New two-step sequence involving a hetero-Diels-Alder and a nonphenolic oxidative coupling reaction: A convergent access to analogs of steganacin

Article abstract of DOI:10.1016/j.tetlet.2011.01.097

A new family of analogs of steganacin, an important antimitotic compound, was accessed. It takes advantage of a completely stereoselective sequence of two key steps. The central dihydropyrane core is built by a highly diastereoselective and facially controlled hetero-Diels-Alder reaction. It is followed by a nonphenolic biaryl oxidative coupling with a complete atropo-stereoselectivity. It leads to a quick way to form cyclic biaryl lignans.

Full text of DOI:10.1016/j.tetlet.2011.01.097

Tetrahedron Letters 52 (2011) 1608–1611
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
New two-step sequence involving a hetero-Diels–Alder and a nonphenolic
oxidative coupling reaction: a convergent access to analogs of steganacin
⇑
Mathieu Y. Laurent , Vivien Stocker, Valéry Momo Temgoua, Gilles Dujardin, Robert Dhal
UMR 6011 CNRS-Université du Maine, Laboratoire de Synthèse Organique (UCO2M), Avenue Olivier Messiaen, 72085 Le Mans Cedex 9, France
a r t i c l e i n f o
a b s t r a c t
Article history:
A new family of analogs of steganacin, an important antimitotic compound, was accessed. It takes advan-
tage of a completely stereoselective sequence of two key steps. The central dihydropyrane core is built by
a highly diastereoselective and facially controlled hetero-Diels–Alder reaction. It is followed by a non-
phenolic biaryl oxidative coupling with a complete atropo-stereoselectivity. It leads to a quick way to
form cyclic biaryl lignans.
Received 14 September 2010
Revised 20 January 2011
Accepted 25 January 2011
Available online 1 February 2011
Ó 2011 Elsevier Ltd. All rights reserved.
Keywords:
Lignan
Steganacin
Hetero-Diels–Alder
Biaryl coupling
Atroposelectivity
Lignans form an important family of natural products with two
propylaryl subunits as a common scaffold, which are intercon-
nected in various ways.1 It shows diverse biological activity such
as anticancer, antiinflammatory, antimicrobial, or antioxidant
activities.2 As inhibitors of microtubules, some well-known exam-
ples are podophyllotoxin,3 steganacin,4 and the related structure
colchicine5 (Fig. 1). Closely related lignans such as etoposide have
anti-topoisomerase II activity (Fig. 1, R = glucose derivative).6
Other natural lignans have a close skeletal arrangement as exem-
plified by metasequirine B.7 Steganacin is a structure of particular
interest because of its structural specificity with a biaryl bridge
embedded in a cyclooctane ring.
In that context, methods to create new controlled stereocenters
with a formation of new carbon–carbon bonds and coupled with
atroposelective biaryl bond are still needed.8 In our laboratory,
we were involved in the development of a highly efficient het-
ero-Diels–Alder reaction in an inverse-electron demand cycloaddi-
tion.9,10 It works between a b,
c-unsaturated a-ketoester as the
electron-deficient heterodiene and a vinyl oxazolidinone as the
chiral electron-rich heterodienophile with complete endo and fa-
cial selectivities.
We report here the access to a new family of homolignans as
potential analogs of steganacin. They should display as a common
feature a cycloheptene substituted with two electron-rich aryl
moieties coupled to an oxacyclohexane ring. These molecules
could be obtained in an enantiomerically pure form by a sequence
Figure 1. Natural lignans or related compounds displaying antimitotic or anti-
topoisomerase II activities.
of two steps: a heterocycloaddition followed by a nonphenolic oxi-
dative coupling (Fig. 2).
Starting heterodienes 6a–c were synthesized in four steps
applying previous methods (Scheme 1).9e They were obtained in
28–30% yields starting from the corresponding aldehydes.
Compounds 11a–b were synthesized in three steps starting
from the corresponding cinnamic acids 7a–b. Aldehydes 9a–b were
obtained in 45–55% yields via a complete (Scheme 2) reduction of
cinnamic acid with LiAlH4 followed by oxidation into aldehyde.11
⇑
Corresponding author. Tel.: +33 2 43 83 33 42; fax: +33 2 43 83 39 02.
E-mail address: mathieu.laurent@univ-lemans.fr (M.Y. Laurent).
0040-4039/$ - see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2011.01.097

M. Y. Laurent et al. / Tetrahedron Letters 52 (2011) 1608–1611
1609
Scheme 2. Reagents and conditions: (a) LiAlH4, THF, 0 °C to rt, 18 h, 88–90%; (b)
PCC, CH2Cl2, 0 °C, 4 h, 55–57%; (c) oxazolidinone 10, PTSA, toluene, Dean–Stark, 3 h,
41–85%.
Figure 2. Retrosynthetic access to analogs of steganacin by a sequence of hetero-
Diels–Alder cycloaddition and oxidative biaryl coupling.
Scheme 3. Cycloaddition reaction.
Table 1
Cycloadducts 12a–f produced via Scheme 3
Entry
Heterodiene
Dienophile
Producta
Yieldb (%)
1
2
3
4
5
6
6a
6b
6c
6a
6b
6c
11a
11a
11a
11b
11b
11b
12a
12b
12c
12d
12e
12f
41
29
32
52
34
33
a
Compounds 12a–c were obtained in pure cyclohexane, compounds 12d–f were
obtained in a mixture cyclohexane/dichloromethane.
b
Isolated yields.
Scheme 1. Reagents and conditions: (a) CH(OMe)3, montmorillonite K10, MeOH,
40 °C, 18 h, 98–100%; (b) TMSCl, Et3N, Et2O, rt, 4 h, 59%; (c) BF3ꢀEt2O, CH2Cl2, ꢁ78 °C
to 0 °C, 2 h; (d) silica, toluene, reflux, 18 h, 29–30% (two steps).
Cycloadducts 12 were then submitted to the oxidative coupling.
Classical conditions involve thallium(III) oxide in a trifluoroacetic
acid medium in the presence of BF3-etherate (electrophilic assis-
tance).14 Different conditions were tested on 12a (Scheme 4, Table
2). Compound 13a was obtained by oxidation under classical con-
ditions (Table 2, entry 1). It shows on NMR spectra disappearance
of two aromatic protons confirming the formation of a biaryl bond.
Its stereochemistry could be assigned on the basis of the character-
istic NOE correlations (Fig. 3). Protons 4b, 8a, 8 on the dihydropy-
ran ring are in a double trans-diaxial relationship as confirmed by
coupling constants (J8–8a = 10.8 Hz and J8a–4b = 11.5 Hz) and by the
strong NOE effect between 4b and 8. This configuration was the re-
sult of the endo and facial selectivities of the hetero-Diels–Alder
cycloaddition. Moreover, proton 13 is close to proton 4b establish-
ing that they were both on the same side of the dihydropyran ring
(upward). This configuration of biaryl bond is the same than that of
natural steganacin.
Varying conditions to find a less toxic oxidative reagent led us
to test various oxidants. No reaction occurred in the presence of
ruthenium(II) oxide (entry 2) and copper(II) acetate (entry 3).
The prolonged reaction time in the case of the copper oxidant led
to degradation products (entry 4). More efficient results were ob-
tained with iron(III) chloride. Stoichiometric amount of iron salt
gave no conversion of the starting material (entry 5) but when
working in excess of reagent (entry 6) the reaction goes to comple-
Enamines 11a–b were then obtained directly in the presence of
(R)-ethyloxazolidinone 10 upon acid catalysis in refluxing toluene
with a Dean–Stark apparatus following the general procedure of
Davies et al.12 This procedure is found to be more straightforward
than our previous one.13 Compounds 11a–b were formed with a
controlled E configuration confirmed by a coupling constant be-
tween ethylenic protons of 14.3–14.5 Hz.
The cycloaddition reaction was conducted using the methodol-
ogy previously disclosed by our team10 to obtain the endo
a com-
pound with a high selectivity. It requires Eu(fod)3 as the catalyst of
the cycloaddition. It has been shown previously10 that the endo
cycloadduct with the opposite facial selectivity could be obtained
with the use of SnCl4 as the Lewis acid.
Compounds 12a–f were obtained in modest to good yields
(Scheme 3, Table 1). NMR analysis of the crude reaction mixture
displays a complete diastereoselectivity.
However, the reaction with 11b shows lower yields due to lack
of solubility. In pure cyclohexane, 11b, which is poorly soluble, was
sensitive to degradation. Cycloaddition was conducted in a mixture
of cyclohexane and dichloromethane. It does not affect the diaste-
reoselectivity of the reaction (compound endo 2R, 3R, 4S was the
only compound on NMR spectra of the crude reaction mixture).

1610
M. Y. Laurent et al. / Tetrahedron Letters 52 (2011) 1608–1611
Scheme 5. Biaryl oxidative coupling of 12a–f.
Table 3
Biaryl compounds 13a–f produced via Scheme 5
Entry
Conditionsa
Product
Yieldb (%)
1
2
3
4
5
6
A
A
A
B
B
B
13a
13b
13c
13d
13e
13f
62
36
70
32
49c
42d
Scheme 4. Biaryl oxidative coupling of 12a.
a
Method A: 0.5 equiv Tl2O3, 3 equiv TFAA, 15 equiv TFA, 2 equiv BF3ꢀEt2O, CH2Cl2,
Table 2
0 °C, 30 min; Method B: 2.5 equiv Mn(OAc)3ꢀ2H2O, 3 equiv TFAA, 15 equiv TFA,
2 equiv BF3ꢀEt2O, CH2Cl2, 0 °C, 30 min.
Biaryl oxidative coupling of 12a (Scheme 4)
b
Isolated yields.
36% of an unknown byproduct is formed.
12% of an unknown byproduct is formed.
Entry Conditionsa
Time
Product
Yieldb
(%)
c
d
1
2
3
4
5
6
7
8
9
0.5 equiv Tl2O3
1.5 equiv RuO2
2 equiv Cu(OAc)2
4 equiv Cu(OAc)2
2.5 equiv FeCl3
11 equiv FeCl3
11 equiv FeCl3
2.5 equiv Mn(OAc)3
1.2 equiv PhI(OTf)2
550
24 h
300
18 h
400
400
18 h
600
13a
—
—
—
—
13a
14
13a
13a
62
0c
0c
essential as byproduct 15 was formed in the reaction with no bor-
on trifluoride etherate (entries 10 and 11). This compound has an
oxazolidinone moiety and a dihydropyran core, which were both
clearly distinguished on the 1H NMR spectra. The disappearance
of one methoxy group and a supplementary characteristic dis-
placement of 176.5 ppm on the 13C NMR spectra attributed to a
quinone carbonyle suggest that 15 was the result of the deprotec-
tion of a methoxy group followed by phenolic oxidative coupling
forming a spiro compound.
0d
0c
28
31
48
49
2 h
300
10
11
0.5 equiv Tl2O3—without BF3ꢀEt2O
2.5 equiv Mn(OAc)3—without
BF3ꢀEt2O
500
13a + 15 38e 18f
13a + 15 32g 18f
300
Conditions were applied to the family of compounds 12. Oxida-
tive coupling products 13 were obtained in modest to good yields
(Scheme 5, Table 3). In all cases only one single diastereoisomer is
formed. The compounds 13a–f show homogeneous 1H and 13C
NMR signals (same displacements, same coupling constants) indi-
cating a close homogeneity in the conformation of the biaryl bond
stereochemistry.
a
All conditions included the presence of 3 equiv TFAA, 15 equiv TFA, 2.5 equiv
BF3ꢀEt2O (excepted when specified), CH2Cl2, 0 °C.
b
Isolated yields.
Starting material recovered.
Degradation products.
Crude NMR ratio 13a/15 77:23.
Isolated yield of 15.
Crude NMR ratio 13a/15 73:27.
c
d
e
f
g
In conclusion, we have validated in this work the sequence of
two key-step of a new pathway to lignan versatile precursors:
highly convergent C19-framework assembly via a hetero-Diels–Al-
der cycloaddition followed by a biaryl oxidative coupling. These two
steps occurred in a completely stereocontrolled manner. It leads to a
quick way to form cyclic biaryl lignans or pseudo-lignans.
Acknowledgments
We would acknowledge F. Legros for technical assistance, P.
Gangnery for recording HRMS and A. Durand for recording NMR
spectra.
Supplementary data
Figure 3. Key NOE correlations of compound 13a.
Supplementary data associated with this article can be found, in
the online version, at doi:10.1016/j.tetlet.2011.01.097.
tion within 40 min. However, under the prolonged reaction time,
in the presence of iron trichloride, compound 13a evolved to 14
as the sole product (entry 7) with the deprotection of the methyl-
enedioxy moiety. Manganese(III) acetate (entry 8) and phenyliod-
onium bis(trifluoroacetate)15 (entry 9) were shown to be more
efficient oxidants leading to 13a in an isolated yield in the range
of 48–49%. The use of boron trifluoride etherate was shown to be
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