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a-Amino acids (a-AAs) are among the most important and useful families of natural products. The objective of our PRF-funded research project is to develop a novel synthetic method for the chemical synthesis of a-AAs that combines classical aminomalonate alkylation/decarboxylation with modern asymmetric catalysis. Specifically, we proposed the alkylation of unsymmetrical aminomalonic esters in which one of the ester substituents is an allyl group (1). The resulting compound 1 can undergo selective decarboxylation at the allyl ester using palladium catalysis to generate an intermediate enolate 2. We further proposed that the judicious selection of a chiral ligand for the palladium catalyst and an appropriate proton source would allow enantioselective protonation of the intermediate enolate giving rise to enantiomerically enriched a-AAs 3. This strategy is operationally straightforward with the potential for a more general substrate scope than existing methods.

Significant progress has been made toward this overall objective during the first year of this project. An efficient synthesis of the target aminomalonic esters 1 was developed and substrates were synthesized in which R¹ was H, CH₃, and Bn. These substrates were subjected to treatment with Pd under a number of different conditions. With R¹ = H, it was observed that treatment with Pd and the (S)-tBu-PHOX ligand resulted in rapid deallylation, but that efficient decarboxylation to provide the desired amino acid 3 was slow and required heating to 80 ¼C. When heated to this temperature in the presence of Meldrum's acid as a proton source, the desired glycine ethyl ester was isolated in 40–94% yield, depending on the solvent used (THF = 40%, toluene = 38%, DMF = 65%, MeCN = 94%). When R¹ = CH₃, the yields were reduced (DMF = 87%, MeCN = 73%); yields were further reduced when R¹ = Bn (DMF = 45%, MeCN = 34%). These results imply that there is a possible steric effect that influences the efficiency with which decarboxylation/protonation occurs. Enantioselectivity of these reactions was poor and we hypothesize that the slow rate of protonation relative to the very rapid rate of deallylation renders the intermediate enolate decoupled from the chiral Pd/ligand complex, thus resulting in a racemic protonation event.

In addition to these studies, we treated aminomalonic esters 1 with Pd in the absence of any proton source. It was observed that C-allylation products 4 were obtained in good yields. Quaternary amino acids of this type are also highly valuable materials and thus this methodology represents a highly convenient strategy to provide access. The presence of allyl functionality provides a versatile synthetic handle for further synthetic modification. This deallylation/decarboxylation/reallylation cycle is not enantioselective. It also requires high temperature and it is likely that the deallylation and decarboxylation occur in distinct steps, with Pd dissociated from the putative enolate intermediate.

We reasoned that substrates that undergo decarboxylation more readily would facilitate the possibility of realizing this chemistry in an enantioselective fashion. One method to improve decarboxylation propensity is to decrease electron deficiency at the site of decarboxylation. In order to accomplish this we prepared cyclic phenyloxazol-5-one derivatives 5. It was reasoned that these derivatives have two advantages over the acyclic malonates: 1) decarboxylation should be more facile; 2) the putative enolate intermediate is cyclic, eliminating concerns with enolate geometry. These allyl carbonates underwent rapid deallylation/decarboxylation and, in the absence of a proton source, reallylation at the a-carbon occurs in rapidly and in high yield (>90%), providing 8. These compounds can be readily hydrolyzed under acidic conditions to give quaternary amino acids 9. We are in the process of determining the enantioselectivity of these reactions and the second year of this funding will be focused, in part, on optimizing enantioselectivity. We anticipate that this will proceed initially by ligand screening in addition to perturbation of reactions conditions.

When substrates 5 were treated with Pd in the presence of Meldrum's acid as a proton source, very little of compound 6 was isolated. Instead, it was found that reallylation to 8 was highly competitive with protonation. In the second year of this grant, we will attempt to circumvent this competitive pathway. Our initial strategy will be to rearrange 5 to 10. We will explore the reactivity of the malonate relative to the carbonate in order to assess the possibility of efficient protonation to form 6. Based on our earlier observation that aminomalonates 1 undergo reasonably efficient protonation upon deallylation/decarboxylation we wish to determine any possible differences in reactivity. If reallylation proves to be highly efficient relative to protonation, other substrate scaffolds will be explored in order to access amino acids.

Funding from the Petroleum Research Fund has had a significant impact on my research program. Our work is mainly focused on the study of peptide self-assembly processes. We routinely use nonnatural amino acids as probes to perturb these assembly processes and the development of novel and efficient methods to access amino acids synthetically will be of great value to our overall research efforts. The PRF has enabled us to undertake this work, which represents a new research direction for our group and promises to make a major impact on our program. The grant, to date, has supported the work of several students, including summer research by an undergraduate student. The grant has peripherally supported work that has resulted in three publications, and we anticipate that the major objectives of the grant will be prepared for publication in the next six months.