Access to β‐Lactams by Enantioselective Palladium(0)‐Catalyzed C(sp3)H Alkylation

β‐Lactams are very important structural motifs because of their broad biological activities as well as their propensity to engage in ring‐opening reactions. Transition‐metal‐catalyzed C? H functionalizations have emerged as strategy enabling yet uncommon highly efficient disconnections. In contrast to the significant progress of Pd⁰‐catalyzed C? H functionalization for aryl–aryl couplings, related reactions involving the formation of saturated C(sp³)? C(sp³) bonds are elusive. Reported here is an asymmetric C? H functionalization approach to β‐lactams using readily accessible chloroacetamide substrates. Important aspects of this transformation are challenging C(sp³)? C(sp³) and strain‐building reductive eliminations to for the four‐membered ring. In general, the β‐lactams are formed in excellent yields and enantioselectivities using a bulky taddol phosphoramidite ligand in combination with adamantyl carboxylic acid as cocatalyst.     

Copper(I)‐Catalyzed Chemoselective Coupling of Cyclopropanols with Diazoesters: Ring‐Opening C−C Bond Formations

Reported herein is an exceptional chemoselective ring‐opening/C(sp³)−C(sp³) bond formation in the copper(I)‐catalyzed reaction of cyclopropanols with diazo esters. The conventional O−H insertion product is essentially suppressed by judicious choice of reaction conditions. DFT calculations provide insights into the reaction mechanism and the rationale for this unusual chemoselectivity.     

Oxidative β‐Csp3−H Functionalization of tBuOH: A Selective Radical/Radical Cross‐Coupling Access to β‐Hydroxy Thioethers

An oxidative β‐Csp³?H functionalization of tert‐butanol (tBuOH) for the construction of C?S bonds through an iodine‐catalyzed Csp³?H/S?H coupling was successfully achieved. Different kinds of mercaptans were shown to be good coupling partners, affording the desired products in good yields. This protocol not only offers a novel method for the synthesis of β‐hydroxy thioethers, but also provides an effective strategy for selective radical/radical cross‐coupling.     

Chemoselective,Substrate‐directed Fluorination of Functionalized Cyclopentane β‐Amino Acids

This work describes a substrate‐directed fluorination of some highly functionalized cyclopentane derivatives. The cyclic products incorporating CH₂F or CHF₂ moieties in their structure have been synthesized from diexo‐ or diendo‐norbornene β‐amino acids following a stereocontrolled strategy. The synthetic study was based on an oxidative transformation of the ring carbon–carbon double bond of the norbornene β‐amino acids, followed by transformation of the resulted ?all cis“ and ?trans“ diformyl intermediates by fluorination with ?chemodifferentiation“.     

Highly Stereoselective β‐Mannopyranosylation via the 1‐α‐Glycosyloxy‐isochromenylium‐4‐gold(I) Intermediates

While the gold(I)‐catalyzed glycosylation reaction with 4,6‐O‐benzylidene tethered mannosyl ortho‐alkynylbenzoates as donors falls squarely into the category of the Crich‐type β‐selective mannosylation when Ph₃PAuOTf is used as the catalyst, in that the mannosyl α‐triflates are invoked, replacement of the ^?OTf in the gold(I) complex with less nucleophilic counter anions (i.e., ^?NTf₂, ^?SbF₆, ^?BF₄, and ^?BAr₄^F) leads to complete loss of β‐selectivity with the mannosyl ortho‐alkynylbenzoate β‐donors. Nevertheless, with the α‐donors, the mannosylation reactions under the catalysis of Ph₃PAuBAr₄^F (BAr₄^F=tetrakis[3,5‐bis(trifluoromethyl)phenyl]borate) are especially highly β‐selective and accommodate a broad scope of substrates; these include glycosylation with mannosyl donors installed with a bulky TBS group at O3, donors bearing 4,6‐di‐O‐benzoyl groups, and acceptors known as sterically unmatched or hindered. For the ortho‐alkynylbenzoate β‐donors, an anomerization and glycosylation sequence can also ensure the highly β‐selective mannosylation. The 1‐α‐mannosyloxy‐isochromenylium‐4‐gold(I) complex ( Cα ), readily generated upon activation of the α‐mannosyl ortho‐alkynylbenzoate ( 1 α ) with Ph₃PAuBAr₄^F at ?35 °C, was well characterized by NMR spectroscopy; the occurrence of this species accounts for the high β‐selectivity in the present mannosylation.     

Manganese(I)‐Catalyzed β‐Methylation of Alcohols Using Methanol as C1 Source

Highly selective β‐methylation of alcohols was achieved using an earth‐abundant first row transition metal in the air stable molecular manganese complex [Mn(CO)₂Br[HN(C₂H₄PⁱPr₂)₂]] 1 ([HN(C₂H₄PⁱPr₂)₂]=MACHO‐ⁱPr). The reaction requires only low loadings of 1 (0.5 mol %), methanolate as base and MeOH as methylation reagent as well as solvent. Various alcohols were β‐methylated with very good selectivity (>99 %) and excellent yield (up to 94 %). Biomass derived aliphatic alcohols and diols were also selectively methylated on the β‐position, opening a pathway to “biohybrid” molecules constructed entirely from non‐fossil carbon. Mechanistic studies indicate that the reaction proceeds through a borrowing hydrogen pathway involving metal–ligand cooperation at the Mn‐pincer complex. This transformation provides a convenient, economical, and environmentally benign pathway for the selective C?C bond formation with potential applications for the preparation of advanced biofuels, fine chemicals, and biologically active molecules     

Photolysis of α,β‐Epoxyketones: A Green Synthesis of β‐Hydroxyenones through Tandem H‐Abstraction,Ring Cleavage and Isomerisation

The photochemical behavior of various substituted epoxycarbonyl compounds consisting of more than one possible photo‐labile site (i.e. δ‐hydrogen, β‐hydrogen and epoxide ring) has been investigated. These compounds on photo‐irradiation produced the β‐hydroxyenones in an eco‐friendly green approach. Mechanistically, these photo‐transformations have been envisaged to occur via an intramolecular β‐hydrogen abstraction by the carbonyl group of benzoyl moiety to generate the 1,3‐biradical followed by epoxide ring opening that isomerizes into the photoproducts. The photolysis of the probed epoxy ketones didn’t furnish any photoproduct through δ‐hydrogen abstraction, whatsoever. This exclusive preference for β‐H abstraction over δ‐H abstraction by carbonyl group has been vindicated by the MM2 energy mini‐ mized program for the investigated photochemical substrates. The structures of these photoproducts were established from the analysis of their spectral parameters (IR, ¹H/¹³C NMR and Mass) and single crystal X‐ray crystallography data.     

4‐Ethoxycarbonyl‐3‐hydroxy‐3‐phenylcyclohexanone

The title compound, ethyl 2‐hydroxy‐4‐oxo‐2‐phenyl­cyclo­hexane­carboxyl­ate, C₁₅H₁₈O₄, was obtained by a Michael–Aldol condensation and has the cyclo­hexanone in a chair conformation. The attached hydroxy, ethoxy­carbonyl and phenyl groups are disposed in β‐axial, β‐equatorial and α‐­equatorial configurations, respectively. An intermolecular hydrogen bond, with an O?O distance of 2.874 (2) Å, links the OH group and the ring carbonyl. Weak intermolecular C—H?O=C (ester and ketone), O—H?O=C (ketone) and C—H?OH hydrogen bonds exist.     

Benzylamine as Hydrogen Transfer Agent: Cobalt‐Catalyzed Chemoselective C=C Bond Reduction of β‐Trifluoromethylated α,β‐Unsaturated Ketones via 1,5‐Hydrogen Transfer

An efficient cobalt‐catalyzed chemoselective reduction of β‐CF₃‐α,β‐unsaturated ketones using benzylamine as hydrogen transfer agent involving intramolecular 1,5‐hydrogen transfer is reported. The reaction proceeded smoothly with a relatively wide range of substrates including those bearing aromatic heterocycles such as a furyl ring system in high yields (74–92 %). This provides an efficient method for the synthesis of β‐CF₃ saturated ketones in one‐pot. This methodology was also applied to the selective C=C reduction of other enone substrates bearing no β‐CF₃‐substituent, of which β‐substituted or β,β‐disubstituted enones are tolerated, giving the desired products in good yields (72–75 %). Mechanistic studies indicate that the reaction involves 1,5‐hydrogen transfer.     

12‐ to 22‐Membered Bridged β‐Lactams as Potential Penicillin‐Binding Protein Inhibitors

As potential inhibitors of penicillin‐binding proteins (PBPs), we focused our research on the synthesis of non‐traditional 1,3‐bridged β‐lactams embedded into macrocycles. We synthesized 12‐ to 22‐membered bicyclic β‐lactams by the ring‐closing metathesis (RCM) of bis‐ω‐alkenyl‐3(S)‐aminoazetidinone precursors. The reactivity of 1,3‐bridged β‐lactams was estimated by the determination of the energy barrier of a concerted nucleophilic attack and lactam ring‐opening process by using ab initio calculations. The results predicted that 16‐membered cycles should be more reactive. Biochemical evaluations against R39 DD‐peptidase and two resistant PBPs, namely, PBP2a and PBP5, revealed the inhibition effect of compound 4d , which featured a 16‐membered bridge and the N‐tert‐butyloxycarbonyl chain at the C3 position of the β‐lactam ring. Surprisingly, the corresponding bicycle, 12d , with the PhOCH₂CO side chain at C3 was inactive. Reaction models of the R39 active site gave a new insight into the geometric requirements of the conformation of potential ligands and their steric hindrance; this could help in the design of new compounds.     

Diastereocontrolled Monoprotodeboronation of β‐Sulfinimido gem‐Bis(boronates): A General and Stereoselective Route to α,β‐Disubstituted β‐Aminoalkylboronates

β‐Aminoalkylboronic acids are bioisosteres of the pharmaceutically important class of β‐amino acids but few stereoselective methods exist for their preparation. The 1,2‐addition of lithiated 1,1‐diborylalkanes onto chiral N‐tert‐butanesulfinyl aldimines produces β‐sulfinimido gem‐bis(boronates) in good to excellent yields with high diastereoselectivity. The optimized conditions involve the use of rubidium fluoride and water, and are compatible with functionalized alkyl, aryl, alkenyl, and alkynyl substituents. Under these conditions, the geminal quaternary alkyl bis(pinacolatoboryl) intermediates undergo a highly diastereoselective monoprotodeboronation to afford a wide range of syn‐α,β‐disubstituted β‐aminoalkylboronates. This novel application of protodeboronation chemistry was shown to result from a kinetically controlled, diastereotopic‐group‐selective B?C bond protolysis dictated by the configuration of the adjacent stereogenic C?N center. Facile acidic cleavage of the sulfinimide auxiliary produces the free aminoboronates with high enantiomeric purity.     

Precursor of a β‐lactamase inhibitor: allyl (4S,8S,9R)‐10‐[(E)‐ethyl­idene]‐4‐methoxy‐11‐oxo‐1‐aza­tri­cyclo­[7.2.0.03,8]­undec‐2‐ene‐2‐carboxyl­ate

The molecular structure of the title tricyclic compound, C₁₇H₂₁NO₄, which is the immediate precursor of a potent synthetic inhibitor {Lek157: sodium (8S,9R)‐10‐[(E)‐ethyl­idene]‐4‐methoxy‐11‐oxo‐1‐aza­tri­cyclo­[7.2.0.0^3,8]­undec‐2‐ene‐2‐carboxyl­ate} with remarkable potency, provides experimental evidence for the previously modelled relative position of the fused cyclo­hexyl ring and the carbonyl group of the β‐lactam ring, which takes part in the formation of the initial tetrahedral acyl–enzyme complex. In this hydro­phobic mol­ecule, the overall geometry is influenced by C—H?O intramolecular hydrogen bonds [3.046 (4) and 3.538 (6) Å, with corresponding normalized H?O distances of 2.30 and 2.46 Å], whereas the mol­ecules are interconnected through intermolecular C—H?O hydrogen bonds [3.335 (4)–3.575 (5) Å].     

Enantioselective Palladium‐Catalyzed Oxidative β,β‐Fluoroarylation of α,β‐Unsaturated Carbonyl Derivatives

The site‐selective palladium‐catalyzed three‐component coupling of deactivated alkenes, arylboronic acids, and N‐fluorobenzenesulfonimide is disclosed herein. The developed methodology establishes a general, modular, and step‐economical approach to the stereoselective β‐fluorination of α,β‐unsaturated systems.     

Ring‐opening polymerization of ϵ‐caprolactone by iodine charge‐transfer complex

The ring‐opening polymerization of ?‐caprolactone (?‐CL) catalyzed by iodine (I₂) was studied. The formation of a charge‐transfer complex (CTC) among triiodide, I, and ?‐CL was confirmed with ultraviolet–visible spectroscopy. The monomer ?‐CL was polymerized in bulk using I₂ as a catalyst to form the polyester having apparent weight‐average molecular weights of 35,900 and 45,500 at polymerization temperatures of 25 and 70 °C, respectively. The reactivity of both, ?‐CL monomer and ?‐CL:I₂ CTC, was interpreted by means of the potential energy surfaces determined by semiempirical computations (MNDO‐d). The results suggest that the formation of the ?‐CL:I₂ CTC leads to the ring opening of the ?‐CL structure with the lactone protonation and the formation of a highly polarized polymerization precursor (?‐CL)⁺. The band gaps approximated from an extrapolation of the oligomeric polycaprolactone (PCL) structures were computed. With semiempirical quantum chemical calculations, geometries and charge distributions of the protonated polymerization precursor (?‐CL)⁺ were obtained. The calculated band gap (highest occupied molecular orbit/lowest unoccupied molecular orbit differences) agrees with the experiment. The analysis of the oligomeric PCL isosurfaces indicate the existence of a weakly lone pair character of the C?O and C? O bonds suggesting a ?‐CL ring‐opening specificity. © 2002 Wiley Periodicals, Inc. J Polym Sci Part B: Polym Phys 40: 714–722, 2002     

New aliphatic poly(ester‐carbonates) based on 5‐methyl‐5‐allyloxycarbonyl‐1,3‐dioxan‐2‐one

The synthesis, characterization, and ring‐opening polymerization of a new cyclic carbonate monomer containing an allyl ester moiety, 5‐methyl‐5‐allyloxycarbonyl‐1,3‐dioxan‐2‐one (MAC), was performed for the first time. MAC was synthesized in five steps in good yield beginning from the starting material, 2,2‐bis(hydroxymethyl)propionic acid. Subsequent polymerization and copolymerizations of the new cyclic carbonate with rac‐lactide (rac‐LA) and ?‐caprolactone (CL) were attempted. Rac‐LA copolymerized well with MAC, but CL copolymerizations produced insoluble products. Oligomeric macroinitiators of MAC and rac‐LA were synthesized from stannous ethoxide, and both macroinitiators were used for the controlled ring‐opening polymerization of rac‐LA. The polymerization kinetics were examined by monitoring the disappearance of the characteristic C? O ring stretch of the monomer at 1240 cm^?1 with real‐time in situ Fourier transform infrared spectroscopy. Postpolymerization oxidation reactions were conducted to epoxidize the unsaturated bonds of the MAC‐functionalized polymers. Epoxide‐containing polymers may allow further organic transformations with various nucleophiles, such as amines, alcohols, and carboxylic acids. NMR was used for microstructure identification of the polymers, and size exclusion chromatography and differential scanning calorimetry were used to characterize the new functionalized poly(ester‐carbonates). © 2003 Wiley Periodicals, Inc. J Polym Sci Part A: Polym Chem 41: 1978–1991, 2003     

Synthesis and structural analysis of functionalized poly (ϵ‐caprolactone)‐based three‐arm star polymers

Hydroxyl‐functionalized three‐arm poly(?‐caprolactone)s (PGCL‐OHs) were synthesized by the ring‐opening polymerization of ?‐caprolactone in the presence of glycerol (as the core) and stannous octoate. The effect of the feed ratio of ?‐caprolactone to glycerol on the ring‐opening polymerization was studied. These three‐arm PGCL‐OHs were then converted into double‐bond‐functionalized three‐arm poly(?‐caprolactone)s (PGCL‐Mas) by the reaction of PGCL‐OH with maleic anhydride in the melt at 130 °C. The quantitative conversion of hydroxyl functionality was achieved at a low molecular weight. The resulting PGCL‐OH and PGCL‐Ma were characterized with gel permeation chromatography, Fourier transform infrared, ¹H NMR, ¹³C NMR, and differential scanning calorimetry. © 2002 Wiley Periodicals, Inc. J Polym Sci Part A: Polym Chem 40: 1127–1141, 2002     

Cobalt‐Catalyzed C8‐Dienylation of Quinoline‐N‐Oxides

An efficient Cp*Co^III‐catalyzed C8‐dienylation of quinoline‐N‐oxides was achieved by employing allenes bearing leaving groups at the α‐position as the dienylating agents. The reaction proceeds by Co^III‐catalyzed C?H activation of quinoline‐N‐oxides and regioselective migratory insertion of the allene followed by a β‐oxy elimination, leading to overall dienylation. Site‐selective C?H activation was achieved with excellent selectivity under mild reaction conditions, and 30 mol % of a NaF additive was found to be crucial for the efficient dienylation. The methodology features high stereoselectivity, mild reaction conditions, and good functional‐group tolerance. C8‐alkenylation of quinoline‐N‐oxides was achieved in the case of allenes devoid of leaving groups as coupling partners. Furthermore, gram‐scale preparation and preliminary mechanistic experiments were carried out to gain insights into the reaction mechanism.     

N‐(p‐Chloro­phenyl)‐3,3‐di­phenyl‐4‐(β‐phenyl­styryl)azetidin‐2‐one

In the title compound, C₃₅H₂₆ClNO, the four‐membered β‐lactam ring is essentially planar, with a maximum deviation of 0.012 (1) Å for the N atom. The C—C bond lengths in the β‐lactam ring are 1.591 (2) and 1.549 (2) Å. The two phenyl rings attached to the β‐lactam ring are nearly perpendicular to each other [83.2 (1)°].     

β‐cyclodextrin‐based polymeric nano‐receptor: the self‐assembly of cyclodextrin‐appended comb‐copolymer

Well‐defined β‐cyclodextrin (β‐CD)‐appended biocompatible comb‐copolymer ethyl cellulose‐graft‐poly (ε‐caprolactone) (EC‐g‐PCL) was synthesized via the combination of ring‐opening polymerization (ROP) and click chemistry. The resulting products were characterized by ¹H NMR, FT‐IR spectroscopy, and GPC. The synthesized comb‐copolymer could assemble to micelles, with the surface covered by β‐CD. The inclusion with ferrocene derivation was investigated by cyclic voltammetric (CV) experiments, which indicated the potential application of the micelles as nano‐receptors for molecule recognization and controlled drug release. Copyright © 2011 John Wiley & Sons, Ltd.     

Water‐Insensitive Synthesis of Poly‐β‐Peptides with Defined Architecture

Biocompatible and proteolysis‐resistant poly‐β‐peptides have broad applications and are dominantly synthesized via the harsh and water‐sensitive ring‐opening polymerization of β‐lactams in a glovebox or using a Schlenk line, catalyzed by the strong base LiN(SiMe₃)₂. We have developed a controllable and water‐insensitive ring‐opening polymerization of β‐amino acid N‐thiocarboxyanhydrides (β‐NTAs) that can be operated in open vessels to prepare poly‐β‐peptides in high yields, with diverse functional groups, variable chain length, narrow dispersity and defined architecture. These merits imply wide applications of β‐NTA polymerization and resulting poly‐β‐peptides, which is validated by the finding of a HDP‐mimicking poly‐β‐peptide with potent antimicrobial activities. The living β‐NTA polymerization enables the controllable synthesis of random, block copolymers and easy tuning of both terminal groups of polypeptides, which facilitated the unravelling of the antibacterial mechanism using the fluorophore‐labelled poly‐β‐peptide.