Excellent Diastereocontrol Research Articles

Stereoselective Hydroxyallylation of Cyclopropenes with Cyclopropanols via NHC Catalysis of Transient Organozinc Species

AbstractA stereoselective hydroxyallylation reaction of cyclopropenes with cyclopropanols is achieved under zinc‐mediated conditions, affording densely functionalized cyclopropanes with excellent diastereocontrol over three contiguous stereocenters within and outside the cyclopropane ring. A racemic variant of the reaction is synergistically promoted by catalytic N‐heterocyclic carbene (NHC) and organic base, whereas chiral amino alcohol‐derived bifunctional NHC enables a catalytic enantioselective variant. The reaction likely involves the generation of enolized zinc homoenolate via ring‐opening of zinc cyclopropoxide and enolization of the resulting homoenolate, followed by its addition to the cyclopropene as a prochiral allylzinc nucleophile. Our mechanistic investigations highlighted the transient nature of enolized homoenolate, which, once generated from thermodynamically predominant cyclopropoxide, immediately proceeds to allylzincation with cyclopropene. The NHC not only promotes the rate‐determining generation of enolized homoenolate but also engages in the allylzincation process. The resulting cyclopropylzinc species undergoes partial in situ protonation while partially remaining intact, thereby leaving an opportunity for trapping with an external electrophile.

Stereoselective Hydroxyallylation of Cyclopropenes with Cyclopropanols via NHC Catalysis of Transient Organozinc Species.

A stereoselective hydroxyallylation reaction of cyclopropenes with cyclopropanols is achieved under zinc-mediated conditions, affording densely functionalized cyclopropanes with excellent diastereocontrol over three contiguous stereocenters within and outside the cyclopropane ring. A racemic variant of the reaction is synergistically promoted by catalytic N-heterocyclic carbene (NHC) and organic base, whereas chiral amino alcohol-derived bifunctional NHC enables a catalytic enantioselective variant. The reaction likely involves the generation of enolized zinc homoenolate via ring-opening of zinc cyclopropoxide and enolization of the resulting homoenolate, followed by its addition to the cyclopropene as a prochiral allylzinc nucleophile. Our mechanistic investigations highlighted the transient nature of enolized homoenolate, which, once generated from thermodynamically predominant cyclopropoxide, immediately proceeds to allylzincation with cyclopropene. The NHC not only promotes the rate-determining generation of enolized homoenolate but also engages in the allylzincation process. The resulting cyclopropylzinc species undergoes partial in situ protonation while partially remaining intact, thereby leaving an opportunity for trapping with an external electrophile.

Asymmetric Two‐Component Alkenyl Catellani Reaction for the Construction of C—N Axial Chirality†

Comprehensive SummaryHerein, we report an asymmetric two‐component alkenyl Catellani reaction for the construction of C—N axial chirality through a palladium/chiral norbornene cooperative catalysis and an axial‐to‐axial chirality transfer process. Various partially aromatic iodinated 2‐pyridones, quinolones, coumarin and uracil substrates react with 2,6‐disubstituted aryl bromides with a tethered amide group, to afford a wide variety of polycyclic C—N atropisomers (38 examples, up to 97% e.e.). The obtained C—N axial chirality originates from the preformed transient C—C axial chirality with high fidelity. The synthetic utility of this chemistry is demonstrated by facile preparation of complex quinoline and pyridine based C—N atropisomers through a N‐deprotection and aromatization sequence. In addition, a remote axial‐to‐central diastereoinduction process dictated by C—N axial chirality is observed with excellent diastereocontrol.

Ir–Na cooperativity controls the diastereoselectivity of borrowing hydrogen C–C alkylation on isosorbide: synthesis methodology and mechanistic investigation

The C–C alkylation of isosorbide derivative was achieved with excellent diastereocontrol using an Ir-based organometallic homogeneous catalyst.

Re-Evaluation of Product Outcomes in the Rh-Catalyzed Ring Expansion of Aziridines with N-Sulfonyl-1,2,3-Triazoles.

N-heterocycles are prevalent in pharmaceuticals and natural products, but traditional methods often do not introduce significant stereochemical complexity into the ring. We previously reported a Rh-catalyzed ring expansion of aziridines and N-sulfonyl-1,2,3-triazoles to furnish dehydropiperazines with excellent diastereocontrol. However, later studies employing ketone-containing carbene precursors showed that [3,9]-bicyclic aziridine formation competes with production of the desired heterocyclic scaffolds. In light of these surprising results, our initial findings were re-examined both experimentally and computationally to reveal how noncovalent interactions and restricted bond rotation in the aziridinium ylide intermediate promote this unexpected reaction pathway.

Enantioselective Synthesis of Acyclic Stereotriads Featuring Fluorinated Tetrasubstituted Stereocenters.

Elaboration of enantioenriched complex acyclic stereotriads represents a challenge for modern synthesis even more when fluorinated tetrasubstituted stereocenters are targeted. We have been able to develop a simple strategy in a sequence of two unprecedented steps combining a diastereoselective aldol-Tishchenko reaction and an enantioselective organocatalyzed kinetic resolution. The aldol-Tishchenko reaction directly generates a large panel of acyclic 1,3-diols possessing a fluorinated tetrasubstituted stereocenter by condensation of fluorinated ketones with aldehydes under very mild basic conditions. The anti 1,3-diols featuring three contiguous stereogenic centers are generated with excellent diastereocontrol (typically >99 : 1 dr). Depending upon the precursors both diastereomers of stereotriads are accessible through this flexible reaction. Furthermore, from the obtained racemic scaffolds, development of an organocatalyzed kinetic resolution enabled to generate the desired enantioenriched stereotriads with excellent selectivity (typically er >95 : 5).

Withdrawal: Asymmetric Alkenyl Catellani Reaction for the Construction of C-N Axial Chirality.

Herein we report an asymmetric two-component vinylogous Catellani reaction for the construction of C-N axial chirality through a palladium/chiral norbornene cooperative catalysis and an axial-to-axial chirality transfer process. Various partially aromatic iodinated 2-pyridones, quinolones, coumarin and uracil substrates react with 2,6-disubstituted aryl bromides with a tethered amide group, to afford a wide variety of polycyclic C-N atropisomers (39 examples, up to 97% ee ). The obtained C-N axial chirality is originated from the preformed transient C-C axial chirality with high fidelity. The synthetic utility of this chemistry is demonstrated by facile preparation of complex quinoline and pyridine based C-N atropisomers through a N -deprotection and aromatization sequence. In addition, a remote axial-to-central diastereoinduction process dictated by C-N axial chirality is observed with excellent diastereocontrol. This research opens a new avenue for asymmetric synthesis.

Nickel-Catalyzed Reductive Asymmetric Aryl-Acylation and Aryl-Carbamoylation of Unactivated Alkenes

Nickel-Catalyzed Reductive Asymmetric Aryl-Acylation and Aryl-Carbamoylation of Unactivated Alkenes

Synthesis of Highly Substituted Cyclobutanones by a One‐Pot Keteniminium‐Enamine Process

AbstractHerein, we describe an effective one‐pot sequence for the regio‐ and stereoselective synthesis of highly substituted cyclobutanones. This process relies on first a [2+2] cycloaddition involving a keteniminium salt intermediate with an alkene followed by isomerization of the resulting cyclobutaniminium salt into its cyclic enamine form and then reaction of the latter with an electrophile. The adduct can be either hydrolyzed or reduced to give the corresponding cyclobutanone or cyclobutanamine, respectively, with excellent diastereocontrol. A variety of electrophiles was tolerated allowing the incorporation of diverse substituents and functionalities onto the cyclobutyl ring. Additionally, the coplanarity of diverse cyclic enamines was investigated through a DFT study.

Isothiourea‐Catalyzed Functionalization of Pyrrolyl‐ and Indolylacetic Acid: Enantioselective Synthesis of Dihydropyridinones and One‐pot Synthesis of Pyridinones

AbstractA protocol for the isothiourea‐catalyzed enantioselective functionalization of pyrrolyl‐ and indolylacetic acids has been developed. Stereodefined dihydropyridinones are accessed through formal [4+2] cycloaddition of an in situ generated isothiouronium enolate with α,β‐unsaturated ketimines. The dihydropyridinones are obtained in moderate to excellent yield (26–97%), excellent diastereocontrol (all >95 : 5 dr) and moderate to excellent enantiocontrol (75 : 25–99 : 1 er). An unusual elimination of pyrrole or indole from the dihydropyridinone to access achiral pyridinones was observed and could be selectively promoted. A further one‐pot synthesis using an acyl imidazole was developed to give pyridinones in good to excellent yields (67–91%).

Rh-Catalyzed Aziridine Ring Expansions to Dehydropiperazines.

Piperazines are prevalent in pharmaceuticals and natural products, but traditional methods do not typically introduce stereochemical complexity into the ring. To expand access to these scaffolds, we report Rh-catalyzed ring expansions of aziridines and N-sulfonyl-1,2,3-triazoles to furnish dehydropiperazines with excellent diastereocontrol. Productive ring expansion proceeds via a pseudo-1,4-sigmatropic rearrangement of an aziridinium ylide species. However, the structural features of the carbene precursor are important, as pyridotriazoles undergo competing cheletropic extrusion to furnish ketimines.

Lead-Mediated Highly Diastereoselective Allylation of Aldehydes with Cyclic Allylic Halides.

Lead was found to efficiently mediate the allylation reactions of carbonyl compounds with cyclic allylic halides in the presence of stoichiometric amounts of lithium chloride and a catalytic amount of GaCl3 (20 mol %), leading to the desired homoallylic alcohols in modest to high yields with excellent diastereocontrol (>99:1 syn/anti) and good functional group tolerance. In contrast, the use of either 2-pyridinecarboxaldehyde as the carbonyl substrate or ( E)-cinnamyl bromide as the allylating agent produced the corresponding product with reversed diastereoselectivity (>99:1 anti/syn).

Molybdenum-Catalyzed Diastereoselective anti-Dihydroxylation of Secondary Allylic Alcohols.

In this protocol, we report a Mo-catalyzed anti-dihydroxylation of secondary allylic alcohols, providing a general method for the preparation of 1,2,3-triols bearing up to three continuous stereocenters with excellent diastereocontrol. The mechanistic studies reveal that this dihydroxylation reaction consists of two steps and up to excellent diastereomeric ratios of the final triol products can be achieved due to the high level of both diastereocontrol in the initial epoxidation and regiocontrol in the following hydrolysis in situ.

An elusive thermal [2 + 2] cycloaddition driven by visible light photocatalysis: tapping into strain to access C2-symmetric tricyclic rings.

A mild and operationally simple methodology is reported for the synthesis of cyclobutane rings imbedded within a C2-symmetric tricyclic framework. The method uses visible light and an iridium-based photocatalyst to drive the oft-stated "forbidden" thermal [2 + 2] cycloaddition of cycloheptenes and analogs. Importantly, it generates cyclobutane with four new stereocenters with excellent stereoselectivity, and perfect regioselectivity. The reaction is propelled forward when the photocatalyst absorbs a visible light photon, which transfers this energy to the cycloheptene. Key to success is, upon excitation to the triplet via sensitization from the photocatalyst, the double bond isomerizes to give the transient, highly strained, trans-cycloheptene. The trans-cycloheptene undergoes a strain relieving thermal, intermolecular [π2s + π2a] cycloaddition with another cis-cycloheptene. X-ray analysis reveals that the major product is the head-to-head, C2-symmetric all trans-cyclobutane. Additionally, a dramatic display structural complexity enhancement is observed with the use of chiral cycloheptenols possessing one stereocenter, which results in the formation of cyclobutanes with six contiguous stereocenters with good to excellent diastereocontrol, and can be used to isolate single stereoisomers of stereochemically complex cyclobutanes in good yield.

Cationic Cascade for Building Complex Polycyclic Molecules from Simple Precursors: Diastereoselective Installation of Three Contiguous Stereogenic Centers in a One-Pot Process.

An expedient strategy for the synthesis of polycyclic small molecules is described. The method first joins together two achiral building blocks (an enyne and an aldehyde or a ketone) using an alkynyl halo-Prins protocol. Then, in the same reaction vessel, acidic conditions initiate a cationic cascade that includes a stereospecific halo-Nazarov electrocyclization and a diastereoselective Friedel-Crafts allylation. The entire sequence forms three carbon-carbon bonds and a carbon-halogen bond, generating halocyclopentene adducts in one pot from simple precursors. The process occurs with excellent diastereocontrol, providing highly functionalized polycycles containing three tertiary or quaternary stereogenic centers in a linear array. It is even possible to install three contiguous all-carbon quaternary centers using this method.

Diastereoselective α-Fluorination of N- tert-Butanesulfinyl Imidates.

A diastereoselective α-fluorination of N- tert-butanesulfinyl imidates was developed. Deprotonation of N- tert-butanesulfinyl imidates with lithium hexamethyldisilazide generates aza-enolates that can be intercepted, with excellent diastereocontrol, by the inexpensive electrophilic fluorinating agent NFSI. This protocol was applied to the preparation of synthetically useful trans-2-fluoro-cyclohexamine with high enantiomeric purity (99.5% ee).

A highly diastereoselective [3+3] annulation reaction of aza-oxyallyl cations and nitrones

An efficient synthesis of 1,2,4-oxadiazinan-5-ones via [3+3] cycloaddition of in situ generated aza-oxyallyl cations with nitrones has been developed. The protocol features easy operation, excellent yields, excellent diastereo-control, broad substrate scope and good functional group tolerance.

Diastereoselective α-Hydroxylation of N-tert-Butanesulfinyl Imidates and N′-tert-Butanesulfinyl Amidines with Molecular Oxygen

Diastereoselective α-hydroxylation using molecular oxygen has been achieved with chiral α-alkyl N-tert-butanesulfinyl imidates and α-aryl N'-tert-butanesulfinyl amidines. The aza-enolates generated from deprotonation of imidates/amidines can be intercepted by O2 with excellent diastereocontrol and subsequently transformed into α-hydroxylation products in the presence of the reductant trimethyl phosphite.

Radical Heterocyclization and Heterocyclization Cascades Triggered by Electron Transfer to Amide-Type Carbonyl Compounds.

Radical heterocyclizations triggered by electron transfer to amide-type carbonyls, using SmI2 -H2 O, provide straightforward access to bicyclic heterocyclic scaffolds containing bridgehead nitrogen centers. Furthermore, the first radical heterocyclization cascade triggered by reduction of amide-type carbonyls delivers novel, complex tetracyclic architectures containing five contiguous stereocenters with excellent diastereocontrol.

Radical Heterocyclization and Heterocyclization Cascades Triggered by Electron Transfer to Amide‐Type Carbonyl Compounds

AbstractRadical heterocyclizations triggered by electron transfer to amide‐type carbonyls, using SmI2‐H2O, provide straightforward access to bicyclic heterocyclic scaffolds containing bridgehead nitrogen centers. Furthermore, the first radical heterocyclization cascade triggered by reduction of amide‐type carbonyls delivers novel, complex tetracyclic architectures containing five contiguous stereocenters with excellent diastereocontrol.