Exploring physicochemical space via a bioisostere of the trifluoromethyl and ethyl groups (BITE): attenuating lipophilicity in fluorinated analogues of Gilenya® for multiple sclerosis

Abstract

The direct, catalytic vicinal difluorination of terminal alkenes via an I(i)/I(iii) manifold was exploited to install a chiral, hybrid bioisostere of the CF3 and Et groups (BITE) in Gilenya®; the first orally available drug for the clinical management of Multiple Sclerosis (MS). This subtle fluorination pattern allows lipophilicity (log D) to be tempered compared to the corresponding CF3 and Et derivatives (CH2CH3 > CH2CF3 > CHFCH2F).

Systematic Investigation of Lipophilicity Modulation by Aliphatic Fluorination Motifs

“…This is in keeping with Müller's analysis, 32 and with Gilmours's Gilenya ® examples (there was a 1.7 logP unit decrease between the respective CH2-CH3 and CHF-CH2F Gilenya ® analogues). 33 The differences in logP tend to slightly increase between compounds having 2 vs 3, 3 vs 4 and 4 vs 5 fluorines present. For motifs with the same number of fluorines, their internal arrangement has an impact on the logP.…”

“…32,37 Subsequently, through the synthesis of Gilenya ® derivatives with alkyl side chains of various lengths, Gilmour has further demonstrated the lower logP of 1,2-difluoroethyl groups compared to their ethyl and trifluoroethyl counterparts. 33 Müller also pointed out that the lipophilicity increase resulting from aliphatic chain extension is compensated when a CF2 group is simultaneously replaced by a vicinal difluoro group (e.g. compare A3, A4 with B4-B6).…”

Lipophilicity trends upon fluorination of isopropyl, cyclopropyl and 3-oxetanyl groups

“…For 4-fluorobutan-1-ol ( G6 ), and 3,4-difluorobutan-1-ol ( G7 ), which have the lowest lipophilicities of the linear butanol series measured so far [ 28 ], the corresponding cyclopropyl isosteres E1 and E4 have a slightly higher lipophilicity, while E3 has the same lipophilicity as G7 . The lipophilicity-reducing power of the vicinal 1,2-difluoromotif in G7 is well-described [ 34 – 35 ], but at least for series D , the motif present in E3 is another efficient candidate when a log P reduction operation is in order. In contrast, other such ring closures (e.g., starting from G2 , D3 , and G8 ) lead to a minute log P decrease.…”

Alkene Vicinal Difluorination: From Fluorine Gas to More Favoured Conditions

“…The vicinal difluoroalkane unit has garnered recent academic attention because it is a bioisostere for trifluoromethyl and ethyl groups, [6][7][8] it has a high density of C(sp 3 )-F bonds, and it has a unique propensity to adopt a gauche conformation in solution. 4,[9][10][11][12] Exploitation of this stereoelectronic effect is an emerging strategy for molecular design, 13,14 and has found application in organocatalysis [15][16][17] and peptide mimetics.…”