Asymmetric Brønsted Acid Catalyzed Synthesis of Triarylmethanes—Construction of Communesin and Spiroindoline Scaffolds

Aza‐ortho‐quinone methides allow the straightforward asymmetric synthesis of natural‐product‐inspired indole scaffolds possessing a quaternary stereocenter. Our approach provides access to diverse communesin and spiroindoline derivatives with high enantioselectivity under mild reaction conditions. Predictable substitution patterns are found to be the key to our regiodivergent protocols.     

Elucidation of the Concise Biosynthetic Pathway of the Communesin Indole Alkaloids

The communesins are a prominent class of indole alkaloids isolated from Penicillium species. Owing to their daunting structural framework and potential as pharmaceuticals, communesins have inspired numerous synthetic studies. However, the genetic and biochemical basis of communesin biosynthesis has remained unexplored. Herein, we report the identification and characterization of the communesin (cns) biosynthetic gene cluster from Penicillium expansum. We confirmed that communesin is biosynthesized by the coupling of tryptamine and aurantioclavine, two building blocks derived from L ‐tryptophan. The postmodification steps were mapped by targeted‐gene‐deletion experiments and the structural elucidation of intermediates and new analogues. Our studies set the stage for the biochemical characterization of communesin biosynthesis. This knowledge will aid our understanding of how nature generates remarkable structural complexity from simple precursors.     

Recent Advances on the Total Syntheses of Communesin Alkaloids and Perophoramidine

The communesin alkaloids are a diverse family of Penicillium‐derived alkaloids. Their caged‐polycyclic structure and intriguing biological profiles have made these natural products attractive targets for total synthesis. Similarly, the ascidian‐derived alkaloid, perophoramidine, is structurally related to the communesins and has also become a popular target for total synthesis. This review serves to summarize the many elegant approaches that have been developed to access the communesin alkaloids and perophoramidine. Likewise, strategies to access the communesin ring system are reviewed.     

Site‐Selective and Metal‐Free Aliphatic CH Oxidation Enabled Synthesis of [5,24,25‐D3]‐(25S)‐Δ7‐Dafachronic acid

Steroid hormones play significant roles in both worms and mammalians. (25S)‐Δ⁷‐Dafachronic acid (Δ⁷‐DA, 1 ) is a member of the dafachronic acid hormonal series that regulates both development and lifespan of C. elegans. Despite its importance, effective tools for the illumination of its mode of action are lacking. Herein, we report an efficient synthesis of trideuterated Δ⁷‐DA, [5,24,25‐D3]‐(25S)‐Δ⁷‐dafachronic acid ([D₃]‐Δ⁷‐DA, 2 ), as a useful chemical tool for subsequent biological studies. Key steps for this bioinspired synthesis approach include site‐selective aliphatic C?H oxidation mediated by methyl(trifluoromethyl)dioxirane (TFDO), and the iridium/phosphine‐oxazoline‐catalyzed late‐stage asymmetric deuterium reduction.     

Molybdenum-catalyzed asymmetric allylic alkylation of 3-alkyloxindoles: reaction development and applications

We report a full account of our work towards the development of Mo‐catalyzed asymmetric allylic alkylation reactions with 3‐alkyloxindoles as nucleophiles. The reaction is complementary to the Pd‐catalyzed reaction with regard to the scope of oxindole nucleophiles. A number of 3‐alkyloxindoles were alkylated successfully under mild conditions to give products with excellent yields and good‐to‐excellent enantioselectivities. Applications of this method to the preparation of indoline alkaloids such as (?)‐physostigmine, ent‐(?)‐debromoflustramine B, and the indolinoquinoline rings of communesin B are reported.     

Synthesis and Biological Evaluation of Lactimidomycin and Its Analogues

The studies culminating in the total synthesis of the glutarimide‐containing eukaryote translation elongation inhibitor lactimidomycin are described. The optimized synthetic route features a Zn^II‐mediated intramolecular Horner–Wadsworth–Emmons (HWE) reaction resulting in a highly stereoselective formation of the strained 12‐membered macrolactone of lactimidomycin on a 423 mg scale. The presence of the E,Z‐diene functionality was found to be key for effective macrocyclizations as a complete removal of these unsaturation units resulted in exclusive formation of the dimer rather than monocyclic enoate. The synthetic route features a late‐stage installation of the glutarimide functionality via an asymmetric catalytic Mukaiyama aldol reaction, which allows for a quick generation of lactimidomycin homolog 55 containing two additional carbons in the glutarimide side chain. Similar to lactimidomycin, this analog was found to possess cytotoxicity against MDA‐MB‐231 breast cancer cells (GI₅₀=1–3 μM) using in vitro 2D and 3D assays. Although lactimidomycin was found to be the most potent compound in terms of anticancer activity, 55 as well as truncated analogues 50 – 52 lacking the glutarimide side‐chain were found to be significantly less toxic against human mammary epithelial cells.     

Total Synthesis of Δ12‐Prostaglandin J3: Evolution of Synthetic Strategies to a Streamlined Process

The total synthesis of Δ¹²‐prostaglandin J₃ (Δ¹²‐PGJ₃, 1 ), a reported leukemia stem cell ablator, through a number of strategies and tactics is described. The signature cross‐conjugated dienone structural motif of 1 was forged by an aldol reaction/dehydration sequence from key building blocks enone 13 and aldehyde 14 , whose lone stereocenters were generated by an asymmetric Tsuji–Trost reaction and an asymmetric Mukaiyama aldol reaction, respectively. During this program, a substituent‐governed regioselectivity pattern for the Rh‐catalyzed C?H functionalization of cyclopentenes and related olefins was discovered. The evolution of the synthesis of 1 from the original strategy to the final streamlined process proceeded through improvements in the construction of both fragments 13 and 14 , exploration of the chemistry of the hitherto underutilized chiral lactone synthon 57 , and a diastereoselective alkylation of a cyclopentenone intermediate. The described chemistry sets the stage for large‐scale production of Δ¹²‐PGJ₃ and designed analogues for further biological and pharmacological studies.     

β‐Co(OH)2 Nanosheets: A Superior Pseudocapacitive Electrode for High‐Energy Supercapacitors

In this work, β‐Co(OH)₂ nanosheets are explored as efficient pseudocapacitive materials for the fabrication of 1.6 V class high‐energy supercapacitors in asymmetric fashion. The as‐synthesized β‐Co(OH)₂ nanosheets displayed an excellent electrochemical performance owing to their unique structure, morphology, and reversible reaction kinetics (fast faradic reaction) in both the three‐electrode and asymmetric configuration (with activated carbon, AC). For example, in the three‐electrode set‐up, β‐Co(OH)₂ exhibits a high specific capacitance of ∼675 F g⁻¹ at a scan rate of 1 mV s⁻¹. In the asymmetric supercapacitor, the β‐Co(OH)₂∥AC cell delivers a maximum energy density of 37.3 Wh kg⁻¹ at a power density of 800 W kg⁻¹. Even at harsh conditions (8 kW kg⁻¹), an energy density of 15.64 Wh kg⁻¹ is registered for the β‐Co(OH)₂∥AC assembly. Such an impressive performance of β‐Co(OH)₂ nanosheets in the asymmetric configuration reveals the emergence of pseudocapacitive electrodes towards the fabrication of high‐energy electrochemical charge storage systems.     

Eight‐Step Enantioselective Total Synthesis of (−)‐Cycloclavine

The first enantioselective total synthesis of (−)‐cycloclavine was accomplished in 8 steps and 7.1 % overall yield. Key features include the first catalytic asymmetric cyclopropanation of allene, mediated by the dirhodium catalyst Rh₂(S‐TBPTTL)₄, and the enone 1,2‐addition of a new TEMPO carbamate methyl carbanion. An intramolecular strain‐promoted Diels–Alder methylenecyclopropane (IMDAMC) reaction provided a pivotal tricyclic enone intermediate with more than 99 % ee after crystallization. The synthesis of (−)‐ 1 was completed by a late‐stage intramolecular Diels–Alder furan (IMDAF) cycloaddition to install the indole.     

CC Coupling of N‐Heterocycles at the fac‐Re(CO)3 Fragment: Synthesis of Pyridylimidazole and Bipyridine Ligands

A new family of cationic rhenium tricarbonyl complexes with either two N‐alkylimidazole (N‐RIm) and one pyridine (Py) ligand, or two pyridine and one N‐RIm ligand, [Re(CO)₃(N‐RIm)_(3?x)(Py)_x]⁺, has been prepared. The reaction of these complexes with a strong base, followed by an oxidant, selectively afforded 2,2’‐pyridylimidazole complexes as the result of intramolecular dehydrogenative C?C coupling reactions. For tris(pyridine) complexes [Re(CO)₃(Py)₃]⁺ the reaction pattern upon a deprotonation/oxidation sequence is maintained, which allows the generation of complexes with 2,2’‐bipyridine ligands. In the particular combination of two different types of pyridine ligand in the cationic fac‐Re(CO)₃ complexes only the cross‐coupling products with asymmetric 2,2’‐bipyridine ligands were obtained; the homocoupling products were not observed.     

Ammonia Synthesis Under Ambient Conditions: Selective Electroreduction of Dinitrogen to Ammonia on Black Phosphorus Nanosheets

Constructing efficient catalysts for the N₂ reduction reaction (NRR) is a major challenge for artificial nitrogen fixation under ambient conditions. Herein, inspired by the principle of “like dissolves like”, it is demonstrated that a member of the nitrogen family, well‐exfoliated few‐layer black phosphorus nanosheets (FL‐BP NSs), can be used as an efficient nonmetallic catalyst for electrochemical nitrogen reduction. The catalyst can achieve a high ammonia yield of 31.37 μg h^?1 mg^?1_cat. under ambient conditions. Density functional theory calculations reveal that the active orbital and electrons of zigzag and diff‐zigzag type edges of FL‐BP NSs enable selective electrocatalysis of N₂ to NH₃ via an alternating hydrogenation pathway. This work proves the feasibility of using a nonmetallic simple substance as a nitrogen‐fixing catalyst and thus opening a new avenue towards the development of more efficient metal‐free catalysts.     

Visible‐Light‐Initiated Manganese Catalysis for C−H Alkylation of Heteroarenes: Applications and Mechanistic Studies

A visible‐light‐driven Minisci protocol that employs an inexpensive earth‐abundant metal catalyst, decacarbonyldimanganese Mn₂(CO)₁₀, to generate alkyl radicals from alkyl iodides has been developed. This Minisci protocol is compatible with a wide array of sensitive functional groups, including oxetanes, sugar moieties, azetidines, tert ‐butyl carbamates (Boc‐group), cyclobutanes, and spirocycles. The robustness of this protocol is demonstrated on the late‐stage functionalization of complex nitrogen‐containing drugs. Photophysical and DFT studies indicate a light‐initiated chain reaction mechanism propagated by ^.Mn(CO)₅. The rate‐limiting step is the iodine abstraction from an alkyl iodide by ^.Mn(CO)₅.     

Diselenastanna‐, ‐sila‐ and ‐carbacycles with an annelated dicarba‐closo‐dodecaborane(12) unit

The reactions of the 1,2‐diselenolato‐1,2‐dicarba‐closo‐dodecaborane(12) dianion 1 with diorganoelement(IV) dichlorides (Ph₂CCl₂, Me₂SiCl₂, Ph₂SiCl₂, Me₂SnCl₂, Ph₂SnCl₂) gave novel five‐member heterocycles along with other products. The molecular structures of the five‐member rings containing CPh₂ ( 2 ) and SnPh₂ ( 9 ) moieties between the selenium atoms were determined by X‐ray analyses. In the case of the chlorosilanes, the analogous five‐member ring containing the SiPh₂ unit ( 4 ) could be identified in mixtures. The expected reaction was accompanied by rearrangement leading to formation of another five‐member ring 6 containing the Ph₂Si? Se? Se moiety. Oxidative addition of the five‐member heterocycles containing tin ( 7, 9 ) to ethene‐bis(triphenylphosphane)platinum(0) gave at low temperature the bis(triphenylphosphane)platinum(II) complexes 12 and 13 , where the Pt(PPh₃)₂ fragment had been inserted into one of the Sn? Se bonds. Extensive decomposition of these complexes was observed above ? 20 °C. The proposed solution‐state structures of the new compounds are supported by multinuclear magnetic resonance data (¹H, ¹¹B, ¹³C, ²⁹Si, ³¹P, ⁷⁷Se, ¹¹⁹Sn and ¹⁹⁵Pt NMR). Copyright © 2007 John Wiley & Sons, Ltd.     

An RCM‐Based Total Synthesis of the Antibiotic Disciformycin B

The total synthesis of the potent new antibiotic disciformycin B ( 2 ) is described, which shows significant activity against methicillin‐ and vancomycin‐resistant Staphylococcus aureus (MRSA/VRSA) strains. The synthetic route is based on macrocyclization of a tetraene substrate to the 12‐membered macrolactone core by ring‐closing olefin metathesis (RCM). Although macrocyclization was accompanied by concomitant cyclopentene formation by an alternative RCM pathway, conditions were established to give the macrocycle as the major product. Key steps in the construction of the RCM substrate include a highly efficient Evans syn‐aldol reaction, the asymmetric Brown allylation of angelic aldehyde, and the stereoselective Zn(BH₄)₂‐mediated 1,2‐reduction of an enone. The synthesis was completed by late‐stage dehydrative glycosylation to introduce the d ‐arabinofuranosyl moiety and final chemoselective allylic alcohol oxidation.     

Selective Late‐Stage Oxygenation of Sulfides with Ground‐State Oxygen by Uranyl Photocatalysis

Oxygenation is a fundamental transformation in synthesis. Herein, we describe the selective late‐stage oxygenation of sulfur‐containing complex molecules with ground‐state oxygen under ambient conditions. The high oxidation potential of the active uranyl cation (UO₂²⁺) enabled the efficient synthesis of sulfones. The ligand‐to‐metal charge transfer process (LMCT) from O 2p to U 5f within the O=U=O group, which generates a U^V center and an oxygen radical, is assumed to be affected by the solvent and additives, and can be tuned to promote selective sulfoxidation. This tunable strategy enabled the batch synthesis of 32 pharmaceuticals and analogues by late‐stage oxygenation in an atom‐ and step‐efficient manner.     

Oxidative Rearrangement Coupling Reaction for the Functionalization of Tetrahydro‐β‐carbolines with Aromatic Amines

The observation of an unexpected oxidative rearrangement coupling reaction led to the development of a novel method for the efficient functionalization of tetrahydro‐β‐carbolines (THβCs). The treatment of THβCs with photogenerated singlet oxygen (¹O₂) afforded unstable dioxetanes, which underwent further transformation to form new bonds in the presence of trifluoroacetic acid. This operationally simple protocol exhibits broad functional‐group tolerance and is suitable for the late‐stage functionalization of complex druglike molecules.     

Palladium‐Catalyzed Arylation of Arylboronic Acids with Yagupolskii–Umemoto Reagents

A Pd‐catalyzed Suzuki cross‐coupling of arylboronic acids with Yagupolskii–Umemoto reagents was explored. In contrary to trifluoromethylations, the Pd‐catalyzed reaction of R?B(OH)₂ and [Ar₂SCF₃]⁺[OTf]^? provided the arylation products (R?Ar) in good to high yields. The reaction confirms that the S?Ar bonds of [Ar₂SCF₃]⁺[OTf]^? can be readily cleaved in the presence of Pd complexes. The relatively electron‐poor aryl groups of asymmetric [Ar¹Ar²SCF₃]⁺[OTf]^? salts are more favorably transferred compared to the electron‐rich ones. This reaction represents the first report of utilization of [Ar₂SCF₃]⁺[OTf]^? as arylation reagents in organic synthesis.     

The Hydrogenation/Transfer Hydrogenation Network in Asymmetric Reduction of Ketones Catalyzed by [RuCl2(binap)(pica)] Complexes

Chiral binap/pica‐Ru^II complexes (binap=(S)‐ or (R)‐2,2′‐bis(diphenylphosphino)‐1,1′‐binaphthyl; pica=α‐picolylamine) catalyze both asymmetric hydrogenation (AH) of ketones using H₂ and asymmetric transfer hydrogenation (ATH) using non‐tertiary alcohols under basic conditions. The AH and ATH catalytic cycles are linked by the metal–ligand bifunctional mechanism. Asymmetric reduction of pinacolone is best achieved in ethanol containing the Ru catalyst and base under an H₂ atmosphere at ambient temperature, giving the chiral alcohol in 97–98 % ee. The reaction utilizes only H₂ as a hydride source with alcohol acting as a proton source. On the other hand, asymmetric reduction of acetophenone is attained with both H₂ (ambient temperature) and 2‐propanol (>60 °C) with relatively low enantioselectivity. The degree of contribution of the AH and ATH cycles is highly dependent on the ketone substrates, solvent, and reaction parameters (H₂ pressure, temperature, basicity, substrate concentration, H/D difference, etc.).     

Asymmetric Total Synthesis of (−)‐Stenine and 9a‐epi‐Stenine

A route for the asymmetric synthesis of (?)‐stenine, a member of the Stemona alkaloid family used as folk medicine in Asian countries, is described. The key features of the sequence employed include stereoselective transformations on a cyclohexane ring controlled by a chiral auxiliary unit and an intramolecular Mitsunobu reaction to construct the perhydroindole ring system. By using an intermediate in the route to (?)‐stenine, an asymmetric synthesis of 9a‐epi‐stenine was also executed. The C(9a) stereocenter in 9a‐epi‐stenine was installed by using a Staudinger/aza‐Wittig reaction of a keto–azide precursor followed by reduction of the resulting imine. The results of this effort demonstrate the applicability of the chiral auxiliary based strategy to the preparation of naturally occurring alkaloids that contain highly functionalized cyclohexane cores.     

Mechanistic Study of a Photocatalyzed CS Bond Formation Involving Alkyl/Aryl Thiosulfate

This study presents thioether construction involving alkyl/aryl thiosulfates and diazonium salt catalyzed by visible‐light‐excited [Ru(bpy)₃Cl₂] at room temperature in 44–86 % yield. Electron paramagnetic resonance studies found that thiosulfate radical formation was promoted by K₂CO₃. Conversely, radicals generated from BnSH or BnSSBn (Bn=benzyl) were clearly suppressed, demonstrating the special property of thiosulfate in this system. Transient absorption spectra confirmed the electron‐transfer process between [Ru(bpy)₃Cl₂] and 4‐MeO‐phenyl diazonium salt, which occurred with a rate constant of 1.69×10⁹ M ^?1 s^?1. The corresponding radical trapping product was confirmed by X‐ray diffraction. The full reaction mechanism was determined together with emission quenching data. Furthermore, this system efficiently avoided the over‐oxidation of sulfide caused by H₂O in the photoexcited system containing Ru²⁺. Both aryl and heteroaryl diazonium salts with various electronic properties were investigated for synthetic compatibility. Both alkyl‐ and aryl‐substituted thiosulfates could be used as substrates. Notably, pharmaceutical derivatives afforded late‐stage sulfuration smoothly under mild conditions.