Synthesis of Isocoumarins and Dihydroisocoumarins
This chapter initially reviews methods for the preparation of isocoumarin derivatives and describes some previous synthetic methods. A new selenium-catalysed synthesis of isocoumarins is discussed and its application for preparation of a range of isocouma
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Synthesis of Isocoumarins and Dihydroisocoumarins
This chapter initially reviews methods for the preparation of isocoumarin derivatives and describes some previous synthetic methods. A new selenium-catalysed synthesis of isocoumarins is discussed and its application for preparation of a range of isocoumarins by reaction of stilbene carboxylic acids with diphenyl diselenide and a hypervalent iodine reagent is described. It was also discovered that dimethyl diselenide and diphenyl disulfide can be used in place of diphenyl diselenide. Using this modification the method was extended to prepare more challenging dihydroisocoumarins.
4.1 Applications of Isocoumarins and Dihydroisocoumarins The isocoumarin skeleton is part of many naturally occurring lactones which display a wide range of biological and pharmacological activities [1–6]. 3,4-Dihydroisocoumarins and their derivatives are compounds that widely exist in nature and serve as key intermediates in the synthesis of biologically active molecules. As these compounds are known to have a wide range of interesting activities such as antifungal, antiallergenic, antiulcer, and antimalarial activities, they are regarded as highly attractive molecules in organic chemistry [3–6]. 3-Aryl-isocoumarin derivatives constitute a pharmacologically important chemical entity which occurs in several natural products. These include thunberginol C, D, and E and hydrangenol [7, 8]. Pharmacological activities of these natural products include the promotion of the adipogenesis of murine 3T3-L1 cells [7] and antiproliferative activity against mouse splenocytes [8]. Other 3-aryl-3,4-dihydroisocoumarins [9] show antifungal activity [10], inhibition of rat basophilic leukaemia RBL-2H3 cells [11], antiproliferative activity against C57/BL6 mouse splenocytes [8], antiallergic activity [12], induction of steroidogenesis [13], phagocytic activity [9], immunomodulatory activity on spleen lymphocyte proliferation (activated by
S. A. Shahzad, Novel Selenium-Mediated Rearrangements and Cyclisations, Springer Theses, DOI: 10.1007/978-3-642-33173-2_4, Springer-Verlag Berlin Heidelberg 2013
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4 Synthesis of Isocoumarins and Dihydroisocoumarins
OH
R2
NO2
R 2 −CH 2 −NO 2
R2 NaBH 4, DMSO
O
NO2
O
OH
Et 3 N, DMSO O R1 244
R1
1. NaOH 2. H 2SO 4, MeOH or 1. NaOMe, MeOH 2. TiCl3 , NH4 OAc 3. H3 O+
R2 O CO2H R1 247
R1
O 245
O 246 R2
Ac 2 O, EtOAc, H
+
20— 85%
O R1
R 1 = H, OMe; R2 = H, Me, Et, Ph
O 248
Scheme 4.1 Synthesis of isocoumarins 248 from phthalaldehydic acids 244
lipopolysaccharide, concanavalin A and phytohaemagglutinin in mice) [14] and antimicrobial activity [15–19]. In a number of natural products, one of the hydroxyl groups in the 3-aryl-3,4-dihydroisocoumarin core is glycosylated; this includes, for example, (–)-hydrangenol 40 -O-glucoside [5] and phyllodulcin 8-Oglucoside [7, 16].
4.2 Previous Synthesis of Isocoumarins and Dihydroisocoumarins 4.2.1 Regiospecific Synthesis of Benzopyran-1-ones In 1988, Hauser and co-workers [20] reported the synthesis of benz
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