Divergent chemical synthesis of prolines bearing fluorinated one-carbon units at the 4-position via nucleophilic 5-endo-trig cyclizations

Article abstract of DOI:10.1021/jo061421n

N-[3-(Trifluoromethyl)homoallyl]sulfonamides, prepared via ring opening of (5)-glycidyl ethers or 2-aryloxiranes with 1-(trifluoromethyl)vinyllithium, underwent intramolecular addition or S_N2′-type reaction in the normally disfavored 5-endo-tri

Full text of DOI:10.1021/jo061421n

Divergent Chemical Synthesis of Prolines Bearing Fluorinated
One-Carbon Units at the 4-Position via Nucleophilic 5-Endo-Trig
Cyclizations
Ryo Nadano, Yu Iwai, Takashi Mori, and Junji Ichikawa*
Department of Chemistry, Graduate School of Science, The UniVersity of Tokyo, Hongo, Bunkyo-ku,
Tokyo 113-0033, Japan
junji@chem.s.u-tokyo.ac.jp
ReceiVed July 8, 2006
N-[3-(Trifluoromethyl)homoallyl]sulfonamides, prepared via ring opening of (S)-glycidyl ethers or
2-aryloxiranes with 1-(trifluoromethyl)vinyllithium, underwent intramolecular addition or SN2′-type reaction
in the normally disfavored 5-endo-trig fashion, leading to 2-substituted 4-(trifluoromethyl)- or 4-(di-
fluoromethylene)pyrrolidines. Both R- and â-face-selective hydrogenation of the 4-difluoromethylene
group afforded syn- and anti-4-(difluoromethyl)pyrrolidines, respectively. These sequences, followed by
the oxidation of a 2-hydroxymethyl or 2-aryl group, successfully provided prolines with a trifluoromethyl,
difluoromethylene, or difluoromethyl group at the 4-position, including optically active prolines.
Introduction
well exemplified by (i) Spirapril6 and Fosinopril,7 angiotensin-
converting enzyme (ACE) inhibitors, (ii) conformationally
stabilized collagen triple helices,8 and (iii) 4-hydroxyproline-
based asymmetric organocatalysts.9
In the field of pharmaceuticals, agrochemicals, materials, and
catalysts, introduction of fluorocarbon substituents has come
into wide use as one of the most efficient methods for the
modification of biological activity as well as physical and
chemical properties.10 Among fluorocarbon substituents, flu-
orinated one-carbon units are quite attractive:11 (i) the incorpora-
Proline is a unique amino acid with a rigid ring structure,
which leads to its special role as a bending template in peptide
chains.1 Its secondary amine moiety with conformational con-
straint has allowed development of proline-based bioactive
compounds,2 ligands,3 and organocatalysts.4 4-Substituted pro-
lines, in particular, have found extensive use in this context,5
* To whom correspondence should be addressed. Tel/Fax: +81-3-5841-4345.
(1) Richardson, J. S.; Richardson, D. C. In Prediction of Protein Structure
and the Principles of Protein Conformation; Fasman, G. D., Ed.; Plenum
Press: New York, 1989; Chapter 1.
(2) ComprehensiVe Medicinal Chemistry. The Rational Design, Mecha-
nistic Study, and Therapeutic Application of Chemical Compounds, Vol. 2:
Enzymes and other Molecular Targets; Hansch, C., Sammes, P. G., Taylor,
J. B., Eds.; Pergamon Press: Oxford, UK, 1990.
(3) ComprehensiVe Asymmetric Catalysts I-III; Jacobsen, E. N., Pfaltz,
A., Yamamoto, H., Eds.; Springer: Berlin, 1999.
(4) (a) List, B. Acc. Chem. Res. 2004, 37, 548. (b) Allemann, C.; Gordillo,
R.; Clemente, F. R.; Cheong, P. H.-Y.; Houk, K. N. Acc. Chem. Res. 2004,
37, 558. (c) Saito, S.; Yamamoto, H. Acc. Chem. Res. 2004, 37, 570. (d)
Notz, W.; Tanaka, F.; Barbas, C. F., III. Acc. Chem. Res. 2004, 37, 580.
(e) Miller, S. J. Acc. Chem. Res. 2004, 37, 601.
(6) Smith, E. M.; Swiss, G. F.; Neustadt, B. R.; McNamara, P.; Gold,
E. H.; Sybertz, E. J.; Baum, T. J. Med. Chem. 1989, 32, 1600.
(7) Krapcho, J.; Turk, C.; Cushman, D. W.; Powell, J. R.; DeForrest, J.
M.; Spitzmiller, E. R.; Karanewsky, D. S.; Duggan, M.; Rovnyak, G.;
Schwartz, J.; Natarajan, S.; Godfrey, J. D.; Ryono, D. E.; Neubeck, R.;
Atwal, K. S.; Petrillo, E. W. J. Med. Chem. 1988, 31, 1148.
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Soc. 2006, 128, 8112 and references therein. (b) Persikov, A. V.; Ramshaw,
J. A. M.; Kirkpatrick, A.; Brodsky, B. J. Am. Chem. Soc. 2003, 125, 11500.
See also: (c) Thomas, K. M.; Naduthambi, D.; Tririya, G.; Zondlo, N. J.
Org. Lett. 2005, 7, 2397.
(5) (a) Zhang, J.; Wang, W.; Xiong, C.; Hruby, V. J. Tetrahedron Lett.
2003, 44, 1413. (b) Nevalainen, M.; Kauppinen, P. M.; Koskinen, A. M. P.
J. Org. Chem. 2001, 66, 2061 and references therein. (c) Tamaki, M.; Han,
G.; Hruby, V. J. J. Org. Chem. 2001, 66, 3593. (d) Osipov, S. N.; Burger,
K. Tetrahedron Lett. 2000, 41, 5659.
(9) Hayashi, Y.; Sumiya, T.; Takahashi, J.; Gotoh, H.; Urushima, T.;
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(10) Organofluorine Chemistry: Principles and Commercial Applica-
tions; Banks, R. E., Smart, B. E., Tatlow, J. C., Eds.; Plenum Press: New
York, 1994.
10.1021/jo061421n CCC: $33.50 © 2006 American Chemical Society
Published on Web 10/18/2006
8748
J. Org. Chem. 2006, 71, 8748-8754

Synthesis of 4-CF3, CF2d, or CF2H-Substituted Prolines
SCHEME 1. Nucleophilic 5-Endo-Trig Cyclizations of
SCHEME 2. Synthesis of 3-CF3-Homoallyl Alcohols
(3-CF3-homoallyl)sulfonamides
which are caused by the strong electron-withdrawing ability of
the CF3 group. Thus, both 4-difluoromethylene- and 4-trifluo-
romethyl-substituted pyrrolidines were selectively derived from
the same sulfonamide precursor, depending on reaction in the
presence or absence of a proton source.
We have also recently developed a synthetic method for
3-(trifluoromethyl)homoallyl alcohols via ring opening of
substituted oxiranes with 1-(trifluoromethyl)vinyllithium in the
presence of BF3‚OEt2, which allowed the synthesis of optically
active homoallyl alcohols (Scheme 2).21 The combination of
the two processes, the oxirane ring opening and the 5-endo-
trig cyclization, followed by introduction of a carboxy group
at the 2-position, could provide 4-substituted proline derivatives
in short steps, as outlined in Figure 1. The introduction of the
carboxy group would be attained by oxidation of a hydroxy-
methyl or an aryl group, derived from the 2-substituent on the
oxirane ring. The chirality of a commercially available, optically
active glycidyl ether could be preserved in the sequence. A
difluoromethylene substituent would be transformed to a dif-
luoromethyl group by hydrogenation, where face-selective
reactions could afford anti- or syn-4-(difluoromethyl)proline
derivatives. On the basis of these considerations, we investigated
synthetic methods for prolines bearing a fluorinated one-carbon
unit at the 4-position.
tion of a trifluoromethyl (CF3) group into organic molecules
increases lipophilicity and affects electron density,12 (ii) a
difluoromethyl (CF2H) group has hydrogen bond donor ability
without nucleophilicity and with high lipophilicity,13 which
makes it a special mimic of a hydroxy group,14 and (iii) a
difluoromethylene (CF2d) group acts as a reactive site toward
nucleophiles15 and a potential isostere of carbonyl groups.16
Thus, prolines with such fluorinated substituents at the
4-position have importance in the design of molecules and,
hence, immense potential. Recently, Goodman and Qing
independently reported synthetic methods for 4-fluorocarbon-
substituted prolines, with both methods starting from natural
amino acids such as L-hydroxyproline and L-serine.17,18 Their
chemical synthesis based on non-natural starting materials is
now a highly desirable goal.
In our recent studies, we have accomplished the construction
of a pyrrolidine ring via nucleophilic 5-endo-trig cyclization
of 2-trifluoromethyl-1-alkenes with a nitrogen functionality
(Scheme 1).19 N-[3-(Trifluoromethyl)homoallyl]sulfonamides
underwent intramolecular SN2′-type reaction under aprotic
conditions to afford 4-difluoromethylene-substituted pyrrolidines
(Scheme 1a), while protic conditions allowed nucleophilic
addition, providing 4-trifluoromethyl-substituted pyrrolidines
(Scheme 1b). This type of 5-endo-trig cyclization has been
considered to be a geometrically disfavored process according
to Baldwin’s rules.20 Such unique reactivity of 2-trifluoromethyl-
1-alkenes is presumably due to the highly electrophilic double
bond and the stabilized R-CF3 carbanion intermediate, both of
We report a short chemical synthesis of proline derivatives
bearing a fluorinated one-carbon unit, such as a trifluoromethyl,
difluoromethylene, or difluoromethyl group, at the 4-position
via (i) oxirane ring opening with 1-(trifluoromethyl)vinyllithium
and (ii) nucleophilic 5-endo-trig cyclization of N-[3-(trifluo-
romethyl)homoallyl]sulfonamides.
Results and Discussion
Preparation of Tosylamide Cyclization Precursors 6. When
(S)-glycidyl 4-(methoxy)benzyl (PMB) ether (S)-2a (99% ee)22
was treated with 1-(trifluoromethyl)vinyllithium, generated in
situ from bromotrifluoropropene 1 in the presence of BF3‚OEt2
at -100 °C, the corresponding partially protected diol (R)-4a
was obtained in 82% yield with 99% ee (Scheme 3).21 In this
process, no racemization was observed. A similar ring opening
of styrene oxide 2b gave homoallylic alcohol 4b in moderate
yield. Homoallylic alcohols 4 were also prepared by the reaction
of 2-(trifluoromethyl)allylsilane 3 with aldehydes.23 Thus,
homoallylic alcohol 4c bearing a 2,4-dimethoxyphenyl group
was obtained in 63% yield.24
(11) (a) Plantier-Royon, R.; Portella, C. Carbohydr. Res. 2000, 327, 119.
(b) Fluorine-Containing Amino Acids, Synthesis and Properties; Kukhar,
V. P., Soloshonok, V. A., Eds.; Wiley: Chichester, West Sussex, England,
1995.
(12) Biomedical Frontiers of Fluorine Chemistry; Ojima, I., McCarthy,
J. R., Welch, J. T., Eds.; American Chemical Society: Washington, DC,
1996.
(13) (a) Erickson, J. A.; McLoughlin, J. I. J. Org. Chem. 1995, 60, 1626.
(b) Kaneko, S.; Yamazaki, T.; Kitazume, T. J. Org. Chem. 1993, 58, 2302
and references therein. For a review, see: (c) Welch, J. T. Tetrahedron
1987, 43, 3123.
(14) (a) Wang, G.; Sakthivel, K.; Rajappan, V.; Bruice, T. W.; Tucker,
K.; Fagan, P.; Brooks, J. L.; Hurd, T.; Leeds, J. M.; Cook, P. D. Nucleosides,
Nucleotides Nucleic Acids 2004, 23, 317. (b) Marcotte, S.; Gerard, B.;
Pannecoucke, X.; Feasson, C.; Quirion, J.-C. Synthesis 2001, 929 and
references therein.
(15) Lee, V. J. In ComprehensiVe Organic Synthesis; Trost, B. M., Ed.;
Pergamon: Oxford, 1991; Vol. 4, pp 69.
(20) (a) Baldwin, J. E. J. Chem. Soc., Chem. Commun. 1976, 734. (b)
Baldwin, J. E.; Cutting, J.; Dupont, W.; Kruse, L.; Silberman, L.; Thomas,
R. C. J. Chem. Soc., Chem. Commun. 1976, 736. (c) Baldwin, J. E.; Thomas,
R. C.; Kruse, L. I.; Silberman, L. J. Org. Chem. 1977, 42, 3846.
(21) Nadano, R.; Ichikawa, J. Synthesis 2006, 128.
(22) Nicolaou, K. C.; Fylaktakidou, K. C.; Monenschein, H.; Li, Y.;
Weyershausen, B.; Mitchell, H. J.; Wei, H.-X.; Guntupalli, P.; Hepworth,
D.; Sugita, K. J. Am. Chem. Soc. 2003, 125, 15433.
(16) Leriche, C.; He, X.; Chang, C. T.; Liu, H. J. Am. Chem. Soc. 2003,
125, 6348 and references therein.
(17) (a) Del Valle, J. R.; Goodman, M. Angew. Chem., Int. Ed. 2002,
41, 1600. See also: (b) Del Valle, J. R.; Goodman, M. J. Org. Chem. 2003,
68, 3923.
(18) (a) Qiu, X.-L.; Qing, F.-L. J. Org. Chem. 2002, 67, 7162. (b) Qiu,
X.-L.; Qing, F.-L. J. Chem. Soc., Perkin Trans. 1 2002, 2052. See also:
(c) Qiu, X.-L.; Qing, F.-L. J. Org. Chem. 2003, 68, 3614.
(19) Ichikawa, J.; Mori, T.; Iwai, Y. Chem. Lett. 2004, 33, 1354.
(23) Yamazaki, T.; Ishikawa, N. Chem. Lett. 1984, 521.
(24) For enantioselective allylation of carbonyl compounds with allylic
silanes, see: (a) Kiyohara, H.; Nakamura, Y.; Matsubara, R.; Kobayashi,
S. Angew. Chem., Int. Ed. 2006, 45, 1615. (b) Wadamoto, M.; Yamamoto,
H. J. Am. Chem. Soc. 2005, 127, 14556 and references therein. (c)
Wadamoto, M.; Ozasa, N.; Yanagisawa, A.; Yamamoto, H. J. Org. Chem.
2003, 68, 5593 and references therein.
J. Org. Chem, Vol. 71, No. 23, 2006 8749

Nadano et al.
FIGURE 1. Synthetic strategy for 4-CF3, CF2d, or CF2H-substituted prolines.
SCHEME 3. Preparation of Tosylamides 6a
SCHEME 4. 5-Endo-Trig Cyclization of Tosylamides 6a
a Reagents and conditions: (i) KOH (5.0 equiv for 6a,b or 1.3 equiv for
6c), 130 °C, 20 h, (CH2OH)2; (ii) NaH (1.2 equiv), 120 °C, 4 h, DMF.
catalyst or trifluoroacetic acid to give tosylamides 6a-c in
excellent yield, respectively.
5-Endo-Trig Cyclization of Tosylamides 6. The cyclization
of tosylamides 6a-c obtained above was attempted by heating
at 130 °C with an excess amount of KOH in ethylene glycol.19
Nucleophilic addition proceeded in a 5-endo-trig fashion under
protic conditions to afford pyrrolidines bearing a trifluoromethyl
group at the 4-position with 2,4-anti stereoselectivity.27 The
results are summarized in Scheme 4.
a Reagents and conditions: (i) BF3‚OEt2 (1.0 equiv), n-BuLi (1.0 equiv),
-100 °C, 15 min, Et2O; then 2a (R ) CH2OPMB, 0.67 equiv), -100 °C,
15 min; (ii) t-BuLi (1.0 equiv), -100 °C, 0.5 h, Et2O; then, BF3‚OEt2 (1.0
equiv), 5 min; then, 2b (R ) Ph, 0.67 equiv), 15 min; (iii) 2,4-
dimethoxybenzaldehyde (1.2 equiv), n-Bu4NF (TBAF, 0.1 equiv), rt, 24 h,
THF; (iv) CH2dCHCH2OCONHTs (HNTsAlloc, 1.2 equiv), EtOCONd
NCO2Et (DEAD, 1.5 equiv), PPh3 (1.5 equiv), 0 °C, 7 d, toluene;26 (v)
piperidine (3.0 equiv), Pd(PPh3)4 (2 mol %), rt, 1.5 h, MeCN; (vi) HNTsBoc
(1.5 equiv), DEAD (2.0 equiv), PPh3 (2.0 equiv), 0 °C, 10 h, THF; (vii)
TFA (10 equiv), rt, 10 h, CH2Cl2; (viii) HNTsAlloc (1.5 equiv), DEAD
(2.0 equiv), PPh3 (2.0 equiv), rt, 10 h, THF; (ix) piperidine (4.0 equiv),
Pd(PPh3)4 (2 mol %), rt, 10 h, MeCN.
Tosylamide (S)-6a cyclized to give pyrrolidine (2S,4R)-7a
in 68% yield as a mixture of 2,4-anti/syn diastereomers (anti/
(27) The 2,4-anti/syn stereochemistry of the pyrrolidine ring was
determined by a NOESY experiment on 2-(4-bromophenyl)-1-(4-methyl-
benzenesulfonyl)-4-(trifluoromethyl)pyrrolidine (7d) as a representative
example. A cross peak between the 2- and 4-protons was not observed in
the major product, but in the minor product. As for the 4-proton of the
pyrrolidine ring, the signal of the anti-isomer was observed at lower field
(δ 2.92) than that of the syn-isomer (δ 2.64), with this spectral criterion
confirming similar stereochemistry for 7a-c.
The desired precursor sulfonamides were furnished as fol-
lows: Homoallylic alcohols 4a-c were converted to the
corresponding Alloc-protected tosylamides 5a and 5c or Boc-
protected tosylamide 5b by the Mitsunobu reaction.25 Depro-
tection of the allyloxycarbonyl (Alloc) or tert-butoxycarbonyl
(Boc) group was effected with piperidine and a palladium
(25) Mitsunobu, O. Synthesis 1981, 1.
(26) In the Mitsunobu reaction of 4a, the yield of 5a was improved by
using toluene instead of THF as a solvent with a decrease in the amount of
elimination product, a diene.
8750 J. Org. Chem., Vol. 71, No. 23, 2006

Synthesis of 4-CF3, CF2d, or CF2H-Substituted Prolines
SCHEME 5. Synthesis of 4-(Trifluoromethyl)proline 9a
SCHEME 6. Synthesis of 4-(Difluoromethylene)proline 11a
a Reagents and conditions: (i) DDQ (1.3 equiv), rt, 2 d, CH2Cl2-MeOH
(10:1); (ii) TEMPO (5 mol %), NaClO2 (1.3 equiv), rt, 7 d, MeCN-pH 7
phosphate buffer (1.3:1).
a Reagents and conditions: (i) RuCl3‚nH2O (2 mol %), NaIO4 (11 equiv),
rt, 4 d (for 7b) or 6 h (for 7c), H2O-CCl4-CH3CN (1.5:1:1).
SCHEME 7. Synthesis of 4-(Difluoromethyl)prolines 15a
syn ) 70:30, anti: 99% ee) without racemization. Since phenyl-
substituted tosylamide 6b (R ) Ph) exhibited better anti
selectivity (anti/syn ) 92:8) than that of alkyl-substituted
precursor 6a, we tried the cyclization of tosylamide 6c bearing
a 2,4-dimethoxyphenyl group, which could be more readily
oxidized to a carboxy group. 4-(Trifluoromethyl)pyrrolidine 7c
was obtained in 74% yield with high diastereoselectivity (anti/
syn ) 90:10) in the 5-endo-trig cyclization of 6c.
We also examined the SN2′-type 5-endo-trig cyclization of
tosylamide 6 under aprotic, basic conditions.19 On treatment of
tosylamide (S)-6a with 1.2 equiv of NaH at 120 °C in DMF,
the corresponding pyrrolidine (S)-8a bearing a difluorometh-
ylene group at the 4-position was obtained in 90% yield without
racemization (Scheme 4). Thus, both trifluoromethylated and
difluoromethylenated pyrrolidines 7 and 8 have been success-
fully constructed via addition reaction or SN2′-type reaction,
starting from a common precursor 6.
Synthesis of 4-Trifluoromethyl-Substituted Proline 9. For
the synthesis of prolines, the substituent at the 2-position should
be oxidized to a carboxy group. Oxidation of the phenyl group in
7b was examined with RuO4, generated in situ from NaIO4 and
a catalytic amount of RuCl3.28 The reaction proceeded slowly
to afford 4-trifluoromethyl-N-tosylproline 9 in 45% yield (Scheme
5). The 2,4-dimethoxyphenyl group in 7c was oxidized with
RuO4 to improve the yield of the desired proline 9 up to 72%.
This sequence provides the desired proline in only five steps
from an oxirane with high 2,4-anti selectivity, which allows
the synthesis of optically active 4-(trifluoromethyl)prolines.
Synthesis of 4-Difluoromethylene-Substituted Proline 11.
The synthesis of (S)-4-difluoromethylene-N-tosylproline (S)-
11 was successfully effected via a two-step procedure: (i)
deprotection of the PMB group in (S)-8a with DDQ (2,3-
dichloro-5,6-dicyano-1,4-benzoquinone) and (ii) conversion of
the hydroxymethyl group to a carboxy group by TEMPO
(2,2,6,6-tetramethylpiperidine-1-oxyl)-catalyzed oxidation with
NaClO2,29,30 both of which proceeded in excellent yield, albeit
at a slow rate (Scheme 6). The optical purity of proline (S)-11
was 99% ee, which shows that no racemization occurred during
this sequence from the starting (R)-glycidol.31
a Reagents and conditions: (i) H2 (1 atm), Pd/C (5%, 0.5 equiv), rt, 6 h,
CHCl3; (ii) TEMPO (5 mol %), NaBr (0.5 equiv), trichloroisocyanuric acid
(5.0 equiv), NaHCO3 (10 equiv), rt, 3 h, acetone-H2O (4:1); (iii) TBSCl
(1.5 equiv), TEA (2.0 equiv), DMAP (0.3 equiv), rt, 12 h, CH2Cl2; (iv) H2
(1 atm), Pd/C (5%, 5 mol %), rt, 1 h, EtOH; (v) TBAF (1.2 equiv), rt, 1 h,
THF; (vi) TEMPO (2 mol %), NaBr (0.2 equiv), trichloroisocyanuric acid
(2.0 equiv), NaHCO3 (6.0 equiv), rt, 3 h, acetone-H2O (4:1).
double bonds in 4-(alkylidene)pyrrolidines, leading to the
stereoselective formation of 4-substituted prolines.17,18 On the
basis of these observations, we pursued face-selective hydro-
genation of the difluoromethylene group, exocyclic double bond
in prolinol 10.32
Hydrogenation of 10 was conducted in the presence of a
palladium catalyst. Whereas the reaction in methanol afforded
a 1:1 mixture of anti- and syn-4-(difluoromethyl)prolinols 12,
good anti selectivity (anti/syn ) 79:21) was observed in a
haloalkane solvent, such as dichloromethane and chloroform
(Scheme 7). On the other hand, high syn selectivity (anti/syn
) 11:89) was attained by protection of the hydroxy group in
10 as bulky TBS ether 13 prior to reduction, which gave syn-
4-(difluoromethyl)pyrrolidine 14 as a major product.33 Each
face-selectivity can be explained by (i) chelation of the hydroxy
group in 10 on the palladium surface (leading to the anti
product) and (ii) a steric effect of the bulky silyl group of 13
(leading to the syn product). The desired anti-4-difluoromethyl-
N-tosylproline anti-15 was obtained by oxidation of anti-12 with
trichloroisocyanuric acid and a catalytic amount of TEMPO29
in excellent yield. A similar oxidation procedure was also
Synthesis of 4-Difluoromethyl-Substituted Proline 15. We
then turned our attention to prolines bearing a 4-difluoromethyl
group. Goodman and Qing reported hydrogenation of endocyclic
double bonds in 4-(trifluoromethyl)pyrrolines and exocyclic
(28) Carlsen, P. H. J.; Katsuki, T.; Martin, V. S.; Sharpless, K. B. J.
Org. Chem. 1981, 46, 3936.
(29) TEMPO-catalyzed oxidation using trichloroisocyanuric acid: (a)
Luca, L. D.; Giacomelli, G.; Porcheddu, A. Org. Lett. 2001, 3, 3041. (b)
Luca, L. D.; Giacomelli, G.; Masala, S.; Porcheddu, A. J. Org. Chem. 2003,
68, 4999. TEMPO-catalyzed oxidation using NaClO2: (c) Zhao, M.; Li,
J.; Mano, E.; Song, Z.; Tschaen, D. M.; Grabowski, E. J. J.; Reider, P. J.
J. Org. Chem. 1999, 64, 2564.
(31) Removal of the tosyl group on the nitrogen was achieved by
photoinduced reduction of the benzyl ester derived from 11 in the presence
of 1,5-dimethoxynaphthalene and ascorbic acid. Hamada, T.; Nishida, A.;
Yonemitsu, O. J. Am. Chem. Soc. 1986, 108, 140.
(32) Although the reduction of a 4-(difluoromethylene)proline derivative
1
was reported to give a single diastereomer in ref 18a, the reported H and
(30) Attempted TEMPO-catalyzed oxidation of 10 with trichloroisocya-
nuric acid was not successful due to affecting the difluromethylene moiety.
13C NMR data proved to be those of a diastereomer mixture. See also:
Qiu, X.-L.; Qing, F.-L. J. Org. Chem. 2005, 70, 3826 and references therein.
J. Org. Chem, Vol. 71, No. 23, 2006 8751

Nadano et al.
being stirred for 10 min, the mixture was heated at 120 °C for 4 h.
The reaction was quenched with phosphate buffer (pH 7, 40 mL),
and organic materials were extracted with EtOAc (30 mL × 3).
The combined extracts were washed with water (30 mL × 4) and
brine (30 mL) and dried over MgSO4. After removal of the solvent
under reduced pressure, the residue was purified by column
chromatography (hexane-EtOAc, 2:1) to give (S)-8a (1.10 g, 90%)
applied to prolinol syn-12, derived from 14 by deprotection of
the silyl group, to afford syn-15.
Conclusion
We have accomplished a divergent, chemical synthesis of
N-protected prolines bearing a fluorocarbon moiety, such as a
trifluoromethyl, difluoromethylene, or difluoromethyl group, at
the 4-position from common tosylamide precursors. The com-
bination of (i) oxirane ring opening with (trifluoromethyl)-
vinyllithium and (ii) 5-endo-trig cyclization of N-(homoallyl)-
sulfonamides has proven to be highly efficient to construct
prolines bearing a trifluoromethyl or a difluoromethylene group,
depending on protic or aprotic reaction media in (ii). Face-
selective hydrogenation of the 4-difluoromethylene group in
prolinol was achieved with or without protection of the
2-hydroxy group to afford anti- or syn-(difluoromethyl)proline
derivatives. The results described herein provide a convenient
access to prolines bearing fluorinated one-carbon units at the
4-position, which could find wide application in the design of
new organocatalysts and the synthesis of the new fluorine-
containing peptides.
as a colorless liquid. [R]25 ) -13.1 (c 1.0, CHCl3). IR (neat):
D
2931, 2860, 1782, 1512, 1348, 1248, 1163, 1093, 1036, 816 cm-1
.
1H NMR: δ 2.12-2.21 (1H, m), 2.41 (3H, s), 2.47 (1H, br d, J )
15.5 Hz), 3.38 (1H, dd, J ) 9.4, 8.1 Hz), 3.63 (1H, dd, J ) 9.4,
4.0 Hz), 3.79 (3H, s), 3.95 (1H, br d, J ) 14.0 Hz), 3.99 (1H, br
d, J ) 14.0 Hz), 3.99-4.03 (1H, m), 4.43 (2H, s), 6.87 (2H, d, J
) 8.3 Hz), 7.21 (2H, d, J ) 8.3 Hz), 7.29 (2H, d, J ) 8.3 Hz),
7.68 (2H, d, J ) 8.3 Hz). 13C NMR: δ 21.4, 27.8, 46.9 (d, JCF
)
4 Hz), 55.1, 59.2, 71.6, 72.9, 85.6 (dd, JCF ) 25, 23 Hz), 113.7,
127.2, 129.1, 129.7, 129.9, 134.8, 143.8, 149.9 (dd, JCF ) 284,
284 Hz), 159.2. 19F NMR: δF 71.3 (1F, d, JFF ) 55 Hz), 74.2 (1F,
d, JFF ) 55 Hz). HRMS (FAB): calcd for C21H24F2NO4S ([M +
H]+) 424.1394, found 424.1390. HPLC (i-PrOH-hexane, 1:30):
retention time 20.4 min major peak, 22.7 min minor peak.
rel-(2R,4S)-1-(4-Methylbenzenesulfonyl)-4-(trifluoromethyl)-
proline (9). To a suspension of NaIO4 (457 mg, 2.14 mmol) in
CH3CN (1 mL) and H2O (1.5 mL) were added a solution of 7c (84
mg, 0.19 mmol) in CCl4 (1.0 mL) and then RuCl3‚H2O (0.8 mg, 4
µmol) at rt. The reaction mixture was stirred for 6 h at rt, and then
water was added to quench the reaction. Organic materials were
extracted with Et2O (15 mL × 3). The combined extracts were
washed with aqueous NaOH (1 M, 15 mL × 3). The combined
aqueous layer was brought to pH 3.0 with aqueous HCl (6 M) and
extracted with Et2O (30 mL × 3). After removal of the solvent
under reduced pressure, 9 (47 mg, 72%, anti/syn ) 90:10) was
obtained as a colorless crystal. IR (neat): 3238, 2956, 2926, 1732,
Experimental Section
rel-(2R,4S)-2-(2,4-Dimethoxyphenyl)-1-(4-methylbenzenesulfo-
nyl)-4-(trifluoromethyl)pyrrolidine (7c). To a solution of 6c (88
mg, 0.21 mmol) in ethylene glycol (3 mL) was added KOH powder
(15 mg, 0.27 mmol) at rt. After the reaction mixture was stirred at
130 °C for 20 h, phosphate buffer (pH 7, 10 mL) was added to
quench the reaction. Organic materials were extracted with EtOAc
(10 mL × 3), and the combined extracts were washed with water
(10 mL × 3) and brine (10 mL) and dried over MgSO4. After
removal of the solvent under reduced pressure, the residue was
purified by column chromatography (hexane-EtOAc, 4:1) to give
7c (65 mg, 74%, anti/syn ) 90:10) as a colorless liquid. IR (neat):
1
1400, 1350, 1271, 1161, 1128, 1039 cm-1. H NMR: (anti-9) δ
2.13 (1H, ddd, J ) 13.4, 9.2, 9.2 Hz), 2.34 (1H, ddd, J ) 13.4,
8.0, 2.7 Hz), 2.46 (3H, s), 3.15 (1H, ddddq, JHF ) 8.0 Hz, J ) 9.2,
8.0, 8.0, 8.0 Hz), 3.37 (1H, dd, J ) 9.9, 8.0 Hz), 3.78 (1H, dd, J
) 9.9, 8.0 Hz), 4.41 (1H, dd, J ) 9.2, 2.7 Hz), 7.37 (2H, d, J )
8.4 Hz), 7.76 (2H, d, J ) 8.4 Hz), 8.04 (1H, br s); (syn-9) δ 2.27
(1H, ddd, J ) 13.5, 8.9, 7.4 Hz), 2.46 (3H, s), 2.51 (1H, ddd, J )
13.5, 8.2, 8.2 Hz), 2.62-2.76 (1H, m), 3.45 (1H, dd, J ) 11.4,
10.4 Hz), 3.77 (1H, dd, J ) 11.4, 8.6 Hz), 4.47 (1H, dd, J ) 8.2,
7.4 Hz), 7.37 (2H, d, J ) 8.4 Hz), 7.79 (2H, d, J ) 8.4 Hz), 8.04
(1H, br s). 13C NMR: (anti-9) δ 21.6, 30.0, 41.6 (q, JCF ) 30 Hz),
47.1, 59.9, 125.7 (q, JCF ) 276 Hz), 127.5, 130.0, 133.8, 144.5,
175.8. 19F NMR: (anti-9) δF 90.9 (d, JFH ) 8 Hz); (syn-9) δF 91.5
(d, JFH ) 8 Hz). Anal. Calcd for C13H14F3NO4S: C, 46.29; H, 4.18;
N, 4.15. Found: C, 46.38; H, 4.25; N, 3.89.
1
3001, 2958, 2839, 1614, 1589, 1506, 1340, 1161, 1034 cm-1. H
NMR: (anti-7c) δ 1.89-2.01 (2H, m), 2.44 (3H, s), 2.84-2.95
(1H, m), 3.42 (1H, dd, J ) 9.8, 9.8 Hz), 3.75 (3H, s), 3.80 (3H, s),
3.84 (1H, dd, J ) 9.8, 9.8 Hz), 5.11 (1H, d, J ) 8.0 Hz), 6.40 (1H,
s), 6.45 (1H, d, J ) 8.4 Hz), 7.26 (1H, d, J ) 8.4 Hz), 7.31 (2H,
d, J ) 8.0 Hz), 7.84 (2H, d, J ) 8.0 Hz); (syn-7c) δ 2.08 (2H, m),
2.41 (3H, s), 2.46 (1H, m), 3.55 (1H, dd, J ) 9.9, 9.9 Hz), 3.62
(3H, s), 3.80 (3H, s), 3.95 (1H, dd, J ) 9.9, 9.9 Hz), 4.86 (1H, dd,
J ) 7.6, 7.6 Hz), 6.28 (1H, s), 6.44 (1H, J ) 8.4 Hz), 7.22 (2H, d,
J ) 8.1 Hz), 7.26 (1H, d, J ) 8.4 Hz), 7.49 (2H, d, J ) 8.1 Hz).
13C NMR: (anti-7c) δ 21.5, 33.3, 41.0 (q, JCF ) 29 Hz), 47.8,
55.1, 55.3, 58.7, 98.6, 103.5, 121.8, 126.2 (q, JCF ) 256 Hz), 127.4,
127.8, 129.6, 134.4, 143.6, 156.6, 160.5. 19F NMR: (anti-7c) δF
91.3 (d, JFH ) 8 Hz); (syn-7c) δF 91.4 (d, JFH ) 8 Hz). HRMS
(FAB): calcd for C20H23F3NO4S ([M + H]+) 430.1300, found
430.1284.
(S)-4-Difluoromethylene-2-hydroxymethyl-1-(4-methylben-
zenesulfonyl)pyrrolidine [(S)-10]. To a solution of (S)-8a (141
mg, 0.333 mmol) in CH2Cl2 (1.5 mL) and MeOH (0.15 mL) was
added 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (DDQ, 98 mg,
0.43 mmol) at rt. After being stirred for 2 d, the reaction mixture
was filtered through a pad of Celite, and the filtrate was evaporated
under reduced pressure. The residue was purified by column
chromatography (hexane-EtOAc, 2:1) to give (S)-10 (92 mg, 91%)
as a pale yellow liquid. [R]25D ) +45.5 (c 1.0, CHCl3). IR (neat):
3529, 2954, 2924, 2854, 1782, 1344, 1271, 1161 cm-1. 1H NMR:
δ 2.23-2.31 (1H, m), 2.39 (1H, br d, J ) 14.5 Hz), 2.45 (3H, s),
2.52 (1H, br s), 3.65 (1H, dd, J ) 11.5, 5.8 Hz), 3.70 (1H, dd, J )
11.5, 4.7 Hz), 3.79-3.86 (1H, m), 3.96 (1H, br d, J ) 14.1 Hz),
4.08 (1H, br d, J ) 14.1 Hz), 7.35 (2H, d, J ) 7.9 Hz), 7.73 (2H,
d, J ) 7.9 Hz). 13C NMR: δ 21.5, 27.5, 47.5 (d, JCF ) 3 Hz),
61.8, 64.4, 84.9 (dd, JCF ) 23, 23 Hz), 127.5, 130.0, 133.7, 144.3,
(S)-4-Difluoromethylene-2-[(4-methoxybenzyloxy)methyl]-1-
[(4-methylbenzene)sulfonyl]pyrrolidine [(S)-8a]. To a solution
of (S)-6a (1.28 g, 2.89 mmol) in DMF (30 mL) was added NaH
(55% dispersion in mineral oil; 151 mg, 3.47 mmol) at 0 °C. After
(33) The 2,4-anti/syn stereochemistry of the pyrrolidine ring was
determined by a NOESY experiment on TBS protected prolinol 14 as a
representative example. Cross peaks between the 2-proton and the 5R-proton
and between the 5â-proton and the difluoromethyl proton were observed
as shown below.
149.9 (dd, JCF ) 283, 283 Hz). 19F NMR: δF 71.7 (1F, ddd, JFF
)
54 Hz, JFH ) 3, 3 Hz), 74.4 (1F, dd, JFF ) 54 Hz, JFH ) 1 Hz).
HRMS (FAB): calcd for C13H16F2NO3S ([M + H]+) 304.0820,
found 304.0828. The ee value was determined to be 99% by HPLC
8752 J. Org. Chem., Vol. 71, No. 23, 2006

Synthesis of 4-CF3, CF2d, or CF2H-Substituted Prolines
(i-PrOH-hexane, 1:10, retention time 12.9 min major peak, 10.9
min minor peak).
rel-(2R,4S)-4-Difluoromethyl-1-(4-methylbenzenesulfonyl)pro-
line (anti-15). To a solution of 12 (19.8 mg, 65 µmol, anti/syn )
79:21) in acetone (2 mL) were added a solution of aqueous NaHCO3
(15%, 0.6 mL), NaBr (3.6 mg, 35 µmol), TEMPO (0.56 mg, 3.6
µmol), and trichloroisocyanuric acid (82 mg, 0.35 mmol). After
the mixture was stirred for 3 h at rt, the reaction was quenched
with H2O (5 mL). Organic materials were extracted with Et2O (5
mL × 3). The combined extracts were washed with aqueous NaOH
(1 M, 5 mL × 3). The combined aqueous layer was brought to pH
3.0 with aqueous HCl (6 M) and extracted with Et2O (30 mL ×
3). After removal of the solvent under reduced pressure, 15 (19.8
mg, 96%, anti/syn ) 79:21) was obtained as colorless crystals. IR
(neat): 3534, 2954, 2924, 2852, 1732, 1340, 1159, 1090, 1034
(S)-4-Difluoromethylene-1-(4-methylbenzenesulfonyl)pro-
line [(S)-11]. To a solution of (S)-10 (144 mg, 0.475 mmol) in
CH3CN (4.8 mL) and phosphate buffer (pH 7, 3.6 mL) were added
2,2,6,6-tetramethylpiperidine-1-oxyl (TEMPO, 3.7 mg, 24 µmol)
and NaClO2 (80%; 70 mg, 0.62 mmol). The reaction mixture was
stirred for 7 d at rt. After aqueous HCl (1 M, 2 mL) was added to
the mixture, organic materials were extracted with Et2O (10 mL ×
4). The combined extracts were washed with aqueous Na2CO3
(10%, 10 mL × 2), and then the combined aqueous layer was
acidified with concd aqueous HCl (2 mL). Organic materials were
extracted by Et2O (10 mL × 3). The combined extracts were washed
with brine (10 mL), and dried over MgSO4. After removal of the
solvent under reduced pressure, (S)-11 (141 mg, 93%) was obtained
1
cm-1. H NMR: δ 1.98 (1H, ddd, J ) 13.3, 9.5, 9.2 Hz), 2.30
(1H, ddd, J ) 13.3, 6.8, 2.8 Hz), 2.46 (3H, s), 2.81-2.93 (1H, m),
3.29 (1H, dd, J ) 10.0, 8.2 Hz), 3.69 (1H, dd, J ) 10.0, 8.0 Hz),
4.38 (1H, dd, J ) 9.2, 2.8 Hz), 5.60 (1H, td, JHF ) 55.3 Hz, J )
4.4 Hz), 7.37 (2H, d, J ) 8.5 Hz), 7.76 (2H, d, J ) 8.5 Hz), 8.20
as a colorless liquid. [R]25 ) -13.7 (c 1.0, CHCl3). IR (neat):
D
3228, 2927, 2879, 1783, 1724, 1350, 1275, 1161, 1095, 1063, 771
1
cm-1. H NMR: δ 2.45 (3H, s), 2.70-2.75 (2H, m), 4.04-4.12
(1H, br s). 13C NMR: δ 21.8, 30.2 (t, JCF ) 3 Hz), 41.7 (t, JCF
)
(2H, m), 4.53 (1H, ddd, J ) 8.4, 4.1, 1.6 Hz), 7.35 (2H, d, J ) 8.1
Hz), 7.62 (1H, br s), 7.75 (2H, d, J ) 8.1 Hz). 13C NMR: δ 21.5,
29.6, 46.5 (d, JCF ) 3 Hz), 60.2, 84.6 (dd, JCF ) 25, 25 Hz), 127.4,
130.0, 134.5, 144.4, 150.1 (dd, JCF ) 286, 286 Hz), 175.6. 19F
NMR: δF 73.1 (1F, d, JFF ) 52 Hz), 75.5 (1F, d, JFF ) 52 Hz).
HRMS (FAB): calcd for C13H14F2NO4S ([M + H]+) 318.0613,
found 318.0601. The ee value was determined to be 99% by HPLC
(i-PrOH-hexane, 1:10, retention time 12.0 min major peak, 9.1
min minor peak).
22 Hz), 47.4 (t, JCF ) 5 Hz), 60.2, 115.8 (t, JCF ) 241 Hz), 127.7,
130.2, 134.3, 144.6, 176.2. 19F NMR: δF 40.2 (1F, ddd, JFF ) 287
Hz, JFH ) 55, 13 Hz), 41.0 (1F, ddd, JFF ) 287 Hz, JFH ) 55, 11
Hz). HRMS (FAB): calcd for C13H16F2NO4S ([M + H]+) 320.0768,
found 320.0742.
2-[(tert-Butyldimethylsilyloxy)methyl]-4-difluoromethylene-
1-(4-methylbenzenesulfonyl)pyrrolidine (13). To a solution of 10
(81 mg, 0.27 mmol) in CH2Cl2 (3 mL) were added t-BuMe2SiCl
(61 mg, 0.41 mmol), NEt3 (54 mg, 0.54 mmol), and 4-dimethyl-
aminopyridine (DMAP, 10 mg, 0.08 mmol) at rt. The reaction
mixture was stirred at rt for 3 h. The reaction was quenched with
water (10 mL), and organic materials were extracted with EtOAc
(15 mL × 3). The combined extracts were washed with brine (10
mL) and dried over Na2SO4. After removal of the solvent under
reduced pressure, the residue was purified by column chromatog-
raphy (hexane-EtOAc, 10:1) to give 13 (105 mg, 94%) as a
colorless liquid. IR (neat): 2954, 2929, 2858, 1782, 1350, 1271,
Benzyl 4-(Difluoromethylene)pyrrolidine-2-carboxylate (16).
After a solution of benzyl 4-difluoromethylene-1-(4-methylbenze-
nesulfonyl)pyrrolidine-2-carboxylate (37 mg, 90 µmol), 1,5-
dimethoxynaphthalene (8.8 mg, 47 µmol), and ascorbic acid (49
mg, 280 µmol) in H2O (1.1 mL) and EtOH (19 mL) was degassed
with argon, the solution was irradiated with high-pressure Hg lamp
at rt for 2 h through a Pyrex tube. Aqueous HCl (1 M, 1 mL) was
added, and the solvent was removed under reduced pressure.
Aqueous HCl (1 M, 5 mL) was added to the residue, and the
aqueous solution was washed with Et2O (5 mL). After the aqueous
layer was brought to alkaline pH with concd aqueous Na2CO3 (5
mL), organic materials were extracted by Et2O (5 mL × 3). The
combined extracts were washed with brine (5 mL) and dried over
MgSO4. After removal of the solvent under reduced pressure, 16
(8.0 mg, 35%) was obtained as a colorless liquid. IR (neat): 3035,
1
1163, 1093, 837, 777, 665 cm-1. H NMR: δ 0.04 (3H, s), 0.05
(3H, s), 0.87 (9H, s), 2.14-2.22 (1H, m), 2.44 (3H, s), 2.49 (1H,
br d, J ) 15.3 Hz), 3.56 (1H, dd, J ) 10.1, 7.1 Hz), 3.75 (1H, dd,
J ) 10.1, 3.6 Hz), 3.92-3.98 (2H, m), 4.01 (1H, br d, J ) 13.8
Hz), 7.32 (2H, d, J ) 8.2 Hz), 7.72 (2H, d, J ) 8.2 Hz). 13C
NMR: δ -5.6, -5.6, 18.1, 21.5, 25.7, 27.4, 47.2 (d, JCF ) 4 Hz),
61.1, 65.5, 86.1 (dd, JCF ) 26, 22 Hz), 127.3, 129.8, 135.1, 143.8,
149.9 (dd, JCF ) 284, 284 Hz). 19F NMR: δF 70.7 (1F, ddddd, JFF
1
2925, 2856, 1783, 1743, 1265, 1219, 1186, 771 cm-1. H NMR:
δ 1.92 (1H, br s), 2.58-2.64 (1H, m), 2.78-2.85 (1H, m), 3.56
(1H, br d, J ) 13.7 Hz), 3.74 (1H, br d, J ) 13.7 Hz), 3.93 (1H,
dd, J ) 7.6, 6.0 Hz), 5.18 (2H, s), 7.32-7.41 (5H, m). 13C NMR:
δ 30.3, 45.5, 60.3, 67.0, 88.0, 128.2, 128.5, 128.7, 135.4, 149.7
) 57 Hz, JFH ) 3, 3, 3, 3 Hz), 73.6 (1F, dd, JFF ) 56 Hz, JFH
)
2 Hz). HRMS (FAB): calcd for C19H30F2NO3SSi ([M + H]+)
418.1684, found 418.1683.
(dd, JCF )128, 128 Hz), 173.3. 19F NMR: δF 71.7 (1F, dq, JFF
)
rel-(2R,4R)-2-[(tert-Butyldimethylsilyloxy)methyl]-4-difluo-
romethyl-1-(4-methylbenzenesulfonyl)pyrrolidine (14). To a
solution of 13 (75 mg, 0.18 mmol) in EtOH (3 mL) was added
Pd/C (5%, 19 mg, 9.0 µmol). The mixture was stirred under H2 (1
atm) at rt for 1 h. The mixture was filtered through a pad of Celite.
After removal of the solvent under reduced pressure, the residue
was purified by column chromatography (hexane-EtOAc, 5:1) to
give 14 (73 mg, 98%, anti/syn ) 11:89) as a colorless liquid. IR
59 Hz, JFH ) 3 Hz), 72.9 (1F, dq, JFF ) 59 Hz, JFH ) 3 Hz).
HRMS (FAB): calcd for C13H14F2NO2 ([M + H]+) 254.0993, found
254.0985.
rel-(2R,4S)-4-Difluoromethyl-2-hydroxymethyl-1-(4-methyl-
benzenesulfonyl)pyrrolidine (anti-12). To a solution of 10 (19.2
mg, 63 µmol) in CHCl3 (5 mL) was added Pd/C (5%, 67 mg, 32
µmol). The mixture was stirred under H2 (1 atm) at rt for 6 h. The
mixture was filtered through a pad of Celite. Removal of the solvent
under reduced pressure gave 12 (90% NMR yield, anti/syn ) 79:
21) as a pale yellow liquid. IR (neat): 3521, 2952, 2881, 1597,
(neat): 2954, 2929, 2858, 1348, 1254, 1161, 1090, 1036, 835 cm-1
.
1H NMR: (syn-14) δ 0.08 (6H, s), 0.89 (9H, s), 1.92 (1H, ddd, J
) 13.4, 8.6, 6.1 Hz), 2.00 (1H, ddd, J ) 13.4, 8.0, 8.0 Hz), 2.02-
2.12 (1H, m), 2.44 (3H, s), 3.30 (1H, dd, J ) 11.7, 8.6 Hz), 3.56
(1H, dd, J ) 11.7, 7.5 Hz), 3.72-3.79 (2H, m), 3.84 (1H, dd, J )
9.9, 3.0 Hz), 5.69 (1H, ddd, JHF ) 56.3, 56.3 Hz, J ) 5.6 Hz),
7.34 (2H, d, J ) 8.4 Hz), 7.72 (2H, d, J ) 8.4 Hz); (anti-14) δ
0.08 (6H, s), 0.89 (9H, s), 2.02-2.12 (2H, m), 2.44 (3H, s), 2.78-
2.89 (1H, m), 3.11 (1H, dd, J ) 9.7, 8.6 Hz), 3.66 (1H, dd, J )
9.7, 6.5 Hz), 3.72-3.79 (3H, m), 5.43 (1H, ddd, JHF ) 57.8, 57.8
Hz, J ) 5.2 Hz), 7.34 (2H, d, J ) 8.4 Hz), 7.72 (2H, d, J ) 8.4
Hz). 13C NMR: (syn-14) δ -5.5, -5.4, 18.2, 21.5, 25.8, 28.4 (dd,
JCF ) 5, 3 Hz), 41.8 (t, JCF ) 22 Hz), 49.0 (dd, JCF ) 7, 4 Hz),
1
1398, 1336, 1155, 1087, 1024, 665 cm-1. H NMR: δ 1.67 (1H,
ddd, J ) 12.9, 8.8, 8.8 Hz), 1.95-2.00 (1H, m), 2.46 (3H, s), 2.71
(1H, br s), 2.71-2.84 (1H, m), 3.16 (1H, dd, J ) 10.1, 8.2 Hz),
3.61-3.73 (3H, m), 3.80 (1H, dd, J ) 10.9, 2.9 Hz), 5.38 (1H,
ddd, JHF ) 56.1, 56.1 Hz, J ) 4.8 Hz), 7.37 (2H, d, J ) 8.0 Hz),
7.74 (2H, d, J ) 8.0 Hz). 13C NMR: δ 21.4, 28.5, 41.0 (t, JCF
)
8 Hz), 48.5 (t, JCF ) 4 Hz), 61.0, 65.2, 116.1 (t, JCF ) 240 Hz),
127.6, 129.9, 133.3, 144.2. 19F NMR: δF 40.5 (1F, ddd, JFF ) 285
Hz, JFH ) 56, 14 Hz), 41.4 (1F, ddd, JFF ) 285 Hz, JFH ) 56, 12
Hz). HRMS (FAB): calcd for C13H18F2NO3S ([M + H]+) 306.0977,
found 306.0966.
60.8, 65.8, 116.5 (t, JCF ) 241 Hz), 127.4, 129.9, 134.8, 143.8. 19
F
J. Org. Chem, Vol. 71, No. 23, 2006 8753

Nadano et al.
NMR: (syn-14) δF 41.8 (1F, ddd, JFF ) 286 Hz, JFH ) 56, 11
Hz), 42.9 (1F, ddd, JFF ) 286 Hz, JFH ) 56, 12 Hz). HRMS
(FAB): calcd for C19H32F2NO3SSi ([M + H]+) 420.1840, found
420.1853.
was quenched with water (5 mL). Organic materials were extracted
with Et2O (5 mL × 3), and the combined extracts were washed
with aqueous NaOH (1 M, 15 mL × 3). The combined aqueous
layer was brought to pH 3.0 with aqueous HCl (6 M) and extracted
with Et2O (30 mL × 3). After removal of the solvent under reduced
pressure, 15 (57 mg, 100%, anti/syn ) 11:89) was obtained as a
colorless crystal. IR (neat): 3546, 3220, 2964, 1733, 1340, 1219,
rel-(2R,4R)-4-Difluoromethyl-2-hydroxymethyl-1-(4-methyl-
benzenesulfonyl)pyrrolidine (syn-12). To a solution of 14 (86 mg,
0.20 mmol, anti/syn ) 11:89) in THF (3 mL) was added TBAF
(1 M in THF; 0.25 mL, 0.25 mmol) at rt. The reaction mixture
was stirred at rt for 1 h. The reaction was quenched with water (10
mL), and organic materials were extracted with EtOAc (15 mL ×
3). The combined extracts were washed with brine (10 mL) and
dried over Na2SO4. After removal of the solvent under reduced
pressure, the residue was purified by column chromatography
(hexane-EtOAc, 10:1) to give 12 (56 mg, 90%, anti/syn ) 11:89)
as a colorless liquid. IR (neat): 3521, 2954, 2885, 1597, 1338,
1
1161, 1035 cm-1. H NMR: δ 2.19 (1H, ddd, J ) 13.5, 6.4, 6.1
Hz), 2.35 (1H, ddd, J ) 13.5, 9.0, 8.8 Hz), 2.41-2.50 (1H, m),
2.46 (3H, s), 3.47 (1H, dd, J ) 11.1, 6.5 Hz), 3.54 (1H, dd, J )
11.1, 7.6 Hz), 4.32 (1H, dd, J ) 9.0, 6.1 Hz), 5.79 (1H, ddd, JHF
) 56.1, 56.1 Hz, J ) 6.0 Hz), 7.38 (2H, d, J ) 8.0 Hz), 7.78 (2H,
d, J ) 8.0 Hz), 8.20 (1H, br s). 13C NMR: δ 21.8, 30.4 (t, JCF
)
3 Hz), 42.3 (t, JCF ) 22 Hz), 48.3 (t, JCF ) 4 Hz), 60.0, 116.1 (t,
JCF ) 240 Hz), 127.9, 130.3, 133.9, 144.8, 176.3. 19F NMR: δF
40.9 (1F, ddd, JFF ) 287 Hz, JFH ) 56, 11 Hz), 42.3 (1F, ddd, JFF
) 287 Hz, JFH ) 56, 13 Hz). Anal. Calcd for C13H15F2NO4S: C,
48.90; H, 4.73; N, 4.39. Found: C, 48.99; H, 4.85; N, 4.12.
1
1219, 1157, 1089, 1026, 771 cm-1. H NMR: δ 1.75-1.86 (1H,
m), 1.93-2.12 (2H, m), 2.46 (3H, s), 2.89 (1H, br s), 3.39 (1H,
dd, J ) 11.8, 8.6 Hz), 3.58 (1H, dd, J ) 11.8, 7.8 Hz), 3.61-3.73
(2H, m), 3.87 (1H, br d, J ) 10.5 Hz), 5.69 (1H, ddd, JHF ) 56.2,
56.2 Hz, J ) 5.4 Hz), 7.37 (2H, d, J ) 8.0 Hz), 7.74 (2H, d, J )
8.0 Hz). 13C NMR: δ 21.5, 28.7, 41.0 (t, JCF ) 22 Hz), 49.2 (t,
JCF ) 4 Hz), 61.8, 64.8, 116.2 (t, JCF ) 240 Hz), 127.5, 130.1,
Acknowledgment. We are grateful to Central Glass Co.,
Ltd., for financial support. We also thank Tosoh F-Tech, Inc.,
for a generous gift of 2-bromo-3,3,3-trifluoropropene.
133.6, 144.3. 19F NMR: δF 41.7 (1F, ddd, JFF ) 286 Hz, JFH
)
56, 11 Hz), 42.7 (1F, ddd, JFF ) 286 Hz, JFH ) 56, 12 Hz). HRMS
(FAB): calcd for C13H18F2NO3S ([M + H]+) 306.0975, found
306.0978.
rel-(2R,4R)-4-Difluoromethyl-1-(4-methylbenzenesulfonyl)-
proline (syn-15). To a solution of 12 (54 mg, 0.18 mmol, anti/syn
) 11:89) in acetone (2 mL) was added a solution of aqueous
NaHCO3 (15%, 0.6 mL), NaBr (4 mg, 0.03 mmol), and TEMPO
(0.56 mg, 3.6 µmol) and then trichloroisocyanuric acid (82 mg,
0.35 mmol). After the mixture was stirred for 3 h at rt, the reaction
Supporting Information Available: Experimental procedures
and spectroscopic data of compounds (R)-4a, 4b, 4c, (S)-5a, 5b,
5c, (S)-6a, 6b, 6c, (2R,4S)-7a, 7b, and 7d; copies of 1H spectra of
compounds 4c, (S)-5a, 5c, (S)-6a, (2R,4S)-7a, 7c, (S)-8a, (S)-10,
(S)-11, anti-12, syn-12, 13, 14, anti-15, and 16. This material is
available free of charge via the Internet at http://pubs.acs.org.
JO061421N
8754 J. Org. Chem., Vol. 71, No. 23, 2006