a-new-straightforward-method-for-lipophilicity-logp-measurement-using

A New Straightforward Method for Lipophilicity (log<em>P</em>) Measurement using <sup>19</sup>F NMR Spectroscopy

Fluorination has become an effective tool to optimize physicochemical properties of bioactive compounds. One of the applications of fluorine introduction ...

University of Southampton

Organofluorine is a weak hydrogen-bond (HB) acceptor. Bernet et al. have demonstrated its capability to perturb OH···O intramolecular hydrogen bonds (IMHBs), using conformationally rigid carbohydrate scaffolds including levoglucosan derivatives. These investigations are supplemented here by experimental and theoretical studies involving six new levoglucosan derivatives, and complement the findings of Bernet et al. However, it is shown that conformational analysis is instrumental in interpreting the experimental data, due to the occurrence of non-intramolecular hydrogen-bonded populations which, although minor, cannot be neglected and appears surprisingly significant. The DFT conformational analysis, together with the computation of NMR parameters (coupling constants and chemical shifts) and wavefunction analyses (AIM, NBO), provides a full picture. Thus, for all compounds, the most stabilized structures show the OH groups in a conformation allowing IMHB with O5 and O6, when possible. Furthermore, the combined approach points out the occurrence of various IMHBs and the effect of the chemical modulations on their features. Thus, two-center or three-center IMHB interactions are observed in these compounds, depending on the presence or absence of additional HB acceptors, such as methoxy or fluorine.

A Study of Intramolecular Hydrogen Bonding in Levoglucosan Derivatives.

The regioselective protection of both methyl galactopyranoside anomers at the 2 and 3-positions as the butane diacetal (BDA) is well known. Here we describe the formation of an unexpected byproduct, which mainly occurs when α-methyl galactopyranoside is reacted with 2,3-butanedione under BF•OEt catalysis. The structure of the byproduct, which did not arise from anomerisation to the β-anomer or from BDA formation at the galactopyranoside 3,4-positions, was elucidated by NMR and X-ray crystallographic analysis, and proved to be the expected BDA protected galactopyranoside, but in which the stereochemistry of both its BDA acetal centres are inverted. Interestingly, the conformation of the resulting six-membered BDA ring was distorted to a skew boat conformation in order to maintain anomeric stabilisation.

Isolation and characterisation of an unexpected byproduct in the regioselective butane diacetal protection of α-methyl galactopyranoside.

Monofluorination at the proline 4-position results in conformational effects, which is exploited for a range of applications. However, this conformational distortion is a hindrance when the natural proline conformation is important. Here we introduce (3S,4R)-3,4-difluoroproline, in which the individual fluorine atoms instil opposite conformational effects, as a suitable probe for fluorine NMR studies.

Article	Year
A Study of Intramolecular Hydrogen Bonding in Levoglucosan Derivatives. Molecules (Basel, Switzerland)\| PubMed ID: 28338623	2017
Isolation and characterisation of an unexpected byproduct in the regioselective butane diacetal protection of α-methyl galactopyranoside. Carbohydrate research\| PubMed ID: 29145075	2018
Minimising conformational bias in fluoroprolines through vicinal difluorination. Chemical communications (Cambridge, England)\| PubMed ID: 29717724	2018

Bruno Linclau

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