Towards Chemoenzymatic Syntheses of Both Enantiomers of Phosphoemeriamine.

An enzyme-promoted addition of nitromethane to the appropriate phosphorylated imine (aza-Henry reaction) intended to be used in the synthesis of the title phosphoemeriamine, a phospha-analog of emeriamine (aminocarnitine), failed due to the tautomerization of the imine to the corresponding enamine. Nevertheless, both enantiomers of phosphoemeriamine were synthesized in high yield and enantiomeric purity using another chemoenzymatic approach, starting with a crucial step involving a CAL-B-mediated acetylation of the appropriate racemic precursor-diethyl 2-amino-3-dimethylaminopropylphosphonate-under kinetic resolution conditions. The enzymatic reaction was very efficient and provided each enantiomeric product in acceptable yield and with enantiomeric excess of 91 and 92%.

Nucleophilic Substitution at Phosphorus Centres - Old and Recent Studies and a Final Solution of Mechanistic and Related Stereochemical Problems.

Among many problems of a fundamental value in the heteroatom chemistry the mechanism and stereochemistry of the nucleophilic substitution reaction at the phosphorus and other heteroatom centres have attracted great attention of phosphorus chemists already in the middle of the last century. This review, which does not have a comprehensive character, summarizes the selected original contributions aimed at solution of the mechanism of S2-P reaction and its relationship with stereochemistry. The breakthrough in these studies was the Westheimer's concept and his rules which is presented at the beginning of this article.

Nucleophilic Substitution at Tricoordinate Sulfur-Alkaline Hydrolysis of Optically Active Dialkoxysulfonium Salts: Stereochemistry, Mechanism and Reaction Energetics.

Optically active dialkoxyisopropylsulfonium salts were obtained by methylation (ethylation) of optically active alkyl isopropanesulfinates using methyl (ethyl) trifluoromethanesulfonate. Alkaline hydrolysis of a series of methoxy(alkoxy)sulfonium salts afforded the two sulfinate products methyl isopropanesulfinate and alkyl isopropanesulfinate, both formed with a slightly prevailing inversion of configuration at the sulfur atom. DFT calculations revealed that this substitution reaction proceeded stepwise according to an addition-elimination (A-E) mechanism involving the formation of high tetracoordinate S sulfurane intermediates.

Correction: Mikołajczyk et al. Nucleophilic Substitution at Heteroatoms-Identity Substitution Reactions at Phosphorus and Sulfur Centers: Do They Proceed in a Concerted (SN2) or Stepwise (A-E) Way? 2022, , 599.

(1) The authors would like to correct mistakes in the title paper [...

Nucleophilic Substitution at Heteroatoms-Identity Substitution Reactions at Phosphorus and Sulfur Centers: Do They Proceed in a Concerted (S2) or Stepwise (A-E) Way?

The mechanisms of three selected identity substitution reactions at phosphorus and sulfur occurring with stereospecific inversion have been investigated using density functional theory (DFT). The first identity reaction between methoxyl anion and methyl ethylphenylphosphinate reported in 1963 has been shown to proceed in a stepwise fashion according to the addition-elimination (A-E) mechanism involving formation of a pentacoordinate phosphorus intermediate (TBI-). In contrast, the results of DFT studies of the identity chloride exchange reaction in (ethoxy)ethylphosphonochloridothionate in acetone solution provided evidence that it proceeds synchronously according to the classical Ingold's S2-P mechanism.

Nucleophilic Substitution at Tetracoordinate Phosphorus. Stereochemical Course and Mechanisms of Nucleophilic Displacement Reactions at Phosphorus in Diastereomeric - and -2-Halogeno-4-methyl-1,3,2-dioxaphosphorinan-2-thiones: Experimental and DFT Studies.

Geometrical - and - isomers of 2-chloro-, 2-bromo- and 2-fluoro-4-methyl-1,3,2-dioxaphosphorinan-2-thiones were obtained in a diastereoselective way by (a) sulfurization of corresponding cyclic P-halogenides, (b) reaction of cyclic phosphorothioic acids with phosphorus pentachloride and (c) halogen-halogen exchange at P-halogenide. Their conformation and configuration at the C-ring carbon and phosphorus stereocentres were studied by NMR (H, P) methods, X-ray analysis and density functional (DFT) calculations. The stereochemistry of displacement reactions (alkaline hydrolysis, methanolysis, aminolysis) at phosphorus and its mechanism were shown to depend on the nature of halogen.

A novel route to a chiral building block for the preparation of cyclopentenyl carbocyclic nucleosides. Synthesis and anticancer activity of enantiomeric neplanocins A.

The synthesis of both enantiomers of 3-[(-butyldimethylsilyl)oxy]methyl-4,5--isopropylidenecyclopent-2-en-1-ol was accomplished in six steps based on optically inactive dimethyl -tartrate. This key intermediate in the synthesis of cyclopentenyl carbocyclic nucleosides was subsequently applied in the preparation of enantiomeric neplanocins A. The toxic effect of these compounds was investigated for a series of suspension and adherent cancer cell lines and normal human fibroblasts.

The Chiral 1:2 Adduct ()()(-)-Ethyl 2-Phenylbutyl Sulphide-Mercury (II) Chloride:(-)[()()-Et(2-PhBu)S.(HgCl)]. Stereoselective Synthesis, Asymmetric Oxidation, Crystal and Molecular Structure and Circular Dichroism Spectra.

Optically active (-)ethyl ()-2-phenylbutyl thioether, (-)()-Et(PhBu)S (), and its new diastereoisomeric mercury (II) chloride adduct, 1:2, (-)[()()-Et(PhBu)S.(HgCl)], () were stereoselectively synthesized; the absorbance (UV) and circular dichroism (CD) spectra were measured and the crystal and molecular structure of complex () was determined by single-crystal X-ray diffraction. Two different Hg centres are present whose coordination environments are built by two short bonds to chloride ligands in one case, and to one chloride and one sulphur in the other one.

Nucleophilic Substitution at Tetracoordinate Sulfur. Kinetics and Mechanism of the Chloride-Chloride Exchange Reaction in Arenesulfonyl Chlorides: Counterintuitive Acceleration of Substitution at Sulfonyl Sulfur by -Alkyl Groups and Its Origin.

The chloride-chloride exchange reaction in arenesulfonyl chlorides was investigated experimentally and theoretically by density functional theory (DFT) calculations. The second order rate constants and activation parameters of this identity reaction were determined for 22 variously substituted arenesulfonyl chlorides using radio-labeled EtNCl. The chloride exchange rates of 11 sulfonyl chlorides bearing -and -substituents (σ constants from -0.

A new and expeditious synthesis of all enantiomerically pure stereoisomers of rosaprostol, an antiulcer drug.

Four enantiomerically pure stereoisomers of rosaprostol (), an antiulcer drug, were efficiently synthesized from the enantiomers of 2-(dimethoxyphosphoryl)-3-hexylcyclopentanone () as chiral substrates. The latter were obtained by resolution of racemic with (+)-()-1-(1-naphthyl)ethylamine. The conversion of (+)- into rosaprostol stereoisomer (-)- was accomplished in four steps in 56% overall yield.

Synthesis of Enantiomerically Pure Stereomers of Rosaprostol.

Enantiopure stereomers of rosaprostol 1, an antiulcer drug, were synthesized from diastereomeric building blocks (-)-5a and (+)-5b. Conversion of (-)-5a into rosaprostol stereomer (-)-(1S,2R,5R)-1a was accomplished in nine steps in 18% overall yield. In this sequence, fully diastereoselective hydrogeneration of the endocyclic carbon double bond in the cyclopentenone ring was key, generating a new stereogenic center (C-2 in 1a).

Synthesis and in vitro cytotoxicity of cross-conjugated prostaglandin A and J series and their hydroxy derivatives.

The synthesis of two cross-conjugated prostaglandin analogues of known neurotrophic activity and their new hydroxy derivatives was accomplished starting from the diastereoisomeric (+)-camphor protected 3-[(dimethoxyphosphoryl)methyl]-4,5-dihydroxycyclopent-2-enones. The cytotoxicity of these compounds was determined against HeLa, K562, HL-60 human cancer cell lines and normal human cells (HUVEC). We found that NEPP11 and its C7-hydroxy derivative demonstrated high anticancer activity against the HeLa and HL-60 human cancer cell lines at concentrations ranging from 1 to 2 μM.

Acid catalyzed alcoholysis of sulfinamides: unusual stereochemistry, kinetics and a question of mechanism involving sulfurane intermediates and their pseudorotation.

The synthesis of optically active sulfinic acid esters has been accomplished by the acid catalyzed alcoholysis of optically active sulfinamides. Sulfinates are formed in this reaction with a full or predominant inversion of configuration at chiral sulfur or with predominant retention of configuration. The steric course of the reaction depends mainly on the size of the dialkylamido group in the sulfinamides and of the alcohols used as nucleophilic reagents.

Molecular modeling of the lipase-catalyzed hydrolysis of acetoxymethyl(i-propoxy)phenylphosphine oxide and its P-borane analogue.

The molecular modeling of the CAL-B-promoted hydrolysis reactions of acetoxymethyl(i-propoxy)phenylphosphine oxide and its P-borane analogue, acetoxymethyl(i-propoxy)-phenylphosphine P-borane, confirms that the reactions proceed with the same stereochemistry and in both cases the (S)-enantiomers are preferentially transformed by the enzyme. Molecular mechanics calculations show that the main reason for the particular stereoselectivity of the substrates is the steric effect of the phenyl group which causes a remarkable hindrance when placed inside the active site. The replacement of the oxygen by a borane group at the phosphorus stereogenic center does not nullify the stereorecognition by the enzyme, although for the P-borane a lower stereoselectivity is observed.

Vicinal diphosphoniums: electrostatic repulsion under covalent constraint.

A series of five vicinal bis(alkyl-triarylphosphoniums) derived from o-bis(diphenyl-phosphino)benzene (o-dppb) is described. Each of them have been prepared by specific methods, and their formal electrostatic and possible van der Waals strain is compared through the P+..

From neutral to anionic eta1-carbon ligands: experimental synthesis and theoretical analysis of a rhodium-yldiide complex.

Deprotonation of a cationic rhodium complex of a chelating semistabilized phosphino-phosphonium sulfinyl-ylide ligand afforded the neutral complex of the corresponding yldiide ligand. Despite the limited stability of the yldiide complex its structure was ascertained by ESI MS and multinuclear (1)H, (31)P, (13)C, and (103)Rh NMR spectroscopy. DFT calculations were carried out at the B3PW91/6-31G*/LANL2DZ*(Rh) level to derive a reasonable gas-phase structure for the yldiide complex or model thereof and gain insight into their electronic structure.

Diphosphine sulfides derived from 2,2'-biphosphole: novel chiral S,S ligands for palladium-catalyzed asymmetric allylic substitution.

Diphosphine sulfides derived from 2,2'-biphosphole have been efficiently synthesized in an enantiomerically pure form by a four step synthetic sequence. These S,S-ligands were used for the first time in Pd-catalyzed asymmetric allylic alkylation. Good yields and enantiomeric excess up to 73% were obtained.

Diastereomers of N-alpha-phenylethyl-t-butylsulfinamide: absolute configurations and predominant conformations.

N-alpha-Phenylethyl-t-butylsulfinamide is a complicated system for determining molecular stereochemistry because of numerous possibilities for assigning the absolute configuration and a predominant conformation. Two diastereomers of N-alpha-phenylethyl-t-butylsulfinamide derived from (-)-(S)-alpha-phenylethyl amine, a (+)-diastereomer and a (-)-diastereomer, have been synthesized and their experimental chiroptical spectroscopic properties have been measured. These properties include vibrational circular dichroism, electronic circular dichroism and optical rotatory dispersion.

General route to racemic and enantiomeric carbo- and heterocyclic vinyl sulfoxides via tandem Michael addition/Horner olefination of alpha-phosphorylvinyl sulfoxides.

A new one-pot synthesis of heterocyclic and carbocyclic vinyl sulfoxides has been developed which involves reaction of alpha-phosphorylvinyl sulfoxides with carbonyl compounds bearing oxygen, nitrogen, and carbon nucleophilic centers. Use of optically active alpha-phosphorylvinyl p-tolyl sulfoxides in this tandem Michael addition/Horner olefination reaction leads to the corresponding optically active cyclic sulfoxides. In this way, a variety of optically active chromene, pyrrolizine, chinoline, and cyclopentene sulfoxides have been efficiently prepared.

First optically active selenurane oxide: resolution of C(2)-symmetric 3,3,3',3'-tetramethyl-1,1'-spirobi [3h,2,1]-benzoxaselenole oxide.

The enantiomers of the first optically active selenurane oxide ever reported, C(2)-symmetric 3,3,3',3'-tetramethyl-1,1'-spirobi[3h,2,1]-benzoxaselenole oxide, were isolated via enantioselective liquid chromatography of the racemate or by spontaneous resolution that occurs during the slow evaporation of its acetonitrile solution or the slow crystallization from the same solvent.

Stable optically pure phosphino(silyl)carbenes: reagents for highly enantioselective cyclopropanation reactions.

The stability of phosphino(trimethylsilyl)carbenes bearing cyclic diamino substituents on phosphorus is strongly dependent on the steric hindrance of the nitrogen substituents. Phosphinocarbenes 3 and 7, derived from the trans-N,N'-diisopropylcyclohexane-1,2-diamine and N,N'-diisopropyl-1,2-ethanediamine, are not observed; instead the 1,3-diphosphete 4 and a novel six-membered heterocycle 8, which results from the dimerization of 3 and the reaction of 7 with its diazo precursor 6, respectively, have been isolated. In contrast, the phosphino(silyl)carbene 14 derived from N,N'-di-tert-butyl-1,2-ethanediamine has been isolated in high yield.

The first nonempirical circular dichroism determination of the absolute configuration of N-phthalimidosulfoximines based on exciton coupling mechanism and a correlation with the absolute configuration of chiral sulfoxides.

A simple nonempirical method for the assignment of absolute configuration of N-phthalimidosulfoximines and related S-chiral sulfoxides, based on exciton-coupled circular dichroism, is presented.

Molecular interactions in 3-carboxy-2-diphenylphosphinoylcyclopentanone.

The results of the X-ray structure analysis of the title compound (I) have been reported in [Synthesis (1997) 356]. Now we continue our efforts to understand the energy situation and the arrangements in the crystal, which will be strongly influenced by the formation of hydrogen bonds with the help of the results of theoretical calculations. Furthermore, the IR spectroscopic measurements will be discussed in comparison to the X-ray data.