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Page 2 of 6 Yamamoto. Chem Synth 2022;2:14 https://dx.doi.org/10.20517/cs.2022.12

In 2010, I decided to change my research area and initiate research toward peptide synthesis. The history of
peptide synthesis really began in the 1960s. At that time, Dr. Merrifield reported an amazingly useful solid
phase peptide synthesis (SPPS), and since then, the method has been broadly used in research labs and
industry. However, this method presents several serious problems that make the application of peptides as a
new modality for the drug market very challenging. The issues of SPPS are as follows: linear synthesis;
racemization; prevention of analysis during synthesis; exceedingly low yields; costly purification. These
problems have also been discussed by major pharmaceutical companies in the important journal,
[5]
J Org Chem . In little over a decade, we succeeded in developing a completely new methodology for peptide
synthesis [Figure 1]. In fact, most of our new methodology depends on substrate-controlled reactions, in
spite of Merrifield’s method that depends on reagent-controlled reactions.

Let me give you some examples of the differences between the two methodologies. Most of the SPPS
method depends on reagent-controlled reactions. Specifically, the method depends on carboxylic acid
activation. Numerous activation reagents have been developed, and in fact, many are commercially
available. Our substrate-controlled reactions depend on tantalum-catalyzed reactions [Figure 2]. Ta metal
has a strong affinity to oxygen but a weaker affinity to nitrogen. This unique property plays an important
role in this transformation and no other metal ions work for this purpose .
[6-8]

Starting with this peptide synthesis, we decided to develop a completely new and transformative
methodology from the previous SPPS methodology.

Importance of convergent synthesis
We have successfully changed from a linear to a convergent synthetic route [Figure 3]. This is related to the
later described protecting group-free strategy, where the protecting group-free protocols for both the head
and tail amino acid and carboxylic acid groups are successfully activated to realize the simultaneous
synthesis from three components (m + n + o). As a result, not only can 50-peptide insulin be synthesized
[9]
but also the 100-peptide limit is closer to being achieved .
Amide to amide transformation is reasonably rare in organic synthesis. In this case, an amide bond is
activated by the Boc group of an amino acid to thus generate a new longer peptide. The method can also be
used for peptide bond formation as a convergent methodology [Figure 4] .
[10]
Use of safe solvents
In order to use solvents safe for humans, we have developed a supersilyl method that increases the
lipophilicity of peptides and have successfully used ordinary solvents, such as ethyl acetate, toluene, and
acetonitrile [Figure 5] .
[10]

Reduction in use of resin materials
Since this is a solution method, the expensive solid resin is not used. In fact, solid phase peptide synthesis is
based on resin, which has a rather large molecular weight and, moreover, is difficult to analyze after the
reaction.

Protecting group-free synthesis
Using various inexpensive metal reactants, the first protection group-free peptide synthesis was enabled by
metal ions of silicon and aluminum [Figure 6]. In both cases, the metal ion plays two roles in organic
[10]
synthesis, namely, carboxylic acid activation and amino group protection .