Synthesis of the carbon skeleton of the griseorhodins

Article abstract of DOI:10.1016/j.tet.2014.11.030

A synthetic strategy to access the carbon skeleton of the griseorhodin family of natural products has been developed. The key step involved the acid-mediated spirocyclisation of a highly functionalised dihydroxyketone. The delicate electronic balance betw

Full text of DOI:10.1016/j.tet.2014.11.030

Tetrahedron 71 (2015) 91e101
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Tetrahedron
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Synthesis of the carbon skeleton of the griseorhodins
,
,
,b,
Darcy J. Atkinson a b, Daniel P. Furkert a b, Margaret A. Brimble a
*
a School of Chemical Sciences, The University of Auckland, 23 Symonds Street, Auckland 1010, New Zealand
b Maurice Wilkins Centre for Molecular Biodiscovery, The University of Auckland, 3 Symonds Street, Auckland 1010, New Zealand
a r t i c l e i n f o
a b s t r a c t
Article history:
A synthetic strategy to access the carbon skeleton of the griseorhodin family of natural products has been
developed. The key step involved the acid-mediated spirocyclisation of a highly functionalised dihy-
droxyketone. The delicate electronic balance between the electron rich naphthalene moiety and the
electron-withdrawing isocoumarin ring system were finely tuned to facilitate the acid-mediated spi-
rocyclisation reaction. The development of this synthetic strategy provides a basis for further synthetic
investigations towards the more structurally complex griseorhodin natural products.
Ó 2014 Elsevier Ltd. All rights reserved.
Received 13 September 2014
Received in revised form 30 October 2014
Accepted 10 November 2014
Available online 20 November 2014
Keywords:
Griseorhodins
Rubromycins
Spiroketal
Sonogashira coupling
1. Introduction
configuration of (S, S, S, S) for griseorhodin A (1) based on
quantum-chemical circular dichroism (CD) calculations and ex-
The griseorhodins are a sub class of compounds within the
structurally related rubromycin family. They were isolated over
several decades with the majority of the compounds isolated from
various strains of Streptomyces.1e8 Structurally, griseorhodins 1e6
all consist of naphthazarin and isocoumarin moieties linked via
a 5,6-spiroketal core (Fig. 1). Piel et al. proposed an absolute
perimental CD measurements, however, compounds 2e6 cur-
rently remain unassigned.9 The griseorhodins are distinguished
from the other members of the larger rubromycin family by the
presence of a methyl group at C-7 as opposed to a methyl ester
(Fig. 2).
The griseorhodins exhibit antimicrobial activity against a range
of bacteria and fungi at micromolar levels.5,6,8,9 Notably, 8-
methoxygriseorhodin C (4) exhibits potent activity against strains
of MRSA (methicillin resistant Staphylococcus aureus, MIC¼0.78
mg/
mL).6 These natural products also exhibit cytotoxic activity against
KB-nasopharynx cells and HLE (human leukocyte elastase).5,9
Fig. 1. Structures of the griseorhodins.
* Corresponding author. Tel.: þ64 9 373 7599; fax: þ64 9 373 7422; e-mail
address: m.brimble@auckland.ac.nz (M.A. Brimble).
Fig. 2. General structures of the griseorhodins and rubromycins.
http://dx.doi.org/10.1016/j.tet.2014.11.030
0040-4020/Ó 2014 Elsevier Ltd. All rights reserved.

92
D.J. Atkinson et al. / Tetrahedron 71 (2015) 91e101
In addition to their potent antimicrobial and cytotoxic proper-
ties, griseorhodins A (1) (IC50 12.2 M) and C (2) (IC50 5.87 M) also
construct the spiroketal core, but disappointingly these revealed
m
m
the inability of a fully-substituted isocoumarin to undergo this
transformation (Scheme 1). Further investigations revealed that the
electron-withdrawing functionality of the isocoumarin had a sub-
stantial effect on acid-mediated spirocyclisations, preventing the
reaction from proceeding.21,22 To circumvent this problem, the use
of electron-rich isocoumarin precursors and modification of the
electrophilic ketone led to the successful formation of spiroketal
products.20,22
In these previous studies, the synthetic targets all contained the
methyl ester functional group at C-7 common to the rubromycin
family (Scheme 1). It has been demonstrated that the methyl ester
contributes substantially to the reduction in nucleophilicity of the
phenol through mesomeric electron-withdrawal, resulting in the
formation of benzofuran or degradation products.21 We hypoth-
esised that exchange of the methyl ester for a methyl group, com-
mon to the griseorhodins would remove the electron-withdrawing
mesomeric effect, thereby facilitating acid-mediated spirocyclisa-
tion to access the griseorhodin spiroketal framework.
inhibit human telomerase.10 Telomerase is a unique ribonucleo-
protein that maintains the ends of chromosomes, through the
synthesis of telomeres. Telomeres are short guanine rich sequences,
which are repeated at the ends of chromosomes to maintain
chromosome length and stability during successive DNA replica-
tion.10 Telomerase is up regulated in 80e90% of cancers while it is
almost completely absent in neighbouring healthy somatic cells,
therefore, serving as a potential target for the development of new
cancer therapeutic agents.11,12 Structural studies have suggested
that the spiroketal moiety of the rubromycins is a key pharmaco-
phore for telomerase inhibition activity.10
The rubromycin family has been known for almost 60 years and
extensive interest from the synthetic community has led to a large
body of literature on the synthesis of various fragments. Three of
the natural products have succumbed to total synthesis starting
with Danishefsky’s seminal preparation of heliquinomycinone.13
Subsequent syntheses of (ꢀ)-
g
-rubromycin,14e18 (ꢀ)-
d-rubromy-
cin19 and an advanced spiroketal intermediate of purpuromycin20
have now been reported. To date however, synthetic in-
vestigations towards the griseorhodin natural products have not
been reported.
2. Results and discussion
Given the variability and unknown effects that the modified
isocoumarin moiety might confer on the key spirocyclisation re-
action, it was decided to initially focus on the synthesis of the
model griseorhodin structure (7) (Scheme 2). Synthesis of 7 would
establish a route that could be readily modified for the preparation
of the griseorhodin natural products. Retrosynthetically, griseo-
rhodin model (7) arises from hexamethoxy protected spiroketal 8.
An acid-mediated spirocyclisation of a dihydroxyketone precursor
9 would be used to construct the spiroketal core. Dihydroxyketone
9 would in turn be accessed from alkynol 10. Sonogashira coupling
of functionalised naphthalene 11 and isocoumarin 12 would allow
for a flexible convergent synthesis providing access to related
systems.
Initial investigations towards the rubromycins from both Reibig
and Kozlowski centered on acid-mediated spirocyclisation to
2.1. Synthesis of alkynol 11
Synthesis of alkynol 11 was achieved following an established
protocol developed by our group during the formal synthesis of
(ꢀ)-
g
-rubromycin (Scheme 3).14 Synthesis of intermediate bro-
moquinone
13
from
commercially
available
1,2,4-
trimethoxybenzene (14) was completed in 53% yield over 5 steps.
Conversion of bromoquinone 13 to the azidoquinone 15 was
Scheme 1. Comparing reaction pathways for isocoumarins under acidic spirocyclisa-
tion conditions.
Scheme 2. Retrosynthetic analysis of griseorhodin model (7).

D.J. Atkinson et al. / Tetrahedron 71 (2015) 91e101
93
required to ensure regioselective reaction with allyl alcohol.14
Claisen rearrangement of allyl ether 16 induced by microwave ir-
radiation was then executed followed by protection of the newly-
exposed hydroxyl group to afford EOM ether 17 in excellent yield.
Reductive dimethylation of 17 then afforded alkene 18. A one pot
dihydroxylation-oxidative cleavage afforded the corresponding al-
dehyde, which was then converted to desired alkynol 11 upon ex-
posure to excess ethynylmagnesium bromide in tetrahydrofuran.
Scheme 5. Synthesis of isocoumarin 12. Reagents and conditions: (a) Br2, CH2Cl2,
ꢁ78 ꢂC / ꢁ5 ꢂC, 1 h (b) EOMCl, iPr2NEt, DMAP, CH2Cl2, 0 ꢂC/rt., o/n. (c) LDA, THF,
dimethyl malonate, ꢁ78 ꢂC, 1 h then 23, THF, ꢁ78 ꢂC/rt., 1 h (d) NaHSO4$SiO2, CH2Cl2,
rt., 16 h (e) Br2, NaOAc, AcOH, rt., 1 h (f) BnBr, K2CO3, acetone, reflux, 2 h (g) KOH,
EtOHeH2O (3:1), reflux, 6 h (h) Ac2O, py, rt., o/n then aq NaOH (1.0 M), 60 ꢂC, 3 h (i)
HClO4 (cat.), EtOAc-Ac2O (5:1), rt., 30 min.
bromination step. Reprotection of the phenol as a benzyl ether
afforded homophthalic ester 25 in 75% yield over two steps. Sa-
ponification of both esters followed by Dakin-West oxidation
afforded keto-acid 26, which cyclised upon treatment with catalytic
perchloric acid in a mixture of EtOAc-Ac2O (5:1) to afford the de-
sired isocoumarin 12.
Scheme 3. Synthesis of alkynol 11. Reagents and conditions: (a) NaN3, MeCN, rt., 3 days.
(b) allyl alcohol, Cs2CO3, PhMe, 60 ꢂC, 1 h (c) PhMe, 140 ꢂC, microwave, 200 W, 30 min
(d) EOMCl, iPr2NEt, DMAP, CH2Cl2, 0 ꢂC/rt., 16 h (e) Na2S2O4, TBABr (cat.), THF-H2O
(1:1) 20 min then MeI, Cs2CO3, Na2S2O4 (cat.), H2, DMF, 60 ꢂC, 3 h (f) OsO4 (cat.), 2,6-
lutidine, NaIO4, dioxane-H2O (3:1), rt., 3.5 h (g) ethynylmagnesium bromide, THF,
0
ꢂC/rt., 1 h.
2.3. Coupling of alkynol 11 and isocoumarin 12
2.2. Synthesis of isocoumarin 12
With both coupling partners 11 and 12 in hand, attention turned
to the Sonogashira coupling and elaboration to spirocyclisation
precursor 9 (Scheme 6). Initial attempts to couple alkynol 11 and
isocoumarin 12 afforded poor yields of cross-coupled product 27
due to the formation of homo-coupled alkynol product 28. All at-
tempts to reduce the formation of this undesired product were
unsuccessful, therefore, 2 equiv of 11 were required to achieve
acceptable yields of the desired cross-coupling product 27. Syn-
thesis continued with IBX oxidation of the 2ꢂ alcohol and treatment
of the corresponding ketone with Pd/C under a hydrogen atmo-
sphere, affording ketone 9 in 79% over two steps. Initial attempts to
effect spirocyclisation of ketone 9 under acidic conditions were
unsuccessful. Exposure of 9 to PPTS in CH2Cl2 afforded dihydrox-
yketone 29 in 90% yield. However, further attempts to effect spi-
rocyclisation of dihydroxyketone 29 using a wide range of both
Brønsted and Lewis acids afforded none of the desired spirocyclised
product 8.
With naphthalene 11 in hand, attention next focused on the
synthesis of isocoumarin 12. Coupling partner 12 is available from
keto-acid 19, which could be prepared from known phenol 20,
available in turn from guaiacol (21) using reported procedures
(Scheme 4).14
2.4. Isocoumarin precursors
Scheme 4. Retrosynthesis of the isocoumarin coupling partner 12.
At this stage it was apparent that exchanging the methyl ester
for a methyl group at C-7 was not sufficient to facilitate the key
spirocyclisation reaction when a fully substituted isocoumarin
fragment was in place. As a result, further structural modification of
the isocoumarin fragment was required to further probe the
functionality, that is, compatible with the key spirocyclisation step.
Consequently, three isocoumarin precursors with differing
functionality were synthesised from intermediate keto-acid 26
(Scheme 7). Methylation of keto acid 26 afforded keto ester 30,
The synthesis of 12 commenced with bromination23 of guaiacol
(21) followed by protection of the resultant phenol as an EOM ether
23 (Scheme 5). Regioselective reaction of the intermediate benzyne
of 23 with the preformed anion of dimethyl malonate in tetrahy-
drofuran at ꢁ78 ꢂC afforded homophthalic ester 24 in 49% yield as
a single product. Acidic cleavage of the EOM group to afford phenol
20 was then required to facilitate the subsequent ortho-

94
D.J. Atkinson et al. / Tetrahedron 71 (2015) 91e101
Scheme 8. Synthesis of 34 and attempted spirocyclisation. Reagents and conditions: (a)
Pd(OAc)2, CuI, PPh3, NEt3, DMF, rt., 24 h (b) IBX, DMSO, rt., 4 h (c) H2, Pd/C, MeOH, rt.,
2 h (d) various Brønsted and Lewis Acids.
Scheme 6. Synthesis of dihydroxyketone 29 and attempted spirocyclisation. Reagents
and conditions: (a) Pd(OAc)2, CuI, PPh3, NEt3, DMF, rt., 24 h (b) IBX, DMSO, rt., 5 h (c) H2,
Pd/C, EtOAc, rt., 1 h (d) PPTS, CH2Cl2, rt., 12 h (e) various Brønsted and Lewis acids.
The failure of both lactone-containing isocoumarins 12 and 31 to
spirocyclise focused our attention on the open chain precursors 30
and 32. Attempts to effect Sonogashira coupling of ketone 30 with
alkynol 11 using the established conditions were hampered due to
undesired lactonisation of 30. The requirement to use excess
alkynol 11 together with the incompatibility of the reaction con-
ditions with ketone 30 necessitated the investigation of alternative
cross-coupling conditions.
which was easily converted to dihydroisocoumarin 31 using NaBH4
and aqueous acid. Alternatively, reduction of keto ester 30 followed
by silyl protection of the alcohol affords TBDPS ether 32. These
three compounds (30e32) were identified as suitable precursors as
they contain appropriate functionality for later conversion to the
desired fully substituted isocoumarin ring system.
Scheme 7. Synthesis of the three isocoumarin precursor coupling partners 30e32. Reagents and conditions: (a) MeI, K2CO3, acetone, 50 ꢂC, 3 h (b) NaBH4, THF-MeOH (1:1), 0 ꢂC,
20 min then 1.0 M HCl, 20 min (c) NaBH4, THF-MeOH (1:1), 0 ꢂC, 20 min (d) TBDPSOTf, 2,6-lutidine, CH2Cl2, ꢁ78 ꢂC, 4 h then rt., o/n.
Attention first turned to the coupling of alkynol 11 with dihy-
droisocoumarin 31 (Scheme 8). Sonogashira coupling of 31 with
alkynol 11 using established conditions proceeded in a poor 23%
yield. Despite this, elaboration to mono EOM protected dihydrox-
yketone 34 was undertaken to investigate the key spirocyclisation
step. Once more, under a range of acidic conditions no spirocyclised
product was obtained. TLC analysis over the duration of the re-
action indicated cleavage of the EOM group but no further products
were identified.
Conditions were sought to effect Sonogashira coupling utilising
a weak base with the exclusion of a copper co-catalyst in order to
minimise the GlasereHay homo-coupling of alkynes.24 Thus, cou-
pling of silyl ether 32 and ketone 30 with alkynol 11 using Pd(OAc)2,
1 10-bis(di-tert-butylphosphino)ferrocene (DtBuPF) and K2CO3 in
NMP at elevated temperatures afforded alkynes 36 and 37, re-
spectively, in moderate to good yield (Scheme 9). Importantly, only
1 equiv of alkynol 11 was required with no evidence for the for-
mation of homo-coupled alkynol 28.

D.J. Atkinson et al. / Tetrahedron 71 (2015) 91e101
95
Scheme 9. Sonogashira coupling of silyl ether 32 and ketone 30 with alkynol 11. Re-
agent and conditions: (a) Pd(OAc)2, DtBuPF, K2CO3, NMP, 150 ꢂC, 1.5 h (b) Pd(OAc)2,
DtBuPF, K2CO3, NMP, 70 ꢂC, 1.5 h.
Scheme 10. Synthesis of spiroketal 40. Reagent and conditions: (a) IBX, DMSO, rt., 5 h
(b) H2, Pd/C, MeOH, rt., 2 h (c) NaHSO4$SiO2, CH2Cl2, rt., 6 h (d) [Fꢁ].
Having established access to both coupled products 36 and 37,
elaboration of 36 to the corresponding mono EOM protected dihy-
droxyketone 39 was performed using the previously developed
oxidation/hydrogenation/debenzylation sequence in 82% over two
steps (Scheme 10). Ketone 39 was treated with silica-supported
presence of a lactone group is the key structure that prevents
successful acid-mediated spirocyclisation of functionalised dihy-
droxyketones to take place. Use of an open chain isocoumarin
precursor however, resulted in the successful synthesis of the gri-
seorhodin model spiroketal (7). The use of an acyclic isocoumarin
precursor is therefore essential to execute further synthetic work
focused on the griseorhodin family of natural products. Continuing
investigations into the installation of the oxygen functionality
around the spiroketal core that distinguishes each member of the
griseorhodin family of natural products, is currently being un-
dertaken in our lab.
14
NaHSO4 to finally afford the desired spiroketal 40 in a moderate
48% yield. However, attempts to cleave the TBDPS group using an
array of fluoride sources were unsuccessful, preventing formation of
the lactone to complete construction of the isocoumarin fragment.
2.5. Synthesis of griseorhodin model (7)
Given that spirocyclisation of ketone 39 to spiroketal 40 had been
demonstrated, attention focused on elaboration of ketone 37 to the
griseorhodin natural product framework (Scheme 11). It was envi-
sioned that after spirocyclisation, the methyl ketone could be con-
verted tothe isocoumarin ring system by treatment with base. Using
the same protocol as previously, ketone 37 was converted to ketone
43 in 85% yield over two steps. Treatment of ketone 43 with silica-
supported NaHSO4 was successful in affording spiroketal 44, albeit
in moderate 53% yield. Base-mediated enolate formation and
spontaneous lactonisation afforded hexamethoxy spiroketal 8. Ox-
idation of the naphthalene ring to the naphthoquinone using con-
ditions described by Kozlowski et al.20 followed by BCl3 mediated
cleavage of the three methoxy groups finally afforded the desired
griseorhodin model spiroketal (7) in 58% yield over two steps.
4. Experimental section
4.1. General information
Unless otherwise stated, all reactions were performed under an
atmosphere of dry nitrogen in oven dried (100 ꢂC) glassware.
Commercially available starting materials and reagents were used
as received unless otherwise noted. Dioxane and tetrahydrofuran
(THF) were freshly distilled over sodium/benzophenone ketyl.
Acetonitrile (MeCN), dichloromethane (CH2Cl2) and ethanol (EtOH)
were freshly distilled from calcium hydride. Triethylamine (Et3N)
was distilled from calcium hydride and stored over potassium hy-
droxide. Dimethylformamide (DMF) was freshly distilled from
ꢀ
3. Conclusion
molecular sieves (Linde type 4 A). Reactions performed at low
temperature were either cooled with an acetone-dry ice bath to
reach ꢁ78 ꢂC or a water-ice bath to reach 0 ꢂC. Reactions were
monitored by thin-layer chromatography (TLC) carried out on E.
A systematic investigation of the functionality used to install the
isocoumarin fragment of the griseorhodins determined that the

96
D.J. Atkinson et al. / Tetrahedron 71 (2015) 91e101
reported as chemical shift in ppm, followed by multiplicity
(s¼singlet, d¼doublet, t¼triplet, q¼quartet, m¼multiplet, b¼broad
or combination thereof), coupling constants where applicable and
relative integral. Mass spectra were recorded on a Bruker microTOF
QII (electrospray ionisation, ESI) mass spectrometer.
4.2. Methyl 3-(benzyloxy)-4-bromo-2-methoxy-6-(2-
methoxy-2-oxoethyl)benzoate (25)
To a stirred solution of phenol 20 (2.0 g, 7.87 mmol) in AcOH
(35 mL) was added NaOAc (0.96 g, 12.0 mmol) and a solution of Br2
(0.44 mL, 8.65 mmol) in AcOH (15 mL) dropwise. The solution was
then stirred at rt for 1 h before being concentrated in vacuo. Water
(15 mL) was then added to the residue and the mixture was
extracted with CH2Cl2 (3ꢃ20 mL). The combined organic extracts
were washed with saturated aqueous NaHCO3 (20 mL), dried over
anhydrous MgSO4, filtered and the filtrate concentrated in vacuo.
The crude product was purified by flash chromatography (hexane-
EtOAc, 2:1) to afford the aryl bromide (2.41 g, 92%) as a yellow oil
that solidified on cooling o/n; Mp¼63.0e64.5 ꢂC; Rf: 0.33 (hexanes-
EtOAc, 2:1); nmax(neat)/cmꢁ1 3409, 2953, 1725, 1580, 1409, 1265,
1135, 1055, 1001, 819; dH (400 MHz; CDCl3) 7.19 (s, 1H), 6.56 (br s,
1H), 3.90 (s, 3H), 3.85 (s, 3H), 3.68 (s, 3H), 3.62 (s, 2H); dC (100 MHz;
CDCl3) 171.1 (C), 166.6 (C), 146.0 (C), 145.7 (C), 129.8 (C), 126.6 (CH),
124.9 (C), 111.6 (CH), 61.9 (CH3), 52.2 (CH3), 52.0 (CH3), 38.0 (CH2);
m/z (ESIþ) [MþNa]þ 354.9784 calcd for C12H13BrNaO6 354.9788.
To a stirred solution of aryl bromide (1.86 g, 5.58 mmol) in ac-
etone (30 mL) was added K2CO3 (1.16 g, 8.23 mmol) and BnBr
(0.66 mL, 5.58 mmol) and the mixture was heated at reflux for 2 h.
The mixture was cooled and filtered through a silica plug and the
plug was washed with EtOAc (50 mL). The filtrate was concentrated
and the residue was dissolved in EtOAc (20 mL). The organic layer
was washed with water (2ꢃ8 mL) and the combined aqueous
washings were extracted with EtOAc (3ꢃ20 mL). The combined
organic extracts were washed with brine (20 mL), dried over an-
hydrous MgSO4, filtered and the filtrate was concentrated in vacuo.
The crude product was purified by flash chromatography (hexanes-
EtOAc, 5:1) to afford the title compound 25 (1.96 g, 81%) as a col-
ourless oil; Rf: 0.29 (hexanes-EtOAc, 5:1); nmax(neat)/cmꢁ1 3022,
2954, 2942, 2868, 1739, 1727, 1586, 1562, 1470, 1446, 1431, 1398,
1398, 1298, 1267, 1255, 1237, 1168, 1062, 1031, 1017, 987, 940, 913,
819, 804, 791, 735, 696, 677; dH (400 MHz; CDCl3) 7.49 (d, J¼2.0 Hz,
2H), 7.27e7.34 (m, 3H), 7.25, (s,1H), 4.96 (s, 2H), 3.87 (s, 3H), 3.84 (s,
3H), 3.61 (s, 3H), 3.59 (s, 2H); dC (100 MHz; CDCl3) 170.1 (C), 166.1
(C), 151.6 (C), 148.4 (C), 136.0 (C), 129.9 (CH), 129.0 (C), 128.3 (C),
128.0 (2 ꢃ CH), 128.0 (2 ꢃ CH), 127.8 (CH), 119.6 (C), 74.6 (CH2), 61.4
(CH3), 51.8 (CH3), 51.5 (CH3), 37.7 (CH2); m/z (ESIþ) [MþNa]þ
445.0256 calcd for C19H19BrNaO6 445.0257.
Scheme 11. Elaboration of 37 to griseorhodin model (7). Reagents and conditions: (a)
IBX, DMSO, rt., 3 h (b) H2, Pd/C, MeOH, rt., 2 h (c) NaHSO4$SiO2, CH2Cl2, rt., 9 h (d) NaH,
THF, 0 ꢂC/rt., 30 min (e) DDQ, MeCNeH2O (10:1), 0 ꢂC, 15 min (f) BCl3, CH2Cl2, 0 ꢂC,
10 min.
Merck silica gel plates using UV light as visualizing agent and an
ethanolic solution of vanillin or ammonium molybdate with heat as
developing agents. Flash column chromatography was performed
4.3. 3-(Benzyloxy)-4-bromo-2-methoxy-6-(2-oxopropyl) ben-
zoic acid (26)
using Kieselgel S 63-100 mm (Riedel-de-Hahn) silica gel and the
indicated solvent system. Melting points were determined on
a Kofler hot-stage apparatus and are uncorrected. Infrared (IR)
spectra were recorded on a Perkin Elmer Spectrum 100 FT-IR
spectrometer using a diamond ATR sampling accessory as neat
solids or liquids. NMR spectra were recorded at ambient tempera-
ture as CDCl3 or MeOD solutions on either a Bruker DRX300
spectrometer operating at 300 MHz for 1H nuclei and 75 MHz for
13C nuclei, a Bruker DRX400 spectrometer operating at 400 MHz for
1H nuclei and 100 MHz for 13C nuclei or a Bruker DRX500 spec-
trometer operating at 500 MHz for 1H nuclei and 120 MHz for 13C
To a stirred solution of ester 25 (1.0 g, 2.36 mmol) in EtOH
(20 mL) was added KOH (1.6 g, 28.5 mmol) and water (6.5 mL). The
mixture was heated at reflux for 6 h before being cooled to rt and
acidified with aqueous HCl (1.0 M, pH¼2). The solution was then
extracted with EtOAc (3ꢃ15 mL). The combined organic extracts
were washed with brine (15 mL), dried over anhydrous MgSO4,
filtered and the filtrate concentrated in vacuo. The crude product
was purified by flash chromatography (CH2Cl2eMeOH, 10:1) to
afford the homophthalic acid (0.91 g, 98%) as viscous colourless oil
that solidified on cooling o/n; Mp¼78.0e80.0 ꢂC; Rf: 0.30
(CH2Cl2eMeOH, 10:1); nmax(neat)/cmꢁ1 3450, 2942, 2507, 1964,
1714, 1670, 1563, 1395, 1266, 1194, 1012, 741; dH (400 MHz; MeOD)
7.42 (d, J¼7.2 Hz, 2H), 7.21e7.28 (m, 4H), 4.87 (s, 2H), 3.80 (s, 3H),
3.62 (s, 2H); dC (100 MHz; MeOD) 174.3 (C), 169.8 (C), 152.6 (C),
nuclei. All chemical shifts are reported in ppm on the
were measured relative to the protium solvent in which the sample
was analysed (CDCl3:
7.26 for 1H NMR, 77.0 for 13C NMR and
MeOD:
3.31 for 1H NMR, 49.0 for 13C NMR). 1H NMR data is
d scale and
d
d
d
d

D.J. Atkinson et al. / Tetrahedron 71 (2015) 91e101
97
149.5 (C), 137.6 (C), 131.4 (CH & C), 130.7 (C), 129.4 (CH), 129.3 (2 ꢃ
4.6. 7-(Benzyloxy)-6-bromo-8-methoxy-3-methylisochroman-
1-one (31)
CH),129.2 (2 ꢃ CH),120.3 (C), 76.0 (CH2), 62.4 (CH3), 39.0 (CH2); m/z
(ESIe) [M e H]ꢁ 392.9992 calcd for C17H14BrO6 392.9979.
To a stirred solution of homophthalic acid (0.796 g, 2.01 mmol)
in Ac2O (20 mL) was added pyridine (0.47 mL, 5.03 mmol) and
stirred at rt for o/n. The excess Ac2O and pyridine was removed in
vacuo and the residue was suspended in aqueous NaOH (20 mL,
1.0 M) and heated at 60 ꢂC for 3 h. The mixture was cooled and
acidified using aqueous HCl (1.0 M, pH¼2). The aqueous solution
was extracted with EtOAc (3ꢃ50 mL) and the combined organic
extracts were washed with brine (30 mL), dried over anhydrous
MgSO4, filtered and the filtrate concentrated in vacuo. The crude
product was purified by flash chromatography (CH2Cl2eMeOH,
16:1) to afford the title compound 26 (0.68 g, 85%) as an orange oil;
Rf: 0.21 (CH2Cl2eMeOH, 16:1); nmax(neat)/cmꢁ1 3478, 2983, 1713,
1559, 1452, 1371, 1260, 1160, 1064, 998, 698; dH (400 MHz; MeOD)
7.56 (d, J¼7.6 Hz, 2H), 7.36e7.55 (m, 3H), 7.29 (s, 1H), 5.05 (s, 2H),
3.93 (s, 3H), 3.82 (s, 2H), 2.20 (s, 3H); dC (100 MHz; MeOD) 208.3
(C), 170.5 (C), 153.9 (C), 150.6 (C), 138.9 (C), 132.7 (CH), 132.3 (C),
132.1 (C), 130.6 (CH), 130.3 (2 ꢃ CH), 130.2 (2 ꢃ CH), 121.3 (C), 77.0
(CH2), 63.3 (CH3), 48.9 (CH2), 30.5 (CH3); m/z (ESIþ) [MþNa]þ
415.0162 calcd for C18H17BrNaO5 415.0152.
To a stirred solution of ketone 30 (0.20 g, 0.49 mmol) in MeOH-
THF (1:1, 8 mL) at 0 ꢂC was added NaBH4 (20.0 mg, 0.54 mmol) in
three portions over 10e15 min. Aqueous HCl (10 mL, 1.0 M) was
then added and the mixture stirred vigorously for 20 min before
being extracted with EtOAc (3ꢃ15 mL). The combined organic ex-
tracts were washed with brine (10 mL), dried over anhydrous
MgSO4, filtered and the filtrate concentrated in vacuo. The crude
product was purified by flash chromatography (hexanes-EtOAc,
5:1) to afford the title compound 31 (0.19 g, quant) as a colourless
oil; Rf: 0.34 (hexanes-EtOAc, 5:1); nmax(neat)/cmꢁ1 3031, 2975,
2950, 2940, 2850, 1715, 1581, 1561, 1453, 1432, 1405, 1373, 1249,
1212, 1076, 1046, 997, 962, 923; dH (400 MHz; CDCl3) 7.52 (d, 2H,
J¼7.0 Hz), 7.31e7.36 (m, 3H), 7.18 (s, 1H), 5.02 (s, 2H), 4.49e4.54 (m,
1H), 3.96 (s, 3H), 2.78e2.81 (m, 2H), 1.44 (d, 3H, J¼6.4 Hz); dC
(100 MHz; CDCl3) 161.4 (C), 156.2 (C), 149.4 (C), 136.7 (C), 136.2 (C),
128.4 (2 ꢃ CH), 128.2 (2 ꢃ CH), 128.2 (CH), 126.3 (C), 124.0 (C), 118.7
(C), 75.1 (CH2), 74.2 (CH), 61.8 (CH3), 34.9 (CH2), 20.3 (CH3); m/z
(ESIþ) [MþNa]þ 399.0212 calcd for C18H17NaBrO4 399.0202.
4.7. Methyl-3-(benzyloxy)-4-bromo-6-(2-((tert-butyldiphe-
nylsilyl)oxy)propyl)-2-methoxybenzoate (32)
4.4. 7-(Benzyloxy)-6-bromo-8-methoxy-3-methyl-1H-iso-
chromen-1-one (12)
To a stirred solution of ketone 30 (0.14 g, 0.35 mmol) in MeOH-
THF (3.0 mL, 1:1) at 0 ꢂC was added NaBH4 (14.5 mg, 0.38 mmol) in
three portions over 10e15 min. Water (5.0 mL) was then added at
the same temperature before the mixture was extracted with EtOAc
(3ꢃ8 mL). The combined organic extracts were washed with brine
(6 mL), dried over anhydrous Na2SO4, filtered and the filtrate con-
centrated in vacuo.
To a stirred solution of keto acid 26 (0.57 g, 1.45 mmol) in EtOAc-
Ac2O (30 mL, 5:1) was added HClO4 (3 drops) and stirred at rt for
30 min. Saturated aqueous NaHCO3 (25 mL) was added and the
aqueous layer was separated and extracted with EtOAc (3ꢃ15 mL).
The combined organic extracts were washed with brine (15 mL),
dried over anhydrous MgSO4, filtered and the filtrate concentrated
in vacuo. The crude product was purified by flash chromatography
(hexanes-EtOAc, 5:1) to afford the title compound 12 (0.51 g, 94%) as
a yellow solid; Mp¼133.4e134.2 ꢂC; Rf: 0.25 (hexanes-EtOAc, 5:1);
nmax(neat)/cmꢁ1 2947, 1733, 1666, 1579, 1462, 1376, 1300, 965, 751;
dH (400 MHz; CDCl3) 7.54 (d, J¼8.0 Hz, 2H), 7.36e7.42 (m, 3H), 7.30
(s, 1H), 6.07 (s, 1H), 5.09 (s, 2H), 4.00 (s, 3H), 2.24 (s, 3H); dC
(100 MHz; CDCl3) 158.8 (C), 156.0 (C), 154.9 (C), 148.8 (C), 136.4 (C),
135.9 (C), 128.7 (CH), 128.4 (2 ꢃ CH), 128.4 (2 ꢃ CH), 126.8 (C), 124.2
(CH), 113.7 (C), 102.1 (CH), 75.6 (CH2), 62.0 (CH3), 19.4 (CH3); m/z
(ESIþ) [MþH]þ 375.0216 calcd for C18H16BrO4 375.0226.
The crude alcohol was dissolved in CH2Cl2 (4 mL) and cooled to
ꢁ78 ꢂC. A solution of TBDPSOTf (0.18 g, 0.70 mmol) in CH2Cl2 (2 mL)
was added followed by 2,6-lutidiene (0.12 mL, 1.04 mmol) and the
mixture was stirred at ꢁ78 ꢂC for 4 h before being warmed to rt o/n
(cooling bath remained in place). Saturated aqueous NaHCO3 (5 mL)
was added and the aqueous layer was separated and extracted with
CH2Cl2 (3ꢃ8 mL). The combined organic extracts were washed with
brine (10 mL), dried over anhydrous MgSO4, filtered and the filtrate
concentrated in vacuo. The crude product was purified by flash
chromatography (hexanes-EtOAc, 19:1) to afford the title compound
32 (0.14 g, 78%) as a colourless oil; Rf: 0.33 (hexanes-EtOAc, 19:1);
nmax(neat)/cmꢁ1 3072, 2941, 2858, 1732, 1560, 1462, 1428, 1400,
1374, 1290, 1267, 1111, 1079, 1011, 994, 822, 739, 702; dH (300 MHz;
CDCl3) 7.36e7.71 (m, 15H), 7.10 (s, 1H), 5.00 (s, 2H), 4.03e4.10 (m,
1H), 3.91 (s, 3H), 3.83 (s, 3H), 2.73 (dd, J¼13.6, 6.8 Hz, 1H), 2.65 (dd,
13.6, 6.8 Hz), 0.99e1.02 (m,12H); dC (75 MHz; CDCl3) 167.4 (C),151.1
(C), 147.5 (C), 136.6 (C), 135.9 (2 ꢃ CH), 134.5 (C), 133.9 (C), 133.8 (C),
130.5 (CH), 129.6 (2 ꢃ CH), 129.5 (2 ꢃ CH), 129.5 (C), 128.6 (2 ꢃ CH),
128.5 (2 ꢃ CH), 128.3 (CH), 127.6 (2 ꢃ CH), 127.5 (2 ꢃ CH), 119.4 (C),
75.2 (CH2), 70.1 (CH), 61.9 (CH3), 52.2 (CH3), 42.6 (CH2), 26.8 (3 ꢃ
CH3), 23.3 (CH3), 19.1 (C); m/z (ESIþ) [MþNa]þ 669.1642 calcd for
4.5. Methyl 3-(benzyloxy)-4-bromo-2-methoxy-6-(2-
oxopropyl)benzoate (30)
To a stirred solution of acid 26 (1.03 g, 2.62 mmol) in acetone
(20 mL) was added K2CO3 (0.34 g, 2.88 mmol) and MeI (0.20 mL,
3.14 mmol) and the mixture was heated at 50 ꢂC for 3 h. The
mixture was then filtered through a silica plug and the plug washed
with EtOAc (40 mL). The filtrate was then concentrated in vacuo.
The residue was dissolved in EtOAc (20 mL) and washed with water
(2ꢃ5 mL). The combined aqueous washings were extracted with
EtOAc (3ꢃ15 mL). The combined organic extracts were washed
with brine (20 mL), dried over anhydrous MgSO4, filtered and the
filtrate concentrated in vacuo. The crude product was purified by
flash chromatography (hexanes-EtOAc, 3:1) to afford the title
compound 30 (0.85 g, 80%) as a yellow oil; Rf: 0.27 (hexanes-EtOAc,
4:1); nmax(neat)/cmꢁ1 2947, 1722, 1559, 1449, 1399, 1288, 1142,
1066, 1011, 826, 735, 697; dH (400 MHz; CDCl3) 7.54 (d, J¼7.2 Hz,
2H), 7.34e7.41 (m, 3H), 7.18 (s, 1H), 5.02 (s, 2H), 3.92 (s, 3H), 3.89 (s,
3H), 3.69 (s, 2H), 2.17 (s, 3H); dC (100 MHz; CDCl3) 204.3 (C), 166.9
(C), 152.1 (C), 148.6 (C), 136.3 (C), 130.3 (CH), 129.9 (C), 128.4 (2 ꢃ
CH), 128.3 (2 ꢃ CH), 128.2 (CH), 120.2 (C), 75.0 (CH2), 61.8 (CH3),
52.2 (CH3), 47.4 (CH2), 29.4 (CH3); m/z (ESIþ) [MþNa]þ 429.0308
calcd for C19H19BrNaO5 429.0300.
C35H39BrNaO5Si 669.1636.
4.8. 7-(Benzyloxy)-6-(4-(3-(ethoxymethoxy)-1,4,5,6,8-
pentamethoxynaphthalen-2-yl)-3-hydroxybut-1-yn-1-yl)-8-
methoxy-3-methyl-1H-isochromen-1-one (27)
To a mixture of bromide 12 (0.134 g, 0.357 mmol), Pd(OAc)2
(8.0 mg, 0.036 mmol), CuI (8.6 mg, 0.045 mmol), PPh3 (18.0 mg,
0.089 mmol) in DMF (4 mL, degassed with N2) was added NEt3
(0.075 mL, 0.54 mmol) followed by the dropwise addition of alkyne
11 (0.30 g, 0.71 mmol) in DMF (2 mL, degassed with N2). The
mixture was degassed with N2 for a further 1 h and then stirred at rt
for 24 h. Aqueous HCl (5 mL, 1.0 M) was added and the aqueous

98
D.J. Atkinson et al. / Tetrahedron 71 (2015) 91e101
layer was separated and extracted with EtOAc (3ꢃ8 mL). The
combined organic extracts were washed with brine, dried over
anhydrous MgSO4, filtered and the filtrate concentrated in vacuo.
The crude product was purified by flash chromatography (hexanes-
EtOAc, 1:1) to afford the title compound 27 (0.16 g, 64%) as a yellow
oil; Rf: 0.33 (hexanes-EtOAc, 1:1); nmax(neat)/cmꢁ1 3462, 2933,
2841, 1733, 1666, 1595, 1454, 1358, 1056, 1005, 521; dH (400 MHz;
CDCl3) 7.57 (d, J¼1.2 Hz, 2H), 7.31e7.41 (m, 3H), 7.09 (s, 1H), 6.66 (s,
1H), 6.07 (s, 1H), 5.37, 5.31 (ABq, JAB¼6.0 Hz, 2H), 5.15 (s, 2H),
4.95e5.00 (m, 1H), 4.00 (s, 3H), 3.98 (s, 3H), 3.97 (s, 3H), 3.87e3.94
(m, 1H), 3.77e3.82 (m, 9H), 3.40e3.42 (m, 2H), 2.23 (s, 3H) 1.26 (t,
J¼6.8 Hz, 3H); dC (100 MHz; CDCl3) 158.7 (C), 154.9 (C), 153.9 (C),
152.7 (C), 151.6 (C), 151.2 (C), 149.7 (C), 148.6 (C), 142.5 (C), 136.7 (C),
136.3 (C), 134.8 (C), 128.3 (2 ꢃ CH), 128.1 (2 ꢃ CH), 127.9 (CH), 125.9
(C), 125.6 (C), 124.2 (CH), 120.9 (C), 114.2 (C), 113.9 (C), 102.4 (CH),
99.3 (C), 98.6 (CH2), 96.2 (CH), 79.1 (C), 75.6 (CH2), 65.5 (CH2), 62.8
(CH), 62.0 (CH3), 61.6 (CH3), 61.5 (CH3), 61.2 (CH3), 56.6 (CH3), 56.5
(CH3), 33.0 (CH2), 19.1 (CH3), 14.9 (CH3); m/z (ESIþ) [MþNa]þ
737.2555 calcd for C40H42NaO12 737.2586.
4.10. 7-Hydroxy-6-(4-(3-hydroxy-1,4,5,6,8-
pentamethoxynaphthalen-2-yl)-3-oxobutyl)-8-methoxy-3-
methyl-1H-isochromen-1-one (29)
To a stirred solution of ether 9 (40.0 mg, 0.064 mmol) in CH2Cl2
(3.0 mL) was added PPTS (0.16 g, 0.64 mmol) and stirred at rt for
12 h. The mixture was filtered through a silica plug and the plug
was washed with CH2Cl2 (15 mL). The solvent was removed in
vacuo and the crude product was purified by flash chromatography
(hexanes-EtOAc,1e2) to afford the title compound 29 (32.2 mg, 90%)
as a yellow oil; Rf: 0.38 (hexanes-EtOAc, 1:2); nmax(neat)/cmꢁ1 3391,
2926, 2850, 1715, 1665, 1607, 1480, 1454, 1357, 1296, 1255, 1210,
1167, 1089, 1007, 988, 942, 878, 817, 734, 657; dH (400 MHz; CDCl3)
6.88 (s, 1H), 6.56 (s, 1H), 6.40 (br s, 1H), 6.36 (br s, 1H), 6.05 (s, 1H),
3.99 (s, 3H), 3.96 (s, 3H), 3.95 (s, 3H), 3.90 (s, 2H), 3.82 (s, 3H), 3.77
(s, 3H), 3.66 (s, 3H), 2.99e3.03 (m, 2H), 2.91e2.95 (m, 2H), 2.19 (s,
3H); dC (100 MHz; CDCl3) 207.8 (C), 159.7 (C), 153.4 (C), 152.2 (2 ꢃ
C), 151.9 (C), 146.9 (C), 146.6 (C), 146.3 (C), 136.9 (C), 135.0 (C), 131.6
(C),128.5 (C),124.7 (C),121.8 (CH),114.2 (C),111.8 (C),111.2 (C),103.3
(CH), 94.5 (CH), 62.6 (CH3), 62.4 (CH3), 62.3 (CH3), 61.9 (CH3), 56.7
(CH3), 56.6 (CH3), 40.9 (CH2), 38.7 (CH2), 25.0 (CH2), 19.2 (CH3); m/z
(ESIþ) [MþNa]þ 591.1837 calcd for C30H32NaO11 591.1828.
4.9. 6-(4-(3-(Ethoxymethoxy)-1,4,5,6,8-
pentamethoxynaphthalen-2-yl)-3-oxobutyl)-7-hydroxy-8-
methoxy-3-methyl-1H-isochromen-1-one (9)
4.11. 7-(Benzyloxy)-6-(4-(3-(ethoxymethoxy)-1,4,5,6,8-
pentamethoxynaphthalen-2-yl)-3-hydroxybut-1-yn-1-yl)-8-
methoxy-3-methylisochroman-1-one (33)
To a stirred solution of alkynol 27 (0.27 g, 0.38 mmol) in DMSO
(4 mL) was added a solution of IBX (0.42 g, 1.51 mmol) in DMSO
(3 mL) and stirred at rt for 5 h. The mixture was diluted with
EtOAc (10 mL) and saturated aqueous Na2SO3 (10 mL). The aque-
ous layer was separated and extracted with EtOAc (3ꢃ10 mL). The
combined organic extracts were washed with brine (15 mL), dried
over anhydrous MgSO4, filtered and the filtrate concentrated in
vacuo. The crude product was purified by flash chromatography
(hexanes-EtOAc, 1:1) to afford the ketone (0.22 g, 80%) as a yellow
oil; Rf: 0.50 (hexanes-EtOAc, 1:1); nmax(neat)/cmꢁ1 2932, 2202,
1737, 1668, 1602, 1455, 1358, 1253, 1172, 1105, 1053, 1005; dH
(400 MHz; CDCl3) 7.50e7.51 (m, 2H), 7.30e7.38 (m, 3H), 6.93 (s,
1H), 6.68 (s, 1H), 5.98 (s, 1H), 5.33 (s, 2H), 5.13 (s, 2H), 4.22 (s, 2H),
4.00 (s, 3H), 3.96 (s, 3H), 3.96 (s, 3H), 3.78e3.84 (m, 2H), 3.82 (s,
3H), 3.80 (s, 3H), 3.75 (s, 3H), 2.21 (s, 3H), 1.23 (t, J¼8.0 Hz, 3H); dC
(100 MHz; CDCl3) 185.1 (C), 158.5 (C), 155.2 (C), 154.6 (C), 153.1 (C),
152.5 (C), 151.7 (C), 150.2 (C), 147.9 (C), 142.6 (C), 136.5 (C), 136.3
(C), 135.0 (C), 128.7 (2 ꢃ CH), 128.4 (2 ꢃ CH), 128.4 (CH), 126.3 (C),
125.4 (CH), 123.0 (C), 118.4 (C), 115.8 (C), 114.2 (C), 102.4 (CH), 98.3
(CH2), 96.1 (CH), 93.5 (C), 85.2 (C), 76.2 (CH2), 65.7 (CH2), 62.3
(CH3), 61.9 (CH3), 61.8 (CH3), 61.5 (CH3), 56.7 (CH3), 56.7 (CH3), 41.5
(CH2), 19.3 (CH3), 15.2 (CH3); m/z (ESIþ) [MþNa]þ 735.2398 calcd
for C40H40NaO12 735.2412.
To a mixture of bromide 31 (0.17 g, 0.46 mmol), Pd(OAc)2
(10.3 mg, 0.046 mmol), CuI (10.4 mg, 0.055 mmol), PPh3 (23.1 mg,
0.11 mmol) in DMF (3 mL, degassed) was added NEt3 (96.0
mL,
0.69 mmol) followed by a solution of alkyne 11 (0.38 g, 0.91 mmol)
in DMF (2 mL, degassed) dropwise. The reaction mixture was
degassed for a further 1 h and then stirred at rt for 24 h. Aqueous
HCl (6 mL, 1.0 M) was added and the mixture extracted with EtOAc
(3ꢃ8 mL). The combined organic extracts were washed with brine
(5 mL), dried over anhydrous MgSO4, filtered and the filtrate con-
centrated in vacuo. The crude product was purified by flash chro-
matography (hexanes-EtOAc, 1:1) to afford the title compound 33
(76.0 mg, 23%) as viscous orange oil; Rf: 0.23 (hexanes-EtOAc, 1:1);
nmax(neat)/cmꢁ1 3454, 2980, 1722, 1602, 1456, 1358, 1251, 1056,
1005; dH (400 MHz; CDCl3) 7.55 (d, J¼7.2 Hz, 2H), 7.30e7.38 (m, 3H),
6.98 (s, 1H), 6.65 (s, 1H), 5.35, 5.29 (ABq, JAB¼6.0 Hz, 2H), 5.11 (s,
2H), 4.97e4.98 (m, 1H), 4.52e4.57 (m, 1H), 3.96e3.98 (m, 9H),
3.87e3.92 (m, 2H), 3.78e3.82 (m, 9H), 3.63 (br s, 1H), 3.38e3.41 (m,
2H), 2.77e2.81 (m, 2H), 1.47 (d, J¼6.4 Hz, 3H), 1.25 (t, J¼7.2 Hz, 3H);
dC (100 MHz; CDCl3) 161.8 (C), 155.5 (C), 152.9 (C), 152.8 (C), 151.3
(C),149.9 (C), 148.8 (C), 142.7 (C),136.9 (C), 136.5 (C), 135.5 (C), 128.5
(2 ꢃ CH), 128.3 (2 ꢃ CH), 128.1 (CH), 126.2 (CH), 125.8 (C), 123.8 (C),
121.1 (C), 119.3 (C), 114.4 (C), 98.9 (C), 98.8 (CH2), 96.4 (CH), 79.4 (C),
75.6 (CH2), 74.4 (CH), 65.7 (CH2), 63.0 (CH), 62.2 (CH3), 61.9 (CH3),
61.8 (CH3), 61.4 (CH3), 56.8 (CH3), 56.7 (CH3), 35.3 (CH2), 33.2 (CH2),
20.5 (CH3), 15.1 (CH3). m/z (ESIþ) [MþH]þ 717.2898 calcd for
To a stirred solution of the ketone (0.21 g, 0.30 mmol) in MeOH
(6 mL) was added 10% Pd/C (0.11 g, 1.01 mmol) and stirred under
a H2 atmosphere for 1 h. The mixture was filtered through a pad of
CeliteÒ, and the pad was washed with EtOAc (30 mL). The filtrate
was concentrated in vacuo to afford the title compound 9 (0.18 g,
99%) as a yellow oil; Rf: 0.49 (hexanes-EtOAc, 1:2); nmax(neat)/
cmꢁ1 3395, 2931, 1715, 1666, 1604, 1479, 1453, 1425, 1383, 1355,
1340, 1208, 1133, 1045, 1003, 935, 732; dH (400 MHz; CDCl3) 6.89
(s, 1H), 6.65 (s, 1H), 6.37 (br s, 1H), 6.06 (s, 1H), 5.25 (s, 2H), 3.99 (s,
3H), 3.96 (s, 3H), 3.95 (s, 3H), 3.93 (s, 2H), 3.80 (s, 3H), 3.78 (s, 3H),
3.78 (q, J¼7.2 Hz, 2H), 3.64 (s, 3H), 2.99e3.03 (m, 2H), 2.88e2.92
(m, 2H), 2.21 (s, 3H), 1.22 (t, J¼6.8 Hz, 3H); dC (100 MHz; CDCl3)
207.9 (C), 159.7 (C), 153.0 (C), 152.3 (C), 151.2 (C), 150.0 (C), 147.7
(C), 147.0 (C), 146.7 (C), 142.7 (C), 137.0 (C), 136.7 (C), 131.7 (C),
126.0 (C), 121.9 (CH), 119.8 (C), 114.4 (C), 111.2 (C), 103.3 (CH), 98.3
(CH2), 96.3 (CH), 65.8 (CH2), 62.4 (CH3), 62.1 (CH3), 61.9 (CH3), 61.6
(CH3), 56.9 (CH3), 56.8 (CH3), 40.8 (CH2), 39.4 (CH2), 25.0 (CH2),
19.3 (CH3), 15.3 (CH3); m/z (ESIþ) [MþNa]þ 649.2238 calcd for
C40H45O12 717.2906.
4.12. 6-(4-(3-(Ethoxymethoxy)-1,4,5,6,8-
pentamethoxynaphthalen-2-yl)-3-oxobutyl)-7-hydroxy-8-
methoxy-3-methylisochroman-1-one (34)
To a stirred solution of alcohol 33 (76 mg, 0.11 mmol) in DMSO
(2 mL) was added a solution of IBX (90 mg, 0.32 mmol) in DMSO
(3 mL) and stirred at rt for 4 h. Saturated aqueous Na2SO3 (4 mL)
was added and aqueous layer was separated and extracted with
EtOAc (3ꢃ5 mL). Combined organic extracts were washed with
brine (3 mL), dried over anhydrous MgSO4, filtered and the filtrate
concentrated in vacuo. The crude product was purified by flash
chromatography (hexanes-EtOAc, 1:1) to afford the ketone
C
33H38NaO12 649.2239.

D.J. Atkinson et al. / Tetrahedron 71 (2015) 91e101
99
(59.0 mg, 80%) as a viscous yellow oil; Rf: 0.26 (hexanes-EtOAc,
1:1); nmax(neat)/cmꢁ1 2930, 2197, 1725, 1674, 1599, 1454, 1416,
1357, 1251, 1209, 1122, 1051, 1004, 927, 756, 699; dH (400 MHz;
CDCl3) 7.48 (d, J¼7.2 Hz, 2H), 7.30e7.38 (m, 3H), 6.84 (s, 1H), 6.64
(s, 1H), 5.29 (s, 2H), 5.09 (s, 2H), 4.48e4.56 (m, 1H), 4.19 (s, 2H),
3.99 (s, 3H), 3.95 (s, 3H), 3.94 (s, 3H), 3.75e3.81 (m, 8H), 3.71 (s,
3H), 2.66e2.81 (m, 2H), 1.47 (d, J¼6.4 Hz, 3H), 1.21 (t, 3H); dC
(100 MHz; CDCl3) 185.2 (C), 161.4 (C), 155.5 (C), 154.0 (C), 153.1 (C),
151.6 (C), 151.0 (C), 147.9 (C), 142.6 (C), 136.6 (C), 136.3 (C), 135.6
(C), 128.7 (2 ꢃ CH), 128.5 (2 ꢃ CH), 128.4 (CH), 127.0 (CH), 126.3
(C), 121.4 (C), 120.7 (C), 118.5 (C), 114.3 (C), 98.3 (CH2), 96.1 (CH),
93.4 (C), 85.5 (C), 76.1 (CH2), 74.5 (CH), 65.7 (CH2), 62.4 (CH3), 62.0
(CH3), 61.8 (CH3, 61.6 (CH3), 56.8 (CH3), 56.8 (CH3), 41.5 (CH2), 35.2
(CH2), 20.5 (CH3), 15.2 (CH3); m/z (ESIþ) [MþNa]þ 737.2564 calcd
for C40H42NaO12 737.2568.
(CH3), 19.0 (C), 15.0 (CH3); m/z (ESIþ) [MþNa]þ 1009.4165 calcd for
C57H66NaO13Si 1009.4136.
4.14. Methyl 3-(benzyloxy)-6-(2-((tert-butyldiphenylsilyl)oxy)
propyl)-4-(4-(3-(ethoxymethoxy)-1,4,5,6,8-
pentamethoxynaphthalen-2-yl)-3-oxobut-1-yn-1-yl)-2-
methoxybenzoate (38)
To a stirred solution of alcohol 36 (47 mg, 0.061 mmol) in DMSO
(1 mL) was added a solution of IBX (60 mg, mmol) in DMSO (1 mL)
and stirred at rt for 5 h. Saturated aqueous Na2SO3 (2 mL) was
added and aqueous layer was separated and extracted with EtOAc
(3ꢃ3 mL). The combined organic extracts were washed with brine
(2 mL), dried over anhydrous MgSO4, filtered and the filtrate con-
centrated in vacuo. The crude product was purified by flash chro-
matography (hexanes-EtOAc, 2:1) to afford the title compound 38
(38.6 mg, 82%) as a yellow oil; Rf: 0.63 (hexanes-EtOAc, 1:1);
nmax(neat)/cmꢁ1 2940, 2864, 2198, 1734, 1677, 1601, 1454, 1353,
1212, 1111, 1053, 1004, 703; dH (400 MHz; CDCl3) 7.30e7.67 (m,
15H), 6.90 (s, 1H), 6.64 (s, 1H), 5.29 (s, 2H), 5.05 (s, 2H), 4.21 (s, 2H),
4.00e4.04 (m, 1H), 3.98 (s, 3H), 3.95 (s, 3H), 3.84 (s, 3H), 3.74e3.82
(m, 11H), 3.71 (s, 3H), 2.70e2.75 (m, 1H), 2.55e2.60 (m, 1H), 1.18 (t,
J¼7.0 Hz, 3H), 0.96e0.97 (m, 12H); dC (100 MHz; CDCl3) 185.1 (C),
167.1 (C), 153.0 (C), 152.3 (C), 151.6 (C) 150.1 (C), 147.9 (C), 142.5 (C),
136.7 (C), 136.5 (C), 135.9 (2 ꢃ CH), 135.8 (CH), 134.5 (C), 133.8 (C),
132.7 (C), 132.5 (C), 131.8 (CH), 129.7 (2 ꢃ CH), 129.6 (2 ꢃ CH), 128.6
(2 ꢃ CH), 128.5 (2 ꢃ CH), 128.3 (CH), 127.6 (2 ꢃ CH), 127.5 (2 ꢃ CH),
126.2 (C), 118.5 (C), 116.7 (C), 114.3 (C), 98.3 (CH2), 96.3 (CH), 92.4
(C), 86.2 (C), 75.9 (CH2), 70.0 (CH), 65.7 (CH2), 62.4 (CH3), 61.8 (CH3),
61.8 (CH3), 61.6 (CH3), 56.8 (CH3), 56.8 (CH3), 52.3 (CH3), 42.7 (CH2),
41.6 (CH2), 26.8 (3 ꢃ CH3), 23.3 (CH3),19.1 (C),15.2 (CH3); m/z (ESIþ)
[MþNa]þ 1007.4008 calcd for C57H64NaO13Si 1007.3974.
To a stirred solution of the ketone (17.4 mg, 0.024 mmol) in
MeOH (3 mL) was added Pd/C (7.0 mg, 0.066 mmol) and stirred
under a H2 atmosphere at rt for 2 h. The mixture was filtered
through a silica plug and the plug was washed with EtOAc (20 mL).
The filtrate was concentrated in vacuo to afford the title compound
34 (15.3 mg, quant) as a viscous yellow oil. Rf: 0.38 (hexanes-EtOAc,
1:2); nmax(neat)/cmꢁ1 3374, 2930, 1715, 1605, 1458, 1357, 1210, 1135,
1053, 1005, 941; dH (400 MHz; CDCl3) 6.75 (s, 1H), 6.64 (s, 1H), 6.33
(br s, 1H), 5.25 (s, 2H), 4.50e4.55 (m, 1H), 3.98 (s, 3H), 3.95 (s, 3H),
3.93 (s, 3H), 3.92 (s, 2H), 3.80 (s, 3H), 3.78 (s, 3H), 3.75 (q, J¼7.2 Hz,
2H), 3.64 (s, 3H), 2.91e2.95 (m, 2H), 2.84e2.89 (m, 2H), 2.74e2.77
(m, 2H), 1.45 (d, J¼6.4 Hz, 3H), 1.22 (t, J¼7.2 Hz, 3H); dC (100 MHz;
CDCl3) 208.2 (C), 161.8 (C), 152.9 (C), 151.1 (C), 150.0 (C), 148.2 (C),
147.7 (C), 146.9 (C), 142.6 (C), 136.6 (C), 134.2 (C), 131.4 (C), 125.9 (C),
123.8 (CH), 119.8 (C), 115.0 (C), 114.3 (C), 98.3 (CH2), 96.2 (CH), 74.9
(CH), 65.7 (CH2), 62.1 (CH3), 62.1 (CH3), 61.8 (CH3), 61.6 (CH3), 56.8
(CH3), 56.7 (CH3), 41.0 (CH2), 39.3 (CH2), 35.2 (CH2), 24.7 (CH2), 20.6
(CH3), 15.2 (CH3); m/z (ESIþ) [MþNa]þ 651.2417 calcd for
C
33H40NaO12 651.2412.
4.15. Methyl 6-(2-((tert-butyldiphenylsilyl)oxy)propyl)-4-(4-
(3-(ethoxymethoxy)-1,4,5,6,8-pentamethoxynaphthalen-2-
yl)-3-oxobutyl)-3-hydroxy-2-methoxybenzoate (39)
4.13. Methyl 3-(benzyloxy)-6-(2-((tert-butyldiphenylsilyl)oxy)
propyl)-4-(4-(3-(ethoxymethoxy)-1,4,5,6,8-
pentamethoxynaphthalen-2-yl)-3-hydroxybut-1-yn-1-yl)-2-
methoxybenzoate (36)
To a stirred solution of alkyne 38 (75 mg, 0.076 mmol) in MeOH
(3 mL) was added Pd/C (10 mg, 0.094 mol) and stirred under a H2
atmosphere at rt for 2 h. The mixture was filtered through a silica
plug and the plug was washed with EtOAc (10 mL). The filtrate was
concentrated in vacuo to afford the title compound 39 (0.068 mg,
quant) as a yellow oil. Rf: 0.20 (hexanes-EtOAc, 2:1); nmax(neat)/
cmꢁ1 3376, 2937, 2859, 1725, 1602, 1447, 1356, 1280, 1207, 1109,
1053, 1005, 939, 822, 741, 704, 611; dH (400 MHz; CDCl3) 7.29e7.65
(m,10H), 6.72 (br s,1H), 6.64 (s,1H), 6.47 (s,1H), 5.24 (s, 2H), 4.00 (s,
3H), 3.94e3.99 (m, 4H), 3.90 (s, 2H), 3.80 (s, 3H), 3.79 (s, 3H), 3.77
(s, 3H), 3.76 (s, 3H), 3.71 (q, J¼8.0 Hz, 2H), 3.63 (s, 3H), 2.56e2.85
(m, 6H), 1.20 (t, J¼8.0 Hz, 3H), 0.94e0.97 (m, 12H); dC (100 MHz;
CDCl3) 210.1 (C), 168.1 (C), 153.0 (C), 151.1 (C), 150.0 (C), 147.7 (C),
145.5 (C), 144.8 (C), 142.6 (C), 136.7 (C), 135.9 (4 ꢃ CH), 134.7 (C),
134.2 (C), 130.1 (2 ꢃ C), 129.4 (2 ꢃ CH), 128.2 (CH), 128.0 (2 ꢃ CH),
127.4 (2 ꢃ CH), 126.2 (C), 126.0 (C), 119.7 (C), 114.3 (C), 98.3 (CH2),
96.3 (CH), 70.7 (CH), 65.7 (CH2), 62.1 (CH3), 61.8 (CH3), 61.7 (CH3),
61.6 (CH3), 56.8 (CH3), 56.8 (CH3), 52.0 (CH3), 42.8 (CH2), 42.4 (CH2),
39.2 (CH2), 26.9 (3 ꢃ CH3), 24.0 (CH2) 23.1 (CH3),19.1 (C),15.2 (CH3);
m/z (ESIþ) [MþNa]þ 921.3852 calcd for C50H62NaO13Si 921.3875.
To a mixture of Pd(OAc)2 (3.47 mg, 0.015 mmol), 1,1ʹ-bis(di-tert-
butyl phosphino)ferrocene (8.80 mg, 0.019 mmol), K2CO3 (53.0 mg,
0.39 mmol), alkyne 11 (32 mg, 0.077 mmol) and aryl bromide 32
(50 mg, 0.077 mmol) under an argon atmosphere was added NMP
(4 mL, degassed with argon). The mixture was heated at 150 ꢂC
(sand bath) for 1.5 h and then cooled to rt. The mixture was filtered
through a silica plug and the plug was washed with EtOAc (50 mL).
The filtrate was washed with water (35 mL), brine (35 mL), dried
over anhydrous MgSO4, filtered and the filtrate concentrated in
vacuo. The crude product was purified by flash chromatography
(hexanes-EtOAc, 2:1) to afford the title compound 36 (64.0 mg, 84%)
as a yellow oil; Rf: 0.52 (hexanes-EtOAc,1:1); nmax(neat)/cmꢁ1 3460,
2930, 2854, 1729, 1600, 1448, 1380, 1357, 1105, 1055, 1005, 940; dH
(400 MHz; CDCl3) 7.31e7.71 (m, 15H), 6.95 (s, 1H), 6.67 (s, 1H), 5.38,
5.33 (ABq, JAB¼8.0 Hz, 2H), 5.10 (s, 2H), 4.97e5.02 (m, 1H),
4.05e4.10 (m, 1H), 3.99 (s, 3H), 3.97 (s, 3H), 3.89 (s, 3H), 3.80e3.83
(m, 14H), 3.59 (d, J¼7.2 Hz, 1H), 3.41e3.44 (m, 2H), 2.76e2.81 (m,
1H), 2.61e2.66 (m, 1H), 1.22e1.26 (m, 3H), 1.01e0.99 (m, 12H); dC
(100 MHz; CDCl3) 167.5 (C), 152.8 (C), 151.3 (C), 151.0 (C), 150.0 (C),
149.8 (C), 148.9 (C), 142.6 (C), 137.0 (C), 136.5 (C), 135.7 (2 ꢃ CH),
134.5 (C), 133.8 (C), 132.2 (C), 130.7 (CH), 130.0 (C), 129.5 (2 ꢃ CH),
129.4 (2 ꢃ CH), 128.4 (2 ꢃ CH), 128.3 (2 ꢃ CH), 128.0 (CH), 127.5 (2 ꢃ
CH), 127.4 (2 ꢃ CH), 125.7 (C), 121.2 (C), 119.6 (C), 114.4 (C), 98.8
(CH2), 96.5 (C), 96.4 (CH), 79.5 (C), 75.4 (CH2), 70.0 (CH), 65.7 (CH2),
62.9 (CH), 62.2 (CH3), 61.7 (CH3), 61.7 (CH3), 61.3 (CH3), 56.8 (CH3),
56.7 (CH3), 52.0 (CH3), 42.6 (CH2), 33.3 (CH2), 26.8 (3 ꢃ CH3), 23.1
4.16. Methyl-6-(2-((tert-butyldiphenylsilyl)oxy)propyl)-
4ʹ,5ʹ,7ʹ,8,8ʹ,9ʹ-hexamethoxy-3ʹH-spiro[chroman-2,2ʹ-naphtho
[2,3-b]furan]-7-carboxylate (40)
To a stirred solution of ketone 39 (52.4 mg, 0.058 mmol) in
CH2Cl2 (4 mL) was added NaHSO4.SiO2 (0.40 g) and stirred at rt for
6 h. The mixture was filtered through cotton wool and washed with
EtOAc (15 mL) and the filtrate was concentrated in vacuo. The crude

100
D.J. Atkinson et al. / Tetrahedron 71 (2015) 91e101
product was purified by flash chromatography (hexanes-EtOAc,
2:1) to afford the title compound 40 (23.1 mg, 48%) as a yellow oil;
Rf: 0.27 (hexanes-EtOAc, 2:1); nmax(neat)/cmꢁ1 2940, 2895, 1731,
1642, 1604, 1441, 1355, 1255, 1206, 1055, 1006, 873, 823, 704; dH
(400 MHz; CDCl3) 7.34e7.69 (m, 10H), 6.59 (s, 1H), 6.57 (s, 1H),
4.03e4.06 (m, 1H), 3.97 (s, 6H), 3.84 (s, 3H) 3.79 (m, 3H), 3.64e3.73
(m, 7H), 3.58 (m, 3H), 3.40 (dd, J¼16.8, 1.2 Hz), 3.17e3.31 (m, 1H),
2.57e2.76 (m, 3H), 2.39 (ddd, J¼13.4, 6.2, 2.2 Hz, 1H), 2.19e2.27 (m,
1H), 0.98e1.01 (m, 12H); dC (100 MHz; CDCl3) 168.1 (C), 153.3 (C),
149.9 (C), 149.1 (C), 148.7 (C), 145.2 (C), 143.3 (C), 137.1 (C), 135.9 (4
ꢃ CH), 134.8 (C), 134.1 (C), 133.0 (C), 129.4 (4 ꢃ CH), 128.9 (C), 127.5
(2 ꢃ CH), 127.4 (CH), 127.2 (C), 126.4 (C), 124.0 (C), 117.8 (C), 113.6
(C), 109.8 (C), 95.1 (CH) 70.6 (CH), 61.9 (CH3), 61.8 (CH3), 61.7 (CH3),
61.5 (CH3), 56.8 (CH3), 56.8 (CH3), 51.9 (CH3), 42.7 (CH2), 39.6 (CH2),
29.9 (CH2), 26.9 (3 ꢃ CH3), 23.3 (CH3), 21.9 (CH2), 19.2 (C); m/z
(ESIþ) [MþNa]þ 845.3328 calcd for C47H54NaO11Si 845.3317.
J¼8.0 Hz, 2H), 7.30e7.37 (m, 3H), 6.77 (s, 1H), 6.64 (s, 1H), 5.29 (s,
2H), 5.07 (s, 2H), 4.17 (s, 2H), 3.98 (s, 3H), 3.94 (s, 3H), 3.87 (s, 3H),
3.86 (s, 3H), 3.76e3.80 (m, 8H), 3.71 (s, 3H), 3.56 (s, 2H), 2.12 (s, 3H),
1.21 (t, J¼8.0 Hz, 3H); dC (100 MHz; CDCl3) 204.3 (C),185.3 (C), 166.8
(C), 153.3 (C), 153.0 (C), 151.6 (C), 151.1 (C), 150.1 (C), 148.0 (C), 142.5
(C), 136.6 (C), 136.3 (C), 131.6 (CH), 131.4 (C), 128.6 (2 ꢃ CH), 128.6 (2
ꢃ CH), 128.4 (CH), 128.3 (C), 126.2 (C), 118.7 (C), 117.5 (C), 114.2 (C),
98.3 (CH2), 96.1 (CH), 92.6 (C), 86.2 (C), 75.9 (CH2), 65.7 (CH2), 62.4
(CH3), 61.8 (CH3), 61.8 (CH3), 61.5 (CH3), 56.7 (CH3), 56.7 (CH3), 52.4
(CH3), 47.5 (CH2), 41.5 (CH2), 29.4 (CH3), 15.2 (CH3); m/z (ESIþ)
[MþK]þ 786.2417 calcd for C41H44KO13 783.2413.
4.19. Methyl 4-(4-(3-(ethoxymethoxy)-1,4,5,6,8-
pentamethoxynaphthalen-2-yl)-3-oxobutyl)-3-hydroxy-2-
methoxy-6-(2-oxopropyl)benzoate (43)
To a stirred solution of alkyne 37 (0.25 mg, 0.36 mmol) in MeOH
(5 mL) was added Pd/C (0.11 mg, 1.01 mmol) and stirred under a H2
atmosphere and stirred at rt for 2 h. The mixture was filtered
through a silica plug and the plug was washed with EtOAc (50 mL).
The filtrate was concentrated in vacuo to afford the title compound
43 (0.22 g, quant) as a yellow oil. Rf: 0.40 (hexanes-EtOAc, 2:3);
nmax(neat)/cmꢁ1 3404, 2935, 2839, 1714, 1601, 1454, 1355, 1344,
1280, 1204, 1047, 1002, 934, 812, 732; dH (400 MHz; CDCl3) 6.74 (br
s, 1H), 6.68 (s, 1H), 6.65 (s, 1H), 5.25 (s, 2H), 3.99 (s, 3H), 3.95 (s, 3H),
3.92 (s, 2H), 3.87 (s, 3H), 3.84 (s, 3H), 3.80 (s, 3H), 3.78 (s, 3H),
3.69e3.76 (m, 2H), 3.64 (s, 3H), 2.88 (s, 4H), 2.11 (s, 3H), 1.21 (t,
J¼7.2 Hz, 3H); dC (100 MHz; CDCl3) 209.7 (C), 206.0 (C), 167.6 (C),
153.0 (C), 151.1 (C), 150.0 (C), 147.7 (C), 146.6 (C), 146.0 (C), 142.6 (C),
136.6 (C), 131.1 (C), 128.0 (CH), 126.0 (C), 124.9 (C), 124.6 (C), 119.7
(C), 114.3 (C), 98.3 (CH2), 96.3 (CH), 65.7 (CH2), 62.1 (CH3), 61.8
(CH3), 61.8 (CH3), 61.6 (CH3), 56.8 (CH3), 56.8 (CH3), 52.1 (CH3), 48.2
(CH2), 42.0 (CH2), 39.3 (CH2), 29.2 (CH3), 24.0 (CH2), 15.2 (CH3); m/z
(ESIþ) [MþNa]þ 681.2518 calcd for C34H42NaO13 681.2495.
4.17. Methyl-3-(benzyloxy)-4-(4-(3-(ethoxymethoxy)-
1,4,5,6,8-pentamethoxynaphthalen-2-yl)-3-hydroxybut-1-yn-
1-yl)-2-methoxy-6-(2-oxopropyl)benzoate (37)
To a mixture of Pd(OAc)2 (0.11 g, 0.49 mmol), 1,1ʹ-bis(di-tert-
butyl phosphino)ferrocene (0.31 g, 0.66 mmol), K2CO3 (1.81 g,
13.1 mmol), alkyne 11 (1.38 g, 3.25 mmol) and aryl bromide 30
(1.34 g, 3.25 mmol) under an argon atmosphere was added NMP
(12 mL, degassed with argon). The mixture was heated at 70 ꢂC
(sand bath) for 1.5 h. After cooling to rt the mixture was filtered
through a silica plug and the plug was washed with EtOAc (50 mL).
The filtrate was washed with water (2ꢃ20 mL) and the combined
aqueous washings were extracted with EtOAc (3ꢃ30 mL). Com-
bined organic extracts were washed with brine (40 mL), dried over
anhydrous MgSO4, filtered and the filtrate concentrated in vacuo.
The crude product was purified by flash chromatography (hexanes-
EtOAc, 2:3) to afford the title compound 37 (1.2 g, 50%) as a viscous
orange oil; Rf: 0.21 (hexanes-EtOAc, 1:1); nmax(neat)/cmꢁ1 3438,
2940, 2846, 1721, 1604, 1555, 1448, 1413, 1352, 1285, 1173, 1043,
1007, 820, 733, 698; dH (400 MHz; CDCl3) 7.55 (d, J¼7.2 Hz, 2H),
7.30e7.39 (m, 3H), 6.99 (s, 1H), 6.65 (s, 1H), 5.35, 5.30 (ABq,
JAB¼6.0 Hz, 2H) 5.11 (s, 2H), 4.94e4.97 (m, 1H), 3.98 (s, 3H), 3.96 (s,
3H), 3.90 (s, 3H), 3.89 (s, 3H), 3.77e3.79 (m, 11H), 3.64 (s, 2H),
3.36e3.40 (m, 3H), 2.14 (s, 3H), 1.25 (t, J¼7.0 Hz, 3H); dC (100 MHz;
CDCl3) 204.9 (C), 167.2 (C), 152.9 (C), 152.2 (C), 151.3 (C), 151.3 (C),
149.8 (C), 148.9 (C), 142.7 (C), 136.9 (C), 136.6 (C), 130.6 (CH), 129.1
(C), 128.5 (C), 128.4 (2 ꢃ CH), 128.3 (2 ꢃ CH), 128.1 (CH), 125.7 (C),
121.2 (C), 120.6 (C), 114.5 (C), 98.8 (CH2), 97.4 (C), 96.5 (CH), 79.4 (C),
75.4 (CH2), 65.8 (CH2), 63.0 (CH), 62.2 (CH3), 61.8 (CH3), 61.8 (CH3),
61.4 (CH3), 56.8 (CH3), 56.8 (CH3), 52.3 (CH3), 47.8 (C), 33.3 (CH2),
29.3 (CH3), 15.1 (CH3); m/z (ESIþ) [MþK]þ 785.2555 calcd for
4.20. Methyl 4ʹ,5ʹ,7ʹ,8,8ʹ,9ʹ-hexamethoxy-6-(2-oxopropyl)-3ʹH-
spiro[chroman-2,2ʹ-naphtho[2,3-b]furan]-7-carboxylate (44)
To a stirred solution of ketone 43 (0.13 g, 0.20 mmol) in CH2Cl2
(4 mL) was added NaHSO4.SiO2 (0.25 g) and stirred at rt for 9 h. The
mixture was filtered through cotton wool and washed with EtOAc
(20 mL). The filtrate was washed with water (2ꢃ5 mL), dried over
anhydrous Na2SO4, filtered and the filtrate concentrated in vacuo.
The crude product was purified by flash chromatography (hexanes-
EtOAc, 2:3) to afford the title compound 44 (61.0 mg, 53%) as a yel-
low oil; Rf: 0.48 (hexanes-EtOAc, 2:3); nmax(neat)/cmꢁ1 2932, 2849,
1723, 1703, 1645, 1602, 1450, 1422, 1353, 1295, 1257, 1225, 1203,
1157, 1108, 1045, 1034, 925, 891, 822, 806; dH (400 MHz; CDCl3) 6.75
(s, 1H), 6.60 (s, 1H), 3.97 (s, 6H), 3.84 (s, 3H), 3.83 (s, 3H), 3.79 (s,
3H), 3.73 (s, 3H), 3.70 (d, J¼16.8 Hz, 1H), 3.66 (s, 2H), 3.63 (s, 3H),
3.38 (d, J¼16.8 Hz, 1H), 3.31e3.41 (m, 1H), 2.85 (ddd, J¼16.4, 5.6,
2.0 Hz, 1H), 2.43 (ddd, J¼13.4, 6.0, 2.4 Hz, 1H), 2.25 (ddd, 13.4, 6.0,
2.4 Hz, 1H), 2.16 (s, 3H); dC (100 MHz; CDCl3) 206.0 (C), 167.7 (C),
153.3 (C), 150.0 (C), 149.0 (C), 148.8 (C), 146.5 (C), 144.5 (C), 137.1 (C),
133.0 (C), 127.2 (C), 126.6 (C), 126.1 (CH), 125.2 (C), 125.1 (C), 117.6
(C), 113.6 (C), 109.8 (C), 95.1 (CH), 61.9 (CH3), 61.8 (CH3), 61.5 (CH3),
61.3 (CH3), 56.8 (CH3), 56.8 (CH3), 52.1 (CH3), 47.9 (CH2), 39.6 (CH2),
29.7 (CH2), 29.4 (CH3), 22.0 (CH2); m/z (ESIþ) [MþNa]þ 605.1991
calcd for C31H34NaO11 605.1993.
C
41H46KO13 785.2570.
4.18. Methyl 4-(4-(3-(ethoxymethoxy)-1,4,5,6,8-
pentamethoxynaphthalen-2-yl)-3-oxobut-1-yn-1-yl)-3-
hydroxy-2-methoxy-6-(2-oxopropyl)benzoate (42)
To a stirred solution of alcohol 37 (1.22 g, 1.63 mmol) in DMSO
(10 mL) was added a solution of IBX (1.83 g, 6.52 mmol) in DMSO
(10 mL) and stirred at rt for 3 h. The reaction mixture was diluted
with EtOAc (10 mL) and saturated aqueous NaSO3 solution (10 mL)
was added and the aqueous layer was separated and extracted with
EtOAc (3ꢃ10 mL). The combined organic extracts were washed
with brine (20 mL), dried over anhydrous MgSO4, filtered and the
filtrate concentrated in vacuo. The crude product was purified by
flash chromatography (hexanes-EtOAc, 3:2) to afford the title
compound 42 (1.0 g, 85%) as a yellow oil; Rf: 0.39 (hexanes-EtOAc,
1:1); nmax(neat)/cmꢁ1 2936, 2842, 2200, 1727, 1672, 1599, 1451,
1365, 1258, 1172, 1047, 1003, 733, 698; dH (400 MHz; CDCl3) 7.48 (d,
4.21. 4,5,7,8,9,10ʹ-Hexamethoxy-7ʹ-methyl-3H,3ʹH-spiro[naph-
tho[2,3-b]furan-2,2ʹ-pyrano[4,3-g]chromen]-9ʹ(4ʹH)-one (8)
To a stirred solution of NaH (34 mg, 0.49 mmol, 60% in mineral
oil) in THF (4 mL) at 0 ꢂC was added a solution of keto-ester 44
(0.14 mg, 0.25 mmol) in THF (2 mL) and stirred for 5 min then

D.J. Atkinson et al. / Tetrahedron 71 (2015) 91e101
101
warmed to rt for 30 min. Saturated aqueous NH4Cl (10 mL) was
added and the aqueous layer separated and extracted with EtOAc
(3ꢃ15 mL). The combined organic extracts were washed with brine
(10 mL), dried over anhydrous MgSO4, filtered and the filtrate
concentrated in vacuo. The crude product was purified by flash
chromatography (hexanes-EtOAc, 2:3) to afford the title compound
8 (65.0 mg, 48%) as a pale yellow solid; Mp¼88.4e89.2 ꢂC; Rf: 0.48
(hexanes-EtOAc, 2:3); nmax(neat)/cmꢁ1 2932, 2842, 1730, 1604,
1462, 1356, 1235, 1207, 1047, 1008, 925, 821, 617; dH (400 MHz;
concentrated in vacuo. The crude product was purified by flash
chromatography (CH2Cl2eMeOH, 99:1) to afford the title compound
7 (7.4 mg, 90%) as a red solid; Mp¼278.1e280.2 ꢂC; Rf: 0.65
(CH2Cl2eMeOH, 98:2); nmax(neat)/cmꢁ1 2922, 2852, 1686, 1648,
1600, 1442, 1330, 1272, 1237, 1140, 1095, 1058, 940, 922, 882, 803;
dH (500 MHz; CDCl3) 13.07 (s, 1H), 12.29 (s, 1H), 11.14 (s, 1H), 6.62 (s,
1H), 6.18 (s, 2H), 3.92 (s, 3H), 3.75 (d, J¼18.0 Hz, 1H), 3.38e3.45 (m,
2H), 2.91 (ddd, J¼17.4, 6.0, 1.6 Hz, 1H), 2.46 (ddd, J¼14.0, 6.0, 2.0 Hz,
1H), 2.27e2.34 (m, 1H), 2.26 (s, 3H); dC (125 MHz; CDCl3) 183.3 (C),
178.6 (C),166.9 (C),159.9 (C),159.5 (C),153.8 (C),152.3 (C),150.8 (C),
150.0 (C), 138.4 (C), 131.4 (C), 130.5 (C), 123.0 (C), 114.4 (CH), 112.9
(C), 111.8 (C), 110.1 (CH), 106.3 (C), 104.9 (C), 104.1 (CH), 56.7 (CH3),
39.5 (CH2), 30.0 (CH2), 22.3 (CH2), 19.3 (CH3); m/z (ESIþ) [MþH]þ
479.0973 calcd for C25H19O10 479.0966.
CDCl3)
d 6.84 (s, 1H), 6.58 (s, 1H), 6.05 (s, 1H), 3.96 (s, 3H), 3.95 (s,
3H), 3.84 (s, 3H), 3.76 (s, 3H), 3.71 (d, J¼16.8 Hz, 1H), 3.70 (s, 3H),
3.68 (s, 3H), 3.45 (d, J¼16.8 Hz, 1H), 3.38e3.47 (m, 1H), 2.94 (ddd,
J¼17.4, 5.8, 1.8 Hz, 1H), 2.44 (ddd, J¼13.4, 6.2, 2.2, 1H), 2.34 (ddd,
J¼13.4, 6.2, 2.2 Hz, 1H), 2.17 (s, 3H); dC (100 MHz; CDCl3) 159.3 (C),
153.2 (C),152.6 (2 ꢃ C),149.9 (C),149.8 (C),148.8 (C),145.0 (C),136.9
(C), 132.8 (C), 132.1 (C), 131.3 (C), 127.0 (C), 119.7 (CH),117.4 (C), 113.6
(C), 112.5 (C), 109.6 (C), 102.7 (CH), 95.0 (CH), 61.7 (CH3), 61.6 (CH3),
61.4 (CH3), 61.1 (CH3), 56.7 (CH3), 56.6 (CH3), 39.4 (CH2), 29.3 (CH2),
22.5 (CH2), 19.2 (CH3); m/z (ESIþ) [MþNa]þ 573.1731 calcd for
Acknowledgements
The authors would like to thank the NZ Foundation for Research,
Science and Technology (FRST) for its financial support through the
International Investment Opportunities Fund (IIOF).
C
30H30NaO10 573.1714.
4.22. 4,9,10ʹ-Trihydroxy-7-methoxy-7ʹ-methyl-3H,3ʹH-spiro
[naphtho[2,3-b]furan-2,2ʹ-pyrano[4,3-g]chromene]-
5,8,9ʹ(4ʹH)-trione (7)
Supplementary data
Supplementary data related to this article can be found at http://
dx.doi.org/10.1016/j.tet.2014.11.030.
To a stirred solution of naphthalene 8 (60.0 mg 0.11 mmol) in
MeCN (4 mL) at 0 ꢂC was added water (0.4 mL) followed by DDQ
(61.8 mg, 0.27 mmol) and stirred for 15 min. Water (2 mL) and
saturated aqueous NaHCO3 (3 mL) were added and the mixture was
extracted with EtOAc (3ꢃ5 mL). The combined organic extracts
were washed with brine (6 mL), dried over anhydrous MgSO4, fil-
tered and the filtrate concentrated in vacuo. The crude product was
purified by flash chromatography (EtOAc, neat) to afford the qui-
none (31.6 mg, 64%) as a yellow solid; Mp¼191.0e193.5 ꢂC; Rf: 0.38
(EtOAc, neat); nmax(neat)/cmꢁ1 2930, 2852, 1729, 1677, 1639, 1585,
1469, 1427, 1364, 1336, 1303, 1228, 1133, 1110, 1054, 1038, 984, 958,
920, 807, 734; dH (400 MHz; CDCl3) 6.87 (s, 1H), 6.08 (s, 1H), 5.96 (s,
1H), 3.93 (s, 3H), 3.83 (s, 3H), 3.77 (s, 3H), 3.77 (s, 3H), 3.71 (d,
J¼17.6 Hz, 1H), 3.45 (d, J¼17.6 Hz, 1H), 3.32e3.46 (m, 1H), 2.96 (ddd,
J¼17.6, 6.0, 2.0 Hz, 1H), 2.44 (ddd, J¼13.6, 6.0, 2.0 Hz, 1H), 2.30 (ddd,
J¼13.6, 6.0, 2.0 Hz, 1H), 2.21 (s, 3H); dC (100 MHz; CDCl3) 183.7 (C),
179.3 (C), 159.3 (C), 159.2 (C), 155.1 (C), 153.1 (C), 153.1 (C), 149.9 (C),
144.5 (C), 141.8 (C), 132.7 (C), 130.8 (C), 127.1 (C), 125.6 (C), 119.9
(CH), 119.4 (C), 112.9 (C), 110.8 (C), 109.9 (CH), 102.7 (CH), 61.5 (CH3),
61.2 (CH3), 60.9 (CH3), 56.3 (CH3), 39.9 (CH2), 29.5 (CH2), 22.3 (CH2),
19.3 (CH3); m/z (ESIþ) [MþNa]þ 543.1271 calcd for C28H24NaO10
543.1262.
References and notes
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0.069 mmol) dropwise and stirred for 10 min. Water (3 mL) was
then added and aqueous layer was separated and extracted with
CH2Cl2 (3ꢃ3 mL). The combined organic extracts were washed with
brine (4 mL), dried over anhydrous MgSO4, filtered and the filtrate