Microwave-assisted Diels-Alder reactions between Danishefsky's diene and derivatives of ethyl α-(hydroxymethyl)acrylate. Synthetic approach toward a biotinylated anti-inflammatory monocyclic cyanoenone

Article abstract of DOI:10.1016/j.tet.2012.12.079

The microwave heating drastically accelerates Diels-Alder cycloadditions between Danishefsky's diene and derivatives of ethyl α-(hydroxymethyl) acrylate whose hydroxyl group is protected with various protective groups to give previously unknown adducts, which are necessary as intermediates for the synthesis of a biotin conjugate of a monocyclic cyanoenone with high anti-inflammatory activity. The reaction time is only 1 h and the average yield is approximately 80%. Compared to the traditional thermal conditions this method requires 1/48th to 1/14th of the time and the yields are 2-7 times more.

Full text of DOI:10.1016/j.tet.2012.12.079

Tetrahedron 69 (2013) 2052e2055
Contents lists available at SciVerse ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Microwave-assisted DielseAlder reactions between Danishefsky’s
diene and derivatives of ethyl a-(hydroxymethyl)acrylate.
Synthetic approach toward a biotinylated anti-inflammatory
monocyclic cyanoenone
,
,b,
*
Suqing Zheng a, Allison Chowdhury a, Iwao Ojima a b, Tadashi Honda a
a Institute of Chemical Biology and Drug Discovery, Stony Brook University, Stony Brook, NY 11794, United States
b Department of Chemistry, Stony Brook University, Stony Brook, NY 11794, United States
a r t i c l e i n f o
a b s t r a c t
Article history:
The microwave heating drastically accelerates DielseAlder cycloadditions between Danishefsky’s diene
and derivatives of ethyl -(hydroxymethyl)acrylate whose hydroxyl group is protected with various
Received 13 November 2012
Received in revised form 12 December 2012
Accepted 14 December 2012
Available online 9 January 2013
a
protective groups to give previously unknown adducts, which are necessary as intermediates for the
synthesis of a biotin conjugate of a monocyclic cyanoenone with high anti-inflammatory activity. The
reaction time is only 1 h and the average yield is approximately 80%. Compared to the traditional thermal
conditions this method requires 1/48th to 1/14th of the time and the yields are 2e7 times more.
Ó 2013 Elsevier Ltd. All rights reserved.
Keywords:
Microwave
DielseAlder reaction
Danishefsky’s diene
a
-(Hydroxylmethyl)acrylate
Monocyclic cyanoenones
1. Introduction
Monocyclic cyanoenones, examined to date, display unique and
interesting features with respect to both chemical reactivity as Mi-
chael acceptors and biological potency.1,2 Among monocyclic cya-
noenones,
3-ethynyl-3-methyl-6-oxocyclohexa-1,4-dienecarb-
onitrile (MCE-1, Fig. 1) functions as a very reactive Michael accep-
tor with thiol nucleophiles. Furthermore an important feature of
MCE-1 is that its Michael addition is reversible (if the addition is
irreversible, the bioavailability would be drastically decreased by
scavenger nucleophiles, such as glutathione). Remarkably, in some
biological assays related to inhibition of inflammation and carcino-
genesis, MCE-1 is more potent than pentacyclic triterpenoids, CDDO
and its methyl ester, bardoxolone methyl, which has shown a sig-
nificant increase in estimated glomerular filtration rate (eGFR),
compared with no change in the placebo group in a multi-center,
double-blind, placebo-controlled Phase 2b clinical trial in type 2
diabetic patients with severe chronic kidney disease (Fig. 1)3e6 and
a tricycle, TBE-31, which is currently the most potent among semi-
synthetic pentacyclic triterpenoids and synthetic tricycles (Fig.1).7,8
* Corresponding author. Tel.: þ1 631 632 7162; fax: þ1 631 632 7942; e-mail
Fig. 1. Structures of CDDO, bardoxolone methyl (BARD), biotinylated bardoxolone
methyl, TBE-31, and MCE-1.
address: tadashi.honda@stonybrook.edu (T. Honda).
0040-4020/$ e see front matter Ó 2013 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tet.2012.12.079

S. Zheng et al. / Tetrahedron 69 (2013) 2052e2055
2053
Table 1
For the clarification of the mechanisms, identification of the
DielseAlder reactions between Danishefsky’s diene 2 and various dienophiles 1
protein targets is essential. Two protein targets of bardoxolone
methyl were identified using its biotin conjugate, biotinylated bar-
doxolone methyl (Fig. 1).9e11 Based on the structure of the biotin
conjugate, we have designed a new biotin conjugate 6 (Scheme 1) for
identifying the protein targets of MCE-1, which can be synthesized
from a new compound 5. For our projected synthesis, previously
unknown compounds 4 are necessary as the intermediates. We have
envisioned that DielseAlder reactions between Danishefsky’s diene 1
and derivatives of ethyl a-(hydroxymethyl)acrylate 2 whose hydroxyl
group is protected with various protective groups, followed by
deprotection, would give new adducts 4 via 3 (Scheme 1). However,
the traditional thermal conditions of the DielseAlder reaction gave
desired adducts 4 only in very low yield (see Table 1), while the cy-
cloadditions between methacrylic acid derivatives 7 [(R0¼Me and
R00¼CO2Me, CHO, CN) and (R0¼CH(OTBS)Me and R00¼CO2Me)], whose
structures are similar to those of 2, and diene 1 under the same
conditions gave the adducts 9 in good yields (86e100%).2,12 Also,
Lewis acid catalyzed conditionsdid not give the adducts probably due
to the instability of diene 1 under the conditions.
Entry
2
Solvent
Toluenea
Temp (ꢀC)
Time (h)
4
Yield (%)
1
2
3
4
2a
2a
2a
2a
130
180
150 (MW)
150 (MW)
48
20
1
4a
4a
4a
4a
25c
45d
72c
87c
o-Dichlorobenzeneb
o-Dichlorobenzene
Neat
1
5
6
7
8
2b
2b
2b
2b
Toluenea
130
180
150 (MW)
150 (MW)
24
21
1
4e
4b
4e
4e
29e
14d
80c
77e
o-Dichlorobenzeneb
o-Dichlorobenzene
Neat
1
9
10
11
2c
2c
2c
Toluenea
o-Dichlorobenzene
Neat
130
150 (MW)
150 (MW)
24
1
1
4e
4c
4c
12e
74c
82c
12
13
14
15
2d
2d
2d
2d
Toluenea
130
180
150 (MW)
150 (MW)
24
14
1
4d
4d
4d
4d
36c
25d
85c
76c
o-Dichlorobenzeneb
o-Dichlorobenzene
Neat
1
16
17
18
19
2e
2e
2e
2e
o-Dichlorobenzeneb
o-Dichlorobenzene
o-Dichlorobenzene
Neat
180
18
1
1
d
4e
4e
d
d
150 (MW)
180 (MW)
150 (MW)
29c
76c
d
1
MW: microwave heating; d: no adduct was produced.
a
In a sealed tube.
Under reflux.
Adduct 4 was obtained from 3 with PPTS in THF at 60 ꢀC for 2 h.
b
c
d
e
Adduct 4 was directly obtained from the cycloaddition without CSA or PPTS.
Adduct 4 was obtained from 3 with CSA in THF at 60 ꢀC for 2 h.
case, we have observed drastic differences between the traditional
methods and the microwave conditions. Herein, we report the
DielseAlder cycloadditions between Danishefsky’s diene 1 and
derivatives of ethyl
wave conditions.
a-(hydroxymethyl)acrylate 2 under the micro-
2. Results and discussion
Known dienophiles 2a,18 2b,19 and 2d20 were synthesized from
the known ethyl
obtained from ethyl acrylate and formaldehyde. New dienophile 2c
was synthesized in 97% yield from 2e with SEMCl in the presence of
ethyldiisopropylamine in CH2Cl2.
Initially we tried to prepare a new adduct 4a whose hydroxyl
group is protected with a TBS group because we considered that this
adduct is the most appropriate intermediate for the synthesis of 5
among various protected adducts 4aed. However, adduct 4a was
obtained in only 25% yield by the cycloaddition between 1 and 2a in
toluene in a sealed tube (at 130 ꢀC) for 48 h, followed by removal of
the protective groups with PPTS in THF (at 60 ꢀC) for 2 h (entry 1 in
Table 1). Even higher temperature conditions (in o-dichlorobenzene
under reflux at 180 ꢀC for 20 h) gave 4a in moderate yield (45%, entry
2). We speculated that this cycloaddition does not give 4a in good
yieldbecause the TBS group is bulky. Secondly, we used dienophile 2b
Scheme 1. Reagents and conditions: (a) heat, solvents; (b) CSA or PPTS, THF at 60 ꢀC;
(c) CSA, Et2O at rt.
a
-(hydroxylmethyl)acrylate (2e),21 which was
In the past few years, microwave-assisted organic synthesis has
been an increasingly popular theme in the scientific community.
DielseAlder reactions have been successful with the aid of micro-
wave heating, as they require, in many cases, the use of high tem-
peratures, long reaction times, and high pressures.13e16 However,
only a few reports about the microwave-assisted cycloadditions
using Danishefsky’s diene 1 have been published.17 During the
exploration of our projected synthesis of 6, we found that micro-
wave heating strongly accelerates our DielseAlder cycloadditions
to give adducts 3 in very good yield whilst the thermal and Lewis
acid catalytic conditions do not. Thus, we have extensively in-
vestigated these reactions using several dienophiles 2aee. In each

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S. Zheng et al. / Tetrahedron 69 (2013) 2052e2055
with a TMS group, which is less bulky than a TBS group, but the
thermal conditions, with toluene in a sealed tube at 130 ꢀC and in o-
dichlorobenzene under reflux (180 ꢀC), gave 4e (after deprotection
with (þ)-10-camphorsulfonic acid (CSA)) and 4b (directly obtained
without deprotectionprocedure) in low yields, respectively (entries 5
and 6). Thirdly, although we used 2c with a SEM group, which is more
stable than a TMS group and less bulky than a TBS group, the thermal
conditions gave 4e whose SEM group was removed in only 12% yield
(entry9). Dienophiles 2aec have silyloxyprotective groups (electron-
donatinggroups) at C3position. Thus, we prepared 2dfrom2e, which
has an acetoxy group (an electron-withdrawing group) at C3 position
because the electronic effect at this position might affect the re-
activity of the dienophiles. However, 2d gave 4d in low yields under
the thermal conditions (entries 12 and 13). Finally, we concluded that
the traditional thermal conditions would not give adducts 4 in good
yield and that we should discontinue this sequence for the synthesis
of 5 and subsequent synthesis of biotin conjugate 6 if improvement
on the cycloaddition reactions is not successful.
NMR spectrometer (400 MHz for 1H and 100 MHz for 13C). The
chemical shifts are reported in (ppm) using the 7.27 signal of
CHCl3 (1H NMR) and the 13C NMR) as in-
77.23 signal of CDCl3
d
d
d
(
ternal standards for deuterated chloroform. Coupling constants are
reported in hertz (Hz) and the apparent multiplicity is described as
s¼singlet, d¼doublet, t¼triplet, q¼quartet, and m¼multiplet. High-
resolution mass spectroscopy data were obtained by an Agilent
6224AA TOF LC/MS system. Precoated TLC plates with silica gel 60
F254 were used for TLC. Flash column chromatography was per-
formed with silica gel (230e400 mesh). All experiments were
performed under a nitrogen atmosphere. All solvents (analytical
grade) including anhydrous solvents and reagents were used as
received. All references to ‘water’ correspond to reverse osmosis
deionized (RODI) water. All references to ‘brine’ refer to a saturated
aqueous sodium chloride solution. The term ‘in vacuo’ refers to
solvent removal by rotary evaporation followed by a lower pressure
environment (ꢁ0.2 Torr).
Although there were not many successful examples of microwave-
assisted DielseAlder reactions using Danishefsky’s diene 1,16,17 we
selected this method for our cycloadditions. Remarkably, under the
microwave heating conditions (at 150 ꢀC for 1 h), followed by
deprotection with PPTS in THF (at 60 ꢀC) for 2 h, the cycloaddition
between 1 and 2a with o-dichlorobenzene or without a solvent gave
4a in 72% and 87% yields, respectively (entries 3 and 4). In comparison
with the thermal conditions, the yield is 1.5e3.5 times higher and the
reaction time is 20e48 times shorter. Other dienophiles 2bed gave
the corresponding adducts 4cee (after deprotection) with a solvent or
without a solvent under the microwave conditions (at 150 ꢀC for 1 h)
in much better yields (2e7 times) and much shorter times (14e24
times) than the thermal conditions (entries 7, 8, 10, 11, 14, and 15).
4.2. Ethyl 2-(((2-(trimethylsilyl)ethoxy)methoxy)methyl)
prop-2-enoate (2c)
To a solution of ethyl a-(hydroxylmethyl)acrylate (2e, 500 mg,
3.9 mmol) and i-PrNEt2 (1.4 mL, 7.7 mmol, 2 equiv) in CH2Cl2
(61 mL) was added SEMCl (775 mg, 4.7 mmol, 1.2 equiv) in an ice-
bath. The mixture was stirred in the ice-bath for 1 h and then at rt
for overnight. The reaction was quenched with water (10 mL). The
organic phase was washed with brine (10 mLꢂ2), dried over
MgSO4, filtered, and concentrated in vacuo to give a residue, which
was purified by flash column chromatography [hexane/EtOAc
(10:1)] to afford 2e (1 g, 97%) as a colorless oil: dH (400 MHz, CDCl3)
6.30 (d, J¼1.5 Hz, 1H), 5.86 (d, J¼1.8 Hz, 1H), 4.73 (s, 2H), 4.29 (t,
J¼1.5 Hz, 2H), 4.25 (q, J¼7.2 Hz, 2H), 3.64 (m, 2H), 1.3 (t, J¼7.2 Hz,
3H), 0.95 (m 2H), 0.02 (s, 9H); dC (100 MHz, CDCl3) 166.0, 137.6,
126.0, 94.6, 66.0, 65.5, 60.9, 18.3, 14.4, ꢃ1.2; HRMS (ESI-TOF) calcd
for C12H24O4SiNa [MþNa]þ, 283.1336; found, 283.1340.
Importantly, while ethyl a-(hydroxymethyl)acrylate (2e) did not give
the adduct under the thermal conditions at all (entry 16), 2e gave the
adduct 4e with o-dichlorobenzene under the microwave conditions
(at 150 ꢀC for 1 h) in 29% yield (entry 17). Notably, higher temperature
conditions with o-dichlorobenzene (at 180 ꢀC for 1 h) drastically in-
creased the yield (76%, entry 18). However, under the neat conditions
with the microwave heating, no adduct was obtained (entry 19),
whilst dienophiles 2aed gave the adducts in high yield under the
same conditions. We speculated that diene 1 might be decomposed
under the neat conditions before it gives the adduct with the dien-
ophile 2e because 2e is less reactive than other dienophiles (indeed,
only 2e did not give the adduct under the thermal conditions).
4.3. Ethyl 4-oxo-1-(((trimethylsilyl)oxy)methyl)cyclohex-2-
enecarboxylate (4b)
A
mixture of ethyl 2-(((trimethylsilyl)oxy)methyl)prop-2-
enoate (2b, 101 mg, 0.5 mmol) and Danishefky’s diene (1, 103 mg,
0.6 mmol, 1.2 equiv) in o-dichlorobenzene (0.5 mL) was heated
under reflux (at 180 ꢀC) for 21 h. o-Dichlorobenzene was removed
in vacuo to give a residue, which was purified by flash column
chromatography [hexane/EtOAc (3:1)] on silica gel to give 4b as an
oil (19 mg, 14%): dH (400 MHz, CDCl3) 6.94 (d, J¼9.3 Hz, 1H), 6.12 (d,
J¼10.2 Hz, 1H), 4.24 (m, 2H), 3.85 (d, J¼11.1 Hz, 1H), 3.79 (d,
J¼11.1 Hz, 1H), 2.48e2.64 (m, 2H), 2.30e2.48 (m, 1H), 2.00e2.20
(m, 1H), 1.29 (t, J¼6.9 Hz, 3H), 0.07 (s, 9H); dC (100 MHz, CDCl3)
198.8, 172.4, 148.8, 130.3, 67.8, 61.6, 50.6, 34.6, 27.9, 14.4, ꢃ0.5;
HRMS (ESI-TOF) calcd for C13H23O4Si [MþH]þ, 271.1360; found,
271.1361.
3. Conclusion
While the DielseAlder cycloadditions between Danishefsky’s
diene 1 and methacrylic acid derivatives 7, whose structures are
similar to those of derivatives of ethyl a-(hydroxymethyl)acrylate 2,
under the traditional thermal conditions gave the adducts 9 in good
yields, 1 and 2 gave the adducts only in very low yields. Notably, we
found that the microwave heating drastically accelerates the cy-
cloadditions between 1 and dienophiles 2 to give the previously
unknown adducts 4. The reaction time is only 1 h and the average
yield is approximately 80%. Compared to the traditional thermal
conditions this method requires 1/48th to 1/14th of the time and
the yields are 2e7 times more. The synthesis of 5 and 6 using 4a as
the intermediate is in progress.
4.4. General procedures for microwave-assisted DielseAlder
reactions
A mixture of dienophile 2 (0.5 mmol) and Danishefky’s diene (1,
103 mg, 0.6 mmol, 1.2 equiv) without a solvent or in o-di-
chlorobenzene (0.5 mL) was heated in the microwave reactor at
150 ꢀC for 1 h. After that, to the reaction mixture (if o-di-
chlorobenzene was used, after it was removed in vacuo) was added
THF (5 mL). To the resulting solution was added PPTS (125 mg,
1.37 equiv) or CSA (130 mg, 1.37 equiv). The mixture was heated at
60 ꢀC for 2 h. After the mixture was cooled down, it was diluted
with CH2Cl2/Et2O (1:2, 100 mL). The solution was washed with
4. Experimental section
4.1. General procedures
All micro-wave assisted DielseAlder reactions were carried out
in a CEM SP-1372D microwave reactor with an infrared tempera-
ture sensor. All NMR spectra were recorded on a Bruker Avance 400

S. Zheng et al. / Tetrahedron 69 (2013) 2052e2055
2055
water (30 mLꢂ2) and brine (30 mLꢂ1), dried over MgSO4, filtered,
and concentrated in vacuo to give a crude adduct 4.
1H), 4.25 (q, J¼7.2 Hz, 2H), 3.85 (d, J¼10.8 Hz, 1H), 3.79 (d,
J¼10.8 Hz, 1H), 2.04e2.32 (m, 3H), 2.10 (ddd, J¼5.4, 9.6, 13.5 Hz,
1H), 1.94 (brs, 1H), 1.30 (t, J¼7.2 Hz, 3H); dC (100 MHz, CDCl3) 198.9,
172.9, 148.2, 130.5, 67.1, 61.9, 50.2, 34.2, 27.7, 14.2; HRMS (ESI-TOF)
calcd for C10H15O4 [MþH]þ, 199.0965; found, 199.0965.
4.4.1. Ethyl 1-(((tert-butyldimethylsilyl)oxy)methyl)-4-oxocyclohex-
2-enecarboxylate (4a). The crude residue, which was obtained
without a solvent in the microwave reactor, was purified by flash
column chromatography [hexane/EtOAc (3:1)] on silica gel to give
4a as an oil (136 mg, 87%): dH (400 MHz, CDCl3) 6.99 (d, J¼10.2 Hz,
1H), 6.08 (d, J¼10.5 Hz,1H), 4.20 (m, 2H), 3.89 (d, J¼9.3 Hz, 2H), 3.74
(d, J¼9.3 Hz, 1H), 2.32e2.52 (m, 3H), 2.02 (ddd, J¼5.7, 9.6, 13.2 Hz,
1H), 1.28 (t, J¼7.2 Hz, 3H), 0.88 (s, 9H), 0.05 (s, 6H); dC (100 MHz,
CDCl3) 198.9, 172.4, 148.8, 130.3, 68.3, 61.7, 50.8, 34.7, 28.0, 25.8,
18.3, 14.4, ꢃ5.5; HRMS (ESI-TOF) calcd for C16H29O4Si [MþH]þ,
313.1830; found, 313.1830. The consistent data of the elemental
analysis were obtained after 4a was converted to 4e (see the ana-
lytical data of 4e below).
Acknowledgements
We thank Dr. Bela Ruzsicska (Stony Brook University) for expert
technicalassistancewithLCeMS. WealsothankDivyaAwasthi(Stony
Brook University) for technical assistance with microwave reactor.
This work was supported by funds from Reata Pharmaceuticals.
Supplementary data
These data include copies of 1H and 13C NMR for all new com-
pounds described in this article. Supplementary data associated
with this article can be found in the online version, at http://
dx.doi.org/10.1016/j.tet.2012.12.079.
4.4.2. Ethyl 4-oxo-1-(((2-(trimethylsilyl)ethoxy)methoxy)methyl)cy-
clohex-2-enecarboxylate (4c). The crude residue, which was ob-
tained without a solvent in the microwave reactor, was purified by
flash column chromatography [hexane/EtOAc (3:1)] on silica gel to
give 4c as an oil (136 mg, 82%): dH (400 MHz, CDCl3) 6.95 (d,
J¼10 Hz, 1H), 6.08 (d, J¼10 Hz, 1H), 4.66 (s, 3H), 4.21 (q, J¼7.2 Hz,
2H), 3.78 (d, J¼11.2 Hz, 1H), 3.70 (d, J¼11.6 Hz, 1H), 3.58 (m, 2H),
2.38e2.58 (m, 2H), 2.09 (ddd, J¼6.4, 11.6, 14.8 Hz, 1H), 1.27 (t,
J¼7.2 Hz, 3H), 0.93 (m, 2H), 0.17 (s, 9H); dC (100 MHz, CDCl3) 198.5,
177.1, 148.3, 130.5, 95.2, 65.6, 61.8, 49.1, 34.6, 28.4, 18.2, 14.4, ꢃ1.2;
HRMS (ESI-TOF) calcd for C16H28O5SiNa [MþNa]þ, 351.1598; found,
351.1591.
References and notes
1. Dinkova-Kostova, A. T.; Talalay, P.; Sharkey, J.; Zhang, Y.; Holtzclaw, W. D.; Xiu
Jun Wang, X. J.; David, E.; Schiavoni, K. H.; Finlayson, S.; Mierke, D. F.; Honda, T.
J. Biol. Chem. 2010, 285, 33747e33755.
2. Zheng, S.; Laxmi, Y. R. S.; David, E.; Dinkova-Kostova, A. T.; Shiavoni, K. H.; Ren,
Y.; Zheng, Y.; Trevino, I.; Bumeister, R.; Ojima, I.; Wigley, W. C.; James, J. B.;
Mierke, D. F.; Honda, T. J. Med. Chem. 2012, 55, 4837e4846.
3. Honda, T.; Rounds, B. V.; Gribble, G. W.; Suh, N.; Wang, Y.; Sporn, M. B. Bioorg.
Med. Chem. Lett. 1998, 8, 2711e2714.
4. Honda, T.; Rounds, B. V.; Bore, L.; Favaloro, F. G., Jr.; Gribble, G. W.; Suh, N.;
Wang, Y.; Sporn, M. B. Bioorg. Med. Chem. Lett. 1999, 9, 3429e3434.
5. Honda, T.; Rounds, B. V.; Bore, L.; Finlay, H. J.; Favaloro, F. G., Jr.; Suh, N.; Wang,
Y.; Sporn, M. B.; Gribble, G. W. J. Med. Chem. 2000, 43, 4233e4246.
6. Pergola, P. E.; Raskin, P.; Toto, R. D.; Meyer, C. J.; Huff, J. W.; Grossman, E. B.;
Krauth, M.; Ruiz, S.; Audhya, P.; Christ-Schmidt, H.; Wittes, J.; Warnock, D. G. N.
Engl. J. Med. 2011, 365, 327e336.
7. Honda, T.; Sundararajan, C.; Yoshizawa, H.; Su, X.; Honda, Y.; Liby, K. T.; Sporn,
M. B.; Gribble, G. W. J. Med. Chem. 2007, 50, 1731e1734.
8. Honda, T.; Yoshizawa, H.; Sundararajan, C.; David, E.; Lajoie, M. j.; Favaloro, F. G.,
Jr.; Janosik, T.; Su, X.; Honda, Y.; Roebuck, B. D.; Gribble, G. W. J. Med. Chem.
2011, 54, 1762e1778.
4.4.3. Ethyl 1-(acetoxymethyl)-4-oxocyclohex-2-enecarboxylate
(4d). The crude residue, which was obtained in o-dichloro-
benzene in the microwave reactor, was purified by flash column
chromatography [hexane/EtOAc (4:1)] on silica gel to give 4d as an
oil (103 mg, 85%): dH (400 MHz, CDCl3) 6.88 (dd, J¼1.2, 10.5 Hz, 1H),
6.12 (d, J¼10.2 Hz, 1H), 4.38 (d, J¼10.8 Hz, 1H), 4.18e4.28 (m, 3H),
2.40e2.64 (m, 3H), 2.08 (s, 3H), 2.02e2.16 (m, 1H), 1.29 (t, J¼7.2 Hz,
3H); dC (100 MHz, CDCl3) 197.9, 171.2, 170.4, 146.6, 131.0, 67.6, 62.0,
48.1, 34.2, 28.2, 20.7, 14.2; HRMS (ESI-TOF) calcd for C12H17O5
[MþH]þ, 214.1071; found, 214.1073.
9. Honda, T.; Janosik, T.; Honda, Y.; Han, J.; Liby, K. T.; Williams, C. R.; Couch, R. D.;
Anderson, A. C.; Sporn, M. B.; Gribble, G. W. J. Med. Chem. 2004, 47, 4923e4932.
10. Ahmad, R.; Raina, D.; Meyer, C.; Kharbanda, S.; Kufe, D. J. Biol. Chem. 2006, 281,
35764e35769.
11. Ahmad, R.; Raina, D.; Meyer, C.; Kufe, D. Cancer Res. 2008, 68, 2920e2926.
12. Miyata, J.; Nemoto, H.; Ihara, M. J. Org. Chem. 2000, 65, 504e512.
13. DelaHoz, A.;Diaz-Ortis, A.;Moreno,A.;Langa,F. Eur.J.Org.Chem.2000, 3659e3673.
14. Pineiro, M.; Pinho e Melo, T. M. V. D. Eur. J. Org. Chem. 2009, 5287e5307.
15. Appukkuttan, P.; Mehta, V. P.; Van der Eycken, E. V. Chem. Soc. Rev. 2010, 39,
1467e1477.
16. For a review of the microwave-assisted organic synthesis see: Kappe, C. O.;
Stadler, A.; Dallinger, D. DielseAlder Reactions In Microwaves in Organic and
Medicinal Chemistry, 2nd ed.; Mannhold, R., Kubinyi, H., Folkers, G., Eds.;
Methods and Principles in Medicinal Chemistry; Wiley-VCH: Weinheim, Ger-
many, 2012; Vol. 52, Chapter 2, Microwave theory, pp 9e40 and Chapter 6.2.1,
DielseAlder reactions, pp 309e318.
17. For example: Burland, P. A.; Coisson, D.; Osborn, H. M. I. J. Org. Chem. 2010, 75,
7210e7218.
18. Crimmins, M. T.; Jacobs, D. L. Org. Lett. 2009, 11, 2695e2698.
19. Amri, H.; Rambaud, M.; Villieras, J. J. Organomet. Chem. 1990, 384, 1e11.
20. Huang, H.; Liu, X.; Deng, J.; Qiu, M.; Zheng, Z. Org. Lett. 2006, 8,
3359e3362.
4.4.4. Ethyl 1-(hydroxymethyl)-4-oxocyclohex-2-enecarboxylate(4e).
A
mixture of ethyl a-(hydroxymethyl)acrylate (2e, 65 mg,
0.5 mmol) and Danishefky’s diene (1, 103 mg, 0.6 mmol, 1.2 equiv)
in o-dichlorobenzene (0.5 mL) was heated at 180 ꢀC for 1 h in the
microwave reactor. After o-dichlorobenzene was removed in vacuo,
THF (5 mL) was added. To the resulting solution was added PPTS
(125 mg, 1.37 equiv). The mixture was heated at 60 ꢀC for 2 h. After
the mixture was cooled down, it was diluted with CH2Cl2/Et2O (1:2,
100 mL). The solution was washed with water (30 mLꢂ2) and brine
(30 mLꢂ1), dried over MgSO4, filtered, and concentrated in vacuo to
give a residue, which was purified by flash column chromatography
[hexane/EtOAc (1:1)] on silica gel to give 4e as an oil (76 mg, 76%).
Found: C, 59.80; H, 7.24. C10H14O4$1/6H2O requires C, 59.69; H, 7.18.
dH (400 MHz, CDCl3) 6.93 (dd, J¼0.9, 10.2 Hz, 1H), 6.13 (d, J¼10.2 Hz,
21. Kippo, T.; Fukuyama, T.; Ryu, I. Org. Lett. 2011, 13, 3864e3867.