Second-order Asymmetric Transformation Research Articles

A synthetic machine learning framework for complex crystallization processes: The case study of the second-order asymmetric transformation of enantiomers

Improving the flexibility and capabilities of pharmaceutical technologies and lowering the process development time while satisfying regulatory constraints translate to highly desired resilient supply chains. Generating and validating the necessary knowledge in-silico before experimentation or plant-scale intervention with minimized human implications is the dream this paper aims to contribute to. The idea is demonstrated through the case study of particle size-controlled second-order asymmetric transformation of enantiomers (SOAT), a crystallization and racemization-based resolution technique. The fundamental processes form a complex network, to which we propose a crystallization-integrated wet milling system, which is promising but has limited general, and no SOAT-specific operation experience. The developed computational framework has three steps: (1) skilled scientists draft potential technologies to solve a well-defined problem; (2) all alternatives are modeled with high fidelity first-principle models, followed by high throughput parametric optimizations (3) data mining is deployed to extract key information from the synthetic database of optimal solutions and take the effectiveness of process design and operation to the next level. In this work, population balance-based models were applied to describe the crystallization, fragmentation, and chemical reaction in the crystallizer and wet mill. The efficient implementation enabled the execution of nearly 1300 global multiobjective process optimizations. Carefully trained classifiers consistently predicted the with or without milling and with or without T-cycling decisions (AUC score exceeding 0.85). Regression methods estimated the product property profile with Pearson coefficients over 0.95. The results agree with the existing SOAT literature based on a literature meta-analysis, but some of the conclusions point beyond the state-of-the-art.

Deracemization in a Complex Quaternary System with a Second-Order Asymmetric Transformation by Using Phase Diagram Studies.

Invited for the cover of this issue is the group of Gérard Coquerel at Université de Rouen Normandie. The image depicts a pyramid-like tetrahedron of the quaternary phase diagram showing where symmetry breaking can take place. Read the full text of the article at 10.1002/chem.201903338.

Deracemization in a Complex Quaternary System with a Second-Order Asymmetric Transformation by Using Phase Diagram Studies.

A productive deracemization process based on a quaternary phase diagram study of a naphthamide derivative is reported. New racemic compounds of an atropisomeric naphthamide derivative have been discovered, and a quaternary phase diagram has been constructed that indicated that four solids are stable in a methanol/H2 O solution. Based on the results of a heterogeneous equilibria study showing the stable domain of the conglomerate, a second-order asymmetric transformation was achieved with up to 97 % ee. Furthermore, this methodology showcases the chiral separation of a stable racemic compound forming system and does not suffer from any of the typical limitations of deracemization, although application is still limited to conglomerate-forming systems. We anticipate that this present study will serve as a fundamental model for the design of sophisticated chiral separation processes.

Resolution of an Atropisomeric Naphthamide by Second-Order Asymmetric Transformation: A Highly Productive Technique

Temperature-cycle-induced deracemization (TCID) has been widely studied in the field of chiral separation, ranging from fundamental research to applications. In this study, the second-order asymmetric transformation (SOAT) of 2-methoxy-1-naphthamide in an azeotropic mixture of ethyl acetate and cyclohexane is compared with TCID, in terms of process productivity. The results indicate that the volumetric productivity using SOAT was over 100-times higher than that using TCID, such that a scale-up by a factor of 10 was easily implemented.

Tandem Alkylation–Second-Order Asymmetric Transformation Protocol for the Preparation of Phenylalanine-Type Tailor-Made α-Amino Acids

In this work, we disclose an advanced general process for the synthesis of tailor-made α-amino acids (α-AAs) via tandem alkylation–second-order asymmetric transformation. The first step is the alkylation of the chiral Ni(II) complex of glycine Schiff base, which is conducted under mild phase-transfer conditions allowing the structural construction of target α-AAs. The second step is based on the methodologically rare second-order asymmetric transformation, resulting in nearly complete precipitation of the corresponding (SC,RN,RC)-configured diastereomer, which can be collected by a simple filtration. The operational convenience and potential scalability of all experimental procedures, coupled with excellent stereochemical outcome, render this method of high synthetic value for the preparation of various tailor-made α-AAs.

Second-order asymmetric transformation and its application for the practical synthesis of α-amino acids.

We report a discovery of a new rimantadine [1-(1-adamantyl)ethanamine]-derived chiral ligand and its application for the preparation of α-amino acids using the second-order asymmetric transformation approach. The operational ease of experimental procedures coupled with excellent chemical yields and stereochemical outcome suggests some potential synthetic generality of this approach.

Coupling Viedma Ripening with Racemic Crystal Transformations: Mechanism of Deracemization

It has been recently observed that coupling Viedma ripening with a seeded in situ metastable racemic crystal to conglomerate transformation leads to accelerated and complete deracemization: crystal transformation–enhanced deracemization. By means of a simple kinetic model, we show that the mechanistic pathway of this new process depends profoundly on the interplay between the crystal transformation and racemization processes, which in turn influence the nucleation process of the counter enantiomer. If the nucleation of the counter enantiomer is suppressed (e.g., by sufficiently fast racemization, low amount of racemic compound or gradual feed, low relative solubility between racemic compound and conglomerate), deracemization proceeds via a second order asymmetric transformation (SOAT) and is limited primarily by the dissolution rate of the racemic crystals and the growth rate of the preferred enantiomer crystals. Breakage and agglomeration accelerate the process, but contrary to conventional Viedma ripening, they are not essential ingredients to explain the observed enantiomeric enrichment. If the nucleation process of the counter enantiomer is not sufficiently suppressed, deracemization is initially controlled by the dissolution rate of the racemic crystals, but Viedma ripening is subsequently required to convert the conglomerate crystals of the counter enantiomer formed by nucleation, resulting in slower deracemization kinetics. In both cases, the combined process leads to faster deracemization kinetics compared to conventional Viedma ripening, while it autocorrects for the main disadvantage of SOAT, i.e., the accidental nucleation of the counter enantiomer. In addition, crystal transformation–enhanced deracemization extends the range of applicability of solid-state deracemization processes to compounds that form metastable racemic crystals.

Asymmetric Transformation of a Double-Stranded, Dicopper(I) Helicate Containing Achiral Bis(bidentate) Schiff Bases

Reactions of the bis(bidentate) Schiff-bases N,N'-bis(6-alkyl-2-pyridylmethylene)ethane-1,2-diamine (where alkyl = H, Me, iPr) (L) with tetrakis(acetonitrile)copper(I) hexafluorophosphate and silver(I) hexafluorophosphate afforded, respectively, the double-stranded, dinuclear metal helicates [T-4-(R,R)]-(+/-)-[M2L2](PF6)2 (M = Cu, Ag). The helicates were characterized by 1H and 13C NMR spectroscopy, conductivity, microanalysis, and single-crystal X-ray structure determinations on selected compounds. Intermolecular ligand exchange and intramolecular inversion rates for the complexes were investigated by 1H NMR spectroscopy. Reversible intermolecular ligand exchange between two differently substituted helicates followed first-order kinetics. The rate constants (k) and corresponding half-lives (t(1/2)) for ligand exchange for the dicopper(I) helicates were k = (1.6-1.8) x 10(-6) s(-1) (t(1/2) = 110-120 h) in acetone-d6, k = 4.9 x 10(-6) s(-1) (t(1/2) = 40 h) in dichloromethane-d2, and k > 2 x 10(-3) s(-1) (t(1/2) < 5 min) in acetonitrile-d3. Ligand exchange for the disilver(I) helicates occurred with k > 2 x 10(-3) s(-1) (t(1/2) < 5 min). Racemization of the dicopper(I) helicate by an intramolecular mechanism was investigated by determination of the coalescence temperature for the diastereotopic isopropyl-Me groups in the appropriate complex, and DeltaG() >> 76 kJ mol(-1) was calculated for the process in acetone-d6, nitromethane-d3, and dichloromethane-d2 with DeltaG() = 75 kJ mol(-1) in acetonitrile-d3. Complete anion exchange of the hexafluorophosphate salt of a dicopper(I) helicate with the enantiomerically pure Delta-(-)-tris(catecholato)arsenate(V) ([As(cat)3]-) in the presence of Dabco gave the two diastereomers (R,R)-[Cu2L2][Delta-(-)-[As(cat)3]]2 and (S,S)-[Cu2L2][Delta-(-)-[As(cat)3]]2 in up to 54% diastereomeric excess, as determined by (1)H NMR spectroscopy. The diastereomerically and enantiomerically pure salt (R,R)-[Cu(2)L2][Delta-(-)-[As(cat)3]]2 crystallized from the solution in a typical second-order asymmetric transformation. The asymmetric transformation of the dicopper(I) helicate is the first synthesis of a diastereomerically and enantiomerically pure dicopper(I) helicate containing achiral ligands.

Transfer of chirality by dithiophosphate ligands and chiral discrimination in the stereoselective formation of square-planar Ni(II) complexes.

In the formation reaction of Ni(2+) with the chiral racemic ligand, (R)(R)bdtp(-)/(S)(S)bdtp(-), bdtp(-) = [SSPOCH)CH(3))CH(CH(3))O](-), cyclo- O,O'-[1,2-dimethylethylene] dithiophosphato ion, the meso-complex Ni[(R)(R)(lambda)bdtp][(S)(S)(delta)-bdtp] is stereoselectively produced. The meso-complex was compared with the enantiopure crystals of (+)(589)Ni[(R)(R)(lambda)bdtp](2) or (-)(589)Ni[(S)(S)(delta)bdtp](2), as well as racemic crystals, rac-(+/-)Ni[bdtp](2), which were prepared from the solution containing the two enantiomers in a 1:1 ratio. Dissociation constants in solutions indicate different stability of the meso and enantiopure complexes depending on the solvent, whereas a more efficient crystal packing, weak H-bonding, and nonbonding interactions contribute to stabilization of the meso-species over the racemic one. Molecular structures show that the outer five-membered ligand ring adopts the half-chair conformation C(2) with either the lambda or the delta chirality and the methyl groups are in equatorial (e) positions. Enantiopure ligands of (+)(589)Ni[(R)(R)(lambda)bdtp](2) and (-)(589)Ni[(S)(S)(delta)bdtp](2) induce chirality into the symmetric SSNiSS chromophore with slightly helical distortion. Thus, their CD spectra exhibit weak negative or positive Cotton effects at 662 nm. CD spectra in L(+)- and D(-)diethyltartrate of the meso-complex and racemic crystal, rac-(+/-)Ni[bdtp](2), exhibit different weak Cotton effects of opposite sign. Complexes dissociate in methanol; rac-(+/-)Ni[bdtp](2) in methanol undergoes a crystallization-induced second-order asymmetric transformation which finally yields crystals of the meso-Ni[(R)(R)(lambda)bdtp][(S)(S)(delta)bdtp] complex.

Synthesis of optically active oligonaphthalenes via second-order asymmetric transformation.

Synthesis of numerous optically active rod-shaped oligo(2,3-dioxyfunctionalized)naphthalenes connected at their 1,4-positions was achieved using oxidative coupling under CuCl2/alpha-methylbenzylamine conditions by second-order asymmetric transformation. We believe this method is practical and should contribute to the field of material science.

Asymmetric three-coordinated nitrogen compounds: spontaneous resolution and absolute asymmetric synthesis

The spontaneous resolution of conglomerates of a dibenzo analogue of Tröger's base 1 and aziridine 2, as well as the second-order asymmetric transformation of (±)-1 into a single enantiomer were carried out for the first time.

Diastereomeric separations and crystal structures of rhodium(iii) and iridium(iii) complexes containing adenosine and related nucleosidesElectronic supplementary information (ESI) available: 1H NMR and CD spectra. See http://www.rsc.org/suppdata/dt/b2/b209148h/

Six C3 cyclic trinuclear complexes [{M(Cp*)(L)}3]3+ (M = RhIII and IrIII; Cp* = η5–C5Me5) containing adenosine nucleosides [L: adenosine (Hado), 2′-deoxyadenosine (Hdeoado) and 5′-acetyl-2′,3′-isopropylideneadenosine (Haipado)] were prepared and characterized by UV/Vis and circular dichroism (CD) spectra, NMR spectroscopy, electrospray ionization mass spectroscopy and X-ray crystal structure analysis. The isolations of one and/or two diastereomers were successfully carried out for the four systems by second-order asymmetric transformation and/or fractional crystallization. Interestingly, a striking kinetic difference was found between the present RhIII– and IrIII–ado systems. The crystal structure of CCC-[{Rh(Cp*)(ado)}3](CF3SO3)3·2.5H2O·CH3OH revealed that the ado ligand adopts a μ-1κN1:2κ2N6,N7 bridging mode and the three purine rings forming a triangle dome-like cavity can include one methanol molecule into its cavity. The absolute configurations were assigned to these complexes based on the crystal structural result and CD spectral arguments. The RhIII–N-methyl adenosine (HNMeado) system exceptionally gave a di-μ-hydroxy anti-dinuclear structure because of the weak coordination ability of the N(6) donor.

Diastereomeric separation of [{M(Cp*)(ado)}3]3+ (M = RhIII, IrIII; ado = adenosinato): crystal structure of an inclusion compound [{Rh(Cp*)(ado)}3](CF3SO3)3·MeOH

A diastereomer with a C3 cyclic trimer [{Rh(adenosine)(Cp*)}3](CF3SO3) 3, which was obtained selectively by a second-order asymmetric transformation, can include one methanol molecule into its triangle dome-like cavity.

The effect of counter cations on second-order asymmetric transformations in fac-Δ- and Λ-tris(R-cysteinato-N,S )cobaltate(III) complexes and the kinetics of mutarotation

A rapid reversible inversion (epimerization) between the Δ-(R,R,R) and Λ-(R,R,R) diastereomers for fac-Δ- and Λ-tris(R-cysteinato-N,S)cobaltate(III) occurs at room temperature in an aqueous solution of each salt. The half-lives for the mutarotation were measured (k = kΛ + kΔ): 80 and 6 minutes at 20 and 40 °C, respectively. The equilibrium constants, K = [Λ-(R,R,R)]/[Δ-(R,R,R)], are 1.2 at 20 °C and 1.0 at 40 °C, which means that the cobalt inversion rate constant kΛ nearly equals kΔ. Eight kinds of metal salts, M3[Co(R-cys-N,S)3] [M = Li+, Na+, K+, Rb+, Cs+; M1/2 = Ca2+, Sr2+, Ba2+], were prepared. It was found that all these salts show a second-order asymmetric transformation under a solid-solution equilibrium at room temperature of the kind first demonstrated for the Ba2+ salt by Arnold and Jackson. The phenomenon led to the Δ-(R,R,R) diastereomer for the salts of Li+, Na+, K+, Rb+, Cs+, Ca2+ and Sr2+, but to the Λ-(R,R,R) diastereomer for Ba2+. These results could be clearly explained by solubility measurements of each diastereomeric salt pair.

Facile interconversions between diastereomers of chloro-bridged palladium(II) dimers of orthometallated (±)-dimethyl[1-(1-naphthyl)ethyl]amine

The important chloro-bridged dipalladium(II) resolving agents (R,R)- and (S,S)-cis-di-μ-chlorobis[1-[1-(dimethylamino)-ethyl]-2-naphthalenyl-C,N]dipalladium, (R,R)- and (S,S)-cis-1, undergo facile rearrangements into unequal mixtures of cis and trans diastereomers upon dissolution in chloroform or dichloromethane, although concentration of the solution in each case affords in high yield the pure cis diastereomer of the dinuclear metal complex as the corresponding mono-solvate in a typical second-order asymmetric transformation. When equimolar solutions of (R,R)-cis- and (S,S)-cis-1 CH2Cl2 in dichloromethane are mixed together, however, an equilibrium is rapidly established between the cis and trans diastereomers of the (R∗,R∗)-(±) and (R∗,S∗) forms of 1 and from which solution configurationally homogeneous (R∗,S∗)-trans-1·CH2Cl2 crystallizes in high yield by second-order asymmetric transformation. The crystal and molecular structures of (R,R)-cis-1·CH2Cl2 and (R∗,S∗)-trans-1·CH2Cl2 have been determined. The optical purities of the individual enantiomers of (R∗,R∗)-(±)-1·CH2Cl2 have been determined by reaction with (1R,2S,5R)-menthyldiphenylphosphine or (1S, 2S, 5R)-neomenthyldiphenylphosphine in chloroform-d1 and analysis of the 31P1H NMR spectra of the resulting solutions of the corresponding bridge-split palladium(II)-phosphine epimers.

A second-order asymmetric transformation of racemic 2-hydroxymethyl[5]thiaheterohelicene into a single enantiomer upon uptake by bovine serum albumin

Racemic 2-hydroxymethylthieno[3,2-e:4,5-e′]di[1]benzothiophene (2-HT) with a labile helical structure was converted into a P enantiomer upon uptake by bovine serum albumin (BSA) in 1 % ethanol-water. The effect of the alteration of the molar ratio [2-HT]: [BSA] on UV and CD spectra of the 2-HT-BSA complex solution revealed that BSA possesses two different substratebinding sites with a distinct ability to recognize chirality of enantiomers of 2-HT. The stability of the 2-HT-BSA complex and the chirality recognition at the two sites of BSA were evaluated by the equilibrium constants and the thermodynamic parameters which were obtained from the temperature-dependence of CD-absorptional intensities. BSA pretreated at 50 ∼ 70 °C in an aqueous solution exhibited a great depression of ability in diseriminating chirality between enantiomers of 2-HT, though it possessed slightly altered ability for uptake of 2-HT, in comparison with untreated BSA.

First Resolution of a Free Secondary Phosphine Chiral at Phosphorus and Stereospecific Formation and Structural Characterization of a Homochiral Secondary Phosphine-Borane Complex.

The R(P) diastereomer of (-)-menthylmesitylphosphine, (R(P))-1, has been isolated with high configurational purity at phosphorus by fractional crystallization of an (R(P))-1/(S(P))-1 = 43/57 mixture from acetonitrile containing a trace of sodium acetylacetonate as a proton scavenger or by deboranation of the corresponding borane complex (S(P))-2 with diethylamine, thereby effecting the first resolution of a secondary phosphine chiral at phosphorus. The crystal and molecular structure of (S(P))-2 has been determined. The ready isolation of (S(P))-2 of 97% diastereomeric purity in 66% yield from an equilibrium (R(P))-2/(S(P))-2 = 28/72 mixture in n-hexane by second-order asymmetric transformation and its quantitative and stereospecific conversion under mild conditions into (R(P))-1 of similar purity augurs well for the future of the resolved secondary phosphines in stereoselective syntheses.

First Resolution of a Free Fluorophosphine Chiral at Phosphorus. Resolution and Reactions of Free and Coordinated (+/-)-Fluorophenylisopropylphosphine.

The trivalent fluorophosphine (+/-)-PFPh(i-Pr), (+/-)-1, has been prepared by halogen exchange of the corresponding chlorophosphine with sodium fluoride in hot sulfolane. The neat fluorophosphine rapidly decomposes by equilibrium redox disproportionation into PF(3)Ph(i-Pr) and (R,R)/(R,S)-Ph(i-Pr)PPPh(i-Pr), but in benzene, (+/-)-1 has considerable thermodynamic stability. The resolution of (+/-)-1 was achieved by a fractional crystallization of the diastereomers (R,R(P))- and (R,S(P))-chloro[1-[1-(dimethylamino)ethyl]-2-naphthalenyl-C,N](fluorophenylisopropylphosphine)palladium(II), (R,R(P))- and (R,S(P))-5, whereby the less soluble (R,R(P)) diastereomer selectively crystallized in 64% yield in a typical second-order asymmetric transformation. Optically pure (S)-(-)-1, -210 (c 0.59, C(6)H(6)), was liberated from (R,R(P))-5 with (R,S)-1,2-phenylenebis(methylphenylphosphine). The optically active phosphine in benzene racemizes over 6 h without significant redox disproportionation. The methoxyphosphine (+/-)-P(OMe)Ph(i-Pr), (+/-)-9, was also resolved by the method of metal complexation. Thus, fractional crystallization of (R,R(P))- and (R,S(P))-chloro[1-[1-(dimethylamino)ethyl]-2-naphthalenyl-C,N](methoxyphenylisopropylphosphine)palladium(II), (R,R(P))- and (R,S(P))-8, followed by liberation of the respective optically active methoxyphosphines from the separated diastereomers with 1,2-bis(diphenylphosphino)ethane, gave (R)-(+)- and (S)-(-)-9 of 92% and 96% ee, respectively. The barrier to unimolecular inversion for (+/-)-9 was determined to be >82.9 +/- 0.5 kJ mol(-)(1) by variable temperature (1)H NMR spectroscopy. The substitution of fluoride in (R,R(P))-5 by methoxide proceeds with predominant inversion of the configuration at phosphorus to give (R,R(P))- and (R,S(P))-8 with (R,S(P))/(R,R(P)) = (1)/(5). The crystal structures of (R,R(P))-5 and (R,R(P))-8 have been determined: (R,R(P))-5 (C(23)H(28)ClFNPPd) crystallizes in the orthorhombic space group P2(1)2(1)2(1) with a = 9.967(2) Å, b = 10.998(4) Å, c = 21.324(3) Å, Z = 4, and R = 0.031; (R,R(P))-8 (C(24)H(31)ClNOPPd) crystallizes in the space group P2(1)2(1)2(1) with a = 10.444(3) Å, b = 12.146(3) Å, c = 19.047(2) Å, Z = 4, and R = 0.026.

Attempted resolution of free (±)-chlorophenylisopropylphosphine

Abstract (±)-Chlorophenylisopropylphosphine has been resolved in a palladium(II) complex containing the phosphine and ortho-metalated ( R )-1-[1-(dimethylamino)ethyl]naphthalene; the configurationally homogeneous ( R , R p ) diastereomer of the complex crystallises from the reaction mixture by typical second-order asymmetric transformation in overall 82% yield. The absolute configuration of the complex was determined by X-ray crystallography. The pure ( R , R p ) diastereomer of the complex reacts quantitatively with methanol in the presence of triethylamine to give the corresponding methoxyphosphine complex with complete stereoselectivity and inversion at phosphorus. All attempts at liberating optically active chlorophosphine from the palladium complex were unsuccessful.

Synthesis of enantiomerically pure binaphthyl derivatives. Mechanism of the enantioselective, oxidative coupling of naphthols and designing a catalytic cycle

Three different mechanisms have been identified for the CuCl 2 -mediated oxidative coupling of naphthols to binaphthyls in the presence of chiral amines (sparteine or α-methylbenzylamine); fair to excellent enantioselection has been observed (up to 100 % ee). The choice of the dominant mechanism appears to be critically dependent on the structure of the partners to be coupled. Thus, for the self-coupling of 2-naphthol (1) the enantioselection is mainly controlled of via a second-order asymmetric transformation of the product 4 (up to 100 % ee). The same mechanism is responsible for the formation of enantiomerically enriched biphenanthrol 9 (76% ee). By contrast, enantiodifferentiation in the formation of 5 and 7 results from the diastereoselective crystallization of the corresponding Cu(II)-amine-binaphtyl complex, wheras an enantioselective coupling operates in the preparation of 6. A catalytic cycle has been designed, employing 10 mol% of CuCl 2 (with AgCl to regenerate Cu II ) and sparteine(20 mol%); when applied to the asymmetric cross-coupling 1+3→6, the product (-)6 was obtained in 41%yield