Asymmetric Synthesis of Unnatural α-Amino Acids: Applications to Natural Products
|Goal: Methodology Development to Synthesize a wide Array of non-proteinogenic Xaas Applied to the Total Synthesis of sorbicillactone A and fumimycin Natural Products||Students: Krishna Yadavalli, Shyam Samantha and Marine Gosselin
Collaborator: Prof. Eric N. Jacobsen (Harvard University)
Funding: NIH-R15 (application fall 2014)
Background. Even though non-proteinogenic α-amino acids (Xaas) are essential structural motifs of proteins, non-ribosomal peptides (NRPs) and marketed drugs, and despite important gains made in recent years, a straightforward and versatile enantioselective synthesis of these molecules has yet to be established. Moreover, the case of α,α-disubstituted Xaas is extremely severe; this important class of non-proteinogenic Xaas represent today an even greater challenge to the synthesis community. Current asymmetric methods for the synthesis of non-proteinogenic Xaas (using enantioselective catalysis or chiral auxiliaries) entail several steps in addition to the key step involving the introduction of the α-stereocenter. As a general strategy to access these Xaas, we believe that multicomponent reactions (MCRs) are ideal provided they are amenable to enantioselective catalysis. In this application, we are excited to propose several innovative 3-CRs catalyzed by chiral (thio)ureas leading to non-racemic Xaas and suitable for an efficient total syntheses of (+)-sorbicillactone A and (−)-fumimycin.
Goals. For this project, we are uniquely poised to develop novel and enantioselective MCRs to access non-proteinogenic Xaas important to the synthesis non-ribosomal peptides which have proven valuable as medicinal agents. Most of the Xaas targeted in our portfolio are essential piece of some of the most utilized chiral auxiliaries and chiral ligands for asymmetric synthesis.
Future perspective. The flexibility of the method proposed in this research program will impact antibiotic peptides synthesis, site-specific peptide modifications, bioconjugation and biological imaging to provide biologists with many applications. We envision to first tackle the synthesis of some intricate antiobiotic peptides as well some small NRPs via the insertion of a fluorescent (arene) probe to demonstrate that peptides can be modified via our method for biological imaging.
- Roche*, S. P.; Samanta, S. S.; Gosselin, M. M. J. Commun. 2014, 50, 2632–2634 “Autocatalytic One Pot Orchestration for the Synthesis of α-Arylated α-Amino Esters.” Mr. Samanta was a second year graduate student and Ms. Gosselin was an undergraduate student from France in internship at FAU.
- Wasa, M.; Liu, R. Y.; Roche*, S. P.; Jacobsen*, E. N. Am. Chem. Soc. 2014, xxx, accepted “Asymmetric Mannich Synthesis of α-Amino Esters by Anion-Binding Catalysis” ja-2014-075163
- Samanta, S. S.; Yadavalli, K.; Roche*, S. P. (in preparation for Org. Chem. 2014) “Efficient and Versatile One Pot Orchestration for the Synthesis of non-proteinogenic α-Amino Esters.”
Tailoring Unnatural Peptides: an Ubiquitous Alternative to Peptide Ligation
|Goal: A 2 step method for the site specific C-terminal functionalization of peptides with high stereocontrol. Stereoselectivity induced by thiourea catalyst control vs innate peptide conformational control.||Students: Krishna Yadavalli and Shyam Samantha|
Collaborator: Prof. Eric N. Jacobsen (Harvard University)
Funding: NIH-R21 (planned submission for spring 2015)
Background. Peptide syntheses in solution (Boc chemistry) for bulk preparation of small bioactive peptides as well as solid phase synthesis (SPPS; Fmoc chemistry) have been extensively developed in the past 50 years. Yet, numerous sub-classes of peptides are untapped because of the complex nature of the amino acid residues that nature incorporates in the peptidyl backbone to achieve their biochemical functions. Therefore, there is an important need to design C- and N-terminal site specific functionalization and “a la carte” modifications of peptidyl backbones to incorporate intricate non-ribosomal residues. This proposal seeks to not only present a synthetic solution for peptide elongation, via an innovative asymmetric multicomponent approach, but also to provide an alternative entry to the classical peptide assembly lines (A) through a tailored iterative synthesis of non-ribosomal peptides (B) (Fig. 1).
Project Summary: New Twists on Old Ideas
Goals. In this project, we are poised to foster a novel and asymmetric method to elongate peptides C-terminus with non-proteinogenic amino ester residues to complement the traditional method for peptide synthesis in solution phase. This unique strategy will contribute to advancing the field of unnatural peptide synthesis by enabling the direct insertion into the peptidic backbone of unique and useful Xaa residues that would be difficult by the current methods. The synthetic approaches proposed to complement each other and will be fully exploited to achieve the synthesis of fully unnatural peptides as proof of principle for an alternative paradigm in peptide synthesis.
Development of Enantioselective α-functionalizations of peptides C-terminus. Examine incorporation of several chiral non-ribosomal residues into peptides which will be catalyzed by chiral (thio)urea H-bond donors catalysts. Several bifunctional catalysts are proposed to study enantioselective Mannich, Friedel-Crafts and allylation reactions at the peptides C-terminal residue. Catalyst-controlled transformations will be developed to overcome the peptidyl backbone innate stereoinduction. Development of an Iterative and Stereoselective Elongation of Peptides. Pursue a stereoselective site-specific α-functionalization of peptidyl C-terminal residues in an iterative manner to accomplish a peptide assembly exclusively composed of non-ribosomal units.
Future Perspective. At the completion of these studies, we expect to identify a simple and versatile stereoselective method for unnatural peptide assembly. We also anticipate that several classes of reactions discovered can be applied for the functionalization of peptides to enable the insertion of a broad array of functional groups. This “on demand” synthesis of unnatural peptides could certainly be broadly applied to the synthesis of complex peptides and glycoproteins.
Publications. Yadavalli, K.; Samanta, S. S.; Roche, S. P. (in preparation for Angew. Chem. Int. Ed. 2015) Tailoring site specific functionalization of peptides C-terminal: an alternative to chemical ligation.