Intramolecular Alkene Research Articles

Rhodium‐Catalyzed Alkene Hydrosilylation via a Hydride Shuttle Process by Diene Ligands: Dramatic Enhancement of Regio‐ and Diastereoselectivity

AbstractA cooperative ligand‐assisted, Rh‐catalyzed intramolecular alkene hydrosilylation of homoallylic silyl ethers (1) was developed to provide 1,3‐trans‐oxasilacyclopentanes (trans‐2) in a highly regio‐ and diastereoselective manner. The modification of metal‐ligand architecture employing an inner‐sphere functional diene ligand (1,3‐cyclohexadiene) and a supporting phosphine ligand (BINAP) was identified as responsible for dramatic enhancement of selectivities. Mechanistic details of a diene ligand‐mediated hydride shuttle process are presented as the potential mechanistic driving force behind the high level of the selectivities.

Alkene hydroamination with a chiral zirconium catalyst. Connecting ligand design, precatalyst structure and reactivity trends

A set of chiral bis(amidate) proligands were synthesized based on a 3,3′-substituted biphenyldiamine backbone. Zirconium precatalysts were synthesized using these proligands in situ and used for catalytic testing for intramolecular alkene hydroamination, achieving moderate enantiomeric excesses. Ligands containing electron-withdrawing substituents were found to be exceptionally reactive, in some cases catalyzing formation of pyrrolidine products at room temperature. Substitution at the 3,3′-position of the biphenyldiamine backbone was observed to significantly impact N,O-chelate binding modes, which in turn affect observed enantioselectivities.

ChemInform Abstract: Chiral Phosphorus‐Based 1,3‐Dipoles: A Modular Approach to Enantioselective 1,3‐Dipolar Cycloaddition and Polycyclic 2‐Pyrroline Synthesis.

AbstractThe title chiral dipoles generated in situ from the corresponding imines, chiral phosphites, and acid chlorides, undergo intramolecular alkene cycloaddition with high enantioselectivity.

ChemInform Abstract: Regiodivergent Access to Five‐ and Six‐Membered Benzo‐Fused Lactams: Ru‐Catalyzed Olefin Hydrocarbamoylation.

We report herein a new strategy of the Ru-catalyzed intramolecular olefin hydrocarbamoylation for the regiodivergent synthesis of five- and six-membered benzo-fused lactams starting from N-(2-alkenylphenyl)formamides. Using a combined catalyst of Ru3(CO)12/Bu4NI in DMSO/toluene cosolvent (catalytic system A), a 5-exo-type cyclization proceeds favorably to form indolin-2-ones as a major product in good to excellent yield. When the reaction was conducted in the absence of halide additives in DMA/PhCl (catalytic system B), 3,4-dihydroquinolin-2-ones were obtained in major in moderate to high yield via a 6-endo cyclization process. An excellent level of regioselectivity was observed with a variety of substrates to deliver 5-exo- or 6-endo-cyclized lactams. It was found that while the selective cyclization was controlled primarily by the choice of catalytic systems employed, it was also greatly influenced by the structural nature of substrates. A halide-bridged trinuclear complex [Ru3(CO)10(μ2-I)]− is postulat...

ChemInform Abstract: Total Synthesis of (‐)‐Englerin A.

AbstractThis new and novel total synthesis gives englerin A in 11% overall yield and includes an intramolecular olefin metathesis ring closure reaction and a highly stereoselective oxygen bridge formation as key steps.

Enzyme Inhibition by Hydroamination: Design and Mechanism of a Hybrid Carmaphycin-Syringolin Enone Proteasome Inhibitor

Hydroamination reactions involving the addition of an amine to an inactivated alkene are entropically prohibited and require strong chemical catalysts. While this synthetic process is efficient at generating substituted amines, there is no equivalent in small molecule-mediated enzyme inhibition. We report an unusual mechanism of proteasome inhibition that involves a hydroamination reaction of alkene derivatives of the epoxyketone natural product carmaphycin. We show that the carmaphycin enone first forms a hemiketal intermediate with the catalytic Thr1 residue of the proteasome before cyclization by an unanticipated intramolecular alkene hydroamination reaction, resulting in a stable six-membered morpholine ring. The carmaphycin enone electrophile, which does not undergo a 1,4-Michael addition as previously observed with vinyl sulfone and α,β-unsaturated amide-based inhibitors, is partially reversible and gives insight into the design of proteasome inhibitors for cancer chemotherapy.

Rhodium‐Catalyzed Sequential Allylic Amination and Olefin Hydroacylation Reactions: Enantioselective Synthesis of Seven‐Membered Nitrogen Heterocycles

Dynamic kinetic asymmetric amination of branched allylic acetimidates has been applied to the synthesis of 2-alkyl-dihydrobenzoazepin-5-ones. These seven-membered-ring aza ketones are prepared in good yield with high enantiomeric excess by rhodium-catalyzed allylic substitution with 2-amino aryl aldehydes followed by intramolecular olefin hydroacylation of the resulting alkenals. This two-step procedure is amenable to varied functionality and proves useful for the enantioselective preparation of these ring systems.

Rhodium‐Catalyzed Sequential Allylic Amination and Olefin Hydroacylation Reactions: Enantioselective Synthesis of Seven‐Membered Nitrogen Heterocycles

AbstractDynamic kinetic asymmetric amination of branched allylic acetimidates has been applied to the synthesis of 2‐alkyl‐dihydrobenzoazepin‐5‐ones. These seven‐membered‐ring aza ketones are prepared in good yield with high enantiomeric excess by rhodium‐catalyzed allylic substitution with 2‐amino aryl aldehydes followed by intramolecular olefin hydroacylation of the resulting alkenals. This two‐step procedure is amenable to varied functionality and proves useful for the enantioselective preparation of these ring systems.

Chiral Phosphorus-Based 1,3-Dipoles: A Modular Approach to Enantioselective 1,3-Dipolar Cycloaddition and Polycyclic 2-Pyrroline Synthesis

The design of a new class of chiral 1,3-dipoles for enantioselective cycloaddition reactions is reported. These phosphorus-based dipoles are easily formed (from imines, acid chlorides, and chiral phosphites), rigidly chiral, and undergo intramolecular alkene cycloaddition with high enantioselectivity. Overall, this provides a straightforward and modular approach to synthesize chiral 2-pyrrolines and pyrrolidines in up to 99% ee.

Total synthesis of (−)-Englerin A

A novel and efficient total synthesis of Englerin A is reported. The synthesis featured an intramolecular olefin metathesis ring closure reaction and a highly stereoselective oxygen bridge formation induced by an iodonium ion. This strategy can be used for the synthesis of natural products Englerin A and Englerin B and can provide flexibility in the preparation of various 9-substituted analogues of Englerin A for further structure–activity relationship studies.

Regiodivergent Access to Five- and Six-Membered Benzo-Fused Lactams: Ru-Catalyzed Olefin Hydrocarbamoylation

We report herein a new strategy of the Ru-catalyzed intramolecular olefin hydrocarbamoylation for the regiodivergent synthesis of five- and six-membered benzo-fused lactams starting from N-(2-alkenylphenyl)formamides. Using a combined catalyst of Ru3(CO)12/Bu4NI in DMSO/toluene cosolvent (catalytic system A), a 5-exo-type cyclization proceeds favorably to form indolin-2-ones as a major product in good to excellent yield. When the reaction was conducted in the absence of halide additives in DMA/PhCl (catalytic system B), 3,4-dihydroquinolin-2-ones were obtained in major in moderate to high yield via a 6-endo cyclization process. An excellent level of regioselectivity was observed with a variety of substrates to deliver 5-exo- or 6-endo-cyclized lactams. It was found that while the selective cyclization was controlled primarily by the choice of catalytic systems employed, it was also greatly influenced by the structural nature of substrates. A halide-bridged trinuclear complex [Ru3(CO)10(μ2-I)](-) is postulated to be an active species in the catalytic system A. Two reaction pathways are proposed, in which the Ru-catalyzed oxidative addition of formyl C-H or N-H bond initiates the subsequent cyclization processes.

Studies on Difficult Intramolecular Hydroaminations in the Context of Four Syntheses of Alkaloid Natural Products

Examples of intramolecular alkene hydroaminations forming six-membered ring systems are rare, especially for systems in which the double bond is disubstituted. Such cyclizations have important synthetic relevance. Herein we report a systematic study of these cyclizations using recently developed Cope-type hydroamination methodologies. Difficult intramolecular alkene hydroaminations were used as key steps in syntheses of 2-epi-pumiliotoxin C, coniine, N-norreticuline and desbromoarborescidine A. This effort required the development of optimized hydroamination conditions to improve the efficiency of the cyclizations. Collectively, our results show that Cope-type cyclizations can be achieved on a variety of challenging substrates and proceed under similar conditions for both N-H and N-substituted hydroxylamines.

ChemInform Abstract: Ligand‐Controlled, Norbornene‐Mediated, Regio‐ and Diastereoselective Rhodium‐Catalyzed Intramolecular Alkene Hydrosilylation Reactions.

Ligand-controlled, norbornene-mediated, regio- and diastereoselective rhodium-catalyzed intramolecular alkene hydrosilylation of homoallyl silyl ethers (1) exploiting either BINAP or 1,6-bis(diphenylphosphino)hexane (dpph) has been developed. This method permits selective access to either trans-oxasilacyclopentanes (trans-2) or oxasilacyclohexanes (3) at will. A substoichiometric amount of norbornene markedly increased both yield and selectivity. A norbornene-mediated hydride shuttle process is discussed.

Total synthesis of (+)-valienamine and (−)-1-epi-valienamine via a highly diastereoselective allylic amination of cyclic polybenzyl ether using chlorosulfonyl isocyanate

The total synthesis of (+)-valienamine and (−)-1-epi-valienamine was concisely accomplished from readily available d-glucose via a highly diastereoselective amination of chiral benzylic ether using chlorosulfonyl isocyanate, intramolecular olefin metathesis, and diastereoselective reduction of cyclic enone using l-Selectride as the key steps.

Teaching Metathesis “Simple” Stereochemistry

Applications of metal-catalyzed olefin metathesis reactions manifested dramatic growth during the late 20th and early 21st centuries, culminating in the 2005 Nobel Prize awarded to three of the pioneers. The standard catalysts developed during that time frame and their descendants have profoundly changed the mindset of the synthetic community, even though they do not provide a handle to control selectivity issues as fundamental as the E/Z geometry of the newly formed double bond. With yet another generation of catalysts in the making that are far superior in this regard, a new wave seems to be building up that is expected to have enormous impact, too. The current state of the art is critically assessed, as are possible alternatives such as the metathesis of triple bonds followed by stereoselective semi-reduction.

An Approach to the Synthesis of Tetrahydroisoquinoline Alkaloids by Alkene Hydroamination: Synthesis of Coralydine

The protoberberine alkaloid coralydine was synthesized in a short sequence by a strategy including an intramolecular alkene hydroamination as the key step, followed by a Pictet–Spengler ­cyclization.

Cobalt‐Catalyzed Intramolecular Olefin Hydroarylation Leading to Dihydropyrroloindoles and Tetrahydropyridoindoles

Cobalt‐Catalyzed Intramolecular Olefin Hydroarylation Leading to Dihydropyrroloindoles and Tetrahydropyridoindoles

Cobalt‐Catalyzed Intramolecular Olefin Hydroarylation Leading to Dihydropyrroloindoles and Tetrahydropyridoindoles

Regiodivergente Katalyse: Cobaltkomplexe mit N-heterocyclischen Carbenliganden (NHC) katalysieren die intramolekulare Olefinhydroarylierung von Indolen mit anhängenden N-Homoallyl- oder Bis(homoallyl)-Einheiten und einer dirigierenden Aldimingruppe an C3. Unter milden Bedingungen entstehen Dihydropyrroloindole und Tetrahydropyridoindole, wobei der Cyclisierungsverlauf von der Brücke abhängt, aber über den NHC-Ligand gesteuert werden kann.

Ligand-Controlled, Norbornene-Mediated, Regio- and Diastereoselective Rhodium-Catalyzed Intramolecular Alkene Hydrosilylation Reactions

Ligand-controlled, norbornene-mediated, regio- and diastereoselective rhodium-catalyzed intramolecular alkene hydrosilylation of homoallyl silyl ethers (1) exploiting either BINAP or 1,6-bis(diphenylphosphino)hexane (dpph) has been developed. This method permits selective access to either trans-oxasilacyclopentanes (trans-2) or oxasilacyclohexanes (3) at will. A substoichiometric amount of norbornene markedly increased both yield and selectivity. A norbornene-mediated hydride shuttle process is discussed.

ChemInform Abstract: Synthesis of Five‐ and Six‐Membered Benzocyclic Ketones Through Intramolecular Alkene Hydroacylation Catalyzed by Nickel(0)/N‐Heterocyclic Carbenes.

AbstractThe convenient method allows the synthesis of indanone and tetralone derivatives.