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1,2,3-Triazines and 1,2,3,5-tetrazines react rapidly, efficiently, and selectively with amidines to form pyrimidines/1,3,5-triazines, exhibiting an orthogonal reactivity with 1,2,4,5-tetrazine-based conjugation chemistry. Whereas the mechanism of the reaction of the isomeric 1,2,4-triazines and 1,2,4,5-tetrazines with alkenes is well understood, the mechanism of the 1,2,3-triazine/1,2,3,5-tetrazine-amidine reaction as well as its intrinsic reactivity remains underexplored. By using 15N-labeling, kinetic investigations, and kinetic isotope effect studies, complemented by extensive computational investigations, we show that this reaction proceeds through an addition/N2 elimination/cyclization pathway, rather than the generally expected concerted or stepwise Diels-Alder/retro Diels-Alder sequence. The rate-limiting step in this transformation is the initial nucleophilic attack of an amidine on azine C4, with a subsequent energetically favored N2 elimination step compared with a disfavored stepwise formation of a Diels-Alder cycloadduct. The proposed reaction mechanism is in agreement with experimental and computational results, which explains the observed reactivity of 1,2,3-triazines and 1,2,3,5-tetrazines with amidines.

Research has been conducted on anhydrolycorinone. The synthesis of this compound carried out via sequential intramolecular Doels-Alder reactions of the substituted 2-amino-1,3,4-oxadiazole is described.

Research has been conducted on the 132 (+)-1,2,9,9a-tetrahydrocyclopropa[c]benz[e]indol-4-one (CBI) analogues of CC-1065 and the duocarmycins that contain dimeric monocyclic, bicyclic and tricyclic heteroaromatic DNA-binding domain replacement. The solution-phase, parallel synthesis and evaluation of the library of these compounds have been carried out and discussed.

Research has been conducted on the series of C3-substituted 1,2,9,9a-tetrahydrocyclopropa[c]benz[e]indol-4-one (CBI) analogues of CC-1065 and duocarmycin alkylation subunits. The synthesis and evaluation of these compounds have been carried out and investigated.

The preparation and evaluation of the 5-methoxycarbonyl-1,2,9,9a-tetrahydrocyclopropa[c]benz[e]indol-4-one is reported. The comparison results of the analogues that incorporate this alkylation subunit are presented.

Results demonstrate a solution-phase synthesis of an analogue of triostin A by substituting D-serine amino acid with D-beta-aminoalanine in the natural antibiotic. Data reveal that this step facilitates solution-phase extraction and purification of the analogue.

Results reveal that the C6 methoxycarbonyl group in duocarmycin SA increases the rate and efficiency of DNA alkylation, whereas the C7 slows the reaction. The increased activity of C6 is due to its extended length for greater DNA binding. Removal of the C6 methyl ester subunit decreases the alkylation rate.

Results show that CPyI analogues possess identical DNA alkylation sequence selectivity and DNA alkylation efficiencies and are activted by metal cations. Data further suggest that even with structural changes in the alkylation subunit, CPyI analogues retain their potent cytotoxic activity.

The total synthesis of the marine natural product ningalin B uses a heteroaromatic azadiene Diels-Alder reaction, which assembles the substituents onto a six-membered 1,2-diazene core followed by a reductive ring contraction reaction to form pyrrole. Data indicate that the reaction involves a [4+2] cycloaddition of 1,2,4,5-tetrazine to the electron-rich alkyne.

The scanning and deletion synthesis of two libraries of 120 Arg-Gly-Asp mimetic compounds reveal the active constituents in the mixture combinatorial libraries in a cytotoxic assay.

Convergent solution-phase combinatorial synthesis is discussed relative to increasing diversity via rigid biaryl and diarylacetylene couplings. Solution-phase synthesis of iminodiacetic acid diamide libraries linked to aryl iodides and palladium-catalyzed dimerization has been studied. Mixtures with 64,980 components have been produced in four steps from N-BOC-iminodiacetic acid anhydride and 21 starting materials that are readily available. Sequential Stille couplings and biaryl formation are used in the synthesis.

Solvolysis pH-rate profiles of two reactive CC-1065/duocarmycin alkylation subunit analogues, N-BOC-CBQ and N-BOC-CNA, shows a reactivity ranging from pH 2 to 12. The study also demonstrated a progressively diminished vinylogous amide conjugation that leads to a corresponding increase in reactivity to conformations proposed by the DNA-bound CC1065. The results indicate that the observed CC-1065 and duocarmycin DNA alkylation reaction at pH 7.4 is not an acid-catalyzed reaction.

Analogue 7 of the duocarmycins and CC-1065 manifested increased solvolysis reactivity at pH 3. Theincrease, which is consistent with the increased electron-withdrawing properties and conjugation of thioamides relative to amides, can be attributed to a diminished vinylogous amide stabilization of the reacting alkylation subunit. Amidine 6, which underwent preferential N2 amidine linkage hydrolysis, was found to be more unstable than 7 despite the diminished electron-withdrawing properties.

A study was conducted to analyze an approach to the solution phase preparation of biaryl libraries from iodoarenes. Pd-C was utilized as a readily available supported catalyst. The isolation and purification of small library mixtures were discussed. Results indicated that the direct convergent solution phase dimerization of combinatorially assembled iodoarene building blocks supports an effective and rapid pathway to symmetrical and unsymmetrical structures.

A carbocyclic C-ring analogue of the alkylation subunits of CC-1065 and duocarmycins, 1,2,9,9a-tetrahydro-1H-cyclopropa(C)benz(e)inden-4-one, was synthesized, a key step of which was implementation of the intramolecular Heck reaction. Results of an examination of its solvolysis reactivity, regioselectivity and mechanism showed that reactivity increased by 3,200 times with the removal of the nitrogen and resulting vinylogous amide stabilization, while reversing the inherent regioselectivity. However, it left the S(sub N)2 reaction mechanism unaltered.

Oleamide is an endogenous fatty acid primary amide that possesses sleep-inducing properties in animals and that has been shown to effect serotonergic receptor responses and block gap junction communication. Herein, the potentiation of the 5-H[T.sub.1A] receptor response is disclosed, and a study of the structural features of oleamide required for potentiation of the 5-H[T.sub.2A] and 5-H[T.sub.1A] response to serotonin (5-HT) is described. Of the naturally occurring fatty acids, the primary amide of oleic acid (oleamide) is the most effective at potentiating the 5-H[T.sub.2A] receptor response. The structural features required for activity were found to be highly selective. The presence, position, and stereochemistry of the [[Delta].sup.9]-cis double bond is required, and even subtle structural variations reduce or eliminate activity. Secondary or tertiary amides may replace the primary amide but follow a well defined relationship requiring small amide substituents, suggesting that the carboxamide serves as a hydrogen bond acceptor but not donor. Alternative modifications at the carboxamide as well as modifications of the methyl terminus or the hydrocarbon region spanning the carboxamide and double bond typically eliminate activity. A less extensive study of the 5-H[T.sub.1A] potentiation revealed that it is more tolerant and accommodates a wider range of structural modifications. An interesting set of analogs was identified that inhibit rather than potentiate the 5-H[T.sub.2A], but not the 5-H[T.sub.1A], receptor response, further suggesting that such analogs may permit the selective modulation of serotonin receptor subtypes and even have opposing effects on the different subtypes.

The synthesis and evaluation of CC-2065 and duocarmycin analogues incorporating the iso-Cl and iso-CBl alkylation subunits are described. The method was founded on a directed ortho metalation of an appropriately functionalized benzene or naphthalene precursor to regiospecifically install iodine at the C-2 position. Agents were observed to exhibit potent cytotoxic activity that correlates with their inherent reactivity which is consistent with previous studies.

A novel method of synthesizing a seven-membered C-ring analog (CNA) of the alkylation subunits of CC-1065 and the duocarmycins was designed through implementation of an alternative intramolecular Heck reaction. The procedure featured the use of palladium acetate as catalyst and 1,3-dihydronaphthalene as the starting material. It was indicated that the ground state destabilization fo the substrate activated the reagent for a rate determining SN2 nucleophilic addition.

The synthesis of fully substituted vancomycin with two 16-membered biaryl ether ring systmes (CD and DE) was reported. A potential solution to the control of the atropisomer stereochemistry was also proposed. It was observed that closure to form the CD ring system provided a 1:1 mixture of atropisomers, while closure of the DE ring system showed a slight preference for the natural atropisomer.

The characteristics of intramolecular nucleophilic aromatic substitution reactions were analyzed during the synthesis of (9R, 12S)- and (9S, 12S)-cycloisodityrosine and their N-methyl derivatives. The benzylic bromination of 2-fluoro-4-methylnitrobenzene by 1,3-dibromo-5,5,-dimethylhydantoin led to the synthesis of (S)- and (R)-3-fluoro-4-nitrophenylalanine methyl ester. Furthermore, 14-membered ring macrocyclization reactions led to formation of a biaryl ether by smooth 14-membered ring closure.