New Progress in the Solid-Phase Synthesis of Sterically Hindered Peptides: Background, Core Breakthroughs, and Implications for Automation Compatibility of the RMMR Strategy

Introduction

Peptides have become an important class of molecules in modern medicinal chemistry and chemical biology. Compared with traditional small molecules, peptides often offer higher target selectivity and stronger molecular recognition capability, while still retaining good structural tunability. As a result, they continue to attract attention in areas such as metabolic diseases, cancer, infections, and rare diseases. At the same time, peptide development still faces several practical limitations, including insufficient protease stability, limited membrane permeability, and the difficulty of efficiently preparing certain complex sequences. To address these issues, researchers have long pursued two broad directions: one is molecular design optimization, and the other is improvement of synthetic methods.

At the molecular design level, non-natural residues such as N-methylated amino acids and α,α-disubstituted amino acids are particularly important. They are often used to modulate peptide backbone conformation and, in many systems, can help improve metabolic stability, membrane permeability, or overall drug-like properties. However, these benefits do not arise automatically; they are often closely related to the modification site, sequence context, and overall conformation. Precisely because these residues are “pharmaceutically valuable but chemically difficult,” improvements in their synthetic methods are especially important.

A paper published in Nature Chemistry in 2025 proposed a new solution to this long-standing challenge. The authors developed an immobilized ribosome-mimicking molecular reactor, abbreviated as RMMR, to improve the coupling efficiency of highly hindered peptides on solid phase, while remaining compatible with existing solid-phase peptide synthesis systems.

Article at a Glance

Section	Core content
Research background	Peptides have become an important class of therapeutic and functional molecules, but stability, membrane permeability, and the synthetic accessibility of complex sequences remain key limiting factors.
Current status	SPPS remains the foundational platform of modern peptide chemistry, and Fmoc-SPPS is currently one of the most widely used mainstream routes with good compatibility with automation.
Core challenge	When sequences contain N-methylated or α,α-disubstituted amino acids, especially multiple consecutive sterically hindered residues, the two-phase acyl-transfer kinetics from solution to solid phase in traditional SPPS deteriorate, often leading to slow and inefficient coupling.
Latest advance	The 2025 Nature Chemistry paper introduced the immobilized ribosome-mimicking molecular reactor RMMR, which promotes bond formation through proximal acyl transfer on the resin surface, thereby reducing the limitations encountered when activated components in conventional SPPS must transfer from the solution phase to amine sites on the resin surface.
Main breakthroughs	This strategy not only improves the coupling efficiency of sterically hindered residues, but also demonstrates the automated solid-phase synthesis of difficult sequences such as cyclosporin A analogues and alamethicin F analogues.
Practical significance	The method emphasizes compatibility with existing SPPS platforms, commercial resins, standard reagents, and conventional synthesizers, making it closer to “a method system that can be integrated into existing workflows” rather than merely a conceptual demonstration.
Conceptual significance	The most important value of this work is not that it “uses a stronger coupling reagent,” but that it changes the reaction logic for forming amide bonds of sterically hindered peptides on solid phase.

1. Key Bottlenecks in Current Solid-Phase Peptide Synthesis

At the synthetic level, Fmoc solid-phase peptide synthesis remains one of the most commonly used methods today. Its advantages lie in the mature supply of building blocks, standardized workflows, and relatively easy integration with automated equipment. Precisely because this system is already highly mature, the synthetic bottlenecks become even more prominent when the target shifts to sterically hindered sequences.

This 2025 Nature Chemistry study pointed out that traditional SPPS often becomes limited by the bond-forming step itself when introducing N-methylated and/or α,α-disubstituted amino acids. Activated carboxylic acids are typically first generated in the solution phase and then react with amine sites on the resin surface. As steric hindrance increases, especially when multiple sterically hindered residues occur consecutively, this step becomes more susceptible to the effects of diffusion, mass transfer, and spatial proximity, thus leading to reduced coupling efficiency. The representative difficult sequences shown in the paper further indicate that these problems become amplified when sterically hindered residues appear consecutively.

Therefore, the real problem addressed by this 2025 work is not “how to make ordinary peptides,” nor is it simply the search for a stronger activating reagent. Rather, it asks: when medicinal chemistry design requires sterically hindered residues, is it possible to redesign the solid-phase peptide synthesis process by rethinking the very mode in which acyl transfer occurs?

Core Reference Card

Item	Information
Title	Immobilized acyl-transfer molecular reactors enable the solid-phase synthesis of sterically hindered peptides
Authors	Siyuan Wei, Xuchun Zhang, Xiaoliang Yang, Fa Liu, Zhu-Jun Yao
Journal	Nature Chemistry
Online publication date	August 6, 2025
Formal citation details	2025, 17(10): 1596–1606
DOI	10.1038/s41557-025-01896-8
Affiliation	Team affiliated with Nanjing University

2. What Problems Does This Study Solve, and Where Do Its Highlights and Breakthroughs Lie?

The core contribution of this 2025 Nature Chemistry paper is not the discovery of yet another stronger coupling reagent, but the proposal of a new strategy for solid-phase peptide synthesis. The authors developed a ribosome-mimicking molecular reactor (RMMR), which is essentially a ribosome-inspired, resin-immobilized bond-promoting unit. By promoting bond formation through proximity-induced acyl transfer on the resin, its aim is to reduce the limitations of traditional SPPS, in which activated carboxylic acids are first generated in solution and then must transfer to amine sites on the resin surface.

2.1 What exactly was done?

First, a new bond-forming concept was proposed.

Rather than continuing to optimize difficult couplings along the line of “using stronger activating reagents,” the authors drew inspiration from how ribosomes promote peptide bond formation and used a more favorable proximal acyl-transfer process on the resin to improve the bond-forming efficiency of sterically hindered peptides on solid phase.

Second, this concept has been experimentally validated.

Both the paper and the research team’s public interpretation indicate that RMMR is not merely a mechanistic hypothesis. It has already been applied in solid-phase synthesis experiments and showed higher coupling efficiency in sterically hindered peptides containing N-methylated amino acids and/or α,α-disubstituted amino acids.

Third, the method validation covered representative difficult sequences.

The paper did not stop at validation on simple model peptides, but further applied the method to more representative sterically hindered and challenging sequences such as cyclosporin A analogues and alamethicin F analogues.

Fourth, it shows good compatibility with existing conditions.

According to the abstract, this strategy can be combined with existing SPPS conditions, uses commercially available resins and reagents, and is compatible with standard synthesizers. This indicates that it is not merely a conceptual design that works only in a special system, but is closer to a new synthetic strategy that can be incorporated into current peptide laboratory workflows.

2.2 What problem does it solve?

The central problem addressed by this work is the long-standing contradiction in solid-phase peptide synthesis whereby sterically hindered residues are “scientifically valuable yet difficult to introduce.” For sequences containing N-methylated and/or α,α-disubstituted amino acids, traditional SPPS is often limited not simply because activation is insufficiently strong, but because activated carboxylic acids are usually formed first in the solution phase and then react with amine sites on the resin surface. When steric hindrance is high, this step becomes more vulnerable to the limitations of diffusion, mass transfer, and spatial proximity, resulting in slow reaction rates and low coupling efficiency.

The significance of RMMR lies in the fact that it does not merely rely on stronger activation conditions to force difficult couplings forward; instead, it redesigns the bond-forming mode of sterically hindered peptides on solid phase through proximity-induced acyl transfer on the resin, thereby improving the coupling efficiency of these difficult sequences.

3. What Research Tasks Is This Advance Suitable For?

Research task or experimental direction	Suitability	Reason
Synthesis of difficult peptides containing N-methylated amino acids	High	This is one of the most directly covered core targets of the paper.
Sterically hindered peptide sequences containing Aib and other α,α-disubstituted amino acids	High	Both the main storyline of the paper and public interpretations indicate that this strategy has clear significance for the solid-phase incorporation of such sterically hindered residues.
Studies on solid-phase coupling methods for multiple consecutive sterically hindered residues	High	Such sequences most clearly reflect the difficulties of traditional SPPS and are among the most convincing application scenarios for RMMR.
Peptide medicinal chemistry optimization involving stability, conformation, and permeability	Medium-high	RMMR directly improves the synthetic accessibility of sterically hindered design elements, thereby helping related medicinal chemistry concepts to be tested; however, actual property improvement still depends on the modification site, sequence context, and overall conformation.
Method development for difficult sequences in automated SPPS	High	The abstract emphasizes compatibility with commercial resins and reagents, as well as with standard synthesizers.
Synthesis of linear precursors of difficult natural product peptides or their analogues	Medium-high	Cyclosporin A and alamethicin F analogues provide representative demonstrations.
Routine preparation of conventional, easily synthesized short peptides	Medium	The method can of course be used for ordinary sequences, but the most prominent value demonstrated in the paper does not lie in this category.
Direct promotion as a universal industrial process at the present stage	Low	Current evidence is more suitable to support its positioning as a new strategy for synthesizing sterically hindered and difficult sequences; broader scale-up and process generality still require further validation.

4. What Inspiring Significance Does This Work Have for Scientific Research?

1. Implications for peptide synthesis methodology

This study suggests that when the efficiency of traditional solid-phase synthesis becomes limited in highly sterically hindered settings, what deserves to be redesigned may not simply be the activating reagent itself, but more importantly the spatial environment in which acyl transfer occurs and the bond-forming pathway. The significance of RMMR lies in shifting the focus from “how to further strengthen activation” to “how to improve the efficiency of difficult couplings through proximity-induced acyl transfer on the resin.”

2. Implications for research on difficult sterically hindered sequences

This paper does not focus on ordinary peptides, but rather on a class of targets that are most easily constrained in traditional SPPS, namely sterically hindered peptides containing N-methylated and/or α,α-disubstituted amino acids. It shows that such sequences, long regarded as “difficult to make,” do not have to rely only on stronger activation or higher equivalents to be addressed; their synthetic accessibility can also be improved by redesigning the mode of solid-phase bond formation.

3. Implications for peptide medicinal chemistry research

N-methylated and α,α-disubstituted residues are closely related to drug-relevant properties such as stability, conformational restriction, and membrane permeability. By extending the method to representative difficult targets such as cyclosporin A and alamethicin F analogues, the paper shows that this work is not only a methodological improvement, but is also directly relevant to the practical synthetic needs of sterically hindered peptides and drug-related sequences.

4. Implications for experimental workflows

The abstract clearly states that this strategy can use commercial resins and reagents and is compatible with standard synthesizers. This means it is closer to a new synthetic strategy that can be integrated into existing SPPS workflows, rather than a conceptual demonstration that works only in a specialized system. For experimental researchers, this directly relates to the practical usability of the method and its value for broader adoption.

5. Future Research Directions and Outlook

Several directions deserve continued attention:

1. Whether RMMR will provide similar benefits for longer, more complex, and more heavily modified sterically hindered sequences containing a greater variety of non-natural residue combinations still requires validation through more examples;

2. Since the paper has already demonstrated compatibility with existing SPPS conditions and standard synthesizers, it will also be worth following its generality and reproducibility across different resins, different sequence types, and different instrument conditions;

3. If this concept can continue to be expanded, it may have more practical impact on both the medicinal chemistry design and automated synthesis of sterically hindered peptides.

The above points are reasonable prospects based on the current paper’s results and should not be taken as conclusions already established by the paper.

6. Product Navigation Table for RMMR-Related Sterically Hindered Peptide Synthesis (Choose Tables 1–4 by Research Task)

Note: The following navigation is organized on the basis of the theme of this article and the related chemicals included in Tables 1–4. It is intended as a reference for experimental design and product selection, with a focus on research related to sterically hindered peptides, difficult couplings, and solid-phase peptide synthesis. It does not represent the full substrate scope individually demonstrated in the original paper.

Research task or experimental objective	Which table to consult first	Why this table should be consulted first	Recommended table(s) to consult next	Navigation note
Want to first build a basic solid-phase peptide synthesis workflow related to RMMR and determine how to choose resins, deprotection reagents, cleavage conditions, and common solvents	Table 1	Table 1 concentrates on core process reagents such as Rink Amide resin, DMF/NMP, piperidine, TFA, TIPS, and DCM, making it the most suitable starting point for establishing a complete SPPS workflow framework	Table 2	For this type of starting task, it is recommended to first clarify the four basic elements of the workflow—resin, deprotection, coupling medium, and cleavage—before moving on to the coupling-system optimization in Table 2.
Want to compare the differences between RMMR and traditional solid-phase coupling systems and establish conventional/high-activity control conditions	Table 2	Table 2 focuses on coupling-related components such as DIC/Oxyma, HBTU, HATU, COMU, PyBroP, Triphosgene, HOBt, and DIPEA, making it the most suitable for constructing traditional control systems	Table 1	The significance of RMMR is not merely “using a stronger coupling reagent.” Therefore, for this type of task, it is best to first use Table 2 to build control conditions, and then use Table 1 to complete the full solid-phase workflow.
Want to study the challenges of incorporating N-methyl amino acids in solid-phase peptide synthesis, or optimize the synthesis conditions of sequences containing consecutive N-methyl residues	Table 3	Table 3 focuses on N-methyl monomers such as Fmoc-Sar-OH, Fmoc-N-Me-Ala-OH, Fmoc-N-Me-Val-OH, Fmoc-N-Me-Ile-OH, Fmoc-N-Me-Leu-OH, and Fmoc-N-Me-Phe-OH, which are among the most central target classes for RMMR	Table 2 / Table 1	For this type of task, one usually begins by selecting residues from Table 3, then moves to Table 2 to choose traditional control systems for difficult couplings, and finally uses Table 1 to configure resin, deprotection, and cleavage conditions.
Want to study the coupling challenges of Aib or other α,α-disubstituted amino acids in solid-phase synthesis, or conduct experiments related to conformationally restricted peptides and peptaibols	Table 4	Table 4 focuses on Aib, cyclopropyl/cyclobutyl/cyclopentyl/cyclohexyl α,α-disubstituted amino acids, and reference molecules related to alamethicin, making it the most suitable for work centered on conformationally restricted sterically hindered residues	Table 2 / Table 1	Unlike the N-methyl route, this type of task focuses on the steric and conformational restriction effects of α,α-disubstituted residues. It is recommended to begin with Table 4 and then combine it with Table 2 to screen coupling systems.
Want to carry out medicinal chemistry design around sterically hindered peptides, for example with emphasis on stability, conformational control, and membrane-permeability-related optimization	Table 3 / Table 4	Tables 3 and 4 correspond to the two most important classes of sterically hindered design elements, namely N-methyl residues and α,α-disubstituted residues, and are therefore the closest to this type of medicinal chemistry optimization task	Table 2	Such studies are usually not simply about “making the peptide,” but about comparing the feasibility of introducing different sterically hindered residues. Therefore, it is recommended to first choose Table 3 or Table 4 according to the design direction, and then consult Table 2 to establish coupling controls.
Want to use highly N-methylated difficult cyclic peptides such as cyclosporin A as references to understand what types of target molecules RMMR is better suited for	Table 3	Table 3 contains not only N-methyl monomers, but also the representative highly N-methylated difficult cyclic peptide reference molecule cyclosporin A, making it the most suitable for helping readers establish an understanding of “target molecule types”	Table 2	This type of task is more target-oriented. It is best to first use Table 3 to understand the characteristics of highly N-methylated difficult peptides, and then return to Table 2 to consider the differences between traditional difficult coupling routes and RMMR.
Want to use Aib-rich sequences such as alamethicin as references to understand the value of RMMR for peptaibols / conformationally restricted sterically hindered peptides	Table 4	Table 4 includes Aib-type monomers and reference molecules related to alamethicin, and most clearly reflects the synthetic challenges of sequences enriched in α,α-disubstituted residues	Table 2	For this type of task, it is best to first identify the target residues and reference molecules in Table 4, and then combine them with Table 2 to choose conventional or high-activity coupling systems for method comparison.
Want to design a complete experimental route for sterically hindered peptides, from monomer selection to coupling systems and then cleavage and post-treatment, in one integrated view	Table 3 / Table 4	If the target mainly involves N-methyl residues, consult Table 3 first; if it mainly involves Aib/cyclic α,α-disubstituted residues, consult Table 4 first. This better matches real-world selection logic	Table 2 / Table 1	For this type of comprehensive task, the most suitable sequence is to consult the tables in the order of “target residue type → coupling system → basic solid-phase workflow conditions.”

Table 1 | Solid-Phase Supports, Deprotection/Cleavage Reagents, and Basic Process Reagents

Category	CAS No.	Aladdin Catalog No.	Name	Grade or Purity	Product Features and Applications
Amide-type solid-phase support resin	431041-83-7	R589109	Rink Amide MBHA resin	100–200 mesh, 1% DVB, 0.3–0.8 mmol/g	A commonly used solid-phase support for preparing C-terminal amide peptides, suitable for the loading, elongation, and final cleavage of sterically hindered peptide chains.
Amide-type solid-phase support resin	183599-10-2	R118279	Rink Amide AM resin	0.3–0.8 mmol/g, 100–200 mesh, 1% DVB	A commonly used amide-type solid-phase support that can serve as a baseline resin system for the synthesis of sterically hindered sequences and for method comparison.
Common polar solvent for coupling/deprotection	68-12-2	D119450	N,N-Dimethylformamide (DMF)	Anhydrous, ≥99.8%	One of the most commonly used solvents in Fmoc-SPPS, suitable for coupling, washing, and deprotection, and also an important reaction medium for the introduction of sterically hindered N-methyl/α,α-disubstituted residues.
Common polar solvent for coupling/resin swelling	872-50-4	M119668	1-Methyl-2-pyrrolidinone (NMP)	Anhydrous, ≥99.5%	A highly polar solvent similar to DMF, commonly used for resin swelling and difficult couplings, helping improve the solubility of sterically hindered monomers and mass transfer in solid-phase systems.
Solvent for resin washing/swelling	75-09-2	D433565	Dichloromethane	Anhydrous, ≥99.8%, containing 40–150 ppm amylene as stabilizer	Commonly used for resin washing, swelling, and pre-/post-cleavage handling, helping ensure adequate resin wetting and smooth solvent switching during solid-phase workflows.
Fmoc deprotection reagent	110-89-4	P1506348	Piperidine solution	Suitable for peptide synthesis, 20% in DMF	A standard reagent for Fmoc deprotection, used in the deprotection step after each chain elongation cycle, and one of the basic conditions for cyclic operation in both RMMR and conventional SPPS.
Main cleavage acid	76-05-1	T103293	Trifluoroacetic acid	For protein sequencing, ≥99%	The core acidic reagent for cleaving solid-phase peptides from the resin and fully removing side-chain protecting groups, and a key component in the release and work-up of crude sterically hindered peptides.
Cleavage scavenger	6485-79-6	T420182	Triisopropylsilane (TIPS)	≥98.5%	A commonly used scavenger in TFA cleavage systems, employed to capture reactive carbocations generated during cleavage, thereby reducing side reactions and protecting sensitive side chains.

Table 2 | Reagents, Additives, and Bases for Conventional and Difficult Couplings

Category	CAS No.	Aladdin Catalog No.	Name	Grade or Purity	Product Features and Applications
Organic base for coupling	7087-68-5	D109322	N,N-Diisopropylethylamine	Distilled, ≥99.5%	A commonly used tertiary amine base in peptide coupling, used to neutralize acids and promote bond formation between activated carboxylic acids and amine sites on the resin; often used together with HATU, HBTU, COMU, DIC, and related reagents in sterically hindered couplings.
Carbodiimide coupling reagent	693-13-0	N420184	N,N'-Diisopropylcarbodiimide	≥98.5%	A commonly used carbodiimide coupling reagent in solid-phase peptide synthesis, typically paired with Oxyma or HOBt for routine coupling and for screening difficult coupling conditions.
Carbodiimide coupling additive	3849-21-6	E138773	Ethyl (hydroxyimino)cyanoacetate	≥98%	An Oxyma-type additive, commonly used together with DIC to improve coupling efficiency and reduce the risk of racemization; an important component in optimizing difficult couplings in modern SPPS.
Classical coupling additive	123333-53-9	H106176	1-Hydroxybenzotriazole Monohydrate	≥97%	A classical coupling additive, often used with DIC and related reagents to improve coupling efficiency and suppress racemization, and suitable as a reference component in traditional SPPS systems.
Common uronium-type coupling reagent	94790-37-1	H106174	HBTU	≥99%	A commonly used uronium-type coupling reagent, suitable for establishing conventional SPPS baseline systems and for comparison with more challenging coupling conditions or RMMR results.
Highly active uronium-type coupling reagent	148893-10-1	H109327	HATU	≥99%	A highly active coupling reagent, commonly used for difficult peptide segments or sterically hindered monomer couplings, suitable for building conventional high-activity control systems to compare the added value of RMMR.
Oxyma-type highly active coupling reagent	1075198-30-9	C340003	COMU	≥98%	An Oxyma-derived highly active coupling reagent, commonly used for difficult sequences to reduce side reactions and improve coupling efficiency, suitable for performance comparison with HATU, HBTU, or the RMMR route.
Highly active phosphonium reagent for difficult coupling	132705-51-2	B113343	Bromo-tris-pyrrolidinophosphonium hexafluorophosphate	≥98%	PyBroP, a classical highly active phosphonium reagent for difficult couplings, especially commonly used for coupling N-methyl amino acids and certain α-methyl amino acids; suitable as a strong-activation control system.
Traditional reference reagent for highly activated difficult coupling	32315-10-9	T103041	Triphosgene	≥99%	One of the reference reagents representing the traditional “stronger activation” approach, and can serve as a control route for the incorporation of sterically hindered amino acids, highlighting that RMMR does not simply rely on stronger activation alone.

Table 3 | N-Methyl Amino Acid Monomers and Representative Highly N-Methylated Molecules

Category	CAS No.	Aladdin Catalog No.	Name	Grade or Purity	Product Features and Applications
N-Methyl amino acid monomer	77128-70-2	F117107	Fmoc-Sar-OH	≥98%	One of the simplest N-methyl amino acid monomers, commonly used as a basic model for N-methyl residue introduction and difficult coupling studies.
N-Methyl amino acid monomer	84000-07-7	F117110	Fmoc-N-Me-Ala-OH	≥97%	A representative N-methyl aliphatic amino acid monomer, suitable for establishing relatively simple yet sterically hindered N-methyl coupling models.
N-Methyl amino acid monomer	84000-11-3	F117124	Fmoc-N-methyl-L-valine	≥98%	A representative branched-chain N-methyl amino acid monomer with relatively high steric hindrance, suitable for constructing sterically hindered peptides and screening coupling conditions.
N-Methyl amino acid monomer	138775-22-1	F117113	Fmoc-N-methyl-L-isoleucine	≥98%	A typical highly sterically hindered branched-chain N-methyl amino acid monomer, suitable for testing the differences between traditional SPPS and RMMR in difficult coupling scenarios.
N-Methyl amino acid monomer	103478-62-2	F117114	Fmoc-N-methyl-L-leucine	≥99%	A representative branched-chain N-methyl amino acid monomer that can be used to construct sterically hindered aliphatic N-methyl sequences and evaluate difficult coupling performance.
N-Methyl amino acid monomer	77128-73-5	F134741	Fmoc-N-Me-Phe-OH	≥99%	A typical N-methyl aromatic amino acid monomer and one of the more difficult sterically hindered residues to couple in traditional SPPS, suitable for evaluating improvement by RMMR in the efficiency of N-methyl residue incorporation.
Representative highly N-methylated difficult cyclic peptide reference molecule	59865-13-3	C106893	Cyclosporin A	Moligand™, ≥98%	A classical representative of highly N-methylated difficult cyclic peptides, useful for understanding the types of target molecules addressed by strategies such as RMMR and their medicinal chemistry value.

Table 4 | α,α-Disubstituted Amino Acid-Related Monomers, Scaffold Reference Molecules, and Aib-Enriched Representative Molecules

Category	CAS No.	Aladdin Catalog No.	Name	Grade or Purity	Product Features and Applications
α,α-Disubstituted amino acid monomer	94744-50-0	F101459	Fmoc-α-Me-Ala-OH	≥97%	An Aib-type Fmoc monomer and a classical representative of α,α-disubstituted amino acids, widely used in conformationally restricted peptide and peptaibol research, and also a key monomer for evaluating sterically hindered coupling capability.
Cyclic α,α-disubstituted amino acid scaffold reference molecule	22059-21-8	A101238	1-Aminocyclopropanecarboxylic acid	≥98%	A conformationally restricted cyclic α,α-disubstituted amino acid scaffold reference molecule, suitable for understanding the structural characteristics and research directions of sterically hindered, conformationally restricted residues; for actual synthesis in Fmoc-SPPS, the corresponding Fmoc-protected monomer should usually be preferred.
Cyclic α,α-disubstituted amino acid scaffold reference molecule	22264-50-2	A102435	1-Amino-1-cyclobutanecarboxylic acid	≥97%	A cyclic α,α-disubstituted amino acid scaffold reference molecule that is both conformationally restricted and significantly sterically hindered, suitable as a type reference for difficult coupling and conformationally restricted peptide design.
Cyclic α,α-disubstituted amino acid scaffold reference molecule	52-52-8	A151472	1-Aminocyclopentanecarboxylic Acid	≥98%	One of the cyclic α,α-disubstituted amino acid scaffold reference molecules, suitable for comparing the steric characteristics and design logic of different conformationally restricted residues.
Cyclic α,α-disubstituted amino acid scaffold reference molecule	2756-85-6	A101237	1-Aminocyclohexanecarboxylic acid	≥98%	A markedly sterically hindered cyclic α,α-disubstituted amino acid scaffold reference molecule, useful for understanding the structural features and application directions of sterically hindered non-natural residues.
Aib-enriched sterically hindered peptide reference molecule	27061-78-5	A132913	Alamethicin	≥98%	A representative Aib-enriched peptaibol molecule that helps illustrate the challenges posed by α,α-disubstituted-amino-acid-enriched sequences in solid-phase synthesis and the application scenarios of RMMR.

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 by “product name/CAS/catalog number” on the Aladdin website.

For more related articles, see below:

A Complete Guide to Choosing Resins for SPPS (Solid-Phase Peptide Synthesis): Fmoc/Boc Routes, C-Terminal Acid/Amide, and a Key-Parameter Navigator

References:

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