A new method for the enantioselective synthesis of unusual amino acids has been developed. The chemoenzymatic aza-Achmatowicz rearrangement of appropriate furylglycine derivatives provided nitrogenous synthons that were readily converted to amino acid building blocks. An application of the new chemistry to the synthesis of the unique pyridazine carboxylic acid component of luzopeptins is presented. Luzopeptin C has potent inhibitory activity towards the reverse transcriptase of HIV as the causative agent of AIDS.

Five new metalloporphyrins, $\rm \lbrack Al\sp{III} (TPPCM)Cl\rbrack,$ $\rm \lbrack Al\sp{III} (TPPCN)Cl\rbrack,$ $\rm \lbrack Al\sp{III} (TPPC)Cl\rbrack,$ $\rm \lbrack Cr\sp{III} (TPPCM)Cl\rbrack,$ and $\rm \lbrack Cr\sp{III} (TPPCN)Cl\rbrack,$ have been synthesized and characterized as a first step toward the bulk synthesis of water-soluble C$\sb{60}\sp{.-}$ salts. According to a literature report, Cr$\rm \sp{II}$(TPP) and (Al$\rm \sp{III}$(TPP)$\sp{.-}\rbrack$ (TPP$\sp{2{-}}$ = tetraphenylporphyrinato) reduce C$\sb{60}$ to C$\sb{60}\sp{.-}$ under proper solvent conditions to form an insoluble $\rm \lbrack Cr\sp{III}(TPP)\rbrack\sp+(C\sb{60}\sp{.-})$ or (Al$\rm \sp{III}$(TPP)$\rbrack\sp+$(C$\sb{60}\sp{.-})$ salt. Here it is proposed to derivatize these Cr$\rm \sp{II}$ and Al$\rm \sp{III}$ tetraphenylporphyrins with substituents on the phenyl rings to produce water-soluble $\rm \lbrack Cr\sp{III} (TPPR)\rbrack\sp+(C\sb{60}\sp{.-})$ and $\rm \lbrack Al\sp{III} (TPPR)\rbrack\sp+(C\sb{60}\sp{.-})$ salts. Initial electrochemical data for precursor $\rm \lbrack Al\sp{III} (TPPCM)Cl\rbrack,$ $\rm \lbrack Al\sp{III} (TPPCN)Cl\rbrack,$ $\rm \lbrack Al\sp{III} (TPPC)Cl\rbrack,$ $\rm \lbrack Cr\sp{III} (TPPCM)Cl\rbrack,$ and $\rm \lbrack Cr\sp{III} (TPPCN)Cl\rbrack$ compounds suggest that adding water-solubilizing substituents does not interfere with the electron transfer between the reduced Al$\rm \sp{III}$ and C$\rm \sp{II}$ metalloporphyrins and C$\sb{60}.$ Hence, there is potential to produce bulk amounts of water-soluble C$\sb{60}\sp{.-}$ by this method. The radical anion has 150 A$\sp2$ of paramagnetic surface area (S = 1/2), and possible utility as a new magnetic resonance imaging contrast agent.

A new reaction has been discovered that forms carbon-carbon bonds at room temperature under catalysis by lanthanide reagents. This reaction occurs between vinyl ethers, which have an oxygen functionality located at the central carbon of the allylic system, and aldehydes and is catalyzed by a 1:1 complex of Yb(fod)$\sb3$ and AcOH. The primary product, 3, is not observed but becomes protected, in situ, by excess vinyl ether present as the solvent, or co-solvent, to form the observed product 4. This reaction is very general and proceeds to form pure vinyl ether products in excellent yields. The vinyl ether products formed through the use of this novel reaction can be used to quickly piece together more complex functionalities such as furanones, cyclopentanes, bromoketones, and benzazepinones. Approaches to the efficient syntheses of these compounds and others will be discussed. Phyllanthocin, 5, the aglycon of the potent antitumor agent Phyllanthoside, has been targeted for synthesis using the ene reaction. Furanone formation, using a functionalized vinyl ether formed in the ene reaction, is the primary goal. Applications to the total synthesis of Phyllanthocin will be discussed.$\sp*$ ftn$\sp*$Please refer to the dissertation for diagrams.

The total synthesis of mitomycins via isomitomycin A is described. Key reactions are a Michael-type coupling reaction between chalcone (94)* and 5-ethylthio-2-trimethylsiloxyfuran, followed by an azido-olefin cyclization. The first route took 30 steps from 2,6-dimethoxytoluene in a overall yield of 6%. The improved second route contains 26 steps with overall yield of 10% from the same staring material. Resolution of an synthetic intermediate resulted in both (+)- and ($-$)-isomitomycin A (15). X-ray crystallographic analysis of an intermediate with known chiral auxiliary which led to the natural ($-$)-isomitomycin A unequivocally determined the absolute stereochemistry of mitomycins. ftn*Please refer to dissertation for diagrams.

A new indole synthesis is described. The key step involves a novel tin-mediated free radical reaction to generate unstable 2-tri-n-butylstannyl-3-substituted indoles, which upon mild acidic workup, furnishes 3-substituted indoles. The 2-tri-n-butylstannyl-3-substituted indoles are also subjected to a one-pot Stille coupling to provide 2,3-disubstituted indoles. Two applications of the above methodology are also described. The efficient total synthesis of (${\pm})$-vincadifformine involves the construction of the indole skeleton by using this indole formation reaction and a novel amine protection-deprotection procedure as crucial steps. A new synthetic approach is explored towards the total synthesis of antitumor agent discorhabdin C. The key step towards the key intermediate has greatly contributed to the development of the novel indole synthesis methodology.

A novel synthetic route via iterative condensations of piperazinedione and substituted benzaldehydes has resulted in the first total synthesis of the complex antibiotic, renieramycin A 1a. Salient features include an acyliminium ion-mediated construction of a diazabicyclo (3.3.1) nonane nucleus, which allows for stereoselective hydrogenation and benzylic oxidation. The stereochemistry of the angelate side chain was unequivocally determined by X-ray crystallographic analysis of the penultimate intermediate, 67b. (DIAGRAM, TABLE OR GRAPHIC OMITTED...PLEASE SEE DAI)

A novel approach for the synthesis of antitumor agents Discorhabdins (1) is described. The synthetic route features a new Paterno-Buchi photo reaction for the spirocyclic ring preparation and cascade Michael reactions for the construction of pyrrolidine unit. The preparation of an advanced intermediate (2) will be discussed.(DIAGRAM, TABLE OR GRAPHIC OMITTED...PLEASE SEE DAI) A parallel investigation deals with the application of an Aza-Achmatowicz rearrangement for the synthesis of carbacephems. Both cis and trans series of bicyclic $\beta$-lactams were easily available through the Aza-Achmatowicz sequence.(DIAGRAM, TABLE OR GRAPHIC OMITTED...PLEASE SEE DAI)

The biosynthesis of the antitumor antibiotic, sparsomycin, produced by Streptomyces sparsogenes, has been investigated. Incorporation studies employing ($\sp{13}$C)-labeled precursors have shown that both L- and D-isomers of S-(methylthio)methyl-cysteine are specifically incorporated into the antibiotic. Furthermore, both L- and D-isomers of S-(methylthio)methylcysteinol are proved to be the advanced intermediates lying beyond S-(methylthio)methylcysteine. S-Methylcysteine is found not to be incorporated intact into the antibiotic; however, an isotopic trapping experiment and preliminary cell-free studies indicate that S-methylcysteine is still quite likely to be an intermediate on the pathway. A very high isotope effect was observed during studies of the loss of hydrogen atoms from the methyl group of S-methylcysteine. The uracil moiety (6) of sparsomycin is found to be derived from the indole fragment of tryptophan. N-Formylanthranilic acid was originally proposed as an intermediate lying beyond tryptophan on the pathway to 6. However, precursor incorporation studies have shown that N-formylanthranilic acid is incorporated by deformylation to anthranilic acid, which is then converted back to tryptophan before incorporation into sparsomycin. Therefore, the originally proposed pathway has to be revised. The final steps in the biosynthesis of uracil moiety are shown to be similar to the biosynthesis of xanthosine monophosphate (XMP).

Concise, efficient total syntheses of cystodytin J, diplamine and shermilamine B have been accomplished. These cytotoxic marine alkaloids display a novel pyridoacridine architecture that was readily assembled by a combination of two new processes developed in our laboratory: a pyridine-forming reaction and a photochemical insertion of a triplet nitrene into a C-H bond. The overall yield of diplamine is 12% over 7 steps. The synthesis of shermilamine B involves 11 steps with the overall yield of 8%. The first total synthesis of the antitumor agent, Micrococcin P1, a member of the biologically important family of thiostrepton antibiotics, is also described. Central to the success of this endeavor was the development of a greatly improved Hantzsch-type pyridine forming reaction. Additional chemical technologies featured in this synthesis include the use of transformations that remove the need for extensive purification of the various intermediates, the use of specially protected threonine units as precursors to the dehydroaminoacid components of micrococcin, extensive use of chemoselective thionation reactions in the presence of multiple reactive functionality, minimal protection, and closure of a 26 member ring. The longest linear sequence involves 23 steps and the overall yield along this pathway is 5.7%

Chapter I describes the stereocontrolled total synthesis of ($-$)-safracin B with antibacterial and antitumor activities. The convergent approach for the synthesis of safracin B can be readily applied to the synthesis of the related isoquinolinequinone family such as saframycins and ecteinascidins. Chapter II discusses the total synthesis of ($-$)-thiangazole, a substance with potent anti-HIV-1 activity in vitro. An efficient synthetic pathway is developed to enable diverse modification of both ends of thiangazole and thus provide a rapid access to a variety of analogs. Chapter III outlines the development of new chemistry of nitrobenzenesulfonamides, N-Boc and N-Alloc nitrobenzene sulfonamides, and alkylsulfonamides for the efficient preparation of secondary amines and protected primary amines.