Silicon Reagent-Assisted Peptide Synthesis: Research Progress and Methodological Value of Peptide Bond Formation from Unprotected Substrates

I. Why Peptide Synthesis Still Needs New Methods

Peptide synthesis has long been organized around the basic sequence of protection–coupling–deprotection. Traditional routes are mature and reliable and, when combined with solid-phase synthesis and liquid-phase fragment assembly, already support the research and preparation of many peptide molecules. At the same time, however, protecting-group manipulations, the consumption of coupling reagents, solvent use, and the burden of purification mean that peptide synthesis still faces persistent challenges, including multiple steps, limited atom economy, and increasing pressure for sustainability.[3,8,9] Recent studies have shown that reducing dependence on protecting groups, improving step economy, and directly using unprotected amino acids while maintaining selectivity and stereochemical control is becoming an important direction in peptide chemistry.

Against this background, silicon reagent-assisted peptide synthesis has attracted attention because, in representative systems, it simultaneously contributes to improved handling of unprotected amino acids, transient selective control between free amines and carboxylic acids, promotion of peptide bond formation, and the subsequent organization of intermediates. Along this line of thinking, a series of studies represented by the Yamamoto group established a relatively clear methodological trajectory from 2021 to 2026: from one-pot peptide formation using unprotected amino acids and unprotected peptides, to the development of silacyclic dipeptide intermediates, and then to direct cross-coupling between unprotected amino acids, peptide fragment coupling, and more streamlined single-silicon-reagent systems.[1,2,4-7]

Key Points of Focus in Traditional Peptide Synthesis and Silicon Reagent-Assisted Routes

Comparison Dimension	Traditional Mainstream Route	Silicon Reagent-Assisted Route
Mode of site differentiation	Mainly relies on pre-installed protecting groups	Places greater emphasis on transient selectivity control during the reaction
Common substrate forms	Protected amino acids or pre-activated components are commonly used	Greater emphasis on unprotected amino acids, unprotected peptides, or less-protected peptide fragments
Main advantages	Mature methodology, extensive accumulated experience, broad applicability	Potential to reduce the burden of protection/deprotection steps and some coupling reagents
Main challenges	Many steps, high reagent consumption, and substantial waste generation	Solubility, chemoselectivity, side reactions, and control of epimerization
Current stage of development	Already a mature mainstream route	Still at an expanding methodological stage

II. The Core Roles of Silicon Reagents in These Systems

1. Improving the Practical Handling of Unprotected Amino Acids

When unprotected amino acids are used directly in peptide bond formation, the first challenge is often not simply whether peptide formation is possible, but whether these substrates can be handled effectively in organic media. A 2025 paper in Chemical and Pharmaceutical Bulletin summarized this issue in four aspects: the solubility of unprotected amino acids in organic solvents, control of side reactions, chemoselective activation of carboxylic acids in the presence of free amines, and epimerization.[6] That study showed that tris(2,2,2-trifluoroethoxy)silane can improve the solubility behavior of amino acids while also serving the dual roles of temporary amine-end regulation and carboxylic acid activation/promotion of bond formation.

The trimethoxysilane route reported in The Journal of Organic Chemistry in 2026 continued to advance this idea. That paper indicated that trimethoxysilane can both help unprotected amino acids dissolve in organic systems and transiently regulate the amino terminus while promoting carboxylic acid coupling during the reaction, thereby enabling one-pot peptide formation between unprotected amino acids and amino acid tert-butyl esters with high stereoselectivity.[7] This shows that silicon reagents here are not single-function reagents, but rather strategic tools that combine substrate organization with reaction promotion.

2. Converting Part of “Pre-Protection” into “Transient Control During the Reaction”

A 2021 JACS paper had already demonstrated that unprotected amino acids and peptides can undergo peptide bond formation under one-pot conditions. According to the abstract, two different silylating reagents were used to perform C-terminal activation and transient N-terminal masking, respectively, affording high yields for a variety of substrates bearing side-chain functional groups without racemization or polymerization.[1] The significance of this result lies in the fact that it partially shifts site differentiation, which had previously relied mainly on pre-installed protecting groups, into selective control achieved during the reaction by the reaction conditions and silicon reagents.

3. Establishing an Extendable Intermediate System through Silacyclic Dipeptides

A 2022 JACS study further moved the focus from simple “peptide formation” to the “organization of intermediates.” The silacyclic dipeptides reported in that work were not only dipeptide products, but also a class of building units that could participate in further chain extension: under suitable conditions, the silacyclic intermediates could behave either as nucleophiles or as electrophiles, and were further applied to the one-pot site-selective construction of tetrapeptides and oligopeptides.[2] This feature means that the silicon reagent-assisted route no longer remains at the level of a conceptual demonstration, but begins to show a structural foundation for convergent liquid-phase peptide assembly.

Main Roles of Silicon Reagents in Representative Systems

Functional Level	Mode of Action	Main References
Improving substrate handling	Improves the solubility and processability of unprotected amino acids in organic systems	[6], [7]
Transient amine-end regulation	Temporarily suppresses or modulates the reactivity of free amines	[1], [6], [7]
Carboxylic acid-end activation / promotion of bond formation	Promotes peptide bond formation between carboxylic acids and amines	[1], [6], [7]
Intermediate organization	Constructs silacyclic dipeptides capable of bidirectional extension	[2], [4]
Stereochemical control in fragment coupling	Minimizes epimerization during peptide fragment coupling	[5]

III. From 2021 to 2026: How the Research Trajectory of Silicon Reagent-Assisted Peptide Synthesis Has Evolved

Representative Advances in Silicon Reagent-Assisted Peptide Synthesis

Year	Representative Work	Core Content	Methodological Significance
2021	One-pot peptide bond formation from unprotected amino acids/peptides	Two silylating reagents were used separately to address the C-terminal and N-terminal issues	Demonstrated that unprotected substrates can be used directly for selective peptide bond formation
2022	Construction and bidirectional extension of silacyclic dipeptides	Formation of extendable silacyclic dipeptide intermediates	Advanced the field from simple “peptide formation” to an “intermediate system that can be further assembled”
2024	Direct cross-coupling between unprotected amino acids	Achieved direct cross-coupling between two unprotected amino acids, followed by further extension	Established an unprotected–unprotected cross-coupling mode
2025	Peptide fragment condensation	Enabled low-epimerization condensation between fragments, reaching octapeptides	Moved the method toward higher-level convergent liquid-phase synthesis
2025	Single-reagent system based on tris(2,2,2-trifluoroethoxy)silane	Free N-terminal peptides could be obtained without additional additives	The reagent system became more concentrated and the operation more streamlined
2026	Single-reagent system based on trimethoxysilane	Used the less expensive, commercially available trimethoxysilane	Continued moving toward more accessible and lower-cost routes

Among these developments, 2024 marked an important turning point in this research line: for the first time, direct cross-coupling between one unprotected amino acid and another unprotected amino acid was achieved, and this was further connected to convergent extension between peptides. This showed that the field had moved beyond the question of whether unprotected substrates could form peptide bonds, toward the higher-level question of whether controlled cross-coupling between unprotected substrates could be achieved.[4]

The 2025 fragment condensation study pushed this route further toward problems that are closer to practical liquid-phase route design: peptide bond formation between peptide fragments while minimizing epimerization, together with the construction of octapeptides. This indicates that the method is no longer limited to demonstrations at the monomer or dipeptide level, but is expanding toward higher-level convergent liquid-phase synthesis.[5]

IV. What Key Problems Does This Silicon Reagent-Assisted Route for Peptide Synthesis Address?

1. Reducing the Step Burden Caused by Dependence on Protecting Groups

One of the most direct values of this type of method is the reduction of protection/deprotection operations. The studies published from 2021 to 2026 all center on unprotected amino acids, unprotected peptides, or minimally protected amino acid tert-butyl esters, showing that this silicon reagent-based route is not simply making local adjustments within the traditional heavily protected framework, but is instead exploring a different organizational mode for peptide synthesis.[1,4-7]

2. Providing a Route for Controlled Cross-Coupling between Unprotected Amino Acids

The statement that “unprotected amino acids can participate in peptide formation” is not equivalent to saying that “unprotected amino acids can undergo direct and controlled cross-coupling with one another.” The 2024 study achieved, for the first time, direct cross-coupling between one unprotected amino acid and another, and further connected this to convergent peptide–peptide extension, advancing the route from general direct peptide formation to a higher level of selective control.[4]

3. Offering a New Low-Epimerization Strategy for Liquid-Phase Fragment Assembly

In liquid-phase peptide synthesis, fragment condensation is beneficial for parallel construction and late-stage convergence, but it is often limited by epimerization. The 2025 fragment condensation study identified “minimal epimerization” as one of its key outcomes, and achieved bond formation between peptide fragments under conditions compatible with multiple functional groups, along with octapeptide construction.[5] This shows that the value of the silicon reagent-assisted route is no longer confined to bond-formation demonstrations at the monomer or short-peptide level, but is extending toward higher-level convergent liquid-phase synthesis.

4. Providing Direction for Greener Peptide Synthesis, While Still Remaining at the Methodological Development Stage

In principle, reducing protecting-group operations and the use of stoichiometric coupling reagents is beneficial for improving atom economy and step economy. Relevant studies and reviews have also shown that reducing the burden of protecting groups and coupling reagents is an important direction in making peptide chemistry greener.[3,8,9] This is a rapidly developing new route for liquid-phase peptide synthesis with the potential to reduce protection/deprotection steps and part of the burden imposed by externally added coupling reagents. However, at the current stage, the published results still focus mainly on methodological feasibility, substrate scope, and validation with medium-length oligopeptides/fragments. On this basis, it is not yet possible to conclude that the method has already undergone systematic process scale-up and full-process green validation.[3-9]

V. Current Positioning and Future Development of Silicon Reagent-Assisted Peptide Synthesis

Published studies have already demonstrated that silicon reagent-assisted peptide synthesis has moved beyond the conceptual stage. It has progressed from one-pot peptide formation using unprotected amino acids and peptides to direct cross-coupling between unprotected amino acids, peptide fragment condensation, and more streamlined single-silicon-reagent systems. These studies show that this route is capable not only of forming peptide bonds, but also of delivering continuous and clearly defined methodological advances in the selective control of unprotected substrates, intermediate extension, and fragment assembly with relatively low epimerization. The existing literature has already confirmed that this silicon reagent-based route is feasible and is continuing to expand. At present, however, it is more appropriate to regard it as a rapidly developing new methodological route, rather than as a mainstream manufacturing process that has already replaced mature synthetic systems such as Fmoc-SPPS.

What will be more worth following in the future is whether the applicability of this strategy can continue to expand to unprotected substrates and complex side chains, whether stereochemical stability can continue to be maintained in longer peptide segments and more complex fragment condensations, and whether more simplified, more accessible, and more general single-silicon-reagent systems can be further developed. The continuous studies of the past two years have already shown clear progress along these directions, and this will determine whether the silicon reagent-based route can move from an important methodological advance toward broader practical application.

VI. References

[1] Muramatsu W, Yamamoto H. Peptide Bond Formation of Amino Acids by Transient Masking with Silylating Reagents. Journal of the American Chemical Society. 2021;143(18):6792-6797. doi:10.1021/jacs.1c02600.

[2] Hattori T, Yamamoto H. Synthesis of Silacyclic Dipeptides: Peptide Elongation at Both N- and C-Termini of Dipeptide. Journal of the American Chemical Society. 2022;144(4):1758-1765. doi:10.1021/jacs.1c11260.

[3] Tatsumi T, Sasamoto K, Matsumoto T, Hirano R, Oikawa K, Nakano M, Yoshida M, Oisaki K, Kanai M. Practical N-to-C peptide synthesis with minimal protecting groups. Communications Chemistry. 2023;6(1):231. doi:10.1038/s42004-023-01030-0.

[4] Hattori T, Yamamoto H. Peptide Bond Formation Between Unprotected Amino Acids: Convergent Synthesis of Oligopeptides. Journal of the American Chemical Society. 2024;146(37):25738-25744. doi:10.1021/jacs.4c08049.

[5] Ishihara K, Hattori T, Yamamoto H. Peptide Bond Formation through Fragment Condensation with Silylating Reagents. The Journal of Organic Chemistry. 2025;90(50):17972-17978. doi:10.1021/acs.joc.5c02488.

[6] Ramakrishna I, Boateng A, Hattori T, Yamamoto H. Tris(2,2,2-trifluoroethoxy)silane-Enabled Peptide Bond Formation between Unprotected Amino Acids and Amino Acid t-Butyl Esters. Chemical and Pharmaceutical Bulletin. 2025;73(9):787-792. doi:10.1248/cpb.c25-00457.

[7] Boateng A, Ramakrishna I, Hattori T, Yamamoto H. Trimethoxysilane-Mediated Peptide Bond Formation from Unprotected Amino Acids and Amino Acid t-Butyl Esters. The Journal of Organic Chemistry. 2026;91(6):2530-2537. doi:10.1021/acs.joc.5c02942.

[8] Isidro-Llobet A, Kenworthy MN, Mukherjee S, Kopach ME, Wegner K, Gallou F, Smith AG, Roschangar F. Sustainability Challenges in Peptide Synthesis and Purification: From R&D to Production. The Journal of Organic Chemistry. 2019;84(8):4615-4628. doi:10.1021/acs.joc.8b03001.

[9] Ferrazzano L, Catani M, Cavazzini A, Martelli G, Corbisiero D, Cantelmi P, Fantoni T, Mattellone A, De Luca C, Felletti S, Cabri W, Tolomelli A. Sustainability in peptide chemistry: current synthesis and purification technologies and future challenges. Green Chemistry. 2022;24:975-1020. doi:10.1039/D1GC04387K.

VII. Product Navigation Table for Silicon Reagent-Assisted Peptide Synthesis (Choose Table 1–Table 4 by Research Task)

Note: The following table provides a guide to representative substrates/coupling components related to this article for experimental design reference. It does not represent the complete substrate scope individually demonstrated in the original papers.

Research Task or Experimental Focus	Recommended Table to Consult First	Why This Table Should Be Prioritized	Which Table to Consult Next
Want to first determine which silicon reagents, additives, and basic reaction systems are used in this route	Table 1	Table 1 concentrates the most central silicon reagents and supporting additives for this topic, making it the best starting point for building an overall understanding of the three roles of “transient silylation, bond formation promotion, and reaction-promoting additives”	Then consult Table 2/Table 3 to select unprotected amino acids according to side-chain type
Want to start from the simplest model reaction and first carry out direct peptide formation from unprotected amino acids or basic condition screening	Table 2	Table 2 focuses on basic model substrates, neutral aliphatic substrates, aromatic substrates, and proline-type substrates, making it more suitable for initial condition screening, method development, and preliminary comparison across different side-chain types	Also consult Table 1 to choose the silicon reagent system; if an amino acid tert-butyl ester coupling partner is needed, then consult Table 4
Want to evaluate compatibility with complex side chains, such as acidic, basic, hydroxy, amide, or sulfur-containing side chains	Table 3	Table 3 more specifically covers highly polar unprotected amino acid substrates, substrates more prone to side reactions, or substrates that place greater demands on selectivity, making it suitable for experiments centered on “side-chain compatibility” and “selective control”	Also consult Table 1, and prioritize optimization starting from combinations of silicon reagents and promoting additives
Want to carry out coupling of the type “unprotected amino acid + amino acid tert-butyl ester” to construct N-terminal free dipeptides or subsequent extension units	Table 4	Table 4 focuses on amino acid tert-butyl ester coupling components and is the closest match to the direct pairing needs of such experiments, making it suitable for first identifying the tert-butyl ester coupling partner	Then consult Table 1 to determine the silicon reagent system, and return to Table 2/Table 3 to choose the unprotected amino acid partner
Want to design an experimental route around silacyclic dipeptides or oligopeptide extension	Table 1 + Table 4	Such routes usually require first defining the silicon reagent system and then identifying suitable amino acid tert-butyl ester coupling components, so Table 1 and Table 4 together are the best starting point	Then, according to the side-chain type of the target sequence, consult Table 2/Table 3 to choose unprotected amino acid substrates
Want to compare how different side-chain types affect reaction efficiency, purity, or retention of stereochemistry	Read Table 2 and Table 3 comparatively	Table 2 is more suitable for common neutral and aromatic substrates, whereas Table 3 is more suitable for polar and highly reactive side chains; reading the two together is best for comparing substrate scope and compatibility	Also consult Table 1 and keep the same silicon reagent system for side-by-side comparison
Want to perform preliminary screening at the monomer level for later convergent peptide assembly or fragment condensation	Table 1	The fragment condensation stage depends more heavily on having first clarified the silicon reagent system, side-chain compatibility, and matching relationships between coupling partners during early screening, so Table 1 is the first section that should be consulted at the front end of the route	Then consult Table 2/Table 3/Table 4 according to fragment origin to complete the preliminary combinational screening of substrates and coupling partners

Table 1 | Core Silicon Reagents and Supporting Additives in Silicon Reagent-Assisted Peptide Synthesis

Category	CAS No.	Aladdin Catalog No.	Name	Specification or Purity	Product Features and Applications
General/supporting interpretive reagent / imidazole-type silylating reagent	18156-74-6	T118634	1-(Trimethylsilyl)imidazole	for GC derivatization, ≥98%	Can be understood as an imidazole-type silylating reagent. In the context of silicon reagent-assisted peptide formation from unprotected amino acids, it is suitable for representing roles such as “transient silylation of the amino terminus/reactivity regulation,” and for understanding how unprotected substrates achieve selective control during the reaction process.
Core literature reagent / N-terminal transient masking silylating reagent	77377-52-7	N121507	N-tert-Butyldimethylsilyl-N-methyltrifluoroacetamide (MTBSTFA)	for GC derivatization, ≥97%, containing 1% TBDMSCl	A key N-terminal transient masking reagent in the representative 2021 system, used to regulate the amino-terminal reactivity of unprotected amino acids or peptides during the reaction process. It is an important component of the early dual-reagent system.
N-terminal transient masking / supporting silylating reagent	10416-59-8	T131644	TMS-BA	for GC derivatization	A common general N,O-silylating reagent that can be used to support understanding of the methodological logic of “transient silylation first, followed by selective bond formation.”
Supporting literature reagent / catalytic promoter	288-32-4	I432539	Imidazole	anhydrous, ACS, ≥99%	Corresponds to the imidazole promoting additive used in the 2021 one-pot peptide formation study from unprotected amino acids. It can be used to promote chemoselective silylation and improve peptide bond formation efficiency. Used to improve the efficiency of peptide formation in silicon reagent systems.
Supporting literature reagent / catalytic fluoride-source promoter	13400-13-0	C755570	Cesium fluoride	UltraBio™, ≥99%(F)	One of the key fluoride sources/promoting additives in the representative 2021 system. It can accelerate chemoselective silylation and bond-forming processes and is an important supporting reagent for understanding the early dual-silicon-reagent system.
Core literature reagent / single-reagent peptide-forming silane	2487-90-3	T107289	Trimethoxysilane	≥95%	The core reagent in the representative 2026 single-reagent system. The literature indicates that it can help unprotected amino acids dissolve in organic solvents and can simultaneously provide transient amino-terminal regulation and promotion of carboxylic acid coupling. It represents a cheaper, commercially available single-reagent direction.

Table 2 | Unprotected Amino Acid Substrates: Neutral Aliphatic, Aromatic, and Basic Model Substrates

Category	CAS No.	Aladdin Catalog No.	Name	Specification or Purity	Product Features and Applications
Unprotected amino acid substrate (most basic model substrate)	56-40-6	G432934	Glycine	UltraBio™, molecular biology grade, ultrapure grade, ≥99%(NT)	The most basic model substrate among unprotected amino acids, commonly used to establish basic reaction models for direct peptide formation, cross-coupling, and single-silicon-reagent systems.
Unprotected amino acid substrate (small-side-chain aliphatic)	56-41-7	A118860	L-Alanine	animal origin-free, USP, JP, Moligand™, European Pharmacopoeia (Ph.Eur), for cell culture, ≥98.5%	A representative unprotected amino acid substrate with the most basic small aliphatic side chain, commonly used to establish basic reaction models and condition comparisons in silicon reagent-assisted peptide formation.
Unprotected amino acid substrate (branched aliphatic)	72-18-4	V139523	L-Valine	animal origin-free, USP, JP, Moligand™, European Pharmacopoeia (Ph.Eur), for cell culture, ≥98.5%	A representative branched aliphatic unprotected amino acid substrate, commonly used to evaluate the applicability of silicon reagent systems to common hydrophobic amino acids and the retention of stereoselectivity.
Unprotected amino acid substrate (branched aliphatic)	61-90-5	L774643	L-Leucine	animal origin-free, USP, JP, Moligand™, European Pharmacopoeia (Ph.Eur), for cell culture, ≥98.5%	A representative branched aliphatic unprotected amino acid substrate, commonly used to evaluate the applicability of silicon reagent systems to common hydrophobic side chains; it is also one of the frequently encountered basic substrates in peptide fragment construction.
Unprotected amino acid substrate (branched aliphatic)	73-32-5	I115775	L-Isoleucine	animal origin-free, USP, JP, Moligand™, European Pharmacopoeia (Ph.Eur), for cell culture, ≥98.5%	A representative β-branched aliphatic unprotected amino acid substrate, suitable for examining the coupling performance of more sterically hindered aliphatic side chains in silicon reagent systems.
Unprotected amino acid substrate (secondary amine type)	147-85-3	P120032	L-Proline	animal origin-free, USP, European Pharmacopoeia (Ph.Eur), for cell culture, ≥99%	A representative secondary amine-type unprotected amino acid substrate, suitable for testing the applicability of silicon reagent systems to substrates such as proline, which have distinctive conformational and reactivity features and are highly informative in methodological evaluation.
Unprotected amino acid substrate (aromatic side chain)	63-91-2	P110425	L-Phenylalanine	animal origin-free, USP, JP, Moligand™, European Pharmacopoeia (Ph.Eur), for cell culture, ≥98.5%	A representative aromatic unprotected amino acid substrate and one of the most frequently used model substrates in peptide methodology, suitable for evaluating compatibility with aromatic side chains.
Unprotected amino acid substrate (phenolic hydroxyl aromatic side chain)	60-18-4	T115962	L-Tyrosine	animal origin-free, USP, JP, Moligand™, European Pharmacopoeia (Ph.Eur), for cell culture, ≥99%	A representative aromatic unprotected amino acid substrate bearing a phenolic hydroxyl group, useful for testing the system’s tolerance toward side chains containing both an aromatic ring and a phenolic hydroxyl group.
Unprotected amino acid substrate (aromatic heterocyclic side chain)	73-22-3	T118579	L-Tryptophan	animal origin-free, USP, JP, Moligand™, European Pharmacopoeia (Ph.Eur), for cell culture, ≥99%	A representative unprotected amino acid substrate with an indole-containing aromatic heterocyclic side chain, used to evaluate the applicability of the system to more sensitive aromatic heterocyclic side chains.
Unprotected amino acid substrate (sulfur-containing side chain)	63-68-3	M101131	L-Methionine	animal origin-free, USP, JP, Moligand™, European Pharmacopoeia (Ph.Eur), for cell culture, ≥99%	A representative unprotected amino acid substrate with a neutral sulfur-containing side chain, suitable for evaluating the compatibility of silicon reagent systems with thioether side chains.

Table 3 | Unprotected Amino Acid Substrates: Acidic, Amide-Type, Hydroxy-Type, Basic, and Highly Polar Side-Chain Substrates

Category	CAS No.	Aladdin Catalog No.	Name	Specification or Purity	Product Features and Applications
Unprotected amino acid substrate (acidic side chain)	56-84-8	L476204	L-Aspartic acid	UltraBio™, ultrapure grade, ≥99.5%(T)	A representative unprotected amino acid substrate with an acidic side chain, useful for evaluating the system’s ability to achieve chemoselective control in the presence of an additional carboxyl group.
Unprotected amino acid substrate (acidic side chain)	56-86-0	L774633	L(+)-Glutamic acid	animal origin-free, USP, JP, European Pharmacopoeia (Ph.Eur), for cell culture, ≥98.5%	A representative unprotected amino acid substrate with an acidic side chain, suitable for examining the compatibility of silicon reagent systems with additional carboxyl-containing side chains, as well as their ability to achieve selective peptide bond formation under unprotected conditions.
Unprotected amino acid substrate (amide side chain)	70-47-3	L478521	L-Asparagine	Moligand™, BioReagent, for cell culture, for insect cell culture	A representative unprotected amino acid substrate with an amide side chain, useful for supplementing evaluation of the system’s substrate scope toward neutral polar side chains.
Unprotected amino acid substrate (amide side chain)	56-85-9	L432946	L-Glutamine	UltraBio™, for cell culture, ultrapure grade, γ-irradiated	A representative unprotected amino acid substrate with an amide side chain, useful for examining the tolerance of silicon reagent systems toward neutral polar side chains.
Unprotected amino acid substrate (hydroxy side chain)	56-45-1	L476400	L-Serine	animal origin-free, USP, Moligand™, European Pharmacopoeia (Ph.Eur), for cell culture, ≥98.5%	A representative unprotected amino acid substrate with a hydroxy-containing side chain, useful for evaluating the compatibility of silicon reagent systems with polar side chains and potential side-reaction sites.
Unprotected amino acid substrate (hydroxy side chain)	72-19-5	T108222	L-Threonine	animal origin-free, USP, JP, Moligand™, European Pharmacopoeia (Ph.Eur), for cell culture, ≥99%	A representative unprotected amino acid substrate bearing a β-hydroxyl group and an additional stereocenter, suitable for examining the stereochemical retention of silicon reagent systems and their compatibility with hydroxy-containing side chains.
Unprotected amino acid substrate (basic side chain)	56-87-1	L598932	L-Lysine	Moligand™, ≥98%, Metal＜500ppm	A representative unprotected amino acid substrate bearing an ε-amino side chain, used to examine the chemoselectivity and control of silicon reagent systems in the presence of an additional amino group.
Unprotected amino acid substrate (basic side chain)	74-79-3	A118651	L-Arginine	animal origin-free, USP, Moligand™, European Pharmacopoeia (Ph.Eur), for cell culture, ≥98.5%	A representative unprotected amino acid substrate with a strongly basic guanidino side chain, used to evaluate the selectivity and compatibility of silicon reagent systems in the presence of highly polar, strongly basic side chains.
Unprotected amino acid substrate (basic heterocyclic side chain)	71-00-1	H108261	L-Histidine	animal origin-free, USP, Moligand™, European Pharmacopoeia (Ph.Eur), for cell culture	A representative unprotected amino acid substrate with an imidazole side chain, useful for evaluating the system’s tolerance toward heterocyclic basic side chains and for observing substrate behavior related to imidazole-type additives/silylation environments.
Unprotected amino acid substrate (sulfur-containing side chain)	52-90-4	L755721	L-Cysteine	UltraBio™, ≥98.5%(RT)	A representative unprotected amino acid substrate with a sulfur-containing and more sensitive thiol side chain, suitable for evaluating the compatibility of silicon reagent systems with highly reactive side chains.

Table 4 | Amino Acid tert-Butyl Ester Coupling Components

Category	CAS No.	Aladdin Catalog No.	Name	Specification or Purity	Product Features and Applications
Amino acid tert-butyl ester coupling component (most basic model component)	27532-96-3	G109218	Glycine tert-butyl ester hydrochloride	≥98%	One of the most basic amino acid tert-butyl ester coupling components, suitable for establishing a basic model for coupling between unprotected amino acids and tert-butyl ester amino acids.
Amino acid tert-butyl ester coupling component (small-side-chain aliphatic)	13404-22-3	A109203	L-Alanine tert-Butyl Ester Hydrochloride	≥97%	A representative amino acid tert-butyl ester coupling component with a small aliphatic side chain, suitable for basic coupling evaluation, condition screening, and comparison with other side-chain types.
Amino acid tert-butyl ester coupling component (branched aliphatic)	13518-40-6	V117015	L-Valine t-butyl ester hydrochloride	≥99%	One of the commonly encountered amino acid tert-butyl ester coupling components in this methodological line, used for pairing with unprotected amino acids to construct N-terminal free dipeptides or peptide units for further extension.
Amino acid tert-butyl ester coupling component (branched aliphatic)	2748-02-9	L116989	L-Leucine tert-butyl ester hydrochloride	≥98%	A representative branched aliphatic amino acid tert-butyl ester coupling component that can be paired with unprotected amino acids under a single-silicon-reagent or silacyclic intermediate strategy to construct hydrophobic peptide units.
Amino acid tert-butyl ester coupling component (aromatic)	15100-75-1	P100455	L-Phenylalanine tert-butyl ester hydrochloride	≥99%	A representative aromatic amino acid tert-butyl ester coupling component, suitable for evaluating the applicability of silicon reagent systems to aromatic side-chain coupling partners.

Note: The above are representative Aladdin products. For more product specifications, please refer to the product list at the end of the article or search the Aladdin website using the product name/CAS number/catalog number.

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