Biomimetic Total Synthesis of Hyperjapones A–E and Hyperjaponols A and C

Hyperjapones A–E and hyperjaponols A–C are complex natural products of mixed aromatic polyketide and terpene biosynthetic origin that have recently been isolated from Hypericum japonicum. We have synthesized hyperjapones A–E using a biomimetic, oxidative hetero‐Diels–Alder reaction to couple together dearomatized acylphloroglucinol and cyclic terpene natural products. Hyperjapone A is proposed to be the biosynthetic precursor of hyperjaponol C through a sequence of: 1) epoxidation; 2) acid‐catalyzed epoxide ring‐opening; and 3) a concerted, asynchronous alkene cyclization and 1,2‐alkyl shift of a tertiary carbocation. Chemical mimicry of this proposed biosynthetic sequence allowed a concise total synthesis of hyperjaponol C to be completed in which six carbon–carbon bonds, six stereocenters, and three rings were constructed in just four steps.     

Asymmetric Synthesis of Densely Functionalized Medium‐Ring Carbocycles and Lactones through Modular Assembly and Ring‐Closing Metathesis of Sulfoximine‐Substituted Trienes and Dienynes

An asymmetric synthesis of densely functionalized 7–11‐membered carbocycles and 9–11‐membered lactones has been developed. Its key steps are a modular assembly of sulfoximine‐substituted C‐ and O‐tethered trienes and C‐tethered dienynes and their Ru‐catalyzed ring‐closing diene and enyne metathesis (RCDEM and RCEYM). The synthesis of the C‐tethered trienes and dienynes includes the following steps: 1) hydroxyalkylation of enantiomerically pure titanated allylic sulfoximines with unsaturated aldehydes, 2) α‐lithiation of alkenylsulfoximines, 3) alkylation, hydroxy‐alkylation, formylation, and acylation of α‐lithioalkenylsulfoximines, and 4) addition of Grignard reagents to α‐formyl(acyl)alkenylsulfoximines. The sulfoximine group provided for high asymmetric induction in steps 1) and 4). RCDEM of the sulfoximine‐substituted trienes with the second‐generation Ru catalyst stereoselectively afforded the corresponding functionalized 7–11‐membered carbocyles. RCDEM of diastereomeric silyloxy‐substituted 1,6,12‐trienes revealed an interesting difference in reactivity. While the (R)‐diastereomer gave the 11‐membered carbocyle, the (S)‐diastereomer delivered in a cascade of cross metathesis and RCDEM 22‐membered macrocycles. RCDEM of cyclic trienes furnished bicyclic carbocycles with a bicyclo[7.4.0]tridecane and bicyclo[9.4.0]pentadecane skeleton. Selective transformations of the sulfoximine‐ and bissilyloxy‐substituted carbocycles were performed including deprotection, cross‐coupling reaction and reduction of the sulfoximine moiety. Esterification of a sulfoximine‐substituted homoallylic alcohol with unsaturated carboxylic acids gave the O‐tethered trienes, RCDEM of which yielded the sulfoximine‐substituted 9–11‐membered lactones. RCEYM of a sulfoximine‐substituted 1,7‐dien‐10‐yne showed an unprecedented dichotomy in ring formation depending on the Ru catalyst. While the second‐generation Ru catalyst gave the 9‐membered exo 1,3‐dienyl carbocycle, the first‐generation Ru catalyst furnished a truncated 9‐membered 1,3‐dieny carbocycle having one CH₂ unit less than the dienyne.     

A Photoredox‐Induced Stereoselective Dearomative Radical (4+2)‐Cyclization/1,4‐Addition Cascade for the Synthesis of Highly Functionalized Hexahydro‐1H‐carbazoles

A stereoselective synthesis of functionalized hexahydrocarbazoles was developed based on an unprecedented photoredox‐induced dearomative radical (4+2)‐cyclization/1,4‐addition cascade between 3‐(2‐iodoethyl)indoles and acceptor‐substituted alkenes. The title reaction simultaneously generates three C−C bonds and one C−H bond, along with three contiguous stereogenic centers. The hexahydro‐1H ‐carbazole products are highly valuable intermediates for the synthesis of novel antibiotics, as well as unnatural ring homologues of polycyclic indoline alkaloids.     

Rh/Cu‐Catalyzed Cascade [4+2] Vinylic C−H O‐Annulation and Ring Contraction of α‐Aryl Enones with Alkynes in Air

An unprecedented Rh‐catalyzed ketone‐directed vinylic C−H activation/[4+2] O ‐annulation of α‐aryl enones with internal alkynes followed by a Cu‐catalyzed ring contraction in air to provide multiaryl‐substituted furan derivatives has been developed. The preliminary mechanism study identifies the active pyrylium salt as the key intermediate.     

μ‐Oxo‐Dinuclear‐Iron(III)‐Catalyzed O‐Selective Acylation of Aliphatic and Aromatic Amino Alcohols and Transesterification of Tertiary Alcohols

A highly chemoselective and reactive μ‐oxo‐dinuclear iron(III) salen catalyst for transesterification was developed. The developed iron complex catalyzed acylation of aliphatic amino alcohols with nearly perfect O‐selectivity, even when using activated esters, for which chemoselectivity is more difficult to control. In addition, O‐selective transesterification of aromatic amino alcohols was achieved for the first time. The high activity of the iron complex enabled the use of sterically congested tertiary alcohols, including unprecedented tert‐butanol.     

Total Synthesis of (−)‐Lundurine A and Determination of its Absolute Configuration

A 15‐step total synthesis of (?)‐lundurine A ( 1 ) from easily accessible (S)‐pyrrolidinone 18 is reported. A Simmons‐Smith reaction allows the efficient, simultaneous assembly of the cyclopropyl C ring, the six‐membered D ring, the seven‐membered E ring, and the quaternary carbon stereocenters at C2 and C7. The absolute configuration of natural (?)‐lundurine A was deduced to be 2R,7R,20R based on the stepwise construction of the stereocenters during the total synthesis.     

Bipolarolides A–G: Ophiobolin‐Derived Sesterterpenes with Three New Carbon Skeletons from Bipolaris sp. TJ403‐B1

Bipolarolides A–G ( 1 – 7 ), seven novel ophiobolin‐derived sesterterpenes with three new types of skeletons, were characterized from fungus Bipolaris sp. TJ403‐B1. Their structures were determined via spectroscopic analyses, X‐ray crystallography, and quantum chemical ¹³C NMR and electronic circular dichroism (ECD) calculations. Compounds 1 and 2 were uniquely defined by a multicyclic caged oxapentacyclo[9.3.0.0^1,6.0^5,9.1^8,12]pentadecane‐bridged system. Compounds 3 and 4 featured an unprecedented 5‐5‐5‐5‐fused core skeleton, while 3 also contained an unexpected C‐3–C‐14 oxygen bridge to construct the caged architecture. Compounds 5 – 7 form a new class of highly modified pentacyclic oxaspiro[4.4]nonane‐containing sesterterpene‐alkaloid hybrids. Their biosynthetic pathways and potential HMG‐CoA reductase inhibitory and antimicrobial activities are also discussed.     

Synthesis of Two Natural Furan‐Cyclized Diarylheptanoids via 2‐Furaldehyde

Two natural diarylheptanoids, 2‐benzyl‐5‐(2‐phenylethyl)furan ( 1 ) and 2‐methoxy‐4‐{[5‐(2‐phenylethyl)furan‐2‐yl]methyl}phenol ( 2 ), were synthesized starting from 2‐furaldehyde. A Wittig reaction of 2‐furaldehyde with benzyltriphenylphosphonium bromide followed by reduction of the alkene C?C bond with Mg gave 2‐(2‐phenylethyl)furan ( 5 ). Lithiation of 5 with BuLi at ?78° followed by alkylation with benzyl bromide gave natural product 1 . In another approach, Friedel? Crafts acylation of compound 5 with benzoyl chloride followed by deoxygenation of the C?O group afforded 1 . The natural product 2 was also synthesized by acylation of 5 with 4‐acetoxy‐3‐methoxybenzoyl chloride ( 16 ) followed by deoxygenation and deacetylation.     

Stereoselective Total Synthesis of (11β)‐11‐Methoxycurvularin

A simple and highly efficient stereoselective total synthesis of (11β)‐11‐methoxycurvularin ( 5 ), a polyketide natural product, was achieved. The synthesis commenced with a Cu‐mediated regioselective opening of (2S)‐2‐methyloxirane ( 6 ) and comprised a Keck asymmetric allylation and intramolecular Friedel–Crafts acylation as key steps (Scheme 2).     

Stereoselective Total Synthesis of Xestodecalactone C

A simple and highly efficient stereoselective total synthesis of xestodecalactone C ( IIb ), a polyketide natural product, was achieved (Scheme 2). The synthesis involved Keck's asymmetric allylation, a iodine‐induced electrophilic cyclization, and an intramolecular Friedel–Crafts acylation as key steps.     

The Synthesis of trans‐Flavan‐3‐ol Gallates by Regioselective Oxidative Etherification and Their Cytotoxicity Mediated by 67 LR

We report on a chiral pool approach for the synthesis of trans‐flavan‐3‐ol gallates from epichlorohydrin. The trans‐flavan‐3‐ol gallates were prepared by the cycloetherification of the phenol at the C2 benzylic position of 2‐acylozyl‐1,3‐diarylpropane during regioselective C?H oxidation. The 1,3‐diarylpropanes were prepared starting from epichlorohydrin by epoxide opening with A and B ring precursors, followed by acylation of the resultant alcohol with galloyl chloride. The availability of both the enantiomers of epichlorohydrin allowed the preparation of the corresponding enantiomer using the same procedure. The cytotoxicity of the compounds against U266 cells was tested, in which 5‐deoxy‐7,3′‐O‐dimethyl gallocatechin gallate exhibited cytotoxicity that was more than ten times stronger than natural (?)‐EGCG. In addition, the absolute configuration of the derivatives did not critically affect the biological activity.     

Supramolecular interactions in carboxylate and sulfonate salts of 2,6‐diamino‐4‐chloropyrimidinium

Two new salts, namely 2,6‐diamino‐4‐chloropyrimidinium 2‐carboxy‐3‐nitrobenzoate, C₄H₆ClN₄⁺·C₈H₄NO₆⁻, (I), and 2,6‐diamino‐4‐chloropyrimidinium p‐toluenesulfonate monohydrate, C₄H₆ClN₄⁺·C₇H₇O₃S⁻·H₂O, (II), have been synthesized and characterized by single‐crystal X‐ray diffraction. In both crystal structures, the N atom in the 1‐position of the pyrimidine ring is protonated. In salt (I), the protonated N atom and the amino group of the pyrimidinium cation interact with the carboxylate group of the anion through N—H…O hydrogen bonds to form a heterosynthon with an R ₂²(8) ring motif. In hydrated salt (II), the presence of the water molecule prevents the formation of the familiar R ₂²(8) ring motif. Instead, an expanded ring [i.e. R ₃²(8)] is formed involving the sulfonate group, the pyrimidinium cation and the water molecule. Both salts form a supramolecular homosynthon [R ₂²(8) ring motif] through N—H…N hydrogen bonds. The molecular structures are further stabilized by π–π stacking, and C=O…π, C—H…O and C—H…Cl interactions.     

Nitrone Directing Groups in Rhodium(III)‐Catalyzed C−H Activation of Arenes: 1,3‐Dipoles versus Traceless Directing Groups

Functionalizable directing groups (DGs) are highly desirable in C?H activation chemistry. The nitrone DGs are explored in rhodium(III)‐catalyzed C?H activation of arenes and couplings with cyclopropenones. N‐tert‐butyl nitrones bearing a small ortho substituent coupled to afford 1‐naphthols, where the nitrone acts as a traceless DG. In contrast, coupling of N‐tert‐butyl nitrones bearing a bulky ortho group follows a C?H acylation/[3+2] dipolar addition pathway to give bicyclics. The coupling of N‐arylnitrones follows the same acylation/[3+2] addition process but delivers different bicyclics.     

Synthesis and characterization of a novel long‐alkyl‐chain ester‐substituted benzimidazole gelator and its octan‐1‐ol solvate

The synthesis of a novel benzimidazole derivative with a long‐chain‐ester substituent, namely methyl 8‐[4‐(1H‐benzimidazol‐2‐yl)phenoxy]octanoate, (3), is reported. Ester (3) shows evidence of aggregation in solution and weak gelation ability with toluene. The octan‐1‐ol solvate, methyl 8‐[4‐(1H‐benzimidazol‐2‐yl)phenoxy]octanoate octan‐1‐ol monosolvate, C₂₂H₂₆N₂O₃·C₈H₁₈O, (4), exhibits a four‐molecule hydrogen‐bonded motif in the solid state, with N—H…O hydrogen bonds between benzimidazole molecules and O—H…N hydrogen bonds between the octan‐1‐ol solvent molecules and the benzimidazole unit. The alkyl chains of the ester and the octan‐1‐ol molecules are in unfolded conformations. The phenylene ring is canted by 10.27 (6)° from the plane of the benzimidazole ring system. H…C contacts make up 20.7% of the Hirshfeld surface coverage. Weak C—H…π interactions involving the benzimidazole alkyl chain and three aromatic rings are observed.     

Design,synthesis, in silico analysis with PPAR‐γ receptor and study of non‐covalent interactions in unsymmetrical heterocyclic/phenyl fleximer

This work deals with the design, synthesis, in silico analysis, crystallization, and the interpretation 2‐cyano‐3‐{4‐[2‐(phthalimid‐nyl)‐propoxy]‐phenyl}‐acrylic acid ethyl ester (7). Analog 7 is designed based on rosiglitazone. The quantitative analysis of Compound 7 has been performed through single‐crystal X‐Ray Diffraction (XRD) and Hirshfeld surface analysis. Fleximer 7 has studied the role of flexibility in non‐covalent interactions and binding affinity with PPAR‐γ receptors. Both phthalimide ring and phenyl rings are linked with propylene linker. 2‐cyano‐3‐{4‐[2‐(phthalimid‐nyl)‐propoxy]‐phenyl}‐acrylic acid ethyl ester has Z = 8 in the crystal packing and stabilized by intermolecular non‐covalent interactions like C? H…O, C? H…N, C? H…л, and л…л, and so forth.     

Biosynthesis of Complex Indole Alkaloids: Elucidation of the Concise Pathway of Okaramines

The okaramines are a class of complex indole alkaloids isolated from Penicillium and Aspergillus species. Their potent insecticidal activity arises from selectively activating glutamate‐gated chloride channels (GluCls) in invertebrates, not affecting human ligand‐gated anion channels. Okaramines B ( 1 ) and D ( 2 ) contain a polycyclic skeleton, including an azocine ring and an unprecedented 2‐dimethyl‐3‐methyl‐azetidine ring. Owing to their complex scaffold, okaramines have inspired many total synthesis efforts, but the enzymology of the okaramine biosynthetic pathway remains unexplored. Here, we identified and characterized the biosynthetic gene cluster (oka ) of 1 and 2 , then elucidated the pathway with target gene inactivation, heterologous reconstitution, and biochemical characterization. Notably, we characterized an α‐ketoglutarate‐dependent non‐heme Fe^II dioxygenase that forged the azetidine ring on the okaramine skeleton.     

Recent Developments in Total Syntheses of Cephalosporolides,Penisporolides, and Ascospiroketals

The possible biogenetic connection of the 10‐membered lactone (decanolide) and the tricyclic [5,5]‐spiroacetal‐cis‐fused‐γ‐lactone (SAFL) natural products was proposed by Hanson in 1985. Mimicking such biosynthetic hypothesis led us to develop a general synthetic strategy for the total syntheses of both decanolide‐type cephalosporolides and SAFL‐type natural products. This biomimetic strategy features two key transformations: i) oxidative ring expansion of bicyclic β‐hydroxy tetrahydropyrans to the decanolides and ii) ring contraction rearrangement of the decanolides to the tricyclic SAFLs. In particular, the phenol derivatives are exploited as the starting materials for the decanolides and then the SAFLs. The successful biomimetic total synthesis allows us to revise the structures and biosynthetic hypothesis of several natural products, along with development of an NMR analysis method for determination of the relative stereochemistry of SAFL‐type compounds. In addition, this account will summarize recent synthetic work by other research groups.     

Amine‐Catalyzed Highly Regioselective and Stereoselective C(sp2)–C(sp2) Cross‐Coupling of Naphthols with trans‐α,β‐Unsaturated Aldehydes

A metal‐free C(sp²)–C(sp²) cross‐coupling approach to highly congested (E)‐α‐naphtholylenals from simple naphthols and enals is described. The mild reaction conditions with pyridine hydrobromideperbromide (PHBP) as the bromination reagent in the presence of piperidine or diphenylprolinol trimethylsilyl (TMS) ether as promoters enable the process in good yields and with high chemoselectivity, regioselectivity, and stereoselectivity. The process involves an unprecedented pathway of in situ regioselective 4‐bromination of 1‐naphthols and the subsequent unusual aromatic nucleophilic substitution of the resulting 4‐bromo‐1‐naphthols with the α‐C(sp²) of enals through a Michael‐type Friedel–Crafts alkylation–dearomatization followed by a cyclopropanation ring‐opening cascade process. The noteworthy features of this strategy are highlighted by the highly efficient creation of a C(sp²)–C(sp²) bond from readily available unfunctionalized naphthols and enals catalyzed by non‐metal, readily available cyclic secondary amines under mild reaction conditions.     

Iodine‐Catalyzed Highly Diastereoselective Synthesis of trans‐2,6‐Disubstituted‐3,4‐Dihydropyrans: Application to Concise Construction of C28–C37 Bicyclic Core of (+)‐Sorangicin A

A novel iodine‐catalyzed highly diastereoselective synthesis of trans‐2,6‐disubstituted‐3,4‐dihydropyrans have been achieved from δ‐hydroxy α,β‐unsaturated aldehydes by treating with allyltrimethyl silane in THF at room temperature with good to excellent yields. This methodology has been successfully implemented for a concise asymmetric synthesis of C28–C37 dioxabicyclo[3.2.1]octane ring system of (+)‐sorangicin A in 8 steps with 21 % overall yield.