Proline-Catalyzed Knoevenagel Condensation/[4+2] Cycloaddition Cascade Reaction: Application to Formal Synthesis of Averufin

Article abstract of DOI:10.1002/ejoc.201500559

A remarkable proline-catalyzed method for the construction of biologically interesting oxygen-bridged tricyclic ketal skeletons was uncovered by starting from a variety of readily available cyclic 1,3-diketones and either 1,4- or 1,5-dicarbonyl substrates. The approach, which mimics a biosynthetic Knoevenagel condensation/[4+2] cycloaddition sequence, establishes a viable synthetic strategy for the efficient formal synthesis of averufin. A remarkable proline-catalyzed Knoevenagel condensation/[4+2] cycloaddition cascade reaction was uncovered for the construction of biologically interesting tricyclic ketal skeletons. This approach mimics a biosynthetic sequence and establishes a viable synthetic strategy for the efficient formal synthesis of averufin.

Full text of DOI:10.1002/ejoc.201500559

FULL PAPER
DOI: 10.1002/ejoc.201500559
Proline-Catalyzed Knoevenagel Condensation/[4+2] Cycloaddition Cascade
Reaction: Application to Formal Synthesis of Averufin
Haibo Tan,*[a] Xinzheng Chen,[b] Huiyu Chen,[b] Hongxin Liu,[a] and Shengxiang Qiu*[a]
Keywords: Organocatalysis / Domino reactions / Cycloaddition / Natural products / Polycycles
A remarkable proline-catalyzed method for the construction
of biologically interesting oxygen-bridged tricyclic ketal
skeletons was uncovered by starting from a variety of readily
available cyclic 1,3-diketones and either 1,4- or 1,5-dicarb-
onyl substrates. The approach, which mimics a biosynthetic
Knoevenagel condensation/[4+2] cycloaddition sequence,
establishes a viable synthetic strategy for the efficient formal
synthesis of averufin.
the treatment of cyclic 1,3-diketones with aliphatic alde-
hydes in the presence of BF3–Et2O can lead to cyclic ketals
in good to excellent yields, but the resultant products were
often obtained as inseparable diastereomeric mixtures.[8]
Nonetheless, there is still no adequate or practical method
to rapidly access these cyclic ketals from the perspective of
the atom economy and synthetic aspects.
Introduction
Tricyclic ketal skeletons and their architectural deriva-
tives represent a diverse family of structurally complex and
biologically significant motifs[1] that are widely found in
many interesting bioactive natural products (Scheme 1A).[2]
These natural products most likely result from a biogenetic
pathway involving
a Knoevenagel condensation/[4+2]
In the last decade, remarkable progress has been made
toward the development of atom-economic reactions by
using organocatalysts under operationally simple and envi-
ronmentally friendly reaction conditions. A few classic or-
ganocatalytic reactions for ketal formation have also been
developed.[9,10] On the basis of literature precedent[7,8] and
inspired by the proposed biosynthetic pathway of the natu-
ral compounds shown in Scheme 1 (B),[11] we designed a
Knoevenagel condensation/[4+2] cycloaddition sequence
that uses an organocatalyst, 1,3-diketones, and either 1,4-
or 1,5-dicarbonyl substrates to rapidly construct the oxy-
gen-bridged tricyclic ketal frameworks under mild condi-
tions, which provides direct access to the formal synthesis
of averufin (1).
cycloaddition sequence that starts from 1,3-benzenediols
and 1,4- versus 1,5-dicarbonyl compounds (Scheme 1, B).
Among them, averufin (1),[2e] dactyloidin (2),[2b] and de-
methyldactyloidin (3)[2c] have been isolated from traditional
medicinal plants or fungi with medical potential. In par-
ticular, averufin (1), a pivotal intermediate in the biogenesis
of sterigmatocystin and aflatoxins,[3] has a potent uncou-
pling effect on mitochondrial respiration and an inhibitory
effect towards cAMP phosphodiesterase (cAMP = cyclic
adenosine monophosphate).[4] The significant biomedical
activity of these natural products has inspired many syn-
thetic efforts to explore elegant strategies and construct
these complex motifs directly.[5–8] Arseniyadis has devel-
oped a creative method that leads to the formation of this
tricyclic ketal skeleton by taking advantage of a sequential
oxidative cleavage/intramolecular [4+2] cycloaddition reac-
tion. However, a major disadvantage of this strategy is the
requirement of strong oxidants and complex diol sub-
strates.[7] Yoshida and co-workers have also observed that
Results and Discussion
To test our hypothesis, we began by treating the model
substrates cyclohexane-1,3-dione (9a) and 4-oxopentanal
(10a, R2 = Me), readily prepared by a Swern oxidation of
5-hydroxypentan-2-one,[12] with l-proline (10 mol-%) in
dichloromethane (DCM) at room temperature under air.[13]
Satisfactorily, the reaction was complete in 3 h and led to
formation of the desired 11b as the major product in 78%
yield (20% ee value) along with a small amount of a by-
product from a Knoevenagel condensation/Michael ad-
dition reaction.[14] In an attempt to improve the selectivity
of this reaction under similar conditions, the solvents, sub-
strate loadings, and potential catalysts including proline de-
rivatives[15] and the MacMillan catalyst[16] were screened.[17]
[a] Program for Natural Product Chemical Biology,
Key Laboratory of Plant Resources Conservation and
Sustainable Utilization, South China Botanical Garden,
Chinese Academy of Sciences,
Guangzhou 510650, P. R. China
E-mail: tanhaibo@scbg.ac.cn
sxqiu@scbg.ac.cn
http://sourcedb.scib.cas.cn/zw/rck/200908/t20090812_
2381894.html
[b] School of Chemical Biology and Biotechnology, Shenzhen
Graduate School of Peking University,
Shenzhen 518055, P. R. China
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.201500559.
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Proline-Catalyzed Formal Synthesis of Averufin
Scheme 1. (A) Biologically active natural products that feature a tricyclic ketal ring system. (B) Biosynthetic hypothesis of tricyclic ketal
formation.
When we gradually increased the loading of 4-oxopentanal common cyclic 1,3-dicarbonyl derivatives 9a–9c. The no-
(10a, R2 = Me) to 2.0 equiv. and used 1,2-dichloroethane table loss in the reactivity and selectivity of 9d–9f is presum-
(DCE) as the solvent and proline (10 mol-%) as the catalyst, ably because of their greater nucleophilicity, which tends to
the yield markedly increased to greater than 90%. Reducing give a higher ratio of the Knoevenagel condensation/
the loading of proline to 5 mol-% did not lead to a notable Michael addition byproducts.
decrease in the yield. Nevertheless, we employed 10 mol-%
When cycloheptane-1,3-dione (9g) was examined, the re-
of proline in the following reactions to achieve a practical action proceeded cleanly in 36 h and afforded the product
reaction time and product yield. (The details for the screen- in 86% yield. In addition to the expected product 11j, a
ing of the reaction conditions are provided in the Support- new inseparable equilibrium species 12 was also obtained
ing Information).
(11j/12, 1:1). The structure of 12 was spectroscopically as-
With the optimal conditions established, we surveyed the signed to be the Knoevenagel condensation intermediate
scope of this reaction by employing various 1,4-dicarbonyl (Scheme 2). The equilibrium between 11j and 12 may be
substrates 10 and cyclic 1,3-dicarbonyl derivatives
9
attributed to the high energy of the unstable 7/6/5-fused
(Table 1). When cyclohexane-1,3-dione (9a) was treated ring system, which is in agreement with Bischofberger’s ob-
with different 1,4-dicarbonyl substrates 10, all of the reac- servation.[18] The result suggests that the [4+2] cycload-
tions proceeded smoothly to deliver the desired tricyclic dition reaction might be reversible. Indeed, when the non-
ketal derivatives 11a–11d in excellent yields (Table 1, En- cyclic pentane-2,4-dione (9h) was used as the substrate, the
tries 1–4). Notably, we observed that the steric hindrance of [4+2] cycloaddition did not proceed, but instead the corre-
substituents on 1,4-dicarbonyl substrates 10 had little influ- sponding linear Knoevenagel condensation product 13 was
ence on the yield of this cascade reaction. The reactivity isolated in 84% yield. When we heated product 13 in tolu-
of cyclic 1,3-diketones 9 were also evaluated by using 4- ene at 90 °C under nitrogen for 3 h, still no cycloaddition
oxopentanal (10a, R2 = Me) as the standard substrate. To product 11k was observed. However, it merits attention that
our delight, disubstituted cyclohexane-1,3-dione 9b also when 13 was heated under air, it provided α-hydroxy-1,3-
proceeded smoothly in the reaction to afford tricycle 11e diketone 15 in 73% yield based on recovered starting mate-
in 87% yield (Table 1, Entry 5). Monosubstituted dione 9c rial (brsm) through aerobic oxidation. This discovery can
underwent the reaction more efficiently than counterpart be used as a green method to synthesize biologically signifi-
9b and afforded the desired tricycle 11f in 90% yield as a cant 3-hydroxy-2,4-dione derivatives.[19]
mixture of diastereomers (1:2 ratio, Table 1, Entry 6). How-
To further extend the scope of this reaction, various 1,5-
ever, 4-hydroxy-6-methyl-2H-pyran-2-one (9d), 4-hydroxy- dicarbonyl substrates 16 were examined (Table 2). The cor-
2H-chromen-2-one (9e), and 4-hydroxy-1-methylquinolin- responding tricyclic ketal products 17a–17i were consist-
2(1H)-one (9f) were converted into the expected tricyclic ently isolated in good to excellent yields. However, the
ketal products 11g–11i in lower yields (57–83%) than the yields in most cases were slightly lower than those of 1,4-
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H. Tan, X. Chen, H. Chen, H. Liu, S. Qiu
FULL PAPER
Table 1. Surveying the reaction scope of 1,4-dicarbonyl substrates.[a]
[a] Reagents and conditions: 1,3-diketone (0.5 mmol), 1,4-dicarbonyl substrate (1.0 mmol), proline (0.05 mmol), DCE (10 mL), room
temp., 0.5–2 h. [b] Yield of isolated product. [c] The product isolated as a mixture of diastereomers (ratio: 1:2).
Scheme 2. Reactivity of strain and noncyclic 1,3-diketones.
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Proline-Catalyzed Formal Synthesis of Averufin
Table 2. Surveying the reaction scope of 1,5-dicarbonyl substrates.[a]
[a] Reagents and conditions: 1,3-diketone (0.5 mmol), 1,5-dicarbonyl substrate (1.0 mmol), proline (0.05 mmol), DCE (10 mL), room
temp., 0.5–2 h. [b] Yield of isolated product. [c] The product was isolated as a mixture of diastereomers (1:2).
dicarbonyl substrates 10 (with the exception of Table 2, En- Me), the corresponding inseparable Knoevenagel condensa-
try 7). Moreover, substituents on 1,5-dicarbonyl substrates tion intermediate was not observed in the reaction of 9g
16 and cyclic 1,3-dicarbonyl substrates 9 had little influence and 5-oxohexanal. Instead, the desired [4+2] cycloaddition
on the efficiency of the catalysis. An obvious decrease in product 17i was obtained in 77% yield as the only product
the yield was observed when the steric bulk of substituent (Table 2, Entry 9).
increased (Table 2, Entries 2–6). It was notable that in con-
After establishing the synthetic methodology, we moved
trast to the reaction of 9g and 4-oxopentanal (10a, R2 = directly to the formal synthesis of averufin (1, Scheme 3).
Scheme 3. The formal total synthesis of averufin (1). Reagents and conditions: (a) PhSeBr (1.5 equiv.), lithium diisopropylamide (LDA,
1.2 equiv.), tetrahydrofuran (THF), –78 °C, 20 min; (b) 2-(phenylsulfonyl)-3-phenyloxaziridine (Davis’ reagent, 1.2 equiv.), 3,5-dimeth-
oxyaniline (2.0 equiv.), CHCl3, room temp., 30 min; (c) NaH (1.5 equiv.), MOMCl (1.5 equiv.), tetra-n-butylammonium bromide (TBAB,
1.0 equiv.), THF, room temp., 5 h.
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H. Tan, X. Chen, H. Chen, H. Liu, S. Qiu
FULL PAPER
General Procedure for Knoevenagel/[4+2] Cascade Reaction: A
flame-dried 50 mL flask was charged with the aldehyde (1.0 mmol)
and DCE (10 mL). The 1,3-diketone (0.5 mmol) was added fol-
lowed by proline (6 mg, 0.05 mmol). The resulting solution was
then stirred at room temperature for 0.5–2 h until the starting mate-
rial was consumed. After 10 min, the mixture was concentrated in
vacuo, and the crude product was purified by short-column flash
chromatography (silica gel; hexane/EtOAc, 3:l) to afford the corre-
sponding product 11–13 and 17.
As expected, the desired starting material 17b was readily
obtained in 83% yield by the proline-mediated Knoevenagel
condensation/[4+2] cycloaddition sequence when the reac-
tion was scaled up from 100 mg to 3.0 g. Treating 17b under
standard conditions with phenylselenyl bromide gave α-
benzeneselenenylation product 18 (92% yield, 5.0 g scale),
which was then treated with the Davis reagent in the pres-
ence of 3,5-dimethoxyaniline to afford phenol 19 (87%
yield, 2.0 g scale).[20] The simple protection of the hydroxy
group of phenol 19 by using chloromethyl methyl ether
(MOMCl) under basic conditions transforms it into key
precursor 20 (94% yield, 1.5 g scale). The analytical data of
20 were identical to those previously reported,[5c] and 20
3,4,5,6,9,10-Hexahydro-2H-2,6-epoxybenzo[b]oxocin-7(8H)-one
(11a): Following the general procedure afforded 11a (93% yield) as
a colorless oil. 1H NMR (400 MHz, CDCl3): δ = 5.83 (dd, J = 3.0,
J = 1.0 Hz, 1 H), 5.14 (t, J = 2.0 Hz, 1 H), 2.28 (m, 4 H), 2.18 (m,
2 H), 2.06 (m, 2 H), 1.97 (m, 2 H) ppm. 13C NMR (100 MHz,
could be further converted into the natural product averufin CDCl3): δ = 194.9, 168.6, 117.5, 101.6, 72.4, 36.1, 34.6, 34.1, 27.2,
20.7 ppm. HRMS (ESI): calcd. for C10H13O3 [M + H]+ 181.0865;
found 181.0858.
+
(1) in three steps.[5c]
2-Methyl-2,3,4,5,8,9-hexahydro-2,5-epoxybenzo[b]oxepin-6(7H)-one
(11b): Following the general procedure afforded 11b (91% yield) as
a colorless oil. 1H NMR (500 MHz, CDCl3): δ = 5.12 (d, J =
6.0 Hz, 1 H), 2.27–2.32 (m, 5 H), 2.11–2.19 (m, 1 H), 1.96–2.05 (m,
4 H), 1.66 (s, 3 H) ppm. 13C NMR (125 MHz, CDCl3): δ = 195.0,
169.8, 116.6, 109.6, 73.7, 38.4, 36.2, 35.7, 27.3, 22.9, 20.8 ppm.
Conclusions
In summary, we have developed a remarkable proline-
catalyzed approach, which mimics a biosynthetic Knoeven-
agel condensation/[4+2] cycloaddition reaction sequence,
for the construction of biologically significant oxygen-
bridged tricyclic ketal skeletons. The rapid construction of
this architecture has potential uses in medicinal chemistry
as well as natural product and diversity-oriented synthesis.
By applying this methodology, we have successfully estab-
lished a viable synthetic strategy to complete the formal
synthesis of averufin (1). The preparation of a variety of
other oxygen-bridged tricyclic ketal skeleton containing
natural products and analogous derivatives are now un-
derway and will be reported in due course.
+
HRMS (ESI): calcd. for C11H15O3 [M + H]+ 195.1021; found
195.1018.
2-Ethyl-2,3,4,5,8,9-hexahydro-2,5-epoxybenzo[b]oxepin-6(7H)-one
(11c): Following the general procedure afforded 11c (89% yield) as
a colorless oil. 1H NMR (500 MHz, CDCl3): δ = 5.15 (d, J =
5.5 Hz, 1 H), 2.30–2.35 (m, 4 H), 1.97–2.24 (m, 8 H), 1.07 (t, J =
7.5 Hz, 3 H) ppm. 13C NMR (125 MHz, CDCl3): δ = 195.0, 170.0,
117.0, 111.8, 73.6, 36.4, 36.3, 35.4, 29.4, 27.4, 20.9, 7.7 ppm.
+
HRMS (ESI): calcd. for C12H17O3 [M + H]+ 209.1178; found
209.1172.
2-Isopropyl-2,3,4,5,8,9-hexahydro-2,5-epoxybenzo[b]oxepin-6(7H)-
one (11d): Following the general procedure afforded 11d (90%
1
yield) as a colorless oil. H NMR (400 MHz, CDCl3): δ = 5.14 (s,
1 H), 2.32 (m, 4 H), 1.85–2.25 (m, 7 H), 1.06 (t, J = 5.8 Hz, 6
H) ppm. 13C NMR (100 MHz, CDCl3): δ = 195.1, 170.2, 116.9,
113.7, 73.6, 36.2, 35.3, 34.6, 34.0, 27.4, 20.8, 16.8, 16.5 ppm.
Experimental Section
General Methods: All reactions were carried out in dry solvents
under nitrogen and anhydrous conditions, unless otherwise noted.
Reagents of high commercial quality were purchased and used
without further purification. Thin layer chromatography was con-
ducted with Tsingdao silica gel plates (60 F-254, 0.25 mm) and vis-
ualized either by exposure to UV light (254 nm) or staining with
potassium permanganate. Silica gel (ZCX-II, 200–300 mesh) for
flash column chromatography was purchased from Qing Dao Hai
Yang Chemical Industry Co. of China. The 1H and 13C NMR spec-
troscopic data were recorded with a Bruker Advance 300 (for 1H
NMR, 300 MHz; for 13C NMR, 75 MHz), a Bruker Advance 400
(for 1H NMR, 400 MHz; for 13C NMR, 100 MHz), or a Bruker
Advance 500 (for 1H NMR, 500 MHz; for 13C NMR, 125 MHz)
spectrometer. Chemical shifts are reported in parts per million rela-
tive to the residual protio solvent or CDCl3 (for 1H NMR, δ =
7.27 ppm; for 13C NMR, δ = 77.00 ppm). Mass spectrometric data
were obtained by using an ABI-Q Star Elite high resolution mass
spectrometer. Anhydrous THF was distilled from sodium-benzo-
phenone until a deep blue color persisted. CH2ClCH2Cl (DCE)
was distilled from calcium hydride, yields refer to chromatographi-
cally purified products, unless otherwise stated. The following ab-
breviations were used for the multiplicities of spectral signals: s
(singlet), d (doublet), t (triplet), q (quartet), m (multiplet), and br.
(broad).
HRMS (ESI): calcd. for C13H19O3 [M + H]+ 223.1334; found
+
223.1333.
2,8,8-Trimethyl-2,3,4,5,8,9-hexahydro-2,5-epoxybenzo[b]oxepin-
6(7H)-one (11e): Following the general procedure afforded 11e
(87% yield) as a colorless oil. 1H NMR (400 MHz, CDCl3): δ =
5.13 (d, J = 5.6 Hz, 1 H), 2.26 (m, 1 H), 2.18 (m, 5 H), 2.04 (m, 2
H), 1.67 (m, 3 H), 1.06 (s, 6 H) ppm. 13C NMR (100 MHz, CDCl3):
δ = 194.8, 168.3, 115.4, 109.6, 73.7, 50.2, 41.1, 38.5, 35.8, 32.5,
28.6, 28.2, 22.9 ppm. HRMS (ESI): calcd. for C13H19O3+ [M + H]+
223.1334; found 223.1325.
2-Methyl-8-phenyl-2,3,4,5,8,9-hexahydro-2,5-epoxybenzo[b]oxepin-
6(7H)-one (11f): Following the general procedure afforded 11f
(90% yield) as a colorless oil. 1H NMR (400 MHz, CDCl3): δ =
7.35 (m, 2 H), 7.26 (m, 3 H), 5.20 (t, J = 7.0 Hz, 1 H), 3.36 (m, 1
H), 2.00–2.80 (m, 8 H), 1.71 (s, 3 H) ppm. 13C NMR (100 MHz,
CDCl3): δ = 194.0, 169.2, 168.9, 142.7, 142.6, 128.8, 128.8, 127.0,
126.6, 126.6, 116.7, 116.3, 110.0, 109.9, 74.0, 73.6, 43.5, 43.3, 39.4,
38.7, 38.3, 35.8, 35.6, 34.9, 23.0, 22.8 ppm. HRMS (ESI): calcd. for
C17H19O3 [M + H]+ 271.1334; found 271.1331.
+
2,8-Dimethyl-4,5-dihydro-2H-2,5-epoxypyrano[4,3-b]oxepin-6(3H)-
one (11g): Following the general procedure afforded 11g (68%
1
yield) as a colorless oil. H NMR (500 MHz, CDCl3): δ = 5.71 (s,
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Proline-Catalyzed Formal Synthesis of Averufin
1 H), 5.17 (s, J = 4.4 Hz, 1 H), 2.37 (m, 1 H), 2.00–2.35 (m, 6 H), 6 H), 0.94 (t, J = 7.4 Hz, 3 H) ppm. 13C NMR (100 MHz, CDCl3):
1.71 (s, 3 H) ppm. 13C NMR (125 MHz, CDCl3): δ = 163.5, 162.6, δ = 195.1, 172.2, 112.0, 103.3, 66.6, 36.5, 34.1, 33.3, 27.8, 27.4,
161.8, 110.3, 102.3, 99.5, 74.3, 38.5, 35.8, 22.9, 20.0 ppm. HRMS 21.0, 15.7, 6.7 ppm. HRMS (ESI): calcd. for C13H19O3 [M + H]+
+
+
(ESI): calcd. for C11H13O4 [M + H]+ 209.0814; found 209.0809.
223.1334; found 223.1334.
2-Methyl-4,5-dihydro-2H-2,5-epoxyoxepino[3,2-c]chromen-6(3H)-
one (11h): Following the general procedure afforded 11h (83 %
yield) as a colorless oil. 1H NMR (400 MHz, CDCl3): δ = 7.71 (dd,
2-Isopropyl-3,4,5,6,9,10-hexahydro-2H-2,6-epoxybenzo[b]oxocin-7-
(8H)-one (17d): Following the general procedure afforded 17d (82%
yield) as a colorless oil. H NMR (400 MHz, CDCl3): δ = 4.89 (d,
1
J = 8.0 Hz, J = 1.6 Hz, 1 H), 7.54 (dt, J = 8.0 Hz, J = 1.6 Hz, 1 J = 4.0 Hz, 1 H), 2.30–2.60 (m, 4 H), 2.06 (m, 2 H), 1.87 (m, 3 H),
H), 7.28 (m, 2 H), 5.33 (m, J = 1.6 Hz, 1 H), 2.49 (m, 1 H), 2.31 1.59 (m, 4 H), 0.95 (q, J = 4.0 Hz, 6 H) ppm. 13C NMR (100 MHz,
(m, 2 H), 2.18 (m, 1 H), 1.86 (m, 3 H) ppm. 13C NMR (100 MHz, CDCl3): δ = 195.1, 172.3, 112.2, 104.9, 66.5, 37.1, 36.4, 31.2, 27.7,
CDCl3): δ = 160.3, 158.8, 153.3, 132.1, 123.9, 122.4, 116.9, 114.9,
27.4, 21.0, 16.3, 15.9, 15.6 ppm. HRMS (ESI): calcd. for
+
111.0, 105.1, 74.6, 38.7, 36.0, 23.0 ppm. HRMS (ESI): calcd. for
C14H21O3 [M + H]+ 237.1491; found 237.1484.
+
C14H13O4 [M + H]+ 245.0814; found 245.0801.
2,9,9-Trimethyl-3,4,5,6,9,10-hexahydro-2H-2,6-epoxybenzo[b]ox-
ocin-7(8H)-one (17e): Following the general procedure afforded 17e
(78% yield) as a colorless oil. 1H NMR (500 MHz, CDCl3): δ =
4.91 (d, J = 4.0 Hz, 1 H), 2.26–2.35 (m, 2 H), 2.14 (q, J = 16.0 Hz,
2,7-Dimethyl-2,3,4,5-tetrahydro-2,5-epoxyoxepino[3,2-c]quinolin-
6(7H)-one (11i): Following the general procedure afforded 11i (57%
yield) as a colorless oil. 1H NMR (400 MHz, CDCl3): δ = 7.84 (dd,
J = 8.0 Hz, J = 1.6 Hz, 1 H), 7.56 (dt, J = 7.2 Hz, J = 1.6 Hz, 1 2 H), 1.87–1.93 (m, 2 H), 1.62–1.72 (m, 4 H), 1.46 (s, 3 H), 1.10 (s,
H), 7.32 (dt, J = 7.6 Hz, 1 H), 7.21 (dt, J = 8.0 Hz, J = 0.8 Hz, 1
H), 5.44 (d, J = 4.2 Hz, 1 H), 3.67 (s, 1 H), 2.05–2.50 (m, 4 H),
3 H), 1.08 (s, 3 H) ppm. 13C NMR (125 MHz, CDCl3): δ = 194.7,
170.0, 110.6, 102.0, 66.8, 50.4, 41.7, 36.0, 32.2, 28.9, 28.1, 27.5,
1.84 (m, 3 H) ppm. 13C NMR (100 MHz, CDCl3): δ = 160.5, 154.5, 27.1, 16.0 ppm. HRMS (ESI): calcd. for C12H25O2Si+ [M + H]+
+
139.3, 130.8, 122.6, 121.6, 115.3, 114.0, 110.6, 109.5, 74.9, 38.5,
229.1618; found 229.1617. HRMS (ESI): calcd. for C14H21O3 [M
+
36.2, 28.9, 23.4 ppm. HRMS (ESI): calcd. for C15H16NO3 [M +
+ H]+ 237.1491; found 237.1493.
H]+ 258.1130; found 258.1128.
2-Methyl-9-phenyl-3,4,5,6,9,10-hexahydro-2H-2,6-epoxybenzo[b]ox-
ocin-7(8H)-one (17f): Following the general procedure afforded 17f
(81% yield) as a colorless oil. 1H NMR (400 MHz, CDCl3): δ =
7.35 (m, 2 H), 7.26 (m, 3 H), 4.98 (s, 1 H), 3.25–3.55 (m, 1 H),
2.60–2.95 (m, 4 H), 1.94 (m, 2 H), 1.55–1.85 (m, 4 H), 1.50 (s, 3
H) ppm. 13C NMR (100 MHz, CDCl3): δ = 194.1, 194.0, 171.2,
170.8, 142.7, 142.7, 128.8, 128.7, 127.0, 126.9, 126.6, 111.8, 111.3,
2-Methyl-4,5,7,8,9,10-hexahydro-2H-2,5-epoxycyclohepta[b]oxepin-
6(3H)-one (11j) and 2-(4-Oxopentylidene)cycloheptane-1,3-dione
(12): Following the general procedure afforded 11j and 12 was
1
(86% total yield) as colorless oils. H NMR (400 MHz, CDCl3): δ
= 6.88 (t, J = 8.0 Hz, 1 H), 5.16 (t, J = 6.0 Hz, 1 H), 2.65 (m, 4
H), 2.56 (m, 6 H), 2.53 (m, 2 H), 2.28 (m, 1 H), 2.16 (s, 3 H), 2.15
(m, 1 H), 1.70–2.10 (m, 10 H), 1.66 (s, 3 H) ppm. 13C NMR 110.0, 102.4, 102.2, 67.0, 66.8, 43.8, 43.3, 39.2, 39.1, 36.0, 35.9,
(100 MHz, CDCl3): δ = 194.0, 169.2, 168.9, 142.7, 142.6, 128.8, 35.5, 35.2, 27.6, 27.4, 27.2, 26.8, 15.9, 15.7 ppm. HRMS (ESI):
+
128.8, 127.0, 126.6, 126.6, 116.7, 116.3, 110.0, 109.9, 74.0, 73.6,
43.5, 43.3, 39.4, 38.7, 38.3, 35.8, 35.6, 34.9, 23.0, 22.8 ppm. HRMS
calcd. for C18H21O3 [M + H]+ 285.1491; found 285.1481.
2,9-Dimethyl-3,4,5,6-tetrahydro-2,6-epoxypyrano[4,3-b]oxocin-
7(2H)-one (17g): Following the general procedure afforded 17g
(78% yield) as a colorless oil. 1H NMR (400 MHz, CDCl3): δ =
5.79 (s, 1 H), 4.99 (d, J = 2.8 Hz, 1 H), 2.10 (s, 1 H), 1.96 (m, 1
(ESI): calcd. for C12H17O3 [M + H]+ 209.1178; found 209.1173.
+
3-Acetyloct-3-ene-2,7-dione (13): Following the general procedure
afforded 13 (84% yield) as a colorless oil. 1H NMR (500 MHz,
CDCl3): δ = 6.67 (t, J = 8.0 Hz, 1 H), 2.66 (t, J = 7.0 Hz, 2 H), H), 1.50–1.80 (m, 4 H), 1.51 (m, 3 H) ppm. 13C NMR (100 MHz,
2.44 (q, J = 6.0 Hz, 2 H), 2.32 (s, 3 H), 2.28 (s, 3 H), 2.15 (s, 3
H) ppm. 13C NMR (125 MHz, CDCl3): δ = 206.5, 203.2, 197.0,
145.7, 145.1, 42.0, 31.4, 29.7, 26.0, 23.6 ppm. HRMS (ESI): calcd.
CDCl3): δ = 165.1, 161.8, 161.7, 102.5, 99.4, 98.1, 67.1, 35.7, 27.4,
+
26.6, 20.0, 15.6 ppm. HRMS (ESI): calcd. for C12H15O4 [M +
H]+ 223.0970; found 223.0969.
+
for C10H15O3 [M + H]+ 183.1021; found 183.1013.
2-Methyl-3,4,5,6-tetrahydro-2,6-epoxyoxocino[3,2-c]chromen-7(2H)-
3,4,5,6,9,10-Hexahydro-2H-2,6-epoxybenzo[b]oxocin-7(8H)-one one (17h): Following the general procedure afforded 17h (80%
(17a): Following the general procedure afforded 17a (67% yield) as
a colorless oil. 1H NMR (300 MHz, CDCl3): δ = 5.57 (m, 1 H),
4.86 (m, J = 3.6 Hz, 1 H), 2.52 (m, 2 H), 2.40 (m, 2 H), 1.80–2.10
yield) as a colorless oil. 1H NMR (400 MHz, CDCl3): δ = 7.78 (dd,
J = 8.0 Hz, J = 1.6 Hz, 1 H), 7.54 (dt, J = 8.0 Hz, J = 1.6 Hz, 1
H), 7.28 (m, 2 H), 5.13 (dd, J = 4.0 Hz, J = 1.6 Hz, 1 H), 2.07 (m,
(m, 4 H), 1.50–1.75 (m, 4 H) ppm. 13C NMR (75 MHz, CDCl3): δ 2 H), 1.86 (m, 2 H), 1.75 (m, 5 H) ppm. 13C NMR (100 MHz,
= 195.1, 171.5, 112.6, 96.7, 65.3, 36.4, 31.3, 27.7, 27.6, 20.9,
CDCl3): δ = 160.4, 160.2, 153.0, 131.9, 123.8, 122.4, 116.8, 114.7,
14.4 ppm. HRMS (ESI): calcd. for C11H15O3 [M + H]+ 195.1021; 103.2, 100.8, 67.5, 35.8, 27.4, 26.6, 15.6 ppm. HRMS (ESI): calcd.
+
+
found 195.1017.
for C15H15O4 [M + H]+ 259.0970; found 259.0964.
2-Methyl-3,4,5,6,9,10-hexahydro-2H-2,6-epoxybenzo[b]oxocin-
7(8H)-one (17b): Following the general procedure afforded 17b
2-Methyl-3,4,5,6,8,9,10,11-octahydro-2,6-epoxycyclohepta[b]oxocin-
7(2H)-one (17i): Following the general procedure afforded 17i (77%
1
(87% yield) as a colorless oil. 1H NMR (500 MHz, CDCl3): δ = yield) as a colorless oil. H NMR (500 MHz, CDCl3): δ = 4.93 (d,
4.93 (d, J = 4.0 Hz, 1 H), 2.38–2.48 (m, 2 H), 2.37 (t, J = 6.2 Hz,
J = 4.0 Hz, 1 H), 2.56–2.62 (m, 4 H), 1.78–1.92 (m, 6 H), 1.65–
2 H), 1.86–2.06 (m, 4 H), 1.55–1.80 (m, 4 H), 1.48 (s, 3 H) ppm. 1.67 (m, 4 H), 1.46 (s, 3 H) ppm. 13C NMR (125 MHz, CDCl3): δ
13C NMR (125 MHz, CDCl3): δ = 195.0, 171.8, 111.9, 102.0, 66.9, = 198.4, 171.2, 113.9, 101.2, 68.3, 41.6, 36.3, 32.4, 27.6, 27.3, 23.5,
21.0, 16.0 ppm. HRMS (ESI): calcd. for C13H19O3 [M + H]+
223.1334; found 223.1327.
+
36.5, 36.1, 27.9, 27.6, 27.1, 21.1, 15.9 ppm. HRMS (ESI): calcd. for
+
C12H17O3 [M + H]+ 209.1178; found 209.1173.
2-Ethyl-3,4,5,6,9,10-hexahydro-2H-2,6-epoxybenzo[b]oxocin-7(8H)- (E)-6-Acetyl-6-hydroxyoct-4-ene-2,7-dione (15): Unsaturated 1,3-di-
one (17c): Following the general procedure afforded 17c (85% yield)
ketone 13 (36 mg, 0.20 mmol) was dissolved in toluene (5 mL), and
the resulting solution was heated to 90 °C under air. After stirring
as a colorless oil. 1H NMR (400 MHz, CDCl3): δ = 4.92 (d, J =
4.0 Hz, 1 H), 2.30–2.60 (m, 4 H), 1.80–2.20 (m, 4 H), 1.50–1.80 (m, at this temperature for 3 h, the mixture was cooled to room tem-
Eur. J. Org. Chem. 2015, 4956–4963
© 2015 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
4961

H. Tan, X. Chen, H. Chen, H. Liu, S. Qiu
FULL PAPER
perature and purified directly by flash chromatography (silica gel;
hexane/EtOAc, 5:l) to afford the corresponding starting material
13 (9.8 mg, 0.05 mmol) and product 15 (18 mg, 47% yield, 73%
104.3, 98.9, 94.1, 67.2, 56.0, 36.2, 28.3, 28.2, 16.1 ppm. HRMS
(ESI): calcd. for C12H15O3 [M + H]+ 206.0623; found 206.0622.
+
7-(Methoxymethoxy)-2-methyl-3,4,5,6-tetrahydro-2H-2,6-epoxy-
benzo[b]oxocine (20): NaH (60% in mineral oil, 42 mg, 1.05 mmol)
was slowly and carefully added to a solution of phenol 19 (141 mg,
0.7 mmol) in THF (10 mL) at 0 °C. The resulting mixture was
stirred at this temperature for 10 min under nitrogen, and then
MOMCl (85 mg, 1.05 mmol) was added followed by TBAB
(225 mg, 0.7 mmol). The ice bath was removed, and the mixture
was stirred at room temperature for an additional 5 h. The crude
mixture was diluted with EtOAc (20 mL), and the reaction was
then quenched with saturated aqueous NH4Cl (10 mL). The re-
sulting mixture was extracted with EtOAc (4ϫ 15 mL), and the
combined organic phases were washed with brine and concentrated
in vacuo. The crude product was purified by flash chromatography
(silica gel; hexane/EtOAc, 4:l) to afford 20 (165 mg, 94% yield) as
a colorless oil. 1H NMR (500 MHz, CDCl3): δ = 7.08 (m, 1 H),
6.59 (d, J = 8.5 Hz, 1 H), 6.49 (d, J = 8.5 Hz, 1 H), 5.29 (d, J =
3.5 Hz, 1 H), 5.18 (m, 2 H), 3.46 (d, J = 1.0 Hz, 3 H), 2.05–1.99
(m, 2 H), 1.75–1.82 (m, 2 H), 1.62–1.65 (m, 2 H), (s, 3 H) ppm.
13C NMR (125 MHz, CDCl3): δ = 154.5, 152.5, 128.1, 111.8, 108.7,
104.3, 98.9, 94.1, 67.2, 56.0, 36.18, 28.3, 28.2, 16.1 ppm. HRMS
1
brsm) as a colorless oil. H NMR (500 MHz, CDCl3): δ = 6.11 (d,
J = 15.6 Hz, 1 H), 5.65 (dt, J = 15.6 Hz, J = 7.2 Hz, 1 H), 3.31
(dd, J = 7.2 Hz, J = 1.0 Hz, 2 H), 2.21 (s, 3 H), 2.16 (s, 6 H) ppm.
13C NMR (125 MHz, CDCl3): δ = 206.3, 191.0, 127.9, 127.8, 110.9,
47.6, 29.7, 24.1 ppm. HRMS (ESI): calcd. for C10H15O3+ [M + H]+
202.1160; found 202.1173.
Formal Synthesis of Averufin
2-Methyl-3,4,5,6,9,10-hexahydro-2H-2,6-epoxybenzo[b]oxocin-
7(8H)-one (17b): A flame-dried 250 mL flask was charged with al-
dehyde 16a (1.14 g, 10.0 mmol), DCE (100 mL), and cyclohexane-
1,3-dione (9a, 506 mg, 5.0 mmol). Proline (115 mg, 1.0 mmol) was
then added. The resulting mixture was stirred at room temperature
for 15 min, and then a second portion of cyclohexane-1,3-dione
(9a, 258 mg, 2.5 mmol) was added. After 15 min, a third portion
of cyclohexane-1.3-dione (9a, 258 mg, 2.5 mmol) was added. The
solution was stirred at room temperature for 20 min until the start-
ing material was consumed. After 10 min, the resulting mixture was
concentrated in vacuo, and the crude product was purified by flash
chromatography (silica gel; hexane/EtOAc, 3:l) to afford product
17b (1.73 g, 83 % yield) as a colorless oil. 1H NMR (500 MHz,
CDCl3): δ = 4.93 (d, J = 4.0 Hz, 1 H), 2.38–2.48 (m, 2 H), 2.37 (t,
J = 6.2 Hz, 2 H), 1.86–2.06 (m, 4 H), 1.55–1.80 (m, 4 H), 1.48 (s,
3 H) ppm. 13C NMR (125 MHz, CDCl3): δ = 195.0, 171.8, 111.9,
102.0, 66.9, 36.5, 36.1, 27.9, 27.6, 27.1, 21.1, 15.9 ppm. HRMS
+
(ESI): calcd. for C14H19O4 [M + H]+ 251.1283; found 251.1273.
Acknowledgments
The authors thank the National Science and Technology Major
Projects of China (grant number 2014ZX10005002-005) and the
Foundation of Key Laboratory of Plant Resources Conservation
and Sustainable Utilization (South China Botanical Garden, Chi-
nese Academy of Sciences) for the financial support. Prof. David
Zhigang Wang (Peking University) is thanked for the helpful dis-
cussions.
+
(ESI): calcd. for C12H17O3 [M + H]+ 209.1178; found 209.1173.
2-Methyl-8-(phenylselenyl)-3,4,5,6,9,10-hexahydro-2H-2,6-epoxy-
benzo[b]oxocin-7(8H)-one (18): To a solution of LDA, which was
freshly prepared from nBuLi (2.5 m solution in hexane, 0.6 mL,
1.5 mmol) and diisopropylamine (152 mg, 1.5 mmol) in dry THF
(10 mL), was slowly added ketone 17b (208 mg, 1.0 mmol) at
–78 °C under nitrogen. After 20 min, a solution of benzenese-
lenenyl bromide (354 mg, 1.5 mmol) in THF (1 mL) was added
dropwise, and the resulting mixture was stirred at –78 °C for an-
other 20 min. The mixture was then warmed room temperature,
and the reaction was quenched with water (10 mL). The resulting
mixture was extracted with EtOAc (4ϫ 10 mL), and the combined
organic phases were dried with Na2SO4 and concentrated in vacuo.
The residue was purified by flash chromatography (silica gel; hex-
ane/EtOAc, 5:l) to afford 18 (334 mg, 92% yield, approximately 5:1
[1] a) L. E. Brown, K. C.-C. Cheng, W. G. Wei, P. W. Yuan, P. Dai,
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1
mixture) as a colorless oil. H NMR (400 MHz, CDCl3): δ = 7.61
(m, 2 H), 7.27 (m, 3 H), 4.95 (m, J = 4.0 Hz, 1 H), 4.03 (m, 1 H),
2.60–2.95 (m, 1 H), 2.10–2.50 (m, 4 H), 1.55–2.0 (m, 6 H), 1.47 (s,
3 H) ppm. 13C NMR (100 MHz, CDCl3): δ = 191.3, 191.2, 170.4,
135.5, 135.3, 129.1, 129.0, 128.2, 127.9, 110.6, 102.3, 102.0, 66.9,
66.8, 46.5, 46.3, 35.9, 27.5, 27.4, 27.0, 27.0, 26.6, 26.0, 25.4, 15.7,
15.7 ppm. HRMS (ESI): calcd. for C18H21O3Se+ [M + H]+
365.0656; found 365.0654.
2-Methyl-3,4,5,6-tetrahydro-2H-2,6-epoxybenzo[b]oxocin-7-ol (19):
To a solution of ketone 18 (181 mg, 0.5 mmol) in CHCl3 (3 mL)
were added 3,5-dimethoxyaniline (153 mg, 1.0 mmol) and the Davis
reagent (165 mg, 0.6 mmol). The resulting mixture was stirred at
room temperature for 30 min and was then concentrated in vacuo.
The crude product was purified by flash chromatography (silica gel;
hexane/EtOAc, 4:1) to afford product 19 (158 mg, 87% yield) as a
colorless oil. 1H NMR (500 MHz, CDCl3): δ = 7.08 (dt, J = 8.5 Hz,
J = 0.5 Hz, 1 H), 6.58 (d, J = 7.5 Hz, 1 H), 6.49 (d, J = 7.5 Hz, 1
H), 5.29 (d, J = 3.5 Hz, 1 H), 5.17 (m, 2 H), 3.46 (d, J = 1.0 Hz, 3
H), 2.02 (m, 2 H), 1.78 (m, 2 H), 1.62 (m, 2 H), 1.54 (s, 3 H) ppm.
13C NMR (125 MHz, CDCl3): δ = 154.5, 152.5, 128.1, 111.8, 108.7,
4962
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© 2015 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2015, 4956–4963

Proline-Catalyzed Formal Synthesis of Averufin
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Received: May 2, 2015
Published Online: June 22, 2015
Z. K. Sun, G. A. Winschel, A. Borovika, P. Nagorny, J. Am.
Eur. J. Org. Chem. 2015, 4956–4963
© 2015 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
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