Chiral Boron Complex-Promoted Asymmetric Diels-Alder Cycloaddition and Its Application in Natural Product Synthesis

Article abstract of DOI:10.1021/acs.joc.5b02248

An efficient method for the asymmetric Diels-Alder cycloaddition of 2'-hydroxychalcones with acyclic or cyclic dienes has been successfully developed. The Diels-Alder cycloaddition is mediated by a chiral boron complex with VANOL, affording the corresponding products in high yields and with excellent diastereo- and enantioselectivities. This reaction enabled the enantioselective construction of cyclohexene skeletons crucial for the total synthesis of a number of Diels-Alder-type natural products (-)-nicolaioidesin C, (-)-panduratine A, (-)-kuwanon I, (+)-kuwanon J, and (-)-brosimones A and B.

Full text of DOI:10.1021/acs.joc.5b02248

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Article
Chiral Boron Complex-Promoted Asymmetric Diels-Alder
Cycloaddition and Its Application in Natural Product Synthesis
Xia Li, Jianguang Han, Alexander X. Jones, and Xiaoguang Lei
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.5b02248 • Publication Date (Web): 14 Dec 2015
Downloaded from http://pubs.acs.org on December 17, 2015
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Chiral Boron ComplexꢀPromoted Asymmetric DielsꢀAlder
Cycloaddition and Its Application in Natural Product Synthesis
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Xia Li,†‡ Jianguang Han,†‡ Alexander X. Jones§ and Xiaoguang Lei*‡§
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†School of Pharmaceutical Science and Technology, Tianjin University, Tianjin, 300072, China
‡National Institute of Biological Sciences (NIBS), Beijing, 102206, China
§Beijing National Laboratory for Molecular Sciences, Key Laboratory of Bioorganic Chemistry
and Molecular Engineering of Ministry of Education, Department of Chemical Biology, College
of Chemistry and Molecular Engineering, Synthetic and Functional Biomolecules Center, and
Center for Life Sciences, Peking University, Beijing, 100871, China
Email: xglei@pku.edu.cn
Table of Contents
ABSTRACT
An efficient method for the asymmetric DielsꢀAlder cycloaddition of 2’ꢀhydroxychalcones with
acyclic or cyclic dienes has been successfully developed. The DielsꢀAlder cycloaddition is
mediated by a chiral boron complex with VANOL, affording the corresponding products in high
yields and with excellent diastereoꢀ and enantioꢀselectivities. This reaction enabled the
enantioselective construction of cyclohexene skeletons crucial for the total synthesis of a number
of DielsꢀAlder type natural products (ꢀ)ꢀnicolaioidesin C, (ꢀ)ꢀpanduratine A, (ꢀ)ꢀkuwanon I,
(+)ꢀkuwanon J, (ꢀ)ꢀbrosimones A and B.
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INTRODUCTION
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Numerous structurally related DielsꢀAlder products have been isolated from various Moraceous
and related plants, 1 such as the chalconoid natural products, nicolaiodesin C (1)2 and panduratin A
(2)3; prenylflavonoid DielsꢀAlder natural products, kuwanon I (3)4 and J (4)5, brosimone A (5)6
and B (6)7; as well as kuwanons G (7)8 and H (8)9 (Fig. 1). These molecules all possess a
cyclohexene ring derived from DielsꢀAlder cycloaddition of a 2’ꢀhydroxychalconeꢀcontaining
dienophile. However, structural variations in the diene and dienophile precursors give rise to
natural products which display striking diversity as well as significant biological activities.10
Accordingly, complex and biologically active DielsꢀAlder type natural products have attracted
broad attention from the synthetic community over the past decade.11 Several synthetic methods
have been developed to promote DielsꢀAlder cycloadditions with 2’ꢀhydroxychalcone dienophiles,
including thermal promotion,12 singleꢀelectron transfer initiation,13 as well as silicaꢀsupported
silver nanoparticle (AgNPs) catalysis.14 However, all these methods are nonꢀenantioselective.
Palomo and coꢀworkers have described the enantioselective total synthesis of (ꢀ)ꢀnicolaioidesin C,
using a chiral camphor auxiliary.15 In 2014, our group reported the first direct asymmetric
DielsꢀAlder cycloaddition with 2’ꢀhydroxychalcone dienophiles, using a chiral VANOLꢀboron
Lewis acid complex.16 We demonstrated the application of our methodology to the synthesis of
complex natural products (ꢀ)ꢀkuwanon I, (+)ꢀkuwanon J, (ꢀ)ꢀbrosimone A and (ꢀ)ꢀbrosimone B.16
In this paper, we report a full account of the development and optimization of the chiral
boronꢀLewis acid mediated DielsꢀAlder cycloaddition, a summary of our syntheses of the above
natural products, and a report on the syntheses of two related natural products: (ꢀ)ꢀnicolaioidesin C
and (ꢀ)ꢀpanduratine A, using this methodology.
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Figure 1. Representative DielsꢀAlder Type Natural Products Derived from 2’ꢀHydroxychalcones
Our studies began with the model reaction between 2’ꢀhydroxychalcone 9 as dienophile and
diene 10. Initially, we examined the effect of Brønsted acid catalysts, such as chiral
BINOLꢀderived phosphoric acid (BA1),17 the more strong acidic catalyst NꢀTriflyl phosphoramide
(BA2),18 (1S)ꢀ(+)ꢀ10ꢀcamphorsulfonic acid (BA3) and tartaric acid (BA4). Unfortunately, all of
these attempts failed, including increasing amount of the catalyst (from catalytic to stoichiometric
amount), raising complex temperature (from room temperature to reflux temperature) and
extending reaction time, even promoted in microwave conditions, presumably because these
Brønsted acids have insufficient efficiency (Table 1). We next turned our attention to chiral Lewis
acid catalysts. 2’ꢀHydroxychalcones have been shown to be resistant to activation by several
traditional Lewis acids, and chiral oxazaborolidine (LA1) and chiral aluminum Lewis acid
complex (LA2) failed to catalyze this cycloaddition (Table 1, entry 3ꢀ4). Inspired by the
enantioselective DielsꢀAlder reactions and chlorinations on the juglone systems,19 we selected the
optically active BINOLꢀboron complex (LA3) to promote the asymmetric DielsꢀAlder
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cycloaddition. To our delight, the chiral boron Lewis acid complex could effectively promote the
cycloaddition of dienophile 9 and diene 10 to afford DielsꢀAlder adduct 11 (Table 1, entry 5). In
this asymmetric DielsꢀAlder reaction, superꢀstoichiometric amount of the chiral boron complex
was needed. When we reduced the amount of the chiral Lewis acid, yield and enantioselectivity of
the cycloaddition adduct decreased (Table 1, entries 5 and 6). We suspected that the chiral
ligandꢀdienophile intermediate may hydrolyze in the presence of water or open to the air, and
indeed higher yields and moderate ee value could be regained at lower complex loading by
addition of activated 5 Å molecular sieves (Table 1, entry 7).
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Table 1. Initial Reaction Screening
Entry Equiv of Ligand Solvent Time (h) Yield (%)a ee (%) b
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2 c
3
BA (2.0)
BA (2.0)
DCM
Toluene
THF
24
0.5
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16
84
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N.R.
N.R.
N.R.
trace
50
N.D.
N.D.
N.D.
N.D.
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LA1 (2.0)
LA2 (2.0)
LA3 (4.0)
LA3 (2.0)
LA3 (2.0)
4
DCM
THF
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7d
THF
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THF
90
43
b
a Conditions: dienophile 9 (1 equiv), diene 10 (20 equiv), room temperature, isolated yield.
Determined by chiral HPLC. c 80 oC, 100 W. d RꢀBINOL, 5 Å MS. THF = tetrahydrofuran, DCM
= dichloromethane, N.D. = not detected
Employing the same DielsꢀAlder reaction conditions as in table 1, entry 7, we screened a
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number of different chiral ligands in order to optimize enantioselectivity (Table 2). We first
considered whether sterically large BINOL substituent groups may improve enantioselectivity, but
found that both the highly bulky chiral binaphthol ligand (L2)19a,c, the chiral reducedꢀtype
binaphthol ligand (L3 and L4)20 and (R, R)ꢀTADDOL ligand (L5) result in relatively low
enantioselectivity in our model reaction. Employing the vaulted 2,2’ꢀbinaphthol (VANOL, L6)
and 3,3’ꢀbiphenanthrol (VAPOL, L7),21 developed by William D. Wulff and coꢀworkers, 1.2
equiv complex loading was found to give the desired adducts with excellent yield and ee value.
Although stoichiometric amount of the chiral boron complex is still required, the chiral ligands
can be recycled repeatedly; both yield and ee value are retained after one and two recycles using
the recovered chiral ligand VANOL in the asymmetric DielsꢀAlder reaction (Table 2, entries 7ꢀ9).
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Table 2. Screening the Chiral Ligand
Entry Ligand Time (h) Yield(%)a ee (%)b
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2
L1
L2
L3
L4
L5
L6
L6
L6
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L7
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a Conditions: Chiral ligand (2 equiv), BH3.THF (2 equiv), AcOH (2 equiv), dienophile 9 (1 equiv),
diene 10 (20 equiv), 5 Å MS, isolated yield. b Determined by chiral HPLC. cL6 (1.2 equiv). d With
recycled ligand, one cycle, 99% recovery L6. e With recycled ligand, two cycles, 97% recovery
L6.
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To determine the substrate generality and limitations of this strategy, several dienes were
subjected to asymmetric DielsꢀAlder reaction under the optimized conditions (Table 3). All the
substituted dienes were converted to the corresponding adducts in satisfactory yield with high ee
value. Single regioisomers was observed for unsymmetrical 2ꢀsubstituted and 1,3ꢀdisubstituted
dienes, and the endo/exo diastereoselectivity for diene 18 was 5.4:1 (Table 3, entries 1, 5 and 6).
Table 3. DielsꢀAlder of Dienophile 9 and Dienes
Yield (%)a
90
Time (h)
6
ee (%)b
Entry
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Diene
Product
OH
O
Ph
Ph
95
Me
11
Me
Me
10
OH
OH
O
Me
Me
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3
4
99
94
92/96c
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Me
Ph
O
Bn
Bn
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96
Bn
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Bn
Ph
4d
OH
O
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90
99
90
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Me
OH
O
91 (endo)
38 (exo)
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H
Ph
Me
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20
exo
H
endo, H
endo:exo = 5.4:1
OH
O
Ph
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94
12
Me
6e
Me
Me
Me
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22
a RꢀVANOL (1.2 equiv), BH3.THF (1.2 equiv), AcOH (1.2 equiv), dienophile 9 (1 equiv), dienes
(20 equiv, unless specified otherwise), diene 14 and 18 (5 equiv), 5 Å MS, yield of isolated
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product. b Determined by chiral HPLC. c RꢀVAPOL (1.2 equiv). d Single endo isomer. e Single
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regioisomer isomer.
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To explain the excellent enantioselectivity observed in the [4+2]ꢀDielsꢀAlder cycloaddition, we
propose an assembly involving 2’ꢀhydroxychalcone and a chiral boronꢀVANOL complex (Figure
2). A calculated model by Chem3D indicates that upon activation of the ketone moiety by the
boron Lewis acid, the chiral VANOL ligand is probably forms a πꢀπ stacking interaction with the
chalcone dienophile, which shields the αꢀface and dictates the stereofacial approach of the diene
from the less hindered βꢀface.
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Figure 2 Proposed Mechanism for the Enantioselective DielsꢀAlder Reaction and structure of the
chiral VANOLꢀboron Lewis acidꢀdienophile complex
Encouraged by the effective asymmetric DielsꢀAlder reaction with a wide variety of substrates,
we decided to apply our strategy to the total syntheses of (ꢀ)ꢀnicolaiodesin C and (ꢀ)ꢀpanduratin A.
Chalcone 23 and myrcene were mixed under the optimal reaction conditions, and then the acetyl
group was removed to afford (ꢀ)ꢀnicolaiodesin C (1) with 96% ee. (ꢀ)ꢀPanduratin A was obtained
from the same reaction sequence, starting from DielsꢀAlder cycloaddition of 1:3 E:Z ocimene (E,
Z)-ocimene22 with chalcone 23 to give the target molecule in 56% yield and 87% ee (Scheme 1).
When pure Zꢀocimene reacted with the dienophile, no DielsꢀAlder adduct was isolated.12c The
lower yield of the DielsꢀAlder step was probably due to the fact that the requisite Eꢀocimene has
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been found to undergo olefin isomerization and polymerization under acid conditions.23
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Scheme 1. Total Syntheses of (ꢀ)ꢀNicolaiodesin C and (ꢀ)ꢀPanduratin A
Reagents and conditions: (1) a) RꢀVANOL (1.2 equiv), AcOH (1.2 equiv), BH3.THF (1.2 equiv);
b) Dienophile 23, 5 Å MS, THF, rt, 1 h; c) Myrcene, rt, 16 h, 88%. (2) a) SꢀVANOL (2.0 equiv),
AcOH (2.0 equiv), BH3.THF (2.0 equiv). b) Dienophile 23, 5 Å MS, THF, rt, 1 h. c) Ocimene
(E:Z = 1:3), rt, 68 h, 57%.
Encouraged by the successful total syntheses of (ꢀ)ꢀnicolaiodesin C and (ꢀ)ꢀpanduratin A, we
then sought to explore the total syntheses of the more complex natural products, (ꢀ)ꢀkuwanon I and
(+)ꢀJ, (ꢀ)ꢀbrosimone A and B. We strived to access all of the four natural products from the
common intermediate 24, which can undergo sigmatropic rearrangement to form orthoꢀprenylated
chalcone 25, a synthetic precursor for kuwanons I and J, or para-prenylated chalcone 26 for
brosimones A and B (Scheme 2).
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Scheme 2. Synthetic Plan for Kuwanons I and J, Brosimones A and B
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The important research work reported by Nomura and coꢀworkers showing the chalcone (Mꢀ1)
was transformed to the methylated kuwanon J (Mꢀ3) upon treatment with the M. alba cell cultures
(Scheme 3).24 The findings indicated that kuwanon J might be biosynthesized by dehydrogenase
and DielsꢀAlderase. Inspired by this elegant biosynthesis study, we envisioned a synthetic route
which could effectively mimic the required transformations catalyzed by dehydrogenase and
DielsꢀAlderase in nature.
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Scheme 3. Biosynthesis of Methylated Kuwanon J
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Our synthetic approach to kuwanons I and J began with preparation of the dienophile. Initially,
prenylation of readily available chalcone 27 under standard conditions afforded Oꢀprenyl chalcone
24, which was subjected to a montmorillonite Kꢀ10 catalyzed sigmatropic rearrangement to afford
the desired chalcone 25 (37%) for kuwanons I and J, [1,5]ꢀsigmatropic rearrangement product 26
(27%) for brosimones A and B, along with deprenylated chalcone 27 (36%) (Scheme 4). Scheme
4 In order to increase the reactivity of dienophile, we converted the MOM protecting groups into
the more electronꢀwithdrawing acetyl groups (35%, 2 steps).
Scheme 4. Synthesis of dieneophile 28
A permethylated orthoꢀprenylated chalcone 29 was selected as the synthetic precursor of diene
32 in order to increase the DꢀA reactivity of the diene. The key biomimetic dehydrogenation to
generate 32 involved a regioselective Schenck ene reaction25 of chalcone 29, reduction and
dehydration of tertiary allylic alcohol 31 to give the desired diene (Scheme 5).
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Scheme 5. Synthesis of diene 32
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With both dienophile 28 and diene 32 in hand, we began to evaluate the chiral boron complex
catalysedꢀDielsꢀAlder cycloaddition (Scheme 6). We were pleased to find that the [4+2]
cycloaddition between dienophile 28 and diene 32 proceeded smoothly under the optimal
conditions to afford endo/exo diastereomers (34 and 33, respectively) in 75% yield with a 1.2:1
ratio. The completion of the syntheses of kuwanons I and J required only removal of the acetyl
and methyl protection groups. Hydrolysis of the products 33 and 34 under basic conditions
afforded the compound 35 and 36. Unfortunately, many attempts at methyl group deprotection of
either 35 or 36 led only to decomposition. We attempted to use other electronꢀdonating protecting
groups of the diene, such as MOM group, MTM group and TIPS group. Unfortunately, the
lateꢀstage global deprotection only led to incomplete deprotection or decomposition. This issue
was resolved by converting the phenolic hydroxyl group to acetyl esters. Ultimately, the usage of
acetyl protecting groups was an essential factor in completing total syntheses of kuwanons I and J,
brosimones A and B (vide infra).
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Scheme 6. Attempted Synthetic Route for Kuwanons I and J
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OMe
MeO
1) VANOL, BH3.THF, AcOH, THF, rt, 25 min
OMe
H
28
32
+
Me
28
Å
2) Dienophile , THF, rt, 5 MS, 1.5 h
OMe O
OH
9
32
3) Diene , rt, 72 h, 75%
O
endo:exo = 1.2:1
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AcO
33
:exo
H
H
34
:endo
OAc
OAc
K2CO3, MeOH/H2O
rt, 72%
OH
OMe
HO
MeO
OH
OMe
H
H
Me
Me
HO
OH
OH
O
OMe O
OH
O
O
HO
35
H
H
:kuwanon I (3)
:kuwanon J (4)
H
H
:exo
36
:endo
OH
OH
OH
OH
In order to complete the total synthesis of these natural products, we turned our attention to
synthesis of acetyl group protected diene (Scheme 7). Initial orthoꢀprenylated chalcone 28 was
subjected to the standard Schenck ene reaction conditions, followed by subsequent reduction with
PPh3 to afford the tertiary allylic alcohol 38 and secondary allylic alcohol 37 in 71% combined
yield with a 2:1 ratio. The diene 39 was further prepared by dehydration of the tertiary allylic
alcohol 38 in 75% yield. Unfortunately, several attempts for the dehydration of secondary allylic
alcohol 37 failed due to low reactivity. Considering the fact that tertiary alcohols are typically
better substrates for dehydration, we screened commonly used photosensitizers and solvents to
improve the selectivity for the tertiary alcohol. We observed that a visible lightꢀmediated26
regioselective Schenck ene reaction using Ru(bpy)3Cl2·6H2O as photosensitizer and MeOH as
solvent significantly improved the ratio for tertiary alcohol (from 2:1 to 8:1). To the best of our
knowledge, this biomimetic transformation represents the first Ru(bpy)3Cl2·6H2Oꢀmediated
regioselective Schenck ene reaction.
We next turned our attention to synthesis of the para-prenylated chalcone diene, which was
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the synthetic precursor for brosimones A and B. It was found that a relatively good
regioꢀselectivity for the Schenck eneꢀreduction of chalcone 40 was obtained by using
tetraphenylporphyrin (TPP) as photosensitizer and MeOH as solvent. The tertiary allylic alcohol
42 and secondary allylic alcohol 41 were afforded in 63% combined yield with 3.2:1 ratio,
respectively. The diene 43 was further prepared by dehydration of the tertiary allylic alcohol 42 in
68% yield (Scheme 7).
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Scheme 7. Biomimetic Synthetic Design for Dienes
With both dienophile 28 and diene 39 in hand, we began to evaluate the key DielsꢀAlder
cycloaddition catalyzed by chiral boron complex in total syntheses of kuwanons I and J (Scheme
8).We envisaged several challenges in the DielsꢀAlder step, due to the electron deficiency of
acetyl protected diene 39 and the large steric size of both substrates. However, we were delighted
to find that under the optimized reaction conditions, the DielsꢀAlder cycloaddition proceeded
smoothly to afford endo/exo diastereomers (45:44 = 1.2:1) in moderate yield and moderate
enantiomeric excess (58% ee for 45, 51% ee for 44).27 The nonꢀeantioselective reaction, using
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only BH3·THF and AcOH yielded 12% of the DielsꢀAlder cycloadducts in the same reaction time.
Therefore, we increased the ligand loading in order to reduce background reaction.28 Increasing
the equivalents of ligand from 1.2 to 2.5, resulted in an obvious improvement in enantioselectivity
(97 % ee for 45, 60 % ee for 44). The best results for exoꢀproduct were obtained when Sꢀ8,
8’ꢀdimethylꢀVANOL (L8) was used as a chiral ligand. Finally, global deprotection of the
DielsꢀAlder cycloadducts exoꢀ44 and endoꢀ45 under mild basic conditions efficiently furnished
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the desired natural products kuwanons I (1) and J (2), both in 70% yield. The H and 13C NMR
spectra of the synthetic kuwanons I and J were consistent with those reported for the natural
products.4,5
Scheme 8 Syntheses of (ꢀ)ꢀKuwanon I and (+)ꢀKuwanon J
(a) Ligand, BH3·THF, AcOH, 5 Å MS, THF, rt, 72 h; (b) K2CO3, MeOH/H2O (10:1), rt, 1 h, 70%.
Entry
Liganda
SꢀVANOL
RꢀVANOL
SꢀVAPOL
L8
Equiv of Ligand Yield (%)b endo:exo ee (%)c endo/exo
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80
19
54
1.2:1
1.1:1
1.1:2
1:1.2
58/51
97/60
40/25
86/84
a 87ꢀ92% of ligand was recovered. b Isolated yield. c Determined by chiral HPLC
The para-prenylated chalcone 40 and diene 43 were utilized in the total synthesis of brosimone
B (Scheme 9). To our surprise, both VANOL and VAPOL ligand can afford endo and exo
diastereomers in good yields and excellent enantiomeric excess for both endo and exo products
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(when SꢀVANOL as ligand, 98% ee for endo 46, 93% ee for exo 47). The structure of endoꢀ
diastereomer 46 was confirmed by 2DꢀNMR. Final deprotection of the acetyl groups of
exoꢀdiastereomer 47 afforded brosimone B (5) in 70% yield.
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Scheme 9. Synthesis of (ꢀ)ꢀBrosimone B
The dimeric natural product, brosimone A is a structurally complex compound derived through
the homodimerization of 43, presumably via a remarkable tandem interꢀ/intramolecular
asymmetric DielsꢀAlder cycloaddition process. To our knowledge, the sequential oneꢀpot interꢀ
and intramolecular DielsꢀAlder cycloaddition cascade was rarely described before.29 Fortunately,
when chiral boron complex was used, all three expected products were obtained, namely
endo-endo 48 in 28% yield with 98% ee, exo-endo 49 in 20% yield (see below for ee value
determination) and exo-exo 50 in 13% yield with 95% ee (entry 1). Finally, global deprotection of
the exo-exo product 50 under mild basic conditions (K2CO3, MeOH) efficiently afforded
brosimone A (6) in 70% yield. The 1H and 13C NMR spectra of the synthetic brosimone A were in
agreement with those reported for the natural product 6(Scheme 10).
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Scheme 10. Synthesis of (ꢀ)ꢀBrosimone A
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The structures of the two natural products analogues endo-endo 48 and exo-endo 49 were
confirmed by different methods (Scheme 11). Sequentially deacetylation and methylation of
endo-endo 48, the permethylation product 51 was obtained in 56% yield over 2 steps. The
structure of the endo-endo 51 was unambiguously determined by Xꢀray crystallographic analysis.
However, it proved not possible to directly measure the ee value of exo-endo 49 due to the
presence of a mixture of conformational isomers in the chiral HPLC chromatogram. An indirect
method was therefore devised, whereby 49 was converted to the known permethylated analogue
53, previously reported by the Porco group.14c Deprotection of the acetyl groups and methylation
of exo-endo 49 afforded 53 in 49% yield over 2 steps. The NMR data for synthetic 53 fully
matched with the compound obtained by permethylation of exo-endo hexamethyl ether.
Unfortunately, the ee value of the exo-endo octamethyl ether 53 was only 31%.
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Scheme 11. Structural confirmation of endo-endo 48 and exo-endo 49
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CONCLUSIONS
An efficient method for the enantioselective DielsꢀAlder of 2’ꢀhydroxychalcone and its
derivatives has been developed, promoted by a chiral VANOLꢀboron Lewis acid complex. The
cycloaddition proceeds smoothly at room temperature to provide the desired products in high yield
and enantioselectivity. This methodology was applied to the enantioselective total syntheses of the
prenylflavonoid DielsꢀAlder type natural products (ꢀ)ꢀnicolaioidesin C, (ꢀ)ꢀpanduratine A,
(ꢀ)ꢀkuwanon I, (+)ꢀkuwanon J, (ꢀ)ꢀbrosimone A and (ꢀ)ꢀbrosimone B. Key elements of the
syntheses include the biosynthesisꢀinspired asymmetric DielsꢀAlder cycloaddition, as well as a
biomimetic dehydrogenation reaction sequence for generation of the required diene precursor,
involving regioselective Schenck ene reaction reduction and dehydration. Furthermore, a
remarkable tandem interꢀ/intramolecular asymmetric DielsꢀAlder cycloaddition process was
applied for the synthesis of brosimone A. Advances in the enantioselective synthesis of other
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related complex natural products with important biological activities and further mechanistic
studies are in progress.
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EXPERIMENTAL SECTION
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General procedure for the asymmetric DielsꢀAlder reaction:19a,c Chiral ligand (1.2 equiv) was
dissolved in anhydrous THF, then the solution was treated sequentially with BH3·THF (1.2 equiv)
and glacial AcOH (1.2 equiv). The resulting mixture was stirred at rt (room temperature) for 30
min, concentrated to dryness and further dried under high vacuum at rt for 30 min. The colorless
residue was dissolved in THF, then added the preꢀactivated 5Å molecular sieve (20 weight equiv)
and dienophile (1.0 equiv), the resulting dark red solution was stirred at rt for 1 h before the diene
(5.0 ꢀ 20 equiv) was added to the reaction mixture. The reaction was stirred at rt and monitored by
TLC. Once completed, the mixture was quenched by addition of H2O (15.0 equiv) and filtered
through the celite, further washed with EtOAc, and the organic filtrates were collected and
concentrated in vacuo. The residue was purified by flash column chromatography to afford the
desired DielsꢀAlder cycloadducts and recovered chiral ligand, unless otherwise stated. The
racemate DielsꢀAlder cycloadduct was prepared using the general procedure, employing the
racemate BINOL or VANOL as the ligand.
Chalcone (9). To a stirred solution of 2’ꢀhydroxyacetophenone (1.2 mL, 10 mmol) in MeOH (50
mL) was added benzaldehyde (1.0 mL, 10 mmol), followed by slow addition of a KOH aqueous
o
solution (20 mol/L, 23 mL). The resulting orange solution was stirred at 40 C for 3 days. The
reaction mixture was diluted with saturated aqueous NH4Cl, adjusted to pH 4 by adding 1 M HCl,
extracted with EtOAc (50 mL × 2), washed with brine, dried over Na2SO4 and concentrated in
vacuo. The residue was purified by flash chromatography (ethyl acetate:petroleum ether = 1:5) to
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afford the compound 9 (2.0 g, 90%) as a yellow solid. 1H NMR (400 MHz, CDCl3) δ 12.83 (s, 1H),
7.95ꢀ7.91 (m, 2H), 7.69ꢀ7.65 (m, 3H), 7.53ꢀ7.49 (m, 1H), 7.49ꢀ7.43 (m, 3H),7.05ꢀ7.03 (m, 1H),
6.98ꢀ6.93 (m, 1H). 13C NMR (100 MHz, CDCl3) δ 193.7, 163.6, 145.5, 136.4, 134.6, 130.9, 129.6,
129.0, 128.6, 120.1, 120.0, 118.8, 118.6. The spectroscopic data for this compound were identical
to those reported in the literature.30
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Chalcone (23). DielsꢀAlder cycloadducts (11/13/15/17/19/20/22/1). These known compound was
prepared according to the reference.13
Compound (24/25/26/27/28/37/38/39/40/41/42/43). These known compounds were prepared
according to the reference.16 DielsꢀAlder cycloadducts (44/45/46/47/48/49/50/51/52/53). The
detail information of these known compounds see also reference 16.
DielsꢀAlder adduct (11). The general procedure was followed by employing RꢀVANOL
(0.026mmol, 1.2 equiv), dienophile chalcone 9 (5 mg, 0.022 mmol, 1 equiv) and diene 10 (45 ꢁL,
20 equiv), the desired compound 11 (6.0 mg, 90%) was isolated as a light yellow solid and as a
single regioisomer. 95.0% ee (isopropanol : hexane = 2:98), retention time 6.0 min and 6.8 min;
[α]24D +20.6 (c 0.91, DCM).
DielsꢀAlder adduct (13). The general procedure was followed by employing RꢀVANOL (25.8 mg,
0.0588 mmol, 1.2 equiv), dienophile chalcone 9 (11 mg, 0.049 mmol, 1 equiv) and diene 10 (131
ꢁL, 20 equiv), the desired compound 13 (15 mg, 99%) was isolated as a light yellow oil. 95.9% ee
(isopropanol:hexane = 2:98), retention time 4.9 min and 5.3 min; [α]23D +39.6 (c 0.84, DCM).
DielsꢀAlder adduct (15). The general procedure was followed by employing RꢀVANOL
(0.073mmol, 1.2 equiv), dienophile chalcone 9 (0.06 mmol, 1 equiv) and diene 14 (71 mg, 5
equiv), the desired compound 15 (25.0 mg, 94%) was isolated as a light yellow solid. 96.5% ee
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(isopropanol : hexane = 2:98), retention time 7.3 min and 8.6 min; [α]18D 16.1 (c 0.86, DCM).
DielsꢀAlder adduct (17). The general procedure was followed by employing RꢀVANOL (0.25
mmol, 1.2 equiv), dienophile chalcone 9 (47 mg, 1 equiv), diene 16 (0.4 mL, 20 equiv), the
desired compound 17 (57.3 mg, 90%) was isolated as a light yellow solid and as a single
endoꢀisomer. 90.2% ee (isopropanol : hexane = 2:98), retention time 7.1 min and 8.9 min; [α]18D
153 (c 0.23, DCM).
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DielsꢀAlder adduct (19) and (20). The general procedure was followed by employing RꢀVANOL
(0.105mmol, 1.2 equiv), dienophile chalcone 9 (0.087 mmol, 1 equiv) and diene 18 (63 mg, 5
equiv), the desired endo DielsꢀAlder adduct 19 and exo DielsꢀAlder adduct 20 (31.08 mg, 99%)
were isolated as white solid. The ratio of exoꢀisomer to endoꢀisomer is 1:5.4. endo DielsꢀAlder
adduct 19: 90.7% ee (isopropanol : hexane = 1:99), retention time 5.2 min and 5.7 min; [α]22D
+170.3 (c 0.96, DCM). exo DielsꢀAlder adduct 20: 37.6% ee (isopropanol:hexane = 2:98),
retention time 4.7 min and 5.3 min; [α]23D ꢀ10.63 (c 0.36, DCM).
DielsꢀAlder adduct (22): The general procedure was followed by employing RꢀVANOL (12 mg,
1.2 equiv), dienophile chalcone 9 (0.022 mmol, 1 equiv) and diene 21 (76 ꢁL, 20 equiv), the
desired compound 22 (8.0 mg, 99%) was isolated as a light yellow oil and as a single regioisomer.
94.3% ee (isopropanol : hexane = 2:98), retention time 4.4 min and 5.1 min; [α]22D +16.38 (c 0.47,
DCM).
(ꢀ)ꢀNicolaioidesin C (1). The general procedure was followed by employing RꢀVANOL (79 mg,
1.2 equiv), dienophile chalcone 23 (47 mg, 0.18 mmol, 1 equiv), 5 Å MS (20 weight equiv to
dienophile) and myrcene (0.52 mL, 20 equiv). The reaction was stirred at rt for 16 h, quenched by
addition of H2O (15.0 equiv) and filtered through the celite, further washed with EtOAc, and the
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organic filtrates were collected and concentrated in vacuo. The residue was purified by flash
chromatography to afford the desired DielsꢀAlder cycloadducts acetylated nicolaioidesin C (59.4
mg, 88%) and recovered chiral ligand (75 mg, 95%). To the resulting light yellow residue was
added 2 mL of MeOH and 2 mL of saturated NaHCO3 solution. The resulting pale yellow
suspension was stirred at room temperature for 4 h, the reaction mixture was adjusted to pH 4 by
adding 1 M HCl, extracted with EtOAc, washed with brine, dried over Na2SO4 and concentrated
in vacuo. The residue was purified by column chromatography (hexane : EtOAc = 4:1), further
separation was achieved by preparative TLC (hexane : EtOAc = 3:2) to afford the nicolaioidesin C
(78%). 95.8% ee (isopropanol:hexane = 10:90), retention time 8.8 min and 10.4 min; [α]26D ꢀ31(c
0.91, MeOH), while [α] 25D = ꢀ25 (c 1.0, MeOH) for (ꢀ)ꢀnicolaioidesin C reported in literature.15
(ꢀ)ꢀPanduratin A (2). The general procedure was followed by employing SꢀVANOL (58 mg, 2.0
equiv), dienophile chalcone 23 (20 mg, 1 equiv) and ocimene (600 mg, 20 equiv). The reaction
was stirred at rt for 68 h, quenched by addition of H2O (15.0 eq) and filtered through the celite,
further washed with EtOAc, and the organic filtrates were collected and concentrated in vacuo. The
residue was purified by flash chromatography to afford the desired DielsꢀAlder adduct acetylated
panduratin A (14.8 mg, 51%, 57% brsm) was isolated as a light yellow oil. The resulting light
yellow residue was dissolved in MeOH (1 mL), then added 1 mL of saturated NaHCO3 solution.
The resulting pale yellow suspension was stirred at room temperature for 8 h, the reaction mixture
was adjusted to pH 4 by adding 1 M HCl, extracted with EtOAc (10 mL), washed with brine (10
mL), the resulting aqueous layer was extracted with EtOAc (10 mL), the combined organic layer
was dried over anhydrous Na2SO4 and concentrated in vacuo. Purification on preparative TLC
(15% EtOAc in hexane) afforded (ꢀ)ꢀpanduratin A (7.8 mg, 58%) as a light yellow solid. The
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spectroscopic data for this compound were identical to those reported in the literature.10d 86% ee
(isopropanol:hexane = 10:90), retention time 4.9 min and 6.6 min; HRMS (ESI) m/z calculated for
C26H30O4 (M+H+): 407.22223, found: 407.22178; [α]23D ꢀ43 (c 0.39, EtOH), while [α] 23D = ꢀ25 (c
0.07, MeOH) for natural (ꢀ)ꢀpanduratin A.
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Chalcone (29). To a stirred solution of chalcone 25 (217.0 mg, 0.46 mmol) in MeOH (4.5 mL) was
slowly added concentrated HCl (330 ꢁL) at rt. The resulting orange solution was stirred at rt for 20 h,
then to the resulting orange solution was slowly added 4 M NaOH (3 mL) at 0 oC and the reaction
was stirred at rt for 2 h. The reaction mixture was diluted with saturated aqueous NH4Cl, adjusted to
pH 4 by adding 1 M HCl, and extracted with EtOAc. The organic layer was successively washed
with water, brine, dried over anhydrous Na2SO4, and evaporated under reduced pressure. The
residue was dissolved in DMF (20 mL), K2CO3 (95 mg, 0.69 mmol) and MeI (37 ꢁL, 0.60 mmol)
were added to the resulting orange solution. The reaction mixture was kept at rt for 24 h and
quenched by addition of H2O (1 mL), and extracted with EtOAc. The organic layer was
successively washed with water, brine, dried over anhydrous Na2SO4, and evaporated under reduced
pressure. The crude residue was purified by flash chromatography (hexane : EtOAc = 4:1) to
afford 29 (54.0 mg, 30%) as a yellow oil. 1H NMR (400 MHz, CDCl3) δ 8.01 (d, J = 16.0 Hz, 1H),
7.59 (d, J = 2.8 Hz, 1H), 7.56 (d, J = 2.8 Hz, 1H), 7.48 (d, J = 16.0 Hz, 1H), 6.71 (d, J = 8.8 Hz,
1H), 6.52 (dd, J = 8.8 Hz, 2.4 Hz, 1H), 6.46 (d, J = 2.4 Hz, 1H), 5.23ꢀ5.15 (m, 1H), 3.88 (s, 3H),
3.87 (s, 3H), 3.85 (s, 3H), 3.75(s, 3H), 3.40 (d, J = 6.7 Hz, 2H), 1.79 (s, 3H),1.69 (s, 3H); 13C
NMR (100 MHz, CDCl3) δ 192.3, 162.8, 161.1, 160.1, 158.7, 138.6, 131.5, 130.1, 129.9, 126.6,
124.4, 123.7, 122.8, 117.3, 106.1, 105.3, 98.3, 63.0, 55.8, 55.5, 25.8, 22.8, 17.8; IR (neat) νmax
2936, 2838, 1652, 1593, 1463, 1333, 1271, 1212, 1092, 1031 cmꢀ1; HRMS (ESI) [M+H]+
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calculated for C24H29O5: 397.2010, found: 397.2013.
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Compound (31). Dried air was bubbled through a CH2Cl2 (40 mL) solution of chalcone 29 (1.9 g,
4.8 mmol) and tetraphenylporphine (10 mg, 0.024 mmol) as the photosensitizer. The reaction
mixture was stirred at room temperature and irradiated with a halogen lamp (150 W) for 1.5 h.
Then triphenylphosphine (1.4 g, 5.3 mmol) was added and the solution was stirred 16 h at room
temperature before concentrated. The residue was purified by column chromatography (hexane :
EtOAc = 3:1) to afford 31 (623 mg, 32%) as a yellow oil. 1H NMR (400 MHz, CDCl3) δ 7.97 (d, J
= 16.0 Hz, 1H), 7.56 (t, J = 8.4 Hz, 2H), 7.44 (d, J = 16.0 Hz, 1H), 6.82 (d, J = 8.9 Hz, 2H), 6.74
(d, J = 8.7 Hz, 1H), 6.51 (dd, J = 8.6, 2.3 Hz, 1H), 6.45 (d, J = 2.2 Hz, 1H), 3.90 (s, 3H), 3.86 (s,
3H), 3.85 (s, 3H), 3.69 (s, 3H), 1.45 (s, 6H); 13C NMR (100 MHz, CDCl3) δ192.5, 162.9, 160.9,
160.1, 158.7, 142.9, 138.9, 130.9, 130.0, 127.2, 124.6, 119.3, 117.2, 116.1, 106.6, 105.4, 98.4, 71.5,
62.1, 55.8, 55.5, 55.5, 29.9, 29.7; IR (neat) νmax 3451, 2970, 1584, 1504, 1458, 1266, 1212, 1097
cmꢀ1; HRMS (ESI) [M+H]+ calculated for C24H29O6: 413.1959, found: 413.1963.
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Compound (30). The secondary allylic alcohol 30 was also isolated in 16% yield as a yellow oil.
1H NMR (400 MHz, CDCl3) δ 7.98 (d, J = 16.0 Hz, 1H), 7.57 (t, J = 8.8 Hz, 2H), 7.42 (d, J = 16.0
Hz, 1H), 6.74 (d, J = 8.8 Hz, 1H), 6.51 (dd, J = 8.6, 2.4 Hz, 1H), 6.45 (d, J = 2.4 Hz, 1H), 5.0 (s,
1H), 4.84(s, 1H), 4.29 (d, J = 8.4 Hz, 1H), 3.89 (s, 3H), 3.86 (s, 3H), 3.84 (s, 3H), 3.73 (s, 3H),
3.06 (dd, J = 13.5, 3.6 Hz, 1H), 2.89 (dd, J = 13.5, 9.0 Hz, 1H), 1.86 (s, 3H); 13C NMR (100 MHz,
CDCl3) δ 192.5, 162.9, 161.0, 160.2, 158.9, 147.6, 139.4, 130.3, 130.2, 126.5, 124.2, 120.6, 117.1,
110.0, 106.3, 105.4, 98.4, 75.8, 62.8, 55.9, 55.5, 55.4, 30.4, 18.1; IR (neat) νmax 3455, 2941, 2838,
1650, 1593, 1462, 1334, 1271, 1211, 1100 cmꢀ1; HRMS (ESI) [M+H]+ calculated for C24H29O6:
413.1959, found: 413.1953.
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Diene (32). A mixture of chalcone 31 (160 mg, 0.39 mmol), acetyl chloride (36 ꢁL, 0.5 mmol) and
pyridine (41 ꢁL, 0.5 mmol) in benzene (3 mL) was heated to 60 oC for 8 h. Then, 15 mL of 5%
aqueous NaHCO3 were poured into the reaction mixture. The aqueous layer was extracted with
EtOAc and the organic layer was washed with brine and dried over MgSO4. After evaporation of
the solvents, the residue was purified by column chromatography (hexane : EtOAc = 9:1) to afford
diene 32 (107 mg, 70% yield) as a yellow oil. 1H NMR (400 MHz, CDCl3) δ 7.99 (d, J = 16.0 Hz,
1H), 7.58 (d, J = 8.8 Hz, 1H), 7.55 (d, J = 8.8 Hz, 1H), 7.45 (d, J = 16.0 Hz, 1H), 7.35 (d, J = 16.4
Hz, 1H), 6.78 (d, J = 14.4 Hz, 1H), 6.75 (d, J = 6.8 Hz, 1H), 6.51 (dd, J = 8.8, 2.4 Hz, 1H), 6.45 (d,
J = 2.4 Hz, 1H), 5.11 (d, J = 11.2 Hz, 2H), 3.92 (s, 3H), 3.86 (s, 3H), 3.84 (s, 3H), 3.71 (s, 3H)
2.01 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 192.4, 162.9, 160.9, 160.1, 158.7, 143.2, 138.9, 136.8,
130.1, 129.9, 127.2, 124.5, 119.8, 119.2, 117.3, 117.2, 106.6, 105.3, 98.3, 62.3, 55.9, 55.5, 55.4,
18.3; IR (neat) νmax 2939, 1651, 1588, 1464, 1334, 1270, 1212, 1099 cmꢀ1; HRMS (ESI) [M+H]+
calculated for C24H27O5: 395.1853, found: 395.1857.
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DielsꢀAlder adduct (34). Racemic VANOL (117.3 mg, 0.27 mmol) was dissolved in THF (10 ml)
.
and treated sequentially with BH3 THF (270 ꢁL, 0.27 mmol) and glacial AcOH (15.5 ꢁL, 0.27
mmol), the resultant mixture was stirred at room temperature for 25 min, and then was
concentrated to dryness and further dried under high vacuum at room temperature for 15 min. The
colorless residue was dissolved in THF (12 mL), the chalcone 28 (104 mg, 0.22 mmol) and 5Å MS
were added, and the resulting dark red solution was stirred at room temperature for 1.5 h, followed
by addition of diene 32 (220 mg, 0.56 mmol). The reaction mixture was stirred at rt for 72 h before
filtered through celite. The organic layers were collected and concentrated. The residue was
purified by column chromatography (hexane : EtOAc = 4:1) to afford a mixture of 34 and other
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DielsꢀAlder adduct 33. The mixture was separated by preparative TLC (hexane : EtOAc = 3:2,
silica gel) to afford DielsꢀAlder adduct 34 (78 mg, 41% yield) as a yellow amorphous solid and
another DielsꢀAlder adduct 33 (65 mg, 34 % yield). 1H NMR (400 MHz, CDCl3) δ 12.55 (s, 1H),
7.88 (d, J = 16.4 Hz, 1H), 7.59 (d, J = 8.4 Hz, 1H), 7.32 (d, J = 8.4 Hz, 1H), 7.27 (d, J = 8.8 Hz,
1H), 7.17 (d, J = 8.4 Hz, 1H), 7.07 (d, J = 12.8 Hz, 0.6 H), 6.82ꢀ6.90 (m, 3H), 6.53 (dd, J = 1.2, 8.4
Hz, 1H), 6.46 (s, 1H), 6.32ꢀ6.42(m, 3 H), 5.49 (s, 1H), 5.00 (t, J = 6.4, 13.2 Hz, 1H), 4.65 (s, 1H),
4.35 (s, 1H), 3.85 (s, 3H), 3.80 (s, 3H), 3.51 (s, 3H), 3.17 (d, J = 6.4 Hz, 5H), 2.35ꢀ2.45(m, 1H),
2.29 (s, 3H), 2.20 (s, 3H), 2.14ꢀ2.16 (m, 1H), 2.08 (s, 3H), 1.81 (s, 3H), 1.67 (s, 3H), 1.62 (s, 3H);
13C NMR (100 MHz, CDCl3) δ 206.0, 192.1, 169.4, 168.8, 168.6, 162.9, 161.9, 160.4, 158.9, 153.8,
148.7, 135.4, 133.0, 132.0, 131.9, 131.4, 130.3, 127.9, 127.2, 126.1, 125.0, 122.4, 122.1, 119.3,
119.1, 118.1, 117.3, 117.0, 116.0, 112.6, 105.4, 105.2, 104.1, 98.2, 97.9, 62.6, 55,4, 55.4, 55.3,
54.7, 53.4, 35.0, 29.6, 25.6, 23.4, 22.5, 21.0, 20.9, 20.5, 17.7; IR (neat) νmax 2967, 2923, 2850,
1766, 1632, 1590, 1414, 1263, 2298 cmꢀ1; HRMS (ESI) [M+H]+ calculated for C50H53O13:
861.3481, found: 861.3473.
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DielsꢀAlder adduct (33). Using the same purification procedure, another DielsꢀAlder adduct 33
(65 mg, 34 % yield) was also obtained as a yellow amorphous solid. 1H NMR (400 MHz, CDCl3) δ
12.79 (s, 1H), 12.72 (s, 1H), 7.98 (m, 1H), 7.60 (d, J = 8.4 Hz, 1H), 7.42(d, 9.2 Hz, 1H),7.36 (d,
15.6 Hz, 1H), 6.85 (d, J = 5.8 Hz, 2H), 6.75ꢀ6.37 (m, 3H), 6.37ꢀ6.18 (m, 1H), 6.11 (d, J = 8.7 Hz,
1H), 5.33 (d, J = 14.4 Hz, 1H), 4.96 (d, J = 6.3 Hz, 1H), 4.75ꢀ4.22 (m, 3H), 3.94 (s, 1H), 3.89 ꢀ3.73
(m, 7H), 3.70 (s, 1H), 3.59ꢀ3.38 (m, 3H), 3.21ꢀ2.86 (m, 3H), 2.50ꢀ2.33 (m, 3H), 2.24 (m, 4H),
2.21ꢀ2.09 (m, 5H), 1.76 (s, 3H), 1.66 (s, 3H), 1.61 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 208.6,
193.1, 169.1, 168.8, 168.3, 163.1, 161.6, 160.2, 160.0, 159.5, 153.9, 148.9, 148.6, 139.4, 131.9,
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131.3, 130.6, 130.4, 130.1, 128.1, 127.6, 126.7, 124.6, 123.9, 121.7, 121.2, 121.1, 119.2, 118.4,
112.1, 105.5, 105.3, 98.5, 98.3, 63.5, 62.7, 56.1, 55.5, 39.1, 38.5, 31.2, 29.7, 25.6, 25.4, 23.0, 22.5,
22.3, 21.1, 20.8, 17.7; IR (neat) νmax 2936, 1773, 1654, 1593, 1505, 1438, 1371, 1215, 1093 cmꢀ1;
HRMS (ESI) [M+H]+ calculated for C50H53O13: 861.3481, found: 861.3473.
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DielsꢀAlder adduct (35). Compound 33 (15 mg, 0.017 mmol) and K2CO3 (7.9 mg, 0.058 mmol)
were dissolved in a MeOH/water (10:1, 1 mL) solution. The reaction mixture was stirred at rt for 1
h, then was quenched by addition of formic acid (42 ꢁL) at 0 oC, and then stirred at rt for an
additional 10 min. The reaction mixture was diluted with water and extracted with EtOAc (10 mL
× 3), washed with brine, dried over anhydrous Na2SO4, and concentrated in vacuo. The residue
was purified by flash chromatography (hexane : EtOAc = 2:1) to afford the exo DielsꢀAlder
adduct 35 (13 mg, 72%), as a yellow amorphous powder. 1H NMR (400 MHz, acetone) δ 13.15 (s,
1H), 13.05 (s, 1H), 7.99 (d, J = 16.0 Hz, 2H), 7.86 (d, J = 16.0 Hz, 2H), 7.76 (m, 3H), 7.64ꢀ7.53
(m, 4H), 7.32 (m, 5H), 7.07 (d, J = 8.0 Hz, 3H), 6.79 (dd, J = 19.6, 11.2 Hz, 2H), 6.73ꢀ6.65 (m,
3H), 6.63ꢀ6.56 (m, 2H), 6.51 (dd, J = 14.4, 8.8 Hz, 3H), 6.43ꢀ6.32 (m, 5H), 6.31ꢀ 6.18 (m, 4H),
5.33 (m, 4H), 4.99 (m, 6H), 4.52ꢀ4.40 (m, 4H), 4.11ꢀ4.02 (m, 6H), 4.01 (d, J = 7.2 Hz, 3H), 3.91
(d, J = 8.2 Hz, 6H), 3.86 (d, J = 5.6 Hz, 10H), 3.78 (d, J = 7.2 Hz, 7H), 3.68 (m, 6H), 3.53 (m, 3H),
3.07 (m, 5H), 2.91ꢀ2.77 (m, 2H), 2.24ꢀ2.09 (m, 4H), 1.99ꢀ1.95 (m, 3H), 1.77 (d, J = 10.8 Hz, 5H),
1.75 (s, 3H), 1.68 ꢀ1.60 (m, 5H), 1.56 (m, 3H), 1.52 (d, J = 9.6 Hz, 4H), 1.44 (s, 3H); 13
C
NMR (100 MHz, acetone) δ 209.1, 208.6, 190.7, 190.5, 163.2, 163.1, 162.7, 162.6, 162.0, 161.3,
161.1, 160.5, 160.4, 160.2, 160.2, 158.5, 156.4, 155.7, 137.8, 137.0, 132.2, 131.9, 130.7, 130.3,
130.0, 129.7, 129.7, 127.2, 126.6, 125.0, 124.5, 124.4, 123.9, 123.8, 122.4, 122.3, 116.7, 114.8,
114.7, 114.2, 114.0, 107.2, 106.6, 106.3, 106.1, 106.0, 105.9, 103.0, 98.3, 98.1, 62.7, 62.7, 55.5,
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55.3, 55.2, 55.1, 54.9, 39.2, 38.7, 26.9, 24.9, 24.8, 22.6, 22.5, 22.4, 21.2, 16.9; IR (neat) νmax 3372,
2923, 2860, 1602, 1461, 1283, 11649, 993 cmꢀ1; HRMS (ESI) [M + H]+ calculated for C44H47O10:
735.3164, found: 735.3170.
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DielsꢀAlder adduct (36). Compound 34 (48.0 mg, 0.06 mmol) and K2CO3 (25.8 mg, 0.19 mmol)
were dissolved in a MeOH/water (10:1, 3 mL) solution. The reaction mixture was stirred at rt for 1
o
h, then was quenched by addition of formic acid (42 ꢁL) at 0 C, and then stirred at rt for an
additional 10 min. The reaction mixture was diluted with water and extracted with EtOAc (10 mL
× 3), washed with brine, dried over anhydrous Na2SO4, and concentrated in vacuo. The residue was
purified by flash chromatography (hexane : EtOAc = 2:1) to afford the endo DielsꢀAlder adduct 36
(29 mg, 72%), as a yellow amorphous powder. 1H NMR (400 MHz, CDCl3) δ 12.32 (s, 1H), 8.02
(d, J = 16.0 Hz, 1H), 7.68 (d, J = 9.2 Hz, 1H), 7.48 (m, 1H), 7.01 (d, J = 8.0 Hz, 1H), 6.56 (dd, J =
8.8, 2.4 Hz, 1H), 6.46 (d, J = 2.0 Hz, 1H), 6.36 (dd, J = 8.4, 4.4 Hz, 3H), 6.29 (s, 1H), 5.41 (s, 1H),
5.05 (s, 1H), 4.68 (s, 1H), 4.29 (s, 1H), 4.15 (dd, J = 11.2, 8.0 Hz, 1H), 3.85 (s, 12H), 3.80 (d, J =
7.2 Hz, 1H), 3.49 (s, 3H), 3.21 (s, 3H), 2.54ꢀ2.13 (m, 2H), 1.80 (s, 3H), 1.66 (m, 6H); 13C NMR
(100 MHz, CDCl3) δ 207.2, 198.1, 163.6, 163.0, 162.5, 160.3, 155.2, 154.8, 135.5, 133.6, 130.8,
130.6, 130.2, 127.7, 124.9, 124.1, 121.8, 121.0, 117.2, 116.6, 113.9, 113.5, 108.4, 107.5, 105.6,
105.4, 104.9, 98.3, 63.0, 60.4, 55.5, 55.1, 52.3, 37.1, 35.5, 29.9, 29.7, 25.7, 23.6, 21.5, 21.0, 17.8;
IR (neat) max 3359, 2962, 2923, 2850, 1589, 1504, 1461, 1267, 1161, 1093 cmꢀ1; HRMS (ESI)
[M+H]+ calculated for C44H47O10: 735.3164, found: 735.3156.
ASSOCIATED CONTENT
Supporting Information
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Copies of NMR spectra and chiral HPLC chromatography for selected compounds, and Xꢀray
crystallographic data (CIF file) for compound 51. This material is available free of charge via the
Internet at http://pubs.acs.org.
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AUTHOR INFORMATION
Corresponding Author
*Eꢀmail: xglei@pku.edu.cn
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
We thank Ms. Mingyan Zhao, Rui Liu, Xiuli Han and Wei Li (NIBS) for NMR, HPLCꢀMS and
GCꢀMS analysis, Dr. Jiang Zhou (Peking University) for HRMS analysis. We are grateful to the
financial support from the National High Technology Projects 973 (2015CB856200) and NNSFC
(21222209, 91313303, and 21472010).
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