Titanocene(III) chloride mediated radical-induced synthesis of 3,4- dihydroisocoumarins: synthesis of ()-hydrangenol, ()-phyllodulcin, ()-macrophyllol and ()-thunberginol G Samir Kumar Mandal, Subhas Chandra Roy * Department of Organic Chemistry, Indian Association for the Cultivation of Science, Jadavpur, Kolkata 700 032, India article info Article history: Received 15 July 2008 Received in revised form 22 September 2008 Accepted 25 September 2008 Available online 7 October 2008 Keywords: Titanocene(III) chloride Dihydroisocoumarins Radical Natural products Synthesis abstract A radical-promoted synthesis of 3,4-dihydroisocoumarins has been achieved in moderate to good yields using titanocene(III) chloride (Cp 2 TiCl) as the radical initiator. The total synthesis of four naturally oc- curring dihydrocoumarins hydrangenol, phyllodulcin, macrophyllol and thunberginol G has been ac- complished using the radical technology. Cp 2 TiCl was prepared in situ from commercially available titanocene dichloride (Cp 2 TiCl 2 ) and Zn-dust in THF under argon. Ó 2008 Elsevier Ltd. All rights reserved. 1. Introduction The 3-aryl-3,4-dihydroisocoumarins constitute a class of natu- rally occurring compounds, which exhibit a broad range of signi- ficant biological activities such as antifungal, antiallergic, antileukaemic, antiulcer and antimalarial activities. 1 Although they are individually different by the number, and type of substituent on the aromatic ring, existence of 8-hydroxy group is very frequent at the core structure in many of them. Hydrangea Dulas Folium (amacha in Japanese), a natural medicine containing 3-aryl-3, 4-dihydroisocoumarins was isolated from the fermented and dried leaves of Hydrangea macrophylla Seringe var. thunbergii Makino, a plant indigenous to Japan. 2 This is widely used in confectionary, drinks, oral refrigerant and a sweetening agent. 3 It is also used to make tea served during the Hanamatsuri (birth of Buddha) cele- bration. Hydrangenol (1) and phyllodulcin (2) are the chief con- stituents (Fig. 1) of this natural medicine along with other. Several biological activities have been shown by phyllodulcin, including antiallergic effects on the Schultz-Dale reaction, 4 inhibition of mi- crosomal lipid peroxidation induced by NADPH and the Fenton- type reaction. 5 It has been shown by Matsuda that hydrangenol (1) suppresses T-lymphocyte proliferation induced by concanavalin A and compared the activity of hydrangenol (1) and thunberginol G (4) for T-lymphocyte suppression and concluded that 3 0 -OH group had no effect 6 in the same (Fig. 1). The discovery that phyllodulcin (2) is 600–800 times as sweet as sucrose and its medicinal im- portance has excited the chemist for structure–taste correlation in sweet dihydrochalcone and bitter flavone compounds. 7 Other dihydroisocoumarins do not show any sweetness property like phyllodulcin. A number of methods have been described for the synthesis of 3-aryl-3,4-dihydroisocoumarin derivatives, but most of these methods involve either ortho- or lateral-lithiation. 8 Other methods reported for the preparation of 3-aryl-3,4-dihydro- isocoumarins involve cyclization of stilbene carboxylic acids, 9 cycloaddition reactions, 10 AlCl 3 -mediated reaction, 11 polyketide- derived synthesis 12 and many others. 13 However, many of these methodologies suffer from harsh reaction conditions, multi-step procedures and inefficiency due to functional group intolerance. The mildness and efficiency of radical-mediated reactions have significantly encouraged synthetic chemists in recent years to uti- lize radical technology in developing novel methodologies and their applications in natural product synthesis. In a continuation of our studies of the synthesis of natural products involving radical-induced reactions, 14 we have developed a mild and novel radical-mediated methodology to construct C-3 substituted 3,4- dihydroisocoumarins in a single operation with moderate to good yields using dicyclopentadienyl titanocene(III) chloride (Cp 2 TiCl) as the radical initiator. Cp 2 TiCl can easily be prepared from the * Corresponding author. Tel.: þ91 33 2473 4971; fax: þ91 33 2473 2805. E-mail address: ocscr@iacs.res.in (S.C. Roy). Contents lists available at ScienceDirect Tetrahedron journal homepage: www.elsevier.com/locate/tet 0040-4020/$ – see front matter Ó 2008 Elsevier Ltd. All rights reserved. doi:10.1016/j.tet.2008.09.075 Tetrahedron 64 (2008) 11050–11057