Nonane Framework Research Articles

Palladium Catalyzed Allylic C-H Oxidation Enabled by Bicyclic Sulfoxide Ligands.

The activation of C-H bonds is a potent tool for modifying molecular structures in chemistry. This article details the steps involved in a novel ligand bearing a bicyclic [3.3.1]-nonane framework and bissulfoxide moiety. A palladium catalyzed allylic C-H oxidation method enables a direct benzyl-allylic functionalization with the bissulfoxide ligand. Bissulfoixde ligand possesses a rapidly constructed bicyclic [3.3.1] framework and it proved to be effective for enabling both N-and C-alkylation. A total of 13 C-H activation productions were reported with good to excellent yields. This report validated that it is necessary to include bissulfoxide as a ligand for superior reactivities. Naftifine was produced utilizing developed C-H functionalization methodology in good overall yields.

An attempt to construct an indole-fused azabicyclo[3.3.1]nonane framework via radical cyclization.

The structural motif of an indole-fused azabicyclo[3.3.1]nonane is common in many biologically significant indole-based natural products. Because of its structural complexity, this N-bridged scaffold has become an enticing target for organic chemists. Many efficient strategies have been developed to access this ring system synthetically, but a radical approach remains unexplored. Herein, we report a radical-based strategy to construct an indole-fused azabicyclo[3.3.1]nonane structural framework. Although our initial attempt to use a Cp2TiCl-mediated radical cyclization method was found to be unsuccessful, an alternative approach using a SmI2-mediated radical cyclization protocol was effective for enabling the desired ring closure, leading to the target indole-fused azabicyclo[3.3.1]nonane ring system. The modular approach developed here can be extended with appropriate functionalities on this indole-fused N-bridged ring system to synthesize many alkaloids.

Enantioselective Total Synthesis of Hyperforin and Pyrohyperforin

AbstractCapitalizing on the late‐stage diversification of an essential 1,3‐diene intermediate, we describe herein a 9‐step enantioselective total synthesis of (+)‐hyperforin and (+)‐pyrohyperforin, starting from commercially available allylacetone. Our convergent synthesis features a series of critical reactions: 1) an enantioselective deconjugative α‐alkylation of α,β‐unsaturated acid using chiral lithium amides as noncovalent stereodirecting auxiliaries; 2) a HfCl4‐mediated carbonyl α‐tert‐alkylation to forge the intricate bicyclo[3.3.1]nonane framework; 3) an abiotic cascade pyran formation; and 4) a selective 1,4‐semihydrogenation of polyenes. During the course of our synthesis, we also identified a 1,2‐cyclopropanediol overbred intermediate which was responsible for the 1,3‐diene precursor formation through a controlled fragmentation.

Enantioselective Total Synthesis of Hyperforin and Pyrohyperforin.

Capitalizing on the late-stage diversification of an essential 1,3-diene intermediate, we describe herein a 9-step enantioselective total synthesis of (+)-hyperforin and (+)-pyrohyperforin, starting from commercially available allylacetone. Our convergent synthesis features a series of critical reactions: 1) an enantioselective deconjugative α-alkylation of α,β-unsaturated acid using chiral lithium amides as noncovalent stereodirecting auxiliaries; 2) a HfCl4 -mediated carbonyl α-tert-alkylation to forge the intricate bicyclo[3.3.1]nonane framework; 3) an abiotic cascade pyran formation; and 4) a selective 1,4-semihydrogenation of polyenes. During the course of our synthesis, we also identified a 1,2-cyclopropanediol overbred intermediate which was responsible for the 1,3-diene precursor formation through a controlled fragmentation.

The (±)-6-Aza[1.0]triblattane Skeleton: Contraction beyond the Wilder-Culberson Ring System.

Synthesis of the 6-aza[1.0]triblattane skeleton and the unexpected construction of the 7-azatetracyclo[4.2.1.02,5.03,7]nonane framework are reported, as inspired by the Wilder-Culberson 1-aza[1.1]triblattane ring system. The key steps to assess the 6-aza[1.0]triblattane include accessing the 1,6-cycloaddition product from reaction of chlorosulfonyl isocyanate with cyclohept-1,3,5-triene followed by intramolecular electrocyclization and aminium radical cyclization.

Enantioselective Total Synthesis of Berkeleyone A and Preaustinoids.

Herein we report the first enantioselective total synthesis of 3,5-dimethylorsellinic acid-derived meroterpenoids (-)-berkeleyone A and its five congeners ((-)-preaustinoids A, A1, B, B1, and B2) in 12-15 steps, starting from commercially available 2,4,6-trihydroxybenzoic acid hydrate. Based upon the recognition of latent symmetry within D-ring, our convergent synthesis features two critical reactions: 1) a symmetry-breaking, diastereoselective dearomative alkylation to assemble the entire carbon core, and 2) a Sc(OTf)3 -mediated sequential Krapcho dealkoxycarbonylation/carbonyl α-tert-alkylation to forge the intricate bicyclo[3.3.1]nonane framework. We also conducted our preliminary biomimetic investigations and uncovered a series of rearrangements (α-ketol, α-hydroxyl-β-diketone, etc.) responsible for the biomimetic diversification of (-)-berkeleyone A into its five preaustinoid congeners.

Enantioselective Total Synthesis of Berkeleyone A and Preaustinoids

AbstractHerein we report the first enantioselective total synthesis of 3,5‐dimethylorsellinic acid‐derived meroterpenoids (−)‐berkeleyone A and its five congeners ((−)‐preaustinoids A, A1, B, B1, and B2) in 12–15 steps, starting from commercially available 2,4,6‐trihydroxybenzoic acid hydrate. Based upon the recognition of latent symmetry within D‐ring, our convergent synthesis features two critical reactions: 1) a symmetry‐breaking, diastereoselective dearomative alkylation to assemble the entire carbon core, and 2) a Sc(OTf)3‐mediated sequential Krapcho dealkoxycarbonylation/carbonyl α‐tert‐alkylation to forge the intricate bicyclo[3.3.1]nonane framework. We also conducted our preliminary biomimetic investigations and uncovered a series of rearrangements (α‐ketol, α‐hydroxyl‐β‐diketone, etc.) responsible for the biomimetic diversification of (−)‐berkeleyone A into its five preaustinoid congeners.

Chiral bipyridine-annulated bicyclo[3.3.1]nonane N-oxide organocatalysts for stereoselective allylation and hydrosilylation reactions

Abstract The synthesis of chiral C2-symmetric bis(bipyridine N,N′-dioxide) and bis(bipyridine N-monooxide) derivatives featuring bipyridine-annulated bicyclo[3.3.1]nonane framework is reported. The new Lewis basic bipyridine N,N′-dioxides exhibited good catalytic activity in the asymmetric allylation of aldehydes with allyltrichlorosilane, furnishing corresponding homoallylic alcohols in up to 75% ee. Reduction of ketimines and β-enamino esters with trichlorosilane catalyzed by bipyridine N,N′-dioxides proceeded in high yields but modest enantioselectivity (38–54% ee); good levels of asymmetric induction (up to 73% ee) were attained in the reduction of α-imino esters at room temperature.

Catalytic Asymmetric Total Synthesis of Macrocyclic Marine Natural Product (–)‐Haliclonin A†

Summary of main observation and conclusionWe describe the full details of our total synthesis of haliclonin A, a macrocyclic natural product suggested to originate from a common biosynthetic intermediate as sarain A. Central to our synthetic route is the strategic employment of nitromethane for several purposes: (1) as an umpolung surrogate of an aminomethyl group; (2) as an ideal nucleophile for the highly enantioselective catalytic asymmetric conjugate addition to forge the challenging all‐carbon quaternary stereogenic center that was used to induce the formations of all other chiral centers of the molecule; and (3) as a C1N1 building block to form the 3‐azabicyclo[3.3.1]nonane framework. The realization of this strategy relied on the development of a novel organocatalytic asymmetric conjugate addition of nitromethane to 3‐alkenyl cyclohex‐2‐enone, and the first Pd‐promoted intramolecular coupling of a thiocarbamate moiety onto an electron‐deficient alkene (enone) to form the 3‐azabicyclo[3,3,1]nonane core. The synthesis also features a SmI2‐mediated intermolecular reductive coupling of an enone with an aldehyde, ring‐closing alkene and alkyne metathesis reactions to build the two aza‐macrocycles, and an unprecedented direct transformation of enol into enone.

Chiral cleft-like methanocyclooctadiindoles: Synthesis, circular dichroism and TDDFT study

Chiral methanocyclooctadiindoles, featuring an indole-annulated bicyclo[3.3.1]nonane framework, were obtained from the corresponding bicyclo[3.3.1]nonane 2,6-, 2,7- and 3,7-diketones via the Fischer indolization reaction. The chiroptical properties of the cleft-like conformationally rigid derivatives, exhibiting a well-defined spatial arrangement of the two indole chromophores, were studied by means of electronic circular dichroism (CD) spectroscopy and time-dependent density functional theory (TDDFT) calculations. The absolute configuration of 7,14-methanocyclooctadiindole derived from an achiral bicyclic 3,7-diketone was established using the exciton chirality method and corroborated by TDDFT calculations.

Total Synthesis of (+)-epi-Condyfoline.

Herein, we report the first asymmetric total synthesis of aspidospermatan indole alkaloid (+)-epi-condyfoline (1) in 15 steps from commercially available 2-methylindole-3-carboxaldehyde. Key steps include (1) our domino Michael/Mannich annulation method of N-sulfinyl metallodienamines to set three contiguous stereocenters, (2) LiHMDS-mediated cyclization of an ω-tosyloxy N-sulfinamide to prepare the signature indole-fused 2-azabicyclo[3.3.1]nonane framework, and (3) DMTSF-promoted spirocyclization of a dithioacetal intermediate to access the final pyrrolidine ring. Functional group manipulations delivered the targeted alkaloid (+)-epi-condyfoline (1) in 13 steps and 1.25% overall yield from N-sulfinylimine (+)-8.

Base-Mediated Cascade Cyclization: Stereoselective Synthesis of Benzooxazocinone.

A new strategy for the synthesis of the oxa-azabicyclo[3.3.1]nonane subunit, a component of the naucleamide E core structure, has been developed. This annulation reaction between 1-substituted 3,4-dihydroisoquinolines and coumarin derivatives conveniently affords the oxa-azabicyclo[3.3.1]nonane framework via a base-mediated cascade cyclization under aqueous conditions. The value of this work lies in the efficient formation of the oxa-azabicyclo[3.3.1]nonane skeleton via a process whereby all the C-C, C-O, and C-N bond formations occur in a single chemical operation. In addition, the subsequent ring opening of these compounds furnished pyridoisoquinoline derivatives.

Synthesis of Star-Shaped Aromatic Derivatives with Chirality Predetermined by Bicyclo[3.3.1]nonane Framework

Star-shaped aromatic derivatives of bicyclo[3.3.1]nonane with predetermined chirality were synthesized by employing the Suzuki and Sonogashira reactions. The C 3-symmetric trifunctional aromatic derivatives based on the lateral bicyclo[3.3.1]nonene moiety possess unique molecular structures. The chiroptical properties of the star-shaped compounds and the corresponding monomeric derivatives were studied, and the absolute configuration was confirmed by using the empirical octant rule for the carbonyl chromophore and the sector rule for the aromatic chromophore.

Total Synthesis of (±)-Berkeleyone A.

A 13-step total synthesis of the fungal meroterpenoid berkeleyone A is reported. The molecular skeleton is formed using the first examples of two critical construction reactions: (1) an epoxide-initiated, β-ketoester-terminated polycyclization, and (2) an isomerization-cyclization cascade to generate the remaining bicyclo[3.3.1]nonane framework. The resulting 6-step synthesis of the carbocyclic core of the berkeleyone natural products has been used to access protoaustinoid A and berkeleyone A, and will aid future biosynthetic investigations into the origin of related natural products.

ChemInform Abstract: Enantioselective Ring Opening of meso‐Epoxides with Silicon Tetrachloride Catalyzed by Pyridine N‐Oxides Fused with the Bicyclo[3.3.1]nonane Framework.

The synthesis of new chiral Lewis basic organocatalysts that contain pyridine N-oxide moieties fused with the bicyclo[3.3.1]nonane framework is reported. The obtained pyridine N-oxides were employed as catalysts in the enantioselective ring opening of meso-epoxides with silicon tetrachloride. Derivative 1b endowed with two 2,4-diaryl-substituted pyridine N-oxide moieties proved to be a particularly effective catalyst for desymmetrization of norbornene oxide 16i to furnish Wagner–Meerwein rearrangement product 20i in unprecedented 96 % ee. Difunctional congener 3, which is striped of the 4-aryl substituents, exhibited moderate to high levels of asymmetric induction (47–88 % ee) with alicyclic epoxide substrates.

ChemInform Abstract: Formal Synthesis of Sarain A: Intramolecular Cycloaddition of an Eight‐Membered Cyclic Nitrone to Construct the 2‐Azabicyclo[3.3.1]nonane Framework.

AbstractA synthetic route to the tetracyclic skeleton of sarain A is developed, featuring an intramolecular cycloaddition of an eight‐membered cyclic nitrone to construct the 2‐azabicyclo[3.3.1]nonane framework and an iodoamidation reaction to form the pyrrolidine ring.

Enantioselective Ring Opening of meso‐Epoxides with Silicon Tetrachloride Catalyzed by Pyridine N‐Oxides Fused with the Bicyclo[3.3.1]nonane Framework

AbstractThe synthesis of new chiral Lewis basic organocatalysts that contain pyridine N‐oxide moieties fused with the bicyclo[3.3.1]nonane framework is reported. The obtained pyridine N‐oxides were employed as catalysts in the enantioselective ring opening of meso‐epoxides with silicon tetrachloride. Derivative 1b endowed with two 2,4‐diaryl‐substituted pyridine N‐oxide moieties proved to be a particularly effective catalyst for desymmetrization of norbornene oxide 16i to furnish Wagner–Meerwein rearrangement product 20i in unprecedented 96 % ee. Difunctional congener 3, which is striped of the 4‐aryl substituents, exhibited moderate to high levels of asymmetric induction (47–88 % ee) with alicyclic epoxide substrates.

Formal Synthesis of Sarain A: Intramolecular Cycloaddition of an Eight-Membered Cyclic Nitrone to Construct the 2-Azabicyclo[3.3.1]nonane Framework.

An enantioselective route to the tetracyclic skeleton of sarain A has been developed. Asymmetric reduction of an ynone introduced a chiral center which was transferred to the contiguous tertiary stereogenic centers through an Ireland-Claisen rearrangement. The 2-azabicyclo[3.3.1]nonane framework was constructed by an unprecedented intramolecular cycloaddition of an eight-membered cyclic nitrone. Using the steric bias of the bicyclic system, the quaternary carbon atom was constructed by a stereoselective aldol reaction. Further ring formations were performed by ring-closing metathesis for the 13-membered ring and an iodoamidation reaction for the pyrrolidine ring. The present synthesis has successfully provided an alternative route to the late-stage intermediate of Overman's synthesis.

Formal Synthesis of Sarain A: Intramolecular Cycloaddition of an Eight‐Membered Cyclic Nitrone to Construct the 2‐Azabicyclo[3.3.1]nonane Framework

AbstractAn enantioselective route to the tetracyclic skeleton of sarain A has been developed. Asymmetric reduction of an ynone introduced a chiral center which was transferred to the contiguous tertiary stereogenic centers through an Ireland–Claisen rearrangement. The 2‐azabicyclo[3.3.1]nonane framework was constructed by an unprecedented intramolecular cycloaddition of an eight‐membered cyclic nitrone. Using the steric bias of the bicyclic system, the quaternary carbon atom was constructed by a stereoselective aldol reaction. Further ring formations were performed by ring‐closing metathesis for the 13‐membered ring and an iodoamidation reaction for the pyrrolidine ring. The present synthesis has successfully provided an alternative route to the late‐stage intermediate of Overman’s synthesis.

A short designed semi-aromatic organic nanotube--synthesis, chiroptical characterization, and host properties.

The first generation of an organic nanotube based on the enantiomerically pure bicyclo[3.3.1]nonane framework is presented. The helical tube synthesised is the longest to date having its aromatic systems oriented parallel to the axis of propagation (length ∼26 Å and inner diameter ∼11 Å according to molecular dynamics simulations in chloroform). The synthesis of the tube, a heptamer, is based on a series of Friedländer condensations and the use of pyrido[3,2-d]pyrimidine units as masked 2-amino aldehydes, as a general means to propagate organic tubular structures and the introduction of a methoxy group for modification toward solubility and functionalization are described. The electronic CD spectra of the tube and molecular intermediates are correlated with theoretical spectra calculated with time-dependent density functional theory to characterize the chirality of the tube. Both experimental (NMR-titrations) and theoretical (molecular dynamics simulations) techniques are used to investigate the use of the tube as a receptor for the acetylcholine and guanidinium cations, respectively.