First Stereoselective Synthesis of the Versatile Chiral Building Block (7aR)-5,6-Dihydro-7a-methyl-1H-indene-2,7(4H,7aH)-dione

Abstract

A versatile chiral building block (7aR)-5,6-dihydro-7a-methyl-1H-indene-2,7(4H,7aH)-dione (4) was firstly enantiomerically synthesized from the microbial transformation ketol product 6 in 61.3% overall yield and over 96% ee.Enantiomerically pure bicyclic enones 1-4 may constitute useful building blocks for elaboration of synthetic strategies in the field of steroids, terpenes and related molecules. 1-4 The enantiomerically enriched forms of Wieland-Miescher ketone 1 and Hajos-Parrish ketone 2 could be efficiently prepared by asymmetric cyclization of their prochiral precursors, 2-methyl-2-(3-oxobutyl)-1,3-cyclohexanedione and 2-methyl-2-(3-oxobutyl)-1,3-cyclopentanedione, respectively, by the use of prolineenamine 2 or catalytic antibody. 3 However, ring construction of the fused cyclopentenones 3 and 4 from their corresponding 1,3-cycloalkanedione derivatives using the standard aldol condition is quite difficult. 4 Though optically active 3 has been asymmetrically synthesized by Trost 5 and Brooks, 6 preparation of the enantiomerically enriched form of 4 has not been reported so far, to our knowledge. 7 In this paper, we present the first enantioselective synthesis of the versatile building block 4 from the ketol 6.Enantiomerically pure ketol 6 could be prepared by microorganism asymmetric reduction of the corresponding prochiral diketone 5, 8 or by enzymatic hydrolysis of prochiral dienol diacetate of 5 developed recently by Renouf et al. 9 Though baker's yeast mediated asymmetric reduction of ketones has been widely used to obtain chiral building blocks since it is cheap, versatile, and easy to perform, 10 baker's yeast reduction of 5 provided a nearly equivalent mixture of diastereomeric ketols 6 and 7. 8 However, the highly reductive fungus, Geotrichum sp., 11 could reduce the diketone 5 more efficiently to give the ketols 6 and 7 in the ratio of 83:17 (Scheme 1). Scheme 1Because the two diastereomeric ketols 6 and 7 could not be separated efficiently by silica gel chromatography, the mixture obtained from microbial reduction of 5 was converted to the corresponding acetals 8 and 9, which could be separated efficiently by chromatography. After treatment with 3 M HCl, compounds 8 and 9 were converted to ketols 6 and 7 in nearly optically pure forms, respectively (Scheme 2).Reagents and conditions: i) Cat. p-TsOH, HOCH 2 CH 2 OH, CH(OEt) 3 ; ii) 3 M HCl. Scheme 2Considering that the hydroxy group would interfere with the subsequent transformations, it was efficiently protected as the tert-butyldimethylsilyl ether 10. Wacker oxidation of the olefin provided the corresponding dione 11 with good yield (83%). Cyclization and dehydration of diDownloaded by: University of North Carolina -Chapel Hill. Copyrighted material.

Asymmetric Synthesis of a Bicyclo[4.3.0]nonene Derivative Bearing a Quaternary Carbon Stereocenter: Desymmetrization of σ-Symmetrical Diketones through Intramolecular Addition of an Alkenyl Anion

“…Oxidation of 4a (40% ee) with PDC in CH 2 Cl 2 gave diketone 17 in 57% yield, which was identified by comparison with the reported proton NMR spectrum. 17 The reported specific rotation of (R)-17 is +47.3 while the specific rotation of synthetic 17 was found to be -18.0 (40% ee). Therefore, the absolute configuration of the quaternary carbon in 17 was determined to be S. From these results, the absolute configurations of the newly formed contiguous tetrasubstituted carbons in 4a were determined to be 1S,6S due to the known cis-fused structure.…”

“…Treatment of 6b with n-BuLi in the presence of ZnCl 2 led to a slightly lowered yield and ee (entry 12). Although various chiral ligands (L2-L6) were evaluated using similar conditions to those of entry 6 (Table 2) in an attempt to improve the yield and ee of 4a, these efforts were unsuccessful (entries [13][14][15][16][17]. The following observations on the chiral ligands are noteworthy: (1) chiral ligands containing oxygen atoms tended to give better enantioselectivities than those possessing nitrogen atoms (entries 6 and 14 vs 16 and 17), (2) a methyl group was a suitable substituent on the oxygen atom of the chiral ligand (entries 6 and 14 vs 13), and 3a phenolic oxygen on the chiral ligand decreased both the yield and ee of 4a (entries 6 and 14 vs 15).…”