A novel approach to combretastatins: From trans-epoxide to CA-4 and its dioxolane derivative

Article abstract of DOI:10.1002/ejoc.200800957

The trans-epoxide derivative of Combretastatin A-4 was stereoselectively prepared in good yield by sulfur ylide mediated epoxidation of silyl-protected isovanillin. From this key intermediate, a formal synthesis of CA-4, by stereoselective deoxygenation and photoisomerization, was achieved. Alternatively, a trans-dioxolane derivative was obtained by stereoselective acetone insertion. Wiley-VCH Verlag GmbH & Co. KGaA, 2009.

Full text of DOI:10.1002/ejoc.200800957

FULL PAPER
DOI: 10.1002/ejoc.200800957
A Novel Approach to Combretastatins: From trans-Epoxide to CA-4 and Its
Dioxolane Derivative
Paolo Lupattelli,*[a] Maurizio D’Auria,[a] Nadia Di Blasio,[a] and Francesca Lenti[a]
Keywords: Oxygen heterocycles / Ylides / Isomerization / Epoxidation
The trans-epoxide derivative of Combretastatin A-4 was
stereoselectively prepared in good yield by sulfur ylide medi-
ated epoxidation of silyl-protected isovanillin. From this key
intermediate, a formal synthesis of CA-4, by stereoselective
deoxygenation and photoisomerization, was achieved. Al-
ternatively, a trans-dioxolane derivative was obtained by
stereoselective acetone insertion.
(© Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim,
Germany, 2009)
Novel stilbenic compounds are usually prepared by using
two main reactions: Wittig and Perkin condensations. In
Introduction
Combretastatin A-4 (1; Figure 1), a natural stilbene from the Wittig reaction, a mixture of the two geometrical iso-
the african Combretum caffrum, is a potent inhibitor of can- mers (Z and E) is always obtained.[1,4] In the Perkin reac-
cer cell growth, inducing irreversible vascular shutdown tion, the Z isomer predominates, but a high-temperature
within solid tumors while leaving normal vasculature in- decarboxylative process is necessary to obtain the final
tact.[1] Its more bioavailable disodium phosphate analogue product.[5] Among the hundreds of combretastatin deriva-
has shown promising results in human cancer clinical tri- tives synthesized so far, those bearing oxygenated func-
als,[2] thus stimulating significant interest in a variety of tional groups on the ethylene chain have shown unusual
CA-4 analogues. Extensive studies have been conducted to properties with respect of their SARs. In particular, dioxol-
examine the structure–activity relationship (SAR) of CA-4 ane-based trans-(S,S)-2 and its enantiomer trans-(R,R)-2
and its analogues. The model structure CA-4 has been showed strong antitubulin activity,[6] whereas the corre-
modified in each of the three elements (ring A, ring B, and sponding cis isomers were inactive,[7] although the Z geom-
double bond), and all these results have been recently re- etry of the two aromatic rings linked by the olefinic group
viewed.[3]
has been claimed as an essential feature for the biological
activity of CA-4.
Recently, stilbene epoxides were tested for cytotoxicity
against the human leukaemia K562 cell line and trans-epox-
ide 3 of CA-4 showed good activity, although it was ineffec-
tive in the inhibition of the tubulin assembly. Nonetheless,
its synthesis remains challenging, as attempts to oxidize
combretastatins have failed, and catalytic ylide-mediated
epoxidation of 3,4,5-trimethoxybenzaldehyde gave ex-
tremely poor yield of 3.[8]
Results and Discussion
Here we describe an expeditious and efficient synthesis
of silyl protected trans-epoxide 4 (Scheme 1) and its useful
alternative transformations into either dioxolane derivatives
or CA-4.
Figure 1. CA-4 and oxygenated derivatives.
During our studies on the synthesis and elaboration of
2,3-diaryloxiranes[9] we took advantage of stoichiometric
sulfur ylide mediated epoxidation of aryl aldehydes, and re-
cently, structurally complex oxyfunctionalized aryl alde-
hydes were also efficiently transformed into the correspond-
[a] Department of Chemistry, University of Basilicata,
Via Nazario Sauro 85, 85100 Potenza Italy
Fax: +39-0971-202223
E-mail: paolo.lupattelli@unibas.it
Supporting information for this article is available on the
WWW under http://www.eurjoc.org or from the author.
Eur. J. Org. Chem. 2009, 141–145
© 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
141

P. Lupattelli, M. D’Auria, N. Di Blasio, F. Lenti
FULL PAPER
berlyst 15 system[13b,14] afforded ketone 8 through acid-pro-
moted rearrangement of the epoxide. In contrast, the direct
conversion into trans-dioxolane 9 by the acetone/Am-
berlyst 15 system[13a] furnished the expected product stereo-
specifically and in good isolated yield (Scheme 2).
On the way to find a new access to Combretastatine A-
4, we looked for an efficient deoxygenation method of epox-
ide 4. Relatively few methods exist for removing oxygen
atoms from epoxides, especially those with a stilbenic struc-
ture.[15] Many of them require expensive reagents and harsh
reaction conditions, which may affect sensitive functional
groups in the molecule.
Scheme 1. Synthesis of trans-epoxide 4.
Recently, ZrCl4/NaI was described as a safe and highly
efficient reagent for the chemoselective deoxygenation of
various epoxides.[16] By using such a procedure, epoxide 4
was stereospecifically converted into trans-stilbene deriva-
tive 10 in good yield (Scheme 3).
ing trans-epoxides.[10] Although it appears of high substrate
scope in both asymmetric and nonasymmetric versions, the
reaction is particularly fine balanced if ylides bearing
weakly anion-stabilizing groups such as substituted benzyl
groups are used.[11] In general, the stereoselectivity is gov-
erned by both the electronic and steric properties of the
reagents and electron-donating groups on either the ylide
or aryl aldehyde lead to lower diastereocontrol. Thus, the
stereoselective synthesis of polyphenolic diaryl epoxides ap-
pears particularly challenging. In principle, two alternative
retrosynthetic approaches are always possible for epoxide 4,
depending on which aryl fragment is derived from the sul-
fur ylide and which one is derived from the aryl aldehyde.
Scheme 3. Deoxygenation of trans-epoxide 4.
The last step for obtaining cis-combretastatine derivative
Initial studies on the transformation of either the commer- 11, affording the formal synthesis of CA-4,[17] required the
cially available isovanillin or 3,4,5-trimethoxybenzaldehyde isomerization of the stilbenic double bond. Among the
5 toward the corresponding sulfur ylide revealed the latter methods described, the photochemical isomerization ap-
as the most suitable starting material. Thus, 5 was easily pears, in principle, to be the best procedure in terms of
converted into the corresponding dimethylsulfonium triflate selectivity, in particular when nonthermodynamic products
6 in three steps and good overall yield.
are wanted.[18] Although photochemical isomerization of 10
The subsequent epoxidation reaction was performed to 11 at 254 nm in ethanol was described,[1] in our hands
with NaH as base to generate the ylide[12] and silyl-pro- the reproduction of the same reaction conditions produced,
tected isovanillin 7 to afford the expected trans-epoxide 4 rapidly, discrete quantities of phenanthrene 12, which in-
stereoselectively and in good isolated yield. In order to test creased with prolonged reaction time. Thus, in order to find
the synthetic scope of such an intermediate we submitted the best reaction conditions in terms of cis/trans ratio and
epoxide 4 to our recently developed regio- and stereoselec- chemical yield, the photoisomerization was run at 254 nm,
tive ring-opening reactions, which were efficient on various at room temperature, in solvents with different polarities.
trans 2,3-diarylepoxides.[13] In particular, the LiBr/Am- The results are listed in Table 1.
Scheme 2. Elaboration of trans-epoxide 4.
142
www.eurjoc.org
© 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2009, 141–145

A Novel Approach to Combretastatins
Table 1. Effect of the solvent on the formation of phenanthrene 12. lated corresponding to a transition HOMO Ǟ NLUMO: a
π–π* is obtained with a more polar character than the first
one, considering that the NLUMO orbital (–0.010 H) is re-
stricted to the second aromatic ring. The increase in the
cis/trans ratio with the polarity of the solvents can be ex-
plained assuming the inversion between the two excited
Entry[a]
Solvent
Time [h]
10 + 11[b]
12[b]
states due to stabilization in polar solvents of the most po-
lar excited state.[22] This stabilization can cause an increase
in ktp giving a higher concentration of the cis isomer in the
photostationary state.
1
2
3
4
5
6
7
8
9
10
n-hexane
n-hexane
n-hexane
benzene
benzene
benzene
acetone
CH3CN
CH3OH
CH3OH
11
17
48
5
96
93
73
93
91
78
100
83
85
87
4
7
27
7
9
22
0
17
15
13
Although CH3OH appears to be the best solvent for the
high cis/trans ratio obtained in relatively short reaction
times, the contemporary formation of phenanthrene 12 and
other byproducts makes this procedure of low synthetic
interest. In low-polar solvents, low cis/trans ratios were ob-
tained, whereas in acetone and acetonitrile an interesting
80:20 cis/trans ratio was achieved, acetone being the solvent
of choice for synthetic purposes as a result of the absence
of any detectable byproduct. Phenanthrene 12 is also an
interesting product, being the silyl-protected derivative of a
natural product isolated from the above-cited Combretum
caffrum[24] and Combretum psidioides.[25] Because this com-
pound can be obtained by oxidative photocyclization from
the parent stilbene derivative,[26] we investigated the pos-
sibility to achieve it by our photocyclization method. After
a screening of solvents and reaction conditions we found
that quantitative yield of 12 was obtained in 130 h from 10
performing the photochemical cyclization in benzene at
room temperature (Scheme 4).
8
14
44
16
4
8
[a] All the reactions were performed by using a 15-W low-pressure
Hg lamp (λmax = 254 nm). [b] Product ratios were determined by
the corresponding relative intensities of GC peaks.
In low-polar solvents (n-hexane, benzene), phenanthrene
12 was detected by GC–MS analysis after a few hours (11 h
in n-hexane, 5 h in benzene) and increased as the olefins
reached the photostationary ratio. In CH3OH, 12 was
formed even faster (15 mol-% after 4 h).[19] By using sol-
vents at intermediate polarity, such as acetone and CH3CN,
12 was practically absent even at prolonged reaction time,
and only after 16 h in acetonitrile was 17 mol-% of this
product detected.
The photostationary cis/trans ratio was also determined
and the results are listed in Table 2.
Table 2. Effect of the solvent in the cis/trans ratio.[a]
Entry
Solvent
cis/trans (11 + 10)
Time [h]
1
2
3
4
5
n-hexane
benzene
acetone
CH3CN
CH3OH
60:40
66:33
80:20
80:20
89:11
48
14
44
16
8
Scheme 4. Photochemical cyclization of trans-stilbene 10.
Conclusions
[a] All reactions were run until the constancy of relative GC peak
intensities.
We developed a new high-yielding stereoselective ap-
proach to oxygenated combretastatine derivatives, and we
were also able to prepare cis-CA-4 and phenanthrene ana-
logues from a common parent trans-stilbene derivative.
These results are not in agreement with those obtained
with other substituted stilbenes. As an example, the photo-
isomerization of 4-methoxy-4Ј-nitrostilbene suffers from a
strong solvent effect. The Z/E ratio upon excitation at
366 nm is 91:9 in petroleum ether and 17:83 in DMF.[20] For
stilbene photoisomerization the Orlandi–Siebrand model is
accepted.[21] On this basis, the [cis]/[trans] = (εtrans/εcis)ktp/
kcp, where ktp and kcp are the kinetic constants for the tran-
sition from the excited singlet state of the trans and cis iso-
mers to a dipolar twisted “phantom” intermediate.[22] Com-
pound 10 showed absorption maxima at λ = 331 and
350 nm (shoulder). Its fluorescence spectrum showed an
emission at λ = 373 nm (λexc = 330 nm). Calculations per-
formed by using TD-DFT/B3LYP/6-31G(d,p) on Gaussian
03[23] showed that the absorption at 331 nm is a π–π* transi-
tion between the HOMO at –0.192 H and the LUMO at
Experimental Section
General: 1H and 13C NMR spectra were recorded at 500 and
125 MHz, respectively. Mass spectra were recorded with a Hewlett–
Packard 6890 chromatograph equipped with a HP 5973 mass detec-
tor. Commercially available reagents were used without further pu-
rification. All reactions were monitored by TLC on silica-gel-
coated plates. Column chromatography was carried out by using
60–240 mesh silica gel at atmospheric pressure.
Dimethyl(3,4,5-Trimethoxybenzyl)sulfonium Triflate 6: To a solu-
tion of 3,4,5-trimethoxybenzyl bromide (900 mg, 3,45 mmol) in
CH2Cl2 (15 mL) at 0 °C was added dimethyl sulfide (0.26 mL) and
–0.053 H (330 nm). However, another S1 state can be popu- silver trifluoromethanesulfonate (1.49 g, 5.80 mmol) under an ar-
Eur. J. Org. Chem. 2009, 141–145
© 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
143

P. Lupattelli, M. D’Auria, N. Di Blasio, F. Lenti
FULL PAPER
gon atmosphere. The reaction was stirred in the dark for 15 min.
The silver bromide was filtered and washed with CH2Cl2 (20 mL),
and the filtrate was concentrate in vacuo. To the dark oil was added
anhydrous Et2O (30 mL) and, after one hour, the formation of a
white solid was observed. The solid was filtered to obtain 838 mg
H) ppm. 13C NMR (125 MHz, CDCl3): δ = –4.6, 18.4, 25.7, 55.4,
56.0, 60.9, 103.1, 112.0, 118.5, 120.4, 126.5, 127.8, 130.3, 133.4,
137.5, 145.1, 151.0, 153.3 ppm. MS: m/z (%) = 430 (32) [M]+, 358
(100), 343 (40). C24H34O5Si (430.61): calcd. C 66.94, H 7.96; found
C 66.90, H 7.89.
1
(62% yield) of pure salt 6. H NMR (500 MHz, CDCl3): δ = 2.91
(Z)-5-(3-tert-Butyldimethylsilyloxy-4-methoxystyryl)-1,2,3-trimeth-
oxybenzene (11): A solution of trans-stilbene 10 (50 mg; 0.1 mmol)
in acetone (20 mL) was irradiated at λ = 254 nm at room tempera-
ture. After 44 h, the irradiation was stopped and the solvent was
evaporated. Chromatographic purification of the crude on silica gel
(petroleum ether/diethyl ether, 6:4) gave 39 mg (78% yield) of pure
(s, 6 H), 3.86 (s, 3 H), 3.87 (s, 6 H), 4.70 (s, 2 H), 6.74 (s, 2 H)
ppm. 13C NMR (125 MHz, CDCl3): δ = 28.9, 47.5, 56.3, 60.8,
105.7, 107.7, 121.6, 132.3, 154.0 ppm. C13H19F3O6S2 (392.41):
calcd. C 39.79, H 4.88; found C 39.70, H 4.90.
trans-3-(4-Methoxy-3-tert-butyldimethylsilyloxyphenyl)-2-(3,4,5-tri-
methoxyphenyl)oxirane (4): To a suspension of NaH (45 mg,
1.8 mmol) in CH2Cl2 (10 mL) was added a solution of sulfonium
salt 6 (560 mg, 1.43 mmol) in CH2Cl2 (5 mL) at 0 °C. After 1 h, a
solution of 3-tert-butyldimethylsilyloxy-4-methoxybenzaldehyde (7;
400 mg, 1.5 mmol) in CH2Cl2 (5 mL) was added, and the reaction
mixture was stirred for 48 h at 0 °C. Cold water (20 mL) was added
to the slurry, and the layers were separated. The aqueous layer was
extracted with CH2Cl2 (3ϫ20 mL); the combined organic phase
was dried with Na2SO4, filtered, and concentrated under vacuum.
Chromatographic purification on silica gel (petroleum ether/diethyl
1
11. H and 13C NMR data were identical to those reported in the
literature.[1] MS: m/z (%) = 430 (32) [M]+, 358 (100), 343 (40).
C24H34O5Si (430.61): calcd. C 66.94, H 7.96; found C 66.85, H
7.95.
7-tert-Butyldimethylsilyloxy-2,3,4,6-tetramethoxyphenanthrene (12):
A solution of trans-stilbene 10 (50 mg; 0.1 mmol) in benzene
(20 mL) was irradiated at λ = 254 nm at room temperature for
130 h. After evaporation of the solvent under vacuum, phenan-
threne 12 (50 mg) was quantitatively obtained as the pure product.
1H NMR (500 MHz, CDCl3): δ = 0.17 (s, 6 H), 1.00 (s, 9 H), 3.71
(s, 6 H), 4.04 (s, 3 H), 4.05 (s, 3 H), 7.08–7.39 (m, 3 H), 7.49 (d, J
= 8.0 Hz, 1 H), 7.54 (d, J = 8.0 Hz, 1 H) ppm. 13C NMR
(125 MHz, CDCl3): δ = –4.57, 18.5, 23.8, 25.6, 25.7, 25.9, 29.6,
55.2, 55.8, 60.4, 61.3, 105.1, 107.9, 118.0, 118.5, 124.3, 125.1, 126.0,
127.2, 128.3, 129.4, 142.3, 144.1, 150.9, 151.5, 151.7 ppm.
C24H32O5Si (428.59): calcd. C 67.26, H 7.53; found C 67.15, H
7.60.
1
ether, 6:4) gave 415 mg (65% yield) of pure epoxide 4 as an oil. H
NMR (500 MHz, CDCl3): δ = 0.17 (s, 6 H), 1.00 (s, 9 H), 3.72 (d,
3
3J = 2.0 Hz, 1 H), 3.80 (d, J = 2.0 Hz, 1 H), 3.82 (s, 3 H), 3.86 (s,
3 H), 3.88 (s, 6 H), 6.58 (s, 2 H), 6.83 (d, J = 2.0 Hz, 1 H), 6.85 (d,
3J = 8.0 Hz, 1 H), 6.91 (dd, J = 8.0 Hz, J = 2.0 Hz, 1 H) ppm. 13C
NMR (125 MHz, CDCl3): δ = –4.6, 18.4, 25.6, 55.5, 56.0, 60.8,
62.6, 62.7, 101.9, 112.0, 117.9, 118.9, 129.3, 132.9, 137.7, 145.2,
151.1, 153.4 ppm. MS: m/z (%) = 446 (4) [M]+, 417 (70), 389 (90),
345 (100). C24H34O6Si (446.61): calcd. C 64.54, H 7.67; found C
64.55, H 7.71.
Supporting Information (see footnote on the first page of this arti-
cle): Additional experimental procedures; selected 1H and 13C
NMR spectra.
trans-5-(3-tert-Butyldimethylsilyloxy-4-methoxyphenyl)-2,2-Dimeth-
yl-4-(3,4,5-trimethoxyphenyl)-1,3-dioxolane (9): To a solution of ep-
oxide 4 (80 mg, 0,18 mmol) in acetone (2 mL) was added Am-
berlyst 15 (220 mgmmol–1) at room temperature. After 16 h, solid
NaHCO3 was added, the mixture was filtered, and the solvent was
removed under vacuum. Chromatographic purification on silica gel
(petroleum ether/diethyl ether, 6:4) gave 45 mg (50% yield) of pure
Acknowledgments
We thank the University of Basilicata for financial support.
[1] G. R. Pettit, S. B. Singh, M. R. Boyd, E. Harnel, R. K. Pettit,
J. M. Schmidt, F. Hogan, J. Med. Chem. 1995, 38, 1666–1672.
[2] P. E. Thorpe, D. J. Chaplin, D. C. Blakey, Cancer Res. 2003, 63,
1144–1147.
[3] G. C. Tron, T. Pirali, G. Sorba, F. Pagliai, S. Busacca, A. A.
Genazzani, J. Med. Chem. 2006, 49, 3033–3044.
[4] S. B. Bedford, C. P. Quarterman, D. L. Rathbone, J. A. Slack,
R. J. Griffin, M. F. G. Stevens, Bioorg. Med. Chem. Lett. 1996,
6, 157–160.
[5] K. Gaukroger, J. A. Hadfield, L. A. Hepworth, N. J. Lawrence,
A. T. McGown, J. Org. Chem. 2001, 66, 8135–8138.
[6] R. Shirai, H. Takayama, A. Nishikawa, Y. Koiso, Y. Hashim-
oto, Bioorg. Med. Chem. Lett. 1998, 8, 1997–2000.
[7] R. Shirai, T. Okabe, S. Iwasaki, Heterocycles 1997, 46, 145–
148.
[8] J. A. Hadfield, K. Gaukroger, N. Hirst, A. P. Weston, N. J.
Lawrence, A. T McGown, Eur. J. Med. Chem. 2005, 40, 529–
541.
[9] See the recent account: C. Bonini, P. Lupattelli, ARKIVOC
2008, viii, 150–182 and references cited therein.
[10] C. Bonini, L. Chiummiento, M. Funicello, M. T. Lopardo, P.
Lupattelli, A. Laurita, A. Cornia, J. Org. Chem. 2008, 73,
4233–4236.
[11] a) V. K. Aggarwal, J. Richardson, Chem. Commun. 2003, 2644–
2651; b) D. R. Edwards, J. Du, C. M. Crudden, Org. Lett. 2007,
9, 2397–2400.
1
dioxolane 9 as an oil. H NMR (500 MHz, CDCl3): δ = 0.12 (s, 6
H), 0.97 (s, 9 H), 1.66 (s, 6 H), 3.77 (s, 3 H), 3.80 (s, 3 H), 3.83 (s,
3
3
6 H), 4.61 (d, J = 8.5 Hz, 1 H), 4.66 (d, J = 8.5 Hz, 1 H), 6.42
(s, 2 H), 6.78 (d, J = 2.0 Hz, 1 H), 6.82–6.83 (m, 2 H) ppm. 13C
NMR (125 MHz, CDCl3): δ = –4.7, 18.4, 25.6, 27.1, 55.5, 56.0,
60.8, 84.8, 85.2, 103.1, 109.1, 111.6, 119.5, 120.4, 129.1, 132.5,
137.5, 144.9, 151.0, 153.1 ppm. MS: m/z (%) = 504 (2) [M]+, 447
(23), 251 (100), 209 (75). C27H40O7Si (504.69): calcd. C 64.26, H
7.99; found C 64.23, H 7.97.
(E)-5-(3-tert-Butyldimethylsilyloxy-4-methoxystyryl)-1,2,3-trimeth-
oxybenzene (10): To a solution of epoxide 4 (200 mg, 0.45 mmol)
in anhydrous CH3CN (5 mL) was added ZrCl4 (53 mg, 0.23 mmol)
and NaI (135 mg, 0.90 mmol, previously dried under vacuum at
200 °C). The reaction mixture was stirred at room temperature for
2 h. Cold water (2 mL) and Et2O (2 mL) were added, and the two
phases were separated. The organic layer was washed with 10%
aqueous Na2S2O3 (10 mL) and water (10 mL) and then dried with
anhydrous Na2SO4. The solvent was removed under vacuum. Chro-
matographic purification of the crude on silica gel (petroleum
ether/diethyl ether, 6:4) gave 110 mg (57% yield) of pure 10 as an
1
oil. H NMR (500 MHz, CDCl3): δ = 0.19 (s, 6 H), 1.04 (s, 9 H),
3
3.83 (s, 3 H), 3.87 (s, 3 H), 3.92 (s, 6 H), 6.72 (s, 2 H), 6.84 (d, J
3
3
= 8.0 Hz, 1 H), 6.85 (d, J = 16.0 Hz, 1 H), 6.91 (d, J = 16 Hz, 1
H), 7.04 (d, J = 2.0 Hz, 1 H), 7.06 (dd, J = 8.5 Hz, J = 2.0 Hz, 1
[12] The use of EtP2, an alternative to NaH and usually considered
more efficient, gave in this case a lower yield of epoxide.
144
www.eurjoc.org
© 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2009, 141–145

A Novel Approach to Combretastatins
[13] a) A. Solladié-Cavallo, E. Choucair, M. Balaz, P. Lupattelli, C.
Bonini, N. Di Blasio, Eur. J. Org. Chem. 2006, 3007–3011; b)
A. Solladié-Cavallo, P. Lupattelli, C. Bonini, J. Org. Chem.
2005, 70, 1605–1611.
[14] P. Lupattelli, C. Bonini, L. Caruso, A. Gambacorta, J. Org.
Chem. 2003, 68, 3360–3362.
K. N. Kudin, J. C. Burant, J. M. Millam, S. S. Iyengar, J. Tom-
asi, V. Barone, B. Mennucci, M. Cossi, G. Scalmani, N. Rega,
G. A. Petersson, H. Nakatsuji, M. Hada, M. Ehara, K. Toyota,
R. Fukuda, J. Hasegawa, M. Ishida, T. Nakajima, Y. Honda,
O. Kitao, H. Nakai, M. Klene, X. Li, J. E. Knox, H. P. Hratch-
ian, J. B. Cross, C. Adamo, J. Jaramillo, R. Gomperts, R. E.
Stratmann, O. Yazyev, A. J. Austin, R. Cammi, C. Pomelli,
J. W. Ochterski, P. Y. Ayala, K. Morokuma, G. A. Voth, P. Sal-
vador, J. J. Dannenberg, V. G. Zakrzewski, S. Dapprich, A. D.
Daniels, M. C. Strain, O. Farkas, D. K. Malick, A. D. Rabuck,
K. Raghavachari, J. B. Foresman, J. V. Ortiz, Q. Cui, A. G. Ba-
boul, S. Clifford, J. Cioslowski, B. B. Stefanov, G. Liu, A. Lia-
shenko, P. Piskorz, I. Komaromi, R. L. Martin, D. J. Fox, T.
Keith, M. A. Al-Laham, C. Y. Peng, A. Nanayakkara, M.
Challacombe, P. M. W. Gill, B. Johnson, W. Chen, M. W.
Wong, C. Gonzalez, J. A. Pople, Gaussian 03, Revision A.1,
Gaussian, Inc., Pittsburgh, PA, 2003.
[15] a) K. B. Gable, E. C. Brown, Synlett 2003, 2243–2245 and ref.
therein; b) G. Righi, P. Bovicelli, A. Sperandio, Tetrahedron
2000, 56, 1733–1737; c) R. C. Larock in Comprehensive Organic
Transformations, John Wiley & Sons, USA, 1999, p. 272.
[16] H. Firouzabadi, N. Iranpoor, M. Jafarpour, Tetrahedron Lett.
2005, 46, 4107–4110.
[17] The silylation of starting isovanillin and the last deprotection
step are known procedures. See ref.[1]
[18] a) D. H. Waldeck, Chem. Rev. 1991, 91, 415–436; b) T. Mori,
Y. Inoue in Synthetic Organic Photochemistry (Eds.: A. G.
Griesbeck, J. Mattay), Marcel Dekker, New York, 2004, pp.
417–452.
[19] Various methoxylated products were also detected in the reac-
tion mixture.
[24]
[25]
G. R. Pettit, S. B. Singh, M. L. Niven, J. M. Schmidt, Can. J.
Chem. 1988, 66, 406–413.
R. M. Letcher, L. R. M. Nhamo, J. Chem. Soc. Perkin Trans.
1 1972, 2941–2946.
[20] D. Schulte-Frohlinde, Justus Liebigs Ann. Chem. 1958, 615,
114–123.
[26] N. J. Lawrence, F. A. Ghani, L. A. Hepworth, J. A. Hadfield,
A. T. McGown, R. G. Pritchard, Synthesis 1999, 9, 1656–1660.
Received: September 30, 2008
[21] G. Orlandi, W. Siebrand, Chem. Phys. Lett. 1975, 30, 352–354.
[22] R. A. Wallis, G. J. Smith, C. L. Dunford, Photochem. Pho-
tobiol. 2004, 80, 257–261.
[23] M. J. Frisch, G. W. Trucks, H. B. Schlegel, G. E. Scuseria,
M. A. Robb, J. R. Cheeseman, J. A. Montgomery Jr, T. Vreven,
Published Online: November 25, 2008
Eur. J. Org. Chem. 2009, 141–145
© 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
145