Retention Of Stereochemistry Research Articles

Halogen/Metal vs. Hydrogen/Metal Exchange: General or Specific Site Selectivity as Exemplified in the Camphene Series

Abstract(Z)‐(3,3‐Dimethylbicyclo[2.2.1]hept‐2‐ylidene)methyllithium can be readily generated by treatment of (Z)‐3‐bromomethylene‐2,2‐dimethylbicyclo[2.2.1]heptane with tert‐butyl‐lithium. At ‐75°C, the organometallic intermediate is configurationally stable and reacts with a variety of electrophiles under stereochemical retention.

Protein Radicals in Myoglobin Dimerization and Myoglobin-Catalyzed Styrene Epoxidation

Two mechanisms have been identified for the H2O2-dependent epoxidation of styrenes by sperm whale myoglobin (Mb) [S. Rao, A. Wilks, and P.R. Ortiz de Montellano,J. Biol. Chem.268, 803–908 (1993)]: (a) ferryl (FeIV= O) oxygen transfer with retention of stereochemistry and incorporation of an oxygen from H2O2, and (b) protein peroxy radical cooxidation with loss of stereochemistry and incorporation of an oxygen from O2. As shown here,cis-β-methylstyrene is preferentially oxidized to thetrans-epoxide when the H2O2:Mb ratio is <0.5 but increasingly to thecis-isomer as the ratio increases to and above 1. At a high (4:1) H2O2:Mb ratio, both the absolute yield and thecis:trans-epoxide ratio increase in proportion to thecis-β-methylstyrene concentration. A protein radical formed in the Mb–H2O2reaction also causes dimer and trimer formation, maximum dimer formation (∼30%) being obtained with 1 equivalent of H2O2. At low H2O2:Mb ratios, the oxidation equivalents utilized for protein oligomerization and styrene oxidation account for the available H2O2. Previous studies have shown that His-64 is important for protein-mediated olefin cooxidation and Tyr-151/Tyr-103 for Mb dimerization. The W7F, W14F, and W7F/W14F Mb mutants have now been prepared and the W14F, but not W7F, mutation shown to modestly decrease cooxidation ofcis-β-methylstyrene to thetrans-epoxide. Neither tryptophan mutation alters dimer formation. Dimer formation is modestly increased rather than decreased by styrene, suggesting that styrene cooxidation and dimerization do not compete. The results indicate that (a)cis-β-methylstyrene cooxidation and protein dimerization, both of which are mediated by protein radicals, are favored at low H2O2:Mb ratios, (b) as the H2O2:Mb ratio increases, the ferryl epoxidation pathway surpasses the cooxidation mechanism, (c) Trp-14 but not Trp-7 influences olefin cooxidation, and (d) different, possibly nonequilibrating, radicals mediate olefin cooxidation and protein dimerization.

An efficient access to ( R)- and ( S)-6,6′-dimethoxy-2,2′-diiodo-1,1′-biphenyl

In a better procedure than the known for (rac)- 2a, the diamine (rac)- 2b was resolved for the first time with the new resolving agent ( R, R)- and ( S, S)-2,3-di(phenylamino-carbonyl)tartaric acid ( 5c) (40–45% weight yields; >99% ee). The diamines ( R)- or (S)- 2a and 2b were converted with >98% stereochemical retention into the diiodides ( R)- and (S)- 3a and 3b and subsequently, without loss of optical purity, diphenylphosphinated to the known diphosphines ( R)- and (S)- 4a and 4b.

Reactions of the Dirhenium(II) Complexes Re(2)X(4)(&mgr;-dppm)(2) (X = Cl, Br; dppm = Ph(2)PCH(2)PPh(2)) with Isocyanides. 11.(1) A Triply Bonded Dirhenium Complex Containing a Labile Acetonitrile Ligand. Synthesis, Structural Characterization, and Reactivity of [(XylNC)(CH(3)CN)ClRe(&mgr;-dppm)(2)ReCl(2)(CO)]O(3)SCF(3).

The reaction of the open bioctahedral form of Re(2)Cl(4)(&mgr;-dppm)(2)(CO)(CNXyl) (1), where XylNC = 2,6-dimethylphenyl isocyanide, with TlO(3)SCF(3) in the presence of acetonitrile proceeds with retention of stereochemistry at the dirhenium unit to afford the complex [Re(2)Cl(3)(&mgr;-dppm)(2)(CO)(CNXyl)(NCCH(3))]O(3)SCF(3) (3). The single-crystal X-ray structure determination of 3 shows that a Re&tbd1;Re bond is retained (the Re-Re distance is 2.378(3) Å) and that it is the chloride ligand trans to the XylNC ligand of 1 which is labilized. Complex 1 reacts with TlO(3)SCF(3) in a noncoordinating solvent to produce the unsymmetrical complex [Re(2)Cl(3)(&mgr;-dppm)(2)(CO)(CNXyl)]O(3)SCF(3) (2), through loss of this same chloride ligand of 1 and CO transfer from the adjacent Re center. The acetonitrile ligand of 3 is very labile and is readily displaced by XylNC and t-BuNC, with retention of stereochemistry, to produce complexes of stoichiometry [Re(2)Cl(3)(&mgr;-dppm)(2)(CO)(CNXyl)(CNR)]O(3)SCF(3) (R = Xyl, 4a; R = t-Bu, 4b). In a noncoordinating solvent, the nitrile ligand of 3 is lost and 2 is formed following CO transfer; this conversion is reversed upon the reaction of 2 with acetonitrile. When 3 is treated with CO, the acetonitrile ligand is again displaced, but in this instance the reaction is accompanied by a structure change to produce an edge-sharing bioctahedral complex of the type [Re(2)(&mgr;-CO)(&mgr;-Cl)(&mgr;-dppm)(2)Cl(2)(CO)(CNXyl)]O(3)SCF(3) (5).

Phosphoenolpyruvate mutase catalysis of phosphoryl transfer in phosphoenolpyruvate: kinetics and mechanism of phosphorus-carbon bond formation.

Phosphoenolpyruvate phosphomutase (PEP mutase) from Tetrahymena pyriformis catalyzes the rearrangement of phosphoenolpyruvate (PEP) to phosphonopyruvate (P-pyr). A spectrophotometric P-pyr assay consisting of the coupled actions of P-pyr decarboxylase, phosphonoacetaldehyde hydrolase, and alcohol dehydrogenase was devised to monitor mutase catalysis. The reaction constants determined for PEP mutase catalyzed conversion of PEP to P-pyr at pH 7.5 and 25 degrees C in the presence of Mg(II) are kcat = 5 s(-1), Km = 0.77 +/- 0.05 mM, and Keq = (2-9) x 10(-4). In the PEP forming direction, kcat = 100 s(-1) and Km = 3.5 +/- 0.1 microM. Retention of stereochemistry at phosphorus and strong inhibition displayed by the pyruvyl enolate analog, oxalate, have been cited as two lines of evidence that PEP mutase catalysis proceeds via a phosphoenzyme-pyruvyl enolate intermediate [Seidel, H. M., & Knowles, J. R. (1994) Biochemistry 33, 5641-5646]. In this study, single turnover reactions of oxalyl phosphate with the PEP mutase were carried out to test the formation of the phosphoenzyme intermediate. If formed. the phosphoenzyme-oxalate complex should be sufficiently stable to isolate. Reaction of the mutase with [32P]oxalyl phosphate in the presence of Mg(II)/Mn(II) cofactor failed to produce a detectable level of the [32P]phosphoenzyme-oxalate complex. In contrast, the same reaction carried out with pyruvate phosphate dikinase (PPDK), an enzyme known to catalyze the phosphorylation of its active site histidine with PEP, occurred at a rate of 4 x 10(-4) s(-1) (15% E-P formed) in the presence Mg(II) and at a rate of 3 x 10(-3) s(-1) (60% E-P formed) in the presence of Mn(II). Both oxalyl phosphate (Ki = 180 +/- 10 microM) and oxalate (Ki = 32 +/- 1O microM) were competitive inhibitors of PEP mutase catalysis, but neither displayed slow, tight binding inhibition. These results do not support the intermediacy of a phosphoenzyme-pyruvyl enolate complex in PEP mutase catalysis.

The Endocyclic Restriction Test: Investigation of the Geometries of Nucleophilic Substitution at Phosphorus(III) and Phosphorus(V)

Double labeling has been used under the endocyclic restriction test to show that transfers of phosphorus from oxygen to carbon in the conversions of lithio phosphinite 1 to alkoxy phosphine 8, of lithio phosphinite 2 to alkoxy phosphine 9, of lithio phosphinate 3 to alkoxy phosphine oxide 10, and of lithio phosphinite borane 4 to alkoxy phosphine borane 11 proceed in an intramolecular fashion. The transfers of stereogenic phosphorus in the conversions of lithio phosphinite (R)-5 to alkoxy phosphine (R)-12, of lithio phosphinate (S)-6 to alkoxy phosphine oxide (S)-13, and of lithio phosphinite borane (R)-7 to alkoxy phosphine borane (R)-14 proceed with retention of stereochemistry at phosphorus. These results rule out the classic in-line SN2 pathway and the geometrically equivalent in-line addition−elimination pathway for these endocyclic transfers of phosphorus. The most likely pathway for these nucleophilic substitutions at phosphorus is initial apical nucleophilic attack followed by pseudorotation and elimination of the apical alkoxy leaving group.

Mechanisms of Reaction of Sulfate Esters: A Molecular Orbital Study of Associative Sulfuryl Group Transfer, Intramolecular Migration, and Pseudorotation

Molecular orbital calculations for the reactions of 2-hydroxyethyl sulfate in neutral and ionized forms were used to examine the free energy profiles for intramolecular sulfuryl group transfer in the gas phase. Detailed analysis of reaction dynamics yielded structures for trigonal bipyramidal pentacoordinate reaction intermediates and for transition states at the MP2/6-31+G*//HF/3-21+ G(*) and MP2/6-31+G*//HF/3-21G(*) levels of calculation for anionic and neutral species, respectively. Application of a continuum dielectric model to these structures provided estimated free energy profiles for reaction in aqueous solution. Comparison with the reactivity of phosphate esters suggests that the empirical guidelines for reactions of phosphates may, in large part, be extended to reactions of sulfate esters. It is predicted that the activation barriers to intramolecular sulfuryl group transfer will be large, in accord with experiment and in contrast with phosphoryl transfer. The explanation is based upon (1) the requirement for the energetically unfavorable protonation of the sulfate moiety for nucleophilic attack on sulfur; and (2) the relatively higher energy of the pentacoordinate relative to the tetracoordinate state for S over P species. However, Berry pseudorotation is facile and does not present a barrier to reaction. The calculations suggest that nucleophilic substitution of alkoxide on the protonated sulfate moiety has a low activation barrier and may occur with inversion or retention of stereochemistry at sulfur.

Mechanistic Studies on Thiaminase I: 1. The Stereochemical Course of the Reaction

Thiaminase I catalyzes the displacement of the thiazole moiety of thiamin by a wide variety of nucleophiles. In this paper, we demonstrate that this reaction proceeds with overall retention of stereochemistry.

Palladium- tert-alkyl isocyanide catalyzed intramolecular bis-silylation of vicinally disubstituted alkenes

Intramolecular bis-silylation of ( Z)- and ( E)-alkenes tethered to disilanyl groups by ether linkage -CH 2CH 2)- proceeded with stereospecific cis-addition to give 5-exo ring-closure products. Phenyl substituents on the silicon atom proximal to the ether oxygen were crucial for the successful bis-silylation reaction. NMR study of a stoichiometric reaction of disilanyl alkenes with bis( tert-alkyl isocyanide)palladium(O) complex showed that facile formation of an intermediate of bis(sily)palladium(II) complexes may determine on the observed high reactivity in the catalytic reaction. Disilanyl ethers derived from ( Z)- and ( E)-2-ethyl-3-hexen-1-ol gave trans-3,4-disubtituted 2-silatetrahydrofurans and those derived from (Z)- and ( E)-4-hepten-2-ol gave cis-3,5-disubstituted 2-silatetrahydrofurans selectively. Application to stereoselective synthesis of triols was demonstrated by H 2O 2 oxidation of the cyclic products with retention of stereochemistry at the silicon substituted carbons.

1994 Merck Frosst Award Lecture New strategies for the stereoselective synthesis of natural and unnatural products via organometallic reagents and catalysts

Samarium in the presence of diiodomethane selectively cyclopropanates an allenic alcohol to yield a methylenecyclopropane with modest to excellent diastereoselectivity. The effect of substituents at the carbinol carbon and the allenic carbon on the diastereoselectivity was investigated. A palladium catalyst was shown to promote the intramolecular cycloaddition of the methylenecyclopropane with an electron-deficient alkyne to yield a methylenecyclopentane. The reaction was stereospecific with retention of stereochemistry as proven by X-ray diffraction. Nickel catalysts accelerate the hydroalumination of oxabicyclo[3.2.1]alkenes, leading to bicyclic trialkylalanes. Upon treatment with a Lewis acid (diisobutylaluminum chloride), the trialkylalanes fragment to provide cycloheptenols. This reaction, followed by an enantioselective enzyme-catalyzed esterification, was used as a key step in a synthesis of the mevinic acid lactone. Keywords: methylenecyclopropane, palladium, stereocontrol, oxabicyclic, nickel.

Studies on electron transfer as mechanistic concept for [4 + 2] cycloadditions, 1. Cycloadditions of 1,4‐bis(dimethylamino)‐1,3‐butadiene to electron‐deficient olefins

Abstract(E,E)‐1 and (E,Z)‐1,4‐bis(dimethylamino)‐1,3‐butadiene (2) as model systems for highly electron‐rich dienes were allowed to react with olefins of increasing electron‐acceptor capacity under standard concentrations (0.4 M solutions of diene and dienophile) and at reaction temperatures from −50°C to a maximum of +60°C (slow decomposition of the diene). Methyl acrylate (3), acrylonitrile (4), and dimethyl methylfumarate (6) did not form cycloadducts with 1 at 35°C in six weeks. Isopropylidenemalononitrile (5) undergoes dimerization. Maleo‐ (9) and fumaronitrile (10) add to 1 with retention of stereochemistry ( ≥98%). Dimethyl maleate (7) isomerizes under the reaction conditions to dimethyl fumarate (8) and reacts with 1 to the cycloadduct of 8. N‐Methylmaleimide (11) gave the expected cycloadduct. The monosubstituted C atoms of the CC double bond of 1,1,2‐tris(methoxycarbonyl)ethene (12) and 2‐cyano‐1,1‐bis(methoxycarbonyl)‐ethene (13) add to C‐2 of 1 to form zwitterions which stabilize themselves by a 1,3‐hydrogen shift to 24 and 25. The reactions of 1 with 1,1‐dicyano‐2‐methoxycarbonylethene (14), 1,1‐dicyano‐2,2‐bis(methoxycarbonyl)ethene (15), and tetracyanoethene (18) provided, though very reactive, no isolable cycloadducts or other identifiable products. Dimethyl dicyanomaleate (16) and dimethyl dicyanofumarate (17) lead in non‐stereospecific reactions with 1 to the same cycloadduct even at −50°C in dichloromethane. The same cycloadduct is obtained from 2 and 17. For the reactions of 16 and 17 with 1 electron transfer from diene to dienophile could be demonstrated. Intermediates were detected 1H‐NMR‐spectroscopically at −95°C which transformed into the cycloadduct when warmed to−50°C. A comparison of the preparative results with oxidation potentials of 1 and 2, and the reduction potentials of the olefins shows, that electron transfer is possible when oxidation and reduction potential are close together. It is concluded from the loss of stereochemistry during the cycloadduct formation in those cases (16 and 17) where electron transfer is observed, and furthermore from retention of stereochemistry (9 and 10) when no electron transfer could be detected, that electron transfer may be a possibility in [4 + 2] cycloadditions, but that it is not the general mechanism of the Diels‐Alder reaction.

Studies on electron transfer as mechanistic concept for [4 + 2] cycloadditions, 2. Cycloadditions of 2,3‐bis(dimethylaminomethylene)bicyclo[2.2.1]heptane and 2,3‐bis(dimethylaminomethylene)bicyclo[2.2.2]octane with electron‐deficient olefins

AbstractElectron transfer as initiating step in [4 + 2] cycloadditions was studied with 2,3‐bis(dimethylaminomethylene)bicyclo‐[2.2.1]heptane (1) and 2,3‐bis(dimethylaminomethylene)bicyclo[2.2.2]octane (2) as models. These dienes, having the necessary synperiplanar configuration for a concerted [4 + 2] cycloaddition were allowed to react with dienophiles of increasing acceptor capacity. Slightly activated alkenes like methyl acrylate and acrylonitrile undergo smooth cycloaddition in contrast to the corresponding open‐chain dienes where cycloaddition with these dienophiles could not be observed. The use of dimethyl fumarate and dimethyl maleate lead to identical cycloaddition products due to an isomerization of dimethyl maleate catalyzed by 1 and 2. Fumaronitrile and maleonitrile proved to be stable under the reaction conditions and lead to different stereoisomers in the cycloaddition to 2. The introduction of three and four acceptor groups, different combinations of cyano and methoxycarbonyl groups, leads to a sudden increase in reactivity towards 1 and 2. At the same time the cycloadditions are no longer stereospecific in those cases where they could be checked, and radical ions could be detected either by ESR spectroscopy or by stopped‐flow visible spectroscopy. This applies in particular to dichloromethane as solvent. Stopped‐flow measurements in combination with a rapid‐scan unit reveals a transient absorption at λ ∽ 420 nm in acetonitrile for 1,1‐dicyano‐2,2‐bis(methoxycarbonyl)ethene and dimethyl dicyanofumarate as dienophiles which is ascribed to zwitterionic intermediates by a comparison with related systems. The cycloadditions of TCNE to 1 and 2 lead to thermally unstable adducts in both cases. Electron transfer was not only observed in solution but could also be detected in the isolated solid products, in particular if they were placed in a polar environment like KBr where complete dissociation in radical ions seems to take place. The relevance of these studies for the mechanism of Diels‐Alder reactions is that suitable model systems can be constructed where electron transfer can be observed. Due to the loss of stereospecificity in these cases it is concluded that complete electron transfer is not the principal mechanism of these [4 + 2] cycloadditions which in their majority occur with retention of stereochemistry in the reactants.

Addition reactions of p-carboranylcarbene. EPR spectra of m-carboranylcarbene and p-carboranylcarbene

p-Carboranylcarbene adds to alkenes with nearly complete retention of stereochemistry, thus implying the singlet state as the predominant reacting species. Nonetheless, EPR spectroscopy shows that the ground state of this intermediate is the triplet, as is the ground state of m-carboranylcarbene.

Tertiary alcohol synthesis from secondary alcohols via C–H insertion

Secondary alcohols are converted into 3(2H)-furanone derivatives via C–H insertion reaction, from which tertiary alcohols are prepared with retention of stereochemistry.

Retention of Stereochemistry in the Formation and Fragmentation of Diosmacyclobutanes, and Other Evidence against a Diradical Mechanism

Two results argue against a diradical intermediate in the exchange of diosmacyclobutanes with free olefins. The diosmacyclobutane Os[sub 2](CO)[sub 8]([mu]-propene) reacts with vinylcyclopropane to give as the sole product a diosmacyclobutane bearing an intact cyclopropane ring. Repeated exchange of trans-ethylene-1,2-d[sub 2] with the same ligand in a diosmacyclobutane shows >99.1% stereochemical excess per exchange half-life. These exchange reactions do not involve mononuclear olefin complexes. 36 refs.

Studies of silicon–nitrogen ring formation from tetrachlorodisilanes

AbstractThe addition of n equiv of MesNHLi (n = 1, 2, 3, 4) and m equiv of 12‐crown‐4 (m = 0.1, 1, 2, 3, 4) to (RsiCl2)2 (R = Mesityl; t‐Butyl) in THF at −78°C resulted in higher yields and improved selectivities of cyclodisilazanes and azadisilacyclopropanes. The reaction of 2 equiv of MesNDLi with (MesSiCl2)2 (I) yielded cis‐2‐chloro‐1,2,3,4‐tetramestylcyclodisilazane (2a) with 95% SiH deuteration. 2a was quantitatively chlorinated with retention of stereochemistry by N‐chlorosuccinimide to give the cis dichlorocyclodisilazane (3). Variable‐temperature 1H NMR studies from −70°C to 25°C in d8‐THF were performed on 1, 2a, 2b, and 3. 1 exhibited little variation throughout the temperature range, whereas 2a, 2b, and 3 showed several rotational isomers. trans‐2,3‐Bis(mesitylamino)‐1,2,3‐trimesitylazadisilacyclopropane was shown to isomerize to the cis isomer in the presence of n‐BuLi or MesNHLi. The molecular structures of 1 and 3 were determined by X‐ray crystallography. Compound 1 crystallized in the monoclinic space group P21/c, with cell parameters a = 16.599(2) Å b = 14.633(2) Å, c = 16.945(2) Å, β = 92.044(13)°, V = 4113.1(8) Å3, Z = 8, d (calcd) = 1.409 g/cm3, and R = 6.88%. Compound 3 ° C6H6 crystallized in the orthorhombic space group Pbca, with cell parameters a = 17.906(4) Å, b = 13.918(3) Å, c = 31.700(6) Å, V = 7900(3) Å3, Z = 8, d (calcd) = 1.194 g/cm3, and R = 7.52%.

Chemistry of extradiol aromatic ring cleavage: isolation of a stable dienol ring fission intermediate and stereochemistry of its enzymatic hydrolytic clevage

The meta-ring fission intermediate on the phenylpropionate catabolic pathway exists as a stable trans-dienol; its breakdown by hydrolase enzyme MhpC proceeds with overall replacement of the succinyl group by a proton from water with retention of stereochemistry.

Metal complexes of benzodiazepines. Kinetic properties of bromazepam toward square planar dimethyl sulfoxide complexes of platinum(II) and palladium(II)

The kinetics of substitution reactions of Me 2SO from the complexes [MX 2(Me 2SO) 2] (M=Pt, X=Cl, CH 3, cis; M=Pd, X=Cl, trans) by the ligands bromazepam or bipy have been investigated in Me 2SO and/or CH 2Cl 2 at 25 °C. The results are interpreted in terms of an associative mechanism for cis-[PtCl 2(Me 2SO) 2] and a dissociative mechanism for cis-[PtMe 2(Me 2SO) 2]. The substitution reaction for the complex trans-[PdCl 2(Me 2SO) 2] proceeds without retention of stereochemistry; a consecutive displacement mechanism or a pseudo-rotation mechanism can be operative. The kinetic behaviour of bromazepam and bipy is very similar.

Versatile synthesis of stereospecifically labelledD-amino acids via labelled aziridines—preparation of (2R,3S)-[3-2H1]- and (2R,3R)-[2,3-2H2]-serine; (2S,2′S,3S,3′S)-[3,3′-2H2]- and (2S,2′S,3R,3′R)-[2,2′,3,3′-2H4]-cystine; and (2S,3S)-[3-2H1-] and (2S,3R)-[2,3-2H2]-β-chloroalanine

Stereospecifically β-labelled protected 2-carboxyaziridines 2, with the stereochemistry of a D-amino acid at C-2, have been prepared by a chemicoenzymic synthesis. Preparation of the labelled malates 5, by hydration of fumaric acid using the enzyme fumarase or by amination with aspartase followed by nitrosation, was followed by conversion into the isoserines 3, by a process involving Curtius rearrangement with retention of stereochemistry at the chirally labelled primary centre. Protection and ring closure gave the aziridines 2, which, on ring opening with the appropriate nucleophiles and deprotection, gave stereospecifically labelled samples of D-serine 16, D-Cystine 20 and β-chloro-D-alanine 22.

Stereochemistry of conversion of the suicide substrates β-chloro-D-alanine-andD- andL-serine O-sulfates into pyruvate byD-amino acid aminotransferase and byL-aspartate aminotransferase

β-Chloro-D-alanine and D-serine O-sulfate are converted into a putative aminoacrylate intermediate by D-amino acid aminotransferase. This either reacts with pyridoxal phosphate to form a reactive inhibitor of the enzyme or it is protonated and hydrolysed to give pyruvate. The protonation reaction is shown to occur with modest stereoselectivity, indicating overall retention of stereochemistry in replacement of the leaving group by hydrogen. The corresponding reaction of L-serine O-sulfate using L-aspartate aminotransferase shows little or no stereosetectivity.