ABSTRACT
Hydrogen-bonding catalysis is an emerging field that facilitates rapid access to medicinally relevant enantioenriched small molecules. Here, we report the first asymmetric total syntheses of four members of the abyssinone class of natural products (I, II, III, and IV 4´-OMe) via quinine- or quinidine-derived thiourea-catalyzed intramolecular conjugate additions of ß-keto ester alkylidenes. This concise strategy includes a tandem deprotection/decarboxylation final step that delivers all four natural products and their corresponding antipodes. A preliminary evaluation of all of these small molecules against a metastatic human prostate cancer cell line has identified that these compounds selectively and differentially inhibit cell growth and downregulate the expression of matrix metalloproteinase-2 (MMP-2) at non-toxic concentrations.
ABSTRACT
Multinuclear NMR spectroscopic studies at low temperature (-110 to -150 degrees C) revealed that lithium p-fluorophenolate and the lithium enolates of cyclohexanone, cyclopentanone and 4-fluoroacetophenone have tetrameric structures in THF/Et(2)O and THF/Et(2)O-HMPA by study of the effects of the addition of HMPA. The Z and E isomers of the lithium enolate of 1,3-bis-(4-fluorophenyl)-2-propanone (5F-Li) show divergent behavior. The Z isomer is completely dimeric in pure diethyl ether, and mostly dimeric in 3:2 THF/ether, where monomer could be detected in small amounts. TMTAN and PMDTA convert Z-5F-Li to a monomeric amine complex, and HMPA converts it partially to monomers, and partially to lithiate species (RO)(2)Li(-) and (RO)(3)Li(2-). Better characterized solutions of these lithiates were prepared by addition of phosphazenium enolates (using P4-(t)Bu base) to the lithium enolate in 1:1 ratio to form triple ion (RO)(2)Li(-) P4H(+), or 2:1 ratio to form the higher lithiate (RO)(3)Li(2-) (P4H(+))(2)) (quadruple ions). The E isomer of 5F-Li is also dimeric in 3:2 THF/Et(2)O solution, but is not detectably converted to monomer either by PMDTA or HMPA. In contrast to Z-5F-Li, the E isomer is tetrameric in diethyl ether even in the presence of excess HMPA. Thus for the two isomers of 5F six different enolate structures were characterized: tetramer, dimer, CIP-monomer, SIP-monomer, triple ion, and quadruple ion.
ABSTRACT
The reactive species in fluoride-mediated carbon-carbon bond-forming reactions was investigated. The regio- and diastereoselectivities of silanes reacting with cyclohexenone in the presence of a catalytic amount of fluoride was compared to the reactivity of analogous solvent-separated lithium ion pairs. Closely analogous behavior was observed, showing that carbanions and not siliconate complexes are the reactive species in the fluoride-catalyzed reactions. Spectroscopic investigations unambiguously show that phenylthiobenzyl anion will form by reaction of silane with tris(dimethylamino)sulfonium difluorotrimethylsilicate (TASF) or crypt[2.1.1]-solvated lithium enolates. The catalytic cycle runs smoothly with the crypt[2.1.1] complex of alpha-(phenylthio)benzyllithium as the initiator and enolate as the carrier of the desilylation reaction.
ABSTRACT
[reaction: see text] There have been a number of reports of the kinetic conjugate (1,4) addition of metalated arylacetonitriles to enones. Several proposals have been made to explain this behavior based on nucleophile structure or aggregation state or on the HSAB properties of the reactants. A reexamination of these studies showed that in each case the 1,4 adducts resulted from equilibration of the kinetically formed 1,2 adducts to the more stable 1,4 adducts. Thus, no conclusions about the origins of 1,4 selectivity can be drawn from these experiments. The 1,2 addition, retro-1,2 addition, 1,4 addition, and retro-1,4 addition of lithiophenylacetonitrile to benzylideneacetone were examined, and a free energy level diagram was constructed for the reaction.
