Stereoselective Total Synthesis of (+)-Aristolactam GI

Article abstract of DOI:10.1021/acs.joc.9b00653

Aristolactams are an important subgroup of aporphinoids, which all share a common phenanthrene chromophore motif that is thought to be responsible for the range of interesting physicochemical and biological properties exhibited by these compounds. Among all of the aristolactams discovered, (+)-aristolactam GI displays a unique structural feature of having the aristolactam scaffold linked via a benzodioxane ring to a phenyl propanoid unit, resulting in the compound being an aporphinoid-lignan hybrid. The synthesis of (+)-aristolactam GI was achieved first by synthesis of an orthogonally protected aristolactam, which was prepared using a Suzuki/aldol cascade to convert a differentially protected isoindolin-1-one to the required phenanthrene. The required enantiopure phenyl propanoid unit was prepared from readily available (R)-methyl lactate. A selective Mitsunobu reaction was used to combine these two key fragments, prior to the formation of the linking benzodioxane in the final step. The absolute stereochemistry of the natural product was confirmed to be 7′S, 8′S.

Full text of DOI:10.1021/acs.joc.9b00653

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Article
Stereoselective Total Synthesis of (+)-Aristolactam GI
Tuan Minh Luong, Lisa I. Pilkington, and David Barker
J. Org. Chem., Just Accepted Manuscript • Publication Date (Web): 11 Apr 2019
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Stereoselective Total Synthesis of (+)-Aristolactam GI
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Tuan M. Luong, Lisa I. Pilkington* and David Barker*
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School of Chemical Sciences, University of Auckland, New Zealand
Email: lisa.pilkington@auckland.ac.nz and d.barker@auckland.ac.nz
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TOC graphic:
Abstract:
Aristolactams are an important subgroup of aporphinoids, which all share a common
phenanthrene chromophore motif that is thought to be responsible for the range of interesting
physicochemical and biological properties exhibited by these compounds. Among all the
aristolactams discovered, (+)-aristolactam GI displays a unique structural feature of having the
aristolactam scaffold linked via a benzodioxane ring to a phenylpropanoid unit, resulting in the
compound being an aporphinoid-lignan hybrid. The synthesis of (+)-aristolactam GI was
achieved firstly by synthesis of an orthogonally protected aristolactam, which was prepared
using a Suzuki/aldol cascade to convert a differentially protected isoindolin-1-one to the
required phenanthrene. The required enantiopure phenyl propanoid unit was prepared from
readily available (R)-methyl lactate. A selective Mitsunobu reaction was used to combine these
two key fragments, prior to the formation of the linking benzodioxane in the final step. The
absolute stereochemistry of the natural product was confirmed to be 7ʹS, 8ʹS.
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Introduction:
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The phenanthrene chromophore, defined as a system of three fused benzene rings, is a common
structural motif occurring in many classes of bioactive natural products.1 The high degree of
conjugation generated by such a scaffold may also be attributable to several interesting
physicochemical properties such as photoconductance and the photochemical and
electroluminescent capabilities found in these organic compounds.2 Among them, a key family
of compounds are the aristolactams (also referred to as aristololactams in literature3), a member
of the aporphinoid class of compounds.4
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Aristolactams were first isolated from the Argentine plant Aristolochia argentina (a pipevine
plant species of the Aristolochiaceae family), which is believed to be the richest natural source
for these types of alkaloids.5 Nevertheless, aristolactam-type alkaloids are not exclusively
restricted to this plant family, but their occurrences in other related families, such as
Annonaceae, Monimimaceae, Menispermaceae and Piperaceae have also been reported.6
Traditionally, plants containing aristolactam-type alkaloids have been employed as the main
ingredients for many remedy formulations in folk medicine practices.1,5,7 Due to this,
aristolactams and their derivatives have earned significant attention from both synthetic
chemists and biochemists for both their structural novelty and wide range of biological
properties such as antitumor, anti-inflammatory, antiplatelet, antimycobacterial and neuro-
protective effects.1
In 2013, Ge et al.8 discovered five novel aporphinoids along with some previously known
alkaloids from the ethanol extracts of the stems of Fissistigma oldhamii (Anninaceae family).
Two of those aporphinoids were found to be aristolactam alkaloids, namely (+)-aristolactam
GI (1) and aristolactam GII (2) (Figure 1).
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O
O
O
MeO
NH
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NH
O
O
HO
HO
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O
Aristolactam GII (2)
(+)-Aristolactam GI (1)
Figure 1: Chemical structures of phemanthrene natural products, (+)-aristolactam GI (1) and
aristolactam GII (2).
The most distinct feature of (+)-aristolactam GI (1) is the unique combination of an
aristolactam moiety (red in Figure 1) and a sinapyl alcohol-like phenylpropanoid unit (blue),
forming a 1,4-benzodioxane neolignan-like moiety. The relative configuration of trans was
elucidated from NMR data (1H, 13C and NOESY NMR spectrum) whilst the absolute
configuration (7ʹS, 8ʹS) was established through comparison of the experimental ECD spectra
with the ECD spectra calculated by time-dependent density functional theory method.8
Lignans are a large class of compounds defined as being the product of the oxidative
dimerization of two or more phenyl propanoid units.9 While lignans are strictly formed by a
C8-C8ʹ linkage between the two phenylpropanoid monomers, neolignans have linkage patterns
other than this between the phenylpropanoid units.9,10 Despite being a relatively rare subclass
of neolignans, 1,4-benzodioxane neolignans exhibit a diverse range of interesting
pharmacological properties, such as antitumor, anitviral and antihypertensive effects.11
Traditionally, the dried stems or roots of F. oldhamii have been used as a folk medicine to treat
rheumatoid arthritis (RA) in southern China.8 It is thought that tumor necrosis factor α (TNFα),
interleukin-1 (IL-1) and interleukin-2 (IL-2) play important roles in the pathophysiology of
RA,12 and therapies targeting these proteins have shown positive outcomes in treatment of
RA.13 Ge et al.8 examined the inhibitory effects of aristolactam GI (1) upon the release of TNFα
and IL-6 induced by lipopolysaccharide (LPS) in murine macrophage RAW264 cell cultures
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and it was shown that aristolactam GI (1) exhibited statistically significant inhibition in the
production of both TNFα and IL-6.
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To date, there has been no total synthesis reported for (+)-aristolactam GI (1). Due to its unique
structural arrangement, having features of both an aristolactam and a 1,4-benzodioxane
neolignan, it was of great interest to synthesize this unusual natural product. While our group
has previously synthesised a number of lignan natural products,14-30 including 1,4-
benzodioxane neolignans,31-34 our methodology has not been extended to such a complex
1,4-benzodioxane such as (+)-aristolactam GI (1).
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Results and Discussion:
We have previously used a divergent synthesis to prepare 1,4-benzodioxane lignans.31-34 In this
approach, a suitable phenol underwent a Mitsunobu reaction with (R)-methyl lactate 3 to give
an ether and an aryl lithiate was then added to the carbonyl of the ester. However, for (+)-
aristolactam GI (1), the presence of the amide carbonyl in the phenanthrene component
required an alternative strategy. Therefore, it was decided to use a convergent approach where
the entire phenyl propanoid fragment 4 would be added to the phenanthrene phenol 5 to give
ether 6 (Scheme 1). The phenyl propanoid unit 4 would be prepared from the addition of the
organolithiate of bromide 7 to (R)-methyl lactate 3, whilst the phenanthrene 4 would be
accessed by the cyclisation of the product of the Suzuki coupling between boronic acid 8 and
aromatic bromide 9, which could be generated from commercially-available 2-hydroxy-4-
methyl benzaldehyde 10.
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OR3
O
MeO
R3O
O
O
O
NH
O
O
NR1
OMe
R3O
HO
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O
(+)-Aristolactam GI (1)
O
OR3
HO
R3O
MeO
Br
MeO
R3O
NR1
+
OH
R3O
OMe
OMe
7
5
4
+
O
O
OH
3
O
B(OH)2
CHO
R2O
R3O
OHC
HO
NR1
+
Br
8
10
9
Scheme 1: Retrosynthesis of (+)-1.
To withstand the various different reaction conditions required later in the synthesis, it was
decided that the hydroxy group of 2-hydroxy-4-methylbenzaldehyde 10 would be protected as
an isopropyl ether, giving aromatic ether 11 (Scheme 2). Initially, aldehyde 11 was subjected
to Dakin oxidation conditions,35 but when this did not yield any of the desired product 12, a
two-step Baeyer Villiger oxidation followed by base hydrolysis was utilised, giving alcohol
12, which was then benzyl protected to give benzyl ether 13 in 84% from 11. Formylation of
13 was achieved through the Vilsmeier-Haack reaction, selectively providing benzaldehyde
14. The Pinnick oxidation of aldehyde 14 gave a benzoic acid which was immediately
converted to methyl ester 15 using SOCl2 in methanol. At this point in the synthesis a change
of benzyl protecting group for another that was more compatible with the forthcoming
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bromination steps was undertaken. Thus, the benzyl group was replaced with an acetyl ester
by the hydrogenolysis of 15, the product of which was then acetylated, providing 16 in 93%
yield over two steps. Aromatic 16 was selectively brominated at the desired position using Br2
and NaOAc, in the presence of I2, in AcOH, giving bromide 17, which was further brominated
at the benzylic position with NBS and AIBN, giving the desired benzyl bromide 18.
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The next step in the synthesis was to form the lactam ring using a primary amine to generate
an isoindolin-1-one. 4-Methoxybenzylamine was chosen due to the varied methods of
removing the 4-methoxybenzyl group and its previous use in the synthesis of various simpler
aristolactams.36,37 Upon treating a solution of benzyl bromide 18 in THF with 4-
methoxybenzylamine, the desired PMB-protected isoindolin-1-one 19 was obtained in 75%
yield. Additionally, these basic conditions allowed for simultaneous hydrolysis of the acetyl
group. At this stage, the robust isopropyl ether was required to be removed prior to generating
the 1,4-benzodioxane. For this, the existing free phenol needed to be temporarily protected
with a mesyl group being chosen due to its compatibility with other protecting groups. Thus
phenol 19 was mesylated and the resulting material immediately subjected to a Lewis acid-
mediated de-isopropylation, providing alcohol 20. Alcohol 20 was immediately protected with
an acid-labile MOM group and the mesyl moiety removed under strongly basic conditions,38
giving phenol 21. It was initially attempted to construct the phenathrene 22 in a one-pot
reaction, involving the Suzuki coupling reaction between bromide 21 and
2-formylphenylboronic acid 8 and concomitant aldol-cyclisation, following the method of Kim
et al.39 While this did provide the desired phenanthrene 22, it was produced only in low yields,
~25%. As a result, this sequence was performed in two separate reactions, first synthesising
the aldehyde intermediate, the generation of which was confirmed through 1H NMR analysis
of the crude product. Once verified, the intermediate was cyclised through a base-mediated
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aldol condensation, giving the desired phenanthrene 22 in twice the yield of the one-pot
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procedure.
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1) m-CPBA, NaHCO3
CH2Cl2, 0 ºC then rt, 22 h
OHC
BnO
i-PrO
HO
i-PrBr, K2CO3
BnBr, NaH
10
DMF, 70 ºC, 26 h
94%
2) KOH, MeOH, rt, 3 h
88% (2 steps)
i-PrO
DMF, 0 ºC then rt, 3 h
95%
i-PrO
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POCl3, DMF
0 ºC then 90 ºC
24 h
73%
Br2, NaOAc, I2 (cat.)
1) H2, Pd/C (10 wt%)
MeOH, rt, 4 h, 98%
1) NaClO2, Na2H2PO4
DMSO/H2O, rt, 25 h
BnO
i-PrO
CHO
AcO
COOCH3
BnO
COOCH3
AcOH
60 ºC, 22 h, 94%
2) Ac2O, pyridine
CH2Cl2, 0 ºC then rt
20 h, 95%
2) SOCl2, MeOH
0 ºC then 55 ºC, 18 h
76% (2 steps)
i-PrO
i-PrO
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16
1) MsCl, Et3N
CH2Cl2, 0 ºC then rt
3 h, 99%
O
AcO
COOCH3
AcO
COOCH3
NBS, AIBN (10 mol%)
CCl4, 80 ºC, 1 h, 85%
NH2PMB
HO
NPMB
THF, rt, 18 h, 75%
i-PrO
2) AlCl3, CH2Cl2
rt, 6 h, 80%
i-PrO
i-PrO
Br
17
Br Br
Br
19
18
O
8
1) , Pd(PPh3)4, 2M K2CO3
1,4-Dioxane/H2O
HO
O
O
1) MOMCl, DIPEA
CH2Cl2, rt, 4 h, 90%
110 ºC, 20 h
NPMB
HO
MsO
HO
MOMO
NPMB
NPMB
2) t-BuOK, THF
0 ºC then rt, 4 h
40% (2 steps)
MOMO
2) LDA,THF
0 ºC then rt, 1 h, 78%
Br
21
Br
20
22
Scheme 2: Synthesis of phenthracene 22.
The synthesis of the phenylpropanoid fragment began with the selective demethylation of 5-
bromo-1,2,3-trimethoxybenzene 23 to give phenol 24, the phenol of which was masked with a
MOM protecting group in 25 (Scheme 3). The alcohol in (R)-methyl lactate 5 was converted
to a TBS ether,40 giving the volatile product 26 in 95% yield. Reduction of ester 26 to an
aldehyde was carried out using DIBAL giving unstable aldehyde 27, which was used in the
next reaction without further purification. The addition of the organo-lithiate of bromide 25,
generated using nBuLi, to aldehyde 27 gave a 6:1 mixture of anti:syn diastereoisomers 28a/28b.
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OMe
MeO
OMe
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Br
23
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AlCl3, CH2Cl2,
50 oC, 21 h
75%
TBSCl, imidazole
CH2Cl2, 0 ºC, 3 h
95%
OH
O
MeO
OMe
O
OTBS
26
Br
24
MOMCl, DIPEA
CH2Cl2, rt, 4 h,
95%
DIBAL, CH2Cl2
- 78ºC, 20 min
OMOM
OMe
MeO
O
+
H
OTBS
Br
25
27
BuLi, THF
-78 ºC then rt
17 h, 31%
n-
OH
MeO
MOMO
OTBS
OMe
28a/28b
anti : syn (6:1)
Scheme 3: Synthesis of alcohols 28a/28b.
The use of alternative organometallic reagents including Grignard and Turbo-Grignard for the
addition of 25 to 27 were found to be less effective, giving complex mixtures of products. The
newly formed mixture of benzylic alcohols 28a/28b were then protected as a MOM ether,
giving 29a/29b and the TBS ether was removed, providing a mixture of alcohols 30a/30b
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(Scheme 4). Initial attempts at the Mitsunobu reaction between alcohols 30a/30b and phenol
22 in THF were not successful, however changing the solvent to toluene and increasing the
temperature were beneficial, providing the desired ether 31. The mixture at the benzylic site
was of no consequence as it has previously been shown that the stereochemistry at this site
does not affect the stereochemistry of a resulting 1,4-benzodioxane. Finally, global
deprotection and concomitant cyclisation of ether 31, using TFA in anisole36,41 gave (+)-
aristolactam GI (1) as a single stereoisomer, with no cis isomer obtained.
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MOMCl, DIPEA
OMOM
CH2Cl2, 40 oC, 20 h
MeO
90%
OTBS
28a/28b
MOMO
OMe
anti : syn (6:1)
29a/29b
TBAF, THF
0 ºC then rt, 19 h
88%
OMOM
OH
MeO
MOMO
OMe
anti : syn (6:1)
30a/30b
22
, DIAD, PPh3
Toluene, 0 ºC then 90 ºC
3 h, 76%
OMOM
O
MeO
O
O
O
NH
O
O
MOMO
NPMB
OMe
MOMO
HO
TFA, Anisole
100 ºC, 25 h, 32%
O
31
(+)-Aristolactam GI (1)
Scheme 4: Synthesis of (+)-aristolactam GI (1).
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The NMR data of synthetic (+)-aristolactam GI (1) matched that reported in literature,8 though
it was found that a number of carbon signals were incorrectly assigned and the use of various
2D methods allowed for their reassignment (see Table S1 for details). The optical rotation of
the synthesised natural product +19.8 (c 0.13, CHCl3) was the same sign as the isolated (+)-1
(+6.0 (c 0.20, CHCl3)) product,8 albeit of a larger magnitude.
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Conclusion:
In summary, the total synthesis of (+)-aristolactam GI (1) has been completed, confirming the
structure of the unique aporphinoid-lignan hybrid. The absolute stereochemistry of the
molecule was then confirmed to be 7ʹS, 8ʹS. The method applied utilised a late stage Mitsunobu
reaction between two advanced intermediates, each of which represented one of the two natural
product families found in the overall molecule. The method here would be applicable to the
preparation of other 1,4-benzodioxane hybrids.
Experimental Procedures:
General Details:
All reactions were carried out under a nitrogen atmosphere in dry, freshly distilled solvents
unless otherwise noted. All optical rotation measurements were determined at 20 °C on the
sodium D line (λ = 589 nm, 0.1 dm cell). NMR spectra were recorded on a either a 300 MHz
or 400 MHz spectrometer. Chemical shifts are reported relative to the solvent peak of
chloroform (δ 7.26 for 1H and δ 77.0 for 13C) or d6-DMSO (δ 2.50 for 1H and δ 39.5 for 13C).
1H NMR data is reported as position (δ), relative integral, multiplicity (s, singlet; d, doublet; t,
triplet; q, quartet; m, multiplet; br, broad peak; qd, quartet of doublets), coupling constant (J,
Hz), and the assignment of the atom. Broadband proton-decoupled 13C NMR data are reported
as position (δ) and assignment of the atom. NMR assignments were performed using HSQC
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and HMBC experiments. High-resolution mass spectroscopy (HRMS) was carried out by either
chemical ionization (CI) or electrospray ionization (ESI) on a MicroTOF-Q mass spectrometer.
Unless noted, chemical reagents were used as purchased.
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Synthesis of compounds:
2-Isopropoxy-4-methylbenzaldehyde, 11. To a stirred solution of 2-hydroxy-4-
methylbenzaldehyde 10 (7.00 g, 51.5 mmol) in anhydrous DMF (80 mL) under an atmosphere
of nitrogen, was added anhydrous K2CO3 (10.7 g, 77.0 mmol). The resulting mixture was
heated to 70 °C using a heating block and stirred for 30 min. Afterwards, i-PrBr (6.20 mL, 66.0
mmol) was added dropwise. The reaction mixture was stirred at this temperature for 26 h before
diluted with sat. aq. NH4Cl solution (100 mL) and extracted with Et2O (5 x 60 mL). The
combined organic extracts were washed with brine (100 mL) and dried (MgSO4). The solvent
was removed in vacuo to afford an oily residue which was then purified by flash
chromatography (15:1 petroleum ether, EtOAc) to yield the title product 11 as a yellow oil
(8.61 g, 94%). Rf (9:1 petroleum ether, EtOAc) 0.54; νmax(film)/cm-1 2980, 2859, 1680 (C=O),
1603, 1255, 1104, 809 and 719; 1H NMR (400 MHz, CDCl3, Me4Si)   10.41 (1H, s, CHO),
7.72 (1H, d, J = 7.7 Hz, 6-H), 6.80 (1H, d, J = 7.7 Hz, 5-H), 6.78 (1H, s, 3-H), 4.67 (1H, sept,
J = 6.0 Hz, OCH(CH3)2), 2.38 (3H, s, 4-CH3), 1.39 (6H, d, J = 6.0 Hz, OCH(CH3)2); 13C{1H}
NMR (100 MHz, CDCl3, Me4Si)   189.8 (CHO), 160.7 (C-2), 147.1 (C-4), 128.3 (C-6),
123.6 (C-1), 121.6 (C-5), 114.6 (C-3), 71.0 (OCH(CH3)2), 22.3 (4-CH3), 22.1 (OCH(CH3)2);
m/z (ESI+): 201 (MNa+, 100%); HRMS (ESI+) Found (MNa+): 201.0892, C11H14NaO2 calcd
201.0886.
2-Isopropoxy-4-methylphenol, 12. To a stirred solution of aldehyde 11 (8.30 g, 46.6 mmol)
in CH2Cl2 (150 mL) under an atmosphere of nitrogen at 0 ºC, was added anhydrous NaHCO3
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(10.57 g, 125.8 mmol) then m-CPBA (77%, 13.58 g, 60.58 mmol). The resulting mixture was
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stirred at 0 C for 1.5 h and then at room temperature for 22 h before diluted with sat. aq.
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Na2S2O3 (100 mL) and extracted with CH2Cl2 (5 x 40 mL). The combined organic extracts
were washed with sat. aq. NaHCO3 (100 mL) and brine (100 mL) and then dried (MgSO4). The
solvent was removed in vacuo to give the crude formate ester which was used directly in the
next step without further purification. To the crude formate ester above, was added a 1.5 M
methanolic KOH solution (60 mL). The resulting mixture was stirred at room temperature for
3 h. The solvent was then removed in vacuo. The residue was then neutralized carefully with
2M HCl until pH 2-3 then extracted with EtOAc (4 x 50 mL), washed with brine (150 mL) and
dried (MgSO4). The solvent was then removed in vacuo to give an orange crude oil which was
purified by flash chromatography (15:1 petroletum ether, EtOAc) to yield the title product 12
as a pale yellow oil (6.81 g, 88% over 2 steps). Rf (9:1 petroleum ether, EtOAc) 0.52;
νmax(film)/cm-1 3540, 2978, 2925, 1509, 1267, 1119, 907 and 795; 1H NMR (400 MHz, CDCl3,
Me4Si)   6.80 (1H, d, J = 8.1 Hz, 6-H), 6.68 (1H, s, 3-H), 6.65 (1H, d, J = 8.1 Hz, 5-H), 5.53
(1H, br s, OH), 4.55 (1H, sept, J = 6.1 Hz, OCH(CH3)2), 2.27 (3H, s, 4-CH3), 1.35 (6H, d, J =
6.1 Hz, OCH(CH3)2); 13C{1H} NMR (100 MHz, CDCl3, Me4Si)   144.4 and 144.3 (C-1 and
C-2), 129.4 (C-4), 121.6 (C-5), 114.4 and 114.2 (C-3 and C-6) , 71.6 (OCH(CH3)2), 22.3
(OCH(CH3)2, 21.1 (4-CH3); m/z (ESI+): 189 (MNa+, 100%); HRMS (ESI+) Found (MNa+):
189.0893, C10H14NaO2 calcd 189.0886.
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1-(Benzyloxy)-2-isopropoxy-4-methylbenzene, 13. To a stirred solution of phenol 12 (484
mg, 2.91 mmol) in dry DMF (15 mL) under an atmosphere of nitrogen at 0 C, was added NaH
(60% in mineral oils, 150 mg, 3.78 mmol). The mixture was stirred at this temperature for 30
min before added BnBr (0.415 mL, 3.49 mmol) dropwise. The resulting mixture was then
warmed to room temperature and left to stir for 3 h before diluted with sat. aq. NH4Cl solution
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(20 mL) and then extracted with Et2O (3 x 15 mL). The combined organic extracts were washed
with H2O (20 mL) then brine (20 mL) and dried (MgSO4). The solvent was then removed in
vacuo to obtain the crude product which was then purified by flash chromatography (30:1 then
15:1 petroleum ether, EtOAc) to yield the title product 13 as a colorless oil (709 mg, 95%). Rf
(9:1 petroleum ether, EtOAc) 0.66; νmax(film)/cm-1 2975, 2925, 1506, 1261, 1108, 734 and 695;
1H NMR (400 MHz, CDCl3, Me4Si)   7.43 (2H, d, J = 7.1 Hz, 2ʹ-H), 7.35 (2H, t, J = 7.1 Hz,
3ʹ-H), 7.28 (1H, t, J = 7.1 Hz, 4ʹ-H), 6.81 (1H, d, J = 8.2 Hz, 6-H), 6.76 (1H, s, 3-H), 6.67 (1H,
d, J = 8.2 Hz, 5-H), 5.07 (2H, s, OCH2Ph), 4.51 (1H, sept, J = 6.1 Hz, OCH(CH3)2), 2.27 (3H,
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s, 4-CH3), 1.34 (6H, d, J = 6.1 Hz, OCH(CH3)2); C{1H} NMR (100 MHz, CDCl3, Me4Si)
  148.1 and 147.8 (C-1 and C-2), 137.8 (C-1ʹ), 131.4 (C-4), 128.4 (C-3ʹ), 127.6 and 127.3
(C-2ʹ and C-4ʹ), 121.9 (C-5), 118.8 (C-3), 115.9 (C-6), 72.1 (OCH(CH3)2, 71.7 (OCH2Ph), 22.3
(OCH(CH3)2, 20.9 (4-CH3); m/z (ESI+): 279 (MNa+, 100%), 188 (15%); HRMS (ESI+) Found
(MNa+): 279.1365, C17H20NaO2 calcd 279.1356.
5-(Benzyloxy)-4-isopropoxy-2-methylbenzaldehyde, 14. To a stirred solution of 13 (700 mg,
2.73 mmol) in dry DMF (10 mL) under an atmosphere of nitrogen at 0 C, was added POCl3
(1.50 mL, 16.38 mmol) dropwise. The reaction mixture was stirred at 0 °C for 1 h, then at
90 °C using a heating block for 24 h before cooled down to room temperature. Ice-cold water
(10 mL) with a few drops of 1 M NaOH was then added to the reaction mixture, which was
left to stir for 30 min. The reaction mixture was then extracted with Et2O (4 x 20 mL). The
combined organic extracts were washed with brine (30 mL) and dried (MgSO4). The solvent
was removed in vacuo to obtain a dark orange residue which was then purified by flash
chromatography (15:1 then 9:1 petroleum ether, EtOAc) to yield the title product 14 as white
crystals (567 mg, 73%). Rf (9:1 petroleum ether, EtOAc) 0.29; mp 75–76 °C; νmax(film)/cm-1
2973, 2773, 1674, 1591, 1511, 1263, 1095, 750 and 701; 1H NMR (300 MHz, CDCl3, Me4Si)
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  10.12 (1H, s, CHO), 7.45 (2H, d, J = 7.2 Hz, 2ʹ-H), 7.39 (1H, s, 6-H), 7.36 (2H, t, J = 7.2
Hz, 3ʹ-H), 7.30 (1H, t, J = 7.2 Hz, 4ʹ-H), 6.71 (1H, s, 3-H), 5.14 (2H, s, OCH2Ph), 4.68 (1H,
sept, J = 6.2 Hz, OCH(CH3)2), 2.60 (3H, s, 2-CH3), 1.40 (6H, d, J = 6.2 Hz, OCH(CH3)2);
13C{1H} NMR (75 MHz, CDCl3, Me4Si)   190.4 (CHO), 153.3 (C4), 147.5 (C5), 137.0 (C1ʹ),
136.2 (C2), 128.5 (C3ʹ), 127.9 (C4ʹ), 127.3 (C2ʹ), 127.1 (C1), 117.4 (C3), 116.3 (C6), 71.6 and
71.4 (OCH(CH3)2 and OCH2Ph), 22.1 (OCH(CH3)2, 18.5 (2-CH3); m/z (ESI+): 307 (MNa+,
100%); HRMS (ESI+) Found (MNa+): 307.1310, C18H20NaO3 calcd 307.1305.
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Methyl 5-(benzyloxy)-4-isopropoxy-2-methylbenzoate, 15. To a stirred solution of aldehyde
14 (2.20 g, 7.74 mmol) in DMSO (30 mL) under an atmosphere of nitrogen, was added a
solution of NaH2PO4 (0.93 g, 7.74 mmol) in H2O (5 mL) and then a solution of NaClO2 (80%,
5.25 g, 46.4 mmol) in H2O (15 mL). The resulting mixture was stirred at room temperature for
25 h before diluted with sat. aq. NaHCO3 (20 mL). Et2O (20 mL) was added then the two layers
were separated. The aqueous layer was acidified with 2M HCl until pH 2-3 and white
precipitates formed. The suspension was extracted with CH2Cl2 (3 x 20 mL). The combined
CH2Cl2 extracts were washed with brine (50 mL) and dried (MgSO4). The solvent was removed
in vacuo to obtain the crude benzoic acid as white crystals (2.21 g, 95%, crude) which was
used directly in the next step without further purification. To a stirred solution of the crude
benzoic acid (2.21 g, 7.36 mmol) in anhydrous MeOH (25 mL) under an atmosphere of
nitrogen at 0 °C, was added SOCl2 (0.80 mL, 11.0 mmol). The reaction mixture was stirred at
50 °C C using a heating block for 18 h. After cooling to room temperature, the solvent was
removed in vacuo. The residue was diluted with H2O (20 mL) and extracted with EtOAc (3 x
20 mL). The combined organic extracts were washed with sat. aq. NaHCO3 (20 mL), then brine
(20 mL) and dried (MgSO4). The solvent was removed in vacuo to obtain a crude product
which was then purified by flash chromatography (9:1 petroleum ether, EtOAc) to yield the
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title product 15 as white crystals (1.85 g, 76 % over 2 steps). Rf (9:1 petroleum ether, EtOAc)
0.49; mp 85–86 °C; νmax(film)/cm-1 2980, 2884, 1713, 1514, 1254, 1151, 744 and 694; 1H NMR
(400 MHz, CDCl3, Me4Si)   7.58 (1H, s, 6-H), 7.45 (2H, d, J = 7.2 Hz, 2ʹ-H), 7.37 (2H, t, J
= 7.2 Hz, 3ʹ-H), 7.30 (1H, t, J = 7.2 Hz, 4ʹ-H), 6.74 (1H, s, 3-H), 5.11 (2H, s, OCH2Ph), 4.63
(1H, sept, J = 6.1 Hz, OCH(CH3)2), 3.84 (3H, s, 1-COOCH3), 2.54 (3H, s, 2-CH3), 1.37 (6H,
d, J = 6.1 Hz, OCH(CH3)2); 13C{1H} NMR (100 MHz, CDCl3, Me4Si)   167.7 (1-COOCH3),
151.5 (C-4), 146.8 (C-5), 137.3 (C-1ʹ), 135.6 (C-2), 128.4 (C-3ʹ), 127.8 (C-4ʹ), 127.4 (C-2ʹ),
121.2 (C-1), 118.6 (C-3), 118.2 (C-6), 71.7 and 71.5 (OCH(CH3)2 and OCH2Ph), 51.6 (1-
COOCH3), 22.1 (OCH(CH3)2), 21.7 (2-CH3); m/z (ESI+): 337 (MNa+, 100%); HRMS (ESI+)
Found (MNa+): 337.1423, C19H22NaO4 calcd 337.1410.
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Methyl 5-acetoxy-4-isopropoxy-2-methylbenzoate, 16. To a stirred solution of benzoate 15
(700 mg, 2.23 mmol) in MeOH (20 mL), was added 10% Pd/C (70 mg, 10 wt-%). The reaction
mixture was stirred under an atmosphere of H2 for 4 h and then filtered through a Celite pad
and concentrated in vacuo to afford the crude phenol (0.489 g, 98%) as a cloudy oil, which was
directly used in the next step without further purification. To a stirred solution of crude phenol
above (0.489 g, 2.18 mmol) in dry CH2Cl2 (20 mL) under an atmosphere of nitrogen at 0 ºC,
was added pyridine (0.27 mL, 3.27 mmol). After being stirred at 0 ºC for 10 min, Ac2O (0.31
mL, 3.27 mmol) was added dropwise. The reaction mixture was stirred at room temperature
for 20 h before diluted with H2O (20 mL) and extracted with CH2Cl2 (4 x 15 mL). The
combined organic extracts were washed with brine (30 mL), dried (MgSO4). The solvent was
removed in vacuo to obtain a crude product which was then purified by flash chromatography
(9:1 petroleum ether, EtOAc) to yield the title product 16 as white crystals (0.551 g, 95%). Rf
(9:1 petroleum ether, EtOAc) 0.31; mp 67–68 ºC; νmax(film)/cm-1 2986, 2976, 2932, 1760, 1709,
1516, 1211, 1198, 1153 and 1108, 798 and 782; 1H NMR (400 MHz, CDCl3, Me4Si)   7.67
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(1H, s, 6-H), 6.77 (1H, s, 3-H), 4.61 (1H, sept, J = 6.1 Hz, OCH(CH3)2), 3.83 (3H, s, 1-
COOCH3), 2.60 (3H, s, 2-CH3), 2.29 (3H, s, CH3COO-5), 1.34 (6H, d, J = 6.1 Hz, OCH(CH3)2);
13C{1H} NMR (100 MHz, CDCl3, Me4Si)   168.9 (CH3COO-5), 166.7 (1-COOCH3), 152.4
and 140.8 (C-4 and C-5), 137.9 (C-2), 125.7 (C-6), 120.9 (C-1), 116.9 (C-3), 71.2
(OCH(CH3)2), 51.6 (1-COOCH3), 22.2 (2-CH3), 21.9 (OCH(CH3)2), 20.5 (CH3COO-5); m/z
(ESI+): 289 (MNa+, 100%); HRMS (ESI+) Found (MNa+): 289.1053, C14H18NaO5 calcd
289.1046.
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Methyl 5-acetoxy-3-bromo-4-isopropoxy-2-methylbenzoate, 17. To a stirred solution of 16
(675 mg, 2.54 mmol) in AcOH (7 mL) under an atmosphere of nitrogen, was added NaOAc
(500 mg, 6.10 mmol) and a catalytic amount of I2 (50 mg) and Br2 (0.65 mL, 12.7 mmol). The
reaction mixture was warmed to 60 ºC using a heating block and stirred at this temperature for
22 h. After being cooled down to room temperature, the reaction mixture was treated with sat.
aq. Na2SO3 (50 mL) and extracted with EtOAc (4 x 15 mL). The combined organic extracts
were washed with sat. aq. NaHCO3 until pH 6-7 and then brine (30 mL) and dried (MgSO4).
The solvent was removed in vacuo to obtain the crude product which was then purified by flash
chromatography (9:1 petroleum ether, EtOAc) gave the title product 17 as a white solid (820
mg, 94%). Rf (9:1 petroleum ether, EtOAc) 0.34; mp 98–99 ºC; νmax(film)/cm-1 2986, 2960,
2926, 1751, 1719, 1182, 1196, 1159, 820 and 744. 1H NMR (400 MHz, CDCl3, Me4Si)   7.59
(1H, s, 6-H), 4.53 (1H, sept, J = 6.1 Hz, OCH(CH3)2), 3.87 (3H, s, 1-COOCH3), 2.68 (3H, s,
2-CH3), 2.32 (3H, s, CH3COO-5), 1.34 (6H, d, J = 6.1 Hz, OCH(CH3)2); 13C{1H} NMR (100
MHz, CDCl3, Me4Si)   168.4 (CH3COO-5), 166.7 (1-COOCH3), 150.5 and 142.0 (C-4 and
C-5), 138.8 (C-2), 126.6 (C-1), 124.5 (C-6), 124.1 (C-3), 77.1 (OCH(CH3)2, 52.3 (1-COOCH3),
22.6 (OCH(CH3)2), 21.0 (2-CH3), 20.8 (CH3COO-5); m/z (ESI+): 367 (81BrMNa+, 100%) and
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369 (79BrMNa+, 100%); HRMS (ESI+) Found (MNa+): 369.0137, C14H1781BrNaO5 calcd
369.0133. Found (MNa+): 367.0157, C14H1779BrNaO5 calcd 367.0152.
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Methyl 5-acetoxy-3-bromo-2-(bromomethyl)-4-isopropoxybenzoate, 18. To a stirred
solution of 17 (100 mg, 0.291 mmol) in CCl4 (5 mL) under N2, was added NBS (67 mg, 0.378
mmol) and AIBN (5 mg, 0.029 mmol). The resulting mixture was stirred at 80 ºC using a
heating block for 1 h. Afterwards, the solvent was removed in vacuo and diluted with H2O (10
mL) and extracted with CH2Cl2 (3 x 10 mL). The organic extracts were then washed with sat.
aq. Na2S2O3 (10 mL) and brine (10 mL) and dried (MgSO4). The solvent was removed in vacuo
to give an orange residue which was purified by flash chromatography (15:1 then 9:1 petroleum
ether, EtOAc) to yield the title product 18 as a white solid (105 mg, 85%). Rf (9:1 petroleum
ether, EtOAc) 0.21; mp 67–68 ºC; νmax(film)/cm-1 2982, 2930, 1759, 1718, 1298, 1188, 1160,
821 and 747; 1H NMR (400 MHz, CDCl3, Me4Si)   7.74 (1H, s, 6-H), 5.19 (2H, s, 2-CH2Br),
4.56 (1H, sept, J = 6.0 Hz, OCH(CH3)2), 3.92 (3H, s, 1-COOCH3), 2.34 (3H, s, CH3COO-5),
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1.36 (6H, d, J = 6.0 Hz, OCH(CH3)2); C{1H} NMR (100 MHz, CDCl3, Me4Si)   167.9
(CH3COO-5), 165.4 (1-COOCH3), 151.3 and 143.9 (C-4 and C-5), 137.9 (C-2), 124.6 (C3),
125.8 (C6), 117.4 (C-1), 77.9 (OCH(CH3)2, 52.7 (1-COOCH3), 30.5 (2-CH2Br), 22.6
(OCH(CH3)2), 20.8 (CH3COO-5); m/z (ESI+): 449 (81Br2MNa+, 50%), 447 (81Br79BrMNa+,
100%) and 445 (79Br2MNa+); HRMS (ESI+) Found (MNa+): 448.9233, C14H1681Br2NaO5 calcd
448.9219. Found (MNa+): 446.9248, C14H1681Br79BrNaO5 calcd 446.9237. Found (MNa+):
444.9267, C14H1679Br2NaO5 calcd 444.9257.
4-Bromo-6-hydroxy-5-isopropoxy-2-(4-methoxybenzyl)isoindolin-1-one, 19. To a stirred
solution of benzyl bromide 18 (1.33 g, 3.15 mmol) in THF (15 mL), was added p-
methoxybenzylamine (2.05 mL, 15.76 mmol). The resulting mixture was stirred at room
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temperature for 18 h before diluted with H2O (50 mL) and extracted with EtOAc (4 x 20 mL).
The combined organic extracts were washed with brine (40 mL) and dried (MgSO4) and
concentrated in vacuo to obtain the crude product which was then purified by flash
chromatography (4:1 to 2:1 petroleum ether, EtOAc) to provide the title product 19 as a white
solid (958 mg, 75%); Rf (1:1 petroleum ether, EtOAc) 0.37; mp 150 ºC; νmax(film)/cm-1 3068,
2982, 2833, 1666, 1458, 1321, 1230, 1092, 806; 1H NMR (400 MHz, CDCl3, Me4Si)   7.42
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(1H, s, 7-H), 7.24 (2H, d, J = 6.6 Hz, 2-H), 6.87 (2H, d, J = 6.6 Hz, 3-H), 6.01 (1H, s, OH),
4.71 (2H, s, NCH2Ar), 4.67 (1H, sept, J = 6.2 Hz, OCH(CH3)2), 4.08 (2H, s, 3-H), 3.79 (3H, s,
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ArOCH3), 1.38 (6H, d, J = 6.2 Hz, OCH(CH3)2); C{1H} NMR (100 MHz, CDCl3, Me4Si)
  167.5 (C=O), 159.3 (C4), 151.4 (C6) and 145.4 (C5), 134.8 (C3a), 129.7 (C7a), 129,6
(C2), 128.9 (C1), 114.2 (C3), 110.2 (C4), 109.5 (C7), 77.8 (OCH(CH3)2, 55.3 (ArOCH3),
49.8 (C3), 46.0 (NCH2Ar), 22.5 (OCH(CH3)2); m/z (ESI+): 430 (81BrMNa+, 100%), 428
(79BrMNa+); HRMS (ESI+) Found (MNa+): 430.0449, C19H2081BrNNaO4 calcd 430.0450.
Found (MNa+): 428.0466, C19H2079BrNNaO4 calcd 428.0468.
7-Bromo-6-isopropoxy-2-(4'-methoxybenzyl)-3-oxoisoindolin-5-yl methanesulfonate. To
a stirred solution of phenol 19 (200 mg, 0.49 mmol) in dry CH2Cl2 (10 mL) under an
atmosphere of nitrogen at 0 °C, was added Et3N (0.10 mL, 0.74 mmol) and then MsCl (0.05
mL, 0.65 mmol). The reaction mixture was stirred at room temperature for 3 h before diluted
with sat. aq. NaHCO3 (15 mL) and extracted with CH2Cl2 (3 x 15 mL). The combined organic
extracts were washed with brine (30 mL) and dried (MgSO4). The solvent was removed in
vacuo to obtain the crude product which was then purified by flash chromatography (2:1
petroleum ether, EtOAc) to yield the title product as a white gummy solid (236 mg, 99%); Rf
(1:1 petroleum ether, EtOAc) 0.51; νmax(film)/cm-1 2973, 2933, 1687, 1512, 1438, 1166, 877,
791 and 766; 1H NMR (400 MHz, CDCl3, Me4Si)   7.81 (1H, s, 4-H), 7.25 (2H, d, J = 8.8
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Hz, 2ʹ-H), 6.87 (2H, d, J = 8.8 Hz, 3ʹ-H), 4.72 (2H, s, NCH2Ar), 4.68 (1H, sept, J = 6.0 Hz,
OCH(CH3)2), 4.15 (2H, s, 1-H), 3.79 (3H, s, OCH3), 3.19 (3H, s, OSO2CH3), 1.38 (6H, d, J =
6.0 Hz, OCH(CH3)2); 13C{1H} NMR (100 MHz, CDCl3, Me4Si)   166.3 (C=O), 159.4 (C4ʹ),
150.7 (C6), 144.2 (C5), 142.0 (C7a), 129.7 (C2ʹ), 129.5 (C3a), 128.5 (C1ʹ), 118.9 (C4), 114.6
(C7), 114.3 (C3ʹ), 78.8 (OCH(CH3)2), 55.3 (OCH3), 50.1 (C1), 46.1 (NCH2Ar), 38.6
(OSO2CH3), 22.5 (OCH(CH3)2); m/z (ESI+): 508 (81BrMNa+, 100%) and 506 (79BrMNa+,
100%); HRMS (ESI+) Found (MNa+): 508.0235, C20H2281BrNNaO6S calcd 508.0225. Found
(MNa+): 506.0252, C20H2279BrNNaO6S calcd 506.0243.
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7-Bromo-6-hydroxy-2-(4ʹ-methoxybenzyl)-3-oxoisoindolin-5-yl methanesulfonate, 20. To
a stirred solution of 7-bromo-6-isopropoxy-2-(4'-methoxybenzyl)-3-oxoisoindolin-5-yl
methanesulfonate (300 mg, 0.62 mmol) in dry CH2Cl2 (15 mL) under an atmosphere of
nitrogen, was added anhydrous AlCl3 (124 mg, 0.93 mmol). The reaction mixture was stirred
at room temperature for 6 h before diluted with sat. aq. NH4Cl (20 mL) and extracted with
CH2Cl2 (3 x 15 mL). The combined organic extracts were washed with brine (30 mL) and dried
(MgSO4). The solvent was removed in vacuo to obtain the crude product which was then
purified by flash chromatography (15:1 CH2Cl2, MeOH) the title product 20 as a white solid
(219 mg, 80%). Rf (9:1 CH2Cl2, MeOH) 0.56; mp 206–207 °C. νmax(film)/cm-1; 3026, 2924,
1645, 1511, 1448, 1360, 1162, 825 and 791; 1H NMR (400 MHz, DMSO-d6)   11.17 (1H,
bs, OH), 7.59 (1H, s, 4-H), 7.22 (2H, d, J = 8.7 Hz, 2ʹ-H), 6.89 (2H, d, J = 8.7 Hz, 3ʹ-H), 4.62
13
(2H, s, NCH2Ar), 4.18 (2H, s, 1-H), 3.72 (3H, s, OCH3), 3.44 (3H, s, OSO2CH3); C{1H}
NMR (100 MHz, DMSO-d6)   165.9 (C=O), 158.6 (C4ʹ), 150.2 (C6), 141.9 (C7a), 137.5
(C5), 129.2 (C2ʹ), 129.0 (C1ʹ), 124.1 (C3a), 117.2 (C4), 114.1 (C3ʹ), 106.9 (C7), 55.1 (OCH3),
49.2 (C1), 44.9 (NCH2Ar), 37.8 (OSO2CH3); m/z (ESI+): 466 (81BrMNa+, 100%) and 464
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(79BrMNa+, 100%); HRMS (ESI+) Found (MNa+): 465.9748, C17H1681BrNNaO6S calcd
465.9755. Found (MNa+): 463.9774, C17H1679BrNNaO6S calcd 463.9774.
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7-Bromo-2-(4ʹ-methoxybenzyl)-6-(methoxymethoxy)-3-oxoisoindolin-5-yl
methanesulfonate. To a stirred solution of phenol 20 (200 mg, 0.45 mmol) in dry CH2Cl2 (10
mL) under an atmosphere of nitrogen, was added DIPEA (0.24 mL, 1.35 mmol) and then
MOMCl (0.07 mL, 0.90 mmol). The reaction mixture was stirred at room temperature for 4 h
before diluted with sat. aq. NH4Cl (20 mL) and extracted with CH2Cl2 (3 x 15 mL). The
combined organic extracts were washed with brine (30 mL) and dried (MgSO4). The solvent
was removed in vacuo to obtain the crude product which was then purified by flash
chromatography (2:1 petroleum ether, EtOAc) to yield the title product as a pale yellow
gummy solid (198 mg, 90%). Rf (1:1 petroleum ether, EtOAc) 0.49; νmax(film)/cm-1 2933, 2837,
1686, 1513, 1438, 1368, 1159, 901, 863 and 791; 1H NMR (300 MHz, CDCl3, Me4Si)   7.80
(1H, s, 4-H), 7.22 (2H, d, J = 8.7 Hz, 2ʹ-H), 6.86 (2H, d, J = 8.7 Hz, 3ʹ-H), 5.23 (2H, s,
OCH2OCH3), 4.71 (2H, s, NCH2Ar), 4.14 (2H, s, 1-H), 3.78 (3H, s, ArOCH3), 3.66 (3H, s,
OCH2OCH3), 3.22 (3H, s, OSO2CH3); 13C{1H} NMR (75 MHz, CDCl3, Me4Si)   166.2
(C=O), 159.3 (C4ʹ), 149.9 (C6), 143.6 (C5), 141.9 (C7a), 130.1 (C3a), 129.5 (C2ʹ), 128.4
(C1ʹ), 118.6 (C4), 114.3 (C3ʹ). 113.8 (C7a), 100.2 (OCH2OCH3), 58.5 (OCH2OCH3), 55.3
(ArOCH3), 49.9 (C1), 46.0 (NCH2Ar), 38.5 (OSO2CH3); m/z (ESI+): 488 (81BrMH+, 100%)
and 486 (79BrMH+, 100%); HRMS (ESI+) Found (MNa+): 510.0008, C19H2081BrNNaO7Scalcd
510.0017. Found (MNa+): 508.0020, C19H2079BrNNaO7S calcd 508.0036.
4-Bromo-6-hydroxy-2-(4ʹ-methoxybenzyl)-5-(methoxymethoxy)isoindolin-1-one, 21. To a
stirred solution of 7-bromo-2-(4ʹ-methoxybenzyl)-6-(methoxymethoxy)-3-oxoisoindolin-5-yl
methanesulfonate (200 mg, 0.41 mmol) in dry THF (10 mL) under an atmosphere of nitrogen
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at 0 °C, was added LDA (2M in THF, 0.31 mL, 0.62 mmol). The reaction mixture was stirred
and slowly warmed to room temperature over 1 h. Afterwards, the mixture was diluted with
sat. aq. NH4Cl (20 mL) and extracted with EtOAc (3 x 15 mL). The combined organic extracts
were washed with brine (30 mL) and dried (MgSO4). The solvent was removed in vacuo to
obtain the crude product which was then purified by flash chromatography (1:1 petroleum ether,
EtOAc) to yield the title product 21 as a pale yellow gummy solid (131 mg, 78%). Rf (1:1
petroleum ether, EtOAc) 0.29; νmax(film)/cm-1 3114, 2922, 2833, 1670, 1463, 1330, 1158, 926
and 905; 1H NMR (400 MHz, CDCl3, Me4Si)   7.44 (1H, s, 7-H), 7.23 (2H, d, J = 8.6 Hz,
2ʹ-H), 6.87 (2H, d, J = 8.6 Hz, 3ʹ-H), 5.14 (2H, s, OCH2OCH3), 4.71 (2H, s, NCH2Ar), 4.08
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(2H, s, 3-H), 3.79 (3H, s, ArOCH3), 3.66 (3H, s, OCH2OCH3); C{1H} NMR (100 MHz,
CDCl3, Me4Si)   167.4 (C=O), 159.3 (C4ʹ), 150.7 (C6), 146.2 (C5), 133.9 (C3a), 130.7 (C7a),
129.6 (C2ʹ), 128.9 (C1ʹ), 114.2 (C3ʹ), 111.8 (C4), 111.2 (C7), 100.2 (OCH2OCH3), 57.9
(OCH2OCH3), 55.3 (ArOCH3), 49.7 (C3), 46.1 (NCH2Ar); m/z (ESI+): 432 (81BrMH+, 100%)
and 430 (79BrMH+, 100%); HRMS (ESI+) Found (MNa+): 432.0232, C18H1881BrNNaO5 calcd
432.0242. Found (MNa+): 430.0252, C18H1879BrNNaO5 calcd 430.0261.
2-Hydroxy-5-(4ʹ-methoxybenzyl)-1-(methoxymethoxy)dibenzo[cd,f]indol-4(5H)-one, 22.
To a stirred solution of 21 (500 mg, 1.23 mmol) in degassed 1,4-dioxane (20 mL) under an
atmosphere of nitrogen, was added 2-formylphenylboronic acid 8 (240 mg, 1.60 mmol),
Pd(PPh3)4 (142 mg, 0.12 mmol) and K2CO3 (2M in H2O, 1.85 mL, 3.69 mmol) subsequently.
The reaction mixture was stirred at 110 °C using a heating block for 20 h before diluted with
H2O and extracted with EtOAc (3 x 30 mL). The combined organic extracts were washed with
brine (50 mL) and dried (MgSO4). The solvent was removed in vacuo to obtain the crude
product, which was used directly in the next step without any further purification. To a stirred
solution of the crude product from the previous step in dry THF (15 mL) under an atmosphere
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of nitrogen at 0 ºC, was added t-BuOK (276 mg, 2.46 mmol). The reaction mixture was stirred
at room temperature for 4 h before diluted with sat. aq. NH4Cl (40 mL) and extracted with
CH2Cl2 (4 x 20 mL). The combined organic extracts were washed with brine (50 mL) then
dried (MgSO4). The solvent was removed in vacuo to obtain the crude product which was then
purified by flash chromatography (1:1 petroleum ether, EtOAc) to yield the title product 22 as
a yellow solid (204 mg, 40%, 75% over 2 steps). Rf (1:1 petroleum ether, EtOAc) 0.37; mp
203–204 °C; νmax(film)/cm-1 3128, 2920, 2849, 1641, 1516, 1434, 1249, 1153, 921 and 832;
1H NMR (400 MHz, DMSO-d6)   10.53 (1H, bs, OH), 9.36-9.33 (1H, m, 10-H), 7.92-7.90
(1H, m, 7-H), 7.71 (1H, s, 3-H), 7.62-7.54 (2H, m, 8-H and 9-H), 7.36 (2H, d, J = 8.6 Hz, 2ʹ-
H), 7.32 (1H, s, 6-H), 6.89 (2H, d, J = 8.6 Hz, 3ʹ-H), 5.51 (2H, s, OCH2OCH3), 5.07 (2H, s,
NCH2Ar), 3.71 (3H, s, ArOCH3), 3.44 (3H, s, OCH2OCH3); 13C{1H} NMR (100 MHz, DSMO-
d6)   166.5 (C=O), 158.5 (C4ʹ), 151.3 (C2), 146.1 (C1), 135.8 (C5a), 134.5 (C6a), 129.4
(C1ʹ), 129.0 (C7), 128.8 (C2ʹ), 127.4 (C10), 127.3 (C8), 126.3 (C10a), 125.3 (C9), 114.0 (C3ʹ),
113.6 (C3), 104.2 (C6), 98.5 (OCH2OCH3), 57.7 (OCH2OCH3), 55.0 (ArOCH3), 42.4
(NCH2Ar); m/z (ESI+): 415 (MNa+, 80%); HRMS (ESI+) Found (MNa+): 438.1297,
C25H21NNaO5 calcd 438.1312.
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4-Bromo-2,6-dimethoxyphenol, 24. To
a
stirred solution of 5-bromo-1,2,3-
trimethoxybenzene 23 (500 mg, 2.02 mmol) in dry CH2Cl2 (20 mL) under an atmosphere of
nitrogen, was added anhydrous AlCl3 (405 mg, 3.03 mmol). The reaction mixture was stirred
at 50 ºC using a heating block for 21 h before diluted with 2 M HCl (20 mL) and extracted with
CH2Cl2 (3 x 20 mL). The combined organic extracts were washed with brine (50 mL) and dried
(MgSO4). The solvent was removed in vacuo to obtain the crude product which was then
purified by flash chromatography (9:1 then 4:1 petroleum ether, EtOAc) to yield the title
product 24 as a white fluffy solid (472 mg, 75%). Rf (4:1 petroleum ether, EtOAc) 0.23; mp
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95–96 °C [lit. 95–97 °C]; 1H NMR (400 MHz, CDCl3, Me4Si)   6.72 (2H, s, 3-H and 5-H),
3.87 (6H, s, ArOCH3); 13C{1H} NMR (100 MHz, CDCl3, Me4Si)   147.6 (C2 and C6), 134.1
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(C1), 111.1 (C4), 108.6 (C3 and C5), 56.5 (OCH3). The H and 13C NMR data were in
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agreement with the literature values.42
5-Bromo-1,3-dimethoxy-2-(methoxymethoxy)benzene, 25. To a stirred solution of phenol
24 (1.00 g, 4.29 mmol) in dry CH2Cl2 (20 mL) under an atmosphere of nitrogen, was added
DIPEA (1.12 mL, 6.44 mmol) and MOMCl (0.36 mL, 4.72 mmol). The reaction mixture was
stirred at room temperature for 4 h before diluted with sat. aq. NH4Cl (50 mL) and extracted
with CH2Cl2 (3 x 20 mL). The combined organic extracts were washed with brine (50 mL) and
dried (MgSO4). The solvent was removed in vacuo to obtain the crude product which was
purified by flash chromatography (4:1 petroleum ether, EtOAc) to yield the title product 25 as
a white solid (1.13 g, 95%). Rf (4:1 petroleum ether, EtOAc) 0.54; mp 85–86 °C; νmax(film)/cm-
1 2972, 2826, 1588, 1230, 1128, 832 and 768; H NMR (400 MHz, CDCl3, Me4Si)   6.72
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(2H, s, 4-H and 6-H), 5.08 (2H, s, OCH2OCH3), 3.83 (6H, s, ArOCH3), 3.58 (3H, s,
13
OCH2OCH3); C{1H} NMR (100 MHz, CDCl3, Me4Si)   153.9 (C1 and C3), 133.8 (C2),
116.6 (C5), 108.9 (C4 and C6), 98.2 (OCH2OCH3), 57.2 (OCH2OCH3), 56.3 (ArOCH3); m/z
(ESI+): 301 (81BrMNa+, 100%) and 299 (79BrMNa+, 100%); HRMS (ESI+) Found (MNa+):
300.9871, C10H1381BrNaO4 calcd 300.9870. Found (MNa+): 298.9892, C10H1379BrNaO4 calcd
298.9889.
Methyl (R)-2-((tert-butyldimethylsilyl)oxy)propanoate, 26. To a stirred solution of methyl
(R)-(+)-lactate 5 (500 mg, 4.81 mmol) in dry CH2Cl2 (15 mL) under an atmosphere of nitrogen
at 0 °C, was added imidazole (490 mg, 7.21 mmol) and TBSCl (942 mg, 6.25 mmol). The
reaction mixture was stirred at this temperature for 3 h before diluted with water and extracted
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with CH2Cl2 (3 x 15 mL). The combined organic extracts were washed with water (20 mL) and
brine (20 mL) then dried (MgSO4). The solvent was removed in vacuo to obtain the crude
product which was then purified by flash chromatography (100% petroleum ether) to yield the
title product 26 as a colorless oil (996 mg, 95%). Rf (19:1 petroleum ether, EtOAc) 0.47; []D
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+25.9 (c 1.00, CHCl3); [lit. []D +26.5 (c 2.44, CHCl3)]; 1H NMR (400 MHz, CDCl3, Me4Si)
  4.33 (1H, q, J = 6.8 Hz, 2-H), 3.72 (3H, s, OCH3), 1.39 (3H, d, J = 6.8 Hz, 3-H), 0.89 (9H,
s, Si(CH3)2C(CH3)3), 0.08 (6H, s, Si(CH3)2C(CH3)3); 13C{1H} NMR (100 MHz, CDCl3, Me4Si)
  174.6 (C=O), 68.4 (C2), 51.9 (OCH3), 25.7 (Si(CH3)2C(CH3)3), 21.4 (C3), 18.3
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(Si(CH3)2C(CH3)3), -4.9 and -5.3 (Si(CH3)2C(CH3)3). The H and 13C NMR data were in
agreement with the literature values.40
(1S,2R)-2-((Tert-butyldimethylsilyl)oxy)-1-(3,5-dimethoxy-4-
(methoxymethoxy)phenyl)propan-1-ol,
28a
and
(1R,2R)-2-((Tert-
butyldimethylsilyl)oxy)-1-(3,5-dimethoxy-4-(methoxymethoxy)phenyl)propan-1-ol, 28b.
To a stirred solution of 26 (500 mg, 2.29 mmol) in dry CH2Cl2 (20 mL) under an atmosphere
of nitrogen at -78 °C, was added DIBAL (1M in toluene, 2.40 mL, 2.40 mmol) slowly and
dropwise. The reaction mixture was stirred at this temperature for 15 min before diluted with
sat. aq. NH4Cl (30 mL) and extracted with CH2Cl2 (3 x 15 mL). The combined organic extracts
were washed with brine (50 mL) and dried (MgSO4). The solvent was removed in vacuo to
obtain the crude aldehyde product 27 which was used directly in the next step without any
further purification. To a stirred solution of 25 (700 mg, 2.54 mmol) in dry and degassed THF
(30 mL) under N2 at -78 °C, was added n-BuLi (2M in cyclohexane, 1.27 mL, 2.54 mmol)
slowly. The mixture was stirred at this temperature for 10 min before adding a solution of the
crude aldehyde above in dry and degassed THF (20 mL). This reaction mixture was stirred and
gradually warmed to room temperature over 17 h before diluted with sat. aq. NH4Cl (40 mL)
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and extracted with EtOAc (4 x 20 mL). The combined organic extracts were washed with brine
(50 mL) and dried (MgSO4). The solvent was removed in vacuo to obtain the crude product
which was then purified by flash chromatography (9:1 then 4:1 petroleum ether, EtOAc) to
yield the title products 28a/28b in a 6:1 (anti/syn) ratio as a poorly separable mixture of
diastereomers (275 mg, 31%) as a colorless oil. 28a; Rf (4:1 petroleum ether, EtOAc) 0.34;
[]D -12.0 (c 0.20, CHCl3); νmax(film)/cm-1 3486, 2930, 2856, 1593, 1462, 1126, 831 and 774;
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1H NMR (400 MHz, CDCl3, Me4Si)   6.57 (2H, s, 2ʹ-H and 6ʹ-H), 5.09 (2H, s,
ArOCH2OCH3), 4.53 (1H, d, J = 4.5 Hz, 1-H), 3.96-3.93 (1H, m, 2-H), 3.84 (6H, s, ArOCH3),
3.58 (ArOCH2OCH3), 1.01 (3H, d, J = 6.3 Hz, 3-H), 0.88 (9H, s, Si(CH2)2C(CH3)3), 0.05 and
0.00 (6H, s, Si(CH2)2C(CH3)3); 13C{1H} NMR (100 MHz, CDCl3, Me4Si)   153.1 (C3ʹ and
C5ʹ), 137.0 (C1ʹ), 133.7 (C4ʹ), 103.6 (C2ʹ and C6ʹ), 98.3 (ArOCH2OCH3), 77.7 (C1), 72.5 (C2),
57.1 (ArOCH2OCH3), 56.1 (ArOCH3), 25.8 (Si(CH2)2C(CH3)3), 18.0 (Si(CH2)2C(CH3)3), 17.7
(C3), -4.5 and -5.0 (Si(CH2)2C(CH3)3). 28b; Rf (4:1 petroleum ether, EtOAc) 0.37; []D -22.9
(c 0.14, CHCl3); 1H NMR (400 MHz, CDCl3, Me4Si)   6.56 (2H, s, 2ʹ-H and 6ʹ-H), 5.09 (2H,
s, ArOCH2OCH3), 4.29 (1H, d, J = 5.8 Hz, 1-H), 3.86-3.82 (1H, m, 2-H), 3.85 (6H, s, ArOCH3),
3.57 (ArOCH2OCH3), 1.11 (3H, d, J = 6.1 Hz, 3-H), 0.89 (9H, s, Si(CH2)2C(CH3)3), 0.04 and
-0.02 (6H, s, Si(CH2)2C(CH3)3); 13C{1H} NMR (100 MHz, CDCl3, Me4Si)   153.1 (C3ʹ and
C5ʹ), 137.5 (C1ʹ), 133.9 (C4ʹ), 103.9 (C2ʹ and C6ʹ), 98.3 (ArOCH2OCH3), 78.8 (C1), 73.7 (C2),
57.1 (ArOCH2OCH3), 56.1 (ArOCH3), 25.8 (Si(CH2)2C(CH3)3), 20.3 (C3), 18.0
(Si(CH2)2C(CH3)3), -4.3 and -4.9 (Si(CH2)2C(CH3)3); m/z (ESI+): 409 (MNa+, 100%); HRMS
(ESI+) Found (MNa+): 409.2009, C19H34NaO6Si calcd 409.2017.
(5S,6R)-5-(3,5-Dimethoxy-4-(methoxymethoxy)phenyl)-6,8,8,9,9-pentamethyl-2,4,7-
trioxa-8-siladecane, 29a and (5R,6R)-5-(3,5-Dimethoxy-4-(methoxymethoxy)phenyl)-
6,8,8,9,9-pentamethyl-2,4,7-trioxa-8-siladecane, 29b. To a stirred solution of the
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diastereomeric mixture 28a and 28b (200 mg, 0.52 mmol) in dry CH2Cl2 (15 mL) under an
atmosphere of nitrogen, was added DIPEA (0.27 mL, 1.56 mmol) and MOMCl (0.08 mL, 1.04
mmol). The reaction mixture was stirred at 40 °C using a heating block for 20 h before diluted
with sat. aq. NH4Cl (20 mL) and extracted with CH2Cl2 (3 x 15 mL). The combined organic
extracts were washed with brine (40 mL) and dried (MgSO4). The solvent was removed in
vacuo to obtain the crude product which was then purified by flash chromatography (9:1
petroleum ether, EtOAc) to yield the two title products 29a and 29b (201 mg, 90%) as an
inseparable 6:1 (anti/syn) viscous yellow oil mixture. 29a; Rf (4:1 petroleum ether, EtOAc)
0.61; νmax(film)/cm-1 2930, 2856, 1593, 1463, 1126, 1102, 830 and 774; 1H NMR (400 MHz,
CDCl3, Me4Si)   6.56 (2H, s, 2ʹ-H and 6ʹ-H), 5.09 (2H, s, ArOCH2OCH3), 4.56-4.51 (2H, m,
5-OCH2OCH3), 4.25 (1H, d, J = 6.7 Hz, 5-H), 3.89-3.84 (1H, m, 6-H), 3.82 (6H, s, ArOCH3),
3.58 (3H, s, ArOCH2OCH3), 3.38 (3H, s, 5-OCH2OCH3), 1.26 (3H, d, J = 6.0 Hz, 11-H), 0.76
(9H, s, Si(CH2)2C(CH3)3), -0.07 and -0.28 (6H, s, Si(CH2)2C(CH3)3); 13C{1H} NMR (100 MHz,
CDCl3, Me4Si)   152.9 (C3ʹ and C5ʹ), 135.9 (C1ʹ), 134.0 (C4ʹ), 105.3 (C2ʹ and C6ʹ), 98.3
(ArOCH2OCH3), 94.2 (5-OCH2OCH3), 82.4 (C5), 72.0 (C6), 57.1 (ArOCH2OCH3), 56.0
(ArOCH3), 55.7 (5-OCH2OCH3), 25.7 (Si(CH2)2C(CH3)3), 20.7 (C11), 17.9
(Si(CH2)2C(CH3)3), -4.8 and -5.3 (Si(CH2)2C(CH3)3). 29b; Rf (4:1 petroleum ether, EtOAc)
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0.61; H NMR (400 MHz, CDCl3, Me4Si)   6.53 (2H, s, 2ʹ-H and 6ʹ-H), 5.10 (2H, s,
ArOCH2OCH3), 4.63-4.57 (2H, m, 5-OCH2OCH3), 4.38 (1H, d, J = 5.5 Hz, 5-H), 4.00-3.95
(1H, m, 6-H), 3.83 (6H, s, ArOCH3), 3.58 (ArOCH2OCH3), 3.36 (5-OCH2OCH3), 1.02 (3H, d,
J = 6.2 Hz, 11-H), 0.87 (9H, s, Si(CH2)2C(CH3)3), 0.07 and 0.02 (6H, s, Si(CH2)2C(CH3)3);
13C{1H} NMR (100 MHz, CDCl3, Me4Si)   153.0 (C3ʹ and C5ʹ), 135.3 (C1ʹ), 133.9 (C4ʹ),
104.7 (C2ʹ and C6ʹ), 98.2 (ArOCH2OCH3), 94.7 (5-OCH2OCH3), 82.2 (C5), 71.8 (C6), 57.1
(ArOCH2OCH3), 56.0 (ArOCH3), 55.7 (5-OCH2OCH3), 25.9 (Si(CH2)2C(CH3)3), 20.0 (C11),
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18.2 (Si(CH2)2C(CH3)3), -4.6 and -4.9 (Si(CH2)2C(CH3)3); m/z (ESI+): 453 (MNa+, 100%);
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HRMS (ESI+) Found (MNa+): 453.2274, C21H38NaO7Si calcd 453.2279.
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(1S,2R)-1-(3,5-Dimethoxy-4-(methoxymethoxy)phenyl)-1-(methoxymethoxy)propan-2-
ol,
30a
and
(1R,2R)-1-(3,5-Dimethoxy-4-(methoxymethoxy)phenyl)-1-
(methoxymethoxy)propan-2-ol 30b. To a stirred solution of mixture 29a and 29b (150 mg,
0.35 mmol) in dry THF (10 mL) under an atmosphere of nitrogen at 0 °C, was added TBAF
(1M in THF, 1.05 mL, 1.05 mmol). The reaction mixture was stirred at 0 °C then room
temperature for 19 h before diluted with sat. aq. NH4Cl (20 mL) and extracted with EtOAc (4
x 15 mL). The combined organic extracts were washed with brine (50 mL) and dried (MgSO4).
The solvent was removed in vacuo to obtain the crude product which was then purified by flash
chromatography (1:1 then 1:2 petroleum ether, EtOAc) to yield the two title products 30a and
30b (97 mg, 88%) as an inseparable 6:1 (anti/syn) colorless solid mixture. 30a; Rf (4:1
petroleum ether, EtOAc) 0.06; mp 67–68 ºC; νmax(film)/cm-1; 3532, 2943, 2912, 2891, 2842,
1595, 1121, 1097, 948, 926 and 907; 1H NMR (400 MHz, CDCl3, Me4Si)   6.54 (2H, s, 2ʹ-
H and 6ʹ-H), 5.08 (2H, s, ArOCH2OCH3), 4.56 (2H, s, 1-OCH2OCH3), 4.37 (1H, d, J = 5.4 Hz,
1-H), 3.93-3.83 (1H, m, 2-H), 3.81 (6H, s, ArOCH3), 3.57 (3H, s, ArOCH2OCH3), 3.37 (3H, s,
1-OCH2OCH3), 1.18 (3H, d, J = 6.3 Hz, 3-H); 13C{1H} NMR (100 MHz, CDCl3, Me4Si)
  153.3 (C3ʹ and C5ʹ), 134.2 and 134.1 (C1ʹ and C4ʹ), 104.6 (C2ʹ and C6ʹ), 98.1
(ArOCH2OCH3), 94.7 (1-OCH2OCH3), 82.4 (C1), 70.7 (C2), 57.1 (ArOCH2OCH3), 56.0
1
(ArOCH3), 55.8 (1-OCH2OCH3), 18.5 (C3). 30b; Rf (4:1 petroleum ether, EtOAc) 0.07; H
NMR (400 MHz, CDCl3, Me4Si)   6.49 (2H, s, 2ʹ-H and 6ʹ-H), 5.08 (2H, s, ArOCH2OCH3),
4.56 (2H, m, 1-OCH2OCH3), 4.21 (1H, d, J = 7.7 Hz, 1-H), 3.93-3.83 (1H, m, 2-H), 3.81 (6H,
s, ArOCH3), 3.57 (ArOCH2OCH3), 3.37 (1-OCH2OCH3), 1.01 (3H, d, J = 6.3 Hz, 3-H); 13C{1H}
NMR (100 MHz, CDCl3, Me4Si)   153.4 (C3ʹ and C5ʹ), 134.4 and 134.3 (C1ʹ and C4ʹ), 104.5
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(C2ʹ and C6ʹ), 98.1 (ArOCH2OCH3), 94.3 (1-OCH2OCH3), 83.6 (C1), 71.1 (C2), 57.1
(ArOCH2OCH3), 56.0 (ArOCH3), 55.8 (1-OCH2OCH3), 18.4 (C3); m/z (ESI+): 339 (MNa+,
100%); HRMS (ESI+) Found (MNa+): 339.1411, C15H24NaO7 calcd 339.1414.
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2-(((2''S)-1-(3''',5'''-dimethoxy-4'''-(methoxymethoxy)phenyl)-1''-
(methoxymethoxy)propan-2''-yl)oxy)-5-(4'-methoxybenzyl)-1-
(methoxymethoxy)dibenzo[cd,f]indol-4(5H)-one, 31. To a stirred solution of phenol 22 (50
mg, 0.12 mmol), alcohol mixture of 30a and 30b (42 mg, 0.13 mmol) and PPh3 (38 mg, 0.14
mmol) in dry toluene (10 mL) under an atmosphere of nitrogen at 0 °C, was added DIAD (30
mg, 0.14 mmol) slowly. The reaction mixture was then stirred at 90 °C using a heating block
for 3 h. The solvent was removed in vacuo to obtain the crude product which was then purified
by flash chromatography (15:1 then 4:1 then 1:1 petroleum ether, EtOAc) to the title product
31 as a yellow brown oil (62 mg, 72%) as a single stereoisomer. The stereochemistry of C1ʹʹ is
undetermined. Rf (1:1 petroleum ether, EtOAc) 0.43; νmax(film)/cm-1 2939, 2839, 1699, 1410,
1237, 1126, 962, 921, 841 and 755; 1H NMR (300 MHz, CDCl3)   9.43-9.37 (1H, m, 10-H),
7.98 (1H, s, 3-H), 7.74-7.71 (1H, m, 7-H), 7.53-7.51 (2H, m, 8-H and 9-H), 7.32 (2H, d, J =
8.7 Hz), 6.91 (1H, s, 6-H), 6.84 (2H, d, J = 8.7 Hz), 6.65 (2H, s, 2ʹʹʹ-H), 5.51-5.47 (2H, m, 1-
OCH2OCH3), 5.12-5.10 (4H, m, 4ʹʹʹ-OCH2OCH3 and NCH2Ar), 4.81-4.76 (2H, m, 1ʹʹ-H and
2ʹʹ-H), 4.63 (2H, s, 1ʹʹ-OCH2OCH3), 3.88 (6H, s, 3ʹʹʹ-OCH3- and 5ʹʹʹ-OCH3), 3.74 (3H, s, 4ʹ-
OCH3), 3.59 (3H, s, 4ʹʹʹ-OCH2OCH3), 3.52 (3H, s, 1-OCH2OCH3), 3.38 (3H, s, 1ʹʹ-
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OCH2OCH3), 1.25-1.22 (3H, m, 3ʹʹ-H); C{1H} NMR (75 MHz, CDCl3)   167.8 (C=O),
159.0 (C4ʹ), 153.4 (C3ʹʹʹ and C5ʹʹʹ), 151.8 (C2), 149.4 (C2), 136.1 (C5a), 134.7 (C6a), 134.4
(C4ʹʹʹ), 134.1 (C1ʹʹʹ), 129.0 (C7), 128.7 (C2ʹ), 128.5 (C1ʹ), 127.8 (C10), 127.4 (C8), 127.0
(C10a), 125.7 (C9), 123.5 (C10c), 121.2 (C3a), 120.9 (C10b), 114.1 (C3ʹ), 113.2 (C3), 105.4
(C6), 104.8 (C2ʹʹʹ and C6ʹʹʹ), 100.0 (1-OCH2OCH3), 98.2 (4ʹʹʹ-OCH2OCH3), 94.4 (1ʹʹ-
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OCH2OCH3), 80.9 (C1ʹʹ), 79.5 (C2ʹʹ), 58.4 (1-OCH2OCH3), 57.1 (4ʹʹʹ-OCH2OCH3), 56.1 (3ʹʹʹ-
OCH3 and 5ʹʹʹ-OCH3), 55.8 (1ʹʹ-OCH2OCH3), 55.2 (4ʹ-OCH3), 43.4 (NCH2Ar), 16.7 (C3ʹʹ); m/z
(ESI+): 736 (MNa+, 100%); HRMS (ESI+) Found (MNa+): 736.2716, C40H43NNaO11 calcd
736.2728.
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(+)-Aristolactam GI, (+)-1. To a stirred solution of 31 (20 mg, 0.028 mmol) in anisole (1 mL)
under N2, was added excess TFA (0.05 mL, 0.70 mmol). The reaction mixture was stirred and
heated at 100 °C using a heating block for 25 h. Afterwards, the volatiles were removed in
vacuo. The residue was diluted with CH2Cl2 (5 mL) and Et3N (5 mL) and left to stir vigorously
for 30 min. Water (10 mL) was added to the mixture. The two layers were separated. The
organic layer was washed with brine (15 mL) and dried (MgSO4). The solvent was removed in
vacuo to obtain the crude product which was then purified by flash chromatography (1:2 then
1:4 petroleum ether, EtOAc) to yield the title product (+)-1 as a yellow solid (4 mg, 32 %). Rf
(1:2 petroleum ether, EtOAc) 0.17; mp over 230 ºC; []D +19.8 (c 0.13, CHCl3); lit.8 []D +6.0
(c 0.20, CHCl3); νmax(film)/cm-1; 3461, 3341, 2922, 2853, 1688, 1588, 1098 and 768; 1H NMR
(400 MHz, DMSO-d6)   10.81 (1H, s, NH), 9.01 (1H, d, J = 8.3 Hz, 5-H), 8.63 (1H, s, OH),
7.97 (1H, d, J = 7.4 Hz, 8-H), 7.67 (1H, s, 2-H), 7.53 (1H, t, J = 7.4 Hz, 7-H), 7.44 (1H, t, J =
7.4 Hz, 6-H), 7.19 (1H, s, 9-H), 6.94 (2H, s, 2ʹ-H and 6ʹ-H), 5.11 (1H, d, J = 7.9 Hz, 7ʹ-H),
4.50-4.44 (1H, m, 8ʹ-H), 3.80 (6H, s, ArOCH3), 1.26 (3H, d, J = 6.4 Hz, 9ʹ-H); 13C{1H} NMR
(100 MHz, DMSO-d6)   168.4 (C=O), 148.2 (C3ʹ and C5ʹ), 146.1 (C4), 144.1 (C3), 136.2
(C4ʹ), 135.2 (C10), 134.6 (C8a), 128.9 (C8), 127.2 (C5), 127.0 (C7), 126.3 (C1ʹ), 125.9 (C4b),
125.0 (C6), 123.5 (C10a), 118.4 (C1), 116.1 (C4a), 113.8 (C2), 105.2 (C2ʹ and C6ʹ), 104.6
(C9), 81.2 (C7ʹ), 73.2 (C8ʹ), 56.2 (3ʹ-OCH3 and 5ʹ-OCH3), 16.8 (C9ʹ); m/z (ESI+): 466 (MNa+,
30%); HRMS (ESI+) Found (MNa+): 466.1256, C26H21NNaO6 calcd 466.1261. The NMR data
matched that reported in literature.8
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