Rhodium-catalyzed enantioselective addition of organoaluminum reagents to N-tosyl ketimines.

Rhodium(I)/Binap complexes catalyze highly enantioselective additions of methyl- and arylaluminum reagents to cyclic α,ß-unsaturated N-tosyl ketimines. Depending on the solvent and substituents at the ring, the reaction occurs either in a 1,2-manner to deliver α-tertiary allylic amines or in a 1,4-manner to yield, after subsequent reduction, 3-substituted cycloalkyl amines. Well known in the case of the respective cycloalkenones, these first transformations of the aza-analogues enable the synthesis of amine structures of pharmaceutical and biochemical interest.

Kinetic resolution of chiral cyclohex-2-enones by rhodium(I)/binap-catalyzed 1,2- and 1,4-additions.

The feasibility of kinetic resolutions of racemic monosubstituted cyclohex-2-enones by Rh/binap-catalyzed reactions was investigated. 1,2-Addition of AlMe(3) to the 5-substituted derivatives furnished allylic alcohols in the matched case, while the less reactive enantiomers were either left over or transformed into trans-3,5-disubstituted cyclohexanones in parallel or sequential 1,4-additions. Altogether, these represent regiodivergent reactions on racemic mixtures. In contrast, 1,4-addition of aryl groups led to inferior results since either catalyst or substrate control dominated.

Synthesis of alpha-amino amides via N,O-acetals derived from Weinreb amides.

An easy and straightforward synthesis of alpha-amino amides via a base-mediated rearrangement of modified Weinreb amides into N,O-acetals is presented. Subsequent arylation, alkylation, alkenylation, or alkynylation of this intermediate affords the corresponding alpha-amino amides in excellent yields. Furthermore, a more generalized protocol for the alpha-arylation of Weinreb amides lacking an alpha-amino moiety is also discussed.

Total synthesis of the potent anticancer Aglaia metabolites (-)-silvestrol and (-)-episilvestrol and the active analogue (-)-4'-desmethoxyepisilvestrol.

Total synthesis of the anticancer 1,4-dioxane containing natural products silvestrol (1) and episilvestrol (2) is described by an approach based on the proposed biosynthesis of these novel compounds. The key steps included an oxidative rearrangement of the protected d-glucose derivative 11 to afford the 1,4-dioxane 12, which could be elaborated to the coupling partner 5 and a photochemical [3 + 2]-cycloadditon between the 3-hydroxyflavone 27 and methyl cinnamate followed by base-induced alpha-ketol rearrangement and reduction to give the cyclopentabenzofuran core 33. The core (-)-6 and 1,4-dioxane fragment 5 were united by a highly stereoselective Mitsunobu coupling with the modified azodicarboxylate DMEAD to afford the axial coupled product 36. Deprotection then gave episilvestrol (2). Silvestrol (1) was synthesized by a coupling between core (-)-6 and the dioxane 44 followed by deprotection. Compound 1 was also synthesized from episilvestrol (2) by a Mitsunobu inversion. In addition, the analogue 4'-desmethoxyepisilvestrol (46) was synthesized via the same route. It was found that 46 and episilvestrol 2 displayed an unexpected concentration-dependent chemical shift variation for the nonexchangeable dioxane protons. Synthetic compounds 1, 2, 38, 46, and 54 were tested against cancer cells lines, and it was found that the stereochemistry of the core was critical for activity. Synthetic analogue 4'-desmethoxyepisilvestrol (46) was also active against lung and colon cancer cell lines.