Solution-Phase Oligonucleotide Synthesis

By far the most common way of synthesizing oligonucleotides is solid-phase synthesis. Solution-phase synthesis methods do exist, however. For example, before solid supports for the immobilization of the first nucleoside (and subsequent nucleotides during chain assembly) became available, oligonucleotides were prepared in solution. Perhaps the best-known example of this early work is Khorana's synthesis of tRNA genes. Recently, synthetic methods that utilize the phosphoramidite building blocks of solid-phase synthesis as inexpensive and readily available starting materials have been developed.

References

Classical Papers

[1] Agarwal, K. L. et al. & Khorana, H. G. Total synthesis of the gene for an alanine transfer ribonucleic acid from yeast. Nature 1970, 227, 27-34. https://doi.org/10.1038/227027a0

[2] Brown, E.L.; Belagaje, R.; Ryan, M.J.; Khorana, H.G. Chemical synthesis and cloning of a tyrosine tRNA gene. Methods Enzymol. 1979, 68, 109-151. https://doi.org/10.1016/0076-6879(79)68010-2

Recent Papers

[3] H. Griesser, M. Tolev, A. Singh, T. Sabirov, C. Gerlach, C. Richert, Solution-phase synthesis of branched DNA hybrids based on dimer phosphoramidites and phenolic or nucleosidic cores. J. Org. Chem. 2012, 77, 2703-2717. https://doi.org/10.1021/jo202505h

[4] A. Singh, M. Tolev, C. Schilling, S. Bräse, H. Griesser, C. Richert, Solution-phase synthesis of branched DNA hybrids via H-phosphonate dimers. J. Org. Chem. 2012, 77, 2718-2728. https://doi.org/10.1021/jo202508n

[5] R. Suchsland, B. Appel, S. Müller. Synthesis of trinucleotide building blocks in solution and on solid phase. Curr. Protoc. Nucleic Acid Chem. 2018, 75, 1, e60. https://doi.org/10.1002/cpnc.60

[6] V. Damakoudi, T. Feldner, E. Dilji, A. Belkin, C. Richert, Hybridization networks of mRNA and branched RNA hybrids. ChemBioChem 2020, 22, 924-930. https://doi.org/10.1002/cbic.202000678