Concise total synthesis of hericerin natural product

Article abstract of DOI:10.1016/j.tetlet.2013.02.027

A concise total synthesis of hericerin, a natural product, is described. The all-synthetic sequence comprises five steps and was accomplished in 34% overall yield starting from commercially available 2-hydroxy-4- methoxybenzaldehyde. The key steps were the introduction of the geranyl group using a ether-phenol rearrangement and the formation of isoindolinone through a Pd(OAc)₂-catalyzed carbonylative ring closure.

Full text of DOI:10.1016/j.tetlet.2013.02.027

Tetrahedron Letters 54 (2013) 2131–2132
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Concise total synthesis of hericerin natural product
⇑
Raúl A. Gómez-Prado, Luis D. Miranda
Instituto de Química, Universidad Autónoma de México, Circuito Exterior S.N., Ciudad Universitaria, Coyoacán 04510, México, D.F., Mexico
a r t i c l e i n f o
a b s t r a c t
Article history:
A concise total synthesis of hericerin, a natural product, is described. The all-synthetic sequence com-
prises five steps and was accomplished in 34% overall yield starting from commercially available 2-
hydroxy-4-methoxybenzaldehyde. The key steps were the introduction of the geranyl group using a
ether–phenol rearrangement and the formation of isoindolinone through a Pd(OAc)2-catalyzed carbony-
lative ring closure.
Received 17 January 2013
Revised 5 February 2013
Accepted 8 February 2013
Available online 26 February 2013
Ó 2013 Elsevier Ltd. All rights reserved.
Keywords:
Hericerin
Synthesis
Ether–phenol rearrangement
Isoindolinone
Pd(OAc)2-catalyzed carbonylation
Introduction
syntheses of related terpenoid-resorcylate natural products herice-
none J and hericenol A, have been described using a palladium(0)-
In recent years, there has been a renewed interest in mush-
rooms as natural sources of pharmacologically important mole-
cules. For instance, the edible mushroom Hericium erinaceus has
been used in traditional Chinese medicine for the treatment of dys-
pepsia, gastric ulcer, and enervation.1 Other valuable properties,
including antioxidant,2 antitumor,3 antimicrobial activities,4 as
well as pollen tube germination/growth inhibition,5 and stimula-
tion of the synthesis of nerve growth factor (NGF)6 have been
attributed to this medicinal mushroom. Among the several biolog-
ically active substances that have been isolated from this mush-
room,6 hericerin 1, has emerged as a promising lead compound
in the search for new agrochemicals. This later molecule displays
important inhibitory activity against pine pollen germination and
tea pollen growth.5 Hericerin, a member of the geranyl resorcylate
family, first isolated in 1991. However, its structure was errone-
ously assigned as its carbonyl regioisomer. Indeed, even the last
year, Miyazawa et al.1 reported the isolation of the identical mole-
cule, which these authors named isohericerin to distinguish it from
the compound originally described in the 1991 report. In an inde-
pendent study, Kobayashi et al.7 have just reported the revision of
the structure based on the synthesis of the molecule. The synthetic
approach used by this research group was based on the construc-
tion of the penta-substituted benzenoid system from 6-bromo-
5,7-dihydroxyphthalide 5-methyl ether, as the key intermediate.8a
This multi-step and low-yielding synthetic sequence is the only
synthesis for 1 described thus far.7,8a Recently, biomimetic total
catalyzed geranyl migration.8b In the course of our studies toward
the synthesis of indolin-1-one related natural products, we became
interested in the synthesis of 1. The main challenge in its synthesis
might be the construction of both the geranyl derived tetra-substi-
tuted benzenoid system, and the isoindolinone nucleus itself, diffi-
cult to prepare using conventional methodologies such as the non-
regiocontrolled monoreduction of phthalimide.9 Thus, in the pres-
ent Letter we report the development of a concise total synthesis of
hericerin, starting from commercially available 2-hydroxy-4-
methoxybenzaldehyde.
The retrosynthesis proposed for this molecule is depicted in
Scheme 1. Our attention was first drawn to the use of the
Pd(OAc)2-catalyzed carbonylation of benzylamines described by
Orito et al.10 We recognized that this protocol might allow the con-
struction of isoindolin-1-one system starting from a less complex
tetra-substituted benzene system through the functionalization
of a C–H bond. The required secondary amine for this latter process
might be prepared by a reductive amination between the corre-
sponding benzaldehyde 2 and phenethylamine. Furthermore, the
[1,3]-sigmatropic rearrangement of prenyl ethers to ortho- and
para-phenols catalyzed by montmorillonite clays, reported by Dau-
ben et al.,11 was of special importance to our synthetic strategy,
since this reaction permitted the easy introduction of the geranyl
chain in the required position, starting from the tri-substituted
benzene 4 and geranyl bromide 3.
The synthesis commenced with alkylation of the commercially
available 2-hydroxy-4-methoxybenzaldehyde (4) with the geranyl
bromide 3 under KOH-basic phase transfer conditions, to efficiently
obtain the phenol ether 5 (Scheme 2). Then, upon treatment of 5
⇑
Corresponding author. Tel.: +52 5556224440.
E-mail address: lmiranda@unam.mx (L.D. Miranda).
0040-4039/$ - see front matter Ó 2013 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tetlet.2013.02.027

2132
R. A. Gómez-Prado, L. D. Miranda / Tetrahedron Letters 54 (2013) 2131–2132
MOM ether was accomplished, followed by the reductive amination of
the crude reaction with phenethylamine and NaBH4, affording the sec-
ondary amine 6 in 82% overall yield upon a single two-step synthetic se-
quence. We were pleased to observe that the desired isoindolin-1-one 7
was obtained in respectable 84% yield upon the carbonylation process of
the amine 6using 5 mol % of Pd(OAc)2 and 50 mol % of Cu(OAc)2, accord-
ing to the procedure described previously.10 This reaction was carried
out under a balloon pressure of CO in toluene. We observed that under
higher CO pressure the yield of the product dropped dramatically and
other side-products were formed. We anticipated that the carbonylation
would prefer the formation of the isoindolin-1-one to the dihydroiso-
quinolin-1-one, due to the presence of the electron-donating groups in
one of the aromatic systems, as observed previously in related N-ben-
zylphenetylamines.10 Finally, deprotection of the phenolic OH was
accomplished under acidic conditions to obtain the natural product her-
icerin 1 in fairly good yield. The product’s spectroscopic data are consis-
tent with those reported previously.7 Furthermore the structure of the
synthetic hericerin was unambiguously established by X-ray crys-
tallographic analysis (Scheme 2).12
In summary, a concise five-step total synthesis of hericerin nat-
ural product is described. The all-synthetic sequence was accom-
plished in 34% overall yield starting from commercially available
2-hydroxy-4-methoxybenzaldehyde (4) and geranyl bromide. The
geranyl group was introduced using a ether-phenol rearrangement
and the isoindolinone was assembled via a Pd(OAc)2-catalyzed car-
bonylative ring closure.
Scheme 1. Retrosynthetic scheme for hericerin 1.
MeO
3, Bu4NI
toluene:KOH 30 % aq.
(1:1 vol.)
CHO
4
Acknowledgments
O
reflux
Financial support from DGAPA-PAPIIT (IN204910) is gratefully
acknowledged. We also thank R. Patiño, A. Peña, R. Gabiño, E. Huer-
ta, I. Chavez, H. García-Rios, L. Velasco, and J. Pérez for technical
support and A. Toscano and S. Hernandez-Ortega for X-ray crystal-
lography (Instituto de Química UNAM). R.A.G.-P. is a CONACYT
(223857) graduate scholarship holder.
5 (95%)
MeO
Montmorillonite KSF
benzene, 20 °C
CHO
OH
2 (55%) + 4 (40%)
Supplementary data
Supplementary data associated with this article can be found, in the
online version, at http://dx.doi.org/10.1016/j.tetlet.2013.02.027.
MeO
a) MOMCl, DIPEA
H
N
CH2Cl2, 0 ºC to 20 °C
Ph
References and notes
b) 2-phenethylamine
MeOH, 4Å M.S., 20 °C
then NaBH4
OMOM
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6
(82%)
0 °C to 20 °C
O
MeO
5 mol % Pd(OAc)2
50 mol % Cu(OAc)2
N
Ph
CO, air, 1 atm
toluene, reflux
OMOM
7 (84%)
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Yuguchi, M.; Yamashita, S.; Tokuda, M. J. Org. Chem. 2006, 71, 5951–5958.
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HCl
MeOH, 20 °C
95%
ORTEP driagram of Hericerin 1
Scheme 2. Concise total synthesis of hericerin natural product.
with montmorillonite KSF in benzene at room temperature, the rear-
ranged tetra-substituted benzene 2 was obtained in 55% yield, along
with 40% of the starting phenol 4. Protection of the phenolic OH as