A short and convenient synthesis of enantiopure cis- And trans-4-hydroxypipecolic acid

Article abstract of DOI:10.1055/s-0029-1216979

The synthesis of (2S,4R)- and (2R,4R)-4-hydroxypipecolic acid has been realized from commercial ethyl (R)-4-cyano-3hydroxybutanoate through palladium-catalyzed methoxycarbonylation of a 4-hydroxy-substituted lactam-derived vinyl phosphate followed by the

Full text of DOI:10.1055/s-0029-1216979

PAPER
3611
A Short and Convenient Synthesis of Enantiopure cis- and
trans-4-Hydroxypipecolic Acid
S
hor
t
Synthesis
r
of 4-H
y
n
droxypipec
o
e
lic
A
cids sto G. Occhiato,*a Dina Scarpi,a Antonio Guarna,a Silvia Tabasso,b Annamaria Deagostino,b Cristina Prandi*b
a
Dipartimento di Chimica Organica ‘U. Schiff’, Università di Firenze, Via della Lastruccia 13, 50019 Sesto Fiorentino, Italy
E-mail: ernesto.occhiato@unifi.it
b
Dipartimento di Chimica Generale e Chimica Organica, Università di Torino, Via P. Giuria 7, 10125 Torino, Italy
E-mail: cristina.prandi@unito.it
Received 26 June 2009
able ethyl (3S)-4-chloro-3-hydroxybutanoate, was based
on the palladium-catalyzed methoxycarbonylation of a 4-
methoxybenzyl-protected lactam-derived vinyl triflate 3
(R = PMB, X = Tf) (Scheme 1) followed by stereocon-
Abstract: The synthesis of (2S,4R)- and (2R,4R)-4-hydroxypipe-
colic acid has been realized from commercial ethyl (R)-4-cyano-3-
hydroxybutanoate through palladium-catalyzed methoxycarbonyla-
tion of a 4-hydroxy-substituted lactam-derived vinyl phosphate fol-
lowed by the stereocontrolled reduction of the enamine double trolled hydrogenation of the enamine double bond. How-
bond. The stereoselective hydrogenation of the suitably 4-hydroxy-
protected enantiomer afforded the cis-(2S,4R)-4-hydroxypipecolic
acid product, obtained in 66% overall yield over seven steps. The
drate (proven animal carcinogenic substance of potential
trans-product (42% overall yield over 8 steps) was instead obtained
by hydride conjugate addition to the same a,b-unsaturated ester.
ever, the preparation of hydroxy ester 2 included the use
of relatively large amounts of nickel(II) chloride hexahy-
relevance to humans) in the reductive step leading to 4-
hydroxy-d-valerolactam 4, as well as the expensive N-
Key word: amino acids, carbonylations, coupling, lactams, palladi-
phenyltriflimide for the preparation of vinyl triflate 3 as
um
the intermediate in the carbonylative step.
OH
OH
OH
OH
4-Hydroxypipecolic acids are naturally occurring non-
proteinogenic a-amino acids often isolated as their hy-
droxylated derivatives which, in many cases, display in-
teresting and potent biological activity. (2S,4R)-4-
Hydroxypipecolic acid [(2S,4R)-1] (Figure 1), isolated
from the leaves of Calliandra pittieri and Strophantus
scandeus,1 is a constituent of the cyclodepsipeptide anti-
biotic virginiamycin S2.2 Its epimer (2R,4R)-1, first isolat-
ed from the leaves of Acacia excelsa,3 is embedded in the
structure of damipipecoline, a serotonine receptor antago-
nist isolated very recently from the Axinella damicornis
sponge,4 as well as in ovalin,5 and in a sulfate derivative
possessing NMDA (N-methyl-D-aspartic acid) receptor
agonistic activity.6
N
H
CO2H
N
H
CO2H
N
H
CO2H
N
H
CO2H
(2R,4R)-
1
(2S,4S)-
1
(2R,4S)-
1
(2S,4R)-
1
PO3H2
Ph
O
CONHtBu
O
H
N
N
N
H
N
O
OH
N
CO2H
H
palinavir
CGS 20281
N
Figure 1 4-Hydroxypipecolic acids and some derivatives
4-Hydroxypipecolic acids are also useful scaffolds for the
preparation of medicinally important compounds.7 In par-
ticular, (2R,4S)-1 has been used as an intermediate in the
synthesis of CGS 20281 (Figure 1), which is one of the
most potent and selective competitive NMDA receptor
antagonists,8 whereas (2S,4R)-1 has been included in the
structure of HIV-protease inhibitors such as palinavir,9
and some antagonists of the cholecistokinin (CCK) hor-
mone.10
OH
OH
OR
N
H
CO2H
N
CO2Me
N
OX
CO2Me
CO2Me
(2S,4R)-1 or
(2R,4R)-1
2
3 X = Tf, P(O)(OPh)2
OPMB
N
OH
N
CO2Et
As a consequence of their importance in medicinal chem-
istry, a number of enantioselective syntheses of 4-hydroxy-
pipecolic acids have been reported,7c,e,11,12 including our
own which was focused on the preparation of (2S,4R)-1.13
This synthesis, which started from commercially avail-
O
(R)-5
CO2Me
4
Scheme 1 Retrosynthetic analysis
SYNTHESIS 2009, No. 21, pp 3611–3616
Advanced online publication: 28.08.2009
DOI: 10.1055/s-0029-1216979; Art ID: Z14009SS
© Georg Thieme Verlag Stuttgart · New York
x
x.
x
x
.
2
0
0
9
We present here a short and high-yielding synthesis of
both cis-(2S,4R)- and trans-(2R,4R)-4-hydroxypipecolic
acid starting from commercial ethyl (R)-4-cyano-3-hy-

3612
E. G. Occhiato et al.
PAPER
droxybutanoate [(R)-5] (96% ee) in which these draw- nylative step were much higher. Moreover diphenyl chlo-
backs were overcome allowing for a facile synthesis.
rophosphate is much cheaper than the triflimides
generally employed for trapping the enolates. The carbo-
nylation was carried out according to standard condi-
tions,13,17 affording ester 10a in 81% yield after
chromatography.18 Hydrogenation of 10a was carried out
over 10% palladium on carbon (50% wet) in ethyl acetate
at 25 °C and afforded 11 as a 19:1 mixture together with
its trans-diastereomer. The presence of sodium hydrogen
carbonate in the reaction mixture was necessary to avoid
loss of the protecting group due to the hydrogen chloride
generated by reduction of the traces of palladium(II) chlo-
ride present in the catalyst.19 We were glad to observe that
the facial selectivity in the hydrogenation was comparable
to that obtained with the O-silyl protecting group.13 Hy-
drolysis of 11 (96% ee, 90% de) eventually furnished
(2S,4R)-1 as its hydrochloride salt in 66% overall yield
over seven steps.
To avoid the use of nickel(II) chloride hexahydrate (and
the tedious procedure of nitrile reduction) in the ring-
closure step, we had first to revise the protection protocol
in order to convert the nitrile into the corresponding lac-
tam by simple hydrogenation. We therefore chose tert-bu-
tyl protection as this is an easily removable O-protecting
group, compatible with the hydrogenation conditions and
strong bases, and it has the advantage that a sterically hin-
dered group would be already installed for the stereocon-
trolled reduction of the enamine double bond.
t-BuOAc,
OtBu
OH
H2, PtO2
HClO4
NC
CO2Et
NC
CO2Et
MeOH, 25 °C
25 °C
6 (94%)
(R)-5
OtBu
OtBu
OtBu
For the synthesis of trans-isomer (2R,4R)-1, after some
failed attempts at reducing allylic alcohol 213 by hydroge-
nation in the presence of Crabtree’s catalyst,20 we opted
for the conjugate reduction of the a,b-unsaturated ester
moiety of intermediate 10a (Scheme 3) which would lead,
after equilibration during the workup, to the prevailing
formation of the thermodynamically more stable trans-
isomers. For this attempt we employed also differently O-
protected compounds 10b and 10c, which were prepared
as reported.13
KHMDS,
n-BuLi,
(PhO)2P(O)Cl
THF, –78 °C
O
MeOCOCl
THF, –78 °C
N
N
OP(O)(OPh)2
N
O
CO2Me
H
CO2Me
7 (100%)
8 (88%)
9 (99%)
OtBu
N
OtBu
Pd(OAc)2, Ph3P,
CO, MeOH
H2, 10% Pd/C
NaHCO3, EtOAc
25 °C
Et3N, DMF
55 °C
CO2Me
N
CO2Me
CO2Me
CO2Me
OR
OR
10a (81%)
OH
11 (100%)
PTSA·H2O
LiEt3BH
OH
MeCN, 25 °C
THF, 0 °C
N
CO2Me
N
CO2Me
N
CO2Me
2 N HCl (aq)
reflux
.
HCl
CO2Me
CO2Me
CO2Me
N
H
CO2H
10a R = tBu
10b R = PMB
10c R = TBS
12a trans/cis 4:1 (93%)
12b trans/cis 2:1 (95%)
12c trans/cis 2.6:1 (91%)
13 (100%, from 12a)
(2S,4R)-1 (100%)
OH
OH
Scheme 2 Preparation of (2S,4R)-1
O
PTSA
2 M HCl (aq)
reflux
.
HCl
+
toluene
100 °C
C
To protect (R)-5 as tert-butyl ether 6 we stirred a solution
of the alcohol in tert-butyl acetate at 25 °C for 24 hours,
in the presence of perchloric acid (0.1 equiv), a procedure
usually employed for the esterification of carboxylic
acids1,14 which provided 6 in 94% yield after chromato-
graphy (Scheme 2).15 The subsequent hydrogenation was
carried out over platinum(IV) oxide in methanol at room
temperature for 48 hours (or in abs EtOH for 24 h), to give
lactam 7 in quantitative yield. Following N-protection, vi-
nyl phosphate 9 was prepared by treatment with potassi-
um hexamethyldisilazanide (0.5 M in toluene) at –78 °C
in tetrahydrofuran, followed by addition of diphenyl chlo-
rophosphate. Lactam-derived vinyl phosphates are report-
ed to be generally much more stable than the
corresponding triflates,16 and so we were pleased to ob-
serve that after an appropriate work-up, phosphate 9
proved stable for days as a crude reaction mixture and it
could be purified by chromatography on silica gel (99%).
We found also that if the phosphate was immediately used
after chromatography, the yields of the subsequent carbo-
N
CO2H
N
N
CO2Me
O
H
CO2Me
CO2Me
(2R,4R)-1 (100%)
14
(2R,4R)-13
(63% from 12a)
Scheme 3 Synthesis of (2R,4R)-1
We first treated compound 10b with 1.2 equivalents of
Super-Hydride (LiEt3BH) in tetrahydrofuran at 0 °C, fol-
lowed by quenching with saturated sodium hydrogen car-
1
bonate solution at –15 °C. The H NMR analysis of the
crude reaction mixture revealed that hydride conjugate
addition occurred without any concurrent reduction of the
ester and the substrate was quantitatively converted into a
2:1 mixture of the trans- and cis-isomers 12b.21 A slightly
higher ratio in favor of the trans-isomer was obtained by
applying the same procedure to the O-silyl-protected
compound 10c. In this case, the ratio between the trans-
and cis-isomers was 2.6:1.21 Eventually, with O-tert-bu-
tyl-protected compound 10a the ratio between the two iso-
Synthesis 2009, No. 21, 3611–3616 © Thieme Stuttgart · New York

PAPER
Short Synthesis of 4-Hydroxypipecolic Acids
3613
13C NMR (50.33 MHz, CDCl3): d = 170.4 (s), 117.5 (s), 75.1 (s),
mers after reduction was 4:1. The chromatographic
separation of the cis- and trans-isomers of 12a–c was dif-
64.3 (d), 60.7 (t), 41.2 (t), 28.1 (q, 3 C), 25.4 (t), 14.1 (q).
ficult and so, after deprotection of the 4-OH group, we ap- MS (EI, 70 eV): m/z (%) = 198 ([M+ – 15], 15), 140 (35), 112 (28),
57 (100).
plied the procedure described by Herdeis for a
lactonization that should involve only the cis-isomer,
leaving therefore the trans-isomer unaltered.22 Thus, the
diastereomeric mixtures of alcohol 13 obtained by depro-
tection of 12a–c were treated with 4-toluenesulfonic acid
in anhydrous toluene at 100 °C for 30 minutes and, after
workup and removal of the solvent, the corresponding
mixtures of 14 and (2R,4R)-13 were obtained. These were
easily separated by chromatography,23 which provided
pure trans-compound (2R,4R)-13 in 44% (from 12b),
50% (from 10c), and 63% (from 12a) yield over three
steps.24 Usual exhaustive hydrolysis of (2R,4R)-13 quan-
titatively provided target (2R,4R)-1 as its hydrochloride
salt. Although the selectivity in the conjugate reduction
was not higher than 4:1, however, this reaction is one of
the last steps of the synthesis and the effective loss of ma-
terial as the undesired cis-isomer is low, especially as the
O-tert-butyl protection-based strategy allows us to obtain
in a very few steps compound 10a in excellent yield.
Anal. Calcd for C11H19NO3: C, 61.95; H, 8.98; N, 6.57. Found: C,
61.98; H, 8.77; N, 6.28.
(R)-4-tert-Butoxypiperidin-2-one (7)
To a stirred soln of 6 (506 mg, 2.38 mmol) in MeOH (10 mL) was
added PtO2 (54 mg, 0.2 mmol) under N2. The mixture was flushed
with H2 and then left under static pressure of H2 (balloon) at 25 °C.
After 48 h the reaction was complete (TLC). The catalyst was fil-
tered, washed with MeOH, and the soln was concentrated under
vacuum, to give pure 7 (408 mg, 100%) as a white solid. The same
reaction can be carried out in abs EtOH, in which case it was com-
plete in 24 h; mp 102.5–103.5 °C.
[a]D20 +17.4 (c 0.35, CHCl3).
1H NMR (400 MHz, CDCl3): d = 5.78 (br s, 1 H), 3.96–3.89 (m, 1
H), 3.50–3.43 (m, 1 H), 3.34–3.20 (m, 1 H), 2.55 (dd, J = 17.6, 5.0
Hz, 1 H), 2.34 (dd, J = 17.6, 6.4 Hz, 1 H), 1.91–1.83 (m, 1 H), 1.79–
1.71 (m, 1 H), 1.12 (s, 9 H).
13C NMR (100.4 MHz, CDCl3): d = 171.6 (s), 74.0 (s), 64.0 (d), 40.7
(t), 38.4 (t), 30.2 (t), 28.3 (q, 3 C).
MS (EI, 70 eV): m/z (%) = 156 ([M+ – 15], 3), 115 (48), 98 (28), 87
(18), 72 (21), 59 (100).
In conclusion we have developed a short and convenient
synthesis of (2S,4R)- and (2R,4R)-4-hydroxypipecolic
acid starting from commercial ethyl (R)-4-cyano-3-hy-
droxybutanoate. Key steps were the palladium-catalyzed
methoxycarbonylation of an O-tert-butyl-protected 4-hy-
droxy-substituted lactam-derived vinyl phosphate and the
stereocontrolled reduction of the enamine double bond.
Anal. Calcd for C9H17NO2: C, 63.13; H, 10.01; N, 8.18. Found: C,
63.03; H, 10.00; N, 8.09.
Methyl (R)-4-tert-Butoxy-2-oxopiperidine-1-carboxylate (8)
To a cooled (–78 °C) soln of 7 (372 mg, 2.17 mmol) in anhyd THF
(9 mL) under N2, was added dropwise 1.6 M BuLi in hexane (1.49
The cis-(2S,4R)-product was obtained in 66% overall mL, 2.39 mmol, 1.1 equiv). After 40 min, methyl chloroformate
(185 mL, 2.39 mmol, 1.1 equiv) was added dropwise, the cooling
bath was removed, and the mixture was allowed to warm to 0 °C and
the mixture was stirred for a further 2 h. Then sat. aq NaHCO3 soln
(6 mL) was slowly added, followed by H2O (15 mL) and the mix-
ture was extracted with Et2O (3 × 20 mL). The combined extracts
were dried (Na2SO4) and filtered and the solvent was evaporated to
give 8 as a yellowish solid that was chromatographed (CH2Cl2–
MeOH, 40:1 + 0.1% Et3N, Rf = 0.32) to give pure 8 (438 mg, 88%)
as a white solid; mp 55–56 °C.
yield over seven steps, the trans-(2R,4R)-product in 42%
over eight steps. As ethyl (S)-4-cyano-3-hydroxybu-
tanoate is easily prepared by standard procedures from
commercial ethyl (R)-4-chloro-3-hydroxybutanoate, the
synthesis of the two enantiomers (2R,4S)- and (2S,4S)-4-
hydroxypipecolic acid is an obvious extension.
Chromatographic separations were performed under pressure on sil-
ica gel 60 (Merck, 70–230 mesh) using flash-column techniques,
PE = petroleum ether; Rf values refer to TLC carried out on 0.25-
mm silica gel plates with the same eluant indicated for column chro-
matography. THF was distilled from Na/benzophenone. CH2Cl2
and heptane were distilled from CaH2. Commercial anhyd DMF and
[a]D20 +15.5 (c 0.47, CHCl3).
1H NMR (400 MHz, CDCl3): d = 3.99–3.93 (m, 1 H), 3.89 (ddd,
J = 12.8, 8.2, 4.7 Hz, 1 H), 3.86 (s, 3 H), 3.67 (ddd, J = 12.8, 7.3,
4.7 Hz, 1 H), 2.69 (dd, J = 16.8, 5.1 Hz, 1 H), 2.53 (dd, J = 16.8, 6.6
Hz, 1 H), 2.06–1.93 (m, 1 H), 1.86–1.76 (m, 1 H), 1.18 (s, 9 H).
13C NMR (100.4 MHz, CDCl3): d = 169.9 (s), 154.8 (s), 74.2 (s),
63.7 (d), 53.9 (q), 43.8 (t), 42.7 (t), 31.2 (t), 28.2 (q, 3 C).
1
cyclohexane were used. H NMR and 13C NMR spectra were re-
corded at 25 °C. MS spectra were carried out by EI at 70 eV. Com-
pounds 2, 10b, and 10c were prepared as reported.13,25
MS (EI, 70 eV): m/z (%) = 229 ([M+], 3), 173 (30), 156 (25), 102
(22), 88 (20), 57(100).
Ethyl (R)-3-tert-Butoxy-4-cyanobutanoate (6)
To a soln of (R)-5 (1.257 g, 8.0 mmol) in t-BuOAc (100 mL) was
added dropwise HClO4 (48 mL, 0.8 mmol) and the mixture was
stirred at 25 °C for 24 h. Then sat. aq Na2CO3 soln (50 mL) was add-
ed, the mixture was extracted with EtOAc (3 × 30 mL) and the com-
bined organic layers were washed with sat. NaHCO3 (50 mL) and
dried (K2CO3). After filtration and evaporation of the solvent, 6
(1.65 g, 97%) was obtained as a pale yellow liquid, which can di-
rectly be used in the next step. Chromatography (EtOAc–n-hexane,
1:3, Rf = 0.3), gave 6 (1.602 g, 94%) as a pale yellow oil.
[a]D20 –9.0 (c 2.00, CHCl3).
1H NMR (200 MHz, CDCl3): d = 4.15–4.03 (m, 1 H + 2 H), 2.62–
2.54 (m, 4 H), 1.26–1.15 (m, 9 H + 3 H).
Anal. Calcd for C11H19NO4: C, 57.62; H, 8.35; N, 6.11. Found: C,
57.41; H, 8.13; N, 6.02.
Methyl (R)-4-tert-Butoxy-6-[(diphenoxyphosphoryl)oxy]-3,4-
dihydropyridine-1(2H)-carboxylate (9)
To a 0.5 M soln of KHMDS in toluene (4.7 mL, 2.35 mmol) in THF
(12.5 mL), cooled to –78 °C and under N2, was added a soln of 8
(430 mg, 1.88 mmol) in THF (5 mL) and the resulting mixture was
stirred for 1.5 h. Then a soln of (PhO)2P(O)Cl (487 mL, 2.35 mmol)
in THF (4 mL) was added and the mixture was stirred at –78 °C for
1 h; the temperature was allowed to rise to 0 °C. Then, 10% aq
NaOH soln (38 mL) was added and the mixture was extracted with
Et2O (3 × 30 mL). The combined extracts were washed with 10%
Synthesis 2009, No. 21, 3611–3616 © Thieme Stuttgart · New York

3614
E. G. Occhiato et al.
PAPER
NaOH (24 mL) and dried (anhyd K2CO3 for 30 min). After filtration
and evaporation of the solvent (without heating and leaving a small
volume of solvent), the crude phosphate was chromatographed (sil-
ica gel 3.5 cm in a column with i.d. of 3 cm, EtOAc–n-hexane,
30:70 + 1% Et3N, Rf = 0.27) to give 9 (856 mg, 99%) as a pale yel-
low oil.
1H NMR (200 MHz, CDCl3): d = 7.32–7.17 (m, 10 H), 4.92 (br s, 1
H), 3.65–3.60 (m, 1 H), 3.52 (s, 3 H), 3.49–3.21 (m, 2 H), 1.82–1.64
(m, 2 H), 1.14 (s, 9 H).
MS (EI, 70 eV): m/z (%) = 273 ([M+], 3]), 214 (52), 199 (13), 158
(100), 140 (32), 114 (39), 57 (42).
Anal. Calcd for C13H23NO5: C, 57.13; H, 8.48; N, 5.12. Found: C,
57.11; H, 8.37; N, 5.07.
(2S,4R)-4-Hydroxypiperidine-2-carboxylic Acid Hydrochloride
Salt [(2S,4R)-1·HCl]7c,13,22b
A suspension of 11 (38.7 mg, 0.14 mmol) in aq 2 M HCl (6 mL) was
refluxed under stirring for 18 h. After cooling, the mixture was
washed with Et2O (2 × 8 mL) and concentrated. The residue was
triturated with acetone and dried under vacuum for 24 h. Salt
(2S,4R)-1·HCl (25 mg, 100%) was obtained as a white foamy solid.
Spectroscopic data as reported.13,22b
13C NMR (50.33 MHz, CDCl3): d = 154.1 (s), 150.4 (s), 141.1 (s),
129.7 (d, 4 C), 125.3 (d, 2 C), 120.1 (d, 4 C), 102.2 (d), 74.1 (s), 61.9
(d), 53.1 (q), 42.9 (t), 32.7 (t), 28.1 (q, 3 C).
Dimethyl (R)-4-tert-Butoxy-5,6-dihydropyridine-1,2(4H)-dicar-
boxylate (10a)
[a]D25 +9.5 (c 0.53 MeOH) [Lit.7c [a]D25 +9.9 (c 1.01 MeOH, 95.8%
ee)].
Phosphate 9 (856 mg, 1.86 mmol) was immediately dissolved in
DMF (4.8 mL), Pd(OAc)2 (42 mg, 0.186 mmol), and Ph3P (97 mg,
0.372 mmol) were added and the soln was stirred for 10 min under
a CO atmosphere (balloon). Then Et3N (516 mL, 3.72 mmol) and
MeOH (3 mL, 74.4 mmol) were added and stirring was continued
at 55 °C (external bath) for 3 h under static CO pressure. The soln
was filtered through Celite and the MeOH was evaporated. The res-
idue was diluted with H2O (40 mL) and extracted with Et2O (3 × 40
mL). The combined extracts were dried (Na2SO4) and filtered and
the solvent was evaporated to give an oily residue that was chro-
matographed (EtOAc–n-hexane, 1:2 + 1% Et3N, Rf = 0.33) to give
10a (408 mg, 81%) as a thick pale yellow oil.
Dimethyl (2R/S,4R)-4-tert-Butoxypiperidine-1,2-dicarboxylate
(12a) and Dimethyl (2R,4R)-4-Hydroxypiperidine-1,2-dicar-
boxylate [(2R,4R)-13]
Dimethyl (2R/S,4R)-4-tert-Butoxypiperidine-1,2-dicarboxylate
(12a); Typical Procedure from 10a
To a soln of 10a (135.6 mg, 0.5 mmol) in anhyd THF (1.7 mL),
cooled at 0 °C and under N2, was added dropwise 1 M LiEt3BH in
THF (600 mL, 0.60 mmol). The mixture was stirred at 0 °C for 1 h,
then it was cooled to –15 °C and quenched with sat. aq NaHCO3
soln (5 mL). The mixture was extracted with CH2Cl2 (5 × 15 mL)
and the combined extracts were washed with H2O (15 mL) and
dried (Na2SO4). After filtration and evaporation of the solvent,
MeOH (5 mL) was added and the solvent evaporated again. This op-
eration was repeated two times providing trans-12a with its cis-iso-
mer; yield: 127 mg (93%); ratio trans/cis 4:1 (by 1H NMR).21
1H NMR (400 MHz, CDCl3): d = 5.02 (br s, major rotamer, 1 H) and
4.86 (br s, minor rotamer, 1 H), 4.16 (br d, J = 12.9 Hz, minor rota-
mer, 1 H) and 4.02 (br d, J = 13.7 Hz, major rotamer, 1 H), 3.76 (s,
3 H), 3.74–3.65 (m, 3 H + 1 H), 3.13–2.91 (m, 1 H), 2.38–2.25 (br
m, 1 H), 1.83–1.67 (m, 1 H), 1.66–1.54 (m, 1 H), 1.51–1.36 (m, 1
H), 1.18 (s, 9 H).
[a]D23 +157 (c 0.54, CHCl3).
1H NMR (400 MHz, CDCl3): d = 5.87 (d, J = 3.9 Hz, 1 H), 4.07–
4.16 (m, 1 H), 3.97 (dt, J = 12.9, 4.3 Hz, 1 H), 3.76 (s, 3 H), 3.71 (s,
3 H), 3.28 (ddd, J = 12.9, 8.9, 4.7 Hz, 1 H), 1.89–1.81 (m, 2 H), 1.21
(s, 9 H).
13C NMR (50.33 MHz, CDCl3): d = 164.7 (s), 153.8 (s), 132.3 (s),
122.5 (d), 74.1 (s), 60.6 (d), 52.8 (q), 51.8 (q), 40.5 (t), 32.4 (t), 27.8
(q, 3 C).
MS (EI, 70 eV): m/z (%) = 271 ([M+], 18), 198 (87), 183 (100), 94
(82), 80 (42), 57 (79).
Dimethyl (2R,4R)-4-Hydroxypiperidine-1,2-dicarboxylate
[(2R,4R)-13]
Anal. Calcd for C13H21NO5: C, 57.55; H, 7.80; N, 5.16. Found: C,
57.41; H, 7.67; N, 5.01.
The above 4:1 mixture of 12a was then dissolved in MeCN (6 mL)
and PTSA·H2O (105 mg, 0.55 mmol) was added, and the mixture
was stirred vigorously at 25 °C for 24 h [TLC monitoring (EtOAc–
n-hexane, 1:1)]. The soln was filtered through a short pad of Celite–
NaHCO3 (1:1) and concentrated. The residue (91 mg) was dissolved
in anhyd toluene (3.0 mL) and PTSA (43 mg, 0.25 mmol) was add-
ed. The mixture was then heated at 100 °C (external bath) with stir-
ring under N2. After 30 min the soln was cooled to r.t. and
concentrated. The residue was chromatographed (EtOAc–PE, 1:1,
Rf = 0.13) to give (2R,4R)-13 (68 mg, 63% from 12a) as a colorless
oil.
Dimethyl (2S,4R)-4-tert-Butoxypiperidine-1,2-dicarboxylate
(11)
To a stirred suspension of NaHCO3 (86 mg) in EtOAc (11 mL) was
added 10% Pd/C (50% wet, 142.5 mg) under N2. The mixture was
flushed with H2 and then stirring was continued for 30 min. The soln
of 10a (114 mg, 0.42 mmol) in EtOAc (1 mL) was added via mi-
crosyringe and the suspension was stirred at r.t. for 4 h under static
H2 pressure. After filtration through a Celite layer, and evaporation
of the solvent, the crude reaction was purified by chromatography
(EtOAc–n-hexane, 1:4, Rf = 0.15), to give 11 (115 mg, 100%) as a
colorless oil; 19:1 diastereomeric mixture.
[a]D25 +21.5 (c 0.6, CHCl3).
1H NMR (400 MHz, CDCl3): d = 5.04 (br s, 1 H) and 4.90 (br s, mi-
nor rotamer, 1 H), 4.18 (br d, J = 12.1 Hz, minor rotamer, 1 H) and
4.06 (br d, J = 12.0 Hz, major rotamer, 1 H), 3.75–3.61 (m, 3 H + 3
H + 1 H), 3.15–2.95 (m, 1 H), 2.47 (br d, J = 11.7 Hz, 1 H), 1.96–
1.84 (m, 1 H), 1.66–1.56 (m, 1 H), 1.47–1.37 (m, 1 H).
13C NMR (100.4 MHz, CDCl3): d = 171.5 (s), 156.4 (s), 65.9 (d),
54.2 (d), 53.1 (q), 52.4 (q), 40.3 (t), 35.4 (t), 33.9 (t).
[a]D25 –14.3 (c 2.00, CHCl3).
1H NMR (400 MHz, CDCl3): d = 4.80 (br d, J = 5.9 Hz, major rot-
amer, 1 H) and 4.64 (br d, J = 5.5 Hz, minor rotamer, 1 H), 3.93 (br
d, J = 13.3 Hz, minor rotamer, 1 H) and 3.78 (br d, J = 13.1 Hz, ma-
jor rotamer, 1 H), 3.86–3.76 (m, 1 H), 3.71 (s, 3 H + 3 H of the major
rotamer), 3.67 (s, 3 H, minor rotamer), 3.56–3.38 (m, 1 H), 2.36–
2.26 (m, 1 H), 1.83–1.75 (m, 1 H), 1.60–1.50 (m, 2 H), 1.11 (s, 9 H).
13C NMR (50.33 MHz, CDCl3): d = 172.4 (s), 158.6 (s) and 158.5
(s), 73.5 (s), 61.9 (d), 52.8 (q), 51.7 (q) and 51.4 (q), 36.6 (t), 33.7
(t), 31.7 (t), 27.9 (q, 3 C).
MS (EI, 70 eV): m/z (%) = 217 ([M+], 1), 158 (100), 140 (14), 114
(62).
Anal. Calcd for C9H15NO5: C, 49.76; H, 6.96; N, 6.45. Found: C,
49.58; H, 6.85; N, 6.37.
Synthesis 2009, No. 21, 3611–3616 © Thieme Stuttgart · New York

PAPER
Short Synthesis of 4-Hydroxypipecolic Acids
3615
Dimethyl (2R/S,4R)-4-(4-Methoxybenzyloxy)piperidine-1,2-di-
carboxylate (12b) and Dimethyl (2R,4R)-4-hydroxypiperidine-
1,2-dicarboxylate [(2R,4R)-13]
washed with Et2O (2 × 8 mL), and concentrated. The residue was
triturated with acetone and dried under vacuum for 24 h. Salt
(2R,4R)-1·HCl (25 mg, 100%) was obtained as a white foamy solid.
Dimethyl (2R/S,4R)-4-(4-Methoxybenzyloxy)piperidine-1,2-di-
carboxylate (12b)
[a]D20 –2.6 (c 0.95, 6 M HCl) [Lit.26a [a]D20 –2.7 (c 1.0, 6 M HCl)].
1H NMR (400 MHz, D2O): d = 4.32–4.26 (br m, 1 H), 4.26 (dd,
Following the typical procedure for 12a using 10b (193 mg, 0.58
mmol) in anhyd THF (2 mL) and 1 M LiEt3BH in THF (690 mL,
0.69 mmol) gave trans-12b with its cis-isomer; yield: 186 mg
(95%); ratio trans/cis 2:1 (by 1H NMR).
1H NMR (400 MHz, CDCl3): d (attributable signals) = 5.06 (br s, 1
H) and 4.91 (br s, minor rotamer, 1 H), 4.48 (s, 2 H), 4.20 (br d,
J = 11.1 Hz, minor rotamer, 1 H) and 4.06 (br d, J = 11.2 Hz, major
rotamer, 1 H), 3.80–3.60 (m, 1 H), 3.81 (s, 3 H), 3.80 (s, 3 H), 3.72
and 3.70 (s, 3 H, two rotamers), 3.11–2.94 (m, 1 H), 2.61–2.50 (br
m, 1 H), 2.02–1.94 (m, 1 H), 1.67–1.56 (m, 1 H), 1.50–1.37(m, 1 H).
J = 12.3, 3.5 Hz, 1 H), 3.43–3.34 (m, 2 H), 2.31 (dt, J = 14.6, 3.2
Hz, 1 H), 2.06 (t, J = 12.6 Hz, 1 H), 1.96–1.89 (m, 2 H) [Lit.26a 1
H
NMR (D2O): d = 4.40–4.20 (m, 2 H), 3.50–3.35 (m, 2 H), 2.33 (td,
J = 14.8, 3.8 Hz, 1 H), 2.20–2.10 (m, 1 H), 2.05–1.90 (m, 2 H)].
Acknowledgment
We thank Ministero dell’Università e della Ricerca (MIUR) and
Università di Firenze for financial support, and Cassa di Risparmio
di Firenze for granting a 400 MHz NMR spectrometer. Dr Luca
Rosi is acknowledged for its help in some high pressure hydrogena-
tion reactions. Dr. Sandro Barge is acknowledged for suggesting the
O-tert-butyl protection procedure. Maurizio Passaponti and Brunel-
la Innocenti are acknowledged for their technical support.
Dimethyl (2R,4R)-4-hydroxypiperidine-1,2-dicarboxylate
[(2R,4R)-13]
The above 2:1 mixture of 12b was dissolved in EtOAc (6.5 mL) and
10% Pd/C (58 mg) was added under N2. The mixture was flushed
with H2 and then left under static pressure of H2 (balloon) at 25 °C.
After 48 h the catalyst was filtered, washed with EtOAc, and the
soln concentrated. The residue (116 mg) was dissolved in anhyd tol-
uene (4 mL) and PTSA (55 mg, 0.32 mmol) was added. The mixture
was then heated at 100 °C (external bath) with stirring and under N2.
After 30 min the soln was cooled to r.t. and concentrated. The resi-
due was chromatographed (EtOAc–PE, 1:1, Rf = 0.13) to give
(2R,4R)-13 (55 mg, 44% from 10b) as a colorless oil. Spectroscopic
and analytical data as reported above.
References
(1) (a) Romeo, J. T.; Swain, L. A.; Bleecker, A. B.
Phytochemistry 1983, 22, 1615. (b) Schenk, V. W.; Schutte,
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Dimethyl (2R/S,4R)-4-(tert-Butyldimethylsiloxy)piperidine-1,2-
dicarboxylate (12c) and Dimethyl (2R,4R)-4-Hydroxypiperi-
dine-1,2-dicarboxylate [(2R,4R)-13]
Dimethyl (2R/S,4R)-4-(tert-Butyldimethylsiloxy)piperidine-1,2-
dicarboxylate (12c)
Following the typical procedure for 12a using 10c (170 mg, 0.52
mmol) in anhyd THF (1.8 mL) and LiEt3BH in THF (620 mL, 0.62
mmol) gave trans-12c with its cis-isomer; yield: 157 mg (91%); ra-
tio trans/cis 2.6:1 (by 1H NMR).
1H NMR (400 MHz, CDCl3): d (attributable signals) = 4.98 (br s,
major rotamer, 1 H) and 4.83 (br s, minor rotamer, 1 H), 4.13 (br d,
J = 13.1 Hz, minor rotamer, 1 H) and 3.98 (br d, J = 12.9 Hz, major
rotamer, 1 H), 3.80–3.60 (m, 1 H), 3.72 (s, 3 H), 3.70 and 3.68 (s, 3
H, two rotamers), 3.10–2.89 (m, 1 H), 2.37–2.27 (br m, 1 H), 1.88–
1.70 (m, 1 H), 1.66–1.50 (m, 1 H), 1.48–1.35 (m, 1 H), 0.85 (s, 9 H),
0.02 (s, 6 H).
(5) Gupta, R. K.; Krishnamurti, M. Phytochemistry 1979, 18,
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Wardrop, E.; Bourgon, L.; Thibeault, D.; Clouette, C.;
Vaillancourt, M.; Cohen, E.; Pargellis, C.; Yoakim, C.;
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Dimethyl (2R,4R)-4-Hydroxypiperidine-1,2-dicarboxylate
[(2R,4R)-13]
The above 2.6:1 mixture of 12c was then dissolved in MeCN (18
mL) and 3 M HCl soln was added (18 mL), and the mixture was
stirred vigorously at 25 °C for 4 h [TLC monitoring (EtOAc–PE,
1:1)]. The soln was transferred into a separatory funnel, neutralized
with sat. NaHCO3, and extracted with EtOAc (4 × 15 mL). The
combined organic layers were dried (Na2SO4), filtered, and concen-
trated. The residue (102 mg) was dissolved in anhyd toluene (3.5
mL) and PTSA (48 mg, 0.28 mmol) was added. The mixture was
then heated at 100 °C (external bath) with stirring and under N2. Af-
ter 30 min the soln was cooled to r.t., and concentrated. The residue
was chromatographed (EtOAc–PE, 1:1, Rf = 0.13) to give (2R,4R)-
13 (56 mg, 50% from 12c) as a colorless oil. Spectroscopic and an-
alytical data as reported above.
(10) Bellier, B.; Da Nascimiento, S.; Meudal, H.; Gincel, E.;
Roques, B. P.; Garbay, C. Bioorg. Med. Chem. Lett. 1998, 8,
1419.
(11) For a recent review on the asymmetric synthesis of pipecolic
acids and derivatives see: (a) Kadouri-Puchot, C.; Comesse,
S. Amino Acids 2005, 29, 101. (b) Cordero, F. M.; Bonollo,
S.; Machetti, F.; Brandi, A. Eur. J. Org. Chem. 2006, 3235.
(2R,4R)-4-Hydroxypiperidine-2-carboxylic Acid Hydrochlo-
ride Salt [(2R,4R)-1·HCl]26
A suspension of (2R,4R)-13 (30 mg, 0.14 mmol) in aq 2 M HCl (17
mL) was refluxed with stirring for 18 h. The mixture was cooled,
Synthesis 2009, No. 21, 3611–3616 © Thieme Stuttgart · New York

3616
E. G. Occhiato et al.
PAPER
(12) (a) Sun, C.-S.; Lin, Y.-S.; Hou, D.-R. J. Org. Chem. 2008,
73, 6877. (b) Lloyd, R. C.; Lloyd, M. C.; Smith, M. E. B.;
Holt, K. E.; Swift, J. P.; Keene, P. A.; Taylor, S. J. C.;
McCague, R. Tetrahedron 2004, 60, 717. (c) Marin, J.;
Didierjean, C.; Aubry, A.; Casimir, J.-R.; Briand, J.-P.;
Guichard, G. J. Org. Chem. 2004, 69, 130. (d) Celestini, P.;
Danieli, B.; Lesma, G.; Sacchetti, A.; Silvani, A.; Passarella,
D.; Virdis, A. Org. Lett. 2002, 4, 1367. (e) Greshock, T. J.;
Funk, R. L. J. Am. Chem. Soc. 2002, 124, 754. (f) Agami,
C.; Bisaro, F.; Comesse, S.; Guesné, S.; Kadouri-Puchot, C.;
Morgentin, R. Eur. J. Org. Chem. 2001, 2385. (g) Sabat,
M.; Johnson, C. R. Tetrahedron Lett. 2001, 42, 1209.
(h) Davis, F. A.; Fang, T.; Chao, B.; Burns, D. M. Synthesis
2000, 2106. (i) Brooks, C. A.; Comins, D. L. Tetrahedron
Lett. 2000, 41, 3551. (j) Haddad, M.; Larchevêque, M.
Tetrahedron: Asymmetry 1999, 10, 4231. (k) Di Nardo, C.;
Varela, O. J. Org. Chem. 1999, 64, 6119. (l) Golubev, A.;
Sewald, N.; Burger, K. Tetrahedron Lett. 1995, 36, 2037.
(13) Occhiato, E. G.; Scarpi, D.; Guarna, A. Eur. J. Org. Chem.
2008, 524.
(21) Compounds trans-12a, trans-12b, and trans-12c13 are easily
differentiated from the corresponding cis-compounds by 1H
NMR analysis. In trans-compounds, the H2 is shifted
downfield [trans-12a: d = 5.02 and 4.86 (two rotamers);
trans-12b: d = 5.06 and 4.91 (two rotamers); trans-12c: d =
4.98 and 4.83 (two rotamers)] and H6axial is upfield shifted
(~3.00 ppm in trans-12a,b,c) compared to the corresponding
protons in the cis-isomers: H2 resonates at cis-12a: d = 4.80
and 4.64, cis-12b: d = 4.77 and 4.62, cis-12c: d = 4.78 and
4.63; H6axial resonates for cis-12a–c at ca. d = 3.45. The same
applies to the corresponding alcohols: in trans-compound 13
H2 resonates at d = 5.04 and 4.90 (two rotamers) and H6axial
at ca. d = 3.0. In the corresponding cis-isomer,13 H2
resonates at d = 4.85 and 4.70 (two rotamers) and H6axial is
shifted downfield to d = 3.4.
(22) (a) Herdeis, C.; Engel, W. Arch. Pharm. (Weinheim) 1993,
326, 297. (b) Herdeis, C.; Engel, W. Arch. Pharm.
(Weinheim) 1992, 325, 419.
(23) Compound 14 was recovered only in traces after
chromatography as it probably decomposed in part.
Compound 14 has a diagnostic downfield shifted H4 proton
to d = 4.97, in accordance with the value (d = 4.90–5.00)
reported for the analogous N-tosyl and N-Cbz compounds
(see ref. 22). 14: 1H NMR (200 MHz, CDCl3): d = 4.97 (m,
1 H), 4.90–4.70 (br m, 1 H), 4.30–4.00 (br m, 1 H), 3.74 (s,
3 H), 3.35–3.15 (br m, 1 H), 2.55–2.40 (m, 1 H), 2.40–2.37
(m, 1 H), 2.14–2.05 (m, 1 H), 1.98–1.85 (m, 1 H).
(24) Compound (2R,4R)-13, possessing trans-stereochemistry, is
easily differentiated by 1H NMR from its cis-isomer
especially as the axially oriented proton on C4 is now
shielded from d = 4.15 to 3.70. Moreover in the trans-
compound there is an NOE enhancement between H4 and
H6axial. Enantiopure cis-isomer (2S,4R)-13 has been already
prepared by us (see ref. 13) and, in its racemic form, by
Hiemstra and Speckamp. See: (a) Esch, P. M.; de Boer, R.
F.; Hiemstra, H.; Boska, I. M.; Speckamp, W. N.
(14) (a) Anelli, P. L.; Fedeli, F.; Gazzotti, O.; Lattuada, L.; Lux,
G.; Rebasti, F. Bioconjugate Chem. 1999, 10, 137.
(b) Chen, H.; Feng, Y.; Xu, Z.; Ye, T. Tetrahedron 2005, 61,
11132.
(15) Purification is not necessary, but a much cleaner lactam is
obtained if the protected nitrile is purified by
chromatography.
(16) For a review see: (a) Occhiato, E. G. Mini-Rev. Org. Chem.
2004, 1, 149. Recent progresses in the use of heterocyclic-
derived vinyl phosphates: (b) Claveau, E.; Gillaizeau, I.;
Blu, J.; Bruel, A.; Coudert, G. J. Org. Chem. 2007, 72, 4832;
and references therein. (c) Lo Galbo, F.; Occhiato, E. G.;
Guarna, A.; Faggi, C. J. Org. Chem. 2003, 68, 6360.
(17) Cacchi, S.; Morera, E.; Ortar, G. Tetrahedron Lett. 1985, 26,
1109.
(18) Elimination of ROH to give an a,b,g,d-unsaturated ester has
been sometime observed by us in the presence of acids, even
when compound 10 was stored in fridge and traces of acids
were present. The same elimination occurs with phosphate 9.
(19) Kaisalo, L. H.; Hase, T. A. Tetrahedron Lett. 2001, 42, 7699.
(20) Crabtree, R. H.; Davis, M. W. J. Org. Chem. 1986, 51, 2655;
The reaction was carried out in CH2Cl2 under H2 at 1 atm (no
conversion after 24 h) and 50 atm. In the latter case we
observed a certain degree of conversion after 24 h (40%) but
the facial selectivity was poor (ratio trans/cis ~3:2).
Tetrahedron 1991, 47, 4063. (b) Esch, P. M.; Boska, I. M.;
Hiemstra, H.; de Boer, R. F.; Speckamp, W. N. Tetrahedron
1991, 47, 4039.
(25) Bartali, L.; Scarpi, D.; Guarna, A.; Prandi, C.; Occhiato, E.
G. Synlett 2009, 913.
(26) (a) Agami, C.; Couty, F.; Poursoulis, M.; Vaissermann, J.
Tetrahedron 1992, 48, 431. (b) Golubev, A. S.; Sewald, N.;
Burger, K. Tetrahedron 1996, 52, 14757.
Synthesis 2009, No. 21, 3611–3616 © Thieme Stuttgart · New York