Lithium hexamethyldisilazide/triethylamine-mediated ketone enolization: remarkable rate accelerations stemming from a dimer-based mechanism

Mechanistic studies of the enolization of 2-methylcyclohexanone mediated by lithium hexamethyldisilazide (LiHMDS; TMS2NLi) in toluene and toluene/triethylamine (Et3N) mixtures are described. Structural studies of LiHMDS/ketone mixtures in toluene reveal cyclic dimer (TMS2NLi)2(ketone). Rate studies using in situ IR spectroscopy show the enolization proceeds via a dimer-based transition structure, [(TMS2NLi)2(ketone)]. NMR spectroscopic studies of LiHMDS/ketone mixtures in the presence of relatively unhindered trialkylamines such as Me2NEt reveal the quantitative formation of cyclic dimers of general structure (TMS2NLi)2(Et3N)(ketone). Rate studies trace a >3000-fold rate acceleration to a dimer-based transition structure, [(TMS2NLi)2(Et3N)(ketone)].     

Ketone enolization by lithium hexamethyldisilazide: structural and rate studies of the accelerating effects of trialkylamines

Mechanistic studies of the enolization of 2-methylcyclohexanone mediated by lithium hexamethyldisilazide (LiHMDS; TMS2NLi) in toluene and toluene/amine mixtures are described. NMR spectroscopic studies of LiHMDS/ketone mixtures in toluene reveal the ketone-complexed cyclic dimer (TMS2NLi)2(ketone). Rate studies using in situ IR spectroscopy show the enolization proceeds via a dimer-based transition structure, [(TMS2NLi)2(ketone)]++. NMR spectroscopic studies of LiHMDS/ketone mixtures in the presence of relatively unhindered trialkylamines such as Me2NEt reveal the quantitative formation of cyclic dimers of general structure (TMS2NLi)2(R3N)(ketone). Rate studies trace a >200-fold rate acceleration to a dimer-based transition structure, [(TMS2NLi)2(R3N)(ketone)]++. Amines of intermediate steric demand, such as Et3N, are characterized by recalcitrant solvation, saturation kinetics, and exceptional (>3000-fold) accelerations traced to the aforementioned dimer-based pathway. Amines of high steric demand, such as i-Pr2NEt, do not observably solvate (TMS2NLi)2(ketone) but mediate enolization via [(TMS2NLi)2(R3N)(ketone)]++ with muted accelerations. The most highly hindered amines, such as i-Bu3N, do not influence the LiHMDS structure or the enolization rate. Overall, surprisingly complex dependencies of the enolization rates on the structures and concentrations of the amines derive from unexpectedly simple steric effects. The consequences of aggregation, mixed aggregation, and substrate-base precomplexation are discussed.     

Reaction of ketones with lithium hexamethyldisilazide: competitive enolizations and 1,2-additions

Reaction of 2-methylcyclohexanone with lithium hexamethyldisilazide (LiHMDS, TMS(2)NLi) displays highly solvent-dependent chemoselectivity. LiHMDS in THF/toluene effect enolization. Rate studies using in situ IR spectroscopy are consistent with a THF concentration-dependent monomer-based pathway. LiHMDS in pyrrolidine/toluene affords exclusively 1,2-addition of the pyrrolidine fragment to form an alpha-amino alkoxide-LiHMDS mixed dimer shown to be a pair of conformers by using (6)Li, (15)N, and (13)C NMR spectroscopies. Rate studies are consistent with a monomer-based transition structure [(TMS(2)NLi)(ketone)(pyrrolidine)(3)](). The partitioning between enolization and 1,2-addition is kinetically controlled.     

Lithium hexamethyldisilazide-mediated ketone enolization: the influence of hindered dialkyl ethers and isostructural dialkylamines on reaction rates and mechanisms

Mechanistic studies of the enolization of 2-methylcyclohexanone mediated by lithium hexamethyldisilazide (LiHMDS; TMS(2)NLi) solvated by hindered dialkyl ethers (ROR') are described. Rate studies using in situ IR spectroscopy show that enolizations in the presence of i-Pr(2)O, 2,2,5,5-tetramethyltetrahydrofuran, and cineole proceed via dimer-based transition structures [(TMS(2)NLi)(2)(ROR')(ketone)]. Comparing the relative solvation energies and the corresponding solvent-dependent activation energies shows that the highly substituted ethers accelerate the enolizations by sterically destabilizing the reactants and stabilizing the transition structures. Comparisons of hindered dialkyl ethers with their isostructural dialkylamines reveal that the considerably higher rates elicited by the amines derive from an analogous relative destabilization of the reactants and relative stabilization of the transition structures.     

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.     

Lithium hexamethyldisilazide-mediated enolizations: influence of chelating ligands and hydrocarbon cosolvents on the rates and mechanisms

Enolizations of 2-methylcyclohexanone by lithium hexamethyldisilazide (LiHMDS) in the presence of three chelating ligands--trans-N,N,N',N'-tetramethylcyclohexanediamine, N,N,N',N'-tetramethylethylenediamine, and dimethoxyethane--reveal an approximate 40-fold range of rates. NMR spectroscopic analyses and rate studies reveal isostructural transition structures based on monomeric LiHMDS for the diamines. Rate studies of LiHMDS/dimethoxyethane-mediated enolizations implicate a substantial number of monomer- and dimer-based mechanisms. The rate laws vary for the three ligands because of ligand-dependent structural differences in both the reactants and the transition structures. The importance of LiHMDS-ketone complexes and the role of hydrocarbon cosolvents are discussed.     

Characterization of beta-amino ester enolates as hexamers via 6Li NMR spectroscopy

Low-temperature 6Li NMR spectroscopic studies on a chiral beta-amino ester enolate reveal a complex mixture of homo- and heterochiral aggregates. Subsequent warming of the samples led to rapid intra-aggregate exchange, resulting in four distinct resonances consistent with an ensemble of hexamers. An implicit fit of the aggregate populations to the Boltzmann distribution provided the free energy differences and equilibrium constants. An X-ray crystal structure obtained from the racemic enolate is consistent with the predominant aggregate in solution.     

Lithium diisopropylamide-mediated enolization: catalysis by hemilabile ligands

Structural, kinetic, and computational studies reveal the mechanistic complexities of a lithium diisopropylamide (LDA)-mediated ester enolization. Hemilabile amino ether MeOCH2CH2NMe2, binding as an eta1 (ether-bound) ligand in the reactant and as an eta2 (chelating) ligand in the transition structure, accelerates the enolization 10,000-fold compared with n-BuOMe. At the onset of the reaction, a dimer-based enolization prevails. As the reaction proceeds, significantly less reactive LDA-enolate mixed dimers appear and divert the reaction through monomer- and mixed dimer-based pathways. The mechanistic and computational investigations lead to a proof-of-principle ligand-catalyzed enolization in which an ancillary ligand allows the catalytic ligand to re-enter the catalytic cycle.     

Asymmetric synthesis of alpha-substituted beta-amino ketones from sulfinimines (N-sulfinyl imines). synthesis of the indolizidine alkaloid (-)-223A

Of the possible four stereoisomers, addition of the lithium enolate of 4-heptanone to sulfinimines resulted in only the syn- and anti-alpha-substituted beta-amino ketones. The formation of the major syn-beta-amino ketone was rationalized in terms of addition of the E-enolate to the C-N double bond of the sulfinimine via a six-member chelated chairlike transition state. The enolates of 4-heptanone were generated using LiHMDS in THF where a 1:2.5 E:Z enolate ratio was noted. In diethyl ether the E:Z ratio was 15:1 in favor of the E-enolate and explained in terms of Ireland's transition state model. Here increased steric interactions between the ethyl group and the carbonyl-LiN(TMS)(2) moiety destabilize the transition state leading to the Z-enolate in the poorly coordinating diethyl ether solvent. This new synthesis of syn-alpha-substituted-beta-amino ketones was applied to the concise enantioselective total synthesis of indolizidine (-)-223A, a 5,6,8-trisubstituted alkaloid isolated from the skin of the dendrobatide frog.     

Asymmetric synthesis of beta-amino carbonyl compounds with N-sulfinyl beta-amino Weinreb amides

[reaction: see text] Diverse organometallic reagents readily add to enantiopure N-sulfinyl beta-amino Weinreb amides providing the corresponding, stable, N-sulfinyl beta-amino carbonyl compounds in good to excellent yields. This new methodology represents a general solution to the problem of beta-amino carbonyl syntheses, which are important chiral building blocks and constituents of natural products. N-Sulfinyl beta-amino Weinreb amides are prepared by reaction of the potassium enolate of N-methoxy N-methylacetamide with sulfinimines (N-sulfinyl imines) or lithium N,O-dimethylhydroxylamine with N-sulfinyl beta-amino esters.     

Efficient one-pot selective reduction of esters in β-ketoesters using LiHMDS and lithium aluminium hydride

The ester functionality in β-keto esters is selectively reduced in one-pot, first by enolization using LiHMDS and then reduced with lithium aluminium hydride. This method produces β-hydroxyl ketones from the corresponding β-keto esters in high yield.     

The Rearrangement of 2-Carbomethoxy-2-Phenylselenocyclohexanone1

In connection with a total synthetic study we prepared 2-carbomethoxy-2-phenylselenocyclohexanone (2)² and attempted to alkylate the ketone at the 6-position. However, to our surprise, base-promoted enolization with lithium diisopropyl amide (LDA) led to some rearrangement to the lithium enolate of 2-carbomethoxy-6-phenyl-selenocyclohexanone (3).     

Ketone enolization with lithium dialkylamides: the effects of structure,solvation, and mixed aggregates with excess butyllithium

The effects of lithium dialkylamide structure, mixed aggregate formation, and solvation on the stereoselectivity of ketone enolization were examined. Of the lithium dialkylamides examined, lithium tetramethylpiperidide (LiTMP) in THF resulted in the best enolization selectivity. The stereoselectivity was further improved in the presence of a LiTMP-butyllithium mixed aggregate. The use of less polar solvents reduced the enolization stereoselectivity. Ab initio calculations predict LDA and LiTMP to form mixed cyclic dimers in ethereal solvents. The calculations also predict LiTMP-alkyllithium mixed aggregates to competitively inhibit the formation of less stereoselective LiTMP-lithium enolate mixed aggregates.     

Urethane N-carboxyanhydrides from beta-amino acids

A general method has been developed for the synthesis of N-tert-butyloxycarbonyl N-carboxyanhydrides from beta-amino acids using Vilsmeier complex. These beta-UNCA are stable, and the reactivity with different nucleophiles (alcohol, amine, lithium enolate) was studied.     

Asymmetric synthesis of beta2-amino acids: 2-substituted-3-aminopropanoic acids from N-acryloyl SuperQuat derivatives

Conjugate addition of lithium dibenzylamide to (S)-N(3)-acryloyl-4-isopropyl-5,5-dimethyloxazolidin-2-one (derived from l-valine) and alkylation of the resultant lithium beta-amino enolate provides, after deprotection, a range of (S)-2-alkyl-3-aminopropanoic acids in good yield and high ee. Alternatively, via a complementary pathway, conjugate addition of a range of secondary lithium amides to (S)-N(3)-(2'-alkylacryloyl)-4-isopropyl-5,5-dimethyloxazolidin-2-ones, diastereoselective protonation with 2-pyridone, and subsequent deprotection furnishes a range of (R)-2-alkyl- and (R)-2-aryl-3-aminopropanoic acids in good yield and high ee. Additionally, the boron-mediated aldol reaction of beta-amino N-acyl oxazolidinones is a highly diastereoselective method for the synthesis of a range of beta-amino-beta'-hydroxy N-acyl oxazolidinones.     

Design and synthesis of a novel class of sugar-peptide hybrids: C-linked glyco beta-amino acids through a stereoselective "acetate" Mannich reaction as the key strategic element

A new type of sugar-amino acid hybrid, which is comprised of a sugar unit (gluco-, galacto-, or mannopyranose) linked through a C-glycosidic linkage to the beta-position of an alpha-unsubstituted beta-amino acid unit, is presented. It is hypothesized that these new compounds, or the oligomeric peptides derived therefrom, might possess the structural features of beta-amino acid oligomers and the chemical and enzymatic resistance of C-glycosides to hydrolysis. The synthetic strategy is based on a new Mannich-type reaction between a chiral acetate enolate equivalent and alpha-amido sulfones derived from the corresponding sugar-C-glycoside aldehydes. While the sugar-C-glycoside aldehyde partner is prepared from well-established transformations on known sugar precursors, the lithium enolate derived from (1R)-endo-2-acetylisoborneol 3 is employed as the key element. This Mannich approach proceeds with essentially perfect diasteromeric control leading to the new beta-amino carbonyl adducts in good yields. Further, cleavage of the camphor auxiliary is smoothly performed by oxidative treatment with ammonium cerium nitrate (CAN). Complementarily, direct peptide-type coupling of the beta-amino carbonyl Mannich adducts with an alpha- or beta-amino acid residue and subsequent CAN-promoted detachment of the auxiliary yields dipeptide fragments bearing a sugar-containing aliphatic side chain and is a process that can be iterated. A preliminary conformational study based on the combination of experimental NMR data and molecular mechanics and molecular dynamics (MD) of one particular adduct is also provided.     

Stereoselective enolizations mediated by magnesium and calcium bisamides: contrasting aggregation behavior in solution and in the solid state

The reactions of magnesium and calcium bis(hexamethyldisilazide) with propiophenone have been studied with a view to determine the utility of these bases in the stereoselective enolization of ketones and to uncover the nature of the metal enolate intermediates produced. Both base systems are highly Z-selective when the reactions are conducted in the presence of polar solvents. However, in situ monitoring of the magnesium system in arene solution revealed a preference for E-enolate formation, which was confirmed by silyl enol ether trapping studies. Solution NMR studies of the magnesium system in toluene-d8 show the presence of a monomer-dimer equilibrium for the intermediate amidomagnesium enolates. This assignment is supported by the characterization of a disolvated amidomagnesium enolate dimer by crystallographic analysis. Comparative studies of the calcium system show distinctly different behavior. This is exemplified by the characterization of a novel solvent-separated ion pair complex and a monomeric amidocalcium enolate in the solid state. Solution NMR studies of the calcium system in pyridine-d5 reveal the co-existence of the heteroleptic amidocalcium enolate, the bisamide, the bisenolate and the ion pair complex.     

Kinetics and mechanism of ketone enolization mediated by magnesium bis(hexamethyldisilazide)

Magnesium bis(hexamethyldisilazide), Mg(HMDS)(2), reacts with substoichiometric amounts of propiophenone in toluene solution at ambient temperature to form a 74:26 mixture of the enolates (E)- and (Z)-[(HMDS)(2)Mg(2)(mu-HMDS){mu-OC(Ph)=CHCH(3)}], (E)-1 and (Z)-1, which contain a pair of three-coordinate metal centers bridged by an amide and an enolate group. The compositions of (E)-1 and (Z)-1 were confirmed by solution NMR studies and also by crystallographic characterization in the solid state. Rate studies using UV-vis spectroscopy reveal the rapid and complete formation of a reaction intermediate, 2, between the ketone and magnesium, which undergoes first-order decay with rate constants independent of the concentration of excess Mg(HMDS)(2) (DeltaH++ = 17.2 +/- 0.8 kcal/mol, DeltaS++ = -11 +/- 3 cal/mol.K). The intermediate 2 has been characterized by low-temperature (1)H NMR, diffusion-ordered NMR, and IR spectroscopy and investigated by computational studies, all of which are consistent with the formulation of 2 as a three-coordinate monomer, (HMDS)(2)Mg{eta(1)-O=C(Ph)CH(2)CH(3)}. Further support for this structure is provided by the synthesis and structural characterization of two model ketone complexes, (HMDS)(2)Mg(eta(1)-O=C(t)Bu(2)) (3) and (HMDS)(2)Mg{eta(1)-O=C((t)Bu)Ph} (4). A large primary deuterium isotope effect (k(H)/k(D) = 18.9 at 295 K) indicates that proton transfer is the rate-limiting step of the reaction. The isotope effect displays a strong temperature dependence, indicative of tunneling. In combination, these data support the mechanism of enolization proceeding through the single intermediate 2 via intramolecular proton transfer from the alpha carbon of the bound ketone to the nitrogen of a bound hexamethyldisilazide.     

BH3-catalyzed oligomerization of ethyl diazoacetate: the role of C-boron enolates

In contrast to trialkyl boranes, the reaction of borane (BH3) and ethyl diazoacetate (EDA) generates dimer, trimer, and oligomers of EDA. The products arise from double, triple, and multiple insertions of CHCO2Et groups in B-C bonds. On the basis of NMR spectroscopic data, trapping experiments, and computational studies, a novel C-boron enolate has been identified as a key intermediate in this reaction. This C-boron enolate species is calculated to be 7.1 kcal/mol (gas phase) more stable than its isomeric O-boron enolate form. Both spectroscopic data and trapping results also reveal the formation of a doubly borylated enolate generated as a side product by a proton transfer between the C- and O-boron monoenolates.