Chiral Auxiliary Research Articles

Diastereoselective Cross-Dehydrogenative Coupling Reactions of Amides with Diarylmethanes Using DDQ through Oxidative C–H Benzylic Activation

AbstractThis study reports the chiral-auxiliary-controlled diastereoselective dehydrogenative coupling of diarylmethanes with amides by using 2,3-dichloro-5,6-dicyano-1,4-benzoquinone as the oxidant. The scope of the proposed reaction is very broad, with a wide variety of substrates and nucleophiles being applicable. The chiral induction can be attributed to the coordination of the oxygen atom on the chiral auxiliary with the carbocation intermediates.

Biocatalytic, Stereoconvergent Alkylation of (Z/E)-Trisubstituted Silyl Enol Ethers.

Alkene functionalization has garnered significant attention due to the versatile reactivity of C=C bonds. A major challenge is the selective conversion of isomeric alkenes into chiral products. Researchers have devised various biocatalytic strategies to transform isomeric alkenes into stereopure compounds; while selective, the enzymes often specifically convert one alkene isomer, thereby diminishing overall yield. To increase the overall yield, scientists have introduced additional driving forces to interconvert alkene isomers. This improves the yield of biocatalytic alkene functionalization at the cost of increased energy consumption and chemical waste. Developing a stereoconvergent enzyme for alkene functionalization offers an ideal solution, although such catalysts are rarely reported. Here we present engineered hemoproteins derived from a bacterial cytochrome P450 that efficiently catalyze the stereoconvergent α-carbonyl alkylation of isomeric silyl enol ethers, producing stereopure products. Through screening and directed evolution, we generated P450BM3 variant SCA-G2, which catalyzes stereoconvergent carbene transfer in E. coli, with high efficiency and stereoselectivity toward various Z/E mixtures of silyl enol ethers. In contrast to established stereospecific transformations that leave one isomer unreacted, SCA-G2 converts both isomers to a stereopure product. This biocatalytic approach simplifies the synthesis of chiral α-branched ketones by eliminating the need for stoichiometric chiral auxiliaries, strongly basic alkali-metal enolates, and harsh conditions, delivering products with high efficiency and excellent chemo- and stereoselectivities.

Monoterpene Thiols: Synthesis and Modifications for Obtaining Biologically Active Substances.

Monoterpene thiols are one of the classes of natural flavors that impart the smell of citrus fruits, grape must and wine, black currants, and guava and are used as flavoring agents in the food and perfume industries. Synthetic monoterpene thiols have found an application in asymmetric synthesis as chiral auxiliaries, derivatizing agents, and ligands for metal complex catalysis and organocatalysts. Since monoterpenes and monoterpenoids are a renewable source, there are emerging trends to use monoterpene thiols as monomers for producing new types of green polymers. Monoterpene thioderivatives are also known to possess antioxidant, anticoagulant, antifungal, and antibacterial activity. The current review covers methods for the synthesis of acyclic, mono-, and bicyclic monoterpene thiols, as well as some investigations related to their usage for the preparation of the compounds with antimicrobial properties.

A Stereoselective Entry to Enantiopure (S)-2-Amino-2-methyl-5-arylpent-4-ynoic Acids and Evaluation of Their Inhibitory Activity against Bacterial Collagenase G

Nowadays, amino acids (AAs) and peptides with bulky side chains hold significant interest for organic synthesis and the modern pharma industry. Non-proteinogenic (or unnatural) AAs are key building blocks used for obtaining pharmaceutically relevant peptides and for the development of chiral molecular catalysts, and they are extensively used in the total synthesis of complex natural compounds. Thus, an elaboration of cost-effective methods for the preparation of novel unnatural AAs to increase their structural diversity is highly desirable. In this context, herein, we present an asymmetric metal-templated synthesis of a number of enantiomerically pure (S)-2-amino-2-methyl-5-arylpent-4-ynoic acids starting from commercially available reagents and Belokon’s chiral auxiliary (S)-BPB, namely (S)-2-(N-benzylprolyl)aminobenzophenone. The construction of a chiral Ni(II) complex from alanine (Ala) and the subsequent propargylation, arylation by the Sonogashira cross-coupling reaction using various aryl halides, and, finally, an acidic decomposition of the obtained complexes deliver to the target complex α,α-disubstituted AAs featuring a triple bond in a side chain. Next, the Fmoc-protected α-AAs and dipeptide were synthesized. Finally, we examined the obtained α-AAs and peptide as collagenase inhibitors.

Probing Chiral Sulfoximine Auxiliaries in Ru(II)-Catalyzed One-Pot Asymmetric C-H Hydroarylation and Annulations with Alkynes.

Developed herein is a chiral sulfoximine-enabled Ru(II)-catalyzed asymmetric C-H activation/functionalization involving intramolecular hydroarylation and functionalization/annulation of alkynes. This process constructs dihydrobenzofuran- or indoline-fused isoquinolinones having a tertiary or quaternary stereocenter with good yields and enantioselectivities (up to 97:3 enantiomeric ratio). The chiral sulfoxide precursor used in synthesizing the enantiopure sulfoximines is spontaneously eliminated during the reaction. It can be recovered without losing enantiopurity (∼99% enantiomeric excess) and reused.

Total synthesis of [13 C2 ]-labeled phytosiderophores of the mugineic and avenic acid families.

We, herein, report the synthesis of 13 C2 -labeled natural products from the mugineic acid and avenic acid family. These phytosiderophores ("plant iron carriers") are built up from non-proteinogenic amino acids and play a key role in micronutrient uptake in gramineous plants. In this work, two central building blocks are prepared from labeled starting materials (13 C2 -bromoacetic acid, 13 C2 -glycine) and further employed in our recently reported divergent, branched synthetic strategy delivering eight isotopically labeled phytosiderophores. The required labeled building blocks (13 C2 -l-allylglycine and a related hydroxylated derivative) were prepared via enantioselective phase-transfer catalysis and enantio- and diastereoselective aldol condensation with a chiral auxiliary, respectively, both potentially valuable themselves for other synthetic routes toward labeled (natural) products.

Asymmetric Hetero-Diels–Alder Reaction of 4-Phenyl-1,2,4-triazole-3,5-dione with 2,4-Dienyl Carboxylic Acids

AbstractThe enantioselective hetero-Diels–Alder reaction of the cyclic azo compound 4-phenyl-1,2,4-triazole-3,5-dione with 2,4-dienyl carboxylic acids was performed using tartaric acid ester as the chiral auxiliary. The corresponding cycloadducts were obtained with enantioselectivities of up to 76% ee. The cis-carboxylic acid produced could be converted into the corresponding cis- and trans-methyl esters by varying the reaction conditions.

Synthesis of (1R)‐1‐(4‐Bromophenyl)‐2,2,2‐trifluoroethan‐1‐amine Hydrochloride through Diastereoselective Trifluoromethylation of a Chiral Sulfinimine

AbstractAn efficient three‐step synthesis of (1R)‐1‐(4‐bromophenyl)‐2,2,2‐trifluoroethan‐1‐amine hydrochloride (1) starting from inexpensive and readily available starting materials was developed. The sequence features a highly diastereoselective trifluoromethylation of a chiral sulfinimine using the Rupert–Prakash reagent TMSCF3 in combination with K3PO4 as an initiator. The diastereomeric purity of the resulting sulfinamide was further improved by direct precipitation of the desired diastereomer from the reaction mixture upon addition of water. The chiral auxiliary was then removed under acidic conditions, resulting in the isolation of chiral benzylamine 1 as its hydrochloride salt in 71 % overall yield and excellent purity (LC/MS: >99 % a/a; e.r.=99 : 1).

Computational Study Focusing on a Comprehensive Conformational Analysis of Transition States for Aza-Spiro Ring Formations with N-Alkoxyamides.

An accurate understanding of conformations in transition states is a critical piece in the theoretical analysis of complex molecular reactions. In this study, we investigated conformationally diverse transition states during intramolecular aza-spiro ring formation with an allylsilane moiety and N-alkoxy iminium ion, a key reaction in the synthesis of fasicularin by Sato and Chida et al., and identified the origins of stereoselectivity of the cyclization. A large number of conformational isomers with forming C-C bonds were comprehensively analyzed using Cremer-Pople puckering parameters. It was found that the conformations of the transition states had different puckering preferences depending on the reactant's double-bond geometry and the product's stereochemical configuration. Furthermore, an asymmetric aza-spiro cyclization with a tolyl group as a chiral auxiliary was investigated, showing that conformational anchoring by both a CH-O hydrogen bond and the CH-π interaction was critical for the asymmetric induction.

Stereoselective Synthesis of α-Disubstituted β-Homoprolines.

An efficient enantioselective synthesis of chiral α-disubstituted β-homoprolines was developed, starting with the stereodivergent allylation of chiral N-tert-butanesulfinyl imines derived from 4-bromobutanal with indium or zinc and using well-established and reliable synthetic transformations. This methodology allows the easy introduction of different substituents at the α-position of the pyrrolidine scaffold and is characterized by the possibility of switching the absolute configuration of the newly formed stereocenter either by changing the configuration of the tert-butanesufinamide chiral auxiliary or by using a different stereodivergent allylation protocol with the same auxiliary.

Diastereoselective Synthesis of Phosphinic Dipeptide Isosteres: Domino Chirality Transfer during a Stereocontrolled P-Michael Reaction.

A highly diastereoselective P-Michael addition of chiral aminophosphinic acids to achiral acrylates has been developed, leading to phosphinic dipeptide isosteres in high yields and dr of up to >50:1. The method allows for the diastereoselective preparation of target compounds without the need for chiral auxiliaries or P-chiral substrates. A possible mechanistic explanation involves a domino chirality transfer from the aminophosphinic acid to the P center, amplified by a crucial benzhydryl ester group, and then to the α-carbon.

Accessing optically pure 5,13-Dimethylaza[7]helicene via selective removal of α-methylbenzylamine chiral auxiliary by catalytic hydrogenation reaction

The synthesis of 5,13-dimethyl-9-aza[7]helicene is reported. A new method to access optically pure helicene with methyl substituent is established. The diastereomeric helical diamine is prepared from 5,13-diformyl-9-aza[7]helicene by attaching a chiral auxiliary and its isomers were physically separated by column chromatography. This diastereomeric diamine with two different benzyl bonds were subjected to Pd–C catalyzed hydrogenation at ambient condition, resulting in the hydrogenolysis at the less substituted site. The enantiomers of 5,13-dimethyl-9-aza[7]helicene were accessed, and their chiroptical properties were investigated.

Toward coherent anti‐Stokes Raman scattering‐Raman optical activity for reaction monitoring in organocatalysis: Chiral vibrational signatures of the two atropisomers (R)‐ and (S)‐MOM‐BINOL in solution

AbstractCoherent anti‐Stokes Raman scattering‐Raman optical activity (CARS‐ROA) is a coherent version of spontaneous ROA spectroscopy, the latter being a well‐established chirally sensitive vibrational spectroscopic technique. A central major advantage of heterodyne‐detected CARS‐ROA over ROA is the drastic reduction of acquisition times from several hours to approximately 1 min due to the high ratio of the chiral Raman signal relative to the achiral CARS background. Here, we present the first demonstration of heterodyne‐detected CARS‐ROA of chiral molecules dissolved in an achiral solvent by using an experimental setup built from a conventional broadband CARS spectrometer. Specifically, the two atropisomers (R/S) of 2,2′‐Bis(methoxymethoxy)‐1,1′‐binaphthyl, a methoxymethyl (MOM) bis‐protected derivative of 1,1′‐Bi‐2‐naphthol (BINOL), dissolved in the achiral organic solvent dichloromethane (DCM) were characterized by employing ~1 ps, 1 mW of pump pulses and ~60 fs, 10 mW of Stokes pulses within approximately 4‐min acquisition time. MOM‐BINOL is an important precursor for the synthesis of a great variety of many chiral auxiliaries including binaphthyl phosphoric acids, which are an important class of chiral organocatalysts used in asymmetric reactions. Overall, this work is a first step toward kinetic reaction monitoring in organocatalysis by coherent ROA providing the necessary short acquisition times.

Optical Resolution of Carboxylic Acid Derivatives of Homoleptic Cyclometalated Iridium(III) Complexes via Diastereomers Formed with Chiral Auxiliaries.

We report on a facile method for the optical resolution of cyclometalated iridium(III) (Ir(III)) complexes via diastereomers formed with chiral auxiliaries. The racemic carboxylic acids of Ir(III) complexes (fac-4 (fac-Ir(ppyCO2H)3 (ppy: 2-phenylpyridine)), fac-6 (fac-Ir(tpyCO2H)3 (tpy: 2-(4'-tolyl)pyridine)), and fac-13 (fac-Ir(mpiqCO2H)3 (mpiq: 1-(4'-methylphenyl)isoquinoline))) were converted into the diastereomers, Δ- and Λ-forms of fac-9 (from fac-6), fac-10 (from fac-4), fac-11 (from fac-6), and fac-14 (from fac-13), respectively, by the condensation with (1R,2R)-1,2-diaminocyclohexane or (1R,2R)-2-aminocyclohexanol. The resulting diastereomers were separated by HPLC (with a nonchiral column) or silica gel column chromatography, and their absolute stereochemistry was determined by X-ray single-crystal structure analysis and CD (circular dichroism) spectra. Spectra of all diastereomers of the Ir(III) complexes are reported. Hydrolysis of the ester moieties of Δ- and Λ-forms of fac-10, fac-11, and fac-14 gave both enantiomers of the corresponding carboxylic acid derivatives in the optically pure forms, Δ-fac and Λ-fac-4, -6, and -13, respectively.

Applications of chiral sulfinyl auxiliaries in the asymmetric synthesis of fluorinated amines and amino acids

This review article covers the developments made in collaboration by groups of Professors V. P. Kukhar and P. Bravo to the synthetic applications of sulfinyl compounds as versatile chiral auxiliaries for asymmetric preparation of fluorinated amines and amino acids. The potential of the sulfinyl chiral auxiliaries in the field of stereoselective transformations of fluorinated substrates is demonstrated by diastereoselective methylene transfer from diazomethane to the carbonyl of β-keto-γ-fluoroalkyl sulfoxides as a general approach for preparation of various fluorinated oxirane derivatives, diastereoselective sulfoxide anions addition to fluorinated imines leading to convenient preparation of α-fluoroalkyl α-amino acids, hydroxy amines, and amines, diastereoselective Mannich-type reaction between N-tert-butanesulfinyl-3,3,3-trifluoroacetaldimine and protected alkyl glycolates furnishing β-trifluoromethyl isoserine derivatives and diastereoselective additions of phosphite or α-phosphonate anions to N-tert-butanesulfinyl-3,3,3-trifluoroacetaldimine using for synthesis of trifluoromethylated α- and β-aminophosphonic acids. Furthermore, diastereoselective additions of Reformatsky reagent derived from bromodifluoroethyl acetate as well as α,α-difluorophosphonate anions to N-p-toluenesulfinyl imines allowing convenient preparation of a,a-difluoro-b-amino acids and α,α-difluoro-β-amino phosphonates in enantiomerically pure form are described. Effect of fluorine on the mechanism and stereochemical outcome of these reactions is briefly discussed

Universal and divergent P-stereogenic building with camphor-derived 2,3-diols

The access to P-stereogenic motifs has always been considered a very challenging and high attractive mission in modern organic synthesis. While several chiral auxiliaries employed by the practical Jugé-Stephan-like methodology have been developed, new type of readily accessible bifunctional ligands toward P-stereogenic building still remain much desirable. Herein, we present a powerful chiral template, camphor-derived 2,3-diols named CAMDOL, which were designed and synthesized from the commercially cheap camphorquinone in high yields at 50 grams scale with a column-free purification. Diverse P(III)-chiral compounds and their borane forms including phosphinous acids, phosphinites, and phosphines, as well as the corresponding P(V)-chiral compounds including phosphinates, phosphine oxides, phosphinothioates, phosphine sulfides, and secondary phosphine oxides were afforded in high yields and ee values through the optimal 2,3-diphenyl CAMDOL platform. An unusual C3-OP bond cleavage following the first P-OC2 bond breaking was observed during the ring-opening process when quenching by NH4Cl solution, which generates a unique but valuable camphor-epoxide scaffold as by-product.

Photoredox Catalytic Installation of an Alkyl/Aryl Side Chain and Deuterium into (S)-Methyleneoxazolidinone: Synthesis of Enantioenriched α-Deuterated α-Amino Acid Derivatives.

A photoredox catalytic asymmetric method has been established for the installation of both aliphatic and aromatic side chains and the introduction of deuterium into the chiral methyleneoxazolidinone simultaneously. Efficient coupling of readily available boronic acids with the chiral auxiliary delivers structurally diverse α-deuterated α-amino acid derivatives with a high level of diastereoselectivity and deuteration.

Synthesis and Optical Resolution of Inherently Chiral Fluorescent Calix[4]arenes and Their Application in Chiral Recognition

AbstractInherently chiral calix[4]arenes were separated by condensation with chiral auxiliary (S)- and (R)-1-phenylethylamine using column chromatography on silica gel; subsequent derivatization with click chemistry furnished compounds with fluorescent properties that can be used for chiral recognition.

Copper(I)-catalyzed asymmetric alkylation of α-imino-esters

Asymmetric alkylation of enolates is one of the most direct and important reactions to prepare α-chiral carbonyl compounds. Except for the classical methods that rely on the use of chiral auxiliaries, asymmetric catalysis emerged as a powerful tool, especially asymmetric phase-transfer catalysis. However, in the field of transition metal catalysis, only limited success with asymmetric alkylation of enolates was achieved. Hereby, we disclose a copper(I)-catalyzed asymmetric alkylation of α-imino-esters with various alkyl halides, including allyl bromides, propargyl bromide, benzyl bromides, α-bromo carbonyl compounds, and alkyl iodides. Both linear and cyclic α-imino-esters serve as competent pronucleophiles in the alkylation, which affords α-amino acid derivatives bearing either a trisubstituted or a tetrasubstituted stereogenic carbon center in high to excellent enantioselectivity. Control experiments indicate that the α-imino-ester is activated by a chiral copper(I)-phosphine complex through coordination, thus enabling facile deprotonation to provide a stabilized copper(I)-enolate in the presence of a mild base. Finally, the mildly basic nature allows the asymmetric alkylation of chiral dipeptides with excellent both chemo- and enantioselectivities.

Asymmetric Synthesis of S(IV) and S(VI) Stereogenic Centers.

Sulfur can form diverse S(IV) and S(VI) stereogenic centers, of which some have gained significant attention recently due to their increasing use as pharmacophores in drug discovery programs. The preparation of these sulfur stereogenic centers in their enantiopure form has been challenging, and progress made will be discussed in this Perspective. This Perspective summarizes different strategies, with selected works, for asymmetric synthesis of these moieties, including diastereoselective transformations using chiral auxiliaries, enantiospecific transformations of enantiopure sulfur compounds, and catalytic enantioselective synthesis. We will discuss the advantages and limitations of these strategies and will provide our views on how this field will develop.