Aspartic Acid Derivatives with Tertiary O-Linked Protecting Groups
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Solution Overview
Problem
Aspartimide formation during peptide synthesis, particularly in sequences containing aspartic acid, leads to significant accumulation of by-products, complicating the separation of desired peptides and increasing production costs due to reduced synthetic accessibility of therapeutically important peptides like GLP-2 analogs.
Innovation Solution
Development of aspartic acid derivatives with a tertiary O-linked carbon atom side-chain protecting group, featuring linear hydrocarbon chains of two to six carbon atoms, which effectively hinders aspartimide formation while maintaining high reactivity in peptide synthesis, using methods such as Fmoc/tBu based solid phase peptide synthesis and Z/tBu based solution synthesis.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Ease of manufacture
If standard Fmoc-Asp(OtBu)-OH derivative is used in peptide synthesis, then the synthesis process is simple and straightforward, but aspartimide formation occurs leading to significant accumulation of by-products
Solution Approach 1:
The patent applies preliminary anti-action by introducing a protecting group (Mpe, Epe, or Php) on the side-chain carboxylic acid of aspartic acid before peptide synthesis. This protecting group prevents the aspartic acid side-chain from participating in aspartimide formation during Fmoc deprotection steps, thereby preemptively counteracting the harmful effect while maintaining synthesis simplicity
Solution Approach 2:
The patent changes the chemical parameter of the aspartic acid derivative by modifying the side-chain protecting group from standard tBu to specifically designed Mpe, Epe, or Php groups with different steric properties. This parameter change optimizes the balance between preventing aspartimide formation and maintaining peptide synthesis reactivity
2Productivity
If Fmoc deprotection steps are performed multiple times to ensure complete conversions, then peptide assembly is thorough, but aspartimide formation accumulates significantly
Solution Approach 1:
The protecting group (Mpe, Epe, or Php) is introduced beforehand to prevent aspartimide formation during each Fmoc deprotection step. This allows multiple deprotection cycles to be performed for complete peptide assembly without significant accumulation of aspartimide by-products, as the protecting group blocks the reactive site throughout the synthesis process
3Productivity
If microwave heating is applied to accelerate coupling and deprotection reactions, then cycle times are shortened and repetitive yields are increased, but aspartimide formation increases
Solution Approach 1:
The side-chain protecting group (Mpe, Epe, or Php) is introduced before microwave heating to prevent aspartimide formation. This allows microwave heating to be applied for accelerated reactions without the harmful effect of increased aspartimide formation, as the protecting group blocks the reactive site even under microwave conditions
4Object-generated harmful factors
If bulky protective groups are used to prevent aspartimide formation, then aspartimide formation is suppressed, but reactivity of the protected amino acids is reduced
Solution Approach 1:
The patent optimizes the steric parameter of the protecting group by selecting Mpe, Epe, or Php groups with specifically tuned bulkiness. These groups provide sufficient steric hindrance to prevent aspartimide formation while maintaining adequate reactivity for peptide synthesis, representing an optimized balance between the two competing requirements
Data Source
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AI summary
The present invention is directed to derivatives of aspartic acid with a new type of side-chain protecting group. The present invention is further directed to methods of their preparation and their use in Fmoc based solid phase peptide synthesis as well as the Z/tBu based solution synthesis of peptides. The use of the aspartic acid derivatives according to the present invention leads to the minimization of base catalyzed aspartimide formation during peptide synthesis and supports the prevention of aspartimide derived impurities.