An efficient synthesis of 4-isochromanones via Parham-type cyclization with Weinreb amide

Article abstract of DOI:10.1016/j.tet.2015.08.028

The synthesis of 4-isochromanones via Parham-type cyclization with Weinreb amide as the internal electrophilic group, t-BuLi as the lithium reagent was described. The reaction was efficient and could be completed in one minute. The application scope of this new protocol was investigated and the desired products could be obtained in good to excellent yields. Besides, the synthetic potential of this method was further demonstrated by the synthesis of natural product (±)-XJP, which was obtained in six steps with overall yield up to 54%.

Full text of DOI:10.1016/j.tet.2015.08.028

Accepted Manuscript
An efficient synthesis of 4-isochromanones via Parham-type cyclization with Weinreb
amide
Chaolei Wang, Zheng Wu, Jia Wang, Jie Liu, Hequan Yao, Aijun Lin, Jinyi Xu
PII:
S0040-4020(15)01220-X
10.1016/j.tet.2015.08.028
TET 27050
DOI:
Reference:
To appear in: Tetrahedron
Received Date: 17 June 2015
Revised Date: 1 August 2015
Accepted Date: 10 August 2015
Please cite this article as: Wang C, Wu Z, Wang J, Liu J, Yao H, Lin A, Xu J, An efficient synthesis of
4-isochromanones via Parham-type cyclization with Weinreb amide, Tetrahedron (2015), doi: 10.1016/
j.tet.2015.08.028.
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An efficient synthesis of 4-isochromanones
via Parham-type cyclization with Weinreb
amide
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Chaolei Wang a,b, Zheng Wu a,b, Jia Wang a,b, Jie Liu a,c*, Hequan Yao a,b, Aijun Lin a,b, Jinyi Xu a,b
aState Key Laboratory of Natural Medicines, China Pharmaceutical University, 24 Tong Jia Xiang, Nanjing
bDepartment of Medicinal Chemistry, China Pharmaceutical University, 24 Tong Jia Xiang, Nanjing
cDepartment of Organic Chemistry, China Pharmaceutical University, 24 Tong Jia Xiang, Nanjing,

1
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Tetrahedron
journal homepage: www.elsevier.com
An efficient synthesis of 4-isochromanones via Parham-type
cyclization with Weinreb amide
Chaolei Wang a,b, Zheng Wu a,b, Jia Wang a,b, Jie Liu a,c*, Hequan Yao a,b, Aijun Lin a,b,and Jinyi Xu a,b
aState Key Laboratory of Natural Medicines, China Pharmaceutical University, 24 Tong Jia Xiang, Nanjing 210009, PR China
bDepartment of Medicinal Chemistry, China Pharmaceutical University, 24 Tong Jia Xiang, Nanjing 210009, PR China
cDepartment of Organic Chemistry, China Pharmaceutical University, 24 Tong Jia Xiang, Nanjing, 210009, PR China
ARTICLE INFO
ABSTRACT
Article history:
Received
Received in revised form
Accepted
The synthesis of 4-isochromanones via Parham-type cyclization with Weinreb amide
as the internal electrophilic group, t-BuLi as the lithium reagent was described. The
reaction was efficient and could be completed in one minute. The application scope of
this new protocol was investigated and the desired products could be obtained in good
to excellent yields. Besides, the synthetic potential of this method was further
demonstrated by the synthesis of natural product (±)-XJP, which was obtained in 6
steps with overall yield up to 54%.
Available online
Keywords:
4-isochromanones
lithium–halogen exchange
Parham-type cyclization
Weinreb amides
(±)-XJP
2009 Elsevier Ltd. All rights reserved
.
1. Introduction
heterocyclic systems.12-16 This strategy has been successfully
employed in our previous work to construct 4-isochromanone
skeleton with carboxylic acid as the internal electrophilic group
in a total synthesis endeavor. 17 However, due to the low yield
and the prolonged reaction time, the application of this reaction
was restricted on our subsequent research. So it was necessary to
improve this method by further efforts. It was found that the
Weinreb amides were much more effective electrophiles than
carboxylic acids in Parham cyclizations in some cases.18-20 Also,
there were some benefits of Weinreb amide, such as stability,
ease of preparation, few side-reaction during nucleophilic
addition.21,22 Based on the findings, we investigated the
feasibility of the synthesis of 4-isochromanones via Parham-type
cyclization with Weinreb amides.
The 4-isochromanones were one kind of important scaffolds
that present in some natural products such as (±)-7, 8- dihydroxy-
3-methylisochroman-4-one [(±)-XJP], which exhibiting favorable
pharmacological properties including antioxidant, antitumour,
antibacterial activities,1-5 and also used as key intermediates in
the synthesis of natural product pentalongin derivatives.6,7
Consequently, the synthesis of 4-isochromanones was of great
interest in the field of organic chemistry and medicinal chemistry.
The preparation of 4-isochromanones was conventionally carried
out by Perkin condensation, Dieckmann condensation, and
intramolecular Friedel–Crafts reaction.8 Additionally, methods
reported lately in the literatures for the preparation of 4-
isochromanones involve Friedel–Crafts acylation of chromium-
carbene-complex-derived ketenes;9 Heck reactions followed by
oxidative cleavage reactions to form the skeleton;7 Organolithium
compounds addition reaction;10 AuCl3 catalyzed cascade
triggered by an internal nucleophile.11 However, these methods
generally suffered from some limitations such as low yields,
multi-step reactions or expensive transition metal catalysts.
2. Results and discussion
In this protocol, an aryllithium generated by lithium–halogen
exchange was expected to undergo an intramolecular cyclization
on to the electrophilic group of the aromatic ring to provide the
target compound. In order to study the influences of the
electrophilic group as well as the lithium reagent on the Parham-
type cyclization, the reaction profiles of substrates using different
type of groups as internal electrophiles were investigated. As
shown in Table 1, the internal electrophiles and the lithium
reagents both played crucial roles in the reaction. When the
precursors were carboxylic acid and ester, the yields were very
low compared with the precursors with amides as internal
The Parham cyclization, which was the intramolecular
cylization of aryllithium and an internal electrophile, has been
used for the assembling of a wide array of carbo- and
___________________
Corresponding author. Tel.: +86 025 83271299; fax: +86 025
83302827; e-mail: jinyixu@china.com (J. Xu), cpu-jill@163.com
(J. Liu).

2
Tetrahedron
ACCEPTED MANUSCRIPT
electrophiles. It should be noted that the cyclization reaction of
conversion even with prolonged reaction time (Entrys 4-6). The
precursor with Weinreb amide completed in just one mintute,
which was much faster than the precursor with morpholine
(Entrys 1-4). Moreover, it was interesting that the reaction was
sensitive to the lithium reagents. The desired product was
obtained in excellent yield when using t-BuLi as the lithium
reagent, however, the use of n-BuLi was less successful and led
to butylated byproduct. Obviously, the steric effect was the key
reason of the different profiles of the reactions. Thus, a more
bulky and less nucleophilic reagent MesLi was chosen for the
lithium–halogen exchange. However, MesLi led to incomplete
best condition was the compound with Weinreb amide as the
precursor and t-BuLi as the lithium reagent (Entry 4). The use of
Weinreb amide as internal electrophiles clearly promoted the
reaction. This observation was explained by a complex-induced
proximity effect (CIPE).23-25 Lithium–halogen exchange could be
favored first by coordination of the organolithium to the amide
group, and then the relatively stable internal chelate tetrahedral
intermediate formed after cyclization was favored to the reaction,
as depicted in Scheme 1.
Table 1. Optimization of the substrates and lithium reagents.a
O
O
O
Br
O
O
1) R2Li, THF, -78oC
2) H2O
O
O
O
R1
Entry
R1
R2Li
Time
4 h
Yieldb(%)
Trace
50
1
2
3
4
5
6
-OCH2CH3
-OH
t-BuLi
t-BuLi
t-BuLi
t-BuLi
n-BuLi
Mes-Li
4 h
4 h
87c
O
N
1 min
1 min
4 h
91
O
N
42
O
N
70
a Reagents and conditions: 1.2 equiv of n-BuLi (1.2 equiv of Mes-Li or 2.2 equiv of t-BuLi), and 1.0 equiv of
substrate in THF, -78 oC, then H2O.
b Isolated yields.
c The starting material cannot converse completely even with prolonged reaction time.
Li
O
O
1) t-BuLi,
THF, -78oC
Br
N
O
2) H2O
O
R
R
O
O
O
R
N
O
1
2
Scheme 1. The internal chelate after cyclization
Subsequently, the application scope of this new protocol was
investigated. Firstly, the precursors of Weinreb amides 1 were
prepared by alkylation of the corresponding (2-bromophenyl)
methanol
4
with 2-bromo-N-methoxy-N-methylacetamide26
under standard conditions in excellent yields (Scheme 2). Then
we applied the optimized condition to various substituted
precursors for exploring the substrate scope. As shown in Table
2, in general, the precursors tested could be smoothly converted
to the desired products in good to excellent yields regardless of
the different substitutions on the aromatic ring. Clearly,
substrates with electron-donating groups on the aromatic ring
gave better yields than electron-withdrawing groups. The
substrates bearing methyl, methoxy, benzyloxy, dimethylamino
groups gave the corresponding products in 88%-94% yields (2b-
2i), while the cyclizations of the substrates with trifluoromethyl
Reagents and conditions: (a) NaBH4, rt, MeOH, 10 min, 95%-
99% yields; (b) NaH, rt, dry DMF, 30 min, 90%-99% yields.
Scheme 2. Synthesis of the precursors with Weinreb amides 1.

3
7
group and ester group on the aromatic rings took place in
moderate yields (2l-2m). The products with fluoro- and chloro-
groups were obtained in 90%-91% yields (2j-2k). Interestingly,
electron-donating groups at C6 position on the aromatic ring
seemed to favor the reaction (2c vs 2d, 2e vs 2f, 2g). It was worth
noting that the compound 2n was a key intermediate in synthesis
of 3-methylpentalongin, from which we could easily synthesize
the final product via the reported route. Additionally, the
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product 2f was confirmed by NMR, MS analysis along with X-
ray diffraction determination (Fig. 1). When we changed the 3-
methyl group by hydrogen atom, the desired product was also
obtained in 82% yield (2o). However, we still could not get the
precursor of 1 according to the Scheme 2 when the 3-methyl
group was replaced with aromatic groups such as a phenyl group.
Table 2. Preparation of 4-isochromanonesa,b
O
Br
O
1) t-BuLi, THF, -78oC
2) H2O
R'
R
R
O
O
O
N
R'
1
2
O
O
O
O
MeO
O
O
MeO
MeO
O
O
MeO
OMe
2d 94%
2bc 91%
2c 91%
2a
91%
O
O
O
O
BnO
MeO
MeO
BnO
O
O
O
O
MeO
OBn
2g 89%
2f 90%
2h 94%
2e
95%
O
O
O
O
O
O
O
O
90%
(H3C)2N
ButOOC
F
Cl
2l 79%
2k
2i 88%
2j 91%
OMe O
O
O
MeO
MeO
O
O
O
79%
F3C
OMe
2n 85%
2o
82%
2m
a Reagents and conditions: 2.2 equiv of t-BuLi, and 1.0 equiv of 1 in THF, -78 oC, 1 min.
b Isolated yields.
c 3.0 equiv t-BuLi was required.
Then, the protocol found here was applied to the synthesis of
of isochroman-4-one. Gratifyingly, the cyclization reaction
following the previously described annulation protocol proceeded
natural product (±)-XJP. (±)-XJP was a structurally unique 4-
isochromanone compound recently isolated from the peel of
Musa sapientum L., and was endowed with potent anti-
hypertensive activity. Although the total synthesis has been
achieved via different synthetic routes, the overall yield were not
satisfying17, 28-29. Herein, we would like to report the synthesis of
the (±)-XJP via the new explored methodology (Scheme 2).
The synthesis was started with the bromobenzyl alcohol 8,
which was synthesized from the commercially available
benzaldehyde 5 via a routine synthesis in 88% overall yield in
three steps30, 31. The precursor with Weinreb amide 9 was
prepared by alkylation of the corresponding (2-bromophenyl)
methanol 8 with 2-bromo-N-methoxy-N-methyl propanamide
under standard condition in 95% yield. With the compound 9 in
hand we turned our attention to the construction of the skeleton
Figure 1. X-ray crystal structure of 2f.

4
Tetrahedron
smoothly to afford the 4-isochromanone 10 in 93% yield, which
were dried (Na2SO4) and concentrated in vacuo. Flash column
ACCEPTED MANUSCRIP
T
was then converted to (±)-XJP via a deprotection operation. The
synthesis was accomplished efficiently in 6 steps with overall
yield up to 54%.
chromatography afforded 2a–2n.
1
4.2.1 3-methylisochroman-4-one (2a) White solid; H NMR
(300 MHz, CDCl3) δ: 7.88 (d, J = 7.6 Hz, 1H), 7.40 (td, J = 7.6
Hz, 1.2 Hz, 1H), 7.25 (t, J = 7.6 Hz, 1H), 7.05 (d, J = 7.6 Hz,
1H), 4.77 (s, 3H), 4.10 (q, J = 6.6 Hz, 1H), 1.38 (d, J = 6.6 Hz,
3H); 13C NMR (75 MHz, CDCl3) δ: 195.81, 142.03, 133.79,
129.15, 127.61, 126.57, 124.32, 78.38, 66.83, 15.69; MS-ESI:
(ESI, pos.ion) m/z: 163.1 [M+H]+; HRMS (ESI) calculated for
C10H11O2 [M+H]+ 163.0759, found 163.0744.
4.2.2 3,7-dimethylisochroman-4-one (2b) White solid; 1H
NMR (300 MHz, CDCl3) δ: 7.70 (s, 1H), 7.22 (dd, J = 7.8 Hz,
1.2 Hz, 1H), 6.96 (d, J = 7.8 Hz, 1H), 4.75 (s, 2H), 4.09 (q, J =
6.6 Hz, 1H), 2.26 (s, 3H), 1.39 (d, J = 6.6 Hz, 3H); 13C NMR (75
MHz, CDCl3) δ: 196.11, 139.22, 137.43, 134.70, 129.00, 126.70,
124.25, 78.38, 66.75, 21.04, 15.74; MS-ESI: (ESI, pos.ion) m/z:
177.1 [M+H]+; HRMS (ESI) calculated for C10H11O2 [M+H]+
177.0916, found 177.0925.
4.2.3 6,7-dimethoxy-3-methylisochroman-4-one (2c) White
solid; H NMR (300 MHz, CDCl3) δ: 7.48 (s, 1H), 7.31 (s, 1H),
Reagents and conditions: (a) BBr3, 0 oC, dry CH2Cl2, 3 h, 95%
yield; (b) BnBr/K2CO3/KI, DMF, 80 oC, overnight, 96% yield; (c)
NaBH4, MeOH, rt, 30 min, 96% yield; (d) 2-bromo-N-methoxy-
N-methylpropanamide, NaH, rt, dry DMF, 30 min, 95% yield; (e)
t-BuLi -78 oC, 1 min, then H2O, 93% yield; (f) Pd-C/H2, THF, rt,
4 h, 70% yield.
1
4.85 (s, 1H), 4.22 (q, J = 6.6 Hz, 1H), 3.95 (s, 3H), 3.93 (s, 3H),
1.51 (d, J = 6.6 Hz, 3H); 13C NMR (75 MHz, CDCl3) δ: 194.72,
153.91, 148.59, 136.93, 122.31, 107.82, 105.83, 77.83, 66.43,
56.09, 55.97, 15.79; MS-ESI: (ESI, pos.ion) m/z: 222.9 [M+H]+;
HRMS (ESI) calculated for C12H15O4 [M+H]+ 223.0965, found
223.0974.
Scheme 3. The synthetic route toward (±)-XJP
4.2.4 7,8-dimethoxy-3-methylisochroman-4-one (2d) White
1
3. Conclusion
solid; H NMR (300 MHz, CDCl3) δ: 7.83 (d, J = 8.6 Hz, 1H),
6.94 (d, J = 8.6 Hz, 1H), 5.14 (d, J = 15.8 Hz, 1H), 4.80 (d, J =
15.8 Hz, 1H), 4.19 (q, J = 6.6 Hz, 1H ), 3.95 (s, 3H), 3.85 (s, 3H),
1.50 (d, J = 6.6 Hz, 3H); 13C NMR (75 MHz, CDCl3) δ: 194.93,
156.85, 135.86, 124.08, 123.06, 111.12, 77.73, 62.84, 60.56,
55.89, 15.68; MS-ESI: (ESI, pos.ion) m/z: 222.9 [M+H]+;
HRMS (ESI) calculated for C12H15O4 [M+H]+ 223.0965, found
223.0972.
In summary, we have developed a practical and efficient
protocol to synthesize the 4-isochromanones via Parham-type
cyclization with Weinreb amide as the precusors. The reaction
proceeded in one minute and produced 4-isochromanones in
good to excellent yields. Additionally, the synthetic potential of
this method was further demonstrated by the synthesis of natural
product (±)-XJP in 6 steps with overall yield up to 54%.
4.2.5 8-(benzyloxy)-7-methoxy-3-methylisochroman-4-one (2e)
1
4. Experimental section
4.1. General
White solid; H NMR (300 MHz, CDCl3) δ: 7.83 (d, J = 8.6 Hz,
1H), 7.38-7.34 (m, 5H), 6.97 (d, J = 8.6 Hz, 1H), 5.07-4.95 (m,
3H), 4.50 (d, J = 15.8 Hz, 1H), 4.80 (d, J = 15.8 Hz, 1H), 4.09 (q,
J = 6.6 Hz, 1H ), 3.97 (s, 3H), 1.43 (d, J = 6.6 Hz, 3H); 13C
NMR (75 MHz, CDCl3) δ: 194.90, 156.88, 141.75, 137.08,
136.40, 128.54, 128.46, 128.37, 124.16, 124.12, 123.09, 111.15,
77.60, 74.80, 74.76, 63.03, 55.91, 15.60; MS-ESI: (ESI, pos.ion)
m/z: 299.1 [M+H]+; HRMS (ESI) calculated for C18H18O4Na
[M+Na]+ 321.1097, found 321.1112.
All commercially available starting materials and solvents
were reagent grade and used without further purification unless
otherwise noted. Anhydrous DMF was obtained by distillation
over CaH2 and anhydrous THF was obtained by distillation over
Na. 1H NMR and 13C NMR spectra were recorded on Bruker-300
spectrometers, and were referenced to the residual peaks of
CHCl3 at 7.26 ppm or DMSO-d6 at 2.50 ppm (1H NMR) and
CDCl3 at 77.23 ppm or DMSO-d6 at 39.52 ppm (13C NMR).
Chemical shifts (δ) were reported relative to residual protic
solvent signals. HRMS was performed on an Agilent 6530 Q-
TOF mass spectrometer, and ESI-MS was carried out on an
Agilent 6120 mass spectrometer. TLC was performed on
Huanghai HSGF 254 silica gel plates (China). Silica gel 60 H
(200-300 mesh), manufactured by Qingdao Haiyang Chemical
Group Co., Ltd (China) was used for general chromatography.
4.2.6 6-(benzyloxy)-7-methoxy-3-methylisochroman-4-one (2f)
1
White solid; H NMR (300 MHz, CDCl3) δ: 7.55 (s, 1H), 7.47-
7.26 (m, 5H), 6.61 (s, 1H), 5.16 (s, 2H), 4.84 (s, 2H), 4.19 (q, J =
6.6 Hz, 1H ), 3.92 (s, 3H), 1.49 (d, J = 6.6 Hz, 3H); 13C NMR (75
MHz, CDCl3) δ: 194.77, 154.57, 147.81, 137.23, 136.33, 128.64,
128.11, 127.55, 122.33, 110.02, 106.18, 77.98, 70.84, 66.60,
56.22, 15.88; MS-ESI: (ESI, pos.ion) m/z: 299.1 [M+H]+; HRMS
(ESI) calculated for C18H18O4Na [M+Na]+ 321.1097, found
321.1110.
4.2. Typical procedure for the synthesis of 4-isochromanones
4.2.7 7-(benzyloxy)-6-methoxy-3-methylisochroman-4-one (2g)
White solid; H NMR (300 MHz, CDCl3) δ: 7.52 (s, 1H), 7.45-
1
To a solution of precursors with Weinreb amides 1a-1n (1
mmol) in dry THF (10 mL), t-BuLi (2.2 mmol) was added at -78
oC, and after 1 min, the reaction was quenched by the addition of
sat. NH4Cl (10 mL). Ethyl acetate (15 mL) was added, the
organic layer was separated, and the aqueous phase was extracted
with ethyl acetate (3ⅹ15 mL). The combined organic extracts
7.28 (m, 5H), 6.64 (s, 1H), 5.22 (s, 2H), 4.81 (m, 2H), 4.22 (q, J
= 6.6 Hz, 1H ), 3.93 (s, 3H), 1.51 (d, J = 6.6 Hz, 3H); 13C NMR
(75 MHz, CDCl3) δ: 194.85, 153.17, 149.20, 136.73, 135.90,
128.73, 128.23, 127.19, 122.67, 77.96, 70.86, 66.47, 56.11, 15.87;
MS-ESI: (ESI, pos.ion) m/z: 299.1 [M+H]+; HRMS (ESI)
calculated for C18H18O4Na [M+Na]+ 321.1097, found 321.1109.

5
4.2.8 7-methoxy-3-methylisochroman-4-one (2h) Colorless oil;
1H NMR (300 MHz, CDCl3) δ: 7.93 (d, J = 8.6 Hz, 1H), 6.83 (dd,
J = 8.6 Hz, 2.4 Hz, 1H), 6.58 (d, J = 2.4 Hz, 1H), 4.81 (s, 1H),
4.24 (q, J = 6.6 Hz, 1H), 3.81 (s, 3H), 1.45 (d, J = 6.6 Hz, 3H);
13C NMR (75 MHz, CDCl3) δ: 194.74, 163.92, 144.48, 129.22,
122.72, 114.05, 108.32, 78.26, 66.91, 55.50, 15.73; MS-ESI:
(ESI, pos.ion) m/z: 193.1 [M+H]+; HRMS (ESI) calculated for
C12H15O4 [M+H]+ 193.0865, found 193.0845.
DMF (20 ml) was added with stirring, and to the stirred
ACCEPTED MANUSCRIPT
solution 2-bromo-N-methoxy-N-methyl propanamide (7.5 mmol)
was added. The mixture was cooled with ice-water bath and
sodium hydride (15 mmol) was added with stirring. Cooling bath
was removed and the mixture was stirred at rt for further 30 min.
The reaction mixture was quenched with water (20 mL),
extracted with ethyl acetate (3 ⅹ 20 mL), and the combined
organic layers were washed with brine, dried with Na2SO4 and
evaporated. The residue was separated with column
chromatography to afford 9 in 95% yield. Colorless oil; 1H NMR
(300 MHz, CDCl3): δ 7.45-7.24 (m, 11H), 6.83 (d, J = 8.8 Hz,
1H), 5.06 (s, 2H), 5.04 (s, 2H), 4.85 (d, J = 10.2 Hz, 1H), 4.57 (d,
J = 10.2 Hz, 1H),4.39 (q, J = 6.6 Hz, 1H), 3.52 (s, 3H), 3.11 (s,
3H), 1.45 (d, J = 6.6 Hz, 3H); 13C NMR (75 MHz, CDCl3): δ
151.54, 148.75, 137.32, 136.43, 131.77, 128.86, 128.65, 128.36,
128.22, 128.11, 127.60, 116.97, 115.37, 76.13, 71.84, 70.99,
65.55, 61.13, 32.24, 18.03; MS-ESI: (ESI, pos.ion) m/z: 514.1
[M+H]+; HRMS (ESI) calcd for C26H29BrNO5 [M+H]+ 514.1224,
found 514.1212.
4.2.9
7-(dimethylamino)-3-methylisochroman-4-one
(2i)
Yellow solid; 1H NMR (300 MHz, CDCl3) δ: 7.89 (d, J = 8.8 Hz,
1H), 6.61 (dd, J = 8.9 Hz, 2.5 Hz, 1H), 6.26 (d, J = 2.4 Hz, 1H),
4.81 (s, 2H), 4.19 (q, J = 6.6 Hz, 1H ), 3.04 (s, 3H), 1.48 (d, J =
6.6 Hz, 3H); 13C NMR (75 MHz, CDCl3) δ: 194.40, 153.67,
144.02, 128.87, 117.86, 110.94, 104.73, 78.25, 67.31, 40.05,
16.04; MS-ESI: (ESI, pos.ion) m/z: 205.8 [M+H]+; HRMS (ESI)
calculated for C12H15NO2Na [M+Na]+ 228.1000, found 228.0986.
4.2.10 7-fluoro-3-methylisochroman-4-one (2j) Yellow solid;
1H NMR (300 MHz, CDCl3) δ: 8.08 (dd, J = 8.6 Hz, 2.4 Hz, 1H),
7.08 (td, J = 8.6 Hz, 2.4 Hz, 1H), 6.89 (dd, J = 8.6 Hz, 2.4 Hz,
1H), 4.91 (s, 2H), 4.25 (q, J = 6.6 Hz, 1H), 1.52 (d, J = 6.6 Hz,
3H); 13C NMR (75 MHz, CDCl3) δ: 194.40, 167.48, 164.08,
145.11, 144.99, 130.08, 129.95, 125.94, 115.49, 115.19, 111.22,
110.92, 78.33, 66.61, 66.59, 15.58; MS-ESI: (ESI, pos.ion) m/z:
181.1 [M+H]+; HRMS (ESI) calculated for C10H10FO2 [M+H]+
181.0665, found 181.0655.
4.3.2 7,8-bis(benzyloxy)-3-methylisochroman-4-one (10) To a
solution of precursor 9 (1 mmol) in dry THF (10 mL), t-BuLi
(2.2 mmol) was added at -78 oC, and after 1 min, the reaction was
quenched by the addition of sat. NH4Cl (10 mL). Ethyl acetate
(15 mL) was added, the organic layer was separated, and the
aqueous phase was extracted with ethyl acetate (3ⅹ15 mL). The
combined organic extracts were dried (Na2SO4) and concentrated
in vacuo. Flash column chromatography afforded 10 in 93%
4.2.11 7-chloro-3-methylisochroman-4-one (2k) White solid;
1H NMR (300 MHz, CDCl3) δ: 7.96 (d, J = 8.4 Hz, 1H), 7.36 (dd,
J = 8.4 Hz, 1.8 Hz, 1H), 7.20 (s, 1H), 4.89 (s, 2H), 4.24 (q, J =
6.6 Hz, 1H), 1.51 (d, J = 6.6 Hz, 3 H); 13C NMR (75 MHz,
CDCl3) δ: 194.86, 143.57, 140.22, 128.51, 128.25, 127.70,
124.45, 78.47, 66.48, 15.64; MS-ESI: (ESI, pos.ion) m/z: 197.0
[M+H]+; HRMS (ESI) calculated for C10H10ClO2 [M+H]+
197.0369, found 197.0356.
1
yield. White solid; H NMR (300 MHz, CDCl3): δ 7.81 (d, J =
8.7 Hz, 1H), 7.47-7.32 (m, 10H), 7.03 (d, J = 8.7 Hz, 1H), 5.23 (s,
2H), 5.09-4.98 (m, 3H), 4.54 (d, J = 15.9 Hz, 1H), 4.10 (q, J =
6.9 Hz, 1H), 1.45 (d, J = 6.9 Hz, 3H); 13C NMR (75 MHz,
CDCl3): δ 194.92, 155.98, 142.16, 137.00, 136.64, 135.94,
128.77, 128.59, 128.54, 128.40, 127.52, 124.04, 123.37, 112.61,
77.66, 74.88, 70.82, 63.09, 15.64; MS-ESI: (ESI, pos.ion) m/z:
397.1 [M+Na]+; HRMS (ESI) calcd for C24H22NaO4 [M+Na]+
397.1410, found 397.1415.
4.2.12 3-methyl-7-(trifluoromethyl)isochroman-4-one (2m)
1
White solid; H NMR (300 MHz, CDCl3) δ: 8.15 (d, J = 8.2 Hz,
4.3.3 (±)-7, 8-dihydroxy-3-methylisochroman-4-one [(±)-XJP]
To a solution of 7, 8-bis (benzyloxy)-3-methylisochroman-4-one
10 (0.26 mmol) in THF (5 mL) was added Pd-C (0.02 g, 10%)
and the mixture was stirred under H2 atmosphere for 4 h at room
temperature. Then the reaction solution was passed through a
short diatomite pad and washed with THF. The combined organic
phase was concentrated in vacuo, and the residue was purified by
a short silica gel column chromatography to give (±)-XJP in 70%
1H), 7.65 (dd, J = 8.2 Hz, 0.6 Hz, 1H), 7.49 (s, 1H), 4.98 (s, 2H),
4.29 (q, J = 6.6 Hz, 1H), 1.53 (d, J = 6.6 Hz, 3 H); 13C NMR (75
MHz, CDCl3) δ: 194.80, 142.57, 136.23, 131.71, 127.50, 124.55,
124.50, 121.70, 121.65, 78.57, 66.68, 15.54; MS-ESI: (ESI,
pos.ion) m/z: 231.1 [M+H]+; HRMS (ESI) calculated for
C11H10F3O2 [M+H]+ 231.0633, found 231.0629.
4.2.13 5,10-dimethoxy-3-methyl-1H-benzo[g]isochromen-4(3H)
-one (2n) Yellow solid; 1H NMR (300 MHz, CDCl3) δ: 8.36 (d, J
= 8.2 Hz, 1H), 8.03 (d, J = 8.2 Hz, 1H,), 7.66 (m, 2H), 5.31 (d, J
= 15.0 Hz, 1H), 4.80 (d, J = 15.0 Hz, 1H), 4.22 (q, J = 6.6 Hz,
1H), 4.01 (s, 3H), 3.87 (s, 3H), 1.55 (d, J = 6.6 Hz, 3H); 13C
NMR (75 MHz, CDCl3) δ:195.71, 155.70, 146.50, 131.57,
129.52, 129.18, 128.09, 126.72, 125.00, 121.98; MS-ESI: (ESI,
pos.ion) m/z: 272.9 [M+H]+; HRMS (ESI) calculated for
C16H16NaO4 [M+Na]+ 295.0941, found 295.0945.
1
yield. White solid; H-NMR (300 MHz, DMSO-d6): δ 10.47 (s,
1H), 8.96 (s, 1H), 7.32 (d, J = 8.4 Hz, 1H), 6.84 (d, J = 8.4 Hz,
1H), 4.92 (d, J = 15.6 Hz, 1H), 4.69 (d, J = 15.6 Hz, 1H), 4.21 (q,
J = 6.6 Hz, 1H), 1.31 (d, J = 6.6 Hz, 3H); 13C-NMR (75 MHz,
DMSO-d6): δ 194.45, 150.46, 139.43, 129.95, 121.31, 118.61,
114.26, 76.44, 62.27, 15.50. MS-ESI: (ESI, neg.ion) m/z: 193.0
[M-H]-; HRMS (ESI) calcd for C10H9O4 [M-H]- 193.0506, found
193.0501.
1
4.2.14 6,7-dimethoxyisochroman-4-one (2o) Yellow solid; H
Acknowledgments
NMR (300 MHz, CDCl3) δ: 7.41 (s, 1H), 6.57 (s, 1H), 4.76 (s,
2H), 4.24 (s, 2H), 3.88 (s, 3H), 3.86 (s, 3H); 13C NMR (75 MHz,
CDCl3) δ: 192.73, 154.23, 148.76, 136.78, 122.72 107.52,
106.06, 72.91, 67.54, 56.18, 56.05; MS-ESI: (ESI, pos.ion) m/z:
208.92 [M+H]+; HRMS (ESI) calculated for C11H12O4 [M+H]+
209.0736, found 209.0750.
This study was financially supported by a grant from
“National Natural Science Fund (No. 81302635), the Project
Program of State Key Laboratory of Natural Medicines, China
Pharmaceutical University (No. SKLNMZZCX201404) and the
Project for Research and Innovation of Graduates in Colleges and
Universities of Jiangsu Province (KYLX_0611).
4.3. Procedure for total synthesis of (±)-XJP
4.3.1 2-((2,3-bis(benzyloxy)-6-bromobenzyl)oxy)-N-methoxy-
N-methyl propanamide (9). A 50 ml round bottom flask was
charged with compound 8 (5 mmol) and argonated. Anhydride
Supplementary Material

6
Tetrahedron
Supplementary data and compound characterizations
ACCEPTED MANUSCRIPT
17. Liu, J.; Ren, H.; Xu, J.; Bai, R.; Yan, Q.; Huang, W.; Wu, X.; Fu, J.;
Wang, Q.; Wu, Q. Bioorg. Med. Chem. Lett. 2009, 19, 1822-1824.
18. Ardeo, A.; Lete, E.; Sotomayor, N. Tetrahedron Lett. 2000, 41, 5211-
5214.
associated with this article can be found in the online version at
______.
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ACCEPTED MANUSCRIPT
Electronic Supporting Information (ESI) for:
An efficient synthesis of 4-isochromanones via
Parham-type cyclization with Weinreb amide
Chaolei Wang a,b, Zheng Wu a,b, Jia Wang a,b, Jie Liu a,c*, Hequan Yao a,b
,
Aijun Lin a,b, Jinyi Xu a,b
aState Key Laboratory of Natural Medicines, China Pharmaceutical University, 24 Tong Jia
Xiang, Nanjing 210009, PR China
bDepartment of Medicinal Chemistry, China Pharmaceutical University, 24 Tong Jia Xiang,
Nanjing 210009, PR China
cDepartment of Organic Chemistry, China Pharmaceutical University, 24 Tong Jia Xiang,
Nanjing, 210009, PR China
Contents
Page
X-ray Structure and data of 2f
1H-NMR and 13C-NMR Spectra
S2-S18
S19-S35
Corresponding authors. Tel.: +86 025 83271299; Fax. +86 025 83302827 (J.X.)；
E-mail: jinyixu@china.com (J. Xu), cpu-jill@163.com (J. Liu).
1

ACCEPTED MANUSCRIPT
Contents:
Table S1 - Crystal Data and Details of the Structure Determination
Table S2 - Final Coordinates and Equivalent Isotropic Displacement Parameters of
the non-Hydrogen atoms
Table S3 - Hydrogen Atom Positions and Isotropic Displacement Parameters
Table S4 - (An)isotropic Displacement Parameters
Table S5 - Bond Distances (Angstrom)
Table S6 - Bond Angles (Degrees)
Table S7 - Torsion Angles (Degrees)
Table S8 - Contact Distances(Angstrom)
Table S9 - Hydrogen Bonds (Angstrom, Deg)
2

ACCEPTED MANUSCRIPT
Table S1 - Crystal Data and Details of the Structure Determination
Formula
C18 H18 O4
298.32
Formula Weight
Crystal System
Space group
Triclinic
P-1
(No. 2)
a, b, c [Angstrom]
alpha, beta, gamma [deg]
V [Ang**3]
8.734(6) 12.109(8) 14.722(10)
98.844(10) 92.973(11)
96.98(1)
1523.1(18)
4
Z
D(calc) [g/cm**3]
Mu(MoKa) [ /mm ]
F(000)
1.301
0.091
632
Crystal Size [mm]
0.22 x 0.24 x 0.27
Data Collection
Temperature (K)
Radiation [Angstrom]
Theta Min-Max [Deg]
Dataset
296
MoKa
0.71073
2.0, 25.0
-10: 10 ; -14: 13 ; -17: 12
8087, 5267, 0.054
2993
Tot., Uniq. Data, R(int)
Observed data [I > 2.0 sigma(I)]
Refinement
Nref, Npar
5267, 390
R, wR2, S
0.1228, 0.3238, 1.09
w = 1/[\s^2^(Fo^2^)+(0.0000P)^2^+14.0000P] where
P=(Fo^2^+2Fc^2^)/
Max. and Av. Shift/Error
0.05, 0.00
-0.77, 0.98
Min. and Max. Resd. Dens. [e/Ang^3]
3

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Table S2 - Final Coordinates and Equivalent Isotropic Displacement
Parameters of the non-Hydrogen atoms
Atom
----
O1
x
y
z
U(eq) [Ang^2]
-----------
---
---
---
0.0599(5) 0.7569(3) 0.7357(2) 0.0906(14)
-0.1297(5) 0.5767(3) 0.7194(3) 0.0961(14)
0.1428(5) 0.8882(3) 1.0851(2) 0.0991(14)
O2
O3
O4
-0.1087(8) 0.6647(4) 1.1295(3)
0.0397(11) 0.8111(6) 1.2413(4)
-0.0021(7) 0.7442(6) 1.1504(4)
0.185(2)
0.137(4)
0.103(2)
C1
C2
C3
-0.1576(6) 0.5994(4) 1.0507(4) 0.0724(16)
-0.0992(5) 0.6430(3) 0.9695(3) 0.0565(16)
0.0037(5) 0.7411(3) 0.9803(3) 0.0543(14)
0.0560(6) 0.8010(4) 1.0722(3) 0.0696(16)
0.0572(6) 0.7813(4) 0.9007(3) 0.0672(16)
0.0154(7) 0.7259(4) 0.8167(3) 0.0722(18)
-0.0914(6) 0.6255(4) 0.8047(3) 0.0654(17)
C4
C5
C6
C7
C8
C9
C10
C11
C12
C13
C14
C15
C16
C17
C36
O5
-0.2312(8) 0.4769(5) 0.6997(5)
0.1747(10) 0.9544(6) 0.6130(5)
0.2076(9) 0.9762(6) 0.5229(4)
0.2871(9) 0.9070(6) 0.4796(5)
0.3289(9) 0.8110(7) 0.5065(5)
0.2932(9) 0.7936(6) 0.5962(4)
0.110(3)
0.141(3)
0.127(3)
0.120(3)
0.125(3)
0.112(3)
0.2114(7) 0.8683(4) 0.6477(3) 0.0752(19)
0.1778(7) 0.8529(5) 0.7437(3) 0.0866(19)
-0.1496(6) 0.5877(4) 0.8816(3) 0.0626(16)
0.3769(5) 0.2179(3) 0.2768(2) 0.0920(14)
0.5648(5) 0.3884(3) 0.2559(2) 0.0857(14)
0.6175(5) 0.3483(3) -0.0929(2) 0.0930(14)
O6
O7
O8
0.3578(7) 0.1044(4) -0.1369(3)
0.151(2)
4

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C18
C19
C20
C21
C22
C23
C24
C25
C26
C27
C28
C29
C30
C31
C32
C33
C34
C35
0.4943(11) 0.1934(7) -0.2467(4)
0.4725(8) 0.1734(5) -0.1529(4)
0.161(4)
0.095(2)
0.5393(6) 0.2648(4) -0.0766(3) 0.0731(19)
0.4939(5) 0.2513(4) 0.0159(3) 0.0542(14)
0.3953(6) 0.1603(4) 0.0280(3) 0.0641(16)
0.3294(7) 0.0714(4) -0.0544(4) 0.0790(19)
0.3547(6) 0.1438(4) 0.1152(3) 0.0631(16)
0.4123(6) 0.2249(4) 0.1897(3) 0.0700(18)
0.5159(6) 0.3178(4) 0.1774(3) 0.0648(16)
0.2902(9) 0.1188(5) 0.2943(4)
0.118(3)
0.6814(7) 0.4825(4) 0.2515(4) 0.0851(19)
0.7171(6) 0.5437(3) 0.3439(3)
0.8707(6) 0.5896(5) 0.3660(4)
0.9164(8) 0.6484(7) 0.4538(5)
0.8085(11) 0.6613(6) 0.5196(4)
0.6549(10) 0.6154(6) 0.4974(4)
0.6092(7) 0.5566(5) 0.4096(4)
0.114(2)
0.198(2)
0.207(3)
0.180(3)
0.200(2)
0.190(3)
0.5536(6) 0.3290(4) 0.0912(3) 0.0667(16)
Table S3 - Hydrogen Atom Positions and Isotropic Displacement Parameters
Atom
----
x
y
z
U(iso) [Ang^2]
-----------
0.2050
---
---
---
H1A
H1B
H1C
H2
-0.03220
0.14220
0.03680
0.08090
-0.26980
-0.12600
0.12380
-0.18940
0.86440
0.85060
0.76220
0.69690
0.59030
0.52550
0.84860
0.41950
1.25440
1.24260
1.28690
1.15240
1.04500
1.05160
0.90760
0.2050
0.2050
0.1240
H3A
H3B
H7
0.0870
0.0870
0.0800
H10A
0.72790
0.1640
5

ACCEPTED MANUSCRIPT
H10B
H10C
H11
-0.24510
-0.32920
0.12330
0.17370
0.32040
0.37800
0.32430
0.27020
0.14130
-0.22360
0.44790
0.60280
0.44640
0.55250
0.37410
0.21860
0.29010
0.19660
0.26530
0.34970
0.64310
0.77350
0.94290
1.01920
0.83910
0.58270
0.50650
0.62190
0.45330
0.48890
1.00580
1.03580
0.92340
0.76020
0.73250
0.83940
0.91960
0.52430
0.12850
0.20690
0.25800
0.12380
0.00250
0.05490
0.07970
0.10310
0.12840
0.05710
0.53120
0.45560
0.58100
0.67910
0.70060
0.62400
0.52590
0.39100
0.63420
0.72350
0.64930
0.49810
0.42360
0.46810
0.62020
0.77740
0.77600
0.87420
-0.28950
-0.25500
-0.25740
-0.14870
-0.05080
-0.05100
0.12340
0.25480
0.35750
0.28240
0.21150
0.22700
0.32210
0.46860
0.57830
0.54140
0.39480
0.08260
0.1640
0.1640
0.1690
0.1530
0.1440
0.1500
0.1350
0.1040
0.1040
0.0750
0.2410
0.2410
0.2410
0.1140
0.0950
0.0950
0.0760
0.1770
0.1770
0.1770
0.1020
0.1020
0.2380
0.2480
0.2150
0.2400
0.2280
0.0800
H12
H13
H14
H15
H17A
H17B
H36
H18A
H18B
H18C
H19
H23A
H23B
H24
H27A
H27B
H27C
H28A
H28B
H30
H31
H32
H33
H34
H35
6

ACCEPTED MANUSCRIPT
Table S4 - (An)isotropic Displacement Parameters
Atom U(1,1) or U U(2,2)
U(3,3)
------
U(2,3)
------
U(1,3)
------
U(1,2)
----
O1
------
------
------
0.118(3) 0.084(2) 0.0574(19)0.0153(17) 0.004(2)
0.126(3) 0.074(2) 0.076(2) 0.0088(19) -0.005(2)
0.132(3) 0.087(2) 0.064(2) 0.0178(18) -0.019(2)
-0.040(2)
-0.027(2)
-0.039(2)
-0.076(4)
0.023(6)
-0.021(4)
0.012(2)
O2
O3
O4
0.337(6) 0.100(3) 0.094(3) -0.005(2)
0.237(9) 0.111(5) 0.065(4) 0.018(4)
0.083(4) 0.159(5) 0.067(3) 0.047(3)
0.078(3) 0.054(2) 0.095(3) 0.032(2)
0.110(3)
0.029(5)
-0.002(3)
0.031(3)
C1
C2
C3
C4
0.057(3) 0.043(2) 0.075(3) 0.0252(19) 0.012(2) 0.0056(19)
0.055(3) 0.047(2) 0.061(2) 0.0154(19) 0.000(2) 0.001(2)
C5
C6
0.077(3) 0.076(3) 0.055(2) 0.023(2)
0.076(3) 0.061(2) 0.063(3) 0.024(2)
0.099(4) 0.051(2) 0.064(3) 0.022(2)
0.074(3) 0.057(3) 0.061(3) 0.012(2)
0.120(5) 0.084(4) 0.102(4) -0.002(3)
-0.003(2) -0.005(3)
0.008(2) -0.016(2)
0.007(3) -0.017(3)
-0.004(2) -0.008(2)
-0.025(4) -0.041(4)
C7
C8
C9
C10
C11
C12
C13
C14
C15
C16
C17
C36
O5
0.225(7) 0.136(5) 0.092(4)
0.167(6) 0.147(5) 0.099(4)
0.043(4)
0.072(3)
0.069(5)
0.062(4)
0.084(5)
0.056(5)
0.139(6) 0.134(5) 0.095(4) 0.053(4)
0.029(4) -0.004(5)
0.147(6) 0.134(6) 0.088(4)
0.148(6) 0.120(5) 0.080(4)
0.096(4) 0.068(3) 0.061(3)
0.103(4) 0.089(3) 0.054(3)
0.064(3) 0.041(2) 0.082(3)
0.134(3) 0.069(2) 0.071(2)
0.004(4)
0.040(3)
0.022(2)
0.019(2)
0.020(2)
0.042(4)
0.023(4)
0.002(5)
0.029(5)
0.008(3) -0.007(3)
-0.010(3) -0.045(3)
0.004(2) -0.008(2)
0.0172(17) 0.032(2) -0.013(2)
O6
0.116(3) 0.072(2) 0.0584(19) 0.0060(17) 0.0131(19) -0.028(2)
O7
0.121(3) 0.076(2) 0.075(2)
0.223(5) 0.116(3) 0.079(3)
0.224(9) 0.163(7) 0.063(4)
0.0141(18) 0.027(2) -0.026(2)
O8
0.001(2)
-0.001(4)
0.012(3) -0.093(3)
0.013(5) -0.078(6)
C18
7

ACCEPTED MANUSCRIPT
C19
C20
C21
C22
C23
C24
C25
C26
C27
C28
C29
C30
C31
C32
C33
C34
C35
0.116(5) 0.087(4) 0.072(3) -0.012(3)
0.025(3)
0.015(3)
0.010(2) -0.001(2)
0.006(2) 0.002(3)
0.007(3) -0.010(3)
-0.007(4)
-0.004(3)
-0.007(2)
0.008(2)
-0.009(3)
-0.004(2)
0.004(2)
-0.007(2)
-0.010(4)
-0.023(3)
0.016(4)
0.006(4)
0.002(4)
0.009(4)
0.037(4)
0.041(4)
-0.007(2)
0.083(4) 0.066(3) 0.066(3)
0.045(2) 0.051(2) 0.063(3)
0.074(3) 0.041(2) 0.076(3)
0.081(4) 0.068(3) 0.080(3)
0.060(3) 0.049(2) 0.078(3)
0.089(4) 0.049(2) 0.076(3)
0.067(3) 0.052(2) 0.071(3)
0.199(6) 0.063(3) 0.095(4)
0.112(4) 0.072(3) 0.061(3)
0.165(4) 0.085(4) 0.103(3)
0.005(2)
0.011(2)
0.023(2)
0.007(2)
0.023(3)
0.007(2)
0.018(3)
0.008(2)
0.066(4)
0.008(3) -0.001(3)
0.042(3)
0.023(3)
0.020(3)
0.011(3)
0.018(3)
0.023(3)
0.023(3)
0.021(2)
0.187(3) 0.213(5) 0.179(4) -0.003(4)
0.192(4) 0.224(5) 0.185(4) -0.007(4)
0.186(4) 0.171(5) 0.171(4)
0.004(4)
0.195(3) 0.222(5) 0.170(4) -0.020(4)
0.183(4) 0.210(5) 0.167(4) -0.015(4)
0.088(3) 0.046(2) 0.064(3)
Table S5 - Bond Distances (Angstrom)
0.010(2)
O1
O1
O2
O2
O3
O4
O4
O5
O5
O6
O6
O7
-C8
1.365(6)
1.442(7)
1.311(6)
1.391(8)
1.206(6)
1.245(9)
1.318(7)
1.347(5)
1.405(8)
1.445(7)
1.344(6)
1.213(6)
C14 -C15
1.413(10)
-C17
-C9
C15 -C16
C16 -C17
1.381(9)
1.493(7)
0.9600
0.9600
0.9600
0.9800
0.9700
0.9700
0.9300
0.9600
0.9600
-C10
-C6
C1
-H1A
-H1B
-H1C
-H2
C1
-C2
C1
-C3
C2
-C25
-C27
-C28
-C26
-C20
C3
-H3B
-H3A
-H7
C3
C7
C10
C10
-H10C
-H10A
8

ACCEPTED MANUSCRIPT
O8
O8
C1
C2
C3
C4
C4
C5
C5
C7
C8
C9
-C19
-C23
-C2
1.280(9)
1.361(7)
1.458(9)
1.508(8)
1.470(7)
1.383(6)
1.386(6)
1.456(6)
1.416(6)
1.323(6)
1.422(7)
1.383(7)
C10 -H10B
C11 -H11
C12 -H12
C13 -H13
C14 -H14
C15 -H15
C17 -H17A
C17 -H17B
C36 -H36
C18 -C19
C19 -C20
C20 -C21
0.9600
0.9300
0.9300
0.9300
0.9300
0.9300
0.9700
0.9700
0.9300
1.456(9)
1.490(8)
1.465(6)
1.354(7)
1.373(6)
1.529(7)
1.387(6)
0.9700
0.9700
0.9300
0.9600
0.9600
0.9600
0.9700
0.9700
0.9300
0.9300
0.9300
0.9300
0.9300
0.9300
-C6
-C4
-C5
-C36
-C6
-C7
-C8
-C9
-C36
C11 -C12
C11 -C16
C12 -C13
C13 -C14
C24 -C25
C25 -C26
C26 -C35
C28 -C29
C29 -C30
C29 -C34
C30 -C31
C31 -C32
C32 -C33
C33 -C34
C18 -H18A
C18 -H18B
C18 -H18C
C19 -H19
1.429(10) C21 -C22
1.296(9) C21 -C35
1.270(11) C22 -C23
1.368(11) C22 -C24
1.383(7)
1.396(7)
1.350(6)
1.445(7)
1.390(7)
1.390(8)
1.390(9)
C23 -H23A
C23 -H23B
C24 -H24
C27 -H27A
C27 -H27B
C27 -H27C
C28 -H28A
1.391(11) C28 -H28B
1.390(13) C30 -H30
1.390(9)
0.9600
0.9600
0.9600
0.9800
C31 -H31
C32 -H32
C33 -H33
C34 -H34
C35 -H35
9

ACCEPTED MANUSCRIPT
Table S6 - Bond Angles (Degrees)
C8
C9
C2
-O1
-O2
-O4
-C17
-C10
-C3
116.0(4)
121.0(5)
132.3(6)
118.7(4)
118.2(4)
126.3(5)
113.9(6)
126.9(6)
116.2(5)
113.8(4)
120.2(4)
120.3(4)
119.5(4)
118.8(4)
120.1(4)
121.0(4)
115.1(4)
122.6(4)
122.3(4)
121.9(5)
126.7(5)
113.5(4)
119.7(4)
119.0(4)
116.2(4)
124.8(5)
124.7(7)
114.2(7)
109.00
C12
C13
C14
C15
C11
C11
O1
-C13 -C14
-C14 -C15
-C15 -C16
-C16 -C17
-C16 -C17
-C16 -C15
127.0(7)
116.1(7)
119.2(6)
119.6(5)
121.8(6)
118.5(6)
106.5(4)
120.9(4)
110.00
109.00
109.00
109.00
110.00
110.00
96.00
C25 -O5
C26 -O6
C19 -O8
-C27
-C28
-C23
-C6
C1
O4
O4
O4
C3
C3
C5
C4
C4
C6
C2
O3
O3
C5
O1
O1
C7
C8
O2
O2
-C2
-C2
-C2
-C3
-C4
-C4
-C4
-C5
-C5
-C5
-C6
-C6
-C6
-C7
-C8
-C8
-C8
-C9
-C9
-C9
-C17
-C36
-C1
-C16
-C9
-C1
C4
-C6
C2
-H1A
-H1C
-H1C
-H1C
-H1B
-H1B
-H2
-C4
H1A -C1
-C5
H1B
C2
-C1
-C1
-C1
-C1
-C2
-C2
-C2
-C3
-C3
-C3
-C3
-C3
-C7
-C7
-C10
-C36
-C36
-C7
H1A
C2
-C6
O4
C1
-C7
-H2
96.00
-C5
C6
-H2
96.00
-C5
C4
-H3B
-H3B
-H3A
-H3A
-H3B
-H7
109.00
108.00
109.00
109.00
109.00
119.00
119.00
109.00
109.00
109.00
110.00
120.5(4)
-C2
H3A
C4
-C8
-C7
O4
O4
C5
-C9
-C9
-C36
-C8
C8
-H7
O2
-H10A
-H10C
-H10C
-H10C
-C23
-C36
H10A -C10
H10B -C10
C12 -C11 -C16
C11 -C12 -C13
H10A -C10 -H10B
O2
-C10
-C22
C21
10

ACCEPTED MANUSCRIPT
O2
-C10 -H10B
110.00
118.00
118.00
123.00
123.00
116.00
117.00
122.00
122.00
120.00
120.00
C21
C23
O8
-C22
-C22
-C23
-C24
-C25
-C25
-C25
-C26
-C26
-C26
-C28
-C29
-C29
-C29
-C24
-C24
-C22
-C25
-C24
-C26
-C26
-C25
-C35
-C35
-C29
-C30
-C34
-C34
121.1(4)
118.4(4)
113.0(4)
118.5(5)
123.0(4)
116.6(4)
120.4(4)
113.9(4)
127.3(5)
118.7(4)
107.8(4)
115.9(5)
124.1(5)
120.0(5)
120.0(5)
120.0(7)
119.9(6)
120.1(6)
120.0(6)
121.8(5)
109.00
C12 -C11 -H11
C16 -C11 -H11
C13 -C12 -H12
C11 -C12 -H12
C12 -C13 -H13
C14 -C13 -H13
C13 -C14 -H14
C15 -C14 -H14
C14 -C15 -H15
C16 -C15 -H15
C22
O5
O5
C24
O6
O6
C25
O6
C16 -C17 -H17B 110.00
H17A -C17 -H17B 109.00
C28
C28
C30
C29
C30
C31
C32
C29
C21
C19
C19
C19
O1
-C17 -H17B
110.00
C16 -C17 -H17A 110.00
-C30 -C31
-C31 -C32
O1
C4
C9
O8
O8
-C17 -H17A 110.00
-C36 -H36
-C36 -H36
-C19 -C18
-C19 -C20
120.00
-C32
-C33
-C33
-C34
120.00
119.9(6)
118.0(5)
117.2(6)
120.6(4)
123.2(4)
116.1(4)
120.1(4)
120.5(4)
119.4(4)
97.00
-C34 -C33
-C35 -C26
-C18 -H18A
-C18 -H18B
-C18 -H18C
C18 -C19 -C20
O7
O7
-C20 -C19
-C20 -C21
109.00
109.00
C19 -C20 -C21
C20 -C21 -C22
C20 -C21 -C35
C22 -C21 -C35
C18 -C19 -H19
C20 -C19 -H19
H18A -C18 -H18B
H18A -C18 -H18C
H18B -C18 -H18C
109.00
109.00
109.00
O8
O6
-C19 -H19
97.00
-C28 -H28B
110.00
97.00
C29 -C28 -H28A
110.00
O8
-C23 -H23A
109.00
C29 -C28 -H28B
110.00
11

ACCEPTED MANUSCRIPT
O8
-C23
-H23B
-H23A
-H23B
109.00
109.00
109.00
108.00
121.00
121.00
109.00
110.00
109.00
110.00
109.00
109.00
110.00
H28A -C28 -H28B
C29 -C30 -H30
C31 -C30 -H30
C30 -C31 -H31
C32 -C31 -H31
C31 -C32 -H32
C33 -C32 -H32
C32 -C33 -H33
C34 -C33 -H33
C29 -C34 -H34
C33 -C34 -H34
C21 -C35 -H35
C26 -C35 -H35
108.00
120.00
120.00
120.00
120.00
120.00
120.00
120.00
120.00
120.00
120.00
119.00
119.00
C22 -C23
C22 -C23
H23A -C23 -H23B
C22 -C24
C25 -C24
-H24
-H24
O5
O5
O5
-C27
-C27
-C27
-H27A
-H27B
-H27C
H27A -C27 -H27B
H27A -C27 -H27C
H27B -C27 -H27C
O6
-C28
-H28A
Table S7 - Torsion Angles (Degrees)
C17 -O1
C17 -O1
-C8
-C8
-C7
-C9
7.5(8)
-175.1(5)
178.0(5)
-2.7(8)
C8
-O1
-C17 -C16
C10 -O2
C10 -O2
-C9
-C9
-C3
-C2
-C2
-C36
-C8
-C4
-C1
-C6
178.8(5)
-15.4(10)
179.4(7)
20.3(11)
6.5(8)
C2
C3
C3
-O4
-O4
-O4
C27 -O5
C27 -O5
C26 -O6
C28 -O6
C28 -O6
C23 -O8
C19 -O8
-C25 -C24
-C25 -C26
-C28 -C29
-C26 -C35
-C26 -C25
-C19 -C18
-C23 -C22
-171.5(5)
-178.6(4)
-6.1(8)
175.3(5)
174.9(6)
28.1(9)
12

ACCEPTED MANUSCRIPT
C23
C1
-O8
-C2
-C2
-C2
-C2
-C3
-C3
-C4
-C4
-C4
-C4
-C4
-C4
-C5
-C5
-C5
-C5
-C5
-C5
-C7
-C7
-C8
-C8
-C8
-C8
-C9
-C9
-C19 -C20
-30.6(9)
-174.4(6)
169.3(6)
-12.6(8)
7.5(9)
-C6
-C6
-C6
-C6
-C4
-C4
-C5
-C5
-C5
-O3
-C5
-O3
-C36
-C5
-C7
-C6
O4
O4
C1
O4
O4
C36
C3
-175.3(5)
3.1(7)
-1.2(6)
0.7(6)
C5
-C36 -C9
-C5 -C6
3.9(7)
C36
C3
179.1(4)
-179.7(4)
-177.6(5)
-2.2(7)
-C5
-C7
C3
-C36 -C9
C4
-C7
-C6
-C7
-C6
-C6
-C6
-C8
-C8
-C9
-C9
-C9
-C9
-C8
-C2
-C8
-C2
-O3
-O3
-C9
-O1
-O2
-C36
-O2
-C36
C7
-176.0(5)
177.5(5)
3.7(7)
C6
C4
C7
2.1(8)
C4
-178.2(5)
2.8(8)
C5
C5
-180.0(5)
1.0(7)
O1
C7
0.0(8)
C7
178.6(5)
-177.6(5)
-3.3(8)
O1
C8
-C36 -C4
-C36 -C4
O2
C12
C16
C12
178.2(5)
2.5(12)
-4.5(12)
-C11 -C16 -C15
-C11 -C12 -C13
-C11 -C16 -C17
178.0(7)
13

ACCEPTED MANUSCRIPT
C11 -C12 -C13 -C14
6.9(12)
-7.0(13)
4.2(11)
-2.4(10)
-177.9(6)
-73.1(7)
111.5(7)
-5.1(9)
C12 -C13 -C14 -C15
C13 -C14 -C15 -C16
C14 -C15 -C16 -C11
C14 -C15 -C16 -C17
C15 -C16 -C17 -O1
C11 -C16 -C17 -O1
C18 -C19 -C20 -O7
O8
O8
-C19 -C20 -C21
-C19 -C20 -O7
14.8(8)
-160.3(6)
170.0(6)
177.7(5)
174.2(5)
-7.4(8)
C18 -C19 -C20 -C21
C19 -C20 -C21 -C35
O7
O7
-C20 -C21 -C22
-C20 -C21 -C35
C19 -C20 -C21 -C22
C35 -C21 -C22 -C23
C20 -C21 -C22 -C23
C20 -C21 -C22 -C24
C20 -C21 -C35 -C26
C35 -C21 -C22 -C24
C22 -C21 -C35 -C26
C24 -C22 -C23 -O8
C23 -C22 -C24 -C25
C21 -C22 -C23 -O8
C21 -C22 -C24 -C25
C22 -C24 -C25 -O5
C22 -C24 -C25 -C26
-0.7(7)
-178.9(5)
-0.5(7)
177.8(5)
-178.9(5)
-0.6(8)
-0.5(8)
170.7(5)
-179.1(5)
-11.0(8)
2.6(8)
178.5(5)
-3.6(8)
O5
-C25 -C26 -O6
-0.6(7)
C24 -C25 -C26 -C35
C24 -C25 -C26 -O6
2.6(8)
-178.6(5)
14

ACCEPTED MANUSCRIPT
O5
O6
-C25 -C26 -C35
-C26 -C35 -C21
-179.3(5)
-179.1(5)
-0.5(8)
C25 -C26 -C35 -C21
O6
O6
-C28 -C29 -C30
-C28 -C29 -C34
144.0(5)
-34.9(7)
-179.0(6)
0.0(8)
C28 -C29 -C30 -C31
C34 -C29 -C30 -C31
C28 -C29 -C34 -C33
C30 -C29 -C34 -C33
C29 -C30 -C31 -C32
C30 -C31 -C32 -C33
C31 -C32 -C33 -C34
C32 -C33 -C34 -C29
178.9(5)
0.0(8)
0.0(10)
-0.1(11)
0.1(11)
0.0(10)
Table S8 - Contact Distances(Angstrom)
O1
O2
O2
O2
O3
O5
O5
O6
O7
O1
O2
O2
O3
O3
O3
.O2
2.546(6)
2.546(6)
3.300(8)
3.373(7)
3.362(7)
3.382(9)
2.545(6)
2.545(6)
3.415(7)
2.8800
C10 .C30_b
C15 .O5_b
C24 .O3_k
C25 .C9_i
3.492(9)
3.382(9)
3.362(7)
3.515(8)
3.492(9)
3.373(7)
3.300(8)
3.401(10)
3.546(10)
3.401(10)
3.415(7)
3.0700
.O1
.C32_a
.C30_b
.C24_c
.C15_h
.O6
C30 .C10_h
C30 .O2_h
C32 .O2_m
C33 .C34_b
C34 .C10_i
C34 .C33_b
C36 .O7_e
.O5
.C36_j
.H32_a
.H32_a
.H30_b
.H24_c
.H7
2.7600
2.6800
C1
C3
C4
C4
.H11_d
.H35_e
.H3B_f
.H2
2.4800
3.0900
2.5800
3.0000
.H19_b
2.8000
2.9900
15

ACCEPTED MANUSCRIPT
O3
O5
O6
O6
O6
O7
O7
O7
O7
O7
O8
C9
.H1B
2.4300
2.9000
2.7200
2.5500
2.6800
2.7000
2.7800
2.9100
2.5200
2.5500
2.8400
3.515(8)
C7
C7
C8
C9
.H17A
2.7700
2.7400
3.0500
3.0900
2.7100
2.5400
2.7200
2.9500
3.0200
2.4900
3.0900
3.0000
3.0300
3.0100
2.5800
2.5000
2.3500
2.2400
2.3100
2.7800
2.3800
2.3500
2.6800
2.9900
2.2400
2.3100
2.7600
3.0700
2.2800
2.2000
.H15_h
.H15_h
.H34
.H17B
.H28B_b
.H28B_b
.H10C_i
.H18B
.H18C
.H2_h
.H36_j
.H35
C10 .H34_g
C10 .H36
C10 .H30_b
C14 .H31_a
C15 .H31_a
C17 .H7
.H17B_k
.C25_g
C21 .H3A_i
C22 .H19
C10 .C34_g
C23 .H7_k
C24 .H27A
C24 .H27C
C25 .H17A_h
C26 .H17A_h
C27 .H24
3.546(10) C22 .H23A_l
3.0100
2.6100
2.8200
3.0100
2.9500
2.4900
3.0200
2.5600
2.8300
3.0500
2.8100
2.9900
2.8000
2.7900
2.8200
2.7800
2.7600
H7
H7
H7
H7
H7
.C23_c
.O3
.H23B_c
.H17A
.H17B
H10A .H30_b
H10A .C36
C27 .H32_b
C28 .H35
H10A .H36
H10B .H34_g
H10C .O6_g
H10C .C34_g
H10C .H34_g
H10C .H36
H10C .C36
C30 .H1C_j
C32 .H27B_b
C33 .H34_b
C34 .H10C_i
C34 .H33_b
C35 .H28A
C35 .H28B
C36 .H10A
C36 .H10C
H11 .C1_d
H11 .H17B
H11 .H1A_d
16

ACCEPTED MANUSCRIPT
H1A .H11_d
H1B .O3
2.2000
2.4300
2.4200
2.8300
2.3900
2.9100
2.9900
3.0900
2.5900
3.0000
2.4900
2.7400
2.7000
2.4200
2.7800
3.0000
2.8000
3.0300
2.5700
2.5000
2.4900
2.4800
2.4400
2.5700
2.1300
2.1300
2.6100
3.0500
2.4400
2.8200
H15 .O5_b
H15 .H17A
H15 .O6_b
H17A .H7
2.9000
2.5700
2.7200
2.3500
2.5700
2.7700
2.9500
3.0100
2.8400
2.2800
2.2400
2.7200
2.2500
2.6800
2.3100
3.0200
2.9500
2.7600
2.8800
3.0200
2.4400
2.8000
2.2500
2.7100
2.8100
2.2400
2.2500
2.3500
2.5500
2.4100
H1B .H18B_b
H1C .C30_e
H1C .H30_e
H17A .H15
H17A .C7
H2
H2
.O7_b
.C4
H17A .C26_b
H17A .C25_b
H17B .O8_c
H17B .H11
H3A .C21_g
H3A .H36
H3B .C4_f
H7
.C17
H17B .H7
H17B .C7
H30 .C10_h
H30 .H28B
H30 .O2_h
H30 .H10A_h
H31 .C15_m
H31 .C14_m
H32 .O2_m
H32 .O1_m
H32 .C27_b
H32 .H27B_b
H33 .C34_b
H33 .H34_b
H34 .C10_i
H34 .C33_b
H34 .H10C_i
H34 .H33_b
H34 .H10B_i
H34 .O6
H18B .O7
H18B .H1B_h
H18C .O7
H19 .C22
H19 .O3_h
H23A .C22_l
H23B .H24
H23B .H7_k
H24 .C27
H24 .O3_k
H24 .H27C
H24 .H23B
H24 .H27A
H27A .H24
H27A .C24
H27B .C32_b
H27B .H32_b
H27C .C24
H35 .H28B
17

ACCEPTED MANUSCRIPT
H27C .H24
H28A .C35
H28A .H35
H28B .H30
H28B .C35
H28B .C9_h
H28B .H35
H28B .C8_h
H30 .H1C_j
2.4400
2.7900
2.3300
2.2500
2.8200
3.0900
2.4100
3.0500
2.3900
H35
H35
H35
H35
H36
H36
H36
H36
H36
.H28A
.O7
2.3300
2.5500
3.0900
2.5600
2.5900
2.3800
2.3100
2.5400
2.5200
.C3_j
.C28
.H3A
.H10A
.H10C
.C10
.O7_e
Table S9 - Hydrogen Bonds (Angstrom, Deg)
C1 -- H1B .. O3
C24 -- H24 .. O3
C36 -- H36 .. O7
0.9600
0.9300
0.9300
2.4300 2.764(8)
2.4800 3.362(7)
2.5200 3.415(7)
100.00
.
158.00 1_544
161.00 1_456
Translation of Symmetry Code to Equiv.Pos
a =[ 1455.00] = [ 1_455] =-1+x,y,z
b =[ 2666.00] = [ 2_666] =1-x,1-y,1-z
c =[ 1566.00] = [ 1_566] =x,1+y,1+z
d =[ 2577.00] = [ 2_577] =-x,2-y,2-z
e =[ 1456.00] = [ 1_456] =-1+x,y,1+z
f =[ 2567.00] = [ 2_567] =-x,1-y,2-z
g =[ 2566.00] = [ 2_566] =-x,1-y,1-z
h =[ 2666.00] = [ 2_666] =1-x,1-y,1-z
i =[ 2566.00] = [ 2_566] =-x,1-y,1-z
j =[ 1654.00] = [ 1_654] =1+x,y,-1+z
k =[ 1544.00] = [ 1_544] =x,-1+y,-1+z
l =[ 2655.00] = [ 2_655] =1-x,-y,-z
m =[ 1655.00] = [ 1_655] =1+x,y,z
18

ACCEPTED MANUSCRIPT
O
O
2a
O
O
2a
19

ACCEPTED MANUSCRIPT
O
O
2b
O
O
2b
20

ACCEPTED MANUSCRIPT
O
MeO
MeO
O
2c
O
MeO
MeO
O
2c
21

ACCEPTED MANUSCRIPT
O
O
MeO
OMe
2d
O
O
MeO
OMe
2d
22