The enantioselective three-component Michael addition-Pictet-Spengler sequence of beta-ketoesters 1, alpha,beta-unsaturated aldehydes 2 and tryptamines 4 represents a facile and rapid one-pot access to highly substituted indoloquinolizidines in moderate to excellent yields and good to excellent enantioselectivities.

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An expedient diastereoselective synthesis of highly functionalized indolo[2,3-α]quinolizidines adopting a cis H2/H12b geometry has been realized by a Pictet-Spengler/lactamization cascade sequence. The absolute stereochemistry at C2, C3, and C12b was governed by the originally created chirality of the Michael adduct through organocatalyzed conjugate addition of dialkyl malonates to α,β-unsaturated aldehydes.

Inhibitors of the proteasome have been extensively studied for their applications in the treatment of human diseases such as hematologic malignancies, autoimmune disorders, and viral infections. Many of the proteasome inhibitors reported in the literature target the non-primed site of proteasome's substrate binding pocket. In this study, we designed, synthesized and characterized a series of novel α-keto phenylamide derivatives aimed at both the primed and non-primed sites of the proteasome. In these derivatives, different substituted phenyl groups at the head group targeting the primed site were incorporated in order to investigate their structure-activity relationship and optimize the potency of α-keto phenylamides. In addition, the biological effects of modifications at the cap moiety, P1、P2 and P3 side chain positions were explored. Many derivatives displayed highly potent biological activities in proteasome inhibition and anticancer activity against a panel of six cancer cell lines, which were further rationalized by molecular modeling analyses. Furthermore, a representative α-ketoamide derivative was tested and found to be active in inhibiting the cellular infection of SARS-CoV-2 which causes the COVID-19 pandemic. These results demonstrate that this new class of α-ketoamide derivatives are potent anticancer agents and provide experimental evidence of the anti-SARS-CoV-2 effect by one of them, thus suggesting a possible new lead to develop antiviral therapeutics for COVID-19.

Alkyl propiolates (HC CCO 2 R), a class of important C 3 unit building blocks, are capable of undergoing Diels-Alder reactions, Michael additions, acetylide formation, halogen addition, and a variety of cyclization reactions to generate heterocycles and aromatics. [1, 2] Whereas this C 3 unit has a rich reactivity profile, [2] the asymmetric catalyzed reactions utilizing alkyl propiolates as reaction partners are relatively limited to the generation of metal acetylides and subsequent addition to electrophiles in the presence of chiral ligands.[3] Thus, extension of the application of alkyl propiolates to other asymmetric catalysis is still highly desirable. Recently, Ryu and co-workers developed a highly enantioselective, catalytic three-component MoritaBaylis-Hillman (MBH) reaction between an ethyl propiolate, TMSI, and aldehyde to give chiral (Z)-b-iodo MBH esters.[4] On the other hand, alkyl propiolates were frequently used in domino reactions and multi-component reactions (MCRs) because of rich reaction sites present in the intermediates in situ generated from them. [2,5] As a continuation of our ongoing project on the development of asymmetric organocatalyzed synthesis of indoloquinolizidine derivatives, [6,7] herein we describe a highly enantioselective onepot three-component synthesis of indoloquinolizidines by utilizing an organocatalyst-controlled conjugate addition [8,9] of b-enaminoesters generated in situ from alkyl propiolates and a,b-enals, and subsequent substrate controlled PictetSpengler cyclization. [10,11] Our conceptual proposal of this approach is shown in Scheme 1. Conjugate addition of tryptamines 1 to alkyl propiolates 2 should give b-enaminoesters 3, [10d] which would then react with a,b-unsaturated aldehydes 4 in the presence of a catalytic amount of a chiral secondary amine and benzoic acid to afford aldehydes 5. This reaction proceeds through the activation of a,b-unsaturated aldehydes 4 by the formation of imminium intermediates.[12] Enaminoesters 3 would attack the a,b-unsaturated immnium intermediate from the less hindered re face to set up the chiral center at C2 of 8. After spontaneous cyclization of aldehydes 5 to [a] Prof.

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We have developed a highly efficient cascade sequence for asymmetric synthesis of indoloquinolizidines with absolute control of cis-H2/H12b relative geometry in good to excellent yields and excellent enantioselectivities. This cascade was triggered by the Ru(II)-TsDPEN-catalyzed asymmetric transfer hydrogenation of imino diesters, with subsequent spontaneous lactamization with discrimination between the two diastereotopic 2-alkoxy-2-oxoethyl groups. The synthetic utility of this strategy was demonstrated by the asymmetric preparation of dihydrocorynantheol, geissoschizol, and isogeissoschizol.

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