Michael Kolb

Synthesis of fluorinated α-amino ketones part I: α-benzamidoalkyl mono- di- and trifluoromethyl ketones

Abstract 2-Phenyl-5(4H)-oxazolones, obtained from α-amino acids, are reacted with di- and trifluoro acetic anhydride by a modified Dakin-West procedure to yield in a one-pot reaction α-benzamidoalkyl-di- and trifluoromethyl ketones in good yields. The monofluoromethyl analogues were also prepared from α-amino acids, however the use of the highly toxic fluoroacetic anhydride was avoided. The key step is the halogen exchange reaction on the corresponding bromomethyl ketone.

Marked and prolonged inhibition of mammalian ornithine decarboxylase in vivo by esters of (E)-2-(fluoromethyl)dehydroornithine

(E)-2-(fluoromethyl)dehydroornithine, a new enzyme-activated irreversible inhibitor of ornithine decarboxylase (ODC) is no more effective than alpha-difluoromethylornithine (DFMO) at inhibiting polyamine biosynthesis in rat hepatoma tissue culture (HTC) cells and in rat organs even though its potency is over 15 times higher than that of DFMO in vitro. The methyl, ethyl, octyl and benzyl esters of (E)-2-(fluoromethyl)dehydroornithine were synthesized as potential prodrugs of the amino acid. When tested at concentration equivalent to the Ki value of the amino acid, they are devoid of ODC-inhibitory property. When measured 6 hr after its addition to the HTC cell culture medium, the absorption of methyl ester was 20 times higher than that of the parent amino acid or that of DFMO, and was accompanied by a more marked intracellular accumulation of (E)-2-(fluoromethyl)dehydroornithine than that achieved by the addition of the parent amino acid. The methyl ester used at 10 times lower concentrations is as effective as its parent amino acid or as DFMO at inhibiting polyamine biosynthesis in HTC cells. Similarly, the methyl and the ethyl esters of (E)-2-(fluoromethyl)dehydroornithine used at 10 times lower doses are as effective as the parent amino acid and as DFMO at inhibiting ODC in the ventral prostate of rat, 6 hr after oral administration. All the esters of (E)-2-(fluoromethyl)dehydroornithine produce a particularly long duration of ODC inhibition in the ventral prostate and in the testes. Repeated administration (25 mg/kg given once a day by gavage) of the methyl ester of (E)-2-(fluoromethyl)dehydroornithine for 8 days to rats results in a constant 80% inhibition of ODC over a 24-hr period, accompanied by a 90% decrease of putrescine and spermidine concentrations in the ventral prostate.

A Convenient Preparation of Iodoalkyl Esters from Lactones

Abstract Summary: The reaction of lactones with trimethylsilyl iodide in the presence of an alcohol provides a short and convenient access to iodoalkyl esters, useful intermediates in organic synthesis.

A practical procedure for the conversion of aldehydes to terminal alkynes by a one carbon homologation

Abstract A convenient method for the conversion of aldehydes to terminal alkynes via the corresponding 1,1-dibromoalkenes is described. The key feature of the process is the use of magnesium in tetrahydrofuran for the debromination step.

Preparative flow techniques. 2. Grignard addition reaction on fluoroaceto-nitrile: Synthesis of 2-amino-2-fluoromethyl-3-pentenenitrile

Abstract A convenient methodology for the use of fluoroacetonitrile in organic synthesis is described. The method, a low-temperature flow technique, is suitable for small scale as well as for large scale applications.