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PubMed2002

Syntheses of 1-alkyl-1,2,4-triazoles and the formation of quaternary 1-alkyl-4-polyfluoroalkyl-1,2,4-triazolium salts leading to ionic liquids.

1,2,4-triazole was alkylated (alkyl = methyl, butyl, heptyl, decyl) at N-1 in >90% isolated yields. The resulting 1-alkyl triazoles were quaternized at N-4 in >98% isolated yields using fluorinated alkyl halides with >98% isolated yields, under neat reaction conditions at 100-120 degrees C to form N1-CH(3)-N4-(CH(2))(2)C(m)F(2)(m)(+ 1)-triazolium (Taz) iodide (m = 1, 6), N1-C(4)H(9)-N4-(CH(2))(2)C(m)F(2)(m)(+ 1)-Taz iodide (m = 1, 4, 6), N1-C(7)H(15)-N4-(CH(2))(2)C(m)F(2)(m)(+ 1)-Taz iodide (m = 1, 4, 6), N1-C(10)H(21)-N4-(CH(2))(2)C(m)F(2)(m)(+1)-Taz iodide (m = 1, 4), and N1-C(n)H(2)(n )(+ 1)-N4-(CH(2))(2)F-Taz bromide (n = 4, 7, 10). Single-crystal X-ray analyses confirmed the structure of [1-CH(3)-4-CH(2)CH(2)CF(3)-Taz](+)I(-). It crystallized in the orthorhombic space group Pccn, and the unit cell dimensions were a = 13.8289(9) A, b = 17.3603(11) A, c = 9.0587(6) A (alpha = beta = gamma = 90 degrees ). Metathesis of these polyfluoroalkyl-substituted triazolium halides with other salts led to the formation of quaternary compounds, some of which comprise ionic liquids, namely, [R(R(f))-Taz](+)Y(-) (Y = NTf(2), BF(4), PF(6), and OTf), in good isolated yields without the need for further purification: N1-CH(3)-N4-(CH(2))(2)C(m)F(2)(m)( +) (1)-Taz Y (m = 1, 6; Y = NTf(2)), N1-C(4)H(9)-N4-(CH(2))(2)C(m)F(2)(m)(+ 1)-Taz Y (m = 1, 4, 6; Y = NTf(2)), N1- C(7)H(15)-N4-(CH(2))(2)C(m)F(2)(m)(+ 1)-Taz Y (m = 1, 4, 6; Y = NTf(2)), N1-C(10)H(21)-N4-(CH(2))(2)C(m)F(2)(m)(+1)-Taz Y (n = 1, 4; Y = NTf(2)), N1-C(n)H(2)(n )(+ 1)-N4-(CH(2))(2)F-Taz Y (n = 7, 10; Y = NTf(2)), N1-C(10)H(21)-N4-(CH(2))(2)F-TazY (Y = OTf), N1-C(7)H(15)-N4-(CH(2))(2)F-TazY (Y = BF(4)), N1-C(4)H(9)-N4-(CH(2))(2)C(m)F(2)(m) (+ 1)-Taz Y (m = 4, 6; Y = PF(6)), N1-C(7)H(15)-N4-(CH(2))(2)C(4)F(9)-Taz Y (Y = PF(6)), N1-C(4)H(9)-N4-(CH(2))(2)C(m)F(2)(m)(+ 1)-Taz Y (m = 4, 6; Y = OTf). All new compounds were characterized by (1)H, (19)F, and (13)C NMR and MS spectra and elemental analyses. T(g)s and T(m)s of ionic liquids were determined by DSC.

Journal Article↗
PubMed2003

Phase-transfer-catalyzed alkylation of guanidines by alkyl halides under biphasic conditions: a convenient protocol for the synthesis of highly functionalized guanidines.

An operationally straightforward and efficient method for the alkylation of carbamate-protected guanidines with various alkyl halides and mesylates is described. This protocol proceeds via deprotonation of the acidic N-carbamate hydrogen of the guanidine under biphasic conditions using a catalytic amount of a tetrabutylammonium salt as a phase-transfer catalyst. In this manner, highly functionalized guanidines can be obtained. The reaction is tolerant of a wide range of functional groups on both the alkyl halide and guanidine component. In addition, the reaction is sufficiently mild such that simple aqueous workup and filtration through a short silica gel column yields the substituted guanidines in high purity. In conjunction with the EDCI-mediated guanylation of disubstituted thioureas with amines, phase-transfer catalyzed alkylation of guanidines via a one-pot, three-component synthesis of substituted guanidines was achieved.

Journal Article↗
PubMed2003

Conformational analysis of p-tert-butylcalix[4]arene derivatives with trans-alkyl substituents on opposite methylene bridges: destabilization of the cone form by axial alkyl substituents.

The stereochemistry of calix[4]arenes substituted by a pair of identical alkyl substituents in a trans fashion at two distal bridges is analyzed. MM3 calculations suggest that increasing the bulk of the alkyl group at the bridges destabilizes those conformations possessing an axial disposition of the substituent. In contrast to the 1,3-dimethyl ether of p-tert-butylcalix[4]arene, which adopts a cone conformation, solution NMR data indicate that the 1,2-alternate conformation is preferred in the dimethyl ether derivatives 5b (alkyl = i-Pr) and 5c (alkyl = t-Bu). In the derivative substituted by the less bulky methyl substituent (5a), both the cone and 1,2-alternate forms coexist in CDCl3. Increasing the polarity of the solvent increases the relative population of the cone form of 5a and 5b. The steric destabilization ensuing from the presence of the axial substituent is so large in the cone conformation of 5c that the 1,2-alternate conformer is the major form even in polar solvents. The cone --> 1,2-alternate interconversion barrier of 5a is 18.2 kcal mol(-1), indicating that the presence of an axial methyl group both destabilizes the cone conformation and decreases its rigidity.

Journal Article↗
PubMed2005

Room-temperature Negishi cross-coupling of unactivated alkyl bromides with alkyl organozinc reagents utilizing a Pd/N-heterocyclic carbene catalyst.

A high-yielding cross-coupling reaction of unactivated alkyl bromides possessing beta-hydrogens with alkylzinc halides utilizing a Pd/N-heterocyclic carbene (NHC) catalyst at room temperature is described. A variety of Pd sources, Pd2(dba)3, Pd(OAc)2, or PdBr2, with the commercially available ligand precursor 1,3-bis(2,6-diisopropylphenyl)imidazolium chloride (IPr.HCl) successfully coupled 1-bromo-3-phenylpropane with n-butylzinc bromide in THF/NMP. An investigation of different NHC precursors showed that the bulky 2,6-diisopropylphenyl moiety was necessary to achieve high coupling yields (75-85%). The corresponding ethyl analogue was moderately active (11%). A range of unsymmetrical NHC precursors were prepared and evaluated. The ligand precursor containing one 2,6-diisopropylphenyl and one 2,6-diethylphenyl afforded the coupling product in 47% yield, clearly suggesting a direct relationship between the steric topography created by the flanking N-substituents and catalyst activity. Under optimal conditions, a number of alkyl bromides and alkylzinc halides possessing common functional groups (amide, nitrile, ester, acetal, and alkyne) were effectively coupled (61-92%). It is noteworthy that beta-substituted alkyl bromides and alkylzinc halides successfully underwent cross-coupling. Also, under these conditions alkyl chlorides were unaffected.

Journal Article↗
PubMed1996

Novel and Efficient Insertions of Carbons Carrying O-, S-, and N-Linked Substituents: Synthesis of alpha-Alkoxyalkyl, alpha-(Alkylthio)alkyl, and alpha-(Carbazol-9-yl)alkyl Ketones.

A wide variety of benzotriazolyl-stabilized anions 2, obtained by the lithiation of 1-(alpha-alkoxyalkyl)-, 1-[alpha-(alkylthio)alkyl]-, and 1-[alpha-(carbazol-9-yl)alkyl]benzotriazoles 1, on reaction with aliphatic and aromatic aldehydes and ketones, followed by rearrangement induced by heating in the presence of zinc bromide, furnish one-carbon-homologated alpha-alkoxyalkyl, alpha-(alkylthio)alkyl, and alpha-(carbazol-9-yl)alkyl ketones 4 in simple one-pot operations in good yields with excellent regioselectivity. In several alkoxymethylene insertions, intermediate 2-alkoxyoxiranes were separated in good yields, demonstrating the epoxide mechanism for the rearrangements and providing a facile approach to polysubstituted 2-alkoxyoxiranes, another class of important compounds.

Journal Article↗
PubMed2003

Influence of lipophilicity on the interactions of N-alkyl-4-phenyl-1,2,3,6-tetrahydropyridines and their positively charged N-alkyl-4-phenylpyridinium metabolites with cytochrome P450 2D6.

The relationship between lipophilicity and CYP2D6 affinity of cyclic tertiary (N-alkyl-4-phenyl-1,2,3,6-tetrahydropyridines) and quaternary (N-alkyl-4-phenylpyridinium) amines was examined. The 1,2,3,6-tetrahydropyridine scaffold was chosen due to its common occurrence in the structures of CYP2D6 ligands such as the Parkinsonian neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) and the dehydrated haloperidol metabolite N-[4-(4-fluorophenyl)-4-oxobutyl]-4-(4-chlorophenyl)-1,2,3,6-tetrahydropyridine (HPTP). Likewise, the pyridinium framework is found in and 4-(4-chlorophenyl)-1-[4-(4-fluorophenyl)-4-oxobutyl]pyridinium and N-methyl-4-phenylpyridinium (MPP(+)), the positively charged metabolites of MPTP and haloperidol. The lack of CYP2D6 inhibition by MPTP and its pyridinium metabolite MPP(+) was due to their hydrophilic nature since higher N-alkyl homologs revealed substantial increases in inhibitory potency against recombinant CYP2D6-mediated bufuralol-1'-hydroxylation. The reasonable correlation between lipophilicity and CYP2D6 inhibition by pyridiniums and 1,2,3,6-tetrahydropyridines was only limited to straight chain N-alkyl analogs, since certain N-alkylaryl analogs of lower lipophilicity were better CYP2D6 inhibitors. CYP2D6 substrate properties of straight chain N-alkyltetrahydropyridines were also governed by lipophilicity, and N-heptyl-4-phenyl-1,2,3,6-tetrahydropyridine was the optimal substrate (K(mapp) = 0.63 microM). Metabolism studies indicated that the N-heptyl analog underwent monohydroxylation on the aromatic ring and on the N-heptyl group suggesting that 1,2,3,6-tetrahydropyridines can bind in more than one conformation in the CYP2D6 active site. Increased lipophilicity of haloperidol metabolites did not correlate with inhibitory potency since the more lipophilic HPTP metabolite was less potent as an inhibitor than reduced-haloperidol and reduced-HPTP. Furthermore, HPTP and reduced-HPTP, of comparable lipophilicity to the N-heptyltetrahydropyridine analog were inactive as CYP2D6 substrates. This observation suggests that steric constraints rather than lipophilicity are responsible for the lack of CYP2D6 substrate properties of cyclic tertiary amines tethered to bulky N-substituents. This phenomenon appears to be a common theme among several cyclic tertiary amine-containing anti-depressants and should be taken into consideration when designing central nervous system agents devoid of CYP2D6 substrate properties.

Catalysis↗
PubMed2006

Infrared and Raman spectroscopy study of alkyl hydroxamic acid and alkyl hydroxamate isomers.

The isomeric structures of alkyl hydroxamic acid, as well as its potassium salt, sodium salt, and an alcohol complex, have been characterized in the solid, liquid, and gaseous states by Fourier transform infrared (FT-IR) and FT-Raman spectroscopy. Raman spectroscopy provides insight into the long-standing debate over the isomeric composition of hydroxamates in the solid state and in an aqueous basic solution. IR and Raman results are not consistent with the enol isomer existing in the solid or liquid states of octyl or decyl hydroxamic acid, potassium hydroxamate, and sodium hydroxamate. The infrared and Raman spectra of these compounds provide clear and convincing evidence regarding their chemical structure, mainly from amide-type carbonyl, NH bending, and OH/NH stretching bands. Vibrational spectroscopy is sensitive to polar (FT-IR) and non-polar (FT-Raman) vibrations and the influence of ionic and hydrogen bonding on these vibrations, and these abilities are particularly useful for characterizing keto versus enol and trans versus cis conformations in alkyl hydroxamic acid and its salts. Evolved gas analysis (EGA) in a nitrogen gas environment of alkyl hydroxamic acid and its salts is also discussed. EGA data reveal that water is not incorporated into the solid-state crystal structure of alkyl hydroxamic acid or the potassium salt; however, the sodium salt form is found to have a stable hydrate conformer that is shown to affect the Z isomer (NH trans to carbonyl, OH cis to carbonyl) IR absorbance bands. EGA data also indicates results that could be of interest to bio-pharmaceutical applications involving nitric oxide donation.

Hydroxamic Acids↗
PubMed1987

Sensitivity of leukemia cell lines to cytotoxic alkyl-lysophospholipids in relation to O-alkyl cleavage enzyme activities.

The human leukemia cell lines K562, HL60, and Raji and the mouse leukemia cell line L1210 showed a differential susceptibility to the action of the alkyl-lysophospholipid (ALP) 1-octadecyl-2-methyl-rac-glycero-3-phosphocholine (ET-18-OCH3). After 48 hours, the 50% growth-inhibition doses (ID50) of ET-18-OCH3 were found to be 0.78 microgram/ml (HL60), 1.53 microgram/ml (Raji), 4.41 micrograms/ml (K562), and 5.05 micrograms/ml (L1210), as determined by [3H]thymidine incorporation. At the same time, cell viability was determined by trypan blue exclusion and revealed median lethal doses (LD50) of 3.5 micrograms/ml (HL60), 15 micrograms/ml (Raji), 24 micrograms/ml (L1210), and 38 micrograms/ml (K562). Since O-alkyl cleavage enzyme previously was suggested as being important in the detoxification of cytotoxic ALPs, the enzyme activity was compared with the susceptibility to ET-18-OCH3 in the distinct cell lines. In comparison to an approximate sevenfold to elevenfold (ID50 and LD50, respectively) difference in the susceptibility of the above leukemia cell lines to ET-18-OCH3, no significant difference in the specific activities (0.13-0.21 nmol/min/mg) of the O-alkyl cleavage enzyme was found in the above leukemia cell lines. Therefore, the differential sensitivity of the above lines investigated cannot be explained by differences in O-alkyl cleavage enzyme activity. Experiments with radiolabeled ET-18-OCH3 in Raji cells suggest, rather, a critical role for phospholipases C and/or D in ALP metabolism.

Animals↗
PubMed1980

Mild alkali-stable phospholipids in chicken egg yolks: characterization of 1-alkenyl and 1-alkyl-sn-glycero-3-phosphoethanolamine, sphingomyelin, and 1-alkyl-sn-glycero-3-phosphocholine.

Chicken egg yolk phospholipids were subjected to mild alkaline hydrolysis. The resulting alkali-stable phospholipids were characterized by chemical chromatographic, and enzymatic methods. Two major phospholipids, 1 - O - alkyl - sn - glycero - 3 - pohosphoethanolamine and sphingomyelin; and two minor phospholipids, 1-O-alkenyl-sn-glycero-3-phosphoethanolamine and 1-O-alkyl-sn-glycero-3-phosphocholine; were identified. The sphingomyelins were converted into ceramides by enzymatic hydrolysis with phospholipase C. Ceramides derived from sphingomyelins with non-hydroxy fatty acids (99% of total ceramides) consisted predominantly of the N-palmitoyl, N-stearoyl, and N-nervonyl species. Ceramides derived from sphingomyelins with hydroxy fatty acids (1% of total ceramides) consisted almost exclusively of the N-alpha-hydroxyeicosanoyl species. The long chain bases of ceramides derived from both species of sphingomyelins (hydroxy and non-hydroxy fatty acids) consisted of 97% D-erythro-sphing-4-enine and 3% D-erythro-sphinganine, 1-O-alkyl-sn-glycero-3-phosphoethanolamine and 1-O-alkyl-sn-glycero-3-phosphocholine were converted to corresponding 1-O-alkyldiacetylglycerols. The 1-O-alkyldiacetylglycerols derived from both ether phospholipids consisted largely of the hexadecyl and octadecyl species. Smaller quantities of the heptadecyl, cis-9-octadecenyl and eicosanyl derivatives were also present.

Animals↗
PubMedDate not supplied

Induction of a protective immunity in mice against Escherichia coli by phenothiazines, 10-[n-(phthalimido)alkyl]-2-substituted-10H-phenothiazines and 1-(2-chloroethyl)-3-(2-substituted-10H-phenothiazines-10-yl)alkyl-1 -ureas .

Abilities of five phenothiazines, six 10-[n-(phthalimido)alkyl]-2-substituted-10H-phenothiazines and six 1-(2-chloroethyl)-3-(2-substituted-10H-phenothiazines-10-yl)alkyl-1- ureas to induce anti-Escherichia coli activity in mice were compared. Seventeen compounds tested in this study had no antibacterial effect in direct contact with Escherichia coli using the disk diffusion method except chlorpromazine (4) with low growth inhibitory action. The pretreatment of mice with several phenothiazines, 10-[n-(phthalimido)alkyl]-2-substituted-10H-phenothiazines or 1-(2-chloroethyl)-3-(2-substituted-10H-phenothiazines-10-yl)alkyl-1- ureas protected the animals from lethal infection of Escherichia coli to various extents. On the basis of these experiments, we assume that the protective effect against Escherichia coli infection might be due to the immunopotentiation or macrophage inducing activity by the compounds, or inactivation of lymphokines induced by the bacteria. Since the infection preventing effect of the tested phenothiazines depends on the chemical structures, the specificity of the biological process can be assumed.

Animals↗
PubMed1982

Correlation of alkylating and mutagenic activities of allyl and allylic compounds: standard alkylation test vs. kinetic investigation.

Thirty-nine allylic and non-allylic compounds have been tested in the standard 4-(p-nitrobenzyl)pyridine (NBP) alkylating procedure and the Salmonella typhimurium mutagenicity assay. Fourteen of these were found directly mutagenic (without addition of S-9 mix activating enzyme system). With twelve of these compounds, a good correlation of alkylating and mutagenic potencies was established; the remaining two do not meet the chemical conditions of the NBP procedure on account of HCl elimination with these two compounds. The other 25 substances were inactive in both systems. The quantitative correlation proved to be almost linear in the lower activity ranges (E approximately 2; revertants/muml approximately 600). The reasons for some deviations from the linear relationship have been analyzed and discussed on the basis of structural features. In addition to the standard alkylation test, a modified NBP-test was performed in order to obtain kinetic data and activation energy values. The results with 6 representative allylic compounds show that the overall correlation is not substantially improved above that of the standard procedure: nonetheless, additional information on reaction characteristics is obtained with some substances.

Alkylating Agents↗
PubMed1990

Distribution of methyl and ethyl adducts following alkylation with monofunctional alkylating agents.

Alkylating agents, because of their ability to react directly with DNA either in vitro or in vivo, or following metabolic activation as in the case of the dialkylnitrosamines, have been used extensively in studying the mechanisms of mutagenicity and carcinogenicity. Their occurrence is widespread in the environment and human exposure from natural and pollutant sources is universal. Since most of these chemicals show varying degrees of both carcinogenicity and mutagenicity, and exhibit compound-specific binding patterns, they provide an excellent model for studying molecular dosimetry. Molecular dosimetry defines dose as the number of adducts bound per macromolecule and relates the binding of these adducts to the human mutagenic or carcinogenic response. This review complies DNA alkylation data for both methylating and ethylating agents in a variety of systems and discusses the role these alkylation products plays in molecular mutagenesis.

Alkylating Agents↗
PubMed1979

Fluoride ion catalyzed alkylation of nucleic acid derivatives using trialkyl phosphates, dialkyl sulfates and alkyl methanesulfonates.

Trimethyl phosphate, dimethyl and diethyl sulfate and methyl and ethyl methanesulfonate all give high yields of alkylation on purines and pyrimidines in the presence of tetrabutylammonium fluoride. Trimethyl phosphate produces near quantitative yields of diesters of nucleic acids but gives virtually no triester formation. The alkyl sulfates produce very high yields of triesters of nucleic acids including cyclic phosphates while the alkyl methanesulfonates are intermediate in reactivity. It was observed that in the absence of fluoride ion the dialkylsulfates gave reasonable yields of thymidine monosulfates.

Alkylating Agents↗
PubMed1996

Effect of alkyl substitution at the amide nitrogen on amide bond cleavage: electrospray ionization/surface-induced dissociation fragmentation of substance P and two alkylated analogs.

Doubly protonated substance P and two analogs alkylated at the ninth position was studied to determine the effect of N-alkylation of the amide nitrogen on the electrospray ionization/surface-induced dissociation (ESI/SID) fragmentation pattern. Thermal decomposition experiments and ab initio calculations were also used in conjunction with the ESI/SID experiments. The increase in relative abundances of the product ions resulting from the cleavage of the amide bond at the alkylation site (relative to the corresponding cleavage for substance P) can be explained by the increased basicity of the amide nitrogen in the context of the 'mobile proton' model. The relative abundances of singly charged b ions suggest a rearrangement of the amide hydrogen located N-terminal to the bond cleaved.

Alkylation↗
PubMed1995

Expression of the human MGMT O6-methylguanine DNA methyltransferase gene in a yeast alkylation-sensitive mutant: its effects on both exogenous and endogenous DNA alkylation damage.

Common Mer- cell lines deficient in O6-methylguanine DNA methyltransferase (MTase) activity probably result from the down-regulation of, rather than mutations in, the MGMT gene. However, the down-regulation of other unrelated genes was also observed in some of these cell lines, making it difficult to determine the precise functions of the MGMT MTase gene. To study the biological function of human MGMT MTase, we seek to utilize a newly created yeast mgt1 mutant deficient in the DNA repair MTase activity. The human MGMT cDNA was cloned into yeast expression vectors so that the MGMT gene is under the control of either an inducible GAL1 promoter or a constitutive ADH1 promoter. Upon galactose induction, the PGAL1-MGMT transformant had about 40-fold MTase activity compared to the wild-type strain. MGMT overexpression protected the yeast mgt1 mutant against alkylation-induced killing and mutation. Limited expression of the MGMT gene in the mgt1 mutant still provides significant alkylation resistance, albeit at a reduced level. The yeast mgt1 mutants increase spontaneous mutation rate, whereas constitutive expression of the MGMT gene lowered the spontaneous mutation rate in the mgt1 mutant to the wild-type level. We suggest that MGMT MTase may play the same role in human cells as the MGT1 MTase in yeast cells. Thus our results demonstrate that the human MGMT gene functionally complements the yeast MTase-deficient mutant in the protection against exogenous and endogenous DNA alkylation damage, which provides a useful tool for the study of in vivo mammalian MTase functions.

Alkylation↗
PubMed1996

Conformational change in human DNA repair enzyme O6-methylguanine-DNA methyltransferase upon alkylation of its active site by SN1 (indirect-acting) and SN2 (direct-acting) alkylating agents: breaking a "salt-link".

Human O6-methylguanine-DNA methyltransferase (MGMT) repairs DNA by transferring alkyl (R-) adducts from O6-alkylguanine (6RG) in DNA to its own cysteine residue at codon 145 (formation of R-MGMT). We show here that R-MGMT in cell extracts, which is sensitive to protease V8 cleavage at the glutamic acid residues at codons 30 (E30) and 172 (E172), can be specifically immunoprecipitated with an MGMT monoclonal antibody, Mab.3C7. This Mab recognizes an epitope of human MGMT including the lysine 107 (K107) which is within the most basic region that is highly conserved among mammalian MGMTs. Surprisingly, the K107L mutant protein is repair-deficient and readily cleaved by protease V8 similar to R-MGMT. We propose that R-MGMT adopted an altered conformation which exposed the Mab.3C7 epitope and rendered that protein sensitive to protease V8 attack. This proposal could be explained by the disruption of a structural "salt-link" within the molecule based on the available structural and biochemical data. The specific binding of Mab.3C7 to R-MGMT has been compared with the protease V8 method in the detection of R-MGMT in extracts of cells treated with low dosages of methyliodide (SN2) and O6-benzylguanine. Their identical behaviors in producing protease V8 sensitive R-MGMT and Mab.3C7 immunoprecipitates suggest that probably methyl iodide (an ineffective agent in producing 6RG in DNA) can directly alkylate the active site of cellular MGMT similar to O6-benzylguanine. The effectiveness of MeI in producing R-MGMT, i.e., inactivation of cellular MGMT, indicates that this agent can increase the effectiveness of environmental and endogenously produced alkylating carcinogens in producing the mutagenic O6-alkylguanine residues in DNA in vivo.

Alkylating Agents↗
PubMed2004

Diastereoselective alkylation of beta-amino esters: structural and rate studies reveal alkylations of hexameric lithium enolates.

Alkylation of beta-amino ester enolates proceeds with high diastereoselectivity. Single crystal, powder, and solution X-ray diffraction studies of the enolate show that the racemic enolate forms prismatic hexamers. 6Li NMR spectroscopic studies on partially racemic enolates reveal complex mixtures of homo- and heterochiral hexamers. An implicit fit of the aggregate populations to the Boltzmann distribution provides the free energy differences and equilibrium constants for the ensemble. Rate studies show that enolate alkylation occurs directly from the hexamer with participation by THF. A mechanism based on the alkylation of a ladder-like aggregate is proposed.

Alkylation↗