Diels–Alder reactions of an elusive 1,3-butadiene bearing 2-carboxy and 4-alkoxy substituents

Article abstract of DOI:10.1016/j.tetlet.2016.08.030

A reactive diene, ethyl 2-methylene-4-(pent-3-oxy)but-2-enoate, bearing electron-withdrawing carboxy and electron-donating pentoxy substituents is prepared and trapped in situ by a variety of dienophiles to form [4+2] cycloaddition products. Diels–Alder reaction of this diene with fumarate esters gives multiply substituted cyclohexenes that are useful for building the scaffold of oseltamivir.

Full text of DOI:10.1016/j.tetlet.2016.08.030

Accepted Manuscript
Diels–Alder reactions of an elusive 1,3-butadiene bearing 2-carboxy and 4-al-
koxy substituents
Szu-Han Chen, Che-Hsuan Chang, Jim-Min Fang
PII:
S0040-4039(16)31017-6
DOI:
http://dx.doi.org/10.1016/j.tetlet.2016.08.030
TETL 48001
Reference:
Tetrahedron Letters
To appear in:
Received Date:
Revised Date:
Accepted Date:
18 June 2016
8 August 2016
9 August 2016
Please cite this article as: Chen, S-H., Chang, C-H., Fang, J-M., Diels–Alder reactions of an elusive 1,3-butadiene
bearing 2-carboxy and 4-alkoxy substituents, Tetrahedron Letters (2016), doi: http://dx.doi.org/10.1016/j.tetlet.
2016.08.030
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Graphical Abstract
Diels–Alder reactions of an elusive 1,3-
butadiene bearing 2-carboxy and 4-alkoxy
substituents
Szu-Han Chen, Che-Hsuan Chang and Jim-Min Fang*

1
Tetrahedron Letters
Diels–Alder reactions of an elusive 1,3-butadiene bearing 2-carboxy and 4-
alkoxy substituents
Szu-Han Chena, Che-Hsuan Changa and Jim-Min Fang a, b, 
aDepartment of Chemistry, National Taiwan University, Taipei 106, Taiwan
bThe Genomics Research Center, Academia Sinica, Taipei 115, Taiwan
ARTICLE INFO
ABSTRACT
Article history:
Received
Received in revised form
Accepted
A reactive diene, ethyl 2-methylene-4-(pent-3-oxy)but-2-enoate, bearing electron-withdrawing
carboxy and electron-donating pentoxy substituents is prepared and trapped in situ by a variety
of dienophiles to form [4+2] cycloaddition products. Diels–Alder reaction of this diene with
fumarate esters gives multiply substituted cyclohexenes that are useful for building the scaffold
of oseltamivir.
Available online
2016 Elsevier Ltd. All rights reserved.
Keywords:
Diels–Alder reaction
Influenza
Oseltamivir
Butadiene
Dienophile
For more than four decades, Diels–Alder reaction is one of the
most powerful transformations in synthetic organic chemistry.1
Diels–Alder reaction is a concerted [4+2] cycloaddition reaction
of diene with alkene to give a cyclohexene product. Not only
does this strategy construct two new C–C σ-bonds in one step,
but it also forms a cyclohexene system up to four contiguous
stereocenters with good regio- and stereoselectivity. Diels–Alder
reactions are particularly useful for the total synthesis of
been successfully applied to react with appropriate dienophiles
for construction of the cyclohexene core structure of
oseltamivir.20–26 In one of Shibasaki’s syntheses of oseltamivir
(Scheme 1),15 the active diene 2 is used to react with dimethyl
fumarate 3 to form a cyclohexene dicarboxylate 4a, which is
hydrolyzed to dicarboxylic acid 4b and then treated with
diphenylphosphoryl azide (DPPA) to give the corresponding
diacyl azide for the subsequent Curtius rearrangement in t-BuOH.
o
pharmacologically active compounds and natural products such
Under the reaction conditions (80 C, 13 h), the resulting C4
3
as terpenoids, alkaloids, and polyketides.2,
The structural
isocyanate group is trapped intramolecularly by the C3 hydroxy
group, and the C5 isocyanate group is trapped intermolecularly
by t-BuOH. The acetylated product 5 is subjected to a palladium-
catalyzed allylic substitution reaction with acetoxymalononitrile,
as the latent carboxylate group at the C1 position. The 3-pentoxy
group is then installed to culminate in the total synthesis of
oseltamivir. Although the silyloxydiene 2 is labile in acid
conditions, its asymmetric Diels–Alder reaction can be carried
out by the catalysis of Ba(Oi-Pr)2 with a chiral multidentate
ligand F2-FujiCAPO.15
modification for the dienes and dienophiles plays a crucial role in
the development of Diels–Alder reactions. Using heteroatom-
substituted electron-rich dienes usually promotes the normal
electron-demand Diels–Alder reactions in a highly regioselective
fashion. An example of such reactive diene is trans-1-methoxy-
3-trimethylsiloxy-1,3-butadiene, also known as Danishefsky's
diene.4–8 Diels–Alder reaction of Danishefsky's diene with
unsymmetrical dienophile is facilitated by the electron-donating
methoxy and silyloxy substituents to give a regioselective adduct,
which is readily subjected to hydrolysis along with elimination of
a methanol molecule under acidic condition to furnish an α,β-
unsaturated cyclohexenone compound. Other variations of
Inspired by Shibasaki’s work, we are interested in exploring
the Diels–Alder reaction of diene 6 (Scheme 2) that bears 3-
pentoxy and ester substituents existing in the multiply substituted
cyclohexene framework of oseltamivir. In contrast to the 1,3-
butadienes that may contain electron-donating substituents to
promote Diels–Alder reactions, diene 6 that contains both
electron-withdrawing carboxy group and electron-donating
alkoxy group has not yet investigated.
Danishefsky’s diene include 1,3-alkoxy-1-trimethylsiloxy-1,3-
9
butadienes (Brassard’s diene)8,
and 1-dialkylamino-3-
trimethylsiloxy-1,3-butadienes (Rawal’s diene),10 which also bear
both electron-donating groups at the C1 and C3 positions of the
diene framework.
Tamiflu, the phosphate salt of oseltamivir (1), is a popular
According to the previously reported procedure,27 3-pentanol
was subjected to allylation, followed by oxidative cleavage of the
C=C double bond, to give alkoxyaldehyde 7 (Scheme 2). The
Morita–Baylis–Hillman reaction of aldehyde 7 with ethyl
12
anti-influenza drug in clinical use.11,
Diels–Alder reactions
15
using 1,3-butadiene,13 1-trimethylsilyoxy-1,3-butadiene (2),14,
furan,16 N-Boc-pyrrole17 and 1-Cbz-1,2-dihydropyridine18, 19 have
———
 Corresponding author (J.-M.F). Tel.: +886 2 33661663; fax: +886 2 23637812; e-mail: jmfang@ntu.edu.tw

2
Tetrahedron Letters
acrylate 8 was promoted by a base DABCO to afford the addition
product 9. Methanesulfonyl chloride was added to 9 at 0 C,
equiv) to afford a [4+2] cycloaddition product of hexahydro-1H-
isoindole 14, which contained the endo and exo isomers in ≥95:5
diastereomeric ratio (d.r.) according to the 1H NMR analysis. The
predominant isomer 14-endo was isolated by chromatography,
and its structure was rigorously determined by spectral methods
and X-ray diffraction analysis. This result is in agreement with a
concerted Diels–Alder reaction of diene 6 with dienophile 13 via
an endo transition state to account for the stereochemistry of
product 14-endo.
o
followed by slow addition of triethylamine via syringe pump to
give the mesylation product 10 in a moderate yield (40%).
Mesylate 10 was unstable in basic conditions. For example,
treatment of mesylate 10 with DBU at room temperature gave a
dimeric compound 12 in low yield (23%) along with other
unidentified side products, but no starting material 10 remained.
Compound 12 was isolated as a diastereomeric mixture (70:30)
by flash chromatography, and the structure was determined by
The reaction of bromo compound 11 with 1,4-naphthoquinone
15 (1 equiv) and Et3N (2 equiv) was performed in refluxing THF
to provide 67% yield of anthraquinone 16,35 which was
presumably derived from the cycloaddition product [A] by
sequential elimination of a 3-pentanol molecule and oxidative
aromatization. The 1H NMR spectrum of 16 displayed 7 aromatic
protons and 5 protons for the ethyl ester. The 13C NMR spectrum
exhibited the characteristic signals for ester (at δC 164.8) and two
ketones of anthraquinone (at δC 182.3 and 182.1).
1
spectral methods including MS, IR, H- and 13C-NMR. The ESI–
HRMS of 12 showed the protonated molecular ion at m/z
425.2906, conforming to the molecular formula (C24H40O6) for
dimerization of the putative diene
6
(C12H20O3). The
regiochemistry of 12 was assigned because its C3 proton (at δ
4.36) appeared as a doublet (J = 3.4 Hz) by coupling with the C2
vinyl proton (at δ 6.89). Thus, Diels–Alder dimerization of the
elusive diene 6 abides by the para regioselectivity, which is in
agreement with a previous study28 on treatment of methyl 3-
hydroxy-2-methylenepentanoate with MsCl/DABCO/DMAP to
render in situ Diels–Alder dimerization. The facile Diels–Alder
dimerization of 1,3-butadiene derivatives bearing an electron-
withdrawing group at the C2 position is known as early as
1953.29 The mechanism of para regioselectivity has been
predicted by frontier molecular orbital (FMO) theory.30–32
A
recent study33 also indicates that a regioselective Diels–Alder
dimerization is related to the biosynthesis of paracaseolide A, a
secondary metabolite isolated from mangrove plant Sonneratia
paracaseolaris.
Scheme 2. Synthesis of mesylate 10 and bromo compound 11 as the
precursors of diene 6. Reagents and reaction conditions: (a) DABCO, 1,4-
dioxane/H2O (1:1), rt, 20 h; 60% for two steps. (b) Et3N, MsCl, CH2Cl2, 0 oC
to rt, 30 min; 40%. (c) DBU, CH2Cl2, rt, 4 h; giving 12 in 23% yield. (d) NBS,
Me2S, CH2Cl2, 0 oC to rt, 18 h; 73%. (e) Et3N, THF, reflux, 20 h; giving 12 in
71% yield.
The bromo compound 11 reacted rapidly with dimethyl
acetylenedicarboxylate (17) (1 equiv) at room temperature in the
presence of Et3N (2 equiv) to give benzene-1,2,4-tricarboxylate
18, albeit in low yield (11%) due to a competitive addition
reaction of Et3N to alkyne 17, giving a side product of dimethyl
(E)-2-diethylaminobut-2-ene-dioate (56%).36 The side product
was effectivley suppressed by using a bulky base N,N-
diisopropylethylamine (DIPEA) instead of Et3N. Thus, the
Scheme 1. A previously reported synthesis of oseltamivir 1 starting with
Diels–Alder reaction of 1-trimethylsilyloxy-1,3-butadiene (2) with dimethyl
fumarate (3).15
Alternatively, alcohol 9 was treated with N-bromosuccinimide
(NBS) and dimethyl sulfide to give a relatively stable bromo
compound 11 via an SN2' reaction. Compound 11 was tentatively
assigned to have (Z)-configuration because the NOESY spectrum
did not show any correlation between the vinyl proton (at δ 7.00)
and the bromomethyl protons (in the region of δ 4.29–4.20).
Dehydrobromination of 11 under basic conditions also proceeded
with a rapid Diels–Alder dimerization of the intermediate diene 6.
This result is consistent with a previous work34 that demonstrates
the facile Diels–Alder dimerization of 1,3-butadiene-2-
o
reaction of 11 with 17 and DIPEA (2 equiv) in CH3CN at 70 C
for 21 h afforded the desired product 18 in 64% yield. Under
such reaction conditions, the Diels–Alder adduct [B] might lose a
3-pentanol molecule to end up with the aromatic product 18.
Using dimethyl 2-methylenemalonate 19 (1.5 equiv) as an
unsymmetric dienophile, its reaction with bromo compound 11 in
the presence of Et3N (2 equiv) afforded the cyclohexene product
20 in 66% yield. The C3 proton at δ 4.54 (d, J = 4.4 Hz) only
coupled with the C2 vinyl proton at δ 7.00, supporting the
structure of 20 instead of its regioisomer.
carboxylate intermediate generated from
a
base-induced
dehydrobromination of tert-butyl 2-bromomethyl-2-butenoate.
Nevertheless, the intermediate diene 6 was successfully
trapped in situ by using activated dienophiles (Scheme 3). Thus,
a THF solution of bromo compound 11 and N-phenylmaleimide
13 (1 equiv) was heated under reflux in the presence of Et3N (2
The reaction of bromo compound 11 with di-tert-butyl
fumarate (5 equiv) in the presence of Et3N (2 equiv) afforded
product 23 (70%) as a mixture of two diastereomers in a ratio of

3
70:30. After chromatography, a sample of 23 (d.r. = 87:13) was
obtained for the subsequent treatment with TFA in CH2Cl2
solution to remove the tert-butyl groups. The major isomer 25a
was recrystallized from CH2Cl2/hexane and determined to have
the 3,4-cis-4,5-trans configuration by X-ray diffraction analysis.
of the hydroxyl group to bromine atom with NBS/Me2S afforded
a relatively stable bromo compound 11. Treatment of 11 with
Et3N generated a reactive diene 6 that contains electron-
withdrawing carboxy and electron-donating pentoxy substituents
at the 2- and 4-positions. Diene 6 could be trapped in situ with
activated alkenes, particularly dialkyl fumarate to afford the
desired Diels–Alder adducts 23 and 24 bearing multiple
substituents on the cyclohexene core structure. The all-trans
isomer could be elaborated to oseltamivir (in racemic form) via a
sequence of reactions that comprise acyl azide formation and
The similar reaction of 11 with dimethyl fumarate (3 equiv)
and Et3N (2 equiv) gave the [4+2] cycloaddition product 24 as a
mixture of two diastereomers (43:57), which could be separated
by repeated chromatography on a silica gel column. The major
isomer 24b was treated with NaOH(aq) in refluxing THF to afford
the corresponding tricarboxylic acid 26b. The X-ray diffraction
analysis revealed that 26b has all-trans configuration.
Interestingly, the ratio of diastereomers in cycloaddition products
(2.3:1 in 23 versus 1:1.3 in 24) is greatly affected by the alkyl
groups (tert-butyl versus methyl) in fumarate esters.
Curtius rearrangement (Scheme 1) as demonstrated by
15
Shibasaki’s team.14,
We are currently investigating the
asymmetric Diels–Alder reaction by using either chiral fumarate
as the dienophile, or chiral 11 as the precursor of chiral diene, or
by using chiral base to promote the cycloaddition.
In conclusion, Morita–Baylis–Hillman reaction of ethyl
acrylate with 2-(3-pentoxy)acetaldehyde, followed by conversion
Scheme 3. Generation of diene 6 from bromo compound 11 for in situ Diels–Alder reactions with dienophiles. ORTEP drawing of cycloaddition products
(left to right): 14-endo, 25a (3,4-cis-4,5-trans isomer) and 26b (all-trans isomer).

4
Tetrahedron Letters
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Acknowledgments
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328.
We thank the Ministry of Science & Technology in Taiwan
and Academia Sinica for financial support.
25. Magano, J. Tetrahedron 2011, 67, 7875–7899.
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Supplementary Material
Crystallographic data (excluding structure factors) for the
structures in this paper have been deposited with the Cambridge
Crystallographic Data Centre as supplementary publication
CCDC 1484953, 1484956 and 1484958. Copies of the data can
be obtained, free of charge, on application to CCDC, 12 Union
Road, Cambridge CB2 1EZ, UK, (fax: +44-(0)1223-336033 or e-
mail: deposit@ccdc.cam.ac.UK). Supplementary data associated
with this article can be found, in the online version, at

5
Diels–Alder reactions of an elusive 1,3-butadiene
bearing 2-carboxy and 4-alkoxy substituents
Highlights:
• An elusive 1,3-butadiene having 2-carboxy and 4-
alkoxy substituents is prepared.
• This reactive diene is trapped with dienophiles to
give cycloaddition products.
• The cycloadduct from fumarate ester can be
elaborated to oseltamivir (Tamiflu).