The total synthesis of (±)-sanggenol F

Article abstract of DOI:10.1016/j.tet.2017.05.022

A concise and efficient total synthesis of sanggenol F (1) in racemic form has been completed via a sequence of 15 steps with an overall yield of 3.1%, starting from commercially available 2,4,6-trihydroxyacetophenone. Meanwhile, a semisynthesis of sanggenol F racemate has also been achieved in 11.1% overall yield via 7 steps with naturally-occurring morin (2) as the starting material. One step and a stepwise approach were employed to construct the two prenyl side chains at 2- and 6-positions by Claisen rearrangement reaction.

Full text of DOI:10.1016/j.tet.2017.05.022

Accepted Manuscript
The total synthesis of (±)-sanggenol F
Xiao Sheng, Xin-Yu Jia, Fei Tang, Yang Wang, Ai-Jun Hou
PII:
S0040-4020(17)30488-X
10.1016/j.tet.2017.05.022
TET 28688
DOI:
Reference:
To appear in: Tetrahedron
Received Date: 4 April 2017
Revised Date: 4 May 2017
Accepted Date: 5 May 2017
Please cite this article as: Sheng X, Jia X-Y, Tang F, Wang Y, Hou A-J, The total synthesis of (±)-
sanggenol F, Tetrahedron (2017), doi: 10.1016/j.tet.2017.05.022.
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The total synthesis of (±)-sanggenol F
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Xiao Shenga, Xin-Yu Jiaa, Fei Tanga, Yang Wanga,*, Ai-Jun Houa,b,*
aSchool of Pharmacy & bState Key Laboratory of Medical Neurobiology, Fudan University, Shanghai 201203,
China

1
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Tetrahedron
journal homepage: www.elsevier.com
The total synthesis of (±)-sanggenol F
Xiao Shenga, Xin-Yu Jiaa, Fei Tanga, Yang Wanga, , Ai-Jun Houa,b,*
aSchool of Pharmacy, Fudan University, Shanghai 201203, China
bState Key Laboratory of Medical Neurobiology, Fudan University, Shanghai 201203, China
ARTICLE INFO
ABSTRACT
Article history:
Received
Received in revised form
Accepted
A concise and efficient total synthesis of sanggenol F (1) in racemic form has been completed
via a sequence of 15 steps with an overall yield of 3.1%, starting from commercially available
2,4,6-trihydroxyacetophenone. Meanwhile, a semisynthesis of sanggenol F racemate has also
been achieved in 11.1% overall yield via 7 steps with naturally-occurring morin (2) as the
starting material. One step and a stepwise approach were employed to construct the two prenyl
side chains at 2- and 6-positions by Claisen rearrangement reaction.
Available online
Keywords:
Sanggenon-type flavanones
Sanggenol F
2009 Elsevier Ltd. All rights reserved
.
Morin
Isoprenylated flavonoids
Claisen rearrangement
1. Introduction
further development of efficient and general synthetic approaches
to the relevant sanggenon-type flavanones would also be highly
desirable. Recently, the semisynthesis of (±)-sanggenol F (1) was
achieved using naturally-occurring morin (2) as the starting
material via 9 steps.4 We herein report the total synthesis of
racemic sanggenol F (1) by using different stategies via a linear
sequence of 15 conventional chemical reaction steps with an
overall yield of 3.1%, starting from the commercially available
2,4,6-trihydroxyacetophenone. The semisynthesis of 1 starting
from 2 via 7 steps is also described in this paper.
Sanggenon-type flavanones are a family of 3-hydroxy-2-
prenylflavanones with an ether linkage between the C-2′ and C-3
and two contiguous stereogenic oxa-quarternary carbon centers.
This group of isoprenylated flavonoids is characteristic
constituents of the genus Morus,1 especially ‘Sang-Bai-Pi’,1f-j
a
traditional Chinese medicine, and have been found to possess
improtant and interesting biological activities.1c,1j,2 Sanggenol F
(1, Fig. 1), isolated from Morus nigra by our group,1a is a typical
sanggenon-type flavanones, which has been reported to promote
adipocyte differentiation and enhance insulin sensitivity in 3T3-
L1 cells.3a-b
2. Results and discussion
In a retrosynthetic sense (Scheme 1), the construction of two
adjacent and fully substituted carbones (2- and 3-positions) can
be viewed as the key to the synthesis of sanggenon-type
flavanones. We envisioned that (±)-sanggenol F (1) may be
accessible via an intramolecular hemiketal formation from
intermediate 3, which in turn was to be derived from double
Claisen rearrangements of the diether intermediate 4. This key
intermediate 4 might be obtained from a precise modification of
the densely functionalized intermediate 2 (morin), by the
selective introduction of two 1,1-dimethyl-2-propenyl groups
(reverse prenyl group) onto the 3- and 5-hydroxyls, respectively,
and MOM protection onto the 2’,4’- and 7-hydroxyls.
Retrosynthetically, morin (2) can be derived from 2,4,6-
trihydroxyacetophenone (6), via an early reported procedure for
the preparation of flavonols which utilized Baker-Venkataraman
rearrangement5 of 5 and subsequent cyclization of the resulting
1,3-diketones, followed by the oxidation of 3-position at the
Fig. 1. Structures of sanggenol F (1) and morin (2).
Despite its favorable biological activities, sanggenol F is
difficult to be obtained in significant amounts by isolation
because of its low content in the Morus plants and the
concomitant occurrence of related phenolics that complicate its
purification. This drawback remarkably hampered its further
bioactivity studies. Therefore, chemical synthesis would be an
effective alternative to provide this compound. In a broader sense,
———
Corresponding authors. E-mail: wangyang@shmu.edu.cn (Y. Wang); ajhou@shmu.edu.cn (A. J. Hou).

2
Tetrahedron
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flavone skeleton. The oxidation step required such oxidants as
dimethyldioxirane (DMDO) and hypervalent iodine derivatives,6
that discouraged the scale-up synthesis of flavonols. Brouillard et
al.7 developed an alternative approach to avoid using such
oxidants and we examined the feasibility of this approach to
synthesize flavonols in the preparation of 2 in this study. Singh
group8 reported the synthesis of 2 starting from the aldol
condensation of 2,4-dihydroxybenzaldehyde and 6 without any
protection of all hydroxyl groups under the conditions of
NaOH/EtOH, but we verified that it doesn’t work and the
protection is necessary.
Scheme 2. Synthesis of morin (2).
Scheme 1. Retrosynthetic analysis of (±)-sanggenol F (1).
As shown in Scheme 2, treatment of 2,4,6-tri-
hydroxyacetophenone (6) with Me2SO4 and K2CO3 in refluxing
acetone gave an excellent yield (97%) of 2-hydro-4,6-dimethoxy-
acetophenone (7)9, which underwent a smooth esterification with
2,4-dimethoxybenzoyl chloride10 in the presence of NaH in THF
to provide ester 5 in 98% yield. Subsequent α-bromination of the
ketonic moiety of 5 with phenyltrimethylammonium tribromide
(PTT) afforded 8 in a yield of 64%, herein it was found that a
batchwise addition of PTT is needed to prevent hydrolysis of the
ester 5. Nucleophilic substitution of bromide in 8 with benzoate
was conducted in refluxing acetonitrile, giving rise to 9 in 69%
yield. The Baker-Venkataraman rearrangement of 9 proceeded
smoothly with NaH in refluxing THF, leading to the isolation of
10 in 83% yield. The subsequent cyclization of 10 in the presence
of H2SO4/AcOH generated the flavone derivative 11 in an
excellent yield (97%). Deprotection of benzoate group in 11 by
saponification and compound 12 were obtained in the yield of
90% after purification. It was reported that complete
demethylation of isoprenylated flavonoids was tough and low
yielding,10,11 so the intermediate 12 was submitted to
demethylation by treating with Py·HCl at 220°C12 to produce
morin (2) in 93% yield. So far, the natural product morin was
synthesized from 6 via 8 steps in an overall yield of 28.3%.
Scheme 3. Synthesis of intermediate 16
Subsequent efforts were made towards the selective protection
of 2, leaving its 3- and 5-hydroxyl groups for the introduction of
two prenyl side chains. After some trials on different protective
groups, methoxymethyl (MOM) proved to be the proper choice.
As shown in Scheme 3, treatment of morin (2) with 8 equivalents
of MOMCl and K2CO3 in acetone at reflux afforded tetra-MOM-
protected intermediate 13 in 53% yield, wherein only 5-OH was
left intact as a result of its intramolecular hydrogen-bonding
interaction with the 4-carbonyl group. With intermediate 13 in
hand, we subsequently tried to selectively cleave the 3-MOM
moiety, which is vicinal to the 4-carbonyl group, by using I2 in
MeOH.13 However, treatment of 13 with I2 in MeOH under reflux
has generated an intractable mixture without trace of 16 as
identified by LC-MS. We reasoned that the intramolecular
hydrogen bond between 5-OH and the 4-carbonyl group in 13
might interfere with the effect of I2/MeOH. To examine such a
possibility, we masked the 5-OH via benzyl group protection, to
give a 93% yield of 14 in which hydrogen bond is no longer
available. Owing to the poor solubility of 14 in MeOH, we tried
I2/MeOH/CH2Cl2 (3:1) for the selective deprotection of 3-MOM
group, which generated also a mixture with trace of 15 regardless

3
of at room temperature or reflux. And gratifyingly, selective
removal of the 3-MOM of 14 was achieved with our efforts by
microwave heating at 60 °C for 45 minutes in catalytic amount
of I2 with MeOH/CH2Cl2 (3:1) as solvent, leading to the
formation of 15 in 55% yield. In this case, it was found that
prolonging the reaction time or increasing the amount of I2 would
result in a more complex mixture. Subsequent removal of benzyl
group of 15 proceeded smoothly under hydrogenolytic conditions
(HCOONH4, Pd-C, CH3OH/EA), providing the desired
intermediate 16 in 91% yield.
methylbut-3-en-2-yl)carbonate under the catalysis of Pd(PPh3)4
ACCEPTED MANUSCRIPT
with Cs2CO3 as base (Scheme 5). After a thorough investigation
on the optimal conditions, the desired product 4 was furnished
accompanied by mono-alkylated product 17 consistently even if
t-butyl(2-methylbut-3-en-2-yl)carbonate was added upto 30
equivalents (monitored by TLC and LC-MS). Considering the
instability of 4 and 17, Claisen rearrangement of the mixture
were carried out in reflux toluene directly and afforded 20 and 18
in yields of 65% and 32%, respectively. The byproduct 18 could
be utilized to afford 20 in 67% yield as described in Scheme 4.
The subsequent introduction of two 1,1-dimethyl-2-propenyl
units (reverse prenyl group) onto 3- and 5-hydroxyls of 16 was
not trivial as it seems. As shown in Scheme 4, the next efforts
were made to obtain two isoprenylated product 20. Treatment of
16 with an excessive amount (5 eq.) of t-butyl(2-methylbut-3-en-
2-yl)carbonate under Pd(PPh3)4 catalysis14 and K2CO3 only gave a
mono-alkylated product 17. No desired di-alkylated compound 4
was detected in this case, presumably as a result of reactivity
difference between two hydroxyls at 3- and 5-positions, since the
hydrogen bond between the 5-OH and 4-carbonyl might also
retard the reaction as before. Interestingly, we found compound
17 was unstable in the process of purification, and it can convert
to 18 in silica gel partially (10% detected from LC-MS). So we
decided to conduct the next step without further purification.
Scheme 5. One step synthesis of intermediate 20 and the synthesis of 1.
It is known that acidic condition is the best choice for not only
the deprotection of MOM groups, but also the formation of
intramolecular hemiketal. The key intermediate 20 was submitted
to different kind of acids such as HCl, CF3COOH, TsOH,
CH3COOH, AlCl3 and ZnBr2 in alcohol or tetrahydrofuran and
all failed to generate the target product 1 except TsOH/CH3OH
with microwave assistance, producing 1 with a poor yield of 15%.
Finally, the optimized reaction conditions were verified as the
solution of hydrogen chloride gas in isopropanol (2.4 M) under
room temperature and (±)-sanggenol F (1) was afforded in 69%
1
yield. The sample of this product was fully characterized by H
NMR, 13C NMR and HRMS, and the data were found to be
identical with those of the natural product.
3. Conclusion
In conclusion, (±)-sanggenol F (1) and morin (2) have been
successfully synthesized by a sequence of 15 and 8 steps starting
from commercially available 2,4,6-trihydroxyacetophenone (6)
with an overall yield of 3.1% and 28.3%, respectively.
Simutaneously, a semi-synthesis of 1 has been accomplished in
11.1% overall yield with naturally-occurring morin as the starting
material via 7 steps. The construction of two prenyl side chains in
the target product could be accomplished in one step or a
stepwise manner, since the densely functionalized flavonol core
necessitates different conditions for the Claisen rearrangements
involved. The migration of the prenyl group to the 2- and/or 5-
position was readily achieved by traditional heating, obviating
the use of an expensive Lewis acid. Moreover, the deprotection
of protective groups and the intramolecular hemiketal formation
could be accomplished in one step effectively. The synthetic
strategy described herein may provide a facile approach to
sanggenol-type flavanones, which will definitely facilitate the
elaboration and diversification of these interesting compounds
for further bioactivity evaluation.
Scheme 4. Stepwise synthesis of the intermediate 20.
Inspired by a reported procedure on the Claisen rearrangement
catalyzed by Lewis acids,15 we examined both Sc(OTf)3 and
Cu(OTf)2 as the catalysts for the Claisen rearrangement reaction
of 17. The results indicated that a moderate yield (35%) of 18
was achieved in the presence of a substoichiometric amount (30
mol%) of Sc(OTf)3, whereas Cu(OTf)2 was found ineffective for
promoting the transformation. Finally, Claisen rearrangement of
17 proceeded smoothly in refluxing toluene,16 to give the mono-
prenylated intermediate 18 in 61% yield for the two steps. Then
we set out to introduce the second 1,1-dimethyl-2-propenyl unit
onto 5-OH of 18. Treatment of 18 with t-butyl(2-methylbut-3-en-
2-yl)carbonate and K2CO3 under the catalysis of Pd(PPh3)4 didn’t
generate 19 at all, even if a longer reaction time gained no
improvement. Inspired by the reaction of 13 to produce 14, we
found using Cs2CO3 as the base to give 19 more effectively for
the prenyl etherification of 5-OH. After Claisen rearrangement of
19, 20 was obtained in the yield of 67% for two steps.
Then we examined the possibility of di-etherification of 16 to
give 20 directly by treating with excess equivalents of t-butyl(2-
4. Experimental section

4
Tetrahedron
ACCEPTED MANUSCRIPT
4.1. General
J = 2.0 Hz, 1H, Ar-H), 6.38 (d, J = 2.0 Hz, 1H, Ar-H), 4.44 (s,
2H, CH2), 3.91 (s, 3H, OCH3), 3.88 (s, 3H, OCH3), 3.87 (s, 3H,
OCH3), 3.83 (s, 3H, OCH3). 13C NMR (150 MHz, CDCl3): δ
191.9, 165.1, 163.1, 162.9, 162.3, 159.1, 151.0, 134.9, 113.8,
110.7, 105.0, 100.9, 99.1, 96.4, 56.1, 56.1, 55.7, 55.6, 37.0. IR
(neat): ν 2947, 1729, 1609, 1296, 1113, 823, 597 cm-1. HRMS
(ESI) calcd mass for C19H19BrNaO7 [M+Na]+ 461.0222, found
461.0206.
Starting materials and reagents were obtained from
commercial suppliers and were used without purification unless
otherwise stated. Melting points were measured in open capillary
tubes using hot stage apparatus and were uncorrected. Reactions
were monitored by analytical thin-layer chromatography (TLC)
on 0.2 mm silica gel plates, and visualization of the developed
chromatogram was enabled by UV absorbance or by using an
ethanolic phosphomolybdic acid dip. Flash chromatography was
performed using silica gel (300-400 mesh) with the specified
solvent system. 1H NMR spectra were recorded at 400 MHz
using TMS as an internal standard and 13C NMR spectra were
measured at 150 MHz with complete proton decoupling. All
chemical shifts are reported in parts per million on the d scale
relative to an internal standard of TMS (1H) or the signals of the
solvent (13C). Infrared (IR) spectra were recorded neat on KBr
tablets with frequencies expressed in cm-1. High-resolution mass
spectra (HRMS) were recorded using either electron impact (EI)
or electrospray ionization (ESI) techniques.
4.5. 2-(2-(Benzoyloxy)acetyl)-3,5-dimethoxyphenyl 2,4-
dimethoxybenzoate (9)
A mixture of 8 (2.03 g, 4.63 mmol) and BzOK (1.5 g, 9.26
mmol) was stirred in CH3CN (20 mL) at refluxing temperature
for 48 h. The mixture was diluted with H2O (50 mL), followed by
extraction with EtOAc (3 × 30 mL). The combined organic phase
was then washed with water (3 × 10 mL) and brine (10 mL).
After concentration in vacuo, the residue was purified by silica
gel column chromatography (25% EtOAc/PE) to afford 9 (1.53 g,
69%) as a white solid. mp 42-43 °C. 1H NMR (400 MHz, CDCl3)
δ 8.04 (m, 3H, Ar-H), 7.54 (br t, J = 7.5 Hz, 1H, Ar-H), 7.41 (br
t, J = 7.5 Hz, 2H, Ar-H), 6.51 (dd, J = 8.7, 2.2 Hz, 1H, Ar-H),
6.49 (d, J = 2.2 Hz, 1H, Ar-H), 6.46 (d, J = 2.0 Hz, 1H, Ar-H),
6.37 (d, J = 2.0 Hz, 1H, Ar-H), 5.28 (s, 2H, CH2), 3.89 (s, 3H,
OCH3), 3.86 (s, 3H, OCH3), 3.85 (s, 3H, OCH3), 3.83 (s, 3H,
OCH3). 13C NMR (150 MHz, CDCl3) δ 194.0, 165.8, 165.0,
163.1, 162.9, 162.3, 159.6, 151.3, 135.1, 133.0, 129.9, 129.9,
128.3, 128.3, 113.7, 111.0, 104.9, 101.0, 99.0, 96.3, 69.6, 56.0,
56.0, 55.7, 55.5. IR (neat): ν 2923, 1727, 1609, 1419, 1213, 830,
712 cm-1. HRMS (ESI) calcd mass for C26NH28O9 [M+NH4]+
498.1759, found 498.1757.
4.2. 2-Hydroxy-4,6-dimethoxyacetophenone (7)
To a refluxing solution of 2,4,6-trihydroxyacetophenone-
monohydrate (6, 10 g, 59.5 mmol) and K2CO3 (16.5 g, 119
mmol) in acetone (150 mL), (CH3)2SO4 was added at three-hour
intervals (3 × 3.76 mL, 119 mmol). The solution was filtered and
the solvent was evaporated to afford 7 (11.3 g, 97%) as a yellow
solid. mp 74-75 °C (Lit17: 73-76 oC). 1H NMR (400 MHz,
CDCl3): δ 6.06 (d, J = 2.0 Hz, 1H, Ar-H), 5.92 (d, J = 2.0 Hz,
1H, Ar-H), 3.86 (s, 3H, OCH3), 3.82 (s, 3H, OCH3), 2.61 (s, 3H,
COCH3). IR (neat): ν 2970, 2833, 1617, 1440, 1157, 895, 597
cm-1.
4.6. 1-(2,4-Dimethoxyphenyl)-3-(2-hydroxy-4,6-
dimethoxyphenyl)-1,3-dioxo-propan-2-yl benzoate (10)
4.3. 2-Acetyl-3,5-dimethoxyphenyl 2,4-dimethoxybenzoate (5)
To a suspension of NaH (60%, 53 mg, 1.26 mmol) in dry THF
(20 mL) was added 9 (400 mg, 0.83 mmol). The mixture was
refluxed for 2 h with stirring. The cooled mixture was poured
into ice water (20 mL) and concentrated in vacuo, extracted with
EtOAc (3 × 40 mL). The organic phase was washed with brine,
dried over MgSO4 and concentrated. The residue was then
purified by silica gel column chromatography (15% EtOAc/PE)
To a solution of 7 (11.3 g, 57.63 mmol) in THF (30 mL), NaH
(60%, 3.46 g, 86.45 mmol) was added at 0°C. After stirring the
mixture for 5 min, 2,4-dimethoxybenzoyl chloride (13.9 g, 69.16
mmol) was added dropwise. The resulting solution was slowly
warmed to room temperature over a period of 3 h and then
poured into ice water (30 mL), followed by extraction with
EtOAc (3 × 30 mL). The organic phase was washed with brine,
dried over MgSO4, and concentrated in vacuo. The residue was
then purified by silica gel column chromatography (PE/EA 10:1)
1
to afford 10 (330 mg, 83%) as a white solid. mp 66-67 °C. H
NMR (400 MHz, CDCl3) δ 13.35 (s, 1H, Ar-OH), 8.09 (br d, J =
8.8 Hz, 3H, Ar-H), 7.56 (br t, J = 7.6 Hz, 1H, Ar-H), 7.44 (s, 1H,
CH), 7.41 (br t, J = 7.6 Hz, 2H, Ar-H), 6.61 (dd, J = 8.8, 2.4 Hz,
1H, Ar-H), 6.42 (d, J = 2.4 Hz, 1H, Ar-H), 6.11 (d, J = 2.4 Hz,
1H, Ar-H), 5.87 (d, J = 2.4 Hz, 1H, Ar-H), 3.87 (s, 3H, OCH3),
3.82 (s, 3H, OCH3), 3.67 (s, 3H, OCH3), 3.52 (s, 3H, OCH3). 13C
NMR (150 MHz, CDCl3) δ 195.4, 189.0, 168.0, 166.8, 165.7,
165.6, 162.0, 161.1, 133.8, 133.2, 130.1, 130.1, 129.6, 128.4,
128.4, 118.0, 106.1, 104.7, 98.3, 94.0, 91.0, 81.8, 55.7, 55.7,
55.5, 55.4. IR (neat): ν 2925, 1725, 1596, 1420, 1160, 823, 711
1
to afford 5 (20.33 g, 98%) as a white solid, mp 105-106 °C. H
NMR (400 MHz, CDCl3): δ 8.03 (d, J = 8.8 Hz, 1H, Ar-H), 6.55
(dd, J = 8.8, 2.0 Hz, 1H, Ar-H), 6.50 (d, J = 2.0 Hz, 1H, Ar-H),
6.38 (s, 2H, Ar-H), 3.90 (s, 3H, OCH3), 3.88 (s, 3H, OCH3), 3.85
(s, 3H, OCH3), 3.81 (s, 3H, OCH3) , 2.47 (s, 3H, COCH3). 13C
NMR (150 MHz, CDCl3): δ 199.8, 164.9, 163.1, 162.1, 161.9,
158.7, 149.7, 134.7, 117.5, 110.8, 104.7, 100.1, 98.9, 96.4, 56.0,
55.8, 55.6, 55.5, 31.9. IR (neat): ν 2943, 1737, 1610, 1157, 1096,
830, 761 cm-1. MS (ESI): [M+H]+: 361.1. HRMS (ESI) calcd
mass for C19H20NaO7 [M+Na]+ 383.1106, found 383.1101.
+
cm-1. MS (ESI): [M+H] : 481.1. HRMS (ESI) calcd mass for
C26H25O9 [M+H]+ 481.1493, found 481.1496.
4.4. 2-(2-Bromoacetyl)-3,5-dimethoxyphenyl 2,4-
dimethoxybenzoate (8)
4.7. 2-(2,4-Dimethoxyphenyl)-5,7-dimethoxy-3-benzoyloxy-
4H-chromen-4-one (11)
To a solution of 5 (1.8 g, 5 mmol) in dry THF (100 mL) was
added PTT (2.1 g, 5.5 mmol) in portions. The reaction mixture
was stirred at room temperature for 2 h, and was then poured into
water (40 mL) and concentrated in vacuo, then extracted with
CH2Cl2 (3 × 80 mL). The combined organic phase was washed
with brine, dried over MgSO4, and concentrated in vacuo. The
residue was purified by silica gel column chromatography (15%
EtOAc/PE) to afford 8 (1.4 g, 64%) as a colorless oil. 1H NMR
(400 MHz, CDCl3): δ 8.01 (d, J = 8.8 Hz, 1H, Ar-H), 6.55 (dd, J
= 8.8, 2.0 Hz, 1H, Ar-H), 6.50 (d, J = 2.0 Hz, 1H, Ar-H), 6.45 (d,
To a solution of 10 (330 mg, 0.69 mmol) in AcOH (20 mL)
was added conc. H2SO4 (0.2 mL). The reaction mixture was
stirred at 60 °C for 2 h, and was then poured into ice water (10
mL) and extracted with EtOAc (3 × 20 mL). The organic phase
was washed with brine, dried over MgSO4 and concentrated. The
residue was then purified by silica gel column chromatography
(50% EtOAc/PE) to afford 11 (309 mg, 97%) as a white solid,
mp 212-213 °C. 1H NMR (400 MHz, CDCl3) δ 8.07 (br d, J = 8.0
Hz, 2H, Ar-H), 7.55 (br t, J = 8.0 Hz, 1H, Ar-H), 7.48 (d, J = 8.8

5
Hz, 1H, Ar-H), 7.41 (br t, J = 8.0 Hz, 2H, Ar-H), 6.55 (dd, J =
8.8, 2.0 Hz, 1H, Ar-H), 6.49 (d, J = 2.0 Hz, 1H, Ar-H), 6.46 (d, J
= 2.0 Hz, 1H, Ar-H), 6.36 (d, J = 2.0 Hz, 1H, Ar-H), 3.92 (s, 3H,
OCH3), 3.88 (s, 3H, OCH3), 3.83 (s, 3H, OCH3), 3.69 (s, 3H,
OCH3). 13C NMR (150 MHz, CDCl3) δ 170.5, 164.1, 164.0,
163.1, 161.4, 159.8, 158.8, 153.2, 135.3, 133.1, 131.4, 130.3,
130.3, 129.5, 128.3, 128.3, 111.9, 109.3, 104.9, 98.7, 96.0, 92.7,
56.3, 55.7, 55.6, 55.5. IR (neat): ν 3433, 2922, 1745, 1610, 1457,
831, 706 cm-1. MS (ESI): [M+H]+: 463.1. HRMS (ESI) calcd for
C26H23O8 [M+H]+ 463.1393, found 463.1386.
5.21 (s, 2H, -OCH2O-), 5.19 (s, 2H, -OCH2O-), 5.01 (s, 2H, -
ACCEPTED MANUSCRIPT
OCH2O-), 3.50 (s, 3H, OCH3), 3.48 (s, 6H, 2×OCH3), 2.98 (s,
3H, OCH3). 13C NMR (150 MHz, CDCl3): δ 178.6, 162.9, 162.1,
160.3, 157.6, 157.3, 156.6, 136.7, 132.0, 114.3, 108.7, 107.0,
103.7, 99.5, 97.6, 94.7, 94.4, 94.3, 94.2, 56.6, 56.4, 56.3, 56.2.
IR (neat): ν 2915, 1656, 1595, 1493, 1243, 1075, 812 cm-1.
HRMS (ESI) calcd for C23H27O11 [M+H]+ 479.1548, found
479.1556.
4.11. 5-(Benzyloxy)-2-(2,4-bis(methoxymethoxy)phenyl)-3,7-
bis(methoxymethoxy)-4H-chromen-4-one (14)
4.8. 2-(2,4-Dimethoxyphenyl)-3-hydroxy-5,7-dimethoxy-4H-
chromen-4-one (12)
To a solution of 13 (20 mg, 0.0410 mmol) in acetone (30 mL),
Cs2CO3 (27 mg, 0.082 mmol) and BnBr (0.01 mL, 0.082 mmol)
were added. After stirring for 4 h under reflux, water (5 mL) was
added to the mixture and extracted with EtOAc (3 × 10 mL). The
organic phase was washed with brine, dried over Na2SO4 and
concentrated. The residue was purified by silica gel column
chromatography (30% EtOAc/PE) to afford 14 (22 mg, 93%) as a
white solid. mp 106-107 oC. 1H NMR (400 MHz, CDCl3): δ 7.63
(br d, J = 7.5 Hz, 2H, Ar-H), 7.45 (d, J = 8.5 Hz, 1H, Ar-H), 7.40
(br t, J = 7.5 Hz, 2H, Ar-H), 7.30 (br t, J = 7.5 Hz,1H, Ar-H),
6.93 (br s, 1H, Ar-H), 6.80 (br d, J = 8.5 Hz, 1H, Ar-H), 6.63 (br
s, 1H, Ar-H), 6.50 (br s, 1H, Ar-H), 5.27 (s, 2H, -OCH2Ph), 5.21
(s, 2H, -OCH2O-), 5.18 (s, 4H, 2×-OCH2O-), 5.05 (s, 2H, -
OCH2O-), 3.49 (s, 3H, OCH3), 3.48 (s, 3H, OCH3), 3.46 (s, 3H,
OCH3), 2.92 (s, 3H, OCH3). 13C NMR (150 MHz, CDCl3): δ
173.6, 161.2, 160.0, 159.9, 159.2, 156.6, 154.3, 138.9, 136.4,
132.1, 128.6, 128.6, 127.7, 126.8, 126.8, 114.9, 110.8, 108.7,
103.7, 98.3, 97.5, 96.0, 94.7, 94.4, 94.4, 70.8, 56.4, 56.4, 56.2,
56.2. IR (neat): ν 1636, 1610, 1430, 1195, 1002 cm-1. HRMS
(ESI) calcd for C30H33O11 [M+H]+ 569.2017, found 569.2034.
To a solution of 11 (20 mg, 0.043 mmol) in ethanol (2 mL),
5% aqueous sodium hydroxide solution was added dropwise. The
reaction mixture was stirred at 60 °C for 2 h, and was then
acidified by 1 M HCl, extracted with EtOAc (3 × 5 mL). The
organic phase was washed with NaHCO3, brine, dried over
MgSO4 and concentrated. The residue was then purified by silica
gel column chromatography (50% EtOAc/PE) to afford 12 (14
1
mg, 90%) as a white solid. mp 156-157 °C. H NMR (400 MHz,
DMSO-d6) δ 8.24 (s, 1H, Ar-OH), 7.36 (d, J = 8.5 Hz, 1H, Ar-
H), 6.69 (d, J = 2.0 Hz, 1H, Ar-H), 6.64 (dd, J = 8.5, 2.0 Hz, 1H,
Ar-H), 6.61 (d, J = 2.0 Hz, 1H, Ar-H), 6.47 (d, J = 2.0 Hz, 1H,
Ar-H), 3.86 (s, 3H, OCH3), 3.85 (s, 3H, OCH3), 3.83 (s, 3H,
OCH3), 3.78 (s, 3H, OCH3). 13C NMR (150 MHz, DMSO-d6) δ
171.7, 164.0, 162.6, 160.7, 159.2, 158.9, 143.6, 139.3, 132.4,
112.8, 107.4, 105.6, 99.3, 96.1, 93.2, 56.7, 56.4, 56.3, 56.0. IR
(neat): ν 3191, 2920, 1620, 1412, 1023, 816, 726 cm-1. HRMS
(ESI) calcd for C19H19O7 [M+H]+ 359.1125, found 359.1127.
4.9. 2-(2,4-Dihydroxyphenyl)-3,5,7-trihydroxy-4H-chromen-
4-one (morin, 2)
4.12. 5-(Benzyloxy)-2-(2,4-bis(methoxymethoxy)phenyl)-3-
hydroxy-7-(methoxymethoxy)-4H-chromen-4-one (15)
The mixture of 12 (79 mg, 0.22 mmol) and Py·HCl (750 mg,
7.2 mmol) in a 50 mL sealed tube was heated to 220 °C for 15
minutes with stirring, then acidified by 1 M HCl, extracted with
EtOAc (3 × 10 mL). The organic phase was washed with brine,
dried over MgSO4 and concentrated. The residue was then
purified by silica gel column chromatography (20%
CH2Cl2/MeOH) to afford 2 (62 mg, 93%) as a brown solid. mp
The solution of 14 (415 mg, 0.73 mmol) and I2 (4 mg, 0.016
mmol) in 2 mL CH3OH / CH2Cl2 (18 mL, 3:1) was microwaved
at 60°C for45 minutes, and was then quenched with aq. water (1
mL). The resulting mixture was extracted with EtOAc (3 × 10
mL), and the combined extracts was washed with water and brine
and concentrated in vacuo. The residue was then purified by
silica gel column chromatography (15% EtOAc/PE) to afford 15
(210 mg, 55%) as a white needle. mp 153-154 oC. 1H NMR (400
MHz, CDCl3): δ 7.63 (br d, J = 7.6 Hz, 2H, Ar-H), 7.49 (d, J =
8.8 Hz, 1H, Ar-H), 7.43 (br t, J = 7.6 Hz, 2H, Ar-H), 7.33 (br t, J
= 7.6 Hz, 1H, Ar-H), 6.94 (d, J = 2.0 Hz, 1H, Ar-H), 6.83 (dd, J
= 8.8, 2.0 Hz, 1H, Ar-H), 6.79 (s, 1H, =C-OH), 6.68 (br s, 1H,
Ar-H), 6.52 (br s, 1H, Ar-H), 5.28 (s, 2H, -OCH2Ar), 5.22 (s, 2H,
-OCH2O-), 5.21 (s, 2H, -OCH2O-), 5.18 (s, 2H, -OCH2O-), 3.50
(s, 3H, OCH3), 3.48 (s, 3H, OCH3), 3.47 (s, 3H, OCH3). 13C
NMR (150 MHz, CDCl3): δ 171.9, 161.5, 160.1, 159.6, 159.3,
156.4, 142.5, 138.8, 136.3, 131.5, 128.7, 128.7, 127.8, 126.8,
126.8, 114.4, 109.1, 107.8, 104.1, 97.7, 95.9, 95.0, 94.4, 94.4,
70.8, 56.5, 56.3, 56.2. IR (neat): ν 3347, 2920, 1611, 1437, 1196,
912, 632 cm-1. HRMS (ESI) calcd for C28H29O10 [M+H]+
525.1755, found 525.1768.
1
286-287 °C. H NMR (400 MHz, DMSO-d6) δ 12.60 (s, 1H, Ar-
OH), 10.71 (s, 1H, Ar-OH), 9.78 (s, 1H, Ar-OH), 9.72 (s, 1H, Ar-
OH), 8.89 (s, 1H, Ar-OH), 7.22 (d, J = 8.4 Hz, 1H, Ar-H), 6.40
(d, J = 2.0 Hz, 1H, Ar-H), 6.35 (dd, J = 8.4, 2.0 Hz, 1H, Ar-H),
6.30 (d, J = 2.0 Hz, 1H, Ar-H), 6.18 (d, J = 2.0 Hz, 1H, Ar-H).
13C NMR (150 MHz, DMSO-d6) δ 176.7, 164.2, 161.4, 160.9,
157.3, 157.2, 149.5, 136.6, 132.1, 109.7, 107.3, 104.0, 103.4,
98.5, 93.8. IR (neat): ν 3526, 2917, 1661, 1179, 833, 796, 637
+
cm-1. HRMS (EI) calcd mass for C15H10O7 302.0427, found
302.0431.
4.10. 2-(2,4-Bis(methoxymethoxy)phenyl)-5-hydroxy-3,7-bis
(methoxymethoxy)-4H-chromen-4-one (13)
A solution of 2 (60 mg, 0.20 mmol) and K2CO3 (220 mg, 1.60
mmol) in acetone (10 mL), MOMCl (0.12 mL, 1.60 mmol) was
added slowly at 0 °C. After stirring for 10 min under this
temperature, the reaction mixture was then stirred for 5 h at room
temperature. Water (5 mL) was added to the mixture and
extracted with EtOAc (3 × 10 mL). The organic phase was
washed with brine, dried over Na2SO4 and concentrated. The
residue was then purified by silica gel column chromatography
(15% EtOAc/PE) to afford 13 (50 mg, 53%) as a yellow granular
4.13. 2-(2,4-Bis(methoxymethoxy)phenyl)-3,5-dihydroxy-7-
(methoxymethoxy)-4H-chromen-4-one (16)
To a solution of 15 (155 mg, 0.30 mmol) and HCOONH4 (19
mg, 1.20 mmol) in 20 mL EtOAc/MeOH (1:3), Pd/C (16 mg, 10
wt%) was added. The mixture was stirred under reflux for 1 h.
The Pd/C solids were removed by filtration through a plug of
celite. Water (5 mL) was added to the mixture and extracted with
EtOAc (3 × 10 mL). The organic phase was washed with brine,
dried over Na2SO4. The solvent was removed on the rotary
evaporator and the residue was then purified by silica gel column
1
solid. mp 101-102 °C. H NMR (400 MHz, CDCl3): δ 12.56 (s,
1H, Ar-OH), 7.43 (d, J = 8.5 Hz, 1H, Ar-H), 6.94 (br s, 1H, Ar-
H), 6.81 (dd, J = 8.5, 1.8 Hz, 1H, Ar-H), 6.54 (d, J = 2.0 Hz, 1H,
Ar-H), 6.47 (d, J = 2.0 Hz, 1H, Ar-H), 5.22 (s, 2H, -OCH2O-),

6
Tetrahedron
ACCEPTED MANUSCRIPT
chromatography (12% EtOAc/PE) to afford 16 (118 mg, 91%)
3.10 (d, J = 7.2 Hz, 2H, -CH2CH=), 1.78 (s, 3H, CH3), 1.68 (s,
o
1
as a yellow granular solid. mp 159-160 C. H NMR (400 MHz,
CDCl3): δ 11.87 (s, 1H, Ar-OH), 7.49 (d, J = 8.6 Hz, 1H, Ar-H),
6.97 (d, J = 2.0 Hz, 1H, Ar-H), 6.85 (dd, J = 8.6, 2.0 Hz, 1H, Ar-
H), 6.58 (d, J = 2.0 Hz, 1H, Ar-H), 6.49 (d, J = 2.0 Hz, 1H, Ar-
H), 6.13 (s, 1H, =C-OH), 5.23 (s, 2H, -OCH2O-), 5.22 (s, 2H, -
OCH2O-), 5.21 (s, 2H, -OCH2O-), 3.50 (s, 3H, OCH3), 3.49 (s,
3H, OCH3), 3.46 (s, 3H, OCH3). 13C NMR (150 MHz, CDCl3): δ
175.7, 163.1, 161.1, 160.4, 157.4, 156.3, 146.5, 136.9, 131.5,
113.9, 109.2, 105.2, 104.0, 99.3, 95.0, 94.4, 94.4, 94.3, 56.4,
56.4, 56.3. IR (neat): ν 3675, 3387, 2988, 2914, 1594, 1250,
1196, 1132, 1076, 892 cm-1. HRMS (ESI) calcd for C21H23O10
[M+H]+ 435.1286, found 435.1282.
3H, CH3), 1.56 (s, 6H, 2×CH3). 13C NMR (150 MHz, CDCl3): δ
194.4, 176.6, 165.1, 161.7, 161.3, 159.1, 154.9, 138.0, 131.8,
127.8, 122.4, 122.0, 115.7, 110.3, 108.5, 105.5, 102.9, 94.4, 94.0,
94.0, 93.3, 89.5, 56.4, 56.3, 56.1, 36.2, 25.8, 25.8, 21.2, 18.0,
17.8. IR (neat): ν 3361, 2919, 2850, 1732, 1635, 1572, 1448,
1219, 1077, 947, 816, 777 cm-1. HRMS (ESI) calcd for C31H39O10
[M+H]+ 571.2538, found 571.2532.
4.16. The synthesis of 20 and 18
To a Schlenk flask dried and degassed by argon was added 16
(20 mg, 0.046 mmol) and Cs2CO3 (59.9 mg, 0.184 mmol),
followed by dry THF (2 mL). To the solution was added tert-
buty-2-methylbut-3-en-2-yl carbonate (0.093 mL, 1.38 mmol) via
syringe, followed by Pd(PPh3)4 (2.6 mg, 0.0023 mmol). The
reaction vessel was stirred at room temperature under argon for
12 h and then water (1 mL) was added, extracted with EtOAc (3
× 5 mL). The organic phase was washed with brine, dried over
Na2SO4 and concentrated. The resultant oil was dissolved in 5
mL toluene and heated to 110 °C with stirring for 9 h. The
solvent was removed on the rotary evaporator and the residue
was then purified by silica gel column chromatography (6%
EtOAc/PE) to afford 20 (17 mg, 65% for two steps) and 18 (7.4
mg, 32% for two steps) as yellow oils.
4.14. 2-(2,4-Bis(methoxymethoxy)phenyl)-5-hydroxy-7-
(methoxymethoxy)-2-(3-methylbut-2-en-1-yl)chroman-3,4-
dione (18)
To a Schlenk flask dried and degassed by argon was added 16
(282 mg, 0.65 mmol) and K2CO3 (179 mg, 1.29 mmol), followed
by dry THF (10 mL). To the solution was added tert-buty-2-
methylbut-3-en-2-yl carbonate (0.18 mL, 2.6 mmol) via syringe,
followed by Pd(PPh3)4 (39.5 mg, 0.034 mmol). The reaction was
stirred at room temperature under argon for 1 h and then water (5
mL) was added, extracted with EtOAc (3 × 10 mL). The organic
phase was washed with brine, dried over Na2SO4 and
concentrated. The resultant oil was dissolved in 10 mL toluene
and heated to 110 °C with stirring for 2 h. The solvent was
removed on the rotary evaporator and the residue was then
purified by silica gel column chromatography (12 % EtOAc/PE)
4.17. The synthesis of (±)-sanggenol F (1)
To a round-bottomed flask, 20 (10 mg, 0.017 mmol) and
HCl(g)/i-PrOH (0.6 mL, 2.4 M) was added at 0°C. After stirring
for 4 h, the reaction mixture was adjusted to neutral with aq.
NaHCO3 and extracted with EtOAc (3 × 5 mL). The combined
extracts was washed with brine, dried over Na2SO4 and
concentrated in vacuo. The residue was then purified by silica gel
column chromatography (15% EtOAc/PE) to afford 1 (5.3 mg,
1
to afford 18 (200 mg, 61% for two steps) as a yellow oil. H
NMR (400 MHz, CDCl3): δ 11.82 (s, 1H，Ar-OH), 7.44 (d, J =
9.2 Hz, 1H, Ar-H), 6.75–6.72 (m, 2H, Ar-H), 6.19 (d, J = 2.0 Hz,
1H, Ar-H), 6.09 (d, J = 2.0 Hz, 1H，Ar-H), 5.19 (s, 2H，-
OCH2O-), 5.16 (s, 2H，-OCH2O-), 5.11 (t, J = 7.5 Hz, 1H, -
CH2CH=), 4.92 (d, J = 7.2 Hz, 1H, -OCH2O-), 4.86 (d, J = 7.2
Hz, 1H, -OCH2O-), 3.47 (s, 3H, OCH3), 3.46 (s, 3H, OCH3), 3.16
(s, 3H, OCH3), 3.12 (d, J = 7.5 Hz, 2H, -CH2CH=), 1.57 (s, 3H,
CH3), 1.56 (s, 3H, CH3). 13C NMR (150 MHz, CDCl3): δ 194.2,
176.5, 167.5, 165.5, 162.9, 159.2, 154.9, 138.3, 127.7, 122.5,
115.5, 108.5, 105.6, 103.0, 96.6, 95.4, 94.4, 94.1, 94.1, 89.8,
56.6, 56.3, 56.2, 36.3, 25.8, 18.0. IR (neat): ν 2969, 2919, 1640,
1568, 1449, 1219, 1147, 1076, 923 cm-1. HRMS (ESI) calcd for
C26H31O10 [M+H]+ 503.1912, found 503.191.
1
69%) as a yellow oil. H NMR (400 MHz, acetone-d6): δ 11.93
(s, 1H, Ar-OH)，9.95 (s, 1H, Ar-OH)，8.79 (s, 1H, Ar-OH)，
7.36 (d, J = 8.0 Hz, 1H, Ar-H), 7.13 (s, 1H, R-OH), 6.52 (br d, J
= 8.0 Hz, 1H, Ar-H)，6.40 (br s, 1H，Ar-H), 5.92 (s, 1H, Ar-H),
5.24 (t, J = 7.0 Hz, 1H, -CH2CH=), 5.19 (t, J = 7.0 Hz, 1H, -
CH2CH=), 3.22 (d, J = 7.0 Hz, 2H, -CH2CH=), 3.13 (dd, J =
14.5, 8.8 Hz, 1H, -CH2CH=), 2.77 (dd, J = 14.5, 6.5 Hz, 1H, -
CH2CH=), 1.73 (s, 3H, CH3), 1.62 (s, 6H, 2×CH3), 1.51 (s, 3H,
CH3). 13C NMR (150 MHz, acetone-d6): δ 188.3, 166.6, 162.6,
161.5, 161.3, 161.2, 136.5, 131.5, 125.7, 123.3, 121.4, 118.7,
109.7, 109.1, 102.6, 100.2, 99.5, 95.3, 91.8, 32.1, 25.9, 25.8,
21.5, 18.1, 17.8. IR (neat): ν 3447, 2969, 2359, 2329, 1633, 1337,
960, 827 cm-1. HRMS (ESI) calcd for C25H27O7 [M+H]+
439.1751, found 439.1747.
4.15. 2-(2,4-Bis(methoxymethoxy)phenyl)-5-hydroxy-7-
(methoxymethoxy)-2,6-bis(3-methylbut-2-en-1-yl)chroman-
3,4-dione (20)
To a Schlenk flask dried and degassed by argon was added 18
(70 mg, 0.14 mmol), Cs2CO3 (90 mg, 0.28 mmol) and dry THF
(5 mL). To the solution was added tert-buty-2-methylbut-3-en-2-
yl carbonate (0.10 mL, 1.4 mmol) via syringe, followed by
Pd(PPh3)4 (10 mg, 0.007 mmol). The reaction was stirred at room
temperature under argon for 2 h and then water (5 mL) was
added, extracted with EtOAc (3 × 5 mL). The organic phase was
washed with brine, dried over Na2SO4 and concentrated. The
resultant oil was dissolved in 5 mL toluene and heated to 110 °C
with stirring for 2 h. The solvent was removed on the rotary
evaporator and the residue was then purified by silica gel column
chromatography (6% EtOAc/PE) to afford 20 (53 mg, 67% for
Acknowledgements
Financial supports from the National Natural Science
Foundation of China (No. 21172044, 21472025, 81222045) are
gratefully acknowledged.
Supplementary data
These data include H, 13C NMR data for the key compounds
described in this article. Supplementary data related to this article
can be found online at XXXX.
1
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