P. C. Ravikumar

Nitrile-Containing Pharmaceuticals: Efficacious Roles of the Nitrile Pharmacophore

Fraser F. Fleming,* Lihua Yao, P. C. Ravikumar, Lee Funk, and Brian C. Shook Department of Chemistry and Biochemistry, Duquesne University, Pittsburgh, Pennsylvania 15282-1530, Mylan Pharmaceuticals Inc., 781 Chestnut Ridge Road, Morgantown, West Virginia 26505, and Johnson & Johnson Pharmaceutical Research and Development, L.L.C., Welsh and McKean Roads, P.O. Box 776, Spring House, Pennsylvania 19477

Synthesis of the Fully Glycosylated Cyclohexenone Core of Lomaiviticin A

We describe two four-step sequences for conversion of the inexpensive reagent ethyl sorbate to either O-allyl-N,N-dimethyl-D-pyrrolosamine or O-allyl-L-oleandrose, protected forms of the 2,6-dideoxy sugar residues found in the complex bacterial metabolite lomaiviticin A. We also report a gram-scale synthesis of the highly-oxygenated cyclohexenone ring of this metabolite, and show this may be coupled with the aforementioned donors to form the bis(glycoside) 6. The longest linear sequence to 6 is nine steps.

Development of Enantioselective Synthetic Routes to (–)-Kinamycin F and (–)-Lomaiviticin Aglycon

The development of enantioselective synthetic routes to (-)-kinamycin F (9) and (-)-lomaiviticin aglycon (6) are described. The diazotetrahydrobenzo[b]fluorene (diazofluorene) functional group of the targets was prepared by fluoride-mediated coupling of a β-trimethylsilylmethyl-α,β-unsaturated ketone (38) with an oxidized naphthoquinone (19), palladium-catalyzed cyclization (39→37), and diazo transfer (37→53). The D-ring precursors 60 and 68 were prepared from m-cresol and 3-ethylphenol, respectively. Coupling of the β-trimethylsilylmethyl-α,β-unsaturated ketone 60 with the juglone derivative 61, cyclization, and diazo transfer provided the advanced diazofluorene 63, which was elaborated to (-)-kinamycin F (9) in three steps. The diazofluorene 87 was converted to the C(2)-symmetric lomaiviticin aglycon precursor 91 by enoxysilane formation and oxidative dimerization with manganese tris(hexafluoroacetylacetonate) (94, 26%). The stereochemical outcome in the coupling is attributed to the steric bias engendered by the mesityl acetal of 87 and contact ion pairing of the intermediates. The coupling product 91 was deprotected (tert-butylhydrogen peroxide, trifluoroacetic acid-dichloromethane) to form mixtures of the chain isomer of lomaiviticin aglycon 98 and the ring isomer 6. These mixtures converged on purification or standing to the ring isomer 6 (39-41% overall). The scope of the fluoride-mediated coupling process is delineated (nine products, average yield = 72%); a related enoxysilane quinonylation reaction is also described (10 products, average yield = 77%). We establish that dimeric diazofluorenes undergo hydrodediazotization 2-fold faster than related monomeric diazofluorenes. This enhanced reactivity may underlie the cytotoxic effects of (-)-lomaiviticin A (1). The simple diazofluorene 103 is a potent inhibitor of ovarian cancer stem cells (IC(50) = 500 nM).

Allylic and Allenic Halide Synthesis via NbCl5- and NbBr5-Mediated Alkoxide Rearrangements

Addition of NbCl(5) or NbBr(5) to a series of magnesium, lithium, or potassium allylic or propargylic alkoxides directly provides allylic or allenic halides. Halogenation formally occurs through a metalla-halo-[3,3] rearrangement, although concerted, ionic, and direct displacement mechanisms appear to operate competitively. Transposition of the olefin is equally effective for allylic alkoxides prepared by nucleophilic addition, deprotonation, or reduction. Experimentally, the niobium pentahalide halogenations are rapid, afford essentially pure (E)-allylic or -allenic halides after extraction, and are applicable to a range of aliphatic and aromatic alcohols, aldehydes, and ketones.

Hypervalent iodine mediated direct one pot transformation of aldehydes to ketones

An environmentally benign, step economical synthesis of ketones directly from aldehydes has been developed using hypervalent iodine as an oxidant. The key features of this protocol are its mild conditions without the use of any heavy and toxic metals for the synthesis of a wide range of ketones.

Synthesis of (±)‐12‐Methoxyherbertenediol Dimethyl Ether

Abstract Efficient total synthesis of (±)‐12‐methoxyherbertenediol dimethyl ether and 12‐homoherbertenediol was accomplished starting from vanillin employing a Claisen rearrangement–RCM reaction–based approach.