Efficient rhodium-catalyzed conjugate addition of arylboronic acids to unsaturated furano esters for the highly stereoselective synthesis of four natural trisubstituted furanolignans

Article abstract of DOI:10.1002/ejoc.200900643

Four natural lignans, (±)-dihydrosesamin (1a), (±)- lariciresinol methyl ether (1b, (±)-sanshodiol methyl ether (1c) and (±)-acuminatin methyl ether (1d), were prepared stereoselectively in five steps from a 4-(arylmethylene)-2-methoxy-tetrahydrofuran der

Full text of DOI:10.1002/ejoc.200900643

SHORT COMMUNICATION
DOI: 10.1002/ejoc.200900643
Efficient Rhodium-Catalyzed Conjugate Addition of Arylboronic Acids to
Unsaturated Furano Esters for the Highly Stereoselective Synthesis of Four
Natural Trisubstituted Furanolignans
Aurélie Mondière,[a] Guillaume Pousse,[a] Didier Bouyssi,*[a] and Geneviève Balme*[a]
Dedicated to Professor Max Malacria on the occasion of his 60th birthday
Keywords: Lignans / Rhodium / Conjugate addition / Boronic acids / Microwave chemistry
Four natural lignans, (Ϯ)-dihydrosesamin (1a), (Ϯ)-lariciresi-
nol methyl ether (1b), (Ϯ)-sanshodiol methyl ether (1c) and
(Ϯ)-acuminatin methyl ether (1d), were prepared stereose-
lectively in five steps from a 4-(arylmethylene)-2-methoxy-
tetrahydrofuran derivative obtained by a MCR reaction. The
lective addition of a boronic acid (Hayashi–Miyaura reaction)
to a 4-ethoxycarbonyldihydrofuran, generating three contig-
uous stereogenic centers with an excellent diastereoselectiv-
ity.
(© Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim,
key step of this synthesis is the microwave-assisted stereose- Germany, 2009)
Consequently, significant efforts have been made towards
Introduction
the construction of this challenging class of compounds
containing three contiguous stereocenters. However, few
methods exist for the preparation of such compounds in a
highly stereoselective manner.[3]
We have recently succeeded in the syntheses of disubsti-
tuted furanolignans and lactone lignans based on an ef-
ficient palladium-catalyzed three-component synthesis of 4-
(arylmethylene)-2-methoxytetrahydrofuran derivatives that
we developed in our group.[4,5] In a further application of
this methodology, we present here a highly stereoselective
and efficient new access to 2,3,4-trisubstituted lignans 1a–
d.
Lignans are a large family of compounds widely found
among natural products.[1] Among them 2,3-trans-3,4-cis-
trisubstituted tetrahydrofuran lignans such as dihydrosesa-
min (1a), lariciresinol methyl ether (1b), sanshodiol methyl
ether (1c) and acuminatin methyl ether (1d) (Figure 1) are
of great interest due to their biological activities including
antitumor, antioxidant, analgesic and antiinflammatory
properties.[2]
Results and Discussion
Our retrosynthetic strategy, outlined in Scheme 1, in-
volves the conjugate addition of an organometallic aryl spe-
cies to the α,β-unsaturated ester 4. The Michael acceptor
4 may, in turn, be obtained by a tandem decarboxylation/
elimination performed on the diester 3, which has been pre-
pared previously in our laboratory.[5]
Figure 1. Four natural 2,3,4-trisubstituted lignans.
The key synthetic challenge in our planned approach is
the conjugate addition step, since three contiguous ste-
reocenters are generated in the course of the reaction and
thus, four possible diastereomeric compounds could be pro-
duced. It was anticipated that the desired stereogenic cen-
ters C-2 and C-4 would be controlled in this step, since the
conjugate addition should occur from the less hindered face
of the dihydrofuran (Scheme 2).
[a] ICBMS, Institut de Chimie et Biochimie Moléculaire et Supra-
moléculaire (UMR CNRS 5246) Université Lyon I, ESCPE
Lyon, Bât Curien,
43 Bd. du 11 novembre 1918, 69622 Villeurbanne, France
Fax: +33-4-72431214
E-mail: bouyssi@univ-lyon1.fr
balme@univ-lyon1.fr
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.200900643.
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4225

A. Mondière, G. Pousse, D. Bouyssi, G. Balme
SHORT COMMUNICATION
Scheme 1. Retrosynthetic analysis.
Scheme 2. Sterically directed conjugate addition of the arylmetal species.
However, whereas the conjugate addition of organome- 7a up to 62%, and unreacted starting material 6 was reco-
tallic reagents to unsaturated carbonyl compounds has been vered in 25% yield (Table 1, Entry 3). Pleasingly, the reac-
well described,[6] few examples of such reaction on 4- tion took place with a high degree of stereoselectivity
(ethoxycarbonyl)- or 4-carboxy-2,3-dihydrofurans are (trans/cis = 95:5) according to the analysis of 1H NMR
known, and in this particular case, the 1,4-addition of orga- spectra of the crude reaction mixture.[12] The 2,3-trans ste-
nometallic species such as Grignard reagents is often fol- reochemistry of the major isomer has been confirmed by
lowed by a ring opening of the heterocycle.[7] We thought X-ray crystallography.[13]
that one possibility of solving this problem was the use of
To shorten the long reaction times, the same conjugate
the rhodium-catalysed addition of organoboronic acids pi- addition was performed under microwave irradiation,[14]
oneered by Hayashi and Miyaura.[8] However, to the best and the best results (82% yield of the 1,4-addition product)
of our knowledge, the Rh-catalyzed conjugate addition to were obtained when the reaction was carried out at 150 °C
trisubstituted α,β-unsaturated ester derivatives has been rel- for 35 min in the presence of 2 equiv. of phenylboronic acid
atively unexplored.[9] Consequently, we decided to evaluate in dioxane/H2O (10:1) (Table 1, Entry 4). A decrease in the
the feasibility of this approach, and initial studies were con- amount of phenylboronic acid affected the yield signifi-
ducted on the readily available unsaturated furano ester 6 cantly (Table 1, Entry 5), and the use of phenylpotassium
as model compound.[10]
organotrifluoroborate salts as boron component resulted in
We first attempted the conjugate addition of phenylbo- lower yield[15] (Table 1, Entry 6).
ronic acid using the conditions reported by Miyaura.[11]
Using the optimized conditions, we further explored the
Thus, treatment of 6 with PhB(OH)2 (2 equiv.) in the pres- scope of this rhodium-catalyzed conjugate addition with a
ence of KOH as base (2 equiv.) and 5 mol-% of the rhodium variety of boronic acids. Some representative results are
catalyst generated from Rh(acac)(CO)2 and dppb in diox- shown in Scheme 3. The reaction generally proceeded in
ane/H2O (6:1) led to the formation of the expected addition good yields and with excellent diastereoselectivity with both
product 7a, but in rather low yields – even after heating at electron-rich and electron-deficient arylboronic acids. In
100 °C for 40 h (Table 1, Entry 1). The use of [RhCl(cod)]2/ some cases (7c–f), the conversion was not satisfactory, and
dppb in place of Rh(acac)(CO)2/dppb gave 7a only in 28% best yields were achieved when using Ba(OH)2 instead of
yield after heating at 100 °C for 24 h (Table 1, Entry 2). In- KOH as base.
creasing of the reaction time to 48 h improved the yield of
Table 1. Optimization of the addition reaction of phenylboronic acid to furan 6.
Entry
ArMet (equiv.)
Heating method, time
Catalyst system
Isolated yield of furan 7a
1
2
3
4
5
6
PhB(OH)2 (2)
PhB(OH)2 (2)
PhB(OH)2 (2)
PhB(OH)2 (2)
PhB(OH)2 (1.5)
PhBF3K (1.2)
thermal (100 °C), 40 h
thermal (100 °C), 24 h
thermal (100 °C), 48 h
microwaves (150 °C), 35 min
microwaves (150 °C), 35 min
microwaves (150 °C), 35 min
Rh(acac)(CO)2 (5 mol-%), dppb (5 mol-%), KOH 1 equiv.
[RhCl(cod)]2 (5 mol-%), dppb (5 mol-%), KOH (1 equiv.)
[RhCl(cod)]2 (5 mol-%), dppb (5 mol-%), KOH (1 equiv.)
[RhCl(cod)]2 (5 mol-%), dppb (5 mol-%), KOH (1 equiv.)
[RhCl(cod)]2 (5 mol-%), dppb (5 mol-%), KOH (1 equiv.)
[RhCl(cod)]2 (5 mol-%), dppb (5 mol-%), KOH (1 equiv.)
9%[a]
28%[a]
62%[a]
82%[b]
15%[b]
12%[b]
[a] Solvent dioxane/H2O (6:1). [b] Solvent dioxane/H2O (10:1).
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Natural Trisubstituted Furanolignans
(5 equiv.). These conditions were successfully applied to di-
ester 3b leading to 4b in 76% yield (Scheme 4).
With these results in hand, we examined the Rh-cata-
lyzed 1,4-addition of arylboronic acids 9a and 9b to unsatu-
rated esters 4a and 4b under optimum conditions as estab-
lished above, and the results of this study are listed in
Scheme 5. Gratifyingly, all the addition reactions gave rise
to only two products 10a–d and 11a–d, epimeric at the C-3
position, together with some recovered starting material,
and in excellent diastereoselectivity (diastereomeric ratio Ͼ
94:6). The major isomers 10a–d were isolated in comparable
yieds 57–59% (88–91% based on recovered starting mate-
rial 4a or 4b) by careful flash chromatography,[19] and the
structure assignments were unambiguously secured by sub-
sequent reduction of their ester group with LiAlH4 leading
to natural lignans 1a–d, respectively, in high yields
(Scheme 5).
Scheme 3. Rh-catalyzed 1,4-addition of several boronic acids to un-
saturated ester 6. [a] KOH, 150 °C. [b] Ba(OH)2·8H2O, 130 °C. [c]
1 h of irradiation.
We next turned our attention to the application of this
rhodium-catalyzed 1,4-addition to the cyclic unsaturated es-
ter 4a. The preparation of this product was envisaged by
demethoxycarbonylation of the known diester 3a followed
by elimination of the methoxy group. However, initial
attempts by using Krapcho’s conditions[16] (NaCl, DMSO,
130 °C) afforded a 1:1 mixture of two products in moderate
yields, the expected unsaturated ester 4a and the methoxy
ester 8a resulting from a subsequent conjugate addition of
lithium methoxide generated during the reaction.[17] After
several unsuccessful attempts to improve the yield of this
demethoxycarbonylation reaction including the use of dif-
ferent solvents (DMF, NMP, addition of H2O), temperature
Scheme 5. Stereoselective synthesis of lignans 1a–d. [a] based on
recovered 4a or 4b.
The 2,3-cis stereochemistry of the minor isomeric esters
(140–200 °C) and salts (NaCl, NaCN), it was found that was again established by the chemical shifts of the methyl
1
addition of TFA[18] avoided the formation of 8a. Neverthe- group in the H NMR spectrum.[12] To further confirm the
less, under optimum conditions (5 equiv. of LiCl, 5 equiv. structure of the minor isomers, a reduction of the crude
of TFA, DMSO, 130 °C) the yield of the tandem decarbox- mixture of esters 10a and 11a with LiAlH4 to the corre-
ylation/elimination product did not exceed 50% and was sponding alcohols 1a and 12a was carried out (Scheme 6).
difficult to reproduce. Consequently, we decided to opti- The NMR spectroscopic data (1H and 13C) for alcohol 12a
mize the tandem reaction under microwave conditions, and were compared with those of 2,3-trans-3,4-trans and 2,3-cis-
higher yields (79%) of 4a were obtained when the reaction 3,4-trans isomers of dihydrosesamin already reported in the
was carried out at a 0.05  concentration in NMP at 180 °C literature[20] and were found to be in accordance with those
for 5 min in the presence of LiCl (10 equiv.) and TFA given for the later 3-epidihydrosesamin.
Scheme 4. Preparation of unsaturated esters 4a–b by tandem decarboxylation/elimination.
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A. Mondière, G. Pousse, D. Bouyssi, G. Balme
SHORT COMMUNICATION
Scheme 6. Elucidation of the structure of the minor compound 11a.
Synthesis 2005, 2913–2919; H. Yoda, K. Kimura, K. Takabe,
Synlett 2001, 400–402.
Conclusions
[4]
S. Garçon, S. Vassiliou, M. Cavicchioli, B. Hartmann, N. Mon-
teiro, G. Balme, J. Org. Chem. 2001, 66, 4069–4073.
L. Ferrié, D. Bouyssi, G. Balme, Org. Lett. 2005, 7, 3143–3146.
P. Perlmutter, in Conjugate Addition Reactions in Organic Syn-
thesis, Pergamon Press, Oxford, 1992; A. Alexakis, in Transi-
tion Metals for Organic Synthesis, vol. 1 (Eds: M. Beller, C.
Bolm), Wiley-WCH, Weinheim, 1998, chapter 3.8.
J. M. Mellor, G. Reid, A. H. El-Sagheer, E.-S. H. El-Tamany,
Tetrahedron 2000, 56, 10039–10055.
a) First report: M. Sakai, H. Hayashi, N. Miyaura, Organome-
tallics 1997, 16, 4229–4231; For recent reviews, see: b) T. Haya-
shi, Synlett 2001, 879–887; c) K. Fagnou, M. Lautens, Chem.
Rev. 2003, 103, 169–196; d) T. Hayashi, K. Yamasaki, Chem.
Rev. 2003, 103, 2829–2844; e) T. Hayashi, Pure Appl. Chem.
2004, 76, 465–475; K. Yoshida, T. Hayashi in Boronic Acids
(Ed.: D. G. Hall), Wiley-VCH, Weinheim, 2005, pp. 171–201;
K. Yoshida, T. Hayashi in Modern Rhodium-Catalyzed Organic
Reactions (Ed.: P. A. Evans), Wiley-VCH, Weinheim, 2005, pp.
55–78; N. Miyaura, Bull. Chem. Soc. Jpn. 2008, 81, 1535–1553.
A low yield is generally observed for the Rh-catalyzed addition
of organoboronic acids to trisubstituted esters due to their ste-
ric hindrance, see: S. Sakuma, M. Sakai, R. Itooka, N. Mi-
yaura, J. Org. Chem. 2000, 65, 5951–5955.
Unsaturated furano ester 6 has been readily prepared from
commercially available 2,3-dihydrofuran according to slightly
modified literature procedures, see: B. M. Trost, J. M. Balko-
vec, M. K.-T. Mao, J. Am. Chem. Soc. 1986, 108, 4974–4983.
We have described a convergent and efficient total syn-
thesis of four members of a trisubstituted tetrahydrofuran
family of lignan natural products exploiting a three-compo-
nent coupling strategy developed in our group. The key step
involves a highly stereoselective rhodium-catalyzed addition
leading to the formation of three contiguous stereocenters.
Further development will be directed toward the enantiose-
lective synthesis of natural lignans through this strategy.
[5]
[6]
[7]
[8]
Experimental Section
General Procedure: 5 mol-% of rhodium complex [Rh(cod)Cl]2 and
5 mol-% of dppb in dioxane (1 mL) were dissolved in a microwave
vial. Then, water (0.1 mL), 1 equiv. of base, 1 equiv. of α,β-unsatu-
rated furan 6 and 2 equiv. of boronic acid were added successively.
The vial was capped and exposed to microwave heating at 150 °C
or 130 °C during the defined time. Time and temperature were de-
pending on the nature of the base: 150 °C for potassium hydroxide
and 130 °C for Ba(OH)2. We obtained a mixture of diastereoiso-
mers where the trans isomer is the major product. The mixture
was washed with water and extracted with dichloromethane. The
organic layers were dried with magnesium sulfate, filtered, and con-
centrated in vacuo. The crude product was purified by flash
chromatography on silica gel to obtain the desired product 7a–g.
[9]
[10]
[11]
[12]
R. Itooka, Y. Iguchi, N. Miyaura, J. Org. Chem. 2003, 68,
6000–6004.
Supporting Information (see also the footnote on the first page of
this article): Experimental procedures and characterization data for
4a–b, 7a–g and 10a–d, 1H and 13C NMR spectra for 4a–b, 7a–g,
10a–d, 1c, and 12a–1a.
1
The isomeric ratio was estimated by the integration in the H
NMR spectra of the respective methoxy proton signals, which
appeared upfield in the trans isomer in comparison with the
corresponding signals in the cis isomer due to the anisotropic
effect of the adjacent aryl group. Stereochemical assignments
of the two diastereomers may also be deduced by comparison
of NMR signals of related substrates, see: D. J. Aldous, A. S.
Batsanov, D. S. Yufit, A. J. Dalençon, W. M. Dutton, P. G.
Steel, Org. Biomol. Chem. 2006, 4, 2912–2927.
CCDC-731725, contains the supplementary crystallographic
data for this paper. These data can be obtained free of charge
from The Cambridge Crystallographic Data Centre via
www.ccdc.cam.ac.uk/data_request/cif.
a) P. S. Iyer, M. O’Malley, M. C. Lucas, Tetrahedron Lett. 2007,
48, 4413–4418; for some recent reviews and books on micro-
wave-assisted syntheses, see: b) P. Lidström, J. Tierney, B. Wa-
they, J. Westman, Tetrahedron 2001, 57, 9225–9283; c) Micro-
waves in Organic Synthesis (Ed.: A. Loupy), Wiley-VCH,
Weinheim, 2002; d) Microwave Assisted Organic Synthesis
(Eds.: J. P. Tierney, P. Lidström), Blackwell, Oxford, UK, 2005.
a) R. A. Batey, A. N. Thadani, D. V. Smil, Org. Lett. 1999, 1,
1683–1686; for reviews on organotrifluoroborate salts, see: b)
G. A. Molander, R. Figueroa, Aldrichim. Acta 2005, 38, 49–56;
c) S. Darses, J.-P. Genêt, Eur. J. Org. Chem. 2003, 4313–4327.
Acknowledgments
A. M. wishes to thank the Ministère de l’Education Nationale, de
la Recherche et de la Technologie for a fellowship. The authors also
thank the centre de diffractométrie Henri Longchambon (Uni-
versité Lyon 1) for X-ray data collection, structure solution and
refinement.
[13]
[14]
[1] a) W. D. MacRae, G. H. N. Towers, Phytochemistry 1984, 23,
1207–1220; b) D. A. Whiting, Nat. Prod. Rep. 1985, 2, 191–
211; D. A. Whiting, Nat. Prod. Rep. 1990, 7, 349–364; c) R. S.
Ward, Nat. Prod. Rep. 1995, 12, 183–205.
[2] D. C. Ayres, J. D. Loike, in Lignans: Chemical, Biological and
Clinical Properties, Cambridge University Press, Cambridge,
1990; O. R. Gottlieb, in New Natural Products and Plant Drugs
with Pharmacological, Biological or Therapeutical Activity,
Springer, Berlin, 1987, pp. 227–248; R. S. Ward, Nat. Prod.
Rep. 1999, 16, 75–96.
[15]
[16]
[3] D. R. Stevens, D. A. Whiting, J. Chem. Soc. Perkin Trans. 1
1992, 633–637; S. Yamauchi, T. Tanaka, Y. Kinoshita, J. Chem.
Soc. Perkin Trans. 1 2001, 2158–2160; B. Banerjee, S. C. Roy,
a) A. P. Krapcho, A. J. Lovely, Tetrahedron Lett. 1973, 14, 957–
960; b) A. P. Krapcho, Synthesis 1982, 805–822; A. P. Krapcho,
Synthesis 1982, 893–914.
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Natural Trisubstituted Furanolignans
[17] Y. M. Kim, T. W. Kwon, S. K. Chung, M. B. Smith, Synth. [20]
Commun. 1999, 29, 343–350.
[18] Selective formation of 4a is assumed to result from protonation
of the intermediate enolate by TFA followed by elimination of
methanol in acidic medium.
a) S. M. Miles, S. P. Marsden, R. J. Leatherbarrow, W. J.
Coates, J. Org. Chem. 2004, 69, 6874–6882.
Received: June 15, 2009
Published Online: July 17, 2009
[19] The use of additional quantities of rhodium catalyst, longer
reaction times or higher temperatures did not increase the iso-
lated yields of 10a–d.
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