Valuable building block for the synthesis of lunularic acid, hydrangeic acid and their analogues

Article abstract of DOI:10.1080/14786419.2016.1274891

A new functionalised sulphone-based building block has been synthesised that enabled C-C bond formation through Julia olefination. The utility of developed building block was demonstrated by successful synthesis of two natural products lunularic acid, hydrangeic acid and initial libraries of their analogues.

Full text of DOI:10.1080/14786419.2016.1274891

Natural Product Research
Formerly Natural Product Letters
ISSN: 1478-6419 (Print) 1478-6427 (Online) Journal homepage: http://www.tandfonline.com/loi/gnpl20
Valuable building block for the synthesis of
lunularic acid, hydrangeic acid and their analogues
Ramesh Mukkamala, Asik Hossain & Indrapal Singh Aidhen
To cite this article: Ramesh Mukkamala, Asik Hossain & Indrapal Singh Aidhen (2017): Valuable
building block for the synthesis of lunularic acid, hydrangeic acid and their analogues, Natural
Product Research, DOI: 10.1080/14786419.2016.1274891
To link to this article: http://dx.doi.org/10.1080/14786419.2016.1274891
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Date: 03 January 2017, At: 06:50

Natural Product research, 2017
http://dx.doi.org/10.1080/14786419.2016.1274891
Valuable building block for the synthesis of lunularic acid,
hydrangeic acid and their analogues
Ramesh Mukkamala, Asik Hossain and Indrapal Singh Aidhen
department of chemistry, Indian Institute of technology Madras, chennai, India
ABSTRACT
ARTICLE HISTORY
received 7 July 2016
accepted 1 december 2016
A new functionalised sulphone-based building block has been
synthesised that enabled C-C bond formation through Julia
olefination. The utility of developed building block was demonstrated
by successful synthesis of two natural products lunularic acid,
hydrangeic acid and initial libraries of their analogues.
KEYWORDS
lunularic acid; hydrangeic
acid; amorfrutin;
cajaninstilbene acid; Julia
olefination; bi-benzyl natural
products
1. Introduction
Development of simple synthetic routes for the synthesis of medicinally important synthetic
molecules, natural products and their analogues is ongoing quest in our laboratory using
building block concept (Senthilmurugan & Aidhen 2010; Mukkamala et al. 2013). The con-
tinued investigation on this concept has resulted in a common building block for the syn-
thesis of two natural products Amorfrutin 1, Cajaninstilbene acid 2 as well as their analogues
represented by general structure 3, 4 (Figure 1). The excellent biological activity displayed
by the analogues 3 and 4 such as peroxisome proliferators-activated receptors agonist
(PPARα, PPARβ/δ, and PPARγ), (Aidhen et al. 2015), necessitated some further studies. The
compounds 3 and 4 were result of systematic variation in the nature of aryl ring B present
in the natural products 1 and 2. The quest to understand the influence of variation in ring
A while keeping the important salicylic acid component of ring A intact, prompted direction
to our additional studies. With this objective, we aimed at synthesis of compounds 5, 6
CONTACT Indrapal singh aidhen
isingh@iitm.ac.in
supplemental data for this article can be accessed at http://dx.doi.org/10.1080/14786419.2016.1274891.
© 2017 Informa uK limited, trading as taylor & Francis Group

2
R. MUKKAMALA ET AL.
without prenyl and methoxy substituents in ring A. In the absence, a convenient route for
ready access to the envisaged compounds developing an alternative route became neces-
sary. Incidentally, the desired compounds 5, 6 are structural variants of two natural products
lunularic acid 7 (Valio et al. 1969) and hydrangeic acid 8 (Yoshikawa et al. 1996). Lunularic
acid 7 is an age-old natural product isolated from liverworts Lunularia cruciata (Valio et al.
1969) that showed interesting plant growth inhibitory and antifungal activity. Few methods
are described for the synthesis of lunularic acid 7 in the literature. They involve hydrogen-
olysis of 3-aryl isocoumarin (Arai et al. 1972, 1973), reduction of dihydroisocoumarins with
sodium borohydride–palladium chloride (Hashimoto et al. 1988), benzylic metalation fol-
lowed by alkylation or Wittig olefination and hydrogenation sequence of appropriate sub-
stituted coupling partners (Eicher et al. 1988; Nguyen et al. 2006). Sonogashira cross-coupling
reaction of functionalised aryl halide or triflate with substituted phenyl acetylene followed
by hydrogenation is yet another method (Fuerstner & Nikolakis 1996). Suzuki cross-coupling
reaction of suitably functionalised aryl coupling partners also paved the way for total syn-
thesis of lunularic acid (Bracher et al. 2000).
A new building block 9 has been developed for the convenient access to 7, 8 and several
of their analogues 5 and 6. This building block is easy to assemble in gram-scale quantity
and allows efficient C-C bond formation through modified Julia olefination reaction
(Scheme 1). Direct olefination of several aromatic aldehydes with 9 provided convenient
Figure 1. structure of important natural products.
Scheme 1. Key building block for synthesis of lunularic acid, hydrangeic acid and their analogues.

NATURAL PRODUCT RESEARCH
3
access to protected intermediate 10. Simple hydrolysis of 10 gave 8 and its analogue 6,
whereas hydrogenation followed by hydrolysis on 10 afforded 7 and its analogue 5.
2. Results and discussion
The synthesis of common building block 9 is delineated in Scheme 2. The known compound
12 was prepared in three steps from commercially available starting material 2-methyl-6-ni-
trobenzoic acid 11 according to literature (Mandal & Roy 2008; Holloway et al. 2003; Shen
et al. 2003). The first step afforded the 2-hydroxy-6-methylbenzoic acid 11a via hydrogena-
tion followed by diazotisation 11. The acetonide-protected compound 11b was obtained
in the second step using SOCl2 and acetone in dimethoxyethane (DME). Finally, benzylic
bromination of 11b offered the corresponding benzyl bromide 12 in good yield using
N-bromosuccinimide (NBS) and catalytic amount of azobisisobutyronitrile (AIBN) in CCl4.
Thio-alkylation of 2-mercaptobenzothiazole with 12 resulted into sulphide 13 in good yield
(91%) using triethylamine and dichloromethane as base and the solvent, respectively.
Scheme 2. (a) Pd/c (10%)/h2, Meoh, rt, 12 h, 90% (b) NaNo2 (1.1 equiv), 9% aq. h2so4 (10 ml for 1.0 g),
at −5 to 0 °c for 30 min then at 50 °c for 2 h, 86% (c) dMaP (4-dimethylaminopyridine) (0.5 equiv), dry
acetone (1.2 equiv), socl2 (1.4 equiv), dMe, rt, 3 h, 80% (d) NBs (1.1 equiv), aIBN (cat), dry ccl4, 80 °c, 20
°
h 93% (e) 2-mercaptobenzothiazole (1.2 equiv), et3N (2. equiv), dry ch2cl2, 0 c to rt, 2 h, 91% (f) h2o2
(30%) (15 equiv), Na2Wo4·2h2o (1.0 equiv), Meoh, rt, 12 h, 87%.
Scheme 3. (a) Nah (1.5 equiv), archo 14a-i (1.3 equiv), dMF, 0 °c to rt, 3-4 h (b) h2/Pd-c (0.1 equiv),
Meoh, rt, 12 h (c) Koh (5.0 equiv), thF/h2o (1:1), 60 °c, 12 h. [dMF = dimethylformamide and
thF = tetrahydrofuran].

4
R. MUKKAMALA ET AL.
Table 1. lunularic acid, hydrangeic acid and their analogues.
7 & 17a-f (Yield %)a
8 & 18a-h (Yield%)a
s.no
Ar in ArCHO
15a-i (Yield %)
16a-i (Yield %)
1
15a (76%)
16a (99%)
2
15b (98%)
16b (66%)
3
4
15c (56%)
15d (68%)
16c (90%)
16d (82%)
5
15e (55%)
16e (99%)
6
7
15f (89%)
15g (91%)
16f (83%)
16g (82%)
8
9
15h (76%)
15i (99%)
16h (98%)
16i (0%)
–
aIsolated yield after column chromatography.
Oxidation of sulphide 13 using 30% H2O2/Na2WO4·2H2O in methanol offered 9 in good yield
(87%) as white crystalline solid (Scheme 2).

NATURAL PRODUCT RESEARCH
5
The building block 9 was now reacted with various substituted aromatic aldehydes 14a-i
using sodium hydride as base and in DMF as solvent. A clean reaction ensued in all cases
affording the corresponding stilbenoids derivatives 15a-i in good to excellent yield as single
E-isomer (Scheme 3 and Table 1). The formation of E-isomer was confirmed from the mag-
nitude of the vicinal coupling constant between two olefinic protons as (3JH–H = 16 – 16.4 Hz)
in the 1H NMR spectrum.
The acetonide protection in stilbenoids 15a-i were conveniently removed by using KOH
in water/THF (1:1) mixture at 60 °C for 12 h to provide the targeted hydrangeic acid 8 and
its analogues 18a-h in good yields (53–88%). The results are summarised in Table 1. The
catalytic hydrogenation of intermediate compounds 15a-i by using H2/Pd-C in methanol
provided the dihydro stilbenoids derivatives 16a-h in good yields. Surprisingly, in case of
substrate 15i (Table 1, entry 9), hydrogenation of double bond was unsuccessful even with
the use of higher hydrogen pressure (50 psi) and long reaction period (24 h). Finally, the
removal of acetonide protection in all substrates 16a-h afforded the lunularic acid 7 and
few of its analogues 17a-f in good to excellent yields (62–88%). The obtainment of lunularic
acid 7 in slightly higher yield (83%) was noticed, when the use of O-benzyl ether protected
benzyaldehyde (Table 1, entry 8) was made for the olefination reaction, compared to the
use of acetyl-protected benzylaldehyde (75%) (Table 1, entry 1). Barring 18 g and 18 h
(Gunes, M and Speicher, A. 2003), all the synthesised compounds 17a-f and 18a-f, analogues
of lunularic acid and hydrangeic acid are hitherto unreported in the literature and hence
worthy of biological evaluation.
3. Conclusion
A common building block 9 has been developed, which has enabled synthesis of several
analogues (17a-f and 18a-h) of lunularic acid 7, hydrangeic acid 8, respectively, hitherto
not reported in the literature and worthy of biological studies.
Acknowledgements
I.S.A. thanks BRNS for the project and IIT-M for infrastructure. R.M. thanks CSIR for an SRF award.
Disclosure statement
No potential conflict of interest was reported by the authors.
References
Aidhen IS, Mukkamala R, Weidner C, Sauer S. 2015. A common building block for the syntheses of
amorfrutin and cajaninstilbene acid libraries toward efficient binding with peroxisome proliferator-
activated receptors. Org Lett. 17:194–197.
AraiY, Kamikawa T, Kubota T. 1972. A convenient synthesis of lunularic acid. Tetrahedron Lett. 13:1615–
1617.
Arai Y, Kamikawa T, Kubota T, Masuda Y, Yamamoto R. 1973. Synthesis and properties of lunularic acid.
Phytochem. 12:2279–2282.
Bracher F, Krauss J, Bornatsch A. 2000. Total synthesis of lunularic acid and lunularine, a new approach
to natural dihydrostilbenes. Nat Prod Lett. 14:305–310.

6
R. MUKKAMALA ET AL.
Eicher T, Tiefensee K, Pick R. 1988. Synthese von Bryophyten-Inhaltstoffen 1. Neue Synthesen der
Lunularsäure und einiger ihrer Derivate. Synthesis. 1988:525–529.
Fuerstner A, Nikolakis K. 1996. Ethynylation of aryl halides by a modified Suzuki reaction. Application
to the syntheses of combretastatin A-4, A-5, and lunularic acid. Liebigs Ann.2107–2113.
Gunes M, Speicher A. 2003. Efficient syntheses of ( )-hydrangenol, ( )-phyllodulcin and ( )-macrophyllol.
Tetrahedron. 59:8799–8802.
HashimotoT, Tori M, AsakawaY. 1988. A highly efficient preparation of lunularic acid and some biological
activities of stilbene and dihydrostilbene derivatives. Phytochem. 27:109–113.
Holloway GA, Hügel HM, Rizzacasa MA. 2003. Formal total synthesis of salicylihalamides A and B. J Org
Chem. 68:2200–2204.
Mandal SK, Roy SC. 2008. Titanocene (III) chloride mediated radical-induced synthesis of 3,
4-dihydroisocoumarins: synthesis of ( )-hydrangenol, ( )-phyllodulcin, ( )-macrophyllol and
( )-thunberginol G. Tetrahedron. 64:11050–11057.
Mukkamala R, Senthilmurugan A, Aidhen IS. 2013. Convenient access to acyl-substituted bis
(styrylbenzenes) based on building blocks using julia olefination and weinreb amide chemistry.
Eur J Org Chem. 2013:2216–2229.
Nguyen T-H, Castanet A-S, Mortier J. 2006. Directed ortho-metalation of unprotected benzoic
acids. Methodology and regioselective synthesis of useful contiguously 3- and 6-substituted
2-methoxybenzoic acid building blocks. Orga Lett. 8:765–768.
Senthilmurugan A, Aidhen IS. 2010. Synthesis of (+)-Varitriol Analogues via Novel and Versatile Building
Blocks Based on Julia Olefination. Eur J Org Chem. 2010:555–564.
Shen R, Lin CT, Bowman EJ, Bowman BJ, Porco JA. 2003. Lobatamide C: Total Synthesis, Stereochemical
Assignment, Preparation of Simplified Analogues, and V-ATPase Inhibition Studies. J Am Chem Soc.
125:7889–7901.
Valio IFM, Burdon RS, Schwabe WW. 1969. New natural growth inhibitor in the liverwort Lunularia
cruciata. Nature (London). 223:1176–1178.
Yoshikawa M, Shimada H, Yagi N, Murakami N, Shimoda H, Yamahara J, Matsuda H. 1996. Development
of bioactive functions in hydrangeae dulcis folium. VI. syntheses of thunberginols A and F and
their 3'-deoxy-derivatives using regiospecific lactonization of stilbene carboxylic acid: structures
and inhibitory activity on histamine release of hydramacrophyllols A and B. Chem Pharm Bull.
44:1890–1898.