A flexible approach to 6,5-benzannulated spiroketals

Article abstract of DOI:10.1002/ejoc.201100345

A novel route to simple 6,5-benzannulated spiroketal analogues has been developed. A convergent Horner-Wadsworth-Emmons olefination enabled ready assembly of the spiroketal precursors. Use of a benzyl protecting group strategy enabled an efficient one-pot

Full text of DOI:10.1002/ejoc.201100345

FULL PAPER
DOI: 10.1002/ejoc.201100345
A Flexible Approach to 6,5-Benzannulated Spiroketals
Zoe E. Wilson,[a] Jonathan G. Hubert,[a] and Margaret A. Brimble*[a]
Keywords: Spiroketals / Olefination / Hydrogenation / Cyclisation / Synthetic methods
A novel route to simple 6,5-benzannulated spiroketal ana- egy enabled an efficient one-pot hydrogenation/deprotec-
logues has been developed. A convergent Horner–Wads-
worth–Emmons olefination enabled ready assembly of the
spiroketal precursors. Use of a benzyl protecting group strat-
tion/spiroketalisation process to be employed providing a ro-
bust method to access a range of substituted aromatic mono-
benzannulated spiroketals.
moloney murine leukaemia viruses.[5] Efficient access to
these natural products, as well as simplified analogues is
therefore desirable in order to probe the promising bioactiv-
ity that these compounds exhibit.
Introduction
Spiroketals are privileged scaffolds that are present in a
range of natural products that exhibit interesting biological
activity.[1] 6,5-Benzannulated spiroketals comprise a rela-
tively small subgroup of spiroketal-containing natural prod-
ucts; however, they have attracted considerable research
interest due to their significant biological activity and struc-
tural diversity.[2]
Examples of 6,5-benzannulated natural products include
berkelic acid (1), paecilospirone (2), and γ-rubromycin (3)
(Figure 1). Berkelic acid (1) exhibits selective activity
against the ovarian cancer cell line OVCAR3, as well as
activity against caspase 1 and matrix metalloproteinase 3
(MMP3).[3] Paecilospirone (2) is an antibiotic exhibiting
weak inhibition of microtubule assembly.[4] γ-Rubromycin
(3) exhibits antibacterial properties as well as inhibitory ef-
fects on human telomerase, HIV-1 reverse transcriptase and
Results and Discussion
It was envisaged that 6,5-benzannulated spiroketals 4–6,
the cyclic cores of natural products 1–3, respectively, could
be accessed from p-methoxybenzyl (PMB) protected dihy-
droxy ketone precursors by using a global deprotection/
cyclisation process. These precursors can be accessed by hy-
drogenation of the corresponding enones such as 7. In turn,
a range of enones are available by Horner–Wadsworth–Em-
mons (HWE) olefination[6] of phosphonates 8–10 with
PMB-protected salicylaldehyde 11 (Scheme 1).
Figure 1. 6,5-Benzannulated spiroketal-containing natural prod-
ucts.
[a] Department of Chemistry, University of Auckland,
23 Symonds Street, Auckland, New Zealand
E-mail: m.brimble@auckland.ac.nz
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.201100345.
Scheme 1. Retrosynthetic analysis for the synthesis of benzannul-
ated spiroketals 4–6.
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A Flexible Approach to 6,5-Benzannulated Spiroketals
Phosphonates 8 and 9 were readily synthesised by facile moderate 40% and 35% yield, respectively. When 21 was
ring opening of γ-butyrolactone (12) or phthalide (13), exposed to the same conditions, no spiroketal product re-
respectively, with potassium hydroxide and p-meth- sulted; rather an aldehyde by-product arising from oxi-
oxybenzyl choride (PMBCl)[7] followed by displacement of dation of the benzylic alcohol formed after PMB cleavage.[9]
the resultant PMB esters 14 and 15 with lithiated dimethyl Acid-catalysed PMB cleavage was therefore investigated.
methylphosphonate (Scheme 2). For the synthesis of ester Spiroketalisation precursors 20–22 were stirred in a solution
16, bis(PMB) protection of acid 17 by using PMBCl, potas- of anhydrous hydrogen chloride (1 m) in tetrahydrofuran
sium carbonate and tetrabutylammonium iodide (TBAI) and dioxane to afford the desired 6,5-benzannulated spi-
proved a more reliable method than ring opening of the roketals 4 and 5 in moderate yield. However, only degrada-
corresponding lactone.
tion and various elimination products were observed in the
attempted synthesis of sensitive spiroketal 6 (Table 1).[5a,10]
Given the difficulties experienced with the synthesis of
spiroketals 4–6, attention next turned to fine-tuning of the
reaction conditions by focusing on the monobenzannulated
spiroketal core 4 of berkelic acid. Upon re-evaluation of
our initial PMB protecting group strategy, it was noted that
use of benzyl protecting groups would allow both the olefin
hydrogenation and deprotection/spiroketalisation reactions
to proceed in one pot. The potential of the established reac-
tion conditions to accommodate various aromatic substitu-
tion patterns was also examined, with spiroketals 23–28
(Figure 2) chosen as targets for this purpose. A focused li-
brary of this important structural scaffold will be useful for
further biological evaluation.
Scheme 2. Synthesis of phosphonates 8–10.
Pleasingly, HWE olefination of phosophonates 8–10 with
PMB-protected salicylaldehyde 11 proceeded smoothly,
with complete diastereoselectivity in favour of the (E)-en-
ones (Table 1). The resultant enones 7, 18 and 19 were then
subjected to chemoselective reduction[8] by employing
Cp2TiCl2, zinc powder and triethylamine hydrochloride to
yield protected dihydroxy ketones 20–22 in respectable
yields (Table 1). Finally, attention turned to the simulta-
neous deprotection/cyclisation step. Treatment of dihydroxy
ketones 20 and 22 with DDQ in dichloromethane/water
(10:1) (Method A, Table 1) afforded spiroketals 4 and 6 in Figure 2. Target tricyclic analogues of berkelic acid.
Table 1. Synthesis of spiroketals 4–6 by HWE olefination, hydrogenation and concomitant deprotection/cyclisation.[a]
[a] Method A [DDQ, CH2Cl2/H2O (10:1)] or Method B [HCl (1 m), THF/dioxane, room temp., 48 h].
Eur. J. Org. Chem. 2011, 3938–3945
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Z. E. Wilson, J. G. Hubert, M. A. Brimble
FULL PAPER
With this idea in mind, the required benzyl-protected step. Concomitant hydrogenation of the double bond and
phosphonate 29 was synthesised as previously reported,[11] hydrogenolysis of the benzyl protecting groups by using hy-
and aldehydes 30–36 were accessed from readily available drogen in the presence of palladium hydroxide or 10% pal-
salicylaldehyde starting materials by routine chemistry.[12]
ladium on carbon effected the unmasking of the dihydroxy
HWE olefination of aldehydes 30–36 with phosphonate ketones, which spontaneously cyclised to the desired spi-
29 proceeded without event to afford the spiroketal precur- roketals 4 and 23–28 in respectable yields. Through fine-
sors 37–43 in 78–96% yield, with complete diastereoselec- tuning of the reaction conditions it was possible to synthe-
tivity in favour of the (E)-enones (Table 2).
size tricyclic spiroketals 23–28 that were monosubstituted
at each possible position around the aromatic ring, thereby
demonstrating that this is an effective method for the syn-
thesis for the spiroketal core of berkelic acid and analogues
(Table 3).
Table 2. HWE olefination of phosphonate 29 with benzaldehydes
30–36.
Table 3. One-pot deprotection cyclisation of enones 37–43.
Entry
Method[a]
Time [h] Product Yield [%]
1
2
3
A [Pd(OH)2 or Pd/C]
72
–
21
72
–
70
62
4
88
68
53
76
80
62
64
B
23
24
25
26
27
28
A (Pd/C)
A [Pd(OH)2]
B
A (Pd/C)
A [Pd(OH)2]
4
5[b]
6
7
[a] Method A: Pd(OH)2 or Pd/C, H2 THF, room temp. Method B:
H-Cube® HC-2 continuous hydrogenation equipment (THALES
Nanotechnology Inc.) with Pd(OH)2 catalyst, a column block tem-
perature of 20 °C, pressure of 20 bar and flow rate of 1 mL/min,
EtOAc/MeOH. [b] Required filtration through Amberlyst 15®
acidic resin (Sigma–Aldrich).
Conclusions
We have developed a flexible route to a focused library of
6,5-benzannulated spiroketals. The key steps include HWE
olefination followed by olefin hydrogenation and global de-
protection/spiroketalisation. The benzannulated spiroketal
cores of berkelic acid, γ-rubromycin and paecilospirone
were synthesised by employing PMB protecting groups;
however, separate hydrogenation and deprotection steps
were required, and only moderate yields of the desired spi-
roketals were obtained. Monobenzannulated spiroketals
analogous to berkelic acid were next targeted to optimise
our synthetic strategy, and these spiroketals were readily
prepared in good yield by using a one-pot hydrogenation/
deprotection/cyclisation process. The methodology reported
herein enabled the synthesis of a range of 6,5-monobenz-
annulated spiroketals containing a variety of aromatic sub-
stitution patterns.
[a] 2 equiv. of 29 and NaH used.
Experimental Section
With cyclisation precursors 37–43 in hand, attention
General Details: All reactions were carried out in flame- or oven-
turned to the final global deprotection/spiroketalisation dried glassware under dry nitrogen. Tetrahydrofuran and diethyl
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A Flexible Approach to 6,5-Benzannulated Spiroketals
1
ether were dried with sodium wire, and dichloromethane was dried
with calcium hydride. All solvents were distilled prior to use. Flash
chromatography was carried out by using 0.063–0.1 mm silica gel
with the appropriate solvent. Thin layer chromatography (TLC)
was performed by using 0.2 mm Kieselgel F254 (Merck) silica
plates, and compounds were visualised by using UV irradiation at
365 nm and/or staining with vanillin in methanolic sulfuric acid, a
solution of ammonium heptamolybdate and cerium sulfate in aque-
ous sulfuric acid, or a solution of potassium permanganate and
potassium carbonate in aqueous sodium hydroxide. Preparative
TLC was carried out on 500 μm Uniplate™ (Analtech) silica gel
(20ϫ20 cm) thin layer chromatography plates. Infrared spectra
were obtained as indicated by using a Perkin–Elmer Spectrum 1000
series Fourier Transform IR (FTIR) spectrometer as a thin film
between sodium chloride plates or a Perkin–Elmer Spectrum One
FTIR spectrometer with a film ATR sampling accessory. Absorp-
tion maxima are expressed in wavenumbers (cm–1). Melting points
were determined with a Kofler hot-stage apparatus and are uncor-
rected. NMR spectra were recorded as indicated with either a
46–48 °C. H NMR (400 MHz, CDCl3): δ = 8.04 (d, J = 8.0 Hz, 1
H, 6-H), 7.80 (d, J = 8.0 Hz, 1 H, 3-H), 7.56 (t, J = 8.0 Hz, 1 H,
4-H), 7.44–7.33 (m, 5 H, 5-H and OCH2PhOCH3), 6.96 (d, J =
8.0 Hz, 4 H, OCH2PhOCH3), 5.33 (s, 2 H, OCH2PhOCH3), 5.04
(s, 2 H, CH2OPMB), 4.62 (s, 2 H, OCH2PhOCH3), 3.81 (s, 6 H, 2
OCH2PhOCH3) ppm. 13C NMR (100 MHz, CDCl3): δ = 166.7,
159.4, 158.9, 140.7, 132.0, 130.2, 129.8, 129.1, 129.0, 128.0, 127.8,
127.4, 126.6, 113.7, 113.5, 72.3, 69.8, 66.2, 54.8 ppm. IR (neat):
ν
˜
max = 2961, 2838, 1709, 1516, 1246, 739 cm–1. HRMS (ESI): calcd.
for C14H18NaO5 [M + Na]+ 415.1516; found 415.1512.
4-Methoxybenzyl 2-{2-[(4-Methoxybenzyl)oxy]phenyl}acetate (16):
p-Methoxybenzyl chloride (2.0 mL, 14.5 mmol) was added to a
stirred solution of 2-(2-hydroxyphenyl)acetic acid (1.00 g,
6.6 mmol), potassium carbonate (1.91 g, 13.8 mmol) and tetrabu-
tylammonium iodide (0.48 g, 2.6 mmol) in acetone (35 mL) and the
mixture heated at 55 °C for 10 h. The solvent was removed in
vacuo, water (30 mL) was added and the reaction mixture extracted
with ethyl acetate (3ϫ30 mL). The combined organic extracts were
washed with brine (50 mL), dried with magnesium sulfate, and the
solvent was removed in vacuo. The resulting oil was purified by
flash chromatography using hexanes/ethyl acetate (4:1) as eluent to
afford 16 (2.39 g, 93%) as a colourless solid; m.p. 47–48 °C. 1H
NMR (400 MHz, CDCl3): δ = 7.29 (d, J = 8.4 Hz, 2 H, ArH),
7.26–7.17 (m, 4 H, ArH), 6.94–6.91 (m, 2 H, ArH), 6.87–6.82 (m,
4 H, ArH), 5.01 (s, 2 H, OCH2PhOCH3), 4.96 (s, 2 H, OCH2-
PhOCH3), 3.80 (s, 3 H, OCH2PhOCH3), 3.79 (s, 3 H, OCH2-
PhOCH3), 3.68 (s, 2 H, 2-H) ppm. 13C NMR (100 MHz, CDCl3):
δ = 171.8, 159.5, 159.2, 156.7, 131.0, 129.9, 129.1, 128.7, 128.5,
128.2, 123.5, 120.7, 113.8, 111.8, 69.7, 66.2, 55.2, 36.3 ppm. IR
1
Bruker Avance 300 spectrometer operating at 300 MHz for H nu-
clei and 75 MHz for 13C nuclei or by using a Bruker DRX-400
spectrometer operating at 400 MHz for 1H nuclei, 100 MHz for 13
C
nuclei and 162 MHz for 31P nuclei. All chemical shifts are reported
in parts per million (ppm) relative to tetramethylsilane (1H) or
CDCl3 (1H and 13C). 1H NMR spectroscopic data is reported as
chemical shift, multiplicity (s, singlet; d, doublet; t, triplet; q, quar-
tet; quint, quintet; dd, doublet of doublets), coupling constant (J
in Hz), relative integral, and assignment. High-resolution mass
spectra were recorded with a VG-70SE at a nominal accelerating
voltage of 70 eV or with a Bruker micrOTOF-Q II mass spectrome-
ter.
(neat): ν
= 3007, 2834, 1733, 1512, 1239, 1152, 1029, 817 cm–1.
˜
max
HRMS (ESI): calcd. for C24H24NaO5 [M + Na]+ 415.1516; found
4-Methoxybenzyl 4-(4-Methoxybenzyloxy)butanoate (14): A mix-
ture of γ-butyrolactone (1.4 mL, 18.2 mmol), p-methoxybenzyl
chloride (8.7 mL, 63.9 mmol) and potassium hydroxide (3.58 g,
63.9 mmol) in toluene (180 mL) was heated to reflux under Dean–
Stark conditions for 48 h. The mixture was cooled to room temp.,
and water (150 mL) was added before extraction with ethyl acetate
(3ϫ150 mL). The combined organic extracts were washed with
aqueous saturated sodium hydrogen carbonate (150 mL) and brine
(150 mL), dried with magnesium sulfate, and the solvent was re-
moved in vacuo. Purification by flash chromatography using hex-
anes/ethyl acetate (4:1) as eluent afforded 14 (5.55 g, 88%) as a
colourless oil. 1H NMR (400 MHz, CDCl3): δ = 7.25 (d, J =
8.4 Hz, 2 H, OCH2PhOCH3), 7.21 (d, J = 8.8 Hz, 2 H, OCH2-
PhOCH3), 6.82–6.85 (m, 4 H, OCH2PhOCH3), 5.01 (s, 2 H, OCH2-
PhOCH3), 4.37 (s, 2 H, OCH2PhOCH3), 3.73 (s, 6 H, 2 OCH2-
PhOCH3), 3.43 (t, J = 6.4 Hz, 4-H), 2.42 (t, J = 7.2 Hz, 2 H, 2-H),
1.87–1.94 (m, 2 H, 3-H) ppm. 13C NMR (100 MHz, CDCl3): δ =
173.0, 159.4, 158.9, 130.3, 129.8, 128.9, 128.0, 113.7, 113.5, 72.2,
415.1512.
General Procedure for Dimethyl Methylphosphonate Addition: n-Bu-
tyllithium (1.6 m in hexanes, 3 equiv.) was added dropwise to a
stirred solution of dimethyl methylphosphonate (3 equiv.) in tetra-
hydrofuran at –78 °C. The mixture was stirred at –78 °C for 30 min,
followed by dropwise addition of a solution of ester (1 equiv.) in
tetrahydrofuran. The reaction mixture was stirred at –78 °C for 2 h,
after which it was quenched with saturated ammonium chloride
and warmed to room temp. The resulting mixture was extracted
with ethyl acetate, the combined organic extracts washed with
brine, dried with magnesium sulfate and the solvent removed in
vacuo before purification by flash chromatography using ethyl acet-
ate as eluent.
Dimethyl {5-[(4-Methoxybenzyl)oxy]-2-oxopentyl}phosphonate (8):
The general procedure was applied by using ester 14 (2.25 g,
6.5 mmol). The product was obtained as a yellow oil (1.89 g, 88%).
1H NMR (400 MHz, CDCl3): δ = 7.23 (d, J = 8.4 Hz, 2 H, OCH2-
PhOCH3) 6.86 (d, J = 8.4 Hz, 2 H, OCH2PhOCH3), 4.40 (s, 2 H,
OCH2PhOCH3), 3.81 (s, 3 H, OCH2PhOCH3), 3.77 [d, J =
11.2 Hz, 6 H, P(OCH3)2], 3.45 (t, J = 6.0 Hz, 2 H, 5-H), 3.08 (d, J
= 18.8 Hz, 2 H, 1-H), 2.71 (t, J = 6.8 Hz, 2 H, 3-H), 1.85–1.92 (m,
2 H, 4-H) ppm. 13C NMR (100 MHz, CDCl3): δ = 201.4, 158.9,
130.2, 129.0, 113.5, 72.3, 68.5, 55.0, 52.8, 41.7, 41.0, 23.5 ppm. IR
68.6, 65.7, 54.9, 30.9, 24.9 ppm. IR (neat): νmax = 2931, 2837, 1731,
˜
1512, 1243, 1162, 1032 cm–1. HRMS (ESI): calcd. for C20H24NaO5
[M + Na]+ 367.1516; found 367.1521.
4-Methoxybenzyl 2-[(4-Methoxybenzyloxy)methyl]benzoate (15): A
mixture of phthalide (1.00 g, 7.5 mmol), p-methoxybenzyl chloride
(5.7 mL, 41.8 mmol) and potassium hydroxide (1.46 g, 26.1 mmol)
in toluene (60 mL) was heated to reflux under Dean–Stark condi-
tions for 48 h. The mixture was cooled to room temp., and water
(50 mL) was added before extraction with ethyl acetate
(3ϫ50 mL). The combined organic extracts were washed with satu-
rated sodium hydrogen carbonate (50 mL) and brine (50 mL), dried
with magnesium sulfate, and the solvent was removed in vacuo.
Purification by flash chromatography using hexanes/ethyl acetate
(9:1) as eluent afforded 15 (2.50 g, 84%) as a colourless solid; m.p.
(neat): ν
= 2956, 2854, 1713, 1513, 1244, 1022 cm–1. HRMS
˜
max
(ESI): calcd. for C15H24O6P [M + H]+ 331.1305; found 331.1310.
Dimethyl [2-(2Ј-{[(4-Methoxybenzyl)oxy]methyl}phenyl)-2-oxoethyl]-
phosphonate (9): The general procedure was applied by using ester
15 (2.50 g, 6.4 mmol). The product was obtained as a pale yellow
oil (2.33 g, 97%). 1H NMR (400 MHz, CDCl3): δ = 7.82 (d, J =
7.6 Hz, 1 H, 6Ј-H), 7.75 (d, J = 8.0 Hz, 1 H, 3Ј-H), 7.54 (t, J =
7.6 Hz, 1 H, 5Ј-H), 7.39 (t, J = 8.0 Hz, 1 H, 4Ј-H), 7.31 (d, J =
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Z. E. Wilson, J. G. Hubert, M. A. Brimble
FULL PAPER
8.8 Hz, 2 H, OCH2PhOCH3), 6.89 (d, J = 8.8 Hz, 2 H, OCH2-
PhOCH3), 7.00–6.97 (m, 2 H, ArH), 6.87 (d, J = 8.4 Hz, 2 H,
PhOCH3), 4.84 (s, 2 H, CH2OPMB), 4.55 (s, 2 H, OCH2PhOCH3), OCH2PhOCH3), 6.79 (d, J = 8.4 Hz, 2 H, OCH2PhOCH3), 4.99,
3.78 (s, 3 H, OCH2PhOCH3), 3.74 [d, J = 11.6 Hz, 6 H, 4.70, 4.42 (s, 6 H, 2 CH2PhOCH3 and CH2OPMB), 3.78 (s, 3 H,
P(OCH3)2], 3.60 (d, J = 22.4 Hz, 2 H, 1-H) ppm. 13C NMR OCH2PhOCH3), 3.72 (s, 3 H, OCH2PhOCH3) ppm. 13C NMR
(100 MHz, CDCl3): δ = 194.4, 159.0, 140.0, 135.4, 132.3, 130.1, (100 MHz, CDCl3): δ = 196.0, 159.4, 159.1, 157.8, 141.6, 138.3,
129.4, 129.1, 127.7, 126.8, 113.5, 72.3, 69.8, 55.0, 52.8, 39.5 ppm.
138.2, 131.7, 130.5, 130.3, 129.6, 129.3, 128.9, 128.4, 128.3, 126.9,
124.0, 121.0, 114.0, 113.6, 112.6, 72.3, 70.2, 69.7, 55.3, 55.2 ppm.
IR (neat): ν
= 2952, 2850, 1675, 1513, 1245, 1025 cm–1. HRMS
˜
max
(ESI): calcd. for C19H23NaO6P [M + Na]+ 401.1124; found
IR (neat): ν
= 2939, 2836, 1640, 1595, 1513, 1240 cm–1. HRMS
max
˜
401.1136.
(ESI): calcd. for C32H31O5 [M + H]+ 495.2166; found 495.2166.
Dimethyl (3-{2Ј-[(4-Methoxybenzyl)oxy]phenyl}-2-oxopropyl)phos-
phonate (10): The general procedure was applied by using ester 16
(1.58 g, 4.0 mmol). The product was obtained as a pale yellow oil
(0.69 g, 46%). 1H NMR (400 MHz, CDCl3): δ = 7.31 (d, J =
1,4-Bis{2-[(4-methoxybenzyl)oxy]phenyl}but-3-en-2-one (19): The
general procedure was applied by using phosphonate 10 (0.25 g,
0.7 mmol) and aldehyde 11 (0.16 g, 0.7 mmol), stirring the reaction
mixture at room temp. for 18 h. The product was obtained as a
8.8 Hz, 2 H, OCH2PhOCH3), 7.24 (dt, J = 7.6, 1.6 Hz, 1 H, 4Ј-H), pale yellow solid (0.29 g, 88%); m.p. 82–83 °C. 1H NMR
7.16 (d, J = 7.6 Hz, 1 H, 6Ј-H), 6.94–6.88 (m, 4 H, OCH2PhOCH3,
3Ј-H, 5Ј-H), 4.97 (s, 2 H, OCH2PhOCH3), 3.84 (s, 2 H, 3-H), 3.79 = 8.0 Hz, 1 H, ArH), 7.31–7.25 (m, 5 H, ArH), 7.23–7.18 (m, 2 H,
(s, 3 H, OCH2PhOCH3), 3.71 [d, J = 11.2 Hz, 6 H, P(OCH3)2], ArH), 6.95–6.87 (m, 6 H, ArH), 6.84 (d, J = 16.4 Hz, 1 H, 3-H),
3.05 (d, J = 22.0 Hz, 2 H, 1-H) ppm. 13C NMR (100 MHz, CDCl3): 6.78 (d, J = 8.4 Hz, 2 H, OCH2PhOCH3), 5.03 (s, 2 H, OCH2-
(400 MHz, CDCl3): δ = 8.00 (d, J = 16.4 Hz, 1 H, 4-H), 7.43 (d, J
δ = 199.6, 159.3, 156.3, 131.3, 129.0, 128.6, 128.6, 122.9, 120.8,
PhOCH3), 4.96 (s, 2 H, OCH2PhOCH3), 3.91 (s, 2 H, 1-H), 3.79
(s, 3 H, OCH2PhOCH3), 3.71 (s, 3 H, OCH2PhOCH3) ppm. 13C
NMR (100 MHz, CDCl3): δ = 198.2, 159.3, 159.1, 157.5, 156.5,
137.9, 131.4, 131.3, 130.0, 128.8, 128.6, 128.5, 128.2, 126.3, 124.3,
124.0, 120.8, 114.0, 113.7, 112.8, 111.8, 70.1, 69.7, 55.2, 55.1,
113.8, 111.6, 69.7, 55.1, 52.8, 45.6, 40.1 ppm. IR (neat): ν
=
˜
max
2955, 1719, 1515, 1239, 1175, 1023, 821, 753 cm–1. HRMS (ESI):
calcd. for C19H23NaO6P [M + H]+ 401.1124; found 401.1119.
General Procedure for Horner–Wadsworth–Emmons Olefination:
Phosphonate (1 equiv.) was taken up in tetrahydrofuran and added
to a suspension of sodium hydride (60% in paraffin oil, 1 equiv.)
in tetrahydrofuran at 0 °C, then warmed to room temperature for
0.5 h. A solution of aldehyde in tetrahydrofuran was then added
and the reaction mixture stirred at room temp. or under reflux until
the reaction was judged complete by TLC. Aqueous saturated am-
monium chloride was added and the reaction mixture extracted
with ethyl acetate. The combined organic extracts were dried with
magnesium sulfate, and the solvent was removed in vacuo before
purification by flash chromatography using hexanes/ethyl acetate
(4:1) as eluent.
42.7 ppm. IR (neat): ν
= 2955, 2836, 1684, 1588, 1514, 1453,
˜
max
1236, 1174, 754 cm–1. HRMS (ESI): calcd. for C32H31O5 [M +
H]+ 495.2166; found 495.2154.
(E)-6-(Benzyloxy)-1-[2-(benzyloxy)phenyl]hex-1-en-3-one (37): The
general procedure was applied by using phosphonate 29 (0.71 g,
2.4 mmol) and aldehyde 30 (0.50 g, 2.4 mmol), stirring the reaction
mixture at reflux for 2.5 h. The product was obtained as a colour-
1
less oil (0.72 g, 79%). H NMR (300 MHz, CDCl3): δ = 7.97 (d, J
= 16.5 Hz, 1 H, 1-H), 7.53 (d, J = 7.8 Hz, 1 H, 6Ј-H), 7.42–7.21
(m, 11 H, 2ϫ C6H5 and 4Ј-H), 6.97–6.92 (m, 2 H, 3Ј-H and 5Ј-H),
6.81 (d, J = 16.5 Hz, 1 H, 2-H), 5.12 (s, 2 H, ArOCH2C6H5), 4.47
(s, 2 H, CH2OCH2C6H5), 3.51 (t, J = 6.3 Hz, 2 H, 6-H), 2.74 (t, J
= 7.2 Hz, 2 H, 4-H), 2.02–1.92 (m, 2 H, 5-H) ppm. 13C NMR
(75 MHz, CDCl3): δ = 200.2, 157.3, 138.4, 137.4, 136.4, 131.4,
128.6, 128.5, 128.1, 127.9, 127.4, 127.1, 126.9, 123.7, 120.9, 112.6,
6-[(4-Methoxybenzyl)oxy]-1-{2-[(4-methoxybenzyl)oxy]phenyl}-
hex-1-en-3-one (7): The general procedure was applied by using
phosphonate 8 (0.10 g, 0.3 mmol) and aldehyde 11 (0.073 g,
0.3 mmol), stirring the reaction mixture at room temp. for 18 h.
The product was obtained as a pale yellow oil (0.11 g, 76%). 1H
NMR (400 MHz, CDCl3): δ = 7.93 (d, J = 16.4 Hz, 1 H, 1-H),
7.54 (dd, J = 8.0, 1.8 Hz, 1 H, 6Ј-H), 7.35 (d, J = 8.8 Hz, 2 H,
72.6, 70.2, 69.3, 37.0, 24.2 ppm. IR (neat): νmax = 2854, 1661, 1597,
˜
1451, 1240, 1103, 743, 695 cm–1. HRMS (EI): calcd. for C26H26O3
[M]+ 386.1882; found 386.1888.
OCH2PhOCH3), 7.31 (dd, J = 7.6, 1.5 Hz, 1 H, 3Ј-H), 7.25–7.23 (E)-6-(Benzyloxy)-1-[2-(benzyloxy)-3-methoxyphenyl]hex-1-en-3-one
(d, J = 8.8 Hz, 2 H, OCH2PhOCH3), 6.98–6.96 (m, 2 H, 4Ј-H and
5Ј-H), 6.91 (d, J = 8.8 Hz, 2 H, OCH2PhOCH3), 6.85 (d, J =
8.8 Hz, 2 H, OCH2PhOCH3), 6.79 (d, J = 16.4 Hz, 1 H, 2-H), 5.08
(38): The general procedure was applied by using phosphonate 29
(0.12 g, 0.4 mmol) and aldehyde 31 (0.10 g, 0.4 mmol), stirring the
reaction mixture at reflux for 1 h and at room temp. for 1 h. The
1
(s, 2 H, OCH2PhOCH3), 4.41 (s, 2 H, OCH2PhOCH3), 3.77 (s, 3 product was obtained as a pale yellow oil (0.14 g, 80%). H NMR
H, OCH2PhOCH3), 3.49 (t, J = 6.4 Hz, 2 H, 6-H), 2.73 (t, J =
(300 MHz, CDCl3): δ = 7.79 (d, J = 16.5 Hz, 1 H, 1-H), 7.44–7.26
(m, 10 H, 2ϫ OCH2C6H5), 7.16 (dd, J = 8.0, 1.7 Hz, 1 H, 6Ј-H),
7.2 Hz, 2 H, 4-H), 1.99–1.92 (m, 2 H, 5-H) ppm. 13C NMR
(100 MHz, CDCl3): δ = 200.6, 159.5, 159.1, 157.6, 137.8, 131.6, 7.09 (t, J = 8.0 Hz, 1 H, 5Ј-H), 6.99 (dd, J = 8.0, 1.7 Hz, 1 H, 4Ј-
130.6, 129.2, 128.9, 128.7, 128.6, 127.0, 124.0, 121.1, 114.1, 113.8,
112.9, 72.5, 70.3, 69.2, 55.3, 55.2, 37.2, 24.4 ppm. IR (neat): ν
H), 6.63 (d, J = 16.5 Hz, 1 H, 2-H), 5.06 (s, 2 H, ArOCH2C6H5),
4.53 (s, 2 H, CH2OCH2C6H5), 3.91 (s, 3 H, OCH3), 3.53 (t, J =
˜
max
= 2934, 1681, 1584, 1514, 1232, 1026, 996 cm–1. HRMS (ESI): 6.2 Hz, 2 H, 6-H), 2.68 (t, J = 7.2 Hz, 2 H, 4-H), 2.07–1.98 (m, 2
calcd. for C28H30NaO5 [M + Na]+ 469.1985; found 469.1998.
H, 5-H) ppm. 13C NMR (75 MHz, CDCl3): δ = 200.3, 153.1, 147.0,
138.4, 137.5, 137.0, 129.2, 128.6, 128.4, 128.3, 128.2, 127.6, 127.5,
127.4, 124.2, 118.7, 114.0, 75.6, 72.8, 69.4, 55.8, 36.3, 24.2 ppm. IR
1-(2-{[(4-Methoxybenzyl)oxy]methyl}phenyl)-3-{2-[(4-methoxy-
benzyl)oxy]phenyl}prop-2-en-1-one (18): The general procedure was
applied by using phosphonate 9 (0.94 g, 2.5 mmol) and aldehyde
11 (0.60 g, 2.5 mmol), stirring the reaction mixture at room temp.
for 18 h. The product was obtained as a yellow oil (1.06 g, 86%).
(neat): νmax = 3032, 2864, 1685, 1594, 1450, 1091, 733 cm–1. HRMS
˜
(EI): calcd. for C27H28NaO4 [M + Na]+ 439.1880; found 439.1878.
(E)-6-(Benzyloxy)-1-[2-(benzyloxy)-4-methoxyphenyl]hex-1-en-3-one
1H NMR (400 MHz, CDCl3): δ = 7.84 (d, J = 16.4 Hz, 1 H, 3-H), (39): The general procedure was applied by using phosphonate 29
7.61 (d, J = 7.6 Hz, 1 H, ArH), 7.56 (d, J = 8.0 Hz, 1 H, ArH),
(0.12 g, 0.4 mmol) and aldehyde 32 (0.10 g, 0.4 mmol), stirring the
7.48–7.43 (m, 2 H, ArH), 7.35 (t, J = 7.6 Hz, 1 H, ArH), 7.30–7.26 reaction mixture at room temp. for 23 h. The product was obtained
1
(m, 4 H, 3 ArH and 2-H), 7.22 (d, J = 8.8 Hz, 2 H, OCH2-
3942
as a colourless oil (0.16 g, 96%). H NMR (300 MHz, CDCl3): δ
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© 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2011, 3938–3945

A Flexible Approach to 6,5-Benzannulated Spiroketals
= 7.91 (d, J = 16.2 Hz, 1 H, 1-H), 7.52–7.25 (m, 11 H, 2ϫ
reaction mixture at room temp. for 17.5 h. The product was ob-
OCH2C6H5 and H6Ј), 6.76 (d, J = 16.2 Hz, 1 H, 2-H), 6.55–6.52 tained as a pale yellow solid (0.27 g, 96%); m.p. 62–63 °C. 1H
(m, 2 H, 3Ј-H and 5Ј-H), 5.14 (s, 2 H, ArOCH2C6H5), 4.50 (s, 2 NMR (400 MHz, CDCl3): δ = 8.17 (d, J = 16.4 Hz, 1 H, 1-H),
H, CH2OCH2C6H5), 3.81 (s, 3 H, OCH3), 3.53 (t, J = 6.3 Hz, 2 H, 7.49–7.19 (m, 17 H, 3 OBn, 2-H and 4Ј-H), 6.62 (d, J = 8.4 Hz, 2
6-H), 2.74 (t, J = 7.2 Hz, 2 H, 4-H), 2.03–1.94 (m, 2 H, 5-H) ppm. H, 3Ј-H and 5Ј-H), 5.17 (s, 4 H, 2 ArOCH2C6H5), 4.50 (s, 2 H,
13C NMR (75 MHz, CDCl3): δ = 200.5, 162.7, 159.0, 138.5, 137.7, CH2OCH2C6H5), 3.50 (t, J = 6.4 Hz, 2 H, 6-H), 2.67 (t, J = 7.4 Hz,
136.4, 130.2, 128.7, 128.3, 128.1, 127.6, 127.5, 127.2, 124.8, 117.0,
2 H, 4-H), 1.98–1.91 (m, 2 H, 5-H) ppm. 13C NMR (100 MHz,
CDCl3): δ = 201.5, 159.2, 138.6, 136.5, 133.3, 131.1, 129.4, 128.6,
128.3, 128.0, 127.6, 127.4, 127.2, 126.9, 113.2, 105.5, 72.8, 70.7,
105.9, 99.9, 72.8, 70.5, 69.6, 55.4, 37.1, 24.5 ppm. IR (neat): ν
˜
max
= 3030, 2856, 1681, 1594, 1272, 1165, 1115, 696 cm–1. HRMS
(ESI): calcd. for C27H28NaO4 [M + Na]+ 439.1880; found 439.1877.
69.6, 37.6, 24.2 ppm. IR (neat): ν
= 3032, 2864, 1685, 1593,
˜
max
1452, 1252, 1091, 733 cm–1. HRMS (ESI): calcd. for C33H32NaO4
[M + Na]+ 515.2193; found 515.2176.
(E)-6-(Benzyloxy)-1-[2,4-bis(benzyloxy)phenyl]hex-1-en-3-one (40):
The general procedure was applied by using phosphonate 29
(0.71 g, 2.4 mmol) and aldehyde 33 (0.75 g, 2.4 mmol), stirring the
reaction mixture at reflux for 2.5 h. The product was obtained as
General Procedure for the Reduction of Enones 7, 18 and 19: Enone
(0.08 mmol) in dichloromethane (3 mL) was added to a stirred sus-
pension of titanocene dichloride (0.008 mmol), zinc dust
(0.2 mmol) and triethylamine hydrochloride (0.4 mmol) in dichlo-
romethane (2 mL). The reaction mixture was stirred at room temp.
for 1 h. Saturated ammonium chloride was added and the reaction
H, mixture filtered through Celite and extracted with ethyl acetate.
The combined organic extracts were washed with brine, dried with
magnesium sulfate, and the solvent was removed in vacuo before
purification by flash chromatography using hexanes/ethyl acetate
(4:1) as eluent.
1
a yellow solid (0.91 g, 78%); m.p. 69–70 °C. H NMR (400 MHz,
CDCl3): δ = 7.89 (d, J = 16.3 Hz, 1 H, 1-H), 7.48–7.46 (m, 1 H,
6Ј-H), 7.41–7.22 (m, 15 H, 3ϫ OCH2C6H5), 6.74 (d, J = 16.3 Hz,
1 H, 2-H), 6.59–6.57 (m, 2 H, 3Ј-H and 5Ј-H), 5.08 (s, 2 H, Ar-
OCH2C6H5), 5.03 (s,
2 H, ArOCH2C6H5), 4.47 (s, 2
CH2OCH2C6H5), 3.50 (t, J = 6.2 Hz, 2 H, 6-H), 2.71 (t, J = 7.3 Hz,
2 H, 4-H), 1.99–1.93 (m, 2 H, 5-H) ppm. 13C NMR (100 MHz,
CDCl3): δ = 200.4, 161.8, 158.9, 138.5, 137.6, 136.3, 130.1, 130.1,
128.6, 128.3, 128.1, 128.0, 127.5, 127.4, 127.1, 124.8, 117.1, 106.7,
100.6, 72.7, 70.4, 70.1, 69.5, 37.0, 24.4 ppm. IR (neat): νmax = 3031,
˜
6-[(4-Methoxybenzyl)oxy]-1-{2-[(4-methoxybenzyl)oxy]phenyl}-
hexan-3-one (20): The general procedure was applied by using en-
one 7 (36 mg, 0.08 mmol). The product was obtained as pale yellow
oil (28 mg, 79%). 1H NMR (400 MHz, CDCl3): δ = 7.33 (d, J =
8.6 Hz, 2 H, OCH2PhOCH3), 7.22 (d, J = 8.6 Hz, 2 H, OCH2-
2855, 1679, 1591, 1562, 1181, 1127, 730 cm–1. HRMS (ESI): calcd.
for C33H33O4 [M + H]+ 493.2373; found 493.2361.
(E)-6-(Benzyloxy)-1-[2,5-bis(benzyloxy)phenyl]hex-1-en-3-one (41):
The general procedure was applied by using phosphonate 29
(0.19 g, 0.6 mmol) and aldehyde 34 (0.10 g, 0.3 mmol) (2.0 equiv. PhOCH3), 7.18–7.11 (m, 2 H, ArH), 6.92–6.83 (m, 6 H, ArH), 4.99
of 29 and NaH used relative to 34), stirring the reaction mixture
(s, 2 H, OCH2PhOCH3), 4.36 (s, 2 H, OCH2PhOCH3), 3.79 (s, 3
H, OCH2PhOCH3), 3.77 (s, 3 H, OCH2PhOCH3), 3.39 (t, J =
at room temp. for 17 h. The product was obtained as a pale yellow
1
solid (0.57 g, 94%); m.p. 66–67 °C. H NMR (300 MHz, CDCl3): 8.4 Hz, 2 H, 6-H), 2.90 (t, J = 10.2 Hz, 2 H, 2-H), 2.69 (t, J =
δ = 7.99 (d, J = 16.5 Hz, 1 H, 1-H), 7.49–7.27 (m, 15 H, 3ϫ 10.2 Hz, 2 H, 1-H), 2.43 (t, J = 9.6 Hz, 2 H, 4-H), 1.86–1.77 (m, 2
OCH2C6H5), 7.22 (d, J = 3.0 Hz, 1 H, 6Ј-H), 6.99 (dd, J = 9.0,
3.0 Hz, 1 H, 4Ј-H), 6.92 (d, J = 9.0 Hz, 1 H, 3Ј-H), 6.80 (d, J
H, 5-H) ppm. 13C NMR (100 MHz, CDCl3): δ = 210.3, 159.3,
159.1, 156.6, 130.5, 130.1, 129.8, 129.3, 129.2, 128.7, 127.3, 120.7,
= 16.5 Hz, 1 H, 2-H), 5.12 (s, 2 H, ArOCH2C6H5), 5.06 (s, 2 H, 113.9, 113.7, 111.7, 72.4, 69.6, 69.0, 55.2, 42.7, 39.3, 25.1,
ArOCH2C6H5), 4.54 (s, 2 H, CH2OCH2C6H5), 3.57 (t, J = 6.2 Hz, 23.8 ppm. IR (neat): ν
= 2933, 1710, 1612, 1513, 1239, 1173,
˜
max
2 H, 6-H), 2.80 (t, J = 7.4 Hz, 2 H, 4-H), 2.07–1.98 (m, 2 H, 5-H)
ppm. 13C NMR (75 MHz, CDCl3): δ = 200.3, 152.9, 152.1, 138.4,
137.3, 136.8, 136.7, 128.5, 128.3, 127.9, 127.5, 127.42, 127.37,
127.2, 127.1, 124.7, 118.2, 114.4, 114.0, 72.7, 71.2, 70.6, 69.4, 37.0,
1032 cm–1. HRMS (ESI): calcd. for C28H32NaO5 [M + Na]+
471.2142; found 471.2133.
1-(2-{[(4-Methoxybenzyl)oxy]methyl}phenyl)-3-{2-[(4-methoxy-
benzyl)oxy]phenyl}propan-1-one (21): The general procedure was
applied by using enone 18 (40 mg, 0.08 mmol). The product was
obtained as a colourless solid (33 mg, 83%); m.p. 81–82 °C. 1H
NMR (400 MHz, CDCl3): δ = 7.66 (d, J = 7.7 Hz, 1 H, ArH), 7.54
(d, J = 7.7 Hz, 1 H, ArH), 7.43 (t, J = 7.6 Hz, 1 H, ArH), 7.34–
7.27 (m, 4 H, ArH), 7.22–7.13 (m, 3 H, ArH), 6.93–6.85 (m, 6 H,
ArH), 5.00, 4.78, 4.48 (s, 6 H, 2 CH2PhOCH3 and CH2OPMB),
3.78 (s, 3 H, OCH2PhOCH3), 3.77 (s, 3 H, OCH2PhOCH3), 3.18
24.3 ppm. IR (neat): ν
= 3031, 2857, 1658, 1603, 1493, 1205,
˜
max
733, 695 cm–1. HRMS (ESI): calcd. for C33H32NaO4 [M + Na]+
515.2193; found 515.2174.
(E)-6-(Benzyloxy)-1-[2-(benzyloxy)-6-methoxyphenyl]hex-1-en-3-one
(42): The general procedure was applied by using phosphonate 29
(0.12 g, 0.4 mmol) and aldehyde 35 (0.10 g, 0.4 mmol), stirring the
reaction mixture at room temp. for 23 h. The product was obtained
1
as a pale yellow oil (0.16 g, 93%). H NMR (400 MHz, CDCl3): δ (t, J = 10.4 Hz, 2 H, 2-H), 3.02 (t, J = 10.4 Hz, 2 H, 3-H) ppm.
= 8.12 (d, J = 16.8 Hz, 1 H, 1-H), 7.46–7.23 (m, 12 H, 2 CH2C6H5
and 4Ј-H and 2-H), 6.63–6.57 (m, 2 H, 3Ј-H and 5Ј-H), 5.17 (s, 2 136.7, 131.3, 130.4, 130.2, 129.7, 129.3, 129.2, 129.0, 128.5, 127.9,
H, ArOCH2C6H5), 4.51 (s, 2 H, CH2OCH2C6H5), 3.89 (s, 3 H, 127.4, 126.8, 120.7, 114.0, 113.7, 111.7, 72.5, 70.1, 69.7, 55.2, 41.3,
13C NMR (100 MHz, CDCl3): δ = 203.8, 159.3, 159.1, 156.7, 139.2,
OCH3), 3.54 (t, J = 6.2 Hz, 2 H, 6-H), 2.74 (d, J = 7.2 Hz, 2 H, 4- 26.1 ppm. IR (neat): ν
= 2934, 2838, 1682, 1512, 1252, 1235,
˜
max
H), 2.02–1.96 (m, 2 H, 5-H) ppm. 13C NMR (100 MHz, CDCl3):
δ = 201.6, 160.2, 159.1, 138.5, 136.5, 133.5, 131.2, 129.3, 128.6,
128.3, 128.0, 127.5, 127.4, 127.1, 112.7, 105.2, 103.9, 72.7, 70.7,
746 cm–1. HRMS (ESI): calcd. for C32H32NaO5 [M + Na]+
519.2142; found 519.2140.
1,4-Bis{2-[(4-methoxybenzyl)oxy]phenyl}butan-2-one (22): The ge-
neral procedure was applied by using enone 19 (40 mg, 0.08 mmol).
The product was obtained as a colourless solid (36 mg, 89%); m.p.
70–71 °C. 1H NMR (400 MHz, CDCl3): δ = 7.27–7.18 (m, 5 H,
ArH), 7.13 (t, J = 7.8 Hz, 1 H, ArH), 7.07–7.04 (m, 2 H, ArH),
6.90–6.81 (m, 8 H, ArH), 4.93 (s, 2 H, OCH2PhOCH3), 4.90 (s, 2
H, OCH2PhOCH3), 3.78 (s, 3 H, OCH2PhOCH3), 3.75 (s, 3 H,
69.6, 55.7, 37.2, 24.4 ppm. IR (neat): νmax = 3032, 2861, 1682, 1593,
˜
1474, 1103, 730 cm–1. HRMS (ESI): calcd. for C27H28NaO4 [M +
Na]+ 439.1880; found 439.1875.
(E)-6-(Benzyloxy)-1-[2,6-bis(benzyloxy)phenyl]hex-1-en-3-one (43):
The general procedure was applied by using phosphonate 29
(0.18 g, 0.6 mmol) and aldehyde 36 (0.18 g, 0.6 mmol), stirring the
Eur. J. Org. Chem. 2011, 3938–3945
© 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
3943

Z. E. Wilson, J. G. Hubert, M. A. Brimble
FULL PAPER
OCH2PhOCH3), 3.61 (s, 2 H, 1-H), 2.86 (t, J = 8.0 Hz, 2 H, 3-H), mixture stirred under hydrogen until the reaction was judged com-
2.70 (t, J = 8.0 Hz, 2 H, 4-H) ppm. 13C NMR (100 MHz, CDCl3):
δ = 208.4, 159.3, 159.2, 156.5, 156.4, 131.2, 130.1, 129.8, 129.3,
128.9, 128.9, 128.6, 128.3, 127.2, 124.1, 120.7, 120.6, 113.9, 111.7,
plete by TLC. The solvent was removed in vacuo, and the reaction
mixture was purified by flash or preparative thin layer chromatog-
raphy. Method B: A solution (0.1 g/50 mL) of the appropriate en-
one in ethyl acetate/methanol (1:1) was hydrogenated by means of
an H-Cube® HC-2 continuous hydrogenation apparatus (THALES
Nanotechnology Inc.) using a 20% palladium hydroxide cartridge
with a flow rate of 1 mL/min and a column block temperature of
20 °C and a pressure of 20 bar in full H2 mode. The solvent was
removed in vacuo and the resulting crude product purified by flash
or preparative thin layer chromatography.
111.6, 69.7, 69.5, 55.2, 44.8, 42.0, 25.0 ppm. IR (neat): νmax = 2961,
˜
2933, 1716, 1514, 1237, 1006 cm–1. HRMS (ESI): calcd. for
C32H32NaO5 [M + Na]+ 519.2142; found 519.2135.
General Procedure for the Cyclisation. Method A: A mixture of di-
hydroxy ketone (1 equiv.) and 2,3-dichloro-5,6-dicyanobenzo-
quinone (DDQ) (3 equiv.) in dichloromethane/water (10:1) was
stirred at room temp. for 7–24 h. Aqueous saturated sodium hydro-
gen carbonate was added, and the solvent was removed in vacuo.
The resulting mixture was extracted with ethyl acetate, the com-
bined organic extracts were washed with aqueous saturated sodium
hydrogen carbonate and brine, and the solvent was removed in
vacuo. The resulting oil was purified by preparative thin layer
chromatography using hexanes/ethyl acetate (4:1) as eluent.
Method B: Anhydrous hydrochloric acid (4 m in dioxane) was
added to a stirred solution of dihydroxy ketone in THF and the
resultant mixture stirred at room temp. for 48 h. The reaction mix-
ture was neutralised with aqueous sodium hydroxide and extracted
with ethyl acetate. The combined organic extracts were washed with
brine, dried with magnesium sulfate, and the solvent was removed
in vacuo before purification by preparative thin layer chromatog-
raphy using hexanes/ethyl acetate (4:1) as eluent.
4Ј,5Ј-Dihydro-3ЈH-spiro[chroman-2,2Ј-furan] (4): Method A: Enone
37 (0.20 g, 0.5 mmol) was reduced in the presence of Pd/C or
Pd(OH)2 catalyst with a reaction time of 72 h; purification was car-
ried out by flash chromatography using hexanes/ethyl acetate (4:1)
to afford a colourless oil (87 mg, 88%). 1H NMR (400 MHz,
CDCl3): δ = 7.16–7.05 (m, 2 H, 5-H and 6-H), 6.91–6.75 (m, 2 H,
7-H and 8-H), 4.13–3.93 (m, 2 H, 5Ј-H), 3.11–2.99 (m, 1 H, 4-H),
2.74 (dt, J = 16.3, 4.9 Hz, 1 H, 4-H), 2.32–1.82 (m, 6 H, 3 CH2)
1
ppm. The H NMR spectroscopic data obtained was in agreement
with that reported in the literature.[1c]
8-Methoxy-4Ј,5Ј-dihydro-3ЈH-spiro[chroman-2,2Ј-furan]
(23):
Method B: Enone 38 (90 mg, 0.2 mmol); purification was carried
out by flash chromatography using hexanes/ethyl acetate (4:1) to
afford a colouress oil (33 mg, 68%). 1H NMR (400 MHz, CDCl3):
δ = 6.81–6.77 (m, 1 H, 6-H), 6.72–6.69 (m, 2 H, 5-H and 7-H),
4.11 (dt, J = 8.0, 6.0 Hz, 1 H, 5-H), 3.97 (dt, J = 8.0, 6.0 Hz, 1 H,
5-H), 3.82 (s, 3 H, OCH3), 3.11–3.02 (m, 1 H, 4-H), 2.78–2.72 (m,
1 H, 4-H), 2.40–2.24 (m, 2 H, CH2), 2.12–1.87 (m, 4 H, 2 CH2)
ppm. 13C NMR (100 MHz, CDCl3): δ = 148.7, 142.7, 122.7, 121.2,
119.8, 109.9, 106.6, 66.2, 56.1, 37.0, 29.9, 24.2, 22.8 ppm. IR (neat):
4Ј,5Ј-Dihydro-3ЈH-spiro[chroman-2,2Ј-furan] (4): Method A: Dihy-
droxy ketone 20 (50 mg, 0.1 mmol); the product was obtained as a
colourless oil (8.0 mg, 40%). Method B: Dihydroxy ketone 20
(33 mg, 0.07 mmol); the product was obtained as colourless oil
1
(8.4 mg, 60%). H NMR (400 MHz, CDCl3): δ = 7.16–7.05 (m, 2
H, 5-H and 6-H), 6.91–6.75 (m, 2 H, 7-H and 8-H), 4.13–3.93 (m,
2 H, 5Ј-H), 3.11–2.99 (m, 1 H, 4-H), 2.74 (dt, J = 4.9, 16.3 Hz, 1
ν
= 2940, 2899, 1585, 1481, 1262, 1190, 1074 cm–1. HRMS
˜
1
max
H, 4-H), 2.32–1.82 (m, 6 H, 3 CH2) ppm. The H NMR spectro-
(ESI): calcd. for C13H17O3 [M + H]+ 221.1172; found 221.1165.
scopic data obtained was in agreement with that reported in the
literature.[1c]
7-Methoxy-4Ј,5Ј-dihydro-3ЈH-spiro[chroman-2,2Ј-furan]
(24):
3ЈH-Spiro[chroman-2,1Ј-isobenzofuran] (5): Method B: Dihydroxy
ketone 21 (50 mg, 0.1 mmol); the product was obtained as a pale
yellow solid (14 mg, 58%); m.p. 70–71 °C. 1H NMR (400 MHz,
CDCl3): δ = 7.45–7.38 (m, 3 H, ArH), 7.34–7.32 (d, J = 7.2 Hz, 1
H, ArH), 7.16–7.07 (m, 3 H, ArH), 6.91 (t, J = 6.4 Hz, 1 H, ArH),
6.81–6.78 (m, 2 H, ArH), 5.30 (d, J = 12.8 Hz, 1 H, 3Ј-H), 5.07 (d,
J = 12.8 Hz, 1 H, 3Ј-H), 3.36–3.24 (m, 1 H, 4-H), 2.89 (ddd, J =
16.3, 5.8, 2.0 Hz, 1 H, 4-H), 2.45 (dt, J = 13.2, 5.8 Hz, 1 H, 3-H),
2.20 (ddd, J = 13.2, 5.7, 2.1 Hz, 1 H, 3-H) ppm. 13C NMR
(100 MHz, CDCl3): δ = 153.2, 140.0, 129.4, 129.1, 127.9, 127.4,
122.0, 121.7, 121.3, 120.8, 117.1, 108.2, 71.7, 30.2, 21.7 ppm. IR
Method A: Enone 39 (0.10 g, 0.2 mmol) was reduced in the pres-
ence of Pd/C catalyst, with a reaction time of 21 h; purification was
carried out by preparative thin layer chromatography using hex-
1
anes/ethyl acetate (4:1) to afford a colourless oil (28 mg, 53%). H
NMR (300 MHz, CDCl3): δ = 6.96 (d, J = 8.3 Hz, 1 H, 5-H), 6.46
(dd, J = 8.3, 2.6 Hz, 1 H, 6-H), 6.36 (d, J = 2.4 Hz, 1 H, 8-H),
4.14–3.94 (m, 2 H, 5Ј-H), 3.75 (s, 3 H, OCH3), 3.03–2.92 (m, 1 H,
4-H), 2.69 (dt, J = 15.9, 5.0 Hz, 1 H, 4-H), 2.30–2.18 (m, 2 H,
CH2), 2.07–1.83 (m, 4 H, 2 CH2) ppm. 13C NMR (75 MHz,
CDCl3): δ = 159.1, 153.8, 129.5, 113.9, 107.3, 106.8, 102.0, 68.1,
55.3, 36.9, 30.1, 24.1, 22.1 ppm. IR (neat): νmax = 2936, 1620, 1583,
˜
(neat): νmax = 3044, 2942, 1583, 1488, 1231, 1002, 745 cm–1. HRMS
˜
1505, 1442, 1155, 1132, 982, 849 cm–1 HRMS (ESI): calcd. for
C13H17O3 [M + H]+ 221.1172; found 221.1168.
(ESI): calcd. for C16H15O2 [M + H]+ 239.1067; found 239.1062.
3H-Spiro[benzofuran-2,2Ј-chroman] (6): Method A: Dihydroxy
ketone 22 (77 mg, 0.2 mmol); the product was obtained as a colour-
less solid (0.013 g, 35%); m.p. 71–72 °C (ref.[13] oil). 1H NMR
(400 MHz, CDCl3): δ = 7.23 (d, J = 8.0 Hz, 1 H, ArH), 7.17–7.09
(m, 3 H, ArH), 6.94–6.90 (m, 2 H, ArH), 6.80–6.78 (m, 2 H, ArH),
3.45 (d, J = 16.4 Hz, 1 H, 3Ј-H), 3.31–3.21 (m, 2 H, 3Ј-H, 4-H),
2.83 (ddd, J = 16.4, 6.0, 2.7 Hz, 1 H, 4-H), 2.33 (ddd, J = 13.2,
6.0, 2.7 Hz, 1 H, 3-H), 2.20 (ddd, J = 13.2, 13.2, 6.0 Hz, 1 H, 3-H)
ppm. The 1H and 13C NMR spectroscopic data obtained was in
agreement with that reported in the literature.[13]
4Ј,5Ј-Dihydro-3ЈH-spiro[chroman-2,2Ј-furan]-7-ol (25): Method A:
Enone 40 (0.10 g, 0.2 mmol) was reduced in the presence of
Pd(OH)2 catalyst, with a reaction time of 72 h; purification was
carried out by preparative thin layer chromatography using hex-
anes/ethyl acetate (4:1) to afford a colourless solid (32 mg, 76%);
m.p. 85–86 °C. 1H NMR (300 MHz, CDCl3): δ = 6.85 (d, J =
8.4 Hz, 1 H, 5-H), 6.33 (dd, J = 8.4, 2.4 Hz, 1 H, 6-H), 6.27 (d, J
= 2.4 Hz, 1 H, 8-H), 5.72 (br. s, 1 H, OH), 4.17–3.93 (m, 2 H, 5Ј-
H), 2.97–2.86 (m, 1 H, 4-H), 2.64 (dt, J = 15.9, 5.1 Hz, 1 H, 4-H),
2.24–2.16 (m, 2 H, CH2), 2.05–1.80 (m, 4 H, 2 CH2) ppm. 13C
NMR (75 MHz, CDCl3): δ = 155.0, 153.5, 129.6, 113.6, 108.2,
General Procedure for the Hydrogenation/Cyclisation of Enones 37–
43. Method A: The appropriate enone was taken up in tetra-
hydrofuran, and catalytic palladium (10% on carbon) or palladium
hydroxide (20% on carbon) was added and the resulting reaction
106.9, 103.8, 68.1, 36.7, 30.0, 23.8, 22.0 ppm. IR (neat): ν
=
˜
max
3359, 2934, 1711, 1622, 1151, 990, 844 cm–1. HRMS (ESI): calcd.
for C13H15O3 [M + H]+ 207.1016; found 207.1009.
3944
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© 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2011, 3938–3945

A Flexible Approach to 6,5-Benzannulated Spiroketals
4Ј,5Ј-Dihydro-3ЈH-spiro[chroman-2,2Ј-furan]-6-ol (26): Method B:
Enone 41 (0.20 g, 0.4 mmol); after hydrogenation, the solvent
stream was run through a 2ϫ4 cm loosely packed column of Am-
berlyst 15® acidic resin (Sigma–Aldrich) before the solvent was re-
moved in vacuo; purification was carried out by flash chromatog-
raphy using hexanes/ethyl acetate (4:1) to afford a colourless solid
[1] a) K. W. Choi, M. A. Brimble, Org. Biomol. Chem. 2009, 7,
1424–1436; b) K. W. Choi, M. A. Brimble, Org. Biomol. Chem.
2008, 6, 3518–3526; c) C. D. Bray, Org. Biomol. Chem. 2008, 6,
2815–2819; d) L.-G. Milroy, G. Zinzalla, G. Prencipe, P.
Michel, S. V. Ley, M. Gunaratnam, M. Beltran, S. Neidle, An-
gew. Chem. 2007, 119, 2545; Angew. Chem. Int. Ed. 2007, 46,
2493–2496; e) G. Zinzalla, L.-G. Milroy, S. V. Ley, Org. Biomol.
Chem. 2006, 4, 1977–2002.
[2] J. Sperry, Z. E. Wilson, D. C. K. Rathwell, M. A. Brimble, Nat.
Prod. Rep. 2010, 27, 1117–1137.
[3] A. A. Stierle, D. B. Stierle, K. Kelly, J. Org. Chem. 2006, 71,
5357–5360.
1
(67 mg, 80%); m.p. 125–126.0 °C. H NMR (400 MHz, CDCl3): δ
= 6.63 (d, J = 8.8 Hz, 1 H, 8-H), 6.55 (dd, J = 8.8, 2.8 Hz, 1 H, 7-
H), 6.50 (d, J = 2.8 Hz, 1 H, 5-H), 5.12 (br. s, 1 H, OH), 4.09–3.94
(m, 2 H, 5Ј-H), 3.02–2.93 (m, 1 H, 4-H), 2.65 (dt, J = 16.8, 4.8 Hz,
1 H, 4-H), 2.26–2.18 (m, 2 H, CH2), 2.07–1.84 (m, 4 H, 2 CH2)
ppm. 13C NMR (100 MHz, CDCl3): δ = 149.2, 146.8, 122.5, 117.6,
[4] a) M. Namikoshi, H. Kobayashi, T. Yoshimoto, S. Meguro,
Chem. Lett. 2000, 308–309; b) M. Namikoshi, H. Kobayashi,
T. Yoshimoto, S. Meguro, K. Akano, Chem. Pharm. Bull. 2000,
48, 1452–1457.
115.3, 114.3, 106.5, 68.0, 36.9, 29.8, 24.0, 22.8 ppm. IR (neat): ν
˜
max
= 3264, 2257, 1646, 1496, 1194, 1074, 914 cm–1. HRMS (ESI):
calcd. for C12H15O3 [M + H]+ 207.1016; found 207.1007.
[5] a) M. Brasholz, S. Soergel, C. Azap, H.-U. Reißig, Eur. J. Org.
Chem. 2007, 3801–3814; b) C. Puder, S. Loya, A. Hizi, A.
Zeeck, Eur. J. Org. Chem. 2000, 729–735; c) T. Ueno, H. Takah-
ashi, M. Oda, M. Mizunuma, A. Yokoyama, Y. Goto, Y. Mi-
zushina, K. Sakaguchi, H. Hayashi, Biochemistry 2000, 39,
5995–6002.
5-Methoxy-4Ј,5Ј-dihydro-3ЈH-spiro[chroman-2,2Ј-furan]
(27):
Method A: Enone 42 (0.10 g, 0.2 mmol) was reduced in the pres-
ence of Pd/C catalyst, with a reaction time of 70 h; purification was
carried out by preparative thin layer chromatography using hex-
anes/ethyl acetate (4:1) to afford a yellow oil (33 mg, 62%). 1H
NMR (300 MHz, CDCl3): δ = 7.06 (t, J = 8.3 Hz, 1 H, 7-H), 6.46–
6.42 (m, 2 H, 6-H, 8-H), 4.12–3.94 (m, 2 H, 5Ј-H), 3.81 (s, 3 H,
OCH3), 2.81–2.77 (m, 2 H, 4-H), 2.31–2.19 (m, 2 H, CH2), 2.08–
1.80 (m, 4 H, 2 CH2) ppm. 13C NMR (75 MHz, CDCl3) 157.6,
153.8, 127.0, 110.8, 109.9, 106.4, 102.2, 68.1, 55.4, 36.7, 29.4, 24.0,
[6] W. S. Wadsworth, W. D. Emmons, J. Am. Chem. Soc. 1961, 83,
1733–1738.
[7] J. Jägel, A. Schmauder, M. Binanzer, M. E. Maier, Tetrahedron
2007, 63, 13006–13017.
[8] A. D. Kosal, B. L. Ashfeld, Org. Lett. 2009, 11, 44.
[9] Aldehyde by-product formed when oxidative PMB cleavage
was attempted on dihydroxy ketone 20.
17.4 ppm. IR (neat): ν
= 2960, 2895, 1591, 1469, 1249,
˜
max
1077 cm–1. HRMS (ESI): calcd. for C13H17O3 [M + H]+ 221.1172;
found 221.1165.
4Ј,5Ј-Dihydro-3ЈH-spiro[chroman-2,2Ј-furan]-5-ol (28): Method A:
Enone 43 (0.20 g, 0.4 mmol) was reduced in the presence of
Pd(OH)2 catalyst, with a reaction time of 65 h, purification was
carried out by flash chromatography using pentane/diethyl ether
1
[10] a) C. Venkatesh, H.-U. Reißig, Synthesis 2008, 3605–3614; b)
S. P. Waters, M. W. Fennie, M. C. Kozlowski, Org. Lett. 2006,
8, 3243–3246.
(3:2) to afford a colourless solid (52 mg, 64%); m.p. 98–99 °C. H
NMR (400 MHz, CDCl3): δ = 6.95 (t, J = 8.4 Hz, 1 H, 7-H), 6.40
(dd, J = 8.4, 0.8 Hz, 1 H, 8-H), 6.34 (dd, J = 8.4, 0.8 Hz, 1 H, 6-
H), 4.76 (br.s, 1 H, OH), 4.10–3.95 (m, 2 H, 5Ј-H), 2.86–2.71 (m,
2 H, 4-H), 2.29–2.18 (m, 2 H, CH2), 2.11–1.83 (m, 4 H, 2 CH2)
ppm. 13C NMR (100 MHz, CDCl3) 154.1, 154.0, 127.1, 109.4,
[11] Z. E. Wilson, M. A. Brimble, Org. Biomol. Chem. 2010, 8,
1284–1286.
[12] Aldehydes 29–35 were readily accessed by standard benz-
ylation, formylation, oxidation and reduction procedures from
commercially available hydroxybenzyl, benzaldehyde and ben-
zoic acid starting materials; a) K.-i. Hayashi, A. Yamazoe, Y.
Ishibashi, N. Kusaka, Y. Oono, H. Nozaki, Bioorg. Med. Chem.
2008, 16, 5331–5334; b) S. Kozuch, T. Leifels, D. Meyer, L.
Sbaragli, S. Shaik, W.-D. Woggon, Synlett 2005, 4, 675–684; c)
A. R. Haight, A. E. Bailey, W. S. Baker, M. H. Cain, R. R.
Copp, J. A. DeMattei, K. L. Ford, R. F. Henry, M. C. Hsu,
R. F. Keyes, S. A. King, M. A. McLaughlin, L. M. Melcher,
W. R. Nadler, P. A. Oliver, S. I. Parekh, H. H. Patel, L. S. Seif,
M. A. Staeger, G. S. Wayne, S. J. Wittenberger, W. Zhang, Org.
Process Res. Dev. 2004, 8, 897–902.
106.9, 106.4, 68.2, 36.8, 34.1, 29.3, 24.0, 17.3 ppm. IR (neat): ν
˜
max
= 3360, 2928, 1616, 1591, 1463, 1007, 773 cm–1. HRMS (ESI):
calcd. for C12H15O3 [M + H]+ 207.1016; found 207.1016.
Supporting Information (see footnote on the first page of this arti-
1
cle): H and 13C NMR spectra for selected compounds.
Acknowledgments
[13] S. P. Waters, M. W. Fennie, M. C. Kozlowski, Tetrahedron Lett.
2006, 47, 5409–5413.
We thank the Royal Society of New Zealand Marsden Fund and
the Maurice Wilkins Centre for Molecular Biodiscovery for finan-
cial support.
Received: March 11, 2011
Published Online: May 18, 2011
Eur. J. Org. Chem. 2011, 3938–3945
© 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
3945