Direct Conjugate Addition Of Inert Aryl Methane Nucleophiles To Enals And Design And Synthesis Of Prodrug Targeting LAT1

The dissertation contains two chapters.The first chapter presents the development of synthetic methods of enantioselective conjugate addition of inert aryl methane nucleophiles to enals with organocatalysts. The direct conjugate addition of inert aryl methane nucleophiles to construct ubiquitous chiral benzylic and related structures presents a formidable synthetic challenge. The difficulty with this class of potential nucleophiles lies in the inert nature of the methyl proton, which is difficult to be deprotonated to form an active nucleophile under a mild condition without using a strong base or high temperature. Inspired by highly nucleophilic nitroalkanes, a new strategy by "temporary" manipulation of electronic properties of reagents to create active methyl nucleophiles for reactions under mild conditions has been implemented. The introduction of the strong-electron withdrawing, versatile nitro group on the aromatic ring activates the methyl group for the effective nucleophilic conjugate addition, while it can be conveniently transformed afterwards into other functionalities. Toward this end, two new inert aryl methane nucleophiles (2,4-dinitrotoluene1c and4-methyl-3-nitro-pyridine Id) have been developed and demonstrated in the direct organoctalytic asymmetric Michael addition to a wide range of α, β-unsaturated aldehydes (50-93%yield and78-97%ee). The Michael adducts are new versatile chiral3-substituted aryl n-butanal serve as privileged scaffold. The electron nature and types (hetero-, fused-, and aryl-) of the substituents attached to the phenyl ring has limited impact on the processes. Also significant is that the less reactive aliphatic α,β-unsaturated aldehyde can be applied in the Michael processes. The "temporary" nitro group can smoothly convert into the amino or iodo group in high yields with no change of the enantioselectivity. We believe that the design strategy described in our studies will offer an effective alternative approach in the development of new C-species nucleophiles and novel chiral building blocks.The second part concerns design and synthesis of the gemcitabine prodrug targeting LAT1. LAT1(large amino acid transporter-1) mainly transport branched chain amino acids and aromatic amino acids. Because LAT1was highly expressed on the BBB and within the tumor cells, and higher than the other tissue of the organism, LAT1was endowed with some unique advantages and target specificity as a target of brain tumor. Therefore LAT1is very suitable as a brain tumor-targeting prodrug transporter. The gemcitabine is a clinically used anticancer drugs, and has been confirmed having good therapeutic potential in the brain tumor. But gemcitabine has not shown satisfied result in the treatment of brain tumors only for BBB. So gemcitabine is regarded as perfect parent drug for designing LAT1transporter prodrug. Considering structural diversity of substrate, synthetic accessibility, and commercial availability, four prodrugs (A-1, A-2, B-1and B-2) containing specific large amino acids in4-amino and5-hydroxymethyl positions, respectively, are designed and synthesized successfully. The structures of these four prodrugs were identified by’H-NMR and (HR and LR) MS. This paper can provide the appropriate lead compounds for the development of LATI-targeting prodrugs for treatment of the brain tumor, an alternative solution for which anticancer drugs are usually difficult to reach the brain tumor. Some assays, such as binding affinity between prodrug and LAT1, stability and rate of biodegradation of prodrug in vitro, and the drug concentration in the brain tumor site, are being pursued in our laboratories.