A new route to (2S,4R)- and (2R,4S)-4-hydroxypipecolic acid

Article abstract of DOI:10.1016/S0957-4166(99)00458-9

Both enantiomers of cis-4-hydroxypipecolic acid have been prepared by asymmetric synthesis using (S)- or (R)-glycidol as the chiral source, and involving a stereoselective hydrogenation of a six-membered cyclic imine. The latter is obtained by reduction and cyclization of a cyano β-hydroxy ketone.

Full text of DOI:10.1016/S0957-4166(99)00458-9

Pergamon
Tetrahedron: Asymmetry 10 (1999) 4231–4237
A new route to (2S,4R)- and (2R,4S)-4-hydroxypipecolic acid
Mansour Haddad ∗ and Marc Larchevêque
Laboratoire de Synthèse Organique associé au CNRS ENSCP, 11 rue Pierre et Marie Curie, 75231 Paris Cedex 05, France
Received 27 September 1999; accepted 18 October 1999
Abstract
Both enantiomers of cis-4-hydroxypipecolic acid have been prepared by asymmetric synthesis using (S)- or (R)-
glycidol as the chiral source, and involving a stereoselective hydrogenation of a six-membered cyclic imine. The
latter is obtained by reduction and cyclization of a cyano β-hydroxy ketone. © 1999 Elsevier Science Ltd. All
rights reserved.
1. Introduction
(2S,4R)-4-Hydroxypipecolic acid 1, isolated from the leaves of Calliandra pittieri and Strophantus
scandeus,1 is a cyclic amino acid whose synthesis has been actively studied over recent years owing to
its biological properties. Indeed, the amide derivative of 1 is incorporated in the structure of palinavir 2,
a member of a new class of potent inhibitors of the human immunodeficiency virus (HIV) protease.2
Moreover, the (2R,4S)-enantiomer of 1 is an intermediate in the preparation of 4-(phosphonoalkyl)-
piperidine-2-carboxylic acid 3 called CGS 20281 which is one of the most potent and selective com-
petitive NMDA (N-methyl-D-aspartic acid) receptor antagonists,3 and could thus have potential interest
in certain CNS disorders such as treatment of epilepsy.
∗
Corresponding author. E-mail: mhaddad@ext.jussieu.fr
0957-4166/99/$ - see front matter © 1999 Elsevier Science Ltd. All rights reserved.
PII: S0957-4166(99)00458-9

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Since the first synthesis of pure enantiomeric (−)-1 by Clarck-Lewis and Mortimer,4 achieved by
chemical transformation of (−)-trans-4-hydroxypipecolic acid (obtained from leaves of Acacia oswaldii),
few total syntheses of 1 in non-racemic form have been described. Fujita et al.5 started from L-lysine as
chiral material, and obtained a mixture of cis- (80%) and trans- (20%) 4-hydroxypipecolic acid. Golubev
et al.6 used L-aspartic acid as starting material, involving an intramolecular Michael addition leading to
the cyclic amino acid; however, the use of hexafluoroacetone as the protecting group made the synthesis
rather expensive. The iminium ion cyclization of chiral homoallylic amine has been exploited to achieve
an asymmetric synthesis of both enantiomers of 1, but diastereomeric separation was necessary.7 The
more recent enantioselective synthesis was due to Di Nardo and Varela,8 with D-glucoheptono-1,4-
lactone as starting product. Nevertheless, at one step of their preparation, they required a separation of
isomeric products resulting in a loss of yield. Here, we wish to describe an alternative route to piperidinic
compound 1, using the commercially available (S)-glycidol as the chiral source.
2. Results and discussion
A retrosynthetic analysis for 1, as shown in Scheme 1, indicated that the cyano ketone 4 could be
an intermediate to access the target compound. Indeed, the phenyl group constitutes a potential acid
function,9 while the cyano group, upon reduction and further imine formation, could be submitted
to a stereoselective hydrogenation to afford 4-hydroxy-1-phenyl piperidine 5, according to the model
proposed for such cyclic imine reduction.10 Consequently, we investigated the preparation of 4. The
latter was obtained from (R)-glycidyl tert-butyldimethylsilyl ether11 as indicated in Scheme 2.
Condensation of 2-lithio-2-phenyl-1,3-dithiane with (R)-glycidyl tert-butyldimethylsilyl ether gave
the alcohol 6 in 83% yield. However, the next step proved more troublesome. The initial idea was
to convert 6 to the epoxide 7 via the corresponding diol. However, all the attempts to achieve this
transformation, in particular the use of Sharpless conditions [MeC(OMe)3, PPTS/Me3SiCl/K2CO3]12
and the monotosylation (direct or through a cyclic stannylene intermediate) followed by base-induced
cyclization,13 gave the desired product with poor yield (about 30%). These results may be explained by
the nucleophilic character of the sulfur atom. Finally, 7 has been isolated in good yield (77%) by the
following procedure: mesylation of the secondary alcohol, selective deprotection of the primary alcohol

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4233
Scheme 1.
Scheme 2.
by tetrabutylammonium fluoride and basic treatment with K2CO3. In the next step, epoxide 7 was reacted
with KCN in the presence of LiClO4, which were the best conditions to access the cyano alcohol 8
(80%).14 Hydrolysis of the dithioketal group by means of Hg(ClO4)2 gave the β-hydroxy ketone 4 in
80% yield.15
With 4 in hand, we then turned our attention towards the ring closure of the latter, which constituted
the crucial step of the synthesis. For this purpose, 4 was submitted to catalytic hydrogenation using
Pd or Pd(OH)2. Unfortunately, in addition to non-reproductible results, the major isolated product was
identified as phenyl-1-piperidine. Such β-elimination of the OH group and total hydrogenation has
already been observed by Varela et al.8 Finally, PtO2 turned out to be a better catalyst to perform this
conversion (no trace of the C-2 epimer was detected by 1H NMR), although the yield was modest (33%).
This was due to the reduction of ketone, which probably occurred before imine formation, affording a
mixture of diols (Scheme 3).
The next few steps for the transformation of 5 into 1 involved selective and differential protection for
the hydroxy and amino groups. This was accomplished in the following manner and without purification
of the intermediates: complete protection by treatment with trifluoroacetic anhydride, selective deprotec-
tion of the hydroxy group with K2CO3 in THF, and protection of the latter as the acetate yielding 9 in
82% yield (Scheme 4).
After oxidation of the phenyl group by sodium periodate in the presence of ruthenium chloride hydrate,
and full deprotection in basic medium, 1 was obtained in 60% yield. As expected, specific rotation

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M. Haddad, M. Larchevêque / Tetrahedron: Asymmetry 10 (1999) 4231–4237
Scheme 3.
Scheme 4.
and spectral properties were in full agreement with the literature.2,16 The (2R,4S)-enantiomer of 1 was
prepared in a similar manner starting from (R)-glycidol.
In conclusion, we have developed a new practical method which allows access to both enantiomers of
cis-4-hydroxypipecolic acid, using as non-racemic chiral starting material either (R)- or (S)-glycidol, and
which does not require any separation of diastereomers.
3. Experimental
1
Infrared spectra were taken on an FT Nicolet 210 spectrometer. H NMR and 13C NMR spectra were
recorded at 200 and 50 MHz, respectively, in CDCl3 unless specified otherwise, using a Bruker AC-200
E apparatus. Chemical shifts are expressed in ppm from internal TMS. Mass spectra were recorded with
a 70 eV ionizing voltage; ammonia was used for chemical ionization. Melting points were determined on
a Kofler apparatus and are uncorrected. Flash chromatography was performed using silica gel 60 (Merck,
230–400 mesh). Optical rotations were measured on a Perkin–Elmer 141 polarimeter.
3.1. (2R)-1-(tert-Butyldimethylsilyloxy)-4-(1,3-dithian-2-yl)-4-phenyl-2-butanol 6
A 1.6 M solution of n-BuLi in hexanes (17.2 mL, 27.5 mmol) was added to a stirred solution of 2-
phenyl-1,3-dithiane (4.91 g, 25 mmol) in dry THF (100 mL) at −25°C under an inert atmosphere. The
solution was stirred at the same temperature for 2 h and (R)-glycidyl tert-butyldimethylsilyl ether (4.7
g, 25 mmol) diluted in THF (20 mL) was added dropwise. The reaction mixture was stirred for 5 h,
quenched with saturated aqueous NH4Cl, diluted with H2O, and extracted with EtOAc. The extract was
washed with water and saturated NaCl, dried over MgSO4, and concentrated to give a residue which was
purified by flash chromatography (cyclohexane:AcOEt, 90:10) to give the alcohol 6 as an oil (8 g, 83%):
[α]22=−10 (c 1.2, CH2Cl2); 1H NMR (200 MHz, CDCl3) δ 0.0 (s, 6H), 0.86 (s, 9H), 1.85–2.0 (m, 10H),
D
2.15–2.34 (m, 2H), 2.55 (d, J=3.2 Hz, 1H), 2.68–2.78 (m, 4H), 3.33 (d, J=5.8 Hz, 2H), 3.70–3.85 (m,
1H), 7.20–7.43 (m, 3H), 7.90–7.98 (m, 2H); 13C NMR (50 MHz, CDCl3) δ −5.6, 18.0, 24.6, 25.7, 27.3,

M. Haddad, M. Larchevêque / Tetrahedron: Asymmetry 10 (1999) 4231–4237
4235
27.6, 47.7, 57.0, 66.8, 68.5, 127.0, 128.3, 128.4, 141.6; MS (EI) m/z 384 (M+, 6.1%), 327 ([M−C4H9]+,
15%), 209 ([M−C8H19SiO2]+, 10%), 195 ([M−C9H21SiO2]+, 15%), 117 (100%).
3.2. (2S)-4-(1,3-Dithian-2-yl)-1,2-epoxy-4-phenylbutane 7
To an ice cold solution of 6 (7.7 g, 20 mmol), triethylamine (4.18 mL, 30 mmol) and 4-
dimethylaminopyridine (120 mg, 1 mmol) in anhydrous dichloromethane (100 mL) under a stream of
argon was added dropwise methanesulfonyl chloride (1.70 mL, 22 mmol). The solution was stirred
for 3 h, diluted with dichloromethane (50 mL) and washed successively with water, 5% aqueous HCl
and saturated aqueous NaHCO3. The solution was dried (MgSO4) and concentrated to give a crude
product which was used without purification. Thus, the above mesylate was diluted in anhydrous THF
(80 mL) and the solution was cooled to 0°C. A 1 M THF solution of tetrabutylammonium fluoride
(containing 5% water, 24 mL, 24 mmol) was added dropwise. The mixture was stirred for 1 h at the same
temperature (the disappearance of the starting material was checked by TLC), after which time K2CO3
(5.52 g, 40 mmol) was added and the solution was stirred for additional 12 h at room temperature. The
next day, water (100 mL) was added and the solution was extracted with ethyl acetate (2×60 mL). The
organic layer was dried over MgSO4, filtered, and evaporated to give a residue which was purified by
flash chromatography (cyclohexane:AcOEt, 85:15) to give the epoxide 7 (3.9 g, 77%): [α]22=+8.7 (c
D
1, CH2Cl2); 1H NMR (200 MHz, CDCl3) δ 1.84–2.16 (m, 4H), 2.24–2.46 (m, 2H), 2.54–2.88 (m, 4H),
2.88–3.04 (m, 1H), 7.20–7.48 (m, 3H), 7.88–8.08 (m, 2H); 13C NMR (50 MHz, CDCl3) δ 24.7, 27.4,
27.5, 47.0, 47.9, 48.3, 57.4, 127.2, 128.5, 128.6, 141.3; MS (EI) m/z 252 (M+, 30%), 195 ([M−C3H5O]+,
100%).
3.3. (3R)-5-(1,3-Dithian-2-yl)-3-hydroxy-5-phenylpentanenitrile 8
A solution of 7 (3.8 g, 15 mmol) in acetonitrile (40 mL) was treated with potassium cyanide (1.47 g,
22.58 mmol) and lithium perchlorate (2.40 g, 22.58 mmol). The resulting reaction mixture was stirred at
70°C for 8 h, and then cooled at room temperature, diluted with water and extracted with ethyl acetate
(2×40 mL). The extract was dried (MgSO4), filtered, and evaporated under vacuum to afford a brown
oil. Purification by flash chromatography (cyclohexane:EtOAc, 60:40) gave the cyano alcohol 8 as a solid
(3.36 g, 80%): [α]22=+36.5 (c 1.4, CH2Cl2); mp 80°C; 1H NMR (200 MHz, CDCl3) δ 1.90–2.04 (m,
D
2H), 2.20–2.60 (m, 4H), 2.64–3.04 (m, 5H), 4.04–4.20 (m, 1H), 7.25–7.50 (m, 3H), 7.85–7.96 (m, 2H);
13C NMR (50 MHz, CDCl3) δ 24.4, 26.0, 27.3, 27.7, 50.2, 56.4, 64.6, 117.1, 127.7, 127.9, 129.0, 141.0;
MS (EI) m/z 279 (M+, 79%), 205 (31%), 195 (37%), 172 (52%), 103 (100%); IR (nujol) νmax 3456 (br),
2930, 2900, 2250 cm−1.
3.4. (3R)-3-Hydroxy-5-oxo-5-phenylpentanenitrile 4
A mixture of 8 (3.36 g, 12 mmol), CaCO3 (12 g, 120 mmol), and Hg(ClO4)2 (9.58 g, 24 mmol) in
THF (120 mL) and H2O (30 mL) was stirred at room temperature for 2 h and then filtered through a short
column of Celite using EtOAc (100 mL). Water was added (100 mL) and the solution was extracted. The
extract was washed with water and brine, dried over MgSO4, filtered, and concentrated to give a residue
which was purified by flash chromatography (cyclohexane:AcOEt, 6:4) yielding 4 as an oil (1.82 g, 80%):
[α]22=−41.7 (c 1.07, CH2Cl2); 1H NMR (200 MHz, CDCl3) δ 2.69 (AB system part of ABX, JAB=16.8
D
Hz, 2H), 3.54 (AB system part of ABX, J not measurable, 2H), 3.96 (d, J=3.8 Hz, 1H), 4.45–4.65 (m,
1H), 7.40–7.65 (m, 3H), 7.85–7.95 (m, 2H); 13C NMR (50 MHz, CDCl3) δ 25.0, 43.5, 63.7, 117.4, 127.9,

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M. Haddad, M. Larchevêque / Tetrahedron: Asymmetry 10 (1999) 4231–4237
128.6, 133.7, 135.9, 198.7; MS (EI) m/z 190 (MH+, 19.7%), 172 (17.7%), 105 (100%); IR (neat) νmax
3500 (br), 2250, 1770, 1600 cm−1.
3.5. (2S,4R)-2-Phenylpiperidine-4-ol 5
The hydroxyketone 4 (1.13 g, 5.97 mmol) was dissolved in EtOH (30 mL), and PtO2 (83% Pt, 60 mg)
was added. Hydrogen (1 atm) was applied, and the reaction mixture was stirred at room temperature for
12 h. After filtration through Celite, the solvent was evaporated. The crude oil obtained was purified
by flash chromatography (CH2Cl2:MeOH, 60:40) to afford 5 as a pale yellow solid (0.35 g, 33%):
22
1
[α] =−10.9 (c 0.53, MeOH); mp 101–102°C; H NMR (200 MHz, CDCl3) δ 1.40–1.60 (m, 2H),
D
1.93–2.16 (m, 2H), 2.46 (sbroad, 2H), 2.76 (dt, J=2.6 Hz and J=12.3 Hz, 1H), 3.10–3.26 (m, 1H), 3.60
(dd, J=2.38 and J=11.48 Hz, 1H), 3.65–3.84 (m, 1H), 7.20–7.40 (m, 5H); 13C NMR (50 MHz, CDCl3)
+
29.6, 35.2, 43.7, 44.9, 60.1, 69.4, 126.5, 127.2, 128.4, 143.6; MS (CI, NH3) m/z 195 (M+NH4 , 4%),
178 (MH+, 100%).
3.6. N-Trifluoroacetyl-(2S,4R)-4-acetoxy-2-phenylpiperidine 9
To an ice cold solution of aminoalcohol 5 (0.3 g, 1.69 mmol) in CH2Cl2 (25 mL) containing Et3N
(1.4 mL, 10 mmol) and dimethylaminopyridine (10 mg, 0.08 mmol) was added via a syringe through a
septum trifluoroacetic anhydride (0.95 mL, 6.77 mmol). After stirring at 23°C for 12 h, water was added
and the solution was extracted, dried over MgSO4, filtered, and evaporated. The crude product obtained
was diluted in THF (25 mL) and K2CO3 (0.46 g, 3.38 mmol) was added. The mixture was stirred for
12 h. Water was added and the reaction mixture was extracted with CH2Cl2. After drying over MgSO4,
the solution was filtered and placed into a one-neck 100 mL round bottomed flask. Triethylamine (0.94
mL, 6.8 mmol) and dimethylaminopyridine (10 mg, 0.08 mmol) were added before cooling to 0°C.
Acetic anhydride (0.32 mL, 3.39 mmol) was added via a syringe through a septum and the solution
was stirred at room temperature for 12 h. Water was added and the solution was extracted. The solution
was dried over magnesium sulfate, filtered, and evaporated to give an oil which was purified by flash
chromatography (cyclohexane:AcOEt, 80:20) to give the protected aminoalcohol 9 as a colorless oil (0.44
g, 82%): [α]22=−45.5 (c 1.05, CH2Cl2); 1H NMR (400 MHz, C6D6, 60°C) δ 1.26 (s, 3H), 1.28–1.37 (m,
D
2H), 1.56 (ddd, J=3.1, 6.6, 15.2 Hz, 1H), 2.39–2.46 (m, 1H), 3.2 (dtbroad, J not measurable, 1H), 3.79 (m,
1H), 4.72 (quint, J=3.5 Hz, 1H), 5.48 (m, 1H), 6.90–6.98 (m, 3H), 7.03–7.08 (m, 2H); 13C NMR (100
MHz, C6D6, 60°C) δ 19.8, 29.4, 31.2, 36.7, 52.4, 66.1, 117.2 (q, J=287 Hz, CF3), 125.2, 126.4, 128.4,
+
139.0, 156.2, 168.8; MS (CI, NH3) m/z 333 (M+NH4 , 100%), 316 (MH+, 1.5%); IR (nujol) νmax 1745,
1700, 1600 cm−1.
3.7. (2S,4R)-4-Hydroxypipecolic acid 1
Compound 9 (0.4 g, 1.27 mmol) was placed into a flask equipped with a magnetic stirrer and containing
2 mL of carbon tetrachloride, 2 mL of acetonitrile, and 3 mL of water. Sodium periodate (4.07 g, 19
mmol) and ruthenium chloride hydrate (13 mg, 0.06 mmol) were added and the solution was vigorously
agitated overnight. On the next day, the solution was filtered through a Celite pad and rinsed several times
with dichloromethane. The dark solution was dried over magnesium sulfate, filtered, and concentrated.
The crude acid thus obtained was diluted in methanol (15 mL); potassium carbonate (1.05 g, 7.6 mmol)
was added, and the mixture was stirred at room temperature for 12 h. The solution was concentrated and
acidified with 1 M HCl. Purification was performed over a column of Dowex 50W-X8 resin (100–200

M. Haddad, M. Larchevêque / Tetrahedron: Asymmetry 10 (1999) 4231–4237
4237
mesh, 20 g) eluted with 5% NH4OH under a light pressure. The ninhydrin positive fractions were
combined and evaporated in vacuo to give a solid which was recrystallized from hot 25% water in
EtOH. Evaporation and drying under vacuum over P2O5 gave pure (2S,4R)-1 as a solid (0.11 g, 60%):
22
25
1
[α] =−17.2 (c 1.05, H2O), lit.2 [α] =−23.5 (c 1, H2O); mp 269°C dec; H NMR (400 MHz, D2O)
D
D
δ 1.47–1.59 (m, 2H), 2.04–2.09 (m, 1H), 2.38–2.44 (m, 1H), 2.95 (dt, J=3.1, 13.2 Hz, 1H), 3.42 (ddd,
J=2.7, 4.4, 13.2 Hz, 1H), 3.60 (dd, J=3.2, 12.9 Hz, 1H), 3.88 (tt, J=4.4, 11 Hz, 1H); 13C NMR (50 MHz,
D2O) δ 31.0, 35.8, 42.5, 58.9, 66.6, 174.4; MS (CI, NH3) m/z 163 (M+NH4 , 40%), 146 (MH+, 100%).
+
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