Diastereoselective Reaction Research Articles

Chiral copper-salen complex grafted over functionalized mesoporous silica as an efficient catalyst for asymmetric Henry reactions and synthesis of the potent drug (R)-isoproterenol

A new chiral Cu(ii)@AFS-1 catalyzed asymmetric Henry reaction (ee = 94%, yield 96%) and diastereoselective Henry reaction have been reported. Additionally, drug (R)-(−)-isoproterenol was synthesized using this protocol.

Alkaloid Synthesis Using Organocatalysts.

This chapter covers the literature since the advent, in the 21st century, of total syntheses of alkaloids using enantio- or diastereoselective organocatalytic reactions to construct the alkaloid scaffolds. The details of these alkaloid syntheses are described separately for each basic skeleton, including indole, indoline, oxindole, and piperidine alkaloids.

Pyrrolidine and oxazolidine ring transformations in proline and serine derivatives of α-hydroxyphosphonates induced by deoxyfluorinating reagents.

Transformations of α-hydroxyphosphonates derived from proline or serine by treatment with different deoxyfluorinating reagents (DAST, Deoxofluor, PyFluor) are reported. Depending on the applied reagent, as well as the protecting group used (N-Cbz, N-Boc, N-Bn) different types of products are observed. The reaction of N-Cbz or N-Boc prolinols with DAST or Deoxofluor due to aziridinium intermediate participation gave fluorinated amino phosphonates such as piperidine and pyrrolidine derivatives and/or oxazolidine-2-ones. Similarly, the analogous reaction of N-Cbz or N-Boc protected serinol yielded oxazolidine-2-ones or its fluorinated analogues. As the second type of product formed by DAST-induced reaction of serine derivatives, aziridines were obtained. Only in the case of deoxyfluorination of N-benzyl prolinols were both diastereoisomers of β-fluoropiperidine-α-phosphonates formed, while the reaction of protected N-benzyl serinols gave fluorinated oxazolidines. Moreover, application of PyFluor gave sulfonate derivatives.

Part I: Diastereoselective Reactions Involving β‐Mono‐ and β,β′‐Disubstituted Alkylidene Oxindoles: Pondering Alkene Geometry

AbstractDiastereoselective reactions supported by metals and nonmetals offer a multifaceted path for the synthesis of robust intermediates of value to academia and industry. The reactions that involve mono‐ and disubstituted electron‐rich and electron‐deficient olefins offer facile construction of stereogenic carbon centers. Recent advances in the development of methods and an understanding of the chemistry of oxindoles has led to approaches that provide high levels of facial control, regiocontrol and diastereoselectivity. Part I of this focus review is devoted to the chemistry of β‐monosubstituted alkylidene oxindoles. Herein, we discuss reports made over the last decade of diastereoselective reactions that involve oxindole‐containing trisubstituted alkenes, which lead to the generation of stereogenic centers and the formation carbocyclic and heterocyclic skeletons.

Part II: Diastereoselective Reactions Involving β‐Mono‐ and β,β′‐Disubstituted Alkylidene Oxindoles: Pondering Alkene Geometry

AbstractPart II encompasses synthetic efforts towards the construction of acyclic and cyclic structures that contain carbon and heteroatoms by employing diastereoselective reactions of β,β′‐disubstituted alkylidene oxindole as the primary substrate. In addition to the construction of acyclic structures, carbocyclic and heterocyclic rings that contain three‐, five‐, six‐, and seven‐membered spirocycles or fused‐rings are also described. A few examples of the arylative cyclization of dienes have also been presented.

Et3N catalyzed the diastereoselective synthesis of functionalized cyclohexanones by condensation of acetoacetanilide and various aldehydes in mild conditions

A facile synthetic strategy has been reported for the diastereoselective synthesis of N,N′-diaryl-2-aryl-6-hydroxy-6-methyl-4-oxocyclohexane-1,3-dicarboxamide via Et3N-catalyzed. Acetoacetanilide undergoes a diastereoselective condensation reaction with various aromatic and aliphatic aldehydes in EtOH at 50 °C to afford desirable products via one-pot pseudo-three-component reaction. The present protocol provides an inexpensive and efficient route to obtain functionalized cyclohexanones containing four quaternary stereogenic centers with high yields from the simple and readily available starting materials under mild conditions in shorter reaction times. The products have been characterized by IR, 1H NMR, and 13C NMR spectroscopy. The stereoselectivity of compounds was established with crystallography and NMR spectroscopy.

Synthesis of (2S)-2-Chloro-2-fluororibolactone via Stereoselective Electrophilic Fluorination.

A novel and efficient route for the preparation of (2S)-2-chloro-2-fluorolactone 29 is described. This approach takes advantage of a highly efficient diastereoselective electrophilic fluorination reaction (94% yield; >50:1 dr).

Asymmetric Total Synthesis of (+)-Intricenyne via an Endocyclization Route to Oxocane Skeleton.

The first total synthesis of (+)-intricenyne consisting of an oxocane skeleton was achieved via an extremely selective endocyclization strategy. The key features of the synthesis include a regio- and diastereoselective epoxide opening reaction, concise elaboration of oxocane cores via abnormally selective endocyclization ether ring formation, and versatile incorporation of the labile functional groups.

Highly Diastereoselective Cationic Cyclization Reactions Convert a Common Monocyclic Enone to Bicyclic Precursors for the Synthesis of Retigeranic Acids A and B

A novel method is demonstrated for the diastereoselective conversion of a monocyclic enone to a pair of bicyclic intermediates which enable the stereocontrolled enantioselective syntheses of retigeranic acids A and B.

Diversity‐Oriented Synthesis of Various Enantiopure Heterocycles by Coupling Organocatalysis with Multicomponent Reactions

Chiral, enantiopure 1,3‐amino alcohols, obtained through an organocatalytic Mannich reaction, have been used as starting materials for a concise sequence involving a diastereoselective Ugi reaction followed by various types of SN2 cyclization. In this way, different enantiopure heterocycles have been prepared, with both scaffold and decoration diversity (up to four diversity inputs).

A simple metal free highly diastereoselective synthesis of heteroaryl substituted (±) cyclohexanols by a branched domino reaction

A self diastereoselective, simple metal free and efficient branch domino reaction gave multiple heteroaryl substituted (±) cyclohexanols with five chiral centres in >95% yields. The reactions that occur are Claisen Schmidt condensation followed by Michael addition and Aldol reactions of heteroaryl carbaldehydes and acetyl pyridine derivatives. Mechanistic study of the reactions shows excellent self diastereoselectivity (dr > 99%) in the intermediate steps which results selectively in the formation of one set of enantiomers out of sixteen possible enantiomeric pairs. The self diastereoselectivity of reaction in all the steps dominates due to the steric hindrance induced by the bulky heteroaryl groups. The stereochemistry of the synthesized compounds is established using single crystal XRD.

A Solid Iridium Catalyst for Diastereoselective Hydrogenation.

An Ir(NHC) supported catalyst is used in the selective hydrogenation of terpinen-4-ol to cis p-menthan-4-ol. Its activity, selectivity and stability are compared to those of a homogeneous homologue [IrCl(COD)MesImPr] and to a commercial Pd/C. The solid Ir catalyst is much more selective than the Pd catalyst (92 vs. 42 % at 80 °C) but also more active, more selective and more stable than the iridium complex in solution. For the first time, a supported catalyst shows an enhanced activity with respect to a complex in a diastereoselective hydrogenation reaction.

Enantio- and Diastereoselective Organocatalytic Conjugate Additions of Nitroalkanes to Enone Diesters.

Enantio- and diastereoselective conjugate addition reactions between nitroethane or nitropropane and enone diesters are reported. A bifunctional triaryliminophosphorane catalyzed the addition reaction with consistently excellent stereoselectivities and yields across a wide range of substrates. By the use of the gem-diester functional handle present in the adducts, local desymmetrization via diastereotopic group discrimination was demonstrated, and a polyfunctionalized lactam with three contiguous stereocenters was synthesized.

Total Synthesis of (+)-Gracilamine Based on an Oxidative Phenolic Coupling Reaction and Determination of Its Absolute Configuration.

The enantioselective total synthesis of (+)-gracilamine (1) is described. The strategy features a diastereoselective phenolic coupling reaction followed by a regioselective intramolecular aza-Michael reaction to construct the ABCE ring system. The configuration at C3a in 1 was controlled by the stereocenter at C9a, which was selectively generated (91 % ee) by an organocatalytic enantioselective aza-Friedel-Crafts reaction developed by our research group. This synthesis revealed that the absolute configuration of (+)-gracilamine is 3aR, 4S, 5S, 6R, 7aS, 8R, 9aS.

Total Synthesis of (+)‐Gracilamine Based on an Oxidative Phenolic Coupling Reaction and Determination of Its Absolute Configuration

AbstractThe enantioselective total synthesis of (+)‐gracilamine (1) is described. The strategy features a diastereoselective phenolic coupling reaction followed by a regioselective intramolecular aza‐Michael reaction to construct the ABCE ring system. The configuration at C3a in 1 was controlled by the stereocenter at C9a, which was selectively generated (91 % ee) by an organocatalytic enantioselective aza‐Friedel–Crafts reaction developed by our research group. This synthesis revealed that the absolute configuration of (+)‐gracilamine is 3aR, 4S, 5S, 6R, 7aS, 8R, 9aS.

Stereoselective Synthesis of 3,3'-Bisindolines by Organocatalytic Michael Additions of Fluorooxindole Enolates to Isatylidene Malononitriles in Aqueous Solution.

A highly diastereoselective organocatalytic reaction for the synthesis of fluorinated 3,3'-bisindolines exhibiting adjacent tetrasubstituted carbon stereocenters is described. A broad variety of heterochiral bisindolines was prepared in 91-99% yield using 3-fluorooxindoles and isatylidene malononitriles in the presence of catalytic amounts of triethylamine in water or aqueous solution. The reaction can be upscaled without compromising yield and diastereoselectivity and the general usefulness of this method was demonstrated with various Michael acceptors and extended to aldol and Mannich reactions.

Regioselectivity and diastereoselectivity of three-component reaction of \u03b1-amino acid, dialkyl acetylenedicarboxylates and 2-arylidene-1,3-indanediones

The 1,3-dipolar cycloaddition of active azomethine ylide, which were generated in situ from addition reaction of α-amino acids with dialkyl acetylenedicarboxylates, with 2-arylidene-1,3-indanediones showed versatile regioselectivity and diastereoselectivity. The reaction of sarcosine and glycine afforded one kind of functionalized spiro[indene-2,3′-pyrrolidines]. The other primary α-amino acids such as alanine, phenylalanine and leucine gave another kind of regioisomeric spiro[indene-2,3′-pyrrolidines]. The cyclic α-amino acids resulted in the corresponding spiro[indene-2,2′-pyrrolizines] and [indene-2,6’-pyrrolo[1,2-c]thiazoles].

Aldol Reaction of N-tert-Butanesulfinyl Imidates under Basic Conditions for Diastereoselective Synthesis of anti-Aldols.

Diastereoselective aldol reaction of N-tert-butanesulfinyl imidates under typical hard enolization conditions is reported. Potassium bis(trimethylsilyl)amide (KHMDS) effectively promotes the aldol reaction of α-aryl- and α-alkyl-substituted imidates, providing anti-aldol adducts in high yields with good to excellent diastereoselectivities. In the case of α-aryl imidates, high conversion depends on adding trimethylsilyl chloride (TMSCl) to the reaction mixture. In the presence of a suitable Lewis acid, cyclohexanone is a good electrophile in the aldol reaction of imidates.

Highly stereoselective asymmetric aldol routes to tert-butyl-2-(3,5-difluorophenyl)-1-oxiran-2-yl)ethyl)carbamates: Building blocks for novel protease inhibitors

Enantioselective syntheses of tert-butyl ((S)-2-(3,5-difluorophenyl)-1-((S)-oxiran-2-yl)ethyl)carbamate and ((S)-2-(3,5-difluorophenyl)-1-((R)-oxiran-2-yl)ethyl)carbamate are described. We utilized asymmetric syn- and anti-aldol reactions to set both stereogenic centers. We investigated ester-derived Ti-enolate aldol reactions as well as Evans’ diastereoselective syn-aldol reaction for these syntheses. We have converted optically active ((S)-2-(3,5-difluorophenyl)-1-((S)-oxiran-2-yl)ethyl)carbamate to a potent β-secretase inhibitor.

Diastereoselective Ritter-like Reaction on Cyclic Trifluoromethylated N,O-Acetals Derived from l-Tartaric Acid.

Despite the presence of the highly electron-withdrawing fluorinated substituent, cyclic α-trifluoromethylated N-acyliminium ions were successfully generated from fluorinated O-acetyl-N,O-acetal l-tartaric acid derivatives. The addition of nitriles on these intermediates occurred with high to excellent syn diastereoselectivity and led, in most cases, to oxazolines and amides as single diastereomers. The diastereoselectivity of the addition and the nature of the reaction product depend on the substituents on the hydroxyl groups of the tartaric acid scaffold. This methodology gave access to enantiopure, highly functionalized 5-(trifluoromethyl)pyrrolidin-2-one derivatives, bearing the fluorinated substituent on a tetrasubstituted carbon.