Search

High frequency of KRAS and TP53 mutations is a unique genetic feature of pancreatic ductal adenocarcinoma (PDAC). TP53 mutation not only renders PDAC resistance to chemotherapies but also drives PDAC invasiveness. Therapies targeting activating mutant KRAS are not available and the outcomes of current PDAC treatment are extremely poor. Here, we report that MMRi62, initially identified as an MDM2-MDM4–targeting small molecule with p53-independent pro-apoptotic activity, shows anti-PDAC activity in vitro and in vivo. We show that MMRi62 inhibits proliferation, clonogenic, and spheroid growth of PDAC cells by induction of cell death. MMRi62-induced cell death in PDAC is characteristic of ferroptosis that is associated with increased autophagy, increased reactive oxygen species, and lysosomal degradation of NCOA4 and ferritin heavy chain (FTH1). In addition to induced degradation of FTH1, MMRi62 also induces proteasomal degradation of mutant p53. Interestingly, MMRi62-induced ferroptosis occurs in PDAC cell lines harboring either KRAS and TP53 double mutations or single TP53 mutation. In orthotopic xenograft PDAC mouse models, MMRi62 was capable of inhibiting tumor growth in mice associated with downregulation of NCOA4 and mutant p53 in vivo. Strikingly, MMRi62 completely abrogated metastasis of orthotopic tumors to distant organs, which is consistent with MMRi62's ability to inhibit cell migration and invasion in vitro. These findings identified MMRi62 as a novel ferroptosis inducer capable of suppressing PDAC growth and overcoming metastasis.

Supplementary Data from Small-Molecule MMRi62 Induces Ferroptosis and Inhibits Metastasis in Pancreatic Cancer via Degradation of Ferritin Heavy Chain and Mutant p53

Supplementary Data from In vitro and In vivo Anticancer Effects of the Novel Vitamin E Ether Analogue RRR-α-Tocopheryloxybutyl Sulfonic Acid in Prostate Cancer

Purpose: Among derivatives of α-vitamin E, α-vitamin E succinate (VES), has attracted much attention due to its potent anti–prostate cancer activity in vitro and in vivo. However, the in vivo antitumor activity of VES might be compromised if administrated orally due to the VES hydrolysis by esterases in the gastrointestinal tract.Experimental Design: New nonhydrolyzable VES ether analogues were synthesized and their growth inhibition was screened by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide growth assay. Among them, RRR-α-tocopheryloxybutyl sulfonic acid (VEBSA) was further characterized by terminal deoxyribonucleotidyl transferase–mediated dUTP nick end labeling apoptosis assay, soft agar assay, and in vivo tumor formation.Results: VEBSA has potent antitumor ability, albeit to a lesser extent than VES, in in vitro cultured prostate cancer LNCaP and PC3 cells. Like VES, VEBSA induced apoptosis, repressed androgen receptor protein expression, and enhanced vitamin D receptor expression, suggesting that VEBSA can go through mechanisms similar to those used by VES to inhibit the growth of prostate cancer cells in vitro. However, 6 weeks of oral consumption of VEBSA, but not of VES, reduced the tumor burden in the xenografted prostate tumors in nude mice. Furthermore, oral intake of VEBSA for 20 weeks inhibited prostate tumor growth and progression more efficiently compared with VES in the prostate cancer tumor model of TRAMP mice.Conclusion: Oral consumption of VEBSA allows a greater anticancer activity compared with VES. Chemoprevention prefers the oral consumption of agents; the advantage of VEBSA over VES to be administrated orally will allow VEBSA to serve as an agent for both preventive and therapeutic purposes for prostate cancer.

Highlights from the Science family of journals

The enantioselective copper-catalyzed oxidative coupling of alkenols with styrenes for the construction of dihydropyrans, isochromans, pyrans and morpholines is reported. A concise formal synthesis of a σ(1) receptor ligand using this alkene carboetherification methodology was demonstrated. Ligand, solvent and base all impact reaction efficiency. DFT transition state calculations are presented.

High frequency of KRAS and TP53 mutations is a unique genetic feature of pancreatic ductal adenocarcinoma (PDAC). TP53 mutation not only renders PDAC resistance to chemotherapies but also drives PDAC invasiveness. Therapies targeting activating mutant KRAS are not available and the outcomes of current PDAC treatment are extremely poor. Here, we report that MMRi62, initially identified as an MDM2-MDM4–targeting small molecule with p53-independent pro-apoptotic activity, shows anti-PDAC activity in vitro and in vivo. We show that MMRi62 inhibits proliferation, clonogenic, and spheroid growth of PDAC cells by induction of cell death. MMRi62-induced cell death in PDAC is characteristic of ferroptosis that is associated with increased autophagy, increased reactive oxygen species, and lysosomal degradation of NCOA4 and ferritin heavy chain (FTH1). In addition to induced degradation of FTH1, MMRi62 also induces proteasomal degradation of mutant p53. Interestingly, MMRi62-induced ferroptosis occurs in PDAC cell lines harboring either KRAS and TP53 double mutations or single TP53 mutation. In orthotopic xenograft PDAC mouse models, MMRi62 was capable of inhibiting tumor growth in mice associated with downregulation of NCOA4 and mutant p53 in vivo. Strikingly, MMRi62 completely abrogated metastasis of orthotopic tumors to distant organs, which is consistent with MMRi62's ability to inhibit cell migration and invasion in vitro. These findings identified MMRi62 as a novel ferroptosis inducer capable of suppressing PDAC growth and overcoming metastasis.

A direct assembly of secondary benzylureas and related amine derivatives via copper-catalyzed carboamination of styrenes with potassium alkyltrifluoroborates and ureas, anilines, or an amide is reported. Terminal and 1,2-disubstituted alkenes, as well as dienes, participate in this three-component coupling reaction. The reaction mechanism likely involves the addition of an alkyl radical to the styrene, followed by metal-mediated oxidative coupling of the resulting benzylic radical with the amine derivative. Factors that impact substrate reactivity and regioselectivity are discussed.

The copper-catalyzed enantioselective intramolecular hydroalkoxylation of unactivated alkenes for the synthesis of tetrahydrofurans, phthalans, isochromans, and morpholines from 4- and 5-alkenols is reported. The substrate scope is complementary to existing enantioselective alkene hydroalkoxylations and is broad with respect to substrate backbone and alkene substitution. The asymmetric induction and isotopic labeling studies support a polar/radical mechanism involving enantioselective oxycupration followed by C–[Cu] homolysis and hydrogen atom transfer. Synthesis of the antifungal insecticide furametpyr was accomplished.

Bridged bicyclic ketals display a range of bioactivities. Their catalytic enantioselective synthesis from achiral, acyclic 1,1-disubstituted alkene diols is disclosed. This reaction combines asymmetric catalysis with a distal radical migration. Alkynes and arenes undergo the group transfer. Product distribution depends on substrate and conditions and informs mechanistic analysis.

Necroptosis is a form of regulated cell death that is characterized by membrane permeabilization. This permeabilization is responsible for the inflammatory properties of necroptosis and is critical for disease states involving this process. We previously showed that very long chain fatty acids (VLCFAs) are functionally involved in necroptosis, potentially through protein fatty acylation. Here, we define the scope of protein acylation by saturated VLCFAs during necroptosis. We show that mixed lineage kinase like protein (MLKL) and phosphoMLKL, key proteins for membrane permeabilization, are exclusively acylated during necroptosis. Reducing the levels of VLCFAs decreases their membrane recruitment, suggesting that acylation by VLCFAs contributes to their membrane localization. Acylation of phosphoMLKL occurs downstream of phosphorylation and oligomerization and appears to be, in part, mediated by ZDHHC5 (a palmitoyl transferase). We also show that disruption of the clathrin-mediated endocytosis increases cell viability during necroptosis, likely by removing phosphoMLKL from the plasma membrane.

This Perspective describes the development of a family of copper(II)-catalyzed alkene difunctionalization reactions that enable stereoselective addition of amine derivatives and alcohols onto pendant unactivated alkenes to provide a range of valuable saturated nitrogen and oxygen heterocycles. 2-Vinylanilines and related substrates undergo alternative oxidative amination or allylic amination pathways, and these reactions will also be discussed. The involvement of both polar and radical steps in the reaction mechanisms have been implicated. Major product formation is a function of the lowest energy pathway, which in turn is a function of structural aspects of the various reaction components.

A new method for the direct conversion of 4-pentenylsulfonamides to 2-formylpyrrolidines and a 2-ketopyrrolidine has been developed. This transformation occurs via aerobic copper-catalyzed alkene aminooxygenation where molecular oxygen serves as both oxidant and oxygen source. The 2-formylpyrrolidines can further undergo oxidative carbon–carbon bond cleavage in situ upon addition of DABCO, providing 2-pyrrolidinones. These transformations have been demonstrated for a range of 4-pentenylsulfonamides. 4-Pentenylalcohols also undergo oxidative cyclization to form γ-lactones predominantly. The reaction is chemoselective, oxidizing one alkene in the presence of others, and is compatible with several functional groups. Application of these reactions to the formal syntheses of baclofen and (+)-monomorine was demonstrated.

A convenient copper-catalyzed intramolecular/intermolecular alkene diamination reaction to synthesize 3-aminomethyl-functionalized isoxazolidines under mild reaction conditions and with generally high levels of diastereoselectivity was achieved. This reaction demonstrates that previously underutilized unsaturated carbamates are good [Cu]-catalyzed diamination substrates. Sulfonamides, anilines, benzamide, morpholine, and piperidine can serve as the external amine source. This relatively broad amine range is attributed to the mild reaction conditions. Reduction of the N-O bond could also be achieved, revealing the corresponding 3,4-diamino-1-alcohols efficiently.

Necroptosis is a form of regulated cell death which results in loss of plasma membrane integrity, release of intracellular contents, and an associated inflammatory response. We previously found that saturated very long chain fatty acids (VLCFAs), which contain ≥20 carbons, accumulate during necroptosis. Here, we show that genetic knockdown of Fatty Acid (FA) Elongase 7 (ELOVL7) reduces accumulation of specific very long chain FAs during necroptosis, resulting in reduced necroptotic cell death and membrane permeabilization. Conversely, increasing the expression of ELOVL7 increases very long chain fatty acids and membrane permeabilization. In vitro, introduction of the VLCFA C24 FA disrupts bilayer integrity in liposomes to a greater extent than a conventional C16 FA. To investigate the microscopic origin of these observations, atomistic Molecular Dynamics (MD) simulations were performed. MD simulations suggest that fatty acids cause clear differences in bilayers based on length and that it is the interdigitation of C24 FA between the individual leaflets that results in disorder in the region and, consequently, membrane disruption. We synthesized clickable VLCFA analogs and observed that many proteins were acylated by VLCFAs during necroptosis. Taken together, these results confirm the active role of VLCFAs during necroptosis and point to multiple potential mechanisms of membrane disruption including direct permeabilization via bilayer disruption and permeabilization by targeting of proteins to cellular membranes by fatty acylation.

The oxidative coupling of alkyltrifluoroborates with heteroatom-tethered vinylarenes leads to a broad range of saturated oxygen and nitrogen heterocycles., Saturated heterocycles are important components of many bioactive compounds. The method disclosed herein enables a general route to a range of 5-, 6- and 7-membered oxygen and nitrogen heterocycles by coupling potassium alkyltrifluoroborates with heteroatom-tethered alkenes, predominantly styrenes, under copper-catalyzed conditions, in the presence of MnO2. The method was applied to the synthesis of the core of the anti-depressant drug citalopram. The reaction scope and observed reactivity is consistent with a polar/radical mechanism involving intermolecular addition of the alkyl radical to the alkene followed by [Cu(iii)]-facilitated C–O (or C–N) bond forming reductive elimination.

In this work we investigate the mechanisms by which very long chain fatty acids (VLCFA) contribute to membrane permeabilization during necroptosis, a form of highly regulated necrotic cell death. We show that inactivating fatty acid elongase ELOVL7 prevents VLCFA accumulation and necroptotic cell death, while it's overexpression causes membrane permeabilization. We show that VLCFA can directly permeabilize lipid bilayers and investigate the basis of these effects by molecular dynamics simulations. Finally, we show that VLCFA can be used as substrates for protein fatty acylation during necroptosis, suggesting another potential mechanism by which VLCFA may mediate membrane permeabilization.

2-Arylpyrrolidines occur frequently in bioactive compounds, and thus, methods to access them from readily available reagents are valuable. We report a copper-catalyzed intermolecular carboamination of vinylarenes with potassium N-carbamoyl-β-aminoethyltrifluoroborates. The reaction occurs with terminal, 1,2-disubstituted, and 1,1-disubstituted vinylarenes bearing a number of functional groups. 1,3-Dienes are also good substrates, and their reactions give 2-vinylpyrrolidines. Radical clock mechanistic experiments are consistent with the presence of carbon radical intermediates and do not support participation of carbocations.

Enantiomerically enriched phthalans were synthesized efficiently via an enantioselective copper-catalyzed alkene carboetherification reaction. In this reaction, 2-vinylbenzyl alcohols enantioselectively cyclize then couple with vinylarenes. The utility of the method was demonstrated by the enantioselective synthesis of (R)-fluspidine, a σ(1) receptor ligand.

A new copper-catalyzed enantioselective aza-Freidel-Crafts reaction between phenols and N-sulfonyl aldimines that provides chiral secondary benzylamines in good to excellent yields and excellent enantioselectivities (up to 99% ee) is disclosed. In particular, excellent scope with alkylimines was observed for the first time. The synthetic utility of the products was demonstrated in the first enantioselective synthesis of a dual orexin receptor antagonist, a compound that contains an amine-bearing stereocenter adjacent to a bis- ortho-functionalized arene.

Bridged bicyclic rings containing nitrogen heterocycles are important motifs in bioactive small organic molecules. An enantioselective copper-catalyzed alkene carboamination reaction that creates bridged heterocycles is reported herein. Two new rings are formed in this alkene carboamination reaction where N-sulfonyl-2-aryl-4-pentenamines are converted to 6-azabicyclo[3.2.1]octanes using [Ph-Box-Cu](OTf)2 or related catalysts in the presence of MnO2 as stoichiometric oxidant in moderate to good yields and generally excellent enantioselectivities. Two new stereocenters are formed in the reaction, and the C-C bond-forming arene addition is a net C-H functionalization.

Chiral saturated oxygen heterocycles are important components of bioactive compounds. Cyclization of alcohols onto pendant alkenes is a direct route to their synthesis, but few catalytic enantioselective methods enabling cyclization onto unactivated alkenes exist. Herein reported is a highly efficient copper-catalyzed cyclization of γ-unsaturated pentenols which terminates in C-C bond formation, a net alkene carboetherification. Both intra- and intermolecular C-C bond formations are demonstrated, thus yielding functionalized chiral tetrahydrofurans as well as fused-ring and bridged-ring oxabicyclic products. Transition-state calculations support a cis-oxycupration stereochemistry-determining step.

We report herein that potassium alkyltrifluoroborates can be utilized in oxidative Heck-type reactions with vinyl arenes. The reaction is catalyzed by a Cu(OTf)2/1,10-phenanthroline with MnO2 as the stoichiometric oxidant. In addition to the alkyl Heck, amination, esterification, and dimerization reactions of alkyltrifluoroborates are demonstrated under analogous reaction conditions. Evidence for an alkyl radical intermediate is presented.

The catalytic asymmetric aminooxygenation of alkenes provides an efficient and straightforward approach to prepare chiral vicinal amino alcohols. We have reported a copper(II)-catalyzed enantioselective intramolecular alkene aminooxygenation, using (2,2,6,6-tetramethylpiperidin-1-yl)oxyl (TEMPO) as the oxygen source, which results in the synthesis of chiral indolines and pyrrolidines. Herein we disclose that kinetics studies indicate the reaction is first order both in substrate and the [Cu(R,R)-Ph-bis(oxazoline)]OTf(2) catalyst and zero order in TEMPO. Furthermore, kinetic isotope effect studies support that the cis-aminocupration step, the addition of N-Cu across the alkene, is the rate-limiting step. Subsequent formation of a carbon radical intermediate and direct carbon radical trapping with TEMPO is the indicated mechanism for the C-O bond formation as suggested by a deuterium labeling experiment. A ligand screen revealed that C(4)-phenyl substitution on the bis(oxazoline) is optimal for high asymmetric induction. The size of the substrate's N-sulfonyl group also influences the enantioselectivity of the reaction. The preparative-scale catalytic aminooxygenation reaction (gram scale) was demonstrated, and an unexpected dependence on reaction temperature was uncovered on the larger scale reaction.

2-Arylpyrrolidines occur frequently in bioactive compounds, and thus, methods to access them from readily available reagents are valuable. We report a copper-catalyzed intermolecular carboamination of vinylarenes with potassium N-carbamoyl-β-aminoethyltrifluoroborates. The reaction occurs with terminal, 1,2-disubstituted, and 1,1-disubstituted vinylarenes bearing a number of functional groups. 1,3-Dienes are also good substrates, and their reactions give 2-vinylpyrrolidines. Radical clock mechanistic experiments are consistent with the presence of carbon radical intermediates and do not support participation of carbocations.

A unique method to affect intramolecular aminooxygenation and dioxygenation of allenols and allenylsulfonamides is described. These operationally simple reactions occur under neutral or basic conditions where copper(II) carboxylates serve as reaction promoter, oxidant, and carboxylate source. Moderate to high yields of heterocycle-functionalized vinyl carboxylate esters are formed with moderate to high levels of diastereoselectivity. Such vinyl carboxylate esters could serve as precursors to α-amino and α-oxy ketones and derivatives thereof.

A new copper(II) 2-ethylhexanoate-promoted addition of an alcohol and an amine across an alkene (oxyamination) is reported. The alcohol addition is intramolecular, while coupling with the amine occurs intermolecularly. Several 2-aminomethyl morpholines were synthesized in good to excellent yields and diastereoselectivities.

(S)-5-Fluoro-2-(2,2,6,6-tetramethylpiperidin-1-yloxymethyl)-1-tosylindoline, a 2-methyleneoxy-substituted chiral indoline, was synthesized on multigram scale using an efficient copper-catalyzed enantioselective intramolecular alkene aminooxygenation. The synthesis is accomplished in four steps and the indoline is obtained in 89% ee (>98% after one recrystallization). Other highlights include efficient gram-scale synthesis of the (4R,5S)-di-Ph-box ligand and efficient separation of a monoallylaniline from its N,N-diallylaniline by-product by distillation under reduced pressure.

Enantioselective copper-catalyzed cyclization of γ-alkenylsulfonamides and a δ-alkenylsulfonamide in the presence of a range of vinyl arenes results in variously functionalized 2-substituted chiral nitrogen heterocycles via a formal alkene C-H functionalization process. Application of this reaction to the concise synthesis of a 5-HT(7) receptor antagonist is demonstrated.

A unique method to affect intramolecular aminooxygenation and dioxygenation of allenols and allenylsulfonamides is described. These operationally simple reactions occur under neutral or basic conditions where copper(II) carboxylates serve as reaction promoter, oxidant, and carboxylate source. Moderate to high yields of heterocycle-functionalized vinyl carboxylate esters are formed with moderate to high levels of diastereoselectivity. Such vinyl carboxylate esters could serve as precursors to α-amino and α-oxy ketones and derivatives thereof.

A new protocol for diastereoselective copper-catalyzed intra-molecular alkene aminooxygenation, which provides methyleneoxy-functionalized disubstituted pyrrolidines and five-membered cyclic ureas from the corresponding γ-alkenyl sulfonamides and N-allylureas, is reported. In addition, some success was achieved in enantioselective desymmetrizations reactions. We discovered that the level of enantioselectivity and diastereoselectivity could be tuned by choice of copper(II) ligands and substrate N-substituent.

Olefin diamination methods provide powerful access to vicinal diamines useful in drug discovery, materials and catalysis.[1] A number of impressive diastereoselective, enantioselective and catalytic olefin diamination methods have been recently reported.[2–7] The intramolecular olefin diamination forms nitrogen heterocycles directly and has predominantly been accomplished by using tethered amine nucleophiles wherein both amine additions occur in intramolecular fashion (cf. Scheme 1). This olefin diamination strategy has been reduced to practice by using palladium,[4a] nickel[4b] and gold[4c] catalysts and stoichiometric copper reagents[3] and has resulted in the synthesis of a number of interesting compounds such as bicyclic sulfamides, ureas and guanidines. An intra/intermolecular alkene diamination would result in the convergent formation of one new nitrogen heterocycle along with the installation of a differently functionalized amine substituent. In a recent report, Michael and co-workers found that the use of a palladium catalyst, in combination with N-fluorobenzenesulfonimide led to the formation of nitrogen heterocycles with –CH2N(SO2Ph)2 substitution.[5] Herein we report a new copper(II)-promoted and catalyzed intra/intermolecular diamination of alkenes that engages a wide range of internal and external amine sources for the formation of differently functionalized and various nitrogen heterocycles. Importantly, this communication reports the first intramolecular diamination protocol where catalyst-based asymmetric induction has been observed (vide infra). Impressive catalytic enantioselective intermolecular olefin diaminations have been reported,[2] but no enantioselective intramolecular variant has been reported.[8] Herein is reported our progress towards this elusive transformation. Scheme 1 Previous work: Copper-promoted doubly intramolecular alkene diamination. ND = neodecanoate. The copper(II)-promoted and catalyzed intra/intermolecular alkene diamination protocols disclosed herein are an advance on earlier studies by our lab which involved the synthesis of bicyclic sulfamides and ureas via a tethered olefin diamination approach (Scheme 1).[3] We have recently found that we can expand this process to involve the participation of an external amine source in the second C-N bond-forming step (Table 1). Table 1 Copper(II)-promoted intra/intermolecular diamination of N-allyl ureas. Thus, heating 1-allyl-1-benzyl-2-phenyl urea (1a) in the presence of copper(II) 2-ethylhexanoate, Cu(EH)2 (3 equiv), Cs2CO3 and aniline (1.5 equiv) in PhCF3 for 24 h provides imidazolidin-2-one 2a in 92% yield (Table 1, Conditions A). Other copper-promoted processes such as intramolecular carboamination,[9] aminoacetoxylation[9e] and hydroamination[9b] can occur with the substrates used in this study (see Supporting Information), but the intra/intermolecular diamination process appears to be most favorable when the reaction is run in the presence of an external amine nucleophile. A number of substituted anilines (substitutents = Cl, CF3, Me, F, OMe, i-Pr, NO2) also participated as the external amine in this diamination process, providing 2b–2i in good to excellent yield (Table 1). The amount of substituted aniline had to be increased to 3 equiv (Conditions B) in order to minimize competititve formation of 2a, a product that can originate from the creation of PhNH2 from partial decomposition of 1a under the reaction conditions. In addition, at least 2 equiv of Cu(EH)2 is necessary to minimize formation of a hydroamination side product (see Supporting Information for optimization tables). Sodium azide,[10] benzamide and p-toluene sulfonamide were also competent nucleophiles in this diamination reaction (entries 10–12, Table 1). The 4,4-disubstituted imidazolidin-2-one 4 was formed efficiently from diamination/cyclization of the corresponding 1,1-disubstituted alkenyl urea 3 (Scheme 2). Gratifyingly, chiral imidazolidin-2-ones 6 were formed with high 4,5-trans selectivity from the corresponding alkenyl urea substrate 5 (Scheme 3). Formation of the trans diastereomer can be rationalized via cyclic transition state A, where the substituent adopts a pseudo-equatorial position. Scheme 2 Diaminations of a 1,1-disubstituted alkenyl urea. Scheme 3 High diastereoselectivity for allylic substituted ureas. N-aryl-γ-pentenyl amides, and sulfonamides with different γ-alkenyl backbones, were also good substrates in this intra/intermolecular diamination reaction (Table 2). Both 2,5-cis and 2,5-trans pyrrolidines can be formed with high diastereoselectivity (Table 2, entries 10–12). Table 2 Copper(II)-promoted intra/intermolecular diamination of γ-alkenyl amides and sulfonamides.[a] In general it appears that electron-deficient anilines are better coupling partners than electron-rich anilines in this reaction. For example, the electron-deficient p-trifluoromethylaniline provided the highest yield with 1a, giving 97% of 2f (Table 1, entry 6), while only the product of substrate decomposition, 2a, was observed in the attempted diamination with p-methoxyaniline with 1a. p-Methoxyaniline was marginally competent in the diamination reaction with N-tosyl-orthoallylaniline (which cannot undergo the same decomposition), giving 12d in 42% yield (Table 2, entry 7). Electron-rich amines may bind too tightly to the copper promoter, thereby inhibiting either or both of the C-N bond forming steps. To gain insight into the formation of the second C-N bond, we subjected the trans-deuterated alkene d-13[9b] to the diamination reaction (Scheme 4). Partial conversion led to isolation of a 1:1 ratio of diamination diastereomers d-14a (64%) and 25% of d-13, recovered without alkene isomerization. We interpret this to indicate the irreversible formation of a transient primary carbon radical (as in Scheme 5), the result of C-Cu(II) bond homolysis.[3,9b] The radical can then recombine with Cu(II) to generate a C-Cu(III) intermediate which may then undergo RNH2 and reductive elimination to produce the observed diamine product (Scheme 5). Scheme 4 Isotopic labeling experiment. Scheme 5 Origin of 2,5-cis-pyrrolidine diastereoselectivity. We interpret the 2,5-cis-pyrrolidine selectivity shown in products 16 and 18 to be the result of the first C-N bond formation occurring through either the chair-like or boat-like transition states in Scheme 5, where the dominant stereochemistry-determining interaction is avoidance of steric hindrance between the alpha-substituent and the N-substituent.[9] This diastereoselectivity can be switched to favor the 2,5-trans-pyrrolidine (cf. 20) by connecting these two substituents directly to one another.[11] Our initial attempts to render this diamination reaction catalytic in copper(II) using MnO2 as stoichiometric oxidant with either N-allyl urea 1a or N-sulfonyl ortho-allylaniline 11a and aniline or NaN3 as nucleophiles led to no reaction. MnO2 is a competent oxidant in our previously reported copper-catalyzed carboamination reaction.[9c,e] Sulfamide and urea substrates such as those shown in Scheme 1 also failed to undergo copper-catalyzed doubly intramolecular alkene diamination. To our delight, however, when p-TolSO2NH2 was used as the nucleophile with substrates 1a and 11a, the catalytic intra/intermolecular alkene diamination reactions occurred efficiently (Table 3). Superior yields (87% vs 72%, entry 1) were obtained when 2,6-di-tert-butyl-4-methyl pyridine was used as base instead of Cs2CO3. Table 3 Copper(II)-catalyzed intra/intermolecular diamination of alkenes.[a] We next challenged the reaction in the catalytic enantioselective manifold. When copper(II) triflate (30 mol%) complexed with (R)-Ph-bis(oxazoline) ligand (37.5 mol%) was used, diamination adduct 12e was obtained in 51% yield and 71% ee (Scheme 6). The major enantiomer is tentatively assigned S by analogy.[9c] This is a promising lead for development of the elusive catalytic enantioselective intramolecular alkene diamination reaction. Mechanistically, this reaction clearly demonstrates copper is present in the C-N bond-forming step (as indicated in Schemes 3 and ​and5).5). Further optimization of the catalytic enantioselective process is underway in our labs. Scheme 6 Enantioselective copper(II)-catalyzed intra/intermolecular alkene diamination (%ee determined by chiral HPLC).

The diastereoselectivity of the copper-promoted intramolecular aminooxygenation of various alkene substrates was investigated. Alpha-substituted 4-pentenyl sulfonamides favor the formation of 2,5-cis-pyrrolidines (dr20:1) giving excellent yields which range from 76-97% while gamma-substituted substrates favor the 2,3-trans pyrrolidine adducts with moderate selectivity (ca. 3:1). A substrate whose N-substituent was directly tethered to the alpha-carbon exclusively yielded the 2,5-trans pyrrolidine. The synthetic utility of the method was demonstrated by a short and efficient formal synthesis of (+)-monomorine.

Purpose: Among derivatives of α-vitamin E, α-vitamin E succinate (VES), has attracted much attention due to its potent anti–prostate cancer activity in vitro and in vivo. However, the in vivo antitumor activity of VES might be compromised if administrated orally due to the VES hydrolysis by esterases in the gastrointestinal tract. Experimental Design: New nonhydrolyzable VES ether analogues were synthesized and their growth inhibition was screened by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide growth assay. Among them, RRR-α-tocopheryloxybutyl sulfonic acid (VEBSA) was further characterized by terminal deoxyribonucleotidyl transferase–mediated dUTP nick end labeling apoptosis assay, soft agar assay, and in vivo tumor formation. Results: VEBSA has potent antitumor ability, albeit to a lesser extent than VES, in in vitro cultured prostate cancer LNCaP and PC3 cells. Like VES, VEBSA induced apoptosis, repressed androgen receptor protein expression, and enhanced vitamin D receptor expression, suggesting that VEBSA can go through mechanisms similar to those used by VES to inhibit the growth of prostate cancer cells in vitro. However, 6 weeks of oral consumption of VEBSA, but not of VES, reduced the tumor burden in the xenografted prostate tumors in nude mice. Furthermore, oral intake of VEBSA for 20 weeks inhibited prostate tumor growth and progression more efficiently compared with VES in the prostate cancer tumor model of TRAMP mice. Conclusion: Oral consumption of VEBSA allows a greater anticancer activity compared with VES. Chemoprevention prefers the oral consumption of agents; the advantage of VEBSA over VES to be administrated orally will allow VEBSA to serve as an agent for both preventive and therapeutic purposes for prostate cancer.

Aim: To investigate the activity of RRR-α-tocopheryloxybutyric acid (TOB), an ether analog of RRR-α-tocopheryl succinate (VES), in prostate cancer cells. Methods: VES and TOB were used to treat prostate cancer LNCaP, PC3, and 22Rv1 cells and primary-cultured prostate fibroblasts. The proliferation rates were determined by MTT assay, the cell viabilities were determined by trypan blue exclusion assay, and the cell deaths were evaluated by using Cell Death Detection ELISA kit. The protein expression levels were determined by Western blot analysis. Results: The MTT growth assay demonstrated that TOB could effectively suppress the proliferation of prostate cancer cells, but not normal prostate fibroblasts. Mechanism dissections revealed that TOB reduced cell viability and induced apoptosis in prostate cancer cells similar to VES. In addition, both TOB and VES suppressed prostate-specific antigen (PSA) at the transcriptional level leading to reduced PSA protein expression. Furthermore, vitamin D receptor (VDR) expression increased after the addition of TOB. Conclusion: Our data suggests that the VES derivative, TOB, is effective in inhibiting prostate cancer cell proliferation, suggesting that TOB could be used for both chemopreventive and chemotherapeutic purposes in the future. (Asian J Androl 2007 Jan; 9: 31–39)

A new method for the synthesis of 2-aminomethyl functionalized 1,4-benzodiazepin-5-ones is presented. The benzodiazepine core is well-known to interact with biological receptors and many pharmaceutical drugs are derived from this structure. The alkene diamination strategy is employed for the first time for the synthesis of 1,4-benzodiazepinones. In this reaction, copper(2-ethylhexanoate)2 serves as promoter and a range of external amines can be coupled with 2-sulfonamido-N-allyl benzamides to generate the 1,4-benzodiazepinones in good yields.

Whereas N-aryl and N-sulfonyl 2-vinyl aniline derivatives form the desired products in moderate to high yields, primary and N-alkyl 2-vinyl aniline analogues are unreactive.

A new method for the synthesis of 2-aminomethyl functionalized 1,4-benzodiazepin-5-ones is presented. The benzodiazepine core is well-known to interact with biological receptors and many pharmaceutical drugs are derived from this structure. The alkene diamination strategy is employed for the first time for the synthesis of 1,4-benzodiazepinones. In this reaction, copper(2-ethylhexanoate)2 serves as promoter and a range of external amines can be coupled with 2-sulfonamido-N-allyl benzamides to generate the 1,4-benzodiazepinones in good yields.

Copper complexes are used as catalysts in modern synthetic chemistry because of their low cost, versatile reactivity, and broad tolerance for functional groups on substrates. Oxidation states in copper complexes can range from Cu to CuIV, and the metal center can participate in either two-electron or single-electron processes, sometimes both in the same catalytic cycle ( 1 – 6 ). This perspective highlights copper's contribution to amination catalysis, specifically the formation of carbon-nitrogen (C–N) bonds by coupling amines or amides with aryl halides (ArX) and alkyl halides (Ullmann-Goldberg reaction), arenes and alkanes [carbon-hydrogen (C–H) bond amination], or alkenes (oxidative amination, aminooxygenation, carboamination, and diamination).

Chiral saturated oxygen heterocycles are important components of bioactive compounds. Cyclization of alcohols onto pendant alkenes is a direct route to their synthesis, but few catalytic enantioselective methods enabling cyclization onto unactivated alkenes exist. Herein reported is a highly efficient copper-catalyzed cyclization of γ-unsaturated pentenols which terminates in CC bond formation, a net alkene carboetherification. Both intra- and intermolecular CC bond formations are demonstrated, thus yielding functionalized chiral tetrahydrofurans as well as fused-ring and bridged-ring oxabicyclic products. Transition-state calculations support a cis-oxycupration stereochemistry-determining step.

Chiral vicinal diamines, including 2-aminomethyl indolines and pyrrolidines, are useful as ligands for catalytic asymmetric reactions and are also found as important components of bioactive compounds. Herein is reported the first copper-catalyzed alkene diamination that occurs with high enantioselectivity. The substrate range is the broadest yet reported for this kind of intra-/intermolecular reaction sequence both with respect to γ-alkenyl sulfonamide substrate and external amine nucleophile. The resulting products expand the availability of substituted 2-aminomethyl indolines and pyrrolidines, privileged compounds in asymmetric catalysis and medicinal chemistry. A unique solution to a challenging oxidation problem related to copper catalyst turnover is also presented.

Enamines and enamides are useful synthetic intermediates and common components of bioactive compounds. A new protocol for their direct synthesis by a net alkene C-H amination and allylic amination by using catalytic Cu(II) in the presence of MnO2 is reported. Reactions between N-aryl sulfonamides and vinyl arenes furnish enamides, allylic amines, indoles, benzothiazine dioxides, and dibenzazepines directly and efficiently. Control experiments further showed that MnO2 alone can promote the reaction in the absence of a copper salt, albeit with lower efficiency. Mechanistic probes support the involvement of nitrogen-radical intermediates. This method is ideal for the synthesis of enamides from 1,1-disubstituted vinyl arenes, which are uncommon substrates in existing oxidative amination protocols.

The development of new reactions that facilitate the creative and efficient synthesis of molecular structures with desirable properties continues to fascinate chemists. The test of a significant contribution is its acceptance over time by the scientific community. The B-alkyl Suzuki-Miyaura cross-coupling reaction appears to be one such reaction. Since its disclosure by Suzuki and Miyaura in 1986, this reaction has been an attractive solution to challenging synthetic problems.