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There are notable differences in reactivity between arylpalladium(II) intermediates generated by carboxylative palladation and those produced in conventional Heck reactions. The more electron-rich alkenes react preferentially with an arylpalladium(II) trifluoroacetate intermediate formed by decarboxylative palladation whereas an opposite trend is found in conventional Heck reactions.

The use of pseudoephedrine as a chiral auxiliary in asymmetric alkylation reactions was investigated. Enolates of pseudoehedrine amides were observed to undergo efficient and highly selective alkylations with a wide range of alkyl halides to yield alpha-substituted products in high yields. These alkylation products were transformed into highly enantiomerically enriched carboxylic acids, alcohols, ketones, and aldehydes.

An efficient, enantioselective synthetic route to (+)-dynemicin A was developed. It starts with the condensation of (-)-menthyl acetoacetate and trans-ethyl crotonate, which yields the crystalline cyclohexanedione. This is then converted to the enantiomerically pure quinone imine in a 23-step process. The most significant step involved in this route was the Diels-Alder cycloaddition of the quinone imine with the isobenzofuran, after which an oxidative workup was performed to generate (+)-dynemicin A in 40% yield. The route allows different structural analogs of (+)-dynemicin A.

The significance of carbohydrate residues relevant to nucleic acid recognition and/or damaging events by the aminoglycoside antitumor agent, neocarzinostatin (NCS) chromophore, was investigated by performing DNA cleavage experiments for NCS and its corresponding aglycon, supplemented by high performance liquid chromatography. The results showed that the carbohydrate residues of the NCS both accelerate the rate and improve the efficiency of DNA cleavage. It did not, however, prove to be the major determinant of the base specificity of DNA cleavage.

A new synthetic route to D- and L-alpha-amino-acids, N-protected alpha-amino acids, and N-methyl-alpha-amino acids is described. The procedure is based on the asymmetric alkylation of pseudoephedrine glycinamide or pseudoephedrine sarcosinamide prepared from pseudoephedrine and glycine methyl ester or sarcosine methyl ester, respectively. The alkylation proceeds efficiently with various alkyl halide substrates to yield highly diastereoselective products. The latter undergo hydrolization to afford salt-free and enantiomeric alpha-amino acids or N-protected analogs such as N-Boc or N-Fmoc.

Thermolysis of 2-methylbenzothiophene and (C5Me5)Rh(PMe3)(Ar)(H) generates a single C-S insertion product and a C-H activation product due to the insertion of rhodium into S-C bond adjacent to the methyl substituent (2k). Continuous heating of the resulting compounds produces an isomer of 2k, in which metal has inserted into the C-S bond adjacent to the aryl moiety by intramolecular pathway. The insertion occurs through a symmetrical S-bound adduct and the activation of C-H through an eta5-coordination to the thiophene.

The synthesis of (plus or minus)-7,8-epoxy-4-basmen-6-one demonstrates a new efficient technique for the production of basmene ring system by the process of macrocyclic free-radical cyclization. The compounds produced exhibit a large extent of stereoselectivity. The new technique reveals that the transition-state molecular modeling for designing such artificial techniques for basmene ring formation is highly productive.

Tunicamycin antibiotics and its C5'-epimes are synthesized on employing a concise synthetic route. Carbon-carbon bonds are efficiently formed in this synthetic route and involves the reductive coupling of aldehydes and allylic alcohols mediated by silicon. This coupling is compatible with sensitive trehalose glycoside linkage in tunicamycins.

Analysis of the neocarzinostatin chromophore-induced cleavage of double-stranded DNA reveals that a chromophore-derived cumulene and a biradical are intermediates of the cleavage. Addition of thiols to the chromophore is the rate-determining step at specific physiological concentrations and pH. Addition of thiols glutathione or cysteine involves a pathway that includes a ternary DNA complex, thiol and chromophore.

The calicheamicin gamma1 and glutathione reaction in the presence of double-stranded DNA yields four products generated by S-S bond exchange. The calicheamicin gamma1 bisulfide group and glutathione thiol function react to give the S-S bond product. There is no evidence of DNA catalysis of thiol function in water.

A concise synthetic route to the synthesis of tunicamycin is presented. The route leads to aminopolyol which may be selectively N-acylated to provide a variety of homologous tunicamycin antibiotics in pure form. Aminopolyol was coupled with a suitably protected uridine 5'-aldehyde derivative to form the C5'-C6' bond which participates in the highly convergent manner of assembling the complete antibiotic structure of tunicamycin.

Thermal rearrangement of compounds containing the (Z)-1,2,4-heptatrien-6-yne functional group leads to aromatic product formation. The electrocyclization reaction forms alpha, 3-dehydrotoluene or corresponding derivatives. This intermediary product is a singlet sigma, P1-biradical with marked polar nature that is divided between polar and free radical pathways. The generating medium and biradical substitution influence the above process.

An unambiguous, enantioselective synthesis of the chromophore component of the cytotoxic protein-chromophore complex kedarcidin is reported. The analysis has shown that the natural kedarcidin chromophore is a single atropisomer, whereas the oriented molecule is a mixture of atropisomers in two different NMR solvents.

A second, enantioselective synthetic route to N1999A2 is described that proceeds by the convergent assembly of the (1-iodovinyl) stannane, the 1,5-hexadiyne-3,4-diol derivative and the substituted naphthoic acid. N1999A2 could be left in the air for 10 minutes in the solid state, at ambient temperature without evident decomposition by subsequent [super 1]H NMR analysis and solutions of N1999A2 in ether or DMSO is stored at -25 degree C for 2 months without detectable decomposition by HPLC analysis.

Research has been conducted on kedarcidin, a chromoprotein antiproliferative agent. The dynamic behavior of the kedarcidin chromophore has been investigated and the results are presented.

Research has been conducted on the terpestacin and fusaproliferin. The synthesis of these compounds carried out via the stereoselective enolate alkylation reactions is described.

The mechanisms involved in the reaction of the (S)-prolinol-derived O-silyl ketene N,O-acetal with aromatic aldehydes are investigated. Experimental data support a proposed scheme which involves the attack of benzaldehyde on the N,O-acetal, which produces a structure with an apically-bound aldehyde. The structure undergoes pseudorotation and C-C bond formation to give the (2S,3R)-anti aldol product.

A synthetic sequence is described that has allowed the preparation of optically active trans-1,2-diol monosilyl ether derivatives from ketones, providing new means for retrosynthetic simplification of differentiated diol and polyol targets. The sequence has involved silyl enol ether formation, Shi asymmetric epoxidation and then regio- and stereospecific addition of hydride, methide, or higher alkylide.

Tetracyclines and tetracycline analogues are prepared by a single-step Michael-Claisen condensation of AB precursor with D-ring precursors of wide structural variability, which is followed by removal of protective groups. The platform for tetracycline synthesis has provided access to a broad range of molecules that is inaccessible by semisynthetic methods and has provided a powerful engine for the discovery and development of new tetracycline antibiotics.

The pseudophedrine as a chiral auxiliary was used to described the practical methods for the stereocontrolled construction of [alpha]-quaternary carbon centers. The oxazolium triflate derivatives developed for the analysis of diastereomeric ratios could find potential application as reactive intermediates for the synthesis of both methyl ketones and aldehydes.

The binding of the natural product avrainvillamide to the oncoprotein nucleophosmin is discussed. The results show that nucleophosmin is highly efficient in suppressing the protein regulating tumor in humans.

The process by which dimeric alkaloid stephacidin B and the monomeric alkaloid avrainvillamide work equally within empirical error to inhibit the yield of four varying human cancer cell lines is described. It is demonstrated that the percentage of the monomer is much higher than that of the dimer in the medium of incubation and that the half-life for the change of stephacidin B as compared to avrainvillamide is short in relation to the half-life of cell division.

A second synthesis of (-)-tetracycline, proceeding in 17 steps from benzoic acid is reported. A demonstration that AB precursor can also be transformed into (-)-tetracycline in seven steps is presented.

An enatioselective synthesis of avrainvillamide is described. It was observed that (-)-avrainvillamide undergoes spontaneous dimerization to form (+)-stephacidin B in the presence of triethylamine.

Practical chemistry for the preparation of N-tert-Butyldimethylsilylhydrazones (TBSH) derivatives is developed from carbonyl-containing compounds. It was indicated that these products have greatly enhanced stabilities relative to simple hydrazone derivatives and they act as superior alternatives to simple hydrazones in Wolff-Kishne-type reduction reactions.

The synthesis of the alkaloids avrainvillamide and stephacidin B is presented. The resulting 3-alkylidene-3H-indole 1-oxide group is identified as a function capable of reversible covalent bond formation with heteroatom-based nucleophiles.

The successful adaptation of prior solution-phase synthesis of saframycin A(sub 5) to a 10-step solid-supported synthesis suitable for the preparation of large number of diverse saframycin analogues with deep-seated structural modifications is presented.

The development of a palladium-catalyzed decarboxylative coupling reaction of arene carboxylates with olefinic substrates is described. A large number of palladium sources, as well as other metals, were screened for their ability to promote the decarboxylative coupling of 2,4,5-trimethoxybenzoic acid with styrene.

A convergent, enantioselective synthetic route to the natural product neocarzinostatin chromophore is discussed. The developed synthetic plan can be readily modified for the preparation of singly and doubly radiolabeled neocarzinostatin chromophore when other means are unavailable for the study of the mechanism of action of neocarzinostatin in vivo.

The realization of the objectives in a synthetic route to (-)-quinocarcin is described and the major bond formations are achieved using simple condensation reactions of alpha-amino aldehyde derivatives. Results reveal the synthetic sequence to (-)-quinocarcin developed and employs as starting materials the N-protected and C-protected alpha-amino aldehydes components.

The synthesis of diazoalkanes by the oxidation of N-tert-butyldimethylsilylhydrazones with (difluoroiodo) benzene has been described. When conducted in presence of a carboxylic acid substrate, the oxidation leads to efficient esterification in situ.

Bishydroquinone derivatives of (-)-saframycin A were synthesized and evaluated to determine antiproliferative activity.

Research into the existence and reactivity of free alpha-amino aldehydes as chemical intermediates is discussed.

A study developed a novel series of C-protective groups for alpha-amino acid aldehydes based upon the amino nitrile function. The experiment relates to research to develop an enantioselective route to the saframycin antibiotics. It will be shown that the synthesized C-protected alpha-amino aldehyde components can be synthesized with high enantiomeric enrichment and can be coupled with N-protected alpha-amino aldehydes in directed condensation reactions while maintaining a high degree of optical purity in the process.

Research was conducted to show that saturated (sp3-hybidized)alkyllithium reagents add to N-tert-butyldimethylsilyl aldehyde tosylhydrazones at -78 degrees C. Another objective was to prove that the resulting adducts can extrude dinitrogen in a free-radical process resulting in a net reductive coupling reaction that often proceeds with remarkable overall efficiency. Results indicate that the approach used offers an efficient construction of sigma bonds to quaternary and aromatic centers not possible through olefination-hydrogenation routes.

An enantioselective synthesis of (+)-neocarzinostatin chromophore aglycone ((+)-2)5 is presented. The final step of the process involved a new reductive deoxygenation of the epoxy alcohol using triphenylphosphine, iodine, and imidazole. The introduction of a low-temperature (-10 degrees C) methanol quench and the use of chromatographic and extractive isolation methods at 4 degrees C modified the transformation. Results suggest that the Schmidt glycosylation can be performed in the presence of a free amino group.

The Barton deoxygenation reaction is widely used in synthetic organic chemistry. A new method for the reductive deoxygenation of unhindered primary and secondary alcohols, proceeding in a single step and without the use of metal hydride reagents, is reported. The method proceeds by Mitsunobu displacement of alcohol with o-nitrobenzenesulfonylhydrazine, followed by o-nitrobenzene-sulfinic acid in situ elimination.

An enantioselective approach to the synthesis of neocarzinostatin chromophore aglycon is described. The substance is a difficult synthetic target due to the strain, structural complexity and high reactivity of the chromophore core. The allylic transposition problem can be avoided by epoxidation of the five-membered ring olefin in a modification of an earlier strategy. Epoxidation also retains a favorable trajectory for the intramolecular acetylide addition reaction and delays until the final stage many of the instability issues which beset earlier strategies.

Neocarzinostatin (holo-NCS) chromophore (1) reacts with small thiols, such as beta-mercaptoethanol (BME), to form a protein-directed BME adduct. This adduct is a hydroxy-isochrome derivative which contains 17 methines and 13 quaternary carbons. A hemiacetal group is present at C5 of the adduct. In 1, transannular nucleophilic, addition to the triple bond and protonation at the vinyl carbanion lead to the substituted alpha,3-dehydrotoluene biradical. Fragmentation of this biradical produces one benzylic radical which reacts with water to give the hydroxy-isochrome derivative, hydroxyisochromene.

Propargylic alcohols are used to prepare a large number of stereospecific allenes and its derivatives via a one-step stereospecific reaction process. The reaction pathway involving a faster Mitsunobu inversion is faster than decomposition of the intermediate 1-alkyl-1-o-nitrobenzenesulfonylhydrazine (NBSH) and gives maximum yield while maintaining the stereospecificity. The allene formed from the corresponding substrate is independent of any contamination by the opposite diastereomer.

A new method for the synthesis of D- or L-alpha-amino acids involving direct alkylation of (+)- or (-)-pseudoephedrine glycinamide is described. The hydrolysis of the alkylation products occurs rapidly in the presence of sodium hydroxide in water or water-methanol mixtures at reflux. The rate of alkaline hydrolysis of alpha-amino amides is much faster than of their hydrocarbon counterparts.

A study of DNA-cleaving and binding properties of dynemicin A and its synthetic homologs shows that E-ring hydroxyl groups are necessary for binding and the carboxylate group destabilizes the DNA-drug complex and help in the DNA cleavage process. After 12-h of reaction period, dynemicin methyl ester and its homologs are unable to produce DNA cleavage. Before reductive activation, the binding between dynemicin and DNA must break.

A synthetic enantioselective pathway involving desilylation, oxidation and deprotection enables the synthesis of quinone imines, which serve as precursors to natural and nonnatural dynemicins. Use of a chiral auxillary/resolving agent, menthol, facilitates enantiodifferentiation in the synthesis. This method gives an yield of 50-70% and these compounds undergo Diels-Alder cycloaddition reactions.

Pseudoephedrine serves as a highly effective, practical and flexible chiral auxiliary for the asymmetric alkylation of carboxamides. Carboxylic acid chlorides and anhydrides, when treated with enantiomer of pseudoephedrine, undergo preferential N-acylation to form tertiary amide derivatives. Such pseudoephedrine amides may serve as direct precursors to chiral aldehydes and ketones of high enantiomeric purity.

A transannular cyclization approach was used to prepare the diterpenoid tobacco isolate 7,8-epoxy-4-basemen-6-one. The macrocycle 5 was stereoselectively produced from the cationic cyclization of the olefinic acid 4. The allene functional group was introduced in high yield, because an organocopper reagent obtained from acetoacetate, was used to transform the alcohol 2 to the enol phosphate 3 in a two-phase procedure. The stereoselective construction of the tricyclic product 9 resulted from the transannular radical cyclization of 8 by a photochemical technique.

Aromatic hydrocarbon 1, 6-didehydroannulene exhibits a first-order cyclization at 60 degrees centigrade, resulting in the formation of biradical 1,5-dehydronaphthalene. The reaction is characterized by a half life of 25 minutes at -51 degrees centigrade, which is the most rapid biradical generating cycloaromatization ever known. Enantiospecific synthesis of the epoxy dienediyne proceeds through a thiol activation of neocarzinostatin chromophore to form cumulene, which after the removal of methanesulfonic acid group yields 1, 6-didehydro/10~annulene intermediate. This intermediate is characterized by a low symmetry which is responsible for the two nondegenerate modes of 1, 5-dehydronapthalene formation.