Synthesis of Pyridazine Derivatives via Aza-Diels-Alder Reactions of 1,2,3-Triazine Derivatives and 1-Propynylamines.

A highly regioselective method was developed for the preparation of pyridazine derivatives via the aza-Diels-Alder reaction of 1,2,3-triazines with 1-propynylamines under neutral conditions. This methodology allowed direct access to a wide range of 6-aryl-pyridazin-3-amines in high yields with good functional group compatibility. Key features of this strategy included a broad substrate scope and simple, metal-free, and neutral reaction conditions.

Direct Dimesitylborylation of Benzofuran Derivatives by an Iridium-Catalyzed C-H Activation with Silyldimesitylborane.

Direct dimesitylborylation of benzofuran derivatives by a C-H activation catalyzed by an iridium(I)/N-heterocyclic carbene (NHC) complex in the presence of Ph2 MeSi-BMes2 afforded the corresponding dimesitylborylation products in good to high yield with excellent regioselectivity. This method provides a straightforward route to donor-(π-spacer)-acceptor systems with intriguing solvatochromic luminescence properties.

Total Synthesis of (+)-Pyrenolide D.

An efficient approach to stereoselective construction of a spiro-γ-lactone core structure via BF3-promoted formal [3 + 2] annulation of aldehydo-aldose derivatives with γ-methylene-γ-butyrolactone has been developed. The spiro-γ-lactone derivative was then used in an efficient total synthesis of (+)-pyrenolide D. The developed chemistry paves the way for total synthesis of structurally diverse natural products containing spiro-lactone cores.

A peptide ligase and the ribosome cooperate to synthesize the peptide pheganomycin.

Peptide antibiotics are typically biosynthesized by one of two distinct machineries in a ribosome-dependent or ribosome-independent manner. Pheganomycin (PGM (1)) and related analogs consist of the nonproteinogenic amino acid (S)-2-(3,5-dihydroxy-4-hydroxymethyl)phenyl-2-guanidinoacetic acid (2) and a proteinogenic core peptide, making their origin uncertain. We report the identification of the biosynthetic gene cluster from Streptomyces cirratus responsible for PGM production. Unexpectedly, the cluster contains a gene encoding multiple precursor peptides along with several genes plausibly encoding enzymes for the synthesis of amino acid 2. We identified PGM1, which has an ATP-grasp domain, as potentially capable of linking the precursor peptides with 2, and validate this hypothesis using deletion mutants and in vitro reconstitution. We document PGM1's substrate permissivity, which could be rationalized by a large binding pocket as confirmed via structural and mutagenesis experiments. This is to our knowledge the first example of cooperative peptide synthesis achieved by ribosomes and peptide ligases using a peptide nucleophile.

Synthesis of Acylborons by Ozonolysis of Alkenylboronates: Preparation of an Enantioenriched Amino Acid Acylboronate.

A concise synthesis of acylborons was achieved by ozonolysis of alkenyl MIDA (N-methyliminodiacetic acid) boronates. This reaction exhibits excellent functional-group tolerance and is applicable to various acyl MIDA boronates and potassium acyltrifluroborates (KATs) which could not be synthesized by previous methods. In addition, α-amino acylborons, which would be essential for peptide ligations, were prepared for the first time. The acylboron of l-alanine was obtained in high enantiopurity and found to be configurationally stable. Oligopeptide synthesis between the α-amino KATs and amino acid in dilute aqueous media was studied.

Catalyst-controlled regiodivergent C-H borylation of multifunctionalized heteroarenes by using iridium complexes.

The regiodivergent C-H borylation of 2,5-disubstituted heteroarenes with bis(pinacolato)diboron was achieved by using iridium catalysts formed in situ from [Ir(OMe)(cod)]2 /dtbpy (cod=1,5-cyclooctadiene, dtbpy: 4,4'-di-tert-butyl-2,2'-bipyridine) or [Ir(OMe)(cod)]2 /2 AsPh3 . When [Ir(OMe)(cod)]2 /dtbpy was used as the catalyst, borylation at the 4-position proceeded selectively to afford 4-borylated products in high yields (dtbpy system A). The regioselectivity changed when the [Ir(OMe)(cod)]2 /2 AsPh3 catalyst was used; 3-borylated products were obtained in high yields with high regioselectivity (AsPh3 system B). The regioselectivity of borylation was easily controlled by changing the ligands. This reaction was used in the syntheses of two different bioactive compound analogues by using the same starting material.

Total synthesis of (-)-thallusin: utilization of enzymatic hydrolysis resolution.

(-)-Thallusin, isolated from a marine bacterium, is the only known natural product to act as an algal morphogenesis inducer. Because (-)-thallusin can only be obtained in exceedingly limited amounts from microbial cultivation, a synthetic supply of this compound is highly desirable. Here, we describe a novel synthetic pathway to (±)-thallusin and the first asymmetric synthesis of (-)-thallusin utilizing the enzymatic hydrolysis resolution with the combination of lipase PS-30 and lipase M Amamo-10.

Iridium-catalyzed ortho-C-H borylation of aromatic aldimines derived from pentafluoroaniline with bis(pinacolate)diboron.

The development of an Ir-catalyzed ortho-C-H borylation of aromatic aldimines derived from pentafluoroaniline is reported. This reaction proceeded at 120 °C to afford the corresponding borylated products in high yield with good regioselectivity using an Ir complex formed in situ from [Ir(OMe)(cod)]2/2(C6F5)3P in the presence of 2-norbornene.

Aromatic C-H silylation of arenes with 1-hydrosilatrane catalyzed by an iridium(I)/2,9-dimethylphenanthroline (dmphen) complex.

Aromatic C-H silylation of neat arenes with 1-hydrosilatrane was found to be efficiently catalyzed by iridium catalysts composed of 1/2[Ir(OMe)(cod)]2 and 2,9-dimethyl-1,10-phenanthroline at 120 °C to afford the corresponding silylated products in high yields. The silylated products can be used for the Hiyama cross-coupling reaction.

Construction of Silicon-Containing Seven-Membered Rings by Catalytic [4 + 2 + 1] Cycloaddition through Rhodium Silylenoid.

A rhodium-catalyzed [4 + 2 + 1] cycloaddition involving 1,3-diene, alkyne, and silylene to afford silicon-containing seven-membered rings was established. In the presence of a rhodium catalyst bearing bis(diphenylphosphino)methane (DPPM), nona-1,3-dien-8-yne derivatives reacted efficiently at 80-110 °C with boryl(isopropoxy)silane or boryl(diethyamino)silane, which reacts as the synthetic equivalent of silylene, to afford 1-silacyclohepta-2,5-dienes (2,5-dihydro-1H-silepines). Regiodivergent and chemo- and stereoselective functionalization of the seven-membered nonconjugated diene was achieved by hydroboration mediated by Cs2CO3 or an iridium catalyst.

Silaphenylmercuric triflate catalyzed reactions: synthesis of a solid-supported mercuric salt catalyst.

Let it flow, let it flow: A procedure to generate the first solid-supported mercuric salt, silaphenylmercuric triflate, is described. Silaphenylmercuric triflate showed remarkable catalytic activity for an indole synthesis, furanoyne cyclization, arylyne cyclization, and tandem carbocyclizations. An efficient flow reaction system for indole synthesis and arylyne cyclization is also described (see figure).

Catalytic Generation of Rhodium Silylenoid for Alkene-Alkyne-Silylene [2 + 2 + 1] Cycloaddition.

An alkene-alkyne-silylene [2 + 2 + 1] cycloaddition takes place in the rhodium-catalyzed reaction of 1,6-enynes with borylsilanes bearing an alkoxy group on the silicon atoms, which react as synthetic equivalents of silylene. The reaction proceeds efficiently in 1,2-dichloroethane at 80-110 °C in the presence of a rhodium catalyst bearing bis(diphenylphosphino)methane (DPPM) as a ligand to afford 1-silacyclopent-2-enes in good to high yields.

Hg(OTf)2-catalyzed arylene cyclization.

Novel Hg(OTf) 2-catalyzed arylene cyclization was achieved with highly efficient catalytic turnover (up to 200 times). The reaction takes place via protonation of allylic hydroxyl group by in situ formed TfOH of an organomercuric intermediate to generate a cationic species. Subsequent smooth demercuration regenerates the catalyst.

Synthesis of 1,2,3-Triazines Using the Base-Mediated Cyclization of ( Z)-2,4-Diazido-2-alkenoates.

A highly efficient and convenient method for the synthesis of 6-aryl-1,2,3-triazine-4-carboxylate esters has been developed using readily accessible ( Z)-4-aryl-2,4-diazido-2-alkenoates. This reaction is performed under mildly basic conditions without the assistance of any transition metals or strong acid.

Hg(OAc)(2).0.1Sc(OTf)(3)-catalyzed cycloisomerization of 2-(4-pentynyl)furan.

[structure: see text]. Although the Hg(OTf)2.3TMU-catalyzed Friedel-Crafts-type reaction of 3-(4-pentynyl)furan afforded the exo cyclization product, the reaction of 2-(4-pentynyl)furan furnished a very low yield. We found a 10:1 mixed reagent of Hg(OAc)2 and Sc(OTf)3 showed remarkable catalytic activity for the latter transformation. The actual reacting species is presumed to be Hg(OAc)(OTf), which is efficiently generated in situ by mixing the two reagents.

Iridium(I)-catalyzed C-H Borylation of α,ß-Unsaturated Esters with Bis(pinacolato)diboron.

A new process has been developed for the iridium(I)-catalyzed vinylic C-H borylation of α,ß-unsaturated esters with bis(pinacolato)diboron (B2 pin2 ). These reactions proceeded in octane at temperatures in the range of 80-120 °C to afford the corresponding alkenylboronic compounds in high yields with excellent regio- and stereoselectivities. The presence of an aryl ester led to significant improvements in the yields of the acyclic alkenylboronates. Crossover experiments involving deuterated substrates as well as a mixture of stereoisomers confirmed that this reaction proceeds via a 1,4-addition/ß-hydride elimination mechanism. Notably, this reaction was also used to develop a one-pot borylation/Suzuki-Miyaura cross-coupling procedure.

Aryl-Allene Cyclization via a Hg(OTf)2-Catalytic Pathway.

Hg(OTf)2-catalyzed aryl-allene cyclization accompanied by formation of a quaternary carbon center has been realized. Deuterium-labeling experiments and computational modeling were used to propose a novel catalytic pathway involving direct H-transfer from the aromatic ring to the vinyl mercury moiety followed by mercury 1,2-migration.

Iridium(I)-catalyzed vinylic C-H borylation of 1-cycloalkenecarboxylates with bis(pinacolato)diboron.

Ir(I)-catalyzed C-H borylation of 1-cycloalkenecarboxylic derivatives with bis(pinacolato)diboron affords various alkenylboronates with functional groups in excellent yields. This reaction was also used in a one-pot borylation/Suzuki-Miyaura cross-coupling procedure.

A carbaboranylmercuric salt catalyzed reaction; highly regioselective cycloisomerization of 1,3-dienes.

The combination of carbaboranylmercuric chloride (new type of bulky Lewis acid) and silver triflate efficiently catalyzes cycloisomerization of 1,3-dienes at room temperature. The catalytic system gives allyl-substituted azacycles and cycloalkanes in excellent yields with high to complete regioselectivity.