Fluorobis(phenylsulfonyl)methane: A fluoromethide equivalent and palladium-catalyzed enantioselective allylic monofluoromethylation

Article abstract of DOI:10.1002/anie.200600625

Selective introduction of fluorine: Monofluoromethylation with the fluoromethide equivalent fluorobis(phenylsulfonyl)methane (1) was crucial in the syntheses of the pharmacologically important compounds monofluorinated (S)-ibuprofen ((S)-2) and 5-deoxy-5-

Full text of DOI:10.1002/anie.200600625

Angewandte
Chemie
Monofluoromethylation
(phenylsulfonyl)methane (1) acts as a synthetic equivalent for
the monofluoromethide species. We found that the palladium-
DOI: 10.1002/anie.200600625
Fluorobis(phenylsulfonyl)methane: A
Fluoromethide Equivalent and Palladium-
Catalyzed Enantioselective Allylic
Monofluoromethylation**
Takeo Fukuzumi, Norio Shibata,* Masayoshi Sugiura,
Hiroyuki Yasui, Shuichi Nakamura, and Takeshi Toru*
The development of efficient methodology for the synthesis
of fluoroorganic compounds has attracted considerable
attention particularly in the field of medicinal chemistry.[1]
Owing to their unique and significant biological properties,
fluorinated drugs have been commonly used in the treatment
of a variety of diseases. Fluorination and fluoroalkylation
reactions are two straightforward operations for the con-
struction of fluorine-containing molecules, and their asym-
metric versions are particularly useful.[2] Enantioselective
electrophilic fluorination and enantioselective nucleophilic
trifluoromethylation reactions probably represent the most
versatile methodologies available for this purpose;[3] however,
we are not aware of any reports of successful enantioselective
catalyzed asymmetric allylic fluorobis(phenylsulfonyl)methy-
lation reaction of allyl acetates 2 utilizing 1 smoothly proceed
to afford the fluorobis(phenylsulfonyl)methylated com-
pounds 3 with very high enantioselectivity up to 97% ee.
We also show how this methodology can be applied to the
synthesis of monofluoromethylated compounds, enantiopure
methyl-fluorinated ibuprofens (S)-and ( R)-4 by reductive
desulfonylation and oxidation of 3a. An efficient access to
fluorinated b-d-carbaribofuranose 5 from 3 f is also de-
scribed.
Inspired by the reports on difluoromethylation by the
groups led by Prakash,[8a] Olah,[8a] and Hu,[8a,b] with difluor-
ophenylsulfonylmethane,[8] we envisaged that 1-fluorobis-
(phenylsulfonyl)methane (1) would be a useful reagent for
enantioselective monofluoromethylation in the palladium-
catalyzed allylic substitution reaction, which has been studied
in detail by us[9] and others.[10] The previously unknown
compound 1 was easily prepared in good yield from bis(phen-
ylsulfonyl)methane, CH2(SO2Ph)2, by monofluorination with
Selectfluor or molecular fluorine.[11a] Palladium-catalyzed
fluorobis(phenylsulfonyl)methylation of (2E)-1,3-bis(4-iso-
butylphenyl)-2-propenyl acetate (2a) with 1 was carried out
in the presence of catalytic amounts of [{Pd(C3H5)Cl}2] and
(S)-1-(1’-diphenylphosphino)ferrocenyl-1’’-naphthyl sulfox-
ide ((S)-PHFS)[9] or (4S)-2-(2-diphenylphosphinophenyl)-4-
isopropyl-1,3-oxazoline ((S)-PHOX)[10c–e] at 08C (Table 1).
monofluoromethylation reactions.[3d] Compounds with
a
monofluoromethyl unit are of great importance with regards
to isostere-based drug design.[4] Indeed, monofluoroacetic
acid is responsible for “lethal synthesis”, and it blocks the
tricarboxylic acid cycle (Krebs cycle).[5] Monofluoromethy-
lated amino acids such as d-fluoroalanine are well known to
act as “suicide substrates” causing inactivation of the enzyme
by alkylative capture of the aminoacrylate-pyridoxal-P spe-
cies.[6] In connection with our work on the asymmetric
syntheses of fluorine-containing organic compounds,[7] we
required a novel methodology for an enantioselective mono-
fluoromethylation reaction. Herein we disclose our first step
toward achieving this goal by demonstrating that 1-fluorobis-
[*] Prof. Dr. N. Shibata, Prof. Dr. T. Toru
Department of Applied Chemistry
Graduate School of Engineering, Nagoya Institute of Technology
Gokiso, Showa, Nagoya 466-8555 (Japan)
Fax: (+81)52-735-5442
E-mail: nozshiba@nitech.ac.jp
toru@nitech.ac.jp
T. Fukuzumi, M. Sugiura, H. Yasui, Dr. S. Nakamura
Department of Applied Chemistry
Graduate School of Engineering, Nagoya Institute of Technology
Gokiso, Showa, Nagoya 466-8555 (Japan)
[**] This research was supported in part by a Grant-in-Aid for Scientific
Research fromthe Ministry of Education, Culture, Sports, Science
and Technology, Japan (17350047, 17590087) and by Japan Science
& Technology (JST) Agency, Innovation Plaza Tokai. T.F. is grateful
for research fellowships fromJSPS. We thank Dr. Jon Bordner, Shin-
ichi Sakemi, and Dr. Masami Nakane, Pfizer Inc., for X-ray
crystallographic analysis.
First, the allylic substitution was examined under our
previously optimized conditions using (S)-PHFS in the
presence of cesium carbonate; however, the result was
disappointing (Table 1, run 1). Next, (S)-PHOX was used as
Supporting information for this article is available on the WWW
under http://www.angewandte.org or fromthe author.
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Table 1: Optimization of the palladium-catalyzed enantioselective allylic fluorobis(phenylsulfonyl)me-
thylation of 2a.
conjugate base. The high reactivity of 1 even
at low temperatures might arise from the
increased acidity of 1 as a result of the
electron-withdrawing ability of fluorine.
However, the effect of a-fluorine substitu-
tion on the stability of an anion generally
arises from a compromise between its
inductive electron-withdrawing ability and
the repulsion between its electron pair and
that on the carbanionic center.[12] The low
stability of the conjugate base of 1 at higher
temperatures could be the reason for the
poor yield in run 11.
The 1-fluorobis(phenylsulfonyl)methy-
lation reaction was also applied to a variety
of allylic acetates (Table 2). Allylic acetates
2b–f having methoxyphenyl, bromophenyl,
and naphthyl groups were smoothly mono-
fluoromethylated to furnish the desired
fluorobis(phenylsulfonyl)methylated prod-
ucts 3b–f in acceptable to high yields with
high enantioselectivities (Table 2, entries 1–
8).[13a] The reason for the loss in chemical
yield for 3c,d (Table 2, entries 2 and 5) is the
partial decomposition of 2c,d. The yield was
improved when the reaction was carried out
Run
Ligand
Base
Solvent[a]
t [h]
Yield [%]/ee[b] [%]
1
2
3
4
5
6
7
8
(S)-PHFS
(S)-PHOX
(S)-PHOX
(S)-PHOX
(S)-PHOX
(S)-PHOX
(S)-PHOX
(S)-PHOX
(S)-PHOX
(S)-PHOX
(S)-PHOX
Cs2CO3
BSA[d]
K2CO3
CH2Cl2 (0.1m)
CH2Cl2 (0.1m)
CH2Cl2 (0.1m)
THF (0.1m)
6
17
14
9
30/9[c]
14/90
31/94
39/96
16/94
12/97
50/94
33/95
83/94
trace/65[h]
23/89
NaH[e]
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
NaH[e]
THF (0.1m)
9
6
CH2Cl2 (0.1m)
CH2Cl2 (0.1m)
CH2Cl2 (0.5m)
CH2Cl2 (1.0m)
CH2Cl2 (1.0m)
dioxane (0.3m)
12[f]
6
9
6
10[g]
11[i]
24[f]
48
[a] The concentration refers to 2a. [b] The ee value was determined by HPLC analysis using CHIRALPAK
AD-H. The absolute stereochemistry was tentatively assigned by comparing the optical rotation of 3a
with that of a non-fluorinated derivative of 3a.[10a,13b] [c] (S)-3a was obtained. [d] The reaction was carried
out in the presence of CsOAc (0.1 equiv). [e] Preformed NaCF(SO2Ph)2 was used. [f] The reaction was
carried out at roomtemperature. [g] CH 2(SO2Ph)2 was used as a nucleophile instead of 1. [h] A non-
fluorinated analogue of (R)-3a was obtained. [i] The reaction was carried out at 738C.
a chiral ligand. Bis(trimethylsilyl)acetamide (BSA) and a
catalytic amount of cesium acetate were examined as
promoters for the reaction according to the procedure
established for palladium-catalyzed allylic substitution using
bis(phenylsulfonyl)methane.[10a] After overnight stirring at
08C, the desired 1-fluorobis(phenylsulfonyl)methylated prod-
uct (R)-3a was obtained with 90% ee, while the conversion
was only 14% (Table 1, run 2). With potassium carbonate or
sodium hydride as a base, the enantioselectivities increased to
96% ee, but the conversion was still low (Table 1, runs 3 and
4). Then the reaction was examined using cesium carbonate as
a base in the concentration range 0.1–1.0m (Table 1, runs 5–
9). The adduct (R)-3a was produced in satisfactory yield with
very high enantioselectivity when the reaction was carried out
with Cs2CO3 at a concentration of 1.0m (Table 1, run 9).[11b] It
should be noted that fluorine substitution has a striking effect
on the reactivity and enantioselectivity of 1 (Table 1, cf. runs 9
and 10). As mentioned above, the allylic substitution reaction
with 1 proceeds smoothly at temperatures below 08C within
several hours and with very high enantioselectivity. In
contrast, the non-fluorinated bis(phenylsulfonyl)methane,
CH2(SO2Ph)2, has rather poor reactivity in allylic substitution
reaction even at room temperature over 24 h, and therefore,
the corresponding addition requires heating at, for example,
738C for 48 h.[10a] Only trace amount of the non-fluorinated
analogue of 3a was obtained with lower enantioselectivity
(65% ee) (Table 1, cf. runs 9 and 10). On the other hand,
when the reaction of 2a with 1 was carried out at elevated
temperatures[10a] (i.e. the optimal conditions for CH2-
(SO2Ph)2), the yield and enantioselectivity decreased
(Table 1, run 11). It may be possible to explain the difference
in reactivity between 1 and CH2(SO2Ph)2 in terms of the
acidity of 1 relative to CH2(SO2Ph)2 and the stability of its
under slightly modified conditions (amounts of reagents,
reaction temperature; Table 2, entries 2–6). The opposite
enantiomer, (S)-3a, is accessible from 2a when (R)-PHOX is
used as a catalyst ligand (Table 2, entry 9).[13b]
After testing acyclic electrophiles in our enantioselective
allylic 1-fluorobis(phenylsulfonyl)methylation reaction with
1, we next examined a similar process with cyclic electro-
philes. Those with five-or six-membered rings are especially
interesting since the products should be useful for the
synthesis of fluorinated analogues of biologically important
Table 2: Palladium-catalyzed enantioselective allylic fluorobis(phenylsul-
fonyl)methylation of allylic acetates 2a–f.
Entry
2
Ar
3
Yield [%]
ee [%][a]
1
2
2b
2c
2c
2c
2d
2d
2e
2 f
2a
Ph
3b
3c
3c
3c
3d
3d
3e
3 f
3a
92
96 (R)[e]
94
97
4-MeOC6H4
4-MeOC6H4
4-MeOC6H4
4-BrC6H4
58
3[b]
4[c]
5
22[b]
74
91
54
95 (R)[e]
94 (R)[e]
92
6[b]
7
4-BrC6H4
69[b]
89
2-naphthyl
2-(6-methoxynaphthyl)
iBuC6H4
8
72
89
91
9[d]
91 (S)[e]
[a] Determined by HPLC analysis using CHIRALPAK AD-H or OD-H.
[b] Reaction conditions: 1 (1.0 equiv), 2 (2.0 equiv), Cs2CO3 (2.0 equiv),
2.5 mol% [{Pd(C3H5)Cl}2], and 5 mol% (S)-PHOX at roomtemperature
for 6 h. Yield is based on 1. [c] The reaction was carried out at room
temperature for 6 h. [d] (R)-PHOX (5 mol%) was used instead of (S)-
PHOX. [e] See reference [13b].
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Angewandte
Chemie
molecules.[10b] A series of chiral ligands commonly employed
were examined under conditions similar to those described
above. We found that (+)-1,2-bis-N-[2’-(diphenylphosphino)-
benzoyl]-(1R,2R)-diaminocyclohexane ((R,R)-DPPBA)[10f]
was effective for the desymmetrization of the meso diester
2g with 1 in the presence of [{Pd(C3H5)Cl}2] and Cs2CO3 to
afford the 1-fluorobis(phenylsulfonyl)methylated adduct 3g
in 87% yield with 95% ee (Scheme 1). Similarly, racemic
acetate 2h underwent efficient enantioselective reaction with
1 under the same conditions to provide enantioenriched 3h in
75% with 96% ee.[13c]
Scheme 2. Enantioselective synthesis of methylfluorinated ibuprofen 4.
NaBH4 gave the monofluoromethylated alchohols (S)-and
(R)-6 in yields of 87% and 85%, respectively, without major
loss of enantiopurity (91% ee). The removal of the sulfonyl
group at the fluorinated carbon by reaction with activated Mg
in methanol afforded the chiral monofluoromethylated com-
pounds (S)-and ( R)-7, and subsequent oxidation with the
Jones reagent gave the S and R enantiomers of 4,[17] which
were previously unknown.[16]
Carbafuranose is a synthetic target attracting much recent
interest in view of both its enzyme inhibitor activities and
antiviral properties.[18] Fluorinated carbohydrates have also
recently received attention for their important role in the
study of enzyme–carbohydrate interactions as well as their
biological activities.[19] Therefore, fluoro sugars with a carbo-
cyclic framework have emerged as important tools in this
area. We examined the synthesis of 5-deoxy-5-fluoro-b-d-
carbaribofuranose (5). The 1-fluorobis(phenylsulfonyl)me-
thylated adduct 3g (Scheme 1) underwent an osmium-cata-
lyzed diastereoselective dihydroxylation; subsequent treat-
ment with 2,2-dimethoxypropane furnished acetonide 8 in
71% yield (Scheme 3). Reductive double-desulfonylation of 8
Scheme 1. Palladium-catalyzed enantioselective allylic fluorobis(phenyl-
sulfonyl)methylation of cyclic acetates 2g,h.
With facile access to this range of enantioenriched
monofluorinated organic compounds, we next considered
synthetic applications. Ibuprofen, a widely marketed non-
steroidal anti-inflammatory drug (NSAID), is an interesting
compound in terms of the pharmacokinetics of its enantio-
mers.[14] Ibuprofen exists as both R and S enantiomers, and it
was revealed the metabolic chiral inversion of (R)-ibuprofen
to the pharmacologically active S enantiomer occurs in
humans. Racemic ibuprofen has been prescribed worldwide,
and the S isomer, called dexibuprofen, is marketed in Austria
and Switzerland. The physico-chemical and pharmacological
properties and metabolic profiles of racemic ibuprofen and
dexibuprofen are quite different, and a better understanding
may be possible from studies of chiral derivatives of
ibuprofen. A variety of ibuprofen derivatives have been
prepared for this purpose including fluorinated ibuprofens;[15]
we are interested in the previously unknown ibuprofen
derivative 4, which bears a fluoromethyl group.[16] Only the
R enantiomer of 4 could potentially an act as a suicide
substrate by b elimination of HF by the enzyme during the
chiral-inversion step, and it might consequently shed new
light on the study of the pharmacokinetics of the enantiomers.
To show the utility of our palladium-catalyzed enantioselec-
tive fluorobis(phenylsulfonyl)methylation reaction, we next
applied the method for the synthesis of the ibuprofen
analogues (S)-and ( R)-4 (Scheme 2). Similar to the conven-
tional synthesis of ibuprofen,[10a] ozonolysis of (R)-and ( S)-3a
in MeOH/CH2Cl2 (3:1) at À788C followed by reduction with
Scheme 3. Enantioselective synthesis of 5-deoxy-5-fluoro-b-d-carbaribo-
furanose (5).
using Mg/NiBr2/MeOH[20] gave monofluoromethylated 9 in
61% yield. Finally, the acetonide moiety on 9 was removed by
acid treatment to afford (+)-5, a previously unknown fluoro
isostere of b-d-carbaribofuranose, quantitatively.[21] The
enantiopurity of (+)-5 was determined to be 95% by chiral
HPLC analysis of triacetate 10.
In conclusion, 1-fluorobis(phenylsulfonyl)methane (1), a
newly designed synthetic equivalent for the fluoromethide
species, affords the enantiopure fluoromethylated products 3
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Communications
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methylfluorinated ibuprofens (S)-and ( R)-4 by reductive
desulfonylation and oxidation. The biologically important
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by dihydroxylation and reductive desulfonylation. The pres-
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Received: February 16, 2006
Revised: May 15, 2006
Published online: July 4, 2006
Keywords: asymmetric synthesis · drug design · fluorine ·
.
fluoromethylation · palladium
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[17] Absolute stereochemistries were determined by comparing the
optical rotations of 4 with those of ibuprofen. (S)-4 (91% ee):
[a]3D0 = + 50.1 (c = 0.57 in EtOH); (R)-4 (91% ee): [a]3D0 = À50.1
(c = 0.68, EtOH); (S)-ibuprofen (91% ee): [a]3D0 = + 60 (c = 2 in
EtOH), see D. G. Kaiser, G. J. Vangiessen, R. J. Reischer, W. J.
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4976 www.angewandte.org
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Angewandte
Chemie
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[21] (+)-5 (95% ee): [a]3D0 = + 10.6 (c = 0.98 in MeOH). b-d-carba-
ribofuranose: [a]2D0 = + 10.0 (c = 1.1 in MeOH). See refer-
ence [18e].
Angew. Chem. Int. Ed. 2006, 45, 4973 –4977
ꢀ 2006 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.angewandte.org 4977