Catalyst-free sp3 C-H acyloxylation: Regioselective synthesis of 1-acyloxy derivatives of the natural product tanshinone IIA

Article abstract of DOI:10.1021/acs.jnatprod.6b00370

Tanshinone IIA is a valuable bioactive natural product isolated from the well-known Chinese herb Danshen. Structural manipulation of the A-ring of tanshinone IIA is rather limited. In this study, a substrate tautomerization-induced catalyst-free benzylic sp³ C-H acyloxylation approach is reported that allows the direct introduction of various acyloxy groups at the A-ring benzylic methylene of various tanshinone IIA substrates, thus avoiding the use of expensive transition metal catalysts and the production of harmful byproducts. This approach features a unique acid-induced reversible enolization/oxa-conjugate addition process followed by oxidation to exclusively give a series of diverse 1-acyloxylated derivatives under simple conditions in a regioselective manner. Compared with the literature procedures, this protocol demonstrates a higher efficiency, a more robust functional-group tolerance, atom economy, and lower cost.

Full text of DOI:10.1021/acs.jnatprod.6b00370

Article
pubs.acs.org/jnp
Catalyst-Free sp3 C−H Acyloxylation: Regioselective Synthesis of
1‑Acyloxy Derivatives of the Natural Product Tanshinone IIA
Chunyong Ding,†,§,⊥ Jie Li,†,‡,⊥ Mingkun Jiao,†,§ and Ao Zhang*,†,‡,§
†CAS Key Laboratory of Receptor Research, Synthetic Organic & Medicinal Chemistry Laboratory, Shanghai Institute of Materia
Medica, Chinese Academy of Sciences, Shanghai 201203, People’s Republic of China
‡ShanghaiTech University, Shanghai 20120, People’s Republic of China
§University of Chinese Academy of Sciences, Beijing 100049, People’s Republic of China
S
* Supporting Information
ABSTRACT: Tanshinone IIA is a valuable bioactive natural product isolated from the well-known Chinese herb Danshen.
Structural manipulation of the A-ring of tanshinone IIA is rather limited. In this study, a substrate tautomerization-induced
catalyst-free benzylic sp3 C−H acyloxylation approach is reported that allows the direct introduction of various acyloxy groups at
the A-ring benzylic methylene of various tanshinone IIA substrates, thus avoiding the use of expensive transition metal catalysts
and the production of harmful byproducts. This approach features a unique acid-induced reversible enolization/oxa-conjugate
addition process followed by oxidation to exclusively give a series of diverse 1-acyloxylated derivatives under simple conditions in
a regioselective manner. Compared with the literature procedures, this protocol demonstrates a higher efficiency, a more robust
functional-group tolerance, atom economy, and lower cost.
method has a low overall efficacy (∼26%) and suffered from the
anshinone IIA (Tan-IIA, 1, Scheme 1) is a pharmacolog-
Tically valuable natural product isolated from the well- instability of 1-bromo Tan-IIA.7b Therefore, the development
of efficient and economically attractive synthetic approaches to
readily modify the A-ring of Tan-IIA is required.
known Chinese herb Danshen that has been used for more
than 2000 years for the treatment of cardiovascular disease in
Asian countries.1 Structurally, Tan-IIA features a benzofuran-
4,5-dione (C-/D-ring) fused to a tetrahydronaphthalene
framework (A-/B-ring),2 and it possesses a broad range of
biological activities, including antitumor activities.3 However,
further clinical development of Tan-IIA is hampered by its poor
drug-like properties,4 thus making this natural product an ideal
lead compound for further structural modifications. Currently,
most of the Tan-IIA derivatives are obtained by modifying the
3-methylbenzofuran-4,5-dione moiety,5 whereas structural
manipulation of the A-ring is rather limited. In 2012, Wu and
co-workers reported the synthesis of a small series of Tan-IIA
A-ring derivatives using a Diels−Alder reaction;6 however, the
yields were low and the substrates were relatively limited.
Direct oxidation or halogenation of the A-ring of Tan-IIA was
also reported, but low yields and poor regioselectivity were
obtained due to competitive reactions of the furan benzylic
methyl moiety.7 For example, Liu and co-workers synthesized a
series of vasodilatory C-1 Tan-IIA benzoates through the
bromination of Tan-IIA followed by nucleophilic substitution
with aromatic acids (Scheme 1b).7c However, this two-step
Recent years have witnessed an explosive development of
C−H activation/functionalization,8 among which transition-
metal-catalyzed sp3 C−H bond activation/acyloxylation has
become an intriguing approach to functionalize inactive C−H
bonds (Scheme 1a).9 However, most currently reported metal-
catalyzed acyloxylations of benzylic sp3 C−H bonds encounter
limitations, such as sensitivity to the environment, the use of
expensive catalysts, and the difficult removal of toxic metal
residues from the products. As a result, increased attention has
been focused on metal-free catalytic processes.10 Recently,
benzylic C−H acetoxylations catalyzed by the nonmetal n-
Bu4NI have been developed by several groups (Scheme 1a).11
However, catalyst-free acyloxylation of benzylic sp3 C−H bonds
under mild reaction conditions, especially as a late-stage
strategy to modify complex bioactive natural products such as
Tan-IIA, remains a challenge. In our ongoing efforts to
chemically diversify tanshinone natural products,12 a catalyst-
Received: April 25, 2016
© XXXX American Chemical Society and
American Society of Pharmacognosy
A
DOI: 10.1021/acs.jnatprod.6b00370
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a
Scheme 1. Various Acyloxylation Approaches to the
Synthesis of Benzylic Esters
Scheme 2. Substrate Scope of Carboxylic Acids
free benzylic sp3 C−H acyloxylation approach has been
developed that leads to a late-stage structural modification of
Tan-IIA with low cost, high selectivity, and high efficiency.
RESULTS AND DISCUSSION
■
Tan-IIA was chosen as the model substrate, and the
corresponding acyloxylation reaction was initially conducted
using n-Bu4NI as the catalyst and tert-butyl hydroperoxide
(TBHP) as the co-oxidant.11a However, the formation of
propanoate 4 was not observed (Scheme 2, entry 1).
Interestingly, the reaction proceeded gradually in the air
without the addition of both n-Bu4NI and TBHP, providing
product 4 in 36% yield after 24 h, along with some unreacted
Tan-IIA (Table 1, entry 2). A control experiment was
performed in the absence of oxygen, but no reaction was
detected (Table 1, entry 3), suggesting that an oxidant was
essential for the acyloxylation reaction. Encouraged by this
result, various oxidants were screened to improve the yield.
Moderate yields could be achieved when silver salts, such as
Ag2CO3 and Ag2O, were employed as the oxidant (Table 1,
entries 4, 5). Cu(OAc)2 promoted this reaction as well, but the
yield was very low (Table 1, entry 6). FeCl3 failed to catalyze
the formation of any targeted product, except for decom-
position of the substrate (Table 1, entry 7). Next, various
organic oxidants were tested, and gratifyingly, TEMPO was
found to be an optimal oxidant, leading to the targeted ester 4
in 95% yield (Table 1, entry 10). Poor yields or decomposition
was observed when 2,3-dichloro-5,6-dicyano-p-benzoquinone
(DDQ), 1,4-benzoquinone (BQ), and TBHP were utilized as
a
Reaction conditions: Tan-IIA (0.1 mmol), acid (0.2 mmol), TEMPO
b
(0.12 mmol), PhCl (1 mL), 120 °C, 24 h. Acetic acid was used as the
solvent. Two isomers were isolated.
c
the oxidants (Table 1, entries 8, 9, 11). Because the use of an
excessive amount of propionic acid as the solvent leads to a
mixture of products when other carboxylic acids are employed
as the acyloxylating partner, alternative solvents were screened
to replace propionic acid. It was found that t-BuOH, DMF, and
DCE failed to facilitate this reaction, leading to decreased yields
(Table 1, entries 12−14). Nonpolar solvents, such as PhCl,
toluene, and mesitylene, were compatible with the reaction in
the presence of 2 equiv of propionic acid (Table 1, entries 15−
17). Among the nonpolar solvents, PhCl was the best solvent,
affording product 4 in 91% isolated yield (Table 1, entry 15).
With the optimized conditions in hand, the substrate scope
of this new C−H acyloxylation reaction was explored with
respect to various carboxylic acids, as shown in Scheme 2. Both
acyclic and cyclic alkyl carboxylic acids efficiently reacted with
Tan-IIA to give the corresponding acyloxylated products 4−10
in 67−91% yields. Among the carboxylic acids, adamantane-
carboxylic acid gave the lowest yield (67% for compound 10),
which was most likely due to the increased steric hindrance.
B
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cyclic moiety, such as thiazole-4- and pyrazine-2-carboxylic
acids, led to products 25 and 26 in lower yields, respectively.
Encouraged by the broad generality of carboxylic acids, the
scope and limitations of the Tan-IIA substrates were
investigated (Scheme 3). Cryptotanshinone,2 a Tan-IIA
Table 1. Optimization of the Reaction Conditions for the
Synthesis of 4
a
Scheme 3. Reactions of Various Tan-IIA-Derived Substrates
a
with Propionic Acid
b
entry
solvent
oxidant
yield (%)
1
propionic acid
propionic acid
propionic acid
propionic acid
propionic acid
propionic acid
propionic acid
propionic acid
propionic acid
propionic acid
propionic acid
t-BuOH
n-Bu4NI/TBHP
0
36
0
2
O2
c
3
no oxidant
4
Ag2CO3
Ag2O
48
50
12
0
5
6
Cu(OAc)2
FeCl3
7
8
DDQ
0
9
BQ
24
95
0
10
11
12
13
14
15
16
17
TEMPO
TBHP
TEMPO
TEMPO
TEMPO
TEMPO
TEMPO
TEMPO
11
21
69
DMF
DCE
d
PhCl
94 (91 )
toluene
86
89
mesitylene
a
Reaction conditions: Tan-IIA (0.1 mmol), propionic acid (0.2
a
b
Reaction conditions: Tan-IIA analogues (0.1 mmol), propionic acid
(0.2 mmol), TEMPO (0.12 mmol), PhCl (1 mL), 120 °C, 24 h.
mmol), oxidant (0.12 mmol), solvent (1 mL), 120 °C, 24 h. Yields
determined by H NMR analysis using 1, 2-dibromoethane as the
internal standard. The reaction was performed under a N2
atmosphere without oxidant. Isolated yield.
1
c
d
analogue possessing a saturated D-ring isolated from the
same herb, was utilized as the substrate to react with propionic
acid under the optimal conditions. The expected propionyloxy
product 27 was obtained as a pair of diastereomers with a ratio
of approximately 1:1 in 65% yield. These two diastereomers
possess identical NMR spectra and could be separated only by
chiral HPLC, not by TLC or a silica gel column. A small class of
Tan-IIA derivatives containing diverse substituents at C-15 of
the furan ring also proceeded smoothly in the reaction,
providing the corresponding products 28−32 in moderate to
good yields. Analogues with a hydroxy or chloro functional
group at C-17 were tolerant to the reaction conditions but
afforded the targeted products 33 and 34 in lower yields (47%).
Note that substrates produced by either breaking the o-quinone
into a diester or masking the o-diketo moiety with diacetate did
not react with propionic acid under the optimal conditions (35
and 36), suggesting that the o-diketo moiety is essential for the
acyloxylation reaction.
TEMPO is widely used as a radical-trapping agent, and no
TEMPO-trapped radical intermediate was observed in this
acyloxylation reaction. Therefore, a radical process could be
excluded for the current acyloxylation pathway. To confirm
whether a hydroxy intermediate was formed first and then
reacted with carboxylic acids to give the ester product,
treatment of the 1-hydroxy derivative 377a with HOAc under
the optimized reaction conditions failed to give the target
acetate 5 (Scheme 4, a). To gain further insight into the
reaction mechanism, HOAc was replaced with KOAc as the
acyloxylating reagent to react with Tan-IIA, which failed to
generate the acetate 5 (Scheme 4, a), suggesting that the
carboxylic acid proton was probably essential to initiate the
reaction. To investigate the exact role of the acidic proton,
Interestingly, this new method was also suitable for N-Boc-
protected amino acids. Acyloxylation with N-Boc-2-aminoacetic
acid afforded the amino ester 11 in 92% yield, whereas the
reaction with (R)-N-Boc-2-aminopropanoic acid produced the
ester 12 as a mixture of two diastereoisomers with a ratio of
approximately 1:1 that could be separated using a silica gel
column. When 2-hydroxyacetic acid was employed as the
acyloxylating agent, the yield of product 13 decreased to 49%,
likely due to the excessively oxidized or decomposed side
products resulting from the hydroxy functional group. α,β-
Unsaturated aliphatic carboxylic acids, such as monoethyl
fumarate and cinnamic acid, participated amicably in this
reaction to furnish products 14 and 15 in good and moderate
yields, respectively. Meanwhile, a wide array of aromatic
carboxylic acids was found to give high yields; among these,
benzoic acid was the best acyloxylating agent, affording product
16 in the highest yield (95%). Variously substituted benzoic
acids were also tolerated in the reaction to provide the
corresponding acyloxylated products 17−21 in moderate to
excellent yields. β-Naphthoic acid was also compatible in the
reaction to give the ester 22 in 80% yield. Remarkably, aryl
carboxylic acids with electron-donating substituents, such as the
o-methoxy group, gave higher yields than those bearing
electron-withdrawing substituents, such as the o-nitro group
(products 17 and 18). In addition, electron-rich heteroaryl
carboxylic acids, such as thiophene-2- and furan-3-carboxylic
acids, also performed well in the reaction to afford the targeted
products 23 and 24 in 81% and 65% yields, respectively. In
contrast, carboxylic acids containing an electron-poor hetero-
C
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However, further oxidation could drive this equilibrium toward
the formation of the acyloxylation product, as suggested by the
fact that no reaction occurred without oxidant. On the other
hand, the C-17 methyl group on the furan ring is not involved
in the formation of the γ-methylene-α,β-unsaturated C-12 oxo
structural unit, which might account for the regioselectivity
favoring C-1.
Scheme 4. Preliminary Reaction Mechanism Studies
In conclusion, a novel catalyst-free sp3 C−H acyloxylation
approach was developed that allows the direct introduction of a
wide range of acyloxy groups regioselectively at C-1 of various
Tan-IIA substrates under simple and mild conditions.
Compared with the literature procedures using palladium or
n-Bu4NI as the catalyst, our protocol demonstrated atom-
economy, lower cost, higher efficiency, and robust functional-
group tolerance. Preliminary mechanistic studies suggest that
this approach is initiated by a unique acid-induced reversible
enolization/oxa-conjugate addition process, followed by
oxidation to exclusively give the C-1 acetoxylated products.
These findings provide an economical and efficient chemical
method to modify the A-ring of the pharmacologically valuable
Tan-IIA. Further application of this approach as well as the
biological evaluation of the resulting acyloxylated derivatives
will be reported in the future.
deuterated acetic acid (AcOD) was used to react with Tan-IIA
in the absence of TEMPO for 24 h under a N2 atmosphere. As
expected, no acetate 5 was found, and NMR analysis of the
recovered Tan-IIA displayed that protons at C-1 and C-15 were
partially exchanged with deuterium, as in the structure of [Dn]-
38 (n = 0, 1, 2) (Scheme 4, b), indicating that the C-1 C−H
bond was activated under the acidic condition. For D-labeling
at C-15, we speculated that an aromatic electrophilic
substitution by D+ occurred due to the high electron density
of the furan ring. It should be noted that [Dn]-38 is a mixture
of several inseparable compounds, most likely including Tan-
IIA, the C-1-deuterated Tan-IIA derivative, the C-15-deuterated
Tan-IIA derivative, and/or both the C-1- and C-15-deuterated
Tan-IIA derivative. The deuteration experiment was also
performed by heating Tan-IIA in toluene-d8, but NMR analysis
showed that no deuterated product was produced (Scheme 4,
b).
EXPERIMENTAL SECTION
■
General Experimental Procedures. All the reactions were
performed in a sealed tube containing a Teflon-coated stir bar and
monitored by TLC (0.2 mm silica-gel-coated HSGF 254 plates) under
UV light at 254 nm. 1H NMR spectra were recorded on a Bruker 500
MHz NMR spectrometer (CDCl3 solvent). The chemical shifts were
reported in parts per million (ppm), downfield from SiMe4 (δ 0.0) and
relative to the signal of CDCl3 (δ 7.26, singlet) or DMSO-d6 (δ 2.54,
singlet). Multiplicities are given as s (singlet), d (doublet), t (triplet), q
(quartet), dd (doublet of doublets), or m (multiplet). The number of
protons for a given resonance is indicated by nH. Coupling constants
are reported as J values in Hz. 13C NMR data are reported in ppm
using CDCl3. Low- and high-resolution mass spectra were obtained
using EI or ESI-TOF.
Based on the results above, a plausible mechanism for the C-
1 acyloxylation was tentatively proposed. As shown in Figure 1,
General Experimental Procedure for the Catalyst-Free
Acyloxylation Reaction. A 10 mL sealed tube was charged with 1
(0.1 mmol), propionic acid (0.2 mmol), and TEMPO (0.12 mmol).
PhCl (1 mL) was added, and the resulting mixture was stirred at 120
°C. The reaction was monitored by TLC until the starting material
disappeared. The solvent was removed in vacuo, and the residue was
purified using a silica gel column with CH2Cl2 as the eluent to give the
acyloxylated products in 45−95% yields.
1,6,6-Trimethyl-10,11-dioxo-6,7,8,9,10,11-hexahydro-
1
phenanthro[1,2-b]furan-9-yl propionate (4): H NMR (300 MHz,
CDCl3) δ 7.71 (s, 2H), 7.24 (s, 1H), 6.48−6.39 (m, 1H), 2.35−2.12
(m, 6H), 2.05−1.81 (m, 2H), 1.60−1.50 (m, 1H), 1.39 (s, 2H), 1.27
(s, 2H), 1.13 (t, J = 7.6 Hz, 1H); 13C NMR (125 MHz, CDCl3) δ
183.0, 175.3, 173.5, 161.2, 150.8, 141.7, 138.2, 134.2, 128.5, 127.1,
123.0, 121.4, 120.3, 67.3, 34.9, 32.4, 31.6, 31.2, 27.7, 24.8, 9.4, 8.9;
ESIMS m/z 389 [M + Na]+; HRESIMS m/z 389.1367 [M + Na]+
(calcd for C22H22O5Na 389.1365).
1,6,6-Trimethyl-10,11-dioxo-6,7,8,9,10,11-hexahydro-
phenanthro[1,2-b]furan-9-yl acetate (5): 1H NMR (300 MHz,
CDCl3) δ 7.68 (d, J = 8.3 Hz, 1H), 7.63 (d, J = 8.3 Hz, 1H), 7.19 (s,
1H), 6.39−6.32 (m, 1H), 2.19 (s, 3H), 2.17−2.09 (m, 1H), 1.98 (s,
3H), 1.98−1.78 (m, 2H), 1.56−1.45 (m, 1H), 1.36 (s, 3H), 1.24 (s,
3H); 13C NMR (125 MHz, CDCl3) δ 182.7, 174.9, 169.9, 161.0,
150.7, 141.7, 137.9, 134.2, 128.3, 126.8, 123.0, 121.2, 120.2, 67.4, 34.8,
32.2, 31.5, 31.0, 24.6, 21.03, 8.8; ESIMS m/z 375 [M + Na]+;
HRESIMS m/z 375.1208 [M + Na]+ (calcd for C21H20O5Na
375.1214).
Figure 1. Proposed Reaction Mechanism.
in the presence of a carboxylic acid at 120 °C, the γ-methylene-
α,β-unsaturated C-11 oxo structural unit of Tan-IIA undergoes
an enolization, leading to the dienol quinonemethide 39, which
was also proposed as a key intermediate by Kusumi and co-
workers in a photoinduced oxidation of Tan-IIA.7a The
resulting dienol structural unit along with the neighboring C-
12 carbonyl group form another reactive α,β,γ,δ-unsaturated
dienone. The further addition of the 1,6-oxa-conjugate of the
carboxylate ion to this dienone system, with its extended
conjugation, affords the C-1 acetoxylated dihydroquinone 40,
which is prone to oxidation to furnish the final product. It
should be noted that the enolization/oxa-conjugate addition
process is reversible, and the equilibrium heavily favored the
formation of the o-quinone Tan-IIA at room temperature.
1,6,6-Trimethyl-10,11-dioxo-6,7,8,9,10,11-hexahydro-
phenanthro[1,2-b]furan-9-yl butyrate (6): 1H NMR (300 MHz,
D
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CDCl3) δ 7.70 (s, 2H), 7.23 (s, 1H), 6.47−6.41(m, 1H), 2.33−2.11
(m, 6H), 2.05−1.81 (m, 2H), 1.73−1.47 (m, 3H), 1.39 (s, 8H), 1.27
(s, 3H), 0.92 (t, J = 7.4 Hz, 3H); 13C NMR (125 MHz, CDCl3) δ
182.8, 175.2, 172.6, 161.1, 150.7, 141.7, 138.1, 134.1, 128.4, 127.0,
123.0, 121.3, 120.2, 67.1, 36.3, 34.8, 32.3, 31.6, 31.2, 24.7, 18.6, 13.8,
8.9; ESIMS m/z 403 [M + Na]+; HRESIMS m/z 403.1527 [M + Na]+
(calcd for C23H24O5Na 403.1521).
121.5, 120.4, 79.7, 68.3, 49.4, 34.9, 32.2, 31.6, 31.2, 28.5, 24.7, 19.12,
8.9; ESIMS m/z 482 [M + H]+; HRESIMS m/z 482.2166 [M + H]+
(calcd for C27H32O7N 482.2179).
1 , 6 , 6 - T r i m e t h y l - 1 0 , 1 1 - d i o x o - 6 , 7 , 8 , 9 , 1 0 , 1 1 -
1
hexahydrophenanthro[1,2-b]furan-9-yl 2-hydroxyacetate (13): H
NMR (300 MHz, CDCl3) δ 7.74 (d, J = 1.2 Hz, 1H), 7.25 (0H), 6.53
(t, J = 3.5 Hz, 1H), 4.17−4.01 (m, 2H), 2.66−2.53 (m, 1H), 2.31−
2.16 (m, 4H), 2.10−1.79 (m, 2H), 1.62−1.51 (m, 1H), 1.40 (s, 3H),
1.28 (s, 3H); 13C NMR (125 MHz, CDCl3) δ 183.0, 174.9, 172.7,
161.1, 150.8, 141.9, 137.0, 134.5, 128.6, 126.9, 123.4, 121.5, 120.4,
68.8, 60.6, 34.9, 32.2, 31.6, 31.1, 24.9, 8.9; ESIMS m/z 391 [M + Na]+;
HRESIMS m/z 391.1159 [M + Na]+ (calcd for C21H20O6Na
391.1158).
Ethyl (1,6,6-trimethyl-10,11-dioxo-6,7,8,9,10,11-
hexahydrophenanthro[1,2-b]furan-9-yl) fumarate (14): 1H NMR
(300 MHz, CDCl3) δ 7.76 (s, 2H), 7.26 (s, 1H), 6.80 (s, 2H), 6.57 (s,
1H), 4.21 (q, J = 7.2 Hz, 2H), 2.37−2.16 (m, 4H), 2.10−1.81 (m,
2H), 1.68−1.49 (m, 1H), 1.42 (s, 3H), 1.36−1.17 (m, 6H); 13C NMR
(125 MHz, CDCl3) δ 182.5, 174.7, 165.2, 164.0, 161.0, 150.8, 141.8,
137.2, 134.4, 134.0, 133.7, 128.6, 126.9, 123.4, 121.5, 120.4, 68.3, 61.3,
34.9, 32.2, 31.7, 31.1, 24.7, 14.2, 8.9; ESIMS m/z 459 [M + Na]+;
HRESIMS m/z 459.1421 [M + Na]+ (calcd for C25H24O7Na
459.1420).
1,6,6-Trimethyl-10,11-dioxo-6,7,8,9,10,11-hexahydro-
1
phenanthro[1,2-b]furan-9-yl hexanoate (7): H NMR (300 MHz,
CDCl3) δ 7.70 (s, 2H), 7.23 (d, J = 1.6 Hz, 1H), 6.48−6.38 (m, 1H),
2.33−2.10 (m, 4H), 2.06−1.81 (m, 2H), 1.72−1.49 (m, 3H), 1.39 (s,
3H), 1.27 (s, 3H), 0.92 (t, J = 7.4 Hz, 1H); 13C NMR (125 MHz,
CDCl3) δ 182.9, 175.2, 172.6, 161.2, 150.7, 141.7, 138.2, 134.2, 128.4,
127.1, 123.0, 121.4, 120.3, 67.2, 36.4, 34.9, 32.4, 31.6, 31.2, 24.7, 18.6,
13.9, 8.9; ESIMS m/z 431 [M + Na]+; HRESIMS m/z 431.1837 [M +
Na]+ (calcd for C25H28O5Na 431.1834).
1,6,6-Trimethyl-10,11-dioxo-6,7,8,9,10,11-hexahydro-
phenanthro[1,2-b]furan-9-yl cyclopropanecarboxylate (8): 1H
NMR (300 MHz, CDCl3) δ 7.71 (d, J = 1.4 Hz, 2H), 7.25−7.19
(m, 1H), 6.45 (t, J = 3.1 Hz, 1H), 2.25 (s, 3H), 2.24−2.09 (m, 1H),
2.04−1.85 (m, 2H), 1.58−1.44 (m, 2H), 1.40 (s, 3H), 1.27 (s, 3H),
1.17−1.05 (m, 1H), 0.98−0.88 (m, 1H), 0.85−0.71 (m, 1H); 13C
NMR (125 MHz, CDCl3) δ 182.8, 175.3, 173.7, 161.2, 150.8, 141.7,
138.1, 134.1, 128.4, 127.1, 123.0, 121.4, 120.3, 67.2, 34.9, 32.4, 31.7,
31.2, 24.7, 13.1, 8.9, 8.6, 8.3; ESIMS m/z 401 [M + Na]+; HRESIMS
m/z 401.1364 [M + Na]+ (calcd for C23H22O5Na 401.1365).
1,6,6-Trimethyl-10,11-dioxo-6,7,8,9,10,11-hexahydro-
1 , 6 , 6 - T r i m e t h y l - 1 0 , 1 1 - d i o x o - 6 , 7 , 8 , 9 , 1 0 , 1 1 -
1
hexahydrophenanthro[1,2-b]furan-9-yl cinnamate (15): H NMR
(300 MHz, CDCl3) δ 7.75 (s, 2H), 7.69 (d, J = 16.1 Hz, 1H), 7.51−
7.42 (m, 2H), 7.39−7.27 (m, 3H), 7.23 (s, 1H), 6.66−6.59 (m, 1H),
6.36 (d, J = 16.0 Hz, 1H), 2.38−2.26 (m, 1H), 2.23 (s, 3H), 2.11−1.90
(m, 2H), 1.67−1.49 (m, 1H), 1.43 (s, 3H), 1.30 (s, 3H); 13C NMR
(125 MHz, CDCl3) δ 182.6, 174.9, 166.0, 161.1, 150.9, 144.8, 141.7,
138.0, 134.8, 134.3, 130.1, 128.95, 128.5, 128.1, 127.0, 123.2, 121.5,
120.4, 118.5, 67.3, 34.9, 32.4, 31.8, 31.2, 24.8, 8.9; ESIMS m/z 463 [M
+ Na]+; HRESIMS m/z 463.1519 [M + Na]+ (calcd for C28H24O5Na
463.1521).
1 , 6 , 6 - T r i m e t h y l - 1 0 , 1 1 - d i o x o - 6 , 7 , 8 , 9 , 1 0 , 1 1 -
hexahydrophenanthro[1,2-b]furan-9-yl benzoate (16): 1H NMR
(300 MHz, CDCl3) δ 7.99−7.88 (m, 2H), 7.76 (d, J = 1.3 Hz, 4H),
7.51−7.42 (m, 1H), 7.38−7.29 (m, 2H), 7.24−7.18 (m, 1H), 6.76−
6.69 (m, 1H), 2.44−2.30 (m, 1H), 2.21 (s, 3H), 2.10−1.93 (m, 2H),
1.64−1.52 (m, 1H), 1.44 (s, 3H), 1.31 (s, 3H); 13C NMR (125 MHz,
CDCl3) δ 182.4, 174.8, 165.6, 161.1, 150.9, 141.7, 137.9, 134.3, 132.7,
130.8, 129.8, 128.5, 128.2, 127.0, 123.2, 121.4, 120.4, 67.7, 35.0, 32.4,
31.9, 31.2, 24.8, 8.9; ESIMS m/z 437 [M + Na]+; HRESIMS m/z
437.1358 [M + Na]+ (calcd for C26H22O5Na 437.1365).
1,6,6-Trimethyl-10,11-dioxo-6,7,8,9,10,11-hexahydro-
phenanthro[1,2-b]furan-9-yl 2-methoxybenzoate (17): 1H NMR
(300 MHz, CDCl3) δ 7.71 (s, 2H), 7.67 (dd, J = 7.9, 1.6 Hz, 1H), 7.37
(td, J = 8.2, 1.7 Hz, 1H), 7.24−7.17 (m, 1H), 6.95−6.82 (m, 2H),
6.75−6.68 (m, 1H), 3.81 (s, 3H), 2.49−2.31 (m, 1H), 2.22 (s, 3H),
2.13−1.96 (m, 2H), 1.65−1.55 (m, 1H), 1.42 (s, 3H), 1.30 (s, 3H);
13C NMR (125 MHz, CDCl3) δ 182.5, 175.0, 165.4, 161.1, 158.8,
150.8, 141.6, 138.0, 134.0, 132.8, 131.5, 128.2, 127.1, 122.9, 121.3,
121.1, 120.2, 120.1, 111.9, 67.7, 55.9, 34.8, 32.3, 31.7, 31.2, 24.7, 8.8;
ESIMS m/z 445 [M + H]+; HRESIMS m/z 445.1657 [M + H]+ (calcd
for C27H25O6 445.1651).
1
phenanthro[1,2-b]furan-9-yl cyclohexanecarboxylate (9): H NMR
(300 MHz, CDCl3) δ 7.71 (s, 2H), 7.23 (d, J = 1.5 Hz, 1H), 6.48−
6.40 (m, 1H), 2.29−2.10 (m, 5H), 2.03−1.79 (m, 4H), 1.76−1.63 (m,
2H), 1.62−1.40 (m, 4H), 1.39 (s, 3H), 1.27−1.12 (m, 6H); 13C NMR
(125 MHz, CDCl3) δ 182.8, 175.3, 174.8, 161.2, 150.7, 141.7, 138.2,
134.1, 128.4, 127.0, 123.0, 121.4, 120.3, 66.8, 43.4, 34.9, 32.3, 31.7,
31.2, 29.2, 29.1, 25.9, 25.6, 25.6, 24.7, 8.9; ESIMS m/z 421 [M + H]+;
HRESIMS m/z 421.2019 [M + H]+ (calcd for C26H29O5 421.2015).
(3r,5r,7r)-1,6,6-Trimethyl-10,11-dioxo-6,7,8,9,10,11-hexahydro-
phenanthro[1,2-b]furan-9-yl adamantane-1-carboxylate (10): 1H
NMR (300 MHz, CDCl3) δ 7.71 (s, 2H), 7.23 (s, 1H), 6.42 (s, 1H),
2.36−2.05 (m, 4H), 2.04−1.73 (m, 10H), 1.73−1.46 (m, 7H), 1.46−
1.10 (m, 7H); 13C NMR (125 MHz, CDCl3) δ 182.7, 176.1, 175.4,
161.2, 150.7, 141.6, 138.4, 134.0, 128.3, 127.1, 122.9, 121.4, 120.3,
66.5, 40.8, 38.9 (3), 36.6 (3), 34.9, 32.4, 31.8, 31.20, 28.1 (3), 24.7,
8.9; ESIMS m/z 473 [M + H]+; HRESIMS m/z 473.2331 [M + H]+
(calcd for C30H33O5 473.2328)
1,6,6-Trimethyl-10,11-dioxo-6,7,8,9,10,11-hexahydro-
phenanthro[1,2-b]furan-9-yl 2-((tert-butoxycarbonyl)amino)-
1
acetate (11): H NMR (300 MHz, CDCl3) δ 7.71 (s, 2H), 7.23 (d,
J = 1.3 Hz, 1H), 6.46−6.39 (m, 1H), 5.19−5.06 (m, 1H), 3.98 (dd, J =
18.2, 7.0 Hz, 1H), 3.70 (dd, J = 18.2, 3.9 Hz, 1H), 2.22 (s, 3H), 2.21−
2.15 (m, 1H), 2.06−1.79 (m, 2H), 1.64−1.45 (m, 1H), 1.41 (s, 9H),
1.38 (s, 3H), 1.26 (s, 3H); 13C NMR (125 MHz, CDCl3) δ 183.0,
174.9, 169.5, 161.1, 155.8, 150.8, 141.8, 137.3, 134.4, 128.5, 127.0,
123.3, 121.4, 120.3, 79.8, 68.5, 42.4, 34.8, 32.2, 31.6, 31.1, 28.4, 24.8,
8.8; ESIMS m/z 490 [M + Na]+; HRESIMS m/z 490.1849 [M + Na]+
(calcd for C26H29O7NNa 490.1842).
( 2 R ) - 1 , 6 , 6 - T r i m e t h y l - 1 0 , 1 1 - d i o x o - 6 , 7 , 8 , 9 , 1 0 , 1 1 -
hexahydrophenanthro[1,2-b]furan-9-yl 2-((tert-butoxycarbonyl)-
amino)propanoate (12). One isomer: 1H NMR (300 MHz,
CDCl3) δ 7.72 (s, 2H), 7.24 (s, 1H), 6.48 (t, J = 3.6 Hz, 1H), 5.13
(d, J = 7.3 Hz, 1H), 4.24 (t, J = 7.3 Hz, 1H), 2.24 (s, 3H), 2.21−2.09
(m, 2H), 2.07−1.77 (m, 2H), 1.63−1.49 (m, 2H), 1.47−1.32 (m,
15H), 1.27 (s, 3H); 13C NMR (125 MHz, CDCl3) δ 183.2, 175.3,
171.8, 161.1, 155.1, 150.8, 141.8, 137.4, 134.3, 128.5, 127.1, 123.3,
121.4, 120.4, 79.5, 68.2, 49.6, 34.9, 32.35, 31.7, 31.1, 28.41, 24.6, 18.98,
8.9; ESIMS m/z 482 [M + H]+; HRESIMS m/z 482.2166 [M + H]+
(calcd for C27H32O7N 482.2179). Another isomer: 1H NMR (300
MHz, CDCl3) δ 7.73 (s, 2H), 7.24 (s, 1H), 6.52−6.46 (m, 1H), 5.20
(d, J = 8.3 Hz, 1H), 4.31−4.15 (m, 1H), 2.25 (s, 3H), 2.22−2.14 (m,
1H), 2.05−1.81 (m, 2H), 1.61−1.49 (m, 1H), 1.43 (s, 9H), 1.40 (s,
3H), 1.27 (s, 6H); 13C NMR (125 MHz, CDCl3) δ 183.0, 175.2,
172.3, 161.2, 155.3, 150.9, 141.8, 137.4, 134.3, 128.6, 127.0, 123.3,
1,6,6-Trimethyl-10,11-dioxo-6,7,8,9,10,11-hexahydro-
1
phenanthro[1,2-b]furan-9-yl 2-nitrobenzoate (18): H NMR (300
MHz, CDCl3) δ 7.95 (d, J = 8.1, 1H), 7.83 (d, J = 7.7, 1H), 7.72 (s,
2H), 7.69−7.60 (m, 1H), 7.58−7.48 (m, 1H), 7.23 (d, J = 1.5 Hz,
1H), 6.75−6.66 (m, 1H), 2.61−2.45 (m, 1H), 2.24 (s, 3H), 2.18−2.02
(m, 1H), 2.01−1.87 (m, 2H), 1.71−1.58 (m, 2H), 1.38 (s, 3H), 1.29
(s, 3H); 13C NMR (125 MHz, CDCl3) δ 183.3, 175.3, 165.0, 161.2,
151.1, 146.6, 141.8, 136.8, 134.4, 133.8, 130.9, 130.2, 129.4, 128.5,
127.1, 123.8, 123.4, 121.4, 120.3, 69.5, 34.8, 32.3, 31.6, 31.1, 24.1, 8.9.
31.1, 24.8, 8.9; ESIMS m/z 482 [M + Na]+; HRESIMS m/z 482.1222
[M + Na]+ (calcd for C26H21O7NNa 482.1216).
1 , 6 , 6 - T r i m e t h y l - 1 0 , 1 1 - d i o x o - 6 , 7 , 8 , 9 , 1 0 , 1 1 -
1
hexahydrophenanthro[1,2-b]furan-9-yl 3-methylbenzoate (19): H
NMR (300 MHz, CDCl3) δ 7.85−7.71 (m, 4H), 7.37−7.21 (m, 3H),
6.79−6.72 (m, 1H), 2.46−2.30 (s, 4H), 2.25 (s, 3H), 2.14−1.96 (m,
E
DOI: 10.1021/acs.jnatprod.6b00370
J. Nat. Prod. XXXX, XXX, XXX−XXX

Journal of Natural Products
Article
2H), 1.66−1.56 (s, 1H), 1.48 (s, 3H), 1.35 (s, 3H); 13C NMR (125
MHz, CDCl3) δ 182.4, 174.9, 165.8, 161.1, 150.9, 141.7, 138.0, 134.3,
133.4, 130.7, 130.3, 128.5, 128.1, 127.0, 126.9, 123.2, 121.5, 120.4,
67.6, 35.0, 32.4, 31.9, 31.2, 24.8, 21.4, 8.9; ESIMS m/z 451 [M + Na]+;
HRESIMS m/z 451.1528 [M + Na]+ (calcd for C27H24O5Na
451.1521).
3H), 2.20−1.90 (m, 2H), 1.69−1.54 (m, 1H), 1.43 (s, 3H), 1.31 (s,
3H); 13C NMR (125 MHz, CDCl3) δ 182.7, 174.7, 163.3, 161.1,
151.0, 147.4, 146.7, 144.3, 143.8, 141.8, 137.1, 134.5, 128.8, 127.1,
123.5, 121.4, 120.3, 69.6, 35.0, 32.4, 31.6, 31.1, 24.8, 8.9; ESIMS m/z
439 [M + Na]+; HRESIMS m/z 439.1276 [M + Na]+ (calcd for
C24H20O5N2Na 439.1270).
1,6,6-Trimethyl-10,11-dioxo-6,7,8,9,10,11-hexahydro-
(1R)-1,6,6-Trimethyl-10,11-dioxo-1,2,6,7,8,9,10,11-
1
1
phenanthro[1,2-b]furan-9-yl 4-nitrobenzoate (20): H NMR (300
octahydrophenanthro[1,2-b]furan-9-yl propionate (27): H NMR
MHz, CDCl3) δ 8.20 (d, J = 8.9 Hz, 2H), 8.11 (d, J = 8.9 Hz, 2H),
7.79 (s, 2H), 7.25−7.22 (m, 1H), 6.73−6.67 (m, 1H), 2.45−2.31 (m,
1H), 2.22 (s, 3H), 2.16−1.90 (m, 2H), 1.69−1.55 (m, 1H), 1.46 (s,
3H), 1.32 (s, 3H); 13C NMR (125 MHz, CDCl3) δ 182.7, 174.7,
163.8, 161.0, 150.9, 150.4, 141.9, 137.1, 136.2, 134.6, 130.9, 128.7,
127.0, 123.5, 123.5, 121.5, 120.4, 69.0, 35.0, 32.4, 31.9, 31.1, 24.8, 8.9;
ESIMS m/z 460 [M + H]+; HRESIMS m/z 460.1403 [M + H]+ (calcd
for C26H22O7N 460.1396).
(300 MHz, CDCl3) δ 7.72 (d, J = 8.2 Hz, 1H), 7.65 (d, J = 8.2 Hz,
1H), 6.48−6.41 (m, 1H), 4.89 (t, J = 9.5 Hz, 1H), 4.36 (dd, J = 9.4, 6.1
Hz, 1H), 3.58 (dt, J = 10.5, 6.8 Hz, 1H), 2.34−2.14 (m, 3H), 2.03−
1.79 (m, 2H), 1.60−1.49 (m, 1H), 1.41−1.31 (m, 6H), 1.26 (s, 3H),
1.12 (t, J = 7.5 Hz, 3H); 13C NMR (125 MHz, CDCl3) δ 183.4, 175.2,
173.3, 170.4, 152.9, 137.5, 133.4, 129.2, 127.3, 125.2, 118.7, 81.7, 67.1,
35.1, 34.8, 32.3, 31.8, 31.3, 27.6, 24.7, 18.9, 9.3; ESIMS m/z 369 [M +
H]+; HRESIMS m/z 369.1707 [M + H]+ (calcd for C22H25O5
369.1702).
1 , 6 , 6 - T r i m e t h y l - 1 0 , 1 1 - d i o x o - 6 , 7 , 8 , 9 , 1 0 , 1 1 -
1
hexahydrophenanthro[1,2-b]furan-9-yl 4-methylbenzoate (21): H
1,6,6-Trimethyl-10,11-dioxo-2-(thiophen-3-yl)-6,7,8,9,10,11-
1
NMR (300 MHz, CDCl3) δ 7.83 (d, J = 8.2 Hz, 2H), 7.78−7.70 (m,
2H), 7.21 (d, J = 1.6 Hz, 1H), 7.13 (d, J = 8.2 Hz, 2H), 6.72 (t, J = 3.2
Hz, 1H), 2.41−2.30 (m, 4H), 2.20 (s, 3H), 2.12−1.92 (m, 2H), 1.64−
1.52 (m, 1H), 1.44 (s, 3H), 1.31 (s, 3H); 13C NMR (125 MHz,
CDCl3) δ 182.4, 174.8, 165.6, 161.1, 150.9, 143.1, 141.7, 138.0, 134.2,
129.8, 128.9, 128.4, 128.0, 127.0, 123.1, 121.4, 120.3, 67.4, 34.9, 32.4,
31.9, 31.2, 24.8, 21.7, 8.9; ESIMS m/z 429 [M + H]+; HRESIMS m/z
429.1705 [M + H]+ (calcd for C27H25O5 429.1702).
1 , 6 , 6 - T r i m e t h y l - 1 0 , 1 1 - d i o x o - 6 , 7 , 8 , 9 , 1 0 , 1 1 -
hexahydrophenanthro[1,2-b]furan-9-yl 2-naphthoate (22): 1H
NMR (300 MHz, CDCl3) δ 8.49 (s, 1H), 7.97 (d, J = 1.5 Hz, 1H),
7.88−7.68 (m, 5H), 7.55−7.40 (m, 2H), 7.20 (d, J = 1.2 Hz, 1H), 6.79
(t, J = 2.9 Hz, 1H), 2.52−2.34 (m, 1H), 2.18 (s, 3H), 2.15−1.98 (m,
2H), 1.69−1.56 (m, 1H), 1.47 (s, 3H), 1.33 (s, 3H); 13C NMR (125
MHz, CDCl3) δ 182.4, 174.7, 165.7, 161.0, 150.9, 141.6, 137.8, 135.4,
134.3, 132.5, 131.0, 129.3, 128.5, 128.0, 128.0, 127.9, 127.8, 127.0,
126.4, 125.6, 123.2, 121.4, 120.3, 67.8, 35.0, 32.4, 31.9, 31.1, 24.9, 8.8;
ESIMS m/z 465 [M + H]+; HRESIMS m/z 465.1699 [M + H]+ (calcd
for C30H25O5 465.1702).
hexahydrophenanthro[1,2-b]furan-9-yl propionate (28): H NMR
(300 MHz, CDCl3) δ 7.78 (d, J = 8.3 Hz, 1H), 7.72 (d, J = 8.3 Hz,
1H), 7.58 (s, 1H), 7.46 (s, 2H), 6.48−6.40 (m, 1H), 2.47 (s, 3H),
2.35−2.13 (m, 3H), 2.06−1.83 (m, 2H), 1.62−1.47 (m, 2H), 1.41 (s,
3H), 1.29 (s, 3H), 1.14 (t, J = 7.5 Hz, 3H); 13C NMR (125 MHz,
CDCl3) δ 182.8, 175.4, 173.4, 158.9, 150.6, 149.0, 138.3, 134.1, 130.8,
128.3, 127.1, 126.7, 125.3, 122.9, 122.0, 121.7, 115.6, 6.34, 34.9, 32.4,
31.6, 31.2, 27.6, 24.7, 9.8, 9.3; ESIMS m/z 471 [M + Na]+; HRESIMS
m/z 471.1233 [M + Na]+ (calcd for C26H24O5NaS 471.1242).
1,6,6-Trimethyl-10,11-dioxo-2-phenyl-6,7,8,9,10,11-hexahydro-
1
phenanthro[1,2-b]furan-9-yl propionate (29): H NMR (300 MHz,
CDCl3) δ 7.86−7.62 (m, 4H), 7.54−7.33 (m, 3H), 6.51−6.36 (m,
1H), 2.50 (s, 3H), 2.36−2.11 (m, 3H), 2.06−1.81 (m, 2H), 1.61−1.51
(m, 1H), 1.41 (s, 3H), 1.29 (s, 3H), 1.14 (t, J = 7.5 Hz, 3H); 13C
NMR (125 MHz, CDCl3) δ 182.9, 175.4, 173.4, 159.4, 151.6, 150.7,
138.2, 134.1, 129.8, 128.9 (3), 128.5, 128.3, 127.2, 126.1 (3), 123.0,
122.0, 116.8, 67.3, 34.9, 32.4, 31.6, 31.2, 27.6, 24.7, 10.23, 9.3; ESIMS
m/z 465 [M + Na]+; HRESIMS m/z 465.1673 [M + Na]+ (calcd for
C28H26O5Na 465.1678).
1 , 6 , 6 - T r i m e t h y l - 1 0 , 1 1 - d i o x o - 6 , 7 , 8 , 9 , 1 0 , 1 1 -
1,6,6-Trimethyl-10,11-dioxo-2-vinyl-6,7,8,9,10,11-hexahydro-
hexahydrophenanthro[1,2-b]furan-9-yl thiophene-2-carboxylate
1
phenanthro[1,2-b]furan-9-yl propionate (30): H NMR (300 MHz,
1
(23): H NMR (300 MHz, CDCl3) δ 7.80−7.65 (m, 3H), 7.44 (d, J
CDCl3) δ 7.77 (d, J = 8.2 Hz, 1H), 7.71 (d, J = 8.3 Hz, 1H), 6.55 (dd,
J = 17.4, 11.4 Hz, 1H), 6.43 (t, J = 3.6 Hz, 1H), 5.81 (d, J = 17.4 Hz,
1H), 5.36 (d, J = 11.5 Hz, 1H), 2.35−2.10 (m, 6H), 2.07−1.82 (m,
2H), 1.69−1.49 (m, 1H), 1.40 (s, 3H), 1.28 (s, 3H), 1.13 (t, J = 7.5
Hz, 3H); 13C NMR (125 MHz, CDCl3) δ 182.8, 175.2, 173.4, 159.6,
151.2, 150.9, 138.3, 134.1, 128.2, 127.3, 123.1, 121.9, 121.5, 118.1,
114.5, 67.3, 34.9, 32.4, 31.6, 31.2, 27.6, 24.7, 9.3, 8.9; ESIMS m/z 415
[M + Na]+; HRESIMS m/z 415.1516 [M + Na]+ (calcd for
C24H24O5Na 415.1521).
= 5.0 Hz, 1H), 7.22 (s, 1H), 7.01 (t, J = 4.3 Hz, 1H), 6.68 (t, J = 3.2
Hz, 1H), 2.42−2.29 (m, 1H), 2.21 (s, 3H), 2.13−1.91 (m, 2H), 1.67−
1.50 (m, 1H), 1.43 (s, 3H), 1.30 (s, 3H); 13C NMR (125 MHz,
CDCl3) δ 182.4, 174.8, 161.2, 161.0, 150.8, 141.7, 137.6, 134.2, 134.2,
133.4, 131.9, 128.4, 127.6, 126.9, 123.2, 121.4, 120.3, 67.9, 34.9, 32.3,
31.8, 31.1, 24.9, 8.9; ESIMS m/z 443 [M + Na]+; HRESIMS m/z
443.0928 [M + Na]+ (calcd for C24H20O5NaS 443.0929).
1,6,6-Trimethyl-10,11-dioxo-6,7,8,9,10,11-hexahydro-
phenanthro[1,2-b]furan-9-yl furan-3-carboxylate (24): 1H NMR
(300 MHz, CDCl3) δ 7.91−7.84 (m, 1H), 7.75 (d, J = 1.1 Hz, 2H),
7.34 (t, J = 1.7 Hz, 1H), 7.23 (d, J = 1.5 Hz, 1H), 6.73−6.62 (m, 2H),
2.37−2.27 (m, 1H), 2.23 (s, 3H), 2.10−1.89 (m, 2H), 1.61−1.51 (m,
1H), 1.42 (s, 3H), 1.30 (s, 3H); 13C NMR (125 MHz, CDCl3) δ
182.5, 174.9, 162.2, 161.1, 150.9, 147.6, 143.5, 141.7, 137.9, 134.3,
128.5, 127.0, 123.2, 121.5, 120.4, 119.7, 110.2, 67.3, 35.0, 32.4, 31.82,
31.2, 24.9, 8.9; ESIMS m/z 427 [M + Na]+; HRESIMS m/z 427.1159
[M + Na]+ (calcd for C24H20O6Na 427.1158).
2-Ethyl-1,6,6-trimethyl-10,11-dioxo-6,7,8,9,10,11-hexahydro-
1
phenanthro[1,2-b]furan-9-yl propionate (31): H NMR (300 MHz,
CDCl3) δ 7.67 (s, 2H), 6.42 (t, J = 3.6 Hz, 1H), 2.65 (q, J = 7.5 Hz,
2H), 2.26 (qd, J = 7.6, 3.2 Hz, 2H), 2.21−2.12 (m, 4H), 2.04−1.78
(m, 2H), 1.59−1.48 (m, 1H), 1.38 (s, 3H), 1.30−1.17 (m, 3H), 1.18−
1.04 (m, 3H); 13C NMR (125 MHz, CDCl3) δ 183.2, 175.3, 173.4,
159.2, 156.2, 150.0, 138.0, 134.0, 128.7, 126.8, 122.7, 121.1, 114.4,
67.3, 34.8, 32.4, 31.6, 31.1, 27.6, 24.7, 19.23, 12.7, 9.34, 8.7; ESIMS m/
z 395 [M + H]+; HRESIMS m/z 395.1852 [M + H]+ (calcd for
C24H27O5 395.1858).
1,6,6-Trimethyl-10,11-dioxo-6,7,8,9,10,11-hexahydro-
1
phenanthro[1,2-b]furan-9-yl thiazole-4-carboxylate (25): H NMR
2-Bromo-1,6,6-trimethyl-10,11-dioxo-6,7,8,9,10,11-hexahydro-
(300 MHz, CDCl3) δ 8.75 (s, 1H), 8.22 (s, 1H), 7.73 (s, 2H), 7.22 (s,
1H), 6.74 (t, J = 3.4 Hz, 1H), 2.43−2.31 (m, 1H), 2.20 (s, 3H), 2.18−
1.89 (m, 2H), 1.68−1.51 (m, 1H), 1.42 (s, 3H), 1.29 (s, 3H); 13C
NMR (125 MHz, CDCl3) δ 182.4, 174.7, 161.1, 160.6, 153.2, 151.0,
148.3, 141.7, 137.4, 134.2, 128.6, 127.6, 127.1, 123.2, 121.3, 120.2,
68.6, 34.9, 32.3, 31.5, 31.1, 24.85, 8.8; ESIMS m/z 422 [M + H]+;
HRESIMS m/z 422.1058 [M + H]+ (calcd for C23H20O5NS
422.1062).
1
phenanthro[1,2-b]furan-9-yl propionate (32): H NMR (300 MHz,
CDCl3) δ 7.79−7.61 (m, 2H), 6.43−6.36 (m, 1H), 2.35−2.10 (m,
6H), 2.05−1.81 (m, 2H), 1.63−1.45 (m, 1H), 1.39 (s, 3H), 1.27 (s,
3H), 1.12 (t, J = 7.5 Hz, 3H); 13C NMR (125 MHz, CDCl3) δ 181.9,
174.1, 173.3, 161.2, 151.2, 138.5, 134.3, 127.6, 126.9, 125.2, 122.9,
121.1, 120.7, 67.2, 34.9, 32.3, 31.6, 31.1, 27.6, 24.7, 9.56, 9.3; ESIMS
m/z 467 [M + Na]+; HRESIMS m/z 467.0452 [M + Na]+ (calcd for
C22H21O5BrNa 467.0470).
1,6,6-Trimethyl-10,11-dioxo-6,7,8,9,10,11-hexahydro-
1
phenanthro[1,2-b]furan-9-yl pyrazine-2-carboxylate (26): H NMR
1-(Chloromethyl)-6,6-dimethyl-10,11-dioxo-6,7,8,9,10,11-
1
hexahydrophenanthro[1,2-b]furan-9-yl propionate (33): H NMR
(300 MHz, CDCl3) δ 9.26 (s, 1H), 8.66 (d, J = 12.4 Hz, 2H), 7.75 (s,
2H), 7.23 (s, 1H), 6.80−6.71 (m, 1H), 2.46−2.30 (m, 1H), 2.20 (s,
(300 MHz, CDCl3) δ 7.77 (s, 2H), 7.57 (s, 1H), 6.46 (s, 1H), 4.72 (s,
F
DOI: 10.1021/acs.jnatprod.6b00370
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Journal of Natural Products
Article
2H), 2.19−2.36 (m, 3H), 1.87−2.06 (m, 2H), 1.55−1.65 (d, 1H), 1.43
(s, 3H), 1.30 (s, 3H), 1.16 (t, J = 7.5 Hz, 3H); 13C NMR (126 MHz,
CDCl3) δ 182.52, 174.80, 173.85, 162.31, 151.97, 143.82, 139.06,
134.73, 128.28, 127.64, 123.76, 123.62, 118.80, 67.65, 35.73, 35.38,
32.74, 32.02, 31.61, 28.03, 25.13, 9.73; EIMS m/z 400 [M+] (6), 343
(100), 292 (26), 277 (47), 263 (46); HREIMS m/z 400.1080 (calcd
for C22H21ClO5 400.1078).
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1-(Hydroxymethyl)-6,6-dimethyl-10,11-dioxo-6,7,8,9,10,11-
1
hexahydrophenanthro[1,2-b]furan-9-yl propionate (34): H NMR
(300 MHz, CDCl3) δ 7.76 (s, 2H), 7.42 (s, 1H), 6.44 (t, J = 3.0 Hz,
1H), 4.68 (d, J = 3.0, 2H), 3.49 (brs, 1H), 2.18−2.32 (m, 3H), 2.07−
1.86 (m, 2H), 1.41 (s, 3H), 1.29 (s, 3H), 1.14 (t, J = 7.5 Hz, 3H); 13C
NMR (126 MHz, CDCl3) δ 181.88, 175.18, 173.18, 162.45, 151.45,
140.70, 138.44, 134.18, 127.61, 126.81, 125.80, 123.05, 119.56, 66.97,
55.01, 34.73, 32.04, 31.34, 30.93, 27.37, 24.45, 9.08; EIMS m/z 382
[M+] (4), 308 (100), 292 (52), 263 (49); HREIMS m/z 382.1424
(calcd for C22H22O6 382.1416).
ASSOCIATED CONTENT
* Supporting Information
■
S
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.jnat-
prod.6b00370.
1H and 13C NMR spectra for compounds 4−34 and
chiral HPLC spectra of compound 27 (PDF)
AUTHOR INFORMATION
Corresponding Author
*Tel (A. Zhang): +86 (021) 50806035. Fax: +86 (021)
50806035. E-mail: aozhang@simm.ac.cn.
■
Author Contributions
⊥C. Ding and J. Li contributed equally to this work.
Notes
The authors declare no competing financial interest.
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5358. (b) Uyanik, M.; Okamoto, H.; Yasui, T.; Ishihara, K. Science
2010, 328, 1376−1379. (c) Uyanik, M.; Suzuki, D.; Yasui, T.; Ishihara,
K. Angew. Chem., Int. Ed. 2011, 50, 5331−5334. (d) Tan, B.; Toda, N.;
Barbas, C. F., III Angew. Chem., Int. Ed. 2012, 51, 12538−12541.
ACKNOWLEDGMENTS
■
This work was financially supported by the National Natural
Science Foundation of China (81402790, 81125021, 81373277,
81430080) and the Pujiang Talent Project from the Shanghai
Commission of Science and Technology (14PJ1410700).
́
́ ́
(e) Legare, M. A.; Courtemanche, M. A.; Rochette, E.; Fontaine, F. G.
Science 2015, 349, 513−516.
(11) (a) Feng, J.; Liang, S.; Chen, S.-Y.; Zhang, J.; Fu, S.-S.; Yu, X.-Q.
Adv. Synth. Catal. 2012, 354, 1287−1292. (b) Huang, J.; Li, L.-T.; Li,
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