3.3- Disubstituted phthalides, synthesis

Sakamoto, M., Sekine, N., Miyoshi, H., and Fujita, T. (2000) Absolute asymmetric phthalide synthesis via the solid-state photoreaction of AW-disubstituted 2-benzoylbenzamides involving a radical pair intermediate, J. Am. Chem. Soc., 122, 10210-10211. 

The Rh(I)-complex of SOLPHOS (59) has been used in a novel synthesis of 3,3-disubstituted phthalides where its complex outperformed BINAP (la) by achieving high enantioselectivities up to 92% ee (Scheme 12, 070L1307). 

Tanaka et al. developed a Rh-catalyzed asymmetric one-pot transesterification and [2+2+2] cyclotrimerization using nonracemic ligand 415 in the synthesis of enantio-enriched 3,3-disubstituted phthalides (R R ) (Scheme 2-39)P The chiral Rh complex with 415 efficiently desymmetrized dipropargyl alcohols 413 (R = R -OC-) in the reaction with 412 to give phthalides 414 (R = R -C=C-) in up to 87% yield and 93% ee. Also, the kinetic resolution of racemic tertiary propargylic alcohols... 

Chiral 3-substituted phthalides are an important core structure in a number of biological compounds (85-87). The synthesis of chiral phthalides has been achieved by Witulski and Zimmerman starting from optically pure propargylic alcohols 76 and acids 75 (Scheme 40) (88). The chiral ester-linked diynes 77 were trimerized with acetylene using RhCKPPhsls as the catalyst to afford the optically pure phthalides 78 in good yields. However, the major drawback of this reaction is the low yield in the esterification step. This reaction is also difficult to apply to the synthesis of 3,3-disubstituted phthalides due to the difficulties in the preparation of optically pure tertiary propargylic alcohols. 

Recently, Tanaka and co-workers developed a Rh-catalyzed asymmetric one-pot transesterification/cyclotrimerization for the synthesis of enantioenriched 3,3-disubstituted phthalides (Scheme 41) (89). 

A facUe synthesis of 3,4-disubstituted isocoumarins and their benzologues is based on the Pd-catalysed annulation of internal alkynes by 2-iodobenzoate esters (Scheme 27). Tri- and tetra- substituted pyran-2-ones are also available by this route <99JOC8770>. 3-Substituted isocoumarins result from the Pd-catalysed 6-endo-dig cyclisation of 2-ethynylbenzoic acids. The 5-exo-dig products, phthalides, are also formed when there is a terminal bulky group on the alkyne moiety <99S1145>. 

The synthesis of phthalides by lithiation route is according to type C and involves, in the first step, the synthesis of the disubstituted compound of the type 14. This is... 

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