Methyl orsellinate

A search for available starting materials with both oxygen atoms present revealed methyl orsellinate 31 so the chlorine could be disconnected next to give 30. Regioselectivity was confined to the formylation of 31 and they did indeed have difficulty with that step. 

Methyl orsellinate 31 was differentially protected and formylated to give 33 after removal of the isopropyl group with TiCl4. Benzylation and oxidation gave the benzoic acid 34 ready for a surprising conclusion to the synthesis. 

There has been considerable activity in the synthesis of orsellinic acids in the past decade. On account of their ready decarboxylation all these procedures also give access to 5-alkylresorcinols. These routes are summarised in the scheme shown. Homologous alkyl acetoacetates (R = R = alkyl) with thallium ethoxide or sodium hydride followed by reaction with diketene (route a) afford the corresponding homologous alkyl orsellinates (ref.23). In a related method (route b) methyl orsellinate (R = Me) results from the interaction of the monoanion with the dianion of methyl acetoacetate (ref.24). 

A closely related methodology (route c) involves the dianion from a diketone (R = Me) with the anion of dimethyl malonate (R = Me) (ref.25). The bis-trimethylsilyl ether from methyl acetoacetate has been interacted with the ketalised acid chloride shown (R = CgH ) to furnish the methoxy carbonyl derivative of olivetol (route d) (ref.26). It was also found that pentane-2,4-dione with dimethyl malonate in the presence of sodium hydride afforded methyl orsellinate (ref.26). In a biomimetic approach (route e) a tetraketone has been enzymically cyclised to give the corresponding orsellinic acid (R=H, R = alkyl) (ref. 27). 

Aigialomycin D is a metabolite of the mangrove fungus Mgialus parvus and was shown to be a kinase inhibitor with modest antimalarial activity. The convergent synthesis showcased here assembled three fragments into the full carbon skeleton (Scheme 836). The ester-containing benzylic bromide 134 was prepared from methyl orsellinate, itself derived from methyl acetoacetate. Thioacetate 135 was formed from d-ribose as will be described, while homoallylic alcohol 136 was commercially available. 

Methyl orsellinate. Methyl 2,4-dihydroxy-6-methylbenzoate (Orsellinsauremethylester, 2,4-Dihydroxy-6-methylbenzoesauremethylester)... 

Dyke HJ, Elix JA, Marcuccio SM, Whitton AA (1987) Oxidation of alkyl 1,6-dihydro-orsellinates. A new method for the synthesis of methyl orsellinate and homologues. Aust J Chem 40 431-434... 

Huneck S, Yoshimura I (1996) Identification of lichen substances. Springer, Berlin, p 493 Hussain MS, Fareed S, Ansari S et al (2012) Current approaches toward production of secondary plant metabolites. J Pharm Bioallied Sci 4 10-20 Ingolfsdottir K, Gudmundsdottir GF (2002) Effects of tenuiorin and methyl orsellinate from the lichen Peltigera leucophlebia on 5-/15-lipoxygenases and proliferation of malignant cell lines in-vitro. Phytomedicine 9 654-658... 

PD-,K-,C+ red Anziaic acid, 4-(9-demethylbarbatic acid, erythrin, ethyl orsellinate, gyrophoric acid, lecanoric acid, methyl 3,5-dichlorolecanorate, methyl- -orsellinate, montagnetol, olivetoric acid, siphulin... 

Methyl orsellinate 208-210 From methyl acetoace-tate and -BuLi with NaFl in THF and subsequent acidification (70)... 

Rycroft DS, Cole WJ, Aslam N, Lamont YM, Gabriel R (1999) Killamiensolide, Methyl Orsellinates and 9,10-Dihydrophenanthrenes from the Liverwort Plagio-chila killarniensis from Scotland and the Azores. Phytochemistry 50 1167... 

From 2,4-dihydroxy-3,6-dimethyl-5-chlorobenzoic acid and methyl P-orsellinate with TFAA From 2,4-dibenzyloxy-3,6-dimethyl-5-chlorobenzoic acid and methyl orsellinate with TFAA and subsequent debenzylation From 4-benzyloxy-2-methoxy-6-n-pentyl-benzoic acid and 2,3-dihydroxy-4-methoxy-6-n-pentylbenzoate with TFAA and subsequent debenzylation... 

Stipitatonic Acid (75). The mechanism for the oxidative cleavage of 3-methyl-orsellinic acid (74) to afford the tropolone stipitatonic acid (75) in Penicillium stipitatum was very elegantly demonstrated with labelling. Two pathways were considered, the dioxygenase recyclization route. Scheme 20, and the mono-oxygenase ring-expansion route, Scheme 21. 

Methyl orsellinate (57) Atranorine (78) Orsellinic acid (79) Lecanoric acid (80) Antioxidant Stereocaulon alpinum Laurer, Ramalina terebrata Hook., and Taylor, Caloplaca regaiis (Vain.) Zahibr [104]... 

Methyl orsellinate (57) Lobaric acid (62) Lecanoric acid (80) Sakikaic acid (88)... 

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