Nickel-Catalyzed Regioselective Intermolecular Dialkylation of Alkenylarenes: Generation of Two Vicinal C(sp3 )-C(sp3 ) Bonds Across Alkenes.

We disclose a Ni-catalyzed regioselective dialkylation reaction of alkenylarenes with α-halocarbonyls and alkylzinc reagents. The reaction produces γ-arylated alkanecarbonyl compounds with the generation of two new C(sp3 )-C(sp3 ) bonds at the vicinal carbons of alkenes. This reaction is effective for the use of primary, secondary and tertiary α-halocarboxylic esters, amides and ketones in conjunction with primary and secondary alkylzinc reagents as the sources of two C(sp3 ) carbons for the dialkylation of terminal and cyclic internal alkenes.

Cu-Catalyzed Cyclization/Coupling of Alkenyl Aldimines with Arylzinc Reagents: Access to Indole-3-diarylmethanes.

We report a Cu(II)-catalyzed cyclization/coupling of alkenyl aldimines with arylzinc reagents to create indole-3-diarylmethane derivatives (Sapkota et al. ChemRxiv 2022, DOI: 10.26434/chemrxiv-2022-d6qn). The current reaction provides a unified modular route from readily available starting materials to indole-3-diarylmethanes in which all three arene cores can be decorated with differential functional substitutions on demand. Since the cyclization/coupling of alkenyl aldimines is unknown to date, the current method widens the scope with regard to both the substrate and product diversity for this class of reaction.

Ni-Catalyzed Regio- and Stereoselective Alkylarylation of Unactivated Alkenes in γ,δ-Alkenylketimines.

We disclose a Ni-catalyzed vicinal alkylarylation of unactivated alkenes in γ,δ-alkenylketimines with aryl halides and alkylzinc reagents. The reaction produces γ-C(sp3)-branched δ-arylketones with the construction of two new C(sp3)-C(sp3) and C(sp3)-C(sp2) bonds. Electron-deficient alkenes play crucial dual roles as ligands to stabilize reaction intermediates and to increase catalytic rates for the formation of C(sp3)-C(sp3) bonds. This alkene alkylarylation reaction is also effective for secondary alkylzinc reagents and internal alkenes, and proceeds with a complete regio- and stereocontrol, affording products with up to three contiguous all-carbon all-cis secondary stereocenters.

Ni-Catalyzed Arylbenzylation of Alkenylarenes: Kinetic Studies Reveal Autocatalysis by ZnX2 *.

We report a Ni-catalyzed regioselective arylbenzylation of alkenylarenes with benzyl halides and arylzinc reagents. The reaction furnishes differently substituted 1,1,3-triarylpropyl structures that are reminiscent of the cores of oligoresveratrol natural products. The reaction is also compatible for the coupling of internal alkenes, secondary benzyl halides and variously substituted arylzinc reagents. Kinetic studies reveal that the reaction proceeds with a rate-limiting single-electron-transfer process and is autocatalyzed by in-situ-generated ZnX2 . The reaction rate is amplified by a factor of three through autocatalysis upon addition of ZnX2 .

Nickel-Catalyzed Regioselective Alkenylarylation of γ,δ-Alkenyl Ketones via Carbonyl Coordination.

We disclose a nickel-catalyzed reaction, which enabled us to difunctionalize unactivated γ,δ-alkenes in ketones with alkenyl triflates and arylboronic esters. The reaction was made feasible by the use of 5-chloro-8-hydroxyquinoline as a ligand along with NiBr2 ⋅DME as a catalyst and LiOtBu as base. The reaction proceeded with a wide range of cyclic, acyclic, endocyclic and exocyclic alkenyl ketones, and electron-rich and electron-deficient arylboronate esters. The reaction also worked with both cyclic and acyclic alkenyl triflates. Control experiments indicate that carbonyl coordination is required for the reaction to proceed.

Ni-Catalyzed Regioselective 1,2-Dialkylation of Alkenes Enabled by the Formation of Two C(sp3)-C(sp3) Bonds.

We disclose a Ni-catalyzed vicinal difunctionalization of alkenes with benzyl halides and alkylzinc reagents, which produces products with two new alkyl-alkyl bonds. This alkene dialkylation is effective in combining secondary benzyl halides and secondary alkylzinc reagents with internal alkenes, which furnishes products with three contiguous all-carbon secondary stereocenters. The products can be readily elaborated to access complex tetralene, benzosuberene, and bicyclodecene cores. The reaction also features as the most efficient alkene difunctionalization process to date with catalyst loadings down to 500 ppm and the catalytic turnover number (TON) and turnover frequency (TOF) registering up to 2 × 103 and 165 h-1 at rt, respectively.

Walking metals: catalytic difunctionalization of alkenes at nonclassical sites.

Migration of metals along a carbon chain is triggered by two of the most common organometallic elementary steps - ß-hydride (ß-H) elimination and alkene hydrometallation. This process heralds a new future for creating bonds at carbon sites that fall outside the tenets of the conventional wisdom for reactivity and bond formation, and provides an opportunity to leverage ß-H elimination to advance the very reaction of alkene difunctionalization it is intrinsically predestined to disrupt. Almost four decades since its genesis, the early adventure for alkene difunctionalization by metal migration was sporadic, and its later development went on a hiatus primarily due to original impetus on arresting ß-H elimination for vicinal alkene difunctionalization. With the recent surge on alkene difunctionalization, efforts have been gradually shifting to harnessing the process of ß-H elimination to difunctionalize alkenes at sites other than the classical vicinal carbons, termed henceforth nonclassical reaction sites for pedagogical simplicity. In this review article, we extricate and examine the origin and the development of such reactions over the years. This review covers a wide range of reactions for the difunctionalization of alkenes at geminal (1,1), allylic (1,3) and remote (1,n) carbon sites with a variety of coupling partners. These reactions have enabled engineering of complex molecular frameworks with the generation of new carbon-carbon (C-C)/C-C, C-C/C-heteroatom (halogens, O, N, B) and C-B/C-B bonds. The development of these unique transformations is also presented with mechanistic hypotheses and experimental evidences put forward by researchers. Judged by the number of reports emerging recently, it is now strikingly evident that the field of alkene difunctionalization by metal migration has begun to gain momentum, which holds a great future prospect to develop into a synthetic method of enormous potential.

An Expedient Route to 9-arylmethylanthracene Derivatives via Tandem Ni-catalyzed Alkene Dicarbofunctionalization and Acid-promoted Cyclization-aromatization.

We report a nickel-catalyzed one pot synthesis of 9-arylmethylanthracene motifs, which find applications in medicinal and material chemistry. In this synthesis, we apply three component alkene dicarbofunctionalization of 2-vinylaldimines with aryl iodides and arylzinc reagent to generate a 1,1,2-diarylethyl scaffold, which then undergoes an acidpromoted cyclization followed by aromatization to furnish 9-arylmethylanthracene cores. With the new method, a number of differently-substituted 9-arylmethylanthracene derivatives can be synthesized in good yields.

Design, synthesis, and evaluation of cystargolide-based ß-lactones as potent proteasome inhibitors.

The peptidic ß-lactone proteasome inhibitors (PIs) cystargolides A and B were used to conduct structure-activity relationship (SAR) studies in order to assess their anticancer potential. A total of 24 different analogs were designed, synthesized and evaluated for proteasome inhibition, for cytotoxicity towards several cancer cell lines, and for their ability to enter intact cells. X-ray crystallographic analysis and subunit selectivity was used to determine the specific subunit binding associated with the structural modification of the ß-lactone (P1), peptidic core, (Px and Py), and end-cap (Pz) of our scaffold. The cystargolide derivative 5k, structurally unique at both Py and P1, exhibited the most promising inhibitory activity for the ß5 subunit of human proteasomes (IC50 = 3.1 nM) and significant cytotoxicity towards MCF-7 (IC50 = 416 nM), MDA-MB-231 (IC50 = 74 nM) and RPMI 8226 (IC50 = 41 nM) cancer cell lines. Cellular infiltration assays revealed that minor structural modifications have significant effects on the ability of our PIs to inhibit intracellular proteasomes, and we identified 5k as a promising candidate for continued therapeutic studies. Our novel drug lead 5k is a more potent proteasome inhibitor than carfilzomib with mid-to-low nanomolar IC50 measurements and it is cytotoxic against multiple cancer cell lines at levels approaching those of carfilzomib.

A total synthesis of (-)-Hortonone C.

A total synthesis of the cytotoxic terpenoid hortonone C was accomplished and its absolute stereochemistry confirmed. Intermediate (+)-4 was synthesized using either an asymmetric conjugate addition strategy, or by elaboration of the Hajos-Parrish ketone. Reduction of (+)-4 under dissolving-metal conditions and trapping the enolate intermediate served to control the cis-stereochemistry at the ring fusion and provide a silyl enol ether necessary for ring expansion. Comparison of optical rotation data confirmed that the absolute configuration of natural hortonone C is (6S,7S,10S).

Total synthesis and absolute stereochemistry of the proteasome inhibitors cystargolides A and B.

The absolute stereochemistry of the cystargolides was determined by total synthesis. Evaluation of synthetic cystargolides and derivatives showed that the natural (2S,3R) stereochemistry is essential for activity. Moreover, benzyl esters (-)-10 and (-)-15 were found to be about 100 times more potent, and to selectively kill MCF-7 cancerous cells.