A new asymmetric synthesis of (2S,3R,4R,5S)-trihydroxypipecolic acid

Article abstract of DOI:10.1016/j.tetasy.2007.06.015

A novel four step synthesis of enantiomerically pure (2S,3R,4R,5S)-trihydroxypipecolic acid, starting from readily available materials, that is, condensation products of (R)-(-)-phenylglycinol with a mesotrihydroxylated glutaraldehyde, is described. The s

Full text of DOI:10.1016/j.tetasy.2007.06.015

Tetrahedron: Asymmetry 18 (2007) 1585–1588
A new asymmetric synthesis of (2S,3R,4R,5S)-
trihydroxypipecolic acid
Andriamihamina Tsimilaza,a Tony Tite,a Sabrina Boutefnouchet,a
Marie-Christine Lallemand,a,* Franc¸ois Tillequina and Henri-Philippe Hussonb,*
aLaboratoire de Pharmacognosie, Faculte´ des Sciences Pharmaceutiques et Biologiques,
`
´
UMR 8638 Associe´e au CNRS et a l’Universite Paris-Descartes, 4, Avenue de l’Observatoire, 75270 Paris Cedex 06, France
bLaboratoire de Chimie The´rapeutique, Faculte´ des Sciences Pharmaceutiques et Biologiques,
`
´
UMR 8638 Associe´e au CNRS et a l’Universite Paris-Descartes, 4, Avenue de l’Observatoire, 75270 Paris Cedex 06, France
Received 7 June 2007; accepted 14 June 2007
Abstract—A novel four step synthesis of enantiomerically pure (2S,3R,4R,5S)-trihydroxypipecolic acid, starting from readily available
materials, that is, condensation products of (R)-(À)-phenylglycinol with a mesotrihydroxylated glutaraldehyde, is described. The scope
and limitations of the reaction have also been investigated.
ꢀ 2007 Elsevier Ltd. All rights reserved.
1. Introduction
Ph
Ph
OH
H
N
O
O
NC
HO
N
NC
HO
N
Chemists have been inspired by the numerous bioactivities
of the non-proteinogenic aminoacid pipecolic acid. There-
fore, derivatives have been developed as well as many
new enantioselective methods towards their synthesis.1
Substituted pipecolic acids are key constituents of many
synthetic and natural bioactive molecules and are useful
building blocks for the preparation of peptides and peptide
mimetics.2 The replacement of simple amino acids by cyclic
amino acids has been carried out in structure–activity rela-
tionship studies towards peptides with improved pharma-
cological profiles.3 These factors have contributed to the
growing interest in finding a convenient and efficient syn-
thetic route to pipecolic acid and related amino acids. Fol-
lowing our research on the synthesis of carbohydrate
mimetics,4,5 we herein report a convenient method, which
O
HO
OH
OH
OH
OH
OH
1a
OH
1b
(2S,3R,4R,5S)-trihydroxy
pipecolic acid
Figure 1.
facile preparation of building blocks 1a and 1b (Fig. 1),
obtained by the condensation of (R)-(À)-phenylglycinol
with a mesotrihydroxylated glutaraldehyde.
Compounds 1a and 1b appeared to be suitable starting
materials for the development of a straightforward prepa-
ration of polyhydroxylated pipecolic acids, via a process
involving only a few synthetic steps.
provides
a very short enantioselective synthesis of
(2S,3R,4R,5S)-trihydroxypipecolic acid (Fig. 1).
Since the use by Husson et al. of (R)- or (S)-phenylglycinol
as a chiral inductor and nitrogen protective group,6–9
a
2. Results and discussion
considerable interest has been devoted to these b-amino-
alcohols.10–12 In a preliminary report,13 we disclosed the
Our first attempts were conducted on 2a, obtained by the
benzylation of major compound 1a (Scheme 1). Treatment
of 2a with triethylsilane used as a reducing agent, in the
presence of titanium(IV) chloride, gave two different
products depending on the reaction temperature.
*
Corresponding authors. Tel.: +33 1 5373 9693; fax: +33 1 4046 9658
(M.-C.L.); e-mail: marie-christine.lallemand@univ-paris5.fr
0957-4166/$ - see front matter ꢀ 2007 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetasy.2007.06.015

1586
A. Tsimilaza et al. / Tetrahedron: Asymmetry 18 (2007) 1585–1588
8
In contrast, when the same reduction was performed at a
Ph
Ph
NC
Ph
OH
lower temperature, the desired compound 3a was obtained
O
1
exclusively (Scheme 1). A careful analysis by H and 13C
O
N
NC
RO
N
N
Et3SiH /TiCl4
CH2Cl2
6
+
O
NMR allowed us to establish its structure and stereochem-
istry. The characteristic features of the 13C NMR spectrum
of 3a included carbon resonances at 49.0 and 68.1 ppm cor-
responding to C-6 and C-8, respectively. The IR spectrum
showed a signal at 3220 cmÀ1, typical for a hydroxyl
function.
BnO
OBn
OR
OSiEt3
OBn
3a
-
OR
1a R=H
2a R=OBn
4
0 °C
35%
48 hours
4 hours
20%
-40 °C
-78 °C
-
-
All our attempts towards hydrolysis of the nitrile of 3a,
into the corresponding carboxylic group, remained unsuc-
cessful. For instance, treatment of 3a with potassium car-
bonate in acetone did not allow us to obtain the desired
lactone, most probably due to the presence of the adjacent
benzyl group at the C-3 position, which hinders the b-face
preventing the hydroxyl attack (Scheme 3).
48 hours
68%
Scheme 1.
At 0 ꢁC, the exclusive formation of lactone 4 was observed,
according to the postulated mechanism represented in
Scheme 2. It is proposed that the process begins with reduc-
tion of the oxazolidine system in the presence of Et3SiH,
permitting the lactone cyclization. Subsequent benzyloxyl
elimination gave the pyridinium intermediate, which was
converted by the reducing agent into the corresponding
1,2 dihydropyridine. Formation of compound 4 was
achieved, after oxidation of triethylsilane, by a nucleophilic
attack of the consequent anion on the conjugated system.
Indeed, when the same reaction sequence was performed
from compound 2b, obtained by the benzylation of minor
compound 1b, compound 3b was obtained and could be
converted into the corresponding lactone 5 in 60% yield
by the use of potassium carbonate in acetone (Scheme 4).
The structure of 3b and 5 were unambiguously deduced
from their spectra data. Indeed, in the ESI mass spectrum
of compound 3b, a pseudomolecular ion [M+Na]+ = 571
was observed. The structure and stereochemistry of 3b were
The stereoselectivity of the reaction is not directly con-
trolled by the steric interaction of the phenyl group, but
by the conformation of the bicyclic ring system. This phe-
nomenon had been previously observed in the Michael
addition of an organocuprate on a related lactone.14 The
structure of compound 4 was ascertained by typical
NMR signals at d = 6.10 ppm and at d = 110.5 ppm, ob-
served in the 1H and 13C NMR spectra, respectively, attrib-
uted to the C-9 position. The equatorial position of the
silyloxy substituent at C-7 is consistent with the constant
(J = 9 Hz) between H-6ax and H-7ax.
1
further corroborated by a careful analysis of the H and
13C NMR spectra. The structure of lactone 5 was ascer-
tained by typical NMR signals at d = 3.33 ppm and at
1
d = 64.0 ppm, observed in the H and 13C NMR spectra,
Ph
NC
Ph
OH
O
K2CO3
N
N
acetone x
O
3
TiCl4
BnO
OBn
BnO
OBn
OBn
OBn
3a
Scheme 3.
Ph
Ph
OH
H
O
NC
H
N
NC
N
Et3SiH /TiCl4
CH2Cl2
Ph
Ph
OH
K2CO3
acetone
BnO
OBn
BnO
OBn
O
NC
N
NC
RO
N
Et3SiH/TiCl4
CH2Cl2
OBn
3a
OBn
2a
TiCl4
BnO
OBn
OR
OBn
OR
Ph
Ph
Ph
O
O
O
1b R=H
3b Yield= 40%
N
N
2b R=OBn
Et3SiH
N
O
O
O
H+
OH
H
Ph
O
N
O
OBn
Et3SiH
1
H2, Pd(OH)2/C
ethanol
N
1a
O
Ph
Et3SiO-
HO
OH
O
4 bars
BnO
OBn
OH
1
N
OBn
5 Yield =60%
(2S,3R,4R,5S)-trihydroxy
O
6
pipecolic acid
9
O2
OSiEt3
Yield = 85%
4
Scheme 2. Postulated mechanism.
Scheme 4.

A. Tsimilaza et al. / Tetrahedron: Asymmetry 18 (2007) 1585–1588
1587
respectively, attributed to the C-1a position (Scheme 4), de-
shielded by the adjacent carbonyl group.
4.5. Hexahydro-3-phenyl-6,7,8-tribenzyloxy-(3R)-
[3a,5b,6a,7b,8a,8ab]-5H-oxazolo[3,2-a]pyridine-5-carbo-
nitrile 2b
Catalytic hydrogenolysis of 5 in ethanol, implying simulta-
neous recovery of the carboxylic function, debenzylation
and removal of the chiral appendage, afforded the desired
compound (Scheme 4). The absolute configuration of
(2S,3R,4R,5S)-trihydroxypipecolic acid was determined
by NMR analysis and by comparing the specific rotation
with that in the literature.15–17
Sodium hydride (865 mg, 36.2 mmol) was added under
argon to a solution of compound 1b (1 g, 3.62 mmol) in
dry DMF (40 mL). The reaction mixture was stirred for
1 h at rt and cooled to 0 ꢁC. A solution of freshly distilled
benzyl bromide (9.5 mL, 79.64 mmol) was then added
dropwise. Stirring was continued for 22 h at rt. After the
addition of methanol (17 mL), the mixture was stirred
continuously for a further hour. The reaction mixture
was then quenched by adding a saturated aqueous sodium
hydrogeno-carbonate solution (30 mL). The mixture was
extracted with CH2Cl2 (4 · 120 mL), the combined organic
layers were dried with Na2SO4 and the solvent was evapo-
rated under reduced pressure. Flash chromatography of
the resulting yellow oil on silica gel (cyclohexane/AcOEt,
9:1) yielded 2b (1.5 g, 75%) as an oil. Rf = 0.48 (cyclo-
hexane/AcOEt, 8:2). [a]D = À35 (c 0.2, CHCl3). IR
3. Conclusion
In conclusion, we have developed a convenient and expedi-
tious method for the synthesis of enantiomerically pure
polyhydroxylated pipecolic acid, starting from readily
available materials. There is a general interest in the syn-
thesis of chiral substrates with a substituted poly-
hydroxypiperidine core, since they are related to
remarkable glycosidase inhibitors. Efforts in this direction
are currently being pursued in our laboratory.
(KBr): m = 2229 cmÀ1 1H NMR (CDCl3): d = 3.74 (t,
.
J = 2.5 Hz, 1H, 6-H), 3.82 (dd, J = 7.5, 8.5 Hz, 1H, 2-H),
3.86 (t, J = 2.5 Hz, 1H, 7-H), 3.93 (t, J = 2.5 Hz, 1H,
8-H), 4.01 (d, J = 2.5 Hz, 1H, 5-H), 4.06 (dd, J = 7.5,
8.5 Hz, 1H, 3-H), 4.31 (t, J = 7.5 Hz, 1H, 2-H), 4.3–4.6
(2d AB, J = 12.5 Hz, 4H, O–CH2-Ph), 4.72 (d,
J = 2.5 Hz, 1H, 8a-H), 4.7–4.9 (2d AB, J = 12.5 Hz,
2H, O–CH2-Ph), 7.2–7.4 (m, 20H, arom.). 13C NMR
(CDCl3): d = 49.3 (C-5), 63.4 (C-3), 72.3 (O–CH2-Ph),
72.4 (O–CH2-Ph), 73.3 (C-8), 73.6 (C-2), 73.7 (O–CH2-
Ph), 74.6 (C-6), 76.5 (C-7), 89.1 (C-8a), 114.7 (CN), 127–
129 (CH arom.), 136.0–139.0 (Cq arom.). MS (ESI):
m/z = 569 [M+Na]+.
4. Experimental
4.1. (2S,3R,4R,5S)-Trihydroxypipecolic acid
Compound 5 (44 mg, 0.08 mmol) in ethanol solution
(7 mL) was hydrogenated in the presence of palladium
hydroxide on carbon (122 mg, 0.17 mmol). After four days
of stirring at rt, the catalyst was removed by filtration over
Celite and the solvent evaporated. Compound 1 was
obtained after recrystallization in a mixture of H2O/
MeOH/acetone as white crystals (12 mg, 85%). [a]D
=
+18 (c 0.01, H2O). 1H NMR (D2O): d = 2.33 (t,
J = 13 Hz, 1H, 6ax-H), 2.86 (d, J = 9 Hz, 1H, 2ax-H),
3.01 (dd, J = 5.5, 13 Hz, 1H, 6eq-H), 3.23 (t, J = 9 Hz,
1H, 4ax-H), 3.30 (t, J = 9 Hz, 1H, 3ax-H), 3.39 (m, 1H,
5ax-H), 8.34 (s, 1H, COOH). 13C NMR (D2O): d = 48.1
(C-6), 64.3 (C-2), 70.8 (C-5), 73.4 (C-4), 77.7 (C-3), 171.0
(COOH). This synthetic material was described previously
in Ref. 9 ([a]D literature = +18.3 1% w/w in H2O).
4.6. 3,4,5-Tribenzyloxy-1-(2-hydroxy-1-phenyl-ethyl)-(1R)-
[1a,2b,3b,4a,5b]piperidine-2-carbonitrile 3a
To 35 mL of dry CH2Cl2 was added compound 2a
(240 mg, 0.44 mmol). The solution was cooled at
À78 ꢁC under argon. Triethylsilane (0.36 mL, 2.2 mmol)
followed by 1 M titanium(IV) chloride (0.66 mL,
0.66 mmol) was added. The reaction mixture was stirred
for 3 h and then quenched by the addition of water. The
mixture was extracted with CH2Cl2 (4 · 20 mL). The
combined organic layers were dried over Na2SO4 and fil-
tered. The solvent was evaporated under reduced pres-
sure. Flash chromatography of the resulting crude on
silica gel (cyclohexane/AcOEt, 8:2) yielded 3a (163 mg,
68%) as an oil. Rf = 0.2 (cyclohexane/ether, 6:4).
4.2. Hexahydro-3-phenyl-6,7,8-trihydroxy-(3R)-
[3a,5b,6b,7a,8b,8ab]-5H-oxazolo[3,2-a]pyridine-5-carbo-
nitrile 1a
The data were described previously in Ref. 13.
[a]D = À36 (c 0.4, CHCl3). IR (KBr): m = 2920 cmÀ1
.
4.3. Hexahydro-3-phenyl-6,7,8-trihydroxy-(3R)-
[3a,5b,6a,7b,8a,8ab]-5H-oxazolo[3,2-a]pyridine-5-carbo-
nitrile 1b
1H NMR (CDCl3): d = 2.58 (t, J = 11 Hz, 1H, 6-H),
3.39 (dd, J = 5, 11 Hz, 1H, 6-H), 3.43 (dd, J = 5, 9 Hz,
1H, 3-H), 3.5–3.7 (m, 3H, 2-H, 5-H, CH-Ph), 3.72 (t,
J = 9 Hz, 1H, 4-H), 3.7–3.8 (m, 2H, CH2OH), 4.4–4.9
(6H, O–CH2-Ph), 7.2–7.4 (m, 20H, arom.). 13C NMR
(CDCl3): d = 49.0 (C-6), 55.2 (C-2), 64.1 (CH-Ph), 68.1
(CH2OH), 73.4 (2 · O–CH2-Ph), 76.0 (O–CH2-Ph), 77.5
(C-5), 78.2 (C-3), 83.4 (C-4), 115.0 (CN), 127–129 (CH
arom.), 137–139 (Cq arom.). MS (ESI): m/z = 571
[M+Na]+.
The data were described previously in Ref. 13.
4.4. Hexahydro-3-phenyl-6,7,8-tribenzyloxy-(3R)-
[3a,5b,6b,7a,8b,8ab]-5H-oxazolo[3,2-a]pyridine- 5-carbo-
nitrile 2a
The data were described previously in Ref. 5.

1588
A. Tsimilaza et al. / Tetrahedron: Asymmetry 18 (2007) 1585–1588
4.7. 3,4,5-Tribenzyloxy-1-(2-hydroxy-1-phenyl-ethyl)-(1R)-
[1a,2b,3a,4b,5a]piperidine-2-carbonitrile 3b
(cyclohexane/AcOEt, 7:3). [a]D = À29 (c 0.02, CHCl3).
1
IR (KBr): m = 1737 cmÀ1. H NMR (CDCl3): d = 2.09 (t,
J = 11 Hz, 1H, 6-H), 3.00 (dd, J = 4.5, 11 Hz, 1H, 6-H),
3.33 (d, J = 9 Hz, 1H, 1a-H), 3.54 (m, 1H, 7-H), 3.60 (t,
J = 9 Hz, 1H, 8-H), 3.73 (t, J = 6 Hz, 1H, 4-H), 3.92 (t,
J = 9 Hz, 1H, 9-H), 4.25 (dd, J = 6, 11.5 Hz, 1H, 3-H),
4.43 (dd, J = 6, 11.5 Hz, 1H, 3-H), 4.5–4.6 (2d AB,
J = 11.5 Hz, 2H, O–CH2-Ph), 4.8–5.2 (4H, O–CH2-Ph),
7.2–7.5 (m, 20H, arom.). 13C NMR (CDCl3): d = 53.9
(C-6), 63.5 (C-4), 64.0 (C-1a), 71.2 (C-3), 72.8 (O–CH2-
Ph), 75.6 (O–CH2-Ph), 75.8 (O–CH2-Ph), 77.7 (C-7), 79.4
(C-9), 87.1 (C-8), 127–129 (CH arom.), 138–139 (Cq arom.)
168.3 (CO). MS (ESI): m/z = 572 [M+Na]+.
Identical procedure as for 3a starting from 2a. Rf = 0.36
(cyclohexane/AcOEt, 7:3). Mp: 114 ꢁC. [a]D = À5 (c 0.2,
CHCl3). IR (KBr): m = 2918 cmÀ1 1H NMR (CDCl3):
.
d = 1.82 (dd, J = 10, 11.5 Hz, 1H, 6-H), 2.50 (br, 1H,
OH), 3.10 (dd, J = 4.5, 11.5 Hz, 1H, 6-H), 3.22 (d,
J = 9 Hz, 1H, 2-H), 3.32 (t, J = 8.5 Hz, 1H, 4-H), 3.6–3.7
(m, 1H, 5-H), 3.8–3.9 (m, 2H, 3-H and CH2OH), 3.98
(dd, J = 10, 11 Hz, 1H, CH-Ph), 4.45 (m, 1H, CH2OH),
4.6–4.9 (6H, O–CH2-Ph), 7.2–7.4 (m, 20H, arom.). 13C
NMR (CDCl3): d = 47.0 (C-6), 56.0 (C-2), 60.6 (CH-Ph),
66.0 (CH2OH), 73.4 (O–CH2-Ph), 75.4 (O–CH2-Ph), 76.0
(O–CH2-Ph), 77.9 (C-5), 79.8 (C-3), 84.0 (C-4), 117.7
(CN), 128–129 (CH arom.), 132–138 (Cq arom.). MS
(ESI): m/z = 571 [M+Na]+.
Acknowledgement
The authors are grateful to Dr. N. Kunesch for her interest
in this research and for fruitful discussions.
4.8. 4-Phenyl-7-(triethyl-silanyloxy)-3,4,7,8-tetrahydro-
(4S)-[4b,7b]-6H-pyrido[2,1-c][1,4]oxazin-1-one 4
References
To 15 mL of dry CH2Cl2 was added compound 3a (100 mg,
0.183 mmol). At 0 ꢁC under argon, triethylsilane (0.15 mL,
0.93 mmol) followed by 1 M titanium(IV) chloride
(0.975 mL, 0.27 mmol) was added. The solution was stirred
at 0 ꢁC under argon for 2 days. The reaction was then
quenched by adding 30 mL of water. The mixture was ex-
tracted with CH2Cl2 (30 mL · 5) and the combined organic
layers were dried over Na2SO4, filtered and the solvent was
evaporated under reduced pressure. Flash chromatography
of the resulting brownish oil on silica gel (cyclohexane/
ether 9:1) yielded 4 (23 mg, 35%) as a yellow oil.
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Rf = 0.35
(cyclohexane/ether,
7:3).
IR
(KBr):
m = 1705 cmÀ1. H NMR (CDCl3): d = 0.60 (q, J = 9 Hz,
6H, Si–CH2–CH3), 0.92 (t, J = 9 Hz, 9H, Si–CH2–CH3),
2.21 (dt, J = 5, 19 Hz, 1H, 8-H), 2.55 (dtd, J = 2, 2.5,
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3-H), 6.10 (t, J = 4.5 Hz, 1H, 9-H), 7.2–7.4 (m, 5H, arom.).
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CH3), 33.0 (C-8), 52.9 (C-6), 59.4 (C-4), 64.1 (C-7), 71.5
(C-3), 110.5 (C-9), 127–129 (CH arom.), 136.6 (Cq arom.),
161.5 (CO). MS (ESI): m/z = 360 [M+H]+.
1
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´
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