Tertiary Chiral Centers Research Articles

Expanding Access to Optically Active Non-Steroidal Anti-Inflammatory Drugs via Lipase-Catalyzed KR of Racemic Acids Using Trialkyl Orthoesters as Irreversible Alkoxy Group Donors

Studies into the enzymatic kinetic resolution (EKR) of 2-arylpropanoic acids (‘profens’), as the active pharmaceutical ingredients (APIs) of blockbuster non-steroidal anti-inflammatory drugs (NSAIDs), by using various trialkyl orthoesters as irreversible alkoxy group donors in organic media, were performed. The enzymatic reactions of target substrates were optimized using several different immobilized preparations of lipase type B from the yeast Candida antarctica (CAL-B). The influence of crucial parameters, including the type of enzyme and alkoxy agent, as well as the nature of the organic co-solvent and time of the process on the conversion and enantioselectivity of the enzymatic kinetic resolution, is described. The optimal EKR procedure for the racemic profens consisted of a Novozym 435-STREM lipase preparation suspended in a mixture of 3 equiv of trimethyl or triethyl orthoacetate as alkoxy donor and toluene or n-hexane as co-solvent, depending on the employed racemic NSAIDs. The reported biocatalytic system provided optically active products with moderate-to-good enantioselectivity upon esterification lasting for 7–48 h, with most promising results in terms of enantiomeric purity of the pharmacologically active enantiomers of title APIs obtained on the analytical scale for: (S)-flurbiprofen (97% ee), (S)-ibuprofen (91% ee), (S)-ketoprofen (69% ee), and (S)-naproxen (63% ee), respectively. In turn, the employment of optimal conditions on a preparative-scale enabled us to obtain the (S)-enantiomers of: flurbiprofen in 28% yield and 97% ee, ibuprofen in 45% yield and 56% ee, (S)-ketoprofen in 23% yield and 69% ee, and naproxen in 42% yield and 57% ee, respectively. The devised method turned out to be inefficient toward racemic etodolac regardless of the lipase and alkoxy group donor used, proving that it is unsuitable for carboxylic acids possessing tertiary chiral centers.

Palladium-catalyzed asymmetric allylic alkylation of 3-amino-2-oxindoles: Synthesis of 3-allyl-3-amino-2-oxindoles

Tartrate derived bi(oxazoline) ligand with palladium (II) species catalyzed asymmetric allylic alkylation reaction to access highly valuable 3-allyl-3-amino-2-oxindoles with vicinal quaternary and tertiary stereocenters in very good yields (up to 91%) and excellent enantioselectivity (up to 98% ee) with moderate to good diastereoselectivity (up to 5:1). The synthetic utility of 3-allyl-3-amino-2-oxindole was further demonstrated to construct spiro(oxindole-3,2′-pyrrolidine) with consecutive one quaternary and three tertiary chiral centers in good stereoselectivity (dr = 8:1 and 80% ee) through metal-free intramolecular iodocyclization reaction.

Highly Selective and Catalytic Generation of Acyclic Quaternary Carbon Stereocenters via Functionalization of 1,3-Dienes with CO2.

The catalytic asymmetric functionalization of readily available 1,3-dienes is highly important, but current examples are mostly limited to the construction of tertiary chiral centers. The asymmetric generation of acyclic products containing all-carbon quaternary stereocenters from substituted 1,3-dienes represents a more challenging, but highly desirable, synthetic process for which there are very few examples. Herein, we report the highly selective copper-catalyzed generation of chiral all-carbon acyclic quaternary stereocenters via functionalization of 1,3-dienes with CO2. A variety of readily available 1,1-disubstituted 1,3-dienes, as well as a 1,3,5-triene, undergo reductive hydroxymethylation with high chemo-, regio-, E/Z-, and enantioselectivities. The reported method features good functional group tolerance, is readily scaled up to at least 5 mmol of starting diene, and generates chiral products that are useful building blocks for further derivatization. Systemic mechanistic investigations using density functional theory calculations were performed and provided the first theoretical investigation for an asymmetric transformation involving CO2. These computational results indicate that the 1,2-hydrocupration of 1,3-diene proceeds with high π-facial selectivity to generate an (S)-allylcopper intermediate, which further induces the chirality of the quaternary carbon center in the final product. The 1,4-addition of an internal allylcopper complex, which differs from previous reports involving terminal allylmetallic intermediates, to CO2 kinetically determines the E/Z- and regioselectivity. The rapid reduction of a copper carboxylate intermediate to the corresponding silyl-ether in the presence of Me(MeO)2SiH provides the exergonic impetus and leads to chemoselective hydroxymethylation rather than carboxylation. These results provide new insights for guiding further development of asymmetric C-C bond formations with CO2.

Enantioselective Synthesis of 5-Alkylated Thiazolidinones via Palladium-Catalyzed Asymmetric Allylic C-H Alkylations of 1,4-Pentadienes with 5 H-Thiazol-4-ones.

A palladium-catalyzed, enantioselective allylic C-H alkylation of 1,4-pentadienes with 5 H-thiazol-4-ones has been developed. Under the cooperative catalysis of a palladium complex of chiral phosphoramidite ligand and an achiral Brønsted acid, a broad range of substituted 5 H-thiazol-4-ones bearing sulfur-containing tertiary chiral centers were accessed from the allylic C-H alkylation in high levels of yields and enantioselectivities. Alkyl and aryl 1,4-pentadienes led to linear and branched allylation products, respectively.

Enantioselective γ-addition reaction of rhodanines to allenoates catalyzed by chiral phosphine-carbamate

Phosphine-catalyzed enantioselective γ-additions of rhodanines to allenoates have been developed for the first time. With the employment of chiral cyclohexane-based phosphines, a wide range of substituted rhodanine derivatives containing tertiary chiral centers were constructed in good yields and high enantioselectivities.

Control of Activation Mode To Achieve Diastereodivergence in Asymmetric Syntheses of Chiral Spiropiperidinone Derivatives.

An efficient organocatalytic cascade reaction has been developed involving a Michael-hemiaminalization relay for the asymmetric synthesis of spiropiperidinone derivatives bearing adjacent quaternary and tertiary chiral centers via LUMO or HOMO activation. Importantly, this methodology demonstrates that applying distinct activation modes to different substrates in the same reaction can diverge diastereoselectivity. To our knowledge, this is also one of the few published cases of primary amine catalytic [3 + 3] cycloaddition reactions involving α-branched β-ketoamides.

ChemInform Abstract: Highly Enantioselective Direct Allylic Alkylation of Butenolides with Morita—Baylis—Hillman Carbonates Catalyzed by Chiral Squaramide‐Phosphine.

An efficient asymmetric vinylogous allylic alkylation of β,γ-butenolides with Morita–Baylis–Hillman carbonates has been developed. With a chiral cyclohexane-based squaramide-phosphine catalyst 5e, optically active γ,γ-disubstituted butenolides containing adjacent quaternary and tertiary chiral centers have been constructed in good-to-excellent yields (up to 98%) and excellent stereoselectivities (87 : 13–99 : 1 dr, 96–99% ee).

ChemInform Abstract: Calcium‐Catalyzed Asymmetric Synthesis of 3‐Tetrasubstituted Oxindoles: Efficient Construction of Adjacent Quaternary and Tertiary Chiral Centers.

AbstractThe asymmetric addition of N‐Boc‐imines (II) to 3‐substituted oxindoles (I) leads to chiral 3,3‐disubstituted oxindoles with 86‐96% diastereoselectivity (the main diastereomer is readily isolated by a column chromatography).

Construction of tertiary chiral centers by Pd-catalyzed asymmetric allylic alkylation of prochiral enolate equivalents

The palladium-catalyzed decarboxylative allylic alkylation of enol carbonates derived from lactams and ketones is described. Employing these substrates with an electronically tuned Pd catalyst system trisubstituted chiral centers are produced. These stereocenters have been previously challenging to achieve using Pd complex/chiral P–N ligand systems.

Calcium-catalyzed asymmetric synthesis of 3-tetrasubstituted oxindoles: efficient construction of adjacent quaternary and tertiary chiral centers.

Chiral Ca-catalyzed asymmetric addition reactions of 3-substituted oxindoles with N-Boc-imines afford 3-tetrasubstituted oxindole derivatives bearing adjacent quaternary and tertiary chiral centers, which are key structures for biological activities. Ubiquitous and nontoxic Ca catalysts (1-10 mol %) work well in this reaction, and high yields (up to 99%) and selectivities (up to >99% ee) of the products with wide substrate scope have been attained. The structures of the chiral Ca catalysts and intermediary Ca enolates are also discussed.

Highly enantioselective construction of tertiary thioethers and alcohols via phosphine-catalyzed asymmetric γ-addition reactions of 5H-thiazol-4-ones and 5H-oxazol-4-ones: scope and mechanistic understandings.

Phosphine-catalyzed highly enantioselective γ-additions of 5H-thiazol-4-ones and 5H-oxazol-4-ones to allenoates have been developed for the first time. With the employment of amino-acid derived bifunctional phosphines, a wide range of substituted 5H-thiazol-4-one and 5H-oxazol-4-one derivatives bearing heteroatom (S or O)-containing tertiary chiral centers were constructed in high yields and excellent enantioselectivities. The reported method provides facile access to enantioenriched tertiary thioethers/alcohols. The mechanism of the γ-addition reaction was investigated by performing DFT calculations, and the hydrogen bonding interactions between the Brønsted acid moiety of the phosphine catalysts and the "C[double bond, length as m-dash]O" unit of the donor molecules were shown to be crucial in asymmetric induction.

Highly enantioselective direct allylic alkylation of butenolides with Morita–Baylis–Hillman carbonates catalyzed by chiral squaramide-phosphine

Asymmetric vinylogous allylic alkylation of β,γ-butenolides with Morita–Baylis–Hillman carbonates has been developed to construct γ,γ-disubstituted butenolides containing adjacent quaternary and tertiary chiral centers.

ChemInform Abstract: Diastereo‐ and Enantioselective Nitro‐Mannich Reaction of α‐Substituted Nitroacetates to N‐Phosphoryl Imines Catalyzed by cinchona Alkaloid Thiourea Organocatalysts.

AbstractThe presented method is highly tolerable to functionalized N‐phosphoryl imines and provides a reliable synthetic route to the corresponding β‐nitro ethylphosphoramidates (III) with adjacent quaternary and tertiary chiral centers in high enantio‐ and diastereoselectivity.

ChemInform Abstract: Asymmetric Organocatalytic Allylic Alkylation of Reissert Compounds: A Facile Access to Chiral 1,1‐Disubstituted 1,2‐Dihydroisoquinolines.

The first asymmetric organocatalytic allylic alkylation of 1,2-dihydro-Reissert compounds and Morita-Baylis-Hillman (MBH) carbonates has been developed, which provided a novel protocol to construct enantioenriched functionalized 1,2-dihydroisoquinolines bearing vicinal quaternary and tertiary chiral centers at C-1 position (up to 94% ee, dr > 20 : 1).

ChemInform Abstract: Hydrolytic Enantioselective Protonation of Cyclic Dienyl Esters and a β‐Diketone with Chiral Phase‐Transfer Catalysts.

AbstractThe process allows the synthesis of optically active enones.

Diastereo- and enantioselective nitro-Mannich reaction of α-substituted nitroacetates to N-phosphoryl imines catalyzed by cinchona alkaloid thiourea organocatalysts

The asymmetric nitro-Mannich reaction of N-phosphoryl imines with α-substituted nitroacetates was performed by using cinchona alkaloid thioureas as organocatalysts in toluene at -20 °C. The present method was highly tolerable to functionalized N-phosphoryl imines and provided a reliable synthetic route to obtain the corresponding β-nitro ethylphosphoramidates with adjacent quaternary and tertiary chiral centers in high yield (up to 86%) and high enantiostereoselectivity (up to 99% ee) and diastereoselectivity (up to 99 : 1, anti-selectivity).

Hydrolytic Enantioselective Protonation of Cyclic Dienyl Esters and a β-Diketone with Chiral Phase-Transfer Catalysts

Hydrolytic enantioselective protonation of dienyl esters and a β-diketone catalyzed by phase-transfer catalysts are described. The latter reaction is the first example of an enantio-convergent retro-Claisen condensation. Corresponding various optically active α,β-unsaturated ketones having tertiary chiral centers adjacent to carbonyl groups were obtained in good to excellent yields and enantiomeric ratios (83-99%, up to 97.5:2.5 er).

Asymmetric organocatalytic allylic alkylation of Reissert compounds: a facile access to chiral 1,1-disubstituted 1,2-dihydroisoquinolines

The first asymmetric organocatalytic allylic alkylation of 1,2-dihydro-Reissert compounds and Morita-Baylis-Hillman (MBH) carbonates has been developed, which provided a novel protocol to construct enantioenriched functionalized 1,2-dihydroisoquinolines bearing vicinal quaternary and tertiary chiral centers at C-1 position (up to 94% ee, dr > 20 : 1).

ChemInform Abstract: Asymmetric Aza‐Henry Reaction with α‐Substituted Nitroacetates Catalyzed by a Bifunctional Thiourea‐Guanidine Catalyst.

AbstractThe process renders possible a facile access to β‐nitroamine derivatives bearing adjacent quaternary and tertiary chiral centers.

Highly Asymmetric Intramolecular Cyclopropanation of Acceptor-Substituted Diazoacetates by Co(II)-Based Metalloradical Catalysis: Iterative Approach for Development of New-Generation Catalysts

3,5-Di(t)Bu-QingPhyrin, a new D(2)-symmetric chiral porphyrin derived from a chiral cyclopropanecarboxamide containing two contiguous stereocenters, has been developed using an iterative approach based on Co(II)-catalyzed asymmetric cyclopropanation of alkenes. The Co(II) complex of 3,5-Di(t)Bu-QingPhyrin, [Co(P2)], has proved to be a general and effective catalyst for asymmetric intramolecular cyclopropanation of various allylic diazoacetates (especially including those with α-acceptor substituents) in high yields with excellent stereoselectivities. The [Co(P2)]-based intramolecular metalloradical cyclopropanation provides convenient access to densely functionalized 3-oxabicyclo[3.1.0]hexan-2-one derivatives bearing three contiguous quaternary and tertiary chiral centers with high enantiomeric purity.