Enantiopure Products Research Articles

Electrooxidative C(sp3)-H Cyanation of Sparteine and Lupanine in Undivided Batch and Continuous-Flow Cells.

Sparteine is widely used as a chiral ligand in asymmetric synthesis, but methods for providing efficient access to functionalized sparteine derivatives are still limited. Herein, we describe an electrochemical α-cyanation of sparteine-type bis-quinolizidine alkaloids. This method features commercially available setups for batch and single-pass continuous flow conditions, enabling easy gram scale synthesis of valuable racemic and enantiopure products. Moreover, insights into the selectivity of the reaction and overoxidation mechanisms are disclosed. This allows for the development of divergent oxidation pathways depending on the electrolysis conditions.

Overcoming the Limitations of Transition-Metal Catalysis in the Chemoenzymatic Dynamic Kinetic Resolution (DKR) of Atropisomeric Bisnaphthols.

Chemoenzymatic dynamic kinetic resolution (DKR), combining a metal racemization catalyst with an enzyme, has emerged as an elegant solution to transform racemic substrates into enantiopure products, while compatibility of dual catalysis is the key issue. Conventional solutions have utilized presynthesized metal complexes with a fixed and bulky ligand to protect the metal from the enzyme system; however, this has been generally limited to anionic ligands. Herein, we report our strategy to solve the compatibility issue by employing a reliable ligand that firmly coordinates in situ to the metal. Such a reliable ligand offers π* orbitals, allowing additional metal-to-ligand d-π* back-donation, which can significantly enhance coordination effects between the ligand and metal. Therefore, we developed an efficient DKR method to access chiral BINOLs from racemic derivatives under dual copper and enzyme catalysis. In cooperation with lipase LPL-311-Celite, the DKR of BINOLs was successfully realized with a copper catalyst via in situ coordination of BCP (L8) to CuCl. A series of functionalized C 2- and C 1-symmetric chiral biaryls could be synthesized in high yields with good enantioselectivity. The racemization mechanism was proposed to involve a radical-anion intermediate, which allows the axial rotation with a dramatic decrease of the rotation barrier.

Organocatalytic Atroposelective Dynamic Kinetic Resolution Involving Ring Manipulations

AbstractAxially chiral architectures exist widely in natural products, biologically relevant molecules, chiral ligands and catalysts as well as functional materials. Therefore, catalytic asymmetric synthesis of atropisomers has become one of the most fast‐growing fields in the community of chemistry and rapid advances have occurred. Among different methods reported, the organocatalytic atroposelective dynamic kinetic resolution (DKR) involving ring manipulations stands out as a cutting‐edge technology to construct axial chirality from the point of atom/step economy. In this DKR strategy, the configurational lability of starting materials originates from chirally‐labile ring structure of cyclic substrates/intermediates or transient ring formation through noncovalent interactions from acyclic substrates. The two atropisomers of starting material are in equilibrium in the reaction medium, ensuring the constant transformation of the less reactive atropisomer into the more reactive one, and then to a single enantiopure product in the presence of an appropriate organocatalyst. This review summarizes recent advancements on this topic, including their scopes, limitations, mechanisms, applications and provides some insights into further developments.

Exact and Ubiquitous Condition for Solid-State Deracemization in Vitro and in Nature.

Solid-state deracemization is the amplification of an enantiomeric excess in suspensions of conglomerate-forming chiral compounds. Although numerous chemical and biochemical compounds deracemize, its governing mechanism has remained elusive. We introduce a novel formulation of the classical population-based model of deracemization through temperature cycles to prove that suspensions deracemize whenever a simple and ubiquitous condition is met: crystal dissolution must be faster than crystal growth. Such asymmetry is a known principle of crystallization, hence explaining the generality of deracemization. Through both experiments and a theoretical analysis, we demonstrate that this condition applies even for very small temperature cycles and for random temperature fluctuations. These findings establish solid-state deracemization as an attractive route to the manufacture of enantiopure products and as a plausible pathway toward the emergence of homochirality in nature.

Diastereoselective Synthesis of α-Aryl-Substituted LnDOTA Chelates from Achiral Starting Materials by Deracemization Under Mild Conditions.

Substituted derivatives of the DOTA framework are of general interest to alter chelate properties and facilitate the conjugation of chelates to other molecular structures. However, the scope of substituents that can be introduced into the α-position has traditionally been limited by the availability of a suitable enantiopure starting materials to facilitate a stereoselective synthesis. Tetra-substituted DOTA derivatives with phenyl and benzoate substituents in the α-position have been prepared. Initial syntheses used enantiopure starting materials but did not afford enantiopure products. This indicates that the integrity of the stereocenters was not preserved during synthesis, despite the homo-chiral diastereoisomer being the major reaction product. The homochiral diastereoisomer could be produced as the major or sole reaction product when starting from racemic or even achiral materials. Deracemization was found to occur during chelation through the formation of an enolate stabilized by the aryl substituent. This general ability of aryl groups to enable deracemization greatly increases the range of substituents that can be introduced into DOTA-type ligands with diastereochemical selectivity.

Accessing Phase-Transfer Catalysts and a Phosphoramidite Ligand via the Asymmetric Intramolecular Hydroamination Reaction

Within the last few years, our group has developed the intramolecular, asymmetric hydroamination (HA) reaction to a point where essentially enantiopure products can be obtained. The question then arose as to whether we can apply the reaction in useful ways beyond the synthesis of natural/pharmaceutically relevant products. In the present paper, we incorporate a select few HA products for the production of new chiral phase-transfer catalysts. These species are synthesized in one or two synthetic steps from new spirocyclic HA products and are applied in a classical substitution reaction, showing negligible enantioselectivity. In a second application, we introduce a novel phosphoramidite ligand, obtained by combining BINOL (1,1′-bi-2-naphthol) and an optically pure HA product with phosphorous trichloride. The representative ligand shows high enantioselectivity and activity in the rhodium-catalyzed conjugate addition reaction (Hayashi–Miyaura reaction).

Direct Enantioselective Addition of Alkynes to Imines by a Highly Efficient Palladacycle Catalyst.

Enantiopure propargylic amines are highly valuable synthetic building blocks. Much effort has been devoted to develop methods for their preparation. The arguably most important strategy is the 1,2‐addition of alkynes to imines. Despite remarkable progress, the known methods using Zn and Cu catalysts suffer from the need for high catalyst loadings, typically ranging from 2–60 mol % for neutral aldimine substrates. Here we report a planar chiral Pd complex acting as very efficient catalyst for direct asymmetric alkyne additions to imines, requiring very low catalyst loadings. Turnover numbers of up to 8700 were accomplished. Our investigation suggests that a Pd‐acetylide complex is generated as a catalytically relevant intermediate by the aid of an acac ligand acting as internal catalytic base. It is shown that the catalyst is quite stable under the reaction conditions and that product inhibition is not an issue. A total of 39 examples is shown which all yielded almost enantiopure products.

Direkte enantioselektive Addition von Alkinen an Imine unter Verwendung eines hocheffizienten Palladacyclus als Katalysator

AbstractEnantiomerenreine Propargylamine sind sehr wertvolle Synthesebausteine. Große Anstrengungen wurden bereits unternommen, um Verfahren zu ihrer Herstellung zu entwickeln. Als vermutlich wichtigste Synthesestrategie ist die 1,2‐Addition von Alkinen an Imine zu nennen. Trotz aussichtsreicher Fortschritte sind für die bekannten Verfahren unter Verwendung von Zn‐ und Cu‐Katalysatoren hohe Katalysatorladungen, die typischerweise im Bereich von 2–60 mol % für neutrale Aldiminsubstrate liegen, notwendig. Wir entwickelten einen planar‐chiralen Pd‐Komplex, welcher als hocheffizienter Katalysator für die direkte asymmetrische Alkin‐Addition an Imine dient und sehr geringe Katalysatorladungen ermöglicht. Umsatzzahlen von bis zu 8700 wurden erreicht. Unsere Untersuchungen legen nahe, dass mit Hilfe eines acac‐Liganden, der als interne katalytische Base fungiert, ein Pd‐Acetylid‐Komplex als katalytisch relevantes Intermediat erzeugt wird. Weiterhin konnten wir zeigen, dass der Katalysator unter den Reaktionsbedingungen weitgehend stabil ist und keine Produktinhibierung auftritt. Insgesamt sind 39 Beispiele aufgeführt, die alle nahezu enantiomerenreine Produkte ergaben.

Alcohols as Alkylating Agents in the Cation‐Induced Formation of Nitrogen Heterocycles

AbstractA Ti(Oi‐Pr)4 promoted 5‐ or 6‐endo‐trig cyclisation to make nitrogen heterocycles is presented. The utilisation of HFIP as a key solvent enables the stereoselective preparation of di‐ & tri‐substituted pyrrolidines and piperidines while forming a new C−C bond at the same time. The process is triggered by a cationic intermediate generated from an allylic or benzylic alcohol and leads to the simultaneous generation of both a C−C and a C−N bond in a single step. Notably, either 2,3‐trans‐ or 2,3‐cis‐substituted heterocycles can be obtained by using a nucleophilic amine bearing different substituents. Lastly, the stereoselective synthesis of enantiopure products was achieved by using readily available enantiopure acyclic starting materials.

Alcohols as Alkylating Agents in the Cation-Induced Formation of Nitrogen Heterocycles.

A Ti(Oi‐Pr)4 promoted 5‐ or 6‐endo‐trig cyclisation to make nitrogen heterocycles is presented. The utilisation of HFIP as a key solvent enables the stereoselective preparation of di‐ & tri‐substituted pyrrolidines and piperidines while forming a new C−C bond at the same time. The process is triggered by a cationic intermediate generated from an allylic or benzylic alcohol and leads to the simultaneous generation of both a C−C and a C−N bond in a single step. Notably, either 2,3‐trans‐ or 2,3‐cis‐substituted heterocycles can be obtained by using a nucleophilic amine bearing different substituents. Lastly, the stereoselective synthesis of enantiopure products was achieved by using readily available enantiopure acyclic starting materials.

Solid-State Deracemization via Temperature Cycles in Continuous Operation: Model-Based Process Design.

Solid-state deracemization via temperature cycles converts a racemic crystal mixture into an enantiopure product by periodic cycling of the temperature in the presence of a racemization catalyst. A continuous counterpart of this conventional batch-operated process is proposed that can be performed in mixed suspension mixed product removal crystallizers (MSMPRCs). More specifically, three different configurations are described to perform periodic forcing via temperature cycles, which differ from each other in the type of the feed and in the withdrawal system. We have developed a model by extending our recent population balance equation model of batch solid-state deracemization via temperature cycles, and we exploit this tool to analyze the start-up and periodic steady-state behavior. Moreover, we compare the performance of the different configurations based on the selected key performance indicators, namely, average periodic steady-state enantiomeric excess and productivity. The process with solution feed yields pure enantiomers, while the solid and suspension-fed process alternatives result in highly enantiomerically enriched crystals. We further design an MSMPRC cascade to overcome this purity limitation. This work discusses guidelines on how to transform the batch process of temperature cycles into a continuous operation, which enables stable, unattended operation and chiral crystal production with consistent product quality.

Chemoenzymatic enantioselective route to get (+) and (−) 4-acetoxy-azetidin-2-one by lipase-catalysed kinetic resolution and their applications

4-Acetoxy-azetidin-2-one is an extremely useful intermediate widely applied for the synthesis of several biologically active β-lactam compounds. However, it is available as a racemic mixture that could limit its application in the synthesis of enantiopure products. Herein we evaluated the use of lipases in a kinetic resolution (KR) process to finally obtain 4-acetoxy-zetidin-2-one as separated pure enantiomers. From a preliminary screening on a set of commercial enzymes, Pseudomonas fluorescens emerged as the most suitable lipase that allowed to obtain good conversions and excellent enantiomeric excesses. On the enantiomerically pure 4-acetoxy-azetidin-2-ones some nucleophilic substitutions and N-thio-alkylation reactions were tested in order to evaluate the stereochemical integrity at the C-4 position.

Synthesis of Pentacoordinated Spiro[4.4]phosphoranes by Reaction of Cyclic Phosphazenyl Anions with Epoxides: Study of their P-Remote Functionalization and Hydrolysis

AbstractThe synthesis of a new family of pentacoordinated spiro[4.4]phosphoranes stabilized by the ortho-benzamide bidentate ligand (oBA, -C6H4-2-C(O)NH-) through reaction of Cα,C ortho -dilithiated phosphazenes with oxiranes is reported. Mixtures of epimers that differ in configuration at the phosphorus atom were obtained with moderate to high yields and diastereoselectivities. C3-Disubstituted derivatives could be separated, which provided access to enantiopure products arising from the reaction with (R)-2-phenyloxirane. Stereomutation was observed by heating the spirophosphoranes at 100 °C. Directed ortho-lithiation of spirophoshoranes followed by electrophilic quench reactions including carbon-based and heteroatom-based electrophiles afforded derivatives functionalized in a remote position with respect to the phosphorus atom. Benzoic acid catalyzed hydrolysis of spirophosphoranes furnished ortho-(γ-hydroxyalkylphosphoryl)benzamides by cleavage of the P–O and P–N bonds with retention of the phosphorus configuration. In contrast, alkaline hydrolysis led to the formation of γ-hydroxyphosphinic acids and benzamide.

Three Steps, Two Enzymes, One Pot, but a Multitude of Nanocompartments: Combined Cycles of Kinetic Resolutions and Re-racemization with Incompatible Biocatalysts.

Deracemizations are clearly preferable to kinetic resolutions in the production of chiral molecules from racemates, as they allow up to 100% chemical and optical yield. Here we present a new process route for multienzymatic deracemizations that is relevant for reaction systems with incompatible reaction conditions of the biocatalysts. This often applies to combinations of lipases used for stereoselective acylation and solvent-sensitive racemases. By encapsulating a model racemase in polymeric vesicles, it was protected from inactivation by the organic solvent up to phase proportions of 99%. As high yields in the lipase reaction required either water proportions well below 1% or racemase-denaturating acyl donor concentrations, a one-pot reaction was implemented through the sequential use of lipase and racemase-containing nanocompartments. This strategy allowed us to perform two kinetic resolutions with intermittent re-racemization in one pot yielding 72% (0.72 mM after 120 h) of an enantiopure product.

Metal‐to‐Ligand Ratio‐Dependent Chemodivergent Asymmetric Synthesis

AbstractChemodivergent asymmetric synthesis was achieved by tuning the metal‐to‐ligand ratio in an organometallic catalytic system. Using N‐(aroyloxy)phthalimide as the precursor of either an oxygen‐centered aroyloxy radical or a nitrogen‐centered phthalimidyl radical, enantioselective oxocyanation or aminocyanation of alkenes was achieved separately through a dual photoredox and copper catalysis. The metal‐to‐ligand ratio can exert chemoselective control while retaining the high enantiopurity of divergent products. Both reactions proceed efficiently with catalyst loading as low as 0.2 mol % and can be performed on a gram scale without loss of chemoselectivity or enantioselectivity. Chemodivergent asymmetric 1,5‐aminocyanation or 1,5‐oxocyanation of vinylcyclopropane can also be realized by this protocol. Mechanistic investigations involving electron paramagnetic resonance (EPR) experiments were performed to shed light on the stereochemical and chemodivergent results.

Metal-to-Ligand Ratio-Dependent Chemodivergent Asymmetric Synthesis.

Chemodivergent asymmetric synthesis was achieved by tuning the metal-to-ligand ratio in an organometallic catalytic system. Using N-(aroyloxy)phthalimide as the precursor of either an oxygen-centered aroyloxy radical or a nitrogen-centered phthalimidyl radical, enantioselective oxocyanation or aminocyanation of alkenes was achieved separately through a dual photoredox and copper catalysis. The metal-to-ligand ratio can exert chemoselective control while retaining the high enantiopurity of divergent products. Both reactions proceed efficiently with catalyst loading as low as 0.2 mol % and can be performed on a gram scale without loss of chemoselectivity or enantioselectivity. Chemodivergent asymmetric 1,5-aminocyanation or 1,5-oxocyanation of vinylcyclopropane can also be realized by this protocol. Mechanistic investigations involving electron paramagnetic resonance (EPR) experiments were performed to shed light on the stereochemical and chemodivergent results.

Direct, Asymmetric Synthesis of Carbocycle‐Fused Uracils via [4+2] Cycloadditions: a Noncovalent Organocatalysis Approach

AbstractThe peculiar versatility of remotely enolizable 6‐methyluracil‐5‐carbaldehydes as useful vinylogous pronucleophiles in direct, asymmetric [4+2] cyclizations with suitable nitroolefins has been demonstrated. Under the strategic exploitation of noncovalent bifunctional organocatalysis, a dearomative remote enolization strategy was implemented, to generate oQDM‐type dienolate intermediates that were efficiently and stereoselectively trapped by either aromatic or aliphatic nitroolefins. A series of functionalized, chiral carbocycle‐fused uracils embedding three contiguous stereocenters were thus collected in one step in good yields, with generally good levels of enantioselectivity, and complete diastereocontrol. Furthermore, the ability to provide enantiopure products via simple one‐cycle recrystallizations and the possibility to further functionalize these scaffolds without losing their chiral integrity were demonstrated.magnified image

Ni-catalyzed enantioselective [2 + 2 + 2] cycloaddition of malononitriles with alkynes

Summary Efficient strategies to assemble enantioenriched pyridine derivatives are highly important, given their significance in both synthetic and medicinal chemistry. Here, we report an enantioselective nickel-catalyzed intermolecular [2 + 2 + 2] cycloaddition of alkyne-tethered malononitriles with alkynes for the synthesis of densely substituted pyridines. The α-all-carbon quaternary center adjacent to pyridine is introduced by desymmetrizing the two cyano groups of disubstituted malononitriles. Notably, terminal alkynes are also tolerated with good regioselectivity to afford tetrasubstituted pyridines. Zinc halide is essential to enable the occurrence of the transformation by promoting the hetero-cyclometallation step. The reaction uses bio-renewable 2-MeTHF as the solvent and features mild reaction conditions, good functional group compatibilities, and enantioselectivities. This study offers a straightforward approach to the valuable enantioenriched heteroarenes from feedstock chemicals by forming three bonds and one quaternary stereocenter simultaneously in a single reaction step.

Stereodivergent Pd/Cu catalysis: asymmetric alkylation of racemic symmetrical 1,3-diphenyl allyl acetates.

We report a stereodivergent Pd/Cu catalyst system that was successfully applied to the asymmetric allylic alkylation of symmetrical 1,3-disubstituted allyl acetates with prochiral imino esters, providing efficient access to enantiopure products bearing vicinal stereocenters in a fully stereodivergent manner. The protocol proceeds smoothly under mild reaction conditions and can accommodate a range of imino esters, delivering the substituted products in high yields and with excellent diastereoselectivities (up to >20 : 1 dr) and enantioselectivities (up to >99% ee).

Pushing the limits: Cyclodextrin-based intensification of bioreductions

The asymmetric reduction of ketones is a frequently used synthesis route towards chiral alcohols. Amongst available chemo- and biocatalysts the latter stand out in terms of product enantiopurity. Their application is, however, restricted by low reaction output, often rooted in limited enzyme stability under operational conditions. Here, addition of 2-hydroxypropyl-β-cyclodextrin to bioreductions of o-chloroacetophenone enabled product concentrations of up to 29 % w/v at full conversion and 99.97 % e.e. The catalyst was an E. coli strain co-expressing NADH-dependent Candida tenuis xylose reductase and a yeast formate dehydrogenase for coenzyme recycling. Analysis of the lyophilized biocatalyst showed that E. coli cells were leaky with catalytic activity found as free-floating enzymes and associated with the biomass. The biocatalyst was stabilized and activated in the reaction mixture by 2-hydroxypropyl-β-cyclodextrin. Substitution of the wild-type xylose reductase by a D51A mutant further improved bioreductions. In previous optimization strategies, hexane was added as second phase to protect the labile catalyst from adverse effects of hydrophobic substrate and product. The addition of 2-hydroxypropyl-β-cyclodextrin (11 % w/v) instead of hexane (20 % v/v) increased the yield on biocatalyst 6.3-fold. A literature survey suggests that bioreduction enhancement by addition of cyclodextrins is not restricted to specific enzyme classes, catalyst forms or substrates.