Stereoselective And Divergent Aza-Adenosine And Aza-Guanosine Syntheses From Xylofuranose In A STING Cyclic Dinucleotide Agonist

Efforts to improve chemical syntheses of aza-nucleosides

The treatment of cancer has been a focus of many biopharmaceutical companies. In the recent past, the companies have allocated their resources to immune ecology to develop the treatment. Among the efforts, the most promising strategy is initiating the Stimulator of Interferon Genes (STING). STING aid in achieving an immune response that results in a durable anticancer outcome (Yuan et al., 2021). One pharmaceutical ingredient (APIs) category entails cyclic theophorous dinucleotides; As illustrated in scheme 1, it structures two un natural 3`-aza-nucleosides cyclized containing 2 stereo genic thiophosphates on 5`-O and 3`-N. The article reports and details the efforts to develop new routes on aza-nucleoside 2 and 3 with exceptional diastereoselective and great yield.

Scheme 1: Showing Cyclic Dinucleotide and Key Aza-Nucleoside Fragment

The procedure commences with xylofuranose 9, where aza-nucleoside 2 was handled in 13 schemes, 7% total yield. Also, aza-nucleoside 3 was conducted in 13 phases, but 7.8% yield. The new routes developed were expected to have significant yield improvement and a reduced number of steps (Yuan et al., 2021). Moreover, it was anticipated the routes would have an enhanced protecting group stratagem, enable the establishment of an adaptable channel for incorporating nitrogenous base, and aid in eradicating dangerous reagents. The process entails several experiments executed under a nitrogen atmosphere employing anhydrous techniques. Each experimental step had its procedures and outcomes, making subsequent steps more efficient and effective.

The first generation synthesis of aza-nucleoside 2 originated from naturally occurring adenosine 4, while aza-nucleoside 3 started from guanosine 5.

Scheme 2: showing summary of first generation synthesis of 2 and 3

The original routes had several challenges that restricted future development. The challenges included: the routes were long and had low yield. Adenosine 2 had 13 steps with a 4% yield for guanosine, while adenosine 3 had 15 steps with a 2% yield. It had outrageous mass intensities and lengthy turnaround times (Yuan et al., 2021). Moreover, some transformations had low chemo regioselectivity. The routes had several protection-deprotection procedures. Last of all, some reagents like ET₃N.HF and benzyl isocyanate was hazardous besides not optimal for manufacturing.

The development of the new route starts a step number 3, which embraces the old route`s challenges and comes up with experimental initiative procedures to correct the challenges (Yuan et al., 2021). The experiments recognize that the two aza-nucleosides, except nitrogenous bases at C-1`, had matching atom diastereochemistry and connections. Intermediate 21 synthesis was achieved in 6 biochemical transformations, three isolation (11,19, and 21), with no chromatography, then a 25% yield.

Following the previous development and experiments, it was noted that 6-benzoylami-nopurine 23 ought to be preblended with BSA and 21 to evade precipitation, and the volume of TMSOTF was perilous. Hence, it was required to protect the most responsive main alcohol in 24, and TBS Protection was initiated (Yuan et al., 2021). The synthesis of aza-nucleoside 2 was achieved in 6 biochemical transformations, three isolation (24,31 and 2), no chromatography, and a 28% yield.

Following the synthesis of aza-adenosine 2, the same knowledge was applied to synthesizing aza-guanosine nucleoside 3. The TBS group from the previous synthesis aided in the acetylation (Yuan et al., 2021). Additionally, it was noted that isobutyl chloride was better than isobutyl anhydride, then Hu?nig’s was ideal. From 21, 3 was prepared in seven synthesis steps, isolating intermediate 37,38, 41, and 3 utilizing crystallizations while going on the way to 31% yield on a gram scale employing no chromatography.

Conclusion

In conclusion, it is fitting to point out that the undertaken procedures have chemically advanced another generation of aza nucleosides 2 and 3 syntheses with enhanced effectiveness (Yuan et al., 2021). The newly developed routes are advantageous since the divergent synthesis shortened the step count from 28 steps (13+15) to 20 steps (6+7+7). For aza adenosine 2, the resultant yield was enhanced from a reduced amount of 4% to 7%, while for aza adenosine 3, the yield was improved from 2% to 7.8%. Similarly, the PMI was reduced by >90% for aza adenosine 3 and 50% for aza adenosine 2. Lastly, the isolations were shortened from 17 (9 in 2 first gen and 8 in 3 first gen) to 9 (2 in 21, 3 in 2 first gen, and 4 in 3 first gen.

References

Yuan, C., Ortiz, A., Xu, Z., Zhu, J., Schmidt, M., Rogers, A., & Eastgate, M. (2021). Stereoselective and Divergent Aza-Adenosine and Aza-Guanosine Syntheses from Xylofuranose, the Key Fragments of a STING Cyclic Dinucleotide Agonist. The Journal Of Organic Chemistry, 87(4), 1925-1933. doi: 10.1021/acs.joc.1c00984