Modular and diverse synthesis of amino acids via asymmetric decarboxylative protonation of aminomalonic acids.

Stereoselective protonation is a challenge in asymmetric catalysis. The small size and high rate of transfer of protons mean that face-selective delivery to planar intermediates is hard to control, but it can unlock previously obscure asymmetric transformations. Particularly, when coupled with a preceding decarboxylation, enantioselective protonation can convert the abundant acid feedstocks into structurally diverse chiral molecules. Here an anchoring group strategy is demonstrated as a potential alternative and supplement to the conventional structural modification of catalysts by creating additional catalyst-substrate interactions. We show that a tailored benzamide group in aminomalonic acids can help build a coordinated network of non-covalent interactions, including hydrogen bonds, π-π interactions and dispersion forces, with a chiral acid catalyst. This allows enantioselective decarboxylative protonation to give α-amino acids. The malonate-based synthesis introduces side chains via a facile substitution of aminomalonic esters and thus can access structurally and functionally diverse amino acids.

Copper-Catalyzed Enantioselective C1,N-Dipolar (3+2) Cycloadditions of 2-Aminoallyl Cations with Indoles.

2-Aminoallyl cations are versatile 1,3-dipoles that could potentially be used for diverse (3+n) cycloaddition reactions. Despite some preliminary studies, the asymmetric catalytic transformation of these species is still underdeveloped. We herein report a binuclear copper-catalyzed generation of 2-aminoallyl cations from ethynyl methylene cyclic carbamates and their enantioselective (3+2) cycloaddition reaction with indoles to construct chiral pyrroloindolines. This transformation features a novel C1,N-dipolar reactivity for 2-aminoallyl cations.

Diverse synthesis of α-tertiary amines and tertiary alcohols via desymmetric reduction of malonic esters.

Amines and alcohols with a fully substituted α-carbon are structures of great value in organic synthesis and drug discovery. While conventional methods towards these motifs often rely on enantioselective carbon-carbon or carbon-heteroatom bond formation reactions, a desymmetric method is developed here by selectively hydrosilylating one of the esters of easily accessible α-substituted α-amino- and -oxymalonic esters. The desymmetrization is enabled by a suite of dinuclear zinc catalysts with pipecolinol-derived tetradentate ligands and can accommodate a diverse panel of heteroatom substituents, including secondary amides, tertiary amines, and ethers of different sizes. The polyfunctionalized reduction products, in return, have provided expeditious approaches to enantioenriched nitrogen- and oxygen-containing molecules, including dipeptides, vitamin analogs, and natural metabolites.

Desymmetric Cyanosilylation of Acyclic 1,3-Diketones.

Diastereo- and enantioselective construction of vicinal stereocenters from easily available starting materials is a challenging task. Here, we report that a bifunctional catalyst prepared from dibutylmagnesium and a pipecolinol-derived tetradentate ligand can enable an asymmetric cyanosilylation of 1,3-diketones to forge a pair of neighboring and acyclic tetrasubstituted carbons. The high stereoselectivity results from the rigid conformation of the diketone in the catalyst pocket, where the Lewis acidic magnesium center, together with the free hydroxyl group as a putative hydrogen bond donor, bind with both carbonyls. Consequently, stereochemically well-defined cyanohydrin silyl ethers with a diverse collection of substituents were prepared. Their rapid derivatization to molecules of higher complexity, such as heterocycles, triols, and fused rings, were also demonstrated.

Desymmetric Partial Reduction of Malonic Esters.

Desymmetrization of easily available disubstituted malonic esters is a rewarding strategy to access structurally diverse quaternary stereocenters. Particularly, asymmetric reduction of malonic esters would generate a functional group with a lower oxidation state than the remaining ester, thus allowing for more chemoselective derivatization. Here, we report a new set of conditions for the zinc-catalyzed desymmetric hydrosilylation of malonic esters that afford aldehydes as the major product. Compared with alcohol-selective desymmetrization, the partial reduction uses a higher concentration of silanes and new pipecolinol-derived tetradentate ligands, proposedly to switch the pathway of zinc hemiacetal intermediates from elimination to silylation. As a result, high aldehyde-to-alcohol ratios and enantioselectivity of aldehydes are obtained from malonic esters with a large collection of substituents. Together with the abundant reactivity of aldehydes, the partial reduction has enabled an expeditious synthesis of bioactive compounds and natural metabolites containing a quaternary stereocenter.

A Unified and Desymmetric Approach to Chiral Tertiary Alkyl Halides.

Enantioenriched tertiary alkyl halides are prevalent in bioactive molecules and can serve as versatile synthetic intermediates to construct complex structures. While conventional access to these motifs often hinges on stereoselective carbon-halogen or carbon-carbon bond formation reactions, desymmetric approaches using halogenated and prochiral tetrasubstituted carbons are largely elusive in comparison. Here, we report that a suite of dinuclear zinc catalysts with a prolinol- or pipecolinol-derived tetradentate ligand can reductively desymmetrize a large collection of easily available halomalonic esters to α-halo-ß-hydroxyesters. These polyfunctionalized tertiary alkyl fluorides, chlorides, and bromides proved to be useful intermediates toward fluorinated drug analogs and polyhalogenated monoterpenes. The facile intramolecular epoxidation of the chiral chloride and bromide products has also enabled expeditious access to natural products containing tertiary alcohol motifs.

Catalytic reductive desymmetrization of malonic esters.

Desymmetrization of fully substituted carbons with a pair of enantiotopic functional groups is a practical strategy for the synthesis of quaternary stereocentres, as it divides the tasks of enantioselection and C-C bond formation. The use of disubstituted malonic esters as the substrate of desymmetrization is particularly attractive, given their easy and modular preparation, as well as the high synthetic values of the chiral monoester products. Here, we report that a dinuclear zinc complex with a tetradentate ligand can selectively hydrosilylate one of the carbonyls of malonic esters to give α-quaternary ß-hydroxyesters, providing a promising alternative to the desymmetric hydrolysis using carboxylesterases. The asymmetric reduction features excellent enantiocontrol that can differentiate sterically similar substituents and high chemoselectivity towards the diester motif of substrates. Together with the versatile preparation of malonic ester substrates and post-reduction derivatization, the desymmetric reduction has enabled the synthesis of a diverse array of quaternary stereocentres with distinct structural features.

GSDME-mediated pyroptosis promotes inflammation and fibrosis in obstructive nephropathy.

Renal tubular cell (RTC) death and inflammation contribute to the progression of obstructive nephropathy, but its underlying mechanisms have not been fully elucidated. Here, we showed that Gasdermin E (GSDME) expression level and GSDME-N domain generation determined the RTC fate response to TNFα under the condition of oxygen-glucose-serum deprivation. Deletion of Caspase-3 (Casp3) or Gsdme alleviated renal tubule damage and inflammation and finally prevented the development of hydronephrosis and kidney fibrosis after ureteral obstruction. Using bone marrow transplantation and cell type-specific Casp3 knockout mice, we demonstrated that Casp3/GSDME-mediated pyroptosis in renal parenchymal cells, but not in hematopoietic cells, played predominant roles in this process. We further showed that HMGB1 released from pyroptotic RTCs amplified inflammatory responses, which critically contributed to renal fibrogenesis. Specific deletion of Hmgb1 in RTCs alleviated caspase11 and IL-1ß activation in macrophages. Collectively, our results uncovered that TNFα/Casp3/GSDME-mediated pyroptosis is responsible for the initiation of ureteral obstruction-induced renal tubule injury, which subsequentially contributes to the late-stage progression of hydronephrosis, inflammation, and fibrosis. This novel mechanism will provide valuable therapeutic insights for the treatment of obstructive nephropathy.

Total synthesis of bryostatin 3.

Bryostatins are a family of 21 complex marine natural products with a wide range of potent biological activities. Among all the 21 bryostatins, bryostatin 3 is structurally the most complex. Whereas nine total syntheses of bryostatins have been achieved to date, bryostatin 3 has only been targeted once and required the highest number of steps to synthesize (43 steps in the longest linear sequence and 88 total steps). Here, we report a concise total synthesis of bryostatin 3 using 22 steps in the longest linear sequence and 31 total steps through a highly convergent synthetic plan by the use of highly atom-economical and chemoselective transformations in which alkynes played a major role in reducing step count.

Catalytic (3+2) Palladium-Aminoallyl Cycloaddition with Conjugated Dienes.

We describe the design and application of tailored aminoallyl precursors for catalytic (3+2) cycloaddition with conjugated dienes via a Pd-aminoallyl intermediate. The new cycloaddition reactions override the conventional (4+3) selectivity of aminoallyl cation cycloaddition through a sequence of Pd-allyl transfer and ring closure. A variety of highly substituted or fused pyrrolidine rings were synthesized using the cycloaddition, and can further undergo [1,3] N-to-C rearrangement to five-membered carbocycles with a different palladium catalyst. The utility of the (3+2) cycloaddition is also demonstrated by the preparation of various derivatives from the bicyclic pyrrolidine products.

Catalytic palladium-oxyallyl cycloaddition.

Exploration of intermediates that enable chemoselective cycloaddition reactions and expeditious construction of fused- or bridged-ring systems is a continuous challenge for organic synthesis. As an intermediate of interest, the oxyallyl cation has been harnessed to synthesize architectures containing seven-membered rings via (4+3) cycloaddition. However, its potential to access five-membered skeletons is underdeveloped, largely due to the thermally forbidden (3+2) pathway. Here, the combination of a tailored precursor and a Pd(0) catalyst generates a Pd-oxyallyl intermediate that cyclizes with conjugated dienes to produce a diverse array of tetrahydrofuran skeletons. The cycloaddition overrides conventional (4+3) selectivity by proceeding through a stepwise pathway involving a Pd-allyl transfer and ring closure sequence. Subsequent treatment of the (3+2) adducts with a palladium catalyst converts the heterocycles to the carbocyclic cyclopentanones.

Cobalt-Catalyzed Intramolecular Alkyne/Benzocyclobutenone Coupling: C-C Bond Cleavage via a Tetrahedral Dicobalt Intermediate.

A Co(0)-catalyzed intramolecular alkyne/benzocyclobutenone coupling through C-C cleavage of benzocyclobutenones is described. Co2(CO)8/P[3, 5-(CF3)2C6H3]3 was discovered to be an effective metal/ligand combination, which exhibits complementary catalytic activity to the previously established rhodium catalyst. In particular, the C8-substituted substrates failed in the Rh system, but succeeded with the Co catalysis. Experimental and computational studies show that the initially formed tetrahedral dicobalt-alkyne complex undergoes C1-C2 activation via oxidative addition with Co(0), followed by migratory insertion and reductive elimination to give the ß-naphthol products.

Site-Selectivity Control in Organic Reactions: A Quest To Differentiate Reactivity among the Same Kind of Functional Groups.

On our path to the perfection of organic synthesis lies the challenge of controlling site selectivity, which is the differentiation of reactivity among the same kind of functional groups. Overcoming this challenge would significantly enhance synthetic efficiency and minimize waste production, which in turn calls for the development of new catalysts, reagents, tactics, and innovative strategies.

A Hydrazone-Based exo-Directing-Group Strategy for ߆C-H Oxidation of Aliphatic Amines.

Described is a new hydrazone-based exo-directing group (DG) strategy developed for the functionalization of unactivated primary ß C-H bonds of aliphatic amines. Conveniently synthesized from protected primary amines, the hydrazone DGs are shown to site-selectively promote the ß-acetoxylation and tosyloxylation via five-membered exo-palladacycles. Amines with a wide scope of skeletons and functional groups are tolerated. Moreover, the hydrazone DG can be readily removed, and a one-pot C-H acetoxylation/DG removal protocol was also discovered.

Practical Direct α-Arylation of Cyclopentanones by Palladium/Enamine Cooperative Catalysis.

Direct arylation of cyclopentanones has been a long-standing challenge because of competitive self-aldol condensation and multiple arylations. Reported herein is a direct mono-α-C-H arylation of cyclopentanones with aryl bromides which is enabled by palladium/amine cooperative catalysis. This method is scalable and chemoselective with broad functional-group tolerance. Application to controlled sequential arylation of cyclopentanones has been also demonstrated.

Transition metal-catalyzed ketone-directed or mediated C-H functionalization.

Transition metal-catalyzed C-H functionalization has evolved into a prominent and indispensable tool in organic synthesis. While nitrogen, phosphorus and sulfur-based functional groups (FGs) are widely employed as effective directing groups (DGs) to control the site-selectivity of C-H activation, the use of common FGs (e.g. ketone, alcohol and amine) as DGs has been continuously pursued. Ketones are an especially attractive choice of DGs and substrates due to their prevalence in various molecules and versatile reactivity as synthetic intermediates. Over the last two decades, transition metal-catalyzed C-H functionalization that is directed or mediated by ketones has experienced vigorous growth. This review summarizes these advancements into three major categories: use of ketone carbonyls as DGs, direct ß-functionalization, and α-alkylation/alkenylation with unactivated olefins and alkynes. Each of these subsections is discussed from the perspective of strategic design and reaction discovery.

Palladium-catalyzed direct ß-arylation of ketones with diaryliodonium salts: a stoichiometric heavy metal-free and user-friendly approach.

We herein report a new protocol for the Pd-catalyzed ß-arylation of ketones without stoichiometric heavy metals. Widely accessible diaryliodonium salts are used as both the oxidant and aryl source. This tandem redox catalysis merges ketone dehydrogenation and conjugate addition without an additional oxidant or reductant. This transformation features the use of a unique bis-N-tosylsulfilimine ligand and the combination of potassium trifluoroacetate/trifluoroacetic acid to maintain an appropriate acidity of the reaction medium. The reaction tolerates both air and moisture, and shows a broad substrate scope. Kinetics studies, along with filtration and poisoning tests, support the involvement of palladium nanoparticles in the catalysis.

Unexpected inheritance pattern of Erianthus arundinaceus chromosomes in the intergeneric progeny between Saccharum spp. and Erianthus arundinaceus.

Erianthus arundinaceus is a valuable source of agronomic traits for sugarcane improvement such as ratoonability, biomass, vigor, tolerance to drought and water logging, as well as resistance to pests and disease. To investigate the introgression of the E. arundinaceus genome into sugarcane, five intergeneric F1 hybrids between S. officinarum and E. arundinaceus and 13 of their BC1 progeny were studied using the genomic in situ hybridization (GISH) technique. In doing so, we assessed the chromosome composition and chromosome transmission in these plants. All F1 hybrids were aneuploidy, containing either 28 or 29 E. arundinaceus chromosomes. The number of E. arundinaceus chromosomes in nine of the BC1 progeny was less than or equal to 29. Unexpectedly, the number of E. arundinaceus chromosomes in the other four BC1 progeny was above 29, which was more than in their F1 female parents. This is the first cytogenetic evidence for an unexpected inheritance pattern of E. arundinaceus chromosomes in sugarcane. We pointed to several mechanisms that may be involved in generating more than 2n gametes in the BC1 progeny. Furthermore, the implication of these results for sugarcane breeding programs was discussed.

Catalytic direct ß-arylation of simple ketones with aryl iodides.

Herein we report a direct ß-arylation of simple ketones with widely available aryl iodides, combining palladium-catalyzed ketone oxidation, aryl-halide activation, and conjugate addition through a single catalytic cycle. Simple cyclic ketones with different ring-sizes, as well as acyclic ketones, can be directly arylated at the ß-position with complete site-selectivity and excellent functional group tolerance.

Palladium-catalyzed carbene migratory insertion using conjugated ene-yne-ketones as carbene precursors.

Palladium-catalyzed cross-coupling reactions between benzyl, aryl, or allyl bromides and conjugated ene-yne-ketones lead to the formation of 2-alkenyl-substituted furans. This novel coupling reaction involves oxidative addition, alkyne activation-cyclization, palladium carbene migratory insertion, ß-hydride elimination, and catalyst regeneration. Palladium (2-furyl)carbene is proposed as the key intermediate, which is supported by DFT calculations. The palladium carbene character of the key intermediate is validated by three aspects, including bond lengths, Wiberg bond order indices, and molecular orbitals, by comparison to those reported for stable palladium carbene species. Computational studies also revealed that the rate-limiting step is ene-yne-ketone cyclization, which leads to the formation of the palladium (2-furyl)carbene, while the subsequent carbene migratory insertion is a facile process with a low energy barrier (<5 kcal/mol).