Barbara Zajc

α-Fluorovinyl Weinreb Amides and α- Fluoroenones from a Common Fluorinated Building Block

Synthesis and reactivity of N-methoxy-N-methyl-(1,3-benzothiazol-2-ylsulfonyl)fluoroacetamide, a building block for Julia olefination, is reported. This reagent undergoes condensation reactions with aldehydes and cyclic ketones to give alpha-fluorovinyl Weinreb amides. Olefination reactions proceed under mild, DBU-mediated conditions, or in the presence of NaH. DBU-mediated condensations proceed with either E- or Z-selectivity, depending upon reaction conditions, whereas NaH-mediated reactions are > or = 98% Z-stereoselective. Conversion of the Weinreb amide moiety in N-methoxy-N-methyl-(1,3-benzothiazol-2-ylsulfanyl)fluoroacetamide to ketones, followed by oxidation, resulted in another set of olefination reagents, namely (1,3-benzothiazol-2-ylsulfonyl)fluoromethyl phenyl and propyl ketones. In the presence of DBU, these compounds react with aldehydes tested to give alpha-fluoroenones with high Z-selectivity. The use of N-methoxy-N-methyl-(1,3-benzothiazol-2-ylsulfanyl)fluoroacetamide as a common fluorinated intermediate in the synthesis of alpha-fluorovinyl Weinreb amides and alpha-fluoroenones has been demonstrated. Application of the Weinreb amide to alpha-fluoro allyl amine synthesis is also shown.

Epoxide and diol epoxide adducts of polycyclic aromatic hydrocarbons at the exocyclic amino group of deoxyguanosine

Abstract Synthesis and separation of the diastereomeric trans N 2 -2′-deoxyguanosine adducts of tetrahydrophenanthrene 3,4-epoxide and benzo[a]pyrene 7,8-diol 9,10-epoxide (benzylic hydroxyl group and epoxide oxygen trans), as well as the incorporation of the former into the pentanucleotide TpApG * pApT, are described.

Fluorinated 1-Phenyl-1H-tetrazol-5-yl Sulfone Derivatives as General Reagents for Fluoroalkylidene Synthesis

Julia-Kocienski olefination reagents 1-fluoropropyl, (cyclopropyl)fluoromethyl, 1-fluoro-2-methyl-2-propenyl, and 1-fluoro-5-hexenyl 1-phenyl-1H-tetrazol-5-yl (PT) sulfones were prepared by metalation followed by electrophilic fluorination. Although metalation-fluorination of n-propyl, 5-hexenyl, and (cyclopropyl)methyl PT-sulfones proceeded under homogeneous conditions, fluorination of 2-methyl-2-propenyl PT-sulfone required heterogeneous fluorination conditions. Condensation reactions of fluoro PT-sulfones with aldehydes resulted in fluoroalkylidenes in high yields. Screening of olefination conditions showed that stereoselectivity depended on reagent and carbonyl structure and can in many cases be tuned either toward E- or Z-selectivity. For example, LHMDS-mediated condensations of 1-fluoropropyl PT-sulfone in the presence of MgBr(2) x OEt(2) were Z-selective with electron-rich aromatic aldehydes, a hindered aromatic aldehyde, and cinnamaldehyde. Low-temperature KHMDS-mediated condensations were E-selective with electron-rich and electron-deficient aromatic aldehydes and Z-selective with n-octanal. Dialkyl, aryl alkyl, and diaryl ketones reacted as well to give fluoro olefin products in 71-99% yields.

Chemistry of organo halogenic molecules. Part 100. Comparative behaviour of xenon diflouride and caesium fluoroxysulphate in the fluorination of enol acetates and ketones

Abstract Xenon difluoride and caesium fluoroxysulphate reacted in methylene chloride or acetonitrile with various enol acetates, diketones, and ketones, yielding mainly α-fluoro ketones, the course of the reaction depending on the reagent and the structure of the organic molecule. Enol acetates from cycloakanones were converted with caesium fluoroxysulphate to α-fluorocycloalkanones in high yield. Xenon difluoride and caesium fluoroxysulphate converted enol acetates of benzocycloalkanones-1 to α-fluorobenzocycloalkanones, while the reactivity of enol acetates of benzocycloalkanones-2 depended on the reagent used. 1,3-Diphenyl- propane-1,3-dione and its enol acetate were converted with XeF 2 and CsSO 4 F to mono and difluoro substituted products, the course of the reaction being dependent on the reagent. Xenon difluoride converted 1-indanone to rearranged 2,2-difluorochromane, while caesium fluoroxysulphate reacted to 1-fluoro-2-indanone with 2-indanone.

Fluoro-Julia Olefination as a Mild, High-Yielding Route to α-Fluoro Acrylonitriles

Synthesis of a novel, stable reagent (1,3-benzothiazol-2-ylsulfonyl)fluoroacetonitrile from readily synthesized ethyl alpha-(1,3-benzothiazol-2-ylsulfanyl)-alpha-fluoroacetate is reported. Aldehydes undergo condensations with (1,3-benzothiazol-2-ylsulfonyl)fluoroacetonitrile in the presence of DBU leading to alpha-fluoro acrylonitriles in high yields and with good Z-stereoselectivity. Lowering of reaction temperature increases the Z selectivity.

Benzo[a]pyrene diol epoxide–deoxyguanosine adducts are accurately bypassed by yeast DNA polymerase ζ in vitro

The possible role of bypass DNA polymerase zeta in mutagenic translesion synthesis past benzo[a]pyrene (BP) 7,8-diol-9,10-epoxide (DE) N(2)-deoxyguanosine (dG) adducts has been examined. We prepared 59-mer DNA templates containing dG adducts derived from trans opening of enantiomers of BP DE-2, in which the 7-hydroxyl group and epoxide oxygen are trans. The 10S-BP DE-dG and 10R-BP DE-dG adducts derive from the (+)- and (-)-DE-2 enantiomers, respectively. The adducted dG is located at a site identified as a G-->T mutational hotspot in random mutagenesis studies of (+)-BP DE-2 in Chinese hamster V-79 cells. Yeast pol zeta (complex of Gst-Rev3p and Rev7p) formed extension products (total of all lengths) of 71, 74 and 88% of a primer annealed to the 10S-BP DE-dG, 10R-BP DE-dG and non-adducted 59-mer templates, respectively. However, only 18 and 19% of the primer was extended to the full-length product on 10S-BP DE-dG and 10R-BP DE-dG adducted templates compared to 55% of the primer on the non-adducted template. A major 34-mer product corresponding to primer elongation up to and including the base before the adduct indicated that nucleotide incorporation opposite both adducts was strongly blocked. Full-length products were isolated from gels and subjected to PCR amplification and cloning. Sequence analysis of more than 300 clones of these full-length products on each template showed that only the correct dCMP was incorporated opposite both the adducted and non-adducted G-hotspot in the template. This corresponds to a probability of mutation lower than 0.3%, the limit of detection, and demonstrates the remarkable fidelity of yeast pol zeta in translesion synthesis past these BP DB-dG lesions in vitro.

Bromination of aromatic molecules with polymer supported reagents

Abstract Crosslinked co-poly/styrene-4-vinyl(N-hexylpyridinium bromide) was converted with bromine or chlorine to insoluble polymer supported complexes 1 or 2 respectively, and their reactivity studied in reactions with various aromatic molecules. Reagent 1 was found in all cases to be milder than reagent 2 and regiospecifically transformed alkoxy and amino substituted benzenes ( 3 ) into 4-bromo derivatives, while corresponding reactions with 2 resulted in dibromo derivatives. Several benzoheterocyclic molecules were converted with 1 to substitution or addition products, i.e. 2,3-dibromo-N-methylpyrrole, 3-bromobenzo/b/thiophene, and 2,3-dibromo-2,3-dihydrobenzofuran. In the series of ortho-alkyl disubstituted benzene derivatives, i.e. o-xylene, indane, and tetraline, where the Mills-Nixon effect was established with various electrophilic reagents, bromination reactions with 2 showed higher β-selectivity than the corresponding reactions with bromine. The rate of bromination in various alkyl substituted benzenes with reagent 2 depended on the magnitude of the alkyl group, as well as the para/ortho regioselectivity, amounting to 100% in the case of tert-butylbenzene.

A Convenient Preparation Of Jv-Bromo-Saccharin, Source Of Electrophilic Bromine

Abstract An extremely straightforward, high yield synthesis of a very reactive electrophilic brominating reagentiV-bromosaccharin is described, allowing its preparation in multi-gram quantities and in high purity.

Regio and stereocontrolled synthesis of aryl cis aminoalcohols from cis glycols

Reaction of aryl substituted cis diols with α-acetoxyisobutyryl chloride results in the formation of trans vicinal chlorohydrin acetates where the halide is benzylic. Displacement of chloride with azide ion, deprotection of the ester and reduction of the azide furnishes the requisite cis aminoalcohols. This facile four-step procedure results in the exclusive replacement of a benzylic hydroxyl with an amino group, with a net retention of stereochemistry. This set of transformations is generally applicable to a wide variety of cis diols, and the overall yields are excellent.

A Rapid, High-Yield Method for 5′-Hydroxyl Protection in Very Reactive and Amino Group Modified Nucleosides Using Dimethoxytrityl Tetrafluoroborate

Abstract The conventional method for 4,4′-dimethoxytrityl (DMT) etherification of the 5′-hydroxyl termini in deoxynucleosides that are either highly reactive or those bearing modifications at the exocyclic amino group can be quite problematic, and in several cases the yields are at best mediocre. Herein, we report a rapid, convenient and general procedure for the facile 5′-hydroxyl protection of these nucleosides in exceptionally high yields using DMT+BF4 −. This reagent is particularly useful for the preparation of 5′-O-DMT ethers of nucleosides that are either synthetically valuable or for those that undergo degradation under standard conditions.