Chiral phthalides [isobenzofuran-1(3H)-ones] comprising of 5-membered lactones are found in large number of plant products with broad and potent biological activities. An article titled “The Structural Diversity of Phthalides from the Apiaceae” by John J. Beck in J. Nat. Prod., 2007, 70 (5), pp 891-900 discloses the bioactivity of chiral phthalides against several illnesses and physiological conditions, including microbial and viral infections, stroke, tuberculosis.
Due to the biological importance of the 3-substituted chiral phthalides, their molecular architectures have become a platform for new synthetic methodology development. Over the past two decades, a variety of methods toward introducing C-3 chirality in phthalides have been established which include i) transfer hydrogenation of ketone [Tetrahedron Lett. 1990, 31, 5509 by Noyori et al]. ii) catalytic enantioselective addition of dialkylzinc reagents to o-phthalaldehyde [J. Org. Chem. 1992, 57, 742 by Butsugan et al]. iii) Nickel-catalyzed tandem reaction to asymmetric synthesis of chiral phthalides [Synlett 2002, 927 by Lin et al]. iv) enantioselective cross alkyne cyclotrimerization in the presence of the cationic complex [RhI{(S)-H8-binap} [Angew. Chem., Int. Ed. 2004, 43, 6510] and rhodium-catalyzed asymmetric one-pot transesterification and [2+2+2] cycloaddition disclosed in M. Org. Lett. 2007, 9, 1307 by Tanaka et al vi) alkynylation of aldehydes (Trost, B. M.; Weiss, A. H. Angew. Chem., Int. Ed. 2007, 46, 7664.), (vii) cyclization approach (Chang, H. T.; Jaganmohan, M.; Cheng, C. H. Chem. Eur. J. 2007, 13, 4356), (viii) organocatalytic aldol-lactonization process (Zhang, H.; Zhang, S.; Liu, L.; Luo, G.; Duan, W.; Wang. W. J. Org. Chem. 2010, 75, 368.) and reductive cyclization of 2-acylarylcarboxylates (Zhang, B.; Xu, M. H.; Lin G. Q. Org. Lett. 2009, 11, 4712).
Ligand accelerated Sharpless Asymmetric Dihydroxylation(AD) of prochiral olefins is widely used for the generation of 1,2-diols. Enantioselectivity is achieved through the addition of enantiomerically-enriched chiral ligands [(DHQD)2PHAL, (DHQ)2PHAL or their derivatives] which are available as prepackaged mixtures (AD-mix a and AD-mix β, AD=asymmetric dihydroxylation) for either enantiopreference. The present inventors in their earlier studies have reported a method that employs AD process followed by Co-catalyzed “one-pot” reductive cyclization (CoCl2—NaBH4) of nitro cyclic sulfites, which led to the construction of 3-substituted tetrahydroquinolin-3-ols. Further, the said process was extended to prepare synthetically useful benzazepines i.e via AD process and catalytically accelerated reductive cyclisation of cyano cyclic sulfites.
In view of the biological importance of 3-substituted chiral phthalides and the limitations envisaged in the prior art processes for preparation of the same, the inventors of present invention believed that AD process followed by catalytic oxidative cyclisation could provide 3-substituted chiral phthalides in high yield and optical purity in short time.
However, the aforesaid processes employ chiral auxiliaries and expensive organometallic reagents that lack broad substrate scope and higher reaction stereo selectivity, also very few process are catalytic and atom economical.
USPTO Backgrounds
USPTO Backgrounds