Presentation Title

Diastereoselective Synthesis of Unnatural Amino Acids via Auxiliary-Directed Enolate Alkylation

Faculty Mentor

Jeffrey S. Cannon

Start Date

17-11-2018 12:30 PM

End Date

17-11-2018 2:30 PM

Location

CREVELING 99

Session

POSTER 2

Type of Presentation

Poster

Subject Area

physical_mathematical_sciences

Abstract

We aim to diastereoselectively synthesize unnatural amino acids (UAAs) by incorporating chiral auxiliaries into substrate compounds prior to performing enolate alkylations. Diastereoselective synthesis of UAAs is worthwhile because the difference in the stereochemistry of a biological molecule dictates its biochemical significance, and selectively synthesizing a specific geometric configuration may prove useful in further studies in biology as well as in pharmaceutical pursuits. To achieve this, our project uses the commercially available and easily synthesized tert-butanesulfinamide auxiliary developed by Ellman. The hypothesis is that the attachment of this chiral auxiliary, followed by an enolate alkylation at the alpha-carbon, followed by the subsequent removal of said auxiliary theoretically affords a diastereomerically enriched product. Previous studies conducted on the scope of stereoselective sulfinamidoester alkylation has shown promising results both in terms of yield and diastereomeric ratios. The immediate next step taken towards diastereoselective synthesis of unnatural amino acids was to investigate the ability of the chiral substrate to control multiple stereocenters. Initial attempts at the aldol reaction and the Ireland-Claisen rearrangements have been challenging, with results showing some promise for future success in optimization and improvements in diastereomeric ratios. We expect that the optimized conditions for the alkylation will serve as the key to unlock the potential of the diastereoselective synthesis for a greater scope of alpha-substitution.

Summary of research results to be presented

We have decided to invest time on the application of the glycine derivative due to its relatively high yield that results in a greater number of trials per synthesis. Its syntheses involves reductive amination followed by reduction using L-Selectride. However, I found that the L-Selectride reductions were not providing me with satisfactory or even consistent yields. In search for a better method, I turned to sodium borohydride (NaBH4) as the alternative reducing agent. Newly optimized conditions of higher yielding synthesis of the glycine derivative allowed us to run more reactions per substrate synthesis. Investigation of the aldol reaction began with reaction conditions similar to the proof-of-concept diastereoselective alkylation reactions. Crude NMR data showed signs of possible product formation, the introduction of two new stereocenters substantially increased the number of peaks, making it difficult to identify the product. With further characterization we found that we were able to make at least two enantiomers from this reaction with NaHMDS serving as the base and benzaldehyde serving as the aldehyde. The Ireland-Claisen rearrangement relies heavily on a chelating metal to form a highly coordinated intermediate; this preserves the enolate’s structural integrity as it warms to ambient temperatures necessary for the rearrangement. All attempts thus far have been futile, with the NMR spectra showing primarily starting material a regeneration of cinnamyl alcohol. For those reactions that leave starting material in the reaction mixture, the issue might be in the generation of the enolate. This issue might be solved by increasing the base equivalence or even trying different bases. What I saw the most, however, was the generation of cinnamyl alcohol. This may imply an enolate intermediate that is not sufficiently coordinated for rearrangement at ambient temperatures. For this, an exploration for a better chelating metal or metal additive equivalence may be necessary.

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Nov 17th, 12:30 PM Nov 17th, 2:30 PM

Diastereoselective Synthesis of Unnatural Amino Acids via Auxiliary-Directed Enolate Alkylation

CREVELING 99

We aim to diastereoselectively synthesize unnatural amino acids (UAAs) by incorporating chiral auxiliaries into substrate compounds prior to performing enolate alkylations. Diastereoselective synthesis of UAAs is worthwhile because the difference in the stereochemistry of a biological molecule dictates its biochemical significance, and selectively synthesizing a specific geometric configuration may prove useful in further studies in biology as well as in pharmaceutical pursuits. To achieve this, our project uses the commercially available and easily synthesized tert-butanesulfinamide auxiliary developed by Ellman. The hypothesis is that the attachment of this chiral auxiliary, followed by an enolate alkylation at the alpha-carbon, followed by the subsequent removal of said auxiliary theoretically affords a diastereomerically enriched product. Previous studies conducted on the scope of stereoselective sulfinamidoester alkylation has shown promising results both in terms of yield and diastereomeric ratios. The immediate next step taken towards diastereoselective synthesis of unnatural amino acids was to investigate the ability of the chiral substrate to control multiple stereocenters. Initial attempts at the aldol reaction and the Ireland-Claisen rearrangements have been challenging, with results showing some promise for future success in optimization and improvements in diastereomeric ratios. We expect that the optimized conditions for the alkylation will serve as the key to unlock the potential of the diastereoselective synthesis for a greater scope of alpha-substitution.