In nature, DNA is formed in the 5′–3′ direction. Early efforts in DNA synthesis were based on biological synthesis, and thus the first synthetic oligonucleotides were produced in the 5′–3′ direction . Har Gobind Khorana, a University of Wisconsin biochemist who won the 1968 Nobel Prize in Physiology or Medicine , led the group that developed the early 5′–3′ synthesis technique using a polystyrene solid support and three different protecting groups.
Though this technique led to important breakthroughs, it was eventually replaced in the 1980s by much a more efficient synthesis method using phosphoramidite monomers (phosphoramidites are nucleotides with protection groups which are removed after synthesis) . The growing oligonucleotide is connected to the solid support, a controlled pore glass bead via the 3′ carbon, and thus synthesis proceeds in the 3′–5′ direction.