E-selective isomerization of stilbenes and stilbenoids through reversible hydroboration

Article abstract of DOI:10.1016/j.tetlet.2011.09.046

Hydroboration of a mixture of E and Z stilbenes and stilbenoids is followed by an elimination reaction to yield the E isomer with high stereoselectivity. The reaction tolerates aromatic substituents with varying stereoelectronic properties, occurs in one pot, and requires only commercially available reagents. An illustration of the isomerization reaction in a synthesis of resveratrol, a biologically active antioxidant, is presented.

Full text of DOI:10.1016/j.tetlet.2011.09.046

Tetrahedron Letters 52 (2011) 6177–6179
Contents lists available at SciVerse ScienceDirect
Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
E-selective isomerization of stilbenes and stilbenoids through reversible
hydroboration
⇑
Erin E. Gray, Lake E. Rabenold, Brian C. Goess
Furman University, Department of Chemistry, 3300 Poinsett Highway, Greenville, SC 29613, USA
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 28 July 2011
Revised 8 September 2011
Accepted 11 September 2011
Available online 16 September 2011
Hydroboration of a mixture of E and Z stilbenes and stilbenoids is followed by an elimination reaction to
yield the E isomer with high stereoselectivity. The reaction tolerates aromatic substituents with varying
stereoelectronic properties, occurs in one pot, and requires only commercially available reagents. An
illustration of the isomerization reaction in a synthesis of resveratrol, a biologically active antioxidant,
is presented.
Ó 2011 Elsevier Ltd. All rights reserved.
Keywords:
Stilbene
Hydroboration
Isomerization
Oxidation
Resveratrol
Stilbenes and their substituted derivatives, stilbenoids, have at-
tracted significant attention for their wide range of useful proper-
ties, which include applications in optics, biochemistry, and
chemotherapy (Fig. 1).1 Generally the two alkene stereoisomers
of a particular E/Z stilbenoid pair exhibit meaningfully different
physiochemical properties. Accordingly, methods for their stereo-
selective chemical synthesis and derivatization have been inten-
sively investigated, along with strategies for the interconversion
of the E and Z stereoisomers.
production of the less stable Z isomer makes photoisomerization
a powerful strategy for the stereoselective stilbenoid synthesis.
Radical-based isomerization methods, such as treatment with
diaryldiselenides,5 iodine,6 or N-bromosuccinimide7 (NBS) offer
good E selectivity, but each method has limitations. For example,
stilbenoids with electron-donating substituents sometimes suffer
from competitive iodination of the aromatic rings when iodine is
used as a catalyst.5 Similarly, aromatic bromination was experi-
enced with an NBS-dibenzoylperoxide-azobisisobutyronitrile
system.7 Selenide catalysis sometimes fails when strongly
electron-withdrawing substituents are present.5
Recently, mild and practical palladium-catalyzed methods have
been developed, but these reactions are not effective when elec-
tron-withdrawing substituents are present.8 Collectively, these
examples illustrate that additional methods for stilbenoid isomer-
ization are still needed.
We envisioned a one-pot, E-selective stilbenoid isomerization
sequence that takes advantage of the reversibility of hydroboration
in the presence of strongly oxidizing electrophiles (Scheme 1). A
mixture of E and Z stilbene isomers would undergo syn addition
of 9-BBN to yield a trialkylborane. The mechanistic reverse of this
addition, a syn elimination, must then occur from an eclipsed con-
former, which would magnify the destabilizing effects of steric
interactions on the conformational equilibrium. Syn elimination
of 9-BBN with the powerful oxidant 2-methyl-2-nitrosopropane
(MNP) from the least crowded eclipsed conformer should then
regenerate the stilbenoid with high E stereoselectivity.9 Elimina-
tion on the borane reagent itself is precluded with 9-BBN as it
would lead to the generation of a bridgehead alkene, making
The most widely utilized strategy for stilbenoid synthesis1,2 is
the Wittig reaction along with its more modern variants, especially
the Horner–Wadsworth–Emmons reaction. A mixture of E and Z
stereoisomers is generally formed, though optimization of condi-
tions can lead to highly selective formation of the E stereoisomer.3
Comparatively fewer methods have been developed for the
selective production of the more thermodynamically stable E stilb-
enoid stereoisomers via isomerization of E/Z mixtures. The most
extensively studied method for the interconversion of the E and
Z stilbenoid stereoisomers is photoisomerization,4 and conditions
for both the Z-to-E and E-to-Z isomerizations have been developed
for a wide range of stilbenoids. Competing photocyclization reac-
tions2a,4 are often observed, and E:Z ratios are generally quite
sensitive to specific conditions, including the substituents on the
substrate, solvent, and nature of additives such as sensitizers and
quenchers. Nonetheless, the ability to tune conditions to favor
⇑
Corresponding author. Tel.: +1 864 294 2318; fax: +1 864 295 3559.
E-mail address: brian.goess@furman.edu (B.C. Goess).
0040-4039/$ - see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2011.09.046

6178
E. E. Gray et al. / Tetrahedron Letters 52 (2011) 6177–6179
N(CH3)2
1) 9-BBN•THF
20 min., µwave, 150 o
2) NaOH, H2O2, H2O
C
HO
OH
R1
OH
OH
OCH3
+
R1
R1
H3CO
OCH3
OH
OCH3
OH
NO2
R1 = H ; 91%
= 2,5-dimethyl ; 86%
= 3,5-dimethoxy ; 81%
= 3-bromo ; 79%
resveratrol
an antioxidant used in fluorescence a tubulin polymerization
spectroscopy inhibitor
DANS
combretastatin A4
Figure 1. Three stilbenoids with useful chemical properties.
Scheme 3. Microwave-assisted hydroboration–oxidation of various stilbenoids.
Yields are of the isolated mixtures of alcohol regioisomers.
t
Bu
N
O
1) 9-BBN•THF
20 min., µwave
B(Alk)2
B(Alk)2
H
H
Ar
Ar
9-BBN
MNP
R2
R2
150 oC
H
H
Ar
H
Ar
Ar
Ar
R1
R1
Ar
Ar
2) MNP, THF
H
unfavorable
sterics
syn-periplanar
elimination
E:Z
R1
R2
Entry
E:Z
% Yield
Scheme 1. Rationale for
route to E stilbenes.
a stereoselective, one-pot, hydroboration–elimination
50:50
50:50
54:46
41:59
52:48
H
H
H
H
H
1
2
3
4
5
6
7
99:1
97:3
98:2
99:1
97:3
95:5
97:3
75
73
69
46
69
75
67
2,5-diCH3
2-CF3
3-Br
2,5-diCH3
4-OCH3
4-OCH3
4-OCH3
1) 9-BBN•THF
15 min., µwave
2) MNP, THF
58:42 3,5-diOCH3
53:47
2-CF3
Scheme 4. Microwave-assisted hydroboration–elimination of various stilbenoids.
E/Z ratios were determined by integration of appropriate peaks in the correspond-
ing 1H NMR.
T
cis : trans
75 oC
0.63 : 1.0
0.14 : 1.0
0.01 : 1.0
< 0.01 : 1.0
100 oC
125 o
150 o
C
C
substrates, indicating that the hydroboration reaction is effective
on stilbenoids bearing common aromatic substituents with varying
steric and electronic properties. A mixture of alcohol regioisomers
was obtained in every case, indicating hydroboration is not regio-
selective. Yields are comparable to those obtained via a rhodium-
catalyzed hydroboration–oxidation of stilbenoids with boronate
esters.10
Scheme 2. Isomerization of cis-stilbene at various temperatures under microwave
irradiation at 300 W for 15 min. Ratios were determined by integration of
appropriate peaks in the crude product 1H NMR.
9-BBN
a particularly good choice of dialkylborane for this
methodology.
We then subjected a similar range of substrates to the isomer-
ization sequence and observed very high levels of E selectivity
(Scheme 4).14 The isomerization is tolerant of both electron-
donating and electron-withdrawing substituents at various posi-
tions on the aromatic rings. The lower yields of the isomerizations
relative to the oxidations (Scheme 3) indicate that the elimination
step proceeds less efficiently than the corresponding oxidation
step. We did not evaluate the substituents that are reduced in
the presence of dialkylboranes15 because a nitro group, which is
relatively stable to dialkylboranes at lower temperatures, was
competitively reduced to an amine at the elevated temperatures
used in this study. A stilbenoid that was brominated in the meta
position (entry 4) also isomerized with high E stereoselectivity
but with an unusually low isolated yield.
To illustrate a complete synthesis route that utilizes this meth-
odology we prepared resveratrol, which has generated significant
interest in the synthesis community given its intriguing biological
activity.16 Given the high E selectivity of our isomerization reac-
tion, we were able to utilize a mild, practical, and high-yielding
Wittig reaction17 despite its low inherent stereoselectivity
(Scheme 5). Our isomerization reaction then yields (E)-trimethoxy-
resveratrol in 75% isolated yield. Boron trichloride-mediated
deprotection of the methyl ethers produces resveratrol in 85%
yield.18
Execution of this strategy requires the development of an effi-
cient stilbenoid hydroboration reaction with 9-BBN. Though hyd-
roboration of stilbenes with boronic esters has been explored,10
the resulting boronate ester intermediate is much less electrophilic
than a trialkylborane and would not be expected to undergo facile
elimination in the presence of MNP. We therefore chose to first
investigate the hydroboration of a model system, cis-stilbene, with
9-BBN. Hydroboration of cis-stilbene with 9-BBN in THF at room
temperature and at reflux was sluggish.11 Considering that both
9-BBN and trialkylboranes decompose readily on exposure to air
and moisture,12 we felt accelerating the reaction time by heating
the reagents in a sealed vessel at temperatures above the boiling
point of THF would be advantageous. Accordingly, we investigated
the extent of isomerization of cis-stilbene at various temperatures
after 15 min of microwave irradiation using our two-step proce-
dure (Scheme 2). At 75 °C, the isomerization was 61% complete,
whereas at 125 °C the isomerization was essentially complete.
No isomerization of cis-stilbene was observed after irradiation for
15 min at 150 °C in the absence of 9-BBN.
To verify the effectiveness of the hydroboration step itself, we
next subjected E/Z stilbenoid mixtures to hydroboration followed
by a standard peroxide-mediated oxidation (Scheme 3).13 Product
alcohols were obtained in good yields on a variety of stilbenoid

E. E. Gray et al. / Tetrahedron Letters 52 (2011) 6177–6179
6179
of an example E/Z stilbenoid starting mixture and crude isomeriza-
tion product from Scheme 4) associated with this article can be
found, in the online version, at doi:10.1016/j.tetlet.2011.09.046.
H
O
Br
PPh3Br
LiOH•H2O
PPh3
toluene
iPrOH
+
110 oC
99 %
H3CO
OCH3
60 o
99 %
C
References and notes
OCH3
OCH3
OCH3
1. Likhtenshtein, G. Stilbenes; Wiley-VCH: Weinheim, 2010.
1) 9-BBN•THF
µwave, 150oC
2) tBuNO, THF
H3CO
2. (a) Becker, K. Synthesis 1983, 5, 341–368; (b) Ferré-Filmon, K.; Delaude, L.;
Demonceau, A.; Noels, A. F. Coord. Chem. Rev. 2004, 248, 2323–2336.
3. (a) Lion, C. J.; Matthews, C. S.; Stevens, M. F. G.; Westwell, A. D. J. Med. Chem.
2005, 48, 1292–1295; (b) Heynekamp, J. J.; Weber, W. M.; Hunsaker, L. A.;
Gonzales, A. M.; Orlando, R. A.; Deck, L. M.; Vander Jagt, D. L. J. Med. Chem. 2006,
49, 7182–7189.
4. Görner, H.; Kuhn, H. J. In Advances in Photochemistry; Neckers, D. C., Volman, D.
H., von Bünau, G., Eds.; John Wiley & Sons: New York, 1995; Vol. 19, pp 1–118.
5. Ali, M. A.; Tsuda, Y. Chem. Pharm. Bull. 1992, 40, 2842–2844.
6. (a) Alonso, F.; Riente, P.; Yus, M. Tetrahedron Lett. 2009, 50, 3070–3073; (b)
Zhang, W.; Go, M. L. Eur. J. Med. Chem. 2007, 42, 841–850.
75 %
H3CO
H3CO
58:42 E:Z
95:5 E:Z
BCl3
nBu4I
HO
HO
CH2Cl2
OCH3
OH
7. Baag, M. M.; Kar, A.; Argade, N. P. Tetrahedron 2003, 59, 6489–6492.
8. (a) Yu, J.; Gaunt, M. J.; Spencer, J. B. J. Org. Chem. 2002, 67, 4627–4629; Another
example demonstrated on cis-stilbene only: (b) Kim, I. S.; Dong, R. D.; Jung, Y.
H. J. Org. Chem. 2007, 72, 5424–5426.
0 o
85 %
C
H3CO
resveratrol
9. Midland, M. M.; Zderic, S. A. J. Am. Chem. Soc. 1982, 104, 525–528.
10. (a) Black, A.; Brown, J. M.; Pichon, C. Chem. Commun. 2005, 5284–5286; Simple
hydroboration with diborane is also known: (b) Brown, H. C.; Subba Rao, B. C. J.
Am. Chem. Soc. 1959, 81, 6428–6434.
11. The hydroboration was approximately 36% complete after 90 min in refluxing
THF.
Scheme 5. Illustration of a typical E stilbenoid synthesis sequence.
In sum, we have developed a new method for the hydroboration
of stilbenes with 9-BBN and have applied this reaction to stereose-
lectively generate E stilbenoid stereoisomers from E/Z mixtures.
While this methodology is not tolerant of functional groups that
are reduced in the presence of dialkylboranes, it is tolerant of both
electron-donating and electron-withdrawing substituents at vari-
ous positions on the aromatic rings and does not suffer from aro-
matic substitution side reactions, making it complementary to
the existing strategies for stilbenoid isomerization.
12. Brown, H. C.; Midland, M. M.; Kabalka, G. W. J. Am. Chem. Soc. 1971, 93, 1024–
1025.
13. Typical procedure: To 1 equiv of substrate E/Z mixture in a microwave vial
under a positive pressure of Ar was added 9-BBN (0.5 M in THF, 1.1 equiv). The
vial was subjected to microwave irradiation (300 W, 20 min.) and then cooled
to room temperature. NaOH (1.5 M in H2O, 2.9 equiv) was added, the solution
was cooled to 0 °C, and H2O2 (30% in H2O, 8.2 equiv) was added dropwise. The
resulting solution was stirred for 30 min at 0 °C. Extractive work-up (Et2O Â 3),
followed by drying of the combined organic layers with MgSO4 and
concentration yielded the crude alcohols. Purification was accomplished via
column chromatography on silica gel.
Acknowledgments
14. Typical procedure: To 1 equiv of substrate E/Z mixture in a microwave vial
under a positive pressure of Ar was added 9-BBN (0.5 M in THF, 1.1 equiv). The
vial was subjected to microwave irradiation (300 W, 20 min) and then cooled
to room temperature. MNP dimer (0.6 equiv) dissolved in THF was added, and
this solution was stirred for 90 min. The bright clue color of the MNP solution
disappeared during this period, at which point the solvent was evaporated to
Financial support from the Arnold and Mabel Beckman Founda-
tion (E.G.), the Howard Hughes Medical Institute Undergraduate
Science Education Program (L.R.) and the Petroleum Research Fund
(#50719-UR1) of the American Chemical Society is gratefully
acknowledged.
yield the crude
E stilbenoids. Purification was accomplished via column
chromatography on silica gel.
15. Brown, H. C.; Krishnamurthy, S.; Yoon, N. M. J. Org. Chem. 1976, 41, 1778–1791.
16. Fan, E.; Zhang, K.; Zhu, M.; Wang, Q. Mini-Rev. Org. Chem. 2010, 7, 272–281.
17. Antonioletti, R.; Bonadies, F.; Ciammaichella, A.; Viglianti, A. Tetrahedron 2008,
64, 4644–4648.
Supplementary data
Supplementary data (1H NMR, 13C NMR, IR, and HRMS spectra
are provided for all new compounds, along with 1H NMR spectra
18. Jeffery, T.; Ferber, B. Tetrahedron Lett. 2003, 44, 193–197.