An approach to benzannelated [5,6]-spiroketals

Article abstract of DOI:10.1055/s-2008-1078057

Heating a variety of 2-hydroxybenzyl acetates bearing a range functional groups on the 4- or 5-position of the aromatic ring at 100°C in neat γ-methylene-γ-butyrolactone (1.0 M) for 20 hours gives a series of benzannelated [5,6]-spiroketals in 75-89% yiel

Full text of DOI:10.1055/s-2008-1078057

2500
LETTER
An Approach to Benzannelated [5,6]-Spiroketals
An
A
pproachtoB
h
enzannelate
r
d[5,6]-
i
piroke
s
tals topher D. Bray
School of Biological and Chemical Sciences, The Walter Besant Building, Queen Mary, University of London,
Mile End Road, London E1 4NS, UK
Fax +44(20)78827427; E-mail: c.bray@qmul.ac.uk
Received 9 May 2008
Abstract: Heating a variety of 2-hydroxybenzyl acetates bearing a
range functional groups on the 4- or 5-position of the aromatic ring
at 100 °C in neat g-methylene-g-butyrolactone (1.0 M) for 20 hours
gives a series of benzannelated [5,6]-spiroketals in 75–89% yield.
Key words: Diels–Alder reactions, spiro compounds, heterocycles,
natural products, ortho-quinone methide
A number of natural products contain a 5,6-spiroketal
moiety, where one, or both, of the rings is benzannelated
e.g. berkelic acid (1), the rubromycins 2 and 3, purpuro-
mycin (4), heliquinomycin (5) and the griseorhodins 6 and
7 (Figure 1).1
All of the natural products 1–7 display a range of biolog-
ical activities, which has contributed to the opinion that
spiroketals are privileged pharmacophores.2 A number of
methods have been developed to access the key benzanne-
lated 5,6-spiroketal of these molecules, however these
have overridingly relied upon cyclodehydration of a keto-
diol precursor, which have themselves required numerous
synthetic steps to construct.3,4 Another issue when consid-
ering the synthesis of a bisbenzannelated [5,6]-spiroketal
from a bisphenolic ketone is the competitive formation of
a benzofuran. This problem is a real concern when the ar-
omatic rings bear electron-withdrawing groups,3c as
would be required for the synthesis of 2–7. It has been not-
ed,1b that new methods are currently needed for the con-
struction of benzannelated [5,6]-spiroketals.
It was recently shown by the current author that a simple
ortho-quinone methide (o-QM)5 can be generated from 2-
hydroxybenzyl acetate (8a) by deprotonation of the phe-
nolic proton with i-PrMgCl at –78 °C and warming the re-
sultant anion to room temperature.6 This process was
sufficiently mild that 2p partners which are highly sensi-
tive to isomerisation, e.g. 2-methylenetetrahydrofuran,
could be employed in ensuing hetero-Diels–Alder reac-
tions. This resulted in a rapid and straightforward way of
making monobenzannelated [5,6]- and [6,6]-spiroketals.
Figure 1
The development of this process was based on an earlier
report by Loubinoux et al.7 who examined the base-medi-
binoux et al., Baldwin and his co-workers had shown that
simply heating 2-hydroxybenzyl acetates led to elimina-
tion of acetic acid and the production of an ortho-quinone
methide.8,9 In the current authors hands, it was found that
the application of 2-methylenetetrahydrofuran in this lat-
ter process unsurprisingly resulted in isomerisation of this
sensitive 2p partner to the corresponding endo isomer. In
the present work, it was considered whether the use of g-
ated nucleophilic displacement of acetate from such pre-
cursors presumably via an intermediate ortho-quinone
methide. However, more recently than the report by Lou-
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Advanced online publication: 12.09.2008
DOI: 10.1055/s-2008-1078057; Art ID: D15108ST
© Georg Thieme Verlag Stuttgart · New York

LETTER
An Approach to Benzannelated [5,6]-Spiroketals
2501
methylene-g-butyrolactone as the 2p partner might be of electron-withdrawing substituents on the aromatic ring
compatible with this latter procedure since it is far less is of note, as is the formation of 9h, since the bromide
likely to undergo isomerisation. This was indeed found to could be further elaborated via a Pd-catalysed cross-cou-
be the case, and simply heating 2-hydroxybenzyl acetate pling reaction. Given the current interest in spiroketals as
(8a) at 100 °C in neat g-methylene-g-butyrolactone (1.0 privileged biological motifs and the potential application
M) for 20 hours gave the benzannelated spiroketal 9a in of this process to the synthesis of natural products, the
84% yield (Scheme 1).10 Perhaps surprisingly, as far as ease of entry to the compounds described here is notewor-
could be determined, none of the excess 2p partner had thy. Details on the biological activity of compounds 9a–k
isomerised, even though under the reaction conditions, it will be reported in due course.
had been exposed to acetic acid at 100 °C.
Acknowledgment
O
O
O
I wish to thank the EPSRC National Mass Spectrometry Service
Centre (Swansea).
O
HO
AcO
O
O
100 °C
– AcOH
References and Notes
8a
9a: 84%
(1) (a) Stierle, A. A.; Stierle, D. B.; Kelly, K. J. Org. Chem.
2006, 71, 5357. (b) Brasholz, M.; Sörgel, S.; Azap, C.;
Reißig, H.-U. Eur. J. Org. Chem. 2007, 3801.
(2) Ueno, T.; Takahashi, H.; Oda, M.; Mizunuma, M.;
Yokoyama, A.; Goto, Y.; Mizushina, Y.; Sakaguchi, K.;
Hayashi, H. Biochemistry 2000, 39, 5995.
(3) (a) Tsang, K. Y.; Brimble, M. A. Tetrahedron 2007, 63,
6015. (b) Sörgel, S.; Azap, C.; Reißig, H.-U. Org. Lett. 2006,
8, 4875. (c) Waters, S. P.; Fennie, M. W.; Kozlowski, M. C.
Org. Lett. 2006, 8, 3243. (d) Waters, S. P.; Fennie, M. W.;
Kozlowski, M. C. Tetrahedron Lett. 2006, 47, 5409.
(e) Tsang, K. Y.; Brimble, M. A.; Bremner, J. B. Org. Lett.
2003, 5, 4425. (f) Capecchi, T.; de Koning, C. B.; Michael,
J. P. J. Chem. Soc., Perkin Trans. 1 2000, 2681.
(g) Capecchi, T.; De Koning, C. B.; Michael, J. P.
Tetrahedron Lett. 1998, 39, 5429.
(4) For a [3+2]-cycloaddition approach, see: (a) Wu, K.-L.;
Wilkinson, S.; Reich, N. O.; Pettus, T. R. R. Org. Lett. 2007,
9, 5537. (b) Lindsey, C. C.; Wu, K. L.; Pettus, T. R. R. Org.
Lett. 2006, 8, 2365.
(5) For an excellent review of ortho-quinone methides, see: Van
De Water, R. W.; Pettus, T. R. R. Tetrahedron 2002, 58,
5367.
Scheme 1
One advantage of this procedure over the previously de-
veloped base-mediated process6a is that the lactone func-
tionality that is retained in the product, allows for further
synthetic manipulation of the furan ring. Therefore, a
range of substituted 2-hydroxybenzyl acetates 8b–k were
examined as ortho-quinone methide precursors.11 It was
found that electron-donating groups (OAc, Me, Cl) were
tolerated during this process at the 4-position of the 2-hy-
droxybenzyl acetates to give the corresponding benzanne-
lated spiroketals 9b–d in 76–78% yield (Table 1).
Importantly, an electron-withdrawing substituent
(CO2Me) could also be incorporated to give 9e without
detriment to the yield (79%). Electron-donating groups
(Me and OMe) as well as halogens (Cl and Br) could also
be introduced on to the 5-position and again notably, elec-
tron-withdrawing groups (NO2, and CO2Me) giving the
spiroketals 9f–k in good yield in every case (Table 1).
(6) (a) Bray, C. D. Org. Biomol. Chem. 2008, 6, 2815. (b) For
a closely related process, see: Marsini, M. A.; Huang, Y.;
Lindsey, C. C.; Wu, K.-L.; Pettus, T. R. R. Org. Lett. 2008,
10, 1477.
(7) Loubinoux, B.; Miazimbakana, J.; Gerardin, P. Tetrahedron
Lett. 1989, 30, 1939.
In conclusion, a rapid approach to the synthesis of aryl-
substituted benzannelated [5,6]-spiroketals has been de-
veloped. A small array of such compounds has been syn-
thesised, many in only two steps from the commercially
available diols. This process proceeds via a series of
ortho-quinone methides, the majority of which have never
been described before. The yields for the hetero-Diels–
Alder reactions were in the range 75–89%. The tolerance
(8) Rodriguez, R.; Moses, J. E.; Adlington, R. M.; Baldwin,
J. E. Org. Biomol. Chem. 2005, 3, 3488.
Table 1 Synthesis of Benzannelated Spiroketals 9 from 2-Hydroxybenzyl Acetates 8
Diol
o-QM precursor
Yield (%) Hetero-Diels–Alder product
Yield (%)
R = H
8a
8b
8c
8d
8e
80
O
9a
9b
9c
9d
9e
84
76
78
76
79
R = OAc
R = Me
R = Cl
91
R
HO
R
HO
O
48
69
77
R
O
O
HO
AcO
R = CO2Me
R = Me
R = Cl
R = Br
R = OMe
R = NO2
R = CO2Me
8f
56
62
60
37
85
49
9f
77
82
80
75
82
89
O
8g
8h
8i
8j
8k
9g
9h
9i
9j
9k
HO
HO
O
HO
AcO
R
R
R
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C. D. Bray
LETTER
(9) (a) Zhou, G.; Zhu, J.; Xie, Z.; Li, Y. Org. Lett. 2008, 10,
721. (b) See also: Zhou, G.; Zheng, D.; Da, S.; Xie, Z.; Li,
Y. Tetrahedron Lett. 2006, 47, 3349.
CH2), 2.64 (ddd, J = 17.6, 9.5, 2.5 Hz, 1 H, 1 H of CH2), 2.52
(ddd, J = 13.1, 9.5, 2.5 Hz, 1 H, 1 H of CH2), 2.19–2.35 (m,
2 H, 2 × 1 H of CH2), 2.06–2.16 (m, 1 H, 1 H of CH2). 13
C
(10) General Procedure: 2-Hydroxybenzyl acetate (8a; 40 mg,
0.24 mmol) in g-methylene-g-butyrolactone (0.24 mL,
1.0 M) was heated at 100 °C for 20 h. The cooled reaction
mixture was purified by flash column chromatography
(SiO2, 25% → 30% EtOAc in PE) to give 9a as a white solid
(36 mg, 84%); mp 107–108 ºC (lit.12 106 ºC); Rf 0.26
(EtOAc–PE, 3:7). IR: 2961, 2920, 1776 (C=O), 1582, 1489,
1447, 1251, 1220, 1170, 1093, 1055 cm–1. 1H NMR (400
MHz, CDCl3): d = 7.07–7.17 (m, 2 H, 2 × ArCH), 6.93 (dt,
J = 7.4, 1.1 Hz, 1 H, ArCH), 6.81 (dd, J = 8.1, 1.1 Hz, 1 H,
ArCH), 3.06–3.18 (m, 1 H, 1 H of CH2), 2.91–3.04 (m, 1 H,
1 H of CH2), 2.79 (ddd, J = 16.5, 6.0, 2.5 Hz, 1 H, 1 H of
NMR (100 MHz, CDCl3): d = 175.5 (C=O), 151.4 (ArCO),
129.0 (ArCH), 127.5 (ArCH), 121.6 (ArCH), 120.9 (ArC),
116.7 (ArCH), 106.2 (OCO), 33.8 (CH2), 30.1 (CH2), 28.2
(CH2), 21.4 (CH2). HRMS (EI): m/z [M + Na]+ calcd for
C12H12O3Na: 227.0684; found: 227.0690.
(11) These were generally prepared in good yield by selective
primary acetylation of the corresponding 2-hydroxybenzyl
alcohols using Ac2O (1.05 equiv) in the presence of catalytic
BF3·OEt2 (5 mol%), see: Weinert, E. E.; Frankenfield, K. N.;
Rokita, S. E. Chem. Res. Toxicol. 2005, 18, 1364.
(12) Mixich, Z. Monatsh. Chem. 1965, 96, 220.
Synlett 2008, No. 16, 2500–2502 © Thieme Stuttgart · New York