Exploiting morph-DAST mediated ring-expansion of substituted cyclic β-amino alcohols for the preparation of cyclic fluorinated amino acids. Synthesis of 5-fluoromethylproline and 5-fluoropipecolic acid

Article abstract of DOI:10.1016/j.tet.2011.02.082

The synthesis of proline analogues bearing a fluorine-containing substituent at the fifth position of the pyrrolidine ring, racemic trans- and cis-5-fluoromethyl prolines, was performed. The key step of the synthesis is a transformation of the CH₂

Full text of DOI:10.1016/j.tet.2011.02.082

Tetrahedron 67 (2011) 3091e3097
Contents lists available at ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Exploiting morph-DAST mediated ring-expansion of substituted cyclic
b-amino alcohols for the preparation of cyclic fluorinated amino acids.
Synthesis of 5-fluoromethylproline and 5-fluoropipecolic acid
a
,
b
,
c
c
b
*
Pavel K. Mykhailiuk
Igor V. Komarov
a
, Svetlana V. Shishkina , Oleg V. Shishkin , Olga A. Zaporozhets ,
a,b
Enamine Ltd., Vul. Oleksandra Matrosova 23, 01103 Kyiv, Ukraine
Department of Chemistry, Kyiv National Taras Shevchenko University, Vul. Volodymyrska 64, 01033 Kyiv, Ukraine
STC, ‘Institute for Single Crystals’, National Academy of Science of Ukraine, 60 Lenina Ave., Kharkiv 61001, Ukraine
b
c
a r t i c l e i n f o
a b s t r a c t
Article history:
The synthesis of proline analogues bearing a fluorine-containing substituent at the fifth position of the
pyrrolidine ring, racemic trans- and cis-5-fluoromethyl prolines, was performed. The key step of the
synthesis is a transformation of the CH OH-group into the CH F-one using morpholinosulfur trifluoride.
2 2
During the synthesis, an efficient procedure to prepare trans- and cis-5-fluoropipecolic acids was
elaborated.
Received 4 December 2010
Received in revised form 6 February 2011
Accepted 28 February 2011
Available online 5 March 2011
Ó 2011 Elsevier Ltd. All rights reserved.
Keywords:
Amino acids
Fluorine
Morph-DAST
Proline
Pipecolic acid
1
. Introduction
O
NC
F
HOOC
F
H
N
COOH
NH
N
N
4
-Fluoroprolines and large molecules containing them have
N
N
gained widespread popularity in the last decades. For example,
they were used in the applications, such as biochemical probes,
enzyme inhibitors, and enzyme substrates. In particular, they were
shown to control cisetrans isomerization of the amide bonds,
which is closely related to biologically relevant processes, primarily
F
N
1
LY-466195
phase I / II)
Melogliptin
(
(phase II)
2
F
to protein folding and unfolding. Moreover, proline analogues
bearing fluoro-containing substituents at the position 4 of the
pyrrolidine ring became very popular within the drug discovery
programs (Fig. 1).3 In part, this is due to a number of the well-
documented and well-elaborated synthetic protocols toward such
compounds.4
NC
F
O
N
NH2
Practical applications of prolines with fluorinated substituents
F
8
9
at the positions 2 and 3 of the pyrrolidine ring, however, received
much less development, since the first synthetic approaches to
these compounds appeared in the literature only recently.
Denagliptin
Fig. 1. Some representative pharmacologically relevant derivatives 4-fluoroprolines:
LY-466195 (antimigraine, Eli Lilly, phase I/II), Melogliptin (dipeptidyl aminopeptidase
IV inhibitor, Glenmark Pharmaceuticals, phase II), Denagliptin (dipeptidyl aminopep-
5
In contrast to the other isomers, chemistry of prolines with
fluorine-containing substituents at the position 5 of the pyrrolidine
6
7
tidase IV inhibitor, GlaxoSmithKline).
ring attracted almost no attention so far. In only 2010 Brigaud et al.
described the synthesis of 5-trifluoromethylpseudoprolines and
studied their conformational behavior. Hence, the development
*
Corresponding author. Fax: þ380 066 2666399; e-mail address: pavel.my-
10
khailiuk@gmail.com (P.K. Mykhailiuk).
0
040-4020/$ e see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2011.02.082

3092
P.K. Mykhailiuk et al. / Tetrahedron 67 (2011) 3091e3097
of synthetic methodologies for a facile and practical preparation of
the prolines, containing fluorinated substituents at the position
synthesisdthe reaction of hydroxymethyl group in 4a with
O(CH CH NSF dunexpectedly resulted in a formation of two
2
2
)
2
3
5
of the pyrrolidine ring is still a challenge. Our interest in such
compounds: the target pyrrolidine 5a (40% yield) and the side
product 6a (29% yield). The mixture of compounds 5a/6a was
successfully separated by flash column chromatography. After
compounds was additionally stimulated by recent work on the
application of fluorinated prolines as the solid state F NMR labels
to study the membrane active peptides. In this strategy, the both
enantiomerically pure and racemic F-amino acids are used. In
this context, the original aim of this work was to develop a reliable
synthetic strategy toward prolines having a common fluorine-
containing substituentdCH
cis-5-fluoromethyl prolines (1b, Fig. 2).
19
11
19
careful revision of the literature, it became clear, that the reaction
19
12
proceeded via the well-documented formation of the cationic
aziridine intermediate (Scheme 3), which underwent ring-opening
by a fluorine-anion to give either 2-fluoromethylpyrrolidine de-
rivative or the corresponding 3-fluoropiperidine.
2
Fdat the fifth position: trans-(1a) and
13
F
R
R
4
3
R
2
N
N
5
N
COOH
COOH
COOH
HO
F
N
H
N
H
N
H
1
Ph
Ph
F
F
Ph
Proline
1a
1b
Alk SF
2
3
Fig. 2. Proline and its fluorinated analogues: trans-5-fluoromethyl proline (1a) and cis-
-fluoromethyl proline (1b).
5
R
2
. Results and discussion
N
F
F
R
O
F
S
N
H
F
Ph
Our retrosynthetic approach to the both 1a and 1b was based on
N
Alk
trans- and cis-N-benzyl-2,5-dicarbomethoxy pyrrolidines 2a and 2b
as the starting materials (Scheme 1). The key step of the synthe-
sisdthe transformation of the CH
expected to be performed with readily available morpholinosulfur
trifluoride (morph-DAST, O(CH
reported literature procedures.
Alk
Ph
2 2
OH-group into CH F-onedwas
Scheme 3. A mechanism of the reaction of substituted prolinols with DAST-analogues
1
4
according to Ref. 19.
2
CH
2
)
2
NSF
3
)
analogously to the
1
5
Indeed, ring-expansion of cyclic
b-amino alcohols induced by
DAST or DAST-analogues was comprehensively described in the
analogously
to Ref. 15
19,20
literature before.
Despite the great potential of this trans-
CO H
CO Me
CO Me
formation, however, to the very best of our knowledge, it did
not find any practical application in the synthesis of 3-fluo-
ropyrrolidine- and 3-fluoropiperidine-containing building blocks
so far. Hence, by isolating compound 6a, we realized that the given
reaction could serve as a powerful tool for the preparation of novel
fluorinated cyclic amino acids. In particular, it became evident that
along with the target amino acid 1a, the synthesis of trans-5-flu-
oropipecolic acid could be accomplished as well.
Notably, according to the literature data the reaction of various
substituted N-benzylprolinols with dialkylaminosufhur trifluorides
always leads to the corresponding N-benzyl-3-fluoropiperidines as
the major reaction products. In our hands, however, the rearranged
piperidine 6a was formed as a minor compound. The reason behind
that is not clear in full, but definitely, the structure of the corre-
sponding substituent has a valuable impact on the ratio of the re-
action products.
N
H
a / 1b
2
N
Bn
2
N
Bn
2
F
F
HO
1
MeO C
CO Me
HO C
CO Me
2
N
Bn
a / 2b
2
2
N
Bn
2
2
19
Scheme 1. Retrosynthetic approach to amino acids 1a, 1b.
The compounds 2a/2b were readily prepared from dimethyl
hexanedioate via a two-step literature protocol.16 Hydrolysis of
trans-isomer 2a with 1 equiv of NaOH in methanol/water mixture
at room temperature provided trans-monoacid 3a in a reasonable
yield of 74% (Scheme 2).17
2
Acidic hydrolysis of the CO Me group in 5a provided N-benzyl
acid 7a$HCl (Scheme 4). Hydrogenation of pyrrolidine 7a$HCl using
10% palladium on charcoal as the catalyst followed by a cation-
1
.
ClCO Et
2
NaOH
MeOH
NEt , THF
3
MeO C
CO Me
HO
2
C
CO
2
Me
2
N
2
N
2. NaBH4
H O
THF-H O
2
2
Ph
Ph
74%
87%
2a
3a
HCl
Pd/H
2
F
5a
CO
2
H
CO H
2
N
N
H
H O
MeOH
34%
morph-DAST
2
F
F
CO Me
CO Me
*HCl
N
2
N
2
CH Cl2
N
CO Me
7a
Ph
(2 steps)
1a
2
2
HO
F
Ph
Ph
4a
5a
6a
(29%)
Ph
F
(
40%)
F
HCl
Pd/H2
MeOH
6
a
Scheme 2. Synthesis of compounds 5a, 6a.
H O
2
N
CO H
2
N
CO H
2
7
3%
H
9a
*
HCl
Next, compound 3a was treated with EtOCOCl in tetrahydrofu-
ran in the presence of NEt as a base, and the formed activated
intermediate was reduced with NaBH to give smoothly the
The key step of the
(
2 steps)
8
a
Ph
3
4
Scheme 4. Synthesis of trans-5-fluoromethyl proline (1a) and trans-5-fluoropipecolic
acid (9a).
18
corresponding trans-alcohol 4a.

P.K. Mykhailiuk et al. / Tetrahedron 67 (2011) 3091e3097
3093
exchange chromatography on CU-2 resin accomplished the syn-
3. Conclusion
thesis of the target trans-5-fluoromethyl proline (1a). Alternatively,
trans-5-fluoropipecolic acid (9a) was conveniently obtained from
piperidine 6a in 73% overall yield. The synthesis of amino acid 9a
In summary, we have performed the synthesis of racemic trans-
(1a) and cis-5-fluoromethyl prolines (1b). During the synthesis we
found an effective strategy for the preparation of cyclic fluorinated
amino acids: morph-DAST mediated ring-expansion of the corre-
21
was previously described in the literature. However, in stark
contrast to our method, the published procedure can scarcely be
considered as a practical method for the preparation of 9a, as the
spondingly substituted cyclic
b-amino alcohols. In particular, syn-
21
last synthetic step was performed in only 6% yield.
thesis of racemic trans-(9a) and novel cis-5-fluoropipecolic acids
Fig. 3. X-ray crystal structures of the compounds 1a and 8a. In crystalline state compound 1a exists in two conformations.
The structures of the compounds 1a and 8a were confirmed by
an X-ray diffractional study (Fig. 3).
(9b) was elaborated. We hope that the discovered strategy will find
wide applications in the synthesis of novel 3-fluoropyrrolidine-, 3-
fluoropiperidine-, etc.-containing amino acids.
Contrary to the trans-isomer 2a, hydrolysis of the cis-isomer 2b
with 1 equiv of NaOH in MeOH/H
sponding monoacid 3b. Instead, a mixture of the starting compound
b and diacid 10 was formed. Presumably, the free COOH group in
cis-compound 3b accelerated the saponification of the neighboring
2
O did not provide the corre-
4. Experimental section
4.1. General
2
16b
carboxymethylgroupbyan intramolecularinteraction. Therefore,
cis-monoacid 3b was prepared from cis-diester 2b by a three-step
procedure following the modified literature protocols. First, com-
pound 2b was treated with 3 equiv of NaOH in water to give after
1H, 13C, and 19F NMR spectra were recorded on a Bruker Avance
500 spectrometer at 499.9 MHz, 124.9 MHz, and 470.3 MHz,
respectively. Chemical shifts are reported in parts per million
2
2
1
13
19
standard work up diacid 10 in 70%yield (Scheme 5). Next, diacid 10
downfield from TMS ( H, C) or CFCl3 ( F) as internal standards.
ꢀ
was heated at 100 C for 10 min with an excess of Ac
2
O to afford
Mass spectra were recorded on an Agilent 1100 LCMSD SL in-
strument by chemical ionization (CI).
anhydride 11.23 Finally, cis-monoacid 3b was obtained by dissolving
compound 11 in absolute MeOH and evaporating the obtained so-
lution.24 Activation of the carboxyl group in 3b using EtOCOCl/NEt
3
4.1.1. rel-(2S,5S)-1-(Phenylmethyl)-2,5-pyrrolidinedicarboxylic acid,
mono-methyl ester (3a). NaOH (0.93 M solution) in water (66.5 mL,
61.9 mmol) was added to a solution of the compound 2a (17.1 g,
61.9 mmol) in MeOH (80 mL) upon stirring over a period of 30 min.
The reaction mixture was stirred for additional 24 h at room tem-
perature. The solvent was evaporated in vacuum and water
(200 mL) was added to the residue. The solution was washed with
EtOAc (3ꢁ50 mL). 12 N aq HCl was added to the water phase to
adjust pH value to 5.4. The reaction mixture was extracted with
EtOAc (3ꢁ100 mL). The combined organic phase was dried over
Na SO , and evaporated in vacuum to give pure 3a (12.0 g,
in THF followed by a reduction of the formed intermediate with
ꢀ
NaBH
4
at 0 C gave cis-alcohol 4b in 51% total yield from diacid 10.
25
2 2 2 3 2 2
Next, alcohol 4b was reacted with O(CH CH ) NSF in CH Cl . Still,
the formation of two productsdcis-pyrrolidine 5b (44% yield) and
cis-piperidine 6b (20% yield)dwas observed. The isomers were
separated by flash column chromatography. Hydrolysis of the car-
boxymethyl group in pyrrolidine 5b using aq HCl gave acid 7b$HCl.
Hydrogenation of the benzyl group in 7b using 10% Pd/C as the
catalyst, followed by a cation-exchange chromatography on SU-2
resin furnished the target cis-5-fluoromethyl proline (1b). Analo-
gously, the novel amino aciddcis-5-fluoropipecolic acid (9b)dwas
prepared from piperidine 6b in 80% overall yield.
2
4
1
45.6 mmol, 74% yield). Yellowish oil. H NMR (500 MHz; DMSO-d ;
6
2
Me Si), d: 12.39 (1H, br s, OH), 7.29 (5H, m, Ph), 3.93 (1H, d, J(H,
4
2
The structures of the compounds 7b and 9b were proven by an
X-ray diffraction study (Fig. 4).
H)¼13.5 Hz, NCHHPh), 3.71 (1H, d, J(H, H)¼13.5 Hz, NCHHPh), 3.66
(1H, m, CH), 3.59 (4H, m, CHþOCH ), 2.18 (2H, m, CH ), 1.84 (2H, m,
3
2

3094
P.K. Mykhailiuk et al. / Tetrahedron 67 (2011) 3091e3097
1
h, water was added, and the mixture was extracted three times
with EtOAc (3ꢁ100 mL). The organic layer was washed with water
, and concentrated under
NaOH
Ac2O
MeO C
CO Me
HO2C
10
CO2H
2
N
2
N
Ref. 22
Ref. 23
7
0%
(2ꢁ100 mL), dried over anhydrous MgSO
4
2
b
Ph
Ph
Ph
vacuum to give crude product 4a (2.3 g, 0.009 mmol, 87% yield) as
a yellowish oil. The compound was used in the next step without
1
1
.
additional purification. H NMR (500 MHz; DMSO-d
; Me
Si),
d
:
2
6
4
NEt
2
3
7.26 (5H, m, Ph), 4.46 (1H, br s, OH), 4.02 (1H, d, J(H, H)¼13.5 Hz,
O
O
N
O
2. NaBH4
2
MeOH
NCHHPh), 3.67 (1H, d, J(H, H)¼13.5 Hz, NCHHPh), 3.58 (3H, s,
HO C
CO Me
2
N
2
Ref. 24
Ref. 25
OCH
), 3.47 (1H, d, J¼7.0, NCHCO
2
Me), 3.41 (1H, m, NCHCHHOH),
3
5
1%
Ph
3.27 (1H, m, NCHCHHOH), 3.17 (1H, br s, NCHCH
2
OH), 2.01 (2H, m,
). C NMR (125 MHz; DMSO-d ; Me Si),
Me), 139.2 (s, quat-C, Ph), 128.7 (s, CH, Ph), 128.7 (s,
CH, Ph), 127.5 (s, CH, Ph), 63.7 (s, NCHCO Me), 62.3 (s, NCHCH OH),
3.0 (s, NCH Ph), 51.3 (s, OCH ), 28.8 (s, 3-CH ), 27.1 (s, 4-CH ). MS
1
1
3b
(from 10)
13
3-CH
2
), 1.70 (2H, m, 4-CH
2
6
4
d: 174.4 (s, CO
2
F
2
2
morph-DAST
5
2
3
2
2
CO Me
CO Me
þ
N
2
N
2
(m/z): 249 (M ).
CH Cl
N
CO Me
2
2
2
HO
F
Ph
Ph
4b
5b
44%)
6b
Ph
4.1.3. rel-(2S,5S)-5-(Fluoromethyl)-1-(phenylmethyl)-proline, methyl
(
(20%)
ester (5a). 4.1.3.1. rel-(2S,5R)-5-Fluoro-1-(phenylmethyl)-2-piperidine-
carboxylic acid, methyl ester (6a). A solution of 4a (3.55 g, 14.3 mmol)
ꢀ
in CH Cl
2 2
(100 mL) was cooled to 0 C under argon. Morpho-DAST
(
2.74 g, 15.7 mmol, 1.1 equiv) was added at once upon stirring. The
reaction mixture was allowed to warm to a room temperature and
was stirred for 72 h. Thereafter, a saturated solution of NaHCO in
water (100 mL) was added. The organic layer was separated and the
water phase was extracted with CH Cl
(2ꢁ50 mL). The combined
organic phase was dried over Na SO , and evaporated under vacuum
HCl
Pd/H2
5
b
CO H
CO H
2
N
2
N
H
H O
2
MeOH
36%
F
F
3
*
HCl
7
b
Ph
(2 steps)
1b
2
2
F
2
4
F
HCl
H O
2
Pd/H2
to give the mixture 5a/6a as a yellowish oil. The isomers were sep-
arated by flash column chromatography using hexane/EtOAc¼18/1 as
6b
N
CO H
MeOH
2
N
H
CO H
2
8
0%
*
HCl
an eluent. Elution afforded isomer 5a first (1.43 g, 5.7 mmol, 40%) as
(
2 steps)
8b
Ph
9b
1
a colorless oil. R
CDCl ; Me Si),
.05 (1H, d, J(H, H)¼13.5 Hz, NCHHPh), 3.85 (1H, d, J(H, H)¼13.5 Hz,
f
¼0.60 (hexane/EtOAc¼6/1). H NMR (500 MHz;
3
4
d
: 7.31 (5H, m, Ph), 4.30 (2H, dd, J¼48.0, 3.5 Hz, CH
2
F),
Scheme 5. Synthesisofcis-5-fluoromethylproline(1b) andcis-5-fluoropipecolic acid(9b).
2
2
4
Fig. 4. X-ray crystal structures of the compounds 7b and 9b.
CH
2
). Spectral data of 3a are in accordance to those reported pre-
NCHHPh), 3.69 (4H, br s, OCH
3
þNCHCH
2
F), 2.25 (1H, m, CHH), 2.14
). C NMR (125 MHz; CDCl ; Me Si),
Me), 139.5 (s, quat-C, Ph), 128.5 (s, CH, Ph), 128.3 (s, CH,
13
viously in Ref 17. Evaporation of the organic phase from the first
extraction provided the recovered starting material 2a (2.5 g,
(1H, m, CHH), 1.78 (2H, m, CH
174.0 (s, CO
2
3
4
d:
2
1
9
.0 mmol, 15% yield).
Ph), 127.1 (s, CH, Ph), 85.5 (d, J(C, F)¼170.0 Hz, CH
2
F), 63.7 (s,
2
CHCO
(s, OCH
(377 MHz; CDCl
2
Me), 61.1 (d, J(C, F)¼21.3 Hz, CHCH
2
F), 53.8 (s, NCH Ph), 51.2
2
3
19
4
.1.2. rel-(2S,5S)-5-(Hydroxymethyl)-1-(phenylmethyl)-2-pyrrolidi-
3
), 28.3 (s, 3-CH
2
), 26.2 (d, J(C, F)¼5.0 Hz, 4-CH
2
). F NMR
F).
: C, 66.91; H, 7.22; N,
5.57. Found: C, 67.00; H, 7.47; N, 5.40. Further elution gave isomer 6a
necarbo-xylic acid (4a). To a solution of monoacid 3a (2.9 g,
3
; CFCl
3
),
d: ꢂ229.50 (td, J(F, H)¼45.2, 18.9 Hz, CH
2
ꢀ
þ
0
.011 mol) in THF (120 mL) at 0 C under argon was added trie-
MS (m/z): 251 (M ). Anal. calcd for C14
H18FNO
2
thylamine (1.7 mL, 0.012 mol), followed by the dropwise addition of
ethyl chloroformate (1.19 mL, 0.012 mol). The reaction mixture was
stirred for 3 h, the triethylamine hydrochloride was filtered off, and
the filter cake was washed three times with THF. The filtrate was
then added dropwise to a suspension of NaBH
in water (5.0 mL) at 0 C. The reaction mixture was stirred at 0 C for
(1.02 g, 4.1 mmol, 29%) as a colorless oil. R
f
¼0.55 (hexane/EtOAc¼6/
1
1). H NMR (500 MHz; CDCl
3
; Me
4
Si),
d: 7.29 (5H, m, Ph), 4.71 (1H, d,
2
2
J(H, F)¼48.0 Hz, CHF), 3.84 (1H, d, J(H, H)¼14.0 Hz, NCHHPh), 3.75
2
3
4
(1.67 g, 0.044 mol)
(s, OCH
3
), 3.64 (1H, d, J(H, H)¼14.0 Hz, NCHHPh), 3.37 (1H, t, J(H,
ꢀ
ꢀ
H)¼5.0 Hz, NCHCO
2
Me), 3.25 (1H, ddd, J¼28.5, 12.0, 2.0 Hz, NCHH),

P.K. Mykhailiuk et al. / Tetrahedron 67 (2011) 3091e3097
3095
2
.60 (1H, td, J¼11.5, 5.5 Hz, NCHH), 2.19 (1H, m, CHH), 1.84 (3H, m,
6.57; N, 5.43. Crystals suitable for X-ray crystallographic analysis
were obtained by a slow evaporation of a diluted solution of
8a$HCl in MeOH.
13
CHHþCH
2 3 4 2
). C NMR (100 MHz; CDCl ; Me Si), d: 173.2 (s, CO Me),
137.8 (s, quat-C, Ph), 129.1 (s, CH, Ph), 128.5 (s, CH, Ph), 127.4 (s, CH,
1
Ph), 87.4 (d, J(C, F)¼171.0 Hz, CHF), 61.7 (s, CHCO
2
Me), 59.9 (s,
2
2
NCH
2
Ph), 52.8 (d, J(C, F)¼23.0 Hz, CH
2
CHF), 51.7 (s, OCH
), 24.5 (d, J(C, F)¼5.0 Hz, 3-CH
; CFCl ),
18FNO
3
), 27.4 (d, J
4.1.7. rel-(2S,5R)-5-Fluoro-2-piperidinecarboxylic acid (9a). All
amount of 8a$HCl obtained in the previous step was dissolved in
MeOH (7 mL) and was hydrogenated at room temperature at
60 atm for 12 h using 10% palladium on charcoal (10 mg) as the
catalyst. The solution was filtered, and the filtrate was evaporated
in vacuum to give the residue, which was purified by cation-ex-
change chromatography on CU-2 resin. Elution with water and then
3
19
(
C, F)¼20.0 Hz, 4-CH
2
2
). F NMR
þ
(377 MHz; CDCl
3
3
d
: ꢂ188.43 (m, CHF). MS (m/z): 251 (M ).
Anal. calcd for C14
H, 7.41; N, 5.76.
H
2
: C, 66.91; H, 7.22; N, 5.57. Found: C, 67.11;
4
.1.4. rel-(2S,5S)-5-(Fluoromethyl)-1-(phenylmethyl)-proline, hydro-
chloride (7a). A suspension of 5a (200 mg, 0.8 mmol) in 6 M aq HCl
10 mL) was heated at reflux for 3 h. The solution was evaporated in
with aq NH
3
(10%) afforded 9a (43 mg, 73% yield after two steps
1
(
from 6a) as a colorless solid. H NMR (500 MHz; CDCl
3
; Me
5.02 (1H, dm, J(H, F)¼45.6 Hz, CHF), 3.95 (1H, t, J(H, H)¼5.0 Hz,
NCHCO
H), 3.61 (1H, ddd, J¼31.6, 13.6, 2.0 Hz, NCHH), 3.37 (1H, m,
NCHH), 2.25 (1H, m, CHH), 2.05 (2H, m, CH
NMR (125 MHz; D O; Me Si), : 172.8 (s, CO
167.5 Hz, CHF), 56.2 (s, CHCO
4
Si), d:
2
3
vacuum to give crude 7a$HCl as a brown oil, which solidifies upon
standing. The compound was used in the next step without addi-
tional purification. H NMR (500 MHz; D
2
1
13
2
O; Me
4
Si),
d: 7.40 (5H, m,
2
), 1.74 (1H, m, CHH).
C
1
Ph), 4.97 (0.5H, d, J¼12.0 Hz, CHHF), 4.85e4.75 (1.5H, m,
2
4
d
2
H), 85.1 (d, J(C, F)¼
2
2
CHHFþCHHF), 4.62 (1H, d, J(H, H)¼12.5 Hz, NCHHPh), 4.37 (1H, d,
2
H), 44.2 (d, J(C, F)¼23.8 Hz,
2
2
3
J(H, H)¼12.5 Hz, NCHHPh), 4.28 (2H, m, CHCO
2
HþNCHCH
2
F), 2.46
). C NMR
NCH
3-CH
2
CHF), 24.9 (d, J(C, F)¼20.0 Hz, 4-CH
2
),
), 20.0 (d, J(C, F)¼5.0 Hz,
: ꢂ188.80 (m, CHF). MS
: C, 48.97; H, 6.85; N,
1
3
19
(
1H, m, CHH), 2.25 (1H, m, CHH), 2.09 (2H, m, CH
2
2
). F NMR (377 MHz; CDCl
3
; CFCl
3
d
þ
(
125 MHz; D O; Me Si), : 171.5 (s, CO H), 130.8 (s, CH, Ph), 130.4 (s,
2
4
d
2
(m/z): 147 (M ). Anal. calcd for C
6
H
10FNO
2
1
CH, Ph), 129.5 (s, CH, Ph), 129.3 (s, quat-C, Ph), 80.0 (d, J(C, F)¼
9.52. Found: C, 48.62; H, 6.47; N, 9.87.
2
170.0 Hz, CH
2
F), 66.3 (d, J(C, F)¼17.5 Hz, CHCH
2
F), 66.0 (s,
), 24.7 (d, J(C, F)¼4.5 Hz,
: ꢂ1.46 (td, J(F, H)¼49.0,
17ClFNO : C, 57.04; H, 6.26; N,
.12. Found: C, 57.33; H, 6.51; N, 5.41.
3
CHCO H), 55.8 (s, NCH
2
2
Ph), 27.4 (s, 3-CH
). F NMR (377 MHz; CDCl ; CFCl ),
2.6 Hz, CH F). Anal. calcd for C13
2
4.1.8. rel-(2S,5R)-1-(Phenylmethyl)-2,5-pyrrolidinedicarboxylic acid
(10). We used a slightly modified procedure to that reported pre-
viously in Ref 15. The authors hydrolyzed the mixture 2a/2b with
NaOH to provide diacid 10 in 68% yield.
19
4
2
5
-CH
2
3
3
d
2
H
2
NaOH (0.93 M solution) in water (66.5 mL, 61.9 mmol) was
added to a solution of the compound 2b (5.7 g, 20.6 mmol) in MeOH
(80 mL) upon stirring over a period of 30 min. The reaction mixture
was stirred for additional 24 h at room temperature. The solvent
was evaporated in vacuum and water (50 mL) was added to the
residue. The solution was washed with EtOAc (3ꢁ50 mL). 12 M aq
HCl was added to the water phase to adjust pH value to 2.0. The
reaction mixture was left in refrigerator at 0 C for 12 h. The pre-
cipitate was filtered off and dried on air to give pure 10 (3.6 g,
14.2 mmol, 70% yield).
4
7
.1.5. rel-(2S,5S)-5-(Fluoromethyl)-proline (1a). All amount of
a$HCl obtained in the previous step was dissolved in MeOH (10 mL)
and was hydrogenated at room temperature at 60 atm for 12 h using
0% palladium on charcoal (10 mg) as the catalyst. The solution was
1
filtered, and the filtrate was evaporated in vacuum to give the resi-
due, which was purified by cation-exchange chromatography on CU-
ꢀ
2
resin. Elution with water and then with aq NH
3
(10%) afforded 1a
40 mg, 34% yield after two steps from 5a). H NMR (400 MHz; D O;
Me Si), : 4.95e4.75 (0.5H, the signal is hidden under the signal of
solvent, CHHF), 4.67 (0.5Hþ0.5H, m, CHHFþCHHF), 4.17 (1H, t, J(H,
H)¼8.0 Hz, CHCO H), 4.55 (0.5H, dd, J¼11.2, 6.4 Hz, CHHF), 4.09 (1H,
m, NCHCH F), 2.41 (1H, m, 4-CHH), 2.17 (1H, m, 4-CHH), 2.05 (1H, dt,
J¼20.6, 8.0 Hz, 3-CHH), 1.91 (1H, dt, J¼20.6, 8.0 Hz, 3-CHH). C NMR
1
(
2
4
d
3
2
4.1.9. rel-(2S,5R)-1-(Phenylmethyl)-2,5-pyrrolidinedicarboxylic acid,
mono-merthyl ester (3b). The synthesis of 11 was performed from
10 according to Ref 23. Compound 3b was obtained from 11
according to Ref 24.
2
13
1
(
125 MHz; D
2
O; Me
4
Si),
d
: 174.1 (s, CO
2
H), 81.2 (d, J(C, F)¼167.5 Hz,
F), 28.7 (s, 3-
). F NMR (377 MHz; CDCl
F). MS (m/z): 147
: C, 48.97; H, 6.85; N, 9.52. Found: C,
8.71; H, 6.50; N, 9.81. Crystals suitable for X-ray crystallographic
analysis were obtained by a slow evaporation of a diluted solution of
2
CH
CH
CFCl
2
F), 62.0 (s, CHCO
2
H), 59.8 (d, J(C, F)¼18.8 Hz, CHCH
2
), 25.3 (d, 3J(C, F)¼6.3 Hz, 4-CH
19
4.1.10. rel-(2S,5R)-5-(Hydroxymethyl)-1-(phenylmethyl)-2-pyrrolidi-
necarbo-xylic acid (4b). Compound 4b has been prepared from 3b
following the Ref 25. Compound 4b was obtained in 51% overall
yield from diacid 10.
2
2
3
;
3
),
d
: ꢂ226.28 (td, J(F, H)¼49.0, 22.6 Hz, CH
2
þ
(
6 2
M ). Anal. calcd for C H10FNO
4
1
a in water.
4.1.11. rel-(2S,5R)-5-(Fluoromethyl)-1-(phenylmethyl)-proline,
methyl ester (5b). 4.1.11.1. rel-(2S,5S)-5-Fluoro-1-(phenylmethyl)-2-
4
.1.6. rel-(2S,5R)-5-Fluoro-1-(phenylmethyl)-2-piperidinecarboxylic
piperidinecarboxylic acid, methyl ester (6b). A solution of 4b (1.76 g,
ꢀ
acid, hydrochloride (8a). A suspension of 6a (100 mg, 0.8 mmol) in
M aq HCl (7 mL) was heated at reflux for 3 h. The solution was
10.0 mmol) in CH
2
Cl
2
(80 mL) was cooled to 0 C under argon at-
6
mosphere. Morpho-DAST (2.74 g, 11.1 mmol,1.1 equiv) was added at
once upon stirring. The reaction mixture was allowed to warm to
a room temperature and was stirred for 72 h. Thereafter, a saturated
evaporated under vacuum to give crude 8a$HCl as a white solid.
The compound was used in the next step without additional pu-
rification. H NMR (400 MHz; DMSO-d
1
6
; Me
4
Si),
d
: 7.59 (2H, s, Ph),
solution of NaHCO
was separated and the water phase was extracted with CH
4
SO ,
3
in water (80 mL) was added. The organic layer
2
2
7
.46 (3H, s, Ph), 5.05 (1H, d, J(H, F)¼46.8 Hz, CHF), 4.52 (1H, d, J
2
Cl
2
2
(
H, H)¼12.8 Hz, NCHHPh), 4.38 (1H, d, J(H, H)¼12.8 Hz, NCHHPh),
(2ꢁ40 mL). The combined organic phases were dried over Na
2
4
.07 (1H, br s, NCHCO
2
H), 3.55 (1H, br s, NCHH), 3.20 (1H, br s,
and evaporated under vacuum to give the mixture 5b/6b as a yel-
lowish oil. The isomers were separated by flash column chroma-
tography using hexane/EtOAc¼15/1 as an eluent. Elution afforded
13
NCHH), 2.34 (1H, m, CHH), 1.92 (3H, m, CHHþCH
2
). C NMR
(
100 MHz; CD
3
OD; Me
4
Si),
d
: 167.3 (s, CO
2
H), 129.6 (s, CH, Ph),
1
128.6 (s, CH, Ph), 127.5 (s, CH, Ph), 126.9 (s, quat-C, Ph), 81.4 (d, J(C,
6b first (0.51 g, 2.0 mmol, 20%) as colorless oil. R
f
¼0.30 (hexane/
2
1
F)¼172.5 Hz, CHF), 57.9 (s, CHCO
C, F)¼25.0 Hz, CH
NMR (377 MHz; DMSO-d
for C13 17ClFNO : C, 57.04; H, 6.26; N, 5.12. Found: C, 57.21; H,
2
Me), 57.7 (s, NCH
2
Ph), 49.5 (d, J
EtOAc¼15/1). H NMR (500 MHz; CDCl
3
; Me
4
Si), d: 7.32 (5H, m, Ph),
1
9
2
2
(
2
2
CHF), 23.4 (br s, 4-CH ), 19.8 (s, 3-CH
; C ),
2
).
F
4.62 (1H, d, J(H, F)¼48.5 Hz, CHF), 3.87 (1H, d, J(H, H)¼10.8 Hz,
2
6
6
F
6
d
: ꢂ182.34 (m, CHF). Anal. calcd
NCHHPh), 3.77 (s, OCH
3
), 3.74 (1H, d, J(H, H)¼10.8 Hz, NCHHPh),
3
H
2
3.37 (1H, dd, J(H, H)¼7.5, 5.0 Hz, NCHCO Me), 3.25 (1H, dt, J¼11.0,
2

3096
P.K. Mykhailiuk et al. / Tetrahedron 67 (2011) 3091e3097
7
.0 Hz, NCHH), 2.76 (1H, td, J¼11.0, 2.0 Hz, NCHH), 2.16 (1H, ddd,
J¼20.5, 8.5, 3.5 Hz, CHH), 1.93 (1H, m, CHH), 1.84 (1H, m, CHH), 1.73
1H, m, CHH). 13C NMR (125 MHz; CDCl
; Me Si), : 173.1 (s,
CO Me), 138.1 (s, quat-C, Ph), 128.8 (s, CH, Ph), 128.3 (s, CH, Ph),
evaporated in vacuum to give crude 8b$HCl as a white solid. The
compoundwas used in the next step without additional purification.
1
(
3
4
d
H NMR (400 MHz; DMSO-d
6
; Me
4
Si),
d
: 7.48 (5H, s, Ph), 5.03 (1H, d,
2
2
2
J(H, F)¼44.8 Hz, CHF), 4.53 (1H, d, J(H, H)¼13.2 Hz, NCHHPh), 4.30
1
2
1
27.3 (s, CH, Ph), 87.2 (d, J(C, F)¼172.5 Hz, CHF), 60.6 (s, CHCO
2
Me),
(1H, d, J(H, H)¼13.2 Hz, NCHHPh), 3.92 (1H, br s, NCHCO
2
H), 3.68
2
5
9.6 (s, NCH
2
Ph), 52.1 (d, J(C, F)¼23.8 Hz, CH
2
CHF), 51.4 (s, OCH ),
3
(1H, t, J¼10.4 Hz, NCHH), 3.20 (1H, t, J¼40.0,10.4 Hz, NCHH), 2.18 (3H,
2
3
19
13
2
7.7 (d, J(C, F)¼20.0 Hz, 4-CH
2
), 25.4 (d, J(C, F)¼8.8 Hz, 3-CH
2
).
F
m, CHHþCH
2
), 1.78 (1H, m, CHH). C NMR (100 MHz; DMSO-d
6
;
2
NMR (377 MHz; CDCl
3
; CFCl
3
),
d
: ꢂ186.57 (dm, J(F, H)¼49.0 Hz,
Me Si), : 171.3 (s, CO
4
d
2
H), 132.0 (s, CH, Ph),130.6 (s, CH, Ph),129.3 (s,
þ
1
CHF). MS (m/z): 251 (M ). Anal. calcd for C14
H
18FNO
2
: C, 66.91; H,
CH, Ph), 127.3 (s, quat-C, Ph), 84.7 (d, J(C, F)¼170.0 Hz, CHF), 63.9 (s,
2
7
.22; N, 5.57. Found: C, 67.21; H, 7.20; N, 5.31. Further elution gave
isomer 5b (1.10 g, 4.4 mmol, 44%) as a colorless oil. R
¼0.25 (hex-
: 7.31 (5H, m,
F), 3.92 (2H, s,
), 3.48 (1H, t, J(H, H)¼8.0 Hz,
Me), 3.20 (1H, m, NCHCH F), 2.07 (1H, m, CHH), 1.96 (2H,
), 1.81 (1H, m, CHH). C NMR (125 MHz; CDCl ; Me Si),
74.5 (s, CO Me), 138.3 (s, quat-C, Ph), 129.3 (s, CH, Ph), 128.2 (s, CH,
Ph), 127.3 (s, CH, Ph), 86.3 (d, J(C, F)¼170.0 Hz, CH
CHCO
17.0 Hz, 4-CH
d
2
Me), 59.9 (s, NCH
2
Ph), 53.1 (br s, NCH
2
CHF), 25.5 (d, J(C, F)¼
). F NMR (377 MHz; DMSO-d ; CFCl ),
17ClFNO : C, 57.04; H, 6.26;
19
f
2
), 22.6 (s, 3-CH
2
6
3
1
ane/EtOAc¼15/1). H NMR (500 MHz; CDCl
3
; Me
4
Si),
d
: ꢂ187.12 (m, CHF). Anal. calcd for C13
H
2
Ph), 4.31e4.14 (2H, dddd, J¼47.5, 22.5, 8.5, 5.5 Hz, CH
2
N, 5.12. Found: C, 57.10; H, 6.35; N, 5.01.
3
NCH
NCHCO
m, CH
2
Ph), 3.58 (3H, s, OCH
3
2
2
4.1.15. rel-(2S,5S)-5-Fluoro-2-piperidinecarboxylic
acid
(9b). All
13
2
3
4
d:
amount of 8b$HCl obtained in the previous step was dissolved in
MeOH (7 mL) and was hydrogenated at room temperature at 60 atm
for 12 h using 10% palladium on charcoal (10 mg) as the catalyst. The
solution was filtered, and the filtrate was evaporated in vacuum to
give the residue, which was purified by cation-exchange chroma-
1
2
1
2
F), 66.7 (s,
F), 58.7 (s, NCH Ph), 51.7
2
CHCO
2
Me), 63.1 (d, J(C, F)¼22.5 Hz, CHCH
2
2
3
19
(
s, OCH
3
), 28.6 (s, 3-CH
2
), 27.2 (d, J(C, F)¼3.8 Hz, 4-CH
),
: ꢂ224.57 (td, J(F, H)¼45.2,11.3 Hz, CH
18FNO : C, 66.91; H, 7.22; N,
2
). F NMR
(
377 MHz; CDCl
3
; CFCl
3
d
2
F).
tography on CU-2 resin. Elution with water and then with aq NH
3
þ
1
MS (m/z): 251 (M ). Anal. calcd for C14
H
2
(10%) afforded 9b (47 mg, 80% yield after two steps from 6a). H NMR
2
5
.57. Found: C, 66.69; H, 6.88; N, 5.31.
(500 MHz; CDCl
3
; Me
4
Si),
d
: 5.02 (1H, d, J(H, F)¼45.5 Hz, CHF), 3.57
(
2H, m, NCHHþNCHCO
2
H), 3.19 (1H, dd, J¼40.6, 14.5 Hz, NCHH), 2.14
13
4.1.12. rel-(2S,5R)-5-(Fluoromethyl)-1-(phenylmethyl)-proline hydro-
(2H, m, CH
2
), 1.79 (2H, m, CH
2
). C NMR (125 MHz; D
2
O; Me
4
Si),
H),
F), 26.8 (d, J(C, F)¼20.0 Hz, 4-CH ),
). F NMR (377 MHz; CDCl ; CFCl ),
: ꢂ226.28 (dtm, J
(F, H)¼33.9, 41.5 Hz, CHF). MS (m/z): 147 (M ). Anal. calcd for
10FNO : C, 48.97; H, 6.85; N, 9.52. Found: C, 48.59; H, 6.63; N,
d:
1
chloride (7b). A suspension of 5b (200 mg, 0.8 mmol) in 6 M aq HCl
10 mL) was heated at reflux for 3 h. The solution was evaporated in
173.7 (s, CO
2
H), 85.0 (d, J(C, F)¼168.8 Hz, CHF), 58.4 (s, CHCO
2
2
2
(
46.3 (d, J(C, F)¼21.1 Hz, NCH
2
CH
2
2
19
vacuum to give crude 7b$HCl as a brown solid. The compound was
used in the next step without additional purification. H NMR
21.0 (s, 3-CH
2
3
3
d
1
þ
(
500 MHz; D
2
O; Me
4
Si),
.65 (1H, d, J(H, H)¼13.0 Hz, NCHHPh), 4.44 (1H, d, J(H, H)¼13.0 Hz,
NCHHPh), 4.29 (1H, dd, J¼9.0, 5.5 Hz, CHCO H), 4.10 (1H, m,
NCHCH F), 2.38 (1H, m, CHH), 2.22 (1H, m, CHH), 2.11 (1H, m, CHH),
2 4 2
.90 (1H, m, CHH). C NMR (125 MHz; D O; Me Si), d: 171.4 (s, CO H),
d
: 7.46 (5H, m, Ph), 4.77e4.68 (2H, m, CH
2
F),
6
C H
2
2
2
4
9.35. Crystals of 9b, suitable for X-ray directional study, were
obtained by a slow evaporation of a diluted solution of 9b in water.
2
2
13
1
Supplementary data
1
8
6
6
31.3 (s, CH, Ph),130.5(s, CH, Ph),129.5 (s, CH, Ph),128.8(s, quat-C, Ph),
1
2
0.7 (d, J(C, F)¼170.0 Hz, CH
2
F), 68.3 (d, J(C, F)¼17.5 Hz, CHCH
2
F),
Crystallographic data for the compounds 1a, 8a, 7b, 9b, struc-
ture description and full spectroscopic data for all new compounds.
Supplementary data related to this article can be found online at
doi:10.1016/j.tet.2011.02.082.
3
7.7 (s, CHCO
2
H), 58.7 (s, NCH
2
Ph), 27.5 (s, 3-CH
2
), 24.7 (d, J(C, F)¼
19
.3 Hz, 4-CH
2
). F NMR (377 MHz; CDCl
F). Anal. calcd for C13
.26; N, 5.12. Found: C, 56.82; H, 6.02; N, 5.20. Crystals of 7b$HCl,
3
; CFCl
3
),
d: ꢂ225.87 (td, J(F,
H)¼49.0, 22.6 Hz, CH
2
2
H17ClFNO : C, 57.04; H,
6
suitable for X-ray diffractional study, were obtained by a slow evap-
oration of a diluted solution of 7b$HCl in MeOH.
References and notes
1. For some recent examples, see: (a) Golbik, R.; Yu, C.; Weyher-Stingl, E.; Huber,
4
7
.1.13. rel-(2S,5R)-5-(Fluoromethyl)-proline (1b). All amount of
b$HCl obtained in the previous step was dissolved in MeOH
R.; Moroder, L.; Budisa, N.; Schiene-Fischer, C. Biochemistry 2005, 44, 16026; (b)
Improta, R.; Benzi, C.; Barone, V. J. Am. Chem. Soc. 2001, 123, 12568; (c) Renner,
C.; Alefelder, S.; Bae, J. H.; Budisa, N.; Huber, R.; Moroder, L. Angew. Chem., Int.
Ed. 2001, 40, 923; (d) Chen, L.; Kim, Y. M.; Kucera, D. J.; Harrison, K. E.; Bah-
manyar, S.; Scott, J. M.; Yazbeck, D. J. Org. Chem. 2006, 71, 5468.
(
1
10 mL) and was hydrogenated at room temperature at 60 atm for
2 h using 10% palladium on charcoal (10 mg) as the catalyst. The
2
. Holmgren, S. K.; Taylor, K. M.; Bretscher, L. E.; Raines, R. T. Nature 1998, 392,
solution was filtered, and the filtrate was evaporated in vacuum to
give the residue, which was purified by cation-exchange chroma-
666.
3
. An MDL Discovery Gate search in October 2010 revealed that 111 derivatives of
tography on CU-2 resin. Elution with water and then with aq NH
3
4-fluoroproline were in clinical trials.
1
4. (a) Qiu, X.-L.; Qing, F.-L. J. Org. Chem. 2003, 68, 3614; (b) Del Valle, J. R.; Goodman,
M. Angew. Chem., Int. Ed. 2002, 41, 923; (c) Qiu, X.-L.; Qing, F.-L. J. Chem. Soc., Perkin
Trans. 1 2002, 18, 2052; (d) Demange, L.; Menez, A.; Dugave, C. Tetrahedron Lett.
1998, 39, 1169; (e) Chorghade, M. S.; Mohapatra, D. K.; Sahoo, G.; Gurjar, M. K.;
Mandlecha, M. V.; Bhoite, N.; Moghe, S.; Raines, R. T. J. Fluorine Chem. 2008, 129,
(
10%) afforded 1b (42 mg, 36% yield after two steps from 5b). H
NMR (500 MHz; D O; Me Si),
2
4
d
: 4.76 (0.5H, dd, J¼11.0, 3.0 Hz,
CHHF), 4.73e4.61 (0.5Hþ0.5H, the signals are hidden within the
signal of solvent, CHHFþCHHF), 4.55 (0.5Hþ0.5H, dd, J¼11.0, 6.5 Hz,
781; (f) Tkachenko, A. N.; Radchenko, D. S.; Mykhailiuk, P. K.; Grygorenko, O. O.;
CHHFþCHHF), 4.13 (1H, dd, J¼8.5, 4.5 Hz, CHCO
2
H), 3.94 (1H, m,
Komarov, I. V. Org. Lett. 2009,11, 5674; (g) Doi, M.; Nishi, Y.; Kiritoshi, N.; Iwata, T.;
Nago, M.; Nakano, H.; Uchiyama, S.; Nakazawa, T.; Wakamiya, T.; Kobayashi, Y.
Tetrahedron 2002, 58, 8453; (h) Von Halasz, S. P.; Glemser, O. Chem. Ber.1971, 104,
1247; (i) Markovskij, L. N.; Pashinnik, V. E.; Kirsanov, A. V. Synthesis 1973, 787; (j)
Middleton, W. J. J. Org. Chem. 1975, 40, 574; (k) Thomas, K. M.; Naduthambi, D.;
Tririya, G.; Zondlo, N. J. Org. Lett. 2005, 7, 2397.
5. Weiss, B.; Alt, A.; Ogden, A. M.; Gates, M.; Dieckman, D. K.; Clemens-Smith, A.;
Ho, K. H.; Jarvie, K.; Rizkalla, G.; Wright, R. A.; Calligaro, D. O.; Schoepp, D.;
Mattiuz, E. L.; Stratford, R. E.; Johnson, B.; Salhoff, C.; Katofiasc, M.; Phebus, L.
A.; Schenck, K.; Cohen, M.; Filla, S. A.; Ornstein, P. L.; Johnson, K. W.; Bleakman,
D. J. Pharmacol. Exp. Ther. 2006, 318, 772.
NCHCH
2
F), 2.26 (1H, m, CHH), 2.10 (2H, m, CH
C NMR (125 MHz; D O; Me Si), : 174.2 (s, CO
68.8 Hz, CH F), 61.8 (s, CHCO
CHCH F), 28.4 (s, 3-CH
377 MHz; D
2
), 1.71 (1H, m, CHH).
1
3
1
2
4
d
2
H), 81.5 (d, J(C, F)¼
2
1
2
2
H), 60.3 (d, J(C, F)¼18.8 Hz,
3
19
2
2
), 24.6 (d, J(C, F)¼6.3 Hz, 4-CH
2
). F NMR
F).
(
2
O; CFCl
3
),
d
: ꢂ224.67 (td, J(F, H)¼45.2, 18.9 Hz, CH
2
þ
MS (m/z): 147 (M ). Anal. calcd for C
6
H10FNO
2
: C, 48.97; H, 6.85; N,
9
.52. Found: C, 49.21; H, 6.46; N, 9.55.
6
. Thomas, A.; Gopalan, B.; Lingam, P.; Rao, V. S.; Shah, D. M. WO2006040625,
006.
. (a) Feng, J.; Zhang, Z.; Wallace, M. B.; Stafford, J. A.; Kaldor, S. W.; Kassel, D. B.;
Navre, M.; Shi, L.; Skene, R. J.; Asakawa, T.; Takeuchi, K.; Xu, R.; Webb, D. R.;
4
.1.14. rel-(2S,5R)-5-Fluoro-1-(phenylmethyl)-2-piperidinecarboxylic
2
acid, hydrochloride (8b). A suspension of 6b (100 mg, 0.8 mmol) in
M aq HCl (7 mL) was heated at reflux for 3 h. The solution was
7
6

P.K. Mykhailiuk et al. / Tetrahedron 67 (2011) 3091e3097
3097
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9
(
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1
1
1
2. (a) Mykhailiuk, P. K.; Afonin, S.; Chernega, A. N.; Rusanov, E. B.; Platonov, M.;
Dubinina, G.; Berditsch, M.; Ulrich, A. S.; Komarov, I. V. Angew. Chem., Int. Ed.
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2
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21. Golubev, A. S.; Schedel, H.; Radics, G.; Fioroni, M.; Thust, S.; Burger, K. Tetra-
hedron Lett. 2004, 45, 1445 However, in that approach to 9a, the last synthetic
step has the yield of only 6%.
003, 4, 1151; (d) Gl a€ zer, R. S. W.; Sachse, C.; D u€ rr, U. H. N.; Wadhwani, P.;
2009, 131, 15596.
1
3. During this work, the synthesis of a derivative of 1a was mentioned in Uoto, K.;
22. Bjorsne, M.; Hoffmann, K.-J.; Ponten, F.; Strandlund, G.; Svensson, P.; Wil-
stermann, M. WO 0232902, 2000.
23. Sturm, P. A.; Henry, D. W. J. Med. Chem. 1974, 17, 481.
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Weinreb, S. M. J. Org. Chem. 1996, 61, 125.
Kawato, H.; Sugimoto, Y.; Naito, H.; Miyazaki, M.; Taniguchi, T.; Aonuma, M.
WO2009151, A1 20091217. The patent, however, is written in Japanese, and no
detailed analytical data for the obtained compounds are given.
14. Morph-DAST was preferred over DAST as a result of its higher thermal stability
and better yields of fluorinated products in certain cases: (a) Messina, P. A.;