A mild, photoactivated 1,3-dipolar cycloaddition procedure was successfully developed for the synthesis of polysubstituted pyrazolines. This procedure involved the in situ generation of the reactive nitrile imine dipoles using a hand-held UV lamp at 302 nm, followed by spontaneous cycloaddition with a broad range of 1,3-dipolarophiles with excellent solvent compatibility, functional group tolerance, regioselectivity, and yield.

It has been shown that various pyrido-, quinolino-, pyrazino-and qunoxalinotetrazoles can efficienly be used as azide components in the Cu-catalyzed click reaction with alkynes. This method allows for efficient synthesis of a wide variety of N-heterocyclic derivatives of 1,2,3-triazoles.1,2,3-Triazoles are biologically important units. 1 Pyridotriazoles and quinolinotriazoles are particularly interesting as they exhibit a wide range of biological properties, including control of arthropod pests, 2a substance-related disorders, 2b ATP-competetive inhibition of vascular endothelial growth factor receptors I and II, 2c antibacterial, 2d and antimicrobacterial activity. Unarguably, the Cu-catalyzed click chemistry 3 of azide with alkyne is the most efficient way to assemble the 1,2,3-triazole ring 4 (eq. 1). However, preparation of pyrido-and quinolinotriazoles is not straightforward since these azides exist in equlibrium between closed form (tetrazole A) and open form (azide B) (eq. 2). 5(1) Usually, the position of this equilibrium depends on several factors, such as nature of substituents, 5 solvent 6 and temperature. 5 Thus, it has been reported 7a that NO 2 group at the C-6 position of tetrazole favors the open form (azide B). On the contrary, tetrazoles with NO 2 , COOH, and Cl groups at the C-8 position, and unsubstituted tetrazole predominantly exist 7,8 in closed form A. It should be mentioned that pyridotetrazole has been employed in the preparation of organometallic complexes of late transition metals. 7a Furthermore, there have been contradictory reports 9,10 on the employment of tetrazoles in the click reaction. For instance, it has been shown that pyridotetrazoles, existing in closed form, are inert toward click reaction under standard conditions. 9 By other hand, there have been two reports10a,b in which single examples of successful click reaction of generated in situ pyridotetrazoles with alkynes were demonstrated. Moreover, when this manuscript was under preparation, a paper describing successful click reaction of purinotetrazole, which mainly exists in open form, has appeared. 10c Accordingly, motivated by the high biological importance of pyridyl-and quinolinylcontaining triazoles 2 and intrigued by the contradictory results on employment of triazoles in click reaction, 9,10 we undertook investigation aming at the development of efficient method for employment of differently substituted tetrazoles in synthesis of heterocyclic derivatives of 1,2,3-triazoles. Herein, we wish to report that various pyrido-quinolino-, pyrazino-and qunoxalinotetrazoles 1 can efficiently be employed in click reaction with alkynes to give the corresponding heterocyclic derivatives of 1,2,3-triazoles 2 (eq. 3).

The non-symmetrical spatial distribution of newly synthesized proteins in animal cells plays a central role in many cellular processes. Here, we report that a simple alkene tag, homoallylglycine (HAG), was co-translationally incorporated into a recombinant protein as well as endogenous, newly synthesized proteins in mammalian cells with high efficiency. In conjunction with a photoinduced tetrazole-alkene cycloaddition reaction ("photoclick chemistry"), this alkene tag further served as a bioorthogonal chemical reporter both for the selective protein functionalization in vitro and for a spatiotemporally controlled imaging of the newly synthesized proteins in live mammalian cells. This two-step metabolic alkene tagging-photo-controlled chemical functionalization approach may offer a potentially useful tool to study the role of the spatiotemporally regulated protein synthesis in mammalian cells.

We report the first use of a photoinduced 1,3-dipolar cycloaddition reaction in "stapling" peptide side chains to reinforce a model peptide helical structure with moderate to excellent yields. The resulting pyrazoline "staplers" exhibit unique fluorescence useful in a cell permeability study.Peptide helices are frequent mediators of key protein-protein interactions that regulate many important biological processes such as stress response and apoptosis. 1 However, when peptide helices are taken out of protein context and placed into aqueous buffer in isolation, they usually adopt random coil conformations, leading to a drastic reduction in biological activity and thus diminished therapeutic potential. Among numerous strategies that aim to stabilize or mimic peptide helices, 2 the most straightforward, yet effective, strategy is sidechain cross-linking ("peptide stapling"). [3][4][5][6] In addition to structural reinforcement, peptide stapling usually leads to increased metabolic stability, improved membrane permeability, and potentially enhanced binding affinity to protein targets due to pre-organization.Since peptide stapling necessitates macrocyclization, an entropically unfavorable process, 7 very few reactions are known to date that give rise to good yields along with the reinforced structures. These include disulfide bond formation, 3 lactam formation, 4 ruthenium-catalyzed ring closing metathesis, 5 and copper-catalyzed azide-acetylene cycloaddition. 6 While these reactions have enabled the synthesis of stapled peptide helices, the development of additional stapling reactions with high yields and predictable structural effect is still highly desirable. Herein, we report the first synthesis of stapled peptide helices using a photoinduced nitrile imine-mediated intramolecular 1,3-dipolar cycloaddion reaction, and the subsequent structural, photophysical, and preliminary cellular uptake studies of the stapled peptides.We recently reported a photoactivated nitrile imine-mediated 1,3-dipolar cycloaddition as a new bioorthogonal reaction for protein labeling both in vitro and in vivo. 8 During these studies, we observed that the nitrile imine species, while reactive toward suitable alkenes, was exceedingly stable in the aqueous medium. To probe whether this unique reactivity profile can be harnessed to "staple" peptides, we appended an alkene and a tetrazole moiety, respectively, to peptide sidechains located at the i and i + 4 positions of Balaram's 3 10 -helix 9 (scheme in Table 1). We chose this peptide helix model because it has been studied previously by Grubbs and co-workers 5a in demonstrating ruthenium-catalyzed ring closing metathesis chemistry for † Electronic supplemental information ( NIH Public Access Author ManuscriptChem Commun (Camb). Author manuscript; available in PMC 2010 October 7. NIH-PA Author ManuscriptNIH-PA Author Manuscript NIH-PA Author Manuscript peptide stapling. We envisioned that upon photoirradiation, tetrazole would undergo the cycloreversion reaction to generate the ni...

A novel gold-catalyzed divergent sysnthesis of furans and pyrroles employing readily available homopropargylic aldehydes and imines have been developed. The regiochemical outcome of this reaction is dependent on the substituent on the terminal alkyne of substrate. Thus, substrates possessing alkyl and aryl substituent at the alkyne moiety produce 2,3,5-substituted furans and pyrroles via a migratory cycloisomerizaton reaction. Whereas, their silicon analogues are capable to undergo a double migratory process leading to 2,3,4-substituted heterocycles.

KAZEM SHIROODI, R.; RIVERA VERA, C. I.; DUDNIK, A. S.; GEVORGYAN*, V.; Tetrahedron Lett. 56 (2015) 23, 3251-3254, http://dx.

Fused Tetrazoles as Azide Surrogates in Click Reaction: Efficient Synthesis of N-Heterocycle-Substituted 1,2,3-Triazoles. -The equilibrium between the closed tetrazole and the opened 2-azido N-heterocyclic form allows a click reaction with terminal alkynes. 1,4-Disubstituted triazoles are formed with good yields. The synthesis of 1,5-triazoles fails. -(CHATTOPADHYAY, B.; RIVERA VERA, C. I.; CHUPRAKOV, S.; GEVORGYAN*, V.; Org. Lett. 12 (2010) 9, 2166-2169,

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