Diastereoselective Synthesis Research Articles

Diastereoselective Synthesis of Dearomatic 2‐oxa‐7‐azaspiro[4.5]decane Derivatives through Gold and Palladium Relay Catalytic Tandem Cyclization of Enynamides with Vinyl Benzoxazinanones

We present a diastereoselective Au/Pd relay catalytic tandem cyclization reaction to produce dearomatic 2‐oxa‐7‐azaspiro[4.5]decane derivatives under mild conditions. This process involves generating furan‐derived azadiene from readily available enynamide, followed by a [2 + 4] cycloaddition with Pd‐π‐allyl dipole decarboxylated from vinyl benzoxazinanone. Our method efficiently constructs the spiro[4.5]decane skeleton, achieving yields ranging from 31‐97% and diastereoselectivities from 6:1 dr to >20:1 dr across 34 examples. This research introduces new cycloaddition sites for azadienes as 1,2‐dipoles and offers a reliable approach for constructing oxa‐azaspiro[4.5]decane frameworks.

The catalytic asymmetric polyene cyclization of homofarnesol to ambrox

Polyene cyclizations are among the most complex and challenging transformations in biology. In a single reaction step, multiple carbon–carbon bonds, ring systems and stereogenic centres are constituted from simple, acyclic precursors1–3. Simultaneously achieving this kind of precise control over product distribution and stereochemistry poses a formidable task for chemists. In particular, the polyene cyclization of (3E,7E)-homofarnesol to the valuable naturally occurring ambergris odorant (−)-ambrox is recognized as a longstanding challenge in chemical synthesis1,4–7. Here we report a diastereoselective and enantioselective synthesis of (−)-ambrox and the sesquiterpene lactone natural product (+)-sclareolide by a catalytic asymmetric polyene cyclization by using a highly Brønsted-acidic and confined imidodiphosphorimidate catalyst in the presence of fluorinated alcohols. Several experiments, including deuterium-labelling studies, suggest that the reaction predominantly proceeds through a concerted pathway in line with the Stork–Eschenmoser hypothesis8–10. Mechanistic studies show the importance of the enzyme-like microenvironment of the imidodiphosphorimidate catalyst for attaining exceptionally high selectivities, previously thought to be achievable only in enzyme-catalysed polyene cyclizations.

Novel silica coated trimetallic ferrite functionalized with amino acid-based protic ionic liquid (Mn0.5Fe0.25Ca0.25Fe2O4-SiO2@[L-Tyr][HSO4]): A versatile bio-nanostructure to catalyze green synthesis of poly-substituted hydroquinolines and pyrido[2,3-d]pyrimidine-triones

In this research a magnetized inorganic-bioorganic nanocomposite prepared through coating the Mn0.5Fe0.25Ca0.25Fe2O4 core by silica layer, and consequent functionalization by the L-tyrosinium hydrogen sulfate ionic liquid. The structure of the hybrid nanocomposite (Mn0.5Fe0.25Ca0.25Fe2O4-SiO2@[L-Tyr][HSO4]) studied by density functional theory (DFT) calculations which contains L-Tyr protonation step and the chemisorption of L-Tyr cation on silica layer. The novel synthesized bio-nanocomposite (Mn0.5Fe0.25Ca0.25Fe2O4-SiO2@[L-Tyr][HSO4]) characterized by Fourier-transform infrared spectroscopy (FT-IR), field emission scanning electron microscopy (FESEM), energy-dispersive X-ray spectroscopy (EDAX), vibrating-sample magnetometery (VSM), thermogravimetric (TGA/DSC), X-ray powder diffractometery (XRD), X-ray fluorescence (XRF), and transmission electron microscopy (TEM) analysis. The hybrid bio-nanocomposite applied for solvent-free diastereoselective synthesis of dispiro[tetrahydroquinoline-bis(2,2-dimethyl[1,3]dioxane-4,6-dione)] derivatives via one-pot pseudo eight-component reaction of meldrum’s acid, aromatic aldehydes, and arylamines at 50 °C. Also, the bio-nanocatalyst utilized for the aqua-mediated green synthesis of 5-aryl-5,6-dihydropyrido[2,3-d]pyrimidine-2,4,7(1H,3H,8H)-triones at 70 °C through the reaction of meldrum’s acid, aryl aldehydes, and 6-aminouracil. The recovery and reusability of the bio-nanohybrid also examined within 2 runs successfully.

Diastereoselective Synthesis of Sulfoxide-Functionalized N-Heterocyclic Carbene Ruthenium Complexes: An Experimental and Computational Study.

The synthesis of sulfoxide-functionalized NHC ligand precursors were carried out by direct and mild oxidation from corresponding thioether precursors with high selectivity. Using these salts, a series of cationic [Ru(II)(η6-p-cymene)(NHC-SO)Cl]+ complexes were obtained in excellent yields by the classical Ag2O transmetallation route. NMR analyses suggested a chelate structure for the metal complexes, and X-ray diffractometry studies of complexes 4 b, 4 c, 4dBArF and 4 e unambiguously confirmed the preference for the bidentate (κ2-C,S) coordination mode of the NHC-SO ligands. Interestingly, only one diastereomer, in the form of an enantiomeric pair, was observed both in 1H NMR and in the solid state for the complexes. DFT calculations showed a possible intrinsic energy difference between the two pairs of diastereomer. The calculated energy barriers suggested that inversion of the sulfoxide is only plausible from the higher energy diastereomer together with bulky substituents. Inverting the configuration at the Ru center instead shows a lower and accessible activation barrier to provide the most stable diastereomer through thermodynamic control, consistent with the observation of a single species by 1H NMR as a pair of enantiomers. All these complexes catalyse the β-alkylation of secondary alcohols. Complex 4dPF6 bearing an NHC-functionalised S-Ad group has been further studied with different primary and secondary alcohols as substrates, showing high reactivity and high to moderate β-ol-selectivities.

Visible‐Light‐Induced Diastereoselective Cascade Cyclization to Construct Polycyclic Spiroindolines

AbstractWe herein reported, a visible‐light‐induced K2S2O8 mediated cascade reaction of 3‐(2‐isocyanoethyl)indoles with α‐oxocarboxylic acids leading to diastereoselective synthesis of polycyclic spiroindolines bearing an N‐formyl unit derivative utilising the alkali metal salt K2S2O8 as a mediator under mild reaction conditions. This study offers an illustration of α‐oxocarboxylic acids and 3‐(2‐isocyanoethyl)indoles‐based reactions as it shows the involvement of glyoxolate ions without decarboxylation to access polycyclic spiroindolines bearing an N‐formyl unit analogue. The batch process can be extended to a continuous flow system using a glass tube loaded with K2S2O8 placed between the PFA capillary reactor, which can greatly advance the reaction efficiency and can even be promoted to gram‐scale synthesis.

Nitrile‐Stabilized Quaternary Ammonium Ylide as an Arylcyanomethylene Transfer Agent: Diastereoselective Synthesis of Spiro‐cyanocyclopropyl‐2‐oxindoles

Nitrile‐stabilized quaternary ammonium ylide as an effective aryl‐cyanomethylene transfer agent has been explored for the first time, which enables a spirocyclopropanation process with conjugated carboxamide of indole heterocycle. The developed In(OTf)3‐catalyzed method provides a straightforward, diastereoselective access to pharmaceutically relevant spiro‐cyclopropane‐2‐oxindole skeleton assembled with an α‐cyano and two (hetero)aromatic substitutions. The common difficulties of a cyclopropanation process, e.g., a conjugated carboxamide as valid substrate, cleavage‐susceptibility of amide bond, substrates scope limited to preferentially electron‐withdrawing group containing molecules, and the competing dehydrocyanation reaction of product generated from nitrile‐stabilized ylide have been overcome in the present spirocyclopropanation process.

An approach for the diastereoselective synthesis of (R)‐(+)‐methyl pipecolate and (+)‐dextro‐erythrophacetoperane from (S)‐(−)‐methylbenzylamine

AbstractA diastereoselective synthesis for the preparation of (R)‐methyl pipecolate and dextro‐erythrophacetoperane, analogs of methylphenidate, drugs used to treat attention deficit hyperactivity disorder, is reported. The key steps involve a high diastereoselective ring‐closing reaction via enolate formation and a diastereoselective ketone reduction reaction. The total synthesis of these valuable drugs could be obtained in only 5 and 8 steps, respectively, starting from (S)‐(−)‐methyl benzylamine.

Diastereoselective [3 + 2] Cycloaddition between Tertiary Amine N-Oxides and Substituted Alkenes to Access 7-Azanorbornanes.

We have developed a diastereoselective synthesis of 43 novel 7-azanorbornanes using tertiary amine N-oxides and substituted alkenes. Our method uses an efficient [3 + 2] cycloaddition, starting from either commercially available or easily accessible precursors to generate yields up to 97% and diastereomeric ratios up to >20:1. Density functional theory (DFT) calculations were performed, suggesting that the observed diastereoselectivity is likely due to steric considerations.

Diastereoselective Synthesis of Cyclopenta[c]chromanones via Pd0-Catalyzed [3+2] Cycloaddition.

A straightforward method for synthesizing cyclopenta[c]chromanones is demonstrated. The strategy involves a [3+2] cycloaddition of VCPs and activated coumarins under Pd-catalyzed conditions. The reaction provides the desired products bearing up to four consecutive stereocenters with high diastereocontrol. Control experiments and density functional theory studies support the proposed mechanism and the observed diastereoselectivity in the product through a thermodynamically controlled pathway.

Diastereoselective Synthesis of Pyridone ribo‐C‐Nucleosides via Heck Reaction and Oxidation

AbstractNucleosides find applications in medicinal chemistry, chemical biology and diagnostics. Among the nucleosides, C‐nucleosides have attracted particular attention because their carbon‐carbon bond between nucleobase and ribose provides stability against degradation. While several well‐established methods exist for the synthesis of 2′‐deoxy‐C‐nucleosides, the preparation of their ribofuranosyl counterparts is more challenging. Established methods for their synthesis give mixtures of anomers and require harsh reagents or conditions. Here we report a diastereoselective glycosylation method involving a Heck reaction between a glycal and an aryl iodide, followed by oxidation of the silyl enol ether with methyl(trifluoromethyl)dioxirane (TFDO). The resulting ketone is then diastereoselectively reduced to the ribonucleoside. The new route has been applied to pyridones and is expected to also yield other ribo‐C‐nucleosides in diastereoselective fashion.

Regio- and Diastereoselective Synthesis of Trisubstituted Alkenes Through Hydroalkylation of Alkynyl Boronamides.

Hydroalkylation of alkynes is a powerful method for alkene synthesis. However, regioselectivity has been difficult to achieve in transformations of internal alkynes hindering applications in the synthesis of trisubstituted alkenes. To overcome these limitations, we explored using boryl groups as versatile directing groups that can control the regioselectivity of the hydroalkylation and subsequently be replaced in a cross-coupling reaction. The result of our exploration is a nickel-catalyzed hydroalkylation of alkynyl boronamides that provides access to a wide range of trisubstituted alkenes with high regio- and diastereoselectivity. The reaction can be accomplished with a variety of coupling partners, including primary and secondary alkyl iodides, α-bromo esters, α-chloro phthalimides, and α-chloro boronic esters. Preliminary studies of the reaction mechanism provide evidence for the hydrometalation mechanism and the formation of alkyl radical intermediates.

Regio‐ and Diastereoselective Synthesis of Trisubstituted Alkenes Through Hydroalkylation of Alkynyl Boronamides

Hydroalkylation of alkynes is a powerful method for alkene synthesis. However, regioselectivity has been difficult to achieve in transformations of internal alkynes hindering applications in the synthesis of trisubstituted alkenes. To overcome these limitations, we explored using boryl groups as versatile directing groups that can control the regioselectivity of the hydroalkylation and subsequently be replaced in a cross‐coupling reaction. The result of our exploration is a nickel‐catalyzed hydroalkylation of alkynyl boronamides that provides access to a wide range of trisubstituted alkenes with high regio‐ and diastereoselectivity. The reaction can be accomplished with a variety of coupling partners, including primary and secondary alkyl iodides, α‐bromo esters, α‐chloro phthalimides, and α‐chloro boronic esters. Preliminary studies of the reaction mechanism provide evidence for the hydrometalation mechanism and the formation of alkyl radical intermediates.

Asymmetric Cascade Dearomatization-Cyclization Reaction of Tryptamines with β,γ-Alkynyl-α-imino Esters: Access to Hexahydropyrrolo[2,3-b]indole-Containing Tetrasubstituted α-Amino Allenoates.

An organocatalytic enantio- and diastereoselective synthesis of hexahydropyrrolo[2,3-b]indole-containing tetrasubstituted α-amino allenoates, exhibiting both axial and central chirality, has been accomplished via cascade dearomatization-cyclization reaction. The γ-addition to β,γ-alkynyl-α-imino esters provides a library of densely substituted highly enantioenriched allenes in high yields and excellent stereoselectivities. In addition, the scope of this methodology has been extended to tryptophol as well. A scale-up reaction and synthetic transformations of the products were performed to demonstrate the practical usefulness of this approach.

Diastereoselective Synthesis of the HIV Protease Inhibitor Darunavir and Related Derivatives via a Titanium Tetrachloride-Mediated Asymmetric Glycolate Aldol Addition Reaction.

Darunavir is a potent HIV protease inhibitor that has been established as an effective tool in the fight against the progression of HIV/AIDS in the global community. The successful application of this drug has spurred the development of derivatives wherein strategic regions (e.g., P1, P1', P2, and P2') of the darunavir framework have been structurally modified. An alternate route for the synthesis of darunavir and three related P1 and P1' derivatives has been developed. This synthetic pathway involves the use of a Crimmins titanium tetrachloride-mediated oxazolidine-2-thione-guided asymmetric glycolate aldol addition reaction. The resultant aldol adduct introduces the P1 fragment of darunavir via an aldehyde. Transamidation with a selected amine (isobutylamine or 2-ethyl-1-butylamine) to cleave the auxiliary yields an amide wherein the P1' component is introduced. From this stage, the amide is reduced to the corresponding β-amino alcohol and the substrate is then bis-nosylated to introduce the requisite p-nitrobenzenesulfonamide component and activate the secondary alcohol for nucleophilic substitution. Treatment with sodium azide yielded the desired azides, and the deprotection of the p-methoxyphenoxy group is achieved with the use of ceric ammonium nitrate. Finally, hydrogenation to reduce both the aniline and azide functionalities with concurrent acylation yields darunavir and its derivatives.

NIS-Promoted Chemodivergent and Diastereoselective Synthesis of Pyrrolinyl and Cyclopentenyl Spiropyrazolones via Regulated Cyclization of Alkylidene Pyrazolones with Enamino Esters.

An N-iodosuccinimide-promoted annulation of alkylidene pyrazolones with enamino esters has been explored to construct a spiropyrazolone moiety through a Michael addition/iodination/intramolecular nucleophilic substitution sequence. When the reaction was performed in acetonitrile at 100 °C, it furnished pyrrolinyl spiropyrazolones exclusively in an anti configuration through N-attacking cyclization. When the reaction was performed in dimethyl sulfoxide at 80 °C in the presence of K2HPO4, it afforded cyclopentenyl spiropyrazolones exclusively in the syn configuration through C-attacking cyclization. A plausible mechanism has also been proposed.

Palladium-Catalyzed (4 + 1) Annulation of 4-Vinylbenzodioxinones with Sulfur Ylides: Diastereoselective Synthesis of Dihydrobenzofuran Derivatives.

Palladium-catalyzed (4 + 1) annulation of 4-vinylbenzodioxinones with sulfur ylides has been developed to afford various dihydrobenzofuran derivatives in moderate to high yields with excellent diastereoselectivities. The scale-up reaction and further derivations of the product worked well, demonstrating the application potential of the current reaction in organic synthesis.

Regio- and diastereoselective synthesis of thioxothiazolidin-indolin-2-ones, oxoindolin-carbamodithioate hybrids, and their base-catalyzed conversion into dispirocyclopentanebisoxindoles

In this publication, we reported a regio-, diastereoselective, and kinetically controlled reaction for synthesizing thioxothiazolidin-indolin-2-ones, oxoindolin-carbamodithioate hybrids, and their base-catalyzed conversion into dispirocyclopentanebisoxindoles. Obtaining only the kinetic thioxothiazolidin-indolin-2-one products together with their straightforward conversion to dispirocyclopentanebisoxindoles, excellent regio- and diastereoselectivity, easy reaction workup, and one-pot synthetic operation are considerable advantages of this work.

Fluorine‐Effect‐Enabled Photocatalytic 4‐Exo‐Trig Cyclization Cascade to Access Fluoroalkylated Cyclobutanes

AbstractCyclobutanes are popular structural units in bioactive compounds and versatile intermediates in synthetic chemistry, but their synthesis is challenging owing to high ring strain. In this study, a novel method for highly regio‐ and diastereoselective synthesis of fluoroalkylcyclobutanes bearing vicinal quaternary and tertiary stereocenters is realized by a photocatalytic 4‐exo‐trig cyclization cascade of thioalkynes or trifluoromethylalkenes. Density functional theory calculations reveal that a unique fluorine effect, arising from hyperconjugative π→σ*C‐F interactions, accounts for the regio‐reversed radical addition at the sterically hindered alkene carbon, which facilitates an unprecedented 4‐exo‐trig ring closure. This chemistry enables the direct and controllable construction of medicinally valuable quaternary‐carbon‐containing cyclobutanes from readily available raw materials, nicely complementing the existing methods.

Fluorine-Effect-Enabled Photocatalytic 4-Exo-Trig Cyclization Cascade to Access Fluoroalkylated Cyclobutanes.

Cyclobutanes are popular structural units in bioactive compounds and versatile intermediates in synthetic chemistry, but their synthesis is challenging owing to high ring strain. In this study, a novel method for highly regio- and diastereoselective synthesis of fluoroalkylcyclobutanes bearing vicinal quaternary and tertiary stereocenters is realized by a photocatalytic 4-exo-trig cyclization cascade of thioalkynes or trifluoromethylalkenes. Density functional theory calculations reveal that a unique fluorine effect, arising from hyperconjugative π→σ*C-F interactions, accounts for the regio-reversed radical addition at the sterically hindered alkene carbon, which facilitates an unprecedented 4-exo-trig ring closure. This chemistry enables the direct and controllable construction of medicinally valuable quaternary-carbon-containing cyclobutanes from readily available raw materials, nicely complementing the existing methods.

Ambrox through the Looking Glass: Chemoenzymatic Synthesis and GC‐Olfactometric Analysis of 15 Ambrox Stereoisomers

AbstractAll eight theoretical stereoisomers of (10S)‐Ambrox have been synthesized by enzymatic polycyclization of the four geometric isomers of homofarnesol with selected squalene hopene cyclases. This includes the highly strained (+)‐(8S,9S)‐Ambrox, an isomer historically considered unlikely to exist. The enantiomeric (10R)‐series has been prepared by a combination of diastereoselective synthesis and preparative chiral HPLC. Thus, for the first time, the synthesis and sensory properties of all but one stereoisomers of Ambrox are presented. The results solve a long standing peradventure: the commercial product (−)‐Ambrox exhibits by far the strongest odour, the previously described 9‐epi‐Ambrox is 26 times weaker. The enantiomer difference between (−)‐and (+)‐Ambrox was also found much higher than in previous reports (1000 vs. 8 times). The (8R)‐configuration was identified as the single most important structural feature for high odour strength.