Synthesis of Diastereomeric 1,4‐Diphosphine Ligands Bearing Imidazolidin‐2‐one Backbone and Their Application in Rh(I)‐Catalyzed Asymmetric Hydrogenation of Functionalized Olefins

The diastereomeric 1,4‐diphosphine ligands, (S,S,S,S)‐ 1a , (R,S,S,R)‐ 1b and (R,S,S,S)‐ 1c , with the imidazolidin‐2‐one backbone were synthesized, and utilized for an investigation of the effects of backbone chirality on the enantioselectivity in the Rh(I)‐catalyzed hydrogenation of various functionalized olefinic substrates. It was found that the catalytic efficiencies are largely dependent on the configurations of the α‐carbons to phosphine. Thus, the Rh complex of the pseudo‐C₂‐symmetrical diphosphine, (R,S,S,S)‐ 1c , showed excellent enantioselectivities (93.0–98.6% ees) in the hydrogenations of a broad spectrum of substrates, and especially in the hydrogenations of methyl α‐(N‐acetyamino)‐β‐arylacrylates (95.3–97.0% ees). However, the enantioselectivities obtained with the C₂‐symmetrical (R,S,S,R)‐ 1b were largely dependent on the substrate (19.8–97.3% ees). The Rh complex of ligand 1a having the (S,S,S,S)‐configuration showed the lowest catalytic efficiency for all of the substrates examined (0–84.8% ees).     

In Situ Formed Bifunctional Primary Amine‐Imine Catalyst: Application to the Construction of Chiral Tertiary Alcohols through Asymmetric Aldol‐Type Reaction

An in situ formation method to obtain chiral bifunctional primary amine‐imine catalysts from the C₂‐symmetric chiral diimines has been developed. The efficiency of this method in the construction of chiral tertiary alcohols which are valuable pharmaceutical intermediates is proved by its application to the asymmetric aldol‐type reaction of cyclic ketones with other activated ketone compounds as the enamine acceptors, i.e., β,γ‐unsaturated α‐keto esters and isatins. In general, good to excellent diastereoselectivities and enantioselectivities (up to 96/4 dr, 96% ee for β,γ‐unsaturated α‐keto esters and up to 91/9 dr, 94% ee for isatins) were obtained. The active primary amine‐imine catalylst and enamine intermediate in the reaction process could be demonstrated by ESI‐MS analysis.     

Highly Enantioselective Phase‐Transfer Catalytic α‐Alkylation of α‐tert‐Butoxycarbonyllactams: Construction of β‐Quaternary Chiral Pyrrolidine and Piperidine Systems

A new enantioselective α‐alkylation of α‐tert‐butoxycarbonyllactams for the construction of β‐quaternary chiral pyrrolidine and piperidine core systems is reported. α‐Alkylations of N‐methyl‐α‐tert‐butoxycarbonylbutyrolactam and N‐diphenylmethyl‐α‐tert‐butoxycarbonylvalerolactam under phase‐transfer catalytic conditions (solid potassium hydroxide, toluene, −40 °C) in the presence of (S,S)‐3,4,5‐trifluorophenyl‐3,3′,5,5′‐tetrahydro‐2,6‐bis(3,4,5‐trifluorophenyl)‐4,4′‐spirobi[4H‐dinaphth[2,1‐c:1′,2′‐e]azepinium] bromide [(S,S)‐NAS Br] (5 mol%) afforded the corresponding α‐alkyl‐α‐tert‐butoxycarbonyllactams in very high chemical (up to 99%) and optical yields (up to 98% ee). Our new catalytic systems provide attractive synthetic methods for pyrrolidine‐ and piperidine‐based alkaloids and chiral intermediates with β‐quaternary carbon centers.     

Benzaldehyde Lyase‐Catalyzed Direct Amidation of Aldehydes with Nitroso Compounds

Benzaldehyde lyase from the Pseudomonas fluorescens catalyzes the reaction of aromatic aldehydes with nitroso compounds and furnishes N‐arylhydroxamic acids in high yields. Aromatic aldehydes and benzoins are converted into enamine‐carbanion‐like intermediates prior to their reaction with nitroso compounds. The kinetic resolution of rac‐2‐hydroxy‐1,2‐diphenylethanones furnished (S)‐benzoins and arylhydroxamic acids with high enantioselectivities and conversions.     

Alteration of the Route to Menaquinone towards Isochorismate-Derived Metabolites

Chorismate and isochorismate constitute branch-point intermediates in the biosynthesis of many aromatic metabolites in microorganisms and plants. To obtain unnatural compounds, we modified the route to menaquinone in Escherichia coli. We propose a model for the binding of isochorismate to the active site of MenD ((1R,2S, 5S,6S)-2-succinyl-5-enolpyruvyl-6-hydroxycyclohex-3-ene-1-carboxylate (SEPHCHC) synthase) that explains the outcome of the native reaction with α-ketoglutarate. We have rationally designed variants of MenD for the conversion of several isochorismate analogues. The double-variant Asn117Arg–Leu478Thr preferentially converts (5S,6S)-5,6-dihydroxycyclohexa-1,3-diene-1-carboxylate (2,3-trans-CHD), the hydrolysis product of isochorismate, with a >70-fold higher ratio than that for the wild type. The single-variant Arg107Ile uses (5S,6S)-6-amino-5-hydroxycyclohexa-1,3-diene-1-carboxylate (2,3-trans-CHA) as substrate with >6-fold conversion compared to wild-type MenD. The novel compounds have been made accessible in vivo (up to 5.3 g L⁻¹). Unexpectedly, as the identified residues such as Arg107 are highly conserved (>94 %), some of the designed variations can be found in wild-type SEPHCHC synthases from other bacteria (Arg107Lys, 0.3 %). This raises the question for the possible natural occurrence of as yet unexplored branches of the shikimate pathway.     

An Engineered Old Yellow Enzyme that Enables Efficient Synthesis of (4R,6R)‐Actinol in a One‐Pot Reduction System

(4R,6R)‐Actinol can be stereo‐selectively synthesized from ketoisophorone by a two‐step conversion using a mixture of two enzymes: Candida macedoniensis old yellow enzyme (CmOYE) and Corynebacterium aquaticum (6R)‐levodione reductase. However, (4S)‐phorenol, an intermediate, accumulates because of the limited substrate range of CmOYE. To address this issue, we solved crystal structures of CmOYE in the presence and absence of a substrate analogue p‐HBA, and introduced point mutations into the substrate‐recognition loop. The most effective mutant (P295G) showed two‐ and 12‐fold higher catalytic activities toward ketoisophorone and (4S)‐phorenol, respectively, than the wild‐type, and improved the yield of the two‐step conversion from 67.2 to 90.1 %. Our results demonstrate that the substrate range of an enzyme can be changed by introducing mutation(s) into a substrate‐recognition loop. This method can be applied to the development of other favorable OYEs with different substrate preferences.     

Alteration of the Diastereoselectivity of 3‐Methylaspartate Ammonia Lyase by Using Structure‐Based Mutagenesis

3‐Methylaspartate ammonia‐lyase (MAL) catalyzes the reversible amination of mesaconate to give both (2S,3S)‐3‐methylaspartic acid and (2S,3R)‐3‐methylaspartic acid as products. The deamination mechanism of MAL is likely to involve general base catalysis, in which a catalytic base abstracts the C3 proton of the respective stereoisomer to generate an enolate anion intermediate that is stabilized by coordination to the essential active‐site Mg^II ion. The crystal structure of MAL in complex with (2S,3S)‐3‐methylaspartic acid suggests that Lys331 is the only candidate in the vicinity that can function as a general base catalyst. The structure of the complex further suggests that two other residues, His194 and Gln329, are responsible for binding the C4 carboxylate group of (2S,3S)‐3‐methylaspartic acid, and hence are likely candidates to assist the Mg^II ion in stabilizing the enolate anion intermediate. In this study, the importance of Lys331, His194, and Gln329 for the activity and stereoselectivity of MAL was investigated by site‐directed mutagenesis. His194 and Gln329 were replaced with either an alanine or arginine, whereas Lys331 was mutated to a glycine, alanine, glutamine, arginine, or histidine. The properties of the mutant proteins were investigated by circular dichroism (CD) spectroscopy, kinetic analysis, and ¹H NMR spectroscopy. The CD spectra of all mutants were comparable to that of wild‐type MAL, and this indicates that these mutations did not result in any major conformational changes. Kinetic studies demonstrated that the mutations have a profound effect on the values of k_cat and k_cat/K_M; this implicates Lys331, His194 and Gln329 as mechanistically important. The ¹H NMR spectra of the amination and deamination reactions catalyzed by the mutant enzymes K331A, H194A, and Q329A showed that these mutants have strongly enhanced diastereoselectivities. In the amination direction, they catalyze the conversion of mesaconate to yield only (2S,3S)‐3‐methylaspartic acid, with no detectable formation of (2S,3R)‐3‐methylaspartic acid. The results are discussed in terms of a mechanism in which Lys331, His194, and Gln329 are involved in positioning the substrate and in formation and stabilization of the enolate anion intermediate.     

(S)‐Selectivity in Phenylacetyl Carbinol Synthesis Using the Wild‐Type Enzyme Acetoin:Dichlorophenolindophenol Oxidoreductase from Bacillus licheniformis

Thiamine diphosphate (ThDP)‐dependent enzymes are well known biocatalysts for the asymmetric synthesis of α‐hydroxy ketones with preferential (R)‐selectivity. Pharmaceutically relevant phenylacetyl carbinol (PAC) has been prepared with absolute (S)‐configuration only on a few occasions using enzyme variants suitably designed through rational site‐directed mutagenesis approaches. Herein, we describe the synthesis of (S)‐phenylacetyl carbinol products with extended reaction scope employing the readily available wild‐type ThDP‐dependent enzyme acetoin:dichlorophenolindophenol oxidoreductase (Ao:DCPIP OR) from Bacillus licheniformis. On a semipreparative scale, cross‐benzoin‐like condensations of methylacetoin (donor) and differently substituted benzaldehydes proceed with almost complete chemoselectivity yielding the target (S)‐1‐hydroxy‐1‐phenylpropan‐2‐one derivatives with high conversion efficiencies (up to 95%) and good enantioselectivities (up to 99%). Ao:DCPIP OR accepts hydroxy‐ and nitrobenzaldehydes and also sterically demanding substrates such as 1‐naphthaldehyde and 4‐(tert‐butyl)benzaldehyde, which are typically poor acceptors in enzymatic transformations. The explorative synthesis of (S)‐phenylpropionyl carbinol mediated by Ao:DCPIP OR via carboligation of benzaldehyde with 3,4‐hexanedione is also reported.

     

Catalytic Scope of the Thiamine‐Dependent Multifunctional Enzyme Cyclohexane‐1,2‐dione Hydrolase

The thiamine diphosphate (ThDP)‐dependent enzyme cyclohexane‐1,2‐dione hydrolase (CDH) was expressed in Escherichia coli and purified by affinity chromatography (Ni‐NTA). Recombinant CDH showed the same C?C bond‐cleavage and C?C bond‐formation activities as the native enzyme. Furthermore, we have shown that CDH catalyzes the asymmetric cross‐benzoin reaction of aromatic aldehydes and (decarboxylated) pyruvate (up to quantitative conversion, 92–99 % ee). CDH accepts also hydroxybenzaldehydes and nitrobenzaldehydes; these previously have not (or only in rare cases) been known as substrates of other ThDP‐dependent enzymes. On a semipreparative scale, sterically demanding 4‐(tert‐butyl)benzaldehyde and 2‐naphthaldehyde were transformed into the corresponding 2‐hydroxy ketone products in high yields. Additionally, certain benzaldehydes with electron withdrawing substituents were identified as potential inhibitors of the ligase activity of CDH.     

Synthesis and Highly Stereoselective Hydrogenation of the Statin Precursor Ethyl (5S)‐5,6‐Isopropylidenedioxy‐3‐oxohexanoate

A search for the large‐scale preparation of (5S)‐5,6‐(isopropylidenedioxy)‐3‐oxohexanoates ( 2 ) – a key intermediate in the synthesis of pharmacologially important statins – starting from (S)‐malic acid is described. The synthesis of the required initial compound methyl (3S)‐3,4‐(isopropylidenedioxy)butanoate ( 1 ) by Moriwake’s reduction of dimethyl (S)‐malate ( 3 ) has been improved. Direct 2‐C chain elongation of ester 1 using the lithium enolate of tert‐butyl acetate has been shown to be successful at a 3‐ to 5‐fold excess of the enolate. Unfortunately, the product, tert‐butyl (5S)‐5,6‐(isopropylidenedioxy)‐3‐oxohexanoate ( 2a ) is unstable during distillation. Ethyl (5S)‐5,6‐(isopropylidenedioxy)‐3‐oxohexanoate ( 2b ) was prepared alternatively on a multigram scale from (3S)‐3,4‐(isopropylidenedioxy)butanoic acid ( 7 ) by activation with N,N′‐carbonyldiimidazole and subsequent reaction with Mg(OOCCH₂COOEt)₂. A convenient pathway for the in situ preparation of the latter is also described. Ethyl ester ( 2b ) can be advantageously purified by distillation. The stereochemistry of the catalytic hydrogenation of β‐keto ester ( 2b ) to ethyl (5S)‐5,6‐(isopropylidenedioxy)‐3‐hydrohyhexanoate (syn‐ 6 and anti‐ 6 ) has been studied using a number of homogeneous achiral and chiral Rh(I) and Ru(II) complexes with phosphine ligands. A comparison of Rh(I) and Ru(II) catalysts with (S)‐ and (R)‐BINAP as chiral ligands revealed opposite activity in dependence on the polarity of the solvent. No influence of the chiral backbone of substrate 2b on the enantioselectivity was noted. A ratio of syn‐ 6 /anti‐ 6 =2.3 was observed with an achiral (Ph₃P)₃RuCl₂ catalyst. Ru[(R)‐Tol‐BINAP]Cl₂ neutralized with one equivalent of AcONa afforded the most efficient catalytic system for the production of optically pure syn‐(5S)‐5,6‐isopropylidenedioxy‐3‐hydroxyhexanoate (syn‐ 6 ) at a preparative substrate/catalyst ratio of 1000:1.     

Substrate‐Determined Diastereoselectivity in an Enzymatic Carboligation

Thiamine diphosphate‐dependent enzymes catalyze the formation of C?C bonds, thereby generating chiral secondary or tertiary alcohols. By the use of vibrational circular dichroism (VCD) spectroscopy we studied the stereoselectivity of carboligations catalyzed by YerE, a carbohydrate‐modifying enzyme from Yersinia pseudotuberculosis. Conversion of the non‐physiological substrate (R)‐3‐methylcyclohexanone led to an R,R‐configured tertiary alcohol (diastereomeric ratio (dr) >99:1), whereas the corresponding reaction with the S enantiomer gave the S,S‐configured product (dr>99:1). This suggests that YerE‐catalyzed carboligations can undergo either an R‐ or an S‐specific pathway. We show that, in this case, the high stereoselectivity of the YerE‐catalyzed reaction depends on the substrate's preference to acquire a low‐energy conformation.     

N‐Iodosuccinimide‐Promoted Rapid Access to Indeno[1,2‐c]pyrroles via [3+2] Annulation of Enamine‐alkynes

We have developed a metal‐free, N‐iodosuccinimide (NIS)‐promoted, cascade strategy for the efficient synthesis of biologically important indeno[1,2‐c]pyrroles via a [3+2] annulation process of enamine‐alkynes. This methodology had shown a very broad scope for diversely functionalized enamines and alkynes. We have also developed a one‐pot, multicomponent strategy for the direct synthesis of indeno‐pyrroles from diynones via enamine‐alkynes. Control experiments supported the involvement of NIS as an electrophilic activator via an ionic mechanism rather than a radical pathway.

     

Biotransformation of l‐menthol by soil‐borne plant pathogenic fungi (Rhizoctonia solani)

The biotransformation of l‐menthol was investigated by using nine isolates of Rhizoctonia solani (AG‐1‐IA Rs24, Joichi‐2, RRG97‐1; AG‐1‐IB TR22, R147, 110.4; AG‐1‐IC F‐1, F‐4 and P‐1) as a biocatalyst. In the cases of Rhizoctonia solani F‐1, F‐4 and P‐1, almost all of the substrate was consumed in 3 days and the major metabolite increased rapidly for the first of 3 days incubation. The structure of the major metabolite was elucidated on the basis of its spectral data. The major metabolite was determined to be (?)‐(1S,3R,4S,6S)‐6‐hydroxymenthol which indicated that l‐menthol was hydroxylated at the C‐6 position. From the main component analysis, the nine isolates of Rhizoctonia solani were divided into two groups based on their ability to transform l‐menthol to (?)‐(1S,3R,4S,6S)‐6‐hydroxymenthol. This is the first report on the biotransformation of l‐menthol by Rhizoctonia solani. © 2001 Society of Chemical Industry     

tRNA Processing by Protein‐Only versus RNA‐Based RNase P: Kinetic Analysis Reveals Mechanistic Differences

In Arabidopsis thaliana, RNase P function, that is, endonucleolytic tRNA 5′‐end maturation, is carried out by three homologous polypeptides (“proteinaceous RNase P” (PRORP) 1, 2 and 3). Here we present the first kinetic analysis of these enzymes. For PRORP1, a specificity constant (k_react/K_m(sto)) of 3×10⁶ M ^?1 min^?1 was determined under single‐turnover conditions. We demonstrate a fundamentally different sensitivity of PRORP enzymes to an Rp‐phosphorothioate modification at the canonical cleavage site in a 5′‐precursor tRNA substrate; whereas processing by bacterial RNase P is inhibited by three orders of magnitude in the presence of this sulfur substitution and Mg²⁺ as the metal‐ion cofactor, the PRORP enzymes are affected by not more than a factor of five under the same conditions, without significantly increased miscleavage. These findings indicate that the catalytic mechanism utilized by proteinaceous RNase P is different from that of RNA‐based bacterial RNase P, taking place without a direct metal‐ion coordination to the (pro‐)Rp substituent. As Rp‐phosphorothioate and inosine modification at all 26 G residues of the tRNA body had only minor effects on processing by PRORP, we conclude that productive PRORP–substrate interaction is not critically dependent on any of the affected (pro‐)Rp oxygens or guanosine 2‐amino groups.     

An efficient strategy overcoming the bottleneck in Candida parapsilosis catalyzing stereoinversion from (R)‐1‐phenyl‐1, 2‐ethanediol to the corresponding counterpart

BACKGROUND: Microbial stereoinversion has been widely used for the biosynthesis of numerous chiral compounds. However, little work has been done to improve the efficiency of microbial stereoinversion. This study investigated the bottleneck in the deracemization of 1‐phenyl‐1,2‐ethanediol (PED), and then the efficiency and the sustainability of biocatalyst was improved significantly by using a strategy. RESULTS: When (S)‐PED concentration exceeded 17.5 g L^?1, it strongly inhibited deracemization. Furthermore, the deficiency of NADPH regeneration also limited such reaction. To overcome these limitations, extractive biocatalysis was developed using adsorbent resin NKII combined with xylose addition for cofactor regeneration. Compared with the initial reaction condition, which only afforded (S)‐PED with 35% optical purity after the first batch reaction at 30 g L^?1 substrate concentration, the cells in the new system could be reused three times and the optical purity remained at a high level of 95%. CONCLUSION: Product inhibition and coenzyme regeneration had a significant effect on catalytic activity of Candida parapsilosis. By using a resin and D‐xylose, the efficiency and reusability of whole‐cell catalyst can be considerably improved, which would be helpful for effective synthesis of high value chiral intermediates. Copyright © 2009 Society of Chemical Industry     

The Synthesis of trans‐Perhydroindolic Acids and their Application in Asymmetric Domino Reactions of Aldehyde Esters with β,γ‐Unsaturated α‐Keto Esters

(2S,3aR,7aS)‐Perhydroindolic acid, the key intermediate in the synthesis of trandolapril, and its trans‐isomers, were readily prepared. These proline‐like molecules are unique in that they contain a rigid bicyclic structure, with two hydrogen atoms trans to each other at the bridgehead carbon atoms. These molecules were used successfully as chiral organocatalysts in asymmetric domino Michael addition/cyclization reactions of aldehyde esters with β,γ‐unsaturated α‐keto esters. They proved to have excellent catalytic behavior, allowing for the synthesis of multi‐substituted, enantiomerically enriched hemiacetal esters. Under optimal conditions (using 10 mol% catalyst loading), a series of β,γ‐unsaturated α‐keto esters was examined with up to 99% de, ee and yield, respectively. Additionally, the enantiomerically enriched hemiacetal esters could be readily transformed into their corresponding bioactive pyrano[2,3‐b]pyrans (possessing a multi‐substituted bicyclic backbone).     

Protein Arginine N‐Methyltransferase Substrate Preferences for Different Nη‐Substituted Arginyl Peptides

Protein arginine N‐methyltransferases (PRMTs) catalyze methyl‐group transfer from S‐adenosyl‐L ‐methionine onto arginine residues in proteins. In this study, modifications were introduced at the guanidine moiety of a peptidyl arginine residue to investigate how changes to the PRMT substrate can modulate enzyme activity. We found that peptides bearing Nη‐hydroxy or Nη‐amino substituted arginine showed higher apparent k_cat values than for the monomethylated substrate when using PRMT1, whereas this catalytic preference was not observed for PRMT4 and PRMT6. Methylation by compromised PRMT1 variants E153Q and D51N further supports the finding that the N‐hydroxy substitution facilitates methyl transfer by tuning the reactivity of the guanidine moiety. In contrast, Nη‐nitro and Nη‐canavanine substituted substrates inhibit PRMT activity. These findings demonstrate that methylation of these PRMT substrates is dependent on the nature of the modification at the guanidine moiety.     

Synthesis of 6‐amino acid substituted 4,6,7,12‐tetrahydro‐4‐oxoindolo[2,3‐a]quinolizines

In the presence of Na₂CO₃ (1S,3S)‐ and (1R,3S)‐1‐(2,2‐dimethoxyethyl)‐2‐(1,3‐dioxobutyl)‐3‐(1,3‐dioxo‐butyl)oxymethyl‐1,2,3,4‐tetrahydrocarboline ( 1 ) were transformed into (1S,3S)‐ and (1R,3S)‐1‐(2,2‐dimethoxyethyl)‐2‐(1,3‐dioxobutyl)‐3‐hydroxymethyl‐1,2,3,4‐tetrahydrocarboline ( 2 ), which were cyclized to (6S)‐3‐acetyl‐6‐hydroxymethyl‐4,6,7,12‐tetrahydro‐4‐oxoindolo[2,3‐a]quinolizine ( 4 ), via(6S,12bS)‐ and (6S,12bR)‐3‐acetyl‐2‐hydroxyl‐6‐hydroxymethyl‐1,2,3,4,6,7,12,12b‐octahydro‐4‐oxoindolo[2,3‐a]quinoline ( 3 ). (6S)‐ 4 was coupled with Boc‐Gly, Boc‐L‐Asp(β‐benzyl ester), or Boc‐L‐Gln to give 6‐amino acid substituted (6S)‐3‐acetyl‐4,6,7,12‐tetrahydro‐4‐oxoindolo[2,3‐a]quinolizines 5a , 5b , or 5c , respectively. After the removal of Boc from (6S)‐ 5a (6S)‐3‐acetyl‐6‐glycyl‐4,6,7,12‐tetrahydro‐4‐oxoindolo[2,3‐a]quinolizine ( 6 ) was obtained. The anticancer activities of (6S)‐ 5 and (6S)‐ 6 in vitro were tested.     

α‐Keto Phenylamides as P1′‐Extended Proteasome Inhibitors

The major challenge for proteasome inhibitor design lies in achieving high selectivity for, and activity against, the target, which requires specific interactions with the active site. Novel ligands aim to overcome off‐target‐related side effects such as peripheral neuropathy, which is frequently observed in cancer patients treated with the FDA‐approved proteasome inhibitors bortezomib ( 1 ) or carfilzomib ( 2 ). A systematic comparison of electrophilic headgroups recently identified the class of α‐keto amides as promising for next generation drug development. On the basis of crystallographic knowledge, we were able to develop a structure–activity relationship (SAR)‐based approach for rational ligand design using an electronic parameter (Hammett’s σ) and in silico molecular modeling. This resulted in the tripeptidic α‐keto phenylamide BSc4999 [(S)‐3‐(benzyloxycarbonyl‐(S)‐leucyl‐(S)‐leucylamino)‐5‐methyl‐2‐oxo‐N‐(2,4‐dimethylphenyl)hexanamide, 6 a ], a highly potent (IC₅₀=38 nM ), cell‐permeable, and slowly reversible covalent inhibitor which targets both the primed and non‐primed sites of the proteasome’s substrate binding channel as a special criterion for selectivity. The improved inhibition potency and selectivity of this new α‐keto phenylamide makes it a promising candidate for targeting a wider range of tumor subtypes than commercially available proteasome inhibitors and presents a new candidate for future studies.     

Room Temperature Highly Enantioselective Nickel‐Catalyzed Hydrovinylation

At room temperature, nickel catalysts based on the new phosphoramidite (11bR)‐N‐[(S)‐1‐(naphthalen‐1‐yl)ethyl]‐N‐[(S)‐1‐(naphthalen‐2‐yl)ethyl]dinaphtho[2,1‐d:1′,2′‐f][1,3,2]dioxaphosphepin‐4‐amine provide excellent selectivities for 3‐arylbut‐1‐enes (93–99%) with high enantioselectivities (90–95% ee) and TOFs (up to 8300 h⁻¹) in the hydrovinylation of electron‐rich and electron‐poor vinylarenes. Within a few minutes, useful chiral building blocks and intermediates can be synthesized using this practical catalytic system.