Triphenylethanediol-Derived 2-Chloro-1,3,2- dioxaphospholane: Synthesis,Structure, and Reaction with Chiral Alcohols

The reaction of (S)-1,1,2-triphenylethanediol (3) with phosphorus trichloride leads to the diastereoselective formation of (S _C,R _P)-2-chloro-1,3,2-dioxaphospholane (2). Its configuration has been determined by single crystal X-ray diffraction. When reacted with racemic secondary alcohols, diastereomeric phosphites are obtained, which display substantial shift differences in the ³¹P NMR spectra. Thus, chlorodioxaphospholane 2 can serve as derivatizing reagent for chiral secondary alcohols permitting to determine their enantiomeric excess.     

Reaction of 5-oxo-2-phenyl-4,4-bis(trifluoromethyl)-4,5-dihydro-1,3,2-benzodioxaphosphepine with chloral. The synthesis and spatial structure of 5-carbaphosphatrane containing a four-membered ring

Phosphorylation of 2-hydroxyphenyl 2,2,2-trifluoro-1-hydroxy-1-(trifluoromethyl)ethyl ketone with dichloro(phenyl)phosphine gave 5-oxo-2-phenyl-4,4-bis(trifluoromethyl)-4,5-di-hydro-1,3,2-benzodioxaphosphepine. Heating of the latter initiated an intramolecular interaction of the P atom with the carbonyl group. Hydrolysis of the intermediate product yielded 3-hydroxy-2-oxo-2-phenyl-3-[2,2,2-trifluoro-1-hydroxy-1-(trifluoromethyl)ethyl]-2,3-di-hydro-1,2λ⁵-benzo[d]oxaphosphole. The reaction was highly stereoselective (P_RC_S/P_SC_R). The reaction of the starting phosphepine with chloral proceeded highly stereoselectively (P_RC_SC_S/P_SC_RC_R) to give a 5-carbaphosphatrane derivative containing a four-membered ring, namely, 1-phenyl-3-trichloromethyl-10,10-bis(trifluoromethyl)-6,7-benzo-2,4,8,9-tetraoxa-1λ⁵-phosphatricyclo[3.3.2.0¹,⁵]decene. The trigonal bipyramid of the 5-carbaphosphatrane derivative is made up of the equatorial O atoms and the apical C atoms.     

A comparison of ferroelectric liquid crystals containing diastereomeric propionic acids derived from natural ethyl lactate

Two diastereomeric carboxylic acids, 2(S)-[2(R)-methylhexyloxy]propionic acid and 2(S)[2(S)-methylhexyloxy]propionic acid, were prepared from ethyl (S)-lactate and (R)-1-iodo2-methylhexane or (S)-1-iodo-2-methylhexane in the presence of Ag₂O. From these acids two liquid crystals, 2 and 3, whose configurations are (S, R) and (S, S) were synthesized and their liquid crystal properties investigated. Although both LCs have the same phase sequence Cr-SmC*-N*-I as well as a wide SmC* phase range, the influence of the relative stereochemistry on their physical properties is clear. The liquid crystal with (S, S)-configuration possesses better properties: lower SmC* phase transition temperature, wider SmC* phase range and higher P_s value. The P_s value difference between the ferroelectric LCs 2 and 3 (97 and 131nCcm^-2, respectively, at T_c - T = 10°C) is unexpectedly large. The consideration, alone, of a zigzag conformation at the chiral molecular part of 2 and 3 is insufficient to explain such a difference.     

Asymmetric synthesis of (R)-S-(1,2,4-triazol-3-yl)cysteines by nucleophilic addition of triazolethiols to a NiII complex with a chiral dehydroalanine Schiff base

An efficient method was developed for the asymmetric synthesis of (R)-S-(1,2,4-triazol-3-yl)cysteines by the addition of 3,4-disubstituted 1,2,4-triazole-5-thiols at the electrophilic C=C bond in a Ni^II complex of a Schiff base of dehydroalanine with (S)-N-(N-benzylprolyl)aminobenzophenone. The stereoselectivity of the formation of diastereomeric complexes with the (S,R) configuration under conditions of thermodynamic control of the nucleophilic addition exceeds 94%. Acid treatment of the reaction mixtures afforded enantiomerically pure (R)-S-hetarylcysteines (ee >98%).     

Asymmetric synthesis ofS-alkyl-substituted (R)-cysteinesvia a chiral NiII complex of the Schiff's base of dehydroalanine with (S)-2-N-(N-benzylprolyl)aminobenzophenone

An efficient procedure was developed for the asymmetric synthesis ofS-alkyl derivatives of (R)-cysteine by nucleophilic addition of alkanethiols (BuⁿSH, Bu^tSH, ortert-C₅H₁₁SH) to the C=C bond of the dehydroalanine fragment in the Ni^II complex of the Schiff's base of Δ-Ala with (S)-2-N-(N-benzylprolyl)aminobenzophenone [(S)-BPB-Δ-Ala]Ni^II. Under conditions of thermodynamic control of the reaction, the diastereomeric excess of the complexes with the (S.R)-configuration was 88–96%. After decomposition of the complexes,(R)-S-butylcysteine,(R)-S-tert-butylcysteine, and(R)-S-tert-pentylcysteine were isolated with an enantiomeric purity of >97%. Published inIzvestiya Akademii Nauk. Seriya Khimicheskaya, No. 8, pp. 1467–1470, August, 2000.     

Characterization of Diastereomeric Equilibria of Pseudotetrahedral Bis[(R or S)-N-1-(Ar)Ethylsalicylaldiminato-κ2N,O]zinc(II) with Λ/Δ-Chirality-At-Metal Induction

A family of bis[(R or S)-N-1-(Ar)ethylsalicylaldiminato-κ²N,O]-Δ/Λ-zinc(II) {Ar=C₆H₅ (ZnRL¹ or ZnSL¹), p-CH₃OC₆H₄ (ZnRL² or ZnSL²) and p-ClC₆H₄ (ZnRL³ or ZnSL³)} compounds was synthesized and investigated by multiple methods. They feature Λ/Δ-chirality-at-metal induction along the pseudo-C₂ axis of the molecules. The chirality induction is quantitative in the solid state, explored by X-ray crystallography and powder X-ray diffraction (PXRD), where R or S-ligated complexes diastereoselectively yield Λ or Δ-configuration at the metal. On the other hand, Λ and Δ-diastereomers co-exist in solution. The Λ⇆Δ equilibrium is solvent- and temperature-dependent. Electronic circular dichroism (ECD) spectra confirm the existence of a diastereomeric excess of Λ-ZnRL¹⁻³ or Δ-ZnSL¹⁻³ in solution. DSC analysis reveals thermally induced irreversible phase transformation from a crystalline solid to an isotropic liquid phase. ECD spectra were reproduced by DFT geometry optimizations and time-dependent DFT (TD-DFT) calculations, providing ultimate proof of the dominant chirality atmetal in solution.     

Replacement of Methoxy by tert-Butyl on a Naphthalene Residue: An Unexpected Reaction During a Snieckus ortho-Lithiation

Summary.  When 1-methoxy-2-naphthalene carboxylic acid diethylamide was reacted with tert-butyl lithium in presence of TMEDA and 3,5-dimethoxybenzaldehyde was subsequently added to the reaction mixture, (P, S/M, R)- and (P, R/M, S)-1-tert-butyl-3-((3,5-dimethoxyphenyl)-hydroxymethyl)-naphthalene-2-carboxylic acid diethylamide were formed instead of the corresponding 1-methoxy derivative. The diastereomeric relationship of the products is due to a sterically severely hindered rotation around the amide-aryl bond. Received May 11, 2001. Accepted May 18, 2001     

Replacement of Methoxy by tert -Butyl on a Naphthalene Residue: An Unexpected Reaction During a Snieckus ortho -Lithiation

 When 1-methoxy-2-naphthalene carboxylic acid diethylamide was reacted with tert-butyl lithium in presence of TMEDA and 3,5-dimethoxybenzaldehyde was subsequently added to the reaction mixture, (P, S/M, R)- and (P, R/M, S)-1-tert-butyl-3-((3,5-dimethoxyphenyl)-hydroxymethyl)-naphthalene-2-carboxylic acid diethylamide were formed instead of the corresponding 1-methoxy derivative. The diastereomeric relationship of the products is due to a sterically severely hindered rotation around the amide-aryl bond.     

A convenient route for the synthesis of s,s-and R,R-warfarin alcohols

S,S-and R,R-warfarin alcohols 3 are prepared in good yield and in 99% d.e. (diastereomeric excess) by the reaction of S- or R-warfarin 1 with S or R-Alpine-Hidride 2.     

Phosphoramidites of Chiral (Rp)-and (Sp)-Configurated d(T[P-18O]-A): Synthesis,Configurational Assignment,and Use as Dimer Blocks in Oligonucleotide Synthesis

The N,N-diisopropylphosphoramidites 10a and 10b of appropriately protected chiral diastereoisomers of d(T[P-¹⁸O]-A) ( 8a and 8b , resp.), chiral by virtue of the isotope ¹⁸O at the P-atom, have been synthesized. The ¹⁸O-isotope was incorporated by oxidation of the phosphite triester 3 with H₂[¹⁸O]/I₂. Separation of the diastereoisomers was accomplished by flash chromatography of the O-3′-deprotected phosphate triesters 5a/b . The absolute configuration at the chiral P-atom was deduced from the methylation products of the fully deprotected diastereoisomers 8a and 8b . Phosphinylation of 5a and 5b yielded the configurationally pure phosphoramidites 10a and 10b , respectively, which were then employed in solid-phase synthesis to yield the self-complementary oligomers d(G-A-G-T-(R_p)-[P-¹⁸O]-A-C-T-C) ( 13 ) and d(G-A-G-T-(S_P)-[P-¹⁸O]-A-C-T-C) ( 14 ), respectively.     

An efficient method for the determination of enantiomeric purity of racemic amino acids using micellar chromatography,a green approach

A simple, sensitive and green micellar liquid chromatographic method (RP-HPLC) was developed for enantioseparation of four racemic amino acids, namely, (RS)-selenomethionine, (RS)-methionine, (RS)-cysteine and (RS)-penicillamine. An aqueous solution of sodium dodecyl sulfate and Brij-35 was prepared and used as mobile phase for HPLC analysis. Activated esters of (S)-ibuprofen, (S)-ketoprofen and (S)-levofloxacin were synthesized by reacting them with N-hydroxybenzotriazole. These esters were characterized by UV, IR, ¹HNMR, HRMS and elemental analysis. These chiral reagents (activated esters) were used for the synthesis of diastereomeric derivatives of the chosen amino acids. The diastereomeric derivatives were separated on a C₁₈ column by micellar liquid chromatography. Chromatographic conditions were optimized by varying concentration of surfactant in aqueous solution, and by varying the concentration and pH of the buffer. The green assessment score was calculated for the developed method (78, an excellent green method score). In addition, density functional theory calculations were performed, using Gaussian 09 rev. A.02 and hybrid density functional B3LYP with a 6-31G* basis set program, in order to develop lowest energy optimized structures of diastereomeric derivatives. The method was validated according to International Conference on Harmonization guidelines and the retention factor (k), selectivity factor (α), resolution factor (R_S) and limit of detection (0.295 ng ml⁻¹) and limit of quantification (0.896 ng ml⁻¹) were calculated.     

Preferred 3D‐Structure of Peptides Rich in a Severely Conformationally Restricted Cyclopropane Analogue of Phenylalanine

Terminally blocked, homo‐peptide amides of (R,R)‐1‐amino‐2,3‐diphenylcyclopropane‐1‐carboxylic acid (c₃diPhe), a chiral member of the family of C^α‐tetrasubstituted α‐amino acids, from the dimer to the tetramer, and diastereomeric co‐oligopeptides of (R,R)‐ or (S,S)‐c₃diPhe with (S)‐alanine residues to the trimer level were prepared in solution and fully characterized. The synthetic effort was extended to terminally protected co‐oligopeptide esters to the hexamer, where c₃diPhe residues are combined with achiral α‐aminoisobutyric acid residues. The preferred conformations of the peptides were assessed in solution by FT‐IR absorption, NMR, and CD techniques, and for seven oligomers in the crystal state (by X‐ray diffraction) as well. This study clearly indicates that c₃diPhe, a sterically demanding cyclopropane analogue of phenylalanine, tends to fold peptides into β‐turn and 3₁₀‐helix conformations. However, when c₃diPhe is in combination with other chiral residues, the conformation preferred by the resulting peptides is also dictated by the chiral sequence of the amino acid building blocks. The (S,S)‐enantiomer of this α‐amino acid, unusually lacking asymmetry in the main chain, strongly favors the left‐handedness of the turn/helical peptides formed.     

Light‐Induced Rearrangement of Thioether‐Substituted Phosphanide Ligands: Scope and Limitations of a Remarkable Isomerization

Treatment of the thioether‐substituted secondary phosphanes R²PH(C₆H₄‐2‐SR¹) [R²=(Me₃Si)₂CH, R¹=Me ( 1_PH ), iPr ( 2_PH ), Ph ( 3_PH ); R²=tBu, R¹=Me ( 4_PH ); R²=Ph, R¹=Me ( 5_PH )] with nBuLi yields the corresponding lithium phosphanides, which were isolated as their THF ( 1 – 5_Pa ) and tmeda ( 1 – 5_Pb ) adducts. Solid‐state structures were obtained for the adducts [R²P(C₆H₄‐2‐SR¹)]Li(L)_n [R²=(Me₃Si)₂CH, R¹=nPr, (L)_n=tmeda ( 2_Pb ); R²=(Me₃Si)₂CH, R¹=Ph, (L)_n=tmeda ( 3_Pb ); R²=Ph, R¹=Me, (L)_n=(THF)_1.33 ( 5_Pa ); R²=Ph, R¹=Me, (L)_n=([12]crown‐4)₂ ( 5_Pc )]. Treatment of 1_PH with either PhCH₂Na or PhCH₂K yields the heavier alkali metal complexes [{(Me₃Si)₂CH}P(C₆H₄‐2‐SMe)]M(THF)_n [M=Na ( 1_Pd ), K ( 1_Pe )]. With the exception of 2_Pa and 2_Pb , photolysis of these complexes with white light proceeds rapidly to give the thiolate species [R²P(R¹)(C₆H₄‐2‐S)]M(L)_n [M=Li, L=THF ( 1_Sa , 3_Sa – 5_Sa ); M=Li, L=tmeda ( 1_Sb , 3_Sb – 5_Sb ); M=Na, L=THF ( 1_Sd ); M=K, L=THF ( 1_Se )] as the sole products. The compounds 3_Sa and 4_Sa may be desolvated to give the cyclic oligomers [[{(Me₃Si)₂CH}P(Ph)(C₆H₄‐2‐S)]Li]₆ (( 3_S )₆) and [[tBuP(Me)(C₆H₄‐2‐S)]Li]₈ (( 4_S )₈), respectively. A mechanistic study reveals that the phosphanide–thiolate rearrangement proceeds by intramolecular nucleophilic attack of the phosphanide center at the carbon atom of the substituent at sulfur. For 2_Pa / 2_Pb , competing intramolecular β‐deprotonation of the n‐propyl substituent results in the elimination of propene and the formation of the phosphanide–thiolate dianion [{(Me₃Si)₂CH}P(C₆H₄‐2‐S)]^2?.     

Polycyclic Phosphorus Sulfide Compounds containing Chiral Amido or Imido Substituents

Reactions of α‐P₄S₃I₂ with (S)‐ or racemic‐RNH₂ (R = CH(Me)Ph) have given solutions containing exo, exo‐ or endo, exo‐α‐P₄S₃(NHR)₂, α‐ or β‐P₄S₃(μ‐NR), or P₄S₂(μ‐NR), as the first compounds with polycyclic phosphorus sulfide skeletons to contain chiral substituents. The expected diastereomers have been characterised by complete analysis of their ³¹P{¹H} NMR spectra, and relative configuration has been assigned in most cases. Considerable diastereomeric differences in coupling constants and chemical shifts were found.     

New ways to determine the absolute configurations of alkyl 6-R-cyclohexa-1,3-dienecarboxylates

Two new methods for the determinatuion of the absolute configuration of methyl 4-methyl-6-(2-methylprop-1-enyl)cyclohexa-1,3-dienecarboxylate are proposed, and the configurations attributed previously to its (+)- and (–)-enantiometers are confirmed. Chiral methyl carboxylate is converted into the corresponding alcohol whose configuration is deduced from either the rate of hydrolysis of the respective racemic acetate in the presence of pancreatic lipase (method 1) or from the difference between the Eu(fod)₃-induced shifts of the MeO signals in the ¹H NMR spectra of the diastereomeric esters of S- or R-Mosher"s acid (method 2).     

A pair of diastereomeric 1:2 salts of (R)‐ and (S)‐2‐methylpiperazine with (2S,3S)‐tartaric acid

The crystal structures of a pair of diastereomeric 1:2 salts of (R)‐ and (S)‐2‐methylpiperazine with (2S,3S)‐tartaric acid, namely (R)‐2‐methylpiperazinediium bis[hydrogen (2S,3S)‐tartrate] monohydrate, (I), and (S)‐2‐methylpiperazinediium bis[hydrogen (2S,3S)‐tartrate] monohydrate, (II), both C₅H₁₄N₂²⁺·2C₄H₅O₆⁻·H₂O, each reveal the formation of well‐defined head‐to‐tail‐connected hydrogen tartrate chains; these chains are linked into a two‐dimensional sheet via intermolecular hydrogen bonds involving hydroxy groups and water molecules, resulting in a layer structure. The (R)‐2‐methylpiperazinediium ions lie between the hydrogen tartrate layers in the most stable equatorial conformation in (I), whereas in (II), these ions are in an unstable axial position inside the more interconnected layers and form a larger number of intermolecular hydrogen bonds than are observed in (I).     

Assignment of relative configurations to acyclic diastereomeric carbinols with the lanthanide shift reagent Eu (fod)3 by 1H and 13C NMR

An assignment of relative configurations has been achieved for the diastereomeric racemates (1R2R,1S2S) and (1R2S,1S2R) of 3,3-dimethyl-1,2-diphenylbutan-1-ol through the comparative analysis of the respective chemical shifts induced by Eu(fod)₃ in the ¹H and ¹³C NMR spectra, and the corresponding conformational distribution.     

An approach to the synthesis and assignment of the absolute configuration of all enantiomers of ethyl hydroxy(phenyl)methane(P-phenyl)phosphinate

Ethyl butyryloxy(phenyl)methane(P-phenyl)phosphinate was hydrolyzed using four bacterial species as biocatalysts. In all cases the reaction was stereoselective and isomers bearing an α-carbon atom with an (S)-configuration were hydrolyzed preferentially. Also a lack of stereoselectivity toward the phosphorus atom was observed. Hydrolysis of one enantiomeric mixture, namely mixture of (S_P,R) and (R_P,S) configuration afforded enantiomerically pure ethyl (R_P,S)-hydroxy(phenyl)methane(P-phenyl)phosphinate, configuration of which was established by X-ray crystallography. The observed ¹H and ³¹P NMR chemical shifts of Mosher esters of ethyl hydroxy(phenyl)methane(P-phenyl)phosphinate were correlated with the configurations of both stereogenic centers of all four stereoisomers.     

Phosphorus NMR Characterisation of P–N Bond Rotamers of a α‐P4S3 Amide with a Conformationally Constrained Chiral Substituent

Reactions of bicyclic α‐P₄S₃I₂ with Hpthiq gave solutions containing α‐P₄S₃(pthiq)I and α‐P₄S₃(pthiq)₂, where Hpthiq is the conformationally constrained chiral secondary amine 1‐phenyl‐1,2,3,4‐tetrahydroisoquinoline. The expected diastereomers have been characterised by complete analysis of their ³¹P{¹H} NMR spectra. Hindered P–N bond rotation in the amide iodide α‐P₄S₃(pthiq)I caused greater broadening of peaks in the room‐temperature spectrum of one diastereomer than in that of the other. At 183 K, spectra of two P–N bond rotamers for each diastereomer were observed and analysed. The minor rotamers showed strong evidence for steric crowding, having large diastereomeric differences in ¹J(P–P) and ²J(P–S–P) couplings (49 Hz, 16 % of value, and 4.4 Hz, 19 % of value, respectively).