Tropane alkaloids are generally known as anticholinergics. Radiolabeled tropane compounds could be brain imaging agents used in biomedical imaging technique positron emission tomography (PET). A novel entry to aryltropane analogs of cocaine was developed based on the conjugate addition reaction of Grignard reagents phenylmagnesium (10), (4'-isopropenylphenyl)magnesium (11), or 2-naphthylmagnesium bromide (12) to α,β-unsaturated esters anhydroecgonine methyl ester (9) or t-butyl ester (13) which gave several aryltropanes (1–8) with high binding affinities for dopamine and serotonin transporters. Basic conditions are frequently employed in the radiolabeling chemistry of many aryltropane cocaine analogs (1–8b, 14–24b). However, isomerization at C-2 position can also occur under basic conditions, resulting in loss of the biologically potent 2β-isomers (1–8b, 14–24b) by conversion to the much less active 2α-isomer (1–8a, 14–24a). Tropinone (25) could be envisaged as a convenient starting material for the synthesis of diverse tropane alkaloids. A novel entry into tropane alkaloid intermediates was developed based on the ring-opening reaction of tropinone. In this reaction, the enolate of tropinone, resulting from deprotonation with lithium diisopropylamide [ LDA , LiN ( CHMe 2)2] or sodium bis(trimethylsilyl)amide [ NaN ( SiMe 3)2] was treated with alkyl chloroformate to give a novel, structurally unique class of tropane alkaloid intermediates 6-N-carboalkyoxy-N-methyl-2-cycloheptenone (26), 1-alkyoxycarboxy-6-N-carboalkoxy-N-methyl-2,7-cyclohept-dien (27) and 6-N-carboalkyoxy-N-methyl-7-carboalkoxy-2,7-cyclohept-dien-ol (28). In this paper we study the conjugate addition reaction of Grignard reagents to α,β-unsaturated esters, the isomerization of aryltropane cocaine analogs, and the ring-opening reaction of tropinone by ab initio MO calculation at the Hartree–Fock (HF) level. The calculation results solely in terms of energetics indicate that the 2α-isomers (equatorial configurations) of aryltropane cocaine analogs are more stable than their 2β-isomers (axial configurations), at the AM1, STO-3G and 3-21G(*) levels, and the Grignard 1,4- and then 1,2-addition (double addition) products (2, 4, 5 and 7) are likely more stable than the Grignard 1,4-addition (single addition) products (1, 3, 6 and 8), respectively, at the STO-3G and 3-21G(*) levels except at the AM1 level. Therefore the tendency of Grignard addition toward double addition is competitive with single addition, and the isomerization tends to the formation of more stable 2α-isomers. Likewise, the calculation results solely in terms of energetics indicate that the stability of the reaction product forms is 28>27>26, at the AM1, STO-3G and 3-21G(*) levels, and the tendency of alkyl chloroformate addition toward double addition to the products 27 and 28 is competitive with single addition to the products 26. Ab initio MO calculations provide a theoretical rationalization for the chemoselectivity of the conjugate addition reaction and the ring-opening reaction, the most stable configurations of reaction products (1–8, 14–24, 26–28), and the isomerization between 1–8b, 14–24b and 1–8a, 14–24a, and between 27 and 28.
Enantioselective Conjugate Addition of Catalytically Generated Zinc Homoenolate
