Synthesis of Naturally Occurring (Z)-3- Benzylidenephthalide and (2) 3-Benzylphthalides{ Raghao S. Mali,* Archna P. Massey and Manohar I. Talele Garware Research Centre, Department of Chemistry, University of Pune, Pune 411007, India A convenient method, involving the generation of the phthalide anion, is described for the synthesis of naturally occurring (Z)-3- benzylidenephthalide (5) and (2) 3-benzylphthalides (6c, 10a^c), starting fromphthalides (7a and 7b). 3-Benzylidenephthalides are found to be synthetically useful intermediates for a wide variety of carbocyclic and hetero- cyclic compounds including some alkaloids.1 The (Z)-3-ben- zylidenephthalide (thunberginol-F 5),2 3-benzylphthalides3±5 (balantiolide 10a) and related phthalides (10b, 10c and 10e) and hydramacrophyllols A and B (6a and 6b) have been iso- lated from natural sources.These phthalides are valuable as they possess interesting biological activities. In view of the importance of 3-benzylidenephthalides, several general methods are reported for their synthesis.8 Since the iso- lation2 of thunberginol-F 5 in 1992, three methods have been reported for its synthesis.11±13 However, the naturally occurring 3-benzylphthalides 10a±c have not been syn- thesised so far.Since considerable work has been done in our laboratory on the synthesis of naturally occurring 3-alkylidenephtha- lides using the iodolactonisation approach, the approach was extended to the synthesis of 3-benzylidenephthalides15 (Scheme 1).The 3-benzylidenephthalides (3 and 4) were obtained in 13 and 12% yields respectively. The stereochem- istry of the 3-benzylidenephthalides (3 and 4) was deter- mined by 1H NMR. As the yields by this approach were poor, the syntheses of thunberginol-F 5 (2) 3-benzylphtha- lides 10a±c and the dimethyl ether 6c of hydramacrophyllols 6a and 6b have been achieved using the phthalide anion route (Scheme 2). For the synthesis of thunberginol-F, the anion of phtha- lide 7a,19 generated in situ18 using LDA in THF at ¡78 8C was treated with veratraldehyde.The hydroxyphthalide 8a was obtained as a mixture of diastereoisomers (1:1.6), in 55% yield. Dehydration of 8a using toluene-p-sulfonic acid in re—uxing benzene gave the trimethyl ether of thunbergi- nol-F, 9a, mp 186 8C (lit.,13 186±188 8C). The conversion of J. Chem. Research (S), 1998, 68±69 J. Chem. Research (M), 1998, 0472±0500 CO2H Ph O O Ph I H O O Ph H O O H Ph I2,aq KI, aq NaHCO3 NaOAc, EtOH reflux + 1 2 3 4 Scheme1 Scheme 2 O HO O H OH OH O OR O R2 OR 5 6a R = R1 = H, R2 = OH b R = R2 = H, R1 = OH c R = Me, R1 = OH, R2 = H 1 2 3 4 5 6 7 1c 2c 3c 4c 5c 6c H R1 $Dedicated to Professor M. S.Wadia on the occasion of his 60th birthday. *To receive any correspondence (e-mail: rsmali@chem.unipune. ernet.in). 68 J. CHEM. RESEARCH (S), 19989a to thunberginol-F 5 using BBr3 has already been reported in the literature.12,13 The syntheses of balantiolide 10a and related phthalides 10b and 10c have been achieved from phthalide 7b.The anion of 5,7-dimethoxyphthalide (7b) was reacted with veratraldehyde and 4-benzyloxy-3-methoxybenzaldehyde to obtain the hydroxyphthalides 8b and 8c. These phthalides 8b and 8c on dehydration using toluene-p-sulfonic acid gave the (Z)-3-benzylidenephthalides 9b and 9c which were hydrogenated, to give (2) O-methylbalantiolide (10b) and the (2) 3-benzylphthalide (10c) in 84 and 77% yields re- spectively.The naturally occurring 3-benzylphthalide, balantiolide (10a), has been synthesised from the benzylidenephthalide 9b via the intermediacy of 9e. The tetramethoxy 3-benzyl- idenephthalide 9b was reacted with AlCl3 in methylene chloride at room temperature, to give phthalide 9e in 82% yield. Hydrogenation of 9e using 10% Pd/C in ethyl acetate gave the (2) 3-benzylphthalide 10a in 71% yield. The 5,6-dimethoxyphthalide (7c)21 on similar sequence of reactions provided (2) 3-(4-methoxybenzyl)-5,6-dimethoxy- phthalide (10d), via the 3-hydroxyphthalide 8d and 3-benzyl- idenephthalide 9d.Using the phthalide anion approach the synthesis of 6c, a dimethyl ether of 6a and 6b, has been achieved in 73% yield from phthalide 7a. We are thankful to Professor N. S. Narasimhan for critical reading of the manuscript and valuable discussions. A.P.M. thanks the CSIR, New Delhi, for the award of a Senior Research Fellowship. M.I.T.thanks UGC New Delhi for the award of a teacher fellowship. Techniques used: IR, 1H NMR, elemental analysis, TLC and column chromatography References: 22 Schemes: 2 Received, 20th October 1997; Accepted, 22nd October 1997 Paper E/7/07565K References cited in this synopsis 1 (a) R. A. Aitken, H. R. Cooper and A. P. Mehrotra, J. Chem. 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