Retention Of Configuration Research Articles

Syntheses of cis- and trans-Jamtine and Their N-Oxides via a Benzyl Configuration-Inversion Approach

A novel synthesis of the tetrahydroisoquinoline alkaloid jamtine and its epimer is reported. The synthetic strategy hinges on a one-pot conjugate reduction/Robinson cyclization sequence and an efficient benzyl configuration inversion by an oxidation/reduction approach. The N-oxide derivatives of the jamtine isomers were also synthesized and identified by X-ray crystallographic analysis. Additionally, a density functional theory calculation for the four possible N-oxide structures was exploited to gain further insight into the structure of the natural product in comparison to those of the synthetic N-oxides, because the NMR data of the synthetic derivatives did not match those reported for natural jamtine N-oxide.

Synthetic Studies on Bilobalide

We disclose our synthetic studies on bilobalide, which features a Diels–Alder reaction of a cyclic anhydride to form two contiguous quaternary carbon centers, desymmetrization of a symmetric diol, and construction of a cyclic acetal under acidic conditions with inversion of configuration at an allylic position.

Asymmetric Electrophilic Reactions in Phosphorus Chemistry

This review is devoted to the theoretic and synthetic aspects of asymmetric electrophilic substitution reactions at the stereogenic phosphorus center. The stereochemistry and mechanisms of electrophilic reactions are discussed—the substitution, addition and addition-elimination of many important reactions. The reactions of bimolecular electrophilic substitution SE2(P) proceed stereospecifically with the retention of absolute configuration at the phosphorus center, in contrast to the reactions of bimolecular nucleophilic substitution SN2(P), proceeding with inversion of absolute configuration. This conclusion was made based on stereochemical analysis of a wide range of trivalent phosphorus reactions with typical electrophiles and investigation of examples of a sizeable number of diverse compounds. The combination of stereospecific electrophilic reactions and stereoselective nucleophilic reactions is useful and promising for the further development of organophosphorus chemistry. The study of phosphoryl group transfer reactions is important for biological and molecular chemistry, as well as in studying mechanisms of chemical processes involving organophosphorus compounds. New versions of asymmetric electrophilic reactions applicable for the synthesis of enantiopure P-chiral secondary and tertiary phosphines are discussed.

Regio- and diastereoselective reactions of chiral secondary alkylcopper reagents with propargylic phosphates: preparation of chiral allenes.

The diastereoselective SN2′-substitution of secondary alkylcopper reagents with propargylic phosphates enables the preparation of stereodefined alkylallenes. By using enantiomerically enriched alkylcopper reagents and enantioenriched propargylic phosphates as electrophiles anti-SN2′-substitutions were performend leading to α-chiral allenes in good yields with excellent regioselectivity and retention of configuration. DFT-calculations were performed to rationalize the structure of these alkylcopper reagents in various solvents, emphasizing their configurational stability in THF.

Stereodivergent synthesis of 2-alkynyl buta-1,3-dienes using Sonogashira coupling with controllable retention or inversion of olefin geometry

A stereodivergent approach to 2-alkynyl buta-1,3-dienes from a single stereoisomer of starting α-bromoenal has been developed. By simply switching the sequence of Sonogashira and Horner-Wadsworth-Emmons reactions, it is possible to obtain these branched dienynes with retention or almost complete inversion of the double bond configuration.

Stereoselective anti-SN2′-Substitutions of Secondary Alkylcopper-Zinc Reagents with Allylic Epoxides: Total Synthesis of (3S,6R,7S)-Zingiberenol

Chiral secondary mixed alkylcopper-zinc reagents were prepared from the corresponding alkyl iodides and reacted with allylic epoxides via an anti-SN2′-substitution and retention of configuration of the chiral alkylorganometallic, leading to chiral allylic alcohols. This method was used in a total synthesis of the natural product (3S,6R,7S)-zingiberenol in 8 steps and 9.7% overall yield [dr (3S,6R) = 99:1; dr (6R,7S) = 81:19] starting from commercially available 3-methyl-2-cyclohexenone.

Steric Enforcement of cis-Epoxide Formation in the Radical C-O-Coupling Reaction by Which (S)-2-Hydroxypropylphosphonate Epoxidase (HppE) Produces Fosfomycin.

(S)-2-Hydroxypropylphosphonate [(S)-2-HPP, 1] epoxidase (HppE) reduces H2O2 at its nonheme-iron cofactor to install the oxirane "warhead" of the antibiotic fosfomycin. The net replacement of the C1 pro-R hydrogen of 1 by its C2 oxygen, with inversion of configuration at C1, yields the cis-epoxide of the drug [(1R,2S)-epoxypropylphosphonic acid (cis-Fos, 2)]. Here we show that HppE achieves ∼95% selectivity for C1 inversion and cis-epoxide formation via steric guidance of a radical-coupling mechanism. Published structures of the HppE·FeII·1 and HppE·ZnII·2 complexes reveal distinct pockets for C3 of the substrate and product and identify four hydrophobic residues-Leu120, Leu144, Phe182, and Leu193-close to C3 in one of the complexes. Replacement of Leu193 in the substrate C3 pocket with the bulkier Phe enhances stereoselectivity (cis:trans ∼99:1), whereas the Leu120Phe substitution in the product C3 pocket diminishes it (∼82:18). Retention of C1 configuration and trans-epoxide formation become predominant with the bulk-reducing Phe182Ala substitution in the substrate C3 pocket (∼13:87), trifluorination of C3 (∼23:77), or both (∼1:99). The effect of C3 trifluorination is counteracted by the more constrained substrate C3 pockets in the Leu193Phe (∼56:44) and Leu144Phe/Leu193Phe (∼90:10) variants. The ability of HppE to epoxidize substrate analogues bearing halogens at C3, C1, or both is inconsistent with a published hypothesis of polar cyclization via a C1 carbocation. Rather, specific enzyme-substrate contacts drive inversion of the C1 radical-as proposed in a recent computational study-to direct formation of the more potently antibacterial cis-epoxide by radicaloid C-O coupling.

Regioselective Iron‐Catalysed Cross‐Coupling Reaction of Aryl Propargylic Bromides and Aryl Grignard Reagents

AbstractAn iron‐catalysed Kumada‐type cross‐coupling reaction between aryl substituted propargylic bromides and arylmagnesium reagents has been developed. Propargylic coupling products were the main or only outcome, and propargyl/allene regioselectivity was shown to depend on the electronic nature of the substituents on the triple bond of the substrate and on the arylmagnesium halide. Best selectivities were observed when electron donating substituents were present in either reagent. The process is stereoespecific, occurs with configuration inversion and no carbon‐based radicals seem to be involved in the mechanism.magnified image

Stereoselective Csp3 -Csp2 Cross-Couplings of Chiral Secondary Alkylzinc Reagents with Alkenyl and Aryl Halides.

We report palladium‐catalyzed cross‐coupling reactions of chiral secondary non‐stabilized dialkylzinc reagents, prepared from readily available chiral secondary alkyl iodides, with alkenyl and aryl halides. This method provides α‐chiral alkenes and arenes with very high retention of configuration (dr up to 98:2) and satisfactory overall yields (up to 76 % for 3 reaction steps). The configurational stability of these chiral non‐stabilized dialkylzinc reagents was determined and exceeded several hours at 25 °C. DFT calculations were performed to rationalize the stereoretention during the catalytic cycle. Furthermore, the cross‐coupling reaction was applied in an efficient total synthesis of the sesquiterpenes (S)‐ and (R)‐curcumene with control of the absolute stereochemistry.

Iron-Mediated Electrophilic Amination of Organozinc Halides using Organic Azides.

A wide range of alkyl‐, aryl‐ and heteroarylzinc halides were aminated with highly functionalized alkyl, aryl, and heterocyclic azides. The reaction proceeds smoothly at 50 °C within 1 h in the presence of FeCl3 (0.5 equiv) to furnish the corresponding secondary amines in good yields. This method was extended to peptidic azides and provided the arylated substrates with full retention of configuration. To demonstrate the utility of this reaction, we prepared two amine derivatives of pharmaceutical relevance using this iron‐mediated electrophilic amination as the key step.

Hanessian-Hullar reaction in the synthesis of highly substituted trans-3,4-dihydroxypyrrolidines: Rhamnulose iminosugar mimics inhibit α-glucosidase

The key step in the syntheses of highly substituted trans-3,4-dihydroxypyrrolidines is introduction of bromide by stereospecific and regiospecific Hanessian-Hullar reactions; benzylidene lactones of l-rhamnonolactone and 6-deoxy-this should be small unnpercase d not l why can I not correct this-gulonolactone allow introduction of N at C2 with inversion or retention of configuration. Initially a protecting group, the benzylidene acetal then provides a bromide at C5 to allow formation of the pyrrolidine ring. With silyl protecting groups, bromide was introduced at C5 with inversion of configuration whereas benzoyl protection gave a mixture of retention and inversion, indicative of neighbouring group participation in a Hanessian-Hullar reaction. Four stereoisomeric pyrrolidines - iminosugar mimics of α- and β-l-rhamnulose and α- and β-6-deoxy-d-sorbose were prepared. Only the α-l-rhamnulose mimic showed moderate inhibition of rhamnosidase but some were good inhibitors of α-glucosidases; none inhibited rhamnose isomerase and they had a small effect as synthetic inducers of the rhamnose catabolic operon in E. coli.

Axial chirality inversion at a spiro carbon leads to efficient synthesis of polyimine macrocycle

The synthesis and conformational preferences of a novel chiral macrocyclic polyimine possessing spiro carbon atoms is described. The key feature of the synthesis is the incorporation of an axially chiral surrounding of quaternary carbon atom having four constitutionally identical substituents into the structure of the macrocycle. This is possible by partial hydrolysis, which enables the inversion of absolute configuration, of the spiro-acetal moiety. This approach allows to obtain the macrocyclic product with almost quantitative yield. The synthesis of rhombimine with enantiopure trans -1,2-diaminocyclohexane and racemic bisaldehyde with spiro carbon atoms yields single macrocyclic product with almost quantitative yield. This is possible by partial reverse hydrolysis and thus ring opening and the inversion of absolute configuration of the a conformationally stable spiro-acetal moiety. • Diastereoselective synthesis of spiro rhombimines. • Absolute configuration of spiro moiety changes during the reaction. • New mechanism for adapting the racemic substrate in the macrocyclization reaction.

Synthesis and Antitumor Activity of C-3(R) Hydroxy Modified Betulinic Acid Derivatives

Four novel betulinic acid (BA) derivatives modified at the C-3 position were prepared by the Mitsunobu reaction and subsequently evaluated for antitumor activity against four common cancer cell lines in vitro. The results from the MTT assay revealed that the four tested compounds showed remarkable cytotoxic activity against four cancer cell lines, much better than BA. Western blotting results indicated that the four compounds, especially compound 2c, caused a significant up-regulation expression of the caspase-12 in CT26 cell. Our results showed that configuration inversions of chiral C-3 of BA could also produce BA derivatives with potent antitumor activity.

Umpolung Strategy for α‐Functionalization of Aldehydes for the Addition of Thiols and other Nucleophiles

AbstractNucleophile–nucleophile coupling is a challenging transformation in organic chemistry. Herein we present a novel umpolung strategy for α‐functionalization of aldehydes with nucleophiles. The strategy uses organocatalytic enamine activation and quinone‐promoted oxidation to access O‐bound quinol‐intermediates that undergo nucleophilic substitution reactions. These quinol‐intermediates react with different classes of nucleophiles. The focus is on an unprecedented organocatalytic oxidative α‐thiolation of aldehydes. The reaction scope is demonstrated for a broad range of thiols and extended to chemoselective bioconjugation, and applicable to a large variety of aldehydes. This strategy can also encompass organocatalytic enantioselective coupling of α‐branched aldehydes with thiols forming quaternary thioethers. Studies indicate a stereoselective formation of the intermediate followed by a stereospecific nucleophilic substitution reaction at a quaternary stereocenter, with inversion of configuration.

Umpolung Strategy for α-Functionalization of Aldehydes for the Addition of Thiols and other Nucleophiles.

Nucleophile-nucleophile coupling is a challenging transformation in organic chemistry. Herein we present a novel umpolung strategy for α-functionalization of aldehydes with nucleophiles. The strategy uses organocatalytic enamine activation and quinone-promoted oxidation to access O-bound quinol-intermediates that undergo nucleophilic substitution reactions. These quinol-intermediates react with different classes of nucleophiles. The focus is on an unprecedented organocatalytic oxidative α-thiolation of aldehydes. The reaction scope is demonstrated for a broad range of thiols and extended to chemoselective bioconjugation, and applicable to a large variety of aldehydes. This strategy can also encompass organocatalytic enantioselective coupling of α-branched aldehydes with thiols forming quaternary thioethers. Studies indicate a stereoselective formation of the intermediate followed by a stereospecific nucleophilic substitution reaction at a quaternary stereocenter, with inversion of configuration.

The asymmetric synthesis of (S,S)-methylphenidate hydrochloride via ring-opening of an enantiopure aziridinium intermediate with phenylmagnesium bromide

The key step in our synthetic strategy towards (S,S)-methylphenidate hydrochloride employs the ring-opening of an in situ formed aziridinium intermediate. Treatment of an α-hydroxy-β-amino ester with methanesulfonic anhydride promoted aziridinium formation and the subsequent addition of phenylmagnesium bromide resulted in stereospecific and regioselective ring-opening to give the corresponding α-phenyl-β-amino ester with overall retention of configuration. Subsequent functional group manipulation followed by N-deprotection and cyclisation generated the piperidine ring within the target compound, and transesterification gave (S,S)-methylphenidate hydrochloride, in only 8 steps from 1,5-pentanediol, in 15% overall yield. These results demonstrate the synthetic utility of enantiopure aziridinium intermediates as substrates for the generation of stereodefined C–C bonds, and crucially this methodology provides access to α-substituted-β-amino ester substrates that are not accessible via enolate alkylation chemistry. The strategy reported herein is potentially applicable to all possible stereoisomers of methylphenidate as well as differentially substituted analogues.

Use of Phenols as Nucleophiles in the Zbiral Oxidative Deamination of N-Acetyl Neuraminic Acid: Isolation and Characterization of Tricyclic 3-Keto-2-deoxy-nonulosonic Acid (KDN) Derivatives via an Intermediate Vinyl Diazonium Ion.

It is well established that the N-nitrosoamide derived from peracetylated derivatives of N-acetyl neuraminic acid on treatment with a mixture of sodium isopropoxide and trifluoroethanol, followed by the addition of acetic acid, gives an oxidative deamination product, in which the AcN(NO)-C5 bond is replaced with a AcO-C5 bond with the retention of configuration, affording a practical synthesis of 2-keto-3-deoxy-d-glycero-d-galactononulosonic acid (KDN) derivatives. Application of other strong acids, including hydrogen fluoride, thioacetic acid, trifluoromethanesulfonic acid, and hydrogen azide, functions similarly to afford KDN derivatives functionalized at the 5-position. We describe our attempts to extend the range of useful nucleophiles employed in this oxidative deamination process to include phenols and thiophenols, resulting in the discovery of a new branch of the general reaction and the formation of a series of products resulting from substitution of the 5-acetamido group and of the 4-acetoxy group from neuraminic acid. A mechanistic rationale for the formation of these products is advanced according to which, in the absence of acids of pKa ≤ 8, the intermediate diazonium ion resulting from the elimination of acetic acid and nitrogen from the nitrosoacetamide undergoes elimination of acetic acid from the 4-position to afford a highly electrophilic alkenediazonium ion. Reversible conjugate addition of the nucleophile to the 4-position then initiates the reaction cascade leading to the ultimate products.

High-Spin Diradical Dication of Chiral π-Conjugated Double Helical Molecule.

We report an air-stable diradical dication of chiral D2-symmetric conjoined bis[5]diazahelicene with an unprecedented high-spin (triplet) ground state, singlet triplet energy gap, ΔEST = 0.3 kcal mol-1. The diradical dication possesses closed-shell (Kekulé) resonance forms with 16 π-electron perimeters. The diradical dication is monomeric in dibutyl phthalate (DBP) matrix at low temperatures, and it has a half-life of more than 2 weeks at ambient conditions in the presence of excess oxidant. A barrier of ∼35 kcal mol-1 has been experimentally determined for inversion of configuration in the neutral conjoined bis[5]diazahelicene, while the inversion barriers in its radical cation and diradical dication were predicted by the DFT computations to be within a few kcal mol-1 of that in the neutral species. Chiral HPLC resolution provides the chiral D2-symmetric conjoined bis[5]diazahelicene, enriched in (P,P)- or (M,M)-enantiomers. The enantiomerically enriched triplet diradical dication is configurationally stable for 48 h at room temperature, thus providing the lower limit for inversion barrier of configuration of 27 kcal mol-1. The enantiomers of conjoined bis[5]diazahelicene and its diradical dication show strong chirooptical properties that are comparable to [6]helicene or carbon-sulfur [7]helicene, as determined by the anisotropy factors, |g| = |Δε|/ε = 0.007 at 348 nm (neutral) and |g| = 0.005 at 385 nm (diradical dication). DFT computations of the radical cation suggest that SOMO and HOMO energy levels are near-degenerate.

Preparation of chiral alcohols by enantioselective reduction of prochiral ketones with Sinapis alba seeds as biocatalyst

The objective of this work is to apply yellow mustard seeds in the enzymatic reduction (biocatalysis) of acetophenone and its derivatives, providing a new biocatalyst for this type of reduction. The reaction parameters were optimized from acetophenone, resulting in 1-phenylethanol, with 68.5% conversion yield and 53% enantiomeric excess (e.e.), analyzed by GC and HPLC, respectively. Reactions to acetophenone and its derivatives were conducted in aqueous medium using buffers pH 6.0 and pH 6.5 in the presence of PVP. A polymer that can act as a protector preventing oxidation of peroxidase enzymes. The results for the derivatives presented low yields (4–18%: substances 5, 7 and 8), moderate (28–40%: substances 3, 4 and 6) and optimum (81%: substance 2) yields, with enantiomeric excesses varying from good to excellent results. Meta-substituted derivatives showed inversion of configuration in the presence of PVP. The biocatalyst was also tested in reactions with other carbonyl compounds, presenting moderate results. In this way, this work offers a new perspective of the application of PVP in biocatalysis reactions and a new biocatalyst for future applications.

Synthesis of glycoconjugate mimics by ‘click chemistry’

Stereo-defined 2-deoxy propargyl glycosides can be used for the synthesis of corresponding 1,4-disubstituted sugar derived triazoles by using only CuI and stereo-defined sugar azide derivatives. The click chemistry which involves copper (I) catalysed alkyne-azide 1,3-dipolar cycloaddition, was used to prepare a library of glycoconjugates mimics. Different sugar propargyl-2-deoxy-O-α-d-glycopyranoside derivatives and β-glycopyranosyl azide derivatives were coupled using catalyst CuI to yield triazole glycoconjugates. The catalyst CuI (2.5 eq.) in CH3CN was found to be most efficient for the synthesis of 1,4-disubstituted triazole scaffolds affording up to 94% of optimized yield and with retention of the anomeric configuration of the starting glycosides. The key feature of this methodology is the absence of sodium l-ascorbate/ascorbic acid which is most active substrate of current research with strong potential for click reactions. In this article, the library of novel stereoselective deoxy sugar derived triazole glycoconjugates have been synthesized and structures were determined by the 1H, 13C & 2D NMR spectroscopy.