Sm／BiCl3 System Mediated Reformatsky Type Reactions of α—Bromoacetophenone with Aldehydes in THF—H2O Solvent

In the presence of samarium-bismuth(Ⅲ） chloride,intermolecular aldol type reations of α-bromoacetophenone with various aldehydes in tetrahydrofuran-water mixed solvent afford β-hydroxy ketones in moderate to good yields under mild and neutral conditions.     

Diastereoselective Synthesis of Pentasubstituted γ‐Butyrolactones from Silyl Glyoxylates and Ketones through a Double Reformatsky Reaction

Three contiguous stereocenters can be established with remarkable diastereoselectivity in a double Reformatsky sequence. Densely functionalized γ‐butyrolactones were assembled rapidly by this approach, in which a ketone is used as the terminal electrophile (see scheme). Secondary transformations of the lactone products enhance their synthetic utility. R¹=Me, H; R²=alkyl, aryl, CF₃; Bn=benzyl, TBS=tert‐butyldimethylsilyl.

     

Biocatalytic Conversion of Cyclic Ketones Bearing α‐Quaternary Stereocenters into Lactones in an Enantioselective Radical Approach to Medium‐Sized Carbocycles

Cyclic ketones bearing α‐quaternary stereocenters underwent efficient kinetic resolution using cyclohexanone monooxygenase (CHMO) from Acinetobacter calcoaceticus. Lactones possessing tetrasubstituted stereocenters were obtained with high enantioselectivity (up to >99 % ee) and complete chemoselectivity. Preparative‐scale biotransformations were exploited in conjunction with a SmI₂‐mediated cyclization process to access complex, enantiomerically enriched cycloheptan‐ and cycloctan‐1,4‐diols. In a parallel approach to structurally distinct products, enantiomerically enriched ketones from the resolution with an α‐quaternary stereocenter were used in a SmI₂‐mediated cyclization process to give cyclobutanol products (up to >99 % ee).     

Diastereoselective SmI2-mediated cyclisation of δ-oxo-α,β-unsaturated esters to cyclopropanols

In the presence of samarium diiodide and a proton source, δ-oxo-γ,γ-disubstituted-α,β-unsaturated esters readily cyclise with complete diastereocontrol to give anti-cyclopropanol products.     

A New Synthetic Method of Highly Substituted Cyclopentadienes from α,β-Unsaturated Alkynones

Promoted by samarium diiodlde in THF, the α, β-unsaturated alkynones were reduced to afford intermolecular reductive cou-pling products. The multiply substituted cyclopentadienes were prepared conveniently in good yields.     

A Photoredox‐Induced Stereoselective Dearomative Radical (4+2)‐Cyclization/1,4‐Addition Cascade for the Synthesis of Highly Functionalized Hexahydro‐1H‐carbazoles

A stereoselective synthesis of functionalized hexahydrocarbazoles was developed based on an unprecedented photoredox‐induced dearomative radical (4+2)‐cyclization/1,4‐addition cascade between 3‐(2‐iodoethyl)indoles and acceptor‐substituted alkenes. The title reaction simultaneously generates three C−C bonds and one C−H bond, along with three contiguous stereogenic centers. The hexahydro‐1H ‐carbazole products are highly valuable intermediates for the synthesis of novel antibiotics, as well as unnatural ring homologues of polycyclic indoline alkaloids.     

Rate Study of Proton Catalyzed SmI2 Reduction of 2‐Heptanone and 1,2‐Epoxydecane

Rate constants directly measured from the GC‐analyzed method for SmI₂ reduction of 2‐heptanone and 1,2‐epoxydecane in the presence of various proton sources were obtained. Water exhibits much stronger catalytic effect than methanol and t‐butanol. Dependence of reaction rates on concentration of SmI₂ and temperature were studied.     

Indium-mediated Reformatsky reaction on lactones: preparation of 2-deoxy-2,2′-dimethyl-3-ulosonic acids

Indium-mediated Reformatsky reactions of simple lactones and aldonolactones with ethyl α-bromoisobutyrate allow the synthesis of the corresponding ketals and ulosonic acid esters, respectively, in good yields.     

A Cascade Strategy Enables a Total Synthesis of (−)‐Gephyrotoxin

A concise and efficient synthesis of (?)‐gephyrotoxin from L ‐pyroglutaminol has been realized. The key step in this approach is a diastereoselective intramolecular enamine/Michael cascade reaction that forms two rings and two stereocenters and generates a stable tricyclic iminium cation. A hydroxy‐directed reduction of this intermediate plays a key role in establishing the required cis‐decahydroquinoline ring system, enabling the total synthesis of (?)‐gephyrotoxin in nine steps and 14 % overall yield. The absolute configuration of the synthetic material was confirmed by single‐crystal X‐ray diffraction and is consistent with the structure originally proposed for material isolated from the natural source.     

Chemoselective Synthesis of β‐Amino Ester or β‐Lactam via Sonochemical Reformatsky Reaction

A series of β‐amino esters were synthesized by the reaction of N‐tosyl aldimine or N‐hydroxy aldimine with bromoacetate by sonochemical Reformatsky reaction. The β‐N‐hydroxyamino ester was obtained and the formed sensitive hydroxylamino functionality was resistant under the reaction condition. The β‐lactam also was synthesized by the reaction of N‐p‐methoxy aldimine as reacting substrate under this sonochemical Reformatsky reaction condition.     

Interception of Cobalt‐Based Carbene Radicals with α‐Aminoalkyl Radicals: A Tandem Reaction for the Construction of β‐Ester‐γ‐amino Ketones

The interception of cobalt‐based carbene radicals with α‐aminoalkyl radicals was combined with the Kornblum–DeLaMare reaction and provides β‐ester‐γ‐amino ketones, which are otherwise difficult to obtain in high chemoselectivity. Mechanistically, this transformation is an interplay of cobalt‐based carbene radicals, organoradicals, and ionic intermediates and involves the construction of two C? C bonds and one C?O bond in a one‐pot process. The reaction also features a wide substrate scope and is highly efficient and insensitive to moisture and air.     

A Minimal β‐Lactone Fragment for Selective β5c or β5i Proteasome Inhibitors

Broad‐spectrum proteasome inhibitors are applied as anticancer drugs, whereas selective blockage of the immunoproteasome represents a promising therapeutic rationale for autoimmune diseases. We here aimed at identifying minimal structural elements that confer β5c or β5i selectivity on proteasome inhibitors. Based on the natural product belactosin C, we synthesized two β‐lactones featuring a dimethoxybenzyl moiety and either a methylpropyl (pseudo‐isoleucin) or an isopropyl (pseudo‐valine) P1 side chain. Although the two compounds differ only by one methyl group, the isoleucine analogue is six times more potent for β5i (IC₅₀=14 nM ) than the valine counterpart. Cell culture experiments demonstrate the cell‐permeability of the compounds and X‐ray crystallography data highlight them as minimal fragments that occupy primed and non‐primed pockets of the active sites of the proteasome. Together, these results qualify β‐lactones as a promising lead‐structure motif for potent nonpeptidic proteasome inhibitors with diverse pharmaceutical applications.     

Synthesis of 2‐Ene‐1,4‐diols by a New Cascade‐Opening of 1,3‐Diepoxides: Towards an Efficient Synthesis of Dihydroxytaxoid Derivatives

Taxing taxanes : A new method for the preparation of alk‐2‐ene‐1,4‐diols from 1,3‐dienes, especially for geometrical constrained derivatives, via dioxirane derivative formation followed by Ti^III‐induced oxirane ring opening, is described. The strategy has been very efficiently implemented to the construction of the 11‐ene‐10,13‐diol moiety present in taxol derivatives.

     

A New Mechanism for β‐Lactamases: Class D Enzymes Degrade 1β‐Methyl Carbapenems through Lactone Formation

β‐Lactamases threaten the clinical use of carbapenems, which are considered antibiotics of last resort. The classical mechanism of serine carbapenemase catalysis proceeds through hydrolysis of an acyl‐enzyme intermediate. We show that class D β‐lactamases also degrade clinically used 1β‐methyl‐substituted carbapenems through the unprecedented formation of a carbapenem‐derived β‐lactone. β‐Lactone formation results from nucleophilic attack of the carbapenem hydroxyethyl side chain on the ester carbonyl of the acyl‐enzyme intermediate. The carbapenem‐derived lactone products inhibit both serine β‐lactamases (particularly class D) and metallo‐β‐lactamases. These results define a new mechanism for the class D carbapenemases, in which a hydrolytic water molecule is not required.