From aspartic acid to dihydropyridone-2-carboxylates: Access to enantiopure 6-substituted 4-oxo- and 4-hydroxypipecolic acid derivatives

Article abstract of DOI:10.1002/ejoc.201300812

We describe a method that starts from a protected (S)-aspartic acid and employs a gold-catalyzed cyclization to give enantiopure dihydropyridone 2-carboxylates, which are then converted into 6-substituted 4-oxo- and 4-hydroxypipecolic acid derivatives. Th

Full text of DOI:10.1002/ejoc.201300812

FULL PAPER
DOI: 10.1002/ejoc.201300812
From Aspartic Acid to Dihydropyridone-2-carboxylates: Access to Enantiopure
6-Substituted 4-Oxo- and 4-Hydroxypipecolic Acid Derivatives
[
a]
[a]
[b]
[a]
[a]
Huy-Dinh Vu, Jacques Renault,* Loïc Toupet, Philippe Uriac, and Nicolas Gouault
Keywords: Amino acids / Nitrogen heterocycles / Gold / Cyclization / Reduction / Diastereoselectivity
We describe a method that starts from a protected (S)-as-
partic acid and employs a gold-catalyzed cyclization to give
enantiopure dihydropyridone 2-carboxylates, which are then
converted into 6-substituted 4-oxo- and 4-hydroxypipecolic
acid derivatives. Thus, the lateral chain carboxylic acid of a
commercially available, protected (S)-aspartic acid forms a
Weinreb amide, which is then converted into an ynone fol-
lowed by a gold-catalyzed cyclization to furnish enantiopure
enaminones in high yields. The steric hindrance from the
protecting group was revealed as an efficient guide for the
selectivity of the reduction reactions. Thus, classical methods
that use palladium or sodium borohydride afford various
enantiopure 6-substituted 4-oxo- and 4-hydroxypipecolic
acid derivatives. In these cases, the substituents have an all-
cis configuration, whereas a Luche reduction furnishes the
2,4-trans analogues. In the case of the 6-unsubstituted en-
aminone, the 1,4-addition of a Grignard reagent furnishes
the 2,6-trans compound. All 6-substituted 4-hydroxy- and 4-
oxopipecolic derivatives were obtained in good yields. The
diastereoselectivity for most of the reactions and the ease of
separation of the diastereomers, in a few cases, render this
method applicable for gram-scale synthesis.
though this strategy is possible through the ring expansion
of a cyclic amino acid such as a proline derivative,[ the
Introduction
3]
Pipecolic acid Ϫ a nonproteinogenic α-amino acid Ϫ and most general method consists of the cyclization of a suitably
its derivatives are important components of natural and functionalized side chain of an amino acid derivative into
[1]
synthetic pharmacologically active molecules. In a recent a six-membered ring. In this case, the starting materials
[
2]
[4]
[5]
[6]
review, Cant and Sutherland recounted the various ways could be serine, homoserine, allysine ethylene acetal,
[
7]
[8]
to access enantiopure pipecolic acid derivatives and pointed glutamic acid, or aspartic acid. In the latter case, a
out their biological characteristics. Among the main strate- Horner–Wadsworth–Emmons reaction of a protected as-
gies, which include chiral pool approaches, asymmetric re- partic phosphonate ester afforded various (E)-enones that
actions, and chemoenzymatic methods, the use of the chiral underwent one-pot reactions to give 6-substituted-4-oxo-l-
pool from α-amino acids is the most common option. Al- pipecolic acids (see Scheme 1). The stereochemistry of the
Scheme 1. Previous routes to pipecolate derivatives from aspartic acid (Tr = triphenylmethyl).
carboxylate at C-2 and the substituent at C-6 could be pre-
[
a] Produits Naturels, Synthèse et Chimie Médicinale, UMR 6226,
Sciences Chimiques de Rennes, Université de Rennes 1,
[
8b]
dominantly cis
or trans depending on the one-pot reac-
[
8a]
2
Avenue du Pr Léon Bernard, 35043 Rennes Cedex, France
tion conditions.
Herein, we present a gold-catalyzed cyclization of an
E-mail: jacques.renault@univ-rennes1.fr
Homepage: http://www.scienceschimiques.univ-rennes.fr
[
b] UMR 6251, Institut de Physique de Rennes, Université de ynone followed by stereoselective reduction reactions to
Rennes 1,
access a full panel of cis and trans 4-oxo- and 4-hydroxy-
pipecolic acid derivatives as single stereoisomers. Starting
from (S)-aspartic acid, we envisage a strategy that involves
2
63 Avenue du Général Leclerc, 35052 Rennes Cedex, France
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.201300812.
Eur. J. Org. Chem. 2013, 6677–6686
© 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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H.-D. Vu, J. Renault, L. Toupet, P. Uriac, N. Gouault
FULL PAPER
Scheme 2. Our present work.
the formation of ynones 3 that contain various R groups treatment of the latter with lithium propylacetylide and lith-
alkyl, aryl, or hydrogen, see Scheme 2). These latter com- ium phenylacetylide furnished ynones 3a and 3b (77% and
(
[
9]
pounds were submitted to gold-catalyzed cyclizations that 89% yield, respectively), and the treatment of 2 with ethyn-
furnished enantiopure dihydropyridone 2-carboxylates 4. ylmagnesium bromide furnished 3c (81%).
Such asymmetric enaminones can be obtained in many
The cyclization reaction was then investigated. We re-
[
10,11]
ways
and are useful intermediates in transforma- cently reported the use of gold catalysts under various con-
[
12]
[13]
[14]
[21]
[22]
tions such as an N-functionalization, 1,2-additions,
ditions to access pyrrolinones, chromones, and piperi-
[
15]
[16]
[9]
1,4-additions,
electrophilic substitutions,
O-function- dines. The main criteria of our investigations focused on
We present various the purity and yield of the desired products under conve-
[
17]
[9,12]
alizations,
or enolate chemistry.
reduction reactions of the enaminone that were selectively nient conditions in comparison to the reaction duration.
directed to the alkene or ketone double bond. The huge We experimented with several gold catalysts as we had done
steric hindrance of both the tert-butyl ester and tert-butoxy- in previous works.[9,21,22] Good results (close to 85% for
carbonyl (Boc) protecting groups proved to be a very ef- 3a and 3b) were obtained with (triphenylphosphane)gold
ficient control element for these chemical transforma- chloride (PPh AuCl) and a silver cocatalyst [silver hexafluo-
3
[
18]
tions. Thus, the reductions Ϫ preceded by a 1,4-addition roantimonate (AgSbF ) or silver triflate (AgOTf)]. The best
6
when R = H Ϫ efficiently led to cis or trans 4-oxo- or 4- results were obtained by using (triphenylphosphane)gold(I)
hydroxypipecolic stereoisomers in good yields and with bis(trifluoromethanesulfonyl)imidate for 3a and 3b with
good stereoselectivities.
nearly quantitative yields in both cases. The gold-catalyzed
cyclization of 3c was more problematic, and because of de-
gradation as well as low reactivity, the best yield reached
only 33% by using (triphenylphosphane)gold triflate. A
Results and Discussion
[
12]
We started from commercially available, protected (S)- known alternative method for the cyclization of ynone 3c
aspartic acid 1. For a reliable check of the optical purity of was attempted. The amino group was deprotected in HCl/
the products, we also prepared the similar racemic mixture AcOEt. Under these conditions, the alkyne was converted
from unprotected (Ϯ)-aspartic acid according to known into a mixture of a chloroalkene and dichloroalkane, which
[
19]
methods and then subjected the compound to each step upon cyclization in alkaline conditions followed by repro-
of the chemical route. Amino acid 1 was converted into the tection furnished 4c in 75% yield from 3c (see Scheme 4).
corresponding Weinreb amide 2 (see Scheme 3) in a nearly These conditions were applied to compounds 3a and 3b,
[
20]
quantitative yield. According to reported procedures, the but partial racemization resulted, which urged us to use the
Scheme 3. Obtaining ynones 3a–3c and their gold-catalyzed cyclization.
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Access to Substituted Pipecolic Acid Derivatives
Scheme 4. Alternative cyclization of 3c.
gold-catalyzed cyclization. Thus, the best cyclization condi- 85% yield respectively). The axial orientation of the tert-
tions enabled us to produce efficiently a gram-scale amount butyloxycarbonyl group, which was observed in X-ray crys-
[
23]
1,3
of enantiopure compounds 4a–4c.
tal structure data, induced a strong 1,3-allylic strain (A
We started our reduction experiments by the conven- strain) with the N-Boc group (see Figure 1) and could ex-
tional hydrogenation of 4a and 4b with palladium as the plain the selectivity of the hydrogenation reactions.
catalyst under 10 bar of hydrogen pressure (see Scheme 5).
We also tried direct Raney nickel reductions of 4a and 4b
Under these conditions, the conversion went to completion, and observed that the hydrogenation of 4b gave 7b (85%),
and we obtained ketones cis-5a and -5b as single stereoiso- whereas the reduction of 4a afforded a 54:46 diastereomeric
1
mers (85% and 75% isolated yield, respectively). These lat- ratio, which was determined by H NMR analysis of the
ter compounds could be treated with sodium borohydride crude mixture [which was used for any dr (diastereomeric
to furnish mainly cis-alcohols 7a and 7b in good yields (84 ratio) reported in this paper]. After chromatography, we ob-
and 90%, respectively). An inversion of the steps in the re- tained 7a (50%) and 10a (32%). Although these latter com-
action route was also used to reduce 4a and 4b. The first pounds were easily separated, the method was considered
reaction efficiently led to 6a and 6b (82% and 90% yield, less effective than the previous ones in terms of yield and
respectively), which required protection from trace amounts ease of purification.
of acid that would lead to iminium ion formation and hy-
drolysis. Further reduction of 6a and 6b by treatment with one was also attempted.
A Luche reduction to achieve a 1,2-reduction of the en-
[
24]
In this case, the conversions
H in the presence of palladium led to 7a and 7b (80% and went to completion, and the complexation of the carbonyl
2
1
Scheme 5. Reductions of enones 4a and 4b (yields of isolated main compound, dr deduced from integration of H NMR signals of crude
reaction mixture).
Eur. J. Org. Chem. 2013, 6677–6686
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H.-D. Vu, J. Renault, L. Toupet, P. Uriac, N. Gouault
FULL PAPER
(–90 °C) with a balance of 90% of 8b and 10% of its dia-
stereomer 6b. When the reaction was performed at room
temperature, a lack of selectivity was noted to give an equi-
molar mixture of diastereomers 8b and 6b. As depicted in
Scheme 5, the hydrogenation of 8a in the presence of Pd/C
took place as expected and furnished the 2,6-cis isomer of
hydroxypipecolic derivative 10a. An X-ray crystal structure
[
23]
analysis of 11a
Ϫ a dinitrophenyl ester of 10a Ϫ con-
firmed its structure. Under similar conditions, 8b furnished
a diastereomeric mixture of 10b and 14b that could be easily
separated (55% and 36% isolated yields, respectively). This
lack of stereoselectivity could be explained by the steric hin-
drance from the 4-hydroxy group (see Figure 1).
Thus, we had failed to obtain 14a with the alkyl chain,
and we then concentrated on the synthesis of this trans ste-
reoisomer. We have envisioned an alternative strategy that
started from enone 4c, which was likely to undergo a 1,4-
addition with a Grignard reagent. In this case, the steric
hindrance at C-2 would guide the addition, as before for
the reduction of the double bond, to give the opposite 2,6-
trans stereoisomer. This reaction, which was favored by the
[
27]
use of an organocopper intermediate,
was carried out
with n-propylmagnesium chloride to afford 12a in a satis-
factory yield (70%, see Scheme 6). Similar attempts using
phenylmagnesium bromide failed to achieve a 1,2-addition
and then dehydration. The reduction of 12a was performed
at various temperatures with little influence on the ratio of
13a and 14a (60:40 at room temperature and 66:34 at
–
90 °C). In contrast, in the presence of CeCl and NaBH4
3
at –90 °C, the reduction mainly led to 14a. In any case, the
conversion rate of these reactions Ϫ close to 100% Ϫ ren-
ders them convenient for preparative methods.
In any of the reduction and 1,4-addition reactions, op-
Figure 1. ORTEP drawings of the X-ray crystal structures of 4b tical purity Ϫ versus racemic compounds Ϫ was checked by
and 8b.
chiral HPLC analysis or experiments using chiral europium
complexes (see Supporting Information). The absolute con-
group with CeCl occurred anti to the carboxylic ester of figurations for the compounds, which were unambiguously
3
enone 4a and 4b to allow for an axial hydride attack at the assessed by using X-ray crystallographic data of com-
more hindered carbonyl face.[ As in the case of com- pounds 4b, 7b, 8b, and 11a
25]
[23]
and by examining the H
1
pounds 6a and 6b, the stability of enol 8a was sensitive to NMR coupling constants, were consistent with the litera-
[
28]
the presence of trace amounts of acid, which rapidly hy- ture.
drolyzed it into 9a.
The results emphasize the importance of the ef-
[
26]
In the case of the 6-phenyl-substi- ficient preparation of stereopure dihydropyridone 2-carb-
tuted 4b, stereoisomer 8b was obtained at low temperature oxylate 4 in our gold-catalyzed cyclization.
1
Scheme 6. Preparation and reduction of 12a (yields of isolated main compound, dr deduced from integration of H NMR signals of
crude reaction mixture).
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Access to Substituted Pipecolic Acid Derivatives
Scheme 7. Deprotection examples of 10.
Finally, we checked the convenience of the deprotection gel chromatography (dichloromethane/ethyl acetate, 8:2) to yield a
f
colorless oil (5.16 g, 92%); R = 0.80 (dichloromethane/ethyl acet-
of compound 10a (see Scheme 7). Using different durations
of reaction time and concentrations of HCl in ethyl acetate
afforded complete or partial removal of the protecting
groups to yield 15a and 16a as hydrochloride salts that
could be converted into the corresponding amine 17a.
2
5
1
ate, 7:3). [α]
CDCl ): δ = 5.70 (d, J = 8.8 Hz, 1 H), 4.45 (dt, J = 8.8 Hz, J =
.2 Hz, 1 H), 3.70 (s, 3 H), 3.14 (m, 4 H), 2.87 (dd, J = 17.1 Hz, J
D 3
= –12.3 (c = 1, CH OH). H NMR (300 MHz,
3
4
=
1
3
4.0 Hz, 2 H), 1.46 (m, 18 H) ppm. C NMR (75 MHz, CDCl
3
):
δ = 171.7, 170.5, 155.7, 81.6, 79.4, 61.2, 50.4, 34.7, 32.0, 28.3,
2
1
3
7.9 ppm. IR (neat): ν˜ = 3425, 2974, 1712, 1661, 1487, 1366,
–
1
+
152 cm . HRMS (ESI): calcd. for C15
55.1845; found 355.1847.
28 2 6
H N O Na [M + Na]
Conclusions
(
(
S)-tert-Butyl
2-(tert-Butoxycarbonylamino)-4-oxonon-5-ynoate
We have described a convenient route for commercially
available, protected aspartic acid to be converted into
ynones, which efficiently underwent a gold-catalyzed cycli-
zation to furnish enantiopure dihydropyridone 2-carboxyl-
ates. These cyclic enaminones were revealed as key interme-
diates to undergo stereocontrolled conversions into various
3a): To a –78 °C solution of pent-1-yne (5.1 g, 7.4 mL, 75.0 mmol)
in anhydrous tetrahydrofuran (THF, 80 mL) was slowly added a
solution of nBuLi (2.5 m in hexane, 18.0 mL, 45.0 mmol). The mix-
ture was stirred for 45 min and then added dropwise to a –78 °C
solution of Weinreb amide 2 (5.0 g, 14.7 mmol) in dry THF
(
120 mL). The reaction mixture was stirred at –78 °C for 1 h and
then at –20 °C for 2 h. An aqueous solution of K HPO (1 m,
that may be components of potentially biologically active 50 mL) was added, and the mixture was extracted with diethyl ether
6-substituted 4-hydroxy- or 4-oxopipecolic acid derivatives
2
4
[
2]
compounds. This method Ϫ also feasible from the corre- (3ϫ 100 mL). The combine organic layers were washed with brine
. After a filtration, the solution
sponding (R)-amino acid Ϫ demonstrated good yields and (4ϫ 100 mL) and dried with MgSO
4
was concentrated under vacuum and chromatographed over silica
gel (petroleum ether/diethyl ether, 8:2) to yield a light yellow oil
(
easy operative conditions, which rendered it very convenient
for the preparation of gram-scale amounts of most of the
described compounds.
2
5
3.85 g, 77%); R
f D
= 0.70 (petroleum ether/diethyl ether, 6:4). [α]
1
=
–4.8 (c = 1, CH OH). H NMR (300 MHz, CDCl ): δ = 5.39 (d,
3
3
J = 8.6 Hz, 1 H), 4.44 (dt, J = 8.6 Hz, J = 4.5 Hz, 1 H), 3.21 (dd,
J = 17.8 Hz, J = 4.6 Hz, 1 H), 3.03 (dd, J = 17.8 Hz, J = 4.6 Hz,
Experimental Section
1
2
H), 2.35 (t, J = 7.1 Hz, 3 H), 1.62 (sext, J = 7.1 Hz, J = 7.3 Hz,
1
3
H), 1.45 (s, 18 H), 1.02 (t, J = 7.3 Hz, 3 H) ppm. C NMR
): δ = 183.9, 168.9, 154.5, 94.7, 81.3, 79.6, 78.8,
49.0, 46.5, 27.3, 26.8, 20.1, 19.9, 12.5 ppm. IR (neat): ν˜ = 3366,
General Methods: All reagents of high quality were purchased from
(75 MHz, CDCl
3
commercial suppliers and used without further purification or were
[
29]
The 1H and C NMR spectroscopic data
13
purified and dried.
were recorded at either 300 or 400 MHz and either 75, 100, or
25 MHz, respectively (using TMS as an internal standard). The δ
–
1
2974, 2214, 1716, 1675, 1495, 1366, 1148 cm . HRMS (ESI): calcd.
for C18
H29NO
5
Na [M + Na]+ 362.1943; found 362.1946.
1
values are given in parts per million (ppm), and the coupling con-
stants (J values) are given in Hertz (Hz). The multiplicity of the
signals is reported as s (singlet), d (doublet), t (triplet), q (quadru-
plet), m (multiplet), and br. s (broad singlet). HRMS analyses were
obtained using a Q-TOF, TOF (time-of-flight), TOF-Q, or an Or-
bitrap instrument for ESI. Thin layer chromatography was per-
formed with precoated silica gel plate (0.2 mm thickness).
(S)-tert-Butyl 2-(tert-Butoxycarbonylamino)-4-oxo-6-phenylhex-5-
ynoate (3b): Compound 3b was obtained from phenylacetylene
(7.66 g, 8.24 mL, 75.0 mmol) by the procedure described for 3a.
Purification over silica (cyclohexane/diethyl ether, 8:2) yielded a
light yellow oil (5.0 g, 89%); R = 0.70 (cyclohexane/diethyl ether,
f
2
5
1
7:3). [α] = –3.8 (c = 1, CH OH). H NMR (300 MHz, CDCl ): δ
D
3
3
= 7.58 (m, 2 H), 7.47 (m, 1 H), 7.39 (m, 2 H), 5.44 (d, J = 8.3 Hz,
H), 4.51 (dt, J = 8.3 Hz, J = 4.6 Hz, 1 H), 3.33 (dd, J = 17.9 Hz,
J = 4.6 Hz, 1 H), 3.18 (dd, J = 17.9 Hz, J = 4.6 Hz, 1 H), 1.46 (m,
1
(S)-tert-Butyl
2-(tert-Butoxycarbonylamino)-4-[methoxy(methyl)-
amino]-4-oxobutanoate (2): A mixture of (S)-4-tert-butoxy-3-(tert-
butoxycarbonylamino)-4-oxobutanoic acid (1, 4.85 g, 16.8 mmol),
N,O-dimethylhydroxyamine hydrochloride (2.29 g, 23.5 mmol), and
TBTU [O-(1H-benzotriazol-1-yl)-N,N,NЈ,NЈ-tetramethyluronium
tetrafluoroborate, 5.94 g, 18.5 mmol] was stirred in N,N-dimethyl-
formamide (DMF, 20 mL) at 0 °C. DIEA (diisopropylethylamine,
1
3
1
1
2
1
3
8 H) ppm. C NMR (75 MHz, CDCl ): δ = 184.7, 169.8, 155.5,
33.2, 131.0, 128.7, 119.6, 92.0, 87.4, 82.5, 79.9, 50.2, 47.5, 28.3,
7.9 ppm. IR (neat): ν˜ = 3368, 2974, 2201, 1715, 1669, 1489, 1366,
–
1
154, 1145, 1086, 757 cm . HRMS (ESI): calcd. for C21
H27NO
5
Na
[
M + Na]+ 396.1787; found 396.1786.
5
.43 g, 7.26 mL, 42.0 mmol) was then added dropwise. The mixture
was stirred at room temperature for 3 h. An aqueous solution of
NaHSO (1 m, 25 mL) was then added, and the mixture was ex-
tracted with ethyl acetate (3ϫ 50 mL). The combined organic lay-
ers were then washed with brine (3ϫ 50 mL), dried with MgSO
and concentrated under vacuum. The residue was purified by silica
(S)-tert-Butyl
2-(tert-Butoxycarbonylamino)-4-oxohex-5-ynoate
(3c): To Weinreb amide 2 (3.33 g, 10.0 mmol) was added ethynyl-
magnesium bromide (0.5 m solution in THF, 100 mL, 50 mmol),
and the mixture was stirred for 12 h at room temperature. A 10%
aqueous solution of HCl was poured into the reaction mixture that
was then extracted with diethyl ether (3ϫ 100 mL). The combined
4
4
,
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H.-D. Vu, J. Renault, L. Toupet, P. Uriac, N. Gouault
FULL PAPER
organic layers were washed with brine, dried with MgSO
and concentrated under vacuum. The crude residue was chromato-
graphed over silica gel (petroleum ether/diethyl ether, 5:5) to yield
4
, filtered,
mediates that were washed with diethyl ether (3ϫ 5 mL). The pre-
cipitate was then dissolved in methanol (20 mL), and DIEA (5 mL)
was added. The mixture was allowed to react at room temperature
for 12 h and then concentrated under vacuum. The residue was
diluted in diethyl ether (50 mL) and filtered. The filtrate was con-
centrated under vacuum, and the residue was dissolved in dichloro-
f
a white solid (2.41 g, 81%); m.p. 89–90 °C. R = 0.80 (petroleum
ether/diethyl ether, 4:6). [α]2
5
1
D
3
= –18.8 (c = 1, CH OH). H NMR
(
300 MHz, CDCl ): δ = 5.37 (d, J = 8.1 Hz, 1 H), 4.47 (m, 1 H),
3
3
1
.31 (s, 1 H), 3.24 (dd, J = 17.9 Hz, J = 4.5 Hz, 1 H), 3.09 (dd, J = methane (30 mL). To this solution were added Boc
7.9 Hz, J = 4.9 Hz, 1 H), 1.45 (s, 18 H) ppm. 13C NMR (75 MHz,
8.58 mmol), DIEA (1. 48 g, 11.4 mmol), and 4-(dimethylamino)
): δ = 184.2, 169.6, 155.4, 82.7, 80.9, 80.0, 79.7, 49.9, 47.6, pyridine (DMAP, 1.05 g, 8.58 mmol), and the mixture was heated
8.3, 27.8 ppm. IR (KBr): ν˜ = 3366, 3245, 2978, 2092, 1686, 1497, at 40 °C for 3 h and then diluted with CH Cl (80 mL). The mix-
2
O (1.87 g,
CDCl
2
1
3
2
2
–1
366, 1155 cm . HRMS (ESI): calcd. for C15
H23NO
5
Na [M +
ture was washed successively with aqueous HCl (1 n solution, 2ϫ
50 mL), aqueous NaOH (1 n solution, 2ϫ 50 mL), and brine (3ϫ
+
Na] 320.1474; found 320.1472.
S)-Di-tert-Butyl 4-Oxo-6-propyl-3,4-dihydropyridine-1,2(2H)-di-
carboxylate (4a): To a solution of ynone 3a (3.20 g, 9.4 mmol) in
,2-dichloroethane (1,2-DCE, 45 mL) was added (triphenylphos-
phane)gold(I) bis(trifluoromethanesulfonyl)imidate (175 mg,
.5 mol-%). The solution was stirred at room temperature for 3 h
5
0 mL). The organic layer was concentrated under vacuum, and
the crude product was chromatographed (petroleum ether/diethyl
ether, 7:3) to yield a light yellow oil (1.28 g, 75%); R = 0.45 (petro-
(
f
1
2
5
1
leum ether/diethyl ether, 6:4). [α]
NMR (300 MHz, CDCl , 296 K): δ = 7.96 (d, J = 7.7 Hz, 0.5 H),
.80 (d, J = 6.9 Hz, 0.5 H), 5.31 (m, 1 H), 5.05 (m, 0.5 H), 4.90
D 3
= +41.8 (c = 1, CH OH). H
3
2
7
and then filtered through Celite. The filtrate was concentrated un-
der vacuum, and the residue was chromatographed over silica gel
1
(
m, 0.5 H), 2.95 (m, 2 H), 1.54 (s, 9 H), 1.43 (s, 9 H) ppm. H
3
NMR (400 MHz, CDCl , 328 K): δ = 7.86 (br. s, 1 H), 5.29 (d, J
(
(
=
petroleum ether/diethyl ether, 6:4) to yield a light yellow oil
2
5
= 8.1 Hz, 1 H), 4.97 (br. s, 1 H), 2.92 (d, J = 16.9 Hz, 1 H), 2.83
(dd, J = 16.6 Hz, J = 7.6 Hz, 1 H), 1.54 (s, 9 H) 1.44 (s, 9 H) ppm.
3.10 g, 97%); R
–138.1 (c = 1, CH
s, 1 H), 5.08 (dd, J = 6.7 Hz, J = 2.0 Hz, 1 H), 2.99 (dddd, J =
f D
= 0.55 (petroleum ether/diethyl ether, 5:5). [α]
1
3 6 6
OH). H NMR (400 MHz, C D ): δ = 5.41
1
3
C NMR (100 MHz, CDCl
3
, 328 K): δ = 190.8, 168.3, 151.5,
(
1
2
43.5, 106.8, 83.9, 83.2, 55.68, 37.9, 28.1, 28.0 ppm. IR (neat): ν˜ =
977, 2933, 1731, 1673, 1304, 1153 cm . HRMS (ESI): calcd. for
Na [M + Na]+ 320.1474; found 320.1475.
1
1
6
5.1 Hz, J = 9.0 Hz, J = 6.0 Hz, J = 0.8 Hz, 1 H), 2.89 (ddd, J =
7.0 Hz, J = 2.0 Hz, J = 1.4 Hz, 1 H), 2.30 (dd, J = 17.0 Hz, J =
.7 Hz, 1 H), 2.23 (ddd, J = 15.1 Hz, J = 9.1 Hz, J = 6.6 Hz, 1
–
1
15 5
C H23NO
13
H) ppm. C NMR (100 MHz, C
6
D
6
): δ = 190.3, 168.9, 159.4,
(2S,6S)-Di-tert-butyl
4-Oxo-6-propylpiperidine-1,2-dicarboxylate
1
52.1, 112.0, 82.6, 82.1, 58.9, 39.0, 38.3, 27.9, 27.7, 21.9, 14.1 ppm.
(5a): To a solution of 4a (0.65 g, 1.91 mmol) in methanol (10 mL)
in an autoclave was added 10% Pd/C (300 mg), and the suspension
was stirred for 24 h under hydrogen (10 bar). The suspension was
filtered through Celite, and the solvent was evaporated under vac-
uum. The crude compound was chromatographed on silica gel (pe-
troleum ether/diethyl ether, 8:2) to yield a colorless oil (0.50 g,
–1
IR (neat): ν˜ = 2975, 1727, 1668, 1586, 1310, 1142 cm . HRMS
+
(
3
ESI): calcd. for C18
62.1943. C18 29NO
found C 64.02, H 8.59, N 4.17.
H29NO
5
Na [M + Na] 362.1943; found
H
5
(339.43): calcd. C 63.69, H 8.61, N 4.13;
(S)-Di-tert-butyl 4-Oxo-6-phenyl-3,4-dihydropyridine-1,2(2H)-di-
2
5
8
5%); R
f
= 0.80 (petroleum ether/diethyl ether, 5:5). [α]
D
= –62.0
, 295 K): δ =
.84 (t, 1 H), 4.51 (br. s, 1 H), 2.78 (dd, J = 16.5 Hz, J = 7.4 Hz,
H), 2.67 (dd, J = 16.5 Hz, J = 7.3 Hz, 2 H), 2.33 (dd, J = 16.3 Hz,
carboxylate (4b): A solution of ynone 3b (4.0 g, 10.7 mmol) in 1,2-
dichloroethane (60 mL) was treated with (triphenylphosphane)-
gold(I) bis(trifluoromethanesulfonyl)imidate (200 mg, 2.5 mol-%)
using the conditions previously described for 4a. The solution was
stirred at room temperature for 3 h, filtered through Celite, and
concentrated under vacuum. The residue was chromatographed
over silica gel (petroleum ether/diethyl ether, 8:2) to yield a white
1
(
c = 1, CH OH). H NMR (400 MHz, CD COCD
3
3
3
4
1
J = 2.7 Hz, 1 H), 1.70 (m, 1 H), 1.47 (m, 18 H), 1.40 (m, 3 H),
1
3
0
.93 (t, J = 7.2 Hz, 3 H) ppm. C NMR (100 MHz, CD
δ = 206.1, 171.7, 155.4, 81.8, 80.6, 55.5, 52.3, 44.3, 40.2, 38.9, 28.5,
8.1, 20.5, 14.2 ppm. IR (neat): ν˜ = 2974, 1728, 1694, 1392, 1366,
3 3
COCD ):
2
solid (3.79 g, 95%); m.p. 150–152 °C. R
f
= 0.90 (petroleum ether/
OH). 1H NMR
= –360.4 (c = 1, CH
3
–
1
+
diethyl ether, 4:6). [α]2
5
1149 cm . HRMS (ESI): calcd. for C18
H31NO
5
Na [M + Na]
(341.45): calcd. C 63.32, H
.15, N 4.10; found C 63.41, H 9.25, N 4.18.
D
3
9
64.2100; found 364.2098. C18H31NO
5
(300 MHz, CDCl
3
): δ = 7.55 (m, 2 H), 7.40 (m, 3 H), 5.58 (d, J =
1
.2 Hz, 1 H), 5.42 (dd, J = 6.2 Hz, J = 1.9 Hz, 1 H), 3.07 (ddd, J
=
=
17.6 Hz, J = 1.9 Hz, J = 1.2 Hz, 1 H), 2.93 (dd, J = 17.6 Hz, J
(2S,6R)-Di-tert-butyl 4-Oxo-6-phenylpiperidine-1,2-dicarboxylate
(5b): To a suspension of 4b (400 mg, 1.07 mmol) in methanol
6.2 Hz, 1 H), 1.45 (s, 9 H), 1.09 (s, 9 H) ppm. 13C NMR
(75 MHz, CDCl
3
): δ = 192.6, 168.8, 157.1, 152.3, 137.9, 129.9, (10 mL) were added 10% Pd/C (170 mg) and triethylamine
1
28.3, 127.0, 113.1, 83.3, 83.1, 58.1, 40.0, 28.0, 27.4 ppm. IR (KBr):
(3 drops). The suspension was stirred for 48 h at room temperature
under hydrogen (10 bar). The reaction mixture was filtered through
Celite, and the filtrate was evaporated under vacuum. The crude
residue was chromatographed over silica gel (petroleum ether/di-
ethyl ether, 6:4) to yield a white oil that crystallized (380 mg, 75%);
–1
ν˜ = 2974, 1731, 1704, 1667, 1592, 1159 cm . HRMS (ESI): calcd.
for C21 374.1968; found 374.1967.
H28NO
5
(
(
S)-Di-tert-butyl 4-Oxo-3,4-dihydropyridine-1,2(2H)-dicarboxylate
4c)
2
5
m.p. 96–97 °C. R
+2.4 (c = 1, CH
.51 (m, 2 H), 7.11 (m, 2 H), 7.01 (tt, J = 7.5 Hz, J = 1.3 Hz, 1
H), 5.14 (br. s, 1 H), 4.85 (br. s, 1 H), 2.74 (dd, J = 17.2 Hz, J =
.7 Hz, 1 H), 2.64 (dd, J = 17.5 Hz, J = 7.1 Hz, 1 H), 2.31 (dd, J
17.2 Hz, J = 5.3 Hz, 1 H), 2.28 (dd, J = 17.5 Hz, J = 5.9 Hz, 1
f D
= 0.65 (petroleum ether/diethyl ether, 6:4). [α]
Method A: To a solution of ynone 3c (1.10 g, 3.70 mmol) in 1,2-
dichloroethane (40 mL) was added (triphenylphosphane)gold tri-
flate (113 mg, 5 mol-%). The solution was stirred at 40 °C for 1 h,
filtered through Celite, and concentrated under vacuum. The resi-
due was chromatographed over silica gel (petroleum ether/diethyl
ether, 6:4) to yield a light yellow oil (0.36 g, 33%).
1
=
3 6 6
OH). H NMR (400 MHz, C D , 343 K): δ =
7
7
=
13
6 6
H), 1.29 (s, 9 H), 1.25 (s, 9 H) ppm. C NMR (100 MHz, C D ,
Method B: Ynone 3c (1.70 g, 5.72 mmol) was dissolved in a solu-
tion of HCl in ethyl acetate (3 m, 10 mL), and the reaction mixture
was left to react at room temperature for 30 min. The addition of
diethyl ether (10 mL) resulted in a precipitate of chlorinated inter-
343 K): δ = 203.4, 170.9, 155.6, 143.6, 128.6, 127.2, 126.7, 81.7,
80.8, 55.7, 55.4, 45.7, 41.0, 28.3, 27.9 ppm. IR (KBr): ν˜ = 2971,
–
1
1723, 1735, 1679, 1385, 1367, 1149 cm . HRMS (ESI): calcd. for
Na [M + Na]+ 398.1943; found 398.1941.
21 5
C H29NO
6682
www.eurjoc.org
© 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2013, 6677–6686

Access to Substituted Pipecolic Acid Derivatives
(
1
2S,4S)-Di-tert-butyl
4-Hydroxy-6-propyl-3,4-dihydropyridine-
H), 1.85 (m, 1 H), 1.59 (m, 1 H), 1.45 (m, 18 H), 1.44 (m, 4 H),
1
3
,2(2H)-dicarboxylate (6a): To a solution of 4a (339 mg, 1.0 mmol) 0.98 (t, J = 7.3 Hz, 3 H) ppm. C NMR (100 MHz, C D ): δ =
6 6
in methanol (10 mL) was added NaBH
tion was stirred for 3 h at room temperature, and then water
20 mL) was slowly added. The reaction mixture was extracted with
ethyl acetate (3ϫ 20 mL). The combined organic layers were dried
with MgSO and concentrated under vacuum. The residue was
purified over silica gel (petroleum ether/diethyl ether, 5:5) to yield
a white oil (0.280 g, 82%); R = 0.55 (petroleum ether/diethyl ether,
4
(76 mg, 2 mmol). The solu-
172.9, 155.4, 80.8, 79.3, 64.4, 52.1, 50.3, 39.1, 33.8, 32.9, 28.6, 28.1,
20.9, 14.3 ppm. IR (neat): ν˜ = 3466, 2973, 2931, 1746, 1670, 1365,
–
1
+
(
1075 cm . HRMS (ESI): calcd. for C18
366.2256; found 366.2256. C18 33NO (343.46): calcd. C 62.95, H
9.68, N 4.08; found C 63.16, H 9.77, N 4.11.
5
H33NO Na [M + Na]
H
5
4
(
2S,4R,6R)-Di-tert-butyl 4-Hydroxy-6-phenylpiperidine-1,2-dicarb-
f
oxylate (7b)
5
:5). [α]2
D 3
= –123.5 (c = 1, CH OH). H NMR (300 MHz,
5
1
CD
3
OD): δ = 5.05 (d, J = 3.7 Hz, 1 H), 4.66 (dd, J = 6.2 Hz, J = Method A: To a solution of 5b (0.200 g, 0.54 mmol) in methanol
(10 mL) was added NaBH (41 mg, 1.08 mmol) at 0 °C. The solu-
tion was stirred for 30 min and diluted with water (20 mL). The
5
1
.2 Hz, 1 H), 4.06 (m, 1 H), 2.83 (m, 1 H), 2.22 (m, 2 H), 2.09 (m,
4
H), 1.55 (m, 2 H), 1.47 (m, 18 H), 0.95 (t, J = 7.4 Hz, 3 H) ppm.
1
3
C NMR (75 MHz, CD
2.5, 62.3, 55.8, 38.6, 36.0, 28.5, 28.3, 22.6, 14.4 ppm. IR (neat): ν˜
3
OD): δ = 172.1, 154.5, 141.0, 114.2, 82.6, mixture was extracted with ethyl acetate (3ϫ 20 mL). The com-
bined organic layers were washed with brine (20 mL). The solution
was dried with MgSO and concentrated under vacuum. The resi-
8
=
–1
3478, 2973, 1697, 1365, 1156, 1108 cm . HRMS (ESI): calcd.
4
+
for C18
H31NO
5
Na [M + Na] 364.2100; found 364.2102.
due was chromatographed over silica gel (dichloromethane/ethyl
acetate, 8:2) to yield a colorless oil (0.18 g, 90%).
(
(
2S,4S)-Di-tert-butyl 4-Hydroxy-6-phenyl-3,4-dihydropyridine-1,2-
2H)-dicarboxylate (6b): To a solution of 4b (1.0 g, 2.68 mmol) in Method B: Enol 6b (0.200 g, 0.54 mmol) was dissolved in methanol
methanol (20 mL) was added NaBH
solution was stirred for 1 h at room temperature, and then water
50 mL) was slowly added. The reaction mixture was extracted with
ethyl acetate (3ϫ 20 mL). The combined organic layers were dried
with MgSO and concentrated under vacuum. The residue was
purified over silica gel (petroleum ether/diethyl ether, 5:5) to yield
a white solid (0.90 g, 90%); m.p. 116–118 °C. R = 0.70 (petroleum
4
(0.20 g, 5.36 mmol). The
(10 mL), and 10% Pd/C (100 mg) was added. The suspension was
stirred for 48 h under hydrogen (10 bar). The suspension was fil-
tered. The filtrate was concentrated under vacuum, and the crude
residue was purified over silica gel (petroleum ether/diethyl ether,
5:5) to yield a white solid (0.17 g, 85%).
(
4
Method C: Enone 4b (0.374 g, 1 mmol) was dissolved in methanol
f
(
20 mL), and Raney Ni (50 mg) was added. The suspension was
ether/diethyl ether, 4:6). [α]2
300 MHz, C ): δ = 7.64 (m, 2 H), 7.12 (m, 3 H), 5.37 (m, 2 H),
.92 (m, 1 H), 2.39 (ddt, J = 14.6 Hz, J = 3.1 Hz, J = 1.4 Hz, 2
H), 1.86 (dt, J = 14.6 Hz, J = 5.8 Hz, 1 H), 1.32 (s, 9 H), 1.06 (s,
5
1
D
3
= –143.3 (c = 1, CH OH). H NMR
stirred at room temperature for 24 h under hydrogen (1 bar). The
suspension was filtered. The filtrate was concentrated under vac-
uum, and the crude residue was purified over silica gel (petroleum
ether/diethyl ether, 5:5) to yield a white solid (0.321 g, 85%); m.p.
(
6 6
D
3
9
1
H) ppm. 13C NMR (75 MHz, C
39.7, 126.8, 117.6, 81.9, 80.9, 62.1, 53.9, 35.6, 27.9, 27.6 ppm. IR
6 6
D ): δ = 171.5, 153.4, 141.0,
2
5
1
24 °C. R
f
= 0.65 (petroleum ether/diethyl ether, 5:5). [α]
D
= +0.4
): δ = 7.69 (m, 2 H),
.23 (m, 2 H), 7.06 (m, 1 H), 4.73 (t, J = 6.7 Hz, 1 H), 4.58 (dd, J
1
(
c = 1, CH OH). H NMR (300 MHz, C D
3
6
6
–
1
(KBr): ν˜ = 3478, 2974, 1736, 1672, 1368, 1160, 1125, 1066 cm .
7
+
HRMS (ESI): calcd. for C21
98.1938.
5
H29NO Na [M + Na] 398.1943; found
=
9
10.3 Hz, J = 5.5 Hz, 1 H), 3.51 (m, 1 H), 1.83 (m, 4 H), 1.39 (s,
H), 1.22 (s, 9 H) ppm. C NMR (75 MHz, C D ): δ = 173.0,
6 6
3
1
3
(2S,4R,6S)-Di-tert-butyl 4-Hydroxy-6-propylpiperidine-1,2-dicarb-
155.9, 146.6, 126.5, 81.0, 80.0, 64.3, 56.7, 55.5, 40.8, 35.3, 28.1,
28.0 ppm. IR (neat): ν = 3444, 2972, 1733, 1661, 1369, 1229, 1152,
oxylate (7a)
˜
–
1
1
5
133, 698 cm . HRMS (ESI): calcd. for C21H31NO Na [M +
Method A: To a solution of 5a (0.45 g, 1.32 mmol) in methanol
+
Na] 400.2100; found 400.2099.
4
(10 mL) was added NaBH (100 mg, 2.64 mmol) at 0 °C. The solu-
tion was stirred for 30 min and diluted with water (20 mL). The
mixture was extracted with ethyl acetate (3ϫ 20 mL). The com-
bined organic layers were washed with brine (20 mL). The solution
was dried with MgSO and concentrated under vacuum, The resi-
4
due was chromatographed over silica gel (dichloromethane/ethyl
acetate, 8:2) to yield a colorless oil (0.38 g, 84%).
(
(
2S,4R)-Di-tert-butyl 4-Hydroxy-6-propyl-3,4-dihydropyridine-1,2-
2H)-dicarboxylate (8a): A mixture of 4a (1.0 g, 2.95 mmol) and
cerium trichloride (CeCl
3
2
·7H O, 1.43 g, 3.83 mmol) in methanol
(
20 mL) was cooled to 0 °C and stirred for 30 min. After the ad-
4
dition of NaBH (0.22 g, 5.89 mmol), the solution was stirred for
1
h, and then water (50 mL) was added. The mixture was extracted
with ethyl acetate (3ϫ 50 mL). The combined organic layers were
dried with MgSO and concentrated under vacuum to yield a white
solid (0.915 g, 91%) that was sufficiently pure and used without
further chromatography; m.p. 102–104 °C. R = 0.8 (dichlorometh-
Method B: Enol 6a (0.45 g, 1.32 mmol) was dissolved in methanol
(10 mL), and 10% Pd/C (210 mg) and triethylamine (3 drops) were
4
added. The suspension was stirred for 24 h at room temperature
under hydrogen (8 bar). The suspension was filtered through Celite,
and the filtrate was concentrated under vacuum. The crude residue
was purified over silica gel (dichloromethane/ethyl acetate, 8:2) to
yield a colorless oil (0.36 g, 80%).
f
2
5
1
ane/ethyl acetate, 8:2). [α]
(400 MHz, CD OD): δ = 4.88 (ddd, J = 3.1 Hz, J = 1.5 Hz, J =
1.0 Hz, 1 H), 4.77 (dd, J = 5.4 Hz, J = 4.1 Hz, 1 H), 4.20 (dddd, J
9.7 Hz, J = 6.2 Hz, J = 3.1 Hz, 1 H), 2.72 (m, J = 14.6 Hz, J =
.1 Hz, J = 1.0 Hz, 1 H), 2.39 (m, 2 H), 1.80 (m, 1 H), 1.49 (m, 2
D 3
= –24.5 (c = 1, CH OH). H NMR
3
=
8
Method C: Enone 4a (0.374 g, 1 mmol) was dissolved in methanol
(20 mL), and Raney Ni (50 mg) was added. The suspension was
1
3
H), 1.42 (m, 18 H), 0.93 (t, J = 7.4 Hz, 3 H) ppm. C NMR
100 MHz, CD OD): δ = 172.0, 154.5, 141.1, 114.3, 82.9, 82.7, 63.0,
8.6, 38.6, 34.6, 28.5, 28.3, 22.7, 14.2 ppm. IR (KBr): ν˜ = 3434,
stirred at room temperature for 24 h under hydrogen (1 bar). The
suspension was filtered. The filtrate was concentrated under vac-
uum, and the crude residue was purified over silica gel (dichloro-
methane/ethyl acetate, 8:2) to yield a colorless oil (0.172 g, 50%);
(
5
2
3
–
1
974, 2932, 1720, 1694, 1365, 1325, 1147 cm . HRMS (ESI): calcd.
for C18
, 323 K): δ = 4.82 (dd, J = (2S,4R)-Di-tert-butyl 4-Hydroxy-6-phenyl-3,4-dihydropyridine-1,2-
.6 Hz, J = 3.9 Hz, 1 H), 4.23 (m, 1 H), 3.62 (m, 1 H), 2.18 (dddd, (2H)-dicarboxylate (8b): A mixture of compound 4b (1.0 g,
J = 14.0 Hz, J = 4.1 Hz, J = 3.9 Hz, J = 1.6 Hz, 1 H), 2.03 (m, 1 2.68 mmol) and CeCl ·7H O (1.3 g, 3.48 mmol) in methanol
H31NO
5
Na [M + Na]+ 364.2100; found 364.2101.
25
f D
R = 0.60 (dichloromethane/ethyl acetate, 8:2). [α] = –14.8 (c = 1,
1
3 6 6
CH OH). H NMR (400 MHz, C D
6
3
2
Eur. J. Org. Chem. 2013, 6677–6686
© 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
6683

H.-D. Vu, J. Renault, L. Toupet, P. Uriac, N. Gouault
(300 MHz, C ): δ = 7.12 (m, 4 H), 7.02 (m, 1 H), 5.00 (m, 1 H),
FULL PAPER
(20 mL) at –90 °C was treated with NaBH
4
(0.2 g, 5.36 mmol) as
6 6
D
described for 8a. Purification by silica gel chromatography (petro-
4.93 (m, 1 H), 3.67 (m, 1 H), 2.40 (m, 1 H), 2.06 (m, 1 H), 1.68
leum ether/diethyl ether, 5:5) yielded a white solid (0.9 g, 90%);
(m, 1 H), 1.53 (m, 1 H), 1.38 (s, 9 H), 1.20 (s, 9 H), 1.07 (d, J =
1
3
m.p. 168–170 °C. R
[α] = –100.3 (c = 1, CH OH). H NMR (300 MHz, C D ): δ =
D 3 6 6
f
= 0.65 (petroleum ether/diethyl ether, 4:6).
4.9 Hz, 1 H) ppm. C NMR (75 MHz, C
6 6
D ): δ = 172.3, 156.9,
25
1
147.1, 128.5, 126.2, 125.7, 81.1, 79.9, 64.2, 57.7, 57.3, 43.8, 35.4,
–
1
7.66 (m, 2 H), 7.08 (m, 3 H), 5.39 (dd, J = 5.0 Hz, J = 4.4 Hz, 1 28.0 ppm. IR (neat): ν˜ = 3405, 2975, 1734, 1653, 1368, 1154 cm .
+
H), 5.13 (dd, J = 3.9 Hz, J = 0.8 Hz, 1 H), 4.41 (m, 1 H), 2.48 (m,
HRMS (ESI): calcd. for C21
5
H31NO Na [M + Na] 400.2100; found
1
9
1
2
1
H), 1.90 (ddd, J = 13.2 Hz, J = 9.2 Hz, J = 5.3 Hz, 1 H), 1.30 (s, 400.2098.
13
6 6
H), 1.08 (s, 9 H) ppm. C NMR (75 MHz, C D ): δ = 170.3,
53.7, 141.3, 141.1, 127.6, 126.6, 116.5, 81.4, 80.9, 63.2, 57.6, 34.8,
(
2S,4S,6S)-Di-tert-butyl 4-(3,5-Dinitrobenzoyloxy)-6-propylpiper-
idine-1,2-dicarboxylate (11a): To a solution of 10a (150 mg,
0.44 mmol) in CH Cl (3 mL) were added DMAP (5 mg,
7.9, 27.6 ppm. IR (KBr): ν˜ = 3407, 2974, 2973, 1742, 1671, 1654,
–1
2
2
5
365, 1154, 1052 cm . HRMS (ESI): calcd. for C21H29NO Na [M
+
0.04 mmol) and 3,5-dinitrobenzoic acid (172 mg, 0.81 mmol). The
solution was stirred at room temperature for 4 h. The reaction mix-
ture was extracted with ethyl acetate (3ϫ 15 mL). The combined
organic layers were washed with a 10% aqueous sodium carbonate
+
Na] 398.1943; found 398.1942.
(S)-tert-Butyl 2-(tert-Butoxycarbonylamino)-4-hydroxy-6-oxonon-
anoate (9a): White solid; m.p. 70 °C. R = 0.55 (dichloromethane/
ethyl acetate, 8:2). H NMR (300 MHz, CDCl
.6 Hz, 1 H), 4.21 (m, 2 H), 3.33 (br. s, 1 H), 2.66 (dd, J = 17.3 Hz,
f
1
3
): δ = 5.38 (d, J = solution (3ϫ 15 mL) and with brine (15 mL) and then concen-
trated under vacuum to yield a yellow solid that crystallized in
methanol (200 mg, 85%); m.p. 60 °C (dec). R = 0.40 (petroleum
6
J = 2.8 Hz, 1 H), 2.56 (dd, J = 17.3 Hz, J = 8.6 Hz, 1 H), 2.41 (t,
J = 7.4 Hz, 3 H), 1.89 (m, 2 H), 1.61 (m, 2 H), 1.46 (m, 18 H),
f
2
5
1
ether/diethyl ether, 6:4). [α]
D 3
= –16.6 (c = 1, CH OH). H NMR
0
2
2
1
3
.92 (t, J = 7.4 Hz, 3 H) ppm. 13C NMR (75 MHz, CDCl
11.8, 171.6, 155.6, 82.0, 79.8, 64.9, 51.9, 48.6, 45.5, 38.7, 28.3,
8.0, 17.0, 13.7 ppm. IR (KBr): ν˜ = 3380, 2982, 1705, 1498, 1370,
152 cm . HRMS (ESI): calcd. for C18
82.2206; found 382.2203.
3
): δ =
(300 MHz, CDCl ): δ = 9.23 (t, J = 2.1 Hz, 1 H), 9.14 (d, J =
3
2.1 Hz, 2 H), 5.41 (tt, J = 11.6 Hz, J = 4.1 Hz, 1 H), 5.01 (m, 1
H), 4.41 (m, 1 H), 2.74 (d, J = 12.0 Hz, 1 H), 2.18 (m, 1 H), 1.82
–1
H33NO
6
Na [M + Na]+ (m, 2 H), 1.67 (m, 2 H), 1.51–1.39 (m, 20 H), 0.97 (t, J = 7.1 Hz,
1
3
3 H) ppm. C NMR (75 MHz, CDCl
3
): δ = 170.8, 161.8, 154.8,
1
3
1
48.7, 134.1, 129.4, 122.4, 82.1, 80.4, 69.1, 53.2, 51.4, 35.4, 33.1,
(
2S,4S,6S)-Di-tert-butyl 4-Hydroxy-6-propylpiperidine-1,2-dicarb-
oxylate (10a): To a solution of 8a (0.73 g, 2.14 mmol) in methanol
10 mL) in an autoclave was added 10% Pd/C (340 mg), and the
1.2, 28.4, 27.9, 20.4, 13.9 ppm. IR (KBr): ν˜ = 2972, 1748, 1722,
–1
687, 1627, 1549, 1341, 1171, 1101 cm . HRMS (ESI): calcd. for
(
10Na [M + Na]+ 560.2220; found 560.2219.
C
25
H
35
N
3
O
suspension was stirred for 24 h under hydrogen (8 bar). The suspen-
sion was filtered through Celite, and the solvent was evaporated
under vacuum. The crude compound was chromatographed over
silica gel (dichloromethane/ethyl acetate, 8:2) to yield a white solid
(2S,6R)-Di-tert-butyl
(12a): To a –78 °C solution of CuBr·S(CH
anhydrous diethyl ether (8 mL) was added n-C
4-Oxo-6-propylpiperidine-1,2-dicarboxylate
(65 mg, 0.3 mmol) in
MgCl (2 m in
3 2
)
3
H
7
(
7
0.69 g, 94%); m.p. 70 °C. R
f
= 0.60 (dichloromethane/ethyl acetate,
THF, 1.4 mL, 288 mg, 2.8 mmol) dropwise. The mixture was stirred
for 15 min at the same temperature. A solution of enone 4c
:3). [α]2
5
= –29.5 (c = 1, CH
OH). H NMR (400 MHz, CD
1
OD):
D
3
3
δ = 4.82 (d, J = 6.0 Hz, 1 H), 4.25 (m, 1 H), 3.85 (tt, J = 11.4 Hz, (145 mg, 0.48 mmol) in anhydrous diethyl ether (2 mL) was then
J = 7.7 Hz, J = 3.9 Hz, 1 H), 2.48 (m, 1 H), 1.93 (m, 1 H), 1.59 added dropwise, and the mixture was allowed to react at –78 °C
m, 1 H), 1.47 (m, 18 H), 1.40 (m, 5 H), 0.94 (t, J = 7.1 Hz, 3 for 5 h. An aqueous saturated solution of NH Cl (10 mL) was
(
4
13
H) ppm. C NMR (100 MHz, CD
3
OD): δ = 172.7, 156.9, 82.7,
added, and the resulting mixture was extracted with diethyl ether
8
1.5, 62.3, 54.8, 53.3, 37.5, 37.1, 35.6, 28.7, 28.2, 21.6, 14.4 ppm.
(3ϫ 30 mL). The combined organic layers were washed with brine
(3ϫ 30 mL), dried with MgSO , and concentrated under vacuum.
4
–
1
IR (KBr): ν˜ = 3434, 2973, 1724, 1694, 1670, 1366, 1154, 1095 cm .
+
HRMS (ESI): calcd. for C18
66.2256.
H33NO
5
Na [M + Na] 366.2256; found
The crude residue was chromatographed over silica gel (petroleum
ether/diethyl ether, 7:3) to yield a white solid (133 mg, 70%); m.p.
3
2
5
9
+
5–98 °C. R
f D
= 0.60 (petroleum ether/diethyl ether, 7:3). [α] =
(2S,4S,6R)-Di-tert-butyl 4-Hydroxy-6-phenylpiperidine-1,2-dicarb-
1
103.5 (c = 1, CH OH). H NMR (400 MHz, C D , 328 K): δ =
3
6
6
oxylate (10b) and (2S,4S,6S)-Di-tert-butyl 4-Hydroxy-6-phenyl-
piperidine-1,2-dicarboxylate (14b): To a solution of 8b (0.55 g,
4
6
1
1
.55 (br. s, 1 H), 4.34 (br. s, 1 H), 2.91 (ddd, J = 17.2 Hz, J =
.4 Hz, J = 0.8 Hz, 1 H), 2.68 (d, J = 18.2 Hz, 1 H), 2.44 (dd, J =
8.2 Hz, J = 7.7 Hz, 1 H), 2.26 (dd, J = 17.2 Hz, J = 1.9 Hz, 1 H),
1.46 mmol) in methanol (10 mL) in an autoclave was added 10%
Pd/C (230 mg), and the suspension was stirred for 24 h under hy-
drogen (8 bar). The suspension was filtered, and the filtrate was
concentrated under vacuum. The crude residue was purified over
silica gel (petroleum ether/diethyl ether, 5:5) to yield the two stereo-
isomers 10b (300 mg, 55%) and 14b (200 mg, 36%). Data for 10b:
.54 (m, 1 H), 1.43 (s, 9 H), 1.27 (s, 9 H), 1.13 (m, 3 H), 0.76 (t, J
13
=
6 6
7.3 Hz, 3 H) ppm. C NMR (125 MHz, C D , 328 K): δ = 204.0,
1
1
72.0, 155.0, 81.6, 80.0, 55.2, 51.2, 42.4, 40.7, 39.9, 28.5, 27.9, 19.9,
–1
3.9 ppm. IR (KBr): ν˜ = 2961, 2930, 1705, 1366, 1154 cm . HRMS
Na [M + Na]+ 364.2100; found
(
ESI): calcd. for C18H31NO
5
White solid (55%); m.p. 157 °C. R
f
= 0.45 (petroleum ether/diethyl
= +5.0 (c = 1, CH
OH). 1H NMR (300 MHz,
): δ = 7.63 (m, 2 H), 7.18 (m, 2 H), 7.04 (m, 1 H), 5.40 (m, 1
364.2103.
ether, 5:5). [α]2
5
D
3
C
6
D
6
(2S,4R,6R)-Di-tert-butyl 4-Hydroxy-6-propylpiperidine-1,2-dicarb-
oxylate (13a): Ketone 12a (341 mg, 1.0 mmol) was dissolved in
MeOH (10 mL), and the temperature was cooled to –90 °C. So-
H), 4.95 (t, J = 5.8 Hz, 1 H), 3.93 (m, 1 H), 2.28 (dt, J = 13.5 Hz,
J = 5.8 Hz, 1 H), 2.14 (dt, J = 14.2 Hz, J = 5.5 Hz, 1 H), 1.59 (m,
1
H), 1.51 (m, 1 H), 1.35 (s, 9 H), 1.27 (s, 9 H), 0.93 (m, 1 H) ppm.
C NMR (75 MHz, C D
6 6
dium borohydride (NaBH
): δ = 171.7, 155.9, 144.3, 127.3, 126.7, solution was stirred for 1 h. Water (20 mL) was then poured into
0.6, 80.0, 61.8, 53.7, 53.3, 37.9, 34.6, 28.3, 27.8 ppm. IR (KBr): ν˜ the reaction mixture that was extracted with ethyl acetate (3ϫ
20 mL). The combined organic layers were dried with MgSO , and
4
, 75 mg, 2.0 mmol) was added, and the
13
8
=
–1
3403, 2974, 1736, 1661, 1400, 1368, 1155 cm . HRMS (ESI):
4
+
calcd. for C21
Data for 14b: Colorless oil (36%); R
H31NO
5
Na [M + Na] 400.2100; found 400.2101.
= 0.60 (petroleum ether/di-
the solvents were evaporated under vacuum. The residue was puri-
fied over silica gel (pentane/diethyl ether, 4:6) to yield a colorless
f
2
5
1
ethyl ether, 5:5). [α]
684
D
= –28.2 (c = 1, CH
3
OH). H NMR
oil (223 mg, 65%); R
f
= 0.30 (petroleum ether/diethyl ether, 5:5).
6
www.eurjoc.org
© 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2013, 6677–6686

Access to Substituted Pipecolic Acid Derivatives
2
5
1
[
α]
δ = 4.20 (t, J = 5.4 Hz, 1 H), 4.09 (m, 2 H), 2.31 (dt, J = 14.7 Hz, (17a): Compound 16a (70 mg, 0.25 mmol) was dissolved in an
J = 5.8 Hz, 1 H), 2.15 (ddd, J = 14.0 Hz, J = 6.8 Hz, J = 2.9 Hz, aqueous 10% Na CO solution (5 mL), and the solution was ex-
H), 2.07 (ddd, J = 14.7 Hz, J = 5.0 Hz, J = 4.4 Hz, 1 H), 1.79 tracted with diethyl ether (3ϫ 10 mL). The combined organic lay-
ddd, J = 14.0 Hz, J = 9.2 Hz, J = 5.2 Hz, 1 H), 1.60 (m, 1 H), ers were dried with MgSO and concentrated under vacuum to
.49 (m, 18 H), 1.38 (m, 3 H), 0.96 (m, 3 H) ppm. C NMR yield a colorless oil (60 mg, 100%). H NMR (300 MHz, CDCl
, 330 K): δ = 172.6, 155.6, 81.4, 80.1, 63.1, 54.1, δ = 4.75 (s, 0.2 H), 4.25 (m, 1 H), 3.66 (dd, J = 12.2 Hz, J = 2.7 Hz,
D
= –10 (c = 0.8, CH
3
OH). H NMR (400 MHz, CDCl
3
, 330 K):
(2S,4S,6S)-tert-Butyl 4-Hydroxy-6-propylpiperidine-2-carboxylate
2
3
1
(
1
(
4
13
1
3
):
100 MHz, CDCl
3
5
3
1
3
1.2, 36.5, 35.1, 34.8, 28.6, 28.2, 20.2, 14.0 ppm. IR (neat): ν˜ =
465, 2960, 2932, 2872, 1739, 1697, 1673, 1391, 1364, 1251,
1 H), 2.96 (m, 1 H), 2.05 (ddd, J = 13.7 Hz, J = 5.2 Hz, J = 2.8 Hz,
1 H), 1.71 (ddd, J = 13.7 Hz, J = 5.2 Hz, J = 2.8 Hz, 1 H), 1.60
–1
H33NO
5
Na [M + Na]+ (ddd, J = 13.7 Hz, J = 12.4 Hz, J = 2.8 Hz, 1 H), 1.46 (s, 9 H),
152 cm . HRMS (ESI): calcd. for C18
66.2256; found 366.2251.
1
3
1.33 (m, 5 H), 0.92 (t, J = 7.0 Hz, 3 H) ppm. C NMR (75 MHz,
CDCl ): δ = 172.9, 81.1, 65.3, 53.8, 49.6, 39.0, 36.1, 28.1, 19.0,
4.2 ppm. IR (neat): ν˜ = 3524, 3375, 2930, 1735, 1414, 1255 cm .
3
(
2S,4S,6R)-Di-tert-butyl 4-Hydroxy-6-propylpiperidine-1,2-dicarb-
oxylate (14a): Cerium chloride (CeCl ·7H O, 558 mg, 1.5 mmol)
and ketone 12a (341 mg, 1.0 mmol) were dissolved in methanol
10 mL) at room temperature, and the mixture was stirred for
–1
1
3
2
Supporting Information (see footnote on the first page of this arti-
1
13
cle): H and C NMR spectra of all compounds and chiral euro-
(
1
pium H NMR or chiral HPLC of compounds 3a–3c, 4a–4c, 5a,
15 min. The temperature was cooled to –90 °C, and NaBH
4
(75 mg,
5b, 6a, 6b, 7a, 7b, 8a, 8b, 10a, 10b, 11a, 12a, 13a, 14a, and 14b.
2.0 mmol) was added. The solution was stirred for 1 h. Water
(
20 mL) was then poured into the reaction mixture that was ex-
tracted with ethyl acetate (3ϫ 20 mL). The combined organic lay-
ers were dried with MgSO , and the solvents were evaporated under
vacuum. The residue was purified over silica gel (pentane/diethyl
Acknowledgments
4
The authors are deeply grateful to M. Le Roch for the technical
assistance with the chiral HPLC and chiral europium NMR spec-
tra, to S. Sinbandhit and P. Jéhan (CRMPO, Université de Rennes
ether, 4:6) to yield a colorless oil (295 mg, 86%); R
f
= 0.35 (pent-
OH). 1H NMR
= –9 (c = 0.7, CH
3
ane/diethyl ether, 4:6). [α]2
5
D
(
4
400 MHz, CDCl
.06 (m, 1 H), 3.95 (m, 1 H), 2.49 (ddd, J = 14.0 Hz, J = 6.7 Hz,
J = 3.9 Hz, 1 H), 2.18 (dt, J = 14.8 Hz, J = 6.1 Hz, 1 H), 1.77 (m,
3
): δ = 4.41 (dd, J = 5.6 Hz, J = 3.9 Hz, 1 H),
1) for the mass spectra and NMR analyses, and to the Ministry of
Education and Training of Vietnam for its financial support.
1
0
1
2
1
H), 1.79 (m, 1 H), 1.67 (m, 2 H), 1.47 (m, 18 H), 1.33 (m, 2 H),
.95 (t, J = 7.3 Hz, 3 H) ppm. 13C NMR (100 MHz, CDCl
): δ =
3
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71.8, 155.4, 81.2, 79.9, 63.5, 53.9, 51.4, 38.5, 34.6, 33.5, 28.4, 28.1,
0.0, 14.1 ppm. IR (neat): ν˜ = 3458, 2962, 2933, 2872, 1739, 1693,
[2] A. A. Cant, A. Sutherland, Synthesis 2012, 44, 1935–1950.
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cles 2006, 68, 2365–2373.
–1
673, 1392, 1365, 1252, 1152 cm . HRMS (ESI): calcd. for
+
C
18
H33NO
5
Na [M + Na] 366.2256; found 366.2256.
(
(
2S,4S,6S)-2-Carboxy-4-hydroxy-6-propylpiperidinium Chloride
15a): Compound 10a (100 mg, 0.29 mmol) was dissolved in a solu-
[
[
[
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stirred at room temperature for 12 h. The suspension was filtered,
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2
2
5
a white solid (59 mg, 90%); m.p. Ͼ260 °C. [α]
D
= –8.6 (c = 1, H
O): δ = 4.28 (m, 1 H), 4.11 (dd, J =
3.4 Hz, J = 3.2 Hz, 1 H), 3.42 (m, 1 H), 2.30 (ddd, J = 15.0 Hz,
2
O).
1
H NMR (300 MHz, D
2
1
J = 5.6 Hz, J = 3.2 Hz, 1 H), 2.05 (ddd, J = 15.3 Hz, J = 5.6 Hz,
J = 3.2 Hz, 1 H), 1.89 (ddd, J = 15.0 Hz, J = 13.0 Hz, J = 2.3 Hz,
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1
H), 1.62 (m, 3 H), 1.36 (m, 2 H), 0.86 (t, J = 7.3 Hz, 3 H) ppm.
13
C NMR (75 MHz, D
2
O): δ = 172.3, 61.7, 52.8, 51.0, 34.5, 33.4,
3
1
1
2.0, 17.7, 12.9 ppm. IR (KBr): ν˜ = 3399, 2958, 2923, 1728, 1367,
155 cm . HRMS (ESI): calcd. for C
88.1287.
–1
9 3
H18NO 188.1287; found
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2S,4S,6S)-2-(tert-Butoxycarbonyl)-4-hydroxy-6-propylpiperidinium
[
[
Chloride (16a): Compound 10a (100 mg, 0.29 mmol) was dissolved
in a solution of HCl in ethyl acetate (1 m, 2 mL), and the mixture
was stirred at room temperature for 5 h. The suspension was fil-
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yield a white solid (70 mg, 86%); m.p. 210 °C. [α]
H
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5
D
= –5.8 (c = 1,
O): δ = 4.31 (m, 1 H), 4.14 (dd, J
13.3 Hz, J = 3.3 Hz, 1 H), 3.45 (m, 1 H), 2.28 (ddd, J = 14.8 Hz,
1
2 2
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=
J = 5.5 Hz, J = 3.3 Hz, 1 H), 2.05 (ddd, J = 15.2 Hz, J = 5.5 Hz,
J = 3.1 Hz, 1 H), 1.87 (ddd, J = 14.8 Hz, J = 13.3 Hz, J = 2.4 Hz,
1
3
5
2
2003, 125, 4018–4019; g) O. G. Mancheno, J. C. Carretero, J.
H), 1.62 (m, 3 H), 1.49 (s, 9 H), 1.38 (m, 2 H), 0.89 (t, J = 7.3 Hz,
H) ppm. 13C NMR (75 MHz, D
O): δ = 169.7, 86.8, 62.6, 54.0,
2.2, 35.5, 34.3, 32.9, 28.0, 18.7, 13.9 ppm. IR (KBr): ν˜ = 3330,
Am. Chem. Soc. 2004, 126, 456–457; h) Y. Yamashita, Y. Mi-
zuki, S. Kobayashi, Tetrahedron Lett. 2005, 46, 1803–1806; i)
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2
–1
960, 2914, 2788, 2748, 2713, 1738 cm . HRMS (ESI): calcd. for
244.1913; found 244.1915.
13 3
C H26NO
Eur. J. Org. Chem. 2013, 6677–6686
© 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
6685

H.-D. Vu, J. Renault, L. Toupet, P. Uriac, N. Gouault
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Received: May 31, 2013
Published Online: August 23, 2013
[
7447.
6686
www.eurjoc.org
© 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2013, 6677–6686