Stereoselective syntheses of 4-fluoro- and 4,4-difluoropipecolic acids

Article abstract of DOI:10.1016/S0040-4039(01)01660-4

Stereoselective syntheses of 4-fluoro- and 4,4-difluoropipecolic acids starting from Z-protected 4-hydroxy- and 4-oxopipecolates via fluorodehydroxylation and fluorodeoxygenation are described.

Full text of DOI:10.1016/S0040-4039(01)01660-4

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 42 (2001) 7941–7944
Stereoselective syntheses of 4-fluoro- and 4,4-difluoropipecolic
acids
Alexander S. Golubev,a,b Hartmut Schedel,a Gabor Radics,a Joachim Sielerc and Klaus Burgera,*
aDepartment of Organic Chemistry, University of Leipzig, Johannisallee 29, D-04103 Leipzig, Germany
bInstitute of Organoelement Compounds, Russian Academy of Sciences, Vavilov str. 28, GSP-1, V-334,
Rus-117813 Moscow, Russia
cDepartment of Inorganic Chemistry, University of Leipzig, Linnestraße 3, D-04103 Leipzig, Germany
Received 30 July 2001; accepted 4 September 2001
Abstract—Stereoselective syntheses of 4-fluoro- and 4,4-difluoropipecolic acids starting from Z-protected 4-hydroxy- and
4-oxopipecolates via fluorodehydroxylation and fluorodeoxygenation are described. © 2001 Elsevier Science Ltd. All rights
reserved.
Coplanarity of peptide bonds confers partitioning of
peptide chains between two energetically preferred rota-
tional states, cis and trans. This molecular heterogeneity
is particularly pronounced when imino acids like pro-
line or pipecolic acid form peptide bonds.1 Recent
studies revealed some characteristical differences in
respect to thermodynamics and kinetics of the cis–trans
isomerism about pipecolic acid peptide bonds com-
pared with prolines.2
Herein, we describe the first syntheses of 4-fluoro- and
4,4-difluoropipecolic acids. The synthetic strategy is
based on DAST fluorination of 4-hydroxy- and 4-
oxopipecolic acid derivatives, respectively. In contrast
to the trans-4-hydroxy-(S)-proline, 4-oxygenated
pipecolic acids, although present as constituent of natu-
ral products,5 are not commercially available to the best
of our knowledge (Scheme 1).
A series of synthetic approaches to enantiopure 4-oxy-
genated pipecolic acids have been recently described.6
The iminium ion cyclization of homoallylic amines with
glyoxylic acid attracted our interest because of its
preparative elegance, the ready accessibility of reagents,
and the availability of both (2S)- and (2R)-configurated
4-oxygenated pipecolic acids.
Peculiarities of the prolyl peptide bond isomerism in
4-fluorine-containing (S)-prolines turned out to be of
particular interest and importance rendering (2S,4R)-4-
fluoro- and (2S,4S)-4-fluoroprolines an excellent tool
for targeted protein design.3 The unique nature of the
element fluorine with its combination of strong elec-
tronegativity and low steric demand, and on the other
hand the option to use 19F NMR spectroscopy in the
absence of endogenous organic fluorocompounds
provide fluorine-containing molecules with a series of
useful biochemical and biomedicinal characteristics.4
Therefore, fluorine-containing pipecolic acid derivatives
represent an interesting new tool for studies of the
cis–trans isomerization of the peptide bond, for peptide
and protein folding experiments, and for the design of
new types of peptidomimetics.
A mixture of cis-4-hydroxy esters (in a ratio of 2:1) was
obtained according to Skiles et al.7b on reaction of
homoallylic amine 1 with glyoxylic acid in a mixture of
acetonitrile/water (1:1) followed by treatment with
ammonia-containing methanol. Diastereomers 2 and 3
can be easily separated by column chromatography on
silica gel even on a 20 g scale (Scheme 2).
Keywords: 4-hydroxypipecolic acid; 4-oxopipecolic acid; 4-
fluoropipecolic acid; 4,4-difluoropipecolic acid; DAST; fluorodehy-
droxylation; fluorodeoxygenation.
* Corresponding author. Fax: (49) 341 9736599; e-mail: burger@
organik.chemie.uni-leipzig.de
Scheme 1.
0040-4039/01/$ - see front matter © 2001 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(01)01660-4

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A. S. Golube6 et al. / Tetrahedron Letters 42 (2001) 7941–7944
Scheme 2. Reagents: (a) acetonitrile–H2O (1:1), 20°C; (b) CH3OH, NH3 (cat).
step in favour of the desired SN2 substitution process.
First, we tried the direct fluorodehydroxylation of cis-4-
hydroxypipecolic esters 2 and 3 with DAST in CH2Cl2.
We found that fluorodehydroxylation of (2S,4R)-4-
hydroxypipecolic ester 2 gave a mixture of two fluorine-
containing compounds in modest yields. Based on 2D
NMR measurements, these compounds were assigned
the structure of (2S,4S,2%S)-4-fluoropipecolate 4 and
(2R,4R,2%S)-4-fluoropipecolate 5. Surprisingly, a mix-
ture of the same compounds was obtained on DAST
fluorodehydroxylation of (2R,4S)-4-hydroxypipecolic
ester 3 (Scheme 3).
The Z-protected methyl cis-4-hydroxy-(S)-pipecolate 8
was obtained from ester 2 on catalytic hydrogenation
and Z-protection in 84% yield. Mitsunobu inversion in
THF with DEAD and formic acid and subsequent
methanolysis gave trans-4-hydroxy-(S)-pipecolate 10 in
53% yield.10 The standard Mitsunobu protocol was
successfully applied without modifications recom-
mended in the literature (Scheme 4).11
DAST fluorodehydroxylation of Z-protected cis-4-
hydroxypipecolate 8 in THF afforded trans-4-fluoro-
(S)-pipecolate 11 in 60% yield. The latter was
deprotected to give trans-4-fluoro-(S)-pipecolic acid
13.12 Likewise, Z-protected trans-4-hydroxy-(S)-pipeco-
late 10 was transformed into cis-4-fluoro-(S)-pipecolate
14 and subsequently into cis-4-fluoro-(S)-pipecolic acid
16 (Scheme 5).13
A fragmentation process of the Grob type seems to be
a plausible explanation for the experimental facts.8
Formation of the iminium ions 6 and 7 accounts for the
observed epimerization at C-2 of the piperidine ring.9
The anchimeric assistance of the methoxycarbonyl
group is responsible for the exclusive formation of the
trans fluoroderivatives 4 and 5. This effect only oper-
ates when the methoxycarbonyl group is placed in
axial position favoring an equatorial attack of the
fluoride ion. Therefore, compounds 2 and 3 are of no
use for a direct stereoselective fluorodehydroxylation
with DAST.
Z-Protected methyl 4-oxo-(S)-pipecolate 17 was
obtained from cis-4-hydroxypipecolate 8 by Swern oxy-
dation in 85% yield. DAST fluorodeoxygenation of
g-ketoester 17 afforded 4,4-difluoroderivative 18 in 39%
yield, which was deprotected to give 4,4-difluoro-(S)-
pipecolic acid 20 (Scheme 6).14
Consequently, we changed the N-protection group,
regarding Z-protected 4-hydroxypipecolic acids being
more suitable for a DAST fluorination. The electron-
withdrawing effect of both the Z-group and the
methoxycarbonyl group should reduce the tendency to
undergo a Grob fragmentation during the fluorination
The configuration of compound 15 was determined by
X-ray structural analysis of the Mosher derivative 2115
synthesized from (R)-a-methoxy-a-trifluoromethyl
phenylacetic acid chloride (Fig. 1). Using the chiral
center of the substructure introduced by Mosher’s
Scheme 3. Reagents: (a) DAST, dichloromethane.
Scheme 4. Reagents: (a) Pd(OH)2/C, H2, HCl in methanol; (b) Z-Cl, 1 M Na2CO3, 0°C; (c) DEAD, Ph3P, HCO2H, THF, 5°C;
(d) CH3OH, HCl (cat.).

A. S. Golube6 et al. / Tetrahedron Letters 42 (2001) 7941–7944
7943
Scheme 5. Reagents: (a) DAST, THF, −50°C to rt; (b) Pd(OH)2/C, H2, HCl in methanol; (c) 6N HCl, 90°C; (d) propylene oxide.
Scheme 6. Reagents: (a) DMSO, (COCl)2, Et3N; (b) DAST, THF; (c) Pd(OH)2/C, H2, HCl in methanol; (d) 6N HCl, 90°C; (e)
propylene oxide.
Figure 1. ORTEP plot of 21 showing the (S)-configuration of C(2) and (R)-configuration of C(4).
reagent—which is (S)-configurated as a reference—we
unequivocally can assign C-2 (S) and C-4 (R) configu-
ration. Thus, the configuration of compound 15 deter-
mined by hetero NOE experiments was confirmed by
X-ray structural analysis.
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The three enantiomers of amino acids 13, 16, and 20,
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(R)-pipecolic acid are obtainable from (2R,4S,2%S)-4-
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Acknowledgements
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1
3427, 2951, 1630, 1385 cm−1; H NMR (D2O, 300 MHz)
l 1.90 (m, 1H), 2.02–2.28 (m, 2H), 2.51 (m, 1H), 3.09 (m,
1H), 3.53 (m, 1H), 3.94 (ddd, J=10, 4, 1 Hz, 1H), 4.92
(dm, J=47 Hz, 1H); 13C NMR (D2O, 75 MHz) l 27.67
(d, JCF=22 Hz), 31.27 (d, JCF=22 Hz), 39.54 (d, JCF=10
Hz), 54.88 (d, JCF=8 Hz), 86.70 (d, JCF=172 Hz),
171.96; 19F NMR (D2O, 280 MHz) l −99.87 (d, J=43
Hz).
7. (a) Gillard, J.; Abraham, A.; Anderson, P. C.; Beaulier,
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14. 4,4-Difluoro-(S)-pipecolic acid (20): white powder; mp
274–276°C (sealed tube, dec.); [h]D=−20 (c=1, H2O); IR
(KBr) w 3435, 2976, 2474, 1611 cm−1; 1H NMR (D2O, 300
MHz) l 2.05–2.35 (m, 3H), 2.59 (m, 1H), 3.15 (td, J=14,
3 Hz, 1H), 3.50 (m, 1H), 3.81 (ddd, J=12, 4, 2 Hz, 1H);
13C NMR (D2O, 75 MHz) l 29.98 (t, JCF=26 Hz), 34.12
(t, JCF=26 Hz), 40.12 (d, JCF=10 Hz), 56.33 (d, JCF=8
Hz), 120.03 (dd, JCF=245, 240 Hz), 172.02; 19F NMR
(D2O, 280 MHz) l −17.18 (d, JFF=241 Hz, 1F), −23.99
(dm, JFF=241 Hz, 1F).
8. Grob, C. A.; Schiess, P. W. Angew. Chem., Int. Ed. Engl.
1967, 6, 1–68.
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Hiemstra, H.; Schoemaker, H. E. Eur. J. Org. Chem.
1999, 1127–1135.
10. Reduction of methyl 4-oxo-(S)-pipecolate with NaBH4 in
methanol in the presence of CeCl3 (Luche reagent) pro-
ceeds with good stereoselectivity providing a 8:1 mixture
of methyl trans-4-hydroxy-(S)-pipecolate 10 and methyl
cis-4-hydroxy-(S)-pipecolate 8 (see also: Ornstein, P. L.;
Arnold, M. B.; Lunn, W. H. W.; Heinz, L. J.; Leander, J.
D.; Lodge, D.; Schoepp, D. D. Bioorg. Med. Chem. Lett.
1998, 8, 389–394). Unfortunately, so far we did not
succeed in separating this mixture by flash chromatogra-
phy on silica gel.
15. X-Ray crystallographic data for 21: Single crystals were
grown from diethyl ether/hexane as colorless crystals; mp
131–133°C; [h]D=−74 (c=1, CHCl3); monoclinic space
group P21; T=223 K; a=8.057(10), b=12.011(1), c=
3
,
,
9.072(1) A, i=97.07(1)°; V=871.3(2) A ; Z=2; Dcalcd
=
1.438 g/cm−3; (STADI 4 Vierkreisdiffraktometer STOE);
omega-theta-scans (0.3°); 4850 data collected; 4639 inde-
pendent reflections; (Rint=0.012); for structure solution
and anisotropic refinement SHELXL-97 and SHELXS-93
(Sheldrick, G. M., Go¨ttingen, 1997) were used; R1=
0.0385; wR2=0.0989 [I>2|(I)]; R1=0.0570; wR2=0.1086
for all data. Crystallographic data for the structural
analysis in this paper have been deposited with the Cam-
bridge Crystallographic Data Centre as supplementary
publication number CCDC 167289. Copies of the data
can be obtained, free of charge, on application to CCDC,
12 Union Road, Cambridge, CB2 1EZ, UK (fax: +44(0)-
1223-336033; e-mail: deposit@ccdc.cam.ac.uk or http://
www.ccdc.cam.ac.uk).
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Roques, B. P.; Garbay, C. Bioorg. Med. Chem. Lett.
1998, 8, 1419–1424.
12. trans-4-Fluoro-(S)-pipecolic acid (13): colorless crystals;
mp 260–264°C (dec.); [h]D=−21 (c=1, H2O); IR (KBr) w
1
3431, 2967, 1632, 1398 cm−1; H NMR (D2O, 300 MHz)
l 1.70–1.96 (m, 2H), 2.07 (m, 1H), 2.43 (m, 1H), 3.11–
3.48 (m, 2H), 3.73–3.79 (dd, J=13, 3 Hz, 1H), 5.03 (dm,
J=48 Hz, 1H); 13C NMR (D2O, 75 MHz) l 26.28 (d,
J
CF=21 Hz), 31.11 (d, JCF=21 Hz), 38.48, 53.91, 85.40
(d, JCF=168 Hz), 173.92; 19F NMR (D2O, 280 MHz) l
−108.60 (m).