A regioselective synthesis of 7-methyl juglone and its derivatives

Article abstract of DOI:10.1080/14786419.2020.1761356

7-Methyl juglone as a naturally occurring naphthoquinone showed striking antibacterial, antifungal, antivirus and anticancer activity. Its derivatives had also been characterized as key intermediates in the preparation of natural naphthoquinones and anthraquinones. Herein, we reported a regioselective synthesis of 7-methyl juglone via the construction of fused polycyclic systems. The key steps of the strategy involved Stobbe condensation of 2,5-dimethoxy benzaldehyde with diethyl succinate, intramolecular cyclization, reduction, acid-facilitated debenzylation and further cerium(IV) ammonium nitrate-mediated oxidation. Compared with the reported methods employing Birch conditions in liquid ammonia or Friedel-Crafts cycloacylation with melting heat of aluminum salts, the reaction conditions in the new synthetic route were milder and suitable for large scale preparations. In addition, all of the starting materials in the synthesis were readily available. It has great implications for the design and synthesis of structurally asymmetric naphthoquinones derivatives.

Full text of DOI:10.1080/14786419.2020.1761356

Natural Product Research
Formerly Natural Product Letters
ISSN: 1478-6419 (Print) 1478-6427 (Online) Journal homepage: https://www.tandfonline.com/loi/gnpl20
A regioselective synthesis of 7-methyl juglone and
its derivatives
Jiahua Cui, Shaoshun Li & Jinping Jia
To cite this article: Jiahua Cui, Shaoshun Li & Jinping Jia (2020): A regioselective
synthesis of 7-methyl juglone and its derivatives, Natural Product Research, DOI:
10.1080/14786419.2020.1761356
To link to this article: https://doi.org/10.1080/14786419.2020.1761356
View supplementary material
Published online: 06 May 2020.
Submit your article to this journal
Article views: 14
View related articles
View Crossmark data
Full Terms & Conditions of access and use can be found at
https://www.tandfonline.com/action/journalInformation?journalCode=gnpl20

NATURAL PRODUCT RESEARCH
https://doi.org/10.1080/14786419.2020.1761356
A regioselective synthesis of 7-methyl juglone and its
derivatives
Jiahua Cuia, Shaoshun Lib and Jinping Jiaa
aSchool of Environmental Science and Engineering, Shanghai Jiaotong University, Shanghai,
b
P.R. China; School of Pharmacy, Shanghai Jiaotong University, Shanghai, P.R. China
ABSTRACT
ARTICLE HISTORY
Received 24 November 2019
Accepted 19 April 2020
7-Methyl juglone as
a naturally occurring naphthoquinone
showed striking antibacterial, antifungal, antivirus and anticancer
activity. Its derivatives had also been characterized as key
intermediates in the preparation of natural naphthoquinones and
anthraquinones. Herein, we reported a regioselective synthesis of
7-methyl juglone via the construction of fused polycyclic systems.
The key steps of the strategy involved Stobbe condensation of
2,5-dimethoxy benzaldehyde with diethyl succinate, intramolecu-
lar cyclization, reduction, acid-facilitated debenzylation and further
cerium(IV) ammonium nitrate-mediated oxidation. Compared with
the reported methods employing Birch conditions in liquid
ammonia or Friedel-Crafts cycloacylation with melting heat of alu-
minum salts, the reaction conditions in the new synthetic route
were milder and suitable for large scale preparations. In addition,
all of the starting materials in the synthesis were readily available.
It has great implications for the design and synthesis of structur-
ally asymmetric naphthoquinones derivatives.
KEYWORDS
Natural naphthoquinones;
7-methyl juglone;
regioselective synthesis;
debenzylation; oxidative
demethylation
1. Introduction
7-Methyl juglone (1, Scheme 1), a biologically active naphthoquinone isolated from
the roots of Drosera aliciae Raym.-Hamet, exhibited marked antibacterial and antifun-
gal effects (Mbaveng and Kuete 2014; Rauf et al. 2016). It demonstrated potent inhibi-
tory activity against the Gram-positive Streptococcus mutans and Streptococcus sanguis
with its MIC values of 156 and 78 lg/mL, respectively (Cai et al. 2000). Towards the
Gram-negative anaerobic rods Prevotella gingivalis, it showed much higher growth
inhibitory activity with the MIC value of 39 lg/mL (Cai et al. 2000). It has been
CONTACT Jiahua Cui
cpucjh@sjtu.edu.cn; Jinping Jia
jpjia@sjtu.edu.cn
Supplemental data for this article can be accessed at https://doi.org/10.1080/14786419.2020.1761356.
ß 2020 Informa UK Limited, trading as Taylor & Francis Group

2
J. CUI ET AL.
Scheme 1. Retrosynthetic analysis of 7-methyl juglone.
identified as an exceptional potent antitubercular agent with its MIC value of only
0.5 lg/mL against the Mycobacterium tuberculosis H37Rv (Mahapatra et al. 2007). For
the drug-resistant Mycobacterium tuberculosis strain, 7-methyl juglone still has poten-
tial tuberculocidal efficacy through the inhibition of DNA gyrase-catalyzed supercoiling
reactions (Karkare et al. 2013).
7-Methyl juglone appeared to be an effective antifungal naphthoquinone with its
MIC value of 80 lg/mL against the pulmonary candidiasis Candida albicans, which was
comparable to that of nystatin as the positive control (Sinha et al. 2009). Recently, its
antivirus (Singh et al. 2001; Mahapatra et al. 2012), anticancer (Kawiak et al. 2012;
Kishore et al. 2014) and anti-inflammatory (Azab et al. 2016) activity have also
been reported.
Apart from its striking biological activities, 7-methyl juglone and its derivatives such
as its methyl ether (2, Scheme 2), benzyl ether (3) and acetate (4) had also been
employed as key intermediates in organic synthesis, especially for the total synthesis
of many other naturally occurring quinones and their derivatives (Kuroyanagi et al.
1971; Laatsch 1980; Krohn and Broser 1984; Van der Kooy and Meyer 2006; O’Keefe
et al. 2010, 2011).
2. Results and discussion
The molecular structure of 7-methyl juglone (1) is quite simple apparently. However,
ascribed to the active chemical reactivity of the 1,4-quinone moiety (A-ring) and its
asymmetric structural scaffold, the concise and efficient synthesis of this natural naph-
thoquinone and its derivatives remains elusive. The most frequently used method for
the preparation of 1 employed the Friedel-Crafts cycloacylation of 4-halo-3-methyl
phenol with maleic anhydride in a melting mixture of anhydrous AlCl3 and NaCl at
high temperature, further acetylation and reductive dehalogenation of the correspond-
ing halo-substituted adducts (Cooke and Dowd 1953; Laatsch 1978, 1980; Musgrave
and Skoyles 2001; Mahapatra et al. 2007). Obviously, there were some serious disad-
vantages in this synthetic strategy such as drastic reaction conditions, troublesome
purifications and very low and poorly reproducible yields. The other method rested on

NATURAL PRODUCT RESEARCH
3
the cycloaddition between 1,4-benzoquinone and silylated dienes and further acidic
hydrolysis (Krohn and Broser 1984; Savard and Brassard 1984; O’Keefe et al. 2011; Jha
et al. 2017). However, the synthesis of the diene intermediate was somewhat tedious
and the total yield was also unsatisfactory. Parker’s method rested on the annelative
synthetic procedure with ethyl 3-methyl-4-cyano-4-(2,5-dimethoxyphenyl) butyrate as
the starting material (Parker and Tallman 1984). However, the elimination of the nitrile
group as a key step was conducted in Birch conditions using metal sodium in liquid
ammonia at ꢀ78 ꢁC and was difficult to scale up. Thus the target compound (1)
obtained was only at a 2 mg level (Parker and Tallman 1984). In addition, the starting
material should be synthesized using the highly toxic sodium cyanide and was not
readily available from general suppliers (Parker and Kallmerten 1980). Therefore, an
efficient multigram synthesis of 1 with a convenient route and high overall yield was
desirable for further drug development, as well as the synthesis of natural quinones
and their derivatives.
The most commonly used method for the synthesis of 7-methyl juglone derivatives
(2, 3 and 4) were the methylation, benzylation or acetylation of the parent compound
1 in the highly reactive methyl iodide (benzyl bromide)/silver(II) oxide mixture or a
heated sodium acetate/acetic anhydride system (Laatsch 1980; Maiti et al. 2005;
Mahapatra et al. 2007; O’Keefe et al. 2010; Kishore et al. 2014). These strategies greatly
depended on the supply of 1 as a raw material. Thus the synthesis of 7-methyl
juglone analogues using intermediates in the synthetic route of 1 should be an alter-
native strategy.
According to the retrosynthetic analysis (Scheme 1), the construction of B-ring via
Stobbe condensation and further Friedel-Crafts acylation, the conversion of an ester
moiety to a methyl group, and subsequent deprotection strategies were economical
and efficient synthetic methods for the preparation of the targeted compound. In our
studies, 2,5-dimethoxy benzaldehyde (Scheme 2, 5) and diethyl succinate were
employed as the starting points, which were readily available from commercial suppli-
ers. The Stobbe condensation between the benzaldehyde 5 and diethyl succinate, and
further intramolecular cyclization of 6 afforded the ethyl 4-acetoxy-5,8-dimethoxy-2-
naphthoate (7) in mild conditions. The reduction of the diester 7 by excessive amount
of LiAlH4 afforded 2-naphthylmethanol derivative 8 stiochiequivalently. The dehydroxy-
lation reaction was carried out under hydrogen atmosphere with palladium hydroxide
on activated charcoal (Pd(OH)2/C, 20 wt. % loading) as the catalyst. The structure of
1
the dehydroxylated product 9 was confirmed by shifting of the H NMR signal belong
to methylene group of the substrate at d 4.77 ppm to upfield (d ¼ 2.45 ppm) upon the
debenzylation reaction. According to previous reports in literatures (Bruce and
Thomson 1955; Wright et al. 2007; Cui et al. 2015), the chelated hydroxyl group in
juglone sensitized this molecule in alkali conditions. The methoxy methyl ether
(MOM), which could be easily cleaved in acidic conditions, was used as the protecting
group in the synthesis. The protection of the phenolic hydroxyl group with MOM in
the presence of NaH and MOMCl provided the bicyclic precursor 10. Further
cerium(IV) ammonium nitrate (CAN)-mediated oxidative demethylation reactions and
acidic deprotection of MOM protecting group furnished the targeted compound in
mild conditions with high yield.

4
J. CUI ET AL.
Scheme 2.ꢁSynthesis of 7-methyl juglone aꢁnd its derivatives. Reagents and conditions: ꢁ(a) NaH,
Toluene, 0 C to r. t.; (b) NaOAc, AcOH, 120 C, Yield: 66% for 2 steps; (c) LiAlH4, THF, 0 C, Yield:
ꢁ
98%; (d) Pd(OH)2/C, 1 atm H2, AcOH-MeOHꢁ(1: 200), r. t., Yield: 95%; (e) MOMCl, NaH, DMF, 0 C to
r. t., Yield: 96%; (f) CAN, DCM-ACN (2:1), 0 C, Yield: 85% for 11, 81% for 2, 80% for 3 and 87% for
ꢁ
ꢁ
4; (g) Diluted H2SO4, MeOH, 5 C, 73%; (h) CH3I, ꢁNaH, DMF, 0 C to r. t., Yield: 97%; (i) BnBr, NaH,
ꢁ
KI, DMF, 0 C to r. t., Yield: 95%; (j) Ac2O, Py, 50 C, Yield: 89%
The heterogenouse catalyst, Pd(OH)2/C, was a commonly used catalyst for the
deprotection of benzyl groups under the hydrogen-rich atmospheres (Blaser et al.
2001). The reaction was conducted via the formation of an aryl-palladium(II) intermedi-
ate and further hydrogenation (Al Soom and Thiemann 2016). However, the debenzy-
lation of 2-naphthylmethanol derivative 8 proceeded slowly even with the use of
excessive amount of the catalyst under refluxed conditions. The acidification of the
reaction mixture with catalytic amount of acetic acid greatly promoted the debenzyla-
tion reaction. As shown in Figure 1, the binding of protons with the hydroxyl group of
the aryl-palladium(II)-hydrogen complex possibly contributed to the cleavage of the
Pd-OH chemical bond in the complex, leading to the hydrogenation of aryl-
palladium(II) intermediate.
We explored the optimum reaction conditions for the debenzylation reaction. When
the proportion of the acetic acid increased from 0.1% to 0.5%, the time required for
the completion of reaction decreased from more than 20 h to less than 4 h. However,
further greatly increased amount of acid in the reaction system led to the generation
of new spots on the baseline of the TLC plate and also a decrease in the yield. The
reason should be ascribed to the possible demethylation of the substrate in acidic
conditions. In the acid-facilitated debenzylation reactions, the quantity of Pd(OH)2/C
(20%), was set at 80 mg per 10 mmol of the substrate, and a 2 ꢂ 10 gram scale hydro-
genation got completed within 4 h at room temperature under hydrogen atmosphere
of 1 atm.
The debenzylation as a heterogeneous catalytic reaction was the key step for the
scalable synthesis of the target compound 1. Meanwhile, the scale-up synthesis had
also been considered as one of the most important factors in heterogeneous catalysis.

NATURAL PRODUCT RESEARCH
5
Figure 1. The plausible mechanism for acid-promoted debenzylation reaction.
Figure 2. The plausible mechanism for CAN-mediated oxidative demethylation.
Therefore, we performed the large laboratory-scale synthesis of 9 (supplementary
material). The substrate 8 (250 gram scale) could be successfully hydrogenated under
hydrogen atmosphere (1 atm) within 4 h at 45 ꢁC, with the stiochiequivalent conversion
to the dehydroxylated product 9.
In CAN-mediated oxidative demethylation, B-ring oxidation was not observed and
the regioselective oxidative demethylation should be ascribed to the presence of the
methoxy group on C(5) of A-ring. CAN was a single-electron oxidant and the electron-
transfer oxidation proceeded via the formation of aryl radicals (Jacob III et al. 1976;
Tanoue and Terada 1988; Nair and Deepthi 2007). The C(5) methoxy group as an elec-
tron-donating group, greatly enriched the electron density of A-ring, leading to an
increase in chemical reactivity of the aromatic ring. Meanwhile, the lone pair electrons
belonging to the oxygen atom contributed to the stabilization of the cation ions (15a)
through a chemical equilibrium (Figure 2).

6
J. CUI ET AL.
3. Experimental
1
Experimental section (experimental procedures, H NMR, 13C NMR and HRMS) is avail-
able in supplementary material.
4. Conclusions
Resting on Stobbe condensation of 2,5-dimethoxy benzaldehyde (5) with diethyl suc-
cinate, an intramolecular cyclization, reduction, acid-facilitated debenzylation and fur-
ther CAN-mediated oxidation, a convenient synthesis of 7-methyl juglone was
established with high overall yield (36.6%, 7 steps). Compared with the reported meth-
ods, there were several advantages in the new synthetic strategy. Firstly, the overall
yield was much higher. Secondly, the reaction conditions were milder and suitable for
the large scale preparations. Thirdly, the starting materials were easy to obtain. It has
great implications for the design and synthesis of structurally asymmetric naphthoqui-
none derivatives.
Disclosure statement
No potential conflict of interest was reported by the authors.
Funding
This program was financially supported by National Natural Science Foundation of China (Grant
No. 21602132 and No. 81673281) and Startup Fund for Youngman Research at SJTU (SFYR at
SJTU, No. 19X100040082). We are grateful to the Instrumental Analysis Center in Shanghai
Jiaotong University for recording the HRMS data of compounds.
References
Al Soom N, Thiemann T. 2016. Hydrogenation of alkenes with NaBH4, CH3CO2H, Pd/C in the
presence of O-and N-benzyl functions. Int J Org Chem. 6 (1):1–11.
Azab A, Nassar A, Azab A. 2016. Anti-inflammatory activity of natural products. Molecules.
21(10):1321.
Blaser H-U, Indolese A, Schnyder A, Steiner H, Studer M. 2001. Supported palladium catalysts for
fine chemicals synthesis. J Mol Catal A-Chem. 173(1–2):3–18.
Bruce D, Thomson R. 1955. Quinones. Part V. The chemistry of naphthazarin. J Chem Soc. Part II:
1089–1096.
Cai L, Wei G-X, van der Bijl P, Wu CD. 2000. Namibian chewing stick, Diospyros lycioides, con-
tains antibacterial compounds against oral pathogens. J Agric Food Chem. 48(3):909–914.
Cooke R, Dowd H. 1953. Colouring matters of Australian Plants. III. Synthesis of 7-Methyljuglone
and related compounds. Aust J Chem. 6(1):53–57.
Cui J, Cui Q, Zhang Q, Li S. 2015. An efficient multigram synthesis of juglone methyl ether. J
Chem Res. 39(9):553–554.
Jacob P, Callery PS, Shulgin AT, Castagnoli N. 1976. A convenient synthesis of quinones from
hydroquinone dimethyl ethers. Oxidative demethylation with ceric ammonium nitrate. J Org
Chem. 41(22):3627–3629.
Jha V, Goyal N, Stevens CK, Stevens E, Sridhar J. 2017. Synthetic method to form 2,20-bis(naph-
thoquinone) compounds. J Org Chem. 82(24):13686–13692.

NATURAL PRODUCT RESEARCH
7
Karkare S, Chung TTH, Collin F, Mitchenall LA, McKay AR, Greive SJ, Meyer JJM, Lall N, Maxwell
A. 2013. The naphthoquinone diospyrin is an inhibitor of DNA gyrase with a novel mechan-
ism of action. J Biol Chem. 288(7):5149–5156.
Kawiak A, Zawacka-Pankau J, Wasilewska A, Stasilojc G, Bigda J, Lojkowska E. 2012. Induction of
apoptosis in HL-60 cells through the ROS-mediated mitochondrial pathway by ramentaceone
from drosera aliciae. J Nat Prod. 75(1):9–14.
Kishore N, Binneman B, Mahapatra A, Van De Venter M, Du Plessis-Stoman D, Boukes G,
Houghton P, Marion Meyer JJ, Lall N. 2014. Cytotoxicity of synthesized 1,4-naphthoquinone
analogues on selected human cancer cell lines. Bioorg Med Chem. 22(17):5013–5019.
Krohn K, Broser E. 1984. Synthetic anthracyclinones. 15. An improved route to 8-demethoxyaran-
ciamycinone and synthesis of the. alpha.-L-daunosamine glycosides. J Org Chem. 49(20):
3766–3771.
Kuroyanagi M, Yoshihira K, Natori S. 1971. Naphthoquinone derivatives from the Ebenaceae. III.
Shinanolone from Diospyros japonica SIEB. Chem Pharm Bull. 19(11):2314–2317.
Laatsch H. 1978. Synthese von stypandron (6-acetyl-5-hydroxyl-7-methyl-1, 4-naphthochinon).
Tetrahedron Lett. 19(36):3345–3348.
Laatsch H. 1980. Synthese von biramentaceon, mamegakinon und rotundichinon. Liebigs Ann
Chem. 1980(8):1321–1347.
Mahapatra A, Mativandlela SP, Binneman B, Fourie PB, Hamilton CJ, Meyer JJM, Van der Kooy F,
Houghton P, Lall N. 2007. Activity of 7-methyljuglone derivatives against Mycobacterium
tuberculosis and as subversive substrates for mycothiol disulfide reductase. Bioorg Med
Chem. 15(24):7638–7646.
Mahapatra A, Tshikalange T, Meyer J, Lall N. 2012. Synthesis and HIV-1 reverse transcriptase
inhibition activity of 1, 4-naphthoquinone derivatives. Chem Nat Compd. 47(6):883–887.
Maiti BC, Musgrave OC, Skoyles D. 2005. The regioselective synthesis of monomethoxynaphthy-
lene diacetates. Tetrahedron. 61(7):1765–1771.
Mbaveng AT, Kuete V. 2014. Review of the chemistry and pharmacology of 7-methyljugulone.
Afr H Sci. 14(1):201–205.
Musgrave OC, Skoyles D. 2001. Ebenaceae extractives. Part 11. 1 The synthesis of 7-methylju-
glone. A re-examination. J Chem Soc, Perkin Trans 1. 2001(11):1318–1320.
Nair V, Deepthi A. 2007. Cerium(IV) ammonium nitrate-a versatile single-electron oxidant. Chem
Rev. 107(5):1862–1891.
O’Keefe BM, Mans DM, Kaelin DE, Martin SF. 2010. Total synthesis of isokidamycin. J Am Chem
Soc. 132(44):15528–15530.
O’Keefe BM, Mans DM, Kaelin DE, Martin SF. 2011. Studies toward the syntheses of
pluramycin natural products. The first total synthesis of isokidamycin. Tetrahedron. 67(35):
6524–6538.
Parker KA, Kallmerten J. 1980. Approaches to anthracyclines. 1. Conjugate aroylation of. alpha.,.
beta.-unsaturated esters. J Org Chem. 45(13):2614–2620.
Parker KA, Tallman EA. 1984. Annelative phenol synthesis: preparation of 7-methyljuglone and 7,
9, 11 trideoxydaunomycinone. Tetrahedron. 40(22):4781–4788.
Rauf A, Uddin G, Khan H, Arfan M, Siddiqui BS. 2016. Bioassay-guided isolation of antibacterial
constituents from Diospyros lotus roots. Nat Prod Res. 30(4):426–428.
Savard J, Brassard P. 1984. Reactions of ketene acetals-14 The use of simple mixed vinylketene
acetals in the annulation of quinones. Tetrahedron. 40(18):3455–3464.
Singh SB, Graham PL, Reamer RA, Cordingley MG. 2001. Discovery, total synthesis, HRV 3C-prote-
ase inhibitory activity, and structure–activity relationships of 2-methoxystypandrone and its
analogues. Bioorg Med Chem Lett. 11(24):3143–3146.
Sinha B, Bansal S, Pattnaik A. 2009. Phytochemical and antimicrobial activity of extracts, fractions
and betulin, 7-methyl juglone obtained from Diospyros paniculata. Journal of Natural
Remedies. 9(1):99–102.
Tanoue Y, Terada A. 1988. The 2-or 6-(a-Hydroxyalkyl-and a-Oxoalkyl)-5, 8-dimethoxy-1, 4-naph-
thoquinones from the Oxidative Demethylation of 2-(a-Hydroxyalkyl-and a-Oxoalkyl)-1, 4, 5,

8
J. CUI ET AL.
8-tetramethoxynaphthalenes with Cerium (IV) Ammonium Nitrate, and the Further
Demethylations to Naphthazarins. BCSJ. 61(6):2039–2045.
Van der Kooy F, Meyer JM. 2006. Synthesis of the antimycobacterial naphthoquinone, 7-methyl-
juglone and its dimer, neodiospyrin. S Afr J Chem. 59(1):60–61.
Wright D, Mitchelmore C, Dawson R, Cutler H. 2007. The influence of water quality on the tox-
icity and degradation of juglone (5-hydroxy 1, 4-naphthoquinone). Environ Technol. 28(10):
1091–1101.