[2+2+2] Cycloadditions of Siloxy Alkynes with 1,2‐Diazines: From Reaction Discovery to Identification of an Antiglycolytic Chemotype

Abstract

The synthesis of new nitrogen-containing heterocycles plays a pivotal role in chemical biology and medicinal chemistry, as reflected by their many applications in the development of pharmacological probes and drugs. [1] Despite notable progress, there is a significant need for the identification of new nitrogen heterocycles which target previously unexplored regions of biogenic chemical space. Among the many possible synthetic strategies to such compounds, cycloadditions involving C-N multiple bonds are particularly attractive as they generate complex cyclic products by simultaneous formation of multiple bonds starting from readily available precursors. [2] Herein, we describe the discovery and development of a formal [2+2+2] cycloaddition of siloxy alkynes with phthalazines, a process that had not been previously described for either 1,2-diazines or electron-rich alkynes. [3][4][5][6][7] This effort has not only afforded heterocyclic products with a unique pentacyclic ring system but has also enabled the identification of a novel chemotype that inhibits glycolytic ATP production by direct blockage of glucose uptake in CHO-K1 cells. As a result of the prevalence of the Warburg effect in many human cancers, such compounds may prove useful in the development of new therapeutics which target reprogrammed energy metabolism of rapidly proliferating cells. [8] Our study began by examining the reaction of phthalazine (1) with the siloxy alkyne 2 in the presence of common Brønsted acids. While no reaction between 1 and 2 was observed in the absence of such additives, even at elevated temperatures, we found that addition of simple pyridinium salts promoted the formation of a new pentacyclic product (3; Scheme 1).After examining a range of mono-and bis(pyridinium) salts in various solvents, we determined the optimum protocol to entail the use of a stoichiometric amount of pyridinium trifluoromethanesulfonimide in CH 2 Cl 2 at room temperature, thus producing the lactam 3 as a single diastereomer in 77 % yield. While most of the known [2+2+2] cycloadditions typically require the presence of a transition-metal catalyst, [9] the present method promotes the condensation under remarkably mild reaction conditions, using only a simple, weak Brønsted acid. The excellent diastereoselectivity of this transformation is also highly noteworthy. The atom connectivity within the reaction product was initially determined to be that in 3 and is based on extensive use of NMR spectroscopic methods. Ultimately, the structure was secured and the relative stereochemistry of the three newly created stereogenic centers was defined through X-ray crystallographic analysis (see below).Interestingly, while a range of substituted mono-and bis(pyridinium) trifluoromethanesulfonimides were found to be effective as reaction promoters, the use of only HNTf 2 , in the absence of pyridine, produced 3 with lower efficiency (48 % yield) and diminished diastereoselectivity (83:17). Furthermore, the use of either pyridinium chloride, pyridinium p-toluenesulfo...

Triflimide (HNTf2) in Organic Synthesis

“…For example, Rawal, Kozmin, and co-workers demonstrated that pyridinium triflimide could serve as an efficient catalyst in an interesting cycloaddition reaction of siloxy alkynes with 1,2-diazines, leading to a range of bioactive polyheterocyclic compounds. 204 In addition to forming adducts with amines as useful Brønsted acid catalysts, triflimide has been extremely successful in forming adducts with Lewis acids to achieve Brønsted acid-assisted Lewis acids. A notable example is the adducts between triflimide and chiral oxazaborolidines first introduced by Ryu and Corey in 2003 (Scheme 103).…”

SABRE hyperpolarized anticancer agents for use in 1H MRI

“…This class of compounds also possesses an N‐heterocyclic ring, which makes them suitable as ligands for coordination to a SABRE catalyst 3,27,38 (Figure 2B). We synthesised 39,40 and tested the four TP isomers, alongside studies involving the inclusion of a fully deuterated isotopologue as co‐ligand to increase percentage polarization. To extend magnetization lifetimes and enhance the timing window for subsequent imaging we also explored application of pseudo‐long lived state strategies 41,42 .…”

“…(A) Structure of the thienopyridazines synthesised 39,40 and hyperpolarized in this study by SABRE, Thieno[2,3‐ d ]pyridazine, (T[2,3‐ d ]P), Thieno[3,4‐ d ]pyridazine (T[3,4‐ d ]P), Thieno[2,3‐ c ]pyridazine (T[2,3‐ c ]P), Thieno[3,2‐ c ]pyridazine (T[3,2‐ c ]P). (B) Potential active SABRE catalyst [IrH 2 (IMes)(T[2,3‐ d ]P) 3 ]Cl; n is T[2,3‐ d ]P and omitted for clarity…”