First example of an atropselective dehydro-Diels-Alder (ADDA) reaction

Article abstract of DOI:10.1016/j.tetlet.2011.06.024

A new concept of a stereoselective synthesis of axially chiral biaryls, formed in the course of the dehydro-Diels-Alder (DDA) reaction, has been disclosed. It is based on asymmetric induction of the newly formed chirality axis by a chirality center, which

Full text of DOI:10.1016/j.tetlet.2011.06.024

Tetrahedron Letters 52 (2011) 4221–4223
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First example of an atropselective dehydro-Diels–Alder (ADDA) reaction
⇑
Pablo Wessig , Charlotte Pick, Uwe Schilde
Institut für Chemie, Universität Potsdam, Karl-Liebknecht-Str. 24-25, D-14476 Potsdam, Germany
a r t i c l e i n f o
a b s t r a c t
Article history:
A new concept of a stereoselective synthesis of axially chiral biaryls, formed in the course of the dehydro-
Diels–Alder (DDA) reaction, has been disclosed. It is based on asymmetric induction of the newly formed
chirality axis by a chirality center, which is present in the two synthesized DDA reactants. Depending on
the different length of the linkers joining the alkyne moieties the DDA reaction may be triggered photo-
chemically or thermally, where only the thermal variant was stereoselective.
Received 16 May 2011
Revised 3 June 2011
Accepted 7 June 2011
Available online 13 June 2011
Ó 2011 Elsevier Ltd. All rights reserved.
Keywords:
Cycloaddition
Atropselectivity
Biaryls
Alkynes
Photochemistry
Biaryls are widespread structural elements in natural products
as well as in synthetic drugs and the development of synthetic
routes is, therefore, an important topic of organic chemistry.1
Due to the often hindered rotation around the bond joining the
two aryl moieties many biaryls exhibit a chirality axis and two
atropisomers occur. Similarly to compounds bearing a chirality
center stereoselective syntheses of biaryls with respect to the chi-
rality axis (atropselective syntheses2) are highly desirable because
the physiological activity of the atropisomers is a priori not
identical.
Most of the synthetic routes to biaryls are based on coupling
reactions between two preexisting aryl derivatives whereas only
few methods are known which rest upon a complete assembly of
one of the aryl moieties. One of the most efficient of these methods
is the dehydro-Diels–Alder (DDA) reaction.3 Despite bearing anal-
ogy to the classical concerted Diels–Alder (DA) reaction (it is also
a [4+2] cycloaddition) the DDA reaction differs from the DA reac-
tion in two important aspects: (1) the DDA normally proceeds
according to a multi-step mechanism and (2) the DDA may be ini-
tiated both thermally and photochemically (the latter is called
photo-dehydro-Diels–Alder (PDDA) reaction).4
weak non-covalent interactions is hardly feasible.5e Herein we
wish to describe the first successful asymmetric DDA reaction
(ADDA reaction) which results from
reactant.
a doubly bridged DDA
Our concept for an ADDA reaction is depicted in Scheme 1. A
chirality center (blue asterisk) acts as the chirality source. The
two components (green in formula A) are joined by the linker X
to facilitate the DDA reaction. Furthermore, the chirality center
and one of the ortho positions of the lower benzene ring are
bridged by the unit Y to ensure an efficient asymmetric induction.
In the first step a C–C single bond is formed between the alkynes
giving the 1,4-diradical B. At this stage the chirality axis is already
X
H
*
Y
X
*
H
*
Y
A
B
In the past years we demonstrated that the PDDA reaction is a
powerful tool for the synthesis of biaryls.5 The self-evident ap-
proach to conceive an asymmetric (thermal or photochemical)
DDA reaction is to achieve an asymmetric induction from a chiral-
ity center present in the reactant onto the new chirality axis, which
is formed in the DDA reaction.6 Recently we found that an efficient
transfer of the stereochemical information which is based solely on
X
X
*
*
H
H
H
*
*
Y
Y
C
D
⇑
Corresponding author.
E-mail address: wessig@uni-potsdam.de (P. Wessig).
Scheme 1. Concept for an ADDA reaction.
0040-4039/$ - see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2011.06.024

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P. Wessig et al. / Tetrahedron Letters 52 (2011) 4221–4223
hydrolytic cleavage of the acetal moiety and PMB protection of one
O
O
of the hydroxy groups of the diol 4 the ester group was saponified
providing the hydroxycarboxylic acid 5.
O
O
Pd(PPh3)2Cl2
CuI, Et3N
We previously10 found that the Yamaguchi macrolactoniza-
tion11 is the method of choice for the ring closure of h-hydroxy-
carboxylic acids such as 5, whereas other methods mainly gave a
dimeric dilactone. Applying this method to 5 furnished, after oxi-
dative cleavage of the PMB group with DDQ, the macrolactone 6
with good yield. In the final step to the DDA reactant 7 the alcohol
6 was coupled with 3-phenylpropiolic acid (Scheme 2).
1
COOMe
81%
I
COOMe
3
2
Dowex 50W
MeOH/H2O
92%
Irradiation of macrolactone 7 in acetone as triplet sensi-
tizer,5b,12 gave 8 with 36% yield. Unfortunately, we observed no
diastereoselectivity at all and the diastereomers 8a and 8b were
formed in similar amounts (Scheme 3). Obviously, the six-mem-
bered dihydropyran-2-one ring, which is formed in the PDDA, is
OH OPMB
OH OH
1. PMB-TCAI /
TfOH, 79%
COOH
COOMe
2. LiOH*H2O
MeOH, 78%
4
5
Cl
O
Et3N
DMAP
51%
Cl
1.
Cl
Cl
2. DDQ, CH2Cl2/H2O, 68%
O
O
O
HO
O
3-PPA
DCC
DMAP
O
O
79%
Ph
6
7
Figure 1. X-ray crystal structures of 8a (left) and 18a (right).
Scheme 2. Synthesis of lactone 7. (PMB-TCAI = p-methoxybenzyl trichloroacetim-
idate, 3-PPA = 3-phenylpropiolic acid).
present (red asterisk) but the rotational barrier is still low. In the
subsequent second C–C-bond formation to the cycloallene C the fi-
nal carbon skeleton is formed and rotation around the chirality axis
is now strongly hindered. The target structure D is formed from C
by hydrogen migration.
It is obvious that the success of our ADDA approach should crit-
ically depend on the length of the linker X and we, therefore, pre-
pared two different compounds A with different linkers X and
investigated their DDA reaction.
O
O
2, Pd(PPh3)4
CuI, Et3N
O
O
80%
COOMe
9
10
The synthesis of the first system begins with a Sonogashira
reaction7 between the known alkyne 18 and methyl 3-(2-iodo-
phenyl)propanoate 25d,9 to give the alkyne 3 with good yield. After
Dowex 50W
MeOH/H2O
70%
OTDS
1. TDSCl/Im
DMF, 57%
PMBO
HO
OH
O
2. PMB-TCAI
TfOH, Et2O
73%
O
O
O
Ph
COOMe
COOMe
7
12
11
hν
TBAF/THF
95%
acetone
36%
O
O
PMBO
PMBO
OH
OH
O
O
LiOH*H2O
MeOH
+
O
O
100%
COOMe
COOH
O
O
8a
8b
13
1 : 1
14
Scheme 3. PDDA reaction of 7 to 8.
Scheme 4. Synthesis of hydroxycarboxylic acid 14. (TDS = thexyl-dimethyl-silyl).

P. Wessig et al. / Tetrahedron Letters 52 (2011) 4221–4223
4223
Cl
O
The unequivocal structural assignment of compounds 8 and 18
was possible by X-ray crystal structure analysis of 8a and 18a
(Fig. 1).16 These structures also clarify the reason for the different
stereoselectivity of 7 and 17. Whereas the dihydropyran-2-one
ring in 8a is puckered and adopts a half-chair conformation, the
dihydrofuran-2-one ring in 18a is nearly planar. Consequently,
the dihydropyran-2-one ring may exist in two different conforma-
tions depending on whether the chirality axis has P- or M-configu-
ration explaining the lack of asymmetric induction.
PMBO
O
Cl
O
Cl
Cl
14
Et3N, DMAP
77%
15
DDQ
CH2Cl2/H2O
70%
In summary, we reported on the dehydro-Diels–Alder (DDA)
reaction of two compounds (7, 17). We found that both the activa-
tion barrier and the stereoselectivity of the DDA reaction critically
depend on the linker X (see Scheme 1). Whereas compound 7 bear-
ing four atoms between the alkyne moieties required photochem-
ical activation and afforded only a 1:1 mixture of diastereomeric
products 8, compound 17 with a shorter linker spontaneously
underwent the DDA reaction with a remarkable diastereomeric ra-
tio of 5:1. To the best of our knowledge this is the first example of
an atropselective dehydro-Diels–Alder reaction.
O
HO
O
O
O
O
O
3-PPA
DCC
DMAP
Ph
16
17
36%
Acknowledgment
O
O
O
O
O
O
The financial support of this work by the Deutsche Forschungs-
gemeinschaft (We1850-5/1) is gratefully acknowledged.
Supplementary data
O
O
Supplementary data (detailed experimental procedures and
characterization data of compounds) associated with this article
can be found, in the online version, at doi:10.1016/
j.tetlet.2011.06.024.
18a
18b
5 : 1
Scheme 5. ADDA reaction to compounds 18a,b.
References and notes
too large to route the reaction preferably to the isomer 8a (cf.
Fig. 1).13
After this rather deflating result we postulated that decreasing
the ring size of the newly formed lactone ring from six to five in
the second system could resolve this problem.
The synthesis of the second system commences with a Sono-
gashira coupling between the chiral alkyne 914 and methyl 3-(2-
iodophenyl)-propanoate 2 giving compound 10. It should be noted
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closure to the macrocyclic lactone 15 (see Scheme 5) required a
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hydroxy group.
To achieve this goal we converted 10 in four steps consisting of
cleavage of the cyclohexylidene acetal, silylation of the primary hy-
droxy group of diol 11, PMB protection of the secondary hydroxy
group and desilylation of the primary hydroxy group to give 13.
Saponification of the ester group provided the h-hydroxycarboxylic
acid 14 (Scheme 4).
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the course of
a photochemical reaction has also been demonstrated: (a)
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Once again, we subjected 14 to the conditions of the Yamaguchi
macrolactonization and obtained the macrocyclic lactone 15 with
good yield. After oxidative cleavage of the PMB group we coupled
the alcohol 16 with 3-phenylpropiolic acid and expected the for-
mation of DDA reactant 17. To our surprise, we were unable to iso-
late compound 17 but directly obtained the DDA products 18 with
a diastereomeric ratio of 5:1, determined by NMR spectroscopy
(Scheme 5). The completely different behavior of 7 and the (hypo-
thetical) ester 17 can be explained by the different number of
atoms between the alkyne moieties. The reduction from four atoms
in 7 to three atoms in 17 dramatically decreases the activation bar-
rier of the thermal DDA reaction. This behavior is well known from
the Bergmann cyclization,15 the first step of which is also a C–C-
bond formation between two alkynes.
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in Scheme 3.
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16. Compound 8a crystallizes in the centrosymmetric space group P21/c so that
both enantiomers exist in the same crystal. Compound 18a crystallizes in the
chiral orthorhombic space group P212121 with C2 in the R configuration. For
details see the Supplementary data, Section 4.