natschke, S. L.; Lee, K-H. Talarolactone A, an isocoumarin derivative
Innovative Research Groups of the National Natural Science fused with dihydrothiophene with selective antimigratory activity
Foundation of China (81721005), the Science and Technology from the endolichenic fungus Talaromyces sp. J. Nat. Prod. 2020, 83,
Major Project of Hubei Province (2021ACA012), the 1716−1720.
Research and Development Program of Hubei Province (16) Zhao, J.-Y.; Wang, X.-J.; Liu, Z.; Meng, F.-X.; Sun, S.-F.; Ye, F.;
(2020BCA058), and the Tongji-Rongcheng Center for Liu, Y.-B. Nonadride and spirocyclic anhydride derivatives from the
Biomedicine, Huazhong University of Science and Technol- plant endophytic fungus Talaromyces purpurogenus. J. Nat. Prod. 2019,
ogy. The authors thank the Analytical and Testing Center at 82, 2953−2962.
(17) Zhao, W.-T.; Shi, X.; Xian, P.-J.; Feng, Z.; Yang, J.; Yang, X.-L.
Huazhong University of Science and Technology for assistance A new fusicoccane diterpene and a new polyene from the plant
in the acquisition of the ECD, UV, and IR spectra.

■
endophytic fungus Talaromyces pinophilus and their antimicrobial
activities. Nat. Prod. Res. 2021, 35, 124−130.
REFERENCES (18) Wang, W.; Wan, X.; Liu, J.; Wang, J.; Zhu, H.; Chen, C.; Zhang,
(1) Williams, D. R.; Robinson, L. A.; Nevill, C. R.; Reddy, J. P. Y. Two new terpenoids from Talaromyces purpurogenus. Mar. Drugs
Strategies for the synthesis of fusicoccanes by nazarov reactions of 2018, 16, No. 150.
dolabelladienones: total synthesis of (+)-fusicoauritone. Angew. (19) Sassa, T.; Sakata, Y.; Nukina, M.; Ikeda, M. Germination-
Chem., Int. Ed. 2007, 46, 915−918. stimulating activity and chemical structure of cotylenin. Nippon
(2) Tang, Y.; Xue, Y.; Du, G.; Wang, J.; Liu, J.; Sun, B.; Li, X.-N.; Kagaku Kaishi 1981, 1981, 895−898.
Yao, G.; Luo, Z.; Zhang, Y. Corrigendum: structural eevisions of a (20) Bie, Q.; Chen, C.; Yu, M.; Guo, J.; Wang, J.; Liu, J.; Zhou, Y.;
class of natural products: Scaffolds of aglycon analogues of fusicoccins Zhu, H.; Zhang, Y. Dongtingnoids A−G: fusicoccane diterpenoids
and cotylenins isolated from fungi. Angew. Chem., Int. Ed. 2018, 57, from a Penicillium Species. J. Nat. Prod. 2019, 82, 80−86.
14970. (21) Zhou, P.; Zheng, M.; Li, X.-N.; Wei, M.; Zhang, M.; Li, Q.;
(3) Hu, Z.; Sun, W.; Li, F.; Guan, J.; Lu, Y.; Liu, J.; Tang, Y.; Du, G.; Zang, Y.; Sun, W.; Wang, J.; Zhu, H.; Chen, C.; Zhang, Y.
Xue, Y.; Luo, Z.; Wang, J.; Zhu, H.; Zhang, Y. Fusicoccane-derived Hypoxylonoids A−G: isopimarane diterpene glycosides from Xylaria
diterpenoids from Alternaria brassicicola: investigation of the hypoxylon. Phytochemistry 2021, 182, No. 112613.
structure-stability relationship and discovery of an IKKβ inhibitor. (22) Lin, F.-L.; Lauterbach, L.; Zou, J.; Wang, Y.-H.; Lv, J.-M.;
Org. Lett. 2018, 20, 5198−5202. Chen, G.-D.; Hu, D.; Gao, H.; Yao, X.-S.; Dickschat, J. S. Mechanistic
(4) Zhang, M.; Yan, S.; Liang, Y.; Zheng, M.; Wu, Z.; Zang, Y.; Yu, characterization of the fusicoccane-type diterpene synthase for
M.; Sun, W.; Liu, J.; Ye, Y.; Wang, J.; Chen, C.; Zhu, H.; Zhang, Y. myrothec-15(17)-en-7-ol. ACS Catal. 2020, 10, 4306−4312.
Talaronoids A−D: four fusicoccane diterpenoids with an unprece- (23) Toyomasu, T.; Tsukahara, M.; Kaneko, A.; Niida, R.;
dented tricyclic 5/8/6 ring system from the fungus Talaromyces Mitsuhashi, W.; Dairi, T.; Kato, N.; Sassa, T. Fusicoccins are
stipitatus. Org. Chem. Front. 2020, 7, 3486−3492. biosynthesized by an unusual chimera diterpene synthase in fungi.
(5) Li, F.; Sun, W.; Guan, J.; Lu, Y.; Zhang, S.; Lin, S.; Liu, J.; Gao, Proc. Natl. Acad. Sci. U.S.A. 2007, 104, 3084−3088.
W.; Wang, J.; Hu, Z.; Zhang, Y. Alterbrassicicene A, a highly (24) Tazawa, A.; Ye, Y.; Ozaki, T.; Liu, C.; Ogasawara, Y.; Dairi, T.;
transformed fusicoccane-derived diterpenoid with potent PPAR-γ Higuchi, Y.; Kato, N.; Gomi, K.; Minami, A.; Oikawa, H. Total
agonistic activity from Alternaria brassicicola. Org. Lett. 2018, 20, biosynthesis of brassicicenes: Identification of a key enzyme for
7982−7986. skeletal diversification. Org. Lett. 2018, 20, 6178−6182.

7340 https://doi.org/10.1021/acs.joc.2c00528
J. Org. Chem. 2022, 87, 7333−7341
The Journal of Organic Chemistry pubs.acs.org/joc Article

(25) Frisch, M. J. T.; G, W. S.; Schlegel, H. B.; Scuseria, G. E.; Robb,

M. A.; Cheeseman, J. R.; Scalmani, G.; Barone, V.; Mennucci, B.;
Petersson, G. A.; Nakatsuji, H.; Caricato, M.; Li, X.; Hratchian, H. P.;
Izmaylov, A. F.; Bloino, J.; Zheng, G.; Sonnenberg, J. L.; Hada, M.;
Ehara, M.; Toyota, K.; Fukuda, R.; Hasegawa, J.; Ishida, M.;
Nakajima, T.; Honda, Y.; Kitao, O.; Nakai, H.; Vreven, T.;
Montgomery, J. A.; Peralta, J. E.; Ogliaro, F.; Bearpark, M.; Heyd,
J. J.; Brothers, E.; Kudin, K. N.; Staroverov, V. N.; Kobayashi, R.;
Normand, J.; Raghavachari, K.; Rendell, A.; Burant, J. C.; Iyengar, S.
S.; Tomasi, J.; Cossi, M.; Rega, N.; Millam, N. J.; Klene, M.; Knox, J.
E.; Cross, J. B.; Bakken, V.; Adamo, C.; Jaramillo, J.; Gomperts, R.;
Stratmann, R. E.; Yazyev, O.; Austin, A. J.; Cammi, R.; Pomelli, C.;
Ochterski, J. W.; Martin, R. L.; Morokuma, K.; Zakrzewski, V. G.;
Voth, G. A.; Salvador, P.; Dannenberg, J. J.; Dapprich, S.; Daniels, A.
D.; Farkas, Ö .; Foresman, J. B.; Ortiz, J. V.; Cioslowski, J.; Fox, D. J.
Gaussian 09, revision D 01; Gaussian, Inc.: Wallingford, CT, 2009.
(26) Zhu, H. J. Organic Stereochemistry: Experimental and Computa-
tional Methods; John Wiley & Sons, 2015.
(27) Liu, Y.; Yu, H. Y.; Wang, Y. M.; Tian, T.; Wu, W. M.; Zhou, M.;
Meng, X. G.; Ruan, H. L. Neuroprotective lignans from the fruits of
Schisandra bicolor var. tuberculata. J. Nat. Prod. 2017, 80, 1117−1124.

Recommended by ACS
Talaromynoids A–I, Highly Oxygenated Meroterpenoids
from the Marine-Derived Fungus Talaromyces
purpureogenus SCSIO 41517 and Their Lipid Accumu...
Zhong-Hui Huang, Shu-Hua Qi, et al.
OCTOBER 01, 2021
JOURNAL OF NATURAL PRODUCTS READ

Talarodrides A–F, Nonadrides from the Antarctic

Sponge-Derived Fungus Talaromyces sp. HDN1820200
Yi Zhao, Tianjiao Zhu, et al.
NOVEMBER 29, 2021
JOURNAL OF NATURAL PRODUCTS READ

Linderasesterterpenoids A and B: Two 7-

Cyclohexyldecahydroazulene Carbon Skeleton
Sesterterpenoids Isolated from the Root of Lindera g...
Zelin Chen, Hui Cui, et al.
MAY 13, 2022
ORGANIC LETTERS READ

Talascortenes A–G, Highly Oxygenated Diterpenoid

Acids from the Sea-Anemone-Derived Endozoic Fungus
Talaromyces scorteus AS-242
Ling-Hong Meng, Bin-Gui Wang, et al.
AUGUST 19, 2020
JOURNAL OF NATURAL PRODUCTS READ
Get More Suggestions >

7341 https://doi.org/10.1021/acs.joc.2c00528
J. Org. Chem. 2022, 87, 7333−7341