A Short and Scalable Synthesis of Orthogonally Protected Bis(aminomethyl)malonic Acid: Access to Bioactive Macrocyclic Peptides

Synthesis ◽  
2017 ◽  
Vol 49 (22) ◽  
pp. 5039-5044
Author(s):  
Muthalagu Vetrichelvan ◽  
Vijayabhaskar Bokkala ◽  
Surendran Renganathan ◽  
Arvind Mathur ◽  
Richard Rampulla ◽  
...  
Keyword(s):  
Amino Acids ◽  
Natural Products ◽  
Total Synthesis ◽  
Malonic Acid ◽  
Good Yield ◽  
Building Blocks ◽  
Nucleophilic Attack ◽  
Macrocyclic Peptides ◽  
Scalable Synthesis ◽  
Key Steps

A short and scalable process for the preparation of multi-gram quantities of orthogonally protected bis(aminomethyl)malonic acid in good yield from readily available starting material is described. These orthogonally protected amino acids are important building blocks to make peptides based drugs, glycoconjugates, and in the total synthesis of peptide natural products. The newly developed route has only six steps with an overall yield of 27%, which involves nucleophilic attack of a malonate on an imide as one of the key steps.

scholarly journals Syntheses of Cyclomarins – Interesting Marine Natural Products with Distinct Mode of Action towards Malaria and Tuberculosis

Synthesis ◽  
2018 ◽  
Vol 51 (01) ◽  
pp. 107-121 ◽  
Author(s):  
Alexander Kiefer ◽  
Uli Kazmaier
Keyword(s):  
Amino Acids ◽  
Plasmodium Falciparum ◽  
Natural Products ◽  
Total Synthesis ◽  
Building Blocks ◽  
Distinct Mode ◽  
Unusual Amino Acids ◽  
Caseinolytic Protease ◽  
A Subunit ◽  
Cyclomarin A

The cyclomarins are cyclic heptapeptides from marine streptomycetes containing four rather unusual amino acids. Interestingly, the cyclomarins address two completely different targets: ClpC1, a subunit of the caseinolytic protease of Mycobacterium tuberculosis (MTB), as well as PfAp3Aase of Plasmodium falciparum. Therefore, the cyclomarins are interesting lead structures for the development of drugs targeting tuberculosis and malaria. As a result, several synthetic protocols towards the synthesis of these unusual building blocks as well as the natural products themselves have been developed, which will be discussed in this review.1 Introduction2 Synthesis of the Building Blocks3 Total Synthesis of Cyclomarin C by Yao and Co-workers4 Total Synthesis of Cyclomarin A and C by Barbie and Kazmaier5 Conclusion

scholarly journals Non-Enzymatic Desymmetrization Reactions in Aqueous Media

Symmetry ◽  
2021 ◽  
Vol 13 (4) ◽  
pp. 720
Author(s):  
Satomi Niwayama
Keyword(s):  
Natural Products ◽  
Total Synthesis ◽  
Functional Groups ◽  
Organic Compounds ◽  
Recent Progress ◽  
Aqueous Media ◽  
Building Blocks ◽  
Organic Reactions ◽  
Environmentally Benign ◽  
Enzymatic Desymmetrization

Symmetric organic compounds are generally obtained inexpensively, and therefore they can be attractive building blocks for the total synthesis of various pharmaceuticals and natural products. The drawback is that discriminating the identical functional groups in the symmetric compounds is difficult. Water is the most environmentally benign and inexpensive solvent. However, successful organic reactions in water are rather limited due to the hydrophobicity of organic compounds in general. Therefore, desymmetrization reactions in aqueous media are expected to offer versatile strategies for the synthesis of a variety of significant organic compounds. This review focuses on the recent progress of desymmetrization reactions of symmetric organic compounds in aqueous media without utilizing enzymes.

One-pot total synthesis of streptindole, arsindoline B and their congeners through tandem decarboxylative deaminative dual-coupling reaction of amino acids with indoles

2015 ◽  
Vol 13 (14) ◽  
pp. 4240-4247 ◽  
Author(s):  
Jiachen Xiang ◽  
Jungang Wang ◽  
Miao Wang ◽  
Xianggao Meng ◽  
Anxin Wu
Keyword(s):  
Amino Acids ◽  
Natural Products ◽  
Total Synthesis ◽  
Coupling Reaction ◽  
One Pot ◽  
The One

This paper described a decarboxylative deaminative dual-coupling reaction of amino acids with indoles to afford BIM scaffolds and its further application to the one-pot total synthesis of natural products.

Dimethylformamide Acetals and Bredereck’s Reagent as Building Blocks in Natural Products Total Synthesis

2020 ◽  
Vol 17 (1) ◽  
pp. 47-66
Author(s):  
Franz Bracher
Keyword(s):  
Natural Products ◽  
Total Synthesis ◽  
Alkylating Agents ◽  
Building Blocks ◽  
Methyl Groups ◽  
Open Chain ◽  
Enol Ethers ◽  
Condensation Products ◽  
Condensation Reactions

Dimethylformamide acetals and Bredereck’s reagent (tert-butoxy-bis(dimethylamino) methane) are versatile C1 building blocks due to their ability to undergo condensation reactions with CH-acidic methyl and methylene moieties. Subsequent modulation of the resulting condensation products enables the preparation of open-chain products like aldehydes, ketones, enones, enol ethers, methyl groups, and, most important in alkaloid total synthesis, the annulation of heterocyclic rings like pyridines, pyridine-N-oxides, bromopyridines, aminopyridines, aminopyrimidines, pyrroles and chromenones. In certain cases, these reagents can act as alkylating agents. The applications of these building blocks in natural products total synthesis are reviewed here.

Discovery and Biocatalytic Application of a PLP-Dependent Amino Acid γ-Substitution Enzyme that Catalyzes C-C Bond Formation

2020 ◽  
Author(s):  
Mengbin Chen ◽  
Chun-Ting Liu ◽  
Yi Tang
Keyword(s):  
Amino Acids ◽  
Biosynthetic Pathway ◽  
Pyridoxal Phosphate ◽  
Biochemical Characterization ◽  
Indole Alkaloid ◽  
Building Blocks ◽  
Nucleophilic Attack ◽  
Keto Esters ◽  
Key Enzyme

Pyridoxal phosphate (PLP)-dependent enzymes can catalyze various transformations of amino acids at alpha, beta, and gamma positions. These versatile enzymes are prominently involved in the biosynthesis of nonproteinogenic amino acids as building blocks of natural products, and are attractive biocatalysts. Here, we report the discovery of a two-step enzymatic synthesis of (2<i>S, </i>6<i>S</i>)-6-methyl pipecolate <b>1</b>, from the biosynthetic pathway of indole alkaloid citrinadin. The key enzyme CndF is PLP-dependent and catalyzes synthesis of (<i>S</i>)-2-amino-6-oxoheptanoate <b>3</b> that is in equilibrium with the cyclic Schiff base. The second enzyme CndE is a stereoselective imine reductase that gives <b>1</b>. Biochemical characterization of CndF showed this enzyme performs gamma-elimination of <i>O</i>-acetyl L-homoserine to generate the vinylglycine ketimine, which is subjected to nucleophilic attack by acetoacetate to form the new C<sub>gamma</sub>-C<sub>delta</sub> bond in <b>3 </b>and complete the gamma-substitution reaction. CndF displays substrate promiscuity towards different beta-keto carboxylate and esters. Using a recombinant <i>Aspergillus </i>strain expressing CndF and CndE, feeding various alkyl-beta-keto esters led to the biosynthesis of 6-substituted L-pipecolates. The discovery of CndF expands the repertoire of reactions that can be catalyzed by PLP-dependent enzymes.

Synthesis of Azido Acids and Their Application in the Preparation of Complex Peptides

Synthesis ◽  
2020 ◽  
Author(s):  
Ryan Moreira ◽  
Michael Noden ◽  
Scott D. Taylor
Keyword(s):  
Amino Acids ◽  
Natural Products ◽  
Total Synthesis ◽  
Cyclic Peptides ◽  
Protecting Groups ◽  
Side Chain ◽  
Coupling Reactions ◽  
Protecting Group

AbstractAzido acids are important synthons for the synthesis of complex peptides. As a protecting group, the azide moiety is atom-efficient, easy to install and can be reduced in the presence of many other protecting groups, making it ideal for the synthesis of branched and/or cyclic peptides. α-Azido acids are less bulky than urethane-protected counterparts and react more effectively in coupling reactions of difficult-to-form peptide and ester bonds. Azido acids can also be used to form azoles on complex intermediates. This review covers the synthesis of azido acids and their application to the total synthesis of complex peptide natural products.1 Introduction2 Synthesis of α-Azido Acids2.1 From α-Amino Acids or Esters2.2 Via α-Substitution2.3 Via Electrophilic Azidation2.4 Via Condensation of N-2-Azidoacetyl-4-Phenylthiazolidin- 2-Thi one Enolates with Aldehydes and Acetals2.5 Synthesis of α,β-Unsaturated α-Azido Acids and Esters3 Synthesis of β-Azido Acids3.1 Preparation of Azidoalanine and 3-Azido-2-aminobutanoic Acids3.2 General Approaches to Preparing β-Azido Acids Other Than Azi doalanine­ and AABA4 Azido Acids in Total Synthesis4.1 α-Azido Acids4.2 β-Azido Acids and Azido Acids Containing an Azide on the Side Chain5 Conclusions

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