Synthesis of medicinally interesting polyfluoro ketones via perfluoroalkyl lithium reagents

Article abstract of DOI:10.1021/jo801469x

(Chemical Equation Presented) The addition of (pentafluoroethyl)- and (heptafluoropropy-1)lithium to various acyl derivatives was studied. Weinreb and morpholine amides led to polyfluoro ketones in high to quantitative yields in short reaction times. Derivatives of 2-fluorocarboxylic acids may produce 1,1,1,2,2,4-hexafluoro ketones and 1,1,1,2,2,3,3,5-octafluoro ketones. The methodology can provide inhibitors for various lipolytic enzymes, including phospholipase A₂.

Full text of DOI:10.1021/jo801469x

A2 classes,9 most recently we have found that 1,1,1,2,2-
pentafluoro-7-phenylheptan-3-one (FKGK11) is a potent and
selective inhibitor of human calcium-independent phospholipase
A2 (GVIA iPLA2)10 that exhibits a very interesting therapeutic
activity in experimental autoimmune encephalomyelitis, the
animal model of multiple sclerosis, and is a valuable tool to
understand the role of intracellular phospholipase A2 in periph-
eral nerve injury.11 Since we have observed that the pentafluo-
roethyl ketone functionality favors GVIA iPLA2 inhibition, we
were interested in developing synthetic methods leading to the
synthesis of FKGK11 and other related pentafluoroethyl ketones
in high yields. In the present work, we present our studies on
the synthesis of pentafluroethyl and heptafluoropropyl ketones
through the nucleophilic addition of organolithium reagents to
various acyl derivatives.
Synthesis of Medicinally Interesting Polyfluoro
Ketones via Perfluoroalkyl Lithium Reagents
Christoforos G. Kokotos, Constantinos Baskakis, and
George Kokotos*
Laboratory of Organic Chemistry, Department of Chemistry,
UniVersity of Athens, Panepistimiopolis,
Athens 15771, Greece
gkokotos@chem.uoa.gr
ReceiVed July 4, 2008
The synthesis of 1,1,1,2,2-pentafluoro-7-phenylheptan-3-one10
was accomplished by conversion of 5-phenylpentanoic acid to
the corresponding chloride followed by treatment with pen-
tafluoropropionic anhydride in the presence of pyridine, ac-
cording to a method12 widely used for the synthesis of
trifluoromethyl ketones. However, this method led to a moderate
yield.10 In literature, methods for the synthesis of pentafluoro-
ethyl ketones include the treatment of phosphonium ylides with
perfluoroalkyl anhydrides13 or esters,14 the addition of phenyl-
lithium to ethyl pentafluoroacetate,15 and the addition of
(pentafluoroethyl)lithium to an aldehyde followed by oxida-
tion.16 Gassman has shown that (pentafluoroethyl)lithium adds
to aldehydes and ketones producing the corresponding secondary
and tertiary alcohols in high yields, while in the case of esters
either ketones or tertiary alcohols are produced in high yields.17
Peptidyl pentafluoroethyl ketones have been prepared by treat-
ment of peptidyl Weinreb amides with (pentafluoroethyl)lith-
ium.5-7,18 The synthesis of peptidyl pentafluoroethyl and
heptafluoropropyl ketones through the reaction of peptide esters
with (perfluoroalkyl)lithium reagents has also been reported.19
In addition, trifluoromethyl and pentafluoroethyl ketones have
The addition of (pentafluoroethyl)- and (heptafluoropropy-
l)lithium to various acyl derivatives was studied. Weinreb
and morpholine amides led to polyfluoro ketones in high to
quantitative yields in short reaction times. Derivatives of
2-fluorocarboxylic acids may produce 1,1,1,2,2,4-hexafluoro
ketones and 1,1,1,2,2,3,3,5-octafluoro ketones. The meth-
odology can provide inhibitors for various lipolytic enzymes,
including phospholipase A2.
In contemporary medicinal chemistry, fluorine substituents
have gained special attention since they may affect either the
drug metabolic stability or the binding affinity in protein-ligand
complexes.1,2 The latter can be a direct effect by interaction of
the fluorine with the protein, or an indirect effect by modulation
of the polarity of other groups of the ligand that interact with
the protein. Since the early report on the design of di- and
trifluoromethyl ketones as inhibitors of serine proteases,3 a great
variety of trifluoromethyl ketones have been synthesized and
studied as inhibitors of various enzymes.4 Furthermore, peptidyl
pentafluoroethyl ketones have been reported to inhibit various
enzymes, for example, elastase5 and hepatitis C virus N53
protease.6,7 Some fluoroketone inhibitors of proteases have
entered clinical trials.8 In the course of our studies for the
development of selective inhibitors for the various phospholipase
(7) Perni, R. B.; Pitlik, J.; Britt, S. D.; Court, J. J.; Courtney, L. F.; Deininger,
D. D.; Farmer, L. J.; Gates, C. A.; Harbeson, S. L.; Levin, R. B.; Lin, C.; Lin,
K.; Moon, Y.-C.; Luong, Y.-P.; O’Malley, E. T.; Rao, B. G.; Thomson, J. A.;
Tung, R. D.; Van Drie, J. H.; Wei, Y. Bioorg. Med. Chem. Lett. 2004, 14, 1441–
1446.
(8) For a review see: Leung, D.; Abbenante, G.; Fairlie, D. P. J. Med. Chem.
2000, 43, 305–341.
(9) Six, D. A.; Barbayianni, E.; Loukas, V.; Constantinou-Kokotou, V.;
Hadjipavlou-Litina, D.; Stephens, D.; Wong, A. C.; Magrioti, V.; Moutevelis-
Minakakis, P.; Baker, S.; Dennis, E. A.; Kokotos, G. J. Med. Chem. 2007, 50,
4222–4235, and references cited therein.
(10) Baskakis, C.; Magrioti, V.; Cotton, N.; Stephens, D.; Constantinou-
Kokotou, V.; Dennis, E. A.; Kokotos, G. J. Med. Chem. Submitted for
publication.
(11) Lopez-Vales, R.; Navarro, X.; Shimizu, T.; Baskakis, C.; Kokotos, G.;
Constantinou-Kokotou, V.; Stephens, D.; Dennis, E. A.; David, S. Brain. doi
10.1093/brain/awn188.
(12) Boivin, J.; Kaim, L. E.; Zard, S. Z. Tetrahedron 1995, 51, 2573–2584.
(13) Qui, W. M.; Shen, Y. C. J. Fluorine Chem. 1988, 38, 249–256.
(14) Begue, J. P.; Bonnet-Delpon, D.; Mesureur, D.; Nee, G.; Wu, S. W. J.
Org. Chem. 1992, 57, 3807–3814.
(1) Mu¨ller, K.; Faeh, C.; Diederich, F. Science 2007, 317, 1881–1886.
(2) Bohm, H.-J.; Banner, D.; Bendels, S.; Kansy, M.; Kuhn, B.; Muller, K.;
Obst-Sander, U.; Stahl, M. ChemBioChem 2004, 5, 637–643.
(3) Gelb, M. H.; Svaren, J. P.; Abeles, R. H. Biochemistry 1985, 24, 1813–
1817.
(4) For a review see: Begue, J.-P.; Bonnet-Delpon, D. Tetrahedron 1991,
47, 3207–3258.
(15) Chen, L. S.; Chen, G. J.; Tamborski, C. J. Fluorine Chem. 1981, 18,
117–129.
(16) Ueda, T.; Kam, C.-M.; Powers, J. C. Biochem. J. 1990, 265, 539–545.
(17) Gassman, P. G.; O’Reilly, N. J. J. Org. Chem. 1987, 52, 2481–2490.
(18) Angelastro, M. R.; Burkhart, J. P.; Bay, P.; Peet, N. P. Tetrahedron
Lett. 1992, 33, 3265–3268.
(5) Angelastro, M. R.; Baugh, L. E.; Bey, P.; Burkhart, J. P.; Chen, T.-M.;
Durham, S. L.; Hare, C. M.; Huber, E. W.; Janusz, M. J.; Koehl, J. R.; Marquart,
A. L.; Mehdi, S.; Peet, N. P. J. Med. Chem. 1994, 37, 4538–4554.
(6) Johansson, A.; Poliakov, A.; Akerblom, E.; Wiklund, K.; Lindeberg, G.;
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Chem. 2003, 11, 2551–2568.
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10.1021/jo801469x CCC: $40.75
Published on Web 10/10/2008
2008 American Chemical Society
J. Org. Chem. 2008, 73, 8623–8626 8623

TABLE 1. Nucleophilic Addition of (Pentafluoroethyl)lithium to
Various Acyl Derivatives
been synthesized by treatment of the lithium salts of tetrapep-
tides with perfluoroalkyl anhydrides.20 Thus, we decided to study
the reaction of (pentafluoroethyl)lithium and (heptafluoropro-
pyl)lithium with various acyl derivatives, including unactivated
and activated esters, acyl fluoride, anhydrides, and amides.
5-Phenylpentanoic acid was chosen as a model substrate and
was converted into the corresponding fluoride, pentafluorophenyl
ester, Weinreb amide, and morpholine amide according to
known methods. The symmetric anhydride of 5-phenylpentanoic
acid as well as the mixed anhydride with monoisobutyl
carbonate were prepared and used in situ. In all cases organo-
lithium reagents were prepared in situ by reaction of pentafluo-
roethyl or heptafluoropropyl iodide with MeLi ·LiBr at -78 °C.
The results of the addition of (pentafluoroethyl)lithium on the
various acyl derivatives are summarized in Table 1.
The methyl ester of 5-phenylpentanoic acid led to a separable
mixture (approximately equimolar) of the corresponding ketone
2 and the tertiary alcohol 3 after 30 min (entry 1, Table 1),
whereas prolonged reaction time led exclusively to tertiary
alcohol 3 (entry 2, Table 1). Direct reaction of the carboxylic
acid with (pentafluoroethyl)lithium produced ketone 2 as a sole
product in low yield, only after 20 h (entries 3 and 4, Table 1).
Activated pentafluorophenyl ester gave tertiary alcohol 3 in high
yield, even after 3 min (entries 5 and 6, Table 1). After 90 min,
alcohol 3 was obtained from acyl fluoride, whereas in short
reaction time the conversion was low and a negligible amount
of ketone 2 was isolated (entries 7 and 8, Table 1). Symmetric
anhydride led to mixtures of 2 and 3 after either 90 or 20 min
(entries 9 and 10, Table 1).
Mixed anhydride led again to a mixture of products (entry
11, Table 1). Primary amide was unable to react within a short
time (entry 12, Table 1); however, both Weinreb amide and
morpholine amide led to the desired product. Ketone 2 was
isolated in almost quantitative yield after 60 to 90 min (entries
13 and 14, Table 1). Also, morpholine amide led to ketone in
high yield after 60 min, while prolonged reaction time has as a
result the decrease of ketone yield, accompanied by an amount
of alcohol 3 (entries 15 and 16, Table 1). As expected, Weinreb
and morpholine functionalities stabilize via chelation of the
tetrahedral intermediate leading to polyfluoro ketones.
To extend the substrate scope, we studied the reaction of five
different amide substrates. Both Weinreb and morpholine amides
of oleic acid gave the corresponding ketone 5 in excellent yields
in 60 min (entries 1 and 2, Table 2). In the same reaction time,
the Weinreb amide of cinnamic acid produced the corresponding
ketone in 74% yield. It should be noticed that in the case of
R,ꢀ-unsaturated carboxylic acids, the synthesis of the corre-
sponding polyfluoro ketones by the general method12 consisting
of the conversion of the acid to chloride and treatment with
perfluoroalkyl anhydride is not feasible. We also studied the
reaction of amides of 5-(4-hexyloxyphenyl)pentanoic acid,
because we had observed that the trifluoromethyl ketone
corresponding to this chain is a potent inhibitor of both
intracellular GIVA cPLA2 and GVIA iPLA2 enzymes.10 In both
cases, the conversion was low within the reaction time studied
and ketone 5 was isolated in low yield (entries 4 and 5, Table
2), indicating that longer reaction times have to be explored,
depending on the substrate. In all cases of Table 2, no tertiary
alcohol was isolated.
a Isolated yield.
On the basis of the successful results described in Table 1,
we studied the corresponding reactions with (heptafluoropro-
pyl)lithium. The results in Table 3 show that only Weinreb
amides gave excellent yields of the ketones.
In addition, we studied the synthesis of pentafluoroethyl and
heptafluoropropyl ketones through a two-step procedure and the
results are summarized in Table 4. Both (pentafluoroethyl)- and
(heptafluoropropyl)lithium reacted with 5-phenylpentanal to
produce the secondary alcohols 9 in high to quantitative yield
(entries 1 and 2, Table 4). Oleyl aldehyde produced the
(20) Jose, B.; Oniki, Y.; Kato, T.; Nishino, N.; Sumida, Y.; Yoshida, M.
Bioorg. Med. Chem. Lett. 2004, 14, 5343–5346.
8624 J. Org. Chem. Vol. 73, No. 21, 2008

TABLE 2. Nucleophilic Addition of (Pentafluoroethyl)lithium to
Various Amide Substrates
TABLE 4. Nucleophilic Addition of (Perfluoroalkyl)lithium to
Aldehydes
a Isolated yield.
a Isolated yield.
TABLE 5. Nucleophilic Addition of (Perfluoroalkyl)lithium to
r-Fluoro Acyl Derivatives
TABLE 3. Nucleophilic Addition of (Heptafluoropropyl)lithium to
Various Acyl Derivatives
a Isolated yield.
In conclusion, we studied the addition of (pentafluoroethyl)-
and (heptafluoropropyl)lithium to various acyl derivatives and
we ended up with Weinreb and morpholine amides leading to
polyfluoro ketones in high to quantitative yields in short reaction
times. A synthetic protocol leading to FKGK11 and related
compounds in high yields was developed and new hexafluoro
and octafluoro ketones were prepared via (perfluoroalkyl)lithium
reagents. Thus, the present study provides methodology for the
synthesis of potential inhibitors for phospholipase A2 and other
lipolytic enzymes, like, for example the enzymes involved in
the endocannabinoid system.
a Isolated yield.
corresponding secondary alcohol (entry 3, Table 4). In the case
of 2-fluoro-5-phenylpentanal, alcohol 9 was obtained in a short
reaction time (entry 4, Table 4). All the secondary alcohols 9
were converted to the desired polyfluoro ketones in high yields
by Dess-Martin oxidation (Table 4). 1,1,1,2,2,4-Hexafluoro
ketones and 1,1,1,2,2,3,3,5-octafluoro ketones may present
special interest as potential enzyme inhibitors and to our
knowledge such polyfluoro ketones have not been synthesized
and studied up to now. To this end, we studied the addition of
(perfluoroalkyl)lithium reagents to Weinreb and morpholine
amides of 2-fluoro-5-phenylpentanoic acid. Both amides gave
the desired ketones in high yields in 30 to 60 min (entries 1, 2,
and 3, Table 5). Even 2-fluoro carboxylic acid was converted
to polyfluoro ketone 11 in moderate yield after 4 h. It should
be noticed that a 2-fluoro carboxylic acid cannot be converted
into the corresponding pentafluoroethyl ketone by conversion
to chloride followed by treatment with pentafluoropropionic
anhydride in the presence of pyridine, probably because the
intermediate ketene required for such a transformation12 cannot
be formed.
Experimental Section
General Procedure for the (Perfluoroalkyl)lithium Addition to
Carbonyl Compounds. To a stirring solution of acyl derivative (0.36
mmol) in Et2O (5 mL) at -78 °C was added pentafluoroiodoethane
(1.80 mmol) or heptafluoroiodopropane (1.80 mmol) followed by
dropwise addition of a MeLi·LiBr solution 1.6 M in ether (1.80
mmol). The reaction mixture was stirred at -78 °C and monitored
by TLC. Once the reaction was finished, the reaction mixture was
poured into H2O and acidified with a 10% solution of KHSO4 (pH
5). The layers were separated and the aqueous layer was extracted
with Et2O (3 × 15 mL). The combined organic layers were washed
with a 5% solution of NaHCO3 (40 mL) and dried over MgSO4.
J. Org. Chem. Vol. 73, No. 21, 2008 8625

The organic solvent was evaporated in vacuo and the residue was
purified, when needed, by column chromatography, eluting with
the appropriate petroleum ether (40-60 °C):EtOAc mixture.
1,1,1,2,2-Pentafluoro-7-phenylheptan-3-one.10 Rf 0.60(EtOAc-
t, J ) 6.6 Hz), 1.76-1.57 (4H, m); 13C NMR (50 MHz, CDCl3) δ
193.9 (t, J ) 26.0 Hz), 141.6, 128.4, 128.3, 125.9, 128.2-103.3
(m), 37.7, 35.4, 30.3, 21.9; 19F NMR (186 MHz, CDCl3) δ -15.9
(3F, t, J ) 9.0 Hz), -56.5 (2F, m), -62.0 (2F, s); MS (ESI) m/z
(%) 329 (M-, 100), 169 (C3F7-, 62). Anal. Calcd for C14H13F7O:
C, 50.92; H, 3.97. Found: C, 50.69; H, 4.16.
1
petroleum ether 5:95); IR (KBr) 1760 cm-1; H NMR (200 MHz,
CDCl3) δ 7.37-7.09 (5H, m), 2.79 (2H, t, J ) 6.2 Hz), 2.67 (2H,
t, J ) 6.6 Hz), 1.79-1.59 (4H, m); 13C NMR (50 MHz, CDCl3) δ
194.2 (t, J ) 26.0 Hz), 141.6, 128.4, 128.3, 125.9, 117.8 (qt, J )
287.0, 34.0 Hz), 106.8 (tq, J ) 267.0, 38.0 Hz), 37.1, 35.5, 30.3,
21.9; 19F NMR (186 MHz, CDCl3) δ -17.2 (3F, s), -58.6 (2F, s);
MS (ESI) m/z (%) 279 (M-, 27), 119 (C2F5-, 100).
1,1,1,2,2,3,3-Heptafluoro-8-henicos-12-en-4-one. Rf 0.85 (EtOAc:
1
petroleum ether 3:7); IR (KBr) 1735 cm-1; H NMR (200 MHz,
CDCl3) δ 5.38-5.24 (2H, m), 2.72 (2H, t, J ) 7.0 Hz), 2.11-1.85
(4H, m), 1.71-1.56 (2H, m), 1.43-1.03 (20H, m), 0.86 (3H, t, J
) 6.2 Hz); 13C NMR (50 MHz, CDCl3) δ 194.4 (t, J ) 25.4 Hz),
130.3, 129.8, 129.8-102.8 (m), 38.1, 32.1, 30.0, 29.9, 29.8, 29.7,
29.5, 29.3, 29.2, 28.9, 27.4, 27.3, 22.9, 22.6, 14.3; 19F NMR (186
MHz, CDCl3) δ -15.9 (3F, t, J ) 9.1 Hz), -56.5 (2F, m), -62.0
(2F, s); MS (ESI) m/z (%) 433 (M-, 9), 169 (C3F7-, 100). Anal.
Calcd for C21H33F7O: C, 58.05; H, 7.66. Found: C, 57.88; H, 7.94.
1,1,1,2,2,3,3,5-Octafluoro-8-phenyloctan-4-one. Rf 0.75 (EtOAc:
1,1,1,2,2-Pentafluoro-7-icos-11-en-3-one. Rf 0.90 (EtOAc:pe-
1
troleum ether 3:7); IR (KBr) 1756 cm-1; H NMR (200 MHz,
CDCl3) δ 5.41-5.21 (2H, m), 2.73 (2H, t, J ) 7.0 Hz), 2.07-1.91
(4H, m), 1.74-1.59 (2H, m), 1.41-1.15 (20H, m), 0.87 (3H, t, J
) 6.2 Hz); 13C NMR (50 MHz, CDCl3) δ 194.6 (t, J ) 26.5 Hz),
130.2, 129.8, 118.1 (qt, J ) 284.9, 34.1 Hz), 107.1 (tq, J 264.8,
37.5 Hz), 37.5, 32.1, 30.0, 29.9, 29.8, 29.6, 29.5, 29.4, 29.3, 29.2,
1
petroleum ether 3:7); IR (KBr) 1766 cm-1; H NMR (200 MHz,
27.4, 27.3, 22.9, 22.5, 14.2; 19F NMR (186 MHz, CDCl3) δ -17.3
CDCl3) δ 7.38-7.03 (5H, m), 5.25 (1H, ddd, J ) 48.0, 8.2, 3.9
Hz), 2.68 (2H, m), 2.01-1.75 (4H, m); 13C NMR (150 MHz,
CDCl3) δ 190.5 (ddd, J ) 27.3, 25.6, 22.3 Hz), 141.0, 128.7, 128.6,
126.4, 119.5-105.6 (m), 92.3 (d, J ) 186.7 Hz), 35.2, 30.9 (d, J
) 21.2 Hz), 26.2; 19F NMR (186 MHz, CDCl3) δ -15.7 (3F, t, J
) 8.9 Hz), -54.7 (2F, dq, J ) 78.8, 8.9 Hz), -61.3 (2F, d, J )
7.5 Hz), -131.8 (1F, m); MS (ESI) m/z (%) 347 (M-, 100). Anal.
Calcd for C14H12F8O: C, 48.29; H, 3.47. Found: C, 48.07; H, 3.59.
-
(3F, s), -58.7 (2F, s); MS (ESI) m/z (%) 383 (M-, 89), 119 (C2F5
,
100). Anal. Calcd for C20H33F5O: C, 62.48; H, 8.65. Found: C,
62.32; H, 8.84.
1,1,1,2,2-Pentafluoro-7-(4-hexyloxyphenyl)heptan-3-one. Rf
0.90 (EtOAc:petroleum ether 3:7); IR (KBr) 1755 cm-1; 1H NMR
(200 MHz, CDCl3) δ 7.06 (2H, d, J ) 8.4 Hz), 6.83 (2H, d, J )
8.4 Hz), 3.93 (2H, t, J ) 6.6 Hz), 2.75 (2H, t, J ) 6.6 Hz), 2.58
(2H, t, J ) 6.2 Hz), 1.81-1.57 (6H, m), 1.55-1.21 (6H, m), 0.91
(3H, t, J ) 6.8 Hz); 13C NMR (50 MHz, CDCl3) δ 194.5 (t, J )
26.5 Hz), 157.7, 133.7, 129.4, 118.1 (qt, J ) 285.3, 33.7 Hz), 114.7,
107.1 (tq, J ) 265.2, 37.9 Hz), 68.2, 37.4, 34.8, 31.8, 30.8, 29.5,
Acknowledgment. The project is cofunded by the European
Social Fund and National Resources (EPEAEK II).
26.0, 22.8, 22.1, 14.3; 19F NMR (186 MHz, CDCl3) δ -17.2 (3F,
Supporting Information Available: Detailed procedures and
-
1
s), -58.6 (2F, s); MS (ESI) m/z (%) 379 (M-, 100), 119 (C2F5
,
characterization data for all compounds and H and 13C NMR
26). Anal. Calcd for C19H25F5O2: C, 59.99; H, 6.62. Found: C,
59.78; H, 6.83.
spectra for polyfluoro ketones and polyfluoro alcohols. This
material is available free of charge via the Internet at
http://pubs.acs.org.
1,1,1,2,2,3,3-Heptafluoro-8-phenyloctan-4-one. Rf 0.60 (EtOAc:
1
petroleum ether 5:95); IR (KBr) 1732 cm-1; H NMR (200 MHz,
CDCl3) δ 7.33-7.12 (5H, m), 2.77 (2H, t, J ) 6.2 Hz), 2.66 (2H,
JO801469X
8626 J. Org. Chem. Vol. 73, No. 21, 2008