Phthalides asymmetric synthesis

Absolute asymmetric synthesis was observed in the solid-state photoreaction of benzoylbenzamide 59 to phthalide 60 however, the reaction mechanism was completely different from that of thioester 57. [35] Recrystallization of these amides 59a-c from the chloroform-hexane solution afforded colorless prisms in all cases. X-ray crystallographic analysis revealed that all prochiral amides 59a-c adopted orthorhombic chiral space group P2 2 2 and were frozen in chiral and helical conformation in the crystal lattice. 

Recently, ketone hydroacylation has been extended to the asymmetric synthesis of phthalides (Scheme 2.45) [91]. Since the ketoaldehyde substrates lack an ether O, decarbonylation was found to be a major competing pathway when noncounterion effect was observed, with N03 being optimal. This methodology was applied to a short synthesis of (S)-(-)-3-n-butylphthalide, an extract of celery [91]. 

Scheme 2.45 Asymmetric synthesis of phthalides via ketone hydroacylation [91].

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. 

Scheme 24 Absolute asymmetric phthalide synthesis via aryl migration.

The enantioselective synthesis of phthalide 227 (the (3 )-isomer), and other substituted phthalides, and the determination of their absolute configuration has been reported <2005CH218>. In a different approach to the same compounds, 2-alkylbenzoic acids were fed to microorganisms known to affect asymmetric hydroxylation. Lactonization of the resulting alcohols yielded the phthalides, used as scents in cosmetics and soaps <1997JPP10243794>. There is sufficient interest in these optically pure compounds for a chiral gas chromatography (GC) stationary phase to have been developed to quantify stereoisomeric mixtures. A silylated /3-CD was employed... 

Figure 15-26. Asymmetric reduction by G. candidum ATCC 34614 for the synthesis of a bioactive phthalide derivative11711.

Accordingly, the synthesis of phthalide 44 began from methyl ketone 27 (Scheme 18). In order to avoid interference of the olefin moiety with haloge-nation of the aromatic ring, asymmetric dihydroxylation was conducted first. Treatment of alkene 27 with AD-mix a in tcrt-butanol/water (1 1) provided diol 27 in a pleasing 87% yield. Inspection of the and NMR spectra did not indicate the presence of a diastereomeric mixture. However, although alkene 27 is structurally well suited to the Sharpless mnemonic, we thought it... 

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... 

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). 

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