Robert M. Moriarty

Synthesis of squalamine. A steroidal antibiotic from the shark

Abstract The title compound was synthesized from 3β-acetoxy-5-cholenic acid ( 2 ) in 17 steps.

Comprehensive Review of Cancer Chemopreventive Agents Evaluated in Experimental Carcinogenesis Models and Clinical Trials

Cancer chemoprevention refers to the use of pharmacological agents to inhibit, delay or reverse the multi-step process of carcinogenesis. The last two decades in particular have witnessed explosive growth in this emerging field of cancer chemoprevention. Extensive efforts to evaluate possible application of various chemopreventive agents, in individuals at high risk of neoplastic development have been carried out. Epidemiological studies suggest a protective role of several agents in reducing the risk of cancer. The protective action of all these agents is explained as a combination of various proposed mechanisms involving anti-oxidant, anti-inflammatory, immunomodulatory action, apoptosis induction, molecular association with carcinogen, cell cycle arrest, cell differentiation induction, antimicrobial effect, and anti- angiogenesis etc. Large numbers of candidate substances such as phytochemicals and their synthetic derivatives have been identified by a combination of in vitro and in vivo studies in a wide range of biological assays. However, a comprehensive description of these chemopreventive agents has not been extensively reviewed. In this review we discuss cancer chemopreventive agents in relation to their source, efficacy in cancer chemopreventive action in vivo and epidemiological data. The experimental carcinogenesis studies in different biological models, in addition to the contribution from our laboratory are summarized.

Organosulfur Compounds in Cancer Chemoprevention

There has been a renewed interest to the application of natural products derived from cruciferous plants and members of Allium genus in chemoprevention of cancer. The potential chemopreventive properties of these vegetables have been attributed to the presence of high level of organosulfur compounds in these plants. Organosulfur compounds have been shown to exert diverse biological effects such as: (a) induction of carcinogen detoxification, (b) inhibition of tumor cell proliferation, (c) antimicrobial effect, (d) free radical scavenging, (e) inhibition of DNA adduct formation, (f) induction of cell cycle arrest and induction of apoptosis etc. It has been suggested that these compounds act as chemopreventive agents through a combination of above mechanisms. Epidemiological and experimental carcinogenesis provides overwhelming evidence to support the claim that individuals consuming diet rich in organosulfur are less susceptible to different types of cancers. The protective effects of OSCs against carcinogenesis have been shown in stomach, esophagus, mammary glands, breast, skin and lungs of experimental animals. Cumulatively all these studies show a strong correlation between cancer prevention and intake of organosulfur compounds in one form or the other. Since the protective effects of all these phytochemicals are as a result of additives and synergistic combination further studies are warranted for complete understanding of chemopreventive action of organosulfur compounds and define the effective dose that has no toxicity in humans. In this review an attempt has been made to summarize the different aspects of organosulfur compounds with relation to their source, chemopreventive mechanistic action, epidemiologic and experimental carcinogenesis.

The Mechanism of 1,4 Alkyl Group Migration in Hypervalent Halonium Ylides: The Stereochemical Course

Rhodium(II)-acetate-catalyzed decomposition of either 1,3-cyclohexanedione phenyliodonium ylide or 5,5-dimethyl-1,3-cyclohexanedione phenyliodonium ylide in the presence of alkyl halides yields the corresponding 3-alkoxy-2-halocyclohex-2-enones via a 1,4 alkyl group migration shown to be concerted and intramolecular. In the case of (S)-alpha-phenethyl chloride, the rearrangement proceeds with essentially 88.6% retention of configuration. Theoretical calculations at the B3LYP/6-31G level reveal an activation energy of 5.4 kcal/mol for the process. A Claisen-like rearrangement occurs in the case where allylic halides, such as dimethylallyl or methallyl chorides, are used. The mechanistic pathway proposed for these processes involves addition of the halogen atom of the alkyl or allyl halide to the rhodium carbenoid from the iodonium ylide to yield a halonium intermediate that undergoes halogen to oxygen group migration. Aryl halides, such as chloro-, bromo-, iodo-, and fluorobenzene, behave differently under the same reaction conditions, yielding the product of electrophilic aromatic substitution, namely, the 2-(4-halophenyl) 1,3-cyclohexanedione.

Metal-free intramolecular aziridination of alkenes using hypervalent iodine based sulfonyliminoiodanes.

Intramolecular aziridination of alkenyl sulfonyliminoiodanes occurs thermally in the absence of conventional metal catalysts such as Rh(II) and Cu(II). In rigid molecular systems, conversions are near quantitative. The scope of the nonmetal process is related to the conformational flexibility of the alkenyl sulfonyliminoiodane. A mechanism is proposed involving formal 2 + 2 cycloaddition of the RSO(2)N=IPh group to the double bond followed by reductive elimination of PhI to yield the sulfonylaziridine. Green chemistry aspects of the process are highlighted.

Hypervalent iodine oxidation of silyl enol ethers. A direct route to α-hydroxy ketones

Hypervalent iodine oxidation of various silyl enol ethers (aromatic, heteroaromatic, and aliphatic) using iodosobenzene–boron trifluoride diethyl ether–water provides a general and direct route for the α-hydroxylation of ketones. The structures of 2-hydroxy-(8) and 3-hydroxy-acetylpyridine (9) are discussed as well as the scope and mechanism of the reaction.

Carbon–carbon bond formation using hypervalent iodine under Lewis acid conditions: scope of the method for the synthesis of butane-1,4-diones

Hypervalent iodine oxidation of the silyl enol ethers of various acetophenones (2a–g), 2-acetylthiophenes (2i–k), 2-acetylfuran (2l) and 2-acetylbenzofuran (2m) with iodosobenzene–boron trifluoride–diethyl ether results in carbon–carbon coupling to yield the corresponding 1,4-disubstituted butane-1,4-dione (3a–m). Cross coupling (dissimilar coupling) between 4-methoxyacetophenone silyl enol ether (2c) and 4-nitroacetophenone silyl enol ether (2e) affords 1-(4-methoxyphenyl)-4-(4-nitrophenyl)butane-1,4-dione (27%); the other minor products (3c)(18%) and (3e)(15%) resulting from similar coupling in this reaction. The sterically hindered aliphatic silyl enol ether (2h) obtained from pinacolone also undergoes smooth coupling whereas other aliphatic ketones do not. This method is likewise unsuccessful in case of nitrogen-containing heterocycles, viz. 2-, 3-, 4-acetylpyridine silyl enol ethers and tropinone silyl enol ether.

Hypervalent iodine oxidation of α,β-unsaturated ketones: chromone, flavone, chalcone, and flavanone

Reaction of the title compounds with PhI(OAc)2 and MeOH–KOH leads to α-hydroxydiemthylacetal β-methoxy products regiospecifically and stereospecifically, as demonstrated by X-ray diffraction.

A new method for indole functionalization. Nucleophilic displacement reactions of [η6-(4- or 5-chloroindole)](η5-cyclopentadienyl)ruthenium(II) hexafluorophosphates

New cyclopentadienylruthenium complexes of 4- or 5-chloroindole prepared by a thermal substitution reaction of (cyclopentadienyltrisacetonitrile)ruthenium with 4- or 5-chloroindole undergo smooth nucleophilic aromatic substitution with various nucleophiles.

Carbon–carbon bond formation using hypervalent iodine under Lewis acid conditions: 1,4-diarylbutane-1,4-diones

Reaction of silyl enol ethers of aryl methyl ketones with PhIO–BF3·Et2O results in coupling to yield 1,4-diketones.