No description available.

No description available.

No description available.

No description available.

No description available.

3-Phenyl-2,3-dihydro-1,2-benzisothiazole 1,1 dioxide (NSC108406), identified as an HIV-1 reverse transcriptase inhibitor, is chosen for lead optimization. A series of analogues are docked using SYBYL FlexiDock into both wild-type (wt) reverse transcriptase (RT) and Tyr181 --> Cys181 (Y181C) RT, from the dataset of efavirenz (Sustiva®) bound to the enzyme. Minimizations using genetic algorithms are performed, and the lowest energy conformations are evaluated. Five structures emerge as good fits either in both enzymes or only in Y181C RT. 3-(m-Cyclopropylphenyl)- and 3-(isopropylfuranyl)-2-methyl-2,3- dihydro-1,2-benzisothiazole 1,1-dioxides do not exhibit improved binding in wt RT over efavirenz. In the Y181C pocket, the furanyl ring oxygen is oriented towards Cys181, and the cyclopropyl group on the phenyl ring makes a strong contact with Tyr183. Three 3-(alkylethynyl)-2,3-dihydro-2-methyl-1,2-benzisothiazole 1,1-dioxides (ethynyl sultams) make very good contacts in both wt and Y181C RT. Synthesis of the ethynyl sultams is attempted using the appropriate alkylethynyllithium reagents with saccharin, but 3,3-bisalkylethynyl-2,3-dihydro- 1,2-benzisothiazole 1,1-dioxides are the principal products. These are methylated to give the bisalkylated sultams. When docked into wt RT, they are consistently placed outside the pocket. In Y181C RT they make similar contacts to nevirapine, a first-generation NNRTI. 3-Chloro-1,2-benzisothiazole 1,1-dioxide is then coupled to the alkylethynyllithium reagents to give the desired monosubstituted products. (R,R)-N-(p-tolunesulfonyl)-1,2-diphenylethylenediamine-rhodium- (pentamethycycopentadienyl)-Cl [(R,R)-TSDPEN-Rh-Cl], an enantioselective catalyst for the reduction of imines, is used in an attempt to produce optically active sultams; however, the products are not optically active. The cyclopropyland cyclobutylethynyl bonds are reduced to the corresponding alkanes. These new cycloalkylethyl sultams, when docked into RT, exhibit a better fit in Y181C than wt RT, similar to that of efavirenz. In a study on the mechanism of the enantioselective reduction of 3-alkylor aryl-imines by (R,R)-TSDPEN-Rh-Cl, a number of imines are docked into the catalyst cavity in two different approaches using the “original” approach that gives the observed enantioselectivity and the “reverse” approach, which is thought to give the opposite enantiomer. Molecular dynamic studies are carried out. In all 3-(aryl/alkyl)imine sultams, an average of at least 10 kcal/mol energy difference is observed between both approaches, showing probable structures for the intermediate complex in the catalytic cycle that accounts product stereochemistry.

The development of synthetic receptors capable of high-affinity complexation of biologically relevant analytes in competitive solvent systems represents an ongoing challenge in molecular recognition. Anion recognition is particularly problematic, which is significant since numerous biological processes are regulated by anions, such as those resulting from phosphorylation. In this dissertation, we present the design and synthesis of a fluorescent sensor containing two cyclen groups that are preorganized to form a binding cleft for anion complexation. The receptor design includes a rigid acridine backbone, which is also exploited for fluorescence signal transduction. Furthermore, click chemistry is employed to facilitate receptor synthesis, and binding studies with various phosphorylated guest molecules are described. Additionally, the development of boronic acid-based carbohydrate receptors is presented. Carbohydrates play important roles in a large number of biochemical processes such as signal transduction and cell surface recognition events. The receptors will be used to study carbohydrate binding through Förster resonance energy transfer (FRET) and surface enhanced Raman spectroscopy (SERS). Another project involves the synthesis of aromatic compounds that can act as auxin herbicides. Auxins are plant hormones that play a major role in the regulation of plant growth and development. A modular synthetic strategy is employed to access a library of small molecules that will be tested for herbicidal activity on a variety of weeds. Finally, the work on the design and synthesis of molecular building blocks to generate covalently-bonded ordered organic frameworks is discussed.

This thesis deals with the development of syntheticmethodologies for the preparation of enantio- anddiastereomerically enriched nitrogen-containingheterocycles. Asymmetric Lewis acid mediated Diels-Alder reactions with2H-azirines as dienophiles have been studied.Diastereoselective reactions with enantiomerically pureauxiliary-derived 2H-azirines afforded substituted bi- andtri-cyclic azaheterocycles comprising a fusedtetrahydropyridine–aziridine moiety in high yields andselectivities. It was found that the 8-phenylmenthol auxiliarywas superior to Oppolzer’s bornane-2,10-sultam in thesereactions. The influence of various Lewis acids on the reactionoutcome was probed and their presence was crucial forsuccessful reactions. The novel enantioselectiveaza-Diels-Alder reaction of benzyl- 2H-azirine-3-carboxylatewas investigated with a range of chiral Lewis acids andprovided the corresponding cycloadducts in moderate to lowyields and selectivities. The 2H-azirines were synthesized fromthe corresponding acrylates via the vinyl azides. An improvedand general procedure for thermolysis of vinyl azides into2Hazirines was developed. Lewis acid mediated radical cyclizations of substitutedN-chloro-4-pentenyl- and 4- hexenylamines gave thecorresponding pyrrolidines in high yields and in moderate tohigh diastereoselectivities. The reactivity andstereoselectivity were found to be strongly influenced by thesubstituents on the alkenylamine. On the other hand, noapparent correlation between the different Lewis acids appliedand the obtained selectivities was observed. The relativestereochemistry of the cyclic products could be predicted usingthe Beckwith-Houk stereochemical model. The pyrrolidines wererearranged via aziridinium ions, which were ring-opened to thecorresponding piperidines. The efforts to developenantioselective radical cyclizations of cationic aminylradicals proved unsuccessful. Reaction conditions and chiralLewis acids were varied, yet, racemic product mixtures wereobtained. The N-chloro-N-alkenylamines were synthesized in goodyields. <b>Keywords:</b>diastereoselective, enantioselective,alkaloid, Lewis acid, chiral ligand, hetero-Diels-Alderreaction, 2H-azirine, aziridine, tetrahydropyridine, chiralauxiliary, vinyl azide, radical cyclization, cationic aminylradical, pyrrolidine, piperidine, aziridinium ion,N-chloro-N-alkenylamine.

This document describes a synthetic approach towards the tricyclic unit contained within the natural product halichlorine based upon a semipinacol rearrangement reaction as a key transformation. A number of synthetic approaches involving the synthesis of halichlorine and the structurally related compounds pinnaic acid and tauropinnaic acid have been published; this work is described in chapter 1. In chapter 2, a detailed account of our first approach towards the tricyclic core of halichlorine is described. This approach involves formation of one of the rings of halichlorine by a ring closing metathesis reaction. To achieve this goal, a new, modified version of Grubbs’ “second generation” ring closing metathesis catalyst was synthesized. This catalyst exhibits high reactivity and successfully closed a 6-membered ring in a compound that contains structural features similar to those found in halichlorine. Our approach towards the synthesis of the tricyclic core of halichlorine led to the development of a new method to form 6-azaspirocyclopentanones. When piperidine-based allylic cyclobutanols are treated with N-bromosuccinimide, a ring expansion reaction takes place that results in the formation of highly functionalized 6-azaspirocyclopentanones. These high yielding, diastereoselective reactions were successful with several ring expansion substrates. The synthesis of the ring expansion substrates led to the development of a new method to construct alkenyl stannanes from isolated enol triflates using lithium trimethylstannyl copper (I) cyanide reagent. The semipinacol rearrangement reactions outlined in chapter 2 gave products with the incorrect relative configuration required for halichlorine. These results led to the development and implementation of a new asymmetric synthetic sequence towards the tricyclic core of halichlorine that is discussed in chapter 3. This synthetic sequence involves the N-bromosuccinimide promoted ring expansion reaction of a piperidine-based allylic cyclobutanol that contains a substituent on the cyclobutane ring. This ring expansion reaction resulted in the formation of a densely functionalized azaspirocyclopentanone that contains four of the five stereocenters and two of the four rings required to make halichlorine. Ultimately a late stage intermediate was achieved in 22 steps (longest linear sequence) from 1,3-propanediol.

This document describes a synthetic approach towards the tricyclic unit contained within the natural product halichlorine based upon a semipinacol rearrangement reaction as a key transformation. A number of synthetic approaches involving the synthesis of halichlorine and the structurally related compounds pinnaic acid and tauropinnaic acid have been published; this work is described in chapter 1. In chapter 2, a detailed account of our first approach towards the tricyclic core of halichlorine is described. This approach involves formation of one of the rings of halichlorine by a ring closing metathesis reaction. To achieve this goal, a new, modified version of Grubbs second generation ring closing metathesis catalyst was synthesized. This catalyst exhibits high reactivity and successfully closed a 6-membered ring in a compound that contains structural features similar to those found in halichlorine. Our approach towards the synthesis of the tricyclic core of halichlorine led to the development of a new method to form 6-azaspirocyclopentanones. When piperidine-based allylic cyclobutanols are treated with N-bromosuccinimide, a ring expansion reaction takes place that results in the formation of highly functionalized 6-azaspirocyclopentanones. These high yielding, diastereoselective reactions were successful with several ring expansion substrates. The synthesis of the ring expansion substrates led to the development of a new method to construct alkenyl stannanes from isolated enol triflates using lithium trimethylstannyl copper (I) cyanide reagent. The semipinacol rearrangement reactions outlined in chapter 2 gave products with the incorrect relative configuration required for halichlorine. These results led to the development and implementation of a new asymmetric synthetic sequence towards the tricyclic core of halichlorine that is discussed in chapter 3. This synthetic sequence involves the N-bromosuccinimide promoted ring expansion reaction of a piperidine-based allylic cyclobutanol that contains a substituent on the cyclobutane ring. This ring expansion reaction resulted in the formation of a densely functionalized azaspirocyclopentanone that contains four of the five stereocenters and two of the four rings required to make halichlorine. Ultimately a late stage intermediate was achieved in 22 steps (longest linear sequence) from 1,3-propanediol.