Crystallization-induced Asymmetric Transformation Research Articles

Attrition-Enhanced Asymmetric Transformation of Axially Chiral Nicotinamides by Dynamic Chiral Salt Formation.

Atroposelective resolution for axially chiral nicotinamides was achieved by dynamic chiral salt formation with L-DBTA using six types of nicotinamides that could not be optically resolved by the preferential crystallization method. Kinetic studies of their racemization indicated that the chiral conformation was retained for a significant period of time. Two methods of crystallization-induced asymmetric transformation were examined by dynamic diastereomeric salt formation: solvent evaporation from a supersaturated solution, and attrition-enhanced asymmetric transformation. The attrition method was more effective for asymmetric amplification of diastereomeric salts of axially chiral materials. Attrition of equimolar amount of the nicotinamide salts with L-DBTA converged to one diastereomer salts, and the corresponding enantiomers in 87-99 % ee were obtained after the chiral acid was removed. Changing the ratio of two of the nicotinamides with L-DBTA to 1 : 2 inverted the axial chirality.

A Crystallization-Induced Asymmetric Transformation using Racemic Phenyl Alanine Methyl Ester Derivatives as Versatile Precursors to Prepare Amino Acids

L-Tyrosine and L-Dopa are the precursors in the biological synthesis of amine neurotransmitters. On the other hand, phenylalanine as an aromatic amino acid (AAA) is a precursor in the synthesis of L-Tyrosine and L-Dopa. For some substrates such as amino acids, resolution by the formation of diastereomers offers an attractive alternative. Among different methods in this case, crystallization-induced asymmetric transformation (CIAT) that is in situ racemization and selective crystallization of a reaction product can be a good choice. Using this method, preparation of L-Tyrosine and L-Dopa has been reported. In the synthetic route, racemic phenyl alanine methyl ester derivatives as versatile precursors were prepared by reducing azlactone derivatives with Mg in methanol as a reducing reagent and then in the resolution step (S)- enantiomer of L-Dopa (3,4-dihydroxyphenylalanine) and L-Tyrosine (4-hydroxyphenylalanine) were achieved via salt formation with (2R,3R)-tartaric acid in the presence of 5-nitro salicylaldehyde in good yield and high optical purity.

Highly diastereoselective crystallization-induced asymmetric transformation of 1,3-disubstituted-tetrahydro-β-carbolines in water

A green and highly stereoselective method for the synthesis of cis or trans-1,3-disubstituted-tetrahydro-β-carbolines has been developed using water as the solvent.

Asymmetric Synthesis and Binding Study of New Long-Chain HPA-12 Analogues as Potent Ligands of the Ceramide Transfer Protein CERT.

A series of 12 analogues of the Cer transfer protein (CERT) antagonist HPA-12 with long aliphatic chains were prepared as their (1R,3S)-syn and (1R,3R)-anti stereoisomers from pivotal chiral oxoamino acids. The enantioselective access to these intermediates as well as their ensuing transformation relied on a practical crystallization-induced asymmetric transformation (CIAT) process. Sonogashira coupling followed by triple bond reduction and thiophene ring hydrodesulfurization (HDS) into the corresponding alkane moieties was then implemented to complete the synthetic routes delivering the targeted HPA-12 analogues in concise 4- to 6-step reaction sequences. Ten compounds were evaluated regarding their ability to bind to the CERT START domain by using the recently developed time-resolved FRET-based homogeneous (HTR-FRET) binding assay. The introduction of a lipophilic appendage on the phenyl moiety led to an overall 10- to 1000-fold enhancement of the protein binding, with the highest effect being observed for a n-hexyl residue in the meta position. The importance of the phenyl ring for the activity was indicated by the reduced potency of the 3-deoxyphytoceramide aliphatic analogues. The 1,3-syn stereoisomers were systematically more potent than their 1,3-anti analogues. In silico studies were used to rationalized these trends, leading to a model of protein recognition coherent with the stronger binding of (1R,3S)-syn HPAs.

Diastereomer Interconversion via Enolization: A Case Study.

The three-component reaction of indole, isobutyraldehyde, and methyl acetoacetate affords methyl 2-(acetyl)-3-(1H-indol-3-yl)-4-methylpentanoate as a single diastereomer. To investigate the origin of the observed diastereoselectivity, the thermodynamics and kinetics of interconversion of diastereomers 1 and 2 in solution were studied by a combination of (1)H nuclear magnetic resonance (NMR) spectroscopy, high-performance liquid chromatography (HPLC), mass spectrometry, and deuteration experiments. The results indicate that interconversion is both acid- and base-catalyzed, and that the alpha carbon is the only stereolabile center in the molecule. The evidence points to an enolization mechanism for the interconversion process. The selective precipitation of 1 in the presence of the equilibrium 1⇆2 eventually results in the exclusive formation of 1 (crystallization-induced asymmetric transformation).

The CERT antagonist HPA-12: First practical synthesis and individual binding evaluation of the four stereoisomers

The first unified synthetic route to the four enantiopure HPA-12 stereoisomers in multi-gram scale is reported based on Crystallization-Induced Asymmetric Transformation (CIAT) technology. This preparative stereoselective synthesis allowed the unprecedented comparative evaluation of HPA-12 stereoisomers regarding their interaction with the CERT START domain. In vitro binding assay coupled to in silico docking approach indicate a possible interaction for the four derivatives. The first TR-FRET homogeneous-phase assay was developed to quantify their binding to the START domain, allowing complete determination of HPA-12 EC50. Results indicate that not only the (1R,3S) lead to the strongest binding, but that both 1R and 3S stereocenters similarly contribute to extent of recognition This automated homogenous assay further opens up promising prospect for the identification of novel potential CERT antagonist by means of high throughput screening.

ChemInform Abstract: Consecutive Dynamic Resolutions of Phosphine Oxides.

A crystallization-induced asymmetric transformation (CIAT) involving a radical-mediated racemization provides access to enantiopure secondary phosphine oxides. A consecutive CIAT is used to prepare enantio- and diastereo-pure tert-butyl(hydroxyalkyl)phenylphosphine oxides.

Consecutive dynamic resolutions of phosphine oxides

A crystallization-induced asymmetric transformation (CIAT) involving a radical-mediated racemization provides access to enantiopure secondary phosphine oxides. A consecutive CIAT is used to prepare enantio- and diastereo-pure tert-butyl(hydroxyalkyl)phenylphosphine oxides.

Application of Crystallization-Induced Asymmetric Transformation to a General, Scalable Method for the Resolution of 2,8-Disubstituted Tröger’s Base Derivatives

A general method for the gram scale resolution of 2-substituted and 2,8-disubstituted Tröger's base (TB) derivatives in 63-91% yield has been achieved through the application of crystallization-induced asymmetric transformation (CIAT). Enantiomeric ratios of the resolved TB derivatives range from 99.1:0.9 to >99.5:0.5. Among the Tröger's base compounds resolved are four synthetically valuable bromo and iodo derivatives.

A concise synthesis of enantiomerically pure aroyl-l-alanines and dihydroaroyl-l-alanines

AbstractStraightforward preparation of enantiomerically highly enriched N-substituted aroylalanines has been developed. This process involves the combination of crystallization-induced asymmetric transformation and a conjugate addition of N-nucleophiles to the corresponding aroylacrylic acids. Further transformations to 3,4-dichlorobenzoylalanine and aroyl-l-alanines via periodate oxidation and stereoselective reduction to N-substituted syn-4-aryl-4-hydroxy-2-aminobutanoic acids are also described.

Expedient and Practical Synthesis of CERT-Dependent Ceramide Trafficking Inhibitor HPA-12 and Its Analogues

The practical stereodivergent route to both syn- and anti-diastereomers of 1-substituted 3-aminobutane-1,4-diols based on the crystallization-induced asymmetric transformation (CIAT) approach was completed. This led to the revision of the reported stereochemistry of the first inhibitor of CERT-dependent ceramide trafficking HPA-12 from (R,R)-anti- to the (R,S)-syn-enantiomer. Due to the expeditiousness of production and inexpensive conditions developed, a series of alkyl- and aryl-substituted analogues of HPA-12 is also reported.

Kinetic Control in the Chiral Recognition of Three-Bladed Propellers

The ion pair of the stereolabile C(3)-symmetric, i(+)o proton complex [1H](+) of diaza-macropentacycle 1 and the configurationally stable Delta-TRISPHAT ([Delta-3](-)) anion exists in the form of two diastereomers, namely, [Delta-(1.H)][Delta-3] and [Lambda-(1.H)][Delta-3], the ratio of which, in terms of diastereomeric excess (de) decreases in the order [D(8)]THF (28%)>CD(2)Cl(2) (22%)>CDCl(3) (20%)>[D(8)]toluene (16%)>C(6)D(6) (7%)>[D(6)]acetone (0%) at thermodynamic equilibrium. Except in the case of [D(6)]acetone, the latter is reached after a period of time that increases from 1 h ([D(8)]THF) to 24 h (CDCl(3)). Moreover, the initial value of the de of [1.H][Delta-3] in CDCl(3), before the thermodynamic equilibrium is reached, depends on the solvent in which the sample has been previously equilibrated (sample "history"). This property has been used to show that the crystals of [1.H][Delta-3] formed by slow evaporation of CH(2)Cl(2)/CH(3)OH mixtures had 100% de, which indicates that [1.H][Delta-3] has enjoyed a crystallization-induced asymmetric transformation. Structural studies in solution (NMR spectroscopy) and in the gas phase by calculations at the semiempirical PM6 level of theory suggest that the optically active anion is docked on the i(+) (endo) external side of the proton complex such that one of the aromatic rings of [Delta-3](-) is inserted into a groove of [1.H](+), a second aromatic ring being placed astride the outside i(+) pocket. Solvent polarity controls the thermodynamics of inversion of the [1.H](+) propeller. However, both polarity and basicity control its kinetics. Therefore, the rate-limiting steps correspond to the ion-pair separation/recombination and [1.H](+)/1 deprotonation/protonation processes, rather than the inversion of [1H](+), the latter being likely to take place in the deprotonated form (1).

The first example of a crystallization-induced asymmetric transformation (CIAT) in the Mannich reaction

The novel synthesis of highly enantioenriched N-substituted α-amino-γ-alkyl(aryl)-γ-oxobutanoic acids is described. The process involves the combination of a crystallization-induced asymmetric transformation (CIAT) and the Mannich reaction. The role of retro-Mannich and retro-Michael reactions in the mechanism of the highly stereoselective transformation is also discussed.

Synthesis and Total Spontaneous Resolution of an Octanuclear Organo(oxo)zinc Complex

The reaction of diethylzinc, pyridine, and water followed by crystallization-induced asymmetric transformation yields homochiral batches of crystals containing the corner-capped octanuclear cubane [Zn8(Et)8O4(py)8]. The crystal structure exhibits channels containing pyridine molecules that are ordered along helices of the same handedness.

Syntheses of chiral 1,3-disubstituted tetrahydro-β-carbolines via CIAT process: highly stereoselective Pictet–Spengler reaction of d-tryptophan ester hydrochlorides with various aldehydes

A highly stereoselective Pictet–Spengler reaction of d-tryptophan methyl ester hydrochloride 1-HCl with various aldehydes via a CIAT (crystallization-induced asymmetric transformation) process is described. It was revealed that the CIAT process should be performed in a mixed solvent of nitromethane and toluene, and a fine tuning of the ratio of nitromethane and toluene for each epimer mixture of 2-HCl was necessary in order to get as high yields and stereoselectivities as possible. Enantiomerically pure cis (or trans) 1,3-disubstituted tetrahydro-β-carbolines 2a– 2v were obtained by recrystallization or flash chromatography after neutralization of the corresponding hydrochloride salts cis- 2-HCl or trans- 2-HCl.

Synchronized stereocontrol of planar chirality by crystallization-induced asymmetric transformation

Synchronized stereocontrol of two planar-chiral units was accomplished by using crystallization-induced asymmetric transformation (CIAT) of cyclophane-type bridged bisnicotinate derivatives 5b and 7. After screening various linkers, ( S)-2-amino-1-butanol and ( S)- tert-leucinol were found to be the most effective for CIAT of the corresponding bridged bisnicotinate 5b and 7, respectively, whose diastereomeric ratio finally reached 97% and 88%, respectively.

Indolyl substituted 4-oxobut-2-enoic acids. Synthesis and aza-Michael additions

Abstract The synthesis of three new substituted 4-hetereoaryl-4-oxobut-2-enoic acids with indole ring substitutedin positions 3-, 5- and 7- is described. The addition of these Michael acceptors to 4-(1-phenylsulphonylpyrrol-3-yl)-4-oxobut-2-enoic acid in conjugate addition was explored using both racemic and chiral amines. In tandem with the crystallization-induced asymmetric transformation (CIAT) protocol the effective methodology for the synthesis of enantiomerically highly enriched substituted 2-amino-4-heteroaryl-4-oxobutanoic acids as multifunctional homotryptophan analogues was developed.

CIAT with simultaneous epimerization at two stereocenters. Synthesis of substituted β-methyl-α-homophenylalanines

Diastereoselective aza-Michael additions of phenylethylamine to 3-aroylbutenoic acids are reported. During these processes, efficient control over two new stereogenic centers on the Michael acceptor has been possible via crystallization-induced asymmetric transformation (CIAT). As an application, a convenient two-step synthesis of anti-beta-methylhomophenylalanines is also described.

A practical improvement of crystallization-induced asymmetric transformation of allene-1,3-dicarboxylates

Enantiomerically pure allene-1,3-dicarboxylates were easily synthesized by using epimerization–crystallization of dissymmetric allene compounds, which were prepared from acetone-1,3-dicarboxylates and naturally abundant chiral alcohols, that is, (−)- and (+)-menthols, borneol, and isoborneol. After scrutinizing the crystallization of several allene-1,3-dicarboxylates in the presence of triethylamine, it was found that allene-1,3-dicarboxylate carrying bornyl groups was the most easily prepared as a single isomer because of it having suitable solubility to be crystallized in hexane at 0 °C to room temperature. Diels–Alder reaction of the enantiomerically pure allene-1,3-dicarboxylates and cyclic dienes, such as N-Boc-pyrrole and cyclopentadiene, afforded endo-adducts having the same configurations at two newly generated stereogenic centers.

Asymmetric Synthesis of Aliphatic α-Amino and γ-Hydroxy α-Amino Acids and Introduction of a Template for Crystallization-Induced Asymmetric Transformation

The asymmetric synthesis of aliphatic α-amino and γ-hydroxy α-amino acids is described. The key step is an aza-Michael addition controlled by crystallization-induced asymmetric transformation (CIAT), affording excellent diastereomeric ratios (dr ≥96:4). Consecutive deoxygenation or stereoselective reduction (dr 99:1) furnish various α-amino and γ-hydroxy α-amino acids, respectively.