Versatile and Enantioselective Total Synthesis of Naturally Active Gnetulin

Article abstract of DOI:10.1002/adsc.201900336

A versatile and efficient enantioselective total synthesis of natural isorhapontigenin dimers (?)-gnetulin, (+)-gnetulin, and (±)-gentulin was proposed. By using this method, we were able to synthesize the dimers from commercial available achiral materials in 13 steps, and achieve a 7%–9% overall yield with >98% enantiomeric excess. The key features of the method include the stereocontrolled enantioselective conjugate reduction of 3-arylindenone catalyzed by methyloxazaborolidine (Me-CBS) and the α-arylation of 3-aryl-1-indanones. Benzylic sulfide was accessed in excellent yield through the InCl₃-catalyzed thio-etherification reaction between 2,3-diarylindanol and bezylic thiol. The method is practical and might thus be useful in the enantioselective synthesis of the optical antipodes of natural indane derivatives with or without methoxy groups at aromatic rings. (Figure presented.).

Full text of DOI:10.1002/adsc.201900336

Title: Versatile and Enantioselective Total Synthesis of Naturally Active
Gnetulin
Authors: Changhui Shang, Yulong Kang, Qingyun Yang, Qibin Zhu,
and Chunsuo Yao
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Advanced Synthesis & Catalysis
10.1002/adsc.201900336
FULL PAPER
DOI: 10.1002/adsc.201((will be filled in by the editorial staff))
Versatile and Enantioselective Total Synthesis of Naturally
Active Gnetulin
#
,a
#,a
a
a
a,
Changhui Shang, Yulong Kang, Qingyun Yang, Qibin Zhu, and Chunsuo Yao *
a
State Key Laboratory of Bioactive Substance and Function of Natural Medicines, Institute of Materia Medica, Chinese
Academy of Medical Sciences & Peking Union Medical College, Beijing 100050, P. R. China
Fax: +86-10-6301-7757; e-mail: yaocs@imm.ac.cn
These authors contributed equally to this work.
#
Received: ((will be filled in by the editorial staff))
Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/adsc.201######.((Please
delete if not appropriate))
Abstract. A versatile and efficient enantioselective total was accessed in excellent yield through the InCl
synthesis of natural isorhapontigenin dimers (–)-gnetulin, thio-etherification reaction between 2,3-diarylindanol and
+)-gnetulin, and (±)-gentulin was proposed. By using this bezylic thiol. The method is practical and might thus be
3
-catalyzed
(
method, we were able to synthesize the dimers from useful in the enantioselective synthesis of the optical
commercial available achiral materials in 13 steps, and antipodes of natural indane derivatives with or without
achieve a 7%–9% overall yield with >98% enantiomeric methoxy groups at aromatic rings.
excess. The key features of the method include the
stereocontrolled enantioselective conjugate reduction of 3-
arylindenone catalyzed by methyloxazaborolidine (Me-CBS) Keywords: asymmetric synthesis; enantioselectivity;
and the α-arylation of 3-aryl-1-indanones. Benzylic sulfide gnetulin; natural products; total synthesis
applicable to the synthesis of isorhapontigenin
Introduction
oligomers because the phenolic hydroxyl groups of
the intermediates in the procedure are usually
Oligostilbenes form a class of natural polyphenols
protected by methyl ethers before the main
derived from resveratrol (1) and isorhapontigenin (2).
frameworks
are
They have attracted considerable interest over the
past three decades owing to their intriguing skeletons
and multifaced activities.[ An increasing number of
synthetic chemists have focused on synthesizing
these natural oligomers, successfully achieving the
total synthesis of various oligomers, especially
stilbene dimers.[ The total synthesis of an array of
resveratrol oligomers, such as trans-δ-viniferin (3),
leachianol F (4), and pallidol (5) can be achieved
through either biomimetic synthesis strategies or
chemically controlled approaches.[3] However, little
attention has been directed to isorhapontigenin
oligomers, such as shegansu B (6), gnetuhainin I (7),
and gnetuhainin F (8), which have the same
Figure 2. Structures of natural gnetulin-like analogues.
1]
2]
[4]
framework as resveratrol oligomers (Figure 1). In
fact, the extra methoxy groups at the aromatic rings
of isorhapontigenin oligomers are the reasons that the
oligomers are rarely synthesized.[5] Generally,
traditional biomimetic synthesis generates different
oligomeric structures in low yield because of
insufficient regioselectivity in the direct oxidative
coupling of isorhapontigenin.[6] Several well-
designed cascade reactions and total synthetic routes
for the chemically controlled synthesis of resveratrol
oligomers are not readily
Figure 1. Some representative natural stilbenes.
1
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Advanced Synthesis & Catalysis
10.1002/adsc.201900336
constructed.[7] To the best of our knowledge, the
asymmetric total synthesis of oligomers, either
resveratrol or isorhapontigenin oligomers except (+)-
paucifloral F (9) is rarely reported.[8] The total
synthesis of oligostilbenes with methoxy groups in
The requisite intermediate (17) was assembled
through the asymmetric conjugate reduction of
indenone (18), which was made available
Scheme 1. Retrosynthetic analysis of (–)-10.
[5]
their aromatic rings are rarely reported as well,
by the intramoleclular Heck reaction of brominated
chalcone (19) prepared from an adol reaction between
3,5-dibenzyloxyacetophenone (20) and 3-methoxy-4-
although most of them can be found as stereoisomers
in nature. Thus, the development of an effective
synthetic route, especially an asymmetric synthetic
route, for the preparation of oligostilbenes with or
without methoxy groups at aromatic rings is of great
importance.
[8]
benzyloxybenzaldehyde (21).
The synthesis started with the preparation of requisite
indenone 18, which was prepared with the
intramolecular Heck reaction of chalcone 19 in dilute
Gnetulin (10), an isorhapontigenin dimer with 2,3-
diphenyl-1-indane and exocyclic double bond frame-
work (gnetulin-like analogue) isolated from different
plants of Gnetum (Gnetaceae), show multifaced
bioactivities (in vitro and in vivo), such as anti-
DMF in 53% yield and with the presence of PdCl .
2
The brominated chalcone 19 was smoothly prepared
in 87% yield with the adol condensation of the
acetophenone 20 (prepared from 22) and
benzaldehyde 21 (prepared from 23) under basic
conditions in the mixed solvent of methanol and
[9]
inflammatory and liver-protective activities. As far
as we know, in addition to gnetulin, only six gnetulin-
[8a]
water (Scheme 2). Notably, unlike in the synthetic
[6a,6b,12]
like analogues (11-16) have been found in nature
route to quadrangularin A,
all the phenolic
10]
(
Figure 2).[ Owing to their fascinating structures
hydroxyl groups were protected by benzyl groups
instead of methyls.
With indenone 18 in hand, we account our effort on
the asymmetric conjugate reduction reaction to
construct the key stereocenter upon the indenone
framework (Scheme 3). Initially, when indenone 18
and largely unexplored potential in medicine, these
natural products have become attractive targets for
total synthesis. Our continuous medicinal chemistry
research on stilbene dimers has enabled us to pursue
the total asymmetric synthesis and structure activity-
relationship study of the naturally active product
gnetulin.
Herein, a versatile and highly enantioselective total
synthetic approach for synthesizing gnetulin has been
achieved for the first time. This practical and efficient
route is useful to the synthesis (especially asymmetric
synthesis) and investigation of naturally active
oligostilbenes with or without methoxy groups at
aromatic rings.
Results and Discussion
Scheme 2. Synthesis of intermediate 18.
Two critical issues need to be addressed for the
development of a versatile, enantioselective approach
for synthesizing gnetulin 10. The first issue is the
selection of a suitable protecting group for the
phenolic hydroxyls. Such group tolerates strong alkali
and acid reaction conditions and can be deprotected
selectively in the presence of methyl ethers and
exocyclic double bonds. The second is the selection
of an appropriate asymmetric catalyst to build two
chiral centers at C-2 and C-3. Therefore, we envison
that the benzyl group is the suitable protecting group,
and the asymmetric reduction of indenone using
baker’s yeast or methyloxazaborolidine (Me-CBS) as
was exposed to 10% Pd/C under hydrogen
atmosphere in methanol and ethyl acetate at 25 °C,
the racemic indanone (±)-17 was obtained in 89%
yield (path I). The benzyl ether was cleaved by the
increase of the reaction temperature to 70 ℃ and
hydrogen pressure to 2 atm rather than by the
reduction of the double bond. The optical antipode
was obtained according to the procedure described by
[7c,11a,11b]
Clark and co-workers.
The enantioselective
conjugate reduction of 18 in an aqueous EtOH
produced
(+)-17
catalyst can be used to build the C-3 chiral
center.[
6c,11]
We mainly aims to design a synthetic
strategy by which natural products and natural
product-like analogues are rendered accessible. A
retrosynthetic route to (–)-10 is outlined in Scheme 1.
We conceived that indanone (17) is a viable
intermediate for the synthesis of (–)-10. For the
stereoselective installment of an aromatic group at the
C-2 position of indanone (17), an asymmetric
palladium-catalyzed α-arylation reaction was initiated.
2
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Advanced Synthesis & Catalysis
10.1002/adsc.201900336
(
2
R)-Me-CBS resulted in the generation of indenol (S)-
4, which generated (S)-(+)-17 by three suprafacial
Scheme 3. Enantioselective conjugate reduction of 18.
Reagents and conditions: Path I: 10% Pd/C, H , MeOH/
2
EtOAc, 0-25 ℃, 81% yield. Path II: baker’s yeast, α-D-
glucose, 1M NaOH, buffer (PH = 7.2), DMSO, 40 ℃, 7d,
1,5-sigmatropic hydrogen migrations in the presence
of DABCO. Similarly, the catalyst (S)-Me-CBS
generated (R)-(–)-17 through (R)-25 in high
stereoselectivity.
The enantioselective conjugate reduction of 3-
arylindenone in high enantiomeric excess was
reported
8
0% yield, 98% ee. Path III: a) (R)-Me-CBS (5% mol),
BH ·THF; b) Et N/DABCO (20% mol), THF, 40 ℃, two
steps: 86% yield, recryst. 98% ee. Path IV: a) (S)-Me-CBS
5% mol), BH ·THF; b) Et N/DABCO (20% mol), THF,
0 ℃, two steps: 89% yield, recryst. 99% ee. Yields of
isolated product are given.
3
3
(
4
3
3
Scheme 4. Proposed mechanisms for the conjugate
reduction of 18.
by Clark and Hedverg in 1998 and 2005, respectively.
However, as far as we know, this is the first to report
that enantiomers can be derived from different Me-
CBS catalysts [(R)-Me-CBS or (S)-Me-CBS]. That is,
as a product, the configuration of 3-arylindanone is
controllable, which depends on that of Me-CBS
catalysts.
with 85% yield and high enantiomeric excess (99%
ee, path II) when baker’s yeast was used as the
catalyst and α-D-glucose was present. However,
when a substrate in gram quantities was employed,
messy work-up and long reaction time led to the
generation of (+)-17 in low yield (< 60%). The
reaction generated only (S)-(+)-17. Nevertheless, we
attempted to develop a reliable method to access (S)-
The absolute configurations of the chiral
intermediates (+)-17 and (–)-17 were determined
[
13]
(
(
+)-17 and (R)-(–)-17 given that (+)-10, (–)-10, and
according to the excitation chirality theory.
The
±)-10 are found in nature.[ Fortunately, we
9]
positive cotton effect at 267 nm (Δε +3.70) observed
achieved our objective after using the method of
Clark and Hedverg.[
11c,11d]
Enantioselective ketone
reduction was achieved by slowly adding 18 to a
solution of the (R)-Me-CBS catalyst and BH ·THF in
3
THF at −20 °C. After quenching and evaporation, the
resulting indenol was treated with base
(
8
Et N/DABCO) in THF at reflux for 3 h. (+)-17 in
6% yield and 98.0% ee (path III) was obtained after
2
in
the
CD
Scheme 5. Pd(OAc)
2
-catalyzed α-arylation reaction of 3-
recrystallization. In this case, the fast quenching of
the reaction mixture is crucial to achieve a high yield
because the intermediate indenol (24 and 25), an
unstable allyl alcohol, is prone to degration and
isomerization in this conditions. Herein, the (R)-Me-
CBS-catalyzed enantioselective reduction of 18
aryl-1-indanone (–)-17.
spectrum (in CH
2
Cl ) indicated the 3S configuration
2
of (+)-17. The negative cotton effect at 267 nm (Δε –
3
.13) in the CD spectrum (in CH
2
Cl ) indicated the
2
3
R configuration of (–)-17. The opposite optical
following the treatment of the base (Et
2
N/DABCO)
20
D
20
D
rotations of (+)-17 and (–)-17 ([α]
= + 22.8 and [α]
=
generated (+)-17 in high yield and excellent ee value.
Interestingly, enantiomer (–)-17 in 89% yield and
–21.2 ) are in agreement with the above conjecture.
After preparing 3-aryl-1-indanone (–)-17, we turned
our attention to the establishment of 2,3-diaryl-1-
indanone (–)-27. The method described by Yangyang
9
9.0% ee (path IV) was obtained with the same
process but with (S)-Me-CBS as the asymmetric
catalyst.
[8a,8b]
and Lee
and phenyl bromide 26 were treated with Pd(OAc)
-(dicyclohexylphosphino)-2',4',6'-tri-i-propyl-1,1'-
was initially used when indanone (–)-17
Meanwhile, the experimental results indicated that
the absolute configuration of the production should
be controlled by the asymmetric catalyst used in the
first step. From a mechanistic view of point, three
suprafacial 1,5-sigmatropic hydrogen migrations
account for the high stereospecificity, as depicted in
Scheme 4.[ In this case, the asymmetric catalyst
2
,
2
bi-phenyl (XPhos), and t-BuONa in toluene at 120 °C
for 3 h, (–)-27 was obtained in moderate yield 53%
after recrystallization (Scheme 5). The bulky benzyl
group at the 3,5-dihydroxyl of the aromatic ring may
account for the low yield in this reaction. Thus, the
less bulky methyl and MOM groups as the protecting
12]
groups
of
3
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Advanced Synthesis & Catalysis
10.1002/adsc.201900336
8
9
1
1
1
ZnBr
BiCl
2
CH
CH
CH
THF
Toluene
dioxane
2
2
2
Cl
Cl
Cl
2
2
2
83
6
95
0
0
0
3
0
1
2
InCl
InCl
InCl
InCl
3
3
3
3
Scheme 6. Synthesis of (–)-10. Reagents and conditions: a
13
a
NaBH
8%. c) mCPBA, NaHCO
CCl : t-BuOH : H O (5 : 5 : 1), 80℃, 2 steps, 89% yield,
9% ee. e) AlCl , PhNMe , DCM, 0 to 25 ℃, 43% yield,
99% ee.
4
, MeOH : THF(1 : 1), 91%. b) 29, InCl
3
, DCM, 0 ℃,
All reactions were carried out at temperature 0-25°C
for 1h.
6
3
, DCM, 0 to 25 ℃. d) KOH,
4
2
9
>
3
2
exposure of (–)-28 and 29 to InCl (1 equiv) in
3
CH Cl produced the desired sulfide (–)-30 in
2
2
quantitative yield (isolated yield: 95%; entry 10).
3
,5-dihydroxyl at the aromatic ring were explored.
Meanwhile, (–)-28 was inert to InCl in THF, toluene,
3
Using methyl as protecting group, the yield was
increased to 88%. When MOM was used, 68% yield
was obtained. The results suggested that the steric
hindrance of the protecting groups of hydroxyls is
crucial to the α-arylation process. Meanwhile, (–)-27
was reduced to indanol (–)-28 efficiently (isolated
yield 91%) by sodium borohydride in THF and
methanol for 30 min (Scheme 6). Although the
products were obtained as a mixture of two isomers
and dioxane (entries 11,12, and 13).
The sulfide (–)-30 was then oxidized by mCPBA for
0.5 h in basic aqueous solution and dichloromethane.
After evaporation, we directly used the crude product
obtained without purification for the Ramberg-
Backlund reaction to furnish (–)-31, which was
identified as E-isomer, in 89% yield (Scheme
[
6b,12,14]
6).
Meanwhile, Z-isomer in approximate 5%
1
yield was obtained and detected by H NMR.
However, Z-isomer and E-isomer were inseparable
because of the bulky hindrance of the benzyl
protecting groups.
(
ratio 20 : 1), the main product was easily separable
by silica gel column chromatography. Moreover,
determining the configuration of the new chiral center
at the C-1 position was unnecessary because the
configuration would be abolished at the later stage.
The fourth suitable aryl ring was introduced into
After (–)-31 was obtained, the benzyl group was
removed selectively in the presence of methyl ether.
When indane (–)-31 was subjected to the conditions
[PhNMe (6 equiv), AlCl (12 equiv)] in CH Cl as
indanol (–)-28 by In(OTf)
3
-catalyzed nucleophilic
at room temperature (Scheme
). When indanols (–)-28 and 29 were exposed to
2
3
2
2
[15]
substitution in CH
2
Cl
2
described in the literature,
no desired compound
6
was observed, as indicated by the TLC. Then, the
In(OTf)
3
through the method described by Cheng and
reaction conditions were optimized intensively. The
Snyder,[
6b,12,14]
20
D
the desired sulfide (–)-30 was obtained
target product indane (–)-10 ([α]
–5.8) was obtained
only in 23% yield (Table 1, entry 1). At this point, we
changed several parameters (the concentrations,
successfully in moderate yield (43%, 99% ee) in the
presence of PhNMe (60 equiv) and AlCl (36 equiv)]
2
3
temperatures, and equivalents of In(OTf)
3
) to
in CH Cl (Scheme 6). The reaction efficiency was
2
2
improve the efficiency, but no satisfactory result was
obtained. A number of lewis acids were then
systematically examined. The key results are depicted
in Table 1. After (–)-28 and 29 were introduced to
improved by adjusting several parameters, but no
satisfactory result was obtained.
In this way we were able to accomplish the
2
0
enantioselective total synthesis of (+)-10 ([α] + 6.3)
D
2
0
Cu(OTf)
0 in low yield (5%–10%; entries 2, 5, and 9) was
obtained. Indanol (–)-28 and thiol 29 were found to
be inert to Sc(OTf) and FeCl (entries 4 and 6). The
desired thio-etherification reaction occurred in the
presence of 1 equiv of Zn(OTf) , AlCl , and ZnBr in
2
, FeCl
3
, and BiCl
3
in dichloromethane, (–)-
from (+)-17 ([α] + 22.8) in 13 steps with an overall
D
3
yield of 7.46% (98% ee). The total synthesis of (±)-
1
0 from (±)-17 was achieved in an overall yield of
1
13
3
2
7
.43% (Figure 3). Specifically, the H and C NMR,
IR, UV spectra and HR-MS-ESI of the synthetic
indanes (+)-10, (–)-10, and (±)-10 are in great
agreement with the respective data reported as natural
2
3
2
dichloro-methane but in modest yield (entries 3, 7,
and 8). The
[9]
products.
Table 1. Synthesis of sulfide (–)-30 catalyzed by
Lewis acid.a
Entry
Catalyst
Solvent
Yield(%)
1
2
3
4
5
6
7
In(OTf)
Cu(OTf)
Zn(OTf)
Sc(OTf)
3
CH
CH
CH
CH
CH
CH
CH
2
Cl
2
Cl
2
Cl
2
Cl
2
Cl
2
Cl
2
Cl
2
2
2
2
2
2
2
23
10
86
0
5
0
2
Figure 3. Structures of synthetic (+)-10 and (±)-10
2
3
FeCl
FeCl
AlCl
3
2
3
Additionally, the stereostructures of compounds (–)-
10 and (+)-10 were also further confirmed by CD
spectra. Compound (–)-10 and (–)-ampelopsin D
68
4
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Advanced Synthesis & Catalysis
10.1002/adsc.201900336
have the same carbon skeleton. The absolute structure
1-(3,5-Bisphenylmethoxyphenyl)ethanone (22a)
of the latter is 2R, 3S with positive cotton effects
To a solution of 22 (10 g, 65.8 mmol) in anhydrous
acetone (400 mL) was added K CO (36.3 g, 263.0 mmol).
2 3
After stirring for 10 min, benzyl bromide (34 g, 223.7
mmol) was added slowly, and stirred for 10 h at room
temperature. After completion, the reaction mixture was
filtered through a short pad of celite, washed with acetone
(
CEs) at 237 and 272 nm and a negative CE at 314
[10b,16]
nm in the CD spectrum.
On the basis of the
negative CD signals at 236 nm (Δε –1.61) and
positive CE at 315 nm (Δε +0.64), the absolute
configuration of (–)-10 was elucidated to be 2S, 3R.
Similarly, the configuration of the synthetic gnetulin
(
500 mL), and concentrated in vacuo. The remaining
residue was then recrystallized in MeOH/CH Cl to furnish
22a (21.2 g, 97%) as a brown solid. H NMR (500 MHz,
CDCl ): δ = 7.33-7.45 (m, 10H), 7.21 (d, J = 2.3 Hz, 2H),
.82 (t, J = 2.3 Hz, 1H), 5.08 (s, 4H), 2.56 (s, 3H); 13
(
+)-10 is 2R,3S according to its CD spectra [238 (Δε
6.43), 315 (Δε –0.21),] and opposite optical rotation
2
2
+
1
20
(
[α] = + 6.3).
D
3
6
C
NMR (125 MHz, CDCl
3
): δ = 197.9, 160.1 (2 × C), 139.1,
Conclusion
1
1
36.5 (2 × C), 128.8 (4 × C), 128.3 (2 × C), 127.8 (4 × C),
07.5 (2 × C), 106.9, 70.5 (2 × C), 26.9; HR - MS (ESI):
The versatile, efficent, and highly enantioselective
total synthesis of natural (–)-gnetulin (13 steps,
+
m/z = 333.1482, calcd for C22
H
21
O
3
[M + H] , 333.1485.
9
7
.11% overall yield) and (+)-gnetulin (13 steps,
.46% overall yield) with methoxy groups at the
2
-Bromo-3,5-bisphenylmethoxyacetophenone (20)
aromatic rings was achieved for the first time in a
straightforward fasion. Commercially available 3,5-
dihydroxy acetophenone and 3-methoxy-4-hydroxyl
benzaldehyde were used as the starting material. The
total synthesis of the natural (±)-gnetulin (13 steps,
NBS (10 g, 66.2 mmol) was added to a solution of 22a (20
g, 60.2 mmol) in anhydrous DMF (400 mL), the mixture
was then stirred for 10 h in the dark at room temperature.
Upon completion, the reaction mixture was extracted with
ethyl acetate (3 × 200 mL). The combined organic layer
was then washed with water and brine, dried over MgSO4
7
.43% overall yield) was also reported by a closely
related report. In the course of the asymmetric
conjugate reduction reaction of 3-aryl indenone, Me-
CBS catalysts with different configura-tions [(R)-Me-
CBS or (S)-Me-CBS] generated different enantiomers
in high yield and excellent enantioselectivity. When
and concentrated in vacuo to give compound 20 (22.5g,
1
9
1%) as a yellow solid. H NMR (500 MHz, acetone - d
6
):
δ = 7.34 - 7.55 (m, 10H), 6.93 (d, J = 2.6 Hz, 1H), 6.75 (d,
J = 2.6 Hz, 1H), 5.26 (s, 2H), 5.16 (s, 2H), 2.53 (s, 3H);
13
C NMR (125 MHz, acetone - d ): δ = 202.4, 159.1, 156.1,
6
InCl
3
was used as the catalyst, benzylic sulfide was
144.4, 136.1 (2 × C), 128.9 (2 × C), 128.8 (2 × C), 128.5,
accessible in excellent yield through the thio-
etherification reaction of 2,3-diarylindanol and
benzyl mercaptan. This report thus showed that the
versatile method may be used for the enantioselective
synthesis of the different optical antipodes of natural
indane derivatives with or without methoxys at the
aromatic rings. The method can be applied to the
enantioselective synthesis of other naturally stilbene
oligomers with biological activity
1
7
C
28.2, 127.7 (2 × C), 127.1 (2 × C), 105.6, 103.6, 100.1,
1.2, 70.7, 30.8; HR-MS (ESI): m/z = 411.0586, calcd for
+
22
H
20
O
3
Br [M + H] , 411.0590.
(
(
2E)-1-(2-Bromo-3,5-bisphenylmethoxyphenyl)-3-
3-methoxy-4-phenylmethoxyphenyl)-2-propen-1-
one (19)
To a solution of 20 (20 g, 48.8 mmol) in MeOH (2000 mL)
was added a solution of NaOH (8 g, 0.20 mol) in water
(
5
200 mL). After stirring for 10 min, compound 21 (14.2 g,
8.6 mmol) was added and the solution was stirred for 10 h
Experimental Section
at 70 ℃in the dark. After completion, the resulting mixture
was filtered to give 19 ( 27.5 g, 87%) as a yellow solid. H
1
3-Methoxy-4-(phenylmethoxy)benzaldehyde (21)
NMR (400 MHz, acetone - d
6
): δ = 7.31-7.57 (m, 17H),
To a solution of 3-methoxy-4-hydroxylbenzaldehyde (23)
10 g, 65.8 mmol) in anhydrous acetone (300 mL) was
added K CO (18.2 g, 131.9 mmol). After stirring for 10
7
6
2
.19 (dd, J = 8.0 Hz, 2 Hz, 1H), 7.09 (d, J = 8.0 Hz, 1H),
(
.97 (d, J = 16.0 Hz, 1H), 6.96 (d, J = 2.6 Hz, 1H), 5.29 (s,
13
2
3
H), 5.19 (s, 2H), 5.18 (s, 2H), 3.89 (s, 3H); C NMR
min, benzyl bromide (23.6 g, 155.3 mmol) was then added
slowly, and the mixture was stirred for 10 h at room
temperature. After completion, the reaction mixture was
filtered through a short pad of celite following rinsing with
acetone (300 mL). The solution was concentrated in vacuo,
(
1
100 MHz, acetone - d
51.1, 147.7, 144.7, 138.0, 137.6 (2 × C), 129-128.2 (12 ×
6
): δ = 194.8, 160.2, 156.9, 152.1,
C), 125.2, 124.3, 114.3, 111.9, 107.1, 103.6, 71.6, 71.2,
1.1, 56.3; HR - MS (ESI): m/z = 635.1424, calcd for
7
+
37 32 5
C H O Br [M + H] : 635.1428.
and recrystallized in MeOH/CH
2
Cl
5%) as a colourless solid. H NMR (500 MHz, acetone -
): δ = 9.87 (s, 1H), 7.52 (m, 3H), 7.45 (d, J = 1.9 Hz, 2H),
.41 (m, 2H), 7.36 (m, 1H), 7.24 (d, J = 8.2 Hz ,1H), 5.26
2
to give 21 (15.1 g,
1
9
d
7
4
,6-Bisphenylmethoxy-3-(3-methoxy-4-phenyl
6
methoxyphenyl)-inden-1-one (18)
1
3
2 3 2 3
PdCl (348 mg, 5% mmol), PPh (1.0 g, 10%) and K CO
(
mmol) in anhydrous DMF (500 mL), the mixture was then
stirred at 140 C for 3 h. After that, the reaction mixture
(
s, 2H), 3.91 (s, 3H); C NMR (125 MHz, acetone - d
191.1, 153.7, 150.1, 136.1, 130.4, 128.9 (2 × C), 128.3,
27.3 (2 × C), 126.8, 112.4, 109.3, 70.5, 56.2; HR - MS
6
): δ
22.1 g, 0.16 mol) was added to a solution of 19 (25 g, 39.4
=
1
o
+
(
15 3
ESI): m/z = 243.1014, calcd for C15H O [M + H] :
was quenched with water, and extracted with ethyl acetate
2
43.1016.
5
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Advanced Synthesis & Catalysis
10.1002/adsc.201900336
(
3 × 500 mL). The combined organic layer was then
1H), 3.70 (s, 3H), 3.19 (dd, J = 8.0 Hz, 19.0 Hz, 1H), 2.63
(dd, J = 2.5 Hz, 19.0 Hz, 1H); 13C NMR (125 MHz,
washed with water and brine, dried over MgSO and
4
concentrated in vaccuo consecutively. The obtained
3
CDCl ): δ = 206.6, 160.8, 156.8, 149.7, 146.8, 140.4, 139.1,
residue was purified by flash column chromatography
137.4, 137.4, 136.4, 136.1, 128.8 (2 × C), 128.7 (2 × C),
128.5 (2 × C), 128.4, 128.0, 127.9, 127.8 (2 × C), 127.3 (2
× C), 127.2 (2 × C), 119.1, 114.2, 111.5, 107.7, 97.2, 71.2,
70.6, 70.0, 56.0, 47.7, 41.3; HR - MS (ESI): m/z =
(
silica gel, petroleum ether : acetone 10 : 1) to produce
1
compound 18 ( 16.6 g, 76%) as a red solid. H NMR (500
MHz, acetone - d ): δ = 7.10 - 7.43 (m, 15H), 7.00 (m,
H ), 6.87 (d, J = 2.1 Hz, 1H), 6.70 (d, J = 9.0 Hz, 1H),
6
+
20
D
2
6
2
557.2318, calcd for C37
22.8 (c 0.20, CH Cl
determined by HPLC with a Chiralpak IA column
H
33
O
5
[M + H] : 557.2323; [α]
= +
.56 (d, J = 2.2 Hz, 1H), 5.70 (s, 1H), 5.14 (s, 2H), 5.05 (s,
2
2
); The enantiomeric excess was
H), 4.88 (s, 2H), 3.62 (s, 3H); 1 C NMR (125 MHz,
3
-
1
acetone - d
6
): δ = 196.4, 166.5, 162.2, 153.8, 149.7, 148.5,
37.0, 136.6, 136.3, 135.8, 128.8 - 127.3 (12 × C), 122.0,
21.7, 121.4, 112.5, 112.0, 105.9, 104.0, 71.2, 70.9, 70.7,
5.8; HR - MS (ESI): m/z = 555.2166, calcd for C37
(hexane : i-PrOH 50 : 50), 25 °C, λ = 320 nm, 0.5 mLmin ,
ee value: 98%, major enantiomer t = 34.9 min, minor
enantiomer t = 24.7 min.
1
1
5
S
R
31 5
H O
+
[
M + H] : 555.2166.
(R)-(–)-4,6-Bisphenylmethoxy-3-(3-methoxy-4-
phenylmethoxyphenyl)-inden-1-one [(–)-17]
4
,6-Bisphenylmethoxy-3-(3-methoxy-4-phenyl
A solution of commercial (S)-Me-CBS 0.1 mL (1 M in
toluene, 0.1 mmol) in dry THF (5 mL) was cooled to -20 ℃
methoxyphenyl)-inden-1-one [(±)-17]
Pd-C (0.2 g, 20%) was added to a solution of 18 (1 g, 1.8
mmol) in anhydrous MeOH (30 mL). The mixture was
stirred at room temperature for 30 min under a hydrogen
atmosphere. The reaction mixture was then filtered through
a short pad of celite, washed with acetone (50 mL), and
3
under argon atmosphere. 1mL BH ·THF (2 M, 2.0 mmol)
was added and the mixture was stirred for 10 min. A
solution of 18 (1.00 g, 1.8 mmol) in THF (2 mL) was
added over 0.5 h via a syringe pump. After completetion,
MeOH (0.6 mL) was added at 0℃ and the mixture was
evaporated in vaccuo to afford a residue as a red oil, which
would be carried forward to the next step without further
purification.
concented in vaccuo to provide compound (±)-17 (0.82 g,
1
8
1%) as a colourless solid. H NMR (500 MHz, CDCl
3
): δ
=
7.45 - 7.20 (m, 13H), 6.94 - 6.91 (m, 3H), 6.77 (m, 2H),
6
5
.61 (d, J = 2.5 Hz, 1H), 6.52 (dd, J = 2.0 Hz, 8.0 Hz, 1H),
.14 (s, 2H), 5.08 (s, 2H), 4.91 (d, J = 11.5 Hz, 1H), 4.84
A mixture of the residue obtained above and DABCO (0.1
g, 0.9 mmol) in dry THF : Et N (15 mL, 20 : 1, v : v) was
3
(
(
2
2
1
1
d, J = 11.5 Hz, 1H), 4.51 (dd, J = 2.5 Hz, 8 Hz, 1H), 3.70
s, 3H), 3.19 (dd, J = 8.0 Hz, 19.0 Hz, 1H), 2.63 (dd, J =
.5 Hz, 19 Hz, 1H); C NMR (125 MHz, CDCl ): δ =
3
06.6, 160.8, 156.8, 149.7, 146.8, 140.4, 139.1, 137.4,
37.4, 136.4, 136.1, 128.8 - 127.2 (16 × C), 119.1, 114.2,
refluxed for 3h. The reaction was monitored by TLC until
the substrate disappeared. Then the reaction mixture was
evaporated under reduced pressure to dryness, which was
recrystallized in acetone to provide (–)-17 (890 mg, 89%
1
3
2 2
yield over two steps) as a white solid. CD (CH Cl ) λmax
11.5, 107.7, 97.2, 71.2, 70.6, 70.0, 56.0, 47.7, 41.3; HR-
(∆ε) 239 (+22.63), 267.5 (–3.13), 313 (–8.25), 345.5
(+8.09) nm; HR - MS (ESI): m/z = 557.2318, calcd for
+
MS (ESI): m/z = 557.2318, calcd for C37
5
H
33
O
5
[M + H] :
+
20
D
57.2323.
C
CH
37
H
33
O
5
[M + H] : 557.2323; [α]
= –21.2 (c 0.75,
1
13
2 2
Cl , 99% ee). H NMR and C NMR spectral data
(
S)-(+)-4,6-Bisphenylmethoxy-3-(3-methoxy-4-phenyl
were in agreement with those of (–)-17.
methoxyphenyl)-inden-1-one [(+)-17]
(
2R,3R)-(–)-2-(3,5-Bisphenylmethoxyphenyl)-4,6-
To a 2000 mL round-bottomed flask charged with an
aqueous phosphate buffer solution (1000 mL, pH = 7)
warmed to 40 °C were added bakers’ yeast (5 g) and α-D-
glucose (6 g). 18 (1 g, 1.81mmol) was dissolved in 5 mL
hot DMSO (1.5 mL), and the solution was added to the
reaction mixture. A neutral pH was maintained through
occasional addition of aqueous solution of NaOH (1 M).
The mixture was stirred continuously for 7 days at 40 °C.
After completion, the reaction mixture was cooled to room
temperature, and EtOH (1000 mL) was added. Then the
mixture was filtered and the filtrate was extracted with
EtOAc/acetone (2:1, 4 × 1500 mL). The organic layer was
bisphenylmethoxy-3-(3-methoxy-4-phenylmetho-
xyphenyl)-2,3-dihydroinden-1-one [(–)-27]
To a vial (100 mL) was added (–)-17 (5 g, 9.0 mmol), 26
(6.6 g, 18.0mmol), Pd(OAc) (89.8 mg, 0.4 mmol), x-Phos
2
(333.2 mg, 0.7 mmol), and t-BuONa (1.0 g, 10.8 mmol) in
a glovebox. After addition of toluene (10 mL), the vial was
sealed with a screw cap and the reaction was heated at 120
o
C for 3 h. The mixture was then cooled to room
temperature, and filt ֠e red through a short pad of celite
following rinsing with EtOAc (50 mL). The combined
organic layer was then washed with water and brine, dried
washed with H
concentrated under reduced pressure to furnish compound
+)-17 (0.8g, 80%) as a colourless solid after column
chromatography (silica gel, petroleum ether : acetone 10 :
2
O and brine, dried over MgSO
4
, and
over MgSO
remaining residue was finally purified by flash column
chromatography (silica gel, petroleum ether : CH Cl
EtOAc 40 : 10 : 1) to give compound (–)-27 (4.0 g, 53%)
as a colourless solid. CD (CH Cl ) λmax (∆ε) 273 (–3.84),
324.5 (–6.02), 358 (+2.63) nm; H NMR (400 MHz,
CDCl ): δ = 7.48 - 7.18 (m, 24H), 7.00 (d, J = 2.0 Hz, 1H),
4
and concentrated under reduced pressure. The
(
2
2
:
1
). CD (CH
12.5 (+8.80), 345.5 (–8.43) nm; H NMR (500 MHz,
): δ = 7.45 - 7.20 (m, 13H), 6.94 - 6.91 (m, 3H), 6.77
m, 2H), 6.61 (d, J = 2.5 Hz, 1H), 6.52 (dd, J = 2.0 Hz, 8.0
Hz, 1H), 5.14 (s, 2H), 5.08 (s, 2H), 4.91 (d, J = 11.5 Hz,
2
Cl
2
) λmax (∆ε) 239 (–22.41), 267 (+3.70),
2
2
1
1
3
CDCl
3
3
(
6.90 (m, 2H), 6.83 (d, J = 2.0 Hz, 1H), 6.79 (d, J = 8.4 Hz,
1H), 6.58 (d, J = 2.0 Hz, 1H), 6.51 (m, 2H), 6.36 (d, J =
1
H), 4.84 (d, J = 11.5 Hz, 1H), 4.51 (dd, J = 2.5 Hz, 8.0 Hz, 2.0 Hz, 2H), 5.15 (s, 2H), 5.11 (s, 2H), 4.96 (s, 4H), 4.92
6
This article is protected by copyright. All rights reserved.

Advanced Synthesis & Catalysis
10.1002/adsc.201900336
(
=
d, J = 12.0 Hz, 1H), 4.85 (d, J = 12.0 Hz, 1H), 4.50 (d, J
(125 MHz, CDCl
3
): δ = 160.7, 160.0 (2 × C), 155.8, 149.6,
1
3
2.8 Hz, 1H), 3.69 (m, 4H); C NMR (125 MHz, CDCl
3
):
149.4, 147.2, 146.7, 146.4, 145.1, 138.3, 137.7, 137.2,
137.0, 136.9 (2 × C), 136.6, 131.4, 128.8 - 126.8 (30 × C),
125.1, 121.2, 119.9, 113.7 (2 × C), 112.5, 112.0, 106.9 (2 ×
C), 101.7, 100.6, 100.4, 71.2, 71.1, 70.5, 70.1 (2 × C), 69.5,
δ = 205.6, 161.1, 160.3 (2 × C), 156.7, 149.7, 147.0, 141.6,
1
1
39.2, 138.5, 137.4, 136.8 (2 × C), 136.7, 136.3, 136.0,
28.8 - 127.1 (25 × C), 119.2, 114.2, 111.5, 108.2, 107.3
(
5
C
2 × C), 100.6, 97.8, 71.2, 70.7, 70.2 (2 × C), 69.9, 65.1,
66.2, 57.2, 56.2, 56.1, 55.9, 35.7; HR - MS (ESI): m/z =
+
6.1, 51.7; HR - MS (ESI): m/z = 845.3469, calcd for
1111.4204, calcd for C72
[α] = –21.2 (c 0.75, CH Cl ).
2 2
H
64
O
8
NaS [M + Na] : 1111.4214;
+
20
D
20
57
H
49
O
7
[M + H] : 845.3473; [α]
= –149 (c 0.17,
D
CH
2 2
Cl ).
(
2S,3R)-(–)-Perbenzylated gnetulin [(–)-31]
(
2R,3R)-(–)-2-(3,5-Bisphenylmethoxyphenyl)-4,6-
To a solution of sulfide (–)-30 (700 mg, 0.64 mmol) in
CH Cl (15 mL) was added solid NaHCO (244 mg, 2.9
mmol) and mCPBA (85%, 448 mg, 2.6 mmol) sequentially
at 0 ℃ to give a milk-colored slurry. After slowly warming
to 25 ℃ and stirring for 30 min, the reaction mixture was
quenched with saturated aqueous NaHCO
poured into water (10 mL), and extracted with CH
10 mL). The combined organic layer was then washed with
brine (3×10 mL), dried over anhydrous sodium sulfate,
filtered, and concentrated in vacuo to give a desired
sulfone intermediate (720 mg) as yellow oil. Then, this oil
bisphenylmethoxy-3-(3-methoxy-4-phenylmetho-
xyphenyl)-2,3-dihydro-1H-inden-1-ol [(–)-28]
2
2
3
4
NaBH (66 mg, 1.77 mmol) and methanol (15 mL) were
added in sequence to a solution of (–)-27 (1.00 g, 1.18
mmol) in THF (15 mL) at room temperature, and the
mixture was stirred for 30 min. Upon completion, the
reaction was quenched with water, the organic layer was
separated, and the aqueous layer was extracted with ethyl
acetate (3×15 mL). Then, the combined organic extracts
were washed with brine (30 mL), dried over anhydrous
sodium sulfate, filtered, and concentrated in vacuo to
3
(10 mL),
Cl (3 ×
2
2
4 2
was dissolved in a mixture of CCl -t-BuOH-H O (22 mL,
1
afford compound (–)-28 (0.92g, 91%) as a white solid. H
NMR (400 MHz, CDCl
v : v : v = 5 : 5 : 1), and KOH (717 mg, 12.8 mmol) was
added at 25 °C. The resulted slurry was then stirred for 4 h
at 80 ℃. Upon completion, the reaction mixture was
3
): δ = 7.48 - 6.78 (m, 25H), 6.75
(
m, 2H), 6.64 (d, J = 2.0 Hz, 1H), 6.56 (m, 2H), 6.51 (t, J
=
1
2.4 Hz, 1H), 6.43 (d, J = 2.4 Hz, 1H), 5.20 (d, J = 6.4 Hz, quenched with saturated aqueous NH
H), 5.11 (s, 2H), 5.10 (s, 2H), 4.96 (s, 4H), 4.84 (d, J = 12
4
Cl (10 mL), poured
Cl (3 × 15
into water (10 mL), and extracted with CH
2
2
Hz, 1H), 4.82 (d, J =12 Hz, 1H), 4.24 (d, J = 7.6 Hz, 1H),
mL). The combined organic layers were washed with brine
(3 × 10 mL), dried over anhydrous sodium sulfate, filtered,
and concentrated in vacuo. The remaining residue was
1
3
3
.68 (s, 3H), 3.21 (t, J = 7.2 Hz, 1H); C NMR (125 MHz,
CDCl ): δ = 160.8, 160.1 (2 × C), 156.0, 149.5, 146.8,
46.2, 144.0, 137.8, 137.6, 137.0, 136.9 (2 × C), 136.6,
28.8 - 126.8 (25 × C), 123.9, 119.9, 113.8, 111.8, 107.2
3
1
1
recrystallized in MeOH-CH
89% over two steps) as a brown solid. CD (CH
2
Cl
2
to produce (–)-31 (610 mg,
Cl
2
2
) λmax
(
(
2 × C), 101.3, 100.5 (2 × C), 100.5, 82.0, 71.2, 70.5, 70.1
(Δε) 230 (–15.13), 249 (+2.38), 264.5 (–12.63), 295 (–
1
2 × C), 69.8, 67.5, 56.1, 54.1; HR - MS (ESI): m/z =
1.71), 316.5 (+0.88), 337 (–0.80), 365.5 (–0.89) nm; H
+
8
069.3434, calcd for C57
H
50
O
7
Na [M + Na] : 869.3449; [α]
NMR (600 MHz, CDCl
(
(
3
): δ = 7.52 - 7.22 (m, 28H), 7.10
br s, 1H), 7.01 (d, J = 6.6 Hz, 2H), 6.95 (br s, 1H), 6.82
br d, 1H), 6.79 (br s, 1H), 6.75 (m, 2H), 6.67 (br s, 1H),
2
D
2 2
= –63.0 (c 0.14, CH Cl ).
6
5
.56 (br d, 2H), 6.53 (br d, 2H), 6.47 (m, 2H),5.16 (s, 2H),
.13 (m, 4H), 5.12 (m, 4H), 4.95 (s, 4H), 4.87 (d, J = 12
(
2S,3R)-(–)-(3-Methoxy-4-phenylmethoxyphenyl)-
-(3,5-bisphenylmethoxyphenyl)-4,6-bisphenylme
2
Hz, 1H), 4.81 (d, J = 12 Hz, 1H), 4.37 ( br s, 1H), 4.30 ( br
thoxyl-3-(3-methoxy-4-phenylmethoxyphenyl)-2,3-
s, 1H), 3.66 (s, 3H), 3.53 (s, 3H); 13C NMR (150 MHz,
dihydro-1H-inden-1-yl)sulfane [(–)-30]
CDCl
3
): δ = 160.7, 160.3 (2 × C), 156.4, 149.4, 149.3,
3
1
1
0
-methoxy-4-benzyloxybenzyl mercaptan 29 (276 mg,
.06 mmol) was added to a suspension of (–)-28 (900 mg,
1
1
1
1
9
1
47.9, 147.3, 147.0, 145.1, 142.5, 139.2, 137.6, 137.2,
37.1, 136.9 (2 × C), 136.8, 130.5, 128.7 - 127.3 (31 × C),
27.3, 123.0, 122.4, 119.0, 114.2, 113.6, 111.9, 111.6,
06.6 (2 × C), 101.1, 71.2, 71.0, 70.6, 70.1 (2 × C), 69.6,
9.8, 96.5, 58.9, 57.6, 56.0, 55.7; HR - MS (ESI): m/z =
3 2 2
.06 mmol) and InCl (141 mg, 1.06 mmol) in CH Cl at
°C. The resultant viscous red mixture was stirred for 30
min at 0 °C in the dark. Upon completion, the reaction
mixture was quenched with saturated aqueous NH Cl (15
+
2
D
0
4
055.4508, calcd for C72
–24.7 (c 0.44, CH Cl
determined by HPLC with a Chiralpak IA column
H
O
[M + H] , 1055.4518; [α]
63
8
mL), filtered through celite, and extracted with ethyl
acetate (3 × 10 mL). The combined organic layer was
washed with water (15 mL) and brine (15 mL), dried over
anhydrous sodium sulfate, filtered, and concentrated in
vacuo. The resulted yellow solid was purified by flash
column chromatography (silica gel, petroleum ether-
=
2
2
); The enantiomeric excess was
-
1
(
hexane : i-PrOH 60 : 40), 25 °C, λ = 320 nm, 1.0 mLmin ,
ee value: >99%, major enantiomer t2S3R = 12.3 min, minor
enantiomer t2R3S = 15.3 min.
acetone 5 : 1) to get sulfide (–)-30 (1100 mg, 95%) as a
(
2S,3R)-(–)-Gnetulin [(–)-10]
1
colourless solid. H NMR (400 MHz, CDCl
3
): δ = 7.48 -
PhNMe
2 3
(1.4 mL, 11.4 mmol) and AlCl (9.9 mg, 6.84
6
1
6
.78 (m, 30H), 6.77 (d, J = 8.0 Hz, 1H), 6.72 (d, J = 2.0 Hz,
H), 6.70 (d, J = 8.0 Hz, 1H), 6.64 (m, 2H), 6.57 (m, 2H),
.51 (t, J = 2.4 Hz, 1H), 6.50 (d, J = 2.5 Hz, 1H), 6.37 (d, J
mmol) were added to a solution of (–)-31 (200 mg, 0.19
o
mmol) in anhydrous CH
at room temperature for 6 h. Upon completion, the reaction
mixture was quenched with saturated aqueous NH Cl, and
2 2
Cl (10 mL) at 0 C, then stirred
=
2.4 Hz, 2H), 5.13 (s, 2H), 5.04 (m, 4H), 4.94 (m, 4H),
4
4
(
.80 (m, 2H), 4.29 (m, 2H), 3.73 (s, 3H), 3.68 (s, 3H), 3.58
dd, J = 13.4 Hz, 2H), 3.46 (t, J = 6.8 Hz, 1H); 1 C NMR
3
extracted with ethyl acetate (3 × 20 mL). The combined
7
This article is protected by copyright. All rights reserved.

Advanced Synthesis & Catalysis
10.1002/adsc.201900336
organic layers were then washed with water and brine,
Shen, X. N. Wang, H. X. Lou, Nat. Prod. Rep. 2009, 26,
916–935.
dried over MgSO
was then purified by flash column chromatography (silica
gel, MeOH : CH Cl = 1 : 10) to give (–)-10 (42 mg, 43%).
4
and concentrated in vacuo. The residue
[
2] a) R. H. Cichewicz, S. A. Kouzi, M. T. Hamann, J. Nat.
Prod. 2000, 63, 29–33; b) Y. Tajaya, K. Terashima, J.
Ito, Y. H. He, M. Tateoka, N. Yamaguchi, M. Niwa;
Tetrahedron 2005, 61, 10285–10290; c) Y. Natori, M.
Ito, M. Anada, H. Nambu, S. Hashimoto, Tetrahedron
Lett. 2015, 56, 7259–7265.
2
2
The spectral data were in excellent agreement with those
reported. CD (MeOH) λmax (Δε) 211 (–8.99), 236.5 (–1.61),
2
83.5 (+0.33), 296 (+0.08), 315.5 (+0.64), 359.5 (–0.51)
1
nm; H NMR (500 MHz, acetone - d
6
6
6
): δ = 7.06 ( br s 1H),
.90 (d, J = 2 Hz, 1H), 6.84 (dd, J = 8.0 Hz, 2.0 Hz, 1H),
.79 (d J = 2.0 Hz, 1H), 6.75 (d, J = 2.0 Hz, 1H), 6.69 (d, J
8.0 Hz, 1H), 6.65 (d, J = 8.0 Hz, 1H), 6.51 (dd, J = 8.0
[3] a) P. Langcake, R. J. Pryce, J.C.S. Chem. Comm. 1977,
208-210; b) T. Song, B. Zhou, G. W. Peng, Q. B.
Zhang, L. Z. Wu, Q. Liu, Y. Wang, Chem. Eur. J. 2014,
20, 678 –682; c) Y. Takaya, K. X. Yan, K. Terashima,
Y. H. He, M. Niwa, Tetrahedron 2002, 58, 9265–9271.
=
Hz, 2.0 Hz, 1H), 6.35 (d, J = 2.0 Hz, 1H), 6.31 (d, J = 2.0
Hz, 1H), 6.20 (t, J = 2.0 Hz, 1H), 4.28 ( br s, 1H), 4.20 (brs,
3
1
H), 3.72 (s, 3H), 3.58 (s, 3H); 1 C NMR (125 MHz,
acetone - d
1
1
6
): δ = 159.8 (2 × C), 159.7, 155.9, 149.2, 148.1,
48.0, 147.4, 146.6, 145.8, 142.8, 138.4, 130.2, 124.5,
23.9, 123.3, 120.0, 115.6 (2 × C), 112.1, 111.7, 106.3 (2 ×
[
4] a) C. S.Yao, M. Lin, L. Wang, Chem. Pharm. Bull.
006, 54, 1053–1057; b) K. S. Huang, Y. H. Wang, R.
L. Li, Phytochemistry 2000, 54, 875–881.
2
C), 103.8, 101.5, 98.4, 60.7, 58.0, 56.2, 56.1; UV (MeOH)
max (logε): 205 (4.5), 225 (4.3), 289 (3.9), 333 (4.0), 348
4.0) nm; IR: νmax = 3351, 2922, 2851, 1704, 1600, 1515,
453, 1428, 1378, 1280, 1156, 1127, 1082, 1031, 838, 819
λ
(
[5] W. L. Li, S. X. Yang, T. Lv, Y. D. Yang, Org. Biomol.
Chem. 2014, 12, 2273–2279.
1
-
1
[6] a) B. Chen, J. P. Lu, X. G. Xie, X. G. She, X. F. Pan,
Chin. J. Org. Chem. 2006, 26, 1300–1302; b) S. A.
Snyder, S. P. Breazzano, A. G. Ross, Y. Lin, A. L.
Zografos, J. Am. Chem. Soc. 2009, 131, 1753–1765.
cm ; HR - MS (ESI): m/z = 515.1698, calcd for C30
H
27
O
8
+
20
D
[
M + H] , 515.1700; [α]
= –5.8 (c 0.12, MeOH); The
enantiomeric excess was determined by HPLC with a
Chiralpak IA column (hexane : i-PrOH 70 : 30), 25 °C, λ =
-
1
3
20 nm, 1.0 mLmin , ee value: 99%, major enantiomer
[
7] a) W. L. Li, H. Li, Y. Li, Z. J. Hou, Angew. Chem. Int
Ed. 2006, 45, 7771–7773; b) J. L. Jeffrey, R. Sarpong,
Org. Lett. 2009, 11, 5450–5453; c) D. J. Kerr, M.
Miletic, N. Manchala, J. M. White, B. L.Flynn, Org.
Lett. 2013, 15, 4118–4121.
t2S3R = 5.8 min, minor enantiomer t2R3S = 9.2 min.
(
2R,3S)- (+)-Gnetulin [(+)-10]
Following the same procedure described above but starting
from the indanone (+)-17, (2R,3S)-(+)-gnetulin (+)-10 was
obtained as a pale powder; overall yield: 7.46%; CD
[8] a) B. H. Lee, Y. L. Choi, S. Shin, J. N. Heo, J. Org.
Chem. 2011, 76, 6611–6618; b) Y. Yang, D. Philips, S.
Pan, J. Org. Chem. 2011, 76, 1902–1905; c) B.
Gabriele, R. Mancuso, L. Veltri, Chem. Eur. J. 2016,
22, 5056–5094.
(
2
MeOH) λmax (∆ε) 211 (+21.06), 238 (+6.43), 270 (–0.92),
96 (+1.11), 315 (-0.21), 363 (+2.03) nm; HR - MS (ESI):
+
27 8
m/z = 515.1700, calcd for C30H O [M + H] , 515.1700;
2
D
0
1
13
[
α] = 6.3 (c 0.10, MeOH, 98% ee). H NMR, C NMR,
[
9] a) Z. S. Siddiqui, M. Rahman, M. A. Khan,
Tetrahedron 1993, 45, 10393–10396; b) K. S. Huang,
Y. H. Wang, R. L. Li , M. Lin, Phytochemistry 2000,
UV and IR spectral data were in great agreement with
those of (2S,3R)-(–)-gnetulin (–)-10.
5
4, 875–881; c) T. Tanaka, I. Iliya, T. Ito, M. Furusawa,
(
±)-Gnetulin [(±)-10]
K. Nakaya, M. Iinuma, Y. Shirataki, N. Matsuura, M.
Ubukata, J. Murata, F. Simozono, K. Hirai, Chem.
Pharm. Bull. 2001, 49, 858–862; d) C. S. Yao, M. Lin,
Nat. Prod. Res. 2005, 19, 443–448; e) S. Saisin, S. Tip-
pyang, P. Phuwapraisirisan, Nat. Prod. Res. 2009, 23,
1472–1477.
Following the same procedure described above but starting
from the indanone (±)-17, (±)-gnetulin (±)-10 was obtained
1
13
as a pale powder; overall yield: 7.43%; H NMR and
NMR spectral data were in great agreement with those of
2S,3R)- (–)-gnetulin (–)-10.
C
(
[
10] a) T. Tanaka, M. Iinuma, H. Murata, Phytochemistry
1
998, 48, 1045–1049; b) Y. M. Zhai, K. Jiang, S. J. Qu,
H. F. Luo, J. J. Tan, C. H. Tan, RSC. Adv. 2016, 6,
0083–50090; c) S. A. Adesanya, R. Nia, M. T. Martin,
Acknowledgements
5
N. Boukamcha, A. Montagnac, M. Pais, J. Nat. Prod.
1999, 62, 1694–1695; d) P. H. Ducrot, A. Koilmann, A.
E. Bala, A. Majira, L. Kerhoas, R. Delorme, J. Einhorn,
Tetrahedron Lett. 1998, 39, 9655–9658; e) T. Ito, T.
Tanaka, M. Iinuma, I. Iliya, K. Nakaya, Z. Ali, Y.
Takahashi, R. Sawa, Y. Shirataki, J. Murata, D.
Darnaedi, Tetrahedron 2003, 59, 5347–5363.
The work was financially supported by the National Natural
Science Funds of China (NNSFC 81502946 and NNSFC
8
1630094), the CAMS Innovation Fund for Medical Sciences
(
CIFMS 2016-I2M-2-002), and the Drug Innovation Major
Project (2018ZX09711-001-005).
References
[
11] a) W. M. Clark, A. J. Kassick, M. A. Plotkin, A. M.
Eldridge, I. Lantos, Org. Lett. 1999, 11, 1839–1842; b)
Y. Kawai, K. Saitou, K. Hida, D. H. Dao, A. Ohno,
Bull. Chem. Soc. Jpn. 1996, 69, 2633–2638; c) C.
[
1] a) M. H. Keylor, B. S. Matsuura, C. R. J. Stephenson,
Chem. Rev. 2015, 115, 8976–9027; b) X. F. Wang, C. S.
Yao, J. Asian Nat. Prod. Res. 2016, 18, 376–407; c) T.
8
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Advanced Synthesis & Catalysis
10.1002/adsc.201900336
Hedberg, P. G. Andersson, Adv. Synth. Catal. 2005,
47, 662–666; d) W. M. Clark, A. M. Tickner-Eldridge,
[14] S. A. Snyder, A. L. Zografos, Y. Lin, Angew. Chem.
Int. Ed. 2007, 46, 8186–8191.
3
G. K. Huang, L. N. Pridgen, M. A. Olsen, R. J. Mills, I.
Lantos, N. H. Baine, J. Am. Chem. Soc. 1998, 120,
[
15] W. L. Li, K. K. He, Y. Li, Z. J. Hou, Acta. Chim. Sin.
005, 63, 1607–1612.
2
4
550–4551.
[
16] a) S. He, B. Wu, Y. J. Pan, L. Y. Jiang, J. Org. Chem.
008, 73, 5233–5241; b) Y. Takaya, K. X. Yan, K.
[
[
12] Z. Chen, J. Zhu, J. Chang, X. Sun, Tetrahedron Lett.
2
2
011, 52, 2815–2817.
Terashima, J. Ito, M. Niwa, Tetrahedron. 2002, 58,
7259–7265.
13] a) N. Harada, J. Iwabuchi, Y. Yokota, H. Uda, J. Am.
Chem. Soc. 1981, 103, 5591–5593; b) N. Harada, K.
Nakanishi, Acc. Chem. Res. 1972, 5, 257–263; c) M.
Koreeda, N. Harada, K. Nakanishi, J. Am. Chem. Soc.
1
974, 96, 266–268.
9
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FULL PAPER
Versatile and Enantioselective Total Synthesis of
Naturally Active Gnetulin
Adv. Synth. Catal. 2019, Volume, Page – Page
Changhui Shang, Yulong Kang, Qingyun Yang,
Qibin Zhu, and Chunsuo Yao*
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