David O'Hagan

HOW GOOD IS FLUORINE AS A HYDROGEN BOND ACCEPTOR

Abstract This study is aimed at evaluating organic fluorine as a hydrogen bonding acceptor. A review of short F…H contacts from all of the organofluorine compounds deposited in the Cambridge Structural Database System (CSDS) was carried out and in parallel a theoretical estimate of the energy of such contacts with inter nuclear distance was executed. A total of 548 structures emerged which contained 1163 unique Cue5f8F bonds and only 166 of these fluorine atoms posessed short Cue5f8F…Hue5f8X contacts of ≤ 2.35A. Contacts between fluorine and hydrogen bound to carbon (Cue5f8F…Hue5f8C) represent the major category of short contacts however these were not judged to be hydrogen bonds as they are weak with energies similar to those of van der Waals complexes. Short contacts between F and the acidic hydrogens of HO or HN are rare in the CSDS with only 12 and 28 occurring respectively. There was only one contact below 2.0A. Ab initio calculations have evaluated the relative stability and optimum distance of Cue5f8F…Hue5f8O bonds between water and fluoromethane and fluoroethene. It emerges that the C(sp 3 )ue5f8F fluorine in fluoromethane can enter into stronger hydrogen bonds than C(sp 2 )ue5f8F of fluoroethene. The X-ray data reinforces the conclusion that C(sp 3 )ue5f8F fluorine is a better hydrogen bond acceptor than C(sp 2 )ue5f8F fluorine. The C(sp 3 )ue5f8F…Hue5f8O bond is less than half the strength (2.38 kcal mol −1 ) of a Cue5f8O…Hue5f8O and the C(sp 2 )ue5f8F…Hue5f8O bond (1.48 kcal mol −1 ) is about half as weak again. Overall however short contacts in the Database which are consistent with an optimal F…H bond are extremely rare.

Synthesis of monofluoro- and difluoro- methylenephosphonate analogues of sn-glycerol-3-phosphate as substrates for glycerol-3-phosphate dehydrogenase and the X-ray structure of the fluoromethylenephosphonate moiety

Abstract The synthesis of the cyclohexylammonium salts of (1 RS , 3S)-3,4-dihydroxy-1-fluorobutylphosphonic acid 3 and (S)-difluoro-3,4-dihydroxybutylphosphonic acid 4 is reported. These compounds are fluorinated phosphonate analogues of sn -glycerol-3-phosphate where the bridging phosphate ester oxygen is replaced by CHF and CF 2 respectively. Kinetic studies are presented for oxidation with NADH linked glycerol-3-phosphate dehydrogenase, which reveal that the CHF-phosphonate 3 performs similarly to the natural substrate sn -glycerol-3-phosphate, and is a better substrate than the CF 2 -phosphonate 4 . The study also reveals that the diastereoisomers of 3 ( 3a and 3b ) are processed at different rates suggesting that the enzyme can discriminate the CHF stereogenic centres. A synthesis and X-ray crystal structure of 2-amino-1-fluoroethylphosphonic acid 7 is described which allows comparison of the geometry and conformation of CHF-phosphonate with that of analogous CH 2 - and CF 2 -phosphonates.

Elicitation of tropane alkaloid biosynthesis in transformed root cultures of Datura stramonium

Abstract Hairy root cultures of Datura stramonium were treated with methyl jasmonate (MeJa), a cell wall preparation from bakers yeast and oligogalacturonides, respectively, and analysed for the accumulation of the tropane alkaloids, littorine, hyoscyamine and scopolamine, and their precursors, phenyllactate and tropine. The treatments increased alkaloid accumulation in the order MeJa>fungal elicitor>oligogalacturonide and, in all cases, this was associated with an increase in tropine but a decline in phenyllactate concentrations. Time–course studies following MeJa treatments confirmed that increased tropane alkaloid synthesis was due to the differential enhancement of tropine biosynthesis.

Fluorine in enzyme chemistry part 2 The preparation of difluoromethylenephosphonate analogues of glycolytic phosphates. Approaching an isosteric and isoelectronic phosphate mimic

Abstract The preparation of difluoromethylenephosphonate analogues of the glycolytic intermediates, glycerol-3-phosphate and 3-phosphoglycerate are described. Attempts to prepare the corresponding analogue of dihydroxyacetone phosphate failed due the facile elimination of hydrogen fluoride from the target molecule. Finally the synthesis of a difluoromethylenephosphonate possessing inhibitory activity against RNA transcriptase from the influenza virus is described.

A short synthesis of (S)-2-(diphenylmethyl)pyrrolidine, a chiral solvating agent for NMR analysis

Abstract A three step synthesis of (S)-2(diphenylmethyl)pyrrolidine 4 is described which allows its preparation on a large scale. The C2 symmetric diamines 5 and 6 have been prepared from 4 and are attractive as potential ligands for asymmetric transformations. Pyrrolidine 4 has been assessed as a chiral solvating agent for the NMR analysis of chiral compounds. It emerges as a good CSA for carboxylic acids and some secondary alcohols.

Isolation of an aldehyde dehydrogenase involved in the oxidation of fluoroacetaldehyde to fluoroacetate in Streptomyces cattleya.

ABSTRACT Streptomyces cattleya is unusual in that it produces fluoroacetate and 4-fluorothreonine as secondary metabolites. We now report the isolation of an NAD+-dependent fluoroacetaldehyde dehydrogenase from S. cattleya that mediates the oxidation of fluoroacetaldehyde to fluoroacetate. This is the first enzyme to be identified that is directly involved in fluorometabolite biosynthesis. Production of the enzyme begins in late exponential growth and continues into the stationary phase. Measurement of kinetic parameters shows that the enzyme has a high affinity for fluoroacetaldehyde and glycoaldehyde, but not acetaldehyde.

The resolution of tertiary α-acetylene- acetate esters by the lipase from candida cylindracea

Abstract The resolution of tettiary alcohols using the Candida cylindracea lipase is explored. In particular strategies are deployed to limit nonenzmatic hydrolysis of the tertiary acetate substrates in buffer, such that a full range of the steric requirements and limitations for successful resolutions can be explored.

Enzyme-catalysed condensation polymerization of 11-hydroxyundecanoic acid with lipase from Candida cylindracea

Abstract The enzyme-catalysed condensation polymerization of 11-hydroxyundecanoic acid in hexane with the lipase from Candida cylindracea is reported. Molecular weights up to 35 000 are attained. A time course study of the polymerization process reveals that oligomers are formed relatively rapidly and that these oligomers then condense to generate higher molecular weight polyesters.

Lipase-catalyzed polymerization of fluorinated lactones and fluorinated hydroxycarboxylic acids

Lipase-catalyzed ring-opening polymerization of 10-fluorodecan-9-olide (1a), 11-fluoroundecan-10-olide (1b), 12-fluorododecan-11-olide (1c) and 14-fluorotetradecan-13-olide (1d) gave optically active products with Mw of 3.000 to 8.000, while 10-fluoroundecan-11-olide (3a) gave an optically inactive polymer with Mw = 11.000. On the other hand, Candida antarctica lipase-catalyzed polymerization of 10- to 14-membered ω-fluoro-(ω-1)-hydroxyalcanoic acids gave optically inactive oligomers with Mw of 3.000 to 11.000 in the presence of molecular sieves, while reactions without molecular sieves gave oligomers with lower molecular weight, but with small optical rotations. 9-Fluoro-10-hydroxydecanoic acid, on the other hand, gave an optically inactive polyester with Mw = 7400.

A short synthesis of (S)-α-(diphenylmethyl)alkyl amines from amino acids

Abstract A range of ( S )-α-(diphenylmethyl)alkyl amines were prepared from the corresponding ( S )-α-amino acid ester hydrochlorides. These amines were derived by direct hydrogenation of their precursor oxazolidinones.