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The additions of the highly reactive reagent, allylmagnesium halide, to α-substituted acyclic chiral ketones proceeded with high stereoselectivity. The stereoselectivity cannot be analyzed by conventional stereochemical models because these reactions do not conform to the requirements of those models. Instead, the stereoselectivity arises from approach of the nucleophile from the most accessible diastereofaces of the lowest energy conformations of the ketones. High stereoselectivity is expected, and the stereochemical outcome can be predicted, with conformationally biased ketones that have sterically distinguishable diastereofaces in which nucleophilic addition is only accessible from one diastereoface. The conformations of the ketones can be determined by combination of computational modeling and, in some cases, determination of structure by X-ray crystallography.

The alkoxy substituents at C4 and C2 of septanoses control the stereochemical outcomes of

Carbometallations of alkenes and alkynes are powerful carbon–carbon bond-forming reactions. The use of compounds containing bonds between carbon and group 13 elements, particularly boron and aluminum, are particularly attractive because of the versatility of subsequent transformations. Uncatalyzed carboboration and carboalumination represent less common classes of reactions. This Short Review discusses uncatalyzed carboboration and carboalumination reactions of alkenes and alkynes, including the reaction design and mechanisms.1 Introduction2 Uncatalyzed Carboboration of Alkenes3 Uncatalyzed Carboboration of Alkynes4 Uncatalyzed Carboalumination of Alkenes5 Uncatalyzed Carboalumination of Alkynes6 Conclusion

Substitution reactions of acyclic β-alkoxy acetals proceeded with generally high diastereoselectivities (>90:10) to form the anti product. Mechanistic experiments supplemented with computational studies suggest that, upon activation of the acetal, the resulting oxocarbenium ion is electrostatically stabilized by the β-alkoxy group. This stabilization defines the conformation of the reactive intermediate, which can be attacked preferentially from the more exposed face, leading to the observed products.

The analysis of the structures of low-energy conformers of different α-haloacetals reveals changes in bond lengths and geometries that correspond to stabilizing orbital interactions that contribute to the ground-state structures of these systems. Several factors, including the electron-donating and electron-accepting abilities of the substituents on the ring, affect the degree of the electronic interactions in these carbohydrate-like systems. The presence of an α-halogen atom that can participate in hyperconjugation has been shown to contribute to the structural characteristics of the low-energy conformer. The experimental evidence is supported by natural bond order (NBO) analysis to identify the types of interactions and to assess their relative importance.

Using a chiral (-)-menthone auxiliary, enantiopure cyclic derivatives of Baylis-Hillman adducts were synthesized. A diastereoselective peroxidation reaction was used to introduce an oxygen atom and establish another stereocenter. The resulting products could be elaborated by employing a one-flask reduction-acetylation protocol followed by a diastereoselective nucleophilic substitution reaction. Removal of the (-)-menthone auxiliary provided an enantiopure triol with a structure related to naturally occurring polyols.

Seven-membered-ring trans-alkenes undergo rapid hydro- and carboalumination reactions in the absence of a catalyst with complete regio- and diastereoselectivity. Control experiments, including deuterium labeling, adding radical inhibitors, and using a radical clock, suggest that these reactions proceed by a concerted mechanism. The products of the reaction possess a new carbon-aluminum bond that can then undergo subsequent transformations, particularly oxidation, providing functionalized products as single stereoisomers.

The hydroperoxidation of alkylidenecyclopropanes and other strained alkenes using an N-hydroxylamine and molecular oxygen occurred in the absence of catalyst, initiator, or light. The oxidation rea...

A radical clock system was developed to investigate single-electron transfer (SET) in the reactions of organomagnesium reagents with carbonyl compounds. The fluorenylcyclopropyl radical clock was selected because it is the fastest known radical clock. Additions of Grignard reagents to aldehydes or methyl ketones provided no evidence for ring-opened products that would indicate reaction through SET. Additions of some Grignard reagents to aromatic ketones, however, resulted in the formation of ring-opened products, suggesting SET.

Unlike many reactions of their six-membered-ring counterparts, the reactions of chiral seven-membered-ring enolates are highly diastereoselective. Diastereoselectivity was observed for a range of substrates, including lactam, lactone, and cyclic ketone derivatives. The stereoselectivity arises from torsional and steric interactions that develop when electrophiles approach the diastereotopic π-faces of the enolates, which are distinguished by subtle differences in the orientation of nearby atoms of the ring.

Hydroperoxides were synthesized in one step from various alkenes using Co(pic)(2) as the catalyst with molecular oxygen and tetramethyldisiloxane (TMDSO). The hydration product could be obtained using a modified catalyst, Co(3-mepic)(2), with molecular oxygen and phenylsilane. Formation of hydroperoxides occurred through a rapid Co─O bond metathesis of a peroxycobalt compound with isopropanol.

The stereoselectivities of reactions of allylmagnesium reagents with chiral ketones cannot be easily explained by stereochemical models. Competition experiments indicate that the complexation step is not reversible, so nucleophiles cannot access the widest range of possible encounter complexes and therefore cannot be analyzed easily using available models. Nevertheless, additions of allylmagnesium reagents to a ketone can still be stereoselective provided that the carbonyl group adopts a conformation that leads to one face being completely blocked from the approach of the allylmagnesium reagent.

Cyclic derivatives of Baylis–Hillman adducts were synthesized. Cobalt-catalyzed peroxidation of these cyclic lactones afforded silyl peroxides in diastereomeric ratios ranging from 91:9 to 97:3.

The hydroperoxidation of alkylidenecyclopropanes and other strained alkenes using an N-hydroxylamine and molecular oxygen occurred in the absence of catalyst, initiator or light. The oxidation reaction proceeds through a radical pathway that is initiated by autoxidation of the alkene substrate. The hydroperoxides were converted to their corresponding alcohols and ketones under mild conditions.

Neighboring-group participation of an ester enabled stereocontrol in substitution reactions of acyclic acetals. The ester group formed a trans-fused dioxolenium ion intermediate, which underwent a substitution reaction at the acetal carbon atom to afford the product with high diastereoselectivity. Neighboring-group participation was confirmed by isolating dioxolane products resulting from nucleophilic addition at C-2 of a 1,3-dioxolenium ion intermediate. Using a pivaloate ester as the participating group in combination with strong nucleophiles produced substitution products with diastereoselectivities of ≥90:10.

This review describes the additions of allylmagnesium reagents to carbonyl compounds and to imines, focusing on the differences in reactivity between allylmagnesium halides and other Grignard reagents. In many cases, allylmagnesium reagents either react with low stereoselectivity when other Grignard reagents react with high selectivity, or allylmagnesium reagents react with the opposite stereoselectivity. This review collects hundreds of examples, discusses the origins of stereoselectivities or the lack of stereoselectivity, and evaluates why selectivity may not occur and when it will likely occur.

The chelation-control model is used to predict stereochemical outcomes of many organometallic reactions. Diastereoselectivity arises due to reaction with a chelated intermediate with sterically differentiated faces. Earlier studies with dimethylmagnesium established that the chelated intermediate is a minor component of the reaction mixture, so reaction with the chelated intermediate must be faster than reaction with a non-chelated intermediate. High diastereoselectivity and chelation-induced rate acceleration are correlated with some hydride reducing agents. There are examples in which diastereoselectivity is high, but chelation-induced rate acceleration is not observed, however. In other cases, chelation-induced rate acceleration is observed, but diastereoselectivity remains low. These experiments illustrate that a revision to the chelation-control model is needed.

The dearomatization of aromatic compounds using cobalt(II) acetylacetonate with triplet oxygen and triethylsilane converts furans, benzofurans, pyrroles, and thiophenes to a variety of products, including lactones, silyl peroxides, and ketones.

Ferroptosis is a non-apoptotic form of regulated cell death caused by the failure of the glutathione-dependent lipid-peroxide-scavenging network. FINO2 is an endoperoxide-containing 1,2-dioxolane that can initiate ferroptosis selectively in engineered cancer cells. We investigated the mechanism and structural features necessary for ferroptosis initiation by FINO2. We found that FINO2 requires both an endoperoxide moiety and a nearby hydroxyl head group to initiate ferroptosis. In contrast to previously described ferroptosis inducers, FINO2 does not inhibit system xc- or directly target the reducing enzyme GPX4, as do erastin and RSL3, respectively, nor does it deplete GPX4 protein, as does FIN56. Instead, FINO2 both indirectly inhibits GPX4 enzymatic function and directly oxidizes iron, ultimately causing widespread lipid peroxidation. These findings suggest that endoperoxides such as FINO2 can initiate a multipronged mechanism of ferroptosis.

The additions of allylmagnesium reagents to carbonyl compounds are important methods in synthetic organic chemistry, but the mechanisms of these reactions are likely to be distinct from mechanisms followed by other organomagnesium reagents. Additions to alkyl aldehydes and ketones are likely to be concerted, proceeding through six-membered-ring transition states. These highly reactive reagents appear to react at rates that approach the diffusion limit, so chemoselectivity is generally low. Furthermore, reactions of allylmagnesium halides with carbonyl compounds are unlikely to follow stereochemical models that require differentiation between competing transition states. This Short Review discusses the current state of understanding of these reactions, including the structure of the reagent and unique aspects of the reactivity of allylmagnesium reagents.1 Introduction2 Reactions with Carbonyl Compounds2.1 Reactivity of Allylmagnesium Halides2.2 Selectivity of Addition3 Structure of Allylmagnesium Reagents3.1 Schlenk Equilibrium and Aggregation3.2 Spectroscopic Studies3.3 X-ray Crystallographic Studies3.4 Computational Studies of Structure4 Reaction Mechanism4.1 Substrate-Dependent Mechanisms4.2 Concerted Mechanisms4.3 Single-Electron Transfer Mechanisms4.4 Open, SE2′-Like Transition State4.5 Computational Studies of Mechanism5 Conclusion

Seven-membered-ring trans-alkenes containing a silicon–oxygen bond reacted rapidly with oxygen gas and electron-deficient alkenes and alkynes to give products with high selectivity. Addition of an electron-donating substituent or incorporating additional strain increased the reactivity by over two orders of magnitude. These results indicate that release of strain is not the only driving force for reactivity.

Silylenes are useful reactive intermediates for the stereoselective construction of compounds containing carbon-silicon bonds. Despite their synthetic utility, the development of either an enantioselective or diastereoselective metal-catalyzed silylene transfer reaction, in which ligands on the metal catalyst control stereoselectivity, has not been achieved. In this article, we report that the structure of the alkene is the most important for controlling stereoselectivity in these reactions. The stereochemical course of kinetically controlled silacyclopropanation reactions was not affected by the nature or chirality of the ligands on the metal. When silylene transfer reactions were reversible, however, products can be formed with a high degree of diastereoselectivity (90 : 10 d.r.).

A cobalt-catalyzed intramolecular silylperoxidation reaction was developed that allows for the conversion of unsaturated diisopropylsilyl ethers to 3-sila-1,2,4-trioxepanes. Reduction of the peroxide unit of the 3-sila-1,2,4-trioxepane yields six-membered ring diisopropylsilylene acetals.

Silacyclopropanes reacted rapidly and selectively with p-benzoquinones to provide oxasilacyclopentanes. Ring-expansion products were observed in the absence of a catalyst, elevated temperatures, or irradiation. As substitution was increased on the silacyclopropane ring, improved stereoselectivity was observed. In some cases, the regiochemistry was controlled depending on the extent of stabilization of the reactive intermediates involved. A radical clock experiment, along with stereochemical studies, confirmed that radical intermediates were involved in the ring-expansion reaction. The scope of this radical reaction was expanded to include dienones, aryl aldehydes, and electron-deficient enones in addition to benzoquinones. In the case of aryl aldehydes and electron-deficient enones, the radical reaction can be used to generate silylenes from silacyclopropanes.

The reactivity of trans-oxasilacycloheptenes in [4+2] cycloadditions depends on the substitution pattern on the seven-membered ring. Unhindered trans-alkenes undergo [4+2] cycloadditions with 1,3-diphenylisobenzofuran faster than the most reactive trans-cyclooctene. Increasing the substitution of the seven-membered ring or increasing the electron density of the trans-alkene decreases reactivity with 1,3-dienes in concerted cycloaddition reactions. Although highly substituted trans-alkenes are unreactive in concerted cycloaddition reactions, these alkenes react rapidly in stepwise reactions with diethyl azodicarboxylate (DEAD), an electrophilic diene.

A CuI-catalyzed oxidation of enynes using N-hydroxybenzotriazole (HOBt) or N-hydroxyphthalimide (NHPI) with molecular oxygen has been developed to yield propargyl hydroperoxides. The reaction occurs under O2 at 0 °C to afford hydroperoxides in 1–4 h. This method provides an alternative to H2O2 or tBuOOH by using molecular oxygen as the source of oxygen atoms. The resulting hydroperoxides can be protected prior to purification and converted into alkoxyamines upon treatment with hydrazine.

Nucleophilic attack on seven-membered-ring oxocarbenium ions is generally highly stereoselective. The preferred mode of nucleophilic attack forms the product in a conformation that minimizes transannular interactions, thus leading to different stereoselectivity as compared to that of reactions involving six-membered-ring oxocarbenium ions.

Allylic Grignard reagents exhibit high reactivity and low selectivity in additions to carbonyl compounds. Additions of allylic Grignard reagents to carbonyl compounds were investigated using prenylmagnesium chloride as a mechanistic probe. When the carbonyl group is relatively unhindered, the addition proceeds through a six-membered transition state with allylic transposition. This process generally occurs with no diastereoselectivity because the reaction rates approach the diffusion limit. With hindered ketones, however, this pathway is disfavored, and the addition proceeds through a transition state resembling that of other Grignard reagents.

trans-Oxasilacycloheptenes are highly reactive strained alkenes. Competition reactions showed that these seven-membered ring trans-alkenes underwent [4+2] cycloaddition reactions faster than a trans-cyclooctene. They also reacted with quinones and dimethyl acetylenedicarboxylate to form adducts with high diastereoselectivity. Kinetic studies showed that ring strain increases nucleophilicity by approximately 10(9).

Nucleophilic substitution reactions of acetals having benzyloxy groups four carbon atoms away can be highly diastereoselective. The selectivity in several cases increased as the reactivity of the nucleophile increased, in violation of the reactivity/selectivity principle. The increase in selectivity with reactivity suggests that multiple conformational isomers of reactive intermediates can give rise to the products.

The hydrolysis of 4-alkoxy-substituted acetals was accelerated by about 20-fold compared to that of sterically comparable substrates that do not have an alkoxy group. Rate accelerations are largest when the two functional groups are linked by a flexible cyclic tether. When controlled for the inductive destabilization, an alkoxy group can accelerate acetal hydrolysis by up to 200-fold. The difference in rates of acetal hydrolysis between a substrate where the alkoxy group was tethered to the acetal group by a five-membered ring compared to one where it was tethered by an eight-membered ring was less than 100-fold, suggesting that fused-ring intermediates were not formed. By comparison, the difference in rates of solvolysis of structurally related tosylates were nearly 10(6)-fold between the five- and eight-membered ring series. This observation implicates neighboring-group participation in the solvolysis of tosylates but not in the hydrolysis of acetals. The acceleration of acetal hydrolysis by an alkoxy group is better explained by electrostatic stabilization of intermediates that accumulate positive charge at the acetal carbon atom.

The isolation and characterization of a trans-oxasilacycloheptene is reported. Single-crystal X-ray crystallographic studies indicate a high level of strain and deviation from ideal geometry. Reactions with several electrophiles demonstrated the nucleophilicity of the C=C double bond, affording oxasilacycloheptane and tetrahydrofuran products as single diastereomers.

Ferroptosis is a form of regulated cell death characterized by the iron-dependent accumulation of lipid hydroperoxides to lethal levels. Emerging evidence suggests that ferroptosis represents an ancient vulnerability caused by the incorporation of polyunsaturated fatty acids into cellular membranes, and cells have developed complex systems that exploit and defend against this vulnerability in different contexts. The sensitivity to ferroptosis is tightly linked to numerous biological processes, including amino acid, iron, and polyunsaturated fatty acid metabolism, and the biosynthesis of glutathione, phospholipids, NADPH, and coenzyme Q10. Ferroptosis has been implicated in the pathological cell death associated with degenerative diseases (i.e., Alzheimer's, Huntington's, and Parkinson's diseases), carcinogenesis, stroke, intracerebral hemorrhage, traumatic brain injury, ischemia-reperfusion injury, and kidney degeneration in mammals and is also implicated in heat stress in plants. Ferroptosis may also have a tumor-suppressor function that could be harnessed for cancer therapy. This Primer reviews the mechanisms underlying ferroptosis, highlights connections to other areas of biology and medicine, and recommends tools and guidelines for studying this emerging form of regulated cell death.

The chelation-control model explains the high diastereoselectivity obtained in additions of organometallic nucleophiles to α-alkoxy ketones but fails for reactions of allylmagnesium halides. Low diastereoselectivity in ethereal solvents results from no chelation-induced rate acceleration. Additions of allylmagnesium bromide to carbonyl compounds are diastereoselective using CH2Cl2 as the solvent even though rate acceleration is still absent. Stereoselectivity likely arises from the predominance of the chelated form in solution. Therefore, a revised chelation-control model is proposed.

Seven-membered-ring trans-alkenes undergo rapid, uncatalyzed carboboration reactions to form trialkylboranes as single diastereomers. In contrast with other trialkylboranes, which can ignite in the presence of oxygen, these trialkylboranes are stable in air. Hindered trialkylboranes can undergo reverse hydroboration reactions to form allylic silanes or can be oxidized to afford highly substituted triols. This reaction sequence permits the construction of compounds with up to five consecutive stereocenters. Control experiments and computational studies support a concerted mechanism for the migratory insertion of the alkene into the carbon–boron bond, similar to the mechanism for hydroboration.

Competition experiments demonstrate that additions of allylmagnesium halides to carbonyl compounds, unlike additions of other organomagnesium reagents, occur at rates approaching the diffusion rate limit. Whereas alkylmagnesium and alkyllithium reagents could differentiate between electronically or sterically different carbonyl compounds, allylmagnesium reagents reacted with most carbonyl compounds at similar rates. Even additions to esters occurred at rates competitive with additions to aldehydes. Only in the case of particularly sterically hindered substrates, such as those bearing tertiary alkyl groups, were additions slower.

The cobalt-catalyzed peroxidation of silyl enol ethers with molecular oxygen and triethylsilane provided silyl monoperoxyketals in 54%-96% yield. These compounds serve as precursors to peroxycarbenium ions, which undergo annulations to provide 1,2-dioxolanes.

The selectivities of nucleophilic substitution reactions of tetrahydropyran acetals promoted by trimethylsilyl trifluoromethanesulfonate depend upon the reaction solvent. Polar solvents favor the formation of S(N)1 products, while nonpolar solvents favor S(N)2 products. Trichloroethylene was identified as the solvent most likely to give S(N)2 products in both C- and O-glycosylation reactions.

(13)C NMR spectroscopic integration employing short relaxation delays was evaluated as a quantitative tool to obtain ratios of diastereomers, regioisomers, constitutional isomers, mixtures of unrelated compounds, peptoids, and sugars. The results were compared to established quantitative methods such as (1)H NMR spectroscopic integration, gas chromatography, and high-performance liquid chromatography and were found to be within3.4% of (1)H NMR spectroscopic values (most examples give results within2%). Acquisition of the spectra took 2-30 min on as little as 10 mg of sample, proving the general utility of the technique. The simple protocol was extended to include end group analysis of low molecular weight polymers, which afforded results in accordance with (1)H NMR spectroscopy and matrix-assisted laser desorption-ionization time-of-flight spectrometry.

Nucleophilic substitution reactions of five-membered ring acetals bearing fused rings reveal that subtle changes in the structure of the fused ring can exert dramatic influences on selectivity. If the fused ring did not constrain the five-membered ring undergoing substitution, selectivity was comparable to what was observed for an unconstrained system (≥92% diastereoselectivity, favoring the product of inside attack on the oxocarbenium ion). If the ring were more constrained by including at least one oxygen atom in the ring, selectivity dropped considerably (to 60% diastereoselectivity in one case). Transition states of the nucleophilic addition of allyltrimethylsilane to selected oxocarbenium ions were calculated using DFT methods. These computational models reproduced the correlation between additional conformational rigidity and selectivity.

Bent out of shape: Silver-catalyzed insertions of silylenes into propargylic CO bonds of epoxides regioselectively form 1,2-silaoxetanes, which add to aldehydes to give the title allenes as single diastereomers (see scheme; Ts=4-toluenesulfonyl). An X-ray crystal structure confirmed the stereochemistry of the allene, which is bent significantly from linearity (164°).

A series of fused-bicyclic acetals containing a disiloxane ring was investigated to evaluate the source of selectivity in silyl-protected 2-deoxyribose systems. The disiloxane ring unexpectedly enables the diaxial conformer of the cation to be stabilized by an electronegative atom at C-3. This low energy conformer subsequently undergoes stereoelectronically controlled nucleophilic addition to give substituted tetrahydrofurans with high diastereoselectivity.

The reactivity of trans-oxasilacycloheptenes in [4+2] cycloadditions depends on the substitution pattern on the seven-membered ring. Unhindered trans-alkenes undergo [4+2] cycloadditions with 1,3-diphenylisobenzofuran faster than the most reactive trans-cyclooctene. Increasing the substitution of the seven-membered ring or increasing the electron density of the trans-alkene decreases reactivity with 1,3-dienes in concerted cycloaddition reactions. Although highly substituted trans-alkenes are unreactive in concerted cycloaddition reactions, these alkenes react rapidly in stepwise reactions with diethyl azodicarboxylate (DEAD), an electrophilic diene.

trans-Oxasilacycloheptenes are highly reactive strained alkenes. Competition reactions showed that these seven-membered ring trans-alkenes underwent [4+2] cycloaddition reactions faster than a trans-cyclooctene. They also reacted with quinones and dimethyl acetylenedicarboxylate to form adducts with high diastereoselectivity. Kinetic studies showed that ring strain increases nucleophilicity by approximately 10(9).

A 1,2-dioxolane (FINO2) was identified as a lead compound from a screen of organic peroxides. FINO2 does not induce apoptosis, but instead initiates ferroptosis, an iron-dependent, oxidative cell death pathway. Few compounds are known to induce primarily ferroptosis. In contrast to the perceived instability of peroxides, FINO2 was found to be thermally stable to at least 150 °C. FINO2 was more potent in cancer cells than nonmalignant cells of the same type. One of the enantiomers was found to be more responsible for the observed activity.

The axial conformer of several 4-substituted cyclohexanone hydrazone salts was found to predominate in solution. Changes in the charge of the molecule and the polarity of the solvent led to changes in the conformational preference of each molecule that were consistent with electrostatic stabilization of the axial conformer. (1)H NMR spectroscopic analysis was utilized to determine the structure of cyclohexanone-derived substrates by comparison to conformationally restricted trans-decalone derivatives and computational models. X-ray crystallography demonstrated that the axial configuration of a pendant benzyloxy group is the preferred conformation of an iminium ion in the solid state. The structure of a neutral hydrazone was also determined to favor the axial configuration for a pendant benzyloxy group in the solid state.

Palladium and nickel catalysts promoted highly selective carbon-carbon bond insertion reactions with di-tert-butyl-alkylidenesilacyclopropanes. Pd(PPh(3))(4) was demonstrated to be the optimal catalyst, allowing for a variety of carbon-carbon pi-bond insertion reactions. Depending on the nature of the carbon-carbon pi bond, the insertion reaction proceeded with either direct insertion into the carbon(sp(2))-silicon bond or with allylic transposition. Ring-substituted alkylidenesilacyclopropanes required a nickel catalyst to afford insertion products. Using Ni(cod)(2) as the carbon-carbon bond insertion catalyst, new double alkyne insertion products and alkene isomerization products were observed.