Pavel Kocovsky

On the Mechanism of Asymmetric Allylation of Aldehydes with Allyltrichlorosilanes Catalyzed by QUINOX, a Chiral Isoquinoline N-Oxide

Allylation of aromatic aldehydes 1a-m with allyl- and crotyl-trichlorosilanes 2- 4, catalyzed by the chiral N-oxide QUINOX (9), has been found to exhibit a significant dependence on the electronics of the aldehyde, with p-(trifluoromethyl)benzaldehyde 1g and its p-methoxy counterpart 1h affording the corresponding homoallylic alcohols 6g, h in 96 and 16% ee, respectively, at -40 degrees C. The kinetic and computational data indicate that the reaction is likely to proceed via an associative pathway involving neutral, octahedral silicon complex 22 with only one molecule of the catalyst involved in the rate- and selectivity-determining step. The crotylation with (E) and (Z)-crotyltrichlorosilanes 3 and 4 is highly diastereoselective, suggesting the chairlike transition state 5, which is supported by computational data. High-level quantum chemical calculations further suggest that attractive aromatic interactions between the catalyst 9 and the aldehyde 1 contribute to the enantiodifferentiation and that the dramatic drop in enantioselectivity, observed with the electron-rich aldehyde 1h, originates from narrowing the energy gap between the (R)- and (S)-reaction channels in the associative mechanism (22). Overall, a good agreement between the theoretically predicted enantioselectivities for 1a and 1h and the experimental data allowed to understand the specific aspects of the reaction mechanism.

Enantioselective allylation of α,β-unsaturated aldehydes with allyltrichlorosilane catalyzed by METHOX.

α,β-Unsaturated aldehydes 6a-j undergo an enantioselective allylation with allylic trichlorosilanes 2a,b in the presence of METHOX (4) as a Lewis basic catalyst (≤10 mol %) to produce the homoallylic alcohols 7a-l at good to high enantioselectivity (83-96% ee). This study shows that the reactivity scope of METHOX can be extended from aromatic to nonaromatic aldehydes.

On the selective N-methylation of BOC-protected amino acids.

The selective N-methylation of BOC-protected valine 1a with MeI and NaH in THF (i.e., in the presence of a free carboxyl group) has been attributed to the protection of the carboxylate by chelation to Na(+). An alternative mechanism, involving the formation of the carbene intermediate generated from MeI and its insertion into the N-H bond, has been ruled out by isotopic labeling.

Synthesis of Enantiopure 1-Arylprop-2-en-1-ols and Their tert-Butyl Carbonates

Enantiomerically pure 1-arylpropenols 8 have been prepared by resolution of the corresponding racemates, using the lipase formulation Novozyme 435. Deprotonation of the latter alcohols with n-BuLi, followed by derivatization with (t-BuO)2CO, afforded the corresponding carbonates 5. Optimization of the process is presented.

Asymmetric synthesis: From transition metals to organocatalysis

Umpolung in the allylation reaction is discussed with examples drawn from transition-metal-catalyzed allylic substitution (with the allylic unit acting as an electrophile) and Lewis base-catalyzed allylation of aldehydes with allyltrichlorosilane (with the allyl acting as a nucleophile). Iridium-catalyzed electrophilic allylation of O-nucleophiles has been employed in our new approach to C-nucleoside analogs, where the C-O bond (rather than C-C) was constructed stereospecifically. Variation of the absolute configuration in the starting segments allowed the synthesis of all four combinations of D/L-α/β-ribosides. In the nucleophilic allylation of aldehydes, chiral pyridine-type N-oxide catalysts are presented, in particular QUINOX and METHOX, and the intriguing behavior of QUINOX is discussed. Here, the π-π interactions between the substrate aldehyde and the catalyst are suggested to rationalize the experimental observations. Good correlation between the calculated energies for the transition states and the experimentally observed enantioselectivities has been obtained.

Molybdenum(II)-Catalyzed Allylic Substitution

Abstract The new Mo(II) triflate complex 5 has been found to catalyze the CC bond forming allylic substitution with silyl enol ethers derived from β-dicarbonyls (e.g., 6 + 12 → 14) and from simple ketones (e.g., 6 + 13 → 16) as nucleophiles.

Synthesis of estrone via a thallium(III)-mediated fragmentation of a 19-hydroxy-androst-5-ene precursor

Estrone (6) has been synthesized from 1, an industrial precursor of androstane steroids, in seven steps. Key features of the strategy include the functionalization of C-19 (1 → 2) and a stereoelectronically controlled, Tl(III)-mediated degradation (2 → 3). Oppenauer oxidation of diol 4 then gave the unsaturated hydroxyketone 5, acid treatment of which induced aromatization affording 6.

Stereochemistry of epoxidation of allylic and homoallylic cyclohexene alcohols

The reactivity of cyclohexene-type allylic alcohols towards epoxidation reagents (peroxy acids and ButO2H with transition metal catalysts) is largely dependent on the magnitude of steric hindrance in the substrate molecules. With unhindered [2(R = H)] or slightly hindered allylic alcohols (4, 8 and 12) the reaction is dominated by the syn-stereodirecting effect of the hydroxy group which results in the exclusive or predominant formation of cis-epoxy alcohols. In contrast, this well established type of stereocontrol fails with sterically congested substrates (23, 26 and 27), which give trans-epoxy alcohols on m-chloroperoxybenzoic acid treatment while the transition metalcatalysed oxidation with ButO2H affords conjugated ketones as the sole products. The latter reaction can serve as a mild procedure for the selective oxidation of hindered allylic alcohols to α,β-unsaturated ketones.