Stereoselective Approach Research Articles

A stereoselective approach in preparation of γ-lactam precursors for oxazolomycin’s synthesis

A stereoselective approach to C-3′ methyl attached γ-lactam derivatives as the precursors of pyroglutamate core of oxazolomycins is described. The synthesis started from d-xylose and utilized [3,3]-heterosigmatropic rearrangement. The key lactamization was achieved with intramolecular aldol reaction and ring-closing metathesis. The accomplished stereoselective aldol cyclization was elucidated with Zimmerman-Traxler transition state models. Stereoselectivity of the aldol reaction was explained as a consequence of chelation and bridgehead atoms linkage. The present work also encompasses proposed structures of (E)- and (Z)- generated enolates during intramolecular aldol reaction. Although stereocenters were not formed during ring-closing metathesis, a stereospecific reduction of prepared double bond functionality was successfully accomplished.

Gold-catalyzed cycloisomerization of enynamides: Regio- and stereoselective approach to tetracyclic spiroindolines

A gold-catalyzed β-site regioselective cycloisomerization of tryptamine derived enynamides is described. A variety of tetracyclic spiroindolines bearing 6/5/5/6-ring system were prepared. During the mechanistic studies, a vinyl gold complex was isolated successfully, which was further characterized by NMR spectrum and X-ray crystal analysis.

Scalable Preparation of Enantioenriched (S)-5-methylhept-2-en-4-one. Synthesis and Aroma Properties of Achiral Analogues Thereof.

(S)-5-Methylhept-2-en-4-one is a key flavour compound in hazelnuts. We have performed its chiral-pool-based chemoenzymatic synthesis with 39% overall yield (73% ee). The four-step aldol-based sequence avoids the use of highly reactive and/or toxic reagents, does not require anhydrous conditions and uses only distillation as the purification method. Thus, such methodology represents a green and scalable alternative to only two stereoselective approaches towards this natural product known so far. In addition, we have designed and prepared a set of new (di)enones as achiral synthetic analogues of the title compound. The results of their sensory analyses clearly show that relatively minor structural changes of the natural molecule significantly alter its olfactory properties. Thus, simple (poly)methylation completely changes the original hazelnut aroma of (S)-5-methylhept-2-en-4-one and shifts the odour of its analogues to eucalyptus, menthol, camphor, and sweet aroma.

Facile Stereoselective Approach to Diverse Spiroheterocyclic Tetrahydropyrans: Concise Synthesis of (+)‐Broussonetine G and H

AbstractA highly diastereoselective copper‐catalyzed multicomponent cyclization of exocyclic enol ethers/enamines with methylene malonate and aldehydes has been developed to furnish spiroheterocyclic tetrahydropyrans in high yields with greater than 95:5 d.r. This method is practical, in that 36 examples, including a range of aldehydes and exo‐vinyl heterocycles, are presented. By applying the newly developed method, the total synthesis of (+)‐broussonetine G and formal synthesis of (+)‐broussonetine H were achieved in a concise way.

Facile Stereoselective Approach to Diverse Spiroheterocyclic Tetrahydropyrans: Concise Synthesis of (+)-Broussonetine G and H.

A highly diastereoselective copper-catalyzed multicomponent cyclization of exocyclic enol ethers/enamines with methylene malonate and aldehydes has been developed to furnish spiroheterocyclic tetrahydropyrans in high yields with greater than 95:5 d.r. This method is practical, in that 36 examples, including a range of aldehydes and exo-vinyl heterocycles, are presented. By applying the newly developed method, the total synthesis of (+)-broussonetine G and formal synthesis of (+)-broussonetine H were achieved in a concise way.

Stereoselective Approaches toward the Synthesis of Nucleoside Antibiotic Core Aminoribosyl Glycyluridine

Antibiotics that have a novel mechanism of action are urgently required for treatment of drug‐resistant microorganisms. Naturally occurring nucleoside antibiotics have shown promising antibacterial activity by inhibiting bacterial translocase MraY, a key enzyme involved in catalysis of the first step of bacterial peptidoglycan biosynthesis. Despite having promising antibiotic properties, a major challenge toward development of this important class of compounds as drug candidates is their complex multistep synthesis. Specifically, efficient synthetic methodologies toward producing the aminoribosylated uridine‐derived core unit in a stereo‐controlled manner is seen as an essential prerequisite for detailed structure‐activity relationship (SAR) studies. This review summarizes approaches available for the stereoselective synthesis of nucleoside core pharmacophores, including both 5′‐C‐glycyluridine (GlyU) as well as it's β‐selective ribosylation.

Transition‐Metal‐Free Cross‐Coupling of Benzothiophenes and Styrenes in a Stereoselective Synthesis of Substituted (E,Z)‐1,3‐Dienes

AbstractA transition metal‐free one‐pot stereoselective approach to substituted (E,Z)‐1,3‐dienes was developed by using an interrupted Pummerer reaction/ligand‐coupling strategy. Readily available benzothiophene S‐oxides, which can be conveniently prepared by oxidation of the parent benzothiophenes, undergo Pummerer coupling with styrenes. Reaction of the resultant sulfonium salts with alkyllithium/magnesium reagents generates underexploited hypervalent sulfurane intermediates that undergo selective ligand coupling, resulting in dismantling of the benzothiophene motif and the formation of decorated (E,Z)‐1,3‐dienes.

Transition-Metal-Free Cross-Coupling of Benzothiophenes and Styrenes in a Stereoselective Synthesis of Substituted (E,Z)-1,3-Dienes.

A transition metal-free one-pot stereoselective approach to substituted (E,Z)-1,3-dienes was developed by using an interrupted Pummerer reaction/ligand-coupling strategy. Readily available benzothiophene S-oxides, which can be conveniently prepared by oxidation of the parent benzothiophenes, undergo Pummerer coupling with styrenes. Reaction of the resultant sulfonium salts with alkyllithium/magnesium reagents generates underexploited hypervalent sulfurane intermediates that undergo selective ligand coupling, resulting in dismantling of the benzothiophene motif and the formation of decorated (E,Z)-1,3-dienes.

A molecular electron density theory study of Diels‐Alder reaction between Danishefsky's diene and (2E)‐3‐phenyl‐2‐(trifluoromethyl) acrylonitrile

AbstractThe Diels‐Alder reaction between Danishefsky's diene (DD 4) and (2E)‐3‐phenyl‐2‐(trifluoromethyl) acrylonitrile (EPTA 5) at 393 K in the presence of toluene has been studied using the molecular electron density theory at the M06‐2X/6‐31G(d,p) computational level. The calculated relative Gibbs free energies indicated that the studied reaction takes place in a complete regioselective and stereoselective manner in which the most nucleophilic center of DD 4 is attacked by the most electrophilic center of EPTA 5 passing through the stationary point of TS2n. It was shown that the TS2n affords the corresponding cycloadduct of CA2n as the unique product in excellent agreement with the experimental outcomes. On the other hand, a great destabilizing steric repulsion between methoxy moiety of DD 4 and the trifluoromethyl moiety of EPTA 5 along the exo stereoselective approach is responsible for the predominance of the endo approach over the exo one. The nucleophilic and electrophilic Parr functions at the reactive sites of the DD 4 and EPTA 5 have been used to explain the regioselectivity of the Diels‐Alder reaction. According to the electron localization function analysis of the intrinsic reaction coordinate profile of the energetically most preferred TS2n, a nonconcerted two‐stage one‐step molecular mechanism has been proposed. The mechanism indicated the formation of C1C6 single bond through coupling of C1 to C6 and subsequent C4C5 single bond through coupling of C4 to C5 at cycloadduct CA2n.

A General Biomimetic Hetero-Diels–Alder Approach to the Core Skeletons of Xenovulene A and the Sterhirsutins A and B

A biomimetic, regio- and stereoselective approach to the 5,6,11-tricyclic core skeleton of xenovulene A, as well as sterhirsutins A and B, is described. The key steps are a biomimetic inverse-electron-demand hetero-Diels-Alder cycloaddition of α-humulene and a ribose-derived vinyl ketone, followed by acid-catalyzed rearrangement of the 1,3-dioxolane that neighbors the resultant cyclic enol ether.

Stereoselective Approach towards the Synthesis of 3R, 5 S Gingerdiol and 3 S, 5 S Gingerdiol

AbstractAn operationally simple and concise stereoselective synthesis of both natural 3R, 5 S gingerdiol and 3 S, 5 S gingerdiol has been achieved from achiral n‐heptanal by employing iterative proline catalysed α‐aminoxylation, followed by Horner−Wadsworth−Emmons or Wittig olefination reactions as key steps. The adducts formed in high enantiopurity as well as syn or anti‐1,3‐diols units were synthesized with excellent diastereoselectivity from γ‐hydroxy aldehyde by using D or L‐ proline.

Leoligin-inspired synthetic lignans with selectivity for cell-type and bioactivity relevant for cardiovascular disease.

Recently, a natural compound leoligin, a furan-type lignan, was discovered as an interesting hit compound with an anti-inflammatory pharmacological activity profile. We developed a modular and stereoselective approach for the synthesis of the edelweiss-derived lignan leoligin and used the synthetic route to rapidly prepare leoligin analogs even on the gram scale. Proof of concept of this approach together with cell-based bio-assays gained structural analogs with increased selectivity towards vascular smooth muscle versus endothelial cell proliferation inhibition, a major benefit in fighting vascular neointima formation. In addition, we identified the structural features of leoligin analogs that define their ability to inhibit the pro-inflammatory NF-κB pathway. Results are discussed in the context of structural modification of these novel synthetic lignans.

Iron-catalyzed boration of cinnamyl carbonates: a highly stereoselective approach to cyclopropylboronates

An efficient approach to cyclopropylboronates with excellent stereoselectivities via iron-catalyzed boration/cyclopropylation of cinnamyl carbonates is developed.

Synthesis of 1-Sulfonylpyrrolidines via Cycloaddition Reactions

Many biologically active compounds possess 1-sulfonyl pyrrolidine structural motif. Therefore, the development of facile methods for the preparation of these compounds in optically pure form is relevant. One of the regio- and stereoselective approaches to the pyrrolidine derivatives is cycloaddition. Thus, this review article is an attempt to survey literature describing synthetic methods for the preparation of 1-sulfonyl pyrrolidine derivatives via various cycloaddition reactions. Keywords: Pyrrolidines, sulfonylamides, cycloadditions, heterocycles, stereoselectivity, synthesis.

Rhodium(II)‐Catalyzed Highly Stereoselective C3 Functionalization of Indolizines with N‐Sulfonyl‐1,2,3‐triazoles

AbstractAn efficient and highly stereoselective approach for the C3 functionalization of indolizines through rhodium(II)‐catalyzed insertion of aza‐vinyl carbenes to synthesize N‐sulfonylamine alkenyl derivatives of indolizines is disclosed. Variably functionalized indolizines underwent C3 functionalization to afford moderate to good yields. Under similar reaction conditions pyrrolo[1,2‐a]quinolines resulted in regioselective C1 functionalization to give their N‐sulfonylamine alkenyl derivatives. The reaction methodology was successfully extended for the preparation of 1,3‐bis(N‐sulfonylamine alkenyl)indolizine derivatives and C3‐functionalized indolizines were used for the preparation of new molecular entities.

A concise asymmetric synthesis of (−)-trans-aerangis lactone

A concise stereoselective approach to functionalized δ-lactone skeleton from monosilylated ethylene glycol as a starting material and its application to the asymmetric total synthesis of (−)-trans-aerangis lactone have been demonstrated. The synthesis utilizes the organocatalyzed MacMillan’s cross aldol reaction as a key step.

A novel and highly stereoselective route for the synthesis of non-racemic 3-substituted isoindolin-1-one targets

A new, versatile and highly stereoselective approach for the synthesis of non-racemic 3-substituted isoindolin-1-ones is described from a readily available chiral template. The potential of this new protocol is demonstrated through the synthesis of an enantiomerically enriched 3-alkyl N-H isoindolin-1-one target with an e.e. of 98%.

Stereoselective Synthesis of Mechanically Planar Chiral Rotaxanes

AbstractChiral interlocked molecules in which the mechanical bond provides the sole stereogenic unit are typically produced with no control over the mechanical stereochemistry. Here we report a stereoselective approach to mechanically planar chiral rotaxanes in up to 98:2 d.r. using a readily available α‐amino acid‐derived azide. Symmetrization of the covalent stereocenter yields a rotaxane in which the mechanical bond provides the only stereogenic element.

Stereoselective Synthesis of Mechanically Planar Chiral Rotaxanes.

Chiral interlocked molecules in which the mechanical bond provides the sole stereogenic unit are typically produced with no control over the mechanical stereochemistry. Here we report a stereoselective approach to mechanically planar chiral rotaxanes in up to 98:2 d.r. using a readily available α‐amino acid‐derived azide. Symmetrization of the covalent stereocenter yields a rotaxane in which the mechanical bond provides the only stereogenic element.

A stereoselective approach towards a small library of cytotoxic isomeric sphingoid bases

Two approaches to a small library of cytotoxic dihydrosphingosine analogues are described. [3,3]-Sigmatropic rearrangements along with an OCM reaction were used as the key steps for the construction of the two isodihydrosphingosines ent-6 and 10, whereas the functional group manipulations, including Grubbs' metathesis chemistry, were applied to known isothiocyanate scaffolds 15 and 16 to provide access to the enantiomeric forms of ent-6 and 10 and diastereomeric isophytosphingosines ent-7.HCl and 14. Cell viability experiments revealed that the target isomeric sphingoid bases were more potent than the traditional anticancer agent cisplatin, with IC50 values in the low micromolar range for the most active compounds.