Asymmetric synthesis of (trifluoromethyl)piperidines: Preparation of highly enantioenriched α′-(trifluoromethyl)pipecolic acids

Article abstract of DOI:10.1055/s-2008-1072768

The first asymmetric synthesis of (trifluoromethyl)pipecolic acids is reported. The synthetic strategy involves as key step an intramolecular Mannich reaction of a homochiral α-Tfm-β-amino ketal, prepared with a high stereoselectively in four steps from a fluoral hemiacetal. Georg Thieme Verlag Stuttgart.

Full text of DOI:10.1055/s-2008-1072768

LETTER
1305
Asymmetric Synthesis of (Trifluoromethyl)piperidines: Preparation of Highly
Enantioenriched a¢-(Trifluoromethyl)pipecolic Acids
Asymmetric Synthesis
o
a
f
(Trifluoro
h
methyl)pipe
i
ridinesd B. Jatoi, Annabelle Bariau, Cécile Esparcieux, Gilles Figueredo, Yves Troin, Jean-Louis Canet*
Laboratoire de Chimie des Hétérocycles et des Glucides, EA 987, Ecole Nationale Supérieure de Chimie de Clermont-Ferrand,
Université Blaise Pascal, BP 187, 63174 Aubière Cedex, France
Fax +33(4)73407008; E-mail: j-louis.canet@univ-bpclermont.fr
Received 22 January 2008
mol% trifluoromethanesulfonic acid6 gave, in 92% yield,
Abstract: The first asymmetric synthesis of (trifluoromethyl)pipe-
the expected amino ketone 4, which was isolated as an in-
separable and almost equimolar mixture of diastereomers.
colic acids is reported. The synthetic strategy involves as key step
an intramolecular Mannich reaction of a homochiral a-Tfm-b-ami-
Subsequent keto protection with 1,3-propanediol under
classical acidic conditions, afforded the corresponding
ketals 5a,b. These compounds, of low polarity, could be
quite easily separated by silica gel column chromatogra-
phy. Individual hydrogenolysis of 5a and 5b then fur-
nished almost quantitatively antipodes of amine 1, both
no ketal, prepared with a high stereoselectively in four steps from a
fluoral hemiacetal.
Key words: fluorine, piperidines, cyclic amino acids, stereoselec-
tivity, intramolecular Mannich reaction
1
showing an excellent optical purity (ee >95%, from H
Owing primarily to the benefits on the bioactivity result-
ing from the incorporation of fluorine atom(s) into organic
molecules,1 fluoroorganic chemistry knows considerable
and continuous progress.2 Nevertheless, some domains
need still to be developed as, for instance, the synthesis of
selectively trifluoromethylated saturated N-heterocycles.
In this area, we recently demonstrated3 that intramolecular
Mannich reaction of b-amino ketal ( )-1, constituted a
valuable tool for the diastereoselective preparation of pip-
eridines ( )-2, bearing a trifluoromethyl (Tfm) group in
the a position4 (Scheme 1).
NMR in the presence of mandelic acid as chiral solvating
agent,7 in comparison with the racemic material).
O
Ph
NH
O
CF3SO3H (10 mol%)
+
Ph
NH2
F3C
Ph
F3C
MeCN, r.t.
92%, de ~0%
3
4
propanediol,
cat. TsOH
NH
Ph
NH
O
O
O
O
+
F3C
F3C
toluene, Δ
65%
H
(+)-5b
(–)-5a
F3C
N
R
H2, Pd(OH)2
MeOH, r.t.
H2, Pd(OH)2
MeOH, r.t.
CF3
95%
95%
O
O
+
RCHO
NH2
O
O
NH2
NH2
( )-1
O
O
O
O
( )-2, up to 96% de
CF3
CF3
(+)-1
(–)-1
Scheme 1
Scheme 2
This method was successfully employed for the elabora-
tion of new series of ( )-Tfm-piperidines, including triflu-
oro analogues of alkaloids.3b Meanwhile, in our minds, its
complete validation passed inevitably through its exten-
sion to the field of enantioselective synthesis, and that
point constitutes one of the objects of the present letter. As
solving this challenging problem4a,g required us to possess
amine 1 in an enantiomerically pure form, its asymmetric
preparation was engaged.
Although allowing a rapid preparation of amines (+)- and
(–)-1 on a multigram scale, the absence of stereoselectiv-
ity for the conjugate addition step lowered significantly
the interest of this approach, prompting us to investigate
an alternative strategy.
We then focused our attention on the asymmetric access
to fluorinated b-amino ketones recently proposed by
Brigaud.8 His methodology involved the diastereoselec-
tive addition of silyl enol ethers onto the stable oxazoli-
dine 6, very conveniently obtained from a fluoral
hemiacetal and (R)-(–)-phenylglycinol. Accordingly, and
as depicted in Scheme 3, a 1:2 diastereomeric mixture of
oxazolidines 6a,b9 was treated with enoxysilane 7 in the
presence of boron trifluoride etherate, at –15 °C in dichlo-
romethane. Under these conditions, the targeted b-amino
ketone (–)-8 was efficiently obtained (89%), within a few
For this purpose, an aza-Michael pathway was considered
at first, and the best results are collected in Scheme 2.
Thus, treatment of readily available5 trifluoropentenone 3
with (R)-(+)-a-methylbenzylamine in the presence of 10
SYNLETT 2008, No. 9, pp 1305–1308
x
x.
x
x.
2
0
0
8
Advanced online publication: 07.05.2008
DOI: 10.1055/s-2008-1072768; Art ID: G02408ST
© Georg Thieme Verlag Stuttgart · New York

1306
W. B. Jatoi et al.
LETTER
H
N
minutes and highly predominantly (de = 94% from GC-
MS of the crude, diastereomers separated by column chro-
matography). Subsequently, a conventional keto protec-
tion–hydrogenolysis sequence afforded in 60% yield the
desired amine (+)-1, whose NMR analysis (vide supra)
showed once again a high enantiomeric purity (>95%). At
this stage, absolute configuration of compounds (+)-1, (–)-110
and intermediates (represented in Schemes 2 and 3) were
assigned, in comparison to Brigaud’s observations.8
H
N
H
N
CO2H
CO2H
CO2H
OH
O
10
11
12
Figure 1
A crucial point to be checked here was the enantiomeric
composition of the predominant compound (+)-13a. Un-
fortunately this couldn’t be achieved directly by usual
NMR or chromatographic techniques, imposing therefore
its derivation. Ester 13a was so transformed into free ami-
no acid 14 whose reaction with (R)-(+)-a-methylbenzyl-
amine in the presence of Mukaiyama’s coupling reagent16
gave the parent amide 15 (Scheme 4). Comparison of GC-
MS traces of crude 15, prepared from racemic 13a and
from its (+)-isomer, then demonstrated an excellent stere-
oisomeric ratio (>95%), proving that no racemization oc-
curred under the acidic and alkaline conditions used for
the cyclization and the saponification steps.
Ph
OTMS
Ph
HO
NH
O
HN
OMe
OH
ref. 8,9
98%
7
F3C
O
F3C
BF3·OEt2, CH2Cl2,
F3C
Ph
–15 °C
(–)-8
6a,b
89%, de = 94%
H2, Pd(OH)2
O
propanediol,
cat. TsOH
HO
NH2
NH
O
O
O
CF3
F3C
toluene, Δ
MeOH, r.t.
60% from 8
(+)-1
9
Scheme 3
Asymmetric synthesis of a¢-Tfm analogues of 10–12
could then be undertaken. As mentioned in Scheme 5,
trans-dithioketalation of piperidine (+)-13a led to dithi-
olane (+)-16, which, after treatment with excess Raney
nickel in refluxing ethanol, furnished very cleanly the
pipecolate (–)-17 in 86% overall yield.
Our next goal was to evaluate the potential of homochiral
amine 1 towards the preparation of enantioenriched Tfm-
piperidines, with the aim to select as application examples
original structures of synthetic and/or biological interest.
In this context, pipecolic acids were considered.11 Effec-
tively, examination of the literature data revealed that, de-
spite the numerous efforts devoted to fluorinated amino
acids,12 none asymmetric synthesis of Tfm-homoprolines
has been reported to date.13 The elaboration of a¢-trifluo-
romethyl analogue of the simplest pipecolic acid (10) was
thus targeted, together with those of its 4-oxo and 4-hy-
droxy congeners 11 and 12, compounds of undeniable bi-
ological interest14,15 (Figure 1).
In contrast to previous observations on the parent free
Tfm-piperidines,3b direct keto-function regeneration of
(+)-13a was here realized by means of treatment with cer-
ic ammonium nitrate17 at 70 °C in acetonitrile–water for
eight hours (78%, other acidic conditions being ineffec-
tive). The 4-piperidone (–)-18 thus rapidly obtained was
then reduced with sodium borohydride at room tempera-
ture in ethanol, to afford in 85% yield the desired3b all-cis-
piperidinol (–)-19, as sole detectable isomer. Finally, sa-
ponification of amino esters 17–19, using 0.3 M aqueous
sodium hydroxide in refluxing methanol, followed by HCl
acidification and migration through an ion-exchange resin
gave efficiently (90–95%) the trifluoromethylated ana-
logues of free amino acids 10, 11, and 12, respectively,
(–)-20, 21 [which exists as its hydrate14b (–)-22], and
(–)-23.18
Treatment of (R)-(+)-1 with ethyl glyoxylate at room tem-
perature in toluene led to the corresponding imine, which,
submitted to our standard acidic cyclization conditions,
yielded, in an interesting 85:15 ratio, the 2,6-cis- and 2,6-
trans-ethyl Tfm-pipecolates 13a,b (65%, Scheme 4).
These diastereoisomers were easily separated by column
chromatography.
H
H
F3C
N
CO2Et
F3C
N
13b
O
CO2Et
OHC-CO2Et
MgSO4, toluene, r.t.
(+)-1
+
O
O
O
O
then TsOH, toluene, 70 °C
65%, de = 70%
85
:
15
(+)-13a
O
Ph
H
N
H
F3C
CO2H
F3C
N
+ N
Cl
N
I –
H
NaOH
Et3N,
then
13a
O
O
O
Ph
MeOH, reflux
then 1 M HCl
then Dowex
93%
NH2
14
15
Scheme 4
Synlett 2008, No. 9, 1305–1308 © Thieme Stuttgart · New York

LETTER
Asymmetric Synthesis of (Trifluoromethyl)piperidines
1307
dergraduate students of the ENSCCF) who checked some experi-
ments during their ‘Projet Technologique’ at the ENSCCF.
H
H
N
F3C
N
CO2Et
Raney Ni
F3C
CO2Et
(CH2SH)2
BF3·OEt2
(+)-13a
EtOH, Δ
90%
CH2Cl2, Δ
96%
S
S
References and Notes
(–)-17
(1) (a) Bégué, J.-P.; Bonnet-Delpon, D. In Chimie Bioorganique
et Médicinale du Fluor; EDP Sciences and CNRS Editions:
Paris, 2005. (b) Bégué, J.-P.; Bonnet-Delpon, D. J. Fluorine
Chem. 2006, 127, 992. (c) Kirk, K. L. J. Fluorine Chem.
2006, 127, 1013. (d) Isanbor, C.; O’Hagan, D. J. Fluorine
Chem. 2006, 127, 303.
(2) (a) Dolbier, W. R. Jr. J. Fluorine Chem. 2005, 126, 157.
(b) Schofield, H. J. Fluorine Chem. 1999, 100, 7.
(3) (a) Bariau, A.; Roblin, J.-P.; Troin, Y.; Canet, J.-L. Synlett
2005, 1731. (b) Bariau, A.; Jatoi, W. B.; Calinaud, P.; Troin,
Y.; Canet, J.-L. Eur. J. Org. Chem. 2006, 3421.
(4) For scarce examples of preparation of a-Tfm-piperidines,
see: (a) Jiang, J.; DeVita, R. J.; Doss, G. A.; Goulet, M. T.;
Wyvratt, M. J. J. Am. Chem. Soc. 1999, 121, 593.
(b) Crousse, B.; Bégué, J.-P.; Bonnet-Delpon, D. J. Org.
Chem. 2000, 65, 5009. (c) Gille, S.; Ferry, A.; Billard, T.;
Langlois, B. R. J. Org. Chem. 2003, 68, 8932.
(+)-16
CAN
MeCN–H2O, 70 °C
78%
H
H
F3C
N
CO2Et
F3C
N
CO2Et
NaBH4
EtOH, r.t.
85%
OH
O
(–)-19
(–)-18
0.3 M aqNaOH
MeOH, Δ
(–)-20, 95%
(–)-22, 90%
(–)-23, 90%
(–)-17
(–)-18
(–)-19
then 1 M HCl
then Dowex
(d) Spanedda, M. V.; Ourévitch, M.; Crousse, B.; Bégué, J.-
P.; Bonnet-Delpon, D. Tetrahedron Lett. 2004, 45, 5023.
(e) Magueur, G.; Legros, J.; Meyer, F.; Ourévitch, M.;
Crousse, B.; Bonnet-Delpon, D. Eur. J. Org. Chem. 2005,
1258. (f) Kim, G.; Kim, J. Tetrahedron Lett. 2005, 46, 423.
(g) Gheorghe, A.; Quiclet-Sire, B.; Vila, X.; Zard, S. Z.
Tetrahedron 2007, 63, 7187. (h) Dobbs, A. P.; Parker, P. J.;
Skidmore, J. Tetrahedron Lett. 2008, 49, 827.
H
N
H
N
H
F3C
CO2H
F3C
CO2H
F3C
N
CO2H
(–)-20
OH
O
21
(–)-23
H
N
(5) Plenkiewicz, H.; Dmowski, W.; Lipinski, M. J. Fluorine
F3C
CO2H
Chem. 2001, 111, 227.
(6) Wabnitz, T. C.; Spencer, J. B. Org. Lett. 2003, 5, 2141.
(7) Parker, D. Chem. Rev. 1991, 91, 1441.
(8) Huguenot, F.; Brigaud, T. J. Org. Chem. 2006, 71, 2159.
(9) Higashiyama, K.; Ishii, A.; Mikami, K. Synlett 1997, 1381.
(10) R-(+)-1, [a]D25 16.0 (c 1.30, CHCl3); S-(–)-1, [a]D25 –16.5 (c
1.15, CHCl3).
HO OH
(–)-22
Scheme 5
(11) For a recent review concerning pipecolic acids and
derivatives, see: Kadouri-Puchot, C.; Comesse, S. Amino
Acids 2005, 29, 101.
(12) For a recent review concerning fluorinated amino acids, see:
(a) Qiu, X.-L.; Meng, W.-D.; Qing, F.-L. Tetrahedron 2004,
60, 6711. (b) See also: Jäckel, C.; Koksch, B. Eur. J. Org.
Chem. 2005, 4483.
(13) For approaches to racemic Tfm-pipecolic acids, see ref. 4h
and: (a) Kobelkova, N. M.; Osipov, S. N.; Kolomiets, A. F.
Russ. Chem. Bull. 2002, 51, 1298. (b) Osipov, S. N.;
Artyushin, O. I.; Kolomiets, A. F.; Bruneau, C.; Picquet, M.;
Dixneuf, P. H. Eur. J. Org. Chem. 2001, 3891. For
selective synthesis of fluorine-containing homoprolines,
see: (c) Golubev, A. S.; Schedel, H.; Radics, G.; Sieler, J.;
Burger, K. Tetrahedron Lett. 2001, 42, 7941. (d) Golubev,
A. S.; Schedel, H.; Radics, G.; Fiorini, M.; Thust, S.; Burger,
K. Tetrahedron Lett. 2004, 45, 1445.
(14) For 4-oxo-pipecolic acid, see: (a) Ref. 11. (b) Partogyan-
Halim, K.; Besson, L.; Aitken, D. J.; Husson, H. P. Eur. J.
Org. Chem. 2003, 268; and references cited therein.
(15) For 4-hydroxy-pipecolic acid, see ref. 11 and: (a) Cordero,
F. M.; Bonollo, S.; Machetti, F.; Brandi, A. Eur. J. Org.
Chem. 2006, 3235; and references cited therein.
In conclusion, with the results disclosed here we have
demonstrated that the intramolecular Mannich reaction of
a-trifluoromethyl-b-amino ketals constitutes a pertinent
tool for the synthesis of highly enantioenriched Tfm-pip-
eridines. Validity of this method was illustrated by, at our
knowledge, the first asymmetric synthesis of Tfm-pipe-
colic acids. These original conformationally constrained
amino acids, compounds of synthetic and biological in-
terest, were simply and efficiently prepared in a maximum
of eight steps starting from commercial fluoral hemiace-
tal. Furthermore, applicable to a wide range of aldehydes,3
this strategy opens a new way to series of homochiral a-
Tfm-piperidines. Complete experimental details, together
with extensions to enantioselective synthesis of Tfm-pip-
eridine based a-, b-, and g-amino acids but also of saturat-
ed Tfm-N-heterobicyclic systems, will be proposed in due
course.
Acknowledgment
(b) Occhiato, E. G.; Scarpi, D.; Guarna, A. Eur. J. Org.
We thank the Ministère de l’Education Nationale, de l’Enseigne-
ment Supérieur et de la Recherche for financial support. W.B.J. is
grateful to Higher Education Commission of Pakistan for research
fellowship. We thank Cristian Catrinescu and Xavier Gaucher (un-
Chem. 2008, 524; and references cited therein.
(16) Huang, H.; Iwasawa, N.; Mukaiyama, T. Chem. Lett. 1984,
1465.
(17) Ates, A.; Gautier, A.; Leroy, B.; Plancher, J.-M.; Quesnel,
Y.; Markò, I. E. Tetrahedron Lett. 1999, 40, 1799.
Synlett 2008, No. 9, 1305–1308 © Thieme Stuttgart · New York

1308
W. B. Jatoi et al.
LETTER
(18) Selected Data for Compounds 20, 22, and 23
(–)-(2S,6R)-6-Trifluoromethyl-pipecolic Acid (20)
White solid; mp 118 °C; [a]D25 –11.2 (c 1.00, MeOH). 1H
NMR (400 MHz, D2O): d = 3.61 (m, 1 H), 3.37 (dd, J = 12,
3 Hz, 1 H), 2.11 (m, 1 H), 2.06–1.95 (m, 2 H), 1.65–1.37 (m,
3 H). 13C NMR (100 MHz, D2O): d = 177.2, 124.6 (q,
JCF = 277 Hz), 60.3, 56.7 (q, JCF = 30 Hz), 27.4, 22.5, 22.0.
19F NMR (376 MHz, CD3OD): d = –78.0. HRMS: m/z calcd
for C7H11F3NO2 [M + H+]: 198.0742; found: 198.0724.
(–)-(2S,6R)-4,4-Dihydroxy-6-trifluoromethyl-pipecolic
Acid (22)
D2O): d = 169.5, 122.6 (q, JCF = 279 Hz), 90.4, 56.1, 54.6 (q,
JCF = 33 Hz), 36.8, 33.2. 19F NMR (376 MHz, CD3OD):
d = –75.1. HRMS: m/z calcd for C7H9NO3F3 [(M – H2O) +
H+]: 212.0535; found: 212.0545.
(–)-(2S,4S,6R)-4-Hydroxy-6-trifluoromethyl-pipecolic
Acid (23)
White solid; mp 145 °C; [a]D25 –9.3 (c 0.95, MeOH). 1H
NMR (400 MHz, D2O): d = 3.92 (tt, J = 11.5, 4.5 Hz, 1 H),
3.62 (m, 2 H), 3.40 (dd, J = 12.5, 3.0 Hz, 1 H), 2.37 (m, 1 H),
2.26 (m, 1 H), 1.44 (q, J = 12.0 Hz, 1 H), 1.38 (td, J = 12.5,
11.0 Hz, 1 H). 13C NMR (100 MHz, D2O): d = 176.6, 124.4
(q, JCF = 277 Hz), 66.3, 58.3, 54.9 (q, JCF = 30 Hz), 36.2,
31.3. 19F NMR (376 MHz, CD3OD): d = –77.8. HRMS: m/z
calcd for C7H11F3NO3 [M + H+]: 214.0691; found: 214.0700.
White solid; mp 95 °C; [a]D25 –2.1 (c 1.00, MeOH). 1H NMR
(400 MHz, D2O): d = 4.34 (m, 1 H), 4.23 (dd, J = 13.0, 3.5
Hz, 1 H), 2.53 (dt, J = 14.0, 3.5 Hz, 1 H), 2.37 (dt, J = 14.0,
3.0 Hz, 1 H), 2.08 (t, J = 13.5 Hz, 2 H). 13C NMR (100 MHz,
Synlett 2008, No. 9, 1305–1308 © Thieme Stuttgart · New York

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