Solid Phase Synthesis Essay

A novel solid-phase synthesis methodology of N-substituted-2-aminothiazolo[4,5-b]pyrazine derivatives was developed. The key step in this synthesis strategy is tandem reaction of isothiocyanate terminated resin 2 with o-halo-2-aminopyrazine, affording cyclized 2-aminothiazolo[4,5-b]pyrazine resin 4. To increase the diversity of our library, Suzuki coupling reaction was performed at the position C6. Further functionalization of 2-aminothiazolo[4,5-b]pyrazine core skeleton with various electrophiles such as alkyl halides, acyl chlorides, and sulfonyl chlorides and cleavage from the resin with TFA in DCM generated N-alkyl-, N-acyl-, and N-sulfonyl-2-aminothiazolo[4,5-b]pyrazine derivatives. This synthetic strategy can efficiently provide a library …show more content…
In SPOS, an excess reagents are used to drive reaction to completion, and products can be easily isolated by simple filtration from solid support.1 Other benefits of solid-phase is the ease of automation and the ability of polymer to “fish out” low concentrations of product molecules from excess of starting material.2 Heterocyclic compounds usually serve as a backbone of hundreds of marketed drugs.3 In this respect, we have been interested in thiazolo[4,5-b]pyrazine core skeleton. Even though thiazolo[4,5-b]pyrazine has not been investigated in detail in the medicinal chemistry area, we have focused on it because of its structural similarity with thiazolopyrimidine (Figure 1). Thiazolopyrimidine core skeleton has shown various biological activities in the medicinal chemistry area such as kinase inhibitors,4 TRPV1 antagonists,5 E. coli and S. aureus SecA inhibitors,6 stearoyl-CoA desaturase (SCD) inhibitor.7 Figure 1 shows similar structural features of thiazolopyrimidine and thiazolopyrazine (Figure 1a, Energy minimized 3D structure). The only difference is the position of nitrogen atom equipped in each core skeleton, and this positional difference causes different polar surface area (Figure 1b). In drug discovery, polar surface area is considered as a key factor to interact with target protein by …show more content…
As a result, solution-phase synthetic method of N-substituted-2-aminothiazolo[4,5-b]pyrazines by tandem reaction of o-aminohalopyrazines with isothiocyanates was reported by Gong et al. in 2012 (Scheme 1(a)).9 Even though various solution-phase synthesis methodologies have already been reported, no solid-phase synthesis approach has been reported until now. Accordingly, we aimed to develop an efficient synthesis route using solid-phase and construct diverse library of compounds. Herein, we report a synthetic methodology of 2-aminothiazolo[4,5-b]pyrazine on solid phase and its further functionalization to provide N-substituted-2-aminothiazolo[4,5-b]pyrazine derivatives based on the solution-phase synthetic route (Scheme

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