Phthalides, chiral 3,3-disubstituted

N,A-Disubstituted 2-benzoylbenzamides 106 also formed chiral crystals in space group P212121. Irradiation of these crystals gave optically active phthalides 107 in high optical and chemical yields [97]. It was concluded from the x-ray structural analysis that the photoreaction promoted intramolecular cyclization to phthalides via a radical pair intermediate, not phenyl migration. 

Retrosynthetically, spiroketal precursor 8 would be accessed via a diaster-eoselective aldol reaction between chiral aldehyde 9 and a-chiral (3-arylated methyl ketone 10 (Scheme 3). Aldehyde 9 would be readily accessible from commercially available ethyl (S)-hydroxybutyrate, while methyl ketone 10 would be constmcted by the Suzuki cross-coupling of trifluoroboratoamide 11 and rotationally symmetric aryl halides 12/13. The use of Br or I in place of Cl in halides 12/13 was intended to increase the reactivity of 12/13 toward oxidative insertion and overcome the steric hindrance imparted by the ortho-disubstituted aromatic framework. The required functionalization of the aromatic ring to install the phthalide motif was envisioned to be possible via iridium-catalyzed CH-borylation either before or after formation of the spiroketal core. Our group already had experience with this remarkable transformation in the context of naphthalene chemistry. 

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. 

The greatest advantage of this approach is the circumvention of the use of optically active tertiary propargylic alcohols. The chiral Rh complex could efficiently desymmetrize the achiral alcohol to give the 3,3-disubstituted phthalides products in up to 87% isolated yield and 93% ee. The kinetic resolution of racemic tertiary propargylic alcohols provided disubstituted phthalides with up to 89% 3deld and up to 93% ee. 

A cationic rhodium(I)/Solphos complex catalyzed regio- and enantioselective one-pot [2 -I- 2 -I- 2] cycloaddition/transesteriflcation of 1,6-diynes, possessing the alkoxy-carbonyl group at an alkyne terminus, with tertiary propargylic alcohols to give chiral 3,3-disubstituted phthalides (Scheme 4.49) [52]. 

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