Background: Animal, epidemiological and clinical studies have demonstrated the anti-tumor activity of pharmacological proteasome inhibitors and the cancer-preventive effects of green tea consumption. Previously, one of our laboratories reported that natural ester bond-containing green tea polyphenols (GTPs), such as (Ϫ)-epigallocatechin-3-gallate [(Ϫ)-EGCG] and (Ϫ)-gallocatechin-3-gallate [(Ϫ)-GCG], are potent and specific proteasome inhibitors. Another of our groups, for the first time, was able to enantioselectively synthesize (Ϫ)-EGCG as well as other analogs of this natural GTP. Our interest in designing and developing novel synthetic GTPs as proteasome inhibitors and potential cancer-preventive agents prompted our current study. Materials and Methods: GTP analogs, (ϩ)-EGCG, (ϩ)-GCG, and a fully benzyl-protected (ϩ)-EGCG [Bn-(ϩ)-EGCG], were prepared by enantioselective synthesis. Inhibition of the proteasome or calpain (as a control) activities under cell-free conditions were measured by fluorogenic substrate assay. Inhibition of intact tumor cell proteasome activity was measured by accumulation of some proteasome target proteins (p27, IB-␣ and Bax) using Western blot analysis.

C-Dialkylation of Meldrum's acid (2a) and 5-benzyl Meldrum's acid (2b) can be achieved through Mitsunobu dehydration using allylic and arylmethyl alcohols as alkylating agents. This is the first time that the Mitsunobu reaction is successfully applied to the C-alkylation of a highly enolizable cyclic β-dicarbonyl system. With primary (allylic and arylmethyl) alcohols, the alkylations always take place at the carbon bearing the hydroxy group. For secondary allylic alcohols, a catalytic amount of Pd(0) must be added to enhance the regioselectivity of C-alkylation over O-alkylation. With (Ph3P)4Pd(0) as a catalyst, the reaction occurs specifically at the less hindered carbon, and the configuration of the resultant double bond is always trans. Attempts to monoalkylate Meldrum's acids 2a and 2b failed.

Five enantiopure allylsilanes 1a-e have been prepared, with arabinose-derived alcohols methyl and benzyl 3,4-O-isopropylidene-and 3,4-O-methylene--L-arabinopyranosides as chiral auxiliaries, and subjected to the asymmetric Hosomi-Sakurai reaction. The effect of Lewis acid on the stereochemical outcome of the reaction was investigated, and BF 3 was found to exhibit higher enantioselectivity than that of SnCl 4 or TiCl 4 . The reaction of benzyl 2-O-(allyldimethylsilyl)-3,4-O-isopropylidene--L-arabinopyranoside (1b) with n-decanal gave the highest ee (45%) in the presence of BF 3 . The steric effect of the chiral auxiliary on the asymmetric Hosomi-Sakurai reaction is demonstrated for the first time although the stereogenic center is remote from the reaction site.