Enantioselective syntheses of trans-3,4-difluoropyrrolidines and investigation of their applications in catalytic asymmetric synthesis

Article abstract of DOI:10.1021/jo0513414

Asymmetric syntheses of enantiopure trans-3,4-difluoropyrrolidines have been prepared by the introduction of fluorine at both centers in a single operation; asymmetric epoxidations and additions to benzaldehyde were conducted using catalysts whose chirality depends on organofluorine asymmetry.

Full text of DOI:10.1021/jo0513414

Enantioselective Syntheses of trans-3,4-Difluoropyrrolidines and
Investigation of Their Applications in Catalytic Asymmetric
Synthesis†
Charles M. Marson*
Department of Chemistry, University College London, Christopher Ingold Laboratories, 20 Gordon Street,
London WC1H 0AJ, U.K.
Robert C. Melling
Department of Chemistry, Queen Mary College, University of London, London E1 4NS, U.K.
c.m.marson@ucl.ac.uk
Received June 29, 2005
Asymmetric syntheses of enantiopure trans-3,4-difluoropyrrolidines have been prepared by the
introduction of fluorine at both centers in a single operation; asymmetric epoxidations and additions
to benzaldehyde were conducted using catalysts whose chirality depends on organofluorine
asymmetry.
Introduction
the incorporation of fluorinated amino acids into proteins
is emerging as a valuable means of designing hyperstable
protein folding, as well as inducing highly specific
protein-protein interactions.3 The significance of mono-
fluoro analogues in biochemistry1,7 is illustrated by the
antimetabolite (2R,3R)-fluorocitric acid, an aconitase
inhibitor that blocks the citric acid cycle.5,7 Replacement
of an sp3 C-H bond by an sp3 C-F bond often has little
effect in terms of size but produces appreciably different
electronic properties, leading to unusual conformational
preferences such as the gauche effect,8 observed in
several types of fluorinated systems including 4-fluoro-
L-proline.9 Replacement of a C-H bond by a C-F bond
can be a useful means of influencing conformation;10 the
spatial orientation of sp3 C-F bonds in organofluorine
compounds has also been identified as significant in
many other fields, including nucleoside and carbohydrate
chemistry, organic liquid crystals,2c and polymers.11 Ad-
ditionally, organofluorine ligands can be at least as
powerful as oxygen ligands in coordinating metals.12 In
Organofluorine compounds have achieved significance
in many areas,1 notably in the areas of materials2 and
bio-organic3 chemistry and through their pharmaceuti-
cally desirable properties.4-6 Many fluorinated R-amino
acids are potent antitumor and antiviral agents,1a,4a and
† This contribution is dedicated to Professor Steven V. Ley on the
occasion of his 60th birthday.
(1) (a) Welch, J. T.; Eswarakrishnan, S. Fluorine in Bio-organic
Chemistry; Wiley: New York, 1991. (b) Wilkinson, J. A. Chem. Rev.
1992, 92, 505-519.
(2) (a) Vlahakis, J. Z.; Wand, M. D.; Lemieux, R. P. J. Am. Chem.
Soc. 2003, 125, 6862-6863. (b) Kirsch, P.; Bremer, M. Angew. Chem.,
Int. Ed. 2000, 39, 4217-4235. (c) Liu, H.; Nohira, H. Liq. Cryst. 1996,
581-586.
(3) (a) Hodges, J. A.; Raines, R. T. J. Am. Chem. Soc. 2003, 125,
9262-9263. (b) Yoder, N. C.; Kumar, K. Chem. Soc. Rev. 2002, 31,
335-341.
(4) (a) Aoloshonok, V. A. In Biomedical Frontiers of Fluorine
Chemistry; Ojima, I., McCarthy, J. R., Welch, J. T., Eds.; American
Chemical Society Symposium Series; American Chemical Society:
Washington, DC, 1996; Vol. 639, pp 26-41. (b) McCarthy, J. A.;
Sunkara, P. S.; Matthews, D. P.; et al. In Biomedical Frontiers of
Fluorine Chemistry; Ojima, I., McCarthy, J. R., Welch, J. T., Eds.;
American Chemical Society Symposium Series; American Chemical
Society: Washington, DC, 1996; Vol. 639, pp 246-264. Hertek, L. W.;
Kroin, J. S.; Grossman, C. S. et al. In Biomedical Frontiers of Fluorine
Chemistry; Ojima, I., McCarthy, J. R., Welch, J. T., Eds.; American
Chemical Society Symposium Series; American Chemical Society:
Washington, DC, 1996; Vol. 639, pp 265-278. Namchuk, M.; Braun,
C.; McCarter, J. D.; Withers, S. G. In Biomedical Frontiers of Fluorine
Chemistry; Ojima, I., McCarthy, J. R., Welch, J. T., Eds.; American
Chemical Society Symposium Series; American Chemical Society:
Washington, DC, 1996; Vol. 639, pp 279-293.
(6) Bouzard, D.; Dicesare, P.; Essiz, M.; Jacquet, J. P.; Kiechel, J.
R.; Remuzon, P.; Weber, A.; Oki, T.; Masuyoshi, M.; Kessler, R. E.;
Fungtomc, J.; Desiderio, J. J. Med. Chem. 1990, 33, 1344-1352.
(7) Kun, E.; Kirsten, E.; Sharma, M. L. Proc. Natl. Acad. Sci. U.S.A
1977, 74, 4942-4946.
(8) Craig, N. C.; Chen, A.; Suh, K. H.; Klee, S.; Mellau, G. C.;
Winnewisser, B. P.; Winnewisser, M. J. Am. Chem. Soc. 1997, 119,
4789-4790.
(9) (a) Holmgren, S. K.; Taylor, K. M.; Bretcher, L. E.; Raines, R. T.
Nature 1998, 392, 666-667. (b) Holmgren, S. K.; Bretcher, L. E.;
Taylor, K. M.; Raines, R. T. Chem. Biol. 1999, 6, 63-70.
(10) Rzepa, H. S.; O’Hagan, D. Chem. Commun. 1997, 645-652.
(5) Bravo, P.; Resnati, G. Tetrahedron: Asymmetry 1990, 1, 661-
692.
10.1021/jo0513414 CCC: $30.25 © 2005 American Chemical Society
Published on Web 11/03/2005
J. Org. Chem. 2005, 70, 9771-9779
9771

Marson and Melling
many of the above areas, there is a need for defined
stereochemistry at the carbon center(s) bearing fluorine;
therefore, efficient means of controlling organofluorine
stereochemistry are of considerable value.
corresponding enantiopure vicinal difluorides,22 displace-
ments on cyclic systems derived from pyrrolidine-3,4-diols
3 were investigated in the present study. A typical route23
to 3 involves the direct condensation of L-tartaric acid
with an amine (RNH2) to give the imide in modest yield
followed by reduction with LiAlH4. Improved protocols
were sought because both steps have disadvantages,
including difficulties in isolation or poor yields. In a
representative procedure, (3R,4R)-diacetoxysuccinic an-
hydride (1)24 was reacted with a primary amine (1 equiv)
in THF at 0 °C, and the intermediate amido acid formed
was treated directly with SOCl2 (24 h, 20 °C) to give the
diacetoxypyrrolidine-2,5-dione 2 in yields of 93% (2a),
71% (2b), and 93% (2c). Later work showed that the
cyclization step could also be conducted using oxalyl
chloride in DMF at -84 °C, by which method 2d was
prepared in 73% yield. The standard procedure of cyclo-
dehydration using acetyl chloride requires long periods
at reflux and in the examples studied here typically
afforded poor yields of the imides 2.
Efforts to reduce the imides 2 with a variety of reagents
including lithium aluminum hydride, sodium borohy-
dride-boron trifluoride-etherate,25 and lithium trieth-
ylborohydride in the presence of boron trifluoride-
etherate and triethylsilane26 were unsuccessful. Modest
success was achieved using THF‚BH3,27 but removal of
the residual boron adducts proved problematic. However,
the pyrrolidine-2,5-diones 2 were successfully reduced
with NaBH4-I2 in THF.27 In a modification of the
published procedure for the hydrolytic workup,28 a two-
stage workup involved stirring with 1:1 acetic acid-
hydrochloric acid (10 M) for 10 h followed by washing
with methanolic KOH (4 M).
With the diols 3 secured, it was envisaged that the
corresponding 3,4-dimesylates might undergo 2-fold dis-
placement because the mesylate of a 4-hydroxyproline
derivative was displaced upon treatment with KF in hot
DMF.29 However, the dimesylate of diol 3a gave no fluoro
compound when treated with KF (5 equiv) in the presence
of a catalytic amount of 18-crown-6 in DMF at 80 °C (14
days). Reaction of the same dimesylate with tetra-n-
butylammonium fluoride (TBAF, 3 equiv) in THF at
reflux gave only 1-cyclohexylpyrrole (84%), the product
of two eliminations.
It was hoped that the ready eliminations during
nucleophilic attack on the 3,4-disubstituted pyrrolidines
could be suppressed by using the highly reactive bistri-
fluoromethanesulfonates (bistriflates). Indeed, reaction
of the diols 3 with Tf2O (2 equiv, 4 h, -85 °C) in the
presence of pyridine (2 equiv) in dichloromethane af-
forded the bistrifluoromethanesulfonates 4. These were
Whereas enantiocontrolled syntheses of monofluoro-
organic compounds are well established, syntheses of
stereopure vicinal difluoro compounds are much
scarcer,13-15 especially those in enantiopure form.16,17 The
difficulty in forming C2 symmetric difluorides is enhanced
by the cis addition that is usually observed18,19 when
molecular fluorine adds to alkenes; where trans addition
has been observed, yields are usually low.19 Whereas
nucleophilic displacement of single hydroxy groups is
usually possible using fluoride sources such as diethyl-
aminosulfur trifluoride (DAST),20 few systems with ad-
ditional proximate hydroxyl groups have been shown to
undergo smooth fluorodehydroxylation. For example,
DAST reacts with cyclohexane-1,2-diol to give only a trace
of 1,2-difluorocyclohexanes, with loss of stereointegrity.21
The reaction of SF4 with enantiomerically pure tartaric
acid leads to exchange of both hydroxy groups for
fluorine, but with complete loss of optical activity, only
the meso difluoro acid is formed.22a Similarly unsuccessful
were attempts to react XeF2 with tartrate esters.14c
Notwithstanding such difficulties, we recently described16a
the enantiocontrolled introduction of fluorine at two
adjacent carbon stereocenters in a single operation, and
here we describe the syntheses of enantiopure vicinal
difluorides 5 and their participation as catalysts in two
asymmetric processes.
Results and Discussion
Because attempted double vicinal displacements of
tartaric acid derivatives by fluoride had not afforded the
(11) Hougham, G. G.; Cassidy, P. E.; Johns, K.; Davidson, T.
Fluoropolymers: Synthesis and Properties; Kluwer Academic: Norwell,
MA, 1999.
(12) Plenio, H.; Diodone, R.; Badura, D. Angew. Chem., Int. Ed. Engl.
1997, 36, 156-158.
(13) For a single example of a racemic vic-difluoro-2,3-dihydrobenzo-
[b]furan, see: Ruzziconi, R.; Sebastiani, G. V. J. Heterocycl. Chem.
1980, 17, 1147-1148.
(14) For meso-difluorides, see: (a) Hudlicky, M. J. Fluorine Chem.
1987, 36, 373-384. (b) Baklouti, A.; El Gharbi, R. J. Fluorine Chem.
1979, 13, 297-314. (c) Patrick, T. B.; Khazaeli, S.; Nadji, S.; Hering-
Smith, K.; Reif, D. J. Org. Chem. 1993, 58, 705-708. (d) Olah, G. A.;
Welch, J. T.; Vankar, Y. D.; Nojima, M.; Kerekes, I.; Olah, G. A. J.
Org. Chem. 1979, 44, 3872-3881.
(15) For the synthesis of (()-erythro- and (()-threo-9,10-difluo-
rostearic acids, see: Tavasli, M.; O’Hagan, D.; Pearson, C.; Petty, M.
C. Chem. Commun. 2002, 1226-1227.
(16) (a) Marson, C. M.; Melling, R. C. J. Chem. Soc., Chem. Commun.
1998, 1223-1234. (b) This method has been used to prepare both
enantiomers of 3,4-difluoropyrrolidine and its 1-benzyl derivative:
Caldwell, C. G.; Chen, P.; He, J. F.; Parmee, E. R.; Leiting, B.; Marsilio,
F.; Patel, R. A.; Wu, J. K.; Eiermann, G. J.; Petrov, A.; He, H. B.; Lyons,
K. A.; Thornberry, N. A.; Weber, A. E. Bioorg. Med. Chem. Lett. 2004,
14, 1265-1268.
(17) Nicoletti, M.; O’Hagan, D.; Slawin, A. M. Z. J. Am. Chem. Soc.
2005, 127, 482-483.
(23) (a) Bourson, J.; Oliveros, L. J. Organomet. Chem. 1982, 229,
77-84. (b) Nagel, U. Angew. Chem., Int. Ed. Engl. 1984, 23, 435-
436.
(24) Shriner, R. L.; Furrow, C. L. Org. Synth. 1955, 35, 49-51.
(25) Nagel, U.; Kinzel, E.; Andrade, J.; Prescher, G. Chem. Ber. 1986,
119, 3326-3343.
(26) (a) Langlois, N.; Rojas, A. Tetrahedron Lett. 1993, 34, 2477-
2480. (b) Pedregal, C.; Ezquerra; Escribano, A.; Carren˜o, M. C.; Ruano,
J. L. G. Tetrahedron Lett. 1994, 35, 2053-2056.
(27) Skarzewski, J.; Gupta, A. Tetrahedron: Asymmetry 1997, 8,
1861-1867.
(18) Rozen, S.; Brand, M. J. Org. Chem. 1986, 51, 3607-3611.
(19) Sato, M.; Hirokawa, T.; Hattori, A.; Toyota, A.; Kaneko, C.
Tetrahedron: Asymmetry 1994, 5, 975-980.
(20) (a) Middleton, W. J. J. Org. Chem. 1975, 40, 574-578. (b)
Hudlicky, M. Org. React. 1988, 35, 513-637.
(21) Shellhamer, D. F.; Austine, D. T.; Gallego, K. M.; Ganesh, B.
R.; Hanson, A. A.; Hanson, K. A.; Henderson, R. D.; Prince, J. M.;
Heasley, V. L. J. Chem. Soc., Perkin Trans. 2 1995, 861-866.
(22) (a) Burmakov, A. I.; Motnyak, L. A.; Kunshenko, B. V.; Alexeva,
L. A.; Yagupolskii, L. M. J. Fluorine Chem. 1981, 19, 151-161. (b)
For a racemic route to mixtures of difluorosuccinic acid derivatives
from maleic anhydride and F2, see: Syvret, R. G.; Vassilaros, D. L.;
Parees, D. M.; Pez, G. P. J. Fluorine Chem. 1994, 67, 277-282.
(28) Prasad, A. S. B.; Kanth, J. V. B.; Periasamy, M. Tetrahedron
1992, 48, 4623-4628.
(29) Gottlieb, A. A.; Fujita, Y.; Udenfriend, S.; Witkop, B. Biochem-
istry 1965, 4, 2507-2513.
9772 J. Org. Chem., Vol. 70, No. 24, 2005

Syntheses of trans-3,4-Difluoropyrrolidines
SCHEME 1
SCHEME 2
SCHEME 3
isolable in the cases of 4a (R ) n-octyl) and 4c (R ) Ph),
but 4b (R ) cyclohexyl) decomposed rapidly during
column chromatography. For the isolable cases, purifica-
tion of the bistriflates by rapid flash column chromatog-
raphy and eluting with solvents cooled to 5 °C was the
preferred procedure and led to much purer difluorides
5. The bistrifluoromethanesulfonates 4 were reacted with
TBAF (3 equiv, 16 h, -85 °C to 20 °C) in THF, resulting
in stereoselective introduction of fluorine with clean
inversion at both centers to give the difluoropyrrolidines
5a, 5b, and 5c in respective yields of 83, 42, and 76%.
Organofluorine compounds find extensive use in ma-
terials11 and liquid crystal applications,2 although to our
knowledge a C2 symmetric 1,2-difluorinated compound
has not been prepared with such an application in mind.
Consequently, it was of interest to prepare N-arylated
derivatives of 5. However, although the diol 3e could be
prepared in 18% from the corresponding imide 2e (pro-
cedures as in Scheme 1), access to 5e by this method was
not possible because reaction of diol 3e with Tf2O did not
afford the corresponding bistriflate 4e. A modified ap-
proach was then examined, in which formation of 5d
would enable access to 5e by a Suzuki coupling (Scheme
2). However, although the imide 2d could be prepared
from the anhydride 1 and 4-iodoaniline in 73% yield,
reduction using NaBH4-I2 failed to provide any of the
desired diol 3d. Consequently, an alkylation approach
was investigated in which 4-iodoaniline was reacted with
the dimesylate 6a in DMF at 100 °C and also with the
ditosylate 6b in DMF at 100 °C, but in neither case was
the desired reaction achieved. In contrast, dialkylation
using (2R,3R)-1,4-diiodobutane-2,3-diol (7) was successful
by reaction with 4-iodoaniline in DMF at 90 °C giving
3d in 34% yield. Using the procedures outlined in Scheme
1, we performed bistriflation of 3d with Tf2O in dichlo-
romethane (1.05 equiv, 4 h, -85 °C) in the presence of
pyridine (2.1 equiv) to afford 4d (37%), which underwent
the desired 2-fold displacement with TBAF (3 equiv, 16
h, -85 to 20 °C) in THF giving 5d in 90% yield. A
modified Suzuki coupling30 of 5d with phenylboronic acid
in aqueous acetone in the presence of Pd(OAc)2 and
K2CO3 completed the synthesis of 5e, albeit in only 24%
yield.
An alkylation approach (Scheme 3) was also successful
in affording the 2-oxyethyl derivatives 5f and 5g, the
latter being tested in asymmetric alkylation of benzal-
dehyde (see below). The diol 8, prepared by MOM
protection of dimethyl L-tartrate and subsequent reduc-
tion with LiAlH4,31 was converted into the dimesylate 9
(49%) by reaction with mesyl chloride and Et3N in
dichloromethane at 0 °C. Dialkylation of ethanolamine
was achieved with 9 by reaction with K2CO3 in the
presence of a catalytic amount of 18-crown-6 in DMF at
100 °C (48 h), thus affording the hydroxyethylpyrrolidine
10a (57%). Benzylation of 10a using NaH followed by
benzyl bromide in THF at reflux afforded the benzyl
derivative 10b (82%) which was deprotected with 10 M
hydrochloric acid to give the diol 3f (69%). Reaction of
(30) Mallory, F. B.; Mallory, C. W.; Ricker, W. M. J. Org. Chem.
1985, 50, 457-461.
(31) Shishido, K.; Sukegawa, Y.; Fukumoto, K.; Kametani, T. J.
Chem. Soc., Perkin Trans. 1 1987, 993-1004.
J. Org. Chem, Vol. 70, No. 24, 2005 9773

Marson and Melling
SCHEME 4
SCHEME 5
diol 3f with Tf2O in dichloromethane (2.1 equiv, 4 h, -85
°C) in the presence of Et3N (2.1 equiv) afforded the
bistriflate 4f (42%) which underwent 2-fold displacement
with TBAF (3 equiv, 16 h, -85 °C to 20 °C) in THF giving
1-(2-benzyloxyethyl)pyrrole (35%) and 5f in 52% yield.
The latter was debenzylated by treatment with Me2S‚
BCl3 in dichloromethane at -85 °C and worked up with
Me2NEt to give (3R,4R)-1-(2-hydroxyethyl)-3,4-difluoro-
pyrrolidine 5g (66%).
show that for the catalytic asymmetric epoxidations in
Scheme 5 fluoro substituents can provide enantioselec-
tion comparable with that of hydroxyl groups, although
no mechanistic analogy is being proposed. Ligation via
the nitrogen atom in 5g is sufficient to induce ee in the
case of ethylation of benzaldehyde and as such may also
apply to 5 in the asymmetric epoxidations (Scheme 5).
In Sharpless asymmetric epoxidations,35 free hydroxyl
groups on the catalyst (dialkyl tartrate) are a prerequisite
for enantioselectivity, consistent with the dimeric catalyst
model;36 that requirement is in marked contrast to the
difluorides 5, whose lack of hydroxyl groups indicates a
different mode of coordination to titanium(IV).
Although nucleophilic displacements of 3-chloropip-
eridines can proceed with retention of configuration by
participation of the nitrogen atom in a bicycloazonium
intermediate,37 we are not aware of an analogy for the
displacement of a 3-substituent on a pyrrolidine ring
relevant to the present work. Although the absolute
configuration of the 3,4-difluoropyrrolidines remains to
be proved, the current evidence (optical rotations opposite
and comparable with the diols and opposite asymmetric
induction compared with diol derivatives; Scheme 4) is
consistent and together with literature precedent for
inversion in monofluoro systems29 supports the configu-
rations assigned on the basis of inversion at both ste-
reogenic centers of the bistriflates.
The presence of fluorine ligands in catalytic organic
reactions is an area of emerging importance.32 In most
cases, the asymmetry of an unrelated organic ligand (e.g.,
binol) has been the source of induction.32 The enantiose-
lective epoxidation of alkenes catalyzed by an R-fluo-
rotropinone33 and our previously disclosed asymmetric
epoxidation16a are two of the few cases described in which
induction depends on asymmetry derived from assembly
around a C-F bond. Consequently, we wished to explore
whether the present enantiopure and C2 symmetric
difluorides could be used in catalytic asymmetric syn-
thesis. Addition of diethylzinc to benzaldehyde proceeds
in high enantiomeric excess (ee) using various chiral
ethanolamine catalysts, for which the reaction serves as
a benchmark of the enantioselectivity of the catalyst;
according to Soai’s model,34 coordination through both
oxygen and nitrogen is necessary, and usually as part of
a dimeric structure. This reaction (conditions in Scheme
4) was investigated using the fluoro alcohol 5g as the
catalyst, which in 2, 5, and 15 mol % afforded 13a in 7,
16, and 16% ee, respectively. Although small, the asym-
metric induction is opposite and similar in size to that
afforded by 5 mol % of the nonfluorinated analogue 10a,
a process that almost certainly involves coordination of
zinc to the pyrrolidine nitrogen atom. The effective size
of the fluoro substituents is manifestly sufficient to afford
appreciable asymmetric induction.
Conclusions
3,4-Difluoropyrrolidines have been synthesized by a
dependable 2-fold displacement of the corresponding
bistriflates. The 2-fold displacement proceeds with excel-
lent stereocontrol and consequently permits 3,4-difluo-
ropyrrolidines to be obtained in either enantiomerically
pure form. Several of the difluoropyrrolidines 5 displayed
significant catalytic properties in asymmetric epoxidation
and asymmetric alkylation of benzaldehyde, thus provid-
ing examples of asymmetric synthesis catalyzed by
compounds whose chirality depends on organofluorine
asymmetry. In addition, N-aryl-3,4-difluoropyrrolidines
Catalysis of the epoxidation of geraniol by difluorides
5a and 5b has also been investigated (Scheme 5);
reactions were conducted in dichloromethane using 15
mol % of Ti(OiPr)4 and 10 mol % of catalyst, the best
result observed affording 13b in 66% ee.16a These results
(32) Duthaler, R. O.; Hafner, A. Angew. Chem., Int. Ed. Engl. 1997,
36, 43-45.
(33) (a) Armstrong, A.; Hayter, B. R. J. Chem. Soc., Chem. Commun.
1998, 621-622. (b) Armstrong, A.; Ahmed, G.; Dominguez-Fernandez,
B.; Hayter, B. R.; Wailes, J. S. J. Org. Chem. 2002, 67, 8610-8617.
(34) Soai, K.; Ookawa, A.; Kaba, T.; Ogawa, K. J. Am. Chem. Soc.
1987, 109, 7111-7115.
(35) Gao, Y.; Hanson, R. M.; Klunder, J. M.; Ko, S. Y.; Masamune,
H.; Sharpless, K. B. J. Am. Chem. Soc. 1987, 109, 5765-5780.
(36) (a) Katsuki, T.; Sharpless, K. B. J. Am. Chem. Soc. 1980, 102,
5974-5976. (b) Finn, M. G.; Sharpless, K. B. J. Am. Chem. Soc. 1991,
113, 106-113.
(37) Reitsema, R. H. J. Am. Chem. Soc. 1949, 71, 2041-2043.
9774 J. Org. Chem., Vol. 70, No. 24, 2005

Syntheses of trans-3,4-Difluoropyrrolidines
of dry nitrogen was added dropwise a solution of oxalyl chloride
(23.5 g, 185 mmol) in dry dichloromethane (50 mL) using a
double-tipped needle of stainless steel. The mixture was then
allowed to warm slowly to 20 °C, and stirring was continued
at 20 °C under an atmosphere of dry nitrogen for an additional
16 h. The mixture was quenched by the addition of aqueous
lithium chloride (120 mL, 2.0 M), and the aqueous layer was
extracted with ethyl acetate (3 × 60 mL). The combined
organic layers were washed with brine (2 × 60 mL) and dried
over MgSO4. The solution was filtered through a sintered glass
funnel, and the filtrate was evaporated under reduced pres-
sure. The residue was dissolved in the minimum quantity of
dichloromethane, applied to the top of a prepacked column,
and purified by flash chromatography over silica gel (3:7 ethyl
acetate/40-60 °C petroleum ether). The appropriate fractions
were combined and filtered through a glass wool plug, and the
eluent was evaporated under reduced pressure to give 2d (28.2
g, 73%) as a purple powder (mp 160-170 °C). A small sample
was recrystallized from ethanol to give 2d as pale blue
prisms: mp 181-182 °C; [R]D31 +59.4 (c 0.4, acetone); IR νmax
(KBr) 3050, 2950 (CH), 1725, 1735 (CdO), 1600, 1500 (Ph)
cm-1; 1H NMR δ 7.81 (2H, J ) 9.5 Hz), 7.11 (2H, J ) 9.5 Hz),
5.61 (2H, s), 2.22 (6H, s); 13C NMR δ 170.1, 168.2, 138.6, 130.6,
127.9, 94.9, 72.9, 20.4; LRMS-FAB m/e (rel intensity %;
positive m-NO2C6H5CO2H MATRIX) 418 ([M + H]+, 100), 417
(M+, 34), 376 (83), 358 (37), 334 (29), 307 (42), 289 (44). Anal.
Calcd for C14H12NO6I: C, 40.28; H, 2.87; N, 3.36; I, 30.46.
Found: C, 40.36; H, 2.74; N, 3.06; I, 30.45.
such as 5e can be expected to exhibit interesting proper-
ties in connection with the liquid crystalline state.
Experimental Section
The following compounds were prepared according to lit-
erature procedures: (3R,4R)-3,4-diacetoxyfuran-2,5-dione (1),24
(3R,4R)-3,4-diacetoxy-1-phenylpyrrolidine-2,5-dione (2c),38
(3S,4S)-1-phenylpyrrolidine-3,4-diol (3c),23b (2R,3R)-1,4-bis-
(methanesulfonyloxy)butane-2,3-diol (6a),39 (2S,3S)-1,4-bis(4-
methylphenylsulfonyloxy)butane-2,3-diol (6b),40 (3R,4R)-1,4-
diiodobutane-1,4-diol (7),41 (2S,3S)-2,3-bis(methoxymethyloxy)-
butane-1,4-diol (8),42 and (4S,5S)-4,5-diiodomethyl-2,2-dimeth-
yl-1,3-dioxolane.43
(3R,4R)-3,4-Diacetoxy-1-n-octylpyrrolidine-2,5-dione
(2a). General Procedure A. To a stirred solution of (3R,4R)-
3,4-diacetoxyfuran-2,5-dione (1) (20.0 g, 93 mmol) in 250 mL
of anhydrous tetrahydrofuran at 0 °C under an atmosphere
of dry nitrogen was added a solution of n-octylamine (12.0 g,
92.6 mmol) in 35 mL of dry tetrahydrofuran dropwise using a
double-tipped needle of stainless steel. The mixture was
allowed to warm slowly to 20 °C, and stirring was continued
at 20 °C under an atmosphere of dry nitrogen for 16 h
(consumption of 1 was confirmed by IR spectroscopy). To the
stirred mixture cooled to -20 °C under an atmosphere of dry
nitrogen was added dropwise a solution of thionyl chloride (44
g, 0.37 mol) in dry tetrahydrofuran (40 mL) using a double-
tipped needle of stainless steel. The mixture was then allowed
to warm slowly to 20 °C, and stirring was continued at 20 °C
under an atmosphere of dry nitrogen for an additional 48 h.
The mixture was quenched by the addition of saturated
aqueous ammonium chloride (120 mL), and the aqueous layer
was extracted with ethyl acetate (3 × 70 mL). The combined
organic layers were washed with brine (2 × 70 mL) and dried
over MgSO4. The solution was filtered through a sintered glass
funnel, and the filtrate was evaporated under reduced pres-
sure. The residue was dissolved in the minimum quantity of
dichloromethane, applied to the top of a prepacked column of
silica gel, and purified by flash chromatography (3:17 ethyl
acetate/40-60 °C petroleum ether). The appropriate fractions
were combined and filtered through a glass wool plug, and the
eluent was evaporated under reduced pressure to give 2a (28.2
(3S,4S)-1-n-Octylpyrrolidine-3,4-diol (3a). General Pro-
cedure B. To a rapidly stirred suspension of (3R,4R)-3,4-
diacetoxy-1-octylpyrrolidine-2,5-dione (2a) (15.0 g, 45.9 mmol)
and sodium borohydride (10.5 g, 275 mmol) in anhydrous
tetrahydrofuran (500 mL) at 0 °C under an atmosphere of dry
nitrogen was added dropwise a solution of iodine (35.0 g, 137
mmol) in dry tetrahydrofuran (100 mL) using a double-tipped
needle of stainless steel. After addition, the mixture was
heated slowly to reflux (consumption of 2a was confirmed by
IR spectroscopy). The mixture was then cooled to 0 °C and
quenched by dropwise addition of methanol (200 mL). To the
stirred slurry maintained at 0 °C was added 1:1 (v/v) glacial
acetic acid/10 M hydrochloric acid until the pH of 2-3 was
reached. The mixture was allowed to warm slowly to 20 °C,
and stirring was continued at 20 °C for 16 h. The mixture was
neutralized by dropwise addition of methanolic potassium
hydroxide (4 M) at 0 °C and then evaporated under reduced
pressure. The residue was dissolved in water (150 mL) and
continuously extracted with 4:1 chloroform/tetrahydrofuran
over 80 h. The organic layer was dried over MgSO4 and filtered,
and the solvent was evaporated. The residue was adsorbed
onto neutral alumina, and the impregnated dispersion was
applied to the top of a prepacked column of silica gel and eluted
with 1:4 methanol/chloroform. The appropriate fractions were
combined, filtered through a glass wool plug, and evaporated
to give 3a (4.64 g, 47%) as a light brown powder (mp 52-56
°C). An analytical sample was obtained by recrystallization
from acetone by the slow diffusion of n-hexane vapors at 5-6
34
g, 93%) as a pale yellow oil: [R]D +71.8 (c 2.5, chloroform);
1
IR νmax (chloroform) 2990, 2905, 1760, 1740 cm-1; H NMR δ
5.51 (2H, s), 3.58 (2H, m), 2.21 (6H, s), 1.62 (2H, m), 1.28 (10H,
m), 0.87 (3H, t, J ) 7.0 Hz); 13C NMR δ 169.9, 169.4, 72.8,
39.6, 31.8, 29.0, 29.0, 27.4, 26.7, 22.6, 20.4, 14.1; LRMS-FAB
m/e (rel intensity %; positive m-NO2C6H5CO2H MATRIX) 328
([M + H]+, 91), 286 (M+, 100), 268 (59), 244 (83), 154 (13), 137
(41), 115 (21), 107 (24); HRMS-FAB calcd for C16H26NO6 [M
+ H]+ 328.1760, found 328.1751.
(3R,4R)-3,4-Diacetoxy-1-(4-iodophenyl)pyrrolidine-2,5-
dione (2d). To a stirred solution of (3R,4R)-3,4-diacetoxyfuran-
2,5-dione (1) (20.0 g, 93 mmol) in dry DMF (100 mL) at 0 °C
under an atmosphere of dry nitrogen was added dropwise a
solution of 4-iodoaniline (20.3 g, 92.6 mmol) in dry DMF (30
mL) using a double-tipped needle of stainless steel. The
mixture was allowed to warm slowly to 20 °C, and stirring
was continued at 20 °C under an atmosphere of dry nitrogen
for 16 h (consumption of 1 was confirmed by IR spectroscopy).
To the stirred mixture cooled to -85 °C under an atmosphere
30
°C, giving 3a as lustrous, white plates: mp 61.5-62 °C; [R]D
+14.8 (c 1.3, chloroform); IR νmax (KBr) 3345, 2915, 2850, 1465
cm-1 1H NMR δ 4.10 (2H, t, J ) 5.0 Hz), 2.9 (2H, br s),
;
2.97 (2H, dd, J ) 6.2, 3.5 Hz), 2.48 (2H, dd, J ) 8.5, 3.5 Hz),
2.45 (2H, m), 1.48 (2H, t, J ) 7.5 Hz), 1.29 (10H, m), 0.87 (3H,
t, J ) 7.5 Hz); 13C NMR δ 78.6, 60.6, 56.3, 31.9, 29.5, 29.3,
28.3, 27.6, 22.7, 14.1; LRMS-FAB m/e (rel intensity %; posi-
tive m-NO2C6H5CO2H MATRIX) 216 ([M + H]+, 100), 198 (3),
154 (5), 142 (10),116 (26), 58 (15); HRMS-FAB calcd for
C12H26NO2 [M + H]+ 216.1964, found 216.1980.
(3S,4S)-1-(4-Iodophenyl)pyrrolidine-3,4-diol (3d). To a
stirred suspension of (3R,4R)-1,4-diiodobutane-1,4-diol (7)41
(2.0 g, 5.9 mmol), potassium carbonate (1.46 g, 14.6 mmol),
and 18-crown-6 (154 mg, 0.59 mmol) in dry DMF (30 mL) at
20 °C was added 4-iodoaniline (1.28 g, 5.85 mmol) in portions.
The mixture was heated to 90 °C, and stirring was continued
(38) Parkes, C. J. Chem. Soc. 1923, 123, 663-669.
(39) Feit, P. W. J. Med. Chem. 1964, 7, 14-17.
(40) Seebach, D.; Kalinowski, H. O.; Bastani, B.; Crass, G.; Daum,
H.; Dorr, H.; Dupreez, N. P.; Ehrig, V.; Langer, W.; Nussler, C.; Oei,
H. A.; Schmidt, M. Helv. Chim. Acta 1977, 60, 301-325.
(41) Adiyaman, M.; Khanapure, S. P.; Hwang, S. W.; Rokach, J.
Tetrahedron Lett. 1995, 36, 7367-7370.
(42) McCaig, A. E.; Meldrum, K. P.; Wightman, R. H. Tetrahedron
1998, 54, 9429-9446.
(43) Rubin, L. J.; Lardy, H. A.; Fischer, H. O. L. J. Am. Chem. Soc.
1952, 74, 425-428.
J. Org. Chem, Vol. 70, No. 24, 2005 9775

Marson and Melling
at 90 °C under an atmosphere of dry nitrogen for 9 days. The
mixture was quenched by the addition of aqueous lithium
chloride (45 mL, 2.0 M), and the aqueous layer was extracted
with ethyl acetate (3 × 30 mL). The combined organic layers
were washed with brine (2 × 30 mL) and dried over MgSO4.
The solution was filtered through a sintered glass funnel, and
the filtrate was adsorbed onto neutral alumina by evaporation.
The impregnated dispersion was applied to the top of a
prepacked column and purified by flash chromatography over
silica gel (9:1 diethyl ether/40-60 °C petroleum ether). The
appropriate fractions were combined and filtered through a
glass wool plug, and the eluent was evaporated under reduced
pressure to give 3d (0.60 g, 34%) as a pink solid (mp 129-131
°C). An analytical sample was obtained by recrystallization
from ethyl acetate as light purple prisms: mp 134.5-135 °C;
atmosphere of dry nitrogen was added dropwise a solution of
trifluoromethanesulfonic anhydride (2.62 g, 9.30 mmol) in 40
mL of dry, degassed dichloromethane using a double-tipped
needle of stainless steel. The mixture was allowed to warm
slowly to 20 °C, and stirring was continued at 20 °C under an
atmosphere of dry nitrogen for 16 h. The mixture was
quenched by addition of saturated aqueous sodium hydrogen
carbonate (35 mL), and the aqueous layer was extracted with
diethyl ether (3 × 20 mL). The combined organic layers were
washed with brine (2 × 20 mL) and dried over Na2SO4. The
solution was filtered through a sintered glass funnel, and the
filtrate was evaporated at 0 °C under reduced pressure (1.0-
1.5 mmHg). The residue was adsorbed onto neutral alumina,
and the impregnated dispersion was applied to the top of a
prepacked column of silica gel and eluted with 1:49 ethyl
acetate/40-60 °C petroleum ether. The appropriate fractions
were combined, filtered through a glass wool plug, and
evaporated to give 4a (0.67 g, 30%) as a clear gel. An analytical
sample was obtained by preparative silica plate thin-layer
chromatography (two-plate elutions with 40-60 °C petroleum
ether at a refrigerated temperature of 5 °C in the dark). The
appropriate band was excised and extracted with methanol
and filtered through a sintered glass microfunnel. The filtrate
was evaporated under reduced pressure, and the residue was
redissolved in chloroform. This solution was filtered through
a fluted paper, and the filtrate was evaporated to give 4a as
plates: mp 35-40 °C; [R]D30 +40.9 (c 0.98, chloroform); IR νmax
31
[R]D +59.4 (c 0.4, acetone); IR νmax (KBr) 3210, 2880, 2850,
1590, 1490 cm-1 1H NMR (DMSO-d6) δ 7.38 (2H, J ) 9.0
;
Hz), 6.34 (2H, J ) 9.0 Hz), 5.03 (2H, d, J ) 3.5 Hz), 4.03 (2H,
br s), 3.30 (4H, m); LRMS-FAB m/e (rel intensity %; posi-
tive m-NO2C6H5CO2H MATRIX) 305 ([M + H]+, 100), 304 (42),
289 (23), 232 (18), 176 (33), 165 (38). HRMS-FAB calcd for
C10H14NO2I [M + H]+ 304.9913, found 304.9913. Anal. Calcd
for C10H12NO2I: C, 39.36; H, 3.96; N, 4.59. Found: C, 39.61;
H, 3.88; N, 4.33.
(3S,4S)-1-(2-Benzyloxyethyl)pyrrolidine-3,4-diol (3f).
To a stirred suspension of (3S,4S)-1-(2-benzyloxyethyl)-3,4-bis-
(methoxymethyloxy)pyrrolidine (10b) (5.0 g, 15.4 mmol) in
methanol (13 mL) at 0 °C under an atmosphere of nitrogen
was added dropwise 10 M hydrochloric acid (13 mL) using a
pressure-equalizing addition funnel. The mixture was allowed
to warm slowly to 20 °C, and stirring was continued at 20 °C
under an atmosphere of nitrogen for 16 h. Volatile material
was removed under reduced pressure, and the residue was
basified by addition of N,N-dimethylethylamine (Caution:
exothermic) at -20 °C under an atmosphere of nitrogen with
stirring. This mixture was allowed to warm slowly to 20 °C
and stirred at that temperature for 2 h under an atmosphere
of nitrogen. The volatile materials were removed under
vacuum, and the residue was dissolved in saturated aqueous
ammonium chloride (30 mL). The suspension was continuously
extracted with ethyl acetate under an atmosphere of nitrogen
for 16 h. The organic layer was collected and concentrated to
approximately one-half of its original volume, to which an
equal volume of 1,4-dioxane was added, and the extraction
continued for an additional 80 h. The organic layers were dried
over Na2SO4 and filtered through a sintered glass funnel, and
the filtrate was adsorbed onto neutral alumina by evaporation.
The impregnated dispersion was applied to the top of a
prepacked column and purified by flash chromatography over
silica gel (1:9 methanol/chloroform). The appropriate fractions
were combined and filtered through a glass wool plug, and the
eluent was evaporated under reduced pressure to give 3f (2.52
g, 69%) as a pale yellow oil. An analytical sample was obtained
by preparative silica plate thin-layer chromatography (two-
plate elutions with 1:19 methanol/chloroform). The appropriate
band was excised and extracted with methanol and filtered
through a sintered glass microfunnel, and the filtrate was
evaporated under reduced pressure. The residue was redis-
solved in chloroform. This solution was filtered through a
fluted paper, and the filtrate was evaporated to give 3f as a
clear oil: [R]D30 -5.05 (c 4.01, chloroform); IR νmax (film) 3355,
2920, 2870, 1620 cm-1; 1H NMR δ 7.40-7.20 (5H, m), 5.30 (2H,
s br), 4.52 (2H, s br), 4.47 (2H, s br), 3.80 (2H, m), 3.68 (2H,
m), 3.40 (4H, m); 13C NMR δ 137.1, 128.7, 128.2, 74.7, 73.5,
65.0, 60.5, 57.5; LRMS-EI m/e (rel intensity %) 237 (M+, 0.1),
208 (10), 164 (120), 116 (73), 91 (100), 65 (12). HRMS-EI calcd
for C13H19NO3 (M+) 237.1365, found 237.1368.
1
(KBr) 2930, 1435, 1310, 1190 cm-1; H NMR δ 5.35 (2H, t, J
) 4.9 Hz), 3.19 (2H, dd, J ) 10.2, 5.5 Hz), 2.86 (2H, dd, J )
10.0, 4.0 Hz), 2.49 (2H, m), 1.48 (2H, m), 1.29 (10H, m), 0.91
(3H, t, J ) 6.0 Hz); 13C NMR δ 118.7 (q, JCF ) 315.4 Hz), 87.9,
57.7, 55.0, 31.8, 29.4, 29.2, 27.8, 27.2, 22.7, 14.1; 19F NMR δ
-79.0 (s); LRMS-EI m/e (rel intensity %) 479 (M+, 2.9), 379
(100), 180 (3.8), 80 (18.3), 41 (14.2). HRMS-EI calcd for
C14H23F6NO6S2 (M+) 479.0871, found 479.0878.
(3R,4R)-1-n-Octyl-3,4-difluoropyrrolidine (5a). General
Procedure D. To a stirred solution of (3S,4S)-3,4-bis(trifluo-
romethanesulfonyloxy)pyrrolidine (4a) (0.64 g, 1.34 mmol) in
anhydrous THF (10 mL) at -85 °C under an atmosphere of
dry nitrogen was added dropwise a solution of tetra-n-
butylammonium fluoride (4.02 mL, 4.02 mmol, 1 M) in dry
THF (15 mL) by means of a stainless steel, double-tipped
needle. The mixture was allowed to warm slowly to 20 °C, and
stirring was continued at 20 °C under an atmosphere of dry
nitrogen for 16 h. The mixture was quenched by addition of
saturated aqueous sodium hydrogen carbonate (35 mL), and
the aqueous layer was extracted with diethyl ether (3 × 20
mL). The combined organic layers were washed with brine (2
× 20 mL) and dried over Na2SO4. The solution was filtered
through a sintered glass funnel, and the filtrate was evapo-
rated at 0 °C under reduced pressure (1.0-1.5 mmHg). The
residue was adsorbed onto neutral alumina, and the impreg-
nated dispersion was applied to the top of a prepacked column
of silica gel and eluted with 1:49 ethyl acetate/40-60 °C
petroleum ether. The appropriate fractions were combined,
filtered through a glass wool plug, and evaporated to give 5a
(0.24 g, 83%) as a clear, viscous oil. An analytical sample was
obtained by preparative silica plate thin-layer chromatography
and three-plate elutions with n-hexane at a refrigerated
temperature of 5 °C in the dark. The appropriate band was
excised and extracted with methanol and filtered through a
sintered glass microfunnel. The filtrate was evaporated under
reduced pressure, and the residue was redissolved in chloro-
form. This solution was filtered through a fluted paper, and
the filtrate was evaporated to give 5a as a soft gel: [R]D30 -20.0
1
(c 1.23, chloroform); IR νmax (KBr) 2930, 1440 cm-1; H NMR
δ 5.15 (2H, dddd, 2JHF ) 53.2 Hz, 3JHF ) 16.3 Hz, 3JHH ) 5.1,
3.0 Hz), 3.14 (2H, m), 2.88 (2H, ddd, 3JHF-trans ) 24.0 Hz, 2JHH
) 11.5, 3JHH ) 3.0 Hz), 2.57 (2H, m), 1.70-1.25 (12H, m), 0.88
(3S,4S)-1-n-Octyl-3,4-bis(trifluoromethanesulfonyloxy)-
pyrrolidine (4a). General Procedure C. To a stirred
suspension of (3S,4S)-1-n-octylpyrrolidine-3,4-diol (3a) (1.00
g, 4.65 mmol) and triethylamine (0.99 g, 9.8 mmol) in 65 mL
of anhydrous, degassed dichloromethane at -85 °C under an
(3H, t, J ) 6.9 Hz); 13C NMR δ 95.0 (dd, 1JCF 181.5 Hz, 2JCF
)
30.0 Hz), 58.0 (d, 2JCF ) 26.0 Hz), 56.4, 31.8, 29.6, 27.6, 24.0,
22.7, 19.7, 13.8; 19F NMR δ -186.4; LRMS-FAB m/e (rel
9776 J. Org. Chem., Vol. 70, No. 24, 2005

Syntheses of trans-3,4-Difluoropyrrolidines
30
intensity %; positive m-NO2C6H5CO2H MATRIX) 220 ([M +
H]+, 100), 184 (13), 142 (33), 120 (26); HRMS-FAB calcd for
C12H24F2N (M+) 220.1890, found 220.1877.
solid: mp between 15 and 25 °C; [R]D -24.3 (c 0.48,
chloroform); IR νmax (film) 3360, 2930, 2860, 2815, 1454 cm-1
;
1H NMR δ 5.13 (2H, dddd, JHF ) 52.2 Hz, JHF )17.9 Hz,
3JHH ) 5.5, 3.5 Hz), 3.64 (2H, t, J ) 6.0 Hz), 3.12 (2H, ddd,
3JHF ) 27.5 Hz, 2JHH ) 11.0 Hz, 3JHH ) 5.5 Hz), 2.86 (2H, ddd,
3JHF ) 25.2 Hz, 2JHH ) 11.0 Hz, 3JHH ) 3.5 Hz), 2.73 (2H, m),
2
3
(3R,4R)-1-[1,1′-Biphenyl-4-yl]-3,4-difluoropyrrolidine
(5e). A thick-walled tube equipped with a gas outlet, a septum,
and a magnetic stirring bar was charged with (3R,4R)-1-(4-
iodophenyl)-3,4-difluoropyrrolidine (5d) (25 mg, 0.08 mmol),
phenylboronic acid (10 mg, 0.09 mmol), potassium carbonate
(28 mg, 0.02 mmol), and 1:1 acetone/distilled water (3.0 mL)
and maintained at 0 °C with stirring under an atmosphere of
dry nitrogen. The apparatus was purged with nitrogen, and
three successive freeze-pump-thaw cycles were performed
at -10 °C with stirring. A solution of palladium(II) acetate in
benzene (0.1 mL, 0.045 M) was added via a syringe. Following
two additional freeze-pump-thaw cycles, the vessel was
charged with nitrogen and maintained at 60 °C with stirring
for 16 h. Upon cooling, the mixture was filtered and the filtrate
was evaporated. The residue was purified by preparative silica
plate thin-layer chromatography (three-plate elutions with
n-hexane at a refrigerated temperature of 5 °C in the dark).
The appropriate band was excised and extracted with metha-
nol and filtered through a sintered glass microfunnel. The
filtrate was evaporated under reduced pressure, and the
residue was redissolved in chloroform. This solution was
filtered through a fluted paper, and the filtrate was evaporated
to give 5e (5.0 mg, 24%) as a gray, semicrystalline material:
[R]D32 -23.4 (c 0.2, chloroform); IR νmax (film) 2850, 1610, 1530,
1.60 (1H, br); 13C NMR (150 MHz) δ 95.3 (dd, JCF ) 180.8
1
Hz, 2JCF ) 29.7 Hz), 59.6, 57.8 (dd, 2JCF ) 22.0 Hz, 3JCF ) 5.7
Hz), 57.1; 19F NMR (565 MHz) δ -183.9 (m); LRMS-EI m/e
(rel intensity %) 151 (M+, 5), 120 (100), 100 (5), 73 (5), 41 (7).
HRMS-EI calcd for C6H11F2NO (M+) 151.0809, found 151.0810.
(2R,3R)-1,4-Diodobutane-2,3-diol (7). A previous account
did not give experimental details.41 To a stirred solution of
(4S,5S)-4,5-diiodomethyl-2,2-dimethyl-1,3-dioxolane43 (15.0 g,
39.4 mmol) in THF (25 mL) at 0 °C under an atmosphere of
dry nitrogen was added dropwise a solution of 4:1 trifluoro-
acetic acid/methanol by means of a pressure-equalizing addi-
tion funnel. The mixture was allowed to warm slowly to 20
°C, and stirring was continued at 20 °C under an atmosphere
of nitrogen for 24 h. The mixture was quenched by addition of
water (20 mL), and the aqueous layer was extracted with ethyl
acetate (3 × 35 mL). The combined organic layers were washed
with brine (2 × 35 mL) and dried over Na2SO4. The solution
was filtered through a sintered glass funnel, and the filtrate
was evaporated at 0 °C under reduced pressure (1.0-1.5
mmHg). The residue was adsorbed onto neutral alumina, and
the impregnated dispersion was applied to the top of a
prepacked column of silica gel and eluted with 1:4 ethyl
acetate/40-60 °C petroleum ether. The appropriate fractions
were combined, filtered through a glass wool plug, and
evaporated to give 7 (4.83 g, 36%) as a yellow solid (mp 110-
115 °C). An analytical sample was obtained by recrystallization
1
1490 cm-1; H NMR δ 7.55 (4H, m), 7.42 (2H, t, J ) 7.5 Hz),
7.27 (1H, t, J ) 6.2 Hz), 6.68 (2H, d, J ) 9.5 Hz), 5.31 (2H,
ddm, 3JHF ) 49.6, 2JHH ) 11.0 Hz), 3.80 (2H, m), 3.66 (2H, m);
13C NMR δC 146.2, 141.2, 130.0, 128.8, 128.1, 126.4, 126.2,
112.3, 92.7 (dd, 1JCF ) 179.8 Hz, 2JCF ) 33.0), 51.8 (dd, 2JCF
)
22.0 Hz, 3JCF ) 5.9); LRMS-FAB m/e (rel intensity %; positive
m-NO2C6H5CO2H MATRIX) 259 (M+, 40), 242 (16), 185 (17),
154 (22), 137 (23), 115 (100); HRMS-FAB calcd for C16H15F2N
(M+) 259.1173, found 259.1160.
34
from chloroform, giving 7 as needles: mp 114.5-115 °C; [R]D
+9.6 (c 1.0, methanol); IR νmax (Nujol) 3215, 1460 cm-1 1H
;
NMR (DMSO-d6) δ 5.25 (2H, d, J ) 7.4 Hz), 3.75 (2H, m), 3.24
(2H, m); LRMS-FAB m/e (%) 341 (M+, 15), 325 (23), 281 (42),
267 (24), 221 (40), 207 (54), 193 (28).
(3R,4R)-1-(2-Hydroxyethyl)-3,4-difluoropyrrolidine (5g).
To a stirred solution of (3S,4S)-1-(2-benzyloxyethyl)-3,4-dif-
luoropyrrolidine 5f (0.332 g, 1.38 mmol) in dry dichlo-
romethane (6 mL) at -85 °C under an atmosphere of dry
nitrogen was added via a syringe a boron trichloride/dimethyl
sulfide complex44 (1.38 mL, 2.76 mmol, 2.0 M) in dichlo-
romethane. The mixture was allowed to warm slowly to 20
°C, and stirring was continued at 20 °C under an atmosphere
of dry nitrogen for 4 h. The mixture was quenched by the
addition of neat N,N-dimethylethylamine (1 mL) (the standard
literature procedure44 employing a saturated sodium hydrogen
carbonate quench did not liberate the pyrrolidine), and diges-
tion was continued at this temperature under an atmosphere
of dry nitrogen for an additional 1 h. Saturated aqueous
ammonium chloride (5 mL) was then added, and the aqueous
layer was extracted with ethyl acetate (3 × 20 mL) and then
with THF (10 mL). The combined organic layers were washed
with brine (2 × 5 mL) and dried over Na2SO4. The solution
was filtered through a sintered glass funnel, and the filtrate
was evaporated. The residue was purified by flash column
chromatography on silica gel eluted with 1:32 methanol/
chloroform precooled to 5 °C. The appropriate fractions were
combined, filtered through a glass wool plug, and evaporated
to give 5g (137 mg, 66%) as a clear oil. An analytical sample
was obtained by preparative silica plate thin-layer chroma-
tography (two-plate elutions with 2:1 chloroform/diethyl ether
at a refrigerated temperature of 5 °C in the dark). The
appropriate band was excised and extracted with methanol
and filtered through a sintered glass microfunnel. The filtrate
was evaporated under reduced pressure, and the residue was
redissolved in chloroform. This solution was filtered through
a fluted paper, and the filtrate was evaporated to give 5g as
a colorless gel, which upon standing gradually became a waxy
(2S,3S)-2,3-Bis(methoxymethyloxy)-4-methylsulfo-
nyloxybutylmethanesulfonate (9). To a stirred solution of
(2S,3S)-2,3-bis(methoxymethyloxy)butane-1,4-diol (8) (15.0 g,
71.4 mmol) and triethylamine (18.1 g, 179 mmol) in dry
dichloromethane (200 mL) at 0 °C under an atmosphere of dry
nitrogen was added dropwise a solution of methanesulfonyl
chloride (20.5 g, 179 mol) in dry dichloromethane (45 mL) by
means of a stainless steel, double-tipped needle. The mixture
was maintained at 0 °C with stirring under an atmosphere of
dry nitrogen for 1 h. The mixture was quenched by addition
of water (50 mL), and the aqueous layer was extracted with
dichloromethane (3 × 40 mL). The combined organic layers
were washed sequentially with water (50 mL), hydrochloric
acid (50 mL, 4 M), saturated aqueous sodium hydrogen
carbonate (50 mL), and brine (2 × 50 mL) and then dried over
MgSO4. The solution was filtered through a sintered glass
funnel, and the filtrate was evaporated. The residue was
adsorbed onto neutral alumina, and the impregnated disper-
sion was applied to the top of a prepacked column of silica gel
and eluted with 1:1 ethyl acetate/40-60 °C petroleum ether.
The appropriate fractions were combined, filtered through a
glass wool plug, and evaporated to give 7 (12.8 g, 49%) as a
pale yellow oil. An analytical sample was obtained by recrys-
tallization from chloroform at -35 °C, giving 9 as needles: mp
27
89.5-90 °C; [R]D +10.4 (c 0.25, chloroform); IR νmax (KBr)
2940, 2900, 1350 cm-1 1H NMR δ 4.72 (4H, d, J ) 3.0 Hz,
;
OCH2O), 4.41 (2H, dd, J ) 4.00 Hz), 4.30 (2H, dd, J ) 4.5
Hz), 4.02 (2H, t, J ) 3.0 Hz, CH), 3.38 (6H, s), 3.04 (6H, s);
13C NMR δC 97.4, 75.0, 68.0, 56.2, 37.5; LRMS-EI m/e (rel
intensity %) 289 [C7H13O8S2, (M+ - C3H9O2), (3)], 289 (4), 185
(5), 151 (8), 98 (7), 85 (47), 45 (100). HRMS-EI calcd for
C7H13O8S2 (M+ - C3H9O2) 289.0052, found 289.0038.
(3S,4S)-1-(2-Hydroxyethyl)-3,4-bis(methoxymethyl-
oxy)pyrrolidine (10a). To a stirred suspension of (2S,3S)-
2,3-bis(methoxymethyloxy)-4-methylsulfonyloxybutylmethane-
(44) Scheurer, A.; Mosset, P.; Saalfrank, R. W. Tetrahedron: Asym-
metry 1997, 8, 1243-1251.
J. Org. Chem, Vol. 70, No. 24, 2005 9777

Marson and Melling
sulfonate (9) (13.0 g, 35.5 mmol), potassium carbonate (14.7
g, 107 mmol), 18-crown-6 (0.89 g, 3.5 mmol), and potassium
iodide (0.59 g, 3.55 mmol) in dry DMF (120 mL) at -10 °C
under an atmosphere of dry nitrogen was added via a syringe
a solution of ethanolamine (2.14 mL, 2.16 g, 35.5 mmol) in
dry triethylamine (3 mL). The mixture was heated slowly to
100 °C and stirred at that temperature for 48 h under an
atmosphere of dry nitrogen. The DMF was removed by
distillation under reduced pressure, and the residue was
suspended in saturated aqueous ammonium chloride (150 mL)
and continuously extracted for 80 h with 3:1 ethyl acetate/
butanone. The organic layer was dried over K2CO3 and filtered
through a sintered glass funnel, and the filtrate was evapo-
rated. The gummy residue was purified by short-path distil-
lation (bp 190-196 °C/1.2 mmHg) to give a glassy solid that
was adsorbed onto neutral alumina, and the impregnated
dispersion was applied to the top of a prepacked column of
silica gel and eluted with 49:1 chloroform/methanol. The
appropriate fractions were combined, filtered through a glass
wool plug, and evaporated to give 10a (4.76 g, 57%) as a yellow
gum. An analytical sample was obtained by preparative silica
plate thin-layer chromatography (two-plate elutions with
chloroform). The appropriate band was excised and extracted
with methanol and filtered through a sintered glass micro-
funnel. The filtrate was evaporated under reduced pressure,
and the residue was redissolved in chloroform. This solution
was filtered through a fluted paper, and the filtrate was
HRMS-FAB calcd for C17H28NO5 [M + H]+ 326.1967, found
326.1962.
Catalytic Asymmetric Ethylation of Benzaldehyde to
Give 1-(R)-Phenylpropanol (11b).45 Representative pro-
cedure (5 mol % catalyst 5g at -20 °C to 20 °C). To a stirred
solution of benzaldehyde (160 mg, 1.52 mmol) and (3S,4S)-1-
(2-hydroxyethyl)-3,4-difluoropyrrolidine (5g) (12 mg, 0.08 mmol)
in 2.0 mL of anhydrous toluene at -20 °C under an atmo-
sphere of dry nitrogen was injected a solution of diethylzinc
(1.64 mL, 1.81 mmol, 1.1 M in toluene). The mixture was
allowed to warm slowly to 20 °C, and stirring was continued
at 20 °C under an atmosphere of dry nitrogen for 16 h. The
mixture was allowed to warm slowly to 20 °C, and stirring
was continued for 3 h at 20 °C under an atmosphere of dry
nitrogen. Progress of the reaction was monitored by thin-layer
chromatography (plate treated with potassium permanganate
solution and then heated). The mixture was quenched with
hydrochloric acid (5 mL, 5 M). The aqueous layer was extracted
with diethyl ether (3 × 5 mL). The combined organic layers
were washed with brine (2 × 5 mL) and dried over MgSO4.
The solution was filtered through a sintered glass funnel, and
the filtrate was evaporated under reduced pressure. The
residue was purified by flash column chromatography over
silica gel (1:9 ethyl acetate/40-60 °C petroleum ether). The
appropriate fractions were combined and filtered through a
glass wool plug, and the eluent was evaporated under reduced
pressure to give 11b as a pale yellow oil (168 mg, 82%). A
sample for HPLC analysis (see following description for
conditions) was obtained from Kugelrohr bulb-to-bulb distil-
31
evaporated to give 10a as a clear viscous oil: [R]D -0.8 (c
0.51, methanol); IR νmax (film) 3420, 2940, 2890 cm-1; 1H NMR
δH 4.64 (2H, d, J ) 7.5 Hz), 4.58 (2H, d, J ) 7.5 Hz), 4.07 (2H,
J ) 4.0 Hz), 3.56 (2H, t, J ) 5.5 Hz), 3.30 (6H, s), 2.92 (2H,
dd, J ) 10.0, 7.0 Hz), 2.70 (1H, br), 2.60 (2H, m), 2.50 (2H, dd,
3JHH ) 11.0, 5.2 Hz); 13C NMR δC 95.8, 81.5, 59.7, 58.7, 57.8,
55.5; LRMS-EI m/e (rel intensity %) 235 (M+, 1.1), 206 (10),
204 (100), 160 (4), 86 (5), 45 (65); HRMS-EI calcd for C10H21-
NO5 (M+) 235.1420, found 235.1420.
36
lation (123 mg, 60%): bp 94-95 °C; [R]D +9.3 (c 1.80,
chloroform), (lit.45 [R]22D -48.6 (c 5.13, chloroform) for the (S)-
enantiomer); IR νmax (film) 3365, 2970, 2870, 1600 cm-1 1H
;
NMR δ 7.37 (5H, m), 4.54 (1H, t, J ) 6.0 Hz), 2.93 (1H, br s),
1.78 (2H, m), 0.92 (3H, t, J ) 7.5 Hz); 13C NMR δ 144.8, 128.4,
127.4, 126.2, 75.9, 31.9, 10.2.
Conditions for HPLC analysis: stationary phase, Daicel
chiralcel OD column (250 × 4.6 mm), recorded on a Shimadzu
SPD-10A VP instrument, 254 nm detection wavelength, iso-
cratic at 20 °C, mobile phase of doubly redistilled propan-2-
ol/n-hexane (1:49, v/v), and 0.5 mL/min flow rate. Found:
R-isomer, tR ) 32.5 min; S-isomer, tR ) 39.7 min.
(3S,4S)-1-(2-Benzyloxyethyl)-3,4-bis(methoxymethoxy-
)pyrrolidine (10b). To a stirred suspension of (3S,4S)-1-(2-
hydroxyethyl)-3,4-bis(methoxymethyloxy)pyrrolidine (10a) (4.50
g, 19.1 mmol) and sodium hydride (0.88 g, 38.3 mmol, rinsed
with n-hexane) in dry tetrahydrofuran (150 mL) at 20 °C under
an atmosphere of dry nitrogen was added via syringe benzyl
bromide (3.59 g, 4.48 mL, 21.0 mmol). The mixture was slowly
brought to reflux, and stirring was continued for 3 h under
an atmosphere of dry nitrogen. Saturated aqueous ammonium
chloride (40 mL) was then added, and the aqueous layer was
extracted with diethyl ether (3 × 40 mL). The combined
organic layers were washed with brine (2 × 30 mL) and dried
over K2CO3. The solution was filtered through a sintered glass
funnel, and the filtrate was evaporated. The residue was
purified by flash column chromatography on silica gel with
gradient elution using methanol/chloroform ranging from 0:100
to 1:49. The appropriate fractions were combined, filtered
through a glass wool plug, and evaporated to give 10b (5.2 g,
82%) as a colorless oil. An analytical sample was obtained by
preparative silica plate thin-layer chromatography (two-plate
elutions with chloroform). The appropriate band was excised
and extracted with methanol and filtered through a sintered
glass microfunnel. The filtrate was evaporated under reduced
pressure, and the residue was redissolved in chloroform. This
solution was filtered through a fluted paper, and the filtrate
was evaporated to give 10b as a clear oil: [R]D30 +5.05 (c 4.36,
Catalytic Asymmetric Epoxidation of Geraniol to Give
(2R,3R)-Epoxygeraniol (13b).35 Representative proce-
dure (10 mol % catalyst 5a at -20 °C to 20 °C). To a stirred
solution of titanium tetraisopropoxide (69 mg, 0.07 mL, 0.24
mmol), geraniol (12) (250 mg, 0.28 mL, 1.62 mmol), and
(3R,4R)-3,4-difluoro-1-octylpyrrolidine (5a) (35 mg, 0.16 mmol,
10 mol %) in dry dichloromethane (0.5 mL) at -20 °C under
an atmosphere of dry nitrogen was added a solution of tert-
butyl hydroperoxide (6.08 M, 0.4 mL) in dry dichloromethane
via a syringe. The mixture was allowed to warm slowly to 20
°C, and stirring was continued at 20 °C under an atmosphere
of dry nitrogen for 12 h. Progress of the reaction was monitored
by thin-layer chromatography (plate treated with anisaldehyde
solution and then heated). The mixture was quenched by the
addition of aqueous acidified iron(II) sulfate (10 mL),35 and
the aqueous layer was extracted with dichloromethane (3 ×
10 mL). The combined organic layers were washed with brine
(2 × 10 mL) and dried over Na2SO4. The solution was filtered
through a sintered glass funnel, and the filtrate was evapo-
rated under reduced pressure. This product was purified by
flash column chromatography over silica gel (20:80 ethyl
acetate/40-60 °C petroleum ether). The appropriate fractions
were combined and filtered through a glass wool plug, and the
eluent was evaporated under reduced pressure to give 13b
(0.247 g, 90%) as a mobile oil: [R]D31 +2.74 (c 1.75, chloroform);
1
chloroform); IR νmax (film) 2890, 2820, 1670 cm-1; H NMR δ
7.31 (5H, m), 4.70 (2H, d, J ) 6.5 Hz), 4.62 (2H, d, J ) 6.5
Hz), 4.52 (2H, s), 4.13 (2H, t, J ) 4.9 Hz), 3.61 (2H, t, J ) 5.5
Hz), 3.36 (6H, s), 3.00 (2H, dd, J ) 10.0, 6.0 Hz), 2.70 (2H, m),
2.63 (2H, dd, J ) 10.0, 5.0 Hz); 13C NMR δ 138.4, 128.4, 127.7,
127.6, 95.7, 81.5, 73.1, 69.0, 59.4, 55.5, 55.4; LRMS-EI m/e
(rel intensity %) 173 (15), 111 (20), 91 (100); LRMS-FAB m/e
(rel intensity %; positive m-NO2C6H5CO2H MATRIX) 326 ([M
+ H]+, 100), 324 (43), 294 (15), 264 (8), 218 (21), 204 (72);
IR νmax (film) 3400, 2900, 2870, 1680 cm-1 1H NMR δ 5.10
;
(1H, t, J ) 6.0 Hz), 3.82 (1H, dd, J ) 12.0, 5.0 Hz), 3.67 (1H,
dd, J ) 12.0, 6.0 Hz), 2.99 (1H, t, J ) 5.0 Hz), 2.60 (1H, br),
(45) Yoshioka, M.; Kawakita, T.; Ohno, M. Tetrahedron Lett. 1989,
30, 1657-1660.
9778 J. Org. Chem., Vol. 70, No. 24, 2005

Syntheses of trans-3,4-Difluoropyrrolidines
27
2.08 (2H, t, J ) 8.0 Hz), 1.68 (3H, s), 1.62 (3H, s), 1.49 (2H,
m), 1.30 (3H, s); 13C NMR δ 132.1, 123.4, 63.2, 61.4, 61.2, 38.5,
25.7, 23.7, 17.6, 16.8; LRMS-FAB m/e (rel intensity %; posi-
tive m-NO2C6H5CO2H MATRIX) 193 ([M + Na]+, 65), 171 (26),
153 (58), 139 (17), 135 (50), 123 (49), 119 (11), 109 (100).
HRMS-FAB calcd for C10H18NaO2 [M + Na]+ 193.1204, found
193.1220.
1-acetoxyepoxygeraniol (115 mg, 92%) as a clear oil: [R]D
+21.1 (c 3.0, chloroform); IR νmax (film) 2965, 2930, 2856, 1745,
1630 cm-1; 1H NMR δ 5.08 (1H, dt, J ) 7.5, 1.5 Hz), 4.32 (1H,
dd, J ) 12.0, 5.0 Hz), 4.05 (1H, dd, J ) 11.5, 6.5 Hz), 2.99
(1H, J ) 7.5, 5.0 Hz), 2.11 (3H, s), 2.08 (2H, q, J ) 5.5 Hz),
1.68 (3H, s), 1.63 (3H, s), 1.48 (2H, m), 1.31 (3H, s); 13C NMR
δC 170.8, 132.2, 123.3, 63.4, 60.5, 59.7, 38.3, 25.7, 23.6, 20.7,
17.6, 16.9.
(2R,3R)-1-Acetoxyepoxygeraniol.35 To a stirred solution
of (2R,3R)-epoxygeraniol (100 mg, 0.65 mmol) and pyridine (94
mg, 0.78 mmol) in anhydrous dichloromethane (5 mL) at 0 °C
under an atmosphere of dry nitrogen was added a solution of
acetic anhydride (144 mg, 0.14 mL, 158 mmol) in dichlo-
romethane (1 mL) via a syringe. The mixture was allowed to
warm slowly to 20 °C, and stirring was continued for 3 h at
20 °C under an atmosphere of dry nitrogen. Progress of the
reaction was monitored by thin-layer chromatography (plate
treated with cerium(IV) sulfate solution and then heated). The
mixture was quenched by the addition of saturated aqueous
sodium carbonate (15 mL) and transferred to a separating
funnel. The aqueous layer was extracted with dichloromethane
(3 × 10 mL). The combined organic layers were washed with
brine (2 × 10 mL) and dried over MgSO4. The solution was
filtered through a sintered glass funnel, and the filtrate was
evaporated under reduced pressure. The residue was purified
by flash column chromatography over silica gel (1:55 ethyl
acetate/40-60 °C petroleum ether). The appropriate fractions
were combined and filtered through a glass wool plug, and the
eluent was evaporated under reduced pressure to give (2R,3R)-
1H NMR shift analysis35 of (2R,3R)-1-acetoxyepoxygerani-
ol: 10 mg (0.05 mmol) in C6D6 (0.5 mL) was treated with
consecutive portions of 10-20 µL of a filtered solution of 35
mg of europium(III) tris[3-(heptafluoropropylhydroxymeth-
ylene)-d-camphorate] and Eu(hfc)3 in 0.5 mL of C6D6. The
acetate signal was measured by quantitative integration at
250 MHz.
Acknowledgment. Support from the Engineering
and Physical Sciences Research Council for a student-
ship (to R.C.M.) under the ROPA initiative is gratefully
acknowledged.
Supporting Information Available: Experimental pro-
cedures and 1H and 13C NMR spectra for all new compounds.
This material is available free of charge via the Internet at
http://pubs.acs.org.
JO0513414
J. Org. Chem, Vol. 70, No. 24, 2005 9779