Stereospecific Reaction Research Articles

Divergent, Stereospecific Mono- and Difluoromethylation of Boronic Esters.

There is considerable interest in incorporating fluorine into agrochemicals and pharmaceuticals to improve their biological properties. Whilst a number of methods have been reported for installing CH2 F and CHF2 groups, they are mainly limited to radical reactions, which are invariably racemic. Herein, we report the divergent, stereospecific reaction of fluoroiodomethyllithium with boronic esters to give α-fluoro-boronic esters. These unique intermediates can be readily transformed into the corresponding mono- or difluoromethylated compounds through proto- or fluorodeboronation, respectively. The use of the highly unstable fluoroiodomethyllithium was key to allowing rapid 1,2-migration over competing decomposition of the carbanion. DFT calculations informed and supported the experimental findings.

A General Approach to Stereospecific Cross-Coupling Reactions of Nitrogen-Containing Stereocenters

A novel strategy employing cyclohexyl spectator ligands in Stille cross-coupling reactions has been developed as a general solution to the long-standing challenge of conducting stereospecific cross-coupling reactions at nitrogen-containing stereocenters. This method enables direct access to enantioenriched products that are difficult (or impossible) to obtain via alternative preparative methods. Selective and predictable transfer of a single secondary alkyl unit can be achieved under reaction conditions that exploit subtle electronic differences between activated and unactivated alkyl units. Through this approach, enantioenriched α-stannylated nitrogen-containing stereocenters undergo Pd-catalyzed arylation and acylation reactions with exceptionally high stereofidelity in all instances investigated. We demonstrate this process by using α-stannylated pyrrolidine, azetidine, and open-chain (benzylic and non-benzylic) nucleophiles in stereospecific reactions. This process will facilitate rapid and reliable access to enantioenriched compounds possessing nitrogen-substituted stereocenters, which constitute ubiquitous structural motifs in biologically active compounds emerging from the drug-discovery process.

Identification of the Active Catalyst for Nickel-Catalyzed Stereospecific Kumada Coupling Reactions of Ethers.

A series of nickel complexes in varying oxidation states were evaluated as precatalysts for the stereospecific cross-coupling of benzylic ethers. These results demonstrate rapid redox reactions of precatalysts, such that the oxidative state of the precatalyst does not dictate the oxidation state of the active catalyst in solution. These data provide the first experimental evidence for a Ni0 -NiII catalytic cycle for a stereospecific alkyl-alkyl cross-coupling reaction, including spectroscopic analysis of the catalyst resting state.

Asymmetric Electrophilic Reactions in Phosphorus Chemistry

This review is devoted to the theoretic and synthetic aspects of asymmetric electrophilic substitution reactions at the stereogenic phosphorus center. The stereochemistry and mechanisms of electrophilic reactions are discussed—the substitution, addition and addition-elimination of many important reactions. The reactions of bimolecular electrophilic substitution SE2(P) proceed stereospecifically with the retention of absolute configuration at the phosphorus center, in contrast to the reactions of bimolecular nucleophilic substitution SN2(P), proceeding with inversion of absolute configuration. This conclusion was made based on stereochemical analysis of a wide range of trivalent phosphorus reactions with typical electrophiles and investigation of examples of a sizeable number of diverse compounds. The combination of stereospecific electrophilic reactions and stereoselective nucleophilic reactions is useful and promising for the further development of organophosphorus chemistry. The study of phosphoryl group transfer reactions is important for biological and molecular chemistry, as well as in studying mechanisms of chemical processes involving organophosphorus compounds. New versions of asymmetric electrophilic reactions applicable for the synthesis of enantiopure P-chiral secondary and tertiary phosphines are discussed.

Recent Advances in Rare Earth Complexes Containing N-Heterocyclic Carbenes: Synthesis, Reactivity, and Applications in Polymerization

N-heterocyclic carbenes (NHCs) are ubiquitous ancillary ligands employed in metal-catalyzed homogeneous reactions and polymerization reactions. Of significance is the use of NHCs as the supporting ligand in second- and third-generation Grubbs catalysts for their application in olefin metathesis and ring-opening metathesis polymerization. While the applications of transition metal catalysts ligated with NHCs in polymerization chemistry are well-documented, the use of analogous rare earth (Ln = Sc, Y, La, Ce, Pr, Nd, Pm, Sm, Eu, Gd, Tb, Dy, Ho, Er, Tm, Yb, and Lu) catalysts in this area remains under-developed, despite the unique role of rare earth elements in regio- and stereo-specific (co)polymerization reactions. By using hetero-atom-tethered chelating NHCs and, more recently, the employment of other structurally related NHCs, NHC-ligated Ln complexes have proven to be promising and fruitful catalysts for selective polymerization reactions. This review summarizes the recent developments in the coordination chemistry of Ln complexes containing NHCs and their catalytic performance in polymerization.

Unexpected Indirect Dynamics in Base-Induced Elimination.

Base-induced elimination (E2) and bimolecular nucleophilic substitution (SN2) are two of the most versatile reactions that are important in preparative organic chemistry. These stereospecific reactions are often found in direct competition with each other. Elimination can proceed via two distinct transition states, referred to as anti and syn, of which anti is commonly energetically favored. To investigate the intrinsic dynamics of base-induced elimination, reactions under single-collision conditions are required. Here, we present reactive scattering results on the prototype reaction of the fluoride anion with tert-butyl halides. The observed mechanistic fingerprints are associated with the E2 reaction, because steric hindrance at the α-carbon suppresses the SN2 reaction [Carrascosa, E.; Meyer, J.; Zhang, J.; Stei, M.; Michaelsen, T.; Hase, W. L.; Yang, L.; Wester, R. Nat. Commun. 2017, 8, 25]. The reaction coordinate shows energetically submerged transition states, with anti favored over syn, and we found a very shallow prereaction well for anti. We predominantly found indirect dynamics for a range of collision energies, which can be separated into three remarkably different mechanisms. At low collision energies, the first is a large impact parameter indirect mechanism which leads to a forward-backward symmetric scattering signature. The second mechanism is attributed to low-impact parameter reactions with a near-statistical partitioning of the total available energy. The majority of events are associated with widespread isotropic scattering. Unexpectedly, the product ion kinetic energy distributions are independent of collision energy. We associate this with dynamic trapping in a prereaction well supported by a large centrifugal potential. These measured fingerprints support that atomistic reaction dynamics cannot be predicted based on stationary arguments alone.

Synthesis of (±)‐cis‐1‐Aryl‐3‐oxo‐2,3‐dihydro‐1H‐benzo[f]chromene‐2‐carbonitriles and (±)‐trans‐4‐Aryl‐2‐oxo‐3,4‐dihydro‐2H‐benzo[h]chromene‐3‐carbonitriles

AbstractThe unexpected stereospecific synthesis of (±)‐cis‐1‐aryl‐3‐oxo‐2,3‐dihydro‐1H‐benzo[f]chromene‐2‐carbonitriles (2) and (±)‐trans‐4‐aryl‐2‐oxo‐3,4‐dihydro‐2H‐benzo[h]chromene‐3‐carbonitriles (4) from (±)‐3‐amino‐1‐aryl‐1H‐benzo[f]chromene‐2‐carbonitriles (1) and (±)‐2‐amino‐4‐aryl‐4H‐benzo[h]chromene‐3‐carbonitriles (3), respectively, by reacting them in formic acid (88%), at reflux, is reported. A DFT analysis has been applied with success to justify these highly stereospecific reactions.

(4 + 3)-Cycloaddition of Donor-Acceptor Cyclopropanes with Thiochalcones: A Diastereoselective Access to Tetrahydrothiepines.

A general approach is described for the formation of tetrahydrothiepines using donor-acceptor cyclopropanes. Thiochalcones, functioning as sulfur-containing four-atom building blocks, were reacted in a Lewis acid catalyzed formal (4 + 3)-cycloaddition reaction with donor-acceptor cyclopropanes as three-atom building blocks. Under mild conditions various tetrahydrothiepines were synthesized in good yields in a stereospecific reaction with high functional group tolerance.

Hanessian-Hullar reaction in the synthesis of highly substituted trans-3,4-dihydroxypyrrolidines: Rhamnulose iminosugar mimics inhibit α-glucosidase

The key step in the syntheses of highly substituted trans-3,4-dihydroxypyrrolidines is introduction of bromide by stereospecific and regiospecific Hanessian-Hullar reactions; benzylidene lactones of l-rhamnonolactone and 6-deoxy-this should be small unnpercase d not l why can I not correct this-gulonolactone allow introduction of N at C2 with inversion or retention of configuration. Initially a protecting group, the benzylidene acetal then provides a bromide at C5 to allow formation of the pyrrolidine ring. With silyl protecting groups, bromide was introduced at C5 with inversion of configuration whereas benzoyl protection gave a mixture of retention and inversion, indicative of neighbouring group participation in a Hanessian-Hullar reaction. Four stereoisomeric pyrrolidines - iminosugar mimics of α- and β-l-rhamnulose and α- and β-6-deoxy-d-sorbose were prepared. Only the α-l-rhamnulose mimic showed moderate inhibition of rhamnosidase but some were good inhibitors of α-glucosidases; none inhibited rhamnose isomerase and they had a small effect as synthetic inducers of the rhamnose catabolic operon in E. coli.

Umpolung Strategy for α‐Functionalization of Aldehydes for the Addition of Thiols and other Nucleophiles

AbstractNucleophile–nucleophile coupling is a challenging transformation in organic chemistry. Herein we present a novel umpolung strategy for α‐functionalization of aldehydes with nucleophiles. The strategy uses organocatalytic enamine activation and quinone‐promoted oxidation to access O‐bound quinol‐intermediates that undergo nucleophilic substitution reactions. These quinol‐intermediates react with different classes of nucleophiles. The focus is on an unprecedented organocatalytic oxidative α‐thiolation of aldehydes. The reaction scope is demonstrated for a broad range of thiols and extended to chemoselective bioconjugation, and applicable to a large variety of aldehydes. This strategy can also encompass organocatalytic enantioselective coupling of α‐branched aldehydes with thiols forming quaternary thioethers. Studies indicate a stereoselective formation of the intermediate followed by a stereospecific nucleophilic substitution reaction at a quaternary stereocenter, with inversion of configuration.

Umpolung Strategy for α-Functionalization of Aldehydes for the Addition of Thiols and other Nucleophiles.

Nucleophile-nucleophile coupling is a challenging transformation in organic chemistry. Herein we present a novel umpolung strategy for α-functionalization of aldehydes with nucleophiles. The strategy uses organocatalytic enamine activation and quinone-promoted oxidation to access O-bound quinol-intermediates that undergo nucleophilic substitution reactions. These quinol-intermediates react with different classes of nucleophiles. The focus is on an unprecedented organocatalytic oxidative α-thiolation of aldehydes. The reaction scope is demonstrated for a broad range of thiols and extended to chemoselective bioconjugation, and applicable to a large variety of aldehydes. This strategy can also encompass organocatalytic enantioselective coupling of α-branched aldehydes with thiols forming quaternary thioethers. Studies indicate a stereoselective formation of the intermediate followed by a stereospecific nucleophilic substitution reaction at a quaternary stereocenter, with inversion of configuration.

Asymmetric Synthesis of Chiral Sulfoximines through the S-Alkylation of Sulfinamides.

Innovation in drug discovery critically depends on the development of new bioisosteric groups. Chiral sulfoximines, which contain a tetrasubstituted sulfur atom that bears one nitrogen, one oxygen, and two different carbon substituents, represent an emerging chiral bioisostere in medicinal chemistry. Chiral sulfoximines are conventionally prepared by a stereospecific nitrene transfer reaction to chiral sulfoxides; however, the number of readily available chiral sulfoxides remains limited. Herein, we report the asymmetric synthesis of a class of hitherto difficult-to-access chiral sulfoximines with two structurally similar alkyl chains. Our synthetic approach is based on the sulfur-selective alkylation of easily accessible chiral sulfinamides with commercially available reagents under simple and safe conditions. This stereospecific S-alkylation offers a general and scalable approach to the asymmetric synthesis of chiral sulfoximines, which represent important substructures in bioactive molecules.

Asymmetric Synthesis of Chiral Sulfoximines through the S‐Alkylation of Sulfinamides

AbstractInnovation in drug discovery critically depends on the development of new bioisosteric groups. Chiral sulfoximines, which contain a tetrasubstituted sulfur atom that bears one nitrogen, one oxygen, and two different carbon substituents, represent an emerging chiral bioisostere in medicinal chemistry. Chiral sulfoximines are conventionally prepared by a stereospecific nitrene transfer reaction to chiral sulfoxides; however, the number of readily available chiral sulfoxides remains limited. Herein, we report the asymmetric synthesis of a class of hitherto difficult‐to‐access chiral sulfoximines with two structurally similar alkyl chains. Our synthetic approach is based on the sulfur‐selective alkylation of easily accessible chiral sulfinamides with commercially available reagents under simple and safe conditions. This stereospecific S‐alkylation offers a general and scalable approach to the asymmetric synthesis of chiral sulfoximines, which represent important substructures in bioactive molecules.

The ARH and Macrodomain Families of α-ADP-ribose-acceptor Hydrolases Catalyze α-NAD+ Hydrolysis.

ADP-ribosyltransferases transfer ADP-ribose from β-NAD+ to acceptors; ADP-ribosylated acceptors are cleaved by ADP-ribosyl-acceptor hydrolases (ARHs) and proteins containing ADP-ribose-binding modules termed macrodomains. On the basis of the ADP-ribosyl-arginine hydrolase 1 (ARH1) stereospecific hydrolysis of α-ADP-ribosyl-arginine and the hypothesis that α-NAD+ is generated as a side product of β-NAD+/ NADH metabolism, we proposed that α-NAD+ was a substrate of ARHs and macrodomain proteins. Here, we report that ARH1, ARH3, and macrodomain proteins (i.e., MacroD1, MacroD2, C6orf130 (TARG1), Af1521, hydrolyzed α-NAD+ but not β-NAD+. ARH3 had the highest α-NADase specific activity. The ARH and macrodomain protein families, in stereospecific reactions, cleave ADP-ribose linkages to N- or O- containing functional groups; anomerization of α- to β-forms (e.g., α-ADP-ribosyl-arginine to β-ADP-ribose- (arginine) protein) may explain partial hydrolysis of ADP-ribosylated acceptors with an increase in content of ADP-ribosylated substrates. Af1521 and ARH3 crystal structures with bound ADP-ribose revealed similar ADP-ribose-binding pockets with the catalytic residues of the ARH and macrodomain protein families in the N-terminal helix and loop. Although the biological roles of the ARHs and macrodomain proteins differ, they share enzymatic and structural properties that may regulate metabolites such as α-NAD+.

Stereospecific Cross-Coupling Reactions Provide Conformationally-Biased Arylalkanes with Anti-Leukemia Activity.

A focused small library of carbamates and alcohols was prepared employing stereospecific Kumada-ring opening reactions of tetrahydropyrans. The core framework of the library members is acyclic and incorporates 1,3-substituents, to provide a conformational bias in avoiding syn-pentane interactions. A new compound with micromolar activity against MOLT-4, CCRF-CEM, and HL-60(TB) leukemia cell lines was identified from this series.

Preparation of Enantioenriched Alkylcarbastannatranes via Nucleophilic Inversion of Alkyl Mesylates for Use in Stereospecific Cross-Coupling Reactions.

We report the preparation of enantioenriched secondary alkylcarbastannatranes via a stereoinvertive SN2 reaction of enantioenriched alkyl mesylates and carbastannatranyl anion equivalents. Using this process, enantioenriched secondary alcohols may be converted into highly enantioenriched alkylcarbastannatranes, which are useful in stereospecific cross-coupling reactions.

Fine-mapping of the substrate specificity of human steroid 21-hydroxylase (CYP21A2)

Cytochrome P450 enzymes (CYPs) are capable of catalyzing regio- and stereo-specific oxy functionalization reactions, which otherwise are major challenges in organic chemistry. In order to make the best possible use of these biocatalysts it is imperative to understand their specificities. Human CYP21A2 (steroid 21-hydroxylase) acts on the side-chain attached to C-17 in ring D of a steroid substrate, but the configuration of ring A also plays a prominent role in substrate cognition. Here, we comprehensively investigated this relationship using sixteen 17,17-dimethyl-18-nor-13-ene steroids with different arrangements of hydroxy-, oxo-, fluoro- and chloro-groups and in the presence or absence of double bonds (Δ1 and/or Δ4) and heteroatoms in ring A. The results show that presence of a 3-oxo group is a strict requirement for a CYP21A2 substrate, while the other configurations tested were all tolerated. This was also confirmed by control experiments using endogenous steroids. While progesterone and 17-hydroxyprogesterone were hydroxylated at C-21, (17-hydroxy-) pregnenolone did not react. Molecular docking experiments indicate that the interaction of the carbonyl group at C-3 to the side-chain Arg234 of the enzyme is indispensable.

Palladium-Catalyzed Stereospecific Oxidative Cascade Reaction of Allenes for the Construction of Pyrrole Rings: Control of Reactivity and Selectivity

A palladium-catalyzed oxidative cascade reaction of α-tosylamide allenes has been developed. The reactivity of the allenes is controlled by the tosylamide group. In the presence of terminal alkynes...

Regio- and stereoselective synthesis of tetra- and triarylethenes by N-methylimidodiacetyl boron-directed palladium-catalysed three-component coupling

The flexible synthesis of tetra- and triarylethenes bearing different aryl groups has been a long-standing challenge in organic synthesis. Here we report a palladium-catalysed syn-diarylation of arylethynyl N-methyliminodiacetyl (MIDA) boronates. The products, triarylalkenyl N-methyliminodiacetyl boronates, allow a step-economic and modular synthesis of tetra- or triarylethenes via a subsequent stereospecific Suzuki-Miyaura coupling reaction or base-promoted protodeborylation, respectively. Use of the sp3-B(MIDA) masked aryl alkyne is the key factor for success by offering an exceptionally good regioselectivity for the boron-retentive coupling. The unusual regioselectivity is believed to arise from the stabilization due to the strong electron donation from the C−Pd σ bond to the p-orbital of boron in the transition state of migratory insertion. A broad range of differently substituted tetra- and triarylethenes are constructed in good yields and geometrical control. Synthetic manipulation of the C-B bond also enables the facile construction of several other types of tetra-substituted alkenes.

Base-Mediated Tandem 1,6-Addition/Cyclization/Isomerization Reactions between para-Quinone Methides and Benzyl Chlorides: Approaches to Diverse Frameworks at Each Cascade Stage

Base-mediated stereospecific tandem reactions using para-quinone methides and carbene-like benzyl chlorides are developed. DBU-mediated 1,6-addition/cyclization/isomerization reactions produce triarylsubstituted alkenes in 43–89% yields and Z/E ratios of 5:1 to 35:1 in favor of the Z-isomers. Single-step 1,6-conjugate additions are realized with the mediation of cesium carbonate, and different triaryl chloroethanes are obtained in yields of 41–54% and excellent diastereoselectivities of more than 20:1. In addition, tandem 1,6-addition/cyclization reactions are achieved using tuned 2,4-disubstituted benzyl chlorides to afford diaryl spirocyclopropyl para-dienones in yields of 35–83% and diastereoselectivities of more than 20:1 in favor of the anti-isomers. The transformations from triaryl chloroethanes and spirocyclopropyl para-dienones into triarylsubstituted alkenes are also demonstrated to support the proposed tandem mechanisms.