Highly Efficient Synthesis of New α‐Arylamino‐α′‐chloropropan‐2‐ones via Oxidative Hydrolysis of Vinyl Chlorides Promoted by Calcium Hypochlorite

The oxidative hydrolysis of different trifluoroacetyl‐protected N‐(2‐chloroallyl)anilines, promoted by calcium hypochlorite, is able to yield several not previously described α‐arylamino‐α′‐chloropropan‐2‐ones, very valuable building blocks that are useful as precursors of several drugs, in excellent yields and short reaction times. The main requirement of the reaction for avoiding the undesired aromatic chlorination (N‐protection) is effectively solved by the use of the easily formed and removed N‐trifluoroacetyl group. Thus, it is possible to perform the oxidative hydrolysis‐deprotection step using a one‐pot strategy, obtaining quantitative yields in very short reaction times.     

N,N′‐Dioxide‐Magnesium Ditriflate Complex‐Catalyzed Asymmetric α‐Hydroxylation of β‐Keto Esters and β‐Keto Amides

The highly catalytic asymmetric α‐hydroxylation of 1‐tetralone‐derived β‐keto esters and β‐keto amides using tert‐butyl hydroperoxide (TBHP) as the oxidant was realized by a chiral N,N′‐dioxide‐magnesium ditriflate [Mg(OTf)₂] complex. A series of corresponding chiral α‐hydroxy dicarbonyl compounds was obtained in excellent yields (up to 99%) with excellent enantioselectivities (up to 98% ee). The products were easily transformed into useful building blocks and the precursor of daunomycin was achieved in an asymmetric catalytic way for the first time.     

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.     

Quasi‐alternating polyesteramides from ε‐caprolactone and α‐amino acids

Glycine‐ɛ‐caprolactone‐based and α‐alanine‐ɛ‐caprolactone‐based polyesteramides with a strong tendency to form alternating sequences (degree of randomness = 1.64 and 1.31) were synthesized by melt polycondensation of intermediate hydroxy‐ and ethyl ester‐terminated amides. These intermediates were synthesized by the reaction of equimolar amounts of ɛ‐caprolactone and glycine or L‐α‐alanine ethyl esters in mild conditions. The structure and microstructure of these polyesteramides are discussed on the basis of an in‐depth nuclear magnetic resonance study. Both polyesteramides are semi‐crystalline, but the glycine‐based one presents the highest melting enthalpy. This polyesteramide also exhibits higher Young's modulus and stress at break than its α‐ and β‐alanine counterparts. © 2016 Wiley Periodicals, Inc. J. Appl. Polym. Sci. 2016 , 133, 44220.     

Asymmetric α‐Hydroxylation of β‐Indanone Esters and β‐Indanone Amides Catalyzed by C‐2′ Substituted Cinchona Alkaloid Derivatives

The highly catalytic asymmetric α‐hydroxylation of β‐indanone esters and β‐indanone amides using peroxide as the oxidant was realized with a new C‐2′ substituted Cinchona alkaloid derivatives. The two enantiomers of α‐hydroxy‐β‐indanone esters could be obtained by simply changing the oxidant. This protocol allows a convenient access to the corresponding α‐hydroxy‐β‐indanone esters and α‐hydroxy‐β‐indanone amides with up to 99% yield and 98% ee.

     

Iterative One‐Pot α‐Glycosylation Strategy: Application to Oligosaccharide Synthesis

Based on the combined use of dimethylformamide (DMF) modulation and neighboring group participation, three iterative one‐pot α‐glycosylation methods, i.e., one‐pot (α,α)‐, one‐pot (β,α)‐, and one‐pot (α,β)‐glycosylations, were developed. These methods are applicable to a range of thioglycosyl donors, confer stereocontrol in α‐/β‐glycosidic bond formation, and thus provide for rapid access to oligosaccharides with various permutations of anomeric configurations. The utility of these one‐pot glycosylation methods is demonstrated in the synthesis of eight non‐natural and natural oligosaccharide targets, including the core 1 serine conjugate, core 8 serine conjugate, the D ‐Gal‐α(1→3)‐D ‐Glc‐α(1→3)‐L ‐Rha trisaccharide unit of the cell wall component in Streptococcus pneumoniae, and the D ‐Glc‐α(1→2)‐D ‐Glc‐α(1→3)‐D ‐Glc trisaccharide terminus of the N‐linked glycan precursor. Confirmation of the anomeric configurations of these oligosaccharides is evidenced by ¹H, ¹³C, ¹³C‐non‐proton decoupling, and heteronuclear correlation 2D NMR experiments. Global deprotection of selected oligosaccharide targets is illustrated.     

Potassium Phosphate‐Catalyzed Chemoselective Reduction of α‐Keto Amides: Route to Synthesize Passerini Adducts and 3‐Phenyloxindoles

A chemoselective reduction of α‐keto amides to biologically important α‐hydroxy amides (mandelamides) by polymethylhydrosiloxane (PMHS) using 5 mol% potassium phosphate (K₃PO₄) as catalyst has been developed. This transition metal‐free protocol discloses excellent chemoselectivity for the ketone reduction of α‐keto amides in the presence of other reducible functionalities like ketone, nitro, halides, nitrile and amide. Also, the chemoselectively reduced α‐hydroxy amide has been derivatized to isocyanide‐free Passerini adducts. The N‐alkyl‐α‐hydroxy amides have been successfully converted to 3‐phenyloxindole derivatives by treatment with methanesulfonyl cholride and triethylamine.

     

The Growing Synthetic Utility of Weinreb′s Amide

The preparation and the synthetic utility of the N‐methoxy‐N‐methyl amides, also called as Weinreb amides, for the preparation of aldehydes and ketones has been discussed. Also the various reagents based on Weinreb′s amide has been compiled.     

Oxygen‐Involved Oxidative Deacetylation of α‐Substituted β‐Acetyl Amides – Synthesis of α‐Keto Amides

α‐Substituted β‐acetyl amides could undergo C C bond cleavage to form α‐keto amides when treated with copper(II) chloride (CuCl₂) and boron trifluoride diethyl etherate (BF₃⋅OEt₂) under an oxygen atmosphere. The yield can be increased by the addition of tert‐butyl hydroperoxide which alone can also effect the reaction. The reaction provides a new protocol for the synthesis of α‐keto amides.

     

Highly Stereoselective Halocyclopropanation of α,β‐Unsaturated Amides

A convenient highly stereoselective synthesis of chloro‐ and bromocyclopropanamides from di‐ tri‐ or tetrasubstituted (E)‐ or (Z)‐α,β‐unsaturated amides with total or high stereoselectivity promoted by chromium dichloride or dibromide is described. The transformation of chlorocyclopropanamides into the corresponding ketones or amines is also reported. A mechanism to explain these transformations is proposed.     

Enantioselective Aza‐Morita–Baylis–Hillman Reaction Using Aliphatic α‐Amidosulfones as Imine Surrogates

The bifunctional catalyst 6′‐deoxy‐6′‐acylamino‐β‐isocupreidine ( 1 ) served both as a base to trigger the in situ generation of N‐sulfonylimine from readily available α‐amidosulfones and as a chiral nucleophile to initiate the enantioselective aza‐Morita–Baylis–Hillman (aza‐MBH) reaction. α‐Methylene‐β‐amino‐β‐alkyl carbonyl compounds, difficultly accessible previously, can now be synthesized in excellent yields and enantioselectivities.     

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.     

Multi‐Enzymatic Synthesis of Optically Pure β‐Hydroxy α‐Amino Acids

A novel enzymatic production system of optically pure β‐hydroxy α‐amino acids was developed. Two enzymes were used for the system: an N‐succinyl L ‐amino acid β‐hydroxylase (SadA) belonging to the iron(II)/α‐ketoglutarate‐dependent dioxygenase superfamily and an N‐succinyl L ‐amino acid desuccinylase (LasA). The genes encoding the two enzymes are part of a gene set responsible for the biosynthesis of peptidyl compounds found in the Burkholderia ambifaria AMMD genome. SadA stereoselectively hydroxylated several N‐succinyl aliphatic L ‐amino acids and produced N‐succinyl β‐hydroxy L ‐amino acids, such as N‐succinyl‐L ‐β‐hydroxyvaline, N‐succinyl‐L ‐threonine, (2S,3R)‐N‐succinyl‐L ‐β‐hydroxyisoleucine, and N‐succinyl‐L ‐threo‐β‐hydroxyleucine. LasA catalyzed the desuccinylation of various N‐succinyl‐L ‐amino acids. Surprisingly, LasA is the first amide bond‐forming enzyme belonging to the amidohydrolase superfamily, and has succinylation activity towards the amino group of L ‐leucine. By combining SadA and LasA in a preparative scale production using N‐succinyl‐L ‐leucine as substrate, 2.3 mmol of L ‐threo‐β‐hydroxyleucine were successfully produced with 93% conversion and over 99% of diastereomeric excess. Consequently, the new production system described in this study has advantages in optical purity and reaction efficiency for application in the mass production of several β‐hydroxy α‐amino acids.

     

One‐Step Catalytic Enantioselective α‐Quaternary 5‐Hydroxyproline Synthesis: An Asymmetric Entry to Highly Functionalized α‐Quaternary Proline Derivatives

The highly enantioselective cascade reaction between N‐protected α‐cyanoglycine esters and α,β‐unsaturated aldehydes is disclosed. The reaction represents a one‐step entry to polysubstituted 5‐hydroxyproline derivatives having a quaternary α‐stereocenter generally in high yields with up to >95:5 dr and 99:1 er. It is also a direct catalytic two‐step entry to functionalized α‐quaternary proline derivatives.     

Enantioselective Phase‐Transfer Catalytic α‐Benzylation and α‐Allylation of α‐tert‐Butoxycarbonyllactones

A new enantioselective α‐benzylation and α‐allylation of α‐tert‐butoxycarbonyllactones was devloped. α‐Benzylation and α‐allylation of α‐tert‐butoxycarbonylbutyrolactone and α‐tert‐butoxycarbonylvalerolactone under phase‐transfer catalytic conditions (50% cesium hydroxide, toluene, −60 °C) in the presence of (S,S)‐3,4,5‐trifluorophenyl‐NAS bromide (1 mol%) afforded the corresponding α‐substituted α‐tert‐butoxycarbonyllactones in very high chemical yields (up to 99%) and optical yields (up to 99% ee). The synthetic potential of this method has been successfully demonstrated by the asymmetric synthesis of unnatural α‐quaternary homoserines, 3‐alkyl‐3‐carboxypyrrolidine and 3‐alkyl‐3‐carboxypiperidine.     

Synthesis and Derivatization of Substituted (R)‐ and (S)‐ C‐Allylglycines

Various (R)‐ and (S)‐C‐allylglycine derivatives were synthesized by means of an auxiliary controlled diastereoselective aza‐Claisen rearrangement. Starting from (S)‐configured auxiliaries derived from optically active proline, an aza‐Claisen rearrangement enabled us to synthesize α(R)‐configured γ,δ‐unsaturated amides. Since (R)‐allylglycine derivatives could be directly generated by reacting N‐allylproline derivatives and various protected glycine fluorides, the corresponding (S)‐enantiomers were built‐up via an initial α‐chloroacetyl chloride rearrangement and a subsequent chloride azide substitution with complete inversion of the configuration. High diastereoselectivities were obtained (>15 : 1). The auxiliary could be efficiently removed by organolithium reactions of the amides furnishing α‐amino ketones. Another allyllithium addition allowed us to introduce a second allyl chain with high diastereoselectivity. Final ring closures by means of metatheses using Grubbs' (I) catalyst gave raise to the formation of enantiopure phenanthridines and cyclohexenes displaying defined substitution patterns ready for alkaloid total syntheses.     

Electrospinning of poly(γ‐benzyl–α,L‐glutamate) microfibers for piezoelectric polymer applications

One of the latest developments in the field of piezoelectric polymers is the use of poly(γ‐benzyl‐α,L‐glutamate) (PBLG), a poly(amino acid) that can be poled along its α‐helical axis and fabricated into thermally stable piezoelectric microfibers via electrospinning. This study demonstrates a method for improving the piezoelectricity of electrospun PBLG microfibers by controlling the orientation of fibers using a method based on a concentrated electric field. The piezoelectricity is verified via customized quasi‐static and dynamic measurement methods, while the correlation between fiber alignment and the piezoelectric constant, d₃₃, in the longitudinal mode of the electrospun PBLG fibers is investigated. When the level of alignment was varied from 50% to 90%, the piezoelectric constant increased linearly, showing a maximum d₃₃ of 27 pC N^?1 and a maximum force sensitivity of 65 mV N^?1 at peak alignment. A fabricated flexible prototype based on electrospun PBLG fibers provides a new solution for the use of PBLG fibers in wearable energy harvesters or composites based on piezoelectric polymer fibers. © 2018 Wiley Periodicals, Inc. J. Appl. Polym. Sci. 2018 , 135, 46440.     

Copper‐Catalyzed Oxidative α‐Alkylation of α‐Amino Carbonyl Compounds with Ethers via Dual C(sp3)‐H Oxidative Cross‐ Coupling

A novel copper‐catalyzed oxidative alkylation of α‐amino carbonyl compounds with ethers has been established for the selective synthesis of α‐etherized α‐amino carbonyl compounds. This oxidative alkylation is achieved by dual C(sp³) H bond oxidative cross‐coupling, and its scope is expanded to α‐amino ketones, α‐amino esters and α‐amino amides.

     

Highly Enantioselective Allylation of Aromatic α‐Keto Phosphonates Catalyzed by Chiral N,N′‐Dioxide‐Indium(III) Complexes

The ramipril derivative N,N′‐dioxide 3g ‐indium(III) complex was found to be an efficient catalyst for the allylation of the aromatic α‐keto phosphonates. The corresponding α‐hydroxy phosphonates were obtained with high yields (up to 98 %) and high enantioselectivities (up to 91 % ee). A bifunctional catalyst system was described with an N‐oxide as Lewis base activating tetraallyltin and indium as Lewis acid activating aromatic α‐keto phosphonates. A possible catalytic cycle has been proposed to explain the mechanism of the reaction.     

Chiral N,N′‐Dioxide–Yttrium Triflate Complexes‐Catalyzed Asymmetric Aldol Cyclization of α‐Keto Esters with α‐Isothiocyanato Imide

A highly effective aldol cyclization of α‐isothiocyanato imide to both β,γ‐unsaturated α‐keto esters and aryl‐substituted α‐keto esters has been developed. A chiral N,N′‐dioxide–yttrium triflate complex was used as the catalyst. A series of cyclic thiocarbamates bearing chiral quaternary stereocenters was synthesized in good to high yields, excellent diastereo‐ (up to 25:1 dr) and enantioselectivities (up to 99 % ee). In addition, the reaction could be carried out on a gram‐scale, and other functionalized derivatives are also conveniently transformed. Interestingly, a discrepancy of diastereoselection was observed between the reactions of β,γ‐unsaturated α‐keto esters and aryl‐substituted α‐keto esters. Moreover, a substrate dependency of non‐linear effects was observed in this reaction. On the basis of the experimental results and the absolute configuration of the products, possible catalytic models have been proposed to explain the origin of the asymmetric process.