Control Of Diastereoselectivity Research Articles

Asymmetric Organocatalytic 1,3-Dipolar Cycloaddition of Azomethine Ylides with β-Substituted Cyclic Enones.

The enantioselective and diastereoselective control of 1,3-dipolar cycloaddition reactions to β-substituted cyclic enones has been developed. The 1,3-dipolar cycloaddition of phthalazinium dicyanomethanides with cyclic dienones affords chiral tetrahydropyrrolo[2,1-a]phthalazine derivatives 3 through vinylogous iminium ion activation by combining a cinchona-based primary amine C3 and a chiral camphorsulfonic acid additive. Conversely, with a weaker 3,5-bis(trifluoromethyl)benzoic acid additive, the 1,3-dipolar cycloaddition of phthalazinium dicyanomethanides with β-substituted cyclic enones leads to chiral hexahydroisoindolo[1,2-a]phthalazin-10(8H)-one derivatives 4 with excellent stereocontrol via endo-dienamine activation.

Radical Allylation of Aldehydes with Allenes by Photoredox Cobalt and Chromium Dual Catalysis

AbstractA dual cobalt and chromium photoredox-catalyzed allylation of aldehydes with allenes through a photo metal-hydride atom transfer (MHAT) process has been developed to yield homoallylic alcohols with exceptional diastereoselective control. This sustainable and efficient method holds significant promise for applications in the synthesis of valuable organic compounds.

Diastereo-divergent synthesis of chiral hindered ethers via a synergistic calcium(II)/gold(I) catalyzed cascade hydration/1,4-addition reaction.

Hindered ethers are ubiquitous in natural products and bioactive molecules. However, developing an efficient method for the stereocontrolled synthesis of all stereoisomers of chiral hindered ethers is highly desirable but challenging. Here we show a strategy that utilizes in situ-generated water as a nucleophile in an asymmetric cascade reaction involving two highly reactive intermediates, 3-furyl methyl cations and ortho-quinone methides (o-QMs), to synthesize chiral hindered ethers. The Ca(II)/Au(I) synergistic catalytic system enables the control of diastereoselectivity and enantioselectivity by selecting suitable chiral phosphine ligands in this cascade hydration/1,4-addition reaction, affording all four stereoisomers of a diverse range of chiral tetra-aryl substituted ethers with high diastereoselectivities (up to >20/1) and enantioselectivities (up to 95% ee). This work provides an example of chiral Ca(II)/Au(I) bimetallic catalytic system controlling two stereogenic centers via a cascade reaction in a single operation.

Highly enantioselective carbene-catalyzed δ-lactonization via radical relay cross-coupling

An N-heterocyclic carbene (NHC) catalyzed enantioselective cyclisation and trifluoromethylation of olefins with cinnamaldehydes via radical relay cross-coupling in the presence of Togni reagent is reported and δ-lactones tolerated with stereogenic centers at β- and γ-positions are obtained in moderate to high yields and with high enantioselectivities. Further computational studies explain that the radical cross-coupling step is the key to determining the enantioselectivity. Energy analysis of key transition states and intermediates also provides a reasonable explanation for the difficulty of diastereoselective control. DFT calculations also reveal that the hydrogen-bonding interaction plays a vital role in the promotion of this chemistry.

Synergistic Pd/Cu-Catalyzed 1,5-Double Chiral Inductions.

Much attention has been focused on the catalytic asymmetric creation of single chiral centers or two adjacent stereocenters. However, the asymmetric construction of two nonadjacent stereocenters is of significant importance but is challenging because of the lack of remote chiral induction models. Herein, based on a C═C bond relay strategy, we report a synergistic Pd/Cu-catalyzed 1,5-double chiral induction model. All four stereoisomers of the target products bearing 1,5-nonadjacent stereocenters involving both allenyl axial and central chirality could be obtained divergently by simply changing the combination of two chiral catalysts with different configurations. Control experiments and DFT calculations reveal a novel mechanism involving 1,5-oxidative addition, contra-thermodynamic η3-allyl palladium shift, and conjugate nucleophilic substitution, which play crucial roles in the control of reactivity, regio-, enantio-, and diastereoselectivity. It is expected that this C═C bond relay strategy may provide a general protocol for the asymmetric synthesis of structural motifs bearing two distant stereocenters.

Azide‐free Enantioselective Synthesis of Clinical Antibiotic (1R,2R)‐Chloramphenicol (Chloromycetin)

AbstractThe enantioselective synthesis of the broad‐spectrum antibiotic (1R,2R)‐chloramphenicol and its congener is described here. Our approach is based on the Evans asymmetric aldol reaction, which involves the use of a chiral ‘glycine enolate equivalent’ derived from N‐(N‐Boc‐glycinyl) oxazolidinone and p‐nitrobenzaldehyde. The reaction is catalyzed by TiCl4 and Hunig's base DIPEA, resulting in the production of both Evans syn‐ and non‐Evans anti‐adducts in a 3 : 1 diastereomeric ratio with 85 % combined yield. We achieved diastereoselectivity control in the reaction using Lewis acid TiCl4 along with DIPEA. Subsequently, the syn‐ and anti‐aldol products were transformed into (1R,2R)‐ and (1R,2S)‐chloramphenicol, respectively, using a three‐step method. The stereochemistry of the clinically used chloramphenicol was confirmed by measuring the optical rotation of the final compounds.

A stereoselective nontraditional Heck reaction mechanism: Origins of enantioselectivity and diastereoselectivity

Nontraditional Heck-type reactions of C = heteroatomic variants have been a great challenge. Herein, we computationally investigate a nontraditional stereoselective Heck mechanism regarding hydrazone C = N-NH2 by using density functional theory (DFT) methods. Calculations indicate that the total potential barrier of the conversion is 25.6 kcal/mol, which is reasonable to be crossed under the current reaction conditions. Unlike C = C π-bonds, the coordination of C = N with transition metal palladium into a η1-complex is confirmed. A larger π-bond insertion barrier for C = N is required, which is rationalized by frontier molecular orbital (FMO) analysis with a wider LUMO-HOMO energy gap. π-bond insertion is the enantioselectivity determining step of the strategy and that the pathway toward the R-isomer exhibits a much lower energy barrier (24.2 vs 40.1 kcal/mol). π-bond insertion is also the diastereoselective control step with using DBBP ligands. Non-covalent interaction (NCI) analysis confirms that greater spatial hindrance is responsible for the stereoselectivity of the protocol. Meanwhile, calculations show that using an acid-promoted tactic can effectively improve the in situ production of hydrazone and significantly reduce the energy barrier.

Diastereoselective Dearomatization of Chalcone‐Based Quinolinium Salts to Assemble Bridged Quinobenzazepine Polycycles

AbstractQuinobenzazepines are useful in medicinal chemistry, but their synthesis is very challenging. Herein, we designed and synthesized a range of multi‐functional chalcone‐based quinolinium salts; their synthetic application in the rapid and straightforward construction of quinobenzazepines was successfully explored. A wide range of oxa‐bridged quinobenzazepine polycycles were afforded serendipitously through a dearomative cascade reaction of our newly developed quinolinium salts and acetylacetone. This synthetic strategy features high bond‐ and ring‐forming efficiency and complete regio‐ and diastereoselective control.

Chiral-at-Ruthenium-SEGPHOS Catalysts Display Diastereomer-Dependent Regioselectivity: Enantioselective Isoprene-Mediated Carbonyl tert-Prenylation via Halide Counterion Effects.

The first correlation between metal-centered stereogenicity and regioselectivity in a catalytic process is described. Alternate pseudo-diastereomeric chiral-at-ruthenium complexes of the type RuX(CO)[η3-prenyl][(S)-SEGPHOS] form in a halide-dependent manner and display divergent regioselectivity in catalytic C-C couplings of isoprene to alcohol proelectrophiles via hydrogen autotransfer. Whereas the chloride-bound ruthenium-SEGPHOS complex prefers a trans-relationship between the halide and carbonyl ligands and delivers products of carbonyl sec-prenylation, the iodide-bound ruthenium-SEGPHOS complex prefers a cis-relationship between the halide and carbonyl ligands and delivers products of carbonyl tert-prenylation. The chloride- and iodide-bound ruthenium-SEGPHOS complexes were characterized in solution and solid phase by 31P NMR and X-ray diffraction. Density functional theory calculations of the iodide-bound catalyst implicate a Curtin-Hammett-type scenario in which the transition states for aldehyde coordination from an equilibrating mixture of sec- and tert-prenylruthenium complexes are rate- and product-determining. Thus, control of metal-centered diastereoselectivity has unlocked the first catalytically enantioselective isoprene-mediated carbonyl tert-prenylations.

Stereodivergent asymmetric hydrogenation of quinoxalines

•Stereodivergent construction of vicinal stereocenters via asymmetric hydrogenation •Concise access to all four stereoisomers of chiral THQs from the same substrates •Cation effect directed diastereoselectivity control Stereodivergent asymmetric synthesis of all the stereoisomers of enantioenriched products, preferably using a catalytic method, is of great interest and importance in both organic synthesis and drug discovery. Herein, we report an unprecedented stereodivergent AH of di-substituted quinoxalines via Mn catalysis, furnishing cis- and rarely accessed trans-chiral tetrahydroquinoxalines (THQs) with high levels of diastereo- and enantioselectivity. This transformation features excellent functional group compatibility and broad applicability. The synthetic utility of this methodology is further highlighted by a concise and stereoselective synthesis of methylated variants of valuable bioactive molecules containing chiral THQ scaffolds. Stereodivergent asymmetric synthesis of all the stereoisomers of enantioenriched products, preferably using a catalytic method, is of great interest and importance in both organic synthesis and drug discovery. Herein, we report an unprecedented stereodivergent AH of di-substituted quinoxalines via Mn catalysis, furnishing cis- and rarely accessed trans-chiral tetrahydroquinoxalines (THQs) with high levels of diastereo- and enantioselectivity. This transformation features excellent functional group compatibility and broad applicability. The synthetic utility of this methodology is further highlighted by a concise and stereoselective synthesis of methylated variants of valuable bioactive molecules containing chiral THQ scaffolds.

Discovery and Engineering of the l-Threonine Aldolase from Neptunomonas marine for the Efficient Synthesis of β-Hydroxy-α-amino Acids via C–C Formation

l-Threonine aldolases (LTAs) are attractive biocatalysts for synthesizing β-hydroxy-α-amino acids (HAAs) via C–C bond formation in pharmaceuticals, although their industrial applications suffer from low activity and diastereoselectivity. Herein, we describe the discovery of an LTA from Neptunomonas marine (NmLTA) that displays both ideal enzymatic activity (64.8 U mg–1) and diastereoselectivity (89.5% diastereomeric excess, de) for the desired product l-threo-4-methylsulfonylphenylserine (l-threo-MTPS). Using X-ray crystallography, site-directed mutagenesis, and computational modeling, we propose a “dual-conformation” mechanism for the diastereoselectivity control of NmLTA, whereby the incoming 4-methylsulfonylbenzaldehyde (4-MTB) could potentially bind at the NmLTA active site in two distinct orientations, potentially forming two diastereoisomers (threo- or erythro-form products). Importantly, two key NmLTA residues H140 and Y319 play critical roles in fine-tuning the binding mode of 4-MTB, supported by our site-mutagenesis assays. Uncovering of the catalytic mechanism in NmLTA guides us to further improve the diastereoselectivity of this enzyme. A triple variant of NmLTA (N18S/Q39R/Y319L, SRL) exhibited both improved diastereoselectivity (de value > 99%) and enzymatic activity (95.7 U mg–1) for the synthesis of l-threo-MTPS compared with that of the wild type. The preparative gram-scale synthesis for l-threo-MTPS with the SRL variant produced a space-time yield of up to 9.0 g L–1 h–1, suggesting a potential role as a robust C–C bond synthetic tool for the industrial synthesis of HAAs at a preparative scale. Finally, the SRL variant accepted a wider range of aromatic aldehyde derivatives as substrates and exhibited improved diastereoselectivity toward para-site substituents. This work provides deep structural insights into the molecular mechanism underlying the catalysis in NmLTA and pinpoints the key structural motifs responsible for regulating the diastereoselectivity control, thereby guiding future attempts for protein engineering of various LTAs from different sources.

Aryne 1,4-Disubstitution and Remote Diastereoselective 1,2,4-Trisubstitution via a Nucleophilic Annulation-[5,5]-Sigmatropic Rearrangement Process.

Both aryne 1,4-disubstitution and 1,2,4-trifunctionalization were accomplished from tertiary amines bearing a penta-2,4-dien-1-yl moiety. These transformations could directly incorporate a C-N and a C-C bond para to each other on an aryne intermediate via a sequential nucleophilic addition and [5,5]-sigmatropic rearrangement. When arynes bearing 3-tethered electrophiles were employed, a cascade regioselective nucleophilic addition, intramolecular cyclization, and remote diastereoselective [5,5]-sigmatropic rearrangement process was observed. Our density functional theory (DFT) calculations revealed that hydrogen-bonding interactions between two C-H hydrogens on the penta-2,4-dien-1-yl chain and the oxygen anion generated upon N-nucleophilic annulation reaction in the [5,5]-sigmatropic rearrangement step is responsible for the remote diastereoselective control in this reaction system.

Aryne 1,4‐Disubstitution and Remote Diastereoselective 1,2,4‐Trisubstitution via a Nucleophilic Annulation‐[5,5]‐Sigmatropic Rearrangement Process

AbstractBoth aryne 1,4‐disubstitution and 1,2,4‐trifunctionalization were accomplished from tertiary amines bearing a penta‐2,4‐dien‐1‐yl moiety. These transformations could directly incorporate a C−N and a C−C bond para to each other on an aryne intermediate via a sequential nucleophilic addition and [5,5]‐sigmatropic rearrangement. When arynes bearing 3‐tethered electrophiles were employed, a cascade regioselective nucleophilic addition, intramolecular cyclization, and remote diastereoselective [5,5]‐sigmatropic rearrangement process was observed. Our density functional theory (DFT) calculations revealed that hydrogen‐bonding interactions between two C−H hydrogens on the penta‐2,4‐dien‐1‐yl chain and the oxygen anion generated upon N‐nucleophilic annulation reaction in the [5,5]‐sigmatropic rearrangement step is responsible for the remote diastereoselective control in this reaction system.

A General Stereoselective Synthesis of [4]Dendralenes.

The first general synthesis of branched tetraenes ([4]dendralenes) involves two or three steps from inexpensive, commodity chemicals. It involves an unprecedented variation on Suzuki-Miyaura cross-coupling, generating two new C-C bonds in a one-flask operation with control of diastereoselectivity. The broad scope of the method is established through the synthesis of more than 60 diversely substituted [4]dendralene molecules, along with substituted buta-1,3-dienes and other [n]dendralenes. [4]Dendralenes are demonstrated to be significantly more kinetically stable than their well-known [3]dendralene counterparts. The first stereoselective synthesis of these compounds is also reported, through the catalyst-controlled generation of both E- and Z-diastereomeric products from the same precursor. Novel, through-conjugated/cross-conjugated hybrid molecules are introduced. The first selective dienophile cycloadditions to substituted [4]dendralenes are reported, thus paving the way for applications in target-oriented synthesis.

Rhodium-catalyzed regioselective addition of thioacids to terminal allenes: enantioselective access to branched allylic thioesters.

Rhodium-catalyzed regio- and enantioselective hydrothiolation of terminal allenes with thioacids is reported for the atom-economic synthesis of chiral branched allylic thioesters. By using a rhodium(I) catalyst system, diversities of terminal allenes and thioacids afforded the corresponding branched thioesters in excellent regioselectivity, high yield, and good enantioselectivity. This method was also explored for Fmoc-protected aminothioacids for diastereoselective synthesis of the corresponding thioesters.

Cp2TiCl-Mediated Reductive Cyclization: Total Synthesis of Pestalotiolactone A, Myrotheciumone A, and Scabrol A.

The first stereoselective total syntheses of fungal secondary metabolites monoterpenoid (+)-pestalotiolactone A, meroterpenoid (-)-myrotheciumone A, and iridoid lactone (+)-scabrol A have been accomplished in an expedient unified approach starting from d-(+)-malic acid employing an epoxide opening-radical cyclization protocol initiated by Cp2Ti(III)Cl as a key step to assemble the core bicyclic lactone moieties of these molecules with complete diastereoselective control. Finally, the deoxygenation and methylation delivered the target natural products.

Heterogeneous Hydroxyl-Directed Hydrogenation: Control of Diastereoselectivity through Bimetallic Surface Composition

Directed hydrogenation, in which product selectivity is dictated by the binding of an ancillary directing group on the substrate to the catalyst, is typically catalyzed by homogeneous Rh and Ir com...

Reactions of Styrylmalonates with Aromatic Aldehydes: Detailed Synthetic and Mechanistic Studies.

Reactions of styrylmalonates with aromatic aldehydes in the presence of Lewis and Brønsted acids and their regularities have been studied in detail. Approaches to the synthesis of various polysubstituted 5,6-dihydropyran-2-ones, indenes, aryl-containing dienes and trienes, cyclopentadienes, and polycyclic lactones have been developed with chemo-, regio-, stereo-, and diastereoselectivity control. The mechanisms of these reactions were studied in depth using multinuclear NMR experiments, monitoring the reactions in the NMR tube, and 18O isotope labeling.

Photocatalytic Generation of π-Allyltitanium Complexes from Butadiene via a Radical Strategy

AbstractThe direct conversion of industrial feedstock chemicals into highly valuable fine chemical intermediates is of great appeal to the synthetic community as well as industrial applications. This study reports a conceptually new radical strategy for the photocatalytic generation of π-allyltitanium complexes from butadiene. This novel and environmentally benign strategy enables the direct three-component allylation of carbonyls with 1,3-butadiene and α-bromocarboxylates, providing rapid access to valuable homoallylic alcohols with exceptional regio- and diastereoselectivity control.

Brønsted Acid‐Promoted Diastereoselective [4+1] Cyclization Reaction of Enamides and Sulfoxonium Ylides

AbstractA metal‐free synthesis of trisubstituted trans‐oxazolines using enamides and sulfoxonium ylides was developed in this study. A [4+1] cyclization reaction was realized by the formation of C−C and C−O bonds under mild conditions, wherein the reaction was catalyzed by HClO4. This strategy produced trans‐oxazolines in good yields with considerable diastereoselective control and is sufficient for large‐scale synthesis.magnified image