Overall Inversion Of Configuration Research Articles

Cyclobutenes: At a Crossroad between Diastereoselective Syntheses of Dienes and Unique Palladium-Catalyzed Asymmetric Allylic Substitutions.

The rich chemistry of cyclobutanes is underpinned by a large body of synthetic literature devoted to their synthesis and decoration. This is motivated by the widespread representation of cyclobutane moieties in biologically active natural products and man-made molecules. Surprisingly, this vast array of knowledge finds no parallel in the chemistry of cyclobutenes, their unsaturated analogues. In particular, a dearth of methods to synthesize enantioenriched cyclobutenes is apparent upon cursory investigation of the literature. As a leading example, the photocycloaddition of maleic anhydride to acetylene or dichloroethylene, probably a benchmark of cyclobutene synthesis, delivers a meso cyclic anhydride which can be further converted to a cyclobutene product by enantioselective desymmetrization by ring opening. Nonetheless, such an approach delivers products with a rather inflexible substitution pattern around the four-membered ring. The lack of general approaches has motivated our group and others to develop novel routes to cyclobutene scaffolds, leading to the development of a strategy that combines photochemistry and catalysis. Indeed, we have coupled the simple and efficient photochemical isomerization of 2-pyrone into a strained bicyclo[2.2.0] lactone with palladium-catalyzed allylic alkylation as a simple and versatile access to functionalized cyclobutenes. Several nucleophiles can be added to the activated, strained intermediate, including malonate anions and azlactones. The products are mono- and bicyclic building blocks richly decorated with functional groups. Importantly, they are formed with high levels of diastereoselectivity as expected by the tenets of palladium-catalyzed allylic alkylation, which posit that the oxidative addition and nucleophilic capture steps proceed with inversion of configuration, resulting in overall retention (inversion + inversion). However, the transposition of the methodology to an asymmetric version subsequently led to the surprising discovery of a family of highly enantioselective, diastereodivergent catalytic processes. Indeed, we observed a ligand-dependent stereochemical outcome for a range of palladium-catalyzed allylic alkylations affording either overall retention or overall inversion of configuration, and that with very high levels of enantio- and diastereoselectivity. The new family of diastereodivergent reactions enables the conversion of the aforementioned racemic bicyclo[2.2.0] lactone into each of 4 stereoisomeric products, at will. Although the mechanistic details at the origin of this unusual stereodivergence are not yet fully elucidated, it became clear through our studies that unique Pd-allyl complexes, residing preferentially as their σ-(monohapto)-bound isomers, are at the heart of the process. The cyclobutenes prepared can also engage in electrocyclic ring-opening reactions (often spontaneous depending on the substitution pattern) that link this chemistry with that of diene and polyene frameworks. Using the strategies laid out above, our group was then able to harness the high stereospecificity of electrocyclic reactions and design modular syntheses of several natural products and natural product fragments. We believe that the methods presented herein shall soon pave the way for the streamlined synthesis of more complex polyenic natural products.

Highly regioselective nickel-catalyzed cross-coupling of N-tosylaziridines and alkylzinc reagents.

Herein, we report the first ligand-controlled, nickel-catalyzed cross-coupling of aliphatic N-tosylaziridines with aliphatic organozinc reagents. The reaction protocol displays complete regioselectivity for reaction at the less hindered C-N bond, and the products are furnished in good to excellent yield for a broad selection of substrates. Moreover, we have developed an air-stable nickel(II) chloride/ligand precatalyst that can be handled and stored outside a glovebox. In addition to increasing the activity of this catalyst system, this also greatly improves the practicality of this reaction, as the use of the very air-sensitive Ni(cod)2 is avoided. Finally, mechanistic investigations, including deuterium-labeling studies, show that the reaction proceeds with overall inversion of configuration at the terminal position of the aziridine by way of aziridine ring opening by Ni (inversion), transmetalation (retention), and reductive elimination (retention).

Remarkable enantioselective α-amination in 1-phenyl-2-(n-alkylamino)-1-propanol

(1R,2R)-1-Phenyl-1-alkyl/arylamino-2-(N-alkylamino)propane hydrochloride salts have been synthesized with high degree of enantiomeric purity from (1S,2R)-(+)-1-phenyl-2-(N-alkylamino)-1-propanol through the corresponding chloro derivatives. This reaction sequence involves three inversions with overall inversion of configuration at C-1.

Iron(III)‐Catalyzed Halogenations by Substitution of Sulfonate Esters

AbstractA novel halogenation reaction from sulfonates catalyzed by iron(III) is described. The reaction can be performed as a stoichiometric or a catalytic version. This reaction provides a convenient strategy for the efficient access to structurally diverse secondary chlorides, bromides and iodides. The stereochemical course of the reaction is governed by the substrate and the experimental conditions. Secondary alcohols modified as quisylates or pysylates are substantially more reactive. Aliphatic quisylates proceed with overall inversion of configuration under catalytic conditions. Chemoselectivity in bismesylates was observed in favour of the secondary mesylate. Additionally, based on the experimental results, a possible catalytic cycle for the halogenation has been proposed.

Clavulanic Acid Dehydrogenase: Structural and Biochemical Analysis of the Final Step in the Biosynthesis of the β-Lactamase Inhibitor Clavulanic Acid,

The ultimate step in the biosynthesis of the medicinally important beta-lactamase inhibitor clavulanic acid is catalyzed by clavulanic acid dehydrogenase (CAD). CAD is responsible for the NAPDH-dependent reduction of the unstable intermediate clavulanate-9-aldehyde to yield clavulanic acid. Here, we report biochemical and structural studies on CAD. Biophysical analyses demonstrate that CAD exists as dimeric and tetrameric species in solution. The reaction performed by CAD was shown to be reversible, allowing the use of clavulanic acid for activity analyses. The crystal structure of CAD was solved using single-wavelength anomalous diffraction with a seleno-methionine derivative. The structure reveals that the individual monomers comprise a single domain possessing the Rossmann fold, characteristic of dinucleotide-binding enzymes. The monomers are arranged as tetramers, similar to other tetrameric members of the short-chain dehydrogenase/reductase family. The structure of the unreactive complex of CAD with clavulanic acid and NADPH suggests how CAD is able to catalyze the reduction of clavulanate-9-aldehyde without fragmentation of the bicyclic beta-lactam ring structure. The relative positions of NADPH and clavulanic acid, in the active site, together with the presence of the latter in an eclipsed conformation, rationalizes previous labeling studies demonstrating that the incorporation of the C5 pro-R, but not pro-S, hydrogen of ornithine/arginine into the C9 position of clavulanic acid occurs with overall inversion of configuration.

Synthesis of C2-symmetric tris-thioethers via optically active mustards

Chiral dihydroxy thioethers derived from l-mandelic and l-lactic acid are activated with SOCl2, SOBr2 and by bis-trifluoroacetate formation to give optically active mustard gas analogues. These compounds serve as substrates for stereospecific nucleophilic substitution reactions with NaSEt and NaSPh to furnish C2-symmetric tris-thioethers with overall inversion of configuration.

Biosynthesis of Phenazine Antibiotics inStreptomyces antibioticus: Stereochemistry of Methyl Transfer from Carbon-2 of Acetate

Stable isotope labeling experiments have shown that the biosynthesis of the monomeric phenazines, the saphenyl esters, and their dimerization products, the esmeraldins, in Streptomyces antibioticus Tu 2706 proceeds from phenazine-1,6-dicarboxylic acid by chain extension with C-2 of acetate to 6-acetylphenazine-1-carboxylic acid, which is reduced to saphenic acid. The latter is incorporated into both halves of the esmeraldins, albeit differentially. By feeding of chiral acetate, degradation of the resulting saphenyl esters and esmeraldins, and configurational analysis of the acetic acid formed, the chain extension process was found to proceed with overall inversion of configuration at the methyl group. This suggests that the decarboxylation of a hypothetical intermediate β-keto acid proceeds in an inversion mode. This result is discussed with reference to analogous C-methylations of polyketide backbones by addition of C-2 of acetate.

From Quinidine to new Enantiopure Materials–Tricyclic Allylic N,O‐Acetals and a Stereospecific, Onepot Conversion of 1,2‐Secondary, Tertiary Diols into Spiroepoxides

AbstractHydrobromination of quinidine (1) with fuming HBr furnished diastereomeric secondary bromides 2a and 2b in 82% yield. After acetylation the resulting bromides 2a–Ac and 2b–Ac could be separated and converted stereospecifically into ethylidene rubanes Z)‐4 and (E)‐4, respectively. cis‐Dihydroxylation of (Z)‐olefin 4 with OsO4 was shown to be feasible by two catalytic variants, giving the two diastereomeric diols 5a and 5b, separable by chromatography. A simple onepot procedure was developed for converting the sterically hindered 1,2‐secondary, tertiary diols stereospecifically into spiroepoxides (5a 6a‐Ac; 5b 6b‐Ac). Our procedure involves overall inversion of configuration. The procedure complements the Kolb–Sharpless route to epoxides from 1,2‐disecondary diols with overall retention of configuration. The other two diastereomeric spiroepoxides 6c and 6d were prepared in one pot under different conditions (chloramine T, then alkali). Two unprecedented tricyclic allylic N,O‐acetals (Z)‐7 and (E)‐7 were also obtained. The structure of spiroepoxide 6c (as a CH2Cl2 monosolvate) and of tricyclic olefinic N,O‐acetal (E)‐7 was corroborated by X‐ray crystallography.

New stereocontrolled synthesis of cyclic sulfonimidates

Cyclic sulfonimidates 3 can be synthesised in enantiomerically pure form from amino alcohols by 1,8-diazabicyclo[5.4.0]undecene-7 (DBU) induced oxidative cyclisation of sulfinamides 1. The very rapid intramolecular reaction of the intermediate sulfonimidoylchlorides 2 allows for complete chirality transfer with overall inversion of configuration at sulfur.

Application of a phase transfer reaction to the synthesis of l-fructose

l-Fructose was prepared in five steps from l-sorbose ( 1). 1,2-O- Isopropylidene-α- l-sorbopyranose ( 2), prepared from 1, was selectively tosylated using phase transfer catalysis to give 1,2-O- isopropylidene-3-O-(p- tolylsulfonyl)-α- l-sorbopyranose ( 3). Formation of a 3,4-anhydro ring, followed by its base-catalyzed opening to effect overall inversion of configuration at both C-3 and C-4 gave 1,2-O- isopropylidene-α- l-fructopyranose ( 5), which was deacetonated to yield l-fructose ( 6).

ChemInform Abstract: Carbenoids. Metal‐Assisted Ionization.

AbstractTreatment of the (S)‐chloro olefin (Ia) with tBuLi (IV) followed by protonolysis with MeOH gives rise to the (R)‐derivative (III) with an optical purity of 31% and with overall inversion of configuration.

Stereochemical course of thiophosphoryl transfer catalyzed by cytosolic phosphoenolpyruvate carboxykinase.

Rat liver cytosolic phosphoenolpyruvate carboxykinase (PEPCK) utilizes inosine 5'-(3-thiotriphosphate) (ITP gamma S) as an excellent substrate, with Km and V values of 0.08 mM and 37 mumol min-1 (mg of protein)-1, respectively, compared with the corresponding values of 0.168 mM and 76 mumol min-1 (mg of protein)-1 for ITP. Thus, the V/Km values for the two substrates are the same. Reaction of (RP)-[gamma-18O2]ITP gamma S with oxalacetate catalyzed by cytosolic PEPCK produces (SP)-thio[18O]phosphoenolpyruvate. Therefore, thiophosphoryl transfer catalyzed by this enzyme proceeds with overall inversion of configuration at P. The reaction mechanism involves an uneven number of phosphotransfer steps, most likely a single step transfer between bound substrates. The results do not support the involvement of a phosphoryl enzyme intermediate in the mechanism.

Mevalonate-5-diphosphate decarboxylase: stereochemical course of ATP-dependent phosphorylation of mevalonate 5-diphosphate.

Chicken liver mevalonate-5-diphosphate decarboxylase catalyzes the reaction of mevalonate 5-diphosphate (MVADP) with ATP to produce isopentenyl diphosphate, ADP, CO2, and inorganic phosphate. The overall reaction involves an anti elimination of the tertiary hydroxyl and carboxyl groups. To investigate the mechanism for transfer of the terminal phosphoryl group of ATP to the C-3 oxygen of MVADP, we have carried out the reaction using stereospecifically labeled (Sp)-adenosine 5'-O-(3-thio[3-17O2,18O]triphosphate) [( gamma-17O2,18O]ATP gamma S) in place of ATP. The configuration of the [17O,18O]thiophosphate produced was found to be Rp, corresponding to overall inversion of configuration at phosphorus in the thiophosphoryl group transfer step. This result is consistent with the direct transfer of the thiophosphoryl group from (Sp)-[gamma-17O2,18O]ATP gamma S to MVADP at the active site. Our result does not indicate the involvement of a covalent thiophosphoryl-enzyme on the reaction pathway.

The stereochemical fate of (2RS,5R)- and (2RS,5S)-[5-3H]ornithine in clavulanic acid biosynthesis

The 5-pro(R) hydrogen of ornithine is retained in the biosynthesis of clavulanic acid where it assumes the 9-pro(S) position with overall inversion of configuration.

Stereochemistry of the decarboxylation of α-acetolactate (2-hydroxy-2-methyl-3-oxobutanoate) by the acetolactate decarboxylase of Klebsiella aerogenes

[3-14C]-α-Acetolactate ([3-14C]-2-hydroxy-2-methyl-3-oxobutanoate) was synthesised and subjected to enzymatic decarboxylation by the acetolactate decarboxylase from Klebsiella pneumoniae. Degradation of the acetoin produced showed that the radioactivity was largely confined to the acetyl component. Together with previous results, this proves that during decarboxylation the carboxy group of α-acetolactate is replaced regiospecifically by hydrogen and that this process takes place with overall inversion of configuration.

The stereochemical course of thiophosphoryl group transfer catalyzed by T4 polynucleotide kinase.

The stereochemical course of the phosphoryl transfer reaction catalyzed by T4 polynucleotide kinase has been determined using the chiral ATP analog, (Sp)-adenosine-5'-(3-thio-3-[18O]triphosphate). T4 polynucleotide kinase catalyzes the transfer of the gamma-thiophosphoryl group of (Sp)-adenosine-5'-(3-thio-3-[18O]triphosphate) to the 5'-hydroxyl group of ApA to give the thiophosphorylated dinucleotide adenyl-5'-[18O]phosphorothioate-(3'-5')adenosine. A sample of adenyl-5'-[18O]phosphorothioate-(3'-5')adenosine was subjected to venom phosphodiesterase digestion. The resulting adenosine-5'-[18O]phosphorothioate was shown to have the Rp configuration, thus indicating that the thiophosphoryl transfer reaction occurs with overall inversion of configuration of phosphorus.

Stereochemistry of Halogenation of some enyl complexes of palladium(II)

The halogenation of some enyl complexes of palladium(II) in dichloromethane was found to proceed with predominant retention of configuration at the carbon bearing palladium but wiht overall inversion of configuration in the presence of added halide ion in methanol. The results are interpreted in terms of an oxidative addition—reductive elimination mechanism.

Synthesis and stereochemistry of optically active [16O,18O]sulphones

Two new syntheses of optically active [16O,18O]sulphones are reported. One uses reactions of known stereochemical course, thus allowing the determination of the absolute configuration of [16O,18O]sulphones. The other, oxidation of sulphoxides by (dichloroiodo)benzene, proceeds via nucleophilic attack at a tetraco-ordinate hexavalent sulphur atom and involves overall inversion of configuration.