α,β-Unsaturated ketones generally undergo addition reactions with nucleophiles with a preference for either 1,2- or 1,4-addition, but rarely both. However, the right combination of reagents allows for consecutive 1,4- and 1,2-additions to occur: Cyclic α,β-unsaturated ketones undergo double additions with lithium(trimethylsilyl)diazomethane, effectively generating various molecular frameworks with complexity and diversity. Owing to the sequential generation of several intermediates of multifaceted reactivity, including diazoalkane derivatives and alkylidene carbenes, it is possible to induce novel Grob-type C−C fragmentations, alkylidene carbene mediated Li−N insertions, and dipolar cycloadditions by controlling the reaction parameters.

α,β-Unsaturated ketones generally undergo addition reactions with nucleophiles with a preference for either 1,2- or 1,4-addition, but rarely both. However, the right combination of reagents allows for consecutive 1,4- and 1,2-additions to occur: Cyclic α,β-unsaturated ketones undergo double additions with lithium(trimethylsilyl)diazomethane, effectively generating various molecular frameworks with complexity and diversity. Owing to the sequential generation of several intermediates of multifaceted reactivity, including diazoalkane derivatives and alkylidene carbenes, it is possible to induce novel Grob-type C−C fragmentations, alkylidene carbene mediated Li−N insertions, and dipolar cycloadditions by controlling the reaction parameters.

The mechanisms of regiodivergent cyclizations of o-alkynylbenzaldehyde acetals and thioacetals catalyzed by Pd and Pt halides are studied. DFT calculations found that both reactions are initiated by electrophilic activation of the acetylenic moiety instead of the previously proposed metal-triggered CX (X=O, S) cleavage. Both the regioselective cyclization of the π-alkyne complex and the chemoselective [1,2]-migration in the carbenoid intermediate were determined as key steps to achieving the observed divergence. For acetal derivatives containing an internal alkyne, the 6-endo-dig cyclization is more favorable and leads to the carbenoid intermediate easily through further steps of CX fragmentation and carbocation cyclization. Then, from the carbenoid intermediate, the [1,2]-migration of sulfur is easier than that of H, Me, and Ph; whereas, a reversed aptitude was predicted for the oxygen analogue, which is consistent with the greater ability of sulfur atoms to stabilize β-carbocations. However, for precursors containing a terminal alkyne, the 5-exo-dig pathway is preferred and only the 1,2-disubstituted indene product is seen, irrespective of the nature of the acetal; thus, a different product from that reported in the literature is predicted for benzaldehyde acetal with a terminal alkyne at the ortho position. This prediction led us to reconsider some of the reported results and hidden realities were uncovered with solid new experimental evidence.

Facile and selective Alder-ene reactions of silylallenes involving the activation of an allenic C(sp²)H over an allylic C(sp³)H bond is described. In this ene reaction, the presence of a silyl substituent was found to be critical for the observed reactivity and selectivity since the corresponding alkyl-substituted allenes show different reaction profiles. Computational studies show that the origin of this unusual reactivity is the lower bond dissociation energy of the α-C(sp²)H bond in silylallenes compared to the corresponding nonsilylated allenes.

Invited for the cover of this issue are the groups of Yuanzhi Xia at Wenzhou University (P.R. China) and Daesung Lee at University of Illinois at Chicago (USA). The image depicts the mechanistic understanding of the regiodivergent cyclizations of­ o-alkynylbenzaldehyde acetals and thioacetals catalyzed by metal halides. Read the full text of the article at 10.1002/chem.201502469.

Concise routes for the total and formal syntheses of the amathaspiramides were developed through a formal [3+2] cycloaddition between lithium(trimethylsilyl)diazomethane and α,β-unsaturated esters. The effectiveness of this new cycloaddition for the construction of Δ²-pyrazolines containing a α-tert-alkylamino carbon center and subsequent facile protonolytic NN bond cleavage allows the synthesis of a key intermediate of the amathaspiramides and other α,α-disubstituted amino acid derivatives.

Concise routes for the total and formal syntheses of the amathaspiramides were developed through a formal [3+2] cycloaddition between lithium(trimethylsilyl)diazomethane and α,β-unsaturated esters. The effectiveness of this new cycloaddition for the construction of Δ²-pyrazolines containing a α-tert-alkylamino carbon center and subsequent facile protonolytic NN bond cleavage allows the synthesis of a key intermediate of the amathaspiramides and other α,α-disubstituted amino acid derivatives.

The different reaction profiles of lithium trimethylsilyldiazomethane with various 4-alkenyl ketones are described. It was found that the individual steps along the reaction pathway including a Brook rearrangement, elimination of lithium trimethylsilanolate to form alkylidene carbenes, and their addition to an alkene to form strained bicyclo[3.1.0]hex-1-ene derivatives were significantly affected by the substituents near or on the alkene moiety. Especially, the dimerization of bicyclo[3.1.0]hex-1-enes depends critically on the substituent pattern of the alkene, which controls the reaction to proceed in a concerted or a stepwise manner. On the basis of X-ray diffraction analysis, the dimers, which are of unprecedented structural complexity, were unambiguously elucidated.

Lipids regulate a wide range of biological activities. Since their local concentrations are tightly controlled in a spatiotemporally specific manner, the simultaneous quantification of multiple lipids is essential for elucidation of the complex mechanisms of biological regulation. Here, we report a new method for the simultaneous in situ quantification of two lipid pools in mammalian cells using orthogonal fluorescent sensors. The sensors were prepared by incorporating two environmentally sensitive fluorophores with minimal spectral overlap separately into engineered lipid-binding proteins. Dual ratiometric analysis of imaging data allowed accurate, spatiotemporally resolved quantification of two different lipids on the same leaflet of the plasma membrane or a single lipid on two opposite leaflets of the plasma membrane of live mammalian cells. This new imaging technology should serve as a powerful tool for systems-level investigation of lipid-mediated cell signaling and regulation.

Installation of amino functionality on organic molecules through direct CN bond formation is an important research objective. To achieve this goal, a 1,2-aminocyanation reaction was developed. The reaction occurs through the formation of pyrazolines by means of a formal dipolar cycloaddition of cyclic α,β-unsaturated ketones with lithium trimethylsilyldiazomethane followed by novel protonolytic NN bond cleavage under mild conditions. This two-step process provides a diverse array of structurally complex free and mono-alkylated α-amino ketones in excellent yields.

Lipids regulate a wide range of biological activities. Since their local concentrations are tightly controlled in a spatiotemporally specific manner, the simultaneous quantification of multiple lipids is essential for elucidation of the complex mechanisms of biological regulation. Here, we report a new method for the simultaneous in situ quantification of two lipid pools in mammalian cells using orthogonal fluorescent sensors. The sensors were prepared by incorporating two environmentally sensitive fluorophores with minimal spectral overlap separately into engineered lipid-binding proteins. Dual ratiometric analysis of imaging data allowed accurate, spatiotemporally resolved quantification of two different lipids on the same leaflet of the plasma membrane or a single lipid on two opposite leaflets of the plasma membrane of live mammalian cells. This new imaging technology should serve as a powerful tool for systems-level investigation of lipid-mediated cell signaling and regulation.

Installation of amino functionality on organic molecules through direct CN bond formation is an important research objective. To achieve this goal, a 1,2-aminocyanation reaction was developed. The reaction occurs through the formation of pyrazolines by means of a formal dipolar cycloaddition of cyclic α,β-unsaturated ketones with lithium trimethylsilyldiazomethane followed by novel protonolytic NN bond cleavage under mild conditions. This two-step process provides a diverse array of structurally complex free and mono-alkylated α-amino ketones in excellent yields.

The cover picture shows a chain of dominoes in motion where one domino topples the one next to it, and so on. The individual dominoes symbolize elementary bond-forming events by which simple alkene and alkyne building blocks are processed in tandem to form products of extended conjugation and polycyclic systems. Many enyne-metathesis-based tandem reactions developed and applied to the synthesis of natural and unnatural products are detailed in the Microreview by J. Li and D. Lee on p. 4269 ff.

Enyne metathesis is a powerful synthetic tool for generating 1,3-dienes by redistributing unsaturated functionalities between an alkene and an alkyne via vinylalkylidene intermediates. Although less explored, enyne metathesis has a unique capacity for forming multiple C=C bonds and polycyclic systems in a tandem fashion. By exploiting these characteristics, various tandem reactions have been developed and applied to the synthesis of natural and unnatural products. This microreview recapitulates the recent advances in enyne-metathesis-based tandem processes under two main categories: Enyne metathesis/metathesis and enyne metathesis/nonmetathesis.

A propargylic ester containing a propargylic alkoxy group has been observed to preferentially undergo [1,2]-acyl shift over [1,3]-shift. In addition, the complementary and contrasting reactivity of vinyl vs. alkynyl platinum carbenoids has been discovered. Vinyl platinum carbenoids are more prone to undergo [1,2]-H shift over addition to π-bonds whereas alkynyl platinum carbenoids preferentially add to π-bonds.