Organic compounds--Synthesis

In the present dissertation, we discuss the development of a stereoselective method for the production of phosphorus compounds that utilizes a phospha-Michael addition reaction. Separately, the design and synthesis of compounds that contain an all-carbon bridged bicyclic scaffold is reported; these compounds were used in initial SAR studies in different in vivo models. In Chapter one is presented a mechanistic framework to develop a highly diastereoselective method catalyzed by phase transfer chemistry leading to phosphinate compounds. In this method, phosphinate nucleophiles were added to various alkenyl ketones as Michael acceptors using crown ethers as phase transfer agents to obtain highly diastereoselective products with the generation of a carbon-based quaternary centers. A closed transition state mechanism is proposed to describe the diastereoselectivity observed in the reactions that is consistent with product outcome as established by X-ray crystallography. Analysis using the 31P NMR technique is also reported to ascertain the diastereomeric ratios in product formation. Using products obtained with the newly developed method, we disclose for the first time a novel phospha-heterocycle with high control of stereochemistry. Relative stereochemistry of the phosphorus containing heterocycle was reported using 2D NMR analysis. In Chapter two focus is placed on the use of acrylates as Michael acceptors in both the diastereoselective and enantioselective studies of phospha-Michael addition. In the asymmetric method development, screening of various chiral catalysts and development of HPLC method to quantify the enantiopurity of products obtained under reaction conditions are reported. The role of crown ether catalysts towards diastereoselectivity is reported.

In this dissertation the synthesis, characterization, and binding properties of
carbohydrate receptors 34-38 was described. Macrocyclic receptor 34 and macrobicyclic
receptor 35 bind monosaccharides in aqueous media through combination of
hydrophobic, electrostatic and hydrogen bonding interactions. The dissociation constants
(Kd) for the complexes between 1 ,8-naphthyridine receptors 34, and 35 with a variety of
neutral and negatively charged monosaccharides in aqueous media were determined by
fluorimetric and UV /vis titration. The observed values are in the range from ~0.3 to >10
mM, within the Kd range reported for lectin/monosaccharide complexes. However,
among monosaccharide substrates tested receptor 34 showed the strongest affinity for
sialic acid (Kd = ~0 . 3 mM), a monosaccharide that plays many important roles in a wide
variety of physiological and pathological processes. Macrocyclic receptor 34 recognizes not only sialic acid in solution, but also binds selectively in vitro to human
cancer cell surface carbohydrate antigens containing terminal sialic acid moieties. In
addition, besides their binding selectivity, receptors 34 and 35 display also the ability to
discriminate between closely related monosaccharide substrates by opposite variation of
the fluorescence emission intensity. Structure-binding relationship study of receptor 34
revealed that H-bonding donor/acceptor pattern and presence of positive charge on
receptor's side arms are crucial for selective monosaccharide binding in aqueous media.

The results we have obtained indicate that the common procedure of utilizing of the mythical Wittig half-reaction to theoretically describe the mechanism of the Wittig olefination reaction does not give consistent results when electron correlation is taken into account in the model hamiltonian. We propose that the reaction of Me3P=CH2 with formaldehyde is the smallest system that can be used to properly model the Wittig olefination reaction. The best compromise between accuracy and computational expense is to compute the molecular geometries with the HF/6-31G* methodology and the energy at the MP2/6-31G*/HF-6-31G* level. We applied the methodology that we have developed to the study of reaction of a series of stabilized, semistabilized and unstabilized ylides with acetaldehyde.

We report the development of a novel hetero-Diels-Alder reaction involving the use of allenyl carbonyls as heterodienes. We have described the synthesis of a variety of allenyl carbonyls via a base promoted and manganese mediated isomerization of alkynyl carbonyls for use in methodology studies. In our model studies, a variety of enamines were utilized effectively as dienophiles to form "hydrolyzed" Diels-Alder adducts while investigating optimal reaction conditions. Initial studies towards the synthesis of an allenyl ester tethered to an aldehyde for an eventual application in an intramolecular Diels-Alder reaction were performed. Possible mechanisms were proposed while computational studies were performed in attempt to rationalize product selectivity.

The conversion of alkynyl carbonyls to allenyl carbonyls via manganese mediated coordinations followed by a based-catalyzed isomerization was carried out using a range of chiral and achiral amine bases. In this work we employed HPLC equipped with a chiral column to determine the enantiomeric excess. Deuterium labeling experiments suggested that the alkyne/allene rearrangement reaction involved an intermediate cumenolate. We also demonstrated that the reaction required a ligand on manganese for an amine base to be used catalytically. Phosphines were tested as a possible ligand because they are neutral two electron donors that binds to transition metals through their lone pairs. It was observed that the rate of the reaction decreased from 24hr to 3hr by use of phosphine as a ligand. It was also confirmed that amine base with pKa lower then DBU (pKa = 13.6) would not carry out the isomerization. Chiral amidine and chiral DBU derivatives were synthesized to carry out the isomerization enantioselectively. Alkoxy base were also used in isomerization that demonstrated enantioselectivity.