Composition of the activated complex in the stereoselective deprotonation of cyclohexene oxide by a chiral lithium amide

Chiral lithium amides are being developed for stereoselective synthesis of chiral allylic alcohols in high yields and with high enantiomeric excess. However, rational design of the amides for improved stereoselectivity by computational methods, for example, has not been possible due to lack of knowledge of the activated complexes involved in the reactions. Kinetic results are presented for the stereoselective deprotonation by lithium (S)-1-(2-pyrrolidinylmethyl)pyrrolidide (1-Li) of cyclohexene oxide 2, in diethyl ether (DEE), to form (S)-2-cyclohexen-1-ol (S)-3 in high enantiomeric excess. The results show that the rate limiting activated complex is composed of one lithium amide monomer and one molecule of 2 and presumably a solvent molecule. The diamine 1 is found to catalyze the deprotonation.     

MM3 force field prediction of the enantioselective preference in the asymmetric synthesis of a chiral 2-cyclohexen-1-ol using a chiral lithium amide reagent

Enantioselective preference in the asymmetric synthesis where cyclohexene oxide is transformed enantioselectively to chiral (S)- or (R)-2-cyclohexen-1-ol by the reaction with the appropriate chiral lithium amide reagent has been evaluated theoretically using the MM3 force field. The plausible possible structures for each precursor (reaction intermediate complex) leading to a (S)- or (R)-2-cyclohexen-1-ol have been optimized with the extended MM3 force field applicable to the lithium amide functional group, and the populations of their (S)- or (R)-reaction intermediate complexes at an ambient temperature (298 K) were calculated. The initial structure for evaluating the reaction intermediates of this asymmetric synthesis was constructed on the basis of the optimized ab initio transition state structure (MP2/6-31+G^∗) comprising lithium amide LiNH₂ and propene oxide. To the thus obtained transition state structure composed of LiNH₂ and propene oxide, the other remaining Cartesian coordinates for the actual reaction intermediates composed of the chiral lithium amides and cyclohexene oxide were added to make the reaction intermediate structure. The conformational search for the reaction intermediate has been carried out by using the Stochastic search Algorithm, and the optimized geometries and their conformational energies (steric energies) have been calculated by the MM3 force field. The populations calculated from the conformational energies of the reaction intermediate leading to the (S)- or (R)-2-cyclohexen-1-ol were shown to be linearly well correlated with the experimentally reported enantiomer excess (% ee) values. The critical factors to control the enantioselectivity were investigated on the basis of the optimized structures of the reaction intermediate complexes. The MM3 force field approach was shown to be applicable to the theoretical evaluation of the enantioselectivity and be useful for designing a new functional chiral lithium amide reagent for the asymmetric synthesis.     

Nucleophilic Square-planar Substitutions. V. Deuterium Isotope Effect on the Substitution of the Bromodiethylenetriamineplatinum(II) Cation by 3-Cyanopyridine

Bromo-[²H₅]diethylenetriamineplatinum(II) bromide has been prepared and characterised, and the kinetics of its reaction with 3-cyanopyridine in deuterium oxide solution have been investigated. The results are compared with those previously reported for the corresponding reaction of the protium complex in protium oxide solution, and the deuterium isotope effect observed is discussed in terms of an associative mechanism.     

Catalytic asymmetric chiral lithium amide-promoted epoxide rearrangement: a NMR spectroscopic and kinetic investigation

The lithium amide derived from the chiral diamine (1R,3S,4S)-3-(1-pyrrolidinyl)methyl-2-azabicyclo[2.2.1]heptane, has been reported to catalytically deprotonate cyclohexene oxide and other epoxides, yielding chiral allylic alcohols in excellent enantiomeric excess. In this work, ⁶Li, ¹H and ¹³C NMR spectroscopy have been used to study the aggregation of the chiral lithium amide in THF and the influence on the aggregation by the addition of additives, such as 1,8-diazabicyclo-[5.4.0]undec-7-ene (DBU). The activated complex under catalytic deprotonation of cyclohexene oxide, that is, with excess Li-DBU and free DBU, is built from one monomer of the chiral lithium amide, one molecule of epoxide and one additional molecule of DBU. The reaction order (?0.97) obtained for the bulk base Li-DBU shows an inverse dependence on the concentration, suggesting a deaggregation of the initial mixed dimer to a monomer-based transition state containing a monomer of the lithium amide.     

A new chiral lithium amide based on (S)-2-[1-(3,3-dimethyl)pyrrolidinylmethyl]pyrrolidine—synthesis,NMR studies and use in the enantioselective deprotonation of cyclohexene oxide

A new chiral lithium amide has been designed starting from (S)-proline. This new chiral lithium amide has been used for asymmetric deprotonation/ring opening of cyclohexene oxide to give (S)-2-cyclohexen-1-ol in 88% yield and 78% enantiomeric excess. NMR studies of the lithium amide and the ligand–substrate complex are also presented.     

Diastereo- and enantioselective aldol reaction of granatanone (pseudopelletierine)

Granatanone (granatan-3-one, 9-methyl-9-azabicyclo[3.3.1]nonan-3-one, pseudopelletierine or pseudopelletrierin) undergoes deprotonation with lithium amides giving a lithium enolate, which reacts with aldehydes diastereoselectively giving exclusively exo isomers and anti/syn selectivity up to 98:2. Granatanone can be enantioselectively lithiated by chiral lithium amides and the resulting non-racemic enolate can be reacted with aldehydes giving aldols with enantiomeric excess up to 93% (99% ee after recrystallization). The absolute and relative configuration of the aldol products was determined by NMR spectroscopy and X-ray analysis.Granatanone; aldol reaction; asymmetric synthesis; enantioselective deprotonation; chiral lithium amide.     

The effects of isotopic substitution and competitive adsorption on the oxidation of aldehydes and alcohols at gold electrodes

The nature of the mechanism of the anodic oxidation of aldehydes in aqueous base on gold electrodes has been probed using isotopic substitution and competitive adsorption studies. A primary kinetic isotope effect of k_H/k_D=3?4 was observed upon substitution of deuterium for protium on the formyl group of benzaldehyde and cyclohexanecarboxaldehyde on gold in aqueous base using the techniques of cyclic voltammetry, rotating disc electrode voltammetry and chronoamperometry. Similar results are reported for the same aldehydes on a silver electrode, and also for the anodic oxidation of 2-propanol and 2-propanol-2-d on gold under similar conditions. Inhibition of the anodic cyclic voltammetric peak for benzaldehyde on gold by a variety of adsorbed species including CN^?, I^?, Br^?, (C₂H₅)₄N⁺ and diethylenetriamine is also described. These observations are used to propose a mechanism for the low potential oxidations of aldehydes and alcohols on gold involving a rate limiting dissociative adsorption step with cleavage of the α-carbon-hydrogen bond.     

Composition and structure of activated complexes in stereoselective deprotonation of cyclohexene oxide by a mixed dimer of chiral lithium amide and lithiated imidazole

Stereoselective deprotonation of cyclohexene oxide, using a mixed dimer built of the chiral lithium amide, lithium (1R,2S)-N-methyl-1-phenyl-2-pyrrolidinyl-propanamide, and 2-lithio-1-methylimidazole, has been studied. The composition of the rate limiting activated complex was determined by kinetics to be built from one mixed dimer molecule and one epoxide molecule. Based on this knowledge computational chemistry has been applied to gain insight into possible structures of the activated complexes.     

Kinetic and NMR spectroscopic studies of chiral mixed sodium/lithium amides used for the deprotonation of cyclohexene oxide

The mixed-metal complex formed from n-butylsodium, n-butyllithium, and a chiral amino ether has been studied by NMR spectroscopy. Three different mixed-metal amides were used as chiral bases for the deprotonation of cyclohexene oxide. The selectivity and initial rate of reaction were compared for sodium-amido ethers, lithium-amido ethers, and mixtures of sodium and lithiumamido ethers in diethyl ether and tetrahydrofuran, respectively. The mixed sodium/lithium amides are more reactive than the single sodium and lithium amides, whereas the stereoselectivities are higher when lithium amides are used. The alkali-metal/gamma-amido ethers exhibit both higher initial reaction rates and stereoselectivities than their beta-amido ether analogues. NMR spectroscopic studies of mixtures of n-butylsodium (nBuNa), n-butyllithium (nBuLi), and the gamma-amino ethers in diethyl ether show the exclusive formation of dimeric mixed-metal amides. In diethyl ether, the lithium atom of the mixed-metal amide is internally coordinated and the sodium atom is exposed to solvent; however, in tetrahydrofuran, both metals are internally coordinated.     

EPR study of nitroxides formed from the reaction of nitric oxide with photolyzed amides

Free radicals generated from UV irradiation of simple aliphatic amides in anaerobic and nitric oxide (NO)‐saturated liquid mixtures or solutions gave EPR spectra of nitroxides. The application of isotopic effects to EPR spectra and the generation of radicals by transient radical attack on substrate molecules or by photolysing amine or acetoin were used to help identify photochemically produced radicals from the amides. The aliphatic amides used were formamide, acetamide and their N‐methyl‐ or deuterium‐substituted derivatives. Transient radicals used to attack the amides via hydrogen‐atom abstraction were generated from the initiator AIBN or AAPH. The observation of various nitroxides indicates the reactivity of NO for trapping acyl, carbamoyl and other carbon‐centered radicals. Possibly mechanistic pathways diagnosed with this trap are proposed. Copyright © 2003 John Wiley & Sons, Ltd.     

Studies on enzymatic oxidation of 3′,4′-dihydroxy-l-phenylalanine to dopachrome using kinetic isotope effect methods

We report the studies on the mechanism of oxidation of 3′,4′-dihydroxy-l-phenylalanine (l-DOPA) to neurotoxic dopachrome catalyzed by enzyme horseradish peroxidase (EC 1.11.1.7) using the kinetic (KIE), and solvent (SIE), isotope effect methods. For kinetic studies two specifically deuterated isotopomers: [2′,5′,6′-²H₃]-l -DOPA was synthesized by the acid catalyzed isotopic exchange between native l-DOPA and heavy water, and [5′-²H]-l-DOPA was synthesized in two step reaction. The first step involved acid catalyzed isotopic exchange between l-tyrosine and deuterated water and resulting product [3′,5′-²H₂]-l-tyrosine was hydroxylated by enzyme tyrosinase (EC 1.14.18.1). The values of deuterium KIEs and SIE’s in the enzymatic oxidation of l-DOPA and its isotopomers are determined using non-competitive spectrophotometric method. The measured values were: KIE on V _max (1.1 and 2.2) and KIE on V _max/K _M (1.7 and 3.2) for [2′,5′,6′-²H₃]-l-DOPA and [5′-²H]-l-DOPA, respectively, while the corresponding values of SIE were: SIE on V _max (2.1, 2.4, and 2.1) and SIE on V _max/K _M (1.3. 1.6, and 1.1) for l-DOPA, [2′,5′,6′-²H₃]-l-DOPA, and [5′-²H]-l-DOPA, respectively. The size of KIE and SIE, typical for secondary isotope effects indicate that both the solvent and presence of deuterium at the 2′-, 5′, and 6′-positions of l-DOPA has the little impact on the enzymatic oxidation of this compound.     

Protophilic isotopic hydrogen exchange of 1-ferrocenyl-2-(nitrophenyl)ethylenes

cis-1-Ferrocenyl-2-(4-nitrophenyl)ethylene enters into the protium/deuterium exchange in basic medium at the expense of hydrogens of the phenyl ring, at ortho positions in respect of the nitro group. The homoaromatic analogue, 4-nitrostilbene, under the same conditions, undergoes isotopic exchange occurring exclusively at the vinylic CH fragment attached to the nitrophenyl group. The difference is eliminated as a result of the shift of the nitro group from position 4 into position 2 of the phenyl ring: cis-1-ferrocenyl-2-(2-nitrophenyl)ethylene enters into H⁺/D⁺ exchange in the same manner as 4-nitrostilbene. Correspondence to: Professor Z.V. Todres.     

The conformation of the hydrogen bonded complex cyclohexene oxide⋯HCl: A rotational study

Cyclohexene oxide and its hydrogen bonded complex cyclohexene oxide⋯HCl have been investigated using a molecular beam Fourier Transform microwave spectrometer. The spectra of the parent species of cyclohexene oxide and its ¹³C and ¹⁸O isotopomers have been measured in their natural abundances. This has allowed obtaining the substitution and effective structures of the monomer heavy atom skeleton. A fast mixing nozzle has been designed to generate the complex preventing the reaction between the components. Only the equatorial conformer of the complex has been detected and its ³⁵Cl and ³⁷Cl isotopic species have been measured in their natural abundances. From the spectroscopic data the hydrogen bond structural parameters were obtained assuming that the structures of the monomers do not change upon complexation. HCl lies in the COC bisecting plane forming a non-linear hydrogen bond to the equatorial non-bonding electron pair at oxygen. The geometries of the axial and equatorial conformers have been optimized at MP2/6-311++G(d,p) level of theory predicting the equatorial conformer as the most stable one. The non-observation of the axial form is discussed.     

Enantioselective Deprotonation of Cyclohexene Oxide to (R)-2-Cyclohexen-1-ol

The reaction of cyclohexene oxide with homochiral lithium amides, prepared from (S)-phenylglycine and (S)-valine has been studied and (R)-2-cyclohexen-1-ol 3 was prepared in a maximum of 72% ee. The optical purity was determined by ¹H NMR measurement of the α-methoxy-α-(trifluoromethyl)phenyl acetic acid (MTPA) derivative of the corresponding alcohol.     

Enzymatic synthesis of dopamine ring labeled with hydrogen isotopes

The synthesis of two isotopomers of L-DOPA, the precursors for labeled dopamine is reported. The ring labeled with deuterium or tritium [2′,5′,6-²H₃]-L-DOPA, and [2′,5′,6-³H₃]-L-DOPA were obtained using acid catalyzed isotopic exchange between L-DOPA and heavy or tritiated water, respectively. Their derivatives, i.e., [2′,5′,6-²H₃], and [2′,5′,6-³H₃]-dopamine were obtained by enzymatic decarboxylation of deuterated or tritiated isotopomers of L-DOPA using enzyme tyrosine decarboxylase (EC 4.1.1.25).     

On the mechanism of reaction of tert-butoxyl radicals with dialkylphosphites

It has been shown by ESR spectroscopy that the title reaction involves abstraction of hydrogen from the phosphite, since at ?10°C the reaction has a kinetic deuterium isotope effect, k_H/k_D, or ～3. The rate constant for hydrogen abstraction is c. 2 × 10⁴ M^?1 s^?1. There is no significant addition of alkoxyl radicals to the phosphite.     

Reinvestigation of the regioselectivity of deprotonation of ketone dimethylhydrazones

The lack of regioselectivity in the deprotonation of ketone dimethylhydrazones by lithium diethylamide has been determined by ¹³C NMR spectroscopy of deuterium labelled samples.     

Reaction of 3-phenylisoxazole with alkyllithiums

Alkyllithiums react with 3-phenylisoxazole giving C₅-H abstraction followed either mainly by ring fragmentation to benzonitrile and ethynolate ion (in the case of t-BuLi) or (less hindered alkyllithiums: n-BuLi, EtLi, MeLi) also by formation of alkylated enaminones. Appreciable amounts of 2-alkyl-4,6-diphenylpyrimidines have also been isolated for certain alkyllithiums (EtLi and MeLi). This is at variance with the reported behaviour with hindered lithium amides (LTMP) for which only C₅-H abstraction followed by ring fragmentation was described. The mechanistic significance of the observed results is discussed.     

Solvent Choice and Kinetic Isotope Effects (KIEs) Dramatically Alter Regioselectivity in the Directed ortho Metalation (DoM) of 1,5‐Dichloro‐2,4‐dimethoxybenzene

The regioselective formation of the 6‐lithio derivative of 1,5‐dichloro‐2,4‐dimethoxybenzene (i.e., 12 ) by directed ortho metalation (DoM) with nBuLi in THF is described. Although literature reports suggest direct deprotonation at C6, a series of time‐course and labelling studies has revealed that deprotonation rather occurs exclusively at C3 followed by isomerization of the anion to C6. By contrast, when DoM was performed in Et₂O, deprotonation again occurred selectively at C3, but now no isomerization occurs, and electrophilic capture produces the regioisomer of that produced in THF. In these labeling studies, it has been found that deuterium has an enormous kinetic isotope effect (KIE) that suppresses not only the original DoM reaction at C3 when deuterium is present there, but also suppresses isomerization to C6 when the label is at that site. Remarkably, this “protecting‐group” role of the deuterium is unique to THF; in ether, full deprotonation of the deuterium at C3 was observed.     

Synthesis of isotopomers of N-(tert-butoxycarbonyl)-4-cyano-l-phenylalanine methyl ester: choice of cyanation solvent

N-(tert-butoxycarbonyl)-4-cyano-l-phenylalanine methyl ester and three isotopomers (C¹⁵N, ¹³CN, and ¹³C¹⁵N) were successfully synthesized in two steps to expand the utility of the nitrile symmetric stretch vibration of this modified amino acid as a vibrational reporter of local environments. The choice of cyanation solvent directly impacted the level of isotopic enrichment of the isotopomers. The commonly used solvent acetonitrile resulted in an isotopic enrichment of only ∼80% with a cyanation reaction time of 4.5 h, however, the cyanation solvent N,N-dimethylformamide afforded the isotopomers with >98% isotopic enrichment.