Generation and hetero-Diels-Alder reactions of an o-quinone methide under mild, anionic conditions: Rapid synthesis of mono-benzannelated spiroketals

Article abstract of DOI:10.1039/b806593d

Deprotonation of o-hydroxybenzyl acetate with ⁱPrMgCl provides a method of generating an o-quinone methide under mild, anionic conditions, such that highly sensitive exo-enol ethers can be employed as 2π partners in hetero-Diels-Alder reactions

Full text of DOI:10.1039/b806593d

View Online / Journal Homepage / Table of Contents for this issue
PAPER
www.rsc.org/obc | Organic & Biomolecular Chemistry
Generation and hetero-Diels–Alder reactions of an o-quinone methide under
mild, anionic conditions: rapid synthesis of mono-benzannelated spiroketals†
Christopher D. Bray*
Received 21st April 2008, Accepted 23rd April 2008
First published as an Advance Article on the web 28th May 2008
DOI: 10.1039/b806593d
Deprotonation of o-hydroxybenzyl acetate with iPrMgCl provides a method of generating an o-quinone
methide under mild, anionic conditions, such that highly sensitive exo-enol ethers can be employed as
2p partners in hetero-Diels–Alder reactions. This process results in mono-benzannelated spiroketals
such as those found in the natural products berkelic acid, the chaetoquadrins or cephalostatin 6.
until the early 1980’s when Ireland and Ha¨bich initially applied
Introduction
this method to the synthesis of insect pheromones.5 Research
Spiroketals are found in a large and diverse range of natural
by Ireland and his group continued to pioneer this reaction
throughout the rest of that decade and on into the early 1990’s.6
Since then this process has been used in various forms by
only a handful of groups,7 and is, in general, underutilised. It
was considered whether such an approach could be applied to
mono-benzannelated spiroketals, since these motifs are found in
a range of biologically interesting natural products, for example
berkelic acid 1,8 chaetoquadrin A (2)9 and cephalostatin 6 (3).10
Within the context of such an approach, the a,b-unsaturated
carbonyl (4p) component would be an o-quinone methide
(Scheme 1).11 The realisation of this concept is the basis of the
current paper.
products. The complex structures and often interesting biological
activity of such molecules has attracted the interest of many
synthetic chemists.1 Indeed, there is growing opinion that
spiroketals are privileged pharmacophores.2 By far the most
common method of forming a spiroketal is the cyclodehydration
of a keto-diol. Often, a large number of steps are required
to synthesise these precursors, and in certain instances
spiroketalisation does not occur.3 Overall these factors can detract
from the attractiveness of such an approach. An alternative, and
often more step efficient strategy for the synthesis of spiroketals
comprises the hetero-Diels–Alder reaction between an a,b-
unsaturated carbonyl (4p) component and an exo-enol ether as a
2p partner. This method was introduced by Paul and Tchelitcheff
in 1954,4 when they showed that acrolein undergoes cycloaddition
with 2-methylenetetrahydrofuran to give a [5,6]-spiroketal. Even
so, the use of this reaction was almost completely overlooked
Scheme 1 Retrosynthesis of a mono-benzannelated spiroketal.
Results and discussion
Baldwin and co-workers have examined the generation of an
o-quinone methide via thermolytic extrusion of AcOH from 4
in the presence of 4,5-dihydro-2,4-dimethylfuran (Scheme 2).12
The major product was the expected benzopyran 5, which was
School of Biological and Chemical Sciences, The Walter Besant Building,
Queen Mary, University of London, Mile End Road, London, E1 4NS,
United Kingdom. E-mail: c.bray@qmul.ac.uk; Fax: +44 (0)20 7882 7427;
Tel: +44 (0)20 7882 3271
† Electronic supplementary information (ESI) available: 1H and 13C NMR
spectra for 8a–g. See DOI: 10.1039/b806593d
Scheme 2 Unexpected observation of a mono-benzannelated spiroketal.
Org. Biomol. Chem., 2008, 6, 2815–2819 | 2815
This journal is
The Royal Society of Chemistry 2008
©

View Online
Table 1 Examining the scope of 2p partners
subsequently saponified to give the racemate of the natural product
alboatrin. However, simple exo-enol ethers readily equilibrate
with their endo-isomers under acidic and sometimes also ther-
mal conditions. This may explain why they also observed the
mono-benzannelated spiroketal 6 (as a mixture of diastereomers)
in 25% yield. Presumably this was the result of cycloaddi-
tion of the intermediate o-quinone methide with 4-methyl-2-
methylenetetrahydrofuran.13
Entry
1
2p partnera
Product
Yieldb
85%
8a
8b
2
68%
If this is the case, then equilibration needed to be avoided
in the present work, since simple exo-enol ethers were to be
employed as starting materials and are thermodynamically the
less stable isomers.14 Therefore the primary requirement was
a method to generate an o-quinone methide under very mild,
anionic conditions.15 Pettus et al. have reported hetero-Diels–
Alder reactions of b-substituted o-quinone methides generated
from O-BOC-salicylic aldehydes upon addition of organometallic
reagents. However, when simple enol ethers were employed as 2p
partners, the reactions where almost exclusively carried out using
the 2p partner as solvent.16 In addition, in related work, when a
fluoride initiated release of a b-unsubstituted o-quinone methide
was investigated, the use of >35 equivalents of 2p partner was
required for efficient cycloaddition.17 Obviously, processes that
require such large excesses of 2p partner do not lend themselves
to natural product synthesis. Loubinoux et al. have reported
3
4
5
6
8c
8d
8e
8f
73%
77%
59%
76%
8
8g
8h
59%
t
that treatment of o-hydroxybenzyl acetate 7 with BuOK in the
presence of only 2 equiv. of a malonate nucleophile leads to overall
nucleophilic substitution of the acetate group, presumably via an
o-quinone methide intermediate.18 However, not only are there no
reports of this procedure being used in conjunction with a hetero-
Diels–Alder reaction, but in addition, elevated temperatures were
9c
11%d
a 10 equivalents. b Isolated yield following flash column chromatography.
◦
required for efficient reaction (>45 C). Consequently, although
c 1.00 equiv. of iPrMgCl used. d 6 : 1 mixture of 8h : 8g.
this method was of interest, there was a need to identify an
alternative base that would allow for the efficient generation of o-
quinone methides at ambient temperature (or below). A solution
of o-hydroxybenzyl acetate 719 in THF was treated with a range
of common bases at 0 ◦C in the presence of 2,3-dihydrofuran
(20 equiv.), as an initial test 2p partner. The reactions were then
−78 ◦C before addition of the 2p partner, the reaction then being
allowed to warm slowly to 25 ◦C over 16 h. Using otherwise
identical conditions, the expected cis-fused benzopyran adduct
8a was obtained in 87% yield. The importance of the number
of equivalents of the 2p partner was then investigated: the use
of only 10 equivalents of 2,3-dihydrofuran led to only a small
drop in the yield of 8a to 85% (Table 1, entry 1), and on
decreasing to only 5 equivalents, the yield of 8a remained at a
respectable 68%. Even when only 2.5 equivalents of the 2p partner
were used, the yield was still 45%. The use of a range of other
2p partners was then examined; 3,4-dihydro-2H-pyran gave the
cis-fused benzopyran adduct 8b in 68% yield (entry 2), whereas
the use of ethyl- and n-butyl vinyl ether gave 8c and 8d in 73%
and 77% yields respectively (entries 3 and 4). When ethyl vinyl
sulfide was used as the 2p partner, the hemi-thioacetal 8e was
obtained in 59% (entry 5). Finally, with a view to establishing
methodology that would allow access to the natural products
1–3, two exo-enol ethers were examined as the 2p partners.
Gratifyingly, the use of 2-methylenetetrahydrofuran5a under the
reaction conditions described above, led to the [5,6]-spiroketal 8f
[dC 106.6 (O2C)] in 76% yield (entry 6), with no sign (as judged by
1H NMR spectroscopy) of any products due to isomerisation of
the 2p partner. Similarly the use of 2-methylenetetrahydropyran5a
gave 8g [dC 95.8 (O2C)] in 59% yield (entry 8). It is particularly
◦
warmed to 25 C and stirred for 16 h. The use of either K2CO3
or Cs2CO3 as base did not lead to any reaction, whereas the
use of n-BuLi led to precipitation of the phenolate anion. In
i
stark contrast, the use of PrMgCl (1.04 equiv.) led to benzopy-
ran adduct 8a in 72% yield following column chromatography
(Scheme 3).
Scheme 3 Examining the number of equivalents of 2,3-dihydrofuran.
Ultimately, it was found to be most experimentally convenient
and higher yielding to deprotonate the phenolic proton of 7 at
2816 | Org. Biomol. Chem., 2008, 6, 2815–2819
This journal is
The Royal Society of Chemistry 2008
©

View Online
noteworthy that when only 1.00 equivalent of iPrMgCl was
employed in the attempted synthesis of 8g (entry 9), a 6 : 1
mixture of 8h : 8g was obtained. The major product, 8h, is
that derived from cycloaddition of the intermediate o-quinone
methide with 6-methyl-3,4-dihydro-2H-pyran, the endo-isomer of
2-methylenetetrahydropyran. This result serves to demonstrate the
importance of ensuring that no phenolic protons from 7 are present
when the exo-enol ether is added, lest isomerisation should occur.
General procedure for the preparation of compounds 8a–g
To a solution of o-hydroxybenzyl acetate 7 (165 mg, 1 mmol) in
◦
i
THF (0.50 cm3) at −78 C was added PrMgCl (2.0 M in THF;
0.52 cm3, 1.04 mmol). The solution was stirred for 15 min before
the addition of the 2p partner (10 equiv.). The solution was then
allowed to warm slowly to 25 ◦C over 16 h after which time, EtOAc
(5 cm3) was added and the resulting solution was filtered through
a short plug of silica (∼3cm2 × 2 cm) using EtOAc (∼20 cm3)
as eluent. The filtrate was reduced in vacuo and the residue was
purified by flash column chromatography (SiO2, EtOAc/40–60
petrol) to give the following compounds:
Conclusion
The development of very mild, anionic reaction conditions for the
generation of an o-quinone methide intermediate has allowed for
the use of highly sensitive exo-enol ethers as 2p partners in hetero-
Diels–Alder reactions. The ease with which the o-quinone methide
is generated from a readily available precursor using a common
base is of note. This rapid, and simple strategy is clearly applicable
to the synthesis of a range of natural products including berkelic
acid 1, chaetoquadrin A (2) and cephalostatin 6 (3).20
2,3,3a,9a-Tetrahydro-4H-1,9-dioxa-cyclopenta[b]naphthalene21 8a
According to the general procedure, o-hydroxybenzyl acetate 7
(167 mg, 1.00 mmol) and 2,3-dihydrofuran (0.76 cm3) gave the
title compound 8a (150 mg, 85%) as white solid; mp 35–36 ◦C;
Rf 0.74 (20% EtOAc in petrol); mmax (film)/cm−1 2954 w, 1584
m, 1487 m, 1453 m, 1232 m, 1181 m, 1095 s, 1061 s, 1040 s;
dH (270 MHz; CDCl3) 7.18–7.04 (2H, m, 2 × ArCH), 6.94–6.86
(2H, m, 2 × ArCH), 5.67 (1H, d, J 4.7, O2CH), 4.07–3.86 (2H,
m, OCH2), 3.08 (1H, dd, J 16.4 and 5.5, O2CHCH), 2.81–2.66
(2H, m, ArCH2), 2.12–1.96 (1H, m, OCH2CH(H)), 1.77–1.61
(1H, m, OCH2CH(H)); dC (67.5 MHz; CDCl3) 153.5 (ArCO),
129.2 (ArCH), 127.9 (ArCH), 121.6 (ArC), 121.4 (ArCH), 117.1
(ArCH), 101.8 (O2C), 68.2 (OCH2), 38.0 (CH), 28.3 (CH2) and
26.4 (CH2).
Experimental
Commercially available reagents were used without further purifi-
cation except THF which was distilled from Na–benzophenone
ketyl. All reactions required anhydrous conditions and were con-
ducted in flame-dried apparatus under an atmosphere of nitrogen.
Analytical thin-layer chromatography (TLC) was performed on
silica gel plates (0.25 mm) precoated with a fluorescent indicator.
Standard flash chromatography procedures were performed using
Kieselgel 60 (40–63 lm). Residual solvent was removed using a
static oil pump (<1 mbar). Melting points were determined using
a Gallenkamp melting point stage and are uncorrected. Infrared
spectra were recorded on a Bruker Tensor 27 FTIR machine using
a MIRacle ATR accessory. 1H and 13C NMR spectra were recorded
in CDCl3 at 270 and 67.5 MHz respectively on a JeoL EX270.
Chemical shifts are reported relative to CHCl3 [1H d 7.27] or
CDCl3 [13C d 77.0]. Mass spectra were obtained by the EPSRC
National Mass Spectrometry Service Centre (Swansea) using a
high resolution double focussing mass spectrometer (Finnigan
MAT 95 XP).
3,4,4a,10a-Tetrahydro-2H,5H-pyrano[2,3-b]chromene21 8b
According to the general procedure, o-hydroxybenzyl acetate 7
(166 mg, 1.00 mmol) and 3,4-dihydro-2H-pyran (0.91 cm3) gave
the title compound 8b (129 mg, 68%) as white solid; mp 59–60 ◦C;
Rf 0.70 (20% EtOAc in petrol); mmax (film)/cm−1 2926 m, 1582 w,
1486 m, 1240 m, 1128 m, 1078 s, 1032 m; dH (270 MHz; CDCl3)
7.18–7.02 (2H, m, 2 × ArCH), 6.93–6.83 (2H, m, 2 × ArCH),
5.35 (1H, d, J 2.3, O2CH), 4.09–3.96 (1H, m, OCH(H)), 3.79–3.68
(1H, m, OCH(H)), 2.95 (1H, dd, J 16.6 and 5.9, ArCH(H)), 2.68
(1H, dd, J 16.6 and 4.8, ArCH(H)), 2.26–2.12 (1H, m, OCHCH),
1.78–1.59 (4H, m, 2 × CH2); dC (67.5 MHz; CDCl3) 152.8 (ArCO),
129.4 (ArCH), 127.4 (ArCH), 120.8 (ArCH), 119.9 (ArC), 116.4
(ArCH), 96.6 (O2C), 62.6 (OCH2), 31.7 (CH), 28.9 (CH2), 24.1
(CH2) and 23.5 (CH2).
o-Hydroxybenzyl acetate12a
7
To a stirred solution of salicyl alcohol (1.00 g, 8.06 mmol) and
Ac2O (0.74 cm3, 7.90 mmol, 0.98 equiv) in anhydrous THF
2-Ethoxychroman17 8c
◦
(10 cm3) at −10 C was added BF3·OEt2 (0.15 cm3, 1.18 mmol,
According to the general procedure, o-hydroxybenzyl acetate 7
(175 mg, 1.05 mmol) and ethyl vinyl ether (1.01 cm3) gave the title
compound 8c (136 mg, 73%) as colourless oil; Rf 0.40 (10% EtOAc
in petrol); mmax (film)/cm−1 2932 w, 1583 m, 1488 m, 1456 m, 1373
w, 1351 w, 1328 w, 1301 w, 1274 w, 1223 s, 1178 m, 1118 s, 1102 s,
1057 s; dH (270 MHz; CDCl3) 7.19–7.05 (2H, m, 2 × ArCH),
6.94–6.80 (2H, m, 2 × ArCH), 5.28 (1H, t, J 2.8, O2CH), 3.92
(1H, dq, J 9.6 and 7.1, OCH(H)), 3.67 (1H, dq, J 9.6 and 7.1,
OCH(H)), 2.91 (1H, m, ArCH(H)), 2.66 (1H, ddd, J 5.7, 11.3
and 16.0, ArCH(H)), 2.14–1.90 (2H, m, CH2), 1.22 (3H, t, J 7.1,
Me); dC (67.5 MHz; CDCl3) 152.3 (ArCO), 129.3 (ArCH), 127.3
(ArCH), 122.7 (ArC), 120.6 (ArCH), 117.0 (ArCH), 97.0 (O2C),
63.7 (OCH2), 26.7 (CH2), 20.6 (CH2) and 15.2 (Me).
0.15 equiv) dropwise over 1 min. The reaction was warmed to
4
◦C and stirred for a further 16 h. The reaction was quenched
at 4 ◦C by the addition of sat. aq. NaHCO3 (10 cm3). The
layers were separated and the aqueous phase was extracted with
EtOAc (10 cm3). The combined organic phases were washed with
water (10 cm3), then dried over MgSO4 and filtered. The solvent
◦
was removed in vacuo (bath temp. <20 C) and the residue was
purified by flash column chromatography (30% EtOAc in petrol)
to give the title compound as a viscous oil, which solidified after
approximately 1 week in the freezer leaving a white waxy solid
(1.04 g, 80%); mp 35–36 ◦C (decomp) (lit.,12a oil); all other data as
previously reported.
This journal is
The Royal Society of Chemistry 2008
Org. Biomol. Chem., 2008, 6, 2815–2819 | 2817
©

View Online
2-Butoxychroman 8d
1101 s, 1076 s, 1044 s, 1034 s; dH (270 MHz; CDCl3) 7.19–7.06
(2H, m, 2 × ArCH), 6.95–6.87 (2H, m, 2 × ArCH), 3.86 (1H,
dt, J 4.1 and 11.2, OCH(H)), 3.69–3.59 (1H, m, OCH(H)), 3.06
(1H, ddd, J 16.3, 13.0 and 6.3, ArCH(H)), 2.65 (1H, ddd, J
16.3, 6.3 and 2.0, ArCH(H)), 2.27–1.54 (8H, m, 4 × CH2); dC
(67.5 MHz; CDCl3) 152.2 (ArCO), 129.1 (ArCH), 127.0 (ArCH),
122.7 (ArC), 120.5 (ArCH), 116.9 (ArCH), 95.8 (O2C), 61.7
(OCH2), 34.8 (CH2), 31.9 (CH2), 25.2 (CH2), 21.0 (CH2) and 18.4
(CH2); m/z (EI) [M + Na]+, C13H16O2Na requires 227.1043, found
227.1040.
According to the general procedure, o-hydroxybenzyl acetate 7
(166 mg, 1.00 mmol) and butyl vinyl ether (1.29 cm3) gave
the title compound 8d (158 mg, 77%) as colourless oil; Rf 0.46
(10% EtOAc in petrol); mmax (film)/cm−1 2932 s, 2871 m, 1583
m, 1489 s, 1457 s, 1224 s, 1213 m, 1177 w, 1119 m, 1103 s,
1064 s; dH (270 MHz; CDCl3) 7.18–7.04 (2H, m, 2 × ArCH),
6.94–6.82 (2H, m, 2 × ArCH), 5.26 (1H, t, J 2.9, O2CH), 3.87
(1H, dt, J 9.7 and 6.7, OCH(H)), 3.61 (1H, dt, J 9.7 and 6.7,
OCH(H)), 3.09–2.93 (1H, m, ArCH(H)), 2.65 (1H, ddd, J 3.7, 5.7
and 16.2, ArCH(H)), 2.13–1.89 (2H, m, O2CHCH2), 1.64–1.50
(2H, m, OCH2CH2), 1.42–1.26 (2H, m, CH2Me), 0.90 (3H, t, J
7.3, Me); dC (67.5 MHz; CDCl3) 152.2 (ArCO), 129.1 (ArCH),
127.1 (ArCH), 122.5 (ArC), 120.4 (ArCH), 116.8 (ArCH), 96.9
(O2C), 67.8 (OCH2), 31.6 (CH2), 26.5 (ArCH2), 20.4 (CH2), 19.1
(CH2) and 13.7 (Me). m/z (EI) 206.1303 [M]+, C13H18O2 requires
206.1303.
Acknowledgements
I wish to thank the EPSRC National Mass Spectrometry Service
Centre (Swansea).
References
1 (a) For reviews, see: V. Vaillancourt, N. E. Pratt, F. Perron and K. F.
Albizati, in Total Synthesis of Natural Products, ed. J. ApSimon, John
Wiley & Sons, New York, 2007, vol. 8, pp. 533–693; (b) J. E. Aho,
P. M. Pihko and T. K. Rissa, Chem. Rev., 2005, 105, 4406–4440;
(c) K. T. Mead and B. N. Brewer, Curr. Org. Chem., 2003, 7, 227–
256.
2 (a) L.-G. Milroy, G. Zinzalla, G. Prencipe, P. Michel, S. V. Ley, M.
Gunaratnam, M. Beltran and S. Neidle, Angew. Chem., Int. Ed., 2007,
46, 2493–2496; (b) T. Ueno, H. Takahashi, M. Oda, M. Mizunuma,
A. Yokoyama, Y. Goto, M. Mizushina, K. Sakaguchi and H. Hayashi,
Biochemistry, 2000, 39, 5995–6002.
3 S. P. Waters, M. W. Fennie and M. C. Kozlowski, Org. Lett., 2006, 8,
3243–3246.
4 R. Paul and S. Tchelitcheff, Bull. Soc. Chim. Fr., 1954, 672–678.
5 (a) R. E. Ireland and D. Ha¨bich, Chem. Ber., 1981, 114, 1418–1427;
(b) R. E. Ireland and D. Ha¨bich, Tetrahedron Lett., 1980, 21, 1389–
1392.
2-Ethylsulfanylchroman 8e
According to the general procedure, o-hydroxybenzyl acetate 7
(166 mg, 1.00 mmol) and ethyl vinyl sulfide (1.01 cm3) gave the
title compound 8e (115 mg, 59%) as light yellow oil; Rf 0.30
(10% EtOAc in petrol); mmax (film)/cm−1 2926 s, 1582 s, 1480 s,
1456 s, 1273 s, 1208 s, 1183 s, 1109 s, 1074 s, 1043 s, 1022 s;
dH (270 MHz; CDCl3) 7.16–7.03 (2H, m, 2 × ArCH), 6.94–
6.81 (2H, m, 2 × ArCH), 5.57 (1H, t, J 4.1, O(S)CH), 3.06–
2.65 (4H, m, SCH2 and CH2), 2.38–2.24 (1H, m, CH(H)), 2.20–
2.08 (1H, m, CH(H)), 1.34 (3H, t, J 7.4, Me); dC (67.5 MHz;
CDCl3) 152.5 (ArCO), 129.6 (ArCH), 127.4 (ArCH), 122.0 (ArC),
121.0 (ArCH), 117.5 (ArCH), 80.3 (SCO), 27.4 (CH2), 24.7 (CH2),
22.7 (CH2) and 15.2 (Me); m/z 194.0764 [M]+, C11H14OS requires
194.0760.
6 R. E. Ireland, J. D. Armstrong, J. Lebreton, R. S. Meissner and M. A.
Rizzacasa, J. Am. Chem. Soc., 1993, 115, 7152–7165.
7 For a recent example, see: M. El Sous, D. Ganame, P. A. Tregloan and
M. A. Rizzacasa, Org. Lett., 2004, 6, 3001–3004.
8 (a) A. A. Stierle, D. B. Stierle and K. Kelly, J. Org. Chem., 2006, 71,
5357–5360. For recent biomimetic studies towards berkelic acid 1, see:
(b) J. Zhou and B. B. Snider, Org. Lett., 2007, 9, 2071–2074.
9 H. Fujimoto, M. Nozawa, E. Okuyama and M. Ishibashi, Chem.
Pharm. Bull., 2002, 50, 330–336.
10 G. R. Pettit, Y. Kamano, C. Dufresne, M. Inoue, N. Christie,
J. M. Schmidt and D. L. Doubek, Can. J. Chem., 1989, 67, 1509–
1513.
11 For an excellent review of o-quinone methides, see: R. W. Van De Water
and T. R. R. Pettus, Tetrahedron, 2002, 58, 5367–5405.
12 (a) R. Rodriguez, J. E. Moses, R. M. Adlington and J. E. Baldwin, Org.
Biomol. Chem., 2005, 3, 3488–3495; (b) R. Rodriguez, R. M. Adlington,
J. E. Moses, A. Cowley and J. E. Baldwin, Org. Lett., 2004, 6, 3617–
3619.
13 A similar result has also been observed in studies toward the xyloketals,
see: J. D. Pettigrew, R. P. Freeman and P. D. Wilson, Can. J. Chem.,
2004, 82, 1640–1648.
14 Glassware that has not been washed in base e.g. KOH, is sufficient
to effect isomerisation of 2-methylenetetrahydropyran to 6-methyl-3,4-
dihydro-2H-pyran, see ref. 5a.
15 Xie and Li along with their co-workers have demonstrated routes to
bis-benzannelated [5,6]- and [6,6]-spiroketals via thermolytic extrusion
of AcOH from o-hydroxybenzyl acetates in the presence of exo-enol
ethers for which isomerisation is not possible, or does not occur readily
under the reaction conditions, see: (a) G. Zhou, J. Zhu, Z. Xie and Y.
Li, Org. Lett., 2008, 10, 721–724; (b) G. Zhou, D. Zheng, S. Da, Z. Xie
and Y. Li, Tetrahedron Lett., 2006, 47, 3349–3352.
mono-Benzannelated [5,6]-spiroketal 8f
According to the general procedure, o-hydroxybenzyl acetate 7
(190 mg, 1.14 mmol) and 2-methylenetetrahydrofuran5a (1.06 cm3)
gave the title compound 8f (166 mg, 76%) as colourless oil; Rf
0.23 (5% EtOAc in petrol); mmax (film)/cm−1 2938 s, 2887 m,
1582 s, 1490 s, 1457 s, 1356 m, 1302 m, 1235 s, 1216 s, 1184 s,
1136 s, 1116 m, 1084 s, 1022 m; dH (270 MHz; CDCl3) 7.15–
7.04 (2H, m, 2 × ArCH), 6.90–6.73 (2H, m, 2 × ArCH), 4.14–
3.93 (2H, m, OCH2), 3.14–2.99 (1H, m, ArCH(H)), 2.76 (1H,
dt, 4.9 and 16.3, ArCH(H)), 2.36–1.82 (6H, m, 3 × CH2); dC
(67.5 MHz; CDCl3) 153.1 (ArCO), 129.2 (ArCH), 127.2 (ArCH),
121.9 (ArC), 120.5 (ArCH), 117.1 (ArCH), 106.7 (O2C), 68.1
(OCH2), 37.0 (O2CCH2), 30.0 (ArCH2), 24.2 (CH2) and 22.8
(CH2); m/z (EI) [M + NH4]+C12H18O2N requires 208.1332, found
208.1332.
mono-Benzannelated [6,6]-spiroketal 8g
According to the general procedure, o-hydroxybenzyl acetate 7
(166 mg, 1.00 mmol) and 2-methylenetetrahydropyran5a (1.08 cm3)
gave the title compound 8g (120 mg, 59%) as white solid; mp 53–
54 ◦C; Rf 0.26 (5% EtOAc in petrol); mmax (film)/cm−1 2937 w,
1581 w, 1486 m, 1454 m, 1231 m, 1215 s, 1156 m, 1142 m,
16 R. M. Jones, C. Selenski and T. R. R. Pettus, J. Org. Chem., 2002,
67, 6911–6915. This article also includes one example of base-initiated
o-quinone methide generation/cycloaddition (50% yield) where the 2p
partner (styrene) was employed as solvent.
2818 | Org. Biomol. Chem., 2008, 6, 2815–2819
This journal is
The Royal Society of Chemistry 2008
©

View Online
17 A. F. Barrero, J. F. Qu´ılez del Moral, M. Mar Herrador, P. Arteaga, M.
Corte´s, J. Benites and A. Rosello´n, Tetrahedron, 2006, 62, 6012–6017.
18 B. Loubinoux, J. Miazimbakana and P. Gerardin, Tetrahedron Lett.,
1989, 30, 1939–1942.
19 Prepared from salicyl alcohol according to: E. E. Weinert, K. N.
Frankenfield and S. E. Rokita, Chem. Res. Toxicol., 2005, 18, 1364–
1370.
20 Following the original submission of this work, Pettus and his
co-workers extended the methodology descibed in ref. 16 to in-
clude exo-enol ethers, see: M. A. Marsini, Y. Huang, C. C. Lind-
sey, K.-L. Wu and T. R. R. Pettus, Org. Lett., 2008, 10, 1477–
1480.
21 L. Diao, C. Yang and P. Wan, J. Am. Chem. Soc., 1995, 117, 5369–
5370.
This journal is
The Royal Society of Chemistry 2008
Org. Biomol. Chem., 2008, 6, 2815–2819 | 2819
©