Synthesis of natural product inulavosin via Ga(OTf)3-Catalyzed Hetero Diels–Alder Dimerization of salicyl alcohol derivative

Article abstract of DOI:10.1080/14786419.2018.1509338

Inulavosin, a natural melanogenesis inhibitor, has been synthesized smoothly from readily available and inexpensive starting materials by using a Ga(OTf)₃-catalyzed room temperature hetero Diels–Alder dimerization of salicyl alcohol derivative and a regioselective phenol monobromination as the key steps.

Full text of DOI:10.1080/14786419.2018.1509338

Natural Product Research
Formerly Natural Product Letters
ISSN: 1478-6419 (Print) 1478-6427 (Online) Journal homepage: http://www.tandfonline.com/loi/gnpl20
Synthesis of natural product inulavosin
via Ga(OTf)3-Catalyzed Hetero Diels–Alder
Dimerization of salicyl alcohol derivative
Pi-Xian Gong, Hui-Jing Li, Meirong Wang, Yun-Fei Cheng & Yan-Chao Wu
To cite this article: Pi-Xian Gong, Hui-Jing Li, Meirong Wang, Yun-Fei Cheng & Yan-
Chao Wu (2018): Synthesis of natural product inulavosin via Ga(OTf)3-Catalyzed Hetero
Diels–Alder Dimerization of salicyl alcohol derivative, Natural Product Research, DOI:
10.1080/14786419.2018.1509338
To link to this article: https://doi.org/10.1080/14786419.2018.1509338
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NATURAL PRODUCT RESEARCH
https://doi.org/10.1080/14786419.2018.1509338
Synthesis of natural product inulavosin via Ga(OTf)3-
Catalyzed Hetero Diels–Alder Dimerization of
salicyl alcohol derivative
Pi-Xian Gonga, Hui-Jing Lia, Meirong Wangb, Yun-Fei Chenga and
Yan-Chao Wua,c
aSchool of Marine Science and Technology, Harbin Institute of Technology, Weihai, P. R. China;
bSchool of Materials Science and Engineering, Harbin Institute of Technology, Weihai, P. R. China;
cBeijing National Laboratory for Molecular Sciences (BNLMS), Institute of Chemistry Chinese
Academy of Sciences, Beijing, P. R. China
ABSTRACT
ARTICLE HISTORY
Received 11 April 2018
Accepted 3 August 2018
Inulavosin, a natural melanogenesis inhibitor, has been synthe-
sized smoothly from readily available and inexpensive starting
materials by using a Ga(OTf)3-catalyzed room temperature hetero
Diels–Alder dimerization of salicyl alcohol derivative and a regio-
selective phenol monobromination as the key steps.
KEYWORDS
Natural product; inulavosin;
synthesis; Ga(OTf)3;
Diels–Alder reaction
1. Introduction
Inulavosin (1, Figure 1), a dimer of thymol (2), was isolated from the roots of Inula
nervosa (Compositae) in 1995 (Yoshida et al. 1995). This racemic natural product
displays a range of biological activities such as antibacterial (Yoshida et al. 1995),
piscicidal (Yoshida et al. 1995), antifungal (Kim et al. 2017), and melanogenesis
inhibitory properties (Fujita et al. 2009; Zhou et al. 2016). Inulavosin (1) is difficult to
obtain in large quantities on account of its limited quantities from natural sources
(Yoshida et al. 1995). To overcome this problem, development of an efficient strategy
for the synthesis of this bioactive natural product becomes a high priority. To date,
synthesis of inulavosin and its derivatives has attracted attention from the synthetic
CONTACT Yan-Chao Wu
ycwu@iccas.ac.cn
Supplemental data for this article can be accessed at https://doi.org/10.1080/14786419.2018.1509338.
ß 2018 Informa UK Limited, trading as Taylor & Francis Group

2
P.-X. GONG ET AL.
9'
3'
10'
5'
2'
8'
6'
10
4'
9
5
2
6
8
1'
7'
O
4
1
7
OH
3
HO
inulavosin (1)
Figure 1. Inulavosin (1) and thymol (2).
thymol (2)
(a) Condensation of phenols with ketones
O
R1 = H
R1
X
+
inulavosin (1)
R2 = Me
R2
OH
R2
X = 3-Me
3
4
R1H2C
O
R1H2C
OH
R1H2C
R2
R2
O
X
X
X
X
X
X
X
O
6
OH
OH
5
7
R1H2C R2
R2
R1
R1
R2
R1
R2
X
X
O
O
X
R
1 = H,
R2= Me
R1H2C R2
8
9
10
OH
(b) Condensation of 4-methylcoumarins with NaOH and ethanediol
1) NaOH, 210 °C,
HOCH2CH2OH
inulavosin (1)
2) aq HCl
O
O
11
(c) This work
OH
Ga(OTf)3,
inulavosin (1)
CH2Cl2, r.t.
OH
12
Scheme 1. Synthetic endeavours on inulavosin (1) and its derivatives.
community (Baker et al. 1951; Kamat et al. 1998; Livant et al. 1997; Menezes et al.
2011). The condensation of m-cresol and acetone in the presence of a protic acid,
such as hydrochloric acid, seems to be one of the simplest methods for the synthesis
inulavosin (Scheme 1a). This synthetic strategy, although has been described previously
(Baker et al. 1951), might be problematic. Indeed, a highly complex mixture was
obtained when m-cresol was condensed with acetone in the presence of various protic
acids (HCl, H2SO4, p-TsOH, MsOH, etc). It is because that phenols (3) can react with alkyl
ketones (4) in the presence of a protic acid to afford ketals (5, Causse 1892), xanthenes
(6, Khosropour et al. 2005), 2,2-diphenylpropanes (7, Malhotra and Banerjee 1990),

NATURAL PRODUCT RESEARCH
3
spirobichromans (8, Harada and Usui 1987), and 2,20,3,30-tetrahydro-1,10-spirobis-indenes
(9, Scheme 1a, Xue et al. 2012). Alkyl ketones (4) can undergo cyclotrimerization in
the presence of a protic acid to give 1,3,5-triarylbenzenes (10, Jing et al. 2005), which
makes this endeavor more demanding (Scheme 1a). To circumvent this problem,
Kamat developed a selective synthesis of inulavosin (1) by treatment of 4,7-dimethyl-
coumarin (11) with sodium hydroxide (NaOH) and ethanediol under harsh conditions
(210 ꢀC) and subsequent reaction with aqueous HCl (Scheme 1b, Kamat et al. 1998). In
this context, herein we report a selective synthesis of inulavosin (1) from salicyl alcohol
12 under milder conditions, which could be used for the preparation of sufficient
quantities of this natural product for biological and medical studies (Scheme 1c).
2. Results and discussion
As shown in Scheme 2, the synthesis of inulavosin (1) commenced with commercially
available and inexpensive m-cresol (13). The high selectivity in the electrophilic
aromatic monobromination of 13 was achieved by carefully controlling the reaction
temperature. Reaction of 13 with NBS in acetonitrile (CH3CN) in the presence of
trifluoromethanesulfonic acid (TfOH) was performed at ꢁ30 ꢀC and slowly warm up to
room temperature, and then stirred at this temperature for 12 h to afford 4-bromophe-
nol 14 in 90% yield. As a phenoxide anion usually tends to facilitate its ortho electro-
philic aromatic bromination according to its average local ionization energy surfaces
calculated by Brown and Cockroft (2013), TfOH was used to suppress the formation of
the phenoxide anion, and thus obviate the ortho electrophilic aromatic bromination of
13. Although a phenol usually tends to facilitate its para electrophilic aromatic substi-
tution (Li et al. 2014), a higher reaction temperature would make more collisions
effective, including the collisions at the position ortho to the phenolic hydroxyl group,
and thereby result in a lower para-selectivity. Thus, the electrophilic aromatic bromina-
tion of 13 was performed at temperatures as low as possible, which made the
collisions at the ortho position ineffective and thus increased the para-selectivity.
Treatment of 14 with acetyl chloride (AcCl) in the presence of AlCl3 in DCE at 90 ꢀC
for 5 h afforded acetophenone 15 in 80% yield, which was subjected to a nucleophilic
addition reaction with methyllithium to provide salicyl alcohol 16 in 90% yield. The
hetero Diels–Alder dimerization of 16 in DCE in the presence of diphenylphosphoric
acid [(PhO)2P(O)OH, 0.1 equiv.] at 100 ꢀC gave 17 in 74% yield within 5 h. However,
the reaction did not take place at a temperature less than 80 ꢀC. After the optimization
of reaction conditions by varying the catalysts [(PhO)2P(O)OH, TFA, H2SO4, BF3 ꢂ Et2O,
LiCl, MgCl2, AlCl3, FeCl3, Cu(OTf)2, Ga(OTf)3, In(OTf)3, etc], the solvents (PhMe, CH3CN,
THF, Et2O, CH2Cl2, hexane, DCE, etc] and the temperature (room temperature to
100 ꢀC), the hetero Diels–Alder dimerization of 16 under mild reaction conditions
has been achieved. Indeed, treatment of 16 in the presence of Ga(OTf)3 at room
temperature for 2 h gave 6,60-dibromoinulavosin (17) in 87% yield. Coupling of 17
with trimethylboroxine afforded 6,60-dimethylinulavosin (18, see Supporting Material
for the synthesis of other inulavosin derivatives) in 85% yield, whereas reduction of 17
under the hydrogenolysis conditions afforded inulavosin (1) in 98% yield (Scheme 2).
On the other hand, hydrogenolysis of 15 followed by reaction with methyllithium

4
P.-X. GONG ET AL.
Br
Br
NBS, TfOH, CH3CN
AlCl3, AcCl
O
30 °C to r.t., 12 h
90%
DCE, 90 °C, 5 h
80%
OH
OH
OH
13
14
15
CH3Li, Et2O
30 °C to r.t.,
5 h, 90%
6'
Br
Br
Ga(OTf)3
OH
OH
6
6Br
CH2Cl2, r.t.,
2 h, 87%
H2, MeOH,
Pd/C, 50 °C,
3 h, 96%
O
17
16
HO
6'
trimethylboroxine
O
6
1,4-dioxane, K2CO3,
100 °C, 8 h, 85%
O
OH
18
19
CH3Li, 30 °C to r.t.,
Et2O, 5 h, 86%
HO
H2, Pd/C, MeOH,
50 °C, 3 h, 98%
Ga(OTf)3, CH2Cl2
r.t., 2 h, 88%
OH
OH
inulavosin (1)
12
Scheme 2. Synthesis of inulavosin (1) and its derivatives 17 and 18. Reagents and conditions:
NBS ¼ N-bromosuccinimide. TfO ¼ triflate. r.t. ¼ room temperature. Ac ¼ acetyl. DCE ¼ 1,2-dichloro-
ethane. Me ¼ methyl.
H
Ga(OTf)3
OH
H
dehydration
tautomerization
OH
O
12
20
hetero
Diels-Alder
reaction
O
O
21
(TfO)3Ga
O
H
HO
20
1
Scheme 3. A possible reaction mechanism for the hetero Diels–Alder dimerization of salicyl
alcohol 12.
afforded salicyl alcohol derivative 12 in 83% overall yield, which underwent Ga(OTf)3-
catalyzed hetero Diels–Alder dimerization to give 1 in 88% yield (Scheme 2). The
spectroscopic and spectrometric data (1 H NMR, 13 C NMR and HRMS) of the synthetic
material are identical to those reported in the literature (Yoshida et al. 1995).
The Ga(OTf)3-catalyzed room temperature hetero Diels–Alder dimerization reaction
facilitated this inulavosin synthesis under obviously milder conditions in comparison
to Kamat inulavosin synthesis (room temperature versus 210 ꢀC, Kamat et al. 1998).
This inulavosin synthesis displays a higher chemoselectivity in comparison to Baker
inulavosin synthesis (a sole product versus a complex mixture, Baker et al. 1951).
Although we are not able at this time to accurately explain the reaction pathways
of the hetero Diels–Alder dimerization of salicyl alcohol 12, a possible mechanism for
this reaction is illustrated in Scheme 3. Dehydration of 12 in the presence of Ga(OTf)3
generates allyl phenol 20, which undergoes an enol-keto tautomerization to form

NATURAL PRODUCT RESEARCH
5
ortho-quinone methide 21 (Chiang and Kresge 2004; Das et al. 2014).16 Finally, the
hetero Diels–Alder reaction of 21 with 20 in the presence of Ga(OTf)3 affords inulavo-
sin (1) (Liang et al. 2010; Gharpure et al. 2013; Zhao et al. 2015; Allen et al. 2017).
3. Conclusions
In conclusion, we described a newly developed gallium(III) triflate-catalyzed room
temperature hetero Diels–Alder dimerization of salicyl alcohols, which is employed to the
practical syntheses of inulavosin and its derivatives. Further applications of this strategy
for the synthesis of other natural products with related skeletons are in progress.
Disclosure statement
No potential conflict of interest was reported by the authors.
Funding
We thank the National Natural Science Foundation of China (21672046, 21372054), and the
Fundamental Research Funds for the Central Universities (HIT.NSRIF.201701).
ORCID
Yan-Chao Wu
http://orcid.org/0000-0002-0111-7484
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