The first enantioselective syntheses of vicinal difluoropyrrolidines and the first catalytic asymmetric synthesis mediated by the C2 symmetry of a -CHFCHF- Unit

Article abstract of DOI:10.1039/a801718b

The first enantiopure vicinal difluorides of C₂ symmetry have been prepared by the introduction of fluorine at both centres in a single operation; the first asymmetric synthesis using a catalyst whose chirality depends on organofluorine asymmetry is described.

Full text of DOI:10.1039/a801718b

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The first enantioselective syntheses of vicinal difluoropyrrolidines and the first
catalytic asymmetric synthesis mediated by the C2 symmetry of a –CHFCHF–
unit
Charles M. Marson*† and Robert C. Melling
Department of Chemistry, Queen Mary and Westfield College, University of London, London, UK E1 4NS
O
O
The first enantiopure vicinal difluorides of C2 symmetry
have been prepared by the introduction of fluorine at both
centres in a single operation; the first asymmetric synthesis
using a catalyst whose chirality depends on organofluorine
asymmetry is described.
OAc
OAc
OAc
OAc
(i) RNH2
O
R
R
N
(ii) SOCl2
O
N
O
1
2
3
The stereoselective synthesis of organofluorine compounds1,2 is
of major importance in many fields, including pharmaceutic-
als,1–3 nucleoside and carbohydrate chemistry,1b bioche-
mistry,4,5 liquid crystals6 and polymers.7 Many fluorinated
a-amino acids are potent antitumour and antiviral agents.1a,4a
The importance of monofluoro analogues as antimetabolites is
illustrated by (2R,3R)-fluorocitric acid, an aconitase inhibitor
that blocks the citric acid cycle.2,5 Additionally, organofluoro
ligands can be more powerful than oxygen ligands in coordinat-
ing metals.8
NaBH4, I2
OH
OTf
OTf
Tf2O
R
R
N
pyridine
OH
4
Bu4NF
F
N
Whereas enantiocontrolled syntheses of monofluoroorganic
compounds are well established, synthesis of an enantiopure
vicinal difluoro compound, especially of C2 symmetry, has not
to the best of our knowledge been reported prior to this
communication.9,10 Generally, molecular fluorine adds to
alkenes with syn-stereoselection, thereby precluding the forma-
tion of C2 symmetric difluorides;11 where trans-addition is
observed yields are usually low.12 For example diethylamino-
sulfur trifluoride (DAST),13 one of the most commonly used
reagents for the conversion of alcohols into fluorides, gives
merely a trace of 1,2-difluorocyclohexanes, and with loss of
stereointegrity compared with the initial cyclohexane-1,2-
diol.14 SF4 acts on (+)- or (2)-tartaric acid, exchanging both
hydroxy groups for fluorine, but with complete loss of optical
activity, by formation of only the meso-difluoroacid.15a With
tartrate esters, XeF2 was similarly unsuccessful.10c Despite
those previous accounts, we here report the enantiocontrolled
introduction of fluorine at two adjacent carbon stereocentres in
a single operation, and describe syntheses of enantiopure vicinal
difluorides 5, and an asymmetric process using some of those
difluorides as catalysts.
F
5a R = Ph
b R = n-C8H17
c R = cyclohexyl
Scheme 1
fluorine with clean inversion at both centres to give the
difluoropyrrolidines 5a–c, in respective yields of 76, 83 and
40%.‡ To the best of our knowledge, 3,4-difluoropyrrolidines
have not been previously prepared, either in racemic or
enantiopure form.
Catalysis of the epoxidation of allylic alcohols by difluorides
5 was investigated; reactions were conducted in CH2Cl2 using
15 mol% of Ti(OPri)4 and 10 mol% of catalyst (Scheme 2, Table
1, entries 2–7). In the absence of a catalyst, racemic 7 was
obtained in 81% yield. Diol 3a afforded 2,3-epoxygeraniol 7
(97%) in 25% ee in favour of the (2S,3S)-enantiomer (entry 2).
ButOOH
O
OH Ti(OPri
)
In view of reports15 that double vicinal displacements of
tartaric acid derivatives by fluoride do not proceed with
enantiocontrol, displacements on cyclic systems were investi-
gated. (3R,4R)-Diacetoxysuccinic anhydride 116 was reacted
with a primary amine (1 equiv., 12 h, 20 °C), and the
intermediate amido acid treated directly with SOCl2 (2 equiv.,
24 h, 20 °C) to give the diacetoxypyrrolidin-2,5-dione 2 (2a, R
= Ph; 2b, R = n-C8H17; 2c, R = cyclohexyl) (Scheme 1). The
pyrrolidin-2,5-diones 2 were reduced with NaBH4–I2 in THF
(12 h) and the diols 3 liberated by a two-stage work-up
involving stirring with 1:1 AcOH–HCl (10 m) for 10 h,
followed by washing with methanolic KOH (2 m). Reaction of
the diols 3 with Tf2O (2 equiv., 4 h, 280 °C) in the presence of
pyridine (2 equiv.) afforded the bis(trifluoromethanesulfonates)
4. These were isolable in the cases of 4a (R = Ph) and 4b
(R = n-octyl) but 4c (R = cyclohexyl) decomposed rapidly
during column chromatography. The bis(trifluoromethanesul-
fonates) 4 were reacted with Bu4NF (3 equiv., 16 h, 280 to
20 °C) in THF, resulting in stereoselective introduction of
OH
90%, 66% ee
4
10 mol% 5b
–20 to 20 °C, 12 h
6
7
Scheme 2
Table 1 Asymmetric epoxidation of geraniol (1.6 mmol) with tert-butyl
hydroperoxide, titanium tetraisopropoxide (15 mol%) and the difluorinated
catalyst 5b (10 mol%)
Yield
(%)
Configura-
Ee (%) tion
Entry Catalyst T/°C
t/h
1
2
3
4
5
6
7
—
3a
5b
5b
5b
5b
5c
220 to 20
12
81
—
25
50
51
66
27
10
racemic
(S,S)
220 to 210 0.67 97
220 to 20
1
1
12
3
68
74
90
23
87
(R,R)
(R,R)
(R,R)
(R,R)
(R,R)
0
220 to 20
280
220 to 20
12
Chem. Commun., 1998
1223

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MHz, CDCl3) 146.6 (s), 129.4 (d), 117.1 (d), 112.0 (d), 92.8 (ddd, 1JCF 180,
The use of 5c (220 to 20 °C over 12 h) afforded 2,3-epoxyger-
aniol (87%) in 10% ee in favour of the (2R,3R)-enantiomer
(entry 7). However, 5b afforded a 90% yield of 2,3-epoxyger-
aniol 7 in 66% ee in favour of the (2R,3R)-enantiomer (entry 5).
Entries 3–5 suggest that fluoro groups may provide greater
enantioselection than hydroxy groups (entry 2), at least in the
case of a C2 vicinal unit which is part of a heterocyclic ring. The
reversal of the major enantiomer of 2,3-epoxygeraniol when
using catalyst 3 compared with catalyst 5 would be expected if
the modes of binding of the hydroxy and fluoro catalysts had
important features in common. Samples of alcohol 7 were
converted into the acetate (1 equiv. Ac2O, 1 equiv. pyridine, 10
mol% DMAP in CH2Cl2 at 0 to 20 °C over 2 h), and the ee
determined by observation of 1H NMR peak of the acetate
methyl group upon treatment with Eu(hfc)3;17 the acetate (10
mg in 0.5 ml of C6D6) was treated with consecutive portions of
10–20 ml of a filtered solution of 35 mg of Eu(hfc)3 in 0.5 ml of
C6D6.
The presence of fluorine ligands in organic reactions
mediated by catalysis is an emerging area of importance.18 To
date, however, the chirality has not been a consequence of the
spatial arrangement of the fluorine atoms, but of the asymmetry
of an unrelated organic ligand (e.g. BINOL).18 Consequently,
the present examples are, to the best of our knowledge, the first
examples of asymmetric synthesis catalyzed by a compound
whose chirality depends upon organofluorine asymmetry.
In the catalytic asymmetric Sharpless epoxidation,19 free
hydroxy groups on the catalyst (dialkyl tartrate) are a pre-
requisite for enantioselectivity. In marked contrast to such
Sharpless catalysts, the difluorides 5 lack hydroxy groups and
are incapable of deprotonation that could lead to ligand
exchange, and yet 5a–c are viable catalysts for asymmetric
epoxidation.
2JCF 33), 51.6 (m); dF(564.8 MHz, CDCl3, internal CFCl3) 2190.3 (m).
1 (a) V. Aoloshonok, in Biomedical Frontiers of Fluorine Chemistry, ed.
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McCarter, and S. G. Withers, ibid., pp. 265–278; M. Namchuk, C.
Braun, J. D. McCarter and S. G. Withers, ibid., pp. 279–293.
2 P. Bravo and G. Resnati, Tetrahedron Asymmetry, 1990, 1, 661.
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5 E. Kun, E. Kirsten and M. L. Sharma, Proc. Natl. Acad. Sci. USA, 1977,
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9 For a single example of a racemic vic-difluoro-2,3-dihydrobenzo[b]
furan, see: R. Ruzziconi and G. V. Sebastiani, J. Heterocycl. Chem.,
1980, 17, 1147.
10 For meso-difluorides see: (a) M. Hudlicky, J. Fluorine Chem., 1987, 36,
373; (b) A. Baklouti and R. El Gharbi, J. Fluorine Chem., 1979, 13, 297;
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12 M. Sato, T. Hirokawa, A. Hattori, A. Toyota and C. Kaneko,
Tetrahedron: Asymmetry, 1994, 5, 975.
Compounds 5a and 5c are particularly suitable substructures
for liquid crystal applications, and difluoropyrrolidines 5 and
their derivatives are currently being evaluated for use as liquid
crystals and other new materials; additional catalytic processes
are also under investigation.
Support from the EPSRC for a studentship (to R. C. M.)
under the ROPA initiative is gratefully acknowledged.
13 W. J. Middleton, J. Org. Chem., 1975, 40, 574; M. Hudlicky, Org.
React., 1988, 35, 513.
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A. A. Hanson, K. A. Hanson, R. D. Henderson, J. M. Prince and
V. L. Heasley, J. Chem. Soc., Perkins Trans. 2, 1995, 861.
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and L. M. Yagupolskii, J. Fluorine Chem., 1981, 19, 151; (b) for a
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242.
Notes and References
† E-mail: c.m.marson@qmw.ac.uk.
‡ All compounds gave satisfactory spectral data (NMR, IR, MS), and all
new compounds gave satisfactory elemental analyses or HRMS. Selected
data for 4a: prisms, mp 126.5–127 °C (hexane), [a]D +46.2 (c 1, CHCl3);
dH(250 MHz, CDCl3) 7.30 (m, 2 H), 6.88 (t, J 9.0, 1 H), 6.60 (d, J 9.0 2 H),
5.52 (t, J 2.5, 2 H) 3.95 (dd, J 11.0, 5.0, 2 H), 3.65 (dd, J 11.0, 3.0, 2 H); dC
(62.2 MHz, CDCl3) 145.5 (d), 129.7 (d), 118.9 (s), 118.5 (q), 112.6 (d), 85.4
(d), 51.3 (t). For 5a: needles, mp 89.5 °C (hexane), [a]D 240.6 (c 3.5,
CHCl3); dH(600 MHz, CDCl3) 7.30 (m, 2 H), 6.76 (t, J 7.0, 1 H), 6.60 (d,
J 7.0, 2 H), 5.30 (dm, 2JHF 49.3, 3JHF 12.6, 2 H), 3.70 (m, 4 H); dC(150.9
17 Y. Gao, R. M. Hanson, J. M. Klunder, S. Y. Ko, H. Masamune and
K. B. Sharpless, J. Am. Chem. Soc., 1987, 109, 5765.
18 R. O. Duthaler and A. Hafner, Angew. Chem., Int. Ed. Engl., 1997, 36,
43.
19 T. Katsuki and K. B. Sharpless, J. Am. Chem. Soc., 1980, 102, 5974.
Received in Liverpool, UK, 2nd March 1998; 8/01718B
1224
Chem. Commun., 1998