Biocompatible and Rapid Cyclization of Peptides with 2,4-Difluoro-6-hydroxy-1,3,5-benzenetricarbonitrile for the Development of Cyclic Peptide Libraries.

We report a biocompatible and rapid reaction between cysteine thiols and 2,4-difluoro-6-hydroxy-1,3,5-benzenetricarbonitrile (DFB), which enables the efficient cyclization of peptides in neutral aqueous solutions. The reaction was further applied to cyclize peptides displayed on the phage surface without reducing phage infectivity, thus affording high-quality cyclic peptide libraries useful for screening of cyclic peptide ligands. Using the DFB-cyclic peptide library, we identified ligands that can distinguish the pro-survival protein Bcl-xl from its close relative Bcl-2. Therefore, this study on one hand reports a useful reaction for the construction of cyclic peptide libraries, and on the other hand presents valuable hits for further design of selective Bcl-xl ligands.

Efficient Conjugation to Phosphorothioate Oligonucleotides by Cu-Catalyzed Huisgen 1,3-Dipolar Cycloaddition.

Improving oligonucleotide delivery is critical for the further development of oligonucleotide-based therapeutics. Covalent attachment of reporter molecules is one of the most promising approaches toward efficient oligonucleotide-based therapies. An efficient methods for the attachment of a variety of reporter groups is Cu(I)-catalyzed Huisgen azide-alkyne 1,3-dipolar cycloaddition. However, the majority of potential oligonucleotide (ON) therapeutics in clinical trials are carrying phosphorothioate (PS) linkages, and this robust conjugation method is not yet established for these ONs due to a general concern of Cu-S interaction. Here, we developed a method allowing for efficient conjugation of peptides to PS oligonucleotides. The method utilizes solid supported oligonucleotides that can be readily transformed into "clickable ONs" by simple linker conjugation and further reacted with an azido containing moiety (e.g., a peptide) using the CuBr × Me2S complex as a superior catalyst in that reaction. This study opens the way for further development of PS oligonucleotide-conjugates by means of efficient Cu(I)-catalyzed Huisgen azide-alkyne 1,3-dipolar cycloaddition.

CuAAC: An Efficient Click Chemistry Reaction on Solid Phase.

Click chemistry is an approach that uses efficient and reliable reactions, such as Cu(I)-catalyzed azide-alkyne cycloaddition (CuAAC), to bind two molecular building blocks. CuAAC has broad applications in medicinal chemistry and other fields of chemistry. This review describes the general features and applications of CuAAC in solid-phase synthesis (CuAAC-SP), highlighting the suitability of this kind of reaction for peptides, nucleotides, small molecules, supramolecular structures, and polymers, among others. This versatile reaction is expected to become pivotal for meeting future challenges in solid-phase chemistry.

Tetramethyleneethane Equivalents: Recursive Reagents for Serialized Cycloadditions.

New reactions and reagents that allow for multiple bond-forming events per synthetic operation are required to achieve structural complexity and thus value with step-, time-, cost-, and waste-economy. Here we report a new class of reagents that function like tetramethyleneethane (TME), allowing for back-to-back [4 + 2] cycloadditions, thereby amplifying the complexity-increasing benefits of Diels-Alder and metal-catalyzed cycloadditions. The parent recursive reagent, 2,3-dimethylene-4-trimethylsilylbutan-1-ol (DMTB), is readily available from the metathesis of ethylene and THP-protected 4-trimethylsilylbutyn-1-ol. DMTB and related reagents engage diverse dienophiles in an initial Diels-Alder or metal-catalyzed [4 + 2] cycloaddition, triggering a subsequent vinylogous Peterson elimination that recursively generates a new diene for a second cycloaddition. Overall, this multicomponent catalytic cascade produces in one operation carbo- and heterobicyclic building blocks for the synthesis of a variety of natural products, therapeutic leads, imaging agents, and materials. Its application to the three step synthesis of a new solvatochromic fluorophore, N-ethyl(6-N,N-dimethylaminoanthracene-2,3-dicarboximide) (6-DMA), and the photophysical characterization of this fluorophore are described.

Batch versus flow photochemistry: a revealing comparison of yield and productivity.

The use of flow photochemistry and its apparent superiority over batch has been reported by a number of groups in recent years. To rigorously determine whether flow does indeed have an advantage over batch, a broad range of synthetic photochemical transformations were optimized in both reactor modes and their yields and productivities compared. Surprisingly, yields were essentially identical in all comparative cases. Even more revealing was the observation that the productivity of flow reactors varied very little to that of their batch counterparts when the key reaction parameters were matched. Those with a single layer of fluorinated ethylene propylene (FEP) had an average productivity 20% lower than that of batch, whereas three-layer reactors were 20% more productive. Finally, the utility of flow chemistry was demonstrated in the scale-up of the ring-opening reaction of a potentially explosive [1.1.1] propellane with butane-2,3-dione.

Gold-catalyzed 1,2-acyloxy migration/intramolecular [3+2] 1,3-dipolar cycloaddtion cascade reaction: an efficient strategy for syntheses of medium-sized-ring ethers and amines.

A highly efficient strategy for the formation of medium-sized-ring ethers and amines based on a gold-catalyzed cascade reaction, involving enynyl ester isomerization and intramolecular [3+2] cyclization, has been developed. Various multisubstituted medium-sized-ring unsaturated ethers and amines were obtained through this transformation. This method represents one of the relatively few transition metal catalyzed intramolecular cycloaddition reactions for medium-sized ring synthesis.

Efficient total synthesis of bioactive natural products: a personal record.

In this account, we have highlighted our most recent works towards the total synthesis of bioactive natural products, which have resulted in the development of several novel synthetic methods. Inspired and guided by strategies based on diversity-oriented synthesis, we have successfully applied the novel synthetic methodologies developed in our lab to the total synthesis of a diverse collection of structurally challenging targets. We have also documented the evolution of these synthetic strategies. The total syntheses described in this account have been organized from the perspective of different molecules whilst still alluding to the parallel synthetic strategies involved.

The facile assembly of bis-, tris- and poly(triazaphosphole) systems using "click" chemistry.

Uncatalysed 1,3-dipolar cycloaddition reactions between two phosphaalkynes, P≡CR (R = Bu(t) or Me), and a series of di-, tri- and poly-azido precursor compounds have given very high yields of a range of triazaphosphole substituted systems. These comprise the 1,1'-bis(triazaphosphole)ferrocenes, [Fe{C5H4(N3PCR)}2], the tris(triazaphosphole)cyclohexane, cis-1,3,5-C6H9(N3PCBu(t))3, and the poly(allyltriazaphosphole)s, {C3H5(N3PCR)}∞. Electrochemical studies on the 1,1'-bis(triazaphosphole)ferrocenes reveal the compounds to undergo reversible 1-electron oxidation processes, at significantly more positive potentials than ferrocene itself. Attempts to chemically oxidise one 1,1'-bis(triazaphosphole)ferrocene with a silver salt, Ag[Al{OC(CF3)3}4] were not successful, and led to the formation of a silver coordination complex, [{Fe[µ-C5H4(N3PCBu(t))]2(µ-Ag)}2][Al{OC(CF3)3}4]2, thereby demonstrating the potential the reported triazaphosphole substituted systems possess as novel ligands in coordination chemistry.

Fast RNA conjugations on solid phase by strain-promoted cycloadditions.

Strain promoted cycloaddition is presented as a tool for RNA conjugation on the solid phase; RNA-cyclooctyne conjugates are prepared by cycloaddition to both azide (strain-promoted azide-alkyne cycloaddition, SPAAC) and nitrile oxide dipoles (strain-promoted nitrile oxide-alkyne cycloaddition, SPNOAC). The conjugation is compatible with 2'-OMe blocks and with 2'-O-TBDMS protection on the ribose moieties of the sugar. Nitrile oxide dipoles are found to be more reactive click partners than azides. The conjugation proceeds within 10 min in aqueous solvents, at room temperature without any metal catalyst and tolerates dipoles of varying steric bulk and electronic demands, including pyrenyl, coumarin and dabcyl derivatives.