Regioselective synthesis of gentisyl alcohol-type marine natural products

Article abstract of DOI:10.1080/14786419.2018.1478831

Gentisyl alcohol-type natural products, possessing various important biological properties, have been synthesized from 4-methoxyphenol by using a selective phenol monohydroxymethylation/monochlorination, a CAN oxidation and a sodium dithionite reduction as the key steps. The natural product synthesis is efficient, atom- and step-economical, and requires no protecting groups.

Full text of DOI:10.1080/14786419.2018.1478831

Natural Product Research
Formerly Natural Product Letters
ISSN: 1478-6419 (Print) 1478-6427 (Online) Journal homepage: http://www.tandfonline.com/loi/gnpl20
Regioselective synthesis of gentisyl alcohol-type
marine natural products
Hong-Shuang Wang, Hui-Jing Li, Long-Fei Wang, Zhi-Lun Shen & Yan-Chao Wu
To cite this article: Hong-Shuang Wang, Hui-Jing Li, Long-Fei Wang, Zhi-Lun Shen & Yan-Chao
Wu (2018): Regioselective synthesis of gentisyl alcohol-type marine natural products, Natural
Product Research, DOI: 10.1080/14786419.2018.1478831
To link to this article: https://doi.org/10.1080/14786419.2018.1478831
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Natural Product research, 2018
https://doi.org/10.1080/14786419.2018.1478831
Regioselective synthesis of gentisyl alcohol-type marine
natural products
Hong-Shuang Wanga, Hui-Jing Lia, Long-Fei Wanga, Zhi-Lun Shena and
Yan-Chao Wua,b
aschool of Marine science andtechnology, harbin Institute of technology, Weihai, P. r. china; bBeijing National
laboratory for Molecular sciences (BNlMs), Institute of chemistry chinese academy of sciences, Beijing, P. r.
china
ABSTRACT
ARTICLE HISTORY
received 21 March 2018
accepted 16 May 2018
Gentisyl alcohol-type natural products, possessing various important
biological properties, have been synthesized from 4-methoxyphenol
by using
monochlorination, a CAN oxidation and a sodium dithionite reduction
as the key steps. The natural product synthesis is efficient, atom- and
step-economical, and requires no protecting groups.
a
selective phenol monohydroxymethylation/
KEYWORDS
Natural products;
synthesis; gentisyl alcohol;
chlorogentisyl alcohol;
hydroxymethylation;
chlorination
1. Introduction
Gentisyl alcohol-type marine natural products (1–6, Figure 1) (Kim et al. 2005; Kwong et al.
2006; Yun et al. 2011; Leutou et al. 2012) possess a wide range of important biological activ-
ities such as angiogenesis (Kim et al. 2006), sphingomyelinase-inhibiting (Uchida et al. 2001),
radical-scavenging (Alfaro et al. 2003), and antitumor (Zhang et al. 2007) properties. For
example, chlorogentisyl alcohol (1) is in fact the first recorded compound from marine fungi
that shows strong bioactivity against both macro- and microfoulers and has non- or
CONTACT hui-Jing li
lihuijing@iccas.ac.cn; Yan-chao Wu
ycwu@iccas.ac.cn
supplemental data for this article can be accessed at https://doi.org/10.1080/14786419.2018.1478831.
© 2018 Informa uK limited, trading as taylor & Francis Group

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H.-S. WANG ET AL.
Figure 1. representatives of gentisyl alcohol-type natural products.
low-toxicity (Kwong et al. 2006), which indicates that it could be a potent antifoulant.
However, most of these gentisyl alcohol-type natural products are difficult to obtain in large
quantities on account of the limited quantities components, and thereby prevented their
pharmacological research or development into commercial products.
The efficient synthesis of chlorogentisyl alcohol (1) and chlorogentisyl quinone (2) from
commercially available and inexpensive starting materials is still a challenge. Séquin-Frey
and Tamm reported the first synthesis of 1 via the Reimer-Tiemann reaction of 2-chloroben-
zene-1,4-diol (7) and subsequent reaction with NaBH4 (Scheme 1(a)). However, the regiose-
lectivity was too poor and the yield of the intermediate 9c was extremely low (0.8%, Scheme
1(a)) (Séquin-Frey and Tamm 1971). Afterwards, McCorkindale and coworkers developed a
regioselective synthesis of 1 from 2,5-dihydroxybenzoic acid (9) in 6 steps via the key ester
intermediate 11 (Scheme 1(b)) (McCorkindale et al. 1972). The synthesis of gentisyl alcohol
(3) via reduction of gentisyl aldehyde (11) (Goksu et al. 2016) or gentisyl quinone (4) (Algi
and Balci 2006) has been reported (Scheme 1(c) and 1(d)). However, 11 is expensive and 4
is not commercially available to date. Obviously, development of an efficient strategy to
reduce the reaction steps is required. Moreover, strategies to divergently access this type of
natural products from a single building block are still absent. Herein we report a practical
synthesis of gentisyl alcohol-type natural products from inexpensive 4-methoxyphenol (12,
17.9 €/500 g, Aldrich) within 2–4 steps (Scheme 1(e)).
2. Results and discussion
Scheme 2 shows the synthesis of gentisyl alcohol (3) and gentisyl quinone (4) from 4-meth-
oxyphenol (12). Treatment of 12 with aqueous formaldehyde and sodium metaborate
(NaBO2) afforded 4-O-methylgentisyl alcohol (13) in 90% yield (Li et al. 2014). Oxidation of
13 with ammonium cerium nitrate (CAN) provided 4 in 80% yield. Reduction of 4 with sodium
dithionite (Na2S2O4) gave 3 in 68% yield.
Scheme 3 illustrates our initial synthetic studies on chlorogentisyl alcohol (1). Vilsmeier-
Haack reaction of 1,4-dimethoxybenzene (14) afforded benzaldehyde 15 in 66% yield.
Unfortunately, chlorination of 15 with various chlorinating reagents such as sulfuryl chloride
(SO2Cl2), N-chlorosuccinimide (NCS), and trichloroisocyanuric acid (TCAA) did not afford the
desired meta-chlorobenzaldehyde 16. Instead, ortho-chlorobenzaldehyde 17 was obtained

NATURAL PRODUCT RESEARCH
3
Scheme 1. synthesis of gentisyl alcohol-type natural products.
Scheme 2. synthesis of gentisyl alcohol (3) and gentisyl quinone (4).
under these conditions. For example, treatment of 15 with TCAA and TFA in 1,2-dichlo-
roethane (DCE) at –40 °C afforded exclusively 17 in 81% yield. Similarly, chlorination of ben-
zaldehyde 18 provided ortho-chlorobenzaldehyde 19 in 90% yield, as the sole regioisomer
under the similar condition (see Supporting Material for the discussion on the positional
selectivity).

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H.-S. WANG ET AL.
Scheme 3. synthetic studies on chlorogentisyl alcohol (1).
Scheme 4. synthesis of chlorogentisyl alcohol (1) and chlorogentisyl quinone (2).
The efficient synthesis of chlorogentisyl alcohol (1) and chlorogentisyl quinone (2) has
been accomplished as shown Scheme 4. Treatment of 7 with SO2Cl2 and Et2O at 0 °C gave
exclusively ortho-chlorophenol 20 in 80% yield (Saper and Snider 2014), demonstrating a
high mono-selectivity with respect to this phenol chlorination. With 20 in hand, we envisaged
then to achieve the facile NaBO2-promoted phenol hydroxymethylation mentioned in
Scheme 2. Unfortunately, treatment of phenol 20 with aqueous formaldehyde in the pres-
ence of NaBO2 did not work at room temperature, while degradation was observed when
the reaction was performed at a higher temperature. Fortuitously, when the reaction was
performed in the presence of lithium carbonate in water, the desired hydroxymethylated
product 21 was isolated (see Supporting Material). Other promoters were further investi-
gated to increase the yield of 21. It was found that treatment of 20 with paraformaldehyde
in the presence of Me2AlCl in CH2Cl2 followed by acidic workup afforded 21 in 90% yield (see
Supporting Material) (Tamiya et al. 2007). Oxidation of 21 with CAN provided 2 in 95% yield,
and reduction of 2 with Na2S2O4 generated 1 in 75% yield.
Synthesis of toluhydroquinone (5) and 4-O-methyltoluhydroquinone (6) is shown in
Scheme 5. Reduction of 4-O-methylgentisyl alcohol (13) with triethylsilane (Et3SiH) in the

NATURAL PRODUCT RESEARCH
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Scheme 5. synthesis of toluhydroquinone (5) and 4-o-methyltoluhydroquinone (6).
presence of trifluoroacetic acid afforded 4-O-methyltoluhydroquinone (6) in 60% yield.
Oxidation of 6 with CAN afforded toluquinone (22) (Hwang et al. 2015) in 85% yield, which,
in turn, underwent reduction with Na2S2O4 to give toluhydroquinone (5) in 70% yield.
3. Conclusions
In conclusion, concise and divergent synthesis of seven gentisyl alcohol-type marine natural
products has been accomplished from 4-methoxyphenol by a highly selective phenol mono-
hydroxymethylation/monochlorination, CAN oxidation and sodium dithionite reduction as
the key steps, which could be used for the preparation of sufficient quantities of these natural
products for biological and medical studies.
Disclosure statement
No potential conflict of interest was reported by the authors.
Funding
This work was supported by the National Natural Science Foundation of China [grant number
21672046], [grant number 21372054]; the Fundamental Research Funds for the Central Universities
[grant number HIT.NSRIF.201701].
ORCID
Yan-Chao Wu
http://orcid.org/0000-0002-0111-7484
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