Organocatalytic enantioselective construction of Si-stereocenters: recent advances and perspectives.

Silicon-stereogenic chiral organosilanes have found increasing applications in synthetic chemistry, medicinal chemistry, and materials science. In this context, various asymmetric catalytic methods have been established for the diverse synthesis of silicon-stereogenic silanes. In particular, asymmetric organocatalysis is emerging as an important and complementary synthetic tool for the enantioselective construction of silicon-stereocenters, along with the rapid development of chiral-metal catalyzed protocols. Its advent provides a powerful platform to achieve functionalized silicon-stereogenic organosilanes with structural diversity, and should lead to great development in chiral organosilicon chemistry. In this Tutorial Review, we highlight these latest achievements from two aspects: desymmetrizations of prochiral tetraorganosilanes and dynamic kinetic asymmetric transformations of racemic organosilanes by employing five organocatalytic activation modes. The advantages, limitations and synthetic value of each protocol, as well as the synthetic opportunities still open for further exploration, are also discussed.

H-Bond Donor-Directed Switch of Diastereoselectivity in the Enantioselective Intramolecular Aza-Henry Reaction of Ketimines.

We report an H-bond donor controlled diastereoselective switchable intramolecular aza-Henry reaction of ketimines derived from α-ketoesters and 2-(2-nitroethyl)anilines, allowing facile access to chiral tetrahydroquinolines bearing an aza-quaternary carbon stereocenter, which are privileged scaffold for medicinal researches. While newly developed cinchona alkaloid derived phosphoramide-bearing quaternary ammonium salt C2 selectively give cis-adducts in up to 20:1 dr and 99% ee, the corresponding urea-bearing analogue C8 preferentially give trans-adducts in up to 20:1 dr and 99% ee.

Highly Enantioselective Construction of Multifunctional Silicon-Stereogenic Silacycles by Asymmetric Enamine Catalysis.

We report the first highly enantioselective construction of silicon-stereocenters by asymmetric enamine catalysis. An unprecedented desymmetric intramolecular aldolization of prochiral siladials was thus developed for the facile access of multifunctional silicon-stereogenic silacycles in high to excellent enantioselectivity. With an enal moiety, these adducts could be readily elaborated for the diverse synthesis of silicon-stereogenic compounds, and for late-stage modification.

The Bifunctional Silyl Reagent Me2 (CH2 Cl)SiCF3 Enables Highly Enantioselective Ketone Trifluoromethylation and Related Tandem Processes.

We report the development of bifunctional trifluoromethylsilyl reagents for selective trifluoromethylation. The newly developed reagent, Me2 (CH2 Cl)SiCF3 , allows highly enantioselective trifluoromethylations of ketones with broad scope. Notably, by taking advantage of the chloromethyl group, a tandem synthesis of chiral trifluoromethylated oxasilacyclopentanes is developed, paving way to α-CF3 tertiary alcohols with vicinal tertiary or quaternary stereocenters. Theoretical studies revealed the important role of nonclassical C-H⋅⋅⋅F-C interactions in stabilizing the transition state, and that the presence of the chlorine atom enhances such interactions for better enantiofacial control.

Construction of gem-Difluoroenol Esters through Catalytic O-Selective Addition of Difluoroenoxysilanes to Ketenes.

The O-site reactivity of difluoroenoxysilanes is disclosed for the first time, which enabled the direct construction of versatile gem-difluoroalkenes through an unprecedented highly efficient addition reaction with ketenes. A series of valuable gem-difluoroenol esters were achieved in good to excellent yields. The synthetic versatility of this protocol is further demonstrated by the gram-scale synthesis and good functional group tolerance.

Catalyst-Free and Solvent-Controlled Divergent Synthesis of Difluoromethylene-Containing S-Heterocycles.

An unprecedented catalyst-free reaction of benzo[b]thiophene-2,3-diones with difluoroenoxysilanes has been developed using either MeOH or H2O as the solvent, which constitutes a facile and efficient protocol for the solvent-controlled divergent synthesis of five- and seven-membered S-heterocycles featuring a gem-difluoromethylene group. A gram-scale synthesis and the diversification of the product transformations to other difluorinated S-heterocycles further highlight its utility.

Traceless Electrophilic Amination for the Synthesis of Unprotected Cyclic ß-Amino Acids.

Electrophilic aminations involve an umpolung of a nitrogen atom, providing an alternate, distinctive synthetic strategy. The recent advent of various designed O-substituted hydroxylamines has significantly advanced this research field. An underappreciated issue is atom economy of the transformations: The necessary activating group on the oxygen atom is left in coproduced waste. Herein, we describe Rh-catalyzed electrophilic amination of substituted isoxazolidin-5-ones for the synthesis of unprotected, cyclic ß-amino acids featuring either benzo-fused or spirocyclic scaffolds. Using the cyclic hydroxylamines allows for retaining both nitrogen and oxygen functionalities in the product. The traceless, redox neutral process proceeds on a gram scale with as little as 0.1 mol % catalyst loading. In contrast to related electrophilic aminations in the literature, a series of mechanistic experiments suggests a unique pathway involving spirocyclization, followed by the skeletal rearrangement. The insights provided herein shed light on a nuanced reactivity of the active species, Rh-nitrenoid generated from the activated hydroxylamine, and extend the knowledge on electrophilic aromatic substitutions.

HClO4 catalysed aldol-type reaction of fluorinated silyl enol ethers with acetals or ketals toward fluoroalkyl ethers.

A highly efficient metal-free aldol-type reaction of various acetals or ketals with fluorinated silyl enol ethers catalysed by less than 1 mol% HClO4 (70 wt%, aq.) is developed. This provides expedient access to a wide array of valuable fluoroalkyl ethers featuring a ketone carbonyl functionality in good to excellent yields (40 examples). Furthermore, the thus obtained adducts are readily elaborated into other fluorine-containing alkyl ethers with a rich structure.

Exploiting ß-Amino Acid Enolates in Direct Catalytic Diastereo- and Enantioselective C-C Bond-Forming Reactions.

In contrast to the widespread use of α-amino acid-equivalent enolates for the preparation of non-natural amino acids, the utilization of ß-amino-acid counterparts has been limited. This deficit has resulted in a short supply of ß2, 2 -amino acids bearing two substituents at the α-carbon, especially for peptide synthesis. Herein, racemic 4-substituted isoxazolidin-5-ones were used as precursors of ß2 -amino acid enolates in the direct catalytic diastereo- and enantioselective C-C bond-forming reactions, constructing two adjacent stereocenters in a highly stereoselective fashion. The obtained adducts were smoothly coupled with α-amino acid-derived α-ketoacids to afford α/ß2, 2 -hybrid dipeptides suitable for 9-fluorenylmethoxycarbonyl (Fmoc)-based solid-phase peptide synthesis. Moreover, the Mannich adducts obtained from isatin-derived imines were converted to spirocyclic ß-lactams, which have recently received increased attention due to their unique biological activities and conformational preferences.

Quaternary ß2,2 -Amino Acids: Catalytic Asymmetric Synthesis and Incorporation into Peptides by Fmoc-Based Solid-Phase Peptide Synthesis.

ß-Amino acid incorporation has emerged as a promising approach to enhance the stability of parent peptides and to improve their biological activity. Owing to the lack of reliable access to ß2,2 -amino acids in a setting suitable for peptide synthesis, most contemporary research efforts focus on the use of ß3 - and certain ß2,3 -amino acids. Herein, we report the catalytic asymmetric synthesis of ß2,2 -amino acids and their incorporation into peptides by Fmoc-based solid-phase peptide synthesis (Fmoc-SPPS). A quaternary carbon center was constructed by the palladium-catalyzed decarboxylative allylation of 4-substituted isoxazolidin-5-ones. The N-O bond in the products not only acts as a traceless protecting group for ß-amino acids but also undergoes amide formation with α-ketoacids derived from Fmoc-protected α-amino acids, thus providing expeditious access to α-ß2,2 -dipeptides ready for Fmoc-SPPS.

Highly Stereoselective Gold-Catalyzed Coupling of Diazo Reagents and Fluorinated Enol Silyl Ethers to Tetrasubstituted Alkenes.

We report a highly stereoselective synthesis of all-carbon or fluorinated tetrasubstituted alkenes from diazo reagents and fluorinated enol silyl ethers, using C-F bond as a synthetic handle. Cationic AuI catalysis plays a key role in this reaction. Remarkable fluorine effects on the reactivity and selectivity was also observed.

The first catalytic asymmetric thioacetalization by chiral phosphoric acid catalysis.

We report here the first catalytic asymmetric thioacetalization of salicylaldehyde and dithiol. Chiral phosphoric acid STRIP C5 is identified as a powerful catalyst for this reaction to afford various chiral dithioacetals in high to excellent yields and enantioselectivities under mild conditions.

A highly efficient Mukaiyama-Mannich reaction of N-Boc isatin ketimines and other active cyclic ketimines using difluoroenol silyl ethers catalyzed by Ph3PAuOTf.

Ph3PAuOTf is identified as a powerful catalyst for the addition of difluoroenol silyl ethers to N-Boc isatin ketimines and other two kinds of active cyclic ketimines. This represents the first Au(i)-catalyzed Mukaiyama-Mannich reaction, and the corresponding non-fluorinated enol silyl ether proves to be even much more reactive under the same conditions. This method paves the way to the total synthesis of difluoromethylated analogues of AG-041R, a gastrin/CCK-B receptor antagonist.

An efficient catalyst-free Mukaiyama-aldol reaction of fluorinated enol silyl ethers with tryptanthrin.

We report an efficient Mukaiyama-aldol reaction of tryptanthrin with fluorinated enol silyl ethers, which is carried out in methanol without the use of any catalyst. This method is applied to the total synthesis of the difluoro analogues of the natural product Phaitanthrin B.

Michael Addition Catalyzed by Chiral Secondary Amine Phosphoramide Using Fluorinated Silyl Enol Ethers: Formation of Quaternary Carbon Stereocenters.

A chiral secondary amine phosphoramide was developed and identified as a powerful catalyst for the Mukaiyama-Michael addition of fluorinated enol silyl ethers to tetrasubstituted olefins. The resulting products are obtained with high enantioselectivities and contain a quaternary carbon stereocenter bearing either a difluoroalkyl or monofluoroalkyl group.

Highly efficient "on water" catalyst-free nucleophilic addition reactions using difluoroenoxysilanes: dramatic fluorine effects.

A remarkable fluorine effect on "on water" reactions is reported. The CF⋅⋅⋅HO interactions between suitably fluorinated nucleophiles and the hydrogen-bond network at the phase boundary of oil droplets enable the formation of a unique microstructure to facilitate on water catalyst-free reactions, which are difficult to realize using nonfluorinated substrates. Accordingly, a highly efficient on water, catalyst-free reaction of difluoroenoxysilanes with aldehydes, activated ketones, and isatylidene malononitriles was developed, thus leading to the highly efficient synthesis of a variety of α,α-difluoro-ß-hydroxy ketones and quaternary oxindoles.

Asymmetric triple relay catalysis: enantioselective synthesis of spirocyclic indolines through a one-pot process featuring an asymmetric 6π electrocyclization.

A rare example of a one-pot process that involves asymmetric triple relay catalysis is reported. The key step is an asymmetric [1,5] electrocyclic reaction of functionalized ketimines. The substrates for this process were obtained in situ in a two-step process that involved the hydrogenation of nitroarenes with a Pd/C catalyst to yield aryl amines and their subsequent coupling with isatin derivatives in a Brønsted acid catalyzed ketimine formation reaction. The electrocyclization was catalyzed by a bifunctional chiral Brønsted base/hydrogen bond donor catalyst. The one-pot process gave the desired products in good yields and with excellent enantioselectivity.

Lei's formula attenuates osteoarthritis mediated by suppression of chondrocyte senescence via the mTOR axis: in vitro and in vivo experiments.

Lei's formula (LSF), a traditional Chinese herbal remedy, is recognized for its remarkable clinical effectiveness in treating osteoarthritis (OA). Despite its therapeutic potential, the exact molecular mechanisms underlying LSF's action in OA have remained enigmatic. Existing research has shed light on the role of the mTOR signaling pathway in promoting chondrocyte senescence, a central factor in OA-related cartilage degeneration. Consequently, targeting mTOR to mitigate chondrocyte senescence presents a promising avenue for OA treatment. The primary objective of this study is to establish LSF's chondroprotective potential and confirm its anti-osteoarthritic efficacy through mTOR inhibition. In vivo assessments using an OA mouse model reveal substantial articular cartilage degeneration. However, LSF serves as an effective guardian of articular cartilage, evidenced by reduced subchondral osteosclerosis, increased cartilage thickness, improved surface smoothness, decreased OARSI scores, elevated expression of cartilage anabolic markers (Col2 and Aggrecan), reduced expression of catabolic markers (Adamts5 and MMP13), increased expression of the chondrocyte hypertrophy marker (Col10), and decreased expression of chondrocyte senescence markers (P16 and P21). In vitro findings demonstrate that LSF shields chondrocytes from H2O2-induced apoptosis, inhibits senescence, enhances chondrocyte differentiation, promotes the synthesis of type II collagen and proteoglycans, and reduces cartilage degradation. Mechanistically, LSF suppresses chondrocyte senescence through the mTOR axis, orchestrating the equilibrium between chondrocyte anabolism and catabolism, ultimately leading to reduced apoptosis and decelerated OA cartilage degradation. LSF holds significant promise as a therapeutic approach for OA treatment, offering new insights into potential treatments for this prevalent age-related condition.

Comparative bioactivity of S-methoprene and novel S-methobutene against mosquitoes (Diptera: Culicidae).

Mosquitoes and mosquito-borne illnesses significantly impact public health and human well-being. To address this concern, environmentally compatible larvicides have become a critical component of integrated mosquito management. However, the number of available larvicides is at a historical low. Currently, larvicides that harness microbials and insect growth regulators account for most products. Screening of new active ingredients (AIs) or improvement of existing AIs is thus necessary to augment the capacity for mosquito control. S-methoprene possesses a similar molecular structure and identical function to mosquito juvenile hormone and has been one of the main targets for research and development. The efficacy and safety of S-methoprene have been well documented since the late 1960s, and numerous products have been commercialized to combat pests of economic importance. However, S-methoprene is vulnerable to environmental factors that lead to its degradation, which has created challenges in formulation development, particularly where extended efficacy is desired. A derivative of S-methoprene, namely S-methobutene, with molecular modification has become available. This derivative has demonstrated an enhanced activity of inhibition of emergence (IE) against species across the Aedes, Anopheles, and Culex genera at IE10, IE50, and IE90. Furthermore, S-methobutene consistently outperformed S-methoprene during a 120-day aging process against the southern house mosquito Cx. quinquefasciatus, where the IE% in S-methobutene was significantly higher than that in S-methoprene on most aging intervals. The former had significantly longer residual activity than the latter. The potential of S-methobutene for further development and application is discussed in consideration of its enhanced activity and stability.

Nickel-catalysed asymmetric hydromonofluoromethylation of 1,3-enynes for enantioselective construction of monofluoromethyl-tethered chiral allenes.

An unprecedented nickel-catalysed enantioselective hydromonofluoromethylation of 1,3-enynes is developed, allowing the diverse access to monofluoromethyl-tethered axially chiral allenes, including the challenging deuterated monofluoromethyl (CD2F)-tethered ones that are otherwise inaccessible. It represents the first asymmetric 1,4-hydrofunctionalization of 1,3-enynes using low-cost asymmetric nickel catalysis, thus opening a new avenue for the activation of 1,3-enynes in reaction development. The utility is further verified by its broad substrate scope, good functionality tolerance, mild conditions, and diversified product elaborations toward other valuable fluorinated structures. Mechanistic experiments and DFT calculations provide insights into the reaction mechanism and the origin of the enantioselectivity.