Samanta, Shyam S.

In this dissertation, we discuss the development of a synthetic method to functionalize various α-haloglycine esters, as key precursors to a large variety of non-proteinogenic α-amino acids (Xaas). At first, we discovered a very practical and high yielding acetyl chloride-mediated cascade reaction to synthesize α-arylated amino esters in one-pot. In this multicomponent reaction (MCR), a primary carbamate was condensed with a glyoxylate, followed by an in situ halogenation which proved essential to trigger the final Friedel−Crafts functionalization. After careful reaction optimization, a plethora of arene nucleophiles were reacted with high regioselectively in CHCl3 at low temperatures (Method A) while less activated arenes reacted more cleanly in CH3CN and at higher temperatures (Method B). To broaden the scope of this reaction to acid sensitive nucleophiles, a one-pot reaction was designed via evaporation of all acid by-products at the α-haloglycine stage. The anion-binding Schreiner’s thiourea catalyst proved to be extremely efficient to promote this complementary approach (Method C) which relies on the chloride leaving group activation by the catalyst to assist the functionalization stage and deliver the α-amino ester product.
In the second chapter, some highly practical and efficient preparations of α-haloglycine esters in one-pot have been developed to generate useful precursors of non-proteinogenic α-amino esters. Also, a mild and unique AcOH(cat.)/AcCl system was found to promote an autocatalytic-like condensation/deoxy halogenation and facilitate the multicomponent assembly of non-proteinogenic α-amino esters. Friedel–Crafts reaction between α-chloroglycine and N-methylindole have been studied in details to understand the mechanistic intricacy of this reaction. Our findings through the initial kinetic profiling support that the arylation likely proceeds via a SN1-like (or SN2C+) mechanism.
In third chapter, we discuss the development of the most challenging α,α-disubstituted amino esters in a multicomponent fashion. Our results highlight that the MCR proceeds via the formation of an enamide intermediate, which is further tautomerized to corresponding iminium to produce the desired product. In collaboration with Eli Lilly at the Automated Synthesis Laboratory (ASL), we have developed silver (I) salts mediated Friedel–Crafts reaction for synthesis of α-trifluoromethylated α-amino esters on a fully automatized robot.

Peptides and proteins with photochemical sensors
are valuable tools when analyzing biochemical processes
and peptide properties. Recent work on
fluorescent α-amino acids (FlAAs) proved extremely
useful in studying protein folding, conformational
changes and reactivity. When fluorescent tags are
appropriately attached to proteins they allow for the
detection of their environment and changes therein.
Research on the topic of site-specific fluorescent
molecules is in its early stages. Several challenges
face the topic of selectively excitable fluorescent
probes. These include limits on the size and lifetime of synthesized proteins and enzymes, attaching the
tag at the target location on a peptide chain which
will take advantage of the photochemical properties
of the tag, and developing molecules that will readily
exhibit environment-sensitive fluorescence.

In order to keep up with the high demand for
biologically active molecules, chemists devised
several synthetic strategies to access novel chemical
spaces. The two main strategies to construct new
scaffolds are to revisit underexploited or forgotten
reactions or to devise new transformations. We are
exploring a unique and underexploited reaction, the
Himbert–Henn cycloaddition, to produce complex
molecular scaffolds in a single step (strategy 1). In a
second novel approach, we are modifying the
Hantzsch 4-component reaction (4CR) by
incorporating an α-amino ester residue to construct
new molecules (strategy 2). Both of these reactions
have great potential to synthesize novel and chiral
molecules from proteinogenic α-amino esters. These
unprecedented and complex polycyclic molecules
have potential application in medicinal chemistry and
natural product synthesis. 4-aza-podophyllotoxins
obtained by the Hantzsch-4CR have been proven to
be potent as anti-leukemia, anti-colon cancer, and
vascular disrupting agents (with nanomolar activity).