Diastereomer Transformation Research Articles

Practical Manufacturing Process for Baloxavir Marboxil: Effective Selection and Replacement of Protective Group toward Enhancement of Crystallization-Induced Diastereomer Transformation

Practical Manufacturing Process for Baloxavir Marboxil: Effective Selection and Replacement of Protective Group toward Enhancement of Crystallization-Induced Diastereomer Transformation

Crystallization-induced diastereomer transformation assists the diastereoselective synthesis of 4-nitroisoxazolidine scaffolds.

This communication describes a solution to the vexing problem of synthesis of 4-nitroisoxazolidine rings from cyclic nitrones and β-nitrostyrenes. The trans-endo adduct 2 is quantitatively synthesised from E-β-nitrostyrene under mild conditions avoiding purification, while the trans-exo adduct 4 is obtained at higher temperatures. Furthermore, a Crystallization-Induced Diastereomer Transformation (CIDT) process was used to epimerise the NO2 bond from 2 to the cis-exo adduct 3 with total conversion assisted by the para-halogen substitution of the aromatic ring without any additives. By combining these approaches, we can establish a simple synthetic methodology that allows the diastereoselective synthesis of three diastereoisomers, overcoming the previous problems described in the literature.

Crystallization-Enabled Stereoconvergent Michael Additions of β-Keto Esters to Nitroolefins.

Asymmetric Michael additions are powerful tools to meet the growing need for stereochemically complex products. While 1,3-dicarbonyls are common nucleophiles, the successful use of configurationally unstable β-keto esters in diastereoselective variants remains understudied. In this Letter, crystalline β-keto esters were leveraged in a two-phase, one-pot merger of an asymmetric Michael addition with a crystallization-induced diastereomer transformation. Tuning the crystallinity of β-keto ester adducts enabled stereoconvergence of the products, which were isolated by filtration.

Development of a Crystallization-Induced Diastereomer Transformation of Oxime Isomers for the Asymmetric Synthesis of (1S,6R)-3,9-Diazabicyclo[4.2.1]nonane.

Herein we report a practical crystallization-induced diastereomer transformation (CIDT) of oxime isomers for the scalable asymmetric synthesis of the bicyclic diamine (1S,6R)-3,9-diazabicyclo[4.2.1]nonane derivative that serves as a valuable building block in medicinal chemistry. The developed approach utilizes (S)-phenylethylamine as a chiral auxiliary handle for CIDT, and the starting nortropinone derivative is prepared in one step from commercially available materials. The resulting E-oxime is subjected to a stereospecific Beckmann rearrangement, followed by reduction of the resulting lactam with LiAlH4 to afford the monoprotected (1S,6R)-3,9-diazabicyclo[4.2.1]nonane derivative. The development of the CIDT and understanding of the mechanistic implications leading to the high selectivity are reported.

Total Synthesis of Hemerocallisamine I Paved by Gram-Scale Synthesis of (2S,4S)-4-Hydroxyglutamic Acid Lactone.

Total synthesis of the 2-formylpyrrole alkaloid hemerocallisamine I is presented, both in racemic and enantiopure form. Our synthetic strategy involves (2S,4S)-4-hydroxyglutamic acid lactone as the key intermediate. Starting from an achiral substrate, the target stereogenic centers were introduced by means of crystallization-induced diastereomer transformation (CIDT) in a highly stereoselective fashion. A Maillard-type condensation was crucial to constructing the desired pyrrolic scaffold.

Enantiopurification of Mandelic Acid by Crystallization-Induced Diastereomer Transformation: An Experimental and Computational Study

Chiral purification is crucial in the pharmaceutical industry due to the dramatic differences in biological activity of the two enantiomers of most chiral drugs. In this work, we demonstrate a new enantiopurification route for an important drug precursor, mandelic acid, by forming a diastereomeric amide with enantiopure 1-phenylethylamine. We show that in the presence of a strong base, the resulting diastereomeric system not only undergoes a reversible epimerization reaction but also exhibits a surprising difference in crystallization behavior, i.e., at room temperature, one epimer forms a metastable gel phase, only converting to a more stable crystal over several days, while the other forms a stable crystalline phase. Exploiting these properties, a facile purification technique via crystallization-induced diastereomer transformation (CIDT) was achieved enabling good product yield (>70%) and excellent optical purity (>92%). Enantiopure mandelic acid (∼91% e.e.) can then be recovered via acid hydrolysis. This work highlights that for compounds that are neither conveniently racemizable nor conglomerate-forming such as mandelic acid, CIDT is a powerful alternative to the deracemization technique, capable of yields greater than the 50% in contrast to traditional resolution techniques.

Enantioselective isothiourea-catalysed reversible Michael addition of aryl esters to 2-benzylidene malononitriles.

Catalytic enantioselective transformations usually rely upon optimal enantioselectivity being observed in kinetically controlled reaction processes, with energy differences between diastereoisomeric transition state energies translating to stereoisomeric product ratios. Herein, stereoselectivity resulting from an unusual reversible Michael addition of an aryl ester to 2-benzylidene malononitrile electrophiles using an isothiourea as a Lewis base catalyst is demonstrated. Notably, the basicity of the aryloxide component and reactivity of the isothiourea Lewis base both affect the observed product selectivity, with control studies and crossover experiments indicating the feasibility of a constructive reversible Michael addition from the desired product. When this reversible addition is coupled with a crystallisation-induced diastereomer transformation (CIDT) it allows isolation of products in high yield and stereocontrol (14 examples, up to 95 : 5 dr and 99 : 1 er). Application of this process to gram scale, plus derivatisations to provide further useful products, is demonstrated.

Guided optimization of a crystallization-induced diastereomer transformation to access a key navoximod intermediate

The crystallization-induced diastereomer transformation of a precursor to navoximod was investigated using online HPLC and optimized with inline racemization.

Stereoselective Synthesis of Highly Functionalized Structures from α‐Bromo α’‐Sulfinyl Ketones

AbstractCrystallization‐Induced Diastereomer Transformation (CIDT) of α‐bromo‐α’‐(R)‐sulfinylketones is reported. The utility of these 1,2‐difunctionalized synthons is convincingly demonstrated by their facile conversion into cyanohydrins and bromohydrins. Furthermore, bromohydrins can be converted into complex arrangements of functionality and stereochemistry through SN2‐like inter and intramolecular transformations.

Total Synthesis of (±)-Azaspirene via Crystallization-induced Diastereomer Transformation

The total synthesis of racemic azaspirene was accomplished over 12 steps in a 17% overall yield via a convergent strategy featuring the coupling of isocyanate and 3(2H)-furanone and an intramolecular aldol reaction to construct the spiro core. Later, a complete conversion was achieved via the crystallization-induced diastereomer transformation of the kinetically favored epimer—produced primarily via spirocyclic construction—to the thermodynamically stable and desirable epimer. Finally, a stereoselective hydration produced the target azaspirene.

Doubly stereoconvergent crystallization enabled by asymmetric catalysis.

Synthetic methods that enable simultaneous control over multiple stereogenic centers are desirable for the efficient preparation of pharmaceutical compounds. Herein, we report the discovery and development of a catalyst-mediated asymmetric Michael addition/crystallization-induced diastereomer transformation of broad scope. The sequence controls three stereogenic centers, two of which are stereochemically labile. The configurational instability of 1,3-dicarbonyls and nitroalkanes, typically considered a liability in stereoselective synthesis, is productively leveraged by merging enantioselective Brønsted base organocatalysis and thermodynamic stereocontrol using a single convergent crystallization. The synthesis of useful γ-nitro β-keto amides containing three contiguous stereogenic centers is thus achieved from Michael acceptors containing two prochiral centers.

Diastereodivergent Synthesis of (+)‐α‐Conhydrine and (−)‐β‐Conhydrine from a η,γ‐Dibromo‐β‐ketosulfoxide

AbstractDiastereodivergent syntheses of the enantiopure hemlock alkaloid (+)‐α‐conhydrine and its diastereomer (−)‐β‐conhydrine are reported. Our approach relies on efficient Crystallization‐Induced Diastereomer Transformation (CIDT) of an epimeric mixture of a η,γ‐dibromo‐β‐ketosulfoxide, optically pure only at the sulfur atom, that provided a stable α‐bromoketone, and diastereoselective β‐ketosulfoxide reduction that led to the corresponding anti and syn‐bromohydrins with high level of asymmetric induction.

Enantioselective synthesis of (-)-tetrabenazine via continuous crystallization-induced diastereomer transformation.

A multi-well continuous CIDT approach with inline racemization of the solution phase is presented. Using two in-house built PATs and a flow reactor, we were able to successfully crystallize an enantiopure salt of TBZ, the active metabolite of the tardive dyskinesia drug valbenazine. Despite discovering an undesired racemic solid phase, inline racemization combined with careful control of crystallization conditions allowed for multigram quantities of enantiopure material to be harvested using our setup. Critically, this control was made possible by the use of PATs to observe and quantify the composition of both the solid and solution phases.

Highly Diastereoselective Synthesis of 2‐Arylpyrrolidine Derivatives via the Crystallization‐induced Diastereomer Transformation

AbstractHerein we report a diastereoselective method for the synthesis of bis(pyrrolidine‐1‐carboxamides) via the acid‐catalyzed reaction of 1‐(4,4‐diethoxybutyl)‐3‐arylureas with resorcinol and its derivatives. The proposed method is operationally simple, does not require metal catalysts or chiral promoters and provides target compounds with high diastereoselectivity.

Crystallization-Induced Diastereomer Transformation of α-Bromo α'-Sulfinyl Ketones. Diastereodivergent Synthesis of (+)-α-Conhydrine and (-)-β-Conhydrine.

Crystallization-Induced Diastereomer Transformation (CIDT) of α-bromo-α'-(R)-sulfinylketones is reported. This process provides not readily accessible enantiopure stereolabile α-bromoketones, which after diastereoselective carbonyl group reduction lead to the corresponding highly value-added anti and syn-bromohydrins with excellent diastereoselectivities. As an application, a diastereodivergent synthesis of enantiopure hemlock alkaloid (+)-α-conhydrine and its diastereomer (-)-β-conhydrine is also described.

Crystallization-induced diastereomer transformation of thiohydantoin derivatives

Crystallization-induced diastereomer transformation of valuable thiohydantoin derivatives was developed for the first time. Three thiohydantoins synthesized from three (R)-N-phenethylthioureas and benzoylformyl chloride were obtained as diasteromeric mixtures. These thiohydantoins have aminal carbons at the chiral center which could be epimerized via ring-opening and –closing reactions under suitable conditions. The suspension of the diastereomixture of thiohydantoins in a small amount of solvent selectively converged to crystals composed of a single diastereomer in a quantitative fashion. Stereoselective switching of diastereoselectivity by CIDT of one thiohydantoin was achieved with a suitable solvent.

Hydrogen Bond Assisted l to d Conversion of α‐Amino Acids

Abstractl to d conversion of unactivated α‐amino acids was achieved by solubility‐induced diastereomer transformation (SIDT). Ternary complexes of an α‐amino acid with 3,5‐dichlorosalicylaldehyde and a chiral guanidine (derived from corresponding chiral vicinal diamine) were obtained in good yield as diastereomerically pure imino acid salt complexes and were hydrolysed to obtain enantiopure α‐amino acids. A combination of DFT computation, NMR spectroscopy, and crystal structure provide detailed insight into how two types of strong hydrogen bonds assist in rapid epimerization of the complexes that is essential for SIDT.

Hydrogen Bond Assisted l to d Conversion of α-Amino Acids.

l to d conversion of unactivated α-amino acids was achieved by solubility-induced diastereomer transformation (SIDT). Ternary complexes of an α-amino acid with 3,5-dichlorosalicylaldehyde and a chiral guanidine (derived from corresponding chiral vicinal diamine) were obtained in good yield as diastereomerically pure imino acid salt complexes and were hydrolysed to obtain enantiopure α-amino acids. A combination of DFT computation, NMR spectroscopy, and crystal structure provide detailed insight into how two types of strong hydrogen bonds assist in rapid epimerization of the complexes that is essential for SIDT.

Crystallization-Induced Diastereoisomer Transformation of Dihydroartemisinic Aldehyde with the Betti Base.

Artemisinin is an important drug to fight malaria. It is produced either by extraction or via a semisynthetic route involving enzyme engineering. A key intermediate to produce artemisinin by the enzymatic route is dihydroartemisinic aldehyde (DHAAl). However, control of the absolute configuration of the stereocenter α to the aldehyde is highly challenging. Herein we report a protocol that allows the diastereomeric enrichment of a mixture of (11R)/(11S)-DHAAl to the desired (11R)-DHAAl by utilizing a crystallization-induced diastereomer transformation induced by the Betti base. In addition, the Betti base can be quantitatively recovered and reused after the reaction.

NMR investigation of photoinduced chiral inversion in (R)/(S)-naproxen–(S)-tryptophan linked system

The inversion of the chiral centers in (R)/(S)-naproxen–(S)-tryptophan linked system under UV irradiation has been detected by the 1H NMR spectroscopy as an example of the (R,S)-diastereomer transformation into (S,S) analogue in an achiral environment.