Selectivity in the Intermolecular Diels–Alder Reaction of Conjugated Trienes: Experimental and Theoretical Approaches

Article abstract of DOI:10.1002/ejoc.201800472

Eleven analogs of the natural product meiogynin A, an inhibitor of proteins of the Bcl-2 family, have been elaborated by an intermolecular Diels–Alder (DA) reaction of various conjugated chloro-trienes, in order to determine the influence of the modification of the south part of meiogynin A on its biological activity. The chloro-trienes were obtained in two to five steps from commercial compounds through a selective hydrochlorination of bromoalkyne intermediates to (Z)-1,2-dihalogenated alkenes followed by a chemoselective Suzuki–Miyaura cross-coupling. The intermolecular DA reaction of these trienes with two α,β-unsaturated carboxylic acids as dienophiles occurred with a perfect regioselectivity and good to excellent diastereoselectivities. These selectivities could be rationalized by DFT calculations.

Full text of DOI:10.1002/ejoc.201800472

DOI: 10.1002/ejoc.201800472
Full Paper
Diels-Alder Reactions
Selectivity in the Intermolecular Diels–Alder Reaction of
Conjugated Trienes: Experimental and Theoretical Approaches
[a]
[a]
[a,b]
[a]
Camille Remeur, Sandy Desrat, Vincent Gandon,
and Fanny Roussi*
Abstract: Eleven analogs of the natural product meiogynin A, hydrochlorination of bromoalkyne intermediates to (Z)-1,2-di-
an inhibitor of proteins of the Bcl-2 family, have been elabo- halogenated alkenes followed by a chemoselective Suzuki–
rated by an intermolecular Diels–Alder (DA) reaction of various Miyaura cross-coupling. The intermolecular DA reaction of these
conjugated chloro-trienes, in order to determine the influence trienes with two α,ꢀ-unsaturated carboxylic acids as dieno-
of the modification of the south part of meiogynin A on its philes occurred with a perfect regioselectivity and good to ex-
biological activity. The chloro-trienes were obtained in two to cellent diastereoselectivities. These selectivities could be ration-
five steps from commercial compounds through a selective alized by DFT calculations.
Introduction
and by Roush for the elegant synthesis of (–)-chlorothricol-
ide.
[
10]
The Diels–Alder reaction is one of the most powerful and versa-
tile reactions in organic chemistry. This cyclization process
enables the straightforward elaboration of complex molecules
in a single operation through the simultaneous formation of
Our team successfully exploited this approach for the bioin-
[
11]
spired total synthesis of meiogynin A 5, a dimeric sesquiter-
[
12]
penoid isolated from the bark of a Malaysian tree, which has
been identified as a natural inhibitor of proteins of the Bcl-2
family. These antiapoptotic proteins are involved in the pro-
grammed cell death (PCD) and are overexpressed in various
cancers, which render them interesting targets for cancer treat-
two carbon–carbon[
1]
[2]
and/or carbon–heteroatom bonds.
Thus, it comes as no surprise that such a simple but efficient
reaction is highly pertinent in natural product synthesis as well
as in the preparation of various medicinally relevant mole-
[
13]
[
1]
ment. Due to the relevant biological properties of meiogynin
A and to its unique structure, several modifications have been
explored, mainly on the lateral chain, and in doing so, highly
cules.
Among the various possible diene/dienophile combinations,
Diels–Alder processes involving conjugated trienes as dienes
have only been sporadically reported, mainly by intramolecular
Diels–Alder (IMDA) or transannular Diels–Alder (TADA) ap-
proaches. Examples include syntheses by Roush and co-workers
[
14]
potent unnatural analogues have been elaborated. The gen-
eral synthetic strategy to obtain these compounds relied on an
organocatalytic intermolecular DA cycloaddition between vari-
ous trienes (1, 7, 11 and 12) and three α,ꢀ-unsaturated carbox-
ylic acids (3a–b and 8) as dienophiles (Scheme 1). The o-bromo-
phenylboronic acid catalyst 2 was assumed to provide activa-
tion, by a LUMO-lowering effect, of dienophiles through the
formation of a covalent monoacylated hemiboronic intermedi-
[
3]
[4]
of superstolide A and spinosyne A, Baldwin's elaboration of
[
5]
spiculoic acid through a highly elegant biomimetic approach,
and Kishi's synthesis of gymnodimine. Recently, studies on
the synthesis of chaetochalasin A by using IMDA reaction of a
[
6]
[
7]
triene was also disclosed. The same synthetic strategy has
also been utilized in the preparation of antimicrobial agents
such as in the enantioselective synthesis the GKK1032s core by
[
15]
ate 4.
Unsurprisingly, the yield of the reaction and the reac-
tivity of the trienes were greatly influenced by their nature: na-
[
11]
tive triene 1 was much more reactive than conjugated triene
[
8]
Inoue. Intermolecular Diels–Alder (DA) of conjugated trienes
used as dienes is much less documented in the literature likely
because of inherent problems with regiochemical fidelity. How-
ever, intermolecular variants have been successfully employed
[
14a,14c]
alcohol 7
for which 8 to 15 days were required for com-
pletion of the reaction whereas conjugated triene acid 11 was
[
14a]
totally unreactive.
Gratifyingly, the installation of a chlorine
atom in the vinylic position (compound 12) could restore the
reactivity of the triene and boosted the reaction (2 days), proba-
bly by raising the HOMO energy level of the reacting external
[
9]
by Stork in 1977 for his impressive synthesis of cytochalasin B
[
a] Institut de Chimie des Substances Naturelles, CNRS-ICSN UPR 2301,
Université Paris-Saclay,
[14d]
diene thanks to mesomeric effects of halide atom.
Avenue de la Terrasse, 91198 Gif-sur-Yvette Cedex, France
E-mail: fanny.roussi@cnrs.fr
http://www.icsn.cnrs-gif.fr/spip.php?article587
b] ICMMO, CNRS UMR 8182, Univ Paris-Sud, Université Paris-Saclay,
Bât. 420, 91405 Orsay cedex, France
In this paper, we wish to report on the intermolecular DA
of chlorotrienes substituted on their phenyl ring at different
positions. The objective of this work was to gain additional ex-
perimental insight into the reactivity of conjugated trienes and
into the observed selectivity, supported by DFT calculations.
Moreover, the products prepared for this study allowed us to
[
Supporting information and ORCID(s) from the author(s) for this article are
available on the WWW under https://doi.org/10.1002/ejoc.201800472.
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Scheme 1. Observed selectivity in the intermolecular Diels–Alder reaction of conjugated trienes.
determine the influence of the modification of the south part bromination sequence using AgF as the Ag source.[17] Alterna-
I
of meiogynin A on its biological activity.
tively, as the one-pot desilylation/bromination sequence was
unsuccessful, intermediate 18 was elaborated in three steps.
Hydrochlorination of bromoalkynes 17–19 and 30 was then
performed, using the conditions described by Zhu, i.e.
Results and Discussion
To access the requisite chloro-trienes, we designed a short syn- [(allyl)PdCl] as the catalyst and cis,cis-1,5-cyclooctadiene as the
2
thesis in which the final step was a Suzuki coupling between a ligand.[16] This robust protocol provided the expected (Z)-4-(2-
dienyl boronic ester and different (Z)-4-(2-bromo-1-chloro- bromo-1-chlorovinyl)phenyl or pyridinyl derivatives 20–22 in
vinyl)phenyl or pyridinyl derivatives. In the literature, prepara- very good yields with excellent regio- and stereoselectivity.
tion of such (Z)-1,2-alkenes is not straightforward, unlike the Compound 21 could be further derivatized by introduction of
elaboration of their trans counterparts. In this regard, in 2012, a methyl or a benzyl group on the phenol function in order to
the Zhu group reported on an elegant approach to (Z)-1,2-di- probe the role of steric hindrance in the ortho position to the
halogenated alkenes by a stereoselective palladium-catalyzed carboxylate group in SAR studies. Interestingly, the hydrochlor-
[
16]
hydrohalogenation of haloalkynes. This very efficient and se- ination of compound 30 run in acetic acid afforded predomi-
lective method was employed to prepare various Z-4-(2-bromo- nately the benzyl acetate 31. Finally, the desired trienes 23–25,
1
-chlorovinyl)phenyl or pyridinyl intermediates 20–22 and 31. 28, 29, 32 were obtained directly from these dihalogenated
The requisite bromo-alkynes 17 and 19 could be obtained in alkenes via chemoselective Suzuki coupling with (E)-4,4,5,5-
two steps starting from commercial aryl halides 14 and 16 by tetramethyl-2-(3-methylbuta-1,3-dien-1-yl)-1,3,2-dioxaborol-
[
11]
a Sonogashira coupling followed by a one-pot desilylation/ ane.
Complete selectivity was observed when attempting
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Scheme 2. Preparation of triene esters. Reagents and conditions: (a) (triisopropylsilyl)acetylene, Pd[(PPh
4 h (for 14, 15) or Et N/THF (1:1), 60 °C, 18 h (for 16); (b) NBS (1.2 equiv.), AgF (1.2 equiv.), CH CN, room temp. (for 14 and 16) or TBAF (1.2 equiv.), THF,
room temp. then NBS (1.2 equiv.), AgNO (10 mol-%), acetone, room temp. for (15); (c) [(allyl)PdCl] (2.5 mol-%), LiCl (2.0 equiv.), cis,cis-1,5-cyclooctadiene
10 mol-%), AcOH, 80 °C, 18 h; (d) (E)-4,4,5,5-tetramethyl-2-(3-methylbuta-1,3-dien-1-yl)-1,3,2-dioxaborolane (3.0 equiv.), Pd(PPh
THF/H O (2:1), 50 °C, 8 h (for 20, 21, 26, 27); (e) (E)-4,4,5,5-tetramethyl-2-(3-methylbuta-1,3-dien-1-yl)-1,3,2-dioxaborolane (3.0 equiv.), Pd(PPh
Cs CO (4.0 equiv.), THF, reflux, 12 h (for 22); (f) Me SO (1.5 equiv.), K CO (3.0 equiv.), acetone, reflux; (g) BnCl (1.0 equiv.), NaH (1.2 equiv.), DMF.
3 2 2 3
) Cl ] (5 mol-%), CuI (0.5 equiv.), Et N, room temp.,
2
3
3
3
2
(
3
)
4
(5 mol-%), K
3
PO
4
(4.0 equiv.),
2
3 4
) (5 mol-%),
2
3
2
4
2
3
chemoselective cross coupling. Nearly all trienes were obtained triene 28. Cis-decalins 42 and 43 were obtained with 95 % dia-
in moderate to good yields when using K PO as a base. An stereoselectivity in favour of the endo products while endo/exo
3
4
exception was noticed for compound 25, which required ratio observed for compound 44 was much lower (80:20). Un-
Cs CO . In the presence of this base, compound 25 could be fortunately, none of the cycloadducts were as active as natural
2
3
[
14]
obtained in acceptable yield of 44 % (Scheme 2).
meiogynin A and previous developed derivatives
with in
Attempts to engage all prepared trienes in regio-specific vitro affinity displacement assays based on the modulation of
Diels–Alder cycloaddition were next initiated using both dieno- Bcl-xL/Bak and Mcl1/Bid interactions. These results indicated
[
14d]
philes 3b and 8 and trienes 12, 23–25, 28, 29, 32, 33
Table 1). Based on literature reports and on our previous re- is useless or detrimental for their activities.
sults, we elected to use a sub-stoichiometric amount of 2-
In order to explain the observed reactivities in the Diels–
that modulation of the south part of this family of compounds
(
bromophenylboronic acid 2, hypothesized to lower the LUMO Alder reaction of these conjugated trienes, DFT calculations
energy of the acrylate dienes 3b and 8 thus enhancing their were performed. All structures (minima and transition states)
[
15]
[18]
ability to react in the cycloaddition process.
trienes underwent a regio-selective cycloaddition to furnish the M06–2X/6-311+G(d,p)// level of theory.
Pleasingly, all were optimized using the Gaussian 09 software package,
at
[
19,20]
The value pre-
compounds 34–44 as a endo/exo inseparable mixture, mostly sented herein are Gibbs free energies (ΔG298, kcal/mol). Triene
in 48 h under mild conditions. On the one hand, no traces of 12, named A below, was used in the computations without
the other possible regioisomers arising from a cycloaddition on simplifications (Scheme 3). The monoacylated hemiboronic
different positions of the trienes or of dienophiles 3b and 8 compound B, exhibiting a para isopropyl substituent was used
could be detected in crude mixtures. With dienophile 3b, good as model Diels–Alder partner. The cycloadducts C and C′ are
diastereoselectivities were measured, with endo/exo ratios of expected from endo and exo [4+2] cycloadditions respectively,
about 85:15. On the other hand, yields greatly depended on taking place at the terminal diene framework of A.
the nature of the trienes. Indeed, high yields were obtained for
Endo and exo cycloadditions could be modelled from A and
compounds 34–38 and 41 but compounds 39 and 40 were B to give C and C′ (Figure 1). Both were concerted asynchro-
obtained in very low yields, accompanied by polymerized tri- nous processes during which the first C–C bond formed in-
enes 23 and 29 after 6 days of reaction. From dienophile 8, volves the less substituted carbons of the two partners. The
cycloadduct 42 was isolated in excellent yield whereas 43 and endo cycloaddition is clearly favored over the exo one, by
[
21]
4
4 were obtained in lower yield, accompanied by polymerized 4.3 kcal/mol. Analysis of the secondary orbital interactions is
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Table 1. Diels Alder reactions of trienes 12, 23–25, 28, 29, 32 and 33.[a]
Scheme 3. Diels–Alder cycloaddition between triene A and simplified dieno-
phile B studied by DFT computations.
endo/exo ratio[b]
Yield [%][c]
Figure 1. Reaction profile (ΔG298, kcal/mol) and geometries of computed tran-
sition states and adducts (selected distances in Å, some hydrogen atoms
have been omitted for clarity).
Entry
Product
1
2
3
4
5
6
7
8
9
34
35
36
37
38
39
40
41
42
43
44
85:15
80:20
80:20
85:15
90:10
80:20
80:20
90:10
> 95:5
> 95:5
80:20
87
62
73
59
47
diene framework of A instead of the external one. It was also
not possible to locate a transition state corresponding to the
addition of the external triene carbon into the most hindered
alkene carbon of B, nor to the disubstituted alkene framework
of B. These computational failures are actually consistent with
the experimental results and show that this kind of cycloaddi-
tion is very sensitive to the steric hindrance of the two partners.
In addition, frontier orbital analysis of A and B indicate that the
largest coefficients are located where the cycloaddition actually
takes place experimentally (Figure 2).
[
d]
14
[
d,e]
< 10
60
96
37
55
[
[
e]
e]
1
1
0
1
[
(
a] Reagents and conditions: compound 3b or 8, 2-bromophenylboronic acid
30 mol-%), CH Cl , 50 °C, 48 h. [b] Determined by integration of the signals
on the H NMR spectra of the crude mixture. [c] Isolated yield (endo/exo
mixture). [d] After 6 days of reaction. [e] Compound not isolated: yield was
estimated according to the 1H NMR spectra of the crude mixture.
2
2
1
Additional calculations were carried out to evaluate the influ-
ence of the chlorine and of the carboxylic acid group on the
presented in the Supporting Information. The two reactions are triene in hypothetical endo cycloadditions anti to the iPr group
exergonic by ca. 13 kcal/mol, with a slight 0.6 kcal/mol prefer- (see the Supporting Information). Without the chlorine atom,
ence for C.
TSc reaches 21.8 kcal/mol, which is quite close from the 20.5
Of note, the cycloaddition takes place in each case anti to value obtained previously (see Figure 1). With the chlorine atom
the iPr group. The endo mode could be computed on the iPr but without the CO H group, the barrier is lowered to 19.0 kcal/
2
face. The exo one could also be, but the corresponding free mol. In the absence of the two, it further lowers to 18.9 kcal/
energy of activation is 0.5 kcal/mol higher than the previously mol. Thus, the cyclization barriers are in a narrow range of
computed one (25.3 kcal/mol). Manifold efforts failed to locate 2.9 kcal/mol depending on the substitution pattern, which
a cycloaddition transition state that would involve the internal plays a limited role. The uncatalyzed process was also com-
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isopropylsilyl)acetylene (0.22 mL, 1.01 mmol, 1.05 equiv.). After 18 h
at room temp., the reaction mixture was quenched with a saturated
solution of NH Cl and the product was extracted with MTBE (three
4
times). The combined organic phases were dried with MgSO , fil-
4
tered and concentrated under reduced pressure. The crude product
was purified by chromatography on silica gel using heptane/ethyl
acetate (10 to 9:1) to give methyl 3-methoxy-4-[(triisopropyl-
1
silyl)ethynyl]benzoate as a yellow oil (270 mg, 0.78 mmol, 82 %). H
NMR (300 MHz, CDCl ): δ = 7.56 (dd, J = 7.9, 1.5 Hz, 1 H), 7.51 (d,
3
J = 1.4 Hz, 1 H), 7.47 (d, J = 7.9 Hz, 1 H), 3.91 (s, 3 H), 3.88 (s, 3 H),
1
1
.1 (s, 21 H) ppm. 13C NMR (75 MHz, CDCl ): δ = 166.9, 160.8, 133.9,
3
31.1, 121.8, 118.0, 111.7, 102.6, 99.0, 56.3, 52.6, 18.9 (6 C), 11.6 (3
–1
C) ppm. IR : ν˜ = 3675, 2943, 2153, 1721, 1284, 1036, 668 cm . HRMS
+
(ESI) m/z calcd. for C H O Si [M + H] 347.2037, found 347.2050.
20 31 3
Figure 2. HOMO of s-cis/s-trans A (left), of s-cis/s-cis A (center left), of s-trans/s-
cis A (center right), and LUMO of B (right) at a contour value of 0.05.
To a solution of 3-methoxy-4-[(triisopropylsilyl)ethynyl]benzoate
396 mg, 1.14 mmol) in dry acetonitrile (32 mL), were added N-
(
bromosuccinimide (244 mg, 1.37 mmol, 1.2 equiv.) and silver fluor-
ide (174 mg, 1.37 mmol, 1.2 equiv.) under argon. After 3 h at room
temp. in the dark, the reaction mixture was filtered through a pad
of Celite® and concentrated under reduced pressure. The crude
product was purified by column chromatography on silica gel using
heptane/ethyl acetate (10 to 8:2) to give methyl 4-(bromoethynyl)-
puted. In this case, the [4+2] cycloaddition barrier is signifi-
cantly increased to 25.3 kcal/mol, as compared to the previously
computed value of 20.5 kcal/mol for the catalyzed process.
Conclusions
3-methoxybenzoate 17 as a white powder (274 mg, 1.02 mmol,
1
8
9 %). Compound 17: M.p. 118–119 °C. H NMR (300 MHz, CDCl ):
3
To summarize, we presented an elegant and straightforward
δ = 7.57 (dd, J = 7.9, 1.5 Hz, 1 H), 7.52 (d, J = 1.4 Hz, 1 H), 7.46 (d,
strategy to access eleven new analogues of meiogynin A from J = 7.9 Hz, 1 H), 3.93 (s, 3 H), 3.91 (s, 3 H) ppm. 13C NMR (75 MHz,
six functionalized conjugated trienes, with a perfect regioselec- CDCl ): δ = 166.7, 160.8, 134.1, 131.6, 121.9, 116.9, 111.6, 76.2, 56.7,
3
tivity and good to excellent diastereoselectivities. DFT computa- 56.3, 52.6 ppm. IR: ν˜ = 2946, 2194, 1711, 1403, 1289, 1108, 869, 757
–
1
+
cm . HRMS (ESI) m/z calcd. for C
H BrO [M + H] 268.9808,
11 10 3
tions have highlighted that this DA reaction is an asynchronous
process. Its regioselectivity was rationalized by steric factors
found 268.9821.
and endo selectivity by a more favorable transition state. Finally, Methyl 4-(Bromoethynyl)-2-hydroxybenzoate (18): To a solution
we could demonstrate that the introduction of a chlorine atom of commercial methyl 4-iodosalicylate (2 g, 7.19 mmol), copper iod-
at a strategic position could increase notably the reactivity of ide (0.68 g, 3.60 mmol, 0.5 equiv.), and bis(triphenylphosphine)pal-
ladium(II) dichloride (0.25 g, 0.36 mmol, 0.05 equiv.) in Et N (20 mL)
under argon, was added dropwise (triisopropylsilyl)acetylene
the trienes, thus the yield of these reactions.
3
(1.70 mL, 7.55 mmol, 1.05 equiv.). After 18 h at room temp., the
reaction mixture was quenched with a saturated solution of sodium
hydroxide and the product was extracted with MTBE (three times).
Experimental Section
General Experimental Procedures: All reagents and solvents were
used as purchased from commercial suppliers or were purified/
dried according to Armarego and Chai.[ The 2-bromophenyl-
boronic acid catalyst 2 was used as received. Purifications by col-
umn chromatography on silica gel were performed using Merck
The combined organic phases were dried with MgSO , filtered and
4
concentrated under reduced pressure. The crude product was puri-
fied by chromatography on silica gel using heptane/ethyl acetate
(10 to 9:1) to give methyl 2-hydroxy-4-[(triisopropylsilyl)ethynyl]-
22]
benzoate as an orange powder (2.34 g, 7.04 mmol, 98 %). Mp 54
1
13
1
Silica Gel 60 (70–230 mesh). H and C NMR spectra were recorded
–56 °C. H NMR (300 MHz, CDCl
3
): δ = 10.72 (s, 1 H), 7.75 (d, J =
on a Bruker AC300 or ARX500 instruments using CDCl , MeOD or
8.1 Hz, 1 H), 7.08 (d, J = 1.6 Hz, 1 H), 6.96 (dd, J = 8.1, 1.6 Hz, 1 H),
3.94 (s, 3 H), 1.12 (s, 21 H) ppm. 13C NMR (75 MHz, CDCl
): δ = 170.4,
161.5, 131.0, 130.0, 123.0, 121.2, 112.4, 106.1, 95.0, 52.7, 18.9 (6 C),
ppm), and multiplicity of signals are reported as follows: s, singlet; 11.6 (3 C) ppm. IR: ν˜ = 3156, 2954, 2864, 2159, 1664, 1443, 1213,
3
[
D ]acetone with trace of non-deuterated residual solvents used as
3
6
a internal references. Chemical shifts are given in parts per million
(
br. s, broad singlet; d, doublet; t, triplet; q, quartet; dd, doublet of
–
1
Si [M + H]+
869, 781 cm . HRMS (ESI) m/z calcd. for C19H O
29 3
doublets; m, multiplet. HRMS analyses were obtained using a Wa- 333.1880, found 333.1891.
ters LCT Premier instrument by ElectroSpray, Ionization (ESI) or by
TBAF (1
M in THF) was added dropwise to a solution of methyl 2-
Atmospheric Pressure Photo-Ionization (APPI). Melting points were
measured with a Büchi Melting Point B-540 apparatus. Optical rota-
hydroxy-4-[(triisopropylsilyl)ethynyl]benzoate (0.5 g, 1.5 mmol) in
dry THF (3 mL) under argon. After 5 h at room temp., the reaction
mixture was quenched with a saturated solution of NH Cl and the
product was extracted with MTBE (three times). The combined or-
ganic phases were dried with MgSO , filtered and concentrated un-
der reduced pressure. The crude product was purified by chroma-
tography on silica gel using heptane/ethyl acetate (10 to 9:1) to give
methyl 4-ethynyl-2-hydroxybenzoate as an orange powder (0.20 g,
1.15 mmol, 76 %). Mp 194–195 °C (decomposition). H NMR
(300 MHz, CDCl ): δ = 10.74 (s, 1 H), 7.78 (d, J = 8.2 Hz, 1 H), 7.10
2
0
tion, [α]D values, were measured using an Anton Paar MCP 300
3
–1
–1
4
instrument and are expressed in deg cm g dm for a concentra-
–
1
tion of compound in g/cm . IR spectra were recorded on a Perkin–
Elmer Spectrum BX-FTIR spectrometer.
4
Methyl 4-(Bromoethynyl)-3-methoxybenzoate (17): To a solution
of commercial methyl 4-iodo-3-methoxybenzoate 4 (280 mg,
1
0
.96 mmol), copper iodide (91 mg, 0.48 mmol, 0.5 equiv.), and
bis(triphenylphosphine)palladium(II) dichloride (33 mg, 0.048 mmol,
.05 equiv.) in Et N (2.5 mL) under argon, was added dropwise (tri-
3
0
(d, J = 1.6 Hz, 1 H), 7.02 (dd, J = 8.2, 1.5 Hz, 1 H), 3.95 (s, 3 H), 3.20
3
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(
1
1
s, 1 H) ppm. 13C NMR (75 MHz, CDCl ): δ = 170.2, 161.4, 130.3,
0.22 mmol, 63 %) from compound 17 (93 mg, 0.35 mmol). Com-
3
1
28.8, 123.4, 121.7, 113.5, 81.9, 76.5, 52.8 ppm. IR: ν˜ = 3155, 2952, pound 20: H NMR (300 MHz, CDCl ): δ = 7.64 (dd, J = 8.0, 1.5 Hz,
3
–
1
676, 1439, 1198, 742, 686 cm .
1 H), 7.58 (d, J = 1.5 Hz, 1 H), 7.52 (d, J = 7.9 Hz, 1 H), 7.04 (s, 1 H),
3
1
.93 (s, 3 H), 3.90 (s, 3 H) ppm. 13C NMR (75 MHz, CDCl ): δ = 166.6,
3
To a solution of methyl 4-ethynyl-2-hydroxybenzoate (530 mg,
3
3
The reaction mixture was stirred, in the dark, at room temp. for 3 h
and then filtered through a pad of Celite®. The filtrate was concen-
trated under reduced pressure and the residue was purified by col-
umn chromatography on silica gel using heptane/ethyl acetate (100
to 95:5) to give methyl 4-(bromoethynyl)-2-hydroxybenzoate 18 as
a yellow solid (590 mg, 2.33 mmol, 77 %). Compound 18: Mp 107–
1
H), 7.76 (d, J = 8.2 Hz, 1 H), 7.05 (d, J = 1.5 Hz, 1 H), 6.93 (dd, J =
8
56.7, 133.5, 132.3, 130.6, 130.0, 122.1, 112.4, 110.5, 56.3, 52.7 ppm.
.01 mmol) in acetone (24 mL) were added NBS (643 mg,
–
1
IR: ν = 2951, 1725, 1426, 1225, 874, 755 cm . HRMS (ESI) m/z calcd.
for C H BrClO [M + ACN + H] 345.9840, found 345.9851.
˜
.61 mmol, 1.2 equiv.) and AgNO (51 mg, 0.30 mmol, 0.1 equiv.).
3
+
11
11
3
Methyl (Z)-4-(2-Bromo-1-chlorovinyl)-2-hydroxybenzoate (21):
Compound 21 was obtained as a white powder (4.37 g, 14.99 mmol,
8
9
6 %) from compound 18 (4.40 g, 17.4 mmol). Compound 18: Mp
1
5.4–97.5 °C. H NMR (300 MHz, CDCl ): δ = 10.78 (s, 1 H), 7.82 (d,
3
J = 8.5 Hz, 1 H), 7.18 (d, J = 1.9 Hz, 1 H), 7.06 (dd, J = 8.5, 1.9 Hz, 1
1
09 °C (decomposition). H NMR (300 MHz, CDCl ): δ = 10.74 (s, 1
13
3
H), 3.96 (s, 3 H) ppm. C NMR (75 MHz, CDCl ): δ = 170.2, 161.8,
3
1
43.2, 130.5, 120.6, 117.5, 116.1, 113.2, 108.3, 52.8 ppm. IR: ν = 3187,
˜
1
3
.2, 1.5 Hz, 1 H), 3.94 (s, 3 H) ppm. C NMR (75 MHz, CDCl ): δ =
–1
3
1671, 1433, 1209, 1092, 846, 773, 688 cm . HRMS (ESI) m/z calcd.
for C H BrClO [M + H] 290.9418, found 290.9429.
1
70.3, 161.5, 130.1, 130.1, 123.0, 121.2, 112.8, 79.5, 53.9, 52.7 ppm.
+
10
9
3
–
1
IR: ν˜ = 3096, 2953, 2191, 1664, 1440, 1213, 781, 690 cm . HRMS
+
Methyl (Z)-5-(2-Bromo-1-chlorovinyl)picolinate (22): Compound
2 was obtained as a white powder (503 mg, 1.82 mmol, 78 %)
from compound 19 (560 mg, 2.33 mmol). Compound 22: Mp 86–
(ESI) m/z calcd. for C H BrO [M + H] 254.9651, found 254.9660.
10 8 3
2
Methyl 5-(Bromoethynyl)picolinate (19): (Triisopropylsilyl)acet-
ylene (6.22 mL, 27.8 mmol, 3 equiv.) was added dropwise to a
suspension of commercial methyl 5-bromopicolinate (2.0 g,
1
8
7 °C. H NMR (300 MHz, CDCl ): δ = 8.88 (d, J = 2.3 Hz, 1 H), 8.15
3
(
(
d, J = 8.2 Hz, 1 H), 8.01 (dd, J = 8.2, 2.0 Hz, 1 H), 7.13 (s, 1 H), 4.02
9
.26 mmol), copper iodide (53 mg, 0.28 mmol, 0.03 equiv.), and
bis(triphenylphosphine)palladium(II) dichloride (130 mg, 0.19 mmol,
.02 equiv.) in Et N/THF (60 mL) under argon. After 18 h at 60 °C,
13
s, 3 H) ppm. C NMR (75 MHz, CDCl ): δ = 165.3, 148.3, 147.4,
3
1
1
35.3, 134.9, 125.2, 109.6, 53.4 ppm. IR: ν˜ = 3073, 2953, 1706, 1315,
0
–1
3
123, 765, 700 cm . HRMS (ESI) m/z calcd. for C H BrClNO [M +
9
8
2
the reaction mixture was filtered through a pad of Celite® and con-
centrated under reduced pressure. The crude mixture was purified
by column chromatography on silica gel using heptane/ethyl acet-
+
H] 275.9421, found 275.9428.
(Z)-4-(2-Bromo-1-chlorovinyl)benzyl Acetate (31): Compound 31
ate (10 to 8:2) to give methyl 5-[(triisopropylsilyl)ethynyl]picolinate was obtained as a red oil (1.56 g, 5.39 mmol, 47 %) accompanied
1
as a yellow oil (2.91 g, 9.17 mmol, 99 %). H NMR (300 MHz, CDCl ):
with 20 % of separable (Z)-[4-(2-bromo-1-chlorovinyl)phenyl]meth-
anol from compound 30 (2.41 g, 11.40 mmol). Compound 32: H
3
1
δ = 8.75 (dd, J = 2.0, 0.8 Hz, 1 H), 8.07 (dd, J = 8.1, 0.8 Hz, 1 H), 7.87
(
(
dd, J = 8.1, 2.0 Hz, 1 H), 4.00 (s, 3 H), 1.11 (s, 21 H) ppm. 13C NMR
NMR (300 MHz, CDCl
8.3 Hz, 2 H), 6.88 (s, 1 H), 5.10 (s, 2 H), 2.11 (s, 3 H) ppm. C NMR
): δ = 171.0, 138.3, 137.6, 136.6, 128.6 (2 C), 127.1 (2
3
): δ = 7.53 (d, J = 8.3 Hz, 2 H), 7.36 (d, J =
1
3
75 MHz, CDCl ): δ = 165.5, 152.7, 146.4, 140.1, 124.6, 124.3, 102.9,
3
9
1
9.1, 53.3, 18.9 (6 C), 11.5 (3 C) ppm. IR: ν˜ = 3675, 2944, 2865, 2159, (75 MHz, CDCl
3
–
1
724, 1307, 1218, 1131, 882, 676 cm . HRMS (ESI) m/z calcd. for C), 105.8, 65.8, 21.2 ppm. IR: ν˜ = 3076, 1735, 1378, 1220, 1018, 770
+
–1
+
C H NO Si [M + H] 318.1889, found 318.1874.
cm . HRMS (ESI) m/z calcd. for C11
H
11BrClO
2
[M + H] 288.9625, not
18
28
2
1
found. Compound 12: m.p. 41 – 43 °C. H NMR (300 MHz, CDCl ):
3
To a solution of methyl 5-[(triisopropylsilyl)ethynyl]picolinate
2.91 g, 9.17 mmol) in dry acetonitrile (97 mL), was added, under
argon and in the dark, N-bromosuccinimide (1.96 g, 11.0 mmol,
.2 equiv.) and silver fluoride (1.39 g, 11.0 mmol, 1.2 equiv.). After
h at room temp., the reaction mixture was filtered through a
δ = 7.53 (d, J = 8.3 Hz, 2 H), 7.36 (d, J = 8.3 Hz, 2 H), 6.87 (s, 1 H),
(
4
1
3
.70 (s, 2 H), 1.87 (s, 1 H) ppm. 13C NMR (75 MHz, CDCl ): δ = 142.5,
3
38.5, 136.1, 127.3 (2 C), 127.1 (2 C), 105.5, 64.9 ppm. IR: ν˜ = 3241,
1
3
–
1
072, 1408, 1217, 1057, 768 cm .
pad of Celite® and concentrated under reduced pressure. The crude
mixture was purified by column chromatography on silica gel using
heptane/ethyl acetate (10 to 8:2) to give methyl 5-(bromoeth-
Methyl (Z)-4-(2-Bromo-1-chlorovinyl)-2-methoxybenzoate (26):
To a solution of compound 21 (400 mg, 1.37 mmol) in acetone
(13 mL) was added potassium carbonate (570 mg, 4.12 mmol,
ynyl)picolinate 19 as a white powder (1.87 g, 7.79 mmol, 85 %). 3.0 equiv.) followed by dropwise addition of dimethyl sulfate
1
Compound 19: Mp: 133–134 °C. H NMR (300 MHz, CDCl ): δ = 8.78
(0.2 mL, 2.05 mmol, 1.5 equiv.). After 2 h of reflux, the reaction
mixture was cooled down and quenched with a saturated solution
3
(
dd, J = 2.1, 0.7 Hz, 1 H), 8.09 (dd, J = 8.1, 0.8 Hz, 1 H), 7.87 (dd,
1
3
J = 8.1, 2.1 Hz, 1 H), 4.00 (s, 3 H) ppm. C NMR (75 MHz, CDCl3):
δ = 165.4, 152.8, 146.8, 140.2, 124.7, 123.7, 76.7, 57.6, 53.4 ppm. IR:
of NH Cl. The aqueous phase was extracted with MTBE (3 times).
4
The combined organic phases were dried with MgSO , filtered and
4
–
1
ν˜ = 3675, 2988, 2197, 1706, 1438, 1311, 1130, 859, 691 cm . HRMS concentrated under reduced pressure. The crude product was puri-
+
(
ESI) m/z calcd. for C H BrNO [M + H] 239.9655, found 239.9715.
fied by column chromatography on silica gel using heptane/ethyl
9
7
2
acetate (10 to 7:3) to give 26 as a white amorphous solid (280 mg,
General Procedure for the Hydrochloration Reaction: To a solu-
tion of bromo-alkyne 17–19, or 30 and LiCl (2.0 equiv.) in AcOH,
were added allylpalladium(II) chloride dimer (2.5 mol-%) and cis,cis-
1
0
7
1
.94 mmol, 69 %). Compound 26: H NMR (300 MHz, CDCl ): δ =
3
.78 (d, J = 8.4 Hz, 1 H), 7.14 (d, J = 1.7 Hz, 1 H), 7.13 (dd, J = 8.5,
1
3
.7 Hz, 1 H), 7.00 (s, 1 H), 3.93 (s, 3 H), 3.89 (s, 3 H) ppm. C NMR
1
,5-cyclooctadiene (10 mol-%). After 18 h at 80 °C, the reaction
(
75 MHz, CDCl ): δ = 166.2, 159.4, 141.5, 137.8, 132.3, 121.0, 118.6,
mixture was cooled down and water was added. The aqueous layer
was then extracted with MTBE (three times) and the combined or-
ganic phases were washed with a saturated solution of NaHCO3,
3
1
1
10.7, 107.7, 56.4, 52.5 ppm. IR: ν˜ = 3077, 2916, 1689, 1400, 1294,
–1
089, 1031, 847, 764 cm . HRMS (ESI) m/z calcd. for C H BrClO
11 11
3
+
[
M + H] 304.9575, found 304.9571.
dried with MgSO , filtered and concentrated under reduced pres-
4
sure. The crude product was purified by column chromatography
on silica gel using a gradient of heptane/ethyl acetate.
Methyl (Z)-2-(Benzyloxy)-4-(2-bromo-1-chlorovinyl)benzo-ate
27): To a solution of compound 21 (100 m g, 0.34 mmol), in
(
Methyl (Z)-4-(2-Bromo-1-chlorovinyl)-3-methoxybenzoate (20):
anhydrous DMF (4 mL) at 0 °C, was added sodium hydride 60 %
Compound 20 was obtained as an orange amorphous solid (66 mg,
(14 mg, 0.4 mmol, 1.2 equiv.). After 30 min at 0 °C, tert-butylammo-
Eur. J. Org. Chem. 0000, 0–0
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6
© 0000 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

Full Paper
nium iodide (1.2 mg, 1 mol-%) and benzyl bromide (40 μL,
.34 mmol, 1 equiv.) were added. After 12 h at room temperature,
Methyl 4-[(1Z,3E)-1-Chloro-5-methylhexa-1,3,5-trien-1-yl]-2-me-
thoxybenzoate (28): From compound 26 (200 mg, 0.65 mmol)
0
the reaction mixture was quenched with water and aqueous phase
was extracted with MTBE (3 times). The combined organic phases
compound 28 was obtained as a light yellow oil (110 mg,
1
0.38 mmol, 64 %). H NMR (300 MHz, CDCl ): δ = 7.80 (d, J = 8.5 Hz,
3
were dried with MgSO , filtered and concentrated under reduced 1 H), 7.25 (d, J = 1.7 Hz, 1 H), 7.25 (dd, J = 8.6, 1.7 Hz, 1 H), 6.91 (d,
4
pressure. The crude product was purified by column chromatogra- J = 9.7 Hz, 1 H), 6.71 (dd, J = 15.3, 9.7 Hz, 1 H), 6.6 (d, J = 15.3 Hz,
1
3
phy on silica gel using heptane/ethyl acetate (10 to 7:3) to give 27
1 H), 5.14 (s, 2 H), 3.95 (s, 3 H), 3.89 (s, 3 H), 1.95 (s, 3 H) ppm.
C
as a white amorphous solid (75 mg, 0.2 mmol, 58 %). Compound
NMR (75 MHz, CDCl ): δ = 166.4, 159.5, 143.0, 142.4, 140.5, 132.1,
3
1
2
7: H NMR (300 MHz, CDCl ): δ = 7.82 (d, J = 8.1 Hz, 1 H), 7.50 (d,
131.5, 128.1, 125.1, 119.9, 119.8, 118.0, 110.3, 56.4, 52.4, 18.7 ppm.
3
+
J = 7.4 Hz, 2 H), 7.40 (t, J = 7.4 Hz, 2 H), 7.33 (t, J = 7.4 Hz, 1 H),
HRMS (ESI) m/z calcd. for C16H18ClO [M + H] 293.0939, found
3
7
.20 (d, J = 1.7 Hz, 1 H), 7.15 (d, J = 8.1 Hz, 1 H), 6.95 (s, 1 H), 5.21
293.0959.
1
3
(s, 2 H), 3.88 (s, 3 H) ppm. C NMR (75 MHz, CDCl ): δ = 166.3,
3
Methyl 2-(Benzyloxy)-4-[(1Z,3E)-1-chloro-5-methylhexa-1,3,5-
trien-1-yl]benzoate (29): From compound 27 (106 mg, 0.29 mmol)
1
1
1
58.4, 141.3, 137.7, 136.5, 132.3, 128.9 (2 C), 128.3, 127.2 (2 C), 121.7,
18.9, 112.6, 107.7, 71.1, 52.5 ppm. IR: ν˜ = 3082, 2948, 1697, 1602,
compound 29 was obtained as a light yellow oil (91 mg, 0.25 mmol,
–
1
406, 1256, 1028, 721 cm . HRMS (ESI) m/z calcd. for C H BrClO
1
7
15
3
13
8
6 %). As this compound was unstable (a correct C NMR spectrum
+
[
M + H] 380.9888, found 380.9894.
could never be obtain), it was immediately engaged in the next
1
General Procedure for the Synthesis of trienes 23–25, 28, 29,
3
step after purification. H NMR (300 MHz, CDCl
8.3 Hz, 1 H), 7.52 (m, 2 H, 18-H), 7.40 (m, 2 H), 7.33 (m, 1 H), 7.30
3
): δ = 7.83 (d, J =
2: To a solution of (Z)-1-bromo-2-chloro-alkene 20, 21, 26, 27, 31
and (E)-4,4,5,5-tetramethyl-2-(3-methylbuta-1,3-dien-1-yl)-1,3,2-di- (m, 2 H), 6.86 (d, J = 10.3 Hz, 1 H), 6.72 (dd, J = 15.4, 10.4 Hz, 1 H),
oxaborolane[12] (3.0 equiv.) in THF/water, 2:1 were added 6.59 (d, J = 15.3 Hz, 1 H), 5.23 (s, 2 H), 5.15 (s, 2 H), 3.90 (s, 3 H),
2.04 (s, 3 H) ppm. HRMS (ESI) m/z calcd. for C22H22ClO
[M + H]+
3
tetrakis(triphenylphosphine) palladium(0) (5 mol-%) and K PO4
3
(4.0 equiv.). The mixture was stirred, in the dark, for 8 h at 50 °C
369.1252, found 369.1261.
then cooled to room temperature. A saturated solution of NH Cl
was added to the crude mixture. The aqueous layer was then ex-
tracted with MTBE (three times) and the combined organic phases
4
4
-[(1Z,3E)-1-Chloro-5-methylhexa-1,3,5-trien-1-yl]benzyl Acet-
ate (32): Starting from compound 31 (500 mg, 1.73 mmol), com-
pound 32 was obtained as a light yellow oil (312 mg, 1.13 mmol,
were dried with MgSO , filtered and concentrated under reduced
1
4
66 %). H NMR (300 MHz, CDCl ): δ = 7.64 (d, J = 8.5 Hz, 2 H), 7.35
3
pressure. The crude mixture was purified by column chromatogra-
phy on silica gel using a gradient of heptane and ethyl acetate.
Same procedure for compound 22, replacing H PO by Cs CO , in
(d, J = 8.5 Hz, 2 H), 6.83 (d, J = 9.6 Hz, 1 H), 6.73 (dd, J = 15.4, 9.6 Hz,
1
H), 6.57 (d, J = 15.4 Hz, 1 H), 5.12 (s, 2 H), 5.11 (s, 2 H), 2.11 (s, 3
3
4
2
3
13
H), 1.97 (s, 3 H) ppm. C NMR (75 MHz, CDCl ): δ = 171.1, 142.5,
3
THF.
139.3, 138.0, 136.6, 132.4, 128.5, 126.7, 126.5, 125.4, 119.1, 66.0, 21.2,
+
18.7 ppm. HRMS (ESI) m/z calcd. for C H ClO [M + H] 277.0990,
Methyl 4-[(1Z,3E)-1-Chloro-5-methylhexa-1,3,5-trien-1-yl]-3-
methoxybenzoate (23): Starting from compound 20 (66 mg,
16 18
2
found 277.1006.
0
.22 mmol), compound 23 was obtained as a light yellow oil
General Procedure for the Diels–Alder Reactions: A solution of
triene (1.2 equiv.), dienophile 3b or 8 (1 equiv.) and 2-bromophenyl-
boronic acid (30 mol-%) in dichloromethane was heated at reflux
for 2 d. The reaction mixture was then concentrated under reduced
pressure and purified by column chromatography on silica gel using
heptane/ethyl acetate (10 to 8:2) + 0.1 % Acetic acid to give the
decalins 34–44.
1
(24 mg, 0.08 mmol, 36 %). H NMR (300 MHz, CDCl ): δ = 7.64 (dd,
3
J = 8.0, 1.5 Hz, 1 H), 7.58 (d, J = 1.5 Hz, 1 H), 7.58 (d, J = 8.0 Hz, 1
H), 6.90 (d, J = 10.2 Hz, 1 H), 6.74 (dd, J = 15.3, 10.2 Hz, 1 H), 6.53
(
d, J = 15.3 Hz, 1 H), 5.10 (s, 2 H), 3.92 (s, 6 H), 1.96 (s, 3 H) ppm.
1
3
C NMR (75 MHz, CDCl ): δ = 166.8, 156.8, 142.6, 139.6, 132.2, 131.7,
3
1
31.2, 130.5, 127.9, 125.3, 122.1, 119.2, 112.4, 56.3, 52.6, 18.7 ppm.
+
HRMS (ESI) m/z calcd. for C16H18ClO [M + H] 293.0939, found
3
(
2R,4aR,5S,8aR)-5-{(Z)-2-[4-(Acetoxymethyl)phenyl]-2-chloro-
2
93.0959.
vinyl}-7-methyl-2-[(R)-6-methylhept-5-en-2-yl]-1,5,8,8a-tetra-
hy-dronaphthalene-4a(2H)-carboxylic Acid (34): Compound 34
(200 mg, 0.39 mmol, 87 %) was obtained from triene 32 (150 mg,
Methyl 4-[(1Z, 3E)-1-Chloro-5-methylhexa-1,3,5-trien-1-yl]-2-hy-
droxybenzoate (24): From compound 21 (100 mg, 0.35 mmol)
compound 24 was obtained as a light yellow oil (370 mg,
0.54 mmol) and dienophile 3b (106 mg, 0.45 mmol), as a pale yellow
1
1
0
(
1
.13 mmol, 38 %). H NMR (300 MHz, CDCl ): δ = 10.76 (s, 1 H), 7.80 oil. Compound 34: [α] 2D 0 = –189.0 (c = 0.1, CDCl ). H NMR (300 MHz,
3
3
d, J = 8.5 Hz, 1 H), 7.28 (d, J = 1.9 Hz, 1 H), 7.17 (dd, J = 8.5, 1.9 Hz,
H), 6.94 (d, J = 9.7 Hz, 1 H), 6.73 (dd, J = 15.2, 9.7 Hz, 1 H), 6.61
d, J = 15.2 Hz, 1 H), 5.15 (s, 2 H), 3.95 (s, 3 H), 1.96 (s, 3 H) ppm.
CDCl ): δ = 7.42 (d, J = 8.5 Hz, 2 H), 7.23 (d, J = 8.5 Hz, 2 H), 5.93
3
(d, J = 9.6 Hz, 1 H), 5.68 (dd, J = 10.2, 2.1 Hz, 1 H), 5.63 (d, J = 7.4 Hz,
1 H), 5.27 (d, J = 4.7 Hz, 1 H), 5.06 (m, 1 H), 5.04 (s, 2 H), 3.63 (dd,
(
1
3
C NMR (75 MHz, CDCl ): δ = 170.4, 161.7, 144.8, 142.4, 140.8, 131.3, J = 9.1, 5.2 Hz, 1 H), 2.57 (m, 1 H), 2.29 (m, 1 H), 2.08 (s, 3 H), 1.90
3
1
30.1, 128.6, 125.2, 120.1, 117.1, 115.4, 112.3, 52.7, 18.7 ppm. HRMS
(m, 4 H), 1.76 (m, 1 H), 1.67 (s, 3 H), 1.63 (s, 3 H), 1.58 (s, 3 H), 1.40
+
13
(ESI) m/z calcd. for C H ClO [M + H] 279.0782, found 279.0788.
(m, 1 H), 1.27 (m, 3 H), 0.75 (d, J = 6.7 Hz, 3 H) ppm. C NMR
15
16
3
(
75 MHz, CDCl ): δ = 178.3, 171.1, 138.5, 136.4, 135.6, 134.5, 132.7,
3
Methyl 5-[(1Z,3E)-1-Chloro-5-methylhexa-1,3,5-trien-1-yl]picoli-
nate (25): From compound 22 (114 mg, 0.41 mmol), compound 25
1
6
2
5
32.4, 131.6, 129.9, 129.3, 128.4 (2 C), 127.5, 127.1 (2 C), 125.0, 117.8,
6.1, 48.3, 45.0, 37.1, 36.8, 34.1, 32.0, 29.2, 28.1, 26.3, 26.0, 23.6,
was obtained as a light yellow oil (70 mg, 0.26 mmol, 65 %). 1
H
–
1.3, 18.0, 16.4 ppm. HRMS (ESI) m/z calcd. for C H ClO [M – H]
31
38
4
NMR (300 MHz, CDCl ): δ = 8.98 (d, J = 1.9 Hz, 1 H), 8.13 (d, J =
3
10.0910, found 510.0917.
8
6
4
1
1
.3 Hz, 1 H), 8.07 (dd, J = 8.3, 2.0 Hz, 1 H), 6.99 (d, J = 9.0 Hz, 1 H),
.73 (dd, J = 15.5, 9.0 Hz, 1 H), 6.68 (d, J = 15.5 Hz), 5.19 (s, 2 H),
(2R,4aR,5S,8aR)-5-[(E)-2-(4-Carboxyphenyl)prop-1-en-1-yl]-7-
methyl-2-[(R)-6-methylhept-5-en-2-yl]-1,5,8,8a-tetra-
47.4, 147.1, 142.2, 141.8, 137.6, 136.9, 134.6, 129.7, 125.1, 124.6, hydronaphthalene-4a(2H)-carboxylic Acid (35): Compound 35
1
3
.00 (s, 3 H), 1.97 (s, 3 H) ppm. C NMR (75 MHz, CDCl ): δ = 165.5,
3
20.8, 53.3, 18.6 ppm. HRMS (ESI) m/z calcd. for C H ClNO [M +
(200 mg, 0.39 mmol, 87 %) was obtained from triene 12 (18 mg,
0.07 mmol) and dienophile 3b (15 mg, 0.06 mmol), as a pale yellow
1
4
15
2
+
H] 264.0786, found 264.0801.
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© 0000 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

Full Paper
oil. Compound 35: [α] 2D 0 = –188.0 (c = 0.1, CHCl ). H NMR (300 MHz, (2R,4aR,5S,8aR)-5-{(Z)-2-Chloro-2-[6-(methoxycarbonyl)pyridin-
1
3
CDCl ): δ = 8.07 (d, J = 8.6 Hz, 2 H), 7.73 (d, J = 8.6 Hz, 2 H), 6.32 3-yl]vinyl}-7-methyl-2-[(R)-6-methylhept-5-en-2-yl]-1,5,8,8a-
3
(
d, J = 9.8 Hz, 1 H), 5.70 (m, 1 H), 5.65 (m, 1 H), 5.33 (d, J = 4.9 Hz,
H), 5.14 (t, J = 7.5 Hz, 1 H), 3.74–3.71 (m, 1 H), 2.75–2.72 (m, 1 H),
.45–2.40 (m, 1 H), 2.04–1.96 (m, 4 H), 1.70 (s, 3 H), 1.69 (s, 3 H), (75 mg, 0.20 mmol) and dienophile 3b (40 mg, 0.17 mmol) as a
tetrahydronaphthalene-4a(2H)-carboxylic Acid (39): Compound
39 (13.8 mg, 0.023 mmol, 14 %) was obtained from triene 29
1
2
1
2
0
1
.63 (s, 3 H), 1.47–1.40 (m, 1 H), 1.33 (m, 3 H), 1.23 (m, 1 H), 0.89 (d,
pale yellow oil. Compound 39: [α] = –210.0 (c = 0.1, CDCl ). H
D
3
1
3
J = 6.7 Hz, 3 H) ppm. C NMR (75 MHz, MeOD): δ = 176.4, 167.8,
NMR (300 MHz, CDCl ): δ = 7.65 (d, J = 8.1 Hz, 1 H), 7.45 (m, 2 H),
3
1
1
2
40.9, 137.5, 134.6, 132.3, 132.3, 132.1, 131.4, 131.3 (2 C), 128.0,
28.0 (2 C), 126.4, 118.5, 49.1, 46.7, 38.3, 38.2, 35.1, 33.1, 30.8, 30.6,
8.9, 27.5, 26.6, 26.5, 24.2 ppm. HRMS (ESI) m/z calcd. for C H ClO
4
7.30 (m, 2 H), 7.24 (m, 1 H), 6.99 (d, J = 1.7 Hz, 1 H), 6.95 (dd, J =
8.1, 1.8 Hz, 1 H), 5.87 (d, J = 9.8 Hz, 1 H), 5.61 (dd, J = 10.0, 2.4 Hz,
1 H), 5.53 (d, J = 8.3 Hz, 1 H), 5.17 (d, J = 4.1 Hz, 1 H), 5.09 (s, 2 H),
4.99 (t, J = 6.9 Hz, 1 H), 3.80 (s, 3 H), 3.54 (m, 1 H), 2.49 (m, 1 H),
2
9
34
[M – H]- 481.2151, found 481.2157.
2
1
.24 (m, 1 H), 1.83 (m, 4 H), 1.71 (m, 1 H), 1.60 (s, 3 H), 1.56 (s, 3 H),
(
2R,4aR,5S,8aR)-5-{(Z)-2-Chloro-2-[4-(methoxycarbonyl)-
.52 (s, 3 H), 1.44 (m, 1 H), 1.29 (m, 3 H), 0.67 (d, J = 6.6 Hz, 3 H)
phenyl]vinyl}-7-methyl-2-[(R)-6-methylhept-5-en-2-yl]-1,5,8,8a-
tetra-hydronaphthalene-4a(2H)-carboxylic Acid (36): Compound
3
13
ppm. C NMR (75 MHz, CDCl ): δ = 179.5, 166.6, 158.3, 143.4, 137.0,
3
1
1
36.0, 132.7, 132.1, 131.7, 131.6, 129.7, 129.1, 128.8 (2 C), 128.1,
27.3 (2 C), 125.0, 120.4, 118.9, 117.3, 112.5, 70.9, 52.3, 48.3, 44.9,
6 (750 mg, 1.50 mmol, 73 %) was obtained from triene 33 (660 mg,
2
.51 mmol) and dienophile 3b (490 mg, 2.09 mmol), as a pale yel-
low oil. Compound 36 [α]D = –222.0 (c = 0.1, CDCl3). 1H NMR
300 MHz, CDCl ): δ = 7.83 (d, J = 8.6 Hz, 2 H), 7.40 (d, J = 8.6 Hz,
2
0
37.0, 36.8, 34.2, 31.9, 29.1, 28.1, 26.3, 26.0, 23.6, 18.0, 16.3 ppm.
HRMS (ESI) m/z calcd. for C37H42ClO [M – H] 601.2721, found
–
(
5
3
601.2762.
2
H), 5.97 (d, J = 9.8 Hz, 1 H), 5.62 (dd, J = 10.0, 2.5 Hz, 1 H), 5.55
d, J = 8.2 Hz, 1 H), 5.19 (d, J = 3.8 Hz, 1 H), 4.99 (t, J = 6.9 Hz, 1 H),
.84 (s, 3 H), 3.57 (dd, J = 9.3, 5.1 Hz, 1 H), 2.51 (m, 1 H), 2.22 (m, 1
H), 1.84 (m, 4 H), 1.68 (m, 1 H), 1.60 (s, 3 H), 1.57 (s, 3 H), 1.52 (s, 3
H), 1.47 (m, 1 H), 1.30 (m, 3 H), 0.66 (d, J = 6.6 Hz, 3 H) ppm. 13
NMR (75 MHz, CDCl ): δ = 179.8, 166.9, 142.6, 136.0, 134.6, 132.6,
(
3
(2R,4aR,5S,8aR)-5-{(Z)-2-Chloro-2-[6-(methoxycarbonyl)pyridin-
3
-yl]vinyl}-7-methyl-2-[(R)-6-methylhept-5-en-2-yl]-1,5,8,8a-
tetrahydronaphthalene-4a(2H)-carboxylic Acid (41): Compound
1 (51 mg, 0.10 mmol, 60 %) was obtained from triene 25 (54 mg,
.20 mmol) and dienophile 3b (40 mg, 0.17 mmol) a pale yellow
C
4
0
3
1
4
31.9, 131.6, 130.0, 129.8, 129.2, 126.8 (2 C), 125.0, 117.4, 52.5, 48.4,
20
1
oil. Compound 41: [α]D = –161.0 (c = 0.1, CDCl ). H NMR (300 MHz,
CDCl ): δ = 8.83 (d, J = 2.3 Hz, 1 H), 7.99 (d, J = 8.2 Hz, 1 H), 7.84
3
5.0, 37.0, 36.8, 34.2, 32.0, 29.1, 28.1, 26.3, 26.0, 23.6, 18.0, 16.3
3
–
ppm. HRMS (ESI) m/z calcd. for C H ClO [M – H] 495.2302, found
3
0
36
4
(
(
dd, J = 8.2, 2.3 Hz, 1 H), 6.20 (d, J = 9.5 Hz, 1 H), 5.65 (m, 2 H), 5.24
d, J = 3.9 Hz, 1 H), 5.05 (t, J = 7.0 Hz, 1 H), 3.95 (s, 3 H), 3.68 (dd,
4
95.2339.
2R,4aR,5S,8aR)-5-{(Z)-2-Chloro-2-[3-hydroxy-4-(methoxy-
carbonyl)phenyl]vinyl}-7-methyl-2-[(R)-6-methylhept-5-en-2-yl]-
,5,8,8a-tetrahydronaphthalene-4a(2H)-carboxylic Acid (37):
Compound 37 (18 mg, 0.035 mmol, 59 %) was obtained from triene
4 (21 mg, 0.08 mmol) and dienophile 3b (15 mg, 0.06 mmol) as a
(
J = 9.5, 3.9 Hz, 1 H), 2.62 (m, 1 H), 2.30 (m, 1 H), 1.93 (m, 4 H), 1.79
(m, 1 H), 1.66 (s, 3 H), 1.65 (s, 3 H), 1.57 (s, 3 H), 1.41 (m, 1 H), 1.12
(m, 3 H), 0.78 (d, J = 6.6 Hz, 3 H) ppm. 13C NMR (75 MHz, CDCl3):
δ = 178.3, 165.2, 147.3, 137.3, 136.7, 135.2, 132.5, 131.8, 131.5, 130.1,
128.2, 125.0, 124.8, 116.9, 53.1, 48.3, 45.3, 37.0, 36.8, 36.6, 34.1, 31.9,
1
2
2
0
1
pale yellow oil. Compound 37 [α]D = –236.0 (c = 0.1, CDCl ). H 29.1, 28.1, 26.3, 26.0, 23.6, 17.9, 16.4 ppm. HRMS (ESI) m/z calcd. for
3
–
NMR (300 MHz, CDCl ): δ = 10.6 (s, 1 H), 7.68 (d, J = 8.3 Hz, 1 H),
C H ClNO [M – H] 496.2255, found 496.2264.
3
29 35
4
7
9
5
.10 (d, J = 1.7 Hz, 1 H), 6.95 (d, J = 8.4, 1.7 Hz, 1 H), 6.07 (d, J =
.6 Hz, 1 H), 5.70 (dd, J = 10.1, 2.3 Hz, 1 H), 5.64 (d, J = 5.5 Hz, 1 H),
.26 (d, J = 4.4 Hz, 1 H), 5.07 (t, J = 6.6 Hz, 1 H), 3.94 (s, 3 H), 3.65
(
2R,4aS,5S,8aR)-5-{(Z)-2-Chloro-2-[4-(methoxycarbonyl)-
phenyl]vinyl}-2-{2-[(4-chlorobenzoyl)oxy]ethyl}-7-methyl-
,3,4,5,8,8a-hexahydronaphthalene-4a(2H)-carboxylic Acid
42): Compound 42 (763 mg, 1.34 mmol, 96 %) was obtained from
triene 28 (549 mg, 2.08 mmol) and dienophile 8 (140 mg,
.70 mmol) as a pale yellow amorphous solid. Compound 42:
1
(
(dd, J = 9.1, 5.5 Hz, 1 H), 2.59 (m, 1 H), 2.30 (m, 1 H), 1.93 (m, 4 H),
1
1
.79 (m, 1 H), 1.67 (s, 3 H), 1.64 (s, 3 H), 1.59 (s, 3 H), 1.49 (m, 1 H),
1
3
.37 (m, 3 H), 0.77 (d, J = 6.6 Hz, 3 H) ppm. C NMR (75 MHz,
0
CDCl ): δ = 178.9, 170.4, 161.6, 145.3, 136.1, 132.8, 131.6, 130.0,
3
2
0
1
[α] = –97.50 (c = 0.5, MeOH). H NMR (500 MHz, [D ]acetone): δ =
D
6
1
3
29.8, 129.6, 125.0, 117.6, 117.3, 115.9, 112.2, 52.6, 48.2, 45.1, 37.0,
6.8, 34.2, 32.0, 29.1, 28.1, 26.3, 26.0, 23.6, 18.0, 16.3 ppm. HRMS
1
3.00–9.00 (br. s, 2 H), 8.04 (d, J = 8.5 Hz, 2 H), 8.00 (d, J = 8.5 Hz,
–
2 H), 7.70 (d, J = 8.4 Hz, 2 H), 7.56 (d, J = 8.4 Hz, 2 H), 6.33 (d, J =
9
1
(ESI) m/z calcd. for C H ClO [M – H] 511.2251, found 511.2295.
30
36
5
.5 Hz, 1 H), 5.77 (dd, J = 10.2, 2.7 Hz, 1 H), 5.70 (d, J = 10.2 Hz,
H), 5.30–5.27 (m, 1 H), 4.44–4.38 (m, 2 H), 3.89 (s, 3 H), 3.75–3.69
(
2R,4aR,5S,8aR)-5-{(Z)-2-Chloro-2-[3-methoxy-4-(methoxy-
carbonyl)phenyl]vinyl}-7-methyl-2-[(R)-6-methylhept-5-en-2-yl]-
,5,8,8a-tetrahydronaphthalene-4a(2H)-carboxylic Acid (38):
Compound 38 (70 mg, 0.13 mmol, 47 %) was obtained from triene
8 (100 mg, 0.34 mmol) and dienophile 3b (67 mg, 0.28 mmol) as
(m, 1 H), 2.76–2.69 (m, 1 H), 2.63–2.56 (m, 1 H), 2.10 (dd, J = 18.1,
1
8
.9 Hz, 1 H), 1.95–1.83 (m, 4 H), 1.78–1.70 (m, 1 H), 1.65 (s, 3 H)
13
ppm. C NMR (75 MHz, [D ]acetone): δ = 175.6, 166.7, 165.9, 143.0,
6
2
1
1
3
39.6, 136.5, 133.1, 132.0 (2 C), 131.6, 131.5, 131.1, 130.8, 130.3 (2 C),
30.2, 129.7 (2 C), 127.3 (2 C), 117.9, 63.8, 52.5, 48.6, 45.8, 35.7, 32.4,
2
0
1
a pale yellow oil. Compound 38: [α]D = –209.0 (c = 0.1, CDCl ). H
NMR (300 MHz, CDCl ): δ = 7.68 (d, J = 8.6 Hz, 1 H), 7.03 (d, J =
3
3
–
1.6, 30.0, 30.1, 23.5 ppm. HRMS (ESI): m/z calcd. for C H Cl O
31
29
2 6
1
.7 Hz), 6.98 (dd, J = 8.5, 1.7 Hz), 6.01 (d, J = 9.6 Hz, 1 H), 5.67 (dd,
–
[
M – H] 567.1341, found 567.1389.
J = 10.1, 2.4 Hz, 1 H), 5.6 (d, J = 8.1 Hz, 1 H), 5.25 (d, J = 4.0 Hz, 1
H), 5.05 (t, J = 6.9 Hz, 1 H), 3.88 (s, 3 H), 3.86 (s, 3 H), 3.6 (dd, J =
(2R,4aR,5S,8aR)-5-{(Z)-2-Chloro-2-[3-methoxy-4-(methoxy-
1
1
1
0.1, 3.1 Hz, 1 H), 2.56 (m, 1 H), 2.29 (m, 1 H), 1.90 (m, 4 H, 4-H),
carbonyl)phenyl]vinyl}-2-{2-[(4-chlorobenzoyl)oxy]ethyl}-7-
.75 (m, 1 H), 1.67 (s, 3 H), 1.63 (s, 3 H), 1.58 (s, 3 H), 1.51 (m, 1 H), methyl-1,5,8,8a-tetrahydronaphthalene-4a(2H)-carboxylic Acid
1
3
.29 (m, 3 H), 0.71 (d, J = 6.7 Hz, 3 H) ppm. C NMR (75 MHz,
(43): Compound 43 (18 mg, 0.030 mmol, 37 %) was obtained from
triene 28 (27 mg, 0.09 mmol) and dienophile 8 (24 mg, 0.08 mmol)
CDCl ): δ = 180.3, 166.4, 159.3, 143.5, 135.9, 132.5, 132.0, 131.7,
3
2
0
1
4
31.5, 129.8, 129.2, 125.0, 119.6, 118.5, 117.3, 110.6, 56.2, 52.3, 48.4,
4.9, 37.0, 36.7, 34.2, 31.9, 29.1, 28.1, 26.2, 26.0, 23.6, 17.9, 16.2
as a pale yellow oil. Compound 43: [α] = –64.0 (c = 0.1, CDCl3).
D
1
H NMR (300 MHz, CDCl ): δ = 7.95 (d, J = 8.6 Hz, 2 H), 7.71 (dd, J =
3
–
ppm. HRMS (ESI) m/z calcd. for C H ClO [M – H] 525.2408, found 8.2 Hz, 1 H), 7.41 (d, J = 8.6 Hz, 2 H), 7.05 (m, 2 H), 6.07 (d, J =
3
1
38
5
5
25.2381.
9.8 Hz, 1 H), 5.73 (td, J = 9.8, 2.7 Hz, 1 H), 5.65 (d, J = 9.8 Hz, 1 H),
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5
3
1
.25 (d, J = 3.7 Hz, 1 H), 4.35 (td, J = 6.4, 2.1 Hz, 2 H), 3.89 (s, 3 H),
mura, T. Toda, T. Hayamizu, K. Sawamura, K. Takao, K. Tadano, Tetrahedron
Lett. 2009, 50, 3356–3358.
[6] J. W. Johannes, S. Wenglowsky, Y. Kishi, Org. Lett. 2005, 7, 3997–4000.
7] E. J. Thomas, M. Willis, Org. Biomol. Chem. 2014, 12, 7537–7550.
8] M. Asano, M. Inoue, K. Watanabe, H. Abe, T. Katoh, J. Org. Chem. 2006,
.87 (s, 3 H), 3.66 (m, 1 H), 2.59 (m, 1 H), 2.48 (m, 1 H), 2.04 (dd, J =
8.1, 7.4 Hz, 1 H), 1.84 (m, 4 H), 1.64 (s, 3 H), 1.25 (s, 1 H) ppm. 13
C
[
[
NMR (75 MHz, CDCl ): δ = 206.7, 179.3, 166.4, 166.0, 159.4, 143.4,
1
C), 119.7, 118.6, 118.5, 117.5, 110.7, 63.3, 56.3, 52.4, 44.7, 34.9, 32.1,
3
–
3
39.7, 135.6, 133.2, 133.1, 132.0, 131.3 (2 C), 129.5, 129.4, 129.0 (2
7
1, 6942–6951.
[
9] G. Stork, Y. Nakahara, Y. Nakahara, W. J. Greenlee, J. Am. Chem. Soc. 1978,
100, 7775–7777.
[10] W. R. Roush, R. J. Sciotti, J. Am. Chem. Soc. 1998, 120, 7411–7419.
1.1, 29.5, 29.0, 23.6 ppm. HRMS (ESI) m/z calcd. for C H Cl O [M
32 31 2 7
–
H] 597.1447, found 597.1461.
[
11] D. Fomekong Fotsop, F. Roussi, A. Leverrier, A. Bretéché, F. Guéritte, J.
Org. Chem. 2010, 75, 7412–7415.
(
2R,4aR,5S,8aR)-5-{(Z)-2-Chloro-2-[2-methoxy-4-(methoxy-
carbonyl)phenyl]vinyl}-2-{2-[(4-chlorobenzoyl)oxy]ethyl}-7-
methyl-1,5,8,8a-tetrahydronaphthalene-4a(2H)-carboxylic Acid
[
12] M. Litaudon, H. Bousserouel, K. Awang, O. Nosjean, M.-T. Martin, M. E.
Tran Huu Dau, H. A. Hadi, J. A. Boutin, T. Sévenet, F. Guéritte, J. Nat. Prod.
(44): Compound 44 (23 mg, 0.038 mmol, 55 %) was obtained from
2009, 72, 480–483.
triene 23 (24 mg, 0.08 mmol) and dienophile 8 (21 mg, 0.07 mmol)
[
13] a) J. C. Reed, Cell Death Differ. 2018, 25, 3–6.
2
0
as a pale yellow oil. Compound 44: [α] = –62.0 (c = 0.1, CDCl3).
[14] a) J. Dardenne, S. Desrat, F. Guéritte, F. Roussi, Eur. J. Org. Chem. 2013,
2116–2122; b) S. Desrat, A. Pujals, C. Colas, J. Dardenne, C. Geny, L. Favre,
V. Dumontet, B. Iorga, M. Litaudon, M. Raphaël, J. Wiels, F. Roussi, Bioorg.
Med. Chem. Lett. 2014, 24, 5086–5088; c) S. Desrat, C. Remeur, F. Roussi,
Org. Biomol. Chem. 2015, 13, 5520–5531; d) S. Desrat, C. Remeur, C. Geny,
G. Rivière, C. Colas, V. Dumontet, N. Birlirakis, B. Iorga, F. Roussi, Chem.
Commun. 2014, 50, 8593–8596.
D
1
H NMR (300 MHz, CDCl ): δ = 7.92 (d, J = 8.4 Hz, 2 H), 7.50 (dd, J =
3
8
2
2
.0, 1.4 Hz, 1 H), 7.45 (dd, J = 11.8, 1.4 Hz, 1 H), 7.37 (d, J = 8.4 Hz,
H), 7.32 (d, J = 8.0 Hz, 1 H), 5.72 (d, J = 9.7 Hz, 1 H), 5.47–5.39 (m,
H), 5.00–4.99 (m, 1 H), 4.06–4.01 (m, 2 H), 3.60 (s, 3 H), 3.51 (s, 3
H), 3.43–3.38 (m, 1 H), 2.26–2.22 (m, 1 H), 2.19–2.13 (m, 1 H), 1.75
m, 1 H), 1.55–1.36 (m, 4 H), 1.34 (s, 3 H), 0.95 (m, 1 H) ppm. 13
NMR (75 MHz, CDCl ): δ = 179.5, 177.8, 166.8, 166.0, 156.7, 139.6,
(
C
[
15] a) R. M. Al-Zoubi, O. Marion, D. G. Hall, Angew. Chem. Int. Ed. 2008, 47,
2876; Angew. Chem. 2008, 120, 2918; b) H. Zheng, D. G. Hall, Tetrahedron
Lett. 2010, 51, 3561–3564.
3
1
38.0, 135.1, 133.0, 132.3, 131.8, 131.2 (2 C), 130.5, 129.9, 129.0 (2
C), 128.2, 121.8, 118.0, 112.2, 63.4, 56.1, 52.6, 48.4, 44.7, 35.0, 32.2,
[16] G. Zhu, D. Chen, Y. Wang, R. Zheng, Chem. Commun. 2012, 48, 5796–
5798.
[17] T. Lee, H. R. Kang, S. Kim, S. Kim, Tetrahedron 2006, 62, 4081–4085.
3
–
1.2, 29.4, 28.9, 23.6 ppm. HRMS (ESI) m/z calcd. for C H Cl O [M
32 31 2 7
H] 597.1447, found 597.1440.
–
[
18] M. J. Frisch, G. W. Trucks, H. B. Schlegel, G. E. Scuseria, M. A. Robb, J. R.
Cheeseman, G. Scalmani, V. Barone, B. Mennucci, G. A. Petersson, H. Na-
katsuji, M. Caricato, X. Li, H. P. Hratchian, A. F. Izmaylov, J. Bloino, G.
Zheng, J. L. Sonnenberg, M. Hada, M. Ehara, K. Toyota, R. Fukuda, J. Hase-
gawa, M. Ishida, T. Nakajima, Y. Honda, O. Kitao, H. Nakai, T. Vreven, J. A.
Montgomery Jr., J. E. Peralta, F. Ogliaro, M. Bearpark, J. J. Heyd, E. Broth-
ers, K. N. Kudin, V. N. Staroverov, R. Kobayashi, J. Normand, K. Raghava-
chari, A. Rendell, J. C. Burant, S. S. Iyengar, J. Tomasi, M. Cossi, N. Rega,
J. M. Millam, M. Klene, J. E. Knox, J. B. Cross, V. Bakken, C. Adamo, J.
Jaramillo, R. Gomperts, R. E. Stratmann, O. Yazyev, A. J. Austin, R. Cammi,
C. Pomelli, J. W. Ochterski, R. L. Martin, K. Morokuma, V. G. Zakrzewski,
G. A. Voth, P. Salvador, J. J. Dannenberg, S. Dapprich, A. D. Daniels, Ö.
Farkas, J. B. Foresman, J. V. Ortiz, J. Cioslowski, D. J. Fox, Gaussian 09,
Revision D.01, Gaussian, Inc., Wallingford CT, 2009.
Acknowledgments
The authors acknowledge the French Agence Nationale pour la
Recherche (ANR2010-JCJC-702-1) for financial support. We also
thank the International French-Malaysian Natural Product Labo-
ratory (NatProLab) between Centre National de la Recherche
Scientifique (CNRS)-ICSN and University Malaya (Malaysia) and
Investissement d'Avenir grant of the Agence Nationale de la
Recherche CEBA: (ANR-10-LABX-25-01) for financial support.
Keywords: Cycloaddition · Triene · DFT calculations ·
Natural products · Reaction mechanisms
[
19] The M06 Suite of Density Functionals for Main Group Thermochemistry,
Thermochemical Kinetics, Noncovalent Interactions, Excited States, and
Transition Elements:Y. Zhao, D. G. Truhlar, Theor. Chem. Acc. 2008, 120,
2
15–241.
20] R. Krishnan, J. S. Binkley, R. Seeger, J. A. Pople, J. Chem. Phys. 1980, 72,
50–654.
[
1] For reviews on Diels–Alder see for example: a) K. C. Nicolaou, S. A. Sny-
der, T. Montagnon, G. Vassilikogiannakis, Angew. Chem. Int. Ed. 2002, 41,
[
[
6
1668–1698; Angew. Chem. 2002, 114, 1742; b) K. Takao, R. Munakata, K.
21] Although the computations follow the experimental trend, they do not
have a quantitative value. Single point calculations were performed us-
ing the following functionals: B3LYP, PBE0, B2PLYP, B2PLYP-D3. The latter
accounts for dispersion effects. The 6–311+G(d,p) basis set was used in
each case. PCM correction to take the solvent effect into account was
also used in each case. The lowest energy difference between the two
TSs was obtained using the computationally very costly B2PLYP-D3/PCM
level, i.e. 2.2 kcal/mol instead of 4.3 kcal/mol, but it remains too high to
fit with the 80:20 selectivity. We thus remained at the M06–2X level in
the rest of the manuscript.
Tadano, Chem. Rev. 2005, 105, 4779–4807; c) M. Juhl, D. Tanner, Chem.
Soc. Rev. 2009, 38, 2983–2992; d) C. C. Nawrat, C. J. Moody, Angew. Chem.
Int. Ed. 2014, 53, 2056–2077; Angew. Chem. 2014, 126, 2086.
2] For a recent review see for example: a) K. Kumar, H. Waldmann, V. Es-
chenbrenner-Lux, Angew. Chem. Int. Ed. 2014, 53, 11146–11157; Angew.
Chem. 2014, 126, 11326.
[
[
[
[
3] a) M. Tortosa, N. A. Yakelis, W. R. Roush, J. Am. Chem. Soc. 2008, 130,
2722–2723; b) For a preliminary communication see: W. R. Roush, J. A.
Champoux, B. C. Peterson, Tetrahedron Lett. 1996, 37, 8989–8992.
4] a) D. J. Mergott, S. A. Frank, W. R. Roush, Proc. Natl. Acad. Sci. USA 2004,
[
22] W. L. F. Amarego, C. L. L. Chai in Purification of Laboratory Chemical (Ed.
Butterworth-Heinemann), Elsevier, Burlington, 6th edn. 2009.
1
01, 11955–11959; b) S. A. M. Winbush, D. J. Mergott, W. R. Roush, J. Org.
Chem. 2008, 73, 1818–1829.
5] a) J. E. D. Kirkham, V. Lee, J. E. Baldwin, Chem. Commun. 2006, 2863–
2865; b) For another synthesis based on the same strategy see: D. Mastu-
Received: March 23, 2018
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Diels-Alder Reactions
C. Remeur, S. Desrat, V. Gandon,
F. Roussi* ........................................... 1–10
Selectivity in the Intermolecular
Diels–Alder Reaction of Conjugated
Trienes: Experimental and Theoreti-
cal Approaches
Eleven analogs of the natural product rated carboxylic acids as dienophiles.
meiogynin A, an inhibitor of proteins The perfect regioselectivity and good
of the Bcl-2 family, have been elabo- to excellent diastereoselectivities of
rated by an intermolecular Diels–Alder these reactions were rationalized by
(
DA) reaction of various conjugated DFT calculations.
chloro-trienes with two α,ꢀ-unsatu-
DOI: 10.1002/ejoc.201800472
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