Stereoselective synthesis of (2S,4R)-4-hydroxypipecolic acid

Article abstract of DOI:10.1002/ejoc.200700849

A new synthetic route to enantiopure (2S,4R)-4-hydroxypipecolic acid from commercial ethyl (3S)-4-chloro-3-hydroxybutanoate is reported. The synthesis is based on the Pd-catalyzed methoxycarbonylation of a 4-alkoxy-substituted δ-valerolactam-derived vinyl triflate followed by the stereocontrolled hydrogenation of the enamine double bond. The final product was obtained after exhaustive hydrolysis in 20 % yield over 10 steps. Wiley-VCH Verlag GmbH & Co. KGaA, 2008.

Full text of DOI:10.1002/ejoc.200700849

FULL PAPER
DOI: 10.1002/ejoc.200700849
Stereoselective Synthesis of (2S,4R)-4-Hydroxypipecolic Acid
Ernesto G. Occhiato,*[a] Dina Scarpi,[a] and Antonio Guarna[a]
Keywords: Amino acids / Natural products / Lactams / Carbonylation / Hydrogenation
A new synthetic route to enantiopure (2S,4R)-4-hydroxy-
pipecolic acid from commercial ethyl (3S)-4-chloro-3-hy-
droxybutanoate is reported. The synthesis is based on the Pd-
catalyzed methoxycarbonylation of a 4-alkoxy-substituted δ-
valerolactam-derived vinyl triflate followed by the stereocon-
trolled hydrogenation of the enamine double bond. The final
product was obtained after exhaustive hydrolysis in 20%
yield over 10 steps.
(© Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim,
Germany, 2008)
triflate prepared from enantiopure lactam 3. Two issues had
to be addressed in the course of this synthesis, the first be-
ing the actual feasibility of the requisite 4-alkoxy- (or sil-
yloxy-)substituted lactam-derived vinyl triflate. It is in fact
known that the stability of vinyl triflates of this type is
strongly affected by both the size and the electronic nature
of the substituents on the lactam ring such that they cannot
in many cases be conveniently used in coupling reactions.[9]
The second issue was the facial selectivity possibly exerted
by the C-4 stereocenter in the catalytic hydrogenation of the
enamine double bond in 2. In the heterogeneous hydrogena-
tion of similar carbocyclic compounds a poor bias on the
stereochemical outcome has always been shown by the al-
lylic OH group.[10,11] So, if such is the case, the use of a
bulky substituent (TBDPS or TBDMS group) on the hy-
droxy group of 2 could help in directing the reduction
towards the less hindered face of the double bond to furnish
the target cis product.[12]
Introduction
Pipecolic acids and their derivatives are useful building
blocks for the preparation of biologically active com-
pounds.[1] In particular, the naturally occurring (2S,4R)-4-
hydroxypipecolic acid (1) (Figure 1), isolated from the
leaves of Calliandra pittieri and Strophantus scandeus[2] and
a constituent of cyclodepsipeptide antibiotics such as vir-
giniamycin S2,[3] has been embedded in the structure of
NMDA receptor antagonists[4] and HIV-protease inhibitors
such as palinavir (Figure 1).[5] Because of its importance in
medicinal chemistry, much effort has been directed towards
the enantioselective synthesis of 1 by the resolution of key
racemic intermediates and by using chiral auxiliaries or
starting materials from the chiral pool.[1c,1e,6]
Figure 1. Structure of (2S,4R)-4-hydroxypipecolic acid (left) and
palinavir (right).
As a part of our study on the use of lactam-derived vinyl
triflates in organic synthesis,[7] we have envisaged a new syn-
thetic route to enantiopure (2S,4R)-4-hydroxypipecolic acid
(1) (Scheme 1) from commercial ethyl (3S)-4-chloro-3-hy-
droxybutanoate (4).[8] The key step in the synthesis is the
stereocontrolled hydrogenation of the double bond in tetra-
hydropyridine-2-carboxylate 2, which in turn could be ob-
tained by Pd0-catalyzed methoxycarbonylation of the vinyl
Scheme 1.
[a] Department of Organic Chemistry “U. Schiff” and Laboratory
of Design, Synthesis and Study of Biologically Active Heterocy-
cles (HeteroBioLab), Università di Firenze,
Results and Discussion
To address the first point we focused our attention on
racemic ethyl 4-chloro-3-hydroxybutanoate (4) (Scheme 2).
This was converted into the corresponding nitrile 5 which
Via della Lastruccia 13, 50019 Sesto Fiorentino (FI), Italy
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E-mail: ernesto.occhiato@unifi.it
524
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Eur. J. Org. Chem. 2008, 524–531

Stereoselective Synthesis of (2S,4R)-4-Hydroxypipecolic Acid
was transformed into differently protected lactams accord- strain generated between the olefinic proton on C-3 and the
ing to a reported methodology.[13] However, we found it bulky equatorial silyloxy group after formation of the enol-
more convenient to protect nitrile 5 as the corresponding ate (Scheme 3, a). To reduce the strain, the 4-silyloxy group
TBDPS ether prior to hydrogenation, thus obtaining piper- should adopt an axial orientation,[15] but this could be
idinone 9 with the protection already installed on the 4-hy- prone to elimination under the reaction conditions.
droxy group. After protection of the N atom, we attempted
to convert lactam 11 into the corresponding vinyl triflate
by treatment with KHMDS in THF at –78 °C and then by
quenching the enolate with N-phenyl triflimide. However,
1
analysis of the H NMR spectrum of the crude reaction
mixture revealed that complete elimination had occurred to
give 14 (45% after chromatography). Moreover, the signals
of the 2-O-silylated compound 15a (1:2 ratio with 14) were
1
observed in the H NMR spectrum.[14] Hoping that a less
bulky 4-substituent would be more compatible with the
conditions for the formation of the triflate, we repeated the
experiment with the TBDMS-protected lactam 12, prepared
from the benzyloxy derivative 10 we already had in hand.
However, in this case elimination was again the major path-
way accompanied by the formation of a greater amount (by
1H NMR analysis of the crude reaction mixture) of the silyl
enol ether 15b (29% after chromatography).[14]
Scheme 3.
It was clear at this point that the required bulky silyl
protection of the 4-hydroxy had to be installed at a later
stage, that is, after the formation of the triflate and subse-
quent Pd-catalyzed carbonylation. This approach was ap-
plied to the synthesis of enantiopure (2S,4R)-4-hydroxy-
pipecolic acid (1), as reported in Scheme 4.
Scheme 2. Reagents and conditions: (a) NaI, acetone, reflux, 3 d;
(b) NaCN, EtOH/H2O, 4:1, 45 °C, 3 h; (c) BnOC(=NH)CCl3,
TfOH (cat), DCM/cyclohexane, 1:2, 0Ǟ25 °C, 22 h; (d) TBDPSCl,
imidazole, DMF, 40 °C, 12 h; (e) NaBH4, NiCl2·6H2O, EtOH, 0 °C,
3 h; then 25 °C, 2.5 h; (f) H2, PtO2, MeOH, 30 °C, 24 h; (g) nBuLi,
MeOCOCl, THF, –78 °C, 4 h; (h) H2, 10% Pd/C, EtOAc, 25 °C,
16 h; (i) TBDMSCl, imidazole, DMF, 30 °C, 5 h; (j) KHMDS,
THF, –78 °C, 1.5 h; then PhNTf2, –78 °C, 1 h.
The low recovery of organic material after chromatog-
raphy suggests in any case that degradation of the sub-
strates had occurred in both experiments. Thus, 4-silyloxy-
substituted lactams appear unsuitable for the preparation
of the corresponding vinyl triflates. Instead, the 4-ben-
zyloxy group of compound 10 was stable under basic condi-
tions so that 10 could be quantitatively converted into the
corresponding vinyl triflate 13. A possible reason for the
particular tendency of enolates (or triflates) of 11 and 12 to
Scheme 4. Reagents and conditions: (a) NaI, acetone, reflux, 3 d;
(b) NaCN, EtOH/H2O, 4:1, 45 °C, 3 h; (c) PMBOC(=NH)CCl3,
BF3·Et2O (cat), DCM/cyclohexane, 1:2, –5Ǟ25 °C, 3 h; (d)
NaBH4, NiCl2·6H2O, EtOH, 0 °C, 3 h; then 25 °C, 2.5 h; (e) nBuLi,
MeOCOCl, THF, –78 °C, 4 h; (f) KHMDS, THF, –78 °C, 1.5 h;
then PhNTf2, –78 °C, 1 h; (g) Pd(OAc)2, Ph3P, CO, MeOH, Et3N,
DMF, 40–45 °C, 3 h; (h) DDQ, CH2Cl2, H2O, 25 °C, 24 h; (i)
TBDPSCl, imidazole, DMF, 40 °C, 3.5 h; (j) TBDMSCl, imidazole,
DMF, 40 °C, 3.5 h; (k) H2, 10% Pd/C, EtOAc, 50 °C, 3 h; (l) 2 
exclusively give the elimination products is the strong A(1,2) HCl, reflux, 23 h.
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525

E. G. Occhiato, D. Scarpi, A. Guarna
FULL PAPER
In contrast to the reported procedure in which the bacte- on the piperidine ring has been demonstrated.[21] Thus, se-
rium Rhodococcus erytropolis was used to desymmetrize a lective deprotection of 25 (Scheme 5) quantitatively gave
dinitrile,[13] we prepared enantiopure nitrile (R)-5 by start- (2S,4R)-21 possessing identical spectroscopic data to that
ing from the commercial ethyl 4-chloro-3-hydroxybutanoate of cis-(Ϯ)-21. TBAF-Mediated deprotection of 24
[(S)-4].[16] Compound 5 was protected as a p-methoxyben- (Scheme 6) in THF was slow and provided mainly the cis
zyl (PMB) ether and then the nitrile group was chemoselec- product 21 together with a certain amount (2.4:1 ratio) of
tively reduced to afford lactam (R)-17 in 74% yield. After the trans diastereomer[22] which was formed because of par-
protection of the N atom,[17] (R)-18 was converted into the tial epimerization under the basic deprotection condi-
corresponding triflate and this was immediately subjected tions.[23,24]
to methoxycarbonylation,[18] providing (R)-19 in 62% yield
over two steps. Deprotection eventually gave key intermedi-
ate (R)-20 in 73% yield. Compound 20 was hydrogenated
at room temperature over Pd/C in both MeOH and ethyl
acetate as the solvent to provide, as expected, an approxi-
mately 2.5:1 mixture of the cis and trans diastereomers of
21. Both TBDPS and TBDMS ethers 22 and 23, respec-
tively, were then prepared and subjected to the same hydro-
genation conditions in ethyl acetate. The reactions did not
occur at room temperature, however, by increasing the tem-
perature to 50 °C hydrogenation was complete after a few
hours giving (2S,4R)-24 and (2S,4R)-25 in quantitative
yields. The cis compound (2S,4R)-24 was obtained as a 17:1
Scheme 6. Reagents and conditions: (a) TBAF, 3-Å molecular
sieves, THF, 9 h.
Finally, exhaustive hydrolysis (2  aqueous HCl, reflux
for 18–24 h) of TBDMS-protected compound 25
(Scheme 4), as well as 21 (Scheme 5), provided dia-
stereomerically pure (2S,4R)-1 as the hydrochloride salt in
95–100% yield.
1
mixture (by H NMR) with its trans isomer. The diastereo-
selectivity was higher in the hydrogenation of the TBDMS-
protected (R)-23 as cis-(–)-25 was obtained in a 23:1 mix-
ture with the trans isomer. Hydrogenation of the double
bond in compounds 22 and 23 does not take place at room
temperature as it generates a strained diaxial 2,4-disubsti-
tuted final compound (Scheme 3, b). The silyloxy group is
pseudoaxial to remove the aforementioned A(1,2) strain and
hydrogenation of the double bond occurs on the opposite
side to give the cis compound. At the same time the 2-
methoxycarbonyl group is forced towards an axial orienta-
tion to relieve the A(1,3) strain with the N-protection,[19]
thus providing a 2,4-diaxial derivative for the formation of
compounds 24 and 25 for which higher temperatures are
required.
Conclusions
In conclusion, a stereoselective synthesis of (2S,4R)-4-
hydroxypipecolic acid (1) has been realized starting from
commercial ethyl (3S)-4-chloro-3-hydroxybutanoate (4) in
10 steps and in 20% overall yield. The synthesis was pos-
sible as 4-benzyloxy-substituted lactam-derived vinyl tri-
flates are sufficiently stable to allow the Pd-catalyzed meth-
oxycarbonylation reaction and the synthesis was based on
the stereoselective enamine double-bond hydrogenation of
the methyl ester consequently obtained. As both enantio-
mers of ethyl 4-chloro-3-hydroxybutanoate are commer-
cially available the methodology can also be used for the
synthesis of the unnatural enantiomer (2R,4S)-1. Finally,
the feasibility of 4-benzyloxy-substituted δ-valerolactam-
derived vinyl triflates sets the stage for Pd-catalyzed cross-
coupling reactions and therefore the synthesis of several
natural products containing the 4-hydroxypiperidine nu-
cleus.
The cis (and diaxial) stereochemistry of 24 and 25 is evi-
3
dent from the low values of the J coupling constants of 2-
H and 4-H (2.7–2.9 Hz for 4-H and 6.2–7.0 Hz for 2-H)
which is consistent with an equatorial orientation of both
protons. Moreover, the equatorial carbinolic proton is
shifted downfield to 4.07 ppm in 24 (and to 4.08 ppm in
25), whereas in the trans isomer of 24 the same proton reso-
nates at higher fields (3.57–3.65 ppm) as it is axially ori-
ented.[20] This assignment was confirmed by converting 24
and 25 into cis-21 (Schemes 5 and 6), known in its racemic
Experimental Section
form, for which the axial orientation of the two substituents Chromatographic separations were performed under pressure on
silica gel 60 (Merck, 70–230 mesh) using flash-column techniques;
Rf values refer to TLC carried out on 0.25-mm silica gel plates with
the same eluent as indicated for column chromatography. THF was
distilled from Na/benzophenone. Dichloromethane, cyclohexane
and heptane were distilled from CaH2. Commercial anhydrous
1
DMF was used. H and 13C NMR spectra were recorded at 25 °C.
Mass spectra were recorded at 70 eV by applying the EI technique.
Racemic ethyl 4-chloro-3-hydroxybutanoate (4) was prepared as re-
ported.[25] Racemic ethyl 3-hydroxy-4-iodobutanoate and ethyl (R)-
3-hydroxy-4-iodobutanoate were prepared from (Ϯ)-4 and com-
Scheme 5. Reagents and conditions: (a) 3  HCl, ACN, 25 °C, 4 h;
(b) 2  HCl, reflux, 18 h.
mercial (S)-4, respectively, as reported.[16,26]
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Stereoselective Synthesis of (2S,4R)-4-Hydroxypipecolic Acid
Ethyl 4-Cyano-3-hydroxybutanoate [(؎)-5]:[27] Racemic ethyl 3-hy- 4-(Benzyloxy)piperidin-2-one [(؎)-8]: NaBH4 (113 mg, 3 mmol) in
droxy-4-iodobutanoate[26] (1.024 g, 3.98 mmol) was dissolved in a
vigorously stirred 4:1 ethanol/water mixture (1.6 mL). The solution
was heated to 45 °C (external bath) and NaCN (273 mg, 5.57 mol)
was added. Vigorous stirring was continued at this temperature for
3 h. The reaction mixture was then cooled, the solvent evaporated
and the residue dissolved in ethyl acetate (6 mL). The solution was
filtered through Celite mixed with silica gel, washed with EtOAc
(3ϫ6 mL), and the solvent was then removed. The orange liquid
obtained was purified by chromatography (CH2Cl2/MeOH, 30:1,
Rf = 0.33) to give (Ϯ)-5 (500 mg, 79%) as a pale yellow liquid with
1H and 13C NMR spectra identical to those reported.[26,27]
small portions (H2 develops) was added to a stirred solution of
NiCl2·6H2O (694 mg, 2.92 mmol) in EtOH (5.5 mL), cooled to
0 °C. After 15 min a solution of nitrile (Ϯ)-6 (360 mg, 1.46 mmol)
in EtOH (6 mL) was added dropwise, followed by the remaining
NaBH4 (1.103 g, 29.2 mmol) which was added in small portions in
3 h [during the addition of NaBH4, further EtOH (8 mL) was
added in small volumes to maintain the fluidity of the black sus-
pension]. After that time, the suspension was stirred for 2.5 h at
room temperature and then water (8 mL) was carefully added and
the mixture was filtered through a Celite layer washing with EtOH
(3ϫ15 mL). The solution was concentrated under vacuum, the res-
idue was dissolved in EtOAc (50 mL) and washed with 10%
NH4OH (aq.) (2ϫ15 mL), brine (15 mL), and finally dried with
Na2SO4. After filtration and evaporation of the solvent, the residue
was purified by chromatography (CH2Cl2/MeOH, 25:1, Rf = 0.21)
to give (Ϯ)-8 (212 mg, 71%) as a white solid. M.p. 95–96 °C. 1H
NMR (CDCl3, 200 MHz): δ = 1.89–2.00 (m, 2 H, 5-H and 5-HЈ),
2.43–2.69 (m, 2 H, 3-H and 3-HЈ), 3.15–3.29 (m, 1 H, 6-H), 3.43–
3.55 (m, 1 H, 6-HЈ), 3.80–3.95 (m, 1 H, 4-H), 4.56 (s, 2 H,
OCH2Ph), 6.73 (br. s, 1 H, NH), 7.20–7.40 (m, 5 H, CHarom) ppm.
13C NMR (CDCl3, 50.33 MHz): δ = 27.2 (t, C-5), 37.6 (t, C-3),
38.0 (t, C-6), 70.2 (t, OCH2Ph), 70.8 (d, C-4), 127.3 (d, 2 Carom),
127.6 (d, 1 Carom), 128.3 (d, 2 Carom), 137.9 (s, 1 Carom), 170.7
(C=O) ppm. MS: m/z (%) = 205 (0.4) [M]+, 99 (86), 91 (100).
C12H15NO2 (205.25): calcd. C 70.22, H 7.37, N 6.82; found C
70.41, H 7.62, N 6.85.
Ethyl 3-(Benzyloxy)-4-cyanobutanoate [(؎)-6]: Benzyl 2,2,2-trichlo-
roacetimidate (1.42 mL, 7.65 mmol) was added to a solution of
(Ϯ)-5 (800 mg, 5.1 mmol) in anhydrous CH2Cl2 (2 mL) and cyclo-
hexane (4 mL) and, after cooling to 0 °C, triflic acid (44 µL,
0.51 mmol) was added dropwise under N2. Stirring was continued
for 15 min at 0 °C before allowing the reaction mixture to warm to
room temperature. After 4 h, the mixture was cooled again to 0 °C
and further amounts of benzyl 2,2,2-trichloroacetimidate (470 µL)
and triflic acid (22 µL) were added. The reaction mixture was left
to stir overnight at room temperature. After 18 h the solution was
filtered through a Celite layer, washing with cyclohexane. The fil-
trate was diluted with EtOAc (30 mL), washed with a saturated
aqueous NaHCO3 solution (2ϫ50 mL), then brine (50 mL), and
finally dried with Na2SO4. After filtration and evaporation of the
solvent, the oily residue was purified by chromatography (EtOAc/
petroleum ether, 1:5, Rf = 0.29) to give (Ϯ)-6 (818 mg, 65%) as
4-(tert-Butyldiphenylsilyloxy)piperidin-2-one [(؎)-9]: PtO2 (50 mg)
was added to a stirred solution of (Ϯ)-7 (480 mg, 1.21 mmol) in
MeOH (6 mL) under N2. The mixture was flushed with H2 and
then left under a static pressure of H2 (balloon) at 30 °C. After
24 h the catalyst was filtered, washing with MeOH (4 mL), and
Et3N (335 µL, 2.42 mmol) was added to the solution which was
stirred for 2 h at room temperature. Then it was concentrated under
vacuum, the residue was diluted with water (20 mL), extracted with
EtOAc (3ϫ15 mL), and dried with Na2SO4. After filtration and
evaporation of the solvent, the residue was purified by chromatog-
raphy (EtOAc, Rf = 0.31) to give (Ϯ)-9 (290 mg, 68%) as a gummy
white solid. 1H NMR (CDCl3, 200 MHz): δ = 1.06 [s, 9 H,
SiC(CH3)3], 1.70–1.79 (m, 2 H, 5-H and 5-HЈ), 2.42 (d, J = 5.1 Hz,
2 H, 3-H and 3-HЈ), 3.07–3.20 (m, 1 H, 6-H), 3.49–3.61 (m, 1 H,
6-HЈ), 4.06–4.21 (m, 1 H, 4-H), 6.20 (br. s, 1 H, NH), 7.31–7.59
(m, 6 H, CHarom), 7.60–7.71 (m, 4 H, CHarom) ppm. Spectroscopic
and analytical data are identical to those reported.[13]
1
pale-yellow thick oil. H NMR (CDCl3, 200 MHz): δ = 1.26 (t, J
= 7.1 Hz, 3 H, OCH2CH3), 2.57–2.82 (m, 4 H, NCCH2 and
CH2CO2Et), 4.05–4.20 (m, 1 H, CHOBn), 4.16 (q, J = 7.1 Hz, 2
H, OCH2CH3), 4.64 (s, 2 H, OCH2Ph), 7.39–7.30 (m, 5 H,
CHarom) ppm. 13C NMR (CDCl3, 50.33 MHz): δ = 14.1 (q,
OCH2CH3), 23.1 (t, C-4), 39.0 (t, C-2), 61.0 (t, OCH2CH3), 71.2
(t, OCH2Ph), 72.3 (d, C-3), 116.9 (s, CN), 127.8 (d, 2 Carom), 128.1
(d, Carom), 128.4 (d, 2 Carom), 136.9 (s, Carom), 170.0 (s, C=O) ppm.
MS: m/z (%) = 247 (1.9) [M]+, 107 (74), 91 (100). C14H17NO3
(247.29): calcd. C 68.00, H 6.93, N 5.66; found C 67.89, H 7.08, N
5.45.
Ethyl 3-(tert-Butyldiphenylsilyloxy)-4-cyanobutanoate [(؎)-7]: Imid-
azole (355 mg, 5.21 mmol) and TBDPSCl (947 µL, 3.70 mmol)
were added to a solution of (Ϯ)-5 (270 mg, 1.72 mmol) in anhy-
drous DMF (2.5 mL) under nitrogen and the resulting solution was
left stirring at 40 °C (external bath). After 12 h the mixture was
diluted with water (15 mL) and extracted with Et2O (3 ϫ20 mL).
The combined organic layers were washed with brine (25 mL) and
dried with Na2SO4. After filtration and evaporation of the solvent,
the oily residue was purified by chromatography (EtOAc/petroleum
ether, 1:8, Rf = 0.27) to give (Ϯ)-7 (518 mg, 76%) as a thick color-
less oil. 1H NMR (CDCl3, 200 MHz): δ = 1.08 [s, 9 H, SiC-
Methyl 4-(Benzyloxy)-2-oxopiperidine-1-carboxylate [(؎)-10]:
A
1.6  solution of nBuLi (1.47 mL, 2.34 mmol) in hexane was added
dropwise to a cooled (–78 °C) solution of lactam (Ϯ)-8 (480 mg,
2.34 mmol) in anhydrous THF (8 mL) under N2. After 30 min a
solution of methyl chloroformate (181 µL, 2.34 mmol) in THF
(3 mL) was added dropwise and the reaction mixture was left stir-
ring for 4 h at –78 °C. Water (4 mL) was then added and the mix-
(CH3)3], 1.21 (t, J = 7.3 Hz, 3 H, OCH2CH3), 2.53 (d, J = 4.4 Hz, ture warmed to room temperature. Further water was added
2 H, NCCH2), 2.67 (d, J = 6.2 Hz, 2 H, CH2CO2Et), 4.06 (q, J =
7.3 Hz, 2 H, OCH2CH3), 4.26–4.40 (m, 1 H, CHOSi), 7.37–7.44
(20 mL) and the mixture extracted with Et2O (3ϫ15 mL), washed
with brine, and dried with Na2SO4. After filtration and evaporation
(m, 6 H, CHarom), 7.64–7.36 (m, 4 H, CHarom) ppm. 13C NMR of the solvent, the residue was purified by chromatography
(CDCl3, 50.33 MHz): δ = 14.0 (q, OCH2CH3), 19.2 [s, SiC(CH3)3],
25.6 (t, C-4), 26.7 [q, 3 C, SiC(CH3)3], 40.8 (t, C-2), 60.7 (t, a pale-yellow oil. H NMR (CDCl3, 200 MHz): δ = 2.00–2.09 (m,
OCH2CH3), 65.7 (d, C-3), 116.9 (s, CN), 127.7 (d, 2 Carom), 127.8 2 H, 5-H and 5-HЈ), 2.76 (d, J = 5.1 Hz, 2 H, 3-H and 3-HЈ), 3.64–
(d, 2 Carom), 130.0 (d, Carom), 130.1 (d, Carom), 132.5 (s, 2 Carom), 3.77 (m, 1 H, 6-H), 3.86 (s, 3 H, OCH3), 3.86–4.00 (m, 2 H, 4-H
(CH2Cl2/MeOH, 40:1, Rf = 0.32) to give (Ϯ)-10 (488 mg, 79%) as
1
135.6 (d, 2 Carom), 135.7 (d, 2 Carom), 169.9 (s, C=O) ppm. MS: m/z
(%) = 395 (0.1) [M]+, 338 (100), 232 (80), 199 (98), 188 (73), 183
(70). C23H29NO3Si (395.57): calcd. C 69.84, H 7.39, N 3.54; found
C 69.48, H 7.30, N 3.40.
and 6-HЈ), 4.55 (s, 2 H, OCH2Ph), 7.31–7.40 (s, 5 H, CHarom) ppm.
13C NMR (CDCl3, 50.33 MHz): δ = 28.2 (t, C-5), 40.9 (t, C-3),
42.3 (t, C-6), 54.0 (q, OCH3), 70.3 (t, OCH2Ph), 70.4 (d, C-4), 127.4
(d, 2 Carom), 127.7 (d, 1 Carom), 128.4 (d, 2 Carom), 137.5 (s, 1 Carom),
Eur. J. Org. Chem. 2008, 524–531
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527

E. G. Occhiato, D. Scarpi, A. Guarna
J = 4.0 Hz, 1
H, 3-H) ppm. 13C NMR (CDCl3,
50.33 MHz): δ = 29.4 (t, C-5), 43.1 (t, C-6), 53.7 (q, OCH3), 68.6
(t, OCH2Ph), 70.5 (d, C-4), 104.9 (d, C-3), 118.3 (q, JC,F = 319 Hz,
CF3), 127.7 (d, 2 Carom), 127.9 (d, 1 Carom), 128.5 (d, 2 Carom),
137.6 (s, 1 Carom), 141.7 (s, C-2), 153.2 (s, N–CO) ppm. MS: m/z
(%) = 304 (0.9) [M – 91]+, 181 (28), 156 (44), 91 (100).
FULL PAPER
151.8 (s, N–CO), 168.9 (C=O) ppm. MS: m/z (%) = 263 (0.4) 5.38 (d,
[M]+, 157 (46), 125 (36), 91 (100). C14H17NO4 (263.29): calcd. C
63.87, H 6.51, N 5.32; found C 63.66, H 6.91, N 5.02.
Methyl 4-(tert-Butyldiphenylsilyloxy)-2-oxopiperidine-1-carboxylate
[(؎)-11]: Prepared as reported above for (Ϯ)-10. Starting from (Ϯ)-
9 (461 mg, 1.29 mmol), the title compound (Ϯ)-11 (469 mg, 88%)
was obtained as a thick pale-yellow oil after chromatography
(EtOAc/petroleum ether, 1:4, Rf = 0.33). 1H NMR (CDCl3,
200 MHz): δ = 1.05 [s, 9 H, SiC(CH3)3], 1.77–1.86 (m, 2 H, 5-H
and 5-HЈ), 2.58 (d, J = 4.4 Hz, 2 H, 3-H and 3-HЈ), 3.57–3.69 (m,
Ethyl (R)-4-Cyano-3-hydroxybutanoate [(–)-5]:[27] Prepared as re-
ported above for (Ϯ)-5. Starting from ethyl (R)-3-hydroxy-4-iodo-
butanoate (2.80 g, 10.88 mmol), (R)-5 (1.384 g) was obtained in
81% yield after chromatography as a light-yellow liquid with 1H
1 H, 6-H), 3.87 (s, 3 H, OCH3), 3.86–4.01 (m, 1 H, 6-HЈ), 4.13– and 13C NMR spectra identical to those reported.[27,28] [α]2D5
=
4.22 (m, 1 H, 4-H), 7.33–7.46 (m, 6 H, CHarom), 7.59–7.68 (m, 4 –31.1 (c = 0.64, CHCl3) {lit.: [α]D = –31.3 (c = 1.0, CHCl3);[27]
H, CHarom) ppm. Spectroscopic and analytical data are identical to
[α]D = –33.1 (c = 1.2, CHCl3)[28]}.
those reported.[13]
Ethyl (R)-4-Cyano-3-[(4-methoxybenzyl)oxy]butanoate [(–)-16]: A
solution of (–)-5 (1.092 g, 6.96 mmol) in dichloromethane (7.5 mL)
was added to a stirred solution of freshly prepared p-methoxyben-
zyl 2,2,2-trichloroacetimidate[29] (3.01 g, 10.65 mmol) in cyclohex-
ane (15 mL) under N2. The solution was cooled to –5 °C and
BF3·Et2O (30 µL) was added dropwise. After 10 min the reaction
mixture was warmed to room temperature and after 2 h a further
amount of trichloroacetimidate (980 mg) was added. After 1 h, the
Methyl 4-(tert-Butyldimethylsilyloxy)-2-oxopiperidine-1-carboxylate
[(؎)-12]: 10% Pd/C (97 mg, 0.091 mmol) was added to a stirred
solution of (Ϯ)-10 (239 mg, 0.91 mmol) in EtOAc (9 mL) under
N2. The mixture was flushed with H2 and then left under a static
pressure of H2 (balloon) at room temperature. After 16 h the cata-
lyst was filtered and the solution concentrated to give the methyl
4-hydroxy-2-oxopiperidine-1-carboxylate intermediate as a color-
1
less oil. H NMR (CDCl3, 200 MHz): δ = 1.80–2.09 (m, 2 H, 5-H mixture was filtered through a Celite layer, washing with a 1:2 mix-
and 5-HЈ), 2.59 (dd, J = 17.2, 5.5 Hz, 1 H, 3-H), 2.80 (dd, J = 17.2, ture of CH2Cl2 and hexane (150 mL). The solution was then
4.8 Hz, 1 H, 3-HЈ), 3.61–3.72 (m, 1 H, 6-H), 3.86 (s, 3 H, OCH3), washed with NaHCO3(sat) (3ϫ50 mL) and dried with Na2SO4.
3.86–4.02 (m, 1 H, 6-HЈ), 4.13–4.33 (m, 1 H, 4-H) ppm.
After filtration and evaporation of the solvent, the oily residue was
purified by chromatography (EtOAc/petroleum ether, 1:4, Rf
=
This was directly dissolved in anhydrous DMF (1.2 mL) under ni-
trogen and imidazole (178 mg, 2.60 mmol) and TBDMSCl
(156 mg, 1.03 mmol) were added. The resulting solution was left
stirring at 30 °C (external bath). After 5 h the mixture was diluted
with water (10 mL) and extracted with Et2O (3ϫ15 mL). The com-
bined organic layers were washed with brine (20 mL) and dried
with Na2SO4. After filtration and evaporation of the solvent, the
oily residue was purified by chromatography (EtOAc/petroleum
ether, 1:4, Rf = 0.27) to give (Ϯ)-12 (171 mg, 69%) as a thick color-
0.29) to give (–)-16 (1.921 g, 99%) as a colorless oil. [α]2D0 = –7.1 (c
= 0.57, CHCl3). 1H NMR (CDCl3, 200 MHz): δ = 1.26 (t, J =
7.3 Hz, 3 H, OCH2CH3), 2.55–2.81 (m, 4 H, NCCH2 and
CH2CO2Et), 3.80 (s, 3 H, OCH3), 4.05–4.20 (m, 1 H, CHOPMB),
4.16 (q, J = 7.3 Hz, 2 H, OCH2CH3), 4.57 (s, 2 H, OCH2Ar), 6.88
(d, J = 8.8 Hz, 2 H, CHarom), 7.27 (d, J = 8.8 Hz, 2 H,
CHarom) ppm. 13C NMR (CDCl3, 50.33 MHz): δ = 14.2 (q,
OCH2CH3), 23.2 (t, C-4), 39.0 (t, C-2), 55.3 (q, OCH3), 60.9 (t,
OCH2CH3), 70.9 (t, OCH2Ar), 71.9 (d, C-3), 113.8 (d, 2 Carom),
116.8 (s, CN), 129.4 (d, 2 Carom), 129.6 (s, Carom), 159.3 (s, Carom),
169.8 (s, C=O) ppm. MS: m/z (%) = 277 (7) [M]+, 137 (100), 121
(87). C15H19NO4·1͞3H2O (283.33): calcd. C 63.59, H 7.00, N 4.94;
found C 63.54, H 6.87, N 4.64.
1
less oil. H NMR (CDCl3, 400 MHz): δ = 0.07 [s, 6 H, Si(CH3)2],
0.87 [s, 9 H, SiC(CH3)3], 1.81–1.90 (m, 1 H, 5-H), 1.92–2.00 (m, 1
H, 5-HЈ), 2.55 (dd, J = 17.0, 4.9 Hz, 1 H, 3-H), 2.68 (dd, J = 17.0,
4.3 Hz, 1 H, 3-HЈ), 3.72 (dt, J = 12.7, 5.3 Hz, 1 H, 6-H), 3.86 (s, 3
H, OCH3), 3.84–3.91 (m, 1 H, 6-HЈ), 4.17–4.23 (m, 1 H, 4-H) ppm.
13C NMR (CDCl3) δ = –4.8 [q, 2 C, Si(CH3)2], 18.0 (s, SiC), 25.7 (R)-4-[(4-Methoxybenzyl)oxy]piperidin-2-one [(+)-17]: Prepared as
[q, 3 C, SiC(CH3)3], 31.3 (t, C-5), 42.2 (t, C-3), 44.2 (t, C-6), 53.9 described above for compound (Ϯ)-8. Starting from (–)-16 (950 mg,
(q, OCH3), 64.8 (d, C-4), 154.9 (s, N–C=O), 169.5 (C=O) ppm.
MS: m/z (%) = 287 (0.3) [M]+, 230 (100), 188 (68), 89 (84).
C13H25NO4Si (287.43): calcd. C 54.32, H 8.77, N 4.87; found C
54.01, H 8.73, N 4.61.
3.43 mmol), title compound (+)-17 (600 mg) was obtained in 74%
yield after chromatography (CH2Cl2/MeOH, 20:1, Rf = 0.29) as a
white solid, m.p. 101–102 °C. [α]2D5 = +7.0 (c = 0.85, CHCl3). 1H
NMR (CDCl3, 200 MHz): δ = 1.89–2.00 (m, 2 H, 5-H and 5-HЈ),
2.44–2.69 (m, 2 H, 3-H and 3-HЈ), 3.16–3.29 (m, 1 H, 6-H), 3.43–
3.56 (m, 1 H, 6-HЈ), 3.81 (s, 3 H, OCH3), 3.80–3.92 (m, 1 H, 4-H),
4.50 (s, 2 H, OCH2Ar), 5.90 (br. s, 1 H, NH), 6.88 (d, J = 8.8 Hz,
2 H, CHarom), 7.26 (d, J = 8.8 Hz, 2 H, CHarom) ppm. 13C NMR
(CDCl3, 50.33 MHz): δ = 27.2 (t, C-5), 35.0 (t, C-3), 38.0 (t, C-6),
55.3 (q, OCH3), 69.9 (t, OCH2Ph), 70.6 (d, C-4), 113.7 (d, 2 Carom),
128.9 (d, 2 Carom), 129.9 (s, Carom), 159.0 (s, 1 Carom), 170.8
(C=O) ppm. MS: m/z (%) = 235 (2) [M]+, 121 (74), 99 (100).
C13H17NO3 (235.28): calcd. C 66.36, H 7.28, N 5.95; found C
66.10, H 7.31, N 5.40.
Methyl 4-(Benzyloxy)-6-{[(trifluoromethyl)sulfonyl]oxy}-1,2,3,4-tet-
rahydropyridine-1-carboxylate [(؎)-13]:
A solution of (Ϯ)-10
(249 mg, 0.950 mmol) in THF (2 mL) was added to a solution of
KHMDS (2.37 mL of a 0.5  solution in toluene, 1.18 mmol) in
THF (5.5 mL), cooled to –78 °C under nitrogen, and the resulting
mixture was stirred for 1.5 h. Afterwards a solution of PhNTf2
(423 mg, 1.18 mmol) in THF (1 mL) was added and left to stir for
1 h at –78 °C before allowing the temperature to rise to 0 °C. Then
a 10% NaOH aqueous solution (10 mL) was added, the mixture
was extracted with Et2O (3ϫ10 mL), washed with 10% NaOH
(10 mL) and water (3ϫ10 mL), and dried with anhydrous K2CO3
for 30 min. After filtration and evaporation of the solvent (without
heating), triflate (Ϯ)-13 (375 mg, 100%) was obtained as a yellow
oil of sufficient purity to allow characterized as such. 1H NMR
Methyl (R)-4-[(4-Methoxybenzyl)oxy]-2-oxopiperidine-1-carboxyl-
ate [(+)-18]: Prepared as reported above for (Ϯ)-10. Starting from
(+)-17 (750 mg, 3.19 mmol), the title compound (+)-18 (832 mg,
89%) was obtained after chromatography (CH2Cl2/MeOH, 40:1, Rf
(CDCl3, 200 MHz): δ = 1.71–1.88 (m, 1 H, 5-H), 1.99–2.13 (m, 1 = 0.27) as a thick pale-yellow oil. [α]2D5 = +9.2 (c = 0.53, CHCl3).
H, 5-HЈ), 3.40 (ddd, J = 15.2, 11.7, 2.6 Hz, 1 H, 6-H), 3.81 (s, 3 H, 1H NMR (CDCl3, 200 MHz): δ = 1.97–2.07 (m, 2 H, 5-H and 5-
OCH3), 4.06–4.20 (m, 2 H, 6-HЈ and 4-H), 4.57 (s, 2 H, OCH2Ph)
HЈ), 2.73 (d, J = 5.1 Hz, 2 H, 3-H and 3-HЈ), 3.63–4.00 (m, 3 H,
528
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© 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2008, 524–531

Stereoselective Synthesis of (2S,4R)-4-Hydroxypipecolic Acid
4-H, 6-H and 6-HЈ), 3.80 (s, 3 H, ArOCH3), 3.86 (s, 3 H, OCH3), 0.17) to give (+)-20 (136 mg, 73%) as a thick colorless oil. [α]2D5
=
4.47 (s, 2 H, OCH2Ar), 6.87 (d, J = 8.8 Hz, 2 H, CHarom), 7.26 (d,
J = 8.8 Hz, 2 H, CHarom) ppm. 13C NMR (CDCl3, 50.33 MHz): δ
= 28.3 (t, C-5), 40.9 (t, C-3), 42.3 (t, C-6), 53.9 (q, ArOCH3), 55.3
+127.7 (c = 0.97, CHCl3). 1H NMR (CDCl3, 200 MHz): δ = 1.87–
1.96 (m, 2 H, 5-H and 5-HЈ), 2.79 (br. s, 1 H, OH), 3.30 (ddd, J =
13.2, 9.2, 5.5 Hz, 1 H, 6-H), 3.74 (s, 3 H, OCH3), 3.80 (s, 3 H,
(q, OCH3), 70.0 (t, OCH2Ar), 70.1 (d, C-4), 113.8 (d, 2 Carom), OCH3), 4.04 (dt, J = 13.2, 4.4 Hz, 1 H, 6-HЈ), 4.24–4.35 (m, 1
129.0 (d, 2 Carom), 129.4 (s, Carom), 154.4 (s, N–C=O), 159.1 (s, 1
Carom), 168.9 (C=O) ppm. MS: m/z (%) = 293 (0.1) [M]+, 240 (57),
121 (100). C15H19NO5 (293.32): calcd. C 61.42, H 6.53, N 4.78;
found C 61.50, H 6.41, N 4.57.
H, 4-H), 5.96 (d, J = 4.4 Hz, 1 H, 3-H) ppm. 13C NMR (CDCl3,
50.33 MHz): δ = 32.1 (t, C-5), 40.2 (t, C-6), 52.4 (q, OCH3), 53.4 (q,
OCH3), 61.1 (d, C-4), 121.0 (d, C-3), 133.0 (s, C-2), 153.9 (s, N–
C=O), 164.9 (C=O) ppm. MS: m/z (%) = 215 (38) [M]+, 183 (79),
155 (59), 127 (47), 114 (49), 97 (74), 59 (100). C9H13NO5 (215.20):
calcd. C 50.23, H 6.09, N 6.51; found C 49.91, H 6.27, N 6.18.
Dimethyl 4-[(4-Methoxybenzyl)oxy]-1,4,5,6-tetrahydropyridine-1,2-
dicarboxylate [(+)-19]: A solution of (+)-18 (520 mg, 1.77 mmol) in
THF (4 mL) was added to a solution of KHMDS (4.38 mL of a
0.5  solution in toluene, 2.19 mmol) in THF (10 mL), cooled to
–78 °C and under nitrogen, and the resulting mixture was stirred
for 1.5 h. Afterwards a solution of PhNTf2 (784 mg, 2.19 mmol) in
THF (3 mL) was added and left to stir for 1 h at –78 °C before
allowing the temperature to rise to 0 °C. Then a 10% NaOH aque-
ous solution (20 mL) was added, the mixture was extracted with
Et2O (3ϫ20 mL), washed with 10% NaOH (20 mL) and water
(3ϫ20 mL), and dried with anhydrous K2CO3 for 30 min. After
filtration and evaporation of the solvent (without heating), the
crude triflate (780 mg) was directly used in the next step without
Dimethyl (R)-4-(tert-Butyldiphenylsilyloxy)-1,4,5,6-tetrahydropyr-
idine-1,2-dicarboxylate [(+)-22]: Imidazole (62 mg, 0.9 mmol) and
TBDPSCl (92 µL, 0.36 mmol) were added to a stirred solution of
(+)-20 (65 mg, 0.3 mmol) in anhydrous DMF (0.5 mL) and the
mixture was stirred for 3.5 h at 40 °C (external bath) under N2.
After cooling to room temperature, water (5 mL) was added and
the solution extracted with Et2O (3ϫ10 mL). The combined or-
ganic layers were washed with brine (10 mL) and dried with
Na2SO4. After filtration and evaporation of the solvent, the oily
residue was purified by chromatography (EtOAc/petroleum ether,
1:4, Rf = 0.33) to give (+)-22 (120 mg, 88%) as a thick colorless
oil. [α]2D5 = +107.7 (c = 1.88, CHCl3). 1H NMR (CDCl3, 200 MHz):
δ = 1.07 [s, 9 H, SiC(CH3)3], 1.60–1.78 (m, 1 H, 5-H), 1.81–1.97
1
purification. H NMR (CDCl3, 200 MHz): δ = 1.71–1.90 (m, 1 H,
5-H), 1.93–2.11 (m, 1 H, 5-HЈ), 3.40 (ddd, J = 15.3, 11.6, 2.5 Hz,
1 H, 6-H), 3.81 (s, 3 H + 3 H, ArOCH3 and OCH3), 4.00–4.18 (m, (m, 1 H, 5-HЈ), 3.43 (td, J = 13.2, 2.6 Hz, 1 H, 6-H), 3.70 (s, 3 H,
2 H, 6-HЈ and 4-H), 4.50 (s, 2 H, OCH2Ar), 5.39 (d, J = 3.8 Hz, 1 OCH3), 3.77 (s, 3 H, OCH3), 3.95 (dt, J = 13.2, 4.8 Hz, 1 H, 6-HЈ),
H, 3-H), 6.88 (d, J = 8.7 Hz, 2 H, CHarom), 7.25 (d, J = 8.7 Hz, 2 4.22–4.29 (m, 1 H, 4-H), 5.77 (d, J = 3.7 Hz, 1 H, 3-H), 7.30–7.49
H, CHarom) ppm.
(m, 6 H, CHarom), 7.57–7.73 (m, 4 H, CHarom) ppm. 13C NMR
(CDCl3, 50.33 MHz): δ = 19.1 (s, SiC), 26.8 [q, 3 C, SiC(CH3)3],
32.5 (t, C-5), 40.4 (t, C-6), 52.2 (q, OCH3), 53.2 (q, OCH3), 62.7
(d, C-4), 121.6 (d, C-3), 127.6 (d, 4 Carom), 129.7 (d, 2 Carom), 132.5
(s, C-2), 133.4 (s, 2 Carom), 135.6 (d, 4 Carom), 154.0 (s, N–C=O),
165.0 (C=O) ppm. MS: m/z (%) = 453 (4) [M]+, 396 (59), 213 (100),
199 (93). C25H31NO5Si (453.60): calcd. C 66.20, H 6.89, N 3.09;
found C 66.54, H 6.53, N 3.02.
The triflate was dissolved in DMF (8 mL), Ph3P (47 mg,
0.177 mmol) and Pd(OAc)2 (19.8 mg, 0.0885 mmol) were added,
and the solution was stirred for 10 min under a CO atmosphere
(balloon). Then Et3N (494 µL, 3.54 mmol) and MeOH (2.9 mL,
70.8 mmol) were added and stirring was continued at 40–45 °C (ex-
ternal bath) for 3 h under a static CO pressure. The solution was
diluted with water (40 mL) and extracted with Et2O (4ϫ20 mL),
washed with brine (20 mL), and dried with Na2SO4. After filtration
and evaporation of the solvent, the oily residue was purified by
chromatography (EtOAc/petroleum ether, 1:2, Rf = 0.34) to give
(+)-19 (368 mg, 62%) as a thick pale-yellow oil. [α]2D5 = +134.0 (c
Dimethyl (R)-4-(tert-Butyldimethylsilyloxy)-1,4,5,6-tetrahydropyr-
idine-1,2-dicarboxylate [(+)-23]: Prepared as reported above for (+)-
22, starting from (+)-20 (78 mg, 0.36 mmol) and TBDMSCl
(64 mg, 0.42 mmol). Chromatography (EtOAc/petroleum ether, 1:5,
Rf = 0.27) provided (+)-23 (108 mg, 91%) as a thick colorless oil.
1
= 1.64, CHCl3). H NMR (CDCl3, 200 MHz): δ = 1.78–1.90 (m, 1
1
H, 5-H), 2.00–2.12 (m, 1 H, 5-HЈ), 3.31 (td, J = 12.1, 3.3 Hz, 1 H,
6-H), 3.72 (s, 3 H, OCH3), 3.79 (s, 3 H, ArOCH3), 3.80 (s, 3 H,
OCH3), 3.92–4.08 (m, 2 H, 6-HЈ and 4-H), 4.52 (s, 2 H, OCH2Ar),
[α]2D5 = +154.0 (c = 0.82, CHCl3). H NMR (CDCl3, 400 MHz): δ
= 0.08 [q, 6 H, Si(CH3)2], 0.87 [s, 9 H, SiC(CH3)3], 1.81–1.87 (m,
1 H, 5-H and 5-HЈ), 3.30 (dt, J = 13.1, 7.0 Hz, 1 H, 6-H), 3.71 (s,
6.04 (d, J = 4.0 Hz, 1 H, 3-H), 6.88 (d, J = 8.8 Hz, 2 H, CHarom), 3 H, OCH3), 3.78 (s, 3 H, OCH3), 3.96 (dt, J = 13.1, 4.3 Hz, 1 H,
7.25 (d, J = 8.8 Hz, 2 H, CHarom) ppm. 13C NMR (CDCl3,
6-HЈ), 4.22 (q, J = 3.9 Hz, 1 H, 4-H), 5.85 (d, J = 3.9 Hz, 1 H, 3-
50.33 MHz): δ = 29.4 (t, C-5), 40.6 (t, C-6), 52.4 (q, OCH3), 53.3 H) ppm. 13C NMR (CDCl3, 100.4 MHz): δ = –4.76 (q, SiCH3),
(q, ArOCH3), 55.3 (q, OCH3), 67.3 (t, OCH2Ar), 70.0 (d, C-4), –4.60 (q, SiCH3), 18.0 (s, SiC), 25.7 [q, 3 C, SiC(CH3)3], 33.0 (t, C-
113.9 (d, 2 Carom), 119.2 (d, C-3), 129.3 (d, 2 Carom), 129.5 (s,
5), 40.3 (t, C-6), 52.3 (q, OCH3), 53.2 (q, OCH3), 61.9 (d, C-4),
Carom), 133.8 (s, C-2), 154.1 (s, N–C=O), 159.3 (s, 1 Carom), 165.0 122.3 (d, C-3), 132.5 (s, C-2), 154.2 (s, N–C=O), 165.2 (s,
(C=O) ppm. MS: m/z (%) = 335 (3) [M]+, 199 (34), 167 (36), 140 C=O) ppm. MS: m/z (%) = 329 (0.1) [M]+, 272 (100), 198 (46).
(36), 121 (100). C17H21NO6 (335.35): calcd. C 60.89, H 6.31, N C15H27NO5Si (329.46): calcd. C 54.68, H 8.26, N 4.25; found C
4.18; found C 60.57, H 6.01, N 4.43.
54.71, H 7.87, N 3.93.
Dimethyl (R)-4-Hydroxy-1,4,5,6-tetrahydropyridine-1,2-dicarboxyl-
Dimethyl (2S,4R)-4-(tert-Butyldiphenylsilyloxy)piperidine-1,2-di-
ate [(+)-20]: H2O (666 µL), followed by DDQ (236 mg, carboxylate [(–)-24]: 10% Pd/C (50% wet, 70 mg) was added to a
1.039 mmol) in small portions, was added to a stirred solution of stirred solution of (+)-22 (100 mg, 0.22 mmol) in EtOAc (6 mL)
(+)-19 (290 mg, 0.866 mmol) in CH2Cl2 (12 mL). After 24 h, and the mixture was flushed first with N2 and then with H2 before
NaHCO3 (sat) (15 mL) and then CH2Cl2 (30 mL) were added. The
phases were separated, the organic layer was washed with NaHCO3
(sat) (20 mL), and the aqueous layer extracted with CH2Cl2
(4ϫ20 mL). The combined organic layers were dried with Na2SO4.
After filtration and evaporation of the solvent, the oily residue was
being left under a static H2 pressure (balloon) at 50 °C (external
bath) for 3 h. After filtration through a Celite layer, the solution
was concentrated to give an oil which was purified by chromatog-
raphy (EtOAc/petroleum ether, 1:4, Rf = 0.33) to give (–)-24 (98 mg,
98%) as thick colorless oil. [α]2D5 = –17.1 (c = 0.63, CHCl3). 1H
NMR (CDCl3, 400 MHz): δ = 1.06 [s, 9 H, SiC(CH3)3], 1.26–1.45
purified by chromatography (EtOAc/petroleum ether, 1:1, Rf
=
Eur. J. Org. Chem. 2008, 524–531
© 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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529

E. G. Occhiato, D. Scarpi, A. Guarna
FULL PAPER
(m, 2 H, 5ax-H and 5eq-H), 1.80 (br. dd, J = 14.1, 6.8 Hz, 1 H, 3ax-
H), 2.51 (br. d, J = 14.1 Hz, 1 H, 3eq-H), 3.52–3.66 (m, 1 H, 6ax-
0.21 mmol) in a 2  HCl aqueous solution (12 mL) was refluxed
for 23 h. The mixture was then cooled to room temperature, ex-
H), 3.66 (s, 3 H, C–CO2CH3), 3.69 and 3.72 (s, 3 H, two rotamers, tracted with Et2O (2ϫ20 mL), and the aqueous layer concentrated
N–CO2CH3), 3.80 (br. d, J = 13.5 Hz, major rotamer, 6eq-H), 3.94 under vacuum. The solid residue was triturated with CH2Cl2
(br. d, J = 12.2 Hz, minor rotamer, 6eq-H), 4.08 (br. quint, J =
2.7 Hz, 1 H, 4eq-H), 4.68 (br. d, J = 6.2 Hz, minor rotamer, 2eq-H), EtOH (2 mL). The solution was filtered, concentrated, and the
4.84 (br. d, J = 6.8 Hz, major rotamer, 2eq-H), 7.34–7.46 (m, 6 white foamy solid was dried under vacuum (0.1 Torr) at 70 °C for
H, CHarom), 7.61–7.69 (m, 4 H, CHarom) ppm. 13C NMR (CDCl3, 3 h to give 1·HCl (36 mg) in 95% yield. M.p. 202–204 °C (de-
100.4 MHz): δ = 19.2 (s, SiC), 26.9 [q, 3 C, SiC(CH3)3], 31.2 and
comp.). [α]2D5 = +7.11 (c = 0.46, MeOH). 1H NMR (D2O,
31.5 (t, two rotamers, C-5), 33.4 (t, C-3), 35.8 and 36.0 (t, two 400 MHz): δ = 1.63–1.73 (m, 1 H, 3ax-H), 1.74–1.83 (m, 1 H, 5ax-
(2ϫ4 mL), discarding the organic phase, and then dissolved in hot
rotamers, C-6), 50.9 and 51.2 (q, two rotamers, N–CO2CH3), 52.1
(q, C–CO2CH3), 52.8 (d, C-2), 64.8 (d, C-4), 127.5 and 127.6 (d,
two rotamers, 4 Carom), 129.7 and 129.8 (d, two rotamers, 2 Carom),
135.4 (s, 2 Carom), 135.7 and 135.8 (d, two rotamers, 4 Carom), 157.0
and 157.6 (s, two rotamers, N–C=O), 172.0 (s, C=O) ppm. MS: m/z
(%) = 455 (0.1) [M]+, 398 (65), 140 (100). C25H33NO5Si (455.62):
calcd. C 65.90, H 7.30, N 3.07; found C 66.81, H 7.51, N 2.88.
H), 2.18 (br. d, J = 14.2, 1 H, 5eq-H), 2.56 (br. d, J = 13.8 Hz, 1
H, 3eq-H), 3.12 (td, J = 12.7, 3.3 Hz, 1 H, 6ax-H), 3.59 (td, J =
12.7, 4.1 Hz, 1 H, 6eq-H), 4.00–4.06 (m 1 H, 4ax-H), 4.07 (dd, J =
1
9.4, 3.9 Hz, 1 H, 2ax-H) ppm. H NMR (CD3OD, 400 MHz): δ =
1.58–1.73 (m, 2 H, 3ax-H and 5ax-H), 2.10 (br. d, J = 14.0, 1 H,
5eq-H), 2.49 (br. d, J = 13.4 Hz, 1 H, 3eq-H), 3.08 (td, J = 12.9,
3.3 Hz, 1 H, 6ax-H), 3.49 (td, J = 12.9, 3.9 Hz, 1 H, 6eq-H), 3.87–
3.95 (m, 1 H, 4ax-H), 4.06 (dd, J = 11.9, 3.5 Hz, 1 H, 2ax-H) ppm.
13C NMR (D2O, 100.4 MHz): δ = 30.2 (t, C-5), 34.0 (t, C-3), 41.8
(t, C-6), 56.0 (d, C-2), 65.1 (d, C-4), 171.4 (s, C=O) ppm.
Dimethyl
(2S,4R)-4-(tert-Butyldimethylsilyloxy)piperidine-1,2-di-
carboxylate [(–)-25]: Prepared as reported above for (–)-24. Starting
from (+)-23 (74 mg, 0.22 mmol), (–)-25 (72 mg, 99%) was obtained
after chromatography (EtOAc/petroleum ether, 1:4, Rf = 0.35) as a
thick colorless oil. [α]2D5 = –16.6 (c = 0.62, CHCl3). 1H NMR
(CDCl3, 400 MHz): δ = 0.01 [s, 6 H, Si(CH3)2], 0.84 [s, 9 H,
SiC(CH3)3], 1.55–1.63 (m, 2 H, 5ax-H and 5eq-H), 1.84 (br. dd, J =
14.2, 7.0 Hz, 1 H, 3ax-H), 2.30–2.39 (br. m, 1 H, 3eq-H), 3.35–3.55
(m, 1 H, 6ax-H), 3.69 (s, 3 H, C–CO2CH3), 3.69 and 3.71 (s, 3 H,
two rotamers, N–CO2CH3), 3.80 (br. d, J = 12.2 Hz, major rotamer,
6eq-H), 3.94 (br. d, J = 12.3 Hz, minor rotamer, 6eq-H), 4.07 (br.
quint, J = 2.9 Hz, 1 H, 4eq-H), 4.63 (br. d, J = 6.6 Hz, minor rot-
amer, 2eq-H), 4.78 (br. d, J = 7.0 Hz, major rotamer, 2eq-H) ppm.
13C NMR (CDCl3, 100.4 MHz): δ = –5.2 (q, SiCH3), –5.0 (q,
SiCH3), 18.1 (s, SiC), 25.7 [q, 3 C, SiC(CH3)3], 31.9 and 32.1 (t,
two rotamers, C-5), 33.8 and 33.9 (t, two rotamers, C-3), 35.7 and
35.9 (t, two rotamers, C-6), 50.9 and 51.2 (q, two rotamers, N–
CO2CH3), 51.9 (q, C–CO2CH3), 52.7 (d, C-2), 63.8 (d, C-4), 156.6
and 157.0 (s, two rotamers, N–C=O), 171.9 (s, C=O) ppm. MS: m/z
(%) = 331 (0.1) [M]+, 274 (100). C15H29NO5Si (331.48): calcd. C
54.35, H 8.82, N 4.23; found C 54.02, H 9.11, N 3.99.
Acknowledgments
We thank the Ministero dell’Università e della Ricerca (MIUR)
and the Università di Firenze for financial support, and the Cassa
di Risparmio di Firenze for granting a 400 MHz NMR spectrome-
ter. Maurizio Passaponti and Brunella Innocenti are acknowledged
for their technical support.
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Dimethyl (2S,4R)-4-Hydroxypiperidine-1,2-dicarboxylate [(–)-21]: A
3  HCl solution (5 mL) was added to a solution of (–)-25 (70 mg,
0.21 mmol) in acetonitrile (5 mL) and the mixture was vigorously
stirred at room temperature. After 4 h, the mixture was neutralized
with NaHCO3 (sat), extracted with EtOAc (3ϫ15 mL), and the com-
bined organic layers dried with Na2SO4. After filtration and evapora-
tion of the solvent, the oily residue was purified by chromatography
(EtOAc/petroleum ether, 1:1, Rf = 0.17) to give (–)-21 (41 mg, 89%)
as a colorless oil. [α]2D5 = –34.4 (c = 0.82, CHCl3). 1H NMR (CDCl3,
400 MHz): δ = 1.59–1.80 (m, 2 H, 5ax-H and 5eq-H), 1.90 (br. dd, J
= 13.6, 6.0 Hz, 1 H, 3ax-H), 2.43 (br. d, J = 13.6 Hz, 1 H, 3eq-H),
3.32–3.51 (m, 1 H, 6ax-H), 3.69 and 3.73 (s, 3 H, two rotamers, N–
CO2CH3), 3.73 (s, 3 H, C–CO2CH3), 3.84 (br. d, J = 12.1 Hz, major
rotamer, 6eq-H), 3.97 (br. d, J = 8.6 Hz, minor rotamer, 6eq-H), 4.15
(br. s, 1 H, 4eq-H), 4.70 (br. s, minor rotamer, 2eq-H), 4.85 (br. s,
major rotamer, 2eq-H) ppm. 13C NMR (CDCl3, 100.4 MHz): δ =
31.2 (t, C-5), 33.3 (t, C-3), 35.5 and 35.8 (t, two rotamers, C-6),
50.8 and 51.1 (q, two rotamers, N–CO2CH3), 52.3 (q, C–CO2CH3),
52.9 (d, C-2), 63.2 (d, C-4), 156.9 and 157.2 (s, two rotamers, N–
C=O), 172.9 (s, C=O) ppm. MS: m/z (%) = 185 (1) [M – 32]+, 158
(100) [M – 59]+, 114 (66). C9H15NO5 (217.22): calcd. C 49.76, H
6.96, N 6.45; found C 49.73, H 7.26, N 6.22.
(2S,4R)-4-Hydroxypiperidine-2-carboxylic Acid Hydrochloride
(1·HCl):[30] A vigorously stirred dispersion of (–)-25 (70 mg,
530
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© 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2008, 524–531

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with the N-protecting group. Much chemistry has been based
on this feature which strongly affects the stereochemical out-
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butanoate are commercially available, the synthesis can be ex-
tended to the (2R,4S) enantiomer of 4-hydroxypipecolic acid.
[9] a) G. R. Dake, M. D. B. Fenster, P. B. Hurley, B. O. Patrick, J.
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[12] Hydrogenation with Noyori’s (R)-BINAP-RuCl2 catalyst and
other catalysts has been employed to create the C-2 stereocen-
ter in the enantioselective synthesis of unsubstituted pipecolic
acids. For examples, see: a) T. J. Wilkinson, N. W. Stehle, P.
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[20]
A small amount of trans-24 was obtained by selective protec-
tion as the TBDPS ether (TBDPSCl, imidazole, DMF, 45 °C,
2 h) of the less hindered OH group of the minor trans isomer
21 present in the mixture (with the cis compound) obtained
1
after hydrogenation of (R)-20. H NMR (CDCl3, 400 MHz): δ
= 1.04 [s, 9 H, SiC(CH3)3], 1.50–1.57 (m, 1 H, 5ax-H), 1.71
(ddd, J = 17.6, 11.1, 6.1 Hz, 1 H, 3ax-H), 1.72–1.84 (m, 1 H,
5eq-H), 2.21–2.30 (br. m, 1 H, 3eq-H), 2.81–3.00 (m, 1 H, 6ax-
H), 3.49 (s, 3 H, C–CO2CH3), 3.57–3.65 (m, 1 H, 4-H), 3.66
and 3.69 (s, 3 H, two rotamers, N–CO2CH3), 3.90 (br. d, J =
13.2 Hz, major rotamer, 6eq-H) and 4.08 (br. d, J = 12.1 Hz,
minor rotamer, 6eq-H), 4.75 (br. s, minor rotamer, 2eq-H), 4.90
(br. s, major rotamer, 2eq-H), 7.33–7.44 (m, 6 H, CHarom), 7.60–
7.69 (m, 4 H, CHarom) ppm.
[21]
[22]
a) P. M. Esch, R. F. de Boer, H. Hiemstra, I. M. Boska, W. N.
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Despite several attempts, cis- and trans-21 were not separated
by silica gel chromatography to properly characterize the trans
compound. To determine the isomeric ratio, however, the fol-
1
lowing H NMR signals (CDCl3, 200 MHz) are diagnostic of
the trans isomer: δ = 1.33–1.47 (m, 1 H), 2.96–3.11 (m, 1 H),
4.11–3.98 (m, 1 H), 5.04 and 4.88 (br. s, two rotamers) ppm.
This was demonstrated by treating the diastereomeric 2.4:1
mixture of cis- and trans-21 with TBAF in THF at room tem-
perature. After 24 h the trans isomer was the major component
of the mixture (the cis/trans ratio was 1:1.5). Deprotection of
24 with HF–pyridine in THF left the starting material unal-
tered after 24 h at room temperature.
a) T. W. Green, P. G. M. Wuts, Protective Groups in Organic
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[23]
[24]
[13] M. K. S. Vink, C. A. Schortinghuis, J. Luten, J. H. van Maarse-
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1
[14] Compound 14 has the following H NMR (CDCl3, 200 MHz)
data: δ = 3.82 (s, 3 H, OCH3), 4.38 (dd, J = 4.1, 1.5 Hz, 2 H,
CH2N), 5.74 (d, J = 5.5 Hz, 1 H, 3-H), 5.77–5.83 (m, 1 H, 4-
H), 5.99–6.04 (m, 1 H, 5-H) ppm. In compounds 15a and 15b
3-H is strongly shielded (4.60 and 4.93 ppm, respectively) as a
silyloxy group is at C-2 in place of the electron-withdrawing
OTf group. Accordingly, in the 13C NMR spectrum of 15b, C-
3 is shifted upfield and resonates at δ = 94.0 ppm. Compound
[25]
[26]
[27]
[28]
1
15b has the following H NMR (CDCl3, 200 MHz) data: δ =
0.20 [s, 6 H, Si(CH3)2], 0.95 [s, 9 H, SiC(CH3)3], 3.74 (s, 3 H,
OCH3), 4.23 (dd, J = 4.4, 1.0 Hz, 2 H, CH2N), 4.93 (d, J =
5.5 Hz, 1 H, 3-H), 5.39–5.47 (m, 1 H, 4-H), 5.88–5.97 (m, 1 H,
5-H) ppm. The formation of 15a and 15b represents quite an
anomalous migration of the silyl-protecting group which could
have occurred intermolecularly.
P. L. Brower, D. E. Butler, C. F. Deering, T. V. Le, A. Millar,
T. N. Nanninga, B. D. Roth, Tetrahedron Lett. 1992, 33, 2279–
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[29]
[30]
D. Bourgeois, D. Craig, F. Grellepois, D. M. Mountford,
A. J. W. Stewart, Tetrahedron 2006, 62, 483–495.
Reported spectroscopic and analytical data for cis-(Ϯ)-1·HCl:
m.p. 203 °C (dec.). 1H NMR (CD3OD, 200 MHz): δ = 1.60–
1.78 (m, 2 H, 3ax-H and 5ax-H), 2.10 (m, J = 13.9 Hz, 1 H, 5eq-
H), 2.38 (m, J = 13.5 Hz, 1 H, 3eq-H), 3.08 (td, J = 12.9,
3.2 Hz, 1 H, 6ax-H), 3.49 (td, J = 12.9, 3.9 Hz, 1 H, 6eq-H),
3.92 (m, 1 H, 4ax-H), 4.06 (dd, J = 12.0, 3.5 Hz, 1 H, 2ax-H) ppm.
13C NMR (CD3OD) δ = 31.66 (t, C-5), 35.54 (t, C-3), 42.58 (t,
C-6), 56.55 (d, C-2), 65.83 (d, C-4), 170.77 (s, C=O) ppm. C.
Herdeis, W. Engel, Arch. Pharm. 1992, 325, 419–423.
Received: September 11, 2007
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Asymmetry 1996, 7, 867–884.
[16] G. P.-J. Hareau, M. Koiwa, S. Hikichi, F. Sato, J. Am. Chem.
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[17] An electron-withdrawing group is necessary to confer stability
to the triflate (see ref.[9]). We chose the methoxycarbonyl group
as the final product before exhaustive hydrolysis is known in
racemic form (see ref.[21]).
[18] S. Cacchi, E. Morera, G. Ortar, Tetrahedron Lett. 1985, 26,
1109–1112.
[19] It is known that in piperidines that bear an alkoxycarbonyl or
a tosyl group on the N atom, 2-alkyl substituents are preferen-
Published Online: November 20, 2007
Eur. J. Org. Chem. 2008, 524–531
© 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
531