Stereocontrolled Synthesis of Tetrafluoropentanols: Multivicinal Fluorinated Alkane Units for Drug Discovery

Article abstract of DOI:10.1021/acs.orglett.9b02662

A stereodivergent synthesis of four diastereomeric 2,3,4,5-tetrafluoropentanols is disclosed. X-ray crystallographic analysis reveals conformations that manifest sequential stereoelectronic gauche effects (σ_C-H/C → σ_C-F*), thereby generating topological diversity via subtle C(sp³)-H to C(sp³)-F exchange. Two representative tetrafluoro arrays have been incorporated into truncated analogues of Gilenya for the management of relapsing remitting multiple sclerosis. These closely similar multivicinal fluoroalkanes have notably different physicochemical profiles and were found to be stable in the presence of human microsomes.

Full text of DOI:10.1021/acs.orglett.9b02662

Letter
pubs.acs.org/OrgLett
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
Stereocontrolled Synthesis of Tetrafluoropentanols: Multivicinal
Fluorinated Alkane Units for Drug Discovery
Patrick Bentler,† Nathalie Erdeljac,† Kathrin Bussmann,† Marie Ahlqvist,‡ Laurent Knerr,§
Klaus Bergander,† Constantin G. Daniliuc,† and Ryan Gilmour*,†
†
̈
̈
̈
̈
Organisch-Chemisches Institut, Westfalische Wilhelms-Universitat Munster, Corrensstr. 40, 48149 Munster, Germany
‡Drug Metabolism and Pharmacokinetics and Medicinal Chemistry, Research and Early Development Cardiovascular, Renal and
§
Metabolism, BioPharmaceuticals R&D, Astrazeneca, SE-431 89 Gothenburg, Sweden
S
* Supporting Information
ABSTRACT: A stereodivergent synthesis of four diastereomeric 2,3,4,5-tetrafluoropentanols is disclosed. X-ray crystallo-
graphic analysis reveals conformations that manifest sequential stereoelectronic gauche effects (σC−H/C → σC−F*), thereby
generating topological diversity via subtle C(sp3)−H to C(sp3)−F exchange. Two representative tetrafluoro arrays have been
incorporated into truncated analogues of Gilenya for the management of relapsing remitting multiple sclerosis. These closely
similar multivicinal fluoroalkanes have notably different physicochemical profiles and were found to be stable in the presence of
human microsomes.
ultivicinal fluoroalkanes uniquely amalgamate the
as a function of noncovalent interactions. The venerable gauche
effect associated with 1,2-difluoroethane is necessarily tele-
scoped in multivicinal fluoroalkanes:3 this gives rise to a
predictable dihedral angle (φFCCF = 60°) as a consequence of
stabilizing hyperconjugative interactions (σC−H → σC−F*).
Repulsive 1,3-fluorine interactions also provide a handle and,
together, with the gauche effect, can be exploited to populate
specific conformers as a function of relative configuration.4 The
potential and versatility of multivicinal fluoroalkanes is
exemplified by O’Hagan’s seminal contributions to under-
standing the physicochemical behavior of this new class of
materials5 and the stereocontrolled synthesis of a fluorinated
analogue of the complex lipid fluorodanicalipin by Carreira and
co-workers.6
M
physicochemical properties of hydrocarbons and per-
fluorocarbons (Figure 1).1 The juxtaposition of localized partial
By merging these two compound classes, it is possible to
explore new areas of chiral, 3D molecular space with enormous
potential in the design of novel bioisosteres for drug discovery.7
Herein, we report a convenient strategy to access four
diastereoisomers of 2,3,4,5-tetrafluoropentan-1-ol from inex-
pensive D-mannitol and demonstrate their structural variation.
Preliminary validation of their potential in drug discovery is also
presented in the synthesis and physicochemical profiling of
analogues of the multiple sclerosis drug, Gilenya.8
Figure 1. Multivicinal fluoroalkanes as asymmetric building blocks.
charge inversion and comparable van der Waals radii, coupled
with fluorine’s relative scarcity in Nature, creates a unique
environment to facilitate the discovery of novel materials with
unexplored function.2 Unlike the achiral parent compound
classes, this organohalogen subset comprises repeating (CHF)
stereocenters, thus allowing for the programmed generation of
stereoisomers with unique physicochemical properties. This is a
consequence of molecular conformation which can be regulated
Our interest in the fluorine gauche effect,3 coupled with our
recent disclosure of the catalytic, enantioselective vicinal
Received: July 29, 2019
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.9b02662
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
a
Scheme 1. Synthesis of Tetrafluoropentanols 5a−d
a
Conditions: (a) D-mannitol, ZnCl2, acetone, rt, 24 h, 88%; (b) (i) NaIO4, NaHCO3,H2O, rt, 4 h, then (ii) K2CO3, (EtO)2P(O)CH2CO2Et, H2O,
0 °C to rt, 18 h, 70%; (c) DIBAL-H, THF, −78 °C to rt, 18 h, 1 90%; (d) Ti(OiPr)4, (*)-DIPT, tBuOOH, CH2Cl2, −25 °C, 64 h, 72/85%; (e)
BnBr, NaH, TBAI, THF, 0 °C to rt, 20 h, 86/77%; (f) acetic acid (70%), rt, 18 h, 89/79%; (g) Deoxofluor (50% in THF), CH2Cl2, 0 °C to rt, 20 h,
73% 2a, 84% 2b; (h) NEt3·3HF, 120 °C, 20 h, 89% 3a, 80% 3b; (i) Tf2O, pyridine, CH2Cl2, −10 °C to rt, 2 h, then (j) NaNO2, DMF, 50 °C, 3 h,
72% 3c, 59% 3d; (k) Deoxofluor (50% in THF), CH2Cl2, 0 °C to rt, 22 h, 76/75/73/85%; (l) Pd/C, H2, Et2O, rt, 18 h, 98% 4a, 98% 4b, 74% 4c,
80% 4d; (m) TsCl, NEt3, DMAP, rt, 18 h, 76% 5a, 89% 5b, 76% 5c, 77% 5d. For full experimental details, see the Supporting Information.
Figure 2. X-ray analyses of alcohols 3a−d showing selected gauche dihedral angles.
difluorination of alkenes,9,10 motivated us to explore larger
congeners of the 1,2-difluororoethylene unit in the context of
focused molecular design. As the 1,2,3,4-tetrafluorobutylene
motif may be considered as the first higher homologue of the
parent 1,2-difluoroethylene unit, a stereodivergent route to
access the various diastereoisomers starting from inexpensive D-
mannitol was devised (Scheme 1).
Allylic alcohol 111 (see Supporting Information) was
processed to compounds 2a and 2b via four-step synthetic
sequences. Reagent-controlled Sharpless asymmetric epoxida-
B
DOI: 10.1021/acs.orglett.9b02662
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
tion provided access to both epoxyalcohol diastereoisomers.12
Subsequent protecting group manipulation provided the
corresponding 1,2-diols, which were suitable substrates for
fluorine incorporation. Following the conditions reported by
Shreeve and co-workers,13 1,2-difluoroalkanes 2a and 2b were
generated in 73 and 84%, respectively. Exposing epoxides 2a and
2b to neat NEt3·3HF at 120 °C for 18 h generated trifluorides 3a
and 3b in a highly regio- and stereoselective manner (89 and
80%, respectively). To access the four possible tetrafluorinated
stereoisomers 4a−d, configurational inversion of the hydroxyl
group in 3a and 3b was performed via a two-step procedure
involving triflation and treatment with sodium nitrite to generate
3c and 3d.14
All four diastereoisomers (3a−d) were crystalline, allowing
the absolute configuration to be confirmed by X-ray analysis
(Figure 2). In all four scenarios, F−C−C−F/OH dihedral
angles were observed that satisfy the torsional requirements for
the stereoelectronic gauche effect. Interestingly, in the case of 3a
and 3c, the characteristic zigzag conformation of the chain is
distorted to avoid repulsive 1,3-interactions. This is mitigated in
structures 3b and 3d due to the 1,3-anti relationship of the
fluorine atoms.
In the syn−anti diastereoisomer 5b, two gauche alignments are
evident from the solid-state analysis. An additional fluorine−
oxygen gauche conformation can also be observed, and there is
no appreciable distortion of the carbon chain.
When considering the tetrafluoro motif as its two constituent
1,2-difluoroethylene units, the internal gauche relationships
contrast sharply with the 2,3-anti relationship in the center of the
structure. This phenomenon is also present in derivative 5d,
where a single anti relationship is wedged between three discrete
gauche effects. These structural data demonstrate that subtle
changes in closely similar structures can have profound effects
on conformational variation. This is evident from an inspection
of the extended packing array of tetrafluorides 5a and 5b (Figure
4; for full structure analysis, see the Supporting Information).
Installation of the final fluorine substituent via invertive
substitution required an excess of Deoxofluor to generate the
tetrafluoro motif (up to 85% yield). Cleaveage of the benzyl
ether using palladium on charcoal under a H2 atmosphere in
diethyl ether liberated the 2,3,4,5-tetrafluoropentanols as highly
volatile solids (sublimation at ∼10−2 mbar and ambient
temperature). To address this volatility issue and provide a
useful handle for further functionalization, tosylates 5a−d were
prepared. In three cases, it was possible to perform single-crystal
diffraction analysis to unequivocally establish the relative and
absolute configuration of products 5a, 5b, and 5d. As is evident
from Figure 3, the final deoxyfluorination event proceeds with
inversion of configuration, and the structures adopt conforma-
tions in which the stereoelectronic gauche effects manifest
themselves. It is interesting to note that, in the case of the all-syn
system 5a, a linear zigzag conformation is observed despite the
repulsive 1,3-interaction.
Figure 4. Extended packing arrays of the all-syn diastereoisomer 5a
(left) and syn,anti diastereoisomer 5b (right).
To explore the potential of these motifs in modulating the
physicochemical profiles of small molecule drugs, the tetrafluoro
arrays in 5a and 5b were incorporated into an analogue of the
multiple sclerosis drug Gilenya (Figure 5).
Whereas both candidates 6a and 6b displayed comparable log
D7.4 values (0.4 and 0.6), notable differences in aqueous
Figure 3. X-ray analyses of tosylates 5a, 5b, and 5d showing selected
gauche dihedral angles.
Figure 5. Comparison of the physicochemical properties of multivicinal
fluoroalkanes 6a and 6b with Gilenya.
C
DOI: 10.1021/acs.orglett.9b02662
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
(b) Zimmer, L. E.; Sparr, C.; Gilmour, R. Fluorine conformational
effects in organocatalysis: an emerging strategy for molecular design.
Angew. Chem., Int. Ed. 2011, 50, 11860−11871.
solubility were observed at pH 4.7 (925 vs 563 μM). Both
compounds were found to be stable in the presence of human
microsomes [Clint (μM/min/mg <4.5), and similar low intrinsic
clearance rates in rat hepatocytes were observed. As expected,
the fluorinated systems displayed physicochemical profiles very
different than that of the parent drug Gilenya,8 further
underscoring the potential of multiply fluorinated motifs in
functional small molecule design.15
In conclusion, a stereodivergent route to four diaster-
eoisomers of the 1,2,3,4-tetrafluoro motif is disclosed from an
inexpensive, chiral pool starting material. Whereas the
configuration of the penultimate C(sp3)−F unit is predeter-
mined by the sugar, the adjoining, contiguous centers can be
programmed to facilitate access to four discrete diaster-
eoisomers. Solid-state structural analysis reveals a predisposition
to adopt conformations that allow for stabilizing hyper-
conjugative interactions of the type (σC−H/C → σC−F*). These
sequential gauche effects give rise to subtle changes in structural
topology and physicochemical properties. Given the biosisos-
teric nature of C(sp3)−H and C(sp3)−F bonds, multivicinal
fluoroalkanes are a versatile class of materials to explore 3D
chemical space.
(3) (a) Thiehoff, C.; Rey, Y. P.; Gilmour, R. The fluorine gauche effect:
a brief history. Isr. J. Chem. 2017, 57, 92−100. (b) Aufiero, M.; Gilmour,
R. Informing molecular design by stereoelectronic theory: the fluorine
gauche effect in catalysis. Acc. Chem. Res. 2018, 51, 1701−1710.
(4) (a) O'Hagan, D.; Rzepa, H. S; Schuler, M.; Slawin, A. M Z The
vicinal difluoro motif: The synthesis and conformation of erythro- and
threo- diastereoisomers of 1,2-difluorodiphenylethanes, 2,3-difluoro-
succinic acids and their derivatives. Beilstein J. Org. Chem. 2006, 2, 19.
(b) Hunter, L.; Jolliffe, K. A.; Jordan, M. J. T.; Jensen, P.; Macquart, R.
B. Synthesis and Conformational Analysis of α,β-Difluoro-γ-amino
Acid Derivatives. Chem. - Eur. J. 2011, 17, 2340−2343. (c) Scheidt, F.;
Selter, P.; Santschi, N.; Holland, M. C.; Dudenko, D. V.; Daniliuc, C.;
Muck-Lichtenfeld, C.; Hansen, M. R.; Gilmour, R. Emulating natural
̈
product conformation by cooperative, non-covalent fluorine inter-
actions. Chem. - Eur. J. 2017, 23, 6142−6149.
(5) (a) Nicoletti, M.; O’Hagan, D.; Slawin, A. M. Z. α,β,γ-
Trifluoroalkanes: A Stereoselective Synthesis Placing Three Vicinal
Fluorines along a Hydrocarbon Chain. J. Am. Chem. Soc. 2005, 127,
482−483. (b) Schuler, M.; O’Hagan, D.; Slawin, A. M. Z. The vicinal
̈
F−C−C−F moiety as a tool for influencing peptide conformation.
Chem. Commun. 2005, 4324−4326. (c) Hunter, L.; O’Hagan, D.;
Slawin, A. M. Z. Enantioselective Synthesis of an All-syn Four Vicinal
Fluorine Motif. J. Am. Chem. Soc. 2006, 128, 16422−16423.
(d) Nicoletti, M.; Bremer, M.; Kirsch, P.; O’Hagan, D. Liquid crystals
carrying stereodefined vicinal difluoro- and trifluoro- alkyl motifs.
Chem. Commun. 2007, 5075−5077. (e) Hunter, L.; Slawin, A. M. Z.;
Kirsch, P.; O’Hagan, D. Synthesis and Structure of Stereoisomeric
Multivicinal Hexafluoroalkanes. Angew. Chem., Int. Ed. 2007, 46, 7887−
7890. (f) Hunter, L.; Kirsch, P.; Hamilton, J. T. G.; O’Hagan, D. The
multi-vicinal fluoroalkane motif: an examination of 2,3,4,5-tetrafluor-
ohexane stereoisomers. Org. Biomol. Chem. 2008, 6, 3105−3108.
(g) Farran, D.; Slawin, A. M. Z.; Kirsch, P.; O’Hagan, D.
Diastereoselective Synthesis of 2,3,4,5,6-Pentafluoroheptanes. J. Org.
Chem. 2009, 74, 7168−7171. (h) Keddie, N. S.; Slawin, A. M.; Lebl, T.;
Philp, D.; O’Hagan, D. All-cis 1,2,3,4,5,6-hexafluorocyclohexane is a
facially polarized cyclohexane. Nat. Chem. 2015, 7, 483−488.
(i) Santschi, N.; Gilmour, R. A Janus Cyclohexane Ring. Nat. Chem.
2015, 7, 467−468.
ASSOCIATED CONTENT
* Supporting Information
■
S
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.orglett.9b02662.
Experimental procedures and characterization data
(PDF)
Accession Codes
CCDC 1941733−1941739 contain the supplementary crystallo-
graphic data for this paper. These data can be obtained free of
charge via www.ccdc.cam.ac.uk/data_request/cif, or by email-
ing data_request@ccdc.cam.ac.uk, or by contacting The Cam-
bridge Crystallographic Data Centre, 12 Union Road, Cam-
bridge CB2 1EZ, UK; fax: +44 1223 336033.
(6) Fischer, S.; Huwyler, N.; Wolfrum, S.; Carreira, E. M. Total
Synthesis of Bromo- and Fluorodanicalipin A. Angew. Chem., Int. Ed.
2016, 55, 2555−2558.
AUTHOR INFORMATION
■
Corresponding Author
*E-mail: ryan.gilmour@uni-muenster.de.
ORCID
(7) (a) Huchet, Q. A.; Kuhn, B.; Wagner, B.; Kratochwil, N. A.;
Fischer, H.; Kansy, M.; Zimmerli, D.; Carreira, E. M.; Muller, K.
̈
Fluorination Patterning: A Study of Structural Motifs That Impact
Physicochemical Properties of Relevance to Drug Discovery. J. Med.
Chem. 2015, 58, 9041−9060. (b) Meanwell, N. A. Fluorine and
Fluorinated Motifs in the Design and Application of Bioisosteres for
Drug Design. J. Med. Chem. 2018, 61, 5822−5880.
Laurent Knerr: 0000-0002-4810-8526
Ryan Gilmour: 0000-0002-3153-6065
Notes
(8) Erdeljac, N.; Kehr, G.; Ahlqvist, M.; Knerr, L.; Gilmour, R.
Exploring Physicochemical Space via a Bioisostere of the Trifluor-
omethyl and Ethyl Groups (BITE): Attenuating Lipophilicity in
Fluorinated Analogues of Gilenya® for Multiple Sclerosis. Chem.
Commun. 2018, 54, 12002−12005.
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
We acknowledge generous financial support from the WWU
nster, the Deutsche Forschungsgemeinschaft (SFB 858), and
the European Commission (RG, ERC Consolidator Grant,
818949 RECON ERC-2018-CoG).
■
́
(9) (a) Molnar, I. G.; Gilmour, R. Catalytic Difluorination of Olefins.
Mu
̈
́
J. Am. Chem. Soc. 2016, 138, 5004−5007. (b) Molnar, I. G.; Thiehoff,
C.; Holland, M. C.; Gilmour, R. Catalytic, Vicinal Difluorination of
Olefins: Creating a Hybrid, Chiral Bioisostere of the Trifluoromethyl
and Ethyl Groups. ACS Catal. 2016, 6, 7167−7173. (c) Scheidt, F.;
REFERENCES
̈
Schafer, M.; Sarie, J. C.; Daniliuc, C. G.; Molloy, J. J.; Gilmour, R.
■
Enantioselective, Catalytic Vicinal Difluorination of Alkenes. Angew.
(1) (a) Hunter, L.; O'Hagan, D. Multivicinal fluoroalkanes: a new
class of organofluorine compounds. Org. Biomol. Chem. 2008, 6, 2843−
2848. (b) O’Hagan, D. Organofluorine Chemistry: Synthesis and
Characterisation of Vicinal Fluoromethylene Motifs. J. Org. Chem.
2012, 77, 3689−3699.
(2) (a) O’Hagan, D. Understanding organofluorine chemistry. An
introduction to the C-F bond. Chem. Soc. Rev. 2008, 37, 308−319.
Chem., Int. Ed. 2018, 57, 16431−16435.
(10) (a) Banik, S. M.; Medley, J. W.; Jacobsen, E. N. Catalytic,
Diastereoselective 1,2-Difluorination of Alkenes. J. Am. Chem. Soc.
2016, 138, 5000−5003. (b) Haj, M. K.; Banik, S. M.; Jacobsen, E. N.
Catalytic, Enantioselective 1,2-Difluorination of Cinnamamides. Org.
Lett. 2019, 21, 4919−4923.
D
DOI: 10.1021/acs.orglett.9b02662
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
(11) Marshall, J. A.; Trometer, J. D.; Cleary, D. G. Stereoselective SN2’
additions of organocuprates to homochiral acyclic vinyloxiranes.
Tetrahedron 1989, 45, 391−402.
(12) (a) Katsuki, T.; Sharpless, K. B. The first practical method for
asymmetric epoxidation. J. Am. Chem. Soc. 1980, 102, 5974−5976.
(b) Ko, S. Y.; Lee, A. W. M.; Masamune, S.; Reed, L. A.; Sharpless, K. B.;
Walker, F. J. Total synthesis of the l-hexoses. Tetrahedron 1990, 46,
245−264.
(13) Singh, R. P.; Shreeve, J. M. Nucleophilic fluorination of amino
alcohols and diols using Deoxofluor. J. Fluorine Chem. 2002, 116, 23−
26.
(14) Albert, R.; Dax, K.; Stutz, A. E. Carbohydrate triflates:
̈
Introduction of substituents by double inversion at C-4″ of kanamycin
A. Carbohydr. Res. 1984, 132, 162−167.
(15) Bentler, P.; Bergander, K.; Daniliuc, C. G.; Muck-Lichtenfeld, C.;
̈
Jumde, R. P.; Hirsch, A. K. H.; Gilmour, R. Inverting Small Molecule-
Protein Recognition by the Fluorine Gauche Effect: Selectivity
Regulated by Multiple H → F Bioisosterism. Angew. Chem. 2019,
131, 11106−11110; Angew. Chem., Int. Ed. 2019, 58, 10990−10994.
E
DOI: 10.1021/acs.orglett.9b02662
Org. Lett. XXXX, XXX, XXX−XXX