Synthesis of the Tetracyclic Cores of the Integrastatins, Epicoccolide A and Epicocconigrone A

Article abstract of DOI:10.1021/acs.joc.9b01796

The integrastatins, epicoccolide A and epicoccongirone A, are natural products containing a unique [6.6.6.6]-tetracyclic core framework that exhibit a broad spectrum of biological activities. A synthesis of the common core of epicoccolide A and epicocconigrone A has been achieved using an umpolung alkylation-lactonization to assemble an isochromanone from which the bridged 1,3-dioxane was readily assembled. A different strategy was required to access the core on the integrastatins; an initial aryllithium addition to an aldehyde, followed by oxidation and treatment of the masked dihydroxyketone with acid gave the desired core structure.

Full text of DOI:10.1021/acs.joc.9b01796

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Article
Synthesis of the Tetracyclic Cores of the
Integrastatins, Epicoccolide A and Epicocconigrone A
Joo Young Jeong, Jonathan Sperry, and Margaret A. Brimble
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.9b01796 • Publication Date (Web): 16 Aug 2019
Downloaded from pubs.acs.org on August 16, 2019
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Synthesis of the Tetracyclic Cores of the Integrastatins, Epicoccolide A and
Epicocconigrone A
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8
9
Joo Young Jeong, Jonathan Sperry and Margaret A. Brimble*
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School of Chemical Sciences, The University of Auckland, 23 Symonds Street, Auckland CBD,
Auckland 1010, New Zealand
m.brimble@auckland.ac.nz
Abstract
The integrastatins, epicoccolide A and epicoccongirone A are natural products containing a
unique [6.6.6.6]-tetracyclic core framework that exhibit a broad spectrum of biological
activities. A synthesis of the common core of epicoccolide A and epicocconigrone A has been
achieved using an umpolung alkylation-lactonisation to assemble an isochromanone from
which the bridged 1,3-dioxane was readily assembled. A different strategy was required to
access the core on the integrastatins; an initial aryllithium addition to an aldehyde, followed by
oxidation and treatment of the masked dihydroxyketone with acid gave the desired core
structure.
O
umpolung
alkylation-
lactonisation
S
H
O
S
S
S
O
3
O
EOMO
O
O
OEOM
H
OMe
O
core of epicoccolide A/
epicocconigrone A
O
O
aryllithium
addition
then oxidation
O
O
O
Me
O
Me
O
H+
OEOM
Me
O
Me
Li
OEOM
Me
OEOM
O
OEOM
Me
core of integrastatins
O
R
O
O
Me
O
O
OH
O
O
H
Me
OMe
OH
H
OH
OH
OH
OH
O
Me
Me
MeO
O
Me
OH
HO
O
HO
OH
O
H
H
OH
OH
Me
OH
epicoccolide A
integrastatin A
integrastatin B
R = CH2OH
R = CHO
epicocconigrone A
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Introduction
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In 2002, Singh and co-workers reported the isolation of the novel fungal metabolites
integrastatins A (1) and B (2) from both an unnamed fungal source (ATCC74478) and an
endophytic fungus Ascochyta sp. (ATCC74477) (Figure 1).1 Both integrastatins A (1) and B
(2) inhibit recombinant HIV-1 integrase, with IC50 values of 1.1 and 2.5 µM,1 respectively, and
possess a structurally unprecedented [6.6.6.6]-tetracyclic core that exists as a racemate. The
significance of the tetracyclic scaffold as a promising pharmacophore was accentuated when
the isolation of another two novel natural compounds, epicoccolide A2 [(2R,10S)-3] and
epicocconigrone A3 (4), were reported in 2013 and 2014, respectively. These natural
compounds displayed a broad spectrum of biological properties including antimicrobial,
antifungal, antioxidant, anticancer and antiviral activities.2-4 Interestingly, while
epicocconigrone A (4) was reported to be racemic, epicoccolide A [(2R,10S)-3] was isolated
as a single enantiomer.
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O
O
O
O
Me
O
O
OH
O
O
R
Me
H
H
OMe
OH
OH
OH
OH
OH
10
Me
HO
Me
HO
2
MeO
O
O
O
Me
H
H
OH
OH
Me
OH
OH
OH
1
3
4
epicocconigrone A ( )
integrastatin A ( )
epicoccolide A [(2R,10S)- ]
R = CH2OH
R = CHO
2
integrastatin B ( )
Figure 1. Integrastatins A (1) and B (2), epicoccolide A [(2R,10S)-3] and epicocconigrone A
(4).
Due to the distinctive molecular framework and intriguing medicinal properties exhibited by
these natural products, efforts towards their total synthesis have been reported by several
groups (Scheme 1). In 2003, Taylor and co-workers reported a synthesis of integrastatin core
5 using Lewis-acid mediated cyclisation of Z-alkene 6 (E:Z = 1:15) to assemble tetracycle 7,
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which delivered core 5 upon benzylic oxidation.5 In 2011, Stoltz and co-workers reported a
formal synthesis of integrastatin core 5,6 using a Wacker type cyclisation of precursor 8 to
assemble tetracycle 7 previously synthesised by Taylor. Ramana and co-workers developed a
domino process involving pinacol cross-coupling of ortho-phthalaldehyde (9) with
benzaldehyde 10 to access tetracycle 11, a potential precursor to the core 12 of epicoccolide A
[(2R,10S)-3]/epicocconigrone A (4).7 The use of acetophenone 13 in this process also enabled
synthesis of tetracycle 14, which underwent oxidation to C-10 methyl analogue 15.7 However,
the methodology was limited to the use of ortho-phthalaldehyde (9) as a substrate, and was not
amenable to the synthesis of products with a C-2 methyl group (i.e. integrastatin core 5). In
2016, Ramana and co-workers reported biomimetic syntheses of cores 12 and 5 via oxidative
dearomatisation cascade of benzofurans 16 and 17, respectively,8 which was subsequently
applied to the first total synthesis of integrastatin B (2).9
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O
R1
R1 = R2 = Me
integrastatin core
5
10
9
12 R1 = R2 = H
3
4
core of epicoccolide A [(2R,10S)- ]/epicocconigrone A ( )
O
R1 = Me R2 = H
2
C-10 methyl analogue
15
O
R2
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8
9
A) Core Construction
Taylor (2003)
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Me
Lewis-acid
mediated cyclisation
O
(94%)
Me
Me
9
[O]
5
O
OBn
(E:Z = 1:15)
(77%)
6
O
Me
7
Stoltz (2011)
Pd-catalysed
oxidative cyclisation
HO Me
(61%)
OH
OH
H
8
9
10
R = H
(42%)
12
15
O
Ramana (2008)
R
O
2
O
H
pinacol coupling
O
11
O
OH
OH
Me
9
10
R = Me
(49%)
[O]
(79%)
9
10
R = H
13 R = Me
O
2
O
H
14
Ramana (2016)
Oxone-mediated
biomimetic
R
R
O
R
O
R
12
and
5
cascade
O
O
O
O
O
R = H (88%)
R = Me (89%)
O
R
R
16
R = H
17 R = Me
B) Total Synthesis of Integrastatin B (2)
Ramana (2016)
Oxone-mediated
Me
O
O
O
O
O
Me
OMe
OAc
OAc
Me
Me
Me
biomimetic
cascade
OMe
OAc
OMe
OH
O
MeO
MeO
O
MeO
O
O
Me
Me
OH
OAc
OAc
OAc
OH
integrastatin B ( )
Me
2
Scheme 1. A) Previous approaches towards the tetracyclic core structures 5, 12 and 15;5-8 B)
Biomimetic total synthesis of integrastatin B (2).9
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Initial synthetic strategy
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We set out to devise a reliable synthetic strategy towards integrastatin core 5 that would
complement those shown in Scheme 1, but also allow for facile introduction of the 9-oxo
functionality and both C-2 and C-10 methyl substituents (Scheme 2). We envisioned to provide
access to both methyl substituents by coupling 1,3-dithiane 18 with acetophenone 1910.
Coupled product 20 would undergo acid-catalysed deprotection/cyclisation to construct
tetracyclic framework 21, which upon dithiane removal would unveil the 9-oxo functionality
of the integrastatin core 5.
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O
Me
OEOM
19
umpolung
alkylation
O
acid-catalysed
deprotection/
cyclisation
O
O
S
Me
O
S
Me
S
S
Me
OH
OEOM
20
18
O
dithiane
removal
Me
S
S
Me
10
10
9
9
O
O
2
2
O
O
Me
Me
21
5
integrastatin core
Scheme 2. Proposed synthesis of integrastatin core 5 (EOM = ethoxymethyl)
Results and discussion
Initial attempts for the umpolung alkylation using 1,3-dithiane 18
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We embarked on the synthesis by preparing 1,3-dithiane 18 (Scheme 3). Acid-catalysed
acetalisation11 of the commercially available 2′-bromoacetophenone (22) afforded acetal 23
which underwent formylation with DMF on treatment with n-BuLi to deliver benzaldehyde 24
in 85% yield. Subsequent Amberlyst® 15-mediated thioacetalisation of 24 afforded 1,3-
10
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dithiane 18, along with a minor amount of separable deprotected product 25.
pTSAH2O
ethylene glycol
n-BuLi then
anh. DMF
O
Me
Br
O
O
Me
Br
toluene
THF, 78 C
Dean-Stark
2 h, 85%
reflux, 24 h, 92%
22
23
Amberlyst 15
O
O
O
Me
S
1,3-propanedithiol
O
O
O
S
Me
Me
S
S
THF, rt, 50 min
18
25
(5%)
(83%),
24
18
25
Scheme 3. Synthesis of 1,3-dithiane 18.
Disappointingly, attempted umpolung alkylation of 1,3-dithiane 18 with acetophenone 1910
failed to deliver coupled product 20 despite using various bases (Scheme 4, A), with only
coupling substrates 18 and 19 recovered in all cases. Deuterium exchange experiments using
n-BuLi, t-BuLi and LDA, conducted to investigate the ease of C-2 lithiation of 1,3-dithiane 18,
did not yield any deuterated product in significant quantities, revealing the impracticality of
using 1,3-dithiane 18 as an umpolung alkylating agent. The difficult C-2 deprotonation could
be due to the donation of oxygen lone pair into the σ*c-s of the dithiane (Scheme 4, B), which
reduces the ability of the σ*c-s to increase the acidity of the C-2 proton.12-18 Efforts were thus
directed towards finding an alternative substrate.
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A) Unsuccessful Attempted Umpolung Alkylation
O
5
Me
6
7
8
9
OEOM
O
O
19
O
S
Me
various bases
O
S
Me
S
S
10
11
12
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Me
OH
OEOM
20
18
B) Possible Rationale
Me
O
O
O
O
S
2
H
Me
2
S
S
H
S
18
good nc-c-s* overlap
oxygen lone pair donation to c-s
proton acidity 
*
Scheme 4. A) Unsuccessful attempted umpolung alkylation of 1,3-dithiane 18 with
acetophenone 19; B) Possible rationale for the difficult C-2 deprotonation of 1,3-dithiane 18.
Use of 1,3-dithane 26 for the construction of epicoccolide A/epicocconigrone A core 12
The unsuccessful deprotonation of the 1,3-dithiane 18 led us to consider using the 1,3-dithiane
26 bearing an ester substituent rather than a 1,3-dioxolane,19-22 which has been used previously
as a substrate for umpolung alkylation reactions (Scheme 5).23 The use of 1,3-dithiane 18 for
the synthesis of the core 12 of epicoccolide A [(2R,10S)-3]/epicocconigrone A (4), lacking the
C-2 and C-10 methyl substituents present in integrastatin core 5, also appeared plausible. Union
of 1,3-dithiane 26 with benzaldehyde 2724 was anticipated to enable access to lactone 28 in
one-pot. Reduction of 28 to lactol 29 followed by acid-catalysed deprotection/intramolecular
cyclisation would construct tetracyclic framework 30, which upon hydrolysis of the dithiane
would deliver core 12 of epicoccolide A [(2R,10S)-3]/epicocconigrone A (4).
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2
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O
4
5
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7
8
OEOM
OMe
O
S
27
S
S
umpolung
alkylation
O
OMe
lactonisation
reduction
S
S
9
EOMO
O
S
O
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O
OEOM
28
26
acid-catalysed
deprotection/
cyclisation
O
dithiane
removal
H
S
S
S
S
H
10
9
O
O
EOMO
O
2
O
H
O
H
OH
29
30
12
the core of epicoccolide A
[(2R,10S)- ]/epicocconigrone
3
4
A ( )
Scheme 5. Proposed synthesis of core 12 using 1,3-dithiane 26 and benzaldehyde 27.
Gratifyingly, the umpolung alkylation of 1,3-dithiane 26 with benzaldehyde 27 triggered
concomitant lactonisation to deliver lactone 28 in 83% yield, which upon DIBAL-H reduction
afforded lactols 29a/b as an inconsequential 4:1 mixture of diastereomers (Scheme 6). The nOe
correlation between H-1 and H-3 in the minor diastereomer 29b indicated a syn-relationship,
while the absence of the analogous nOe correlation in the major diastereomer 29a suggested
these protons were in an anti-relationship. Subsequent treatment of 29a/b with EOM
deprotection conditions using silica supported-NaHSO425 delivered tetracycle 30 in good yield.
Finally, hydrolysis of the dithiane 30 successfully unveiled the 9-oxo functionality of the target
core 12 of epicoccolide A [(2R,10S)-3]/epicocconigrone A (4) in good yield. The successful
synthesis of 12 was confirmed by the agreement of the NMR spectroscopic data to those
reported by Ramana and co-workers.8
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4
5
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8
OEOM
27
O
OMe
S
S
S
S
S
S
S
LDA
DIBAL-H
3
3
S
H
H
9
EOMO
O
EOMO
O
1
EOMO
O
1
THF
78 C to rt
40 min, 83%
THF, 78 C
1 h, 73%
4:1 d.r.
nOe
10
11
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HO
H
OH
29b
minor
O
H
O
26
28
29a
major
HgO
H
10
S
H
S
S
S
NaHSO4
SiO2
BF3Et2O
diastereoselective
9
10
O
O
CH2Cl2, rt
2 h, 71%
HO
O
THF-H2O
0 C to rt
1 h, 74%
2
2
O
O
H
H
30
12
the core of epicoccolide A
3
[(2R,10S)- ]/epicocconigrone A
4
( )
Scheme 6. Synthesis of the core 12 of epicoccolide A [(2R,10S)-3]/epicocconigrone A (4).
Application of the umpolung alkylation strategy towards integrastatin core 5
The successful synthesis of core 12 now provided us with a reliable platform for the synthesis
of integrastatin core 5, which required installation of the C-2 and C-10 methyl substituents
(Scheme 7). Introduction of the C-10 methyl substituent would be achieved by assembling 1,3-
dithiane 26 with acetophenone 19, instead of the previously used benzaldehyde 27 to yield
lactone 31. Installation of the C-2 methyl substituent would require the addition of MeLi to
lactone 31, where the adduct 32 would undergo the putative acid-catalysed
deprotection/cyclisation process to construct tetracyclic framework 21, followed by hydrolysis
of the dithiane to deliver integrastatin core 5.
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2
3
O
4
5
6
7
8
9
Me
OEOM
19
OMe
O
O
OMe
umpolung
alkylation
S
S
S
S
MeLi
S
Me
S
EOMO
O
10
11
12
13
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22
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O
Me
OEOM
O
26
31
acid-catalysed
deprotection/
cyclisation
O
dithiane
hydrolysis
Me
S
S
S
S
Me
10
9
O
Me
O
EOMO
O
2
O
Me
O
Me
Me OH
32
21
5
integrastatin core
Scheme 7. Proposed synthesis of integrastatin core 5 using 1,3-dithiane 26 and acetophenone
19.
Synthetic investigations towards integrastatin core 5 began with the union of acetophenone 19
with 1,3-dithiane 26 to give the desired lactone 31 albeit in a low 12% yield, along with the
recovered coupling substrates 19 and 26 (Scheme 8). Unfortunately, the low yield could not be
improved despite extensive optimisation of the reaction conditions (time, concentration,
reagent ratios and temperature) limiting the scale to 100-200 mg with the best yield of 12%
(see Supporting Information). However, addition of MeLi to lactone 31 was successful,
delivering cyclisation precursor 32 as a single diastereomer. Although ultimately
inconsequential, it was assumed that the methyl groups in 32 were in an anti-relationship to
avoid an undesirable 1,3-diaxial interaction, which was also supported by the absence of an
nOe correlation between these methyl substituents.
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4
5
6
7
8
9
Me
OEOM
19
O
OMe
S
S
S
S
S
LDA
MeLi
3
Me
S
Me
EOMO
O
THF
THF
78 C, 2 h
47%
EOMO
O
1
10
11
12
13
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78 C to rt
2 h, 12%
Me
OH
O
26
31
32
Scheme 8. Installation of the two methyl substituents.
Next, we shifted our attention to the concomitant EOM deprotection/cyclisation step to
construct tetracyclic framework 21 (Table 1). Unfortunately, this was challenging as the use of
the previously established conditions25 (entry 1), hydrochloric acid (entries 2-4) or pTSA·H2O
(entries 5-6) only led to decomposition, recovery of the starting material or formation of a
complex mixture. Disappointed by these results, it was postulated that the added steric
hindrance by C-1 and C-3 methyl substituents created a conformational lock, which hampered
the desired deprotection-cyclisation process. Moreover, undertaking synthetic studies towards
integrastatin core 5 using precursor 32 required access to large amounts of this intermediate,
which was difficult due to the poor yield obtained for the umpolung alkylation step. At this
point, we concluded that the umpolung alkylation approach was too inefficient to enable
synthesis of integrastatin core 5, and a revised strategy was required.
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Table 1. Attempted synthesis of cyclisation product 21.
5
6
7
8
9
S
S
S
S
Me
table
3
O
Me
EOMO
O
1
10
11
12
13
14
15
16
17
18
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21
22
23
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O
Me
OH
Me
32
21
entry
acid
solvent
temp.
time
results
complex mixture
NaHSO4·SiO2
CH2Cl2
1
2
rt
16 h
32
32
aq. 2M HCl
aq. 2M HCl
aq. 2M HCl
pTSA·H2O
pTSA·H2O
THF
THF
THF
rt
6 h
6 h
recovered
recovered
60 °C
60 °C
3
4
5
6
16 h
decomposition
toluene
EtOH
45 °C
55 °C
30 min
1 h
decomposition
complex mixture
Revised synthesis of integrastatin core 5
Upon consideration of the problems encountered thus far, our planned synthesis was modified
use a more reactive aryllithium species to unify the two fragments (Scheme 9). This required
changing the electrophile to the 2-phenylacetaldehyde 33, which upon reaction with the
aryllithium 34 would give 35. Oxidation would afford the cyclisation precursor 36 that upon
global deprotection-cyclisation would deliver integrastatin core 5.
O
OEOM
Me
OEOM
33
O
O
lithium-halogen
exchange
aryllithium
addition
O
O
Me
O
O
HO
Me
Me
OEOM
Me
Br
Li
OEOM
23
34
35
O
global
O
O
deprotection/
cyclisation
Me
Me
[O]
O
O
OEOM
Me
O
Me
OEOM
5
36
integrastatin core
Scheme 9. Revised synthetic strategy towards integrastatin core 5.
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Our revised synthesis commenced with protection of commercially available 2-bromophenol
(37) as its EOM ether 38 (Scheme 10). Alkylation of the resultant bromide 38 with methyl
pyruvate delivered hydroxyester 39 which was subsequently masked as EOM ether 40.
Subsequent reduction of ester 40 afforded aldehyde 33 in 74% yield over two steps, which was
then subjected to the coupling reaction with aryllithium 34, generated in situ by treating
bromide 23 with n-BuLi. Gratifyingly, coupled product 35 was successfully afforded in 83%
yield as an inconsequential 4:1 mixture of inseparable diastereomers, where the newly formed
configuration at C-1 was removed in the subsequent oxidation step to afford cyclisation
precursor 36. Finally, subjection of precursor 36 to global deprotection/cyclisation conditions
using pTSA·H2O resulted in assembly of the target integrastatin core 5 in excellent yield. This
transformation likely proceeds via the diastereoselective intramolecular attack of oxonium ion
41 by the phenol proceeding under thermodynamic control to favour the formation of the stable
isomer 5. The spectroscopic data for integrastatin core 5 was in agreement with that previously
reported by Ramana.8
10
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12
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23
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O
OMe
n-BuLi then
methyl pyruvate
O
OMe
OH
NaH
EOMCl
Cs2CO3
EOMCl
Br
Br
OEOM
Me
Me
THF
78 C to rt
1 h, 72%
THF
0 C to rt
4 h, 81%
DMF
0 C to rt
6 h, 85%
OH
OEOM
OEOM
OEOM
37
38
39
40
9
O
10
11
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O
1. DIBAL-H, CH2Cl2
Me
O
O
O
78 C to rt, 1 h
DMP, NaHCO3
O
Li
2.
O
DMP
NaHCO3
pTSAH2O
34
Me
HO
Me
CH2Cl2, rt, 3 h
O
OEOM
Me
1
1
74% (2 steps)
CH2Cl2, rt
4 h, 76%
THF
MeOH, 60C
3 h, 96%
OEOM
Me
OEOM
Me
OEOM
78 C to rt
1.5 h, 72%
OEOM
OEOM
33
35
36
(83%)
4:1 d.r.
O
O
O
O
O
R
Me
Me
Me
OMe
OH
diastereoselective
10
OH
O
2
MeO
O
O
Me
OH
1
R = CH2OH
Me
Me
41
OH
5
integrastatin A ( )
integrastatin core
2
integrastatin B ( ) R = CHO
Scheme 10. Synthesis of integrastatin core 5.
Conclusion
To conclude, two convergent synthetic approaches to the unique tetracyclic core 12 of
epicoccolide A [(2R,10S)-3]/epicocconigrone A (4) and the core 12 of the integrastatins is
described. An umpolung alkylation approach enabled successful synthesis of 12, the core of
epicoccolide A [(2R,10S)-3] and epicocconigrone A (4), offering an efficient route towards the
tetracyclic scaffold that may be applicable for the total syntheses of the natural products
themselves. Although the synthesis of integrastatin core 5 via this approach was not possible,
a revised aryllithium addition strategy was successful, which should also be amenable for the
total syntheses of integrastatin A (1) and B (2). Evaluation of the applicability of the established
synthetic approaches towards the total syntheses of the integrastatins, epicoccolide A
[(2R,10S)-3] and epicocconigrone A (4) is the subject of future investigations.
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Experimental Section
General information
7
8
9
Unless otherwise noted, all reactions were performed under an atmosphere of dry nitrogen in
oven-dried (100 °C) glassware. Commercially available starting materials and reagents were
used as received unless otherwise noted. All the solvents used were dried by passage through
a column of activated alumina under nitrogen using an LC Technology solvent purification
system. Thin layer chromatography (TLC) was performed using F254 0.2 mm silica plates,
followed by visualization with UV irradiation at 254 nm, and staining with ethanolic vanillin
or potassium permanganate solution. Flash column chromatography was performed using
63−100 μm silica gel. Melting points were determined on a Kofler hot-stage apparatus and are
uncorrected. Infrared (IR) spectra were recorded with an FT-IR spectrometer using a diamond
ATR sampling accessory. NMR spectra were recorded at ambient temperature in CDCl3 or
(CD3)2SO solutions using a spectrometer operating at 400 MHz for 1H nuclei and 100 MHz for
13C nuclei. All chemical shifts are reported in ppm on the δ scale and were measured relative
to the protium solvent in which the sample was analysed: CDCl3 (δ 7.26 ppm for 1H NMR and
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13
1
δ 77.2 ppm for C{1H} NMR) or (CD3)2SO (δ 2.50 ppm for H NMR and δ 39.5 ppm for
13C{1H} NMR), with relative integral. Coupling constants, J, are reported in Hertz [Hz] where
applicable. Multiplicities are reported as “s” (singlet), “d” (doublet), “t” (triplet), “q” (quartet),
“m” (multiplet), “br” (broad or combination thereof). Where distinguishable from those due to
a major isomer/diastereomer or rotamer, resonances due to the minor isomer, diastereomer and
rotamer are denoted by an asterisk (*). High-resolution mass spectra were recorded on a
microTOF QII (electrospray ionization, ESI) mass spectrometer.
Synthesis of 1,3-dithiane 18. 2-(2-Bromophenyl)-2-methyl-1,3-dioxolane (23). To a stirred
solution of 2′-bromoacetophenone (22) (1.00 g, 5.02 mmol) in toluene (50 mL) at rt was added
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p-TSA·H2O (19 mg, 0.10 mmol) and ethylene glycol (558 μL, 10.0 mmol). The reaction
mixture was heated under reflux with a Dean-Stark apparatus for 24 h. The mixture was then
cooled to rt and diluted with sat. aq. NaHCO3 (30 mL). The resultant mixture was extracted
with Et2O (100 mL × 3) and the combined organic extracts were washed with H2O (100 mL),
brine (100 mL), dried over anhydrous MgSO4, filtered and concentrated in vacuo. Purification
by flash column chromatography (petroleum ether-EtOAc 9:1) afforded title compound 23
(1.12 g, 4.61 mmol, 92%) as a colourless oil; Rf = 0.43 (petroleum ether-EtOAc 9:1); 1H NMR
(400 MHz, CDCl3): δ 7.66 (dd, J = 7.8, 1.8 Hz, 1H), 7.59 (dd, J = 7.9, 1.2 Hz, 1H), 7.28 (td, J
= 7.4, 1.2 Hz, 1H), 7.13 (td, J = 7.6, 1.7 Hz, 1H), 4.10–4.01 (m, 2H), 3.80–3.71 (m, 2H), 1.81
(s, 3H); 13C{1H} NMR (100 MHz, CDCl3): δ 141.2, 135.1, 129.6, 128.1, 127.3, 120.7, 108.9,
64.4, 25.4. The spectroscopic data were in agreement with literature values.11
10
11
12
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21
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23
24
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2-(2-Methyl-1,3-dioxolan-2-yl)benzaldehyde (24). To a stirred solution of bromide 23 (1.00 g,
4.11 mmol) in THF (20 mL) at −78 °C was added n-BuLi (4.74 mL, 6.17 mmol, 1.3 M in
cyclohexane) dropwise over a period of 15 min. The mixture was stirred at −78 °C for 30 min
then anhydrous DMF (1.27 mL, 16.5 mmol) was added. The reaction mixture was gradually
warmed to rt and stirred for a further 1 h. Sat. aq. NH4Cl (10 mL) was added and the layers
were separated. The aqueous layer was extracted with EtOAc (60 mL × 3) and the combined
organic extracts were washed with brine (60 mL), dried over anhydrous MgSO4, filtered and
concentrated in vacuo. Purification by flash column chromatography (petroleum ether-EtOAc
4:1) afforded title compound 24 (672 mg, 3.50 mmol, 85%) as a pale yellow oil; Rf = 0.26
1
(petroleum ether-EtOAc 9:1); IR (neat) νmax 2990, 2892, 1687, 1189 cm-1; H NMR (400
MHz, CDCl3): δ 10.69 (s, 1H), 7.89 (d, J = 7.5 Hz, 1H), 7.65 (d, J = 7.8 Hz, 1H), 7.51 (td, J =
7.6, 1.2 Hz, 1H), 7.39 (t, J = 7.6 Hz, 1H), 4.08–4.00 (m, 2H), 3.76–3.68 (m, 2H), 1.79 (s, 3H);
13C{1H} NMR (100 MHz, CDCl3): δ 193.1, 145.3, 134.2, 133.2, 128.5, 128.2, 126.4, 108.7,
64.5, 29.5; HRMS (ESI/Q-TOF) m/z: [M+Na]+ calcd. for C11H12NaO3, 215.0679; found,
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215.0680. Full characterisation data provided as the synthesis of 24 has been reported in
5
6
literature without full characterisation data.26-28
7
8
9
2-(2-(1,3-dithian-2-yl)phenyl)-2-methyl-1,3-dioxolane
(18)
and
1-(2-(1,3-dithian-2-
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
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26
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60
yl)phenyl)ethan-1-one (25). To a stirred solution of aldehyde 24 (300 mg, 1.56 mmol) in THF
(30 mL) at rt was added 1,3-propanedithiol (204 µL, 2.03 mmol) followed by the addition of
Amberlyst® (800 mg) in one portion. The reaction mixture was stirred at rt for 50 min then
filtered through a pad of Celite® and washed with CH2Cl2 (20 mL). The filtrate and washings
were combined and concentrated in vacuo. Purification by flash column chromatography
(petroleum ether-Et2O 9:1) afforded title compounds 18 (366 mg, 1.30 mmol, 83%) as a
colourless oil and 25 (18 mg, 75.5 µmol, 5%) as a colourless solid; Compound 18: Rf = 0.29
(petroleum ether-Et2O 4:1); IR (neat) νmax 2988, 2928, 2895, 1193 cm-1; 1H NMR (400 MHz,
CDCl3): δ 7.73 (dd, J = 7.8, 1.5 Hz, 1H), 7.55 (dd, J = 7.8, 1.4 Hz, 1H), 7.30 (td, J = 7.4, 1.7
Hz, 1H), 7.24 (td, J = 7.5, 1.4 Hz, 1H), 6.05 (s, 1H), 4.10–4.01 (m, 2H), 3.82–3.74 (m, 2H),
3.16–3.08 (m, 2H), 2.91–2.85 (m, 2H), 2.22–2.15 (m, 1H), 2.00–1.92 (m, 1H), 1.77 (s, 3H);
13C{1H} NMR (100 MHz, CDCl3): δ 139.4, 137.0, 130.6, 128.9, 128.2, 126.5, 109.1, 64.5, 48.4,
32.7, 27.6, 25.6; HRMS (ESI/Q-TOF) m/z: [M+Na]+ calcd. for C14H18NaO2S2, 305.0640;
found, 305.0642. Compound 25: Rf = 0.10 (petroleum ether-Et2O 4:1); m.p. 118.5–123.3 °C;
IR (neat) νmax 2900, 1718, 1678, 1248 cm-1; 1H NMR (400 MHz, CDCl3): δ 7.80 (dd, J = 7.8,
1.2 Hz, 1H), 7.63 (dd, J = 7.8, 1.3 Hz, 1H), 7.48 (td, J = 7.6, 1.3 Hz, 1H), 7.36 (td, J = 7.6, 1.2
Hz, 1H), 6.08 (s, 1H), 3.14–3.07 (m, 2H), 2.91–2.86 (m, 2H), 2.63 (s, 3H), 2.20–2.14 (m, 1H),
13
1.97–1.89 (m, 1H); C{1H} NMR (100 MHz, CDCl3): δ 202.1, 138.3, 136.9, 132.2, 130.0,
129.0, 128.1, 47.4, 32.5, 30.2, 25.4; HRMS (ESI/Q-TOF) m/z: [M+Na]+ calcd. for
C12H14NaOS2, 261.0378; found, 261.0386.
Synthesis of the core
5
of epicoccolide A/epicocconigrone A. 3-(2-
(ethoxymethoxy)phenyl)spiro[isochromane-4,2'-[1,3]dithian]-1-one (28). To a stirred solution
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of diisopropylamine (231 μL, 1.65 mmol) in THF (5 mL) at −78 °C was added n-BuLi (1.03
mL, 1.65 mmol, 1.6 M in hexanes) dropwise over a period of 3 min. The mixture was stirred
at −78 °C for 30 min then a solution of 1,3-dithiane 2619-22 (350 mg, 1.38 mmol) in THF (2 mL)
was added dropwise over a period of 3 min. The mixture was stirred at −78 °C for 20 min then
a solution of benzaldehyde 2724 (298 mg, 1.65 mmol) in THF (2 mL) was added dropwise over
3 min. The reaction mixture was stirred at −78 °C for 10 min then gradually warmed to rt and
stirred for a further 30 min. Sat. aq. NH4Cl (5 mL) was added and the layers were separated.
The aqueous layer was extracted with EtOAc (30 mL × 3) and the combined organic extracts
were washed with sat. aq. NaHCO3 (30 mL) and brine (30 mL), dried over anhydrous MgSO4,
filtered and concentrated in vacuo. Purification by flash column chromatography (petroleum
ether-EtOAc 4:1) afforded title compound 28 (461 mg, 1.15 mmol, 83%) as a colourless solid;
Rf = 0.17 (petroleum ether-EtOAc 4:1); m.p. 83.0–87.5 °C; IR (neat) νmax 3073, 2978, 2905,
1718, 1236, 1103 cm-1; 1H NMR (400 MHz, CDCl3): δ 8.15 (dd, J = 7.7, 1.2 Hz, 1H), 8.08 (d,
J = 7.7 Hz, 1H), 7.68 (td, J = 7.6, 1.3 Hz, 1H), 7.49 (td, J = 7.6, 0.8 Hz, 1H), 7.42 (d, J = 7.4 Hz,
1H), 7.29 (ddd, J = 8.7, 7.1, 1.6 Hz, 1H), 7.20 (dd, J = 8.3, 0.7 Hz, 1H), 6.91 (t, J = 7.2 Hz,
1H), 6.47 (s, 1H), 5.24 (s, 2H), 3.73 (qd, J = 7.0, 2.8 Hz, 2H), 2.91 (ddd, J = 14.2, 10.3, 4.0 Hz,
1H), 2.64–2.58 (m, 3H), 1.99–1.84 (m, 2H), 1.22 (t, J = 7.1 Hz, 3H); 13C{1H} NMR (100 MHz,
CDCl3): δ 164.4, 156.1, 143.1, 134.4, 130.65, 130.57, 129.8, 129.0, 126.5, 125.0, 124.8, 121.5,
114.4, 93.8, 77.2, 64.6, 52.0, 27.6, 27.5, 23.4, 15.2; HRMS (ESI/Q-TOF) m/z: [M+Na]+ calcd.
for C21H22NaO4S2, 425.0852; found, 425.0857.
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3-(2-(Ethoxymethoxy)phenyl)spiro[isochromane-4,2'-[1,3]dithian]-1-ol (29a/b). To a stirred
solution of lactone 28 (300 mg, 0.75 mmol) in THF (7.5 mL) at −78 °C was added DIBAL-H
(970 μL, 0.97 mmol, 1 M in toluene) dropwise. The reaction mixture was stirred at −78 °C for
1 h then quenched with MeOH (2 mL). The resultant mixture was gradually warmed to rt then
filtered through a pad of Celite® and washed with EtOAc (50 mL). The filtrate and washings
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were combined and washed with H2O (25 mL) and brine (25 mL), dried over anhydrous MgSO4,
filtered and concentrated in vacuo. Purification by flash column chromatography (petroleum
ether-EtOAc 4:1) afforded title compounds 29a and 29b (220 mg, 0.54 mmol, 73%) as a 4:1
mixture of inseparable diastereomers, as a colourless solid; Rf = 0.17 (petroleum ether-EtOAc
4:1); m.p. 57–60 °C; IR (neat) νmax 3406, 2915, 1491, 1231 cm-1; 1H NMR (400 MHz, CDCl3):
δ 8.28 (dd, J = 8.0, 0.8 Hz, 0.8H), 8.24* (dd, J = 8.0, 1.2 Hz, 0.2H), 8.13 (dd, J = 7.8, 1.6 Hz,
0.8H), 8.04* (dd, J = 7.7, 1.4 Hz, 0.2H), 7.46–7.07 (m, 6H), 6.24 (s, 0.8H), 6.12 (d, J = 3.8 Hz,
0.8H), 6.08* (d, J = 9.0 Hz, 0.2H), 5.83* (s, 0.2H), 5.30 (s, 2H), 3.81–3.74 (m, 2H), 2.70–2.64*
(m, 0.2H), 2.50–2.39 (m, 3H), 2.27 (ddd, J = 14.6, 10.9, 4.0 Hz, 0.8H), 1.93–1.83 (m, 2H),
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13
1.30* (t, J = 7.1 Hz, 0.6H), 1.24 (t, J = 7.1 Hz, 2.4H); C{1H} NMR (100 MHz, CDCl3): δ
155.7, 155.4*, 139.5*, 139.1, 134.9, 131.1, 131.0*, 129.9, 129.7*, 129.5, 128.7, 128.6*, 128.4*,
128.3, 127.6, 127.5*, 127.1, 125.7*, 121.7*, 121.6, 114.4, 113.9*, 94.9*, 93.5*, 93.4, 92.2,
70.1, 64.5, 60.5*, 52.4*, 52.1, 29.2*, 29.1, 27.7*, 27.4, 23.8, 15.2, 14.3*; HRMS (ESI/Q-TOF)
m/z: [M+Na]+ calcd. for C21H24NaO4S2, 427.1008; found, 427.0999.* = denotes the minor
diastereomer.
2H,10H-spiro[[1',3']dithiane-2',9-[2,10]epoxydibenzo[b,f]oxocine] (30). To a stirred solution
of EOM ether 29a/b (178 mg, 0.44 mmol) in CH2Cl2 (2 mL) at rt was added freshly prepared
NaHSO4·SiO2 (159 mg, 0.88 mmol). The reaction mixture was stirred at rt for 2 h then filtered
through a pad of SiO2 and washed with CH2Cl2 (20 mL). The filtrate and washings were
combined and concentrated in vacuo. Purification by flash column chromatography (petroleum
ether-EtOAc 9:1) afforded title compound 30 (102 mg, 0.31 mmol, 71%) as a pale brown solid;
Rf = 0.23 (petroleum ether-EtOAc 4:1); m.p. 223.2–226.5 °C; IR (neat) νmax 2981, 2893, 1484,
1226 cm-1; 1H NMR (400 MHz, CDCl3): δ 7.90 (dd, J = 7.5, 1.3 Hz, 1H), 7.38 (dd, J = 7.8, 1.4
Hz, 1H), 7.39–7.29 (m, 3H), 7.16 (td, J = 7.8, 1.6 Hz, 1H), 6.88 (td, J = 7.6, 1.2 Hz, 1H), 6.78
(dd, J = 8.3, 1.1 Hz, 1H), 6.38 (s, 1H), 5.48 (s, 1H), 3.38–3.25 (m, 2H), 3.01–2.81 (m, 2H),
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2.31–2.24 (m, 1H), 2.18–2.07 (m, 1H); C{1H} NMR (100 MHz, CDCl3): δ 149.9, 134.9,
5
6
132.0, 130.6, 130.1, 129.6, 128.9, 128.0, 127.3, 119.9, 119.6, 116.9, 92.4, 70.3, 55.2, 29.2, 27.9,
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24.2; HRMS (ESI/Q-TOF) m/z: [M+Na]+ calcd. for C18H16NaO2S2, 351.0484; found, 351.0475.
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2H-2,10-epoxydibenzo[b,f]oxocin-9(10H)-one (12). To a stirred solution of dithiane 30 (93 mg,
0.28 mmol) in THF-H2O (17:3 v/v, 2.0 mL) at 0 °C was added a suspension of HgO (42 mg,
0.19 mmol) in THF-H2O (17:3 v/v, 2.0 mL) followed by the addition of BF3·Et2O (23 µL, 0.19
mmol). The reaction mixture was gradually warmed to rt and stirred for 1 h. The resultant
mixture was diluted with CH2Cl2 (15 mL) then filtered over a pad of Celite® and washed with
CH2Cl2 (15 mL). The filtrate and washings were combined and diluted with H2O (15 mL). The
layers were separated and the aqueous layer was extracted with CH2Cl2 (20 mL × 3). The
combined organic extracts were washed with H2O (15 mL), dried over MgSO4 and
concentrated in vacuo. Purification by flash column chromatography (petroleum ether-EtOAc
9:1) afforded the title compound 12 (50 mg, 0.21 mmol, 74%) as a colourless solid; Rf = 0.20
(petroleum ether-EtOAc 19:1); m.p. 115–117 °C (lit. 115–116 °C)8; IR (neat) νmax 2919, 1697,
1587, 1485, 1291 cm-1; 1H NMR (400 MHz, CDCl3): δ 7.99 (d, J = 7.9 Hz, 1H), 7.66 (t, J =
7.6 Hz, 1H), 7.52–7.46 (m, 2H), 7.23–7.19 (m, 2H), 6.93 (td, J = 7.6, 0.9 Hz, 1H), 6.83 (dd, J
13
= 8.6, 0.9 Hz, 1H), 6.48 (s, 1H), 5.34 (s, 1H); C{1H} NMR (100 MHz, CDCl3): δ 192.3,
149.3, 137.7, 135.0, 130.3, 130.2, 127.1, 126.9, 126.4, 126.3, 121.9, 117.4, 117.3, 93.3, 75.2;
HRMS (ESI/Q-TOF) m/z: [M+Na]+ calcd. for C15H10NaO3, 261.0522; found 261.0517. The
spectroscopic data were in agreement with literature values.8
Elaboration
towards
integrastatin
core
5.
3-(2-(ethoxymethoxy)phenyl)-3-
stirred solution of
methylspiro[isochromane-4,2'-[1,3]dithian]-1-one (31). To
a
diisopropylamine (331 μL, 2.36 mmol) in THF (7 mL) at −78 °C was added n-BuLi (1.48 mL,
2.36 mmol, 1.6 M in hexanes) dropwise over a period of 5 min. The reaction mixture was
stirred at −78 °C for 30 min then a solution of 1,3-dithiane 2619-22 (500 mg, 1.97 mmol) in THF
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(2 mL) was added dropwise. The mixture was stirred at −78 °C for 20 min then a solution of
acetophenone 1910 (458 mg, 2.36 mmol) in THF (2 mL) was added. The reaction mixture was
stirred at −78 °C for 10 min then gradually warmed to rt and stirred for a further 2 h. Sat. aq.
NH4Cl (5 mL) was added and the layers were separated. The aqueous layer was extracted with
EtOAc (30 mL × 3) and the combined organic extracts were washed with sat. aq. NaHCO3 (30
mL), H2O (30 mL) and brine (30 mL), dried over anhydrous MgSO4, filtered and concentrated
in vacuo. Purification by flash column chromatography (petroleum ether-EtOAc 9:1) afforded
title compound 31 (98 mg, 0.24 mmol, 12%) as a colourless oil; Rf = 0.43 (petroleum ether-
EtOAc 4:1); IR (neat) νmax 2970, 2900, 1719, 1597, 1487, 1227, 1105 cm-1; 1H NMR (400
MHz, 65 °C, (CD3)2SO): δ 8.09 (d, J = 7.8 Hz, 1H), 7.90 (dd, J = 7.7, 0.8 Hz, 1H), 7.73 (td, J
= 7.6, 1.1 Hz, 1H), 7.65 (d, J = 7.8 Hz, 1H), 7.48 (t, J = 7.9 Hz, 1H), 7.29 (td, J = 7.8, 1.4 Hz,
1H), 7.16 (d, J = 8.3 Hz, 1H), 6.92 (t, J = 7.6 Hz, 1H), 5.23 (ABq, ΔδAB = 0.023, JAB = 6.6 Hz,
2H), 3.73 (q, J = 7.0 Hz, 2H), 2.78–2.71 (m, 1H), 2.65–2.55 (m, 2H), 2.41–2.34 (m, 1H), 2.06
(s, 3H), 1.84–1.69 (m, 2H), 1.17 (t, J = 7.1 Hz, 3H); 13C{1H} NMR (100 MHz, 65 °C,
(CD3)2SO): δ 162.5, 155.4, 143.2, 133.5, 131.0, 129.6, 129.3, 128.0, 127.1, 126.9*, 125.8,
125.4*, 124.1, 121.0*, 119.8, 115.4, 113.6*, 93.3, 92.7*, 88.5, 63.8, 63.5*, 59.3, 27.3, 26.0,
24.4*, 23.9, 21.8, 14.6; HRMS (ESI/Q-TOF) m/z: [M+Na]+ calcd. for C22H24NaO4S2, 439.1008;
found, 439.1015. NMR spectroscopic data recorded at 65 °C to obtain improved resolution of
signals. * = denotes the minor rotameric isomer.
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3-(2-(ethoxymethoxy)phenyl)-1,3-dimethylspiro[isochromane-4,2'-[1,3]dithian]-1-ol (32). To
a stirred solution of lactone 31 (100 mg, 0.24 mmol) in THF (4 mL) at −78 °C was added MeLi
(109 μL, 0.29 mmol, 2.65 M in dimethoxymethane) dropwise. The reaction mixture was stirred
at −78 °C for 2 h then quenched with sat. aq. NH4Cl (2 mL). The resultant mixture was
gradually warmed to rt and stirred for a further 30 min. The layers were separated and the
aqueous layer was extracted with EtOAc (20 mL × 3). The combined organic extracts were
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washed with brine (20 mL), dried over anhydrous MgSO4, filtered and concentrated in vacuo.
Purification by flash column chromatography (petroleum ether-EtOAc 4:1) afforded title
compound 32 (49 mg, 0.11 mmol, 47%) as a colourless oil; Rf = 0.40 (petroleum ether-EtOAc
1
7:3); IR νmax(neat)/cm-1 3439, 2975, 2912, 1690, 1595, 1485, 1446, 1297, 1259, 1218; H
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NMR (400 MHz, 105 °C, (CD3)2SO): δ 7.62–7.59 (m, 1H), 7.15–7.11 (m, 2H), 7.02–6.91 (m,
4H), 6.61–6.56 (m, 1H), 5.22 (s, 2H), 3.76–3.66 (m, 2H), 2.49–2.35 (m, 4H), 2.25 (s, 3H), 1.98
(s, 3H), 1.72–1.67 (m, 2H), 1.20 (t, J = 7.1 Hz, 3H); C{1H} NMR (100 MHz, 105 °C,
13
(CD3)2SO): δ 167.5, 153.6, 152.9*, 140.5, 136.4*, 136.1*, 132.6, 130.5*, 130.2, 129.5, 129.1*,
128.9, 128.8, 127.4*, 127.2, 126.7*, 126.1, 125.3*, 120.9*, 120.3, 115.3*, 113.7*, 113.4, 109.7,
92.8*, 92.6, 89.4, 63.4, 62.3*, 52.1, 31.9, 30.7, 28.7, 24.0, 21.5, 14.4, 14.3*; HRMS (ESI/Q-
TOF) m/z: [M+Na]+ calcd. for C23H28NaO4S2, 455.1321; found, 455.1321. NMR spectroscopic
data recorded at 105 °C to obtain improved resolution of signals. * = denotes the minor
rotameric isomer.
Revised synthesis of integrastatin core 5. 1-Bromo-2-(ethoxymethoxy)benzene (38). To a
stirred solution of 2-bromophenol (37) (600 mg, 3.47 mmol) in DMF (12 mL) at rt was added
Cs2CO3 (2.26 g, 6.93 mmol). The mixture was cooled to 0 °C then EOMCl (643 μL, 6.93
mmol) was added dropwise. The reaction mixture was gradually warmed to rt and stirred for a
further 6 h. The mixture was then diluted with H2O (10 mL) and Et2O (50 mL) and the layers
were separated. The aqueous layer was extracted with Et2O (50 mL × 3) and the combined
organic extracts were washed with H2O (50 mL × 3) and brine (50 mL), dried over anhydrous
MgSO4, filtered and concentrated in vacuo. Purification by flash column chromatography
(petroleum ether-Et2O 97:3) afforded title compound 38 (681 mg, 2.95 mmol, 85%) as a
colourless oil; Rf = 0.43 (petroleum ether-EtOAc 19:1); IR (neat) νmax 2975, 2815, 1579, 1278,
1231 cm-1; H NMR (400 MHz, CDCl3): δ 7.54 (dd, J = 7.9, 1.6 Hz, 1H), 7.25 (ddd, J = 8.6,
1
7.5, 1.5 Hz, 1H), 7.18 (dd, J = 8.3, 1.5 Hz, 1H), 6.88 (td, J = 7.6, 1.4 Hz, 1H), 5.30 (s, 2H),
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3.79 (q, J = 7.0 Hz, 2H), 1.23 (t, J = 7.0 Hz, 3H); 13C{1H} NMR (100 MHz, CDCl3): δ 154.0,
133.5, 128.5, 123.1, 116.4, 113.0, 93.9, 64.8, 15.2; HRMS (ESI/Q-TOF) m/z: [M+Na]+ calcd.
for C9H11BrNaO2, 252.9835; found, 252.9829.
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Methyl 2-(2-(ethoxymethoxy)phenyl)-2-hydroxypropanoate (39). To a stirred solution of
bromide 38 (1.48 g, 6.40 mmol) in THF (20 mL) at −78 °C was added n-BuLi (6.40 mL,
8.33 mmol, 1.3 M in cyclohexane) dropwise. The mixture was stirred at −78 °C for 15 min
then a solution of methyl pyruvate (1.16 mL, 12.8 mmol) in THF (5 mL) was added dropwise.
The reaction mixture was stirred at −78 °C for 30 min then gradually warmed to rt and stirred
for a further 1 h. Sat. aq. NH4Cl (10 mL) was added and the layers were separated. The aqueous
layer was extracted with EtOAc (50 mL × 3) and the combined organic extracts were washed
with H2O (50 mL) and brine (50 mL), dried over anhydrous MgSO4, filtered and concentrated
in vacuo. Purification by flash column chromatography (petroleum ether-EtOAc 7:3) afforded
title compound 39 (1.17 g, 4.61 mmol, 72%) as a pale yellow oil; Rf = 0.51 (petroleum ether-
1
EtOAc 7:3); IR (neat) νmax 3476, 3096, 2979, 1737, 1487, 1102 cm-1; H NMR (400 MHz,
CDCl3): δ 7.46 (dd, J = 7.8, 1.6 Hz, 1H), 7.28 (ddd, J = 8.6, 7.6, 1.5 Hz, 1H), 7.14 (dd, J = 8.3,
1.0 Hz, 1H), 7.03 (td, J = 7.5, 1.0 Hz, 1H), 5.20 (ABq, ΔδAB = 0.033, JAB = 6.8 Hz, 2H), 4.00
(s, 1H), 3.75–3.62 (m, 2H), 3.69 (s, 3H), 1.79 (s, 3H), 1.21 (t, J = 7.1 Hz, 3H); 13C{1H} NMR
(100 MHz, CDCl3): δ 176.6, 154.8, 131.6, 129.6, 126.4, 121.9, 114.6, 93.4, 74.2, 64.7, 52.7,
24.5, 15.1; HRMS (ESI/Q-TOF) m/z: [M+Na]+ calcd. for C13H18NaO5, 277.1046; found,
277.1054.
Methyl 2-(ethoxymethoxy)-2-(2-(ethoxymethoxy)phenyl)propanoate (40). NaH (733 mg,
18.3 mmol, 60% dispersion in mineral oil) was rinsed three times with hexanes and suspended
in THF (5 mL). To the stirred suspension at 0 °C was added a solution of tertiary alcohol 39
(585 mg, 2.30 mmol) in THF (2.3 mL) dropwise. The mixture was gradually warmed to rt and
stirred for 30 min. The reaction mixture was then cooled to 0 °C and EOMCl (425 μL,
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4.58 mmol) was added dropwise. The mixture was gradually warmed to rt and stirred for 4 h
then cooled to 0 °C. H2O (5 mL) was added and the resultant mixture was gradually warmed
to rt then the layers were separated. The aqueous layer was extracted with Et2O (50 mL × 3)
and the combined organic extracts were washed with H2O (50 mL) and brine (50 mL), dried
over anhydrous MgSO4, filtered and concentrated in vacuo. Purification by flash column
chromatography (petroleum ether-EtOAc 5:1) afforded title compound 40 (582 mg, 1.86 mmol,
81%) as a colourless oil; Rf = 0.34 (petroleum ether-EtOAc 9:1); IR (film) νmax 2975, 2882,
1739, 1487 cm-1; 1H NMR (400 MHz, CDCl3): δ 7.58 (dd, J = 7.8, 1.6 Hz, 1H), 7.27 (td, J =
7.8, 1.4 Hz, 1H), 7.16 (dd, J = 8.2, 1.0 Hz, 1H), 7.04 (td, J = 7.5, 1.2 Hz, 1H), 5.15 (ABq, ΔδAB
= 0.017, JAB = 6.8 Hz, 2H), 4.86 (ABq, ΔδAB = 0.016, JAB = 7.3 Hz, 2H), 3.72–3.58 (m, 4H),
3.68 (s, 3H), 1.75 (s, 3H), 1.22 (t, J = 7.1 Hz, 3H), 1.16 (t, J = 7.1 Hz, 3H); 13C{1H} NMR (100
MHz, CDCl3): δ 173.3, 154.2, 131.2, 129.1, 126.3, 121.7, 114.4, 93.4, 90.7, 78.7, 64.4, 63.8,
52.3, 23.5, 15.2, 15.1; HRMS (ESI/Q-TOF) m/z: [M+Na]+ calcd. for C16H24NaO6, 335.1465;
found, 335.1467.
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2-(Ethoxymethoxy)-2-(2-(ethoxymethoxy)phenyl)propanal (33). To a stirred solution of ester
40 (200 mg, 0.64 mmol) in CH2Cl2 (2 mL) at −78 °C was added DIBAL-H (1.30 mL,
1.30 mmol, 1 M in toluene) dropwise. The reaction mixture was gradually warmed to rt and
stirred for a further 1 h then quenched with MeOH (2 mL). The resultant mixture was filtered
through a pad of Celite® and washed with CH2Cl2 (10 mL). The filtrate and washings were
combined and diluted with H2O (10 mL). The layers were separated and the aqueous layer was
extracted with CH2Cl2 (20 mL × 3). The combined organic extracts were washed with brine
(20 mL), dried over anhydrous MgSO4, filtered and concentrated in vacuo to give alcohol,
which was used directly in the next step without further purification.
To a stirred solution of crude alcohol and NaHCO3 (538 mg, 6.40 mmol) in CH2Cl2 (5 mL) at
rt was added DMP (271 mg, 0.64 mmol). The reaction mixture was stirred for 3 h then
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quenched with sat. aq. Na2S2O3 (3 mL). The layers were separated and the aqueous layer was
extracted with CH2Cl2 (20 mL × 3). The combined organic extracts were dried over anhydrous
MgSO4, filtered and concentrated in vacuo. Purification by flash column chromatography
(petroleum ether-EtOAc 9:1) afforded title compound 33 (134 mg, 0.47 mmol, 74% over two
steps) as a pale yellow oil; Rf = 0.34 (petroleum ether-EtOAc 9:1); IR (neat) νmax 2977, 2886,
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1735, 1487 cm-1; H NMR (400 MHz, CDCl3): δ 9.66 (s, 1H), 7.55 (dd, J = 7.8, 1.7 Hz, 1H),
7.29 (ddd, J = 8.3, 7.4, 1.7 Hz, 1H), 7.16 (dd, J = 8.3, 1.2 Hz, 1H), 7.05 (td, J = 7.5, 1.2 Hz,
1H), 5.16 (s, 2H), 4.74 (ABq, ΔδAB = 0.027, JAB = 7.4 Hz, 2H), 3.71–3.51 (m, 4H), 1.64 (s, 3H),
1.20 (t, J = 7.1 Hz, 3H), 1.13 (t, J = 7.1 Hz, 3H); 13C{1H} NMR (100 MHz, CDCl3): δ 199.0,
154.1, 129.9, 128.7, 127.9, 121.9, 114.4, 93.1, 90.4, 81.5, 64.7, 63.6, 20.1, 15.1, 15.0; HRMS
(ESI/Q-TOF) m/z: [M+Na]+ calcd. for C15H22NaO5, 305.1359; found, 305.1363.
2-(Ethoxymethoxy)-2-(2-(ethoxymethoxy)phenyl)-1-(2-(2-methyl-1,3-dioxolan-2-yl)phenyl)
propan-1-ol (35). To a stirred solution of bromide 23 (97 mg, 0.40 mmol) in THF (2 mL) at
−78 °C was added n-BuLi (520 µL, 0.40 mmol, 1.3 M in cyclohexane) dropwise. The mixture
was stirred at −78 °C for 20 min then a solution of aldehyde 33 (113 mg, 0.40 mmol) in THF
(1 mL) was added dropwise. The reaction mixture was gradually warmed to rt and stirred for
1 h then quenched with sat. aq. NH4Cl (1 mL). The layers were separated and the aqueous layer
was extracted with EtOAc (10 mL × 3). The combined organic extracts were washed with brine
(10 mL), dried over anhydrous MgSO4, filtered and concentrated in vacuo. Purification by flash
column chromatography (petroleum ether-EtOAc 7:3) afforded title compound 35 (148 mg,
0.33 mmol, 83%), as a 4:1 mixture of inseparable diastereomers, obtained as a colourless oil;
Rf = 0.14 (petroleum ether-EtOAc 4:1); IR (neat) νmax 3509, 2975, 2937, 2879, 1485, 1222 cm-1;
1H NMR (400 MHz, CDCl3): δ 8.31* (dd, J = 7.9, 1.4 Hz, 0.2H), 7.70* (dd, J = 7.8, 1.6 Hz,
0.2H), 7.64* (dd, J =7.9, 1.5 Hz, 0.2H), 7.59 (dd, J = 7.7, 1.6 Hz, 0.8H), 7.45 (dd, J = 7.7,
1.4 Hz, 0.8H), 7.40–7.26 (m, 3H), 7.24–7.10 (m, 2H), 6.99–6.94 (m, 0.8H), 5.94 (d, J = 4.5
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Hz, 0.8H), 5.90* (d, J = 7.3 Hz, 0.2H), 5.35* (ABq, ΔδAB = 0.014, JAB = 7.2 Hz, 0.4H), 5.25
(ABq, ΔδAB = 0.050, JAB = 7.1 Hz, 1.6H), 4.97* (ABq, ΔδAB = 0.086, JAB = 7.0 Hz, 0.4H), 4.86
(ABq, ΔδAB = 0.018, JAB = 7.0 Hz, 1.6H), 4.12–3.75 (m, 6.4H), 3.68–3.57 (m, 1.6H), 1.95 (s,
2.4H), 1.81* (s, 0.6H), 1.78 (s, 2.4H), 1.69* (s, 0.6H), 1.32* (t, J = 7.1 Hz, 0.6H), 1.31 (t, J =
7.1 Hz, 2.4H), 1.29* (t, J = 7.1 Hz, 0.6H), 1.26 (t, J = 7.1 Hz, 2.4H); 13C{1H} NMR (100 MHz,
CDCl3): δ 156.1, 155.4*, 141.34*, 141.28, 139.6*, 138.7, 130.8*, 130.5, 130.04*, 130.02,
129.2*, 129.0, 128.9*, 127.9*, 127.2, 127.1, 125.9, 125.8*, 121.4*, 121.3, 115.2*, 115.0, 109.6,
109.4, 93.4, 93.1*, 91.5*, 90.7, 84.9, 84.7*, 74.8, 72.7*, 64.6*, 64.5, 64.2*, 64.14*, 64.12*,
64.07, 63.9, 63.8, 28.4*, 28.2, 23.5, 22.1*, 15.3, 15.2*, 15.1; HRMS (ESI/Q-TOF) m/z:
[M+Na]+ calcd. for C25H34NaO7, 469.2197; found, 469.2198. * = denotes the minor
diastereomer.
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2-(Ethoxymethoxy)-2-(2-(ethoxymethoxy)phenyl)-1-(2-(2-methyl-1,3-dioxolan-2-
yl)phenyl)propan-1-one (36). To a stirred solution of secondary alcohol 35 (148 mg, 0.33 mmol)
and NaHCO3 (278 mg, 3.31 mmol) in CH2Cl2 (3 mL) at rt was added DMP (211 mg, 0.50
mmol) portionwise. The reaction mixture was stirred for 4 h then quenched with
sat. aq. Na2S2O3 (1 mL). The resultant mixture was stirred for a further 30 min then the layers
were separated. The aqueous layer was extracted with CH2Cl2 (20 mL × 3) and the combined
organic extracts were dried over anhydrous MgSO4, filtered and concentrated in vacuo.
Purification by flash column chromatography (petroleum ether-EtOAc 9:1) afforded title
compound 36 (112 mg, 0.25 mmol, 76%) as a yellow oil; Rf = 0.28 (petroleum ether-EtOAc
4:1); IR (neat) νmax 2975, 2936, 2880, 1701, 1487, 1226 cm-1; 1H NMR (400 MHz, CDCl3): δ
7.57 (dd, J = 8.2, 1.2 Hz, 1H), 7.52 (dd, J = 7.8, 1.7 Hz, 1H), 7.35–7.28 (m, 3H), 7.20 (dd, J =
8.3, 1.0 Hz, 1H), 7.15 (td, J = 7.6, 1.0 Hz, 1H), 7.01 (td, J = 7.5, 1.2 Hz, 1H), 5.16 (ABq, ΔδAB
= 0.027, JAB = 7.1 Hz, 2H), 4.70 (ABq, ΔδAB = 0.058, JAB = 7.1 Hz, 2H), 3.96–3.87 (m, 2H),
3.70–3.62 (m, 4H), 3.56–3.38 (m, 2H), 2.02 (s, 3H), 1.86 (s, 3H), 1.18 (t, J = 7.1 Hz, 3H), 1.05
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(t, J = 7.1 Hz, 3H); C{1H} NMR (100 MHz, CDCl3): δ 204.6, 155.6, 143.1, 137.1, 129.8,
129.4, 129.10, 129.06, 126.8, 126.4, 121.4, 115.3, 109.4, 93.1, 90.7, 86.3, 64.7, 64.3, 64.1,
63.7, 28.7, 23.3, 15.14, 15.12, one quaternary carbon obscured by the peak overlap at δ 129.8
ppm, also confirmed by mass spectrometry; HRMS (ESI/Q-TOF) m/z: [M+Na]+ calcd. for
C25H32NaO7, 467.2040; found, 467.2033.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
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55
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2,10-Dimethyl-2H-2,10-epoxydibenzo[b,f]oxocin-9(10H)-one (5). To a stirred solution of
EOM ether 36 (50 mg, 0.11 mmol) in MeOH (2 mL) at rt was added p-TSA·H2O (11 mg, 56
µmol). The reaction mixture was heated at 60 °C for 3 h then cooled to rt. The resultant mixture
was diluted with H2O (5 mL) and EtOAc (5 mL) then the layers were separated. The aqueous
layer was extracted with EtOAc (10 mL × 3) and the combined organic extracts were washed
with brine (10 mL), dried over anhydrous MgSO4, filtered and concentrated in vacuo.
Purification by flash column chromatography (petroleum ether-EtOAc 19:1) afforded title
compound 5 (28 mg, 0.10 mmol, 96%) as a colourless solid; Rf = 0.51 (petroleum ether-EtOAc
9:1); m.p. 95.2–99.5 °C (lit. 104–105 °C)8; IR (neat) νmax 2921, 2851, 1693, 1600, 1482, 1266
cm-1; 1H NMR (400 MHz, CDCl3): δ 7.96 (dd, J = 7.8, 1.2 Hz, 1H), 7.61 (td, J = 7.6, 1.4 Hz,
1H), 7.52 (dd, J = 7.9, 1.1 Hz, 1H), 7.41 (td, J = 7.5, 1.0 Hz, 1H), 7.17–7.12 (m, 2H), 6.90 (td,
J = 7.6, 1.2 Hz, 1H), 6.76 (dd, J = 7.9, 1.1 Hz, 1H), 2.04 (s, 3H), 1.86 (s, 3H); 13C{1H} NMR
(100 MHz, CDCl3): δ 194.1, 150.5, 140.7, 134.7, 129.8, 129.4, 127.7, 126.4, 125.62, 125.59,
121.8, 121.5, 117.3, 97.0, 78.1, 27.1, 20.7; HRMS (ESI/Q-TOF) m/z: [M+Na]+ calcd. for
C17H14NaO3, 289.0835; found 289.0831. The spectroscopic data were in agreement with
literature values.8
Supporting Information
Copies of H and C{1H} NMR spectra of the compounds, NOESY spectra for compounds
1
13
29a/b and 32, a table of H and C{1H} NMR comparisons for compounds 5 and 12, and a
1
13
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table of conditions investigated in attempted optimisation of the umpolung alkylation of
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compounds 19 and 26.
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9
Acknowledgments
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We thank The University of Auckland for the award of a Doctoral Scholarship to J.Y.J.
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