Total synthesis of honokiol by selective samarium-mediated allylic benzoate reduction

Article abstract of DOI:10.1016/j.tetlet.2016.06.066

The total synthesis of the biologically relevant compound honokiol has been completed featuring a samarium-mediated bis-benzoyl ester reduction to simultaneously install both allyl substituents found in the natural product. This reaction was performed after a Suzuki coupling was used to generate the biphenyl core, thereby avoiding problems associated with the acidity of these allyl groups and their propensity to isomerize. In this way, the synthesis of honokiol could be completed in 4 steps and 42% overall yield.

Full text of DOI:10.1016/j.tetlet.2016.06.066

Tetrahedron Letters 57 (2016) 3441–3443
Contents lists available at ScienceDirect
Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Total synthesis of honokiol by selective samarium-mediated allylic
benzoate reduction
⇑
Alicia M. Wright, Gregory W. O’Neil
Department of Chemistry, Western Washington University, Bellingham, WA 98225, USA
a r t i c l e i n f o
a b s t r a c t
Article history:
The total synthesis of the biologically relevant compound honokiol has been completed featuring a
samarium-mediated bis-benzoyl ester reduction to simultaneously install both allyl substituents found
in the natural product. This reaction was performed after a Suzuki coupling was used to generate the
biphenyl core, thereby avoiding problems associated with the acidity of these allyl groups and their
propensity to isomerize. In this way, the synthesis of honokiol could be completed in 4 steps and 42%
overall yield.
Received 23 May 2016
Revised 11 June 2016
Accepted 14 June 2016
Available online 16 June 2016
Keywords:
Honokiol
Ó 2016 Elsevier Ltd. All rights reserved.
Total synthesis
Samarium
Reduction
Allylbenzene
Honokiol (1) is a neolignan contained in the bark of Magnolia
officinalis that continues to elicit significant interest due to its
synthesis of honokiol, ultimately using our samarium chemistry
to incorporate both allyl groups simultaneously. The synthesis
could be accomplished in 4 steps and 42% overall yield.
Previously, we had reported that commercial aldehydes 10 and
11 could be converted to 8 and 9 via allylic benzoates 12 and 13 by
samarium-mediated benzoyl ester reduction (Scheme 2).8 With
water as the proton source, 8 and 9 were obtained in 60% and
76% yield respectively, with only marginal selectivity for the
1
range of promising biological activities including both antitumor
2
and anti-angiogenic properties (Fig. 1). Isolation of honokiol from
the natural source is hampered by the presence of its isomeric
compound magnolol (2).3 The different bioactivities of magnolol
yet very similar physical properties to honokiol makes separation
both necessary and challenging.5 Thus several groups have pur-
4
6
6a
sued a total synthesis of honokiol, the first by Takeya et al. in
986 and more recently Harada et al. in 2014.6h Many of these
syntheses have utilized an aromatic Claisen rearrangement
non-conjugated
(c) versus the conjugated (a) isomer (c:
1
a = 85:15 for 8 and 65:35 for 9, Scheme 2). After some experimen-
9
tation it was found that by switching to methanol as the additive,
6
a,c–f
(Fig. 1).
This reaction is however limited in terms of
both the yields and selectivities for these reactions greatly
regiochemistry, used primarily to generate ortho-allyl substituted
phenols. For instance Reddy et al. reported obtaining roughly
improved, affording 8 and 9 in P90% yield and >10:1 selectivity
7
for the c-isomer. Hasegawa has reported that samarium diiodide
10
1
:1 mixtures of honokiol (1) and isohonokiol (3) from the bis-O-
is less stable with water than methanol in tetrahydrofuran, gen-
erating Lewis acidic Sm(III) that may explain in part the improve-
ments afforded by methanol. Efforts are ongoing to better
understand the effects of additives and proton sources in these
reactions.
6
f
allylbiphenyl 4.
Recently, our group reported a general approach to non-conju-
gated olefins of this type by samarium-mediated benzoyl ester
elimination/isomerization.8 The reaction is proposed to occur via
an organosamarium intermediate of type 5, accessible via allylic
benzoates 6 or 7 (Scheme 1). Internal delivery of a proton from a
coordinated proton donor (e.g., water) then leads selectively to
non-conjugated products as the major isomer. We then demon-
strated that this reaction could be used to synthesize two properly
functionalized allyl-substituted benzenes 8 and 9 en route to a
synthesis of honokiol. Herein we report a completion of the
With improved access to compounds 8 and 9, we then began
our investigations into their coupling to form the biphenyl core
of honokiol. Initial experiments involved conversion of 8 or 9 into
their corresponding organometallic compounds (Mg, Zn, Li) and
subsequent palladium catalyzed cross-coupling (Scheme 3).1
Unfortunately none of these reactions produced appreciable
amounts of the desired cross-coupled product 14 as detectable
by NMR or GC–MS. We surmised that the failure of these reactions
1,12
1
3
⇑
Corresponding author. Tel.: +1 360 650 6283; fax: +1 360 650 2826.
E-mail address: oneilg@wwu.edu (G.W. O’Neil).
could be blamed on the acidic benzylic/allylic protons (pK
a
ꢀ33)
that were interfering with the metal–halogen exchange. This was
http://dx.doi.org/10.1016/j.tetlet.2016.06.066
040-4039/Ó 2016 Elsevier Ltd. All rights reserved.
0

3
442
A. M. Wright, G. W. O’Neil / Tetrahedron Letters 57 (2016) 3441–3443
X
Y
X = H, Y = OH; honokiol (1)
X = OH, Y = H; magnolol (2)
OMe
HO
0
[M]
or
OMe
Mg or
8
or 9
tBuLi
then ZnCl )
2
OH
[M]
OH
(
R1
tBuLi (2.2 eq)
then D
[M] = Mg, Li, or Zn
2
O
Pd0,
8 or 9
O
Δ or MW
ref. 6f
1:3 = 40:55 to 60:40
O
2
R
R
R
1
1
= H, R2 = allyl; 1
OMe
D
OMe
OMe
2
4
= allyl, R = H; 3
Figure 1. Natural products honokiol (1) and magnolol (2) and previous Claisen
rearrangement-based synthesis.
14
not observed
Scheme 3. Attempted cross-coupling of compounds 8 and 9.
OBz
OBz
SmI
2
or
H
2
O
OMe
6
7
OMe
Z
Z
B pin , Pd(OAc)
2
Bpin
or
2
2
H
O
8
o r 9
SmIII
H
SmLn
NaOAc, K CO
Bpin
2
3
1
3
3
Ar
Ar
5
X
major
OH
Δ1,2 + Δ2,3
preferred
1
OMe
OH
Br
OMe
Scheme 4. Allylic isomerization during conversion of 8 and 9 to their correspond-
ing boronate esters.
+
Br
8
honokiol
9
Br
O
B
Scheme 1. Synthesis of allylbenzenes by samarium-mediated benzoyl ester
elimination/isomerization and application to honokiol from products 8 and 9.
B
2
pin
2
O
MeO
CHO
Pd(dppf)Cl
KOAc
2
,
MeO
MeO
1
5
11
CHO
OMe
CHO
OMe
with or without
Br
Br SmI2
ROH
MgBr
isolation
8
MeO
Br
then BzCl
quant.
10
12
OBz
R = H, γ/α = 85:15, (60%)
R = Me, γ/α = 95:5, (94%)
CHO
CHO
1
0
16
MeO
aq. Na
Pd( Bu
2
CO
P)
3
,
75-100%
OMe
CHO
OMe
t
CHO
(multi-gramscale)
3
2
MgBr
SmI
2
9
Br
Br
then BzCl
Scheme 5. Suzuki coupling-based synthesis of dialdehyde 16.
ROH
11
13
OBz
(
98%)
R = H, γ/α = 65:35, (76%)
R = Me, γ/α = 91:9, (90%)
cross-coupling of aldehydes 10 and 11. Boronate ester formation
from 11 proved higher yielding than from 10 under the same con-
ditions, presumably as a result of increased sterics from the
neighboring methoxy group (Scheme 5). We therefore focused on
finding suitable conditions for the coupling of bromide 10 with
boronate ester 15. Ultimately the use of bis(tri-tert-butylphos-
1
5
Scheme 2. Optimized synthesis of honokiol fragments 8 and 9 by samarium
benzoyl ester reduction.
further supported by a deuterium labeling experiment performed
on compound 9. Treatment of 9 with BuLi (2.2 equiv) and quench-
t
2 3
phine)palladium as catalyst and aq Na CO as base in dioxane at
ing with D
observed at the benzylic position by H NMR.
We therefore turned our attention to a Suzuki coupling since
the requisite boronate esters could be prepared and isolated under
2
O afforded a mixture of compounds with labeling
70 °C proved optimal, giving the dialdehyde 16 in excellent yield.
1
This cross-coupling could be performed with or without isolation
t
of the boronate ester 15 (i.e., adding 10 and Pd( Bu
3
P)
2
directly
to the flask in which 15 was formed) and on multi-gram scale in
consistently high yields.
Conversion of 16 to the bis-benzoylester could be performed in
a single step by vinyl Grignard addition and trapping with benzoyl
chloride (Scheme 6), although we generally opted to isolate the
intermediate diol 17 for easier purification. Acylation of 17 with
14
more mild palladium catalysis. However under the conditions
1
5
tried, we found that conversion of 8 and 9 to their corresponding
boronate esters was accompanied by some alkene isomerization
(Scheme 4). The sensitivity of these allyl groups toward isomeriza-
6c
6d
tion had also been described by both Chen and Denton in their
syntheses of honokiol, requiring the somewhat specialized S-Phos
ligand for their cross-couplings.
2
benzoyl chloride followed by treatment with SmI /MeOH resulted
in very clean reduction of both benzoyl esters, giving dimethyl-
In an attempt to avoid the problems encountered with the
allyls, a new synthesis was devised whereby these groups would
be installed at a later stage. More specifically, we envisioned
inverting the samarium and palladium steps, forming the biphenyl
core first followed by benzoyl ester synthesis and bis-samarium
reduction. To that end, we began by investigating the Suzuki
honokiol (18) in 98% yield and >10:1 selectivity for both non-
conjugated allyls by H NMR analysis. It is worth noting the ability
1
of this samarium procedure to generate sensitive olefins that
are prone to isomerization under conditions like palladium
6
c,d
catalysis,
as yet another example of the utility of samarium
1
6
diiodide for organic synthesis. At this point we had bisected

A. M. Wright, G. W. O’Neil / Tetrahedron Letters 57 (2016) 3441–3443
3443
OMe
OH
can be found, in the online version, at http://dx.doi.org/10.1016/j.
tetlet.2016.06.066.
OMe
MgBr
71%)
1. BzCl, pyr.
16
(
17
2. SmI , MeOH
References and notes
2
(
98%)
OH
1. (a) Li, L.; Han, W.; Gu, Y.; Qiu, S.; Lu, Q.; Jin, J.; Luo, J.; Hu, X. Cancer Res. 2007,
6
7. 4985-4903; (b) Pan, H.-C.; Lai, D.-W.; Lan, K.-H.; Shen, C.-C.; Wu, S. M.; Chiu,
OMe
OMe
C.-S.; Wang, K.-B.; Sheu, M.-L. Carcinogenesis 2013, 34, 2568–2579; (c) Kim, G.
D.; Oh, J.; Park, H.-J.; Bae, K.; Lee, S. K. Int. J. Oncol. 2013, 43, 600–610.
(a) Bai, X.; Cerimele, F.; Ushiko-Fukai, M.; Waqas, M.; Campbell, P. M.;
Govindarajan, B.; Der, C. J.; Battle, T.; Frank, D. A.; Ye, K.; Murad, E.; Dubiel, W.;
Soff, G.; Arbiser, J. L. J. Biol. Chem. 2003, 278, 3551–3557; (b) Fried, L. E.; Arbiser,
J. L. Antioxid. Redox Signaling 2009, 11, 1139–1148; (c) Ma, L.; Chen, J.; Wang, X.;
Liang, X.; Luo, Y.; Zhu, W.; Wang, T.; Peng, M.; Li, S.; Jie, S.; Peng, A.; Wei, Y.;
Chen, L. J. Med. Chem. 2011, 54, 6469–6481.
6 5 3 3
B(C F ) , Et SiH
honokiol (1)
2
.
then TBAF
61%)
1
8
(
Scheme 6. Completion of the synthesis of honokiol.
3
.
.
Lee, Y. J.; Lee, Y. M.; Lee, C. K.; Jung, J. K.; Han, S. B.; Hogn, J. T. Pharmacol. Ther.
2011, 130, 157–176.
Amorati, R.; Zotova, J.; Baschieri, A.; Valgimigli, L. J. Org. Chem. 2015, 80, 10651–
the synthesis of Srinivas,6g however as opposed to AlCl
reported for the demethylation of 18, our best yields were obtained
using the tris(pentafluorophenyl)borane/Et SiH system introduced
by Gevorgyan et al. In this way, the synthesis of honokiol was
completed in 42% overall yield from commercial aldehydes 10
and 11.
In sum, a novel total synthesis of the medicinally important
compound honokiol has been completed featuring a samarium-
mediated bis-benzoyl ester reduction to simultaneously install
both allyl substituents found in the natural product. By incorporat-
ing these groups at a later stage, we were able to avoid problems
associated with allylic deprotonation or isomerization observed
under palladium catalyzed cross-coupling conditions. It is
anticipated that this sequence may be scaled up to make larger
quantities of honokiol available for further biological testing
3
/DMS they
4
10659.
3
5. (a) Slanina, J.; Glatz, Z. J. Chromatogr., B 2004, 812, 215–229; (b) Wang, X.;
Wang, Y.; Geng, Y.; Li, F.; Zheng, C. J. Chromatogr., A 2004, 1036, 1061–1067; (c)
Amblard, F.; Delinsky, D.; Arbiser, J. L.; Schinazi, R. F. J. Med. Chem. 2006, 49,
1
7
3426–3427.
6. (a) Takeya, T.; Okubo, T.; Tobinaga, S. Chem. Pharm. Bull. 1986, 34, 2066–2075;
(b) Esumi, T.; Makado, G.; Zhai, H.; Shimizu, Y.; Mitsumoto, Y.; Fukuyama, Y.
Bioorg. Med. Chem. Lett. 2004, 14, 2621–2625; (c) Chen, C.-M.; Liu, Y.-C.
Tetrahedron Lett. 2009, 50, 1151–1152; (d) Denton, R. M.; Scragg, J. T.; Galofré,
A. M.; Gui, X.; Lewis, W. Tetrahedron 2010, 66, 8029–8035; (e) Tripathi, S.;
Chan, M.-H.; Chen, C. Bioorg. Med. Chem. Lett. 2012, 22, 216–221; (f) Reddy, B.
V.; Rao, R. N.; Reddy, N. S. S.; Somaiah, R.; Yadav, J. S.; Subramanyam, R.
Tetrahedron Lett. 2014, 55, 1049–1051; (g) Srinivas, J.; Singh, P. P.; Varma, Y. K.;
Hyder, I.; Kumar, H. M. S. Tetrahedron Lett. 2014, 55, 4295–4297; (h) Harada, K.;
Arioka, C.; Miyakita, A.; Kubo, M.; Fukuyama, Y. Tetrahedron Lett. 2014, 55,
6001–6003; See also: (i) Yang, C.; Zhi, X.; Hu, H. Mini-Rev. Med. Chem. 2016, 16,
404–426.
7
8
.
.
Castro, A. M. M. Chem. Rev. 2004, 104, 2939–3002.
Schaefer, S. L.; Roberts, C. L.; Volz, E. O.; Grasso, M. R.; O’Neil, G. W. Tetrahedron
Lett. 2013, 54, 6125–6128.
Acknowledgment
9.
Dahlén, A.; Hilmersson, G. Eur. J. Org. Chem. 2004, 3393–3403.
1
0. (a) Hasegawa, E.; Curran, D. P. J. Org. Chem. 1993, 58, 5008–5010; (b) Hasegawa,
E.; Ishiyama, K.; Fujita, T.; Kato, T.; Abe, T. J. Org. Chem. 1997, 62, 2396–2400.
1. Danishefsky, S.; Yan, C. F.; McCurry, P. M. J. Org. Chem. 1977, 42, 1821–1823.
2. Giannerini, M.; Fañanás-Mastral, M.; Feringa, B. L. Nat. Chem. 2013, 5, 667–672.
3. Bowden, K.; Cook, R. S. J. Chem. Soc., Perkin Trans. 2 1972, 1407–1411.
Financial support from the National Science Foundation
CHE-1151492 is gratefully acknowledged.
1
1
1
(
Supplementary data
14. Ishiyama, T.; Murata, M.; Miyaura, N. J. Org. Chem. 1995, 60, 7508–7510.
15. Zhu, L.; Duquette, J.; Zhang, M. J. Org. Chem. 2003, 68, 3729–3732.
16. Szostak, M.; Procter, D. J. Angew. Chem., Int. Ed. 2012, 51, 9238–9256.
17. Gevorgyan, V.; Rubin, M.; Benson, S.; Liu, J.-X.; Yamamoto, Y. J. Org. Chem. 2000,
65, 6179–6186.
Supplementary data (analytical data and experimental proce-
dures for compounds 16, 17, 18, and 1) associated with this article