Total synthesis of virgatolide b via exploitation of intramolecular hydrogen bonding

Article abstract of DOI:10.1021/jo5008527

A full account of the enantioselective total synthesis of virgatolide B is reported. Key features of the synthesis include an sp³-sp² Suzuki-Miyaura cross-coupling of a β-trifluoroboratoamide with an aryl bromide, regioselective intramolecular carboalkoxylation, and a 1,3-anti-selective Mukaiyama aldol reaction. Intramolecular hydrogen bonding governed the regioselectivity of the key spiroketalization step, affording the natural product as a single regioisomer.

Full text of DOI:10.1021/jo5008527

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Article
Total Synthesis of Virgatolide B via Exploitation
of Intramolecular Hydrogen Bonding
Paul A. Hume, Daniel P. Furkert, and Margaret A. Brimble
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/jo5008527 • Publication Date (Web): 16 May 2014
Downloaded from http://pubs.acs.org on May 21, 2014
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Total Synthesis of Virgatolide B via Exploitation of Intramolecular
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Hydrogen Bonding
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Paul A. Hume, Daniel. P. Furkert and Margaret A. Brimble*
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School of Chemical Sciences, University of Auckland, 23 Symonds Street, Auckland 1142,
New Zealand; Maurice Wilkins Centre for Molecular Biodiscovery
*Corresponding author: Fax +64(9)3737422; E-mail: m.brimble@auckland.ac.nz
Abstract: A full account of the enantioselective total synthesis of virgatolide B is reported.
Key features of the synthesis include an sp3-sp2 Suzuki-Miyaura cross-coupling of
a
β-trifluoroboratoamide with an aryl bromide, regioselective intramolecular
carboalkoxylation and a 1,3-anti-selective Mukaiyama aldol reaction. Intramolecular
hydrogen bonding governed the regioselectivity of the key spiroketalisation step, affording
the natural product as a single regioisomer.
Introduction
Virgatolides A-C (1-3, Figure 1) are a family of [6,6]-benzannulated spiroketals, isolated in
2011 by Che et al. during an investigation into fungal metabolites produced by the genus
Pestalotiopsis.1 During preliminary biological screening, an ethyl acetate extract of a
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fermentation culture of P. virgatula (L147) exhibited cytotoxicity towards HeLa (cervical
epithelium) cells. Separation of the constituents furnished virgatolides A-C (IC50 19.0, 22.5,
and 20.6 µM respectively) together with previously described pestaphthalides A and B
(4 and 5).2 Virgatolides A-C share a common tetracyclic core and differ only in their
stereochemistry and substitution at C-4 and C-13. The structure and relative stereochemistry
of 1 was unambiguously secured by X-ray crystallography, and the absolute stereochemistry
then determined by comparison of the CD-spectrum to those of 4 and 5. The structures of 2
and 3, including their relative and absolute stereochemistry, were established by NMR and
HRMS analysis and by comparison of their CD-spectra with 1, 4 and 5. Importantly, the
stereochemical information at C-4 and C-5 in 2 and 3 could not be directly correlated with
that of the spiroketal moiety. The absolute configuration of the spiroketal ring system in 2
and 3 was therefore assumed to be analogous to that present in 1 in view of the likely
biosynthetic connection between compounds 1-3.1 Naturally occurring [6,6]-benzannulated
spiroketals are rare, with the only other known examples being chaetoquadrins A-C,3
citreoviranol,4 demethylcitreoviranol,4 the dimeric cyandiones5 dehydrocollatolic acid,6
peniphenone A7 and the peniciketals.8 The novel molecular architecture, biological activity
and unconfirmed stereochemical assignments of 1-3 captured our interest, and we were thus
inspired to develop a synthetic approach to the virgatolides. We herein report the full details
of this synthetic undertaking.9
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Figure 1. Virgatolides A-B (1-3), and pestaphthalides A (4) and B (5).
Retrosynthetic analysis
Virgatolide B (2) was chosen as the structural prototype of the virgatolides and a synthetic
strategy was developed with the expectation that a successful synthesis would also enable
access to the remaining two congeners (Scheme 1).
Scheme 1. Retrosynthetic Analysis of Virgatolide B (2).
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Retrosynthetically, disconnection of the spiroketal ring system in virgatolide B (2) provides
ketone 6. It was postulated that intramolecular hydrogen bonding between the phthalide
carbonyl and the neighbouring phenol would result in an energetic differential between 2 and
the spiroketal regioisomer formed upon spirocyclisation of the alternate phenolic oxygen. We
hypothesized that this would favour formation of 2 via acid-catalysed equilibration of the
spiroketal core. The acyclic spiroketal precursor 7 is accessed via a diastereoselective aldol
reaction between methyl ketone 9 and aldehyde 8. Aldehyde 8 is readily available from
commercially available ethyl (S)-3-hydroxybutyrate via known chemistry.10-11
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Methyl ketone 9 contains an α-chiral β-arylated ketone side chain, a motif posing some
synthetic challenges. There are few direct methods for the construction of such subunits,12-14
which have to date been accessed by benzylation of enolates,15-16 conjugate addition of aryl
organometallics,17 Negishi cross-coupling18-20 or catalytic asymmetric hydrogenation of
α,β-unsaturated carbonyls compounds.21-24 Each of these methods suffer from non-trivial
drawbacks.12 Our synthetic strategy sought to employ methodology developed by Molander
et al.12 for the Suzuki cross-coupling of enantiomerically-enriched potassium
β-trifluoroboratoamide 10 with a suitable aryl halide coupling partner 11. The remaining
consideration was the level of substitution of the aryl halide coupling partner, i.e. whether the
phthalide moiety was fully assembled prior to cross-coupling, or whether the aryl halide
contained a suitable handle for elaboration to the phthalide at a later stage.
Results and Discussion
Attempted Preparation of a Fully Substituted Halo-Phthalide Coupling Partner
Our initial strategy sought to employ a fully substituted halo-phthalide coupling partner in the
key Suzuki cross-coupling. We therefore focussed on regioselective halogenation of
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phthalides 12-14, hoping to introduce a bromide or iodide selectively at C-6. The resulting
halide would then undergo Suzuki cross-coupling with trifluoroboratoamide 10 (Scheme 2).
Scheme 2. Proposed Coupling of Halo-Phthalide 15 with 10
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Toward that end, phthalides 12-14 were prepared from commercially available
2,4,6-trihydroxybenzoic acid 16 (Scheme 3), analogous to the work of Kitahara et al.25
Selective esterification,26 benzylation,27 and methylation followed by conversion of the
remaining hydroxyl group to the triflate provided 17 in moderate yield over four steps. Stille
cross-coupling with allyltributyltin and base-mediated isomerization to the
thermodynamically favoured E-alkene 19 completed the installation of the carbon
framework. For the purposes of our initial investigation, phthalide 20 was generated as a
racemic mixture via osmium-catalysed cis-dihydroxylation of olefin 19. EOM and TBS
protected phthalides 12 and 13 were prepared from 20. Phthalide 14 was then formed by
hydrogenolysis of the benzyl ether present in 12.
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Scheme 3. Synthesis of Phthalides 12-14
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Reagents and conditions: a) Me2SO4, K2CO3, acetone, rt, 16 h, 56%; b) BnBr, K2CO3, NaI,
acetone, reflux, 3 h, 62%; c) DIAD, PPh3, MeOH, THF, rt, 2 h, 64%; d) PhNTf2, NEt3,
CH2Cl2, reflux, 48 h, 96% e) allyltributyltin, Pd(PPh3)4, LiCl, THF, reflux, 48 h; f) t-BuOK,
THF, 40 °C, 24 h, 83% over two steps; g) OsO4, NMO, acetone-water (10:1), rt, 16 h, 90%;
h) EOMCl, DIPEA, DMAP, CH2Cl2, rt, 48 h, quant.; i) TBDMSOTf, 2,6-lutidine, CH2Cl2,
−78°C, 4 h, quant.; j) H2, Pd/C, MeOH, rt, 24 h, 89%.
Selective halogenation of phthalides 12-14 at C-6 was required to generate the correct carbon
framework upon cross-coupling with 10. However, prediction of the preferred site for
electrophilic aromatic substitution based on simple substituent-directing considerations was
challenging for these substrates. Halogenation of 12-14 was conducted with both NBS and
iodine. However, despite some literature precedent,28-29 in all cases halogenation occurred
exclusively at C-4 (Table 1). Attempted halogenation of several phthalide precursors (19, 21,
22) also proved unsuccessful, resulting in either selective halogenation at C-4 or halogenation
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at both positions leading to inseparable product mixtures. These results indicated an inherent
bias towards halogenation at C-4 which would likely be difficult to overturn.
Table 1. Attempted Synthesis of 15a-i
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Entry
Substrate
Methoda
Yield (%)
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-
23
93
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93
88
62
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82
-
24
-
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12
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A
B
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15
21
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46b
3 component mixture
aMethod A: NBS, CH2Cl2, 0 °C to rt. Method B: I2, AgO2CF3, CH2Cl2, 0 °C to rt. bRemaining
material was isolated as an inseparable mixture of 21 and monobrominated species.
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Use of a Simplified Halide Coupling Partner for the Suzuki Coupling
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Following unsuccessful efforts to achieve the synthesis of compounds 15a-i, we noted that
use of a simpler, rotationally symmetric halide coupling partner would remove the
requirement for regioselective functionalisation of the aromatic nucleus. The required
functionalisation was envisioned to be possible via iridium-catalysed CH-borylation at a later
stage.12,30-32 Attention therefore now focussed on the cross-coupling of halo-resorcinol
derivatives 25-28 with trifluoroboratoamide 10.
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Trifluoroboratoamide 10 was prepared by the method of Molander12 and the key Suzuki
cross-coupling
reaction
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resorcinol
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25-2833-34
(Table 2). Attempted cross-coupling of 10 with bromide 25 resulted in the formation of
protodeboronated amide 31, identified by NMR and HRMS (entry 1). Use of iodide 26
resulted in the formation of a complex mixture (entry 2). However, use of protected aryl
bromide 27 resulted in a pleasing 60% yield of coupled product 29, despite the
electron-rich, ortho-disubstituted nature of the coupling partner (entry 3). Low levels
(10-20%) of oxidised amide 30 were also obtained. Amide 30 co-eluted with a
catalyst-derived species and thus could not be obtained in an analytically pure form, but was
identified using a combination of NMR and HRMS. Coupling of iodide 28 with 10 afforded
amide 29 only in low yields even using extended reaction times (entry 4).
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Table 2. Suzuki Cross-Coupling of 10 and Aryl Halides 25-28.
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Entry
1
Conditions
Yield (%)
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76
25, Pd(OAc)2, RuPhos,
K2CO3, toluene-H2O,
85 °C, 3 h
26, Pd(OAc)2, RuPhos,
K2CO3, toluene-H2O,
85 °C, 19 h
27, Pd(OAc)2, RuPhos,
K2CO3, toluene-H2O,
85 °C, 3 h
28, Pd(OAc)2, RuPhos,
K2CO3, toluene-H2O,
85 °C, 22 h
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60
10
Pleased with the successful union of 10 and 27, we now sought to investigate the construction
of the spiroketal core prior to further functionalisation of the aromatic ring. Treatment of
amide 29 with methyllithium generated methyl ketone 32 in good yield (Scheme 5).35-36
Attention then turned to the key aldol reaction between 32 and aldehyde 33.
An initial investigation into Paterson-type aldol reactions ((+)-Ipc2BCl, NEt3) to effect union
of ketone 32 with aldehyde 33 provided aldol products only with moderate
diastereoselectivity (d.r.~2:1) prompting the investigation of other methods.37-38 Pleasingly,
conversion of 32 to the corresponding TMS-enol ether, followed by reaction with aldehyde
33 in a substrate-controlled Mukaiyama aldol reaction afforded 34 as a single diastereomer in
excellent yield. The stereochemistry of the newly generated chiral center was not assigned at
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this stage, since cyclisation would allow assignment of the configuration by NOESY analysis.
With the carbon framework required for the spiroketal core in place, the key spirocyclisation
process was now investigated to ascertain whether the desired spiroketalisation would be
possible on a more advanced intermediate.
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Scheme 4. Synthesis of Acetals 35 and 36
Reagents and conditions: a) MeLi, Et2O, −78 °C to 0 °C, 30 min then diisopropylamine,
AcOH, 80%; b) TMSOTf, NEt3, CH2Cl2, 0 °C, 30 min; c) 33, BF3·OEt2, CH2Cl2, −78 °C,
2 min then add silyl enol ether, 1.5 h, 82% over two steps; d) H2, Pd(OH)2/C, MeOH, rt, 1 h,
90%; e) TIPSOTf, 2,6-lutidine, CH2Cl2, −78°C, 40 min, 75%.
The PMB group in aldol product 34 was removed first, allowing formation of a cyclic acetal
that would hopefully minimize the propensity for acid-catalysed elimination to take place.
Hydrogenolysis of 34 in methanol afforded methoxy acetal 35 as a 3:1 mixture of anomers at
C-2 (Scheme 4). Fortunately, treatment of 35 with TIPSOTf afforded TIPS ether 36 as a
single diastereomer.
A survey of acidic deprotection conditions was now undertaken to effect spirocyclisation of
35 and TIPS ether 36 (Scheme 5). Unfortunately, treatment of 35 and 36 with
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NaHSO4·SiO2,39 PPTS,40 HCl, CSA, Amberlyst®-1541 or Bi(OTf)3 all failed to effect
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formation of spiroketal 37. NMR analysis revealed the formation of complex product
mixtures containing olefinic resonances, presumably resulting from acid-catalysed
elimination. Reactions in methanol generated methylated by-products likely formed via
elimination and subsequent addition of a solvent molecule. Realising that masking the ketone
as an acetal did not remove the tendency of the molecule to undergo subsequent elimination;
the deprotection sequence of the PMB and EOM groups was reversed (i.e. 34→38).
However, similar results were also obtained in this case.
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Scheme 5. Attempted Formation of Spiroketal 37.
Revised Halide Coupling Partner for the Suzuki Coupling
Although formation of spiroketal 37 from acetals 35 and 36 was unsuccessful, we were
satisfied with the success achieved in the key Suzuki cross-coupling and aldol reactions. We
therefore sought to modify the aryl halide coupling partner to allow construction of the
spiroketal core. The revised aryl bromide coupling partner 42 contains an (E)-alkene side
chain (Scheme 6). The alkene side-chain facilitates construction of the phthalide moiety by
Sharpless
asymmetric
dihydroxylation,
halogenation
and
palladium-catalysed
carboalkoxylation later in the synthesis. BOM was chosen as the desired protecting group as
it was expected to be well tolerated in the key Suzuki cross-coupling step and cleavage via
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hydrogenolysis would obviate the problems associated with the use of acid-mediated
deprotection conditions.
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Scheme 6. Synthesis of Bromide 42
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Reagents and conditions: a) Br2, 20% aq. HCl, reflux, 2 h, 99%; b) BOMCl, DIPEA, CH2Cl2,
rt, 16 h, 87%: c) DIBAL-H, CH2Cl2, −78°C to 0 °C, 20 min, 95%; d) SO3·py, DIPEA,
DMSO, 0 °C, 15 min, quant.; e) ethyltriphenylphosphonium iodide, KOtBu, 18-crown-6,
CH2Cl2, rt, 89%; f) Ru(CO)ClH(PPh3)3, toluene, reflux, 24 h, 90%.
The synthesis of aryl bromide 42 was therefore undertaken from 3,5-dihydroxybenzoic acid
39. Selective bromination43 of 39 followed by global BOM protection provided ester 40.
Reduction of 40 with DIBAL-H followed by Parikh-Doehring oxidation44 generated aldehyde
41 which underwent smooth Wittig reaction with ethyltriphenylphosphonium iodide
affording E/Z alkene 42 as an inseparable 6:1 mixture of isomers. Isomerisation to 42 was
readily achieved by subjecting the mixture to ruthenium (II) catalysis in refluxing toluene.45
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Scheme 7. Synthesis of Spiroketal 47 and Attempted Conversion to Virgatolide B (2)
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Reagents and conditions: a) Pd(OAc)2, RuPhos, K2CO3, toluene-H2O, (4:1), 85°C, 1.5 h,
55%; b) MeLi, THF, −78°C to 0°C, 30 min, 85%; c) TMSOTf, NEt3, DMAP, CH2Cl2, 0°C,
30 min; d) 33, BF3·OEt2, CH2Cl2, −78 °C, 2 min, then add silyl enol ether, −78 °C, 3 h, 58%
over two steps; e) K2OsO2(OH)4, (DHQ)2PHAL, K3Fe(CN)6, K2CO3, MeSO2NH2, t-BuOH-
H2O (1:1), 0 °C, 18 h, 90%; f) H2, Pd/C, EtOAc, rt, 4 h, 55%; g) NIS, DMF, −40 °C, 24 h,
60%; h) CO, PdCl2(PPh3)2, N2H4·H2O, K2CO3, 60°C or rt, 3 h or 24 h.
Despite the increased steric demand of 42, Suzuki coupling with 10 proceeded cleanly,
furnishing amide 43 which was readily elaborated to methyl ketone 44 (Scheme 7). 44
underwent Mukaiyama aldol reaction with aldehyde 33 furnishing aldol 45 as a single
diastereomer. Asymmetric dihydroxylation of 45 then afforded 46 as a single diastereomer by
NMR.
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Pleasingly, the BOM groups were readily removed by hydrogenolysis, allowing successful
formation of spiroketal 47 following global deprotection. Having successfully formed the
spiroketal core of the virgatolide skeleton, all that remained was to complete the installation
of the phthalide moiety. Iodination of 47 was non-selective, forming an inseparable
regioisomeric mixture of iodides 48 and 49 although we postulated that upon installation of
the carbonyl group, hydrogen-bonding would facilitate convergence to 2 via acid-catalysed
equilibration. Disappointingly however, attempted carbonylation of 48/49 to give 2 resulted
only in protodehalogenation, regenerating spiroketal 47 thus preventing construction of the
phthalide moiety.
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Revised Synthetic Strategy
Although the use of BOM groups had enabled access to the spiroketal core of virgatolide B
(2), late stage construction of the phthalide moiety had proven problematic. It was noted that
the free phenol ortho to the iodide could be contributing to the protodehalogenation observed
upon attempted carbonylation. Rather than introduce unnecessary protecting group chemistry,
it was decided to conduct the carbonylation step prior to the aldol reaction, re-ordering the
sequence of synthetic events. Critically, it was noted that carbonylation of the rotationally
symmetric aromatic nucleus prior to spiroketalisation would avoid the requirement to effect
regioselective functionalisation of the aromatic ring and hopefully prevent any
protodehalogenation taking place during the carboalkoxylation step. The intramolecular
hydrogen bonding would then govern the regioselectivity of the spiroketalisation.
Attention therefore next focussed on assembly of methyl ketone phthalide 52 (Scheme 8),
which would be converted to a silyl enol ether to effect the key Mukaiyama aldol reaction
with aldehyde 33 to provide spirocyclisation precursor 55.
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Scheme 8. Synthesis of Virgatolide B (2)
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Reagents and conditions: a) K2OsO2(OH)4, (DHQ)2PHAL, K3Fe(CN)6, K2CO3, MeSO2NH2,
t-BuOH-H2O (1:1), 0 °C to rt, 18 h, 87%; b) I2, CF3CO2Ag, 0 °C, 1, h, 72%; c) CO,
Pd(PPh3)4, DIPEA, 100°C, 18 h, 75%; d) TMSOTf, NEt3 DMAP, CH2Cl2, 0°C, 15 min;
e) 33, BF3·OEt2, CH2Cl2, −78 °C, 2 min. then 54, −78 °C, 1.5 h; f) sat. aq. K2CO3 (5 drops),
MeOH, rt, 30 min, 65% over three steps; g) H2, Pd/C, EtOAc, rt, 3 h; h) CSA, CH2Cl2, 16 h,
55% over 2 steps.
Accordingly, Sharpless asymmetric dihydroxylation46-47 of 44 using AD-mix α afforded diol
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50 in high yield as a single diastereoisomer as determined by H and C NMR analysis
(Scheme 8). Selective mono-iodination of the aromatic ring afforded iodide 51 with only
traces of the easily separable di-iodinated product being formed. The formation of a single
diastereoisomer in the asymmetric dihydroxylation was confirmed by subjecting a sample of
44 to non-selective cis-dihydroxylation followed by monoiodination. Inspection of the
13C NMR in this case clearly revealed the presence of two diastereoisomers due to the pre-
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existing chiral centre. Carbonylation of homochiral iodide 51 with concomitant
intramolecular alkoxylation48-53 afforded phthalide 52 in 75% yield. Gratifyingly, the
cyclisation process was found to be completely selective for formation of 52 over
isochromanone 53, even at the elevated temperature at which the reaction was conducted,
indicating a strong kinetic preference for formation of the five membered ring.
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Attention finally turned to the key aldol reaction to unite phthalide 52 with aldehyde 33.
Simultaneous conversion of 52 to the TMS enol ether and protection of the secondary alcohol
as a TMS ether was effected with TMSOTf. Reaction of the crude enol ether with aldehyde
33 was conducted analogously to the procedure used to construct aldol product 34 (Scheme
4). Upon completion of the reaction, the crude aldol adduct was dissolved in methanol and
treated with saturated aqueous potassium carbonate, liberating the latent alcohol
functionality. Ketone 55 was isolated in 65% yield over three steps as a single diastereomer.
Finally, global deprotection followed by equilibration with a catalytic quantity of CSA
yielded the target natural product, virgatolide B (2) in 55% over two steps. Pleasingly, the
spiroketal isomer 56 was not observed, fully consistent with our postulation that
intramolecular hydrogen-bonding would govern the spirocyclisation step. Spectroscopic data
(1H NMR, 13C NMR, and HRMS analyses) for synthetic virgatolide B (2) were in full
agreement with those reported for the natural product.1 Furthermore, the absolute
stereochemistry of naturally occurring virgatolide B was confirmed by comparison of the
optical rotation values ([α]!!" +19.1 (c 0.25 in MeOH), {lit. +25.0, (c 0.07 in MeOH)}.
Conclusion
In summary, the first total synthesis of virgatolide B (2) has been achieved in a concise
manner (16 steps longest linear sequence) confirming the stereochemical assignment of the
natural product. The carbon framework was assembled using an sp3-sp2 Suzuki Miyaura
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cross-coupling of a chiral trifluoroboratoamide and an aryl bromide, and a highly
diastereoselective 1,3-anti Mukaiyama aldol reaction. Preservation of the rotational
symmetry of the aromatic nucleus was found to be essential to circumvent problems
associated with regioselective halogenation. Hydrogen-bonding between the phthalide
carbonyl and the peri phenol was exploited to direct the regiochemistry of spiroketal
formation. The overall approach should be scalable and amenable to the construction of
analogues and the remaining members of this family of natural products.
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Experimental Section
General Procedures
Unless otherwise noted, all reactions were performed under an oxygen-free atmosphere of
nitrogen using standard techniques. Tetrahydrofuran (THF) and diethyl ether were freshly
distilled over sodium/benzophenone ketyl. CH2Cl2 and MeOH were freshly distilled from
calcium hydride. All other reagents were used as received unless otherwise noted. Yields
refer to chromatographically and spectroscopically (1H NMR) homogeneous materials, unless
otherwise stated. Reactions were monitored by thin-layer chromatography (TLC) carried out
on silica gel plates using UV light as visualizing agent and an ethanolic solution of vanillin
and ammonium molybdate and heat as developing agents. Silica gel (60, 230-400 mesh) was
used for flash column chromatography. Preparatory TLC was carried out on 500 µm,
20 × 20 cm silica gel thin layer chromatography plates. NMR spectra were recorded at room
temperature in CDCl3, CD3OD, (CD3)3CO, C6D6 or (CD3)SO solutions on either a
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spectrometer operating at 300 MHz for H nuclei and 75 MHz for 13C nuclei or a
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spectrometer operating at 400 MHz for H nuclei and 100 MHz for C nuclei. Chemical
shifts are reported in parts per million (ppm) on the δ scale and coupling constants, J, are in
hertz (Hz). Multiplicities are reported as “s” (singlet), “br s” (broad singlet), “d” (doublet),
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“dd” (doublet of doublets), “ddd” (doublet of doublets of doublets), “t” (triplet) and “m”
(multiplet). Where distinct from those due to the major rotamer, resonances due to minor
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rotamers are denoted by an asterix. H and 13C NMR resonances were assigned using a
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combination of DEPT 135, COSY, HSQC, HMBC, and NOESY spectra. Infrared (IR)
spectra were recorded as a thin film on a composite of zinc selenide and diamond crystal on a
FT-IR system transform spectrometer. Melting points are uncorrected. High-resolution mass
spectra (HRMS) were obtained using a spectrometer operating at a nominal accelerating
voltage of 70 eV or on a TOF-Q mass spectrometer.
Methyl-4-(benzyloxy)-2-hydroxy-6-methoxybenzoate
To a stirred solution of methyl-4-(benzyloxy)-2,6-dihydroxybenzoate (4.4 g, 16 mmol),
PPh3 (4.3 g, 16 mmol) and MeOH (0.98 mL, 24 mmol) in THF (120 mL) at 0 °C was added
DIAD (3.2 mL, 16 mmol) dropwise. The solution was allowed to warm to room temperature,
stirred for 2 h and quenched with sat. aq. NH4Cl (40 mL). The aqueous phase was extracted
with EtOAc (2 × 100 mL), the combined organic extracts dried over MgSO4 and concentrated
in vacuo. Purification by flash chromatography (hexanes/EtOAc 8:1) afforded the title
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compound (3.0 g, 10 mmol, 63%) as a colourless solid; m.p. 116-117 °C (lit., 106 °C)54; H
NMR (400 MHz, CDCl3): δ 12.03 (1H, s, OH), 7.44-7.35 (5H, m, Ar-H), 6.20 (1H, d, J = 2.4
Hz, Ar-H), 6.06 (1H, d, J = 2.4 Hz, Ar-H), 5.06 (2H, s, CH2), 3.92 (3H, s, CH3), 3.82 (3H, s,
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CH3); C NMR (100 MHz, CDCl3): δ 171.7 (C=O), 165.9 (C), 164.5 (C), 162.2 (C), 136.0
(C), 128.7 (Ar-CH × 2), 128.3 (Ar-CH), 127.7 (Ar-CH × 2), 96.8 (C), 94.4 (Ar-CH), 92.2
(Ar-CH), 70.2 (CH2), 56.1 (CH3), 52.2 (CH3). The spectroscopic data were in agreement with
that reported in the literature.54
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(E)-methyl 4-(benzyloxy)-6-methoxy-2-(prop-1-en-1-yl)benzoate 19
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To a solution of methyl 4-(benzyloxy)-2-methoxy-6(((trifluoromethyl)sulfonyl)oxy)-
benzoate 17 (1.9 g, 4.5 mmol) and LiCl (0.58 g, 14 mmol) in degassed THF (8 mL) was
added Pd(PPh3)4 (0.26 g, 0.2 mmol) and allyltributylstannane (1.6 mL, 5.1 mmol). The
reaction mixture was heated to 80 °C, stirred for 48 h and then allowed to cool to room
temperature. THF (40 mL) and tBuOK (1.5 g, 13 mmol) were added and the reaction mixture
heated to 45 °C with stirring for 8 h. The reaction mixture was cooled to room temperature
and diluted with EtOAc (100 mL). The layers were separated and the combined organic
extracts washed successively with aq. NH3 (25% v/v, 25 mL), aq. HCl (1 M, 25 mL) and sat.
aq. NaHCO3 (25 mL). The organic extract was dried over MgSO4 and concentrated in vacuo.
Purification by flash chromatography (hexanes/EtOAc 5:1) afforded the title compound 19
(1.2 g, 3.8 mmol, 84%) as a colourless oil; 1H NMR (400 MHz, CDCl3): δ 7.43-7.31 (5H, m,
Ar-H), 6.67 (1H, d, J = 2.0 Hz, Ar-H), 6.42 (1H, d, J = 2.0 Hz, Ar-H), 6.36 (1H, dd, J = 15.6,
1.6 Hz, CH), 6.18 (1H, dq, J = 15.6, 6.5 Hz, CH), 5.10 (2H, s, CH2), 3.89 (3H, s, CH3), 3.76
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(3H, s, CH3), 1.85 (3H, dd, J = 6.5, 1.6 Hz, CH3); C NMR (100 MHz, CDCl3): δ 168.4
(C=O), 160.3 (C), 157.8 (C), 137.7 (C), 136.4 (C), 129.0 (CH), 128.4 (Ar-CH × 2), 127.9
(CH), 127.5 (Ar-CH), 127.3 (Ar-CH × 2), 115.3 (C), 102.4 (Ar-CH), 97.9 (Ar-CH), 69.9
(CH2), 55.7 (CH3), 52.0 (CH3), 18.5 (CH3); IR (film) νmax 2950, 1724, 1599, 1427, 1260,
1155, 1097, 1039, 961, 700 cm-1; HRMS (ESI+) for C19H20O4 [M+Na]+ requires 335.1254
found 335.1240.
5-(benzyloxy)-3-(1-hydroxyethyl)-7-methoxyisobenzofuran-1(3H)-one 20
To a solution of (E)-methyl 4-(benzyloxy)-2-methoxy-6-(prop-1-en-1-yl)benzoate 19 (370
mg, 1.2 mmol) in acetone- H2O (1:1, 9.5 mL) was added NMO (150 mg, 1.3 mmol) and
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OsO4 (2.5% w/w in BuOH, 0.31 mL, 0.024 mmol) and the resultant mixture stirred at room
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temperature for 16 h. The reaction mixture was diluted with EtOAc (30 mL), the layers
separated and the organic layer washed successively with sat. aq. Na2S2O4 (5 mL), H2O (5
mL) and brine (5 mL). The organic extract was dried over MgSO4 and concentrated in vacuo.
Purification by flash chromatography (hexanes/EtOAc 1:1) afforded the title compound 20
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(310 mg, 0.98 mmol, 82%) as a white solid; m.p. 75-78 °C; H NMR (400 MHz, CDCl3):
δ 7.49-7.31 (5H, m, Ar-H), 6.64 (1H, s, Ar-H), 6.47 (1H, s, Ar-H), 5.19 (1H, d, J = 4.0 Hz,
CH), 5.08 (2H, ABq, ΔδAB = 0.02, JAB = 11.5 Hz, CH2), 4.15-4.13 (1H, m, CH), 3.85 (3H, s,
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CH3), 2.65 (1H, br s, OH), 1.23 (3H, d, J = 6.4 Hz, CH3); C NMR (100 MHz, CDCl3):
δ 168.3 (C=O), 165.6 (C), 159.4 (C), 151.9 (C), 135.5 (C), 128.6 (Ar-CH × 2), 128.3 (Ar-
CH), 127.5 (Ar-CH × 2), 107.3 (C), 99.7 (Ar-CH), 99.3 (Ar-CH), 82.5 (CH), 70.6 (CH2),
68.2 (CH), 55.8 (CH3), 18.1 (CH3); IR (film) νmax 3452, 2935, 1716, 1603, 1347, 1317, 1213,
1161, 1064, 762, 689 cm-1; HRMS (ESI+) for C18H18O5 [M+Na]+ requires 337.1046 found
337.1060.
5-(benzyloxy)-3-(1-(ethoxymethoxy)ethyl)-7-methoxyisobenzofuran-1(3H)-one 12
To a stirred solution of 5-(benzyloxy)-3-(1-hydroxyethyl)-7-methoxyisobenzofuran-1(3H)-
one 20 (250 mg, 0.80 mmol) and DIPEA (1.1 mL, 6.4 mmol) in THF (7 mL) at 0 ºC was
added EOMCl (0.75 mL, 8.0 mmol). The resultant solution was allowed to warm to room
temperature and stirred for 48 h. The reaction was quenched with sat. aq. NaHCO3 (7 mL),
and extracted with EtOAc (3 × 20 mL). The combined organic extracts washed with brine (10
mL), dried over MgSO4 and concentrated in vacuo. Purification by flash chromatography
(hexanes/EtOAc 3:1) afforded the title compound 12 (290 mg, 0.77 mmol, 96%) as a
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colourless oil; H NMR (400 MHz, CDCl3): δ 7.40-7.30 (5H, m, Ar-H), 6.65 (1H, s, Ar-H),
6.48 (1H, s, Ar-H), 5.27 (1H, d, J = 3.6 Hz, CH), 5.10 (2H, s, CH2), 4.63 (2H, ABq, ΔδAB =
0.06, JAB = 7.0 Hz, CH2), 4.18-4.14 (1H, m, CH), 3.87 (3H, s, CH3), 3.48-3.39 (2H, m, CH2),
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1.12 (3H, t, J = 6.8 Hz, CH3), 1.01 (3H, d, J = 6.4 Hz, CH3); C NMR (100 MHz, CDCl3):
δ 167.9 (C=O), 165.3 (C), 159.3 (C), 151.8 (C), 135.5 (C), 128.5 (Ar-CH × 2), 128.2 (Ar-
CH), 127.4 (Ar-CH × 2), 107.6 (C), 99.7 (Ar-CH), 99.5 (Ar-CH), 93.8 (CH2), 80.5 (CH),
72.4 (CH), 70.5 (CH2), 63.3 (CH2), 55.8 (CH3), 14.8 (CH3), 14.7 (CH3); IR (film) νmax 2976,
2934, 1756, 1604, 1450, 1326, 1211, 1157, 1019, 840 cm-1; HRMS (ESI+) for C21H24O6
[M+Na]+ requires 395.1465 found 395.1467.
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5-(benzyloxy)-3-(1-((tert-butyldimethylsilyl)oxy)ethyl)-7-methoxyisobenzofuran-1(3H)-
one 13
To a stirred solution of phthalide 20 (100 mg, 0.32 mmol) in CH2Cl2 (2 mL) at −78 °C under
nitrogen was added 2,6-lutidine (0.15 mL, 1.3 mmol) and tert-butyldimethylsilyl triflate (0.20
mL, 0.95 mmol). The resultant solution was stirred at −78 °C for 4 h, and then quenched by
the addition of sat. aq. NaHCO3 (2 mL). Upon warming to room temperature, the layers were
separated, and the aqueous layer further extracted with CH2Cl2 (3 × 5 mL). The combined
organic extracts were dried over MgSO4 and concentrated in vacuo. Purification by flash
chromatography afforded the title compound 13 (140 mg, 0.32 mmol, 100%) as a colourless
oil; 1H NMR (400 MHz, CDCl3): δ 7.36-7.31 (5H, m, Ar-H), 6.68 (1H, d, J = 2.0 Hz, Ar-H),
6.49 (1H, d, J = 2.0 Hz, Ar-H), 5.15 (1H, d, J = 3.7 Hz, CH), 5.09 (2H, s, CH2), 4.25-4.18
(1H, m, CH), 3.87 (3H, s, CH3), 0.96 (3H, d, J = 6.6 Hz, CH3), 0.82 (9H, s, CH3), 0.04 (3H,
s, CH3), −0.02 (3H, s, CH3); 13C NMR (100 MHz, CDCl3): δ 168.2 (C=O), 165.3 (C), 159.4
(C), 152.2 (C), 135.7 (C), 128.7 (Ar-CH × 2), 128.3 (Ar-CH), 127.4 (Ar-CH × 2), 108.0 (C),
99.9 (Ar-CH), 99.5 (Ar-CH), 81.6 (CH), 70.4 (CH2), 68.2 (CH), 55.8 (CH3), 25.5 (CH3 × 3),
17.8 (C), 17.6 (CH3), −4.6 (CH3), −5.1 (CH3); IR (film) νmax 2953, 2929, 2856, 1755, 1602,
1471, 1322, 1210, 1154, 1021, 957, 833, 732 cm-1; HRMS (ESI+) for C24H32O5Si [M+Na]+
requires 451.1911, found 451.1897.
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To a stirred solution of 5-(benzyloxy)-3-(1-(ethoxymethoxy)ethyl)-7-methoxyisobenzofuran-
1(3H)-one 12 (110 mg, 0.29 mmol) in MeOH (6 mL) was added Pd/C (11 mg, 10% w/w) and
stirred under H2 at room temperature for 24 h. The reaction mixture was filtered through
Celite® and concentrated in vacuo. Purification by flash chromatography afforded the title
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compound 14 (74 mg, 0.26 mmol, 89%) as a colourless solid; m.p. 134-137 ºC; H NMR
(400 MHz, CDCl3): δ 7.76 (1H, br s, OH), 6.63 (1H, s, Ar-H), 6.49 (1H, s, Ar-H), 5.31 (1H,
d, J = 3.6 Hz, CH), 4.66 (2H, ABq, ΔδAB = 0.06, JAB = 7.0 Hz, CH2), 4.20-4.17 (1H, m, CH),
3.88 (3H, s, CH3), 3.50-3.44 (2H, m, CH2), 1.15 (3H, t, J = 7.2 Hz, CH3), 1.10 (3H, d, J = 6.4
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Hz, CH3); C NMR (100 MHz, CDCl3): δ 169.6 (C=O), 164.4 (C), 159.9 (C), 152.0 (C),
106.5 (C), 101.9 (Ar-CH), 99.5 (Ar-CH), 94.0 (CH2), 81.3 (CH), 72.5 (CH2), 63.6 (CH), 55.8
(CH3), 15.1 (CH3), 14.9 (CH3); IR (film) νmax 3274, 2976, 2927, 1708, 1599, 1439, 1169,
966, 845, 689 cm-1; HRMS (ESI+) for C14H18O6 [M+Na]+ requires 305.0996 found 305.0997.
(E)-methyl 4,6-dihydroxy-2-(prop-1-en-1-yl)benzoate 21
To a stirred solution of alkene 19 (100 mg, 0.32 mmol) in CH2Cl2 (1.6 mL) under argon at
−78 °C was added BBr3 (1M in CH2Cl2, 1.6 mL) over 20 min. The solution was strirred at
−78 °C for a further 20 min and then quenched by the addition of H2O (1 mL). Upon
warming to room temperature, the layers were separated and the aqueous layer further
extracted with CH2Cl2 (2 mL). The combined organic extracts were dried over MgSO4 and
concentrated in vacuo. Purification by flash chromatography (hexanes/EtOAc 5:1) afforded
1
the title compound 21 (67 mg, 0.28 mmol, 87%); m.p. 117-119 ºC; H NMR (400 MHz,
CDCl3): δ 11.63 (1H, s, OH), 6.92 (1H, dq, J = 15.5, 1.8 Hz, CH), 6.40 (1H, d, J = 2.5 Hz,
Ar-H), 6.33 (1H, s, J = 2.5 Hz, Ar-H), 5.93 (1H, dq, J = 15.5, 6.5 Hz, CH), 5.63 (1H, s, OH),
3.92 (3H, s, CH3), 1.87 (3H, dd, J = 6.5, 1.8 Hz, CH3); 13C NMR (100 MHz, CDCl3): δ 171.8
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(C=O), 164.6 (C), 160.5 (C), 144.4 (C), 131.8 (CH), 128.3 (CH), 108.4 (Ar-CH), 104.2 (C),
102.2 (Ar-CH), 52.2 (CH3), 18.7 (CH3); IR (film) νmax 3342, 1911, 1644, 1577, 1325, 1267,
1178, 1018, 832, 690 cm-1; HRMS (ESI+) for C11H12O4 [M+Na]+ requires 231.0628 found
231.0631.
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(E)-methyl 4-(benzyloxy)-6-hydroxy-2-(prop-1-en-1-yl)benzoate 22
A stirred suspension of alkene 21 (42 mg, 0.19 mmol), K2CO3 (27 mg, 0.19 mmol) and
benzyl bromide (27 µL, 0.23 mmol) in acetone (1.0 mL) was heated under reflux for 16 h.
The reaction mixture was allowed to cool to room temperature, H2O (2.0 mL) added and the
resultant solution extracted with EtOAc (3 × 5 mL). The combined organic extracts were
dried over Na2SO4 and concentrated in vacuo. Purification by flash chromatography afforded
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the title compound 22 (41 mg, 0.14 mmol, 68%) as a colourless solid; m.p. 82-85 ºC; H
NMR (400 MHz, CDCl3): δ 11.63 (1H, s, OH), 7.39-7.27 (5H, m, Ar-H), 6.92 (1H, dq, J =
15.4, 1.6 Hz, CH), 6.53 (1H, d, J = 2.5 Hz, Ar-H), 6.42 (1H, d, J = 2.5 Hz, Ar-H), 5.91 (1H,
dq, J = 15.4, 6.5 Hz, CH), 4.99 (2H, s, CH2), 3.86 (3H, s, CH3), 1.85 (3H, dd, J = 6.5, 1.6 Hz,
13
CH3); C NMR (100 MHz, CDCl3): δ 171.7 (C=O), 164.9 (C), 163.1 (C), 143.5 (C), 136.2
(C), 132.0 (CH), 128.6 (Ar-CH × 2), 128.1 (Ar-CH), 127.7 (CH), 127.5 (Ar-CH × 2), 108.5
(Ar-CH), 103.8 (C), 100.6 (Ar-CH), 69.9 (CH2), 51.9 (CH3), 18.6 (CH3); IR (film) νmax 2916,
1646, 1607, 1568, 1430, 1328, 1252, 1168, 1029, 962, 731, 692 cm-1; HRMS (ESI+) for
C18H18O4 [M+Na]+ requires 321.1097 found 321.1099.
5-(benzyloxy)-4-bromo-3-(1-(ethoxymethoxy)ethyl)-7-methoxyisobenzofuran-1(3H)-one
23a
To a stirred solution of 5-(benzyloxy)-3-(1-(ethoxymethoxy)ethyl)-7-methoxyisobenzofuran-
1(3H)-one 12 (60 mg, 0.16 mmol) in CH2Cl2 (1.5 mL) at 0 ºC was added
N-bromosuccinimide (32 mg, 0.18 mmol) in three portions over 30 min. The resultant
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mixture was allowed to warm to room temperature and stirred for 16 h and concentrated in
vacuo. Purification by flash chromatography (hexanes/EtOAc 3:1) afforded the title
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compound 23a (68 mg, 0.15 mmol, 93%) as a colourless solid; m.p. 148-150 °C; H NMR
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(400 MHz, CDCl3): δ 7.43-7.34 (5H, m, Ar-H), 6.51 (1H, s, Ar-H), 5.24 (2H, s, CH2), 5.17
(1H, s, CH), 4.72 (1H, q, J = 6.2 Hz, CH) 4.44 (1H, d, J = 7.2 Hz, CH2), 4.28 (1H, d, J = 7.2
Hz, CH2), 3.91 (3H, s, CH3), 3.20 (1H, m, CH2), 2.99 (1H, m, CH2), 1.45 (3H, d, J = 6.4 Hz,
CH3), 1.01 (3H, t, J = 6.8 Hz, CH3); 13C NMR (100 MHz, CDCl3): δ 167.4 (C=O), 160.7 (C),
158.7 (C), 150.0 (C), 135.2 (C), 128.7 (Ar-CH × 2), 128.4 (Ar-CH), 127.0 (Ar-CH × 2),
109.4 (C), 97.7 (Ar-CH), 96.0 (C), 93.0 (CH2), 83.2 (CH), 71.5 (CH2), 68.8 (CH), 63.0
(CH2), 56.2 (CH3), 17.4 (CH3), 14.8 (CH3); IR (film) νmax 2976, 1760, 1601, 1358, 1202,
1183, 1028, 985 cm-1; HRMS (ESI+) for C21H23O6Br [M+Na]+ requires 473.0570 found
473.0562.
5-(benzyloxy)-3-(1-(ethoxymethoxy)ethyl)-4-iodo-7-methoxyisobenzofuran-1(3H)-one
23b
To a stirred solution of 5-(benzyloxy)-3-(1-(ethoxymethoxy)ethyl)-7-methoxyisobenzofuran-
1(3H)-one 12 (60 mg, 0.16 mmol) and silver trifluoracetate (53 mg, 0.24 mmol) in CH2Cl2
(3.2 mL) was added I2 (61 mg, 0.24 mmol) in CH2Cl2 (1.7 mL) dropwise over 30 min. The
reaction mixture was stirred at room temperature for 30 min, then filtered through Celite®.
Sat. aq. Na2S2O3 (1 mL) and NaOH (1M, 1 mL) were added to the filtrate with stirring. The
layers were separated and the aqueous layer further extracted with CH2Cl2 (2 × 3 mL). The
combined organic extracts were dried over MgSO4 and concentrated in vacuo. Purification
by flash column chromtography (hexanes/EtOAc 2:1) afforded the title compound 23b (77
mg, 0.15 mmol, 96%) as a colourless solid; m.p. 146-148 ºC; 1H NMR (400 MHz, CDCl3): δ
7.49-7.32 (5H, m, Ar-H), 6.45 (1H, s, Ar-H), 5.24 (2H, s, CH2), 5.06 (1H, d, J = 1.0 Hz, CH),
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4.82 (1H, qd, J = 6.5 Hz, 1.0 Hz, CH), 4.43 (1H, d, J = 7.6 Hz, CH2), 4.25 (1H, d, J = 7.6 Hz,
CH2), 3.94 (3H, s, CH3), 3.20-3.16 (1H, m, CH2), 2.97-2.93 (1H, m, CH2), 1.47 (3H, d, J =
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6.5 Hz, CH3), 1.00 (3H, t, J = 7.0 Hz, CH3); C NMR (100 MHz, CDCl3): δ 167.6 (C=O),
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162.8 (C), 159.9 (C), 153.9 (C), 135.3 (C), 128.8 (Ar-CH × 2), 128.4 (Ar-CH), 127.0 (Ar-CH
× 2), 110.3 (C), 97.0 (Ar-CH), 96.8 (CH2), 84.9 (CH), 71.6 (CH2), 68.8 (C), 68.7 (CH), 63.0
(CH2), 56.2 (CH3), 17.4 (CH3), 14.9 (CH3); IR (film) νmax 2969, 2928, 1744, 1592, 1439,
1241, 1199, 1181, 1021, 974, 844, 743 cm-1; HRMS (ESI+) for C21H23O6I [M+Na]+ requires
521.0432 found 521.0427.
5-(benzyloxy)-4-bromo-3-(1-((tert-butyldimethylsilyl)oxy)ethyl)-7-
methoxyisobenzofuran-1(3H)-one 23c
To a stirred solution of phthalide 13 (35 mg, 0.082 mmol) in CH2Cl2 (1 mL) at 0 °C was
added N-bromosuccinimide (16 mg, 0.090 mmol) portionwise over 30 min. The resultant
solution was allowed to warm to room temperature and stirred for 18 h. The reaction was
quenched by the addition of H2O (1 mL) and the layers separated. The aqueous layer was
further extracted with CH2Cl2 (3 × 3 mL), the combined organic extracts dried over Na2SO4
and concentrated in vacuo. Purification by flash chromatography (hexanes/EtOAc 10:1)
afforded the title compound 23c (38 mg, 0.075 mmol, 93%) as a colourless solid; m.p. 150.3-
153.7 ºC; 1H NMR (400 MHz, CDCl3): δ 7.47-7.34 (5H, m, Ar-H), 6.48 (1H, s, Ar-H), 5.26
(2H, ABq, ΔδAB = 0.03, JAB = 12.2 Hz, CH2), 5.14 (1H, d, J = 1.0 Hz, CH), 4.72 (1H, qd, J =
6.4, 1.0 Hz, CH), 3.89 (3H, s, CH3), 1.44 (3H, d, J = 6.4 Hz, CH3), 0.57 (9H, s, CH3), −0.06
13
(3H, s, CH3), −0.39 (3H, s, CH3); C NMR (100 MHz, CDCl3): δ 167.8 (C=O), 160.8 (C),
158.9 (C), 150.7 (C), 135.5 (C), 128.9 (Ar-CH × 2), 128.5 (Ar-CH), 127.1 (Ar-CH × 2),
110.1 (C), 98.1 (Ar-CH), 96.3 (C), 84.1 (CH), 71.7 (CH2), 65.7 (CH), 56.5 (CH3), 25.4 (CH3
× 3), 21.2 (CH3), 17.6 (C), −4.3 (CH3), −5.6 (CH3); IR (film) νmax 2954, 2929, 2856, 1751,
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1600, 1441, 1361, 1203, 1047, 956, 835, 775, 728 cm-1; HRMS (ESI+) for BrC24H31O5Si
[M+Na]+ requires 529.1016 found 529.1014.
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5-(benzyloxy)-3-(1-((tert-butyldimethylsilyl)oxy)ethyl)-4-iodo-7-methoxyisobenzofuran-
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1(3H)-one 23d
To a stirred solution of phthalide 13 (25 mg, 0.058 mmol) and silver trifluoroacetate (19 mg,
0.088 mmol) in CH2Cl2 (1.2 mL) was added a solution of I2 (22 mg, 0.088 mmol) in CH2Cl2
(0.6 mL) over 30 min. The resultant suspension was stirred at room temperature for 3 h and
then filtered through Celite®. Excess I2 was scavenged by the addition of sat. aq. Na2S2O3
(0.5 mL). The layers were separated and the aqueous layer further extracted with EtOAc (3 ×
5 mL). The combined organic extracts were dried over MgSO4 and concentrated in vacuo.
Purification by flash chromatography afforded the title compound 23d (29 mg, 0.052 mmol,
1
90%) as a colourless solid; m.p. 170.0-173.0 ºC; H NMR (400 MHz, CDCl3): δ 7.49-7.35
(5H, m, Ar-H), 6.43 (1H, s, Ar-H), 5.26 (2H, ABq, ΔδAB = 0.02, JAB = 12.3 Hz, CH2), 5.02
(1H, s, CH), 4.79 (1H, q, J = 6.5 Hz, CH), 3.90 (3H, s, CH3), 1.45 (3H, d, J = 6.5 Hz, CH3),
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0.57 (9H, s, CH3), −0.06 (3H, s, CH3), −0.41 (3H, s, CH3); C NMR (100 MHz, CDCl3): δ
168.0 (C=O), 162.8 (C), 160.1 (C), 154.5 (C), 135.5 (C), 128.9 (Ar-CH × 2), 128.5 (Ar-CH),
127.1 (Ar-CH × 2), 111.0 (C), 97.3 (Ar-CH), 85.7 (CH), 71.8 (CH2), 69.1 (C), 65.6 (CH),
56.5 (CH3), 25.4 (CH3 × 3), 21.1 (CH3), 17.6 (C), -4.3 (CH3), -5.4 (CH3); IR (film) νmax 2928,
2855, 1760, 1594, 1358, 1180, 1043, 957, 837, 776 cm-1; HRMS (ESI+) for C24H31IO5Si
[M+H]+ requires 555.1058 found 555.1058.
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4-bromo-3-(1-(ethoxymethoxy)ethyl)-5-hydroxy-7-methoxyisobenzofuran-1(3H)-one 23e
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and
4,6-dibromo-3-(1-(ethoxymethoxy)ethyl)-5-hydroxy-7-methoxyisobenzofuran-
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1(3H)-one 24e
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To a stirred solution of 3-(1-(ethoxymethoxy)ethyl)-5-hydroxy-7-methoxyisobenzofuran-
1(3H)-one 14 (30 mg, 0.11 mmol) in CH2Cl2 (2.0 mL) at 0 ºC was added N-
bromosuccinimide (21 mg, 0.12 mmol) in 3 portions over 30 min. The reaction mixture was
allowed to warm to room temperature, stirred for 24 h and concentrated in vacuo. Purification
by flash chromatography (hexanes/EtOAc 1:1) afforded the title compounds 23e (24 mg, 0.07
mmol, 62%) and 24e (7 mg, 0.02 mmol, 15%) as colourless solids.
4-bromo-3-(1-(ethoxymethoxy)ethyl)-5-hydroxy-7-methoxyisobenzofuran-1(3H)-one 23e
Contains 14% starting material and N-hydroxysuccinimide by NMR.
m.p. 145-150 ºC; 1H NMR (400 MHz, CDCl3): δ 6.66 (1H, s, Ar-H), 5.19 (1H, d, J = 1.0 Hz,
CH), 4.70-4.66 (1H, m, CH), 4.49 (1H, d, J = 7.5 Hz, CH2), 4.32 (1H, d, J = 7.5 Hz, CH2),
3.92 (3H, s, CH3), 3.27-3.19 (1H, m, CH2), 3.07-2.99 (1H, m, CH2), 1.47 (3H, d, J = 6.5 Hz,
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CH3), 1.04 (3H, t, J = 7.0 Hz, CH3); C NMR (100 MHz, CDCl3): δ 177.5 (C=O), 168.1
(Ar-C), 159.7 (Ar-C), 159.2 (Ar-C), 150.3 (Ar-C), 109.7 (Ar-C) 100.2 (Ar-CH), 93.2 (CH2),
83.3 (CH), 69.0 (CH), 63.4 (CH2), 56.4 (CH3), 17.6 (CH3), 15.0 (CH3); IR (film) νmax 3171,
1975, 2932, 1709, 1594, 1360, 1211, 1070, 976, 836 cm-1; HRMS (ESI+) for BrC14H17O6
[M+Na]+ requires 383.0101 found 383.0102.
4,6-dibromo-3-(1-(ethoxymethoxy)ethyl)-5-hydroxy-7-methoxyisobenzofuran-1(3H)-one
24e
m.p. 118-121 ºC; 1H NMR (400 MHz, CDCl3): δ 5.22 (1H, d, J = 1.6 Hz, CH), 4.69 (1H, qd,
J = 6.4, 1.6 Hz, CH), 4.50 (1H, d, J = 7.0 Hz, CH2), 4.32 (1H, d, J = 7.0 Hz, CH2), 4.18 (3H,
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s, CH3), 3.27-3.20 (1H, m, CH2), 3.02-2.95 (1H, m, CH2), 1.49 (3H, d, J = 6.4 Hz, CH3), 1.03
(3H, t, J = 6.9 Hz, CH3); 13C NMR (100 MHz, CDCl3): δ 166.2 (C=O), 156.3 (C), 155.1 (C),
148.8 (C), 113.4 (C), 106.4 (C), 97.3 (C), 93.3 (CH2), 83.5 (CH), 69.1 (CH2), 63.5 (CH3),
63.3 (CH), 17.6 (CH3), 15.0 (CH3); IR (film) νmax 3223, 2927, 1732, 1586, 1364, 1159, 1089,
1017, 772 cm-1; HRMS (ESI+) for Br2C14H16O6 [M+Na]+ requires 460.9206 found 460.9198.
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3-(1-(ethoxymethoxy)ethyl)-5-hydroxy-4-iodo-7-methoxyisobenzofuran-1(3H)-one 23f
and 3-(1-(ethoxymethoxy)ethyl)-5-hydroxy-4,6-diiodo-7-methoxyisobenzofuran-1(3H)-
one 24f
To a stirred solution of 3-(1-(ethoxymethoxy)ethyl)-5-hydroxy-7-methoxyisobenzofuran-
1(3H)-one 14 (37 mg, 0.13 mmol) and silver trifluoroacetate (43 mg, 0.19 mmol) in CH2Cl2
(2.6 mL) was added I2 (29 mg, 0.19 mmol), in CH2Cl2 (1.5 mL) over 30 min. The reaction
mixture was stirred at room temperature for 16 h and filtered through Celite®. Sat. aq.
Na2S2O3 (1.0 mL) was added to the filtrate. The layers were separated, the aqueous layer
further extracted with CH2Cl2 (2 × 3 mL), the combined organic extracts dried over Na2SO4
and concentrated in vacuo. Purification by flash chromatography (hexanes/EtOAc 1:1)
afforded the title compounds 23f (29.5 mg, 0.070 mmol, 56%) and 24f (14.3 mg, 0.030
mmol, 20%) as colourless solids.
3-(1-(ethoxymethoxy)ethyl)-5-hydroxy-4-iodo-7-methoxyisobenzofuran-1(3H)-one 23f
Contains 15% starting material by NMR.
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m.p. 149-151 ºC (Some trace material did not melt until 169 ºC); H NMR (400 MHz,
CDCl3): δ 6.68 (1H, s, Ar-H), 5.08 (1H, d, J = 1.0 Hz, CH), 4.78 (1H, qd, J = 6.6 Hz, 1.0
Hz, CH), 4.47 (1H, d, J = 7.2 Hz, CH2), 4.28 (1H, d, J = 7.2 Hz, CH2), 3.91 (3H, s, CH3),
3.22-3.18 (1H, m, CH2), 3.00-2.97 (1H, m, CH2), 1.47 (1H, d, J = 6.6 Hz, CH3), 1.03 (3H, t, J
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= 7.2 Hz, CH3); C NMR (100 MHz, CDCl3): δ 168.6 (C=O), 162.3 (C), 160.1 (C), 154.1
(C), 109.9 (C), 99.2 (Ar-CH), 93.0 (CH2), 85.1 (CH), 68.5 (CH), 67.1 (C), 63.3 (CH2), 56.2
(CH3), 17.4 (CH3), 15.0 (CH3); IR (film) νmax 3172, 2975, 2926, 1708, 1586, 1447, 1362,
1212, 1070, 980, 834, 732 cm-1; HRMS (ESI+) for C14H17IO6 [M+Na]+ requires 430.9962
found 430.9966.
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3-(1-(ethoxymethoxy)ethyl)-5-hydroxy-4,6-diiodo-7-methoxyisobenzofuran-1(3H)-one
24f
m.p. 119-121 ºC; 1H NMR (400 MHz, CDCl3): δ 5.10 (1H, d, J = 1.5 Hz, CH), 4.77 (1H, qd,
J = 6.5, 1.5 Hz, CH), 4.48 (1H, d, J = 7.5 Hz, CH2), 4.29 (1H, d, J = 7.5 Hz, CH2), 4.17 (3H,
s, CH3), 3.24-3.16 (1H, m, CH2), 2.96-2.88 (1H, m, CH2), 1.51 (3H, d, J = 6.5 Hz, CH3), 1.02
(3H, t, J = 7.2 Hz, CH3); 13C NMR (100 MHz, CDCl3): δ 166.1 (C=O), 159.7 (C), 159.3 (C),
154.4 (C), 113.2 (C), 93.3 (CH2), 91.0 (C), 85.3 (CH), 83.0 (C), 68.9 (CH), 63.5 (CH2), 63.3
(CH3), 17.6 (CH3), 15.1 (CH3); IR (film) νmax 3365, 2983, 2928, 1748, 1574, 1401, 1170,
1068, 1012, 730 cm-1; HRMS (ESI+) for C14H16I2O6 [M+Na]+ requires 556.8928 found
556.8932.
(E)-methyl 4-(benzyloxy)-3-bromo-6-methoxy-2-(prop-1-en-1-yl)benzoate 23g
To a stirred solution of 19 (50 mg, 0.16 mmol) in CH2Cl2 at 0 °C was added N-
bromosuccinimide (31 mg, 0.18 mmol) in three portions over 30 min. The reaction mixture
was stirred at 0 °C for 3 h and stored at 0 °C overnight. The solution was allowed to warm to
room temperature and concentrated in vacuo. Purification by flash chromatography
(hexanes/EtOAc 5:1) afforded the title compound 23g as a colourless solid; m.p. 89-91 ºC; 1H
NMR (400 MHz, CDCl3): δ 7.48-7.29 (5H, m, Ar-H), 6.47 (1H, d, J = 16.0 Hz, CH), 6.41
(1H, s, Ar-H), 5.86 (1H, dq, J = 16.0, 6.4 Hz, CH), 5.16 (2H, s, CH2), 3.80 (3H, s, CH3), 3.74
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