Experimental Judgment in Oxyma Coupling Systems: Coupling Efficiency, Racemization Control, and the HCN Risk in DIC-Based Systems

Introduction

 

In amide bond formation, Oxyma [ethyl 2-cyano-2-(hydroxyimino)acetate, commonly marketed as OxymaPure] is usually classified as a coupling additive used to reduce racemization. That definition captures only part of its role. Representative studies published in 2009 clearly established Oxyma as a replacement additive for HOBt [1-hydroxybenzotriazole] and HOAt [1-hydroxy-7-azabenzotriazole]. The discussion extends beyond coupling efficiency and racemization suppression and also involves the safety issues associated with benzotriazole-based additives.

 

Since then, the experimental significance of Oxyma has become more clearly focused on several specific points of judgment: whether coupling efficiency can be improved during carboxylic acid activation while maintaining stereochemical stability; whether certain base-driven side reactions can be mitigated in solid-phase synthesis; whether it is better suited than common hydroxyl-containing additives for acid-sensitive solid supports, especially under 2-chlorotrityl chloride resin conditions; and how to address issues related to hydrogen cyanide formation in systems involving DIC [N,N′-diisopropylcarbodiimide].

 

Experimental judgment with Oxyma usually revolves around four aspects: whether coupling efficiency is insufficient, whether optical purity declines, whether base-sensitive side reactions are amplified, and whether the current system is already limited by DIC/Oxyma-related side reactions and hydrogen cyanide issues. Different problems call for different reagent combinations, carbodiimide choices, and solvent arrangements.

 

1. Layering of Oxyma-Related Experimental Issues

 

In Oxyma-based systems, experimental judgment usually needs to separate four categories of issues: first, carboxylic acid activation and coupling efficiency; second, retention of stereochemical integrity at chiral centers; third, base-driven side reactions and compatibility with acid-sensitive solid supports; and fourth, hydrogen cyanide generation under DIC-involved conditions. Different categories require different reagent choices, media arrangements, and comparison sequences.

 

1.1 | Categories of Experimental Issues That Should Be Evaluated Separately in Oxyma Systems

 

Experimental issue	Common manifestations	Key point of evaluation	Priority direction for comparison
Insufficient coupling efficiency	Incomplete coupling, slow conversion of sterically hindered substrates, difficulty in fragment coupling	First determine whether Oxyma can improve both conversion and crude purity at the same time	Parallel comparison of Oxyma/carbodiimide systems with stand-alone coupling reagents
Inadequate racemization control	Decline in optical purity, amplified racemization in difficult amino acids or fragment couplings	The focus is not only yield, but whether retention of stereochemical integrity improves	Compare Oxyma, its parent-derived variants, and highly active coupling reagents
Pronounced base-driven side reactions	Accumulation of impurities after repeated deprotection, decline in sequence purity, reduced stability of acid-sensitive solid supports	It is necessary to distinguish whether the problem arises from the deprotection step, the amount of base used during coupling, or the tolerance of the resin itself	Compare deprotection bases, acid scavenger bases, the form of Oxyma, and solid-support conditions
DIC-limited conditions	Scale-up, long hold times, or multiple cycles under DIC/DMF conditions	The key question is whether the DIC/Oxyma combination should still be retained and whether the medium should be adjusted	Compare different carbodiimides, as well as media such as DMF, NBP, and NBP/ethyl acetate

 

2. Experimental Tasks Corresponding to Different Oxyma-Derived Systems

 

Different Oxyma-derived systems correspond to different experimental tasks. COMU is an Oxyma-based uronium stand-alone coupling reagent; PyOxP, PyOxB, and PyOxim are Oxyma-based phosphonium coupling reagents; K-Oxyma is particularly suitable for acid-sensitive solid-support conditions, especially couplings involving 2-chlorotrityl chloride resin; Oxyma derivatives bearing a glycerol ketal scaffold are mainly used for low-racemization couplings in aqueous or high-water-content media; and Oxyma-B and Oxyma-T are mainly used for higher-demand comparisons in racemization control.

 

2.1 | Main Use Scenarios for Different Oxyma Systems and the First Items to Confirm Experimentally

 

System	Main use scenario	Representative characteristic	First items to confirm experimentally
Oxyma + carbodiimide	Initial screening for conventional couplings	A classical additive-based route, commonly used to compare coupling efficiency, racemization control, and side reactions	Type of carbodiimide, whether DIC is used, solvent composition, reagent ratio, and hold time after activation
COMU	Couplings requiring activation by a stand-alone coupling reagent	An Oxyma-based uronium reagent that integrates the activated species and leaving group into the same reagent	Substrate steric hindrance, crude purity, convenience of workup, and differences from stand-alone reagents such as HATU and HBTU
PyOxP / PyOxB	Difficult couplings, sterically hindered substrates, cyclization-type couplings	Oxyma-based phosphonium reagents that show strong activating ability and a lower tendency toward racemization in difficult models	Conversion of difficult substrates, cyclization efficiency, crude purity, and differences from uronium-type reagents
K-Oxyma	Acid-sensitive solid-support conditions, especially couplings involving 2-chlorotrityl chloride resin	The potassium salt form of Oxyma, which removes the acidic burden of free Oxyma while retaining acylation-promoting ability	Resin stability, peptide-chain loss after loading, coupling efficiency, and whether additional organic base is required
Oxyma derivatives bearing a glycerol ketal scaffold	Low-racemization amide bond formation in aqueous or high-water-content media	Can be combined with EDC·HCl and sodium bicarbonate to achieve low-racemization coupling in water	Aqueous solubility, compatibility of the base system, substrate stability in water, and workup method
Oxyma-B	Couplings requiring higher optical purity	In multiple models, it suppresses racemization better than OxymaPure and related benzotriazole systems	Whether optical purity improves significantly, and whether that improvement is accompanied by changes in yield or reaction rate
Oxyma-T	Situations requiring further comparison of racemization control	In stepwise solution-phase models, Oxyma-T gives lower racemization than HOBt, HOAt, OxymaPure, and Oxyma-B	Stepwise coupling and fragment coupling should be evaluated separately, with separate comparison of racemization level and conversion

 

3. Hydrogen Cyanide Formation and Condition Selection in DIC/Oxyma Systems

 

In DIC/Oxyma systems, HCN formation is a demonstrated side reaction. The focus of evaluation should be placed on carbodiimide type, solvent composition, reagent ratio, and hold time after activation.

 

1. HCN formation is not an incidental impurity, but an experimentally demonstrated side reaction in DIC/Oxyma systems.

A 2019 process chemistry study showed that in DMF at 20 °C, Oxyma and DIC generate HCN during amino acid activation; when Oxyma and DIC are present in excess relative to the substrate, HCN can continue to accumulate even after amino acid activation has been completed.

 

2. Both HCN formation and accumulation are influenced by multiple condition variables.

Variables that need to be confirmed separately include carbodiimide type, solvent composition, reagent ratio, and hold time after activation. All of these factors affect the rate of HCN formation and the extent of HCN accumulation, although not in the same way.

 

3. Under DIC/Oxyma conditions, solvent changes affect both HCN formation and coupling rate.

A 2020 study reported that under the investigated carboxylic acid/Oxyma/DIC = 1:1:1 conditions, the rate of HCN formation decreases in the order DMF > NBP > NBP/ethyl acetate (1:1) > NBP/ethyl acetate (1:4), whereas the rate of amide bond formation increases in the order DMF ≈ NBP < NBP/ethyl acetate (1:1) < NBP/ethyl acetate (1:4).

 

4. Comparisons within DIC/Oxyma systems should not focus on Oxyma alone.

Whether DIC should still be retained, whether DMF should still be used, whether the reagents are present in excess, and whether the activated solution has unproductive hold time are all parameters that need to be compared separately.

 

5. Alternative carbodiimides are no longer merely hypothetical options, but literature-supported comparison directions.

A 2021 study showed that reactions of TBEC and EDC·HCl with OxymaPure do not generate HCN, and they can therefore serve as alternative comparison directions to DIC/Oxyma.

 

3.1 | Experimental Variables to Confirm First in DIC/Oxyma Systems

 

Experimental situation	Variables to confirm	Priority comparison items
DIC/Oxyma/DMF used as a routine coupling condition	Whether DIC and DMF must both be retained	Differences among DIC/DMF, DIC/NBP, DIC/NBP/ethyl acetate (1:1), and DIC/NBP/ethyl acetate (1:4)
Reagents are present in excess and there is a waiting period after activation	Extent of excess Oxyma and DIC; hold time after activation	First reduce the amounts of Oxyma and DIC, then compare the effect of different preactivation or standing times on HCN accumulation
HCN must be controlled while coupling efficiency is maintained	Combined effect of solvent changes on HCN formation rate and amide bond formation rate	Compare DMF, NBP, NBP/ethyl acetate (1:1), and NBP/ethyl acetate (1:4)
The process has already entered scale-up, automation, or continuous batch operation	Residence time after preparation of the activated solution; hold time in equipment or tubing; handling of waste streams and volatiles	First compare the actual hold time from preparation to use of the activated solution in the current process, then decide whether carbodiimide and solvent should be changed at the same time
A full redesign of the coupling conditions is planned	Whether the current limitation already originates from DIC/Oxyma itself	Compare DIC/Oxyma with TBEC/Oxyma and EDC·HCl/Oxyma

 

4. Product Navigation Table for Oxyma Coupling Systems (Choose Table 1-Table 4 by Research or Experimental Goal)

 

Research or experimental goal	Which table to read first	Why start with this table	Which table to cross-reference next	Reason for cross-reference
To first distinguish which components in the Oxyma system are free additives, which are potassium salts or enhanced racemization-suppressing derivatives, and which already belong to stand-alone coupling reagents	Table 1	Table 1 separates additives, derived additives, and stand-alone coupling reagents, making it easier to clarify the experimental role of each reagent first	Table 2	Then compare them with HOBt, HOAt, and their corresponding coupling reagents to determine whether the current replacement is occurring at the additive level or at the level of the entire activation mode
To compare differences between the Oxyma route and benzotriazole-based systems in coupling efficiency, racemization suppression, and reagent selection	Table 2	Table 2 brings together HOBt, HOAt, and the corresponding uronium and phosphonium reagents, making it easier to establish an external reference first	Table 1, Table 3	Table 1 is used to map Oxyma-type additives and stand-alone coupling reagents, while Table 3 is used to determine whether the difference also relates to carbodiimide selection
To begin conventional coupling-condition screening from an “additive plus carbodiimide” route and then decide whether to switch to a stand-alone coupling reagent	Table 1	First distinguish whether Oxyma, K-Oxyma, or enhanced racemization-suppressing derivatives should be compared, so that additive routes and stand-alone coupling reagent routes are not mixed together at the outset	Table 3	Then compare carbodiimides such as DCC, DIC, EDC·HCl, and TBEC to determine whether the main difference originates from the activating reagent
To focus on the hydrogen cyanide issue when DIC is combined with Oxyma, or to compare differences among carbodiimides	Table 3	Table 3 directly corresponds to several classes of carbodiimides, making it easier to see first which class of activating reagent is primarily responsible for the issue	Table 4, Table 1	Table 4 allows further comparison of the effects of solvent, base, and solid-phase conditions on this issue, while Table 1 helps determine whether the route should instead shift to stand-alone coupling reagents
To adjust conditions around solvent replacement, greener media, and resin compatibility	Table 4	Table 4 brings solvents, bases, and resins together, making it easier to compare directly how medium changes affect coupling and side reactions	Table 3	After changing the medium, it is often also necessary to determine whether the carbodiimide should be adjusted at the same time
To study base-sensitive side reactions, especially the relationship between deprotection bases, acid scavenger bases, and coupling conditions	Table 4	Table 4 directly corresponds to piperidine, DIPEA, sodium bicarbonate, and common media, making it easier to determine first which step is mainly responsible for the problem	Table 1	Then determine whether to continue adjusting the base and medium or switch to another type of Oxyma reagent or stand-alone coupling reagent
To compare the compatibility of Oxyma, potassium salt oxime additives, and highly active systems on acid-sensitive solid supports	Table 4	The 2-chlorotrityl chloride resin in Table 4 is the direct starting point for judging solid-phase compatibility	Table 1, Table 2	Table 1 can be used to compare differences within Oxyma systems, while Table 2 can introduce highly active benzotriazole-based systems as references
To screen conditions for difficult couplings, sterically hindered substrates, or couplings requiring high optical purity	Table 1	Table 1 centrally lists reagents such as Oxyma-B, COMU, and PyOxim that are better suited to high-demand coupling tasks	Table 2, Table 4	Table 2 can add external references such as HATU and PyAOP, while Table 4 can further examine whether the current bottleneck also involves solvent, base, or solid support
To move from small-scale trials to scale-up while balancing efficiency, purity, workup, and hydrogen cyanide issues	Table 3	The choice of activating reagent directly affects the type of by-products, the workup strategy, and the tendency toward hydrogen cyanide generation	Table 1, Table 4	Table 1 can be used to compare whether switching to a stand-alone coupling reagent would simplify the system, while Table 4 can supplement the impact of solvent, base, and resin on actual operation

 

Table 1 | Core Oxyma Additives, Enhanced Racemization-Suppressing Derivatives, and Oxyma-Based Stand-Alone Coupling Reagents

 

Category	CAS No.	Aladdin Cat. No.	Name	Specification or Purity	Product Features and Applications
Core oxime-type coupling additive	3849-21-6	E138773	Ethyl (hydroxyimino)cyanoacetate	≥98%	The parent Oxyma compound, commonly used with DIC, DCC, EDC·HCl, and related reagents for carboxylic acid activation. It is suitable as a baseline comparator for coupling efficiency, racemization suppression, and side-reaction profiles.
Potassium salt oxime additive	158014-03-0	K468794	K-Oxyma	≥97%	Suitable for side-by-side comparison with free Oxyma, especially under acid-sensitive solid-phase conditions such as 2-chlorotrityl chloride resin, for evaluating resin stability, acylation efficiency, and performance after prolonged contact.
Enhanced racemization-suppressing oxime additive	5417-13-0	H679971	5-hydroxyimino-1,3-dimethyl-hexahydropyrimidine-2,4,6-trione	≥97%	Suitable for screening couplings involving racemization-prone fragments, difficult amino acids, or demanding optical purity, and for comparing its racemization-suppressing performance with that of Oxyma.
Oxyma-derived coupling reagent	1426821-11-5	B932309	Boc-Oxyma	≥98%	Can be used directly for carboxylic acid activation. It is suitable for side-by-side comparison with the “free additive plus carbodiimide” route in terms of activation mode, stoichiometric setup, and workup differences, and can also be used in related comparisons of amide, ester, and thioester formation.
Oxyma-based uronium coupling reagent	1075198-30-9	C340003	COMU	≥98%	Commonly used for amide bond formation in both solution- and solid-phase synthesis. It is suitable for comparison with HATU, HBTU, or DIC/Oxyma systems in activation efficiency, racemization suppression, and workup convenience.
Oxyma-based uronium coupling reagent	136849-72-4	E102847	TOTU	≥98%	Suitable for comparison with TBTU and COMU to evaluate tetrafluoroborate-type uronium reagents in terms of activation efficiency, substrate compatibility, and side-reaction profiles in solution- or solid-phase synthesis.
Oxyma-based phosphonium coupling reagent	153433-21-7	P196188	PyOxim	≥98%	Suitable for sterically hindered substrates, cyclizations, and other difficult couplings, and useful for comparing activation strength, reaction cleanliness, and racemization suppression against uronium-type Oxyma reagents.

 

Table 2 | Comparison of Triazole-Based Additives and Their Corresponding Stand-Alone Coupling Reagents

 

Category	CAS No.	Aladdin Cat. No.	Name	Specification or Purity	Product Features and Applications
Classical triazole-based additive	2592-95-2	H684271	1-Hydroxybenzotriazole (HOBt)	≥99%	A classical coupling additive suitable for comparison with Oxyma-type additives in terms of carboxylic acid activation efficiency, racemization suppression, and side-reaction differences.
High-activity triazole-based additive	39968-33-7	H109328	1-Hydroxy-7-azabenzotriazole	≥99%	More active than HOBt and suitable for side-by-side comparison with Oxyma and enhanced racemization-suppressing oxime additives in difficult couplings and cases requiring high optical purity.
HOAt-type uronium coupling reagent	148893-10-1	H109327	HATU	≥99%	A highly active stand-alone coupling reagent suitable for comparison with COMU and PyOxim in condition screening for sterically hindered substrates and difficult couplings.
HOBt-type uronium coupling reagent	94790-37-1	H106174	HBTU	≥99%	A commonly used reagent for routine peptide coupling and a suitable baseline reference for Oxyma-based stand-alone coupling reagents.
HOBt-type tetrafluoroborate uronium coupling reagent	125700-67-6	T109338	TBTU	≥98%	Suitable for comparison with TOTU to evaluate differences between two tetrafluoroborate-type uronium coupling reagents in activation efficiency and workup behavior.
HOBt-type phosphonium coupling reagent	128625-52-5	P109336	1H-Benzotriazol-1-yloxytripyrrolidinophosphonium Hexafluorophosphate	≥98%	A classical phosphonium coupling reagent suitable for comparison with PyOxim or uronium-type reagents in difficult couplings, cyclizations, and slower-reacting substrates.
HOAt-type phosphonium coupling reagent	156311-83-0	A109335	(7-Azabenzotriazol-1-yloxy)tripyrrolidinophosphonium hexafluorophosphate	≥97%	A highly active phosphonium reagent suitable for parallel comparison with HATU and PyOxim in coupling tasks requiring stronger activation.

 

Table 3 | Carbodiimide Activators and HCN-Risk-Related Comparators

 

Category	CAS No.	Aladdin Cat. No.	Name	Specification or Purity	Product Features and Applications
Classical carbodiimide activator	538-75-0	D106074	N,N′-Dicyclohexylcarbodiimide	≥99%	A classical carboxylic acid activator suitable for establishing a carbodiimide-coupling baseline with Oxyma, HOBt, and HOAt, and for comparing by-product removal and reaction cleanliness.
DIC-type carbodiimide activator	693-13-0	N420184	N,N'-Diisopropylcarbodiimide	≥98.5%	Commonly used with Oxyma in both solution- and solid-phase coupling. It is also a key comparator for evaluating oxadiazole by-products, the tendency toward HCN generation, and the effects of addition sequence and hold time.
Water-soluble carbodiimide activator	25952-53-8	E106172	N-(3-Dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride	≥98%	Suitable for carboxylic acid activation in solution phase, in aqueous-containing conditions, or where water-wash workup is convenient. It can also be combined with Oxyma or its potassium salt to compare differences from DIC and DCC in activation mode and workup.
TBEC-type carbodiimide activator	1433-27-8	T340901	1-tert-Butyl-3-ethylcarbodiimide	≥98%	Can be used with Oxyma to examine a lower tendency toward HCN generation relative to DIC, and to compare its coupling performance under green-media and scale-up conditions.

 

Table 4 | Media, Bases, and Solid-Support-Related Components

 

Category	CAS No.	Aladdin Cat. No.	Name	Specification or Purity	Product Features and Applications
Mild inorganic base	144-55-8	S432109	Sodium bicarbonate	Anhydrous grade, reagent grade, high purity, ≥99.5%	Suitable for pH adjustment under aqueous or relatively mild conditions, and useful for comparing the effects of weak-base conditions on activation efficiency, substrate tolerance, and side reactions.
Common polar amide solvent	68-12-2	D119450	N,N-Dimethylformamide (DMF)	Anhydrous grade, ≥99.8%	A commonly used medium in Oxyma/carbodiimide systems and solid-phase peptide synthesis, and also an important reference solvent for comparing the tendency toward HCN formation in DIC/Oxyma combinations.
Organic base for deprotection	110-89-4	P1506346	Piperidine solution	Biotechnology grade, ≥99.5%	Commonly used for Fmoc deprotection and also frequently used to amplify differences in base-sensitive side reactions such as aspartimide formation, making it useful for comparing the interplay between coupling systems and deprotection steps.
Common acid scavenger base	7087-68-5	D109322	N,N-Diisopropylethylamine	Distilled grade, ≥99.5%	Commonly paired with stand-alone coupling reagents or carboxylic acid activation systems to modulate acylation rate and compare the effects of base loading on racemization and side reactions.
Component of green mixed solvent systems	141-78-6	E116133	Ethyl acetate	GR, ≥99.5%	Commonly combined with 1-butyl-2-pyrrolidone and similar solvents to partially replace DMF, and useful for comparing the effects of medium changes on coupling efficiency, resin swelling, and the tendency toward HCN generation.
Green polar solvent	3470-98-2	B124554	1-Butyl-2-pyrrolidone	≥98% (GC)	Can serve as a replacement medium for DMF and can form mixed solvents with ethyl acetate. It is suitable for comparing solid-phase coupling efficiency, resin compatibility, and workup convenience.
Acid-sensitive solid support	934816-82-7	C590778	2-Chlorotrityl Chloride Resin	100-200 mesh, 1% DVB, 0.4-3.0 mmol/g	Commonly used for acid-sensitive peptide-chain loading and solid-phase coupling, and suitable for comparing the effects of Oxyma, K-Oxyma, and highly active coupling reagents on resin stability and coupling performance under solid-phase conditions.

 

Note: The above are representative Aladdin products. For additional product specifications, please search the Aladdin website by “product name/CAS/catalog number.”

 

References

 

[1] Subirós-Funosas R, Prohens R, Barbas R, El-Faham A, Albericio F. Oxyma: An efficient additive for peptide synthesis to replace the benzotriazole-based HOBt and HOAt with a lower risk of explosion. Chem. Eur. J. 2009;15(37):9394-9403. doi:10.1002/chem.200900614.

 

[2] El-Faham A, Subirós-Funosas R, Prohens R, Albericio F. COMU: A safer and more effective replacement for benzotriazole-based uronium coupling reagents. Chem. Eur. J. 2009;15(37):9404-9416. doi:10.1002/chem.200900615.

 

[3] Subirós-Funosas R, El-Faham A, Albericio F. PyOxP and PyOxB: The Oxyma-based novel family of phosphonium salts. Org. Biomol. Chem. 2010;8(16):3665-3673. doi:10.1039/C003719B.

 

[4] Subirós-Funosas R, El-Faham A, Albericio F. Use of Oxyma as pH modulatory agent to be used in the prevention of base-driven side reactions and its effect on 2-chlorotrityl chloride resin. Biopolymers. 2012;98(2):89-97. doi:10.1002/bip.21713.

 

[5] Wang Q, Wang Y, Kurosu M. A new Oxyma derivative for nonracemizable amide-forming reactions in water. Org. Lett. 2012;14(13):3372-3375. doi:10.1021/ol3013556.

 

[6] Cherkupally P, Acosta GA, Nieto-Rodriguez L, Spengler J, Rodriguez H, Khattab SN, El-Faham A, Shamis M, Luxembourg Y, Prohens R, Subirós-Funosas R, Albericio F. K-Oxyma: A strong acylation-promoting, 2-CTC resin-friendly coupling additive. Eur. J. Org. Chem. 2013;(28):6372-6378. doi:10.1002/ejoc.201300777.

 

[7] Jad YE, Khattab SN, de la Torre BG, Govender T, Kruger HG, El-Faham A, Albericio F. Oxyma-B, an excellent racemization suppressor for peptide synthesis. Org. Biomol. Chem. 2014;12(42):8379-8385. doi:10.1039/C4OB01612B.

 

[8] Jad YE, de la Torre BG, Govender T, Kruger HG, El-Faham A, Albericio F. Oxyma-T, expanding the arsenal of coupling reagents. Tetrahedron Lett. 2016;57(31):3523-3525. doi:10.1016/j.tetlet.2016.06.109.

 

[9] McFarland AD, Buser JY, Embry MC, Held CB, Kolis SP. Generation of hydrogen cyanide from the reaction of Oxyma (ethyl cyano(hydroxyimino)acetate) and DIC (diisopropylcarbodiimide). Org. Process Res. Dev. 2019;23(9):2099-2105. doi:10.1021/acs.oprd.9b00344.

 

[10] Erny M, Lundqvist M, Rasmussen JH, Ludemann-Hombourger O, Bihel F, Pawlas J. Minimizing HCN in DIC/Oxyma-mediated amide bond-forming reactions. Org. Process Res. Dev. 2020;24(7):1341-1349. doi:10.1021/acs.oprd.0c00227.

 

[11] Manne SR, Sharma A, Sazonovas A, El-Faham A, de la Torre BG, Albericio F. Understanding OxymaPure as a peptide coupling additive: A guide to new Oxyma derivatives. ACS Omega. 2022;7(7):6007-6023. doi:10.1021/acsomega.1c06342.

 

[12] Fantoni T, Orlandin A, Di Stefano I, Macis M, Tolomelli A, Ricci A, Cabri W, Ferrazzano L. Solid phase peptide synthesis using side-chain unprotected arginine and histidine with Oxyma Pure/TBEC in green solvents. Green Chem. 2024;26:10929-10939. doi:10.1039/D4GC03209H.

 

[13] Manne SR, Luna O, Acosta GA, Royo M, El-Faham A, Orosz G, de la Torre BG, Albericio F. Amide formation: Choosing the safer carbodiimide in combination with OxymaPure to avoid HCN release. Org. Lett. 2021;23(17):6900-6904. doi:10.1021/acs.orglett.1c02466.

 

For more related articles, please see below:

 

The Methodological Value of Boc-Oxyma: Low-Racemization Coupling, Route Continuity, and Extended Applications

 

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