Base‐Selective Five‐ versus Six‐Membered Ring Annulation in Palladium‐Catalyzed C–C Coupling Cascade Reactions: New Access to Electron‐Poor Polycyclic Aromatic Dicarboximides

Palladium‐catalyzed base‐selective annulation of dibromonaphthalimide to different aryl boronate esters by combined Suzuki–Miyaura cross‐coupling and direct C−H arylation afforded a series of new five‐ and six‐membered ring annulated electron‐poor polycyclic aromatic hydrocarbons. Cesium carbonate (Cs₂CO₃) as auxiliary base in these C−C coupling cascade reactions led exclusively to six‐membered ring annulation, while the use of organic base diazabicycloundecene (DBU) afforded the corresponding five‐membered ring annulated products. This base‐dependent selective mode of annulation is attributed to different mechanistic pathways directed by the applied base. The selective annulation was revealed by single crystal X‐ray analysis of the respective five‐ and six‐membered ring annulated products. The optical and redox properties of the new polycyclic aromatic dicarboximides were characterized by UV/Vis absorption and fluorescence spectroscopy and cyclic voltammetry.     

Synthesis of Cyclopenta‐HBCs and their Regioselective Chlorination During Oxidative Cyclodehydrogenation

Hexa‐peri‐hexabenzocoronenes with a bay‐fused five‐membered ring are synthesized from fluorenyl precursors. The key oxidative cyclodehydrogenation step is accompanied by regioselective chlorination that is enhanced by methylation at the cyclopenta‐ring or increased reaction concentration. The CpHBC products undergo mild electrophilic aromatic bromination, without catalyst, to afford adducts suitable for π‐extension by cross‐coupling.     

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.     

Synthesis of Cyclic Alkenylsiloxanes by Semihydrogenation: A Stereospecific Route to (Z)‐Alkenyl Polyenes

Cyclic alkenylsiloxanes were synthesized by semihydrogenation of alkynylsilanes—a reaction previously plagued by poor stereoselectivity. The silanes, which can be synthesized on multigram scale, undergo Hiyama–Denmark coupling to give (Z)‐alkenyl polyene motifs found in bioactive natural products. The ring size of the silane is crucial: five‐membered cyclic siloxanes also couple under fluoride‐free conditions, whilst their six‐membered homologues do not, enabling orthogonality within this structural motif.     

Reactivity comparison of five‐ and six‐membered cyclic carbonates with amines: Basic evaluation for synthesis of poly(hydroxyurethane)

The reaction of six‐ and five‐membered cyclic carbonates, 5‐(2‐propenyl)‐1,3‐dioxan‐2‐one ( 1 ) and 4‐(3‐butenyl)‐1,3‐dioxolan‐2‐one ( 2 ) with hexylamine and benzylamine was carried out in N,N‐dimethylacetamide at 30, 50, and 70 °C. The six‐membered cyclic carbonate 1 proceeded quantitatively with hexylamine at 30 °C for 24 h, while the five‐membered cyclic carbonate 2 converted in 34%. The reaction rate constants at 50 °C are evaluated as follows; 1.42 L/mol · h ( 1 with hexylamine) > 0.29 L/mol · h ( 1 with benzylamine) > 0.04 L/mol · h ( 2 with hexylamine) > 0.01 L/mol · h ( 2 with benzylamine). The activation energies in the reactions of 1 and 2 with hexylamine were estimated to be 10.1 and 24.6 kJ/mol, respectively. The ring‐strain energy was calculated by the semi‐empirical method using the PM3 Hamiltonian. The ring‐strain energy of the six‐membered cyclic carbonate was 2.86 kcal/mol larger than that of five‐membered one. © 2000 John Wiley & Sons, Inc. J Polym Sci A: Polym Chem 39: 162–168, 2001     

Asymmetric Total Synthesis of (+)‐Ryanodol and (+)‐Ryanodine

(+)‐Ryanodine ( 1 ) is the ester derivative of 1H‐pyrrole‐2‐carboxylic acid and the complex terpenoid (+)‐ryanodol ( 2 ), which possesses eleven contiguous stereogenic centers on the ABCDE‐ring system. Compound 1 is known to be a potent modulator of intracellular calcium release channels, whereas the activity of 2 is significantly weaker. To chemically construct 1 , the multiple oxygen functional groups must be installed on the fused pentacycle in stereoselective fashions and the extremely hindered C3‐hydroxy group must be acylated in a site‐selective manner. First, the total synthesis of 2 was accomplished by introducing the five stereocenters from the previously prepared enantiopure ABDE‐ring 7 . Stereoselective construction of the C3‐secondary, C2‐ and C6‐tertiary alcohols was achieved by three nucleophilic reactions. The C9‐ and C10‐trisubstituted carbon centers were regio‐ and stereoselectively introduced by hydroboration/oxidation of the six‐membered C‐ring, which was formed by the ring‐closing metathesis reaction. Direct esterification of the C3‐alcohol with pyrrole‐2‐carboxylic acid proved unsuccessful; therefore, we developed a new, two‐step protocol for attachment of the pyrrole moiety. The C3‐hydroxy group was first converted into the less sterically cumbersome glycine ester, which was then transformed into the pyrrole ring through condensation with 1,3‐bis(dimethylamino)allylium tetrafluoroborate. This procedure resulted in the first total synthesis of 1 .     

Polyaddition of bis(seven‐membered cyclic carbonate) with diamines: A novel and efficient synthetic method for polyhydroxyurethanes

This article deals with the polyaddition of a novel bis(seven‐membered cyclic carbonate), 1,2‐bis[3‐(1,3‐dioxepan‐2‐one‐5‐yl)‐propylthio]ethane, with the diamines 4,9‐dioxa‐1,12‐dodecanediamine and p‐xylylenediamine. The polyaddition was carried out at 30–70 °C for 6–24 h in dimethyl sulfoxide to obtain the corresponding polyhydroxyurethanes with number‐average molecular weights of 10,900–35,700 in good yields. The reaction of a monofunctional seven‐membered cyclic carbonate, 5‐allyl‐1,3‐dioxepan‐2‐one (7CC), with monoamines was also carried out to examine the reactivity in comparison with that of six‐ and five‐membered cyclic carbonates. The reaction rate constants of 7CC with n‐hexylamine and benzylamine were estimated to be 48.5 and 11.0 L/mol · h, respectively, in dimethyl sulfoxide‐d₆ (initial reagent concentration = 1 M) at 30 °C. The seven‐membered cyclic carbonate ring was 2.98 and 5.82 kcal/mol more strained than those of the six‐ and five‐membered cyclic carbonates, respectively, according to a semiempirical molecular orbital calculation with the PM3 Hamiltonian. © 2001 John Wiley & Sons, Inc. J Polym Sci Part A: Polym Chem 39: 4091–4100, 2001     

2,2′‐Anhydro‐1‐(3′,5′‐di‐O‐acetyl‐β‐D‐arabinofuranosyl)uracil,a cyclouridine nucleoside with a C4′‐endo furanosyl conformation

2,2′‐Anhydro‐1‐(3′,5′‐di‐O‐acetyl‐β‐D‐arabinofuranosyl)uracil, C₁₃H₁₄N₂O₇, was obtained by refluxing 2′,3′‐O‐(methoxymethylene)uridine in acetic anhydride. The structure exhibits a nearly perfect C4′‐endo (⁴E) conformation. The best four‐atom plane of the five‐membered furanose ring is O—C—C—C, involving the C atoms of the fused five‐membered oxazolidine ring, and the torsion angle is only −0.4 (2)°. The oxazolidine ring is essentially coplanar with the six‐membered uracil ring [r.m.s. deviation = 0.012 (5) Å and dihedral angle = −3.2 (3)°]. The conformation at the exocyclic C—C bond is gauche–trans which is stabilized by various C—H...π and C—O...π interactions.     

(1R,3S)‐Camphoramic acid

The title chiral compound, 3‐amino­carbonyl‐1,2,2‐tri­methyl­cyclo­pentane‐1‐carboxylic acid, C₁₀H₁₇NO₃, was prepared from (1R,3S)‐camphoric acid. The five‐membered ring adopts a conformation which is intermediate between a twist and an envelope. Elongations of the C—C bonds and contractions of the C—C—C bond angles are observed within the five‐membered ring. A ¹H NMR spectrum was recorded to assist in distinguishing the amide group from the carboxyl group.     

Iridium‐Catalyzed Silylation of Five‐Membered Heteroarenes: High Sterically Derived Selectivity from a Pyridyl‐Imidazoline Ligand

The steric effects of substituents on five‐membered rings are less pronounced than those on six‐membered rings because of the difference in bond angles. Thus, the regioselectivities of reactions of five‐membered heteroarenes that occur with selectivities dictated by steric effects, such as the borylation of C?H bonds, have been poor in many cases. We report that the silylation of five‐membered‐ring heteroarenes occurs with high sterically derived regioselectivity when catalyzed by the combination of [Ir(cod)(OMe)]₂ (cod=1,5‐cyclooctadiene) and a phenanthroline ligand or a new pyridyl‐imidazoline ligand that further increases the regioselectivity. The silylation reactions with these catalysts produce high yields of heteroarylsilanes from functionalization at the most sterically accessible C?H bonds of these rings under conditions that the borylation of C?H bonds with previously reported catalysts formed mixtures of products or products that are unstable. The heteroarylsilane products undergo cross‐coupling reactions and substitution reactions with ipso selectivity to generate heteroarenes that bear halogen, aryl, and perfluoroalkyl substituents.     

Total Synthesis of Talatisamine

Talatisamine ( 1 ) is a member of the C₁₉‐diterpenoid alkaloid family, and exhibits K⁺ channel inhibitory and antiarrhythmic activities. The formidable synthetic challenge that 1 presents is due to its highly oxidized and intricately fused hexacyclic 6/7/5/6/6/5‐membered‐ring structure (ABCDEF‐ring) with 12 contiguous stereocenters. Here we report an efficient synthetic route to 1 by the assembly of two structurally simple fragments, chiral 6/6‐membered AE‐ring 7 and aromatic 6‐membered D‐ring 6 . AE‐ring 7 was constructed from 2‐cyclohexenone ( 8 ) through fusing an N‐ethylpiperidine ring by a double Mannich reaction. After coupling 6 with 7 , an oxidative dearomatization/Diels–Alder reaction sequence generated fused pentacycle 4 b . The newly formed 6/6‐membered ring system was then stereospecifically reorganized into the 7/5‐membered BC‐ring of 3 via a Wagner–Meerwein rearrangement. Finally, Hg(OAc)₂ induced an oxidative aza‐Prins cyclization of 2 , thereby forging the remaining 5‐membered F‐ring. The total synthesis of 1 was thus accomplished by optimizing and orchestrating 33 transformations from 8 .     

3′,4′‐Bis(4‐chloro­phenyl)­spiro­[chroman‐3,5′(4′H)‐isoxazol]‐4‐one

The title compound, C₂₃H₁₅Cl₂NO₃, crystallizes with two independent mol­ecules in the asymmetric unit. The chroman­one moiety consists of a benzene ring fused with a six‐membered heterocyclic ring which adopts a sofa conformation. The five‐membered spiro­isoxazoline ring is in an envelope conformation. The p‐chloro­phenyl rings bridged by the five‐membered ring are nearly perpendicular to each other. The chromanone moiety of one mol­ecule packs into the cavity formed by the p‐chloro­phenyl rings of a second mol­ecule through the formation of C—H?π interactions. The structure is stabilized by weak C—H?O, C—H?Cl and C—H?π interactions.     

Total Synthesis of 1‐Hydroxytaxinine

1‐Hydroxytaxinine ( 1 ) is a cytotoxic taxane diterpenoid. Its central eight‐membered B‐ring possesses four oxygen‐functionalized centers (C1, C2, C9, and C10) and two quaternary carbon centers (C8 and C15), and is fused with six‐membered A‐ and C‐rings. The densely functionalized and intricately fused structure of 1 makes it a highly challenging synthetic target. Reported here is an efficient radical‐based strategy for assembling 1 from A‐ and C‐ring fragments. The A‐ring bearing an α‐alkoxyacyl telluride moiety underwent intermolecular coupling with the C‐ring fragment by a Et₃B/O₂‐promoted decarbonylative radical formation. After construction of the C8‐quaternary stereocenter, a pinacol coupling reaction using a low‐valent titanium reagent formed the B‐ring with stereoselective installation of the C1,C2‐diol. Subsequent manipulations at the A‐ and C‐rings furnished 1 in 26 total steps.     

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.     

Total Synthesis of the Antibiotic Kendomycin: A Macrocyclization Using the Tsuji–Trost Etherification

A highly stereocontrolled, convergent total synthesis of kendomycin [(?)‐TAN2162], an ansa‐macrocyclic antibiotic, is reported. The key of the strategy is an unprecedented Tsuji–Trost macrocyclic etherification, followed by a transannular Claisen rearrangement to construct the 18‐membered carbocyclic framework. The oxa‐six‐ and five‐membered rings were also stereoselectively constructed respectively by a cascade oxidative cyclization at an unfunctionalized benzylic position and using a one‐pot epoxidation/5‐exo‐tet epoxide opening.     

Beryllepin,C6H6Be,and “Beryllium‐Inserted Benzenes,” C6H6Ben,n = 2–6: A Density Functional Computational Investigation

The seven‐membered beryllium‐containing heterocycle beryllepin, C₆H₆Be, has been examined computationally at the B3LYP/6‐311++G** density functional level of theory. Beryllepin is best described as a planar singlet heterocyclic conjugated triene with marginal aromatic character containing a C–Be–C moiety forced to be nonlinear (∠C‐Be‐C = 146.25°) by the cyclic constraints of the seven‐membered ring. The molecule can be considered to be derived from a benzene‐like system in which a neutral beryllium atom has been inserted between two adjacent carbon atoms. The 11 other possible “beryllium‐inserted benzenes,” C₆H₆Be_n, n = 2–6, have also been investigated. Only two of these heterocyclic systems, the eight‐membered 1,4‐diberyllocin and the nine‐membered 1,4,7‐triberyllonin, were found to be stable, singlet‐ground‐state systems, albeit with little aromatic character. Of the remaining nine beryllium‐inserted benzenes, with the exception of the 11‐membered ring containing five beryllium atoms and the 12‐membered ring containing six beryllium atoms, which were calculated to exist as a ground state pentet and septet, respectively, all were calculated to be ground state triplet systems.     

Hemsleyaconitines F and G,Two Novel C19‐Diterpenoid Alkaloids Possessing a Unique Skeleton from Aconitum hemsleyanum

Hemsleyaconitines F and G ( 1 and 2 , resp.) were isolated from the EtOH extract of Aconitum hemsleyanum. Their structures were elucidated by extensive analyses of the IR, 1D‐ and 2D‐NMR, and MS data. The two C₁₉‐diterpenoid alkaloids 1 and 2 possess a novel skeleton, featuring a five‐membered D‐ring between C(9), C(13), C(14), C(15), and C(16), which is quite different from the previously isolated six‐membered D‐ring analogs.     

Electrophilic substitution reaction of indole,part XXIV: Synthesis,characterization, and crystal structure of a novel heterocyclic compound

The reaction of indole with cyclohexanone in the presence of the Lewis acid, boron trifluoride diethyl etherate, resulted in the synthesis of a novel and interesting product ( 1 ) in addition to the bis(indolyl)methane system ( 2 ). The structure of this novel compound has been determined by NMR (¹H and ¹³C) and X‐ray crystal structure analysis. Compound 1 is a (1:2) addition reaction product of indole with cyclohexanone. The spiro six‐membered ring is in the classic chair conformation. An epoxide bridge at C‐4a/C‐10b and the two hydroxyl groups at C‐5a, C‐10a are all on the same side of the central five membered ring. J. Heterocyclic Chem., (2011).     

Mechanistic Study on the Cleavage and Reorganization of C(sp3)?H and CN Bonds in Carbodiimides: Synthesis of 1,2‐Dihydrothiopyrimidines and 2,3‐Dihydropyrimidinthiones through Four‐Component Coupling

This study sheds light on the cleavage and reorganization of C(sp³)? H and C?N bonds of carbodiimides in a three‐component reaction of terminal alkynes, sulfur, and carbodiimides by a combination of methods including 1) isolation and X‐ray analysis of six‐membered‐ring lithium species 2‐S , 2) trapping of the oxygen‐analogues ( B‐O and D‐O ) of both four‐membered‐ring intermediate B‐S and ring‐opening intermediate D‐S , 3) deuterium labeling studies, and 4) theoretical studies. These results show that 1) the reaction rate‐determining step is [2+2] cycloaddition, 2) the C?N bond cleavage takes place before C(sp³)? H bond cleavage, 3) the hydrogen attached to C6 in 2‐S originates from the carbodiimide, and 4) three types of new aza‐heterocycles, such as 1,2‐dihydrothiopyrimidines, N‐acyl 2,3‐dihydropyrimidinthiones, and 1,2‐dihydropyrimidinamino acids are constructed efficiently based on 2‐S . All results strongly support the idea that the reaction proceeds through [2+2] cycloaddition/4π electrocyclic ring‐opening/1,5‐H shift/6π electrocyclic ring‐closing as key steps. The research strategy on the synthesis, isolation, and reactivity investigation of important intermediates in metal‐mediated reactions not only helps achieve an in‐depth understanding of reaction mechanisms but also leads to the discovery of new synthetically useful reactions based on the important intermediates.     

Total Synthesis and Biological Evaluation of (+)‐Gambieric Acid A and Its Analogues

In this study, we report the first total synthesis and complete stereostructure of gambieric acid A, a potent antifungal polycyclic ether metabolite, in detail. The A/B‐ring exocyclic enol ether 32 was prepared through a Suzuki–Miyaura coupling of the B‐ring vinyl iodide 18 and the alkylborate 33 and subsequent closure of the A‐ring by using diastereoselective bromoetherification as the key transformation. Suzuki–Miyaura coupling of 32 with acetate‐derived enol phosphate 49 , followed by ring‐closing metathesis of the derived diene, produced the D‐ring. Subsequent closure of the C‐ring through a mixed thioacetalization completed the synthesis of the A/BCD‐ring fragment 8 . The A/BCD‐ and F′GHIJ‐ring fragments (i.e., 8 and 9 ) were assembled through Suzuki–Miyaura coupling. The C25 stereogenic center was elaborated by exploiting the intrinsic conformational property of the seven‐membered F′‐ring. After the oxidative cleavage of the F′‐ring, the E‐ring was formed as a cyclic mixed thioacetal (i.e., 70 ) and then stereoselectively allylated by using glycosylation chemistry. Ring‐closing metathesis of the diene 3 thus obtained closed the F‐ring and completed the polycyclic ether skeleton. Finally, the J‐ring side chain was introduced by using a Julia–Kocienski olefination in the presence of CeCl₃ to complete the total synthesis of gambieric acid A ( 1 ), thereby unambiguously establishing its complete stereostructure. The present total synthesis enabled us to evaluate the antifungal and antiproliferative activities of 1 and several synthetic analogues.