Enantioselective ring expansion of prolinols: An efficient and short synthesis of 2-phenylpiperidin-3-ol derivatives and 3-hydroxypipecolic acids

Article abstract of DOI:10.1055/s-0029-1217568

A very short route to 2-phenylpiperidin-3-ol derivatives and 3-hydroxypipecolic acids is described. The approach uses two key steps: a one-pot reduction/Grignard addition sequence applied to alkyl proline esters and a ring expansion applied to the corresp

Full text of DOI:10.1055/s-0029-1217568

LETTER
2157
Enantioselective Ring Expansion of Prolinols: An Efficient and Short
Synthesis of 2-Phenylpiperidin-3-ol Derivatives and 3-Hydroxypipecolic Acids
S
ynthesis of 3-Hyd
n
roxypipecol
n
ic
A
cids e Cochi,a Benjamin Burger,a Cristina Navarro,a Domingo Gomez Pardo,*a Janine Cossy,*a Yang Zhao,b
Theodore Cohenb
a
Laboratoire de Chimie Organique, ESPCI ParisTech, CNRS, 10 Rue Vauquelin, 75231 Paris Cedex 05, France
Fax +33(1)40794660; E-mail: janine.cossy@espci.fr; E-mail: domingo.gomez-pardo@espci.fr
Department of Chemistry, University of Pittsburgh, Chevron Science Center, 219 Parkman Avenue, Pittsburgh, PA 15260, USA
b
Received 10 April 2009
Abstract: A very short route to 2-phenylpiperidin-3-ol derivatives
and 3-hydroxypipecolic acids is described. The approach uses two
key steps: a one-pot reduction/Grignard addition sequence applied
to alkyl proline esters and a ring expansion applied to the corre-
sponding prolinols.
CF3
O
O
O
CF3
N
Key words: reduction, Grignard addition, aziridinium, ring expan-
sion, 2-phenylpiperidin-3-ols, 3-hydroxypipecolic acids
H
N
CF3
H
CF3
(+)-I: (+)-L-733,060
II
O
CF3
Functionalized chiral piperidines are present in a great va-
riety of natural products and synthetic compounds with
important biological activity.1 For our part, we were inter-
ested in the synthesis of 2-substituted piperidin-3-ols, as
these compounds are frequently encountered in living sys-
tems due to their ability to mimic carbohydrates in a vari-
ety of enzymatic processes.2 2-Phenylpiperidin-3-ols A,
which are precursors of non-peptidic NK-1 receptor an-
tagonists such as I3 and II,4 have a cis-relationship be-
tween the phenyl and the ether group on the piperidine
ring, and are important for high-affinity binding to the hu-
man NK-1 receptor (Figure 1).5 Furthermore, 3-hydroxy-
pipecolic acids B are also of importance as they are
attractive chiral building blocks for the synthesis of bio-
logically active natural products such as tetrazomine III,
which possesses antitumor and antibiotic properties.6
These compounds can be considered as ring-expanded ho-
mologues of prolinols or constrained analogues of serine,
which permit their use in conformational and ligand-bind-
ing studies involving bioactive peptides and peptidomi-
metics (Figure 1).7
N
H
OH
*
*
OH
*
*
N
N
CO2H
(–)-I: (–)-L-733,061
R
H
A
B
OMe
Me
H
O
OH
N
H
H
N
N
H
H
OMe
tetrazomine III
(antitumor and antibiotic)
O
Figure 1
piperidin-3-ols A and 3-hydroxypipecolic acids B using
the ring expansion of prolinols C. As these prolinols can
be synthesized from either L-proline or D-proline, all the
stereoisomers of 3-hydroxypipecolic acids should be at-
tainable using this methodology (Scheme 1).
Access to optically active prolinols C was achieved either
from the commercially available N-Boc-L-proline methyl
ester (1a) or from N-benzyl-L-proline ethyl ester (1b) in a
one-pot reaction.14a–14c These two compounds were trans-
formed into the corresponding amino alcohols 2a/3a
and 2b/3b, respectively, using DIBAL-H followed by
the addition of phenylmagnesium bromide (CH2Cl2,
–78 °C → r.t.).15 In the case of N-Boc proline ester 1a, the
ratio 2a/3a was excellent (99:1).14d In contrast, in the case
of N-benzyl proline ester 1b a 1:1 ratio of 2b/3b was ob-
served. The diastereomers 2a and 3a as well as 2b and 3b
could be separated by flash chromatography on silica gel
(Scheme 2).13a
Various synthetic strategies have been reported for the
synthesis of compounds of type I, II and B using, for ex-
ample, resolution techniques or asymmetric synthesis.8–10
In the course of our studies on the synthesis and applica-
tions of optically active 3-hydroxypiperidines via a ring
expansion of prolinols,11,12 we were interested in the ring
expansion of prolinols C in order to produce 2-phenyl-
piperidin-3-ols A (Scheme 1).
After the recent publication by O’Brien et al.13a of the
asymmetric synthesis of piperidines from pyrrolidines, we
would like to disclose our very short route to 2-phenyl-
As reported by one of us,14c the excellent diastereoselec-
tivity obtained in the transformation of 1a into 2a and 3a,
can be explained by the formation of aluminoxyacetal in-
termediates R1 and R2, in which the aluminum atom is
coordinated to the most basic oxygen atom of the N-Boc
SYNLETT 2009, No. 13, pp 2157–2161
Advanced online publication: 16.07.2009
DOI: 10.1055/s-0029-1217568; Art ID: G12509ST
© Georg Thieme Verlag Stuttgart · New York
x
x
.x
x
.2
0
0
9

2158
A. Cochi et al.
LETTER
OH
Ph
H
*
*
CO2H
N
H
N
R1
H
H
Ph
L-proline
A
*
*
CO2R2
*
N
N
OH
R1
R1
D
OH
H
*
*
C
CO2H
N
H
N
H
CO2H
D-proline
B
Scheme 1
OR2
H
H
H
Ph
Ph
DIBAL-H, –78 °C, 30 min
then PhMgBr, –78 °C, r.t.
+
N
N
N
O
OH
OH
R1
R1
R1
R1 = Boc
2 = Me
1a
2a
2b
3a
3b
57%
55%
R
99:1
R
R
1 = Bn
2 = Et
1b
50:50
Scheme 2
BrMg Ph
H
H
H
BrMgPh
H
OMe
(R)
OMe
(R)
(S)
N
(S)
O
N
O
O
O
Al
t-BuO
R3
t-BuO
Al
R1
H
DIBAL-H
CH2Cl2
OMe
(S)
N
– MeOMgBr
SNi
retention
epimerization
MgBr2
O
Boc
H
OMe
1a
H
(S)
N
(S)
O
O
H
t-BuO
Al
Ph
(S)
(S)
N
R2
OH
Boc
2a
Scheme 3
group (Scheme 3). Due to the presence of MgBr2 in the Having 2b and 3b in hand, these products were trans-
commercially available Grignard reagent, R2 epimerizes formed into 3-hydroxypiperidines 4 and 5 via aziridini-
to R1. Indeed, calculations have shown that R1 is more ums R4 and R5 using our standard conditions e.g. TFAA
stable than R2.14c The aluminoxyacetal R1 can then un- (3–4 equiv), Et3N (4–7 equiv), 3 h, 100 °C under micro-
dergo a SNi reaction with phenylmagnesium bromide, wave (MW) irradiation and then saponification using
with retention of configuration, to furnish 2a as the major NaOH.12 Both compounds 4 and 5 were obtained in quan-
isomer (Scheme 3).
titative yield with excellent diastereoselectivities (up to
99%) and enantioselectivities (up to 99%) (Scheme 5).12s,16
The complexation of the aluminum with the N-Boc group
was necessary in order to obtain excellent diastereoselec-
tivity, since when an N-benzyl group was present in 1b, no
diastereoselectivity was observed.14c
1) TFA, CH2Cl2
r.t., 2 h, 87%
H
H
Ph
Ph
(S)
(S)
(S)
(S)
N
N
2) BnCl, K2CO3, CH2Cl2,
reflux, 4 h, 73%
We have to point out that 2a can be converted into 2b
by treatment with TFA (CH2Cl2, r.t., 2h) followed by a
N-benzylation (BnCl, K2CO3, CH2Cl2, reflux) (Scheme 4).
OH
OH
Boc
Bn
2a
2b
Scheme 4
Synlett 2009, No. 13, 2157–2161 © Thieme Stuttgart · New York

LETTER
Synthesis of 3-Hydroxypipecolic Acids
2159
TFAA (4 equiv), Et3N (7 equiv)
THF, 3 h, MW 100 °C
9 in good yields. Treatment of these latter compounds
with RuCl3·3H2O and NaIO4 (CCl4, MeCN, H2O, r.t.) fol-
lowed by saponification (K2CO3, MeOH, r.t.) furnished
the desired 3-hydroxypipecolic acids (–)-10 and (–)-11,
respectively, in 67% and 76% yield (for the two steps)
(Scheme 7).21
OH
Ph
Ph
OH
N
then NaOH (aq)
quantitative
Bn
N
Bn
2b
4
dr = 99%
ee = 99%
H
Ph
N
H
CF3CO2
In conclusion, by using a diastereoselective DIBAL-H re-
duction/Grignard addition sequence and a ring expansion
of prolinols, compounds D were transformed into 2-phe-
nylpiperidin-3-ols in two steps, which were transformed
into 3-hydroxypipecolic acids in five steps. Following
the same strategy, 3-hydroxypipecolic acids (+)-10 and
(+)-11 should be obtained from D-proline. The synthesis
of biologically active piperidines using these methodolo-
gies is under progress in our laboratory, and the results
will be reported in due course.
Bn
R4
TFAA (3 equiv), Et3N (4 equiv)
THF, 3 h, MW 100 °C
OH
Ph
Ph
OH
N
then NaOH aq
quantitative
Bn
N
Bn
3b
5
dr = 99%
ee = 99%
H
H
N
CF3CO2
Ph
Bn
CF3
R5
H2, Pd/C
OH
Ph
OH
Ph
Boc2O
EtOAc
42%
ref. 19
O
Scheme 5
CF3
N
N
N
H
Ph
Bn
4
Boc
6
Thus, compounds of type C can be transformed in two
steps into compounds of type A.13b,17,18
(−)-I
CF3
We were able to transform 4 into 6,19 which is an interme-
diate involved in the synthesis of the non-peptidic NK-1
receptor antagonist L-733,061, after hydrogenation in the
presence of Boc2O. Compound 7,20 which is an intermedi-
ate used in the synthesis of two non-peptidic NK-1 recep-
tor antagonists L-733,060 and spiropiperidine II, was
obtained from 5 also in a one-pot reaction (H2, Pd/C,
Boc2O) (Scheme 6).
OH H2, Pd/C
Boc2O
OH
Ph
ref. 20
O
CF3
EtOAc
83%
N
Ph
N
Bn
5
N
H
Ph
Boc
7
(+)-I
ref. 20
Furthermore, the substituted piperidin-3-ols 4 and 5 were
converted into the corresponding 3-hydroxypipecolic ac-
ids (–)-10 and (–)-11, respectively. First, compounds of
type A (4 and 5) were acetylated (Ac2O, Et3N, DMAP,
CH2Cl2, r.t., 98–96%) and, after careful hydrogenation
[H2, Pd(OH)2, H-CubeTM (Thales Nanotechnology Inc.),
45 °C, 77–83%], a trifluoroamidation was achieved
(DMAP, TFAA, Et3N, CH2Cl2, r.t., 98%) leading to 8 and
O
O
N
Ph
II
CF3
H
Scheme 6
1) NaIO4, RuCl3/H2O
MeCN, H2O, CCl4,
r.t., 18 h
1) Ac2O, DMAP, Et3N,
OH
Ph
CH2Cl2, r.t., 16 h (98%)
OAc
Ph
OH
2) H2, Pd(OH)2, 45 °C,
EtOH, H-Cube (77%)
3) DMAP, TFAA, Et3N,
CH2Cl2, r.t., 16 h (98%)
2) K2CO3, MeOH, r.t., 15 h
67% (2 steps)
N
N
N
CO2H
Bn
H
O
CF3
4
8
(–)-10
1) NaIO4, RuCl3/H2O
MeCN, H2O, CCl4,
r.t., 18 h
1) Ac2O, DMAP, Et3N,
CH2Cl2, r.t., 16 h (96%)
OH
OH
Ph
OAc
Ph
2) H2, Pd(OH)2, 45 °C,
EtOH, H-Cube (83%)
3) DMAP, TFAA, Et3N,
CH2Cl2, r.t., 16 h (98%)
2) K2CO3, MeOH, r.t., 15 h
76% (2 steps)
N
H
CO2H
N
N
Bn
O
CF3
5
9
(–)-11
Scheme 7
Synlett 2009, No. 13, 2157–2161 © Thieme Stuttgart · New York

2160
A. Cochi et al.
LETTER
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Acknowledgments
We would like to thank the internship students for their work: C.
Chapus, M.-F. Laroche, E. Collard de Macquerh, M. Willot and S.
Bendenia. The work at Pittsburgh was supported by the National
Science Foundation under Grant No. 0102289.
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Synlett 2009, No. 13, 2157–2161 © Thieme Stuttgart · New York

LETTER
1170. (m) Roudeau, R.; Gomez Pardo, D.; Cossy, J.
Synthesis of 3-Hydroxypipecolic Acids
2161
127.2 (d), 127.0 (d), 126.8 (d), 125.5 (d), 70.2 (d), 69.2 (d),
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Tetrahedron 2007, 63, 9082. (q) Métro, T.-X.;
58.3 (t), 54.7 (t), 24.0 (t), 23.2 (t). MS: m/z (%) = 160
(100)[M+· – CHOHPh·], 91 (71) [PhCH2 ].
+
(16) General procedure for the ring expansion of pyrrolidines
to piperidines: Trifluoroacetic anhydride (3–4 equiv) was
added to a stirred solution of N-alkyl pyrrolidine (1 equiv) in
THF under argon at r.t. and Et3N (4–7 equiv) was added. The
solution was stirred and heated at 100 °C for 3 h under
microwave irradiation. The resulting solution was cooled to
r.t. and a solution of aqueous 3.75 M NaOH was added. After
stirring for 30 min, EtOAc was added and the two layers
were separated. The aqueous layer was extracted with
EtOAc and the combined organic layers were dried over
anhydrous MgSO4 and evaporated under reduced pressure to
give the crude product.
Gomez Pardo, D.; Cossy, J. J. Org. Chem. 2007, 72, 6556.
(r) Métro, T.-X.; Gomez Pardo, D.; Cossy, J. Synlett 2007,
2888. (s) Cossy, J.; Gomez Pardo, D.; Dumas, C.; Mirguet,
O.; Déchamps, I.; Métro, T.-X.; Burger, B.; Roudeau, R.;
Appenzeller, J.; Cochi, A. Chirality 2009, in press.
(13) (a) Bilke, J. L.; Moore, S. P.; O’Brien, P.; Gilday, J. Org.
Lett. 2009, 11, 1935. (b) O’Brien et al. (ref 13a) have shown
that the ring expansion of substituted pyrrolidinols 2b and 3b
using TFAA (1.5 equiv), Et3N (3 equiv), in refluxing THF
for 48 h, led to the ring-expanded compounds.
(14) (a) Ibuka, T.; Habashita, H.; Otaka, A.; Fujii, N.; Ogushi, Y.;
Uyehara, T.; Yamamoto, Y. J. Org. Chem. 1991, 56, 4370.
(b) Ito, H.; Ikeuchi, Y.; Taguchi, T.; Hanzawa, Y.; Shiro, M.
J. Am. Chem. Soc. 1994, 116, 5469. (c) Zhao, Y. Master's
Thesis; University of Pittsburgh: Pittsburgh, 2005; http://
etd.library.pitt.edu/ETD/available/etd-12072005-173655/.
(d) The excellent diastereoselectivity in the DIBAL-H/
Grignard sequence was probably due to catalysis of the
conversion of R2 to R1 (Scheme 3) due to the presence of
MgBr2 in the Grignard reagent, whereas ZnCl2 or heat was
used for this purpose in Ref. 14c
(15) Ester reduction/alkylation method: DIBAL-H (1.0 M in
hexane, 2.61 mL, 2.61 mmol, 1.2 equiv) was added to a
solution of N-benzylproline ethyl ester (500 mg, 2.17 mmol,
1 equiv) in CH2Cl2 (10 mL) at –78 °C. The resulting solution
was stirred at –78 °C for 30 min, followed by the addition of
commercially available PhMgBr (1.0 M in THF, 6.52 mL,
6.52 mmol, 3 equiv) dropwise at –78 °C. The solution was
then allowed to slowly warm to r.t. overnight. Sat. aq NH4Cl
(10 mL) was added to quench the reaction. Sat. sodium
tartrate solution (10 mL) was added to the resulting gel. The
mixture was stirred at r.t. for 30 min, then the organic layer
was extracted with CH2Cl2 (3 × 15 mL). The combined
organic layers were dried over anhydrous MgSO4 and
concentrated in vacuo to give a separable mixture of
diastereomers 2b and 3b, which was purified by flash
chromatography (SiO2; EtOAc–PE, 8:2) to give 2b as a
yellow solid (155 mg, 27.5%) and 3b as a pale-yellow oil
(155 mg, 27.5%).
Compound 4: Chromatography (SiO2; EtOAc–PE, 7:3),
Rf = 0.33 (EtOAc–PE, 7:3); ee >99% determined by
supercritical fluid chromatography on Daicel Chiralpak OD-
H column (MeOH 5%, flow rate 5 mL/min, t = 3.94 min);
[a]D20 –25 (c 1.15, CHCl3). IR (neat): 3588, 3016, 2946,
1493, 1454 cm–1. 1H NMR (CDCl3, 400 MHz): d = 7.51–
7.19 (m, 10 H), 3.87 (d, J = 13.6 Hz, 1 H), 3.74 (m, 1 H),
3.34 (d, J = 1.7 Hz, 1 H), 3.0 (m, 1 H), 2.88 (d, J = 13.6 Hz,
1 H), 2.05–1.89 (m, 3 H), 1.61 (m, 1 H), 1.47 (m, 1 H). 13
C
NMR (CDCl3, 100 MHz): d = 141.1 (s), 139.1 (s), 128.7 (d),
128.6 (d), 128.5 (d), 128.4 (d), 128.3 (d), 128.2 (d), 128.1
(d), 128.0 (d), 127.4 (d), 126.6 (d), 73.9 (d), 72.4 (d), 59.4 (t),
53.4 (t), 31.3 (t), 19.9 (t). MS: m/z (%) = 267 (3)[M+·], 266
(3), 222 (15), 210 (6), 194 (15), 177 (13), 176 (100) [M+· –
·
+
PhCH2 ], 106 (10), 91 (52) [PhCH2 ].
Compound 5:17,20b Chromatography (SiO2; EtOAc–PE,
8:2), Rf = 0.2 (EtOAc–PE, 8:2); ee >99% determined by
supercritical fluid chromatography on Daicel Chiralpak OD-
H column (MeOH 5%, flow rate 5 mL/min, t = 4.14 min);
mp 139–141 °C; [a]D20 +27 (c 1, CHCl3). IR (neat): 3588,
3016, 2946, 1493, 1454 cm–1. 1H NMR (CDCl3, 400 MHz):
d = 7.55–7.14 (m, 10 H), 3.66 (d, J = 13.6 Hz, 1 H), 3.59 (m,
1 H), 2.91 (d, J = 8.6 Hz, 1 H), 2.89 (m, 1 H), 2.83 (d,
J = 13.6 Hz, 1 H), 2.09 (m, 1 H), 1.93 (m, 1 H), 1.70–1.60
(m, 2 H), 1.38 (m, 1 H). 13C NMR (CDCl3, 100 MHz): d =
141.1 (s), 139.6 (s), 128.8 (d), 128.7 (d), 128.6 (d), 128.2 (d),
128.1 (d), 127.9 (d), 127.8 (d), 127.6 (d), 126.9 (d), 126.7
(d), 76.0 (d), 73.9 (d), 59.3 (t), 52.4 (t), 32.5 (t), 23.3 (t). MS:
m/z (%) = 267 (3)[M+·], 266 (3), 222 (15), 210 (6), 194 (15),
·
177 (13), 176 (100) [M+· – PhCH2 ], 106 (10), 91 (52)
Compound 2b:17,20b Rf = 0.1 (EtOAc–PE, 8:2); mp 93–
95 °C; [a]D20 +106 (c 1.1, CHCl3). IR (neat): 3017, 1495,
1454 cm–1. 1H NMR (CDCl3, 400 MHz): d = 7.43–7.20 (m,
10 H), 4.39 (d, J = 5.2 Hz, 1 H), 3.67 (d, J = 13.0 Hz, 1 H),
3.34 (d, J = 13.0 Hz, 1 H), 3.08 (m, 1 H), 2.96 (m, 1 H), 2.40
(m, 1 H), 1.94 (m, 1 H), 1.80–1.71 (m, 3 H). 13C NMR
(CDCl3, 100 MHz): d = 143.8 (s), 139.5 (s), 128.8 (d), 128.7
(d), 128.6 (d), 128.4 (d), 128.4 (d), 128.3 (d), 128.3 (d),
127.1 (d), 127.0 (d), 126.2 (d), 75.3 (d), 70.2 (d), 61.2 (t),
54.3 (t), 29.4 (t), 24.3 (t). MS: m/z (%) = 160 (100)[M+· –
[PhCH2 ].
+
(17) Langlois et al. have shown that the ring expansion of
substituted pyrrolidinols 3b using TFAA (1.5 equiv), Et3N
(3 equiv), in refluxing THF for 44 h, led to the ring-expanded
compound 5 in 22% yield, together with the starting
material, see: Calvez, O.; Chiaroni, A.; Langlois, N.
Tetrahedron Lett. 1998, 39, 9447.
(18) For a related rearrangement under different conditions, see:
Lee, J.; Hoang, T.; Lewis, S.; Weissman, S. A.; Askin, D.;
Volante, R. P.; Reider, P. J. Tetrahedron Lett. 2001, 42,
6223.
CHOHPh·], 91 (71) [PhCH2 ].
+
Compound 3b:17,20b Rf = 0.2 (EtOAc–PE, 8:2); [a]D20 –54 (c
1, CHCl3). IR (neat): 3620, 2940, 2820, 1496, 1457 cm–1. 1H
NMR (CDCl3, 400 MHz): d = 7.41–7.19 (m, 10 H), 4.89 (d,
J = 3.1 Hz, 1 H), 4.18 (d, J = 12.7 Hz, 1 H), 3.46 (d, J = 12.7
Hz, 1 H), 3.05 (m, 1 H), 2.89 (m, 1 H), 2.33 (dd, J = 17, 8.1
Hz, 1 H), 1.73 (m, 1 H), 1.65–1.56 (m, 2 H), 1.32 (m, 1 H).
13C NMR (CDCl3, 100 MHz): d = 141.5 (s), 139.1 (s), 128.8
(d), 128.6 (d), 128.4 (d), 128.3 (d), 128.1 (d), 127.6 (d),
(19) (a) Liu, L.-X.; Ruan, Y.-P.; Guo, Z.-Q.; Huang, P.-Q. J. Org.
Chem. 2004, 69, 6001. (b) Takahashi, K.; Nakano, H.;
Fujita, R. Tetrahedron Lett. 2005, 46, 8927.
(20) (a) Calvez, O.; Langlois, N. Tetrahedron Lett. 1999, 40,
7099. (b) Calvez, O. PhD Dissertation; Université Paris XI
Orsay: France, 2001.
(21) Haddad, M.; Larchevêque, M. Tetrahedron: Asymmetry
1999, 10, 4231.
Synlett 2009, No. 13, 2157–2161 © Thieme Stuttgart · New York

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