A stereoselective total synthesis of cis-(2R,3S)-3-hydroxypipecolic acid

Article abstract of DOI:10.3184/030823407X218020

A stereoselective total synthesis of (2R,3S)-3-hydroxypipecolic acid starting from an enantiomerically pure α-amino alcohol is reported. The synthesis involved a regioselective mesylation and subsequent cyclisation as key steps.

Full text of DOI:10.3184/030823407X218020

JOURNAL OF CHEMICAL RESEARCH 2007
MAY, 313–316
RESEARCH PAPER 313
A stereoselective total synthesis of cis-(2R,3S)-3-hydroxypipecolic acid
Phannarath Phansavath and Mansour Haddad*
Laboratoire de Synthèse Sélective Organique et Produits Naturels, UMR CNRS 7573
Ecole Nationale Supérieure de Chimie de Paris, 11 rue Pierre et Marie Curie, 75231 Paris Cedex 05, France
A stereoselective total synthesis of (2R,3S)-3-hydroxypipecolic acid starting from an enantiomerically pure a-amino
alcohol is reported. The synthesis involved a regioselective mesylation and subsequent cyclisation as key steps.
Keywords: l-serine, amino alcohol, hydroxypipecolic acid, piperidine
3-Hydroxypipecolic acid is a nonproteinogenic cyclic a-amino
acid whose structure is found in a variety of biologically-active
natural and non-natural compounds. For instance, the trans-
3-hydroxypipecolic acid 1 is an advanced intermediate in the
synthesis of (–)-swainsonine 3,1 a potent a-d-mannosidase
inhibitor,2 while the related cis-isomer 2 structure is contained
in tetrazomine 4,3 an antitumor antibiotic (Scheme 1).
The 3-hydroxypipecolic acid framework has been used as
a conformationally constrained a-amino b-hydroxy acid in
the synthesis of peptidomimetics,4 and has been incorporated
in the preparation of biologically active compounds such as
immunosupressants,5 enzyme inhibitors,6 and anticancer7
or anti-HIV8 agents. Consequently, a number of synthetic
studies have been directed towards the synthesis of cis- or
trans-3-hydroxypipecolic acid.9 Among the four possible
isomers of 3-hydroxypipecolic acid, only few syntheses of
the (2R,3S)-enantiomer 5 have been reported.9f As part of a
program directed towards the synthesis of biologically-active
products using the enantiomerically pure a-amino alcohol 6
(derived from l-serine) as a chiral building block,10 we report
an efficient synthesis of cis-(2R,3S)-3-hydroxypipecolic acid
5 (Scheme 2).
Thus, the target compound would be obtained from 6 via
alcohol 12 through a cyclisation reaction.
HO
OH
H
OH
OH
OH
N
H
CO2H
N
H
CO2H
N
3
1
2
OH
Me
H
HO
O
N
H
N
N
H
O
NH
OMe
4
Scheme 1 Structures of trans- and cis-3-hydroxypipecolic acid 1 and 2, swainsonine 3 and tetrazomine 4.
OH
TBDPSO
O
N
N
H
CO2H
Cbz
5
6
OH
MeO2C
OH
NHCbz
12
Scheme 2 Retrosynthetic analysis for cis-(2R,3S)-3-hydroxypipecolic acid 5.
* Correspondent. E-mail: mansour-haddad@enscp.fr.
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314 JOURNAL OF CHEMICAL RESEARCH 2007
With the selectively protected alcohol 10 in hand, the
synthesis of cis-(2R,3S)-3-hydroxypipecolic acid 5 was
continued as depicted in Scheme 4. Conversion of 10
into the corresponding carboxylic acid 11 was performed
using sodium periodate and catalytic ruthenium chloride
in carbon tetrachloride/acetonitrile/water (1/1/1.5) at room
temperature.12 Subsequent concomitant esterification of the
carboxylic acid, deprotection of the amino alcohol moiety
and hydrolysis of the acetate function were then obtained by
simply heating compound 11 in methanol in the presence of a
catalytic amount of hydrochloric acid. Under these conditions,
the corresponding diol 12 was obtained with a satisfactory
90% yield.
Initial attempts to achieve a one-pot selective mesylation
of the primary alcohol and cyclisation were unsuccessful.
Indeed, treatment of 12 with methanesulfonyl chloride and
triethylamine at –78°C afforded the corresponding mesylate
but no cyclisation was observed. Increasing the reaction
temperature to 0°C gave the expected piperidine in only
Results and discussion
The synthesis of compound 12 required hydroboration of 6
in order to introduce the primary alcohol function. However,
first attempts of hydroboration of the alkene 6 using either
9-BBN or BH3:Me2S resulted in cleavage of the tert-
butyldiphenylsilyl (TBDPS) protecting group, affording
the corresponding diol, thus impeding the remainder of the
synthesis. We decided to replace the TBDPS group by a tert-
butyldimethylsilyl (TBS) group. Thus, the parent compound 8
was prepared from the known amino alcohol 711 by treatment
with 2,2-dimethoxypropane in the presence of catalytic
p-toluenesulfonic acid (Scheme 3).
Hydroboration of compound 8 was initially carried out with
9-BBN which afforded non-reproducible results. However, the
use of BH3:Me2S gave the expected alcohol 9 in 76% yield.
After protection of 9 as an acetate, removal of the TBS group
by treatment with tetrabutylammonium fluoride afforded the
corresponding alcohol 10 in 78% yield.
OH
a
TBSO
O
N
TBSO
Cbz
NHCbz
8
7
OAc
3
OH
3
c,d
HO
Cbz
b
TBSO
Cbz
O
O
N
N
9
10
Scheme 3 Reagents and conditions: (a) Dimethoxypropane, cat. PTSA, benzene, D, 3 h, 95%; (b) BH3:Me2S, THF, 0°C, 3 h then
EtOH, 3M NaOH, 30% aq. H2O2, rt, 3 h, 76%; (c) Ac2O, Et3N, DMAP, CH2Cl2, 0°C to rt, 14 h; (d) nBu4NF, THF, rt, 3 h, 78% (2 steps).
OAc
OAc
3
3
a
HO2C
Cbz
b
HO
Cbz
O
O
N
N
11
10
OH
OH
c,d
OH
MeO2C
3
N
CO2Me
H
NHCbz
13
12
OH
e
N
H
CO2H
5
Scheme 4 Reagents and conditions: (a) RuCl3.H2O, NaIO4, CCl4/CH3CN/H2O, r.t., 8 h, 82%; (b) MeOH, cat. HCl, D, 8 h, 90%; (c) MsCl,
Et3N, CH2Cl2, –78°C, 3 h; (d) H2, Pd/C, MeOH, rt, 12 h, 60% (2 steps); (e) NaOH, EtOH, H2O, rt, 12 h then Dowex 50W-X8, 80%.
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JOURNAL OF CHEMICAL RESEARCH 2007 315
+ H]+. Anal. Calcd. for C23H39NSiO5: C, 63.1; H, 9.0; N, 3.2. Found:
C, 63.1; H, 9.2; N, 3.3%.
30% yield, with a lot of side-products being formed. Finally,
the hydroxypipecolic acid core was prepared in stages. Thus,
the mesylation reaction was quenched at –78°C and the crude
product was subjected to hydrogenolysis in the presence of
Pd/C to afford the corresponding primary amine, which
in turn led to the expected cyclisation product 13 in 60%
overall yield. After saponification and purification on Dowex
50W-X8, cis-(2R,3S)-3-hydroxypipecolic acid 5 was finally
obtained in 80% yield. The spectroscopic data of 5 were found
to be in agreement with those reported previously.3
(4S,5S)-5-(3-Acetoxypropyl)-4-hydroxymethyl-2,2-dimethyl-
oxazolidine-3-carboxylic acid benzyl ester (10): To a solution of
alcohol 9 (2.0 g, 4.57 mmol) in CH2Cl2 (50 ml) were added Et3N
(1.28 ml, 9.14 mmol), acetic anhydride (648 ml, 6.85 mmol) and a
catalytic amount of 4-DMAP (40 mg). The reaction mixture was
stirred at room temperature for 4 h, quenched with saturated aqueous
NaHCO3 and extracted with CH2Cl2. The combined organic layers
were dried over MgSO4and concentred to afford the expected acetate
as a yellow oil which was used in the next reaction without further
purification. To a solution of the acetate in THF (30 ml) was added
dropwise nBu4NF (1M solution in THF, 6.85 ml). After stirring at
room temperature for 8 h, water (50 ml) was added and the mixture
was extracted with CH2Cl2. The combined organic layers were dried
over MgSO4 and concentrated. Purification of the residue by flash
chromatography (cyclohexane/ethyl acetate: 6/4) afforded 10 (1.30 g,
78%) as a viscous oil. [a]D25 = –1.8 (c 2.5, MeOH). IR (neat): 3460,
2934, 1736, 1700, 1408 cm–1. 1H NMR (400 MHz, C6D6, 60°C)
δ 1.34–1.74 (m, 4H), 1.45 (s, 3H), 1.57 (s, 3H), 1.70 (s, 3H), 3.50–
3.72 (m, 3H), 3.73–3.89 (m, 1H), 3.90–4.05 (m, 2H), 5.05 (AB
system, 2H, J = 12.2 Hz), 7.00–7.30 (m, 5H). 13C NMR (100 MHz,
C6D6, 70°C) two conformers δ 25.4, 25.8, 26.3, 26.6, 27.5, 28.0,
30.9, 61.5, 63.5, 64.0, 65.4, 67.2, 67.4, 76.5, 77.3, 94.9, 128.5, 128.7,
137.1, 153.7, 169.9. MS (CI, NH3) m/z 383 [M + NH4]+, 366 [M +
H]+. Anal. Calcd. for C19H27NO6: C, 62.45; H, 7.4; N, 3.8. Found: C,
62.9; H, 7.6; N, 3.9%.
Conclusion
In conclusion, a short and efficient synthesis of cis-(2R,3S)-
3-hydroxypipecolic acid 5 has been achieved using the
enantiomerically pure a-amino alcohol 7 as a chiral building
block. In terms of efficiency (9 steps from 7, 20% overall
yield), our synthetic route to 5 compares favourably with the
other reported syntheses. Moreover, since the antipode of 7 is
easily available (from D-serine), the synthesis developed here
can be applied to the preparation of ent-5.
Experimental
All solvents were reagent grade and distilled under argon prior to use.
Amines were distilled from potassium hydroxide and CH2Cl2 from
calcium hydride. THF was distilled from sodium benzophenone.
All commercially available reagents were used without further
(2R,3S)-2-Benzyloxycarbonylamino-3,6-dihydroxy-hexanoic
acid methyl ester (12): To a suspension of 10 (1.25 g, 3.42 mmol)
and sodium periodate (2.2 g, 10.26 mmol) in a 1/1/1.5 mixture of
CCl4/MeCN/H2O (28 ml) was added ruthenium trichloride hydrate
(35 mg, 0.16 mmol) and the mixture was stirred vigorously for
4 h at room temperature. The dark solution was filtered through a
Celite pad and rinsed with CH2Cl2. The organic phase was separated,
dried over MgSO4 and concentrated. The crude acid was dissolved
in MeOH (40 ml), conc. HCl (1 drop) was added, and the mixture
was refluxed overnight. After evaporation of the solvent, water
(60 ml) was added and the mixture was extracted with AcOEt.
Purification of the residue by flash chromatography (cyclohexane/
1
purification. H and 13C NMR spectra were recorded either at 400
and 100 MHz, respectively, on an Avance 400 Bruker spectrometer,
or at 300 and 75 MHz, respectively, on an Avance 300 Bruker
spectrometer. IR spectra were recorded on an IRFT Nicolet 210
spectrometer. Mass spectra (MS) were measured on a Nermag R10-
10C mass spectrometer (DCI/NH3). Flash column chromatography
was performed on Merck silica gel (0.040–0.063 mesh). TLC analysis
was performed on Merck silica gel 60 PF 254 and sprayed with either
phosphomolybdic acid or ninhydrin. Specific rotations were recorded
on a Perkin-Elmer 241 polarimeter. Elemental analyses were
performed by the Service Régional de Microanalyse de l’Université
Pierre et Marie Curie.
25
ethyl acetate: 2/8) afforded 12 (0.8 g, 75%) as an oil. [a]D = –2.4
(c 1.5, CH2Cl2). IR (neat): 3380, 2955, 2919, 2847, 1716, 1531 cm–1.
1H NMR (300 MHz, CDCl3) δ 1.40–1.70 (m, 4H), 3.42–3.76
(m, 2H), 3.67 (s, 3H), 4.05 (d, 1H, J = 7.8 Hz), 4.29 (d, 1H,
J = 9.3 Hz), 5.04 (s, 2H), 5.70 (d, 1H, J = 9.3 Hz), 7.10–7.35 (m,
5H). 13C NMR (75 MHz, CDCl3) δ 28.8, 31.3, 52.5, 58.4, 62.5, 67.1,
71.8, 128.0, 128.1, 128.5, 136.2, 156.8, 171.7. MS (CI, NH3) m/z 329
[M + NH4]+, 312 [M + H]+.Anal. Calcd for C15H21NO6: C, 57.9; H, 6.8;
N, 4.5. Found: C, 58.1; H, 7.0; N, 4.5%.
(4S,5S)-5-Allyl-4-(tert-butyldimethylsilanyloxymethyl)-2,2-
dimethyl-oxazolidine-3-carboxylic acid benzyl ester (8): A mixture of
amino alcohol 7 (5.7 g, 15 mmol), 2,2-dimethoxypropane (5.5 ml,
45 mmol) and p-toluenesulfonic acid (28.5 mg, 15 mmol) in dry
benzene (100 ml) was heated for 3 h under azeotropic conditions. Ether
(80 ml) was added to the cooled reaction mixture and the solution was
washed with brine. The organic layer was dried over MgSO4, filtered
and concentrated. Purification of the residue by flash chromatography
(cyclohexane/ethyl acetate: 9/1) afforded 8 (5.0 g, 80%) as an oil.
(2R,3S)-3-Hydroxypiperidine-2-carboxylic acid methyl ester (13):
To a solution of 12 (1.09, 3.5 mmol) in CH2Cl2, were added triethyl-
amine (1.0 ml, 7.0 mmol) and mesyl chloride (285 mL, 3.67 mmol)
at –78°C. The mixture was stirred at –78°C for 3 h, then water (40 ml)
was added. The organic phase was separated and washed with brine,
dried over MgSO4 and concentrated to afford the crude mesylate. To a
degassed solution of the crude mesylate in MeOH (30 ml) was added
10% Pd/C (30 mg). The resulting mixture was purged three times with
hydrogen and stirred at room temperature for 12 h under hydrogen at
atmospheric pressure. The reaction mixture was then filtered on Celite,
rinsed with MeOH, and concentrated. Purification of the residue by
flash chromatography (CH2Cl2/MeOH: 9/1) afforded pure 13 (557 mg,
25
[a]D = + 10.3 (c 2.7, CH2Cl2). IR (neat): 3069, 2933, 2889, 2854,
1708, 1642, 1466, 1405, 1352, 1256, 850 cm–1. 1H NMR (400 MHz,
C6D6, 50°C) δ 0.90 (s, 9H), 1.59 (s, 3H), 1.71 (s, 3H), 2.35 (t, 2H,
J = 6.4 Hz), 3.70–4.05 (m, 3H), 4.30 (q, 1H, J = 6.4 Hz), 5.00 (dd,
1H, 3Jcis = 10.2 and 2J = 1.7 Hz), 5.03 (d, 1H, 2J = 12.4 Hz), 5.06 (dd,
3
2
2
1H, Jtrans = 17.1 and J = 1.7 Hz), 5.14 (d, 1H, J = 12.4 Hz), 5.84
3
3
3
(ddt, 1H, Jtrans = 17.1, Jcis = 10.2 and J = 6.4 Hz), 7.06–7.25 (m,
5H). 13C NMR (100 MHz, C6D6, 50°C) d –5.3, 18.4, 26.0, 26.8, 27.8,
39.4, 53.2, 63.2, 66.9, 77.7, 94.9, 117.3, 128.5, 128.7, 134.6, 137.3,
152.6. MS (DCI/NH3) m/z 420 [M + H]+.
25
60%) as an oil. [a]D + 12.7 (c 1.6, MeOH). IR (neat) 3359, 3025,
2965, 2923, 1750 cm–1. 1H NMR (400 MHz, MeOD) d 1.69 (br d, 1H,
J = 14.2 Hz), 1.83 (tdd, 1H, J = 13.7, 4.2 and 2.3 Hz), 1.98 (br d, 1H,
J = 14.2 Hz), 2.12 (qt, 1H, J = 13.7 and 4.2 Hz), 3.05 (td, 1H, J = 12.9
and 3.1 Hz), 3.30–3.43 (m, 1H), 3.88 (s, 3H), 4.15 (d, 1H, J = 1.8 Hz),
4.48 (br s, 1H). 13C NMR (75 MHz, MeOD) δ 31.3, 49.0, 54.2, 63.0,
65.8, 170.7. MS (CI, NH3) m/z 160 [M+ + 1].
(4S,5S)-4-(tert-Butyldimethylsilyloxymethyl)-5-(3-hydroxy-
propyl)-2,2-dimethyl-oxazolidine-3-carboxylic acid benzyl ester (9):
To a solution of 8 (4.7 g, 11.2 mmol) in THF (50 ml) was added
at 0°C borane-methyl sulfide complex (10M, 2.8 ml, 28 mmol).
The reaction mixture was stirred at this temperature for 24 h, then
30% aqueous H2O2 (3.6 ml), 3M NaOH (4 ml) and EtOH (4 ml) were
added. After stirring at room temperature for 3 h, water (100 ml) was
added and the solution was extracted with CH2Cl2. The combined
organic layers were dried over MgSO4 and concentrated. Purification
of the residue by flash chromatography (cyclohexane/ethyl acetate:
7/3) afforded 9 (3.72 g, 76%) as a colourless oil. [a]D25 = + 4.9 (c 1.2,
CH2Cl2). IR (neat): 3445, 2955, 2927, 2879, 2855, 1703, 1472, 1408,
(2R, 3S)-3-Hydroxypipecolic acid (5): To a solution of 13
(240 mg, 1.5 mmol) in EtOH (10 ml), was added 3M NaOH
(2 ml) and the mixture was stirred at room temperature for 12 h.
The reaction mixture was concentrated and acidified with 3M
HCl. The remaining aqueous solution was eluted with 5% NH4OH
through a column packed with Dowex 50W-X8 resin (100–200 mesh,
20 g). The ninhydrin positive fractions were collected and lyophilised
1
1257, 838 cm–1. H NMR (400 MHz, C6D6, 70°C) d 0.02 (s, 6H),
25
to furnish the low-melting solid 5 (175 mg, 80%). [a]D + 17.5
0.90 (s, 9H), 1.00–1.15 (m, 1H), 1.50–1.90 (m, 10H), 3.34–3.50 (m,
2H), 3.62–3.72 (m, 1H), 3.76–3.98 (m, 2H), 4.15–4.28 (m, 1H), 5.10
(AB system, 2H, J = 12.2 Hz), 7.00–7.30 (m, 5H). 13C NMR (100
MHz, C6D6, 60°C) d –5.3, 18.4, 26.1, 26.9, 28.0, 29.6, 31.8, 62.4,
62.6, 64.0, 67.0, 78.3, 94.8, 128.5, 128.6. MS (DCI/NH3) m/z 438 [M
1
(c 0.6, H2O). H NMR (400 MHz, D2O) d 1.70–1.85 (m, 2H), 1.91-
2.01 (m, 2H), 2.99 (dt, 1H, J = 12.9 and 3.1 Hz), 3.38 (m, 1H), 3.65
(d, 1H, J = 2.0 Hz), 4.49 (br s, 1H). 13C NMR (75 MHz, D2O) d 16.5,
29.4, 44.1, 62.8, 64.6, 173.0. MS (CI, NH3) m/z 146 [M+ + 1].
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316 JOURNAL OF CHEMICAL RESEARCH 2007
8
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Received 2 May 2007; accepted 4 June 2007
Paper 07/4629 doi: 10.3184/030823407X218020
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