Ying-Chun Chen

Trienamines Derived from Interrupted Cyclic 2,5‐Dienones: Remote δ,ε‐CC Bond Activation for Asymmetric Inverse‐Electron‐Demand Aza‐Diels–Alder Reaction

A special challenge in the field of asymmetric catalysis is the realization of remote stereocontrol. The problem can be extended to remote sites which must be activated to ensure better reactivity. While most early examples of remote asymmetric inductions rely on enzyme catalysis or intramolecular relay of chiral information through the substrate, current studies have demonstrated that chiral catalysts can facilitate enantioselectivity in variety of reactions. In particular, our group and the group of Jørgensen found that the well-established enamine chemistry of saturated carbonyl compounds could be expanded to polyconjugated 2,4-dienals based on the principle of vinylogy, thus leading to the remote e-site activation and still allowing highly stereoselective cycloadditions at b,e-sites of in situ formed linear trienamine intermediates. Moreover, such an activation mode was successfully applied to 2,4-dienone analogues. Unfortunately, it was not possible to utilize 2,4-dienones with an enolizable a’-alkyl substitution because the cross-conjugated trienamine species were preferably generated. In fact, we also found that the cyclic 2,4-dienone 1 would predominantly generate the cross-conjugated trienamine I, catalyzed by a primary amine, and then react with a dienophile by a a’,b-regioselective [4+2] annulation pathway (Scheme 1). To overcome the inherent preference for the formation of cross-conjugated trienamines from 2,4-dienones bearing an enolizable a’-alkyl group, we envisaged that an appropriately positioned d,e-C=C bond, as shown for the interrupted 3-allyl cyclohexen-2-one 2a (Scheme 1), would induce the generation of the desired polyconjugated linear trienamine II, rather than the dienamine III which has a higher energy. Thus, the electron-donating effects of the amine could be transmitted through the conjugated p system, and raise the HOMO energy of the remote d,e-C=C group to participate in asymmetric reactions. Based on the above considerations, we initially investigated the reaction of the 2,5-dienone 2 a and the 1-azadiene 3a, containing a 1,2-benzoisothiazole-1,1-dioxide moiety, in the presence of 9-amino-9-deoxyepiquinidine (C1) and benzoic acid (A1). To our gratification, the reaction proceeded smoothly in toluene at 35 8C, and the inverse-electrondemand aza-Diels–Alder cycloaddition product 4a was isolated in 63% yield with exclusive d,e-regioselectivity. More pleasingly, both diastereo(endo, > 19:1) and enantioselectivity (98% ee) are remarkable, even though the d,e-C= C bond is quite remote from chiral amine catalyst (Table 1, entry 1). It should be addressed that almost no reaction occurred for the reaction of the conjugated 2,4-dienone 1 and 3a under the same catalytic conditions, thus further verifying that the appropriately positioned d,e-C=C bond is crucial for inducing the formation of the required linear trienamine intermediate. 9-Amino-9-deoxyepiquinine (C2) afforded the product with the opposite configuration in excellent stereoselectivity (Table 1, entry 2), but C3, having with a free OH group, failed to catalyze the reaction (Table 1, entry 3). The acid additives had significant effects on the reaction. Salicylic acid (A2) produced better reactivity (Table 1, entry 4), and a slower reaction and even poor conversion was observed by using either A3 or A4 (Table 1, entries 5 and 6). Other solvents were tolerated though lower yields were obtained (Table 1, entries 7–10). Notably, the reaction still proceeded smoothly with a decreased amount (10 mol % or 5 mol %) of C1 in combination with A2, and better results were obtained after a longer reaction time (Table 1, entries 11 and 12). Consequently, a number of cyclic 2,5-dienones and electron-deficient 1-azadienes were investigated (Table 2). For the reactions of 2a, a variety of 3-vinyl-1,2-benzoisothiaScheme 1. Strategy for the formation of linear trienamine intermediate.

Catalyst-Controlled Switch in Chemo- and Diastereoselectivities: Annulations of Morita-Baylis-Hillman Carbonates from Isatins.

Regulating both the chemo- and diastereoselectivity, divergently, of a reaction is highly attractive but extremely challenging. Presented herein is a catalyst-controlled switch in the chemo- and diastereodivergent annulation reactions of Morita-Baylis-Hillman carbonates, derived from isatins and 2-alkylidene-1H-indene-1,3(2H)-diones, in exclusive α-regioselectivity. α-Isocupreine efficiently catalyzed [2+1] reactions to access cyclopropane derivatives, and the diastereodivergent [3+2] annulations were accomplished by employing either a chiral phosphine or a DMAP-type molecule. All reactions exhibited excellent chemoselectivities, and good to remarkable stereoselectivities were furnished, thus leading to a collection of compounds with skeletal and stereogenic diversity. Moreover, DFT computational calculations elucidated the catalyst-based switch in mechanism.

Enantioselective Formal [3+3] Cycloadditions of Ketones and Cyclic 1‐Azadienes by Cascade Enamine–Enamine Catalysis

An asymmetric formal [3+3] cycloaddition process with diversely structured aliphatic ketones and electron-deficient cyclic 1-azadienes was developed by cascade enamine-enamine catalysis of a cinchona-based primary amine. This sequence involved a domino Michael addition-Mannich reaction to afford spirocyclic architectures in excellent diastereo- and enantioselectivity. Importantly, high regioselectivity was realized for a number of unsymmetrical aliphatic ketone substrates.

Asymmetric Diels-Alder Cycloadditions of Trifluoromethylated Dienophiles Under Trienamine Catalysis.

β-Trifluoromethyl (CF3 ) enones were proved to act as good dienophiles in asymmetric normal-electron-demand Diels-Alder cycloadditions with 2,4-dienals under trienamine catalysis with a chiral secondary amine. The sequential reductive amination transformations with benzylamine produced cis- and trans-fused chiral trifluoromethylated octahydroisoquinolines in a diastereodivergent manner by using NaBH(OAc)3 and NaBH3 CN as the reductants, respectively. Moreover, other types of activated alkenes that bear a CF3 group have also been successfully utilized to construct a diverse range of chiral cyclic frameworks in high stereoselectivity.

The cyclohexene derivative MC-3129 exhibits antileukemic activity via RhoA/ROCK1/PTEN/PI3K/Akt pathway-mediated mitochondrial translocation of cofilin

The effects of MC-3129, a synthetic cyclohexene derivative, on cell viability and apoptosis have been investigated in human leukemia cells. Exposure of leukemia cells to MC-3129 led to the inhibition of cell viability and induction of apoptosis through the dephosphorylation and mitochondrial translocation of cofilin. A mechanistic study revealed that interruption of the RhoA/ROCK1/PTEN/PI3K/Akt signaling pathway plays a crucial role in the MC-3129-mediated dephosphorylation and mitochondrial translocation of cofilin and induction of apoptosis. Our in vivo study also showed that the MC-3129-mediated inhibition of the tumor growth in a mouse leukemia xenograft model is associated with the interruption of ROCK1/PTEN/PI3K/Akt signaling and apoptosis. Molecular docking suggested that MC-3129 might activate the RhoA/ROCK1 pathway by targeting LPAR2. Collectively, these findings suggest a hierarchical model, in which the induction of apoptosis by MC-3129 primarily results from the activation of RhoA/ROCK1/PTEN and inactivation of PI3K/Akt, leading to the dephosphorylation and mitochondrial translocation of cofilin, and culminating in cytochrome c release, caspase activation, and apoptosis. Our study reveals a novel role for RhoA/ROCK1/PTEN/PI3K/Akt signaling in the regulation of mitochondrial translocation of cofilin and apoptosis and suggests MC-3129 as a potential drug for the treatment of human leukemia.