Lewis Base-Catalyzed Enantioselective Conjugate Reduction of β,β-Disubstituted α,β-Unsaturated Ketones with Trichlorosilane: E/Z-Isomerization, Regioselectivity, and Synthetic Applications

Abstract

The chiral bisphosphine dioxide-catalyzed asymmetric conjugate reduction of acyclic β,β-disubstituted α,β-unsaturated ketones with trichlorosilane affords saturated ketones having a stereogenic carbon center at the carbonyl βposition with high enantioselectivities. Because the E/Zisomerizations of enone substrates occur concomitantly, reduction products with the same absolute configurations are obtained from either (E)-or (Z)-enones. Conjugate reduction is accelerated in the presence of an electron-rich aryl group at the β-position of the enone owing to its carbocation-stabilizing ability. Computational studies were also conducted in order to elucidate the origin of the observed enantioselectivity. The regio-and enantioselective reductions of dienones were realized and applied to the syntheses of ar-turmerone, turmeronol A, mutisianthol, and jungianol, which are optically active sesquiterpenes.

Aromatic-Turmerone Analogs Protect Dopaminergic Neurons in Midbrain Slice Cultures through Their Neuroprotective Activities

“…It is speculated that the electrophilic β-carbon of Atl and A2 mainly interacts with cysteine residues of Keap1 and that this interaction is structurally attenuated by the methyl group attached to the β-carbon of Atl. The addition of the highly electron-donating groups attached to the aromatic ring of A2 may stabilize the transition state of the reaction with nucleophilic molecules [ 20 , 43 , 44 ] and may activate Nrf2 more potently.…”

“…The chemical structures of ar-turmerone analogs are shown in Figure 1A-H. The synthetic procedures of (S)-ar-turmerone, (R)-ar-turmerone, ar-atlantone, turmeronol A, α-atlantone, and analog 1 have been described previously [19,20]. Analogs 2 and 3 were prepared according to the reported method [20,21].…”

“…It remains unknown whether its R-enantiomer and racemic mixture have similar biological activities to those of the S-enantiomer. In addition, we have previously synthesized several analogs of ar-turmerones [19,20]. The aims of the present study were (1) to investigate whether ar-turmerone protects dopaminergic neurons in the midbrain slice cultures and (2) to examine ar-turmerone analogs that have higher activities than S-Tur in inhibiting microglial activation and protecting dopaminergic neurons using microglial BV2 cells and midbrain slice cultures.…”

The Development of Organocatalytic Asymmetric Reduction of Carbonyls and Imines Using Silicon Hydrides

“…[90] Recently, the same group reported a chiral bisphosphine dioxide catalyzed asymmetric conjugate reduction of acyclic β,β-disubstituted α,β-unsaturated ketones. [91] With BINAPO 48 as catalyst, the reaction proceed smoothly under mild condition and provided the saturated ketones bearing a β-chiral center with high yields (up to 99 %) and excellent enantioselectivities (up to 98 % ee) (Scheme 21a). As for the β,β-dialkyl-substituted substrate, 1.0 equivalent of 2,6-lutidine was beneficial to increase both yields and enantioselectivities.…”

Rational Design of New Dihydrobenzooxophosphole-Based Lewis Base Organocatalysts

“…We initiated a DFT study with Gaussian 16 14 at the B3LYP/6-31G(d) level 15 to understand the origin of the catalyst reactivity in these reductions. According to the proposed mechanism, 16 the stereodetermining step involves a 1,4-addition of a silicon hydride to the enone via a sixmembered transition state. In this transition state, the cationic silicon coordinates to the carbonyl oxygen, geometrically placing the silicon hydride near the -carbon of the enone.…”