Asymmetric syntheses of all stereoisomers of 3-hydroxyproline; A constituent of several bioactive compounds

Article abstract of DOI:10.1055/s-0032-1316734

Synthesis of an unusual β-hydroxy-α-amino acid, 3-hydroxyproline, and its derivatives have been achieved enantioselectively by employing Sharpless asymmetric epoxidation and reductive cyclization as the key steps. Georg Thieme Verlag Stuttgart ? New York.

Full text of DOI:10.1055/s-0032-1316734

PAPER
▌2889
paper
Asymmetric Syntheses of All Stereoisomers of 3-Hydroxyproline;
A Constituent of Several Bioactive Compounds
Asymmetric Syntheses of All Stereoisomers of 3-Hydroxyproline
Togapur Pavan Kumar, Srivari Chandrasekhar*
Division of Natural Products Chemistry, CSIR-Indian Institute of Chemical Technology, Hyderabad – 500007, India
Fax +91(40)27160512; E-mail: srivaric@iict.res.in
Received: 28.04.2012; Accepted after revision: 04.07.2012
isomers, employing Sharpless asymmetric epoxidation
and reductive cyclization as the key steps.
Abstract: Synthesis of an unusual β-hydroxy-α-amino acid, 3-hy-
droxyproline, and its derivatives have been achieved enantioselec-
tively by employing Sharpless asymmetric epoxidation and
reductive cyclization as the key steps.
OH
OH
Key words: amino acid, Sharpless asymmetric epoxidation, azido
epoxide, reductive cyclization, 3-hydroxyproline
COOH
COOH
N
H
N
H
1
2
OH
OH
β-Hydroxy-α-amino acids in threo or erythro form consti-
tute an important class of unusual amino acids which do
not occur in nature abundantly that have attracted the at-
tention of biologists as well as chemists.1 3-Hydroxypro-
lines (Figure 1), a significant member of this class, are
found as key structural components in biologically active
compounds. Specifically, (2S,3S)-3-hydroxyproline
(trans-3-hydroxy-L-proline, 1) and its diastereomer
(2S,3R)-3-hydroxyproline (cis-3-hydroxy-L-proline, 2)
are an important scaffold in several pharmaceutical com-
pounds such as the antibiotic telomycin,2 tripropeptins,3
plusbacins,4 empedopeptin,5 DNA gyrase inhibitor cyclo-
thialidine (6),6 and cyclopeptide alkaloids [e.g., ziziphine-
N (5)]7 (Figure 2). Further 1 and 2 also serve as valuable
chiral building blocks in organic synthesis for the con-
struction of ziziphine-N and related cyclopeptide
alkaloids7 and in the synthesis of polyhydroxylated bioac-
tive natural products8 and hybrid oligonucleotides.9
COOH
COOH
N
H
N
H
Figure 1 Structures of 1 and its stereoisomers 2–4
OMe
O
O
N
O
NH
N
O
S
OH
O
O
OH
H
N
O
HN
N
O
O
O
Me2N
O
HO
OH
NH2
HOOC
NH
ziziphine-N
(5)
Compound 1 is a natural product first isolated from hydro-
lysates of Mediterranean sponge and later from collagen
hydrolysates of various sources.10 Small deposits of 1, to
cyclothialidine
(6)
an extent of 1–5%, were also found in seeds and mature Figure 2 Structures of representative bioactive compounds
leaves of the edible Madagascan legume Lemuropsium
edule H. Perrier. Compound 1 showed potent antifeedant
Accordingly, the synthesis of (2S,3S)-3-hydroxyproline
(1) was achieved starting from commercially available
but-3-yn-1-ol (7, Scheme 1). In the first step, but-3-yn-1-
ol (7) was protected as the 4-methoxybenzyl ether with
sodium hydride/4-methoxybenzyl bromide in tetrahydro-
furan and further homologated to 8 using ethylmagnesium
bromide/formaldehyde. Compound 8 was reduced with
lithium aluminum hydride in tetrahydrofuran to give allyl-
ic alcohol 9 in good yield. Sharpless asymmetric
epoxidation14 of 9 with (+)-diethyl L-tartrate and tert-bu-
tyl hydroperoxide afforded the enantiomerically enriched
epoxide 10 in 72% yield. The tert-butyldimethylsilyl pro-
tection of the free hydroxy group of 10 produced com-
pound 11 in 92% yield. The subsequent deprotection of
the 4-methoxybenzyl group with 2,3-dichloro-5,6-dicya-
nobenzo-1,4-quinone in 85% yield followed by tosylation
activity against larvae of Spodopptera littoralis and S. li-
tura and cytotoxic activity to human fibroblast cells.11
In view of the above significance, the syntheses of 3-hy-
droxyproline and prolinols have gained considerable at-
tention from the synthetic community. Several syntheses
of 1 and other isomers with varying levels of success have
been reported.10b,12
The majority of these strategies were based on either an
enzymatic method or the chiron approach. In association
with our work on the synthesis of peptides with unusual
amino acids,13 our aim was a new synthesis of 1 and its
SYNTHESIS 2012, 44, 2889–2894
Advanced online publication: 16.08.2012
0
0
3
9
-
7
8
8
1
1
4
3
7
-
2
1
0
X
DOI: 10.1055/s-0032-1316734; Art ID: SS-2012-Z0400-OP
© Georg Thieme Verlag Stuttgart · New York

2890
T. P. Kumar, S. Chandrasekhar
PAPER
HO
a, b
OH
c
d
PMBO
f, g
OH
OPMB
7
8
9
O
O
O
e
TsO
PMBO
OH
PMBO
OTBS
OTBS
OTBS
10
11
12
OH
OTBS
O
j, k
OH
l
h
i
N3
OTBS
N
N
Boc
Boc
13
(2R,3S)-14
(2R,3S)-15
OH
OTBS
OH
m
COOH
COOH
N
COOH
N
H
N
Boc
H
2
1
(2S,3S)-16
OH
OH
OH
O
OTBS
PMBO
OH
COOH
COOH
N
N
H
N
Boc
(2S,3R)-14
H
3
4
ent-10
Scheme 1 Reagents and conditions: (a) NaH, PMB-Br, THF, 0 °C, then r.t., 12 h, 90%. (b) EtMgBr, (CH2O)n, THF, r.t., 87%. (c) LiAlH4, THF,
0 °C, 2 h, 79%. (d) L-(+)-DET, Ti(Oi-Pr)4, CH2Cl2, TBHP, –20 °C, overnight, 72%. (e) TBSCl, imidazole, CH2Cl2, r.t., 3 h, 92%. (f) DDQ,
CH2Cl2–H2O (8:2), 3 h, 0 °C to r.t., 85%. (g) TsCl, Et3N, CH2Cl2, 0 °C to r.t., 4 h, 80%. (h) NaN3, DMF, 80 °C, 5 h, 60%. (i) 1. Pd/C, H2, MeOH,
r.t., 24 h; 2. Boc2O, NaOH, CH2Cl2, r.t., 3 h, 45%. (j) TBSCl, imidazole, CH2Cl2, r.t., 4 h, 90%. (k) HF·py, THF, r.t., 4 h, 82%. (l) TEMPO,
PhI(OAc)2, MeCN–H2O (1:1), r.t., 6 h, 65%. (m) 6 M HCl, EtOH, reflux, 3 h, 80%.
with tosyl chloride/triethylamine in dichloromethane re- known procedures (Mitsunobu inversion) and this con-
sulted in compound 12 in 80% yield, which was further verted into cis (2S,3R)-isomer 2, likwise (2S,3R)-14
subjected to nucleophilic displacement using sodium [formed via ent-10 in the synthesis of 3 using D-(–)-DET]
azide in N,N-dimethylformamide at 70 °C to furnish the could be converted into its cis-isomer (2S,3S)-14 which
azido epoxide 13 in 60% yield. The conversion of com- was converted into (2R,3S)-isomer 4.12p Thus all the four
pound 13 into hydroxypyrrolidine (2R,3S)-14 was enantiomers of 3-hydroxyproline are achieved by a simple
achieved in a one-pot operation. The reduction of azide 13 protocol.
with hydrogen using palladium on carbon in methanol to
In conclusion we have successfully achieved the enan-
tioselective synthesis of 3-hydroxyproline 1 and its ste-
reoisomers using Sharpless asymmetric epoxidation and
reductive cyclization as the key steps.
the amine followed by subsequent epoxide opening (a 5-
endo-tet ring closure)15 by the amine, in situ cyclization,
and Boc protection provided the required hydroxypyrro-
lidine (2R,3S)-14 in 45% yield.
Compound (2R,3S)-14 was subjected to tert-butyldimeth-
ylsilyl protection of the secondary hydroxy group fol-
lowed by selective deprotection of the primary silyl ether
(HF·py, THF) to give (2R,3S)-15 (74% yield over 2 steps).
Oxidation of (2R,3S)-15 in to acid (2S,3S)-16 using
2,2,6,6-tetramethylpiperidin-1-oxy/(diacetoxyiodo)ben-
zene followed by Boc deprotection (HCl/EtOH) gave the
desired (2S,3S)-3-hydroxyproline (1). The other enantio-
mer of 1, (2R,3R)-3-hydroxyproline (3) was synthesized
in a procedure analogous to Scheme 1, from 9 by perform-
ing Sharpless asymmetric epoxidation using D-(–)-DET,
instead of L-(+)-DET, resulting in an isomeric epoxy alco-
hol ent-10.
1H and 13C NMR spectra were recorded in CDCl3 solvent on 300
MHz, 500 MHz, or 75 MHz spectrometers at r.t. with TMS as inter-
nal standard. FT-IR spectra were recorded as KBr thin films or neat.
All the reagents and solvents were reagent grade and used without
further purification unless specified otherwise. Technical grade
EtOAc and petroleum ether used for column chromatography were
distilled prior to use. Column chromatography was carried out using
silica gel (60–120 mesh) packed in glass columns. All the reactions
were performed under an atmosphere of N2 in oven-dried glassware
with magnetic stirring.
4-(4-Methoxybenzyloxy)but-1-yne
To a stirred soln of homopropargyl alcohol (7, 10.0 g, 142.9 mmol)
in anhyd THF (100 mL) at 0 °C was added NaH (6.8 g, 285.7 mmol,
60% dispersion in mineral oil) and the mixture was stirred for 30
min. To this, PMB-Br (26.4 g, 142.9 mmol) was added and the mix-
ture was stirred for 12 h at r.t. The mixture was quenched with sat.
NH4Cl (30 mL) and the organic compound was extracted with
EtOAc (3 × 50 mL). The combined organic layer was washed with
H2O (1 × 50 mL) and brine (1 × 50 mL), dried (Na2SO4), and con-
centrated under reduced pressure. The crude product was purified
Thus, both the ‘anti’ enantiomers 1 and 3 were synthe-
sized from a common precursor by simply changing the
Sharpless asymmetric epoxidation conditions. Intermedi-
ate (2R,3S)-14 could be converted into (2R,3R)-14 by
Synthesis 2012, 44, 2889–2894
© Georg Thieme Verlag Stuttgart · New York

PAPER
Asymmetric Syntheses of All Stereoisomers of 3-Hydroxyproline
2891
by column chromatography (EtOAc–hexanes, 10:90) to obtain
PMB-protected alcohol (24.4 g, 90%) as a colorless liquid.
IR (neat): 3305, 2965, 2397, 1611, 1243, 1172, 1091, 886, 756 cm–1.
1H NMR (300 MHz, CDCl3): δ = 7.28 (d, J = 8.8 Hz, 2 H), 6.88 (dt,
J = 2.4, 8.8 Hz, 2 H), 4.49 (s, 2 H), 3.81 (s, 3 H), 3.57 (t, J = 7.0 Hz,
2 H), 2.49 (dt, J = 2.4, 7.0 Hz, 2 H), 1.99 (t, J = 2.6 Hz, 1 H).
13C NMR (125 MHz, CDCl3): δ = 159.2, 130.0, 129.3, 113.7, 81.3,
72.6, 69.2, 67.8, 55.2, 19.8.
MS (ESI): m/z = 191 [M + H]+.
24.3 mmol) in CH2Cl2 (20 mL) was added to the mixture and it was
stirred overnight at the same temperature. The reaction was
quenched by adding H2O (160 mL) and stirred vigorously while
warming the mixture slowly to r.t. The mixture was filtered through
a Celite pad and the filtrate containing aqueous and organic layers
was extracted with CH2Cl2 (3 × 50 mL). The combined organic lay-
ers were washed with brine (30 mL), dried (Na2SO4), and concen-
trated under reduced pressure. The residue was purified by column
chromatography (EtOAc–hexanes, 1:1) to obtain the pure epoxy al-
cohol 10 (4.21 g, 72%) as a colorless oil.
[α]D25 –25.2 (c 1.1, CHCl3).
IR (neat): 3425, 2962, 1713, 1171 cm–1.
HRMS: m/z [M
+
H]+ calcd for C12H15O2: 191.2363;
found:191.2366.
1H NMR (300 MHz, CDCl3): δ = 7.25 (d, J = 8.7 Hz, 2 H), 6.89 (d,
J = 8.5 Hz, 2 H), 4.44 (s, 2 H), 3.84–3.72 (m, 5 H), 3.57 (t, J = 6.0
Hz, 2 H), 3.08–2.98 (m, 1 H), 2.96–2.93 (m, 1 H), 1.90–1.76 (m, 2
H).
13C NMR (125 MHz, CDCl3): δ = 158.8, 129.7, 128.7, 113.3, 72.4,
66.0, 61.3, 58.0, 54.7, 53.3, 31.5.
MS (ESI): m/z = 261 [M + Na]+.
HRMS: m/z [M + Na]+ calcd for C13H18NaO4: 261.1102; found:
5-(4-Methoxybenzyloxy)pent-2-yn-1-ol (8)
EtMgBr was prepared by adding EtBr (25.2 g, 230.3 mmol) to Mg
metal (5.5 g, 230.3 mmol) in anhyd THF (120 mL) at r.t. After 1 h,
4-(4-methoxybenzyloxy)but-1-yne (22.0 g, 115.2 mmol) was dis-
solved in THF (30 mL) and added to the mixture, stirring was con-
tinued for a further 1 h and then paraformaldehyde (13.8 g, 460.7
mmol) was added and stirring continued for 12 h. The mixture was
quenched with sat. NH4Cl (50 mL) and the organic compound was
extracted with EtOAc (3 × 100 mL). The combined organic layers
were washed with H2O (100 mL) and brine (100 mL), dried
(Na2SO4), and concentrated under reduced pressure. The crude
product was purified by column chromatography (EtOAc–hexanes,
25:75) to obtain 8 (22.2 g, 87%) as a colorless liquid.
261.1114.
(2S,3S)-2-[(tert-Butyldimethylsiloxy)methyl]-3-[2-(4-Methoxy-
benzyloxy)ethyl]oxirane (11)
A soln of 10 (4.0 g, 16.8 mmol) and imidazole (1.37 g, 20.1 mmol)
in CH2Cl2 (60 mL) was treated with TBSCl (2.72 g, 18.4 mmol) at
0 °C. The mixture was stirred for 4 h at r.t. H2O (30 mL) was added
to the mixture and aqueous layer was extracted with CH2Cl2 (3 × 30
mL). The combined organic layers were washed with brine (20
mL), dried (Na2SO4), and concentrated in vacuo. The residue ob-
tained was purified by column chromatography (EtOAc–hexanes,
1:9) to afford 11 (5.42 g, 92%) as a colorless oil.
IR (neat): 3401, 3003, 2416, 1611, 1508, 1302, 1172, 1086, 932
cm–1.
1H NMR (300 MHz, CDCl3): δ = 7.27 (d, J = 8.8 Hz, 2 H), 6.88 (dt,
J = 2.4, 8.6 Hz, 2 H), 4.58 (s, 2 H), 4.24 (s, 2 H), 3.81 (s, 3 H), 3.55
(t, J = 6.9 Hz, 2 H), 2.51 (t, J = 7.0 Hz, 2 H), 1.72 (t, J = 6.0 Hz, 1 H).
13C NMR (125 MHz, CDCl3): δ = 159.2, 129.8, 129.3, 113.7, 82.7,
79.6, 72.4, 67.8, 55.1, 50.9, 19.2.
[α]D25 –21.4 (c 1.2, CHCl3).
IR (neat): 2929, 2856, 1662, 1364 cm–1.
1H NMR (300 MHz, CDCl3): δ = 7.27 (d, J = 8.7 Hz, 2 H), 6.89 (d,
J = 8.5 Hz, 2 H), 4.46 (s, 2 H), 3.85 (d, J = 3.4 Hz, 1 H), 3.82 (s, 3
H), 3.68–3.57 (m, 3 H), 3.02–2.97 (m, 1 H), 2.93–2.89 (m, 1 H),
2.00–1.88 (m, 1 H), 1.84–1.73 (m, 1 H), 0.91 (s, 9 H), 0.08 (s, 6 H).
13C NMR (75 MHz, CDCl3): δ = 159.0, 130.2, 129.0, 113.6, 72.6,
66.5, 63.2, 58.8, 55.2, 53.6, 31.6, 25.7, 18.0, –5.6.
MS (ESI): m/z = 353 [M + H]+.
HRMS: m/z [M + H]+ calcd for C19H33O4Si: 353.3218; found:
MS (ESI): m/z = 243 [M + Na]+.
HRMS: m/z [M + Na]+ calcd for C13H16NaO3: 243.1883; found:
243.1884.
(E)-5-(4-Methoxybenzyloxy)pent-2-en-1-ol (9)
To a stirred soln of LiAlH4 (10 g, 55.5 mmol) in anhyd THF (100
mL) at 0 °C under a N2 atmosphere, a soln of 8 (6.0 g, 27.2 mmol)
in anhyd THF (25 mL) was added slowly and the mixture was
stirred for 2 h. The mixture was quenched with sat. NH4Cl (5 mL)
and filtered through Celite, dried (Na2SO4), and concentrated in
vacuo. The crude residue was purified by column chromatography
(EtOAc–hexanes, 1:4) to afford 9 (4.83 g, 79%) as a colorless liq-
uid.
353.3231.
2-{(2S,3S)-3-[(tert-Butyldimethylsiloxy)methyl]oxiran-2-yl}eth-
anol
IR (neat): 3379, 2927, 1722, 1160 cm–1.
1H NMR (300 MHz, CDCl3): δ = 7.26 (d, J = 8.8 Hz, 2 H), 6.88 (dt,
J = 2.4, 8.8 Hz, 2 H), 5.81–5.62 (m, 2 H), 4.44 (s, 2 H), 4.09 (s, 2
H), 3.81 (s, 3 H), 3.49 (t, J = 6.6 Hz, 2 H), 2.36 (m, 2 H).
13C NMR (75 MHz, CDCl3): δ = 159.1, 130.3, 130.1, 129.2, 128.8,
113.7, 72.4, 69.2, 63.3, 55.1, 32.5.
MS (ESI): m/z = 245 [M + Na]+.
HRMS: m/z [M + Na]+ calcd for C13H18NaO3: 245.2458; found:
To a stirred soln of 11 (4.0 g, 11.3 mmol) in CH2Cl2–H2O (8:2, 40
mL) at 0 °C, DDQ (2.6 g, 11.3 mmol) was added and the mixture
was stirred for 3 h at r.t. The mixture was quenched with sat.
NaHCO3 (20 mL) and filtered through Celite and the aqueous layer
was extracted with CH2Cl2 (3 × 30 mL), washed with brine (30 mL),
dried (Na2SO4), and concentrated in vacuo. The crude residue was
purified by column chromatography (EtOAc–hexanes, 2:8) to af-
ford PMB deprotected alcohol; (2.2 g, 85%) as a colorless liquid.
245.2469.
[α]D25 –19.8 (c 1.0, CHCl3).
IR (neat): 3440, 2930, 1386, 1116 cm–1.
{(2S,3S)-3-[2-(4-Methoxybenzyloxy)ethyl]oxiran-2-yl}metha-
nol (10)
1H NMR (300 MHz, CDCl3): δ = 3.85–3.62 (m, 4 H), 3.05–2.85 (m,
2 H), 2.08–1.91 (m, 1 H), 1.80–1.62 (m, 2 H), 0.91 (s, 9 H), 0.08 (s,
6 H).
13C NMR (75 MHz, CDCl3): δ = 63.4, 59.8, 58.0, 54.2, 33.9, 26.0,
18.4, –5.2.
In a dry 2-neck round-bottom flask, 4Å molecular sieves powder (4
g) was placed and the flask was evacuated with a flame under argon.
To the flask was injected CH2Cl2 (100 mL) and the soln was cool to
–20 °C. Then Ti(Oi-Pr)4 (7.9 mL, 26.7 mmol) and L-(+)-DET (5.6
mL, 27.2 mmol) were added sequentially. After stirring for 5 min,
3.6 M TBHP in toluene (13.5 mL, 48.6 mmol) was added dropwise
over 15 min. After stirring for 30 min at –20 °C, a soln of 9 (5.4 g,
MS (ESI): m/z = 233 [M + H]+.
© Georg Thieme Verlag Stuttgart · New York
Synthesis 2012, 44, 2889–2894

2892
T. P. Kumar, S. Chandrasekhar
PAPER
HRMS: m/z [M + H]+ calcd for C11H25O3SiNa: 233.1567; found:
[α]D25 –38.6 (c 1.5, CHCl3).
233.1566.
IR (neat): 3376, 2928, 2768 1705, 1491, 1112, 837 cm–1.
(2S,3S)-2-[(tert-Butyldimethylsiloxy)methyl]-3-[2-(tosyl-
oxy)ethyl]oxirane (12)
1H NMR (300 MHz, CDCl3): δ = 4.40 (s, 1 H), 3.91 (dd, J = 9.8, 3.2
Hz 1 H), 3.50 (m, 4 H), 2.11 (s, 2 H), 1.85 (s, 1 H), 1.46 (s, 9 H),
0.89 (s, 9 H), 0.08 (s, 6 H).
13C NMR (75 MHz, CDCl3): δ = 154.5, 79.1, 73.8, 66.3, 62.4, 44.4,
31.5, 28.1, 25.2, 17.8, –5.7.
MS (ESI): m/z = 332 [M + H]+.
HRMS: m/z [M + H]+ calcd for C16H34NO4Si: 332.2252; found:
To a soln of the above alcohol (2.0 g, 8.6 mmol) in CH2Cl2 (30 mL)
was added Et3N (2.6 g, 25.8 mmol) and TsCl (1.96 g, 10.3 mmol) at
0 °C and the mixture was stirred at r.t. for 3 h. The mixture was
quenched with sat. aq NH4Cl and extracted with CH2Cl2 (3 × 20
mL). The combined organic layers were washed with H2O (20 mL)
and brine (20 mL), dried (anhyd Na2SO4), and concentrated in vac-
uo. The residue was purified by column chromatography (silica gel,
hexanes–EtOAc, 9:1) to afford 12 (2.62 g, 80%) as a colorless oil.
332.2251.
[α]D25 –18.5 (c 1.2, CHCl3).
IR (neat): 2923, 2852, 1642, 1465, 1176, 1097, 836, 664 cm–1.
1H NMR (300 MHz, CDCl3): δ = 7.75 (d, J = 8.6 Hz, 2 H), 7.32 (d,
J = 6.9 Hz, 2 H), 4.10 (t, J = 4.2 Hz, 2 H), 3.74 (dd, J = 6.7, 3.2 Hz,
1 H), 3.56 (dd, J = 6.8, 3.2 Hz, 1 H), 2.84–2.71 (m, 2 H), 2.44 (s, 3
H), 2.10–1.90 (m, 1 H), 1.81–1.65 (m, 1 H), 0.88 (s, 9 H), 0.08 (s, 6
H).
13C NMR (75 MHz, CDCl3): δ = 144.3, 133.8, 129.8, 128.1, 66.7,
63.1, 58.5, 52.0, 31.6, 26.0, 21.8, 18.5, –5.1.
MS (ESI): m/z = 409 [M + Na]+.
HRMS: m/z [M + Na]+ calcd for C18H30NaO5SSi: 409.1475; found:
tert-Butyl (2R,3S)-3-(tert-Butyldimethylsiloxy)-2-[(tert-butyldi-
methylsiloxy)methyl]pyrrolidine-1-carboxylate
A soln of (2R,3S)-14 (0.54 g, 1.63 mmol) and imidazole (0.12 g,
1.63 mmol) in CH2Cl2 was treated with TBSCl (0.25 g, 1.63 mmol)
at 0 °C. The mixture was stirred for 4 h at r.t. H2O (30 mL) was add-
ed to the mixture and aqueous layer was extracted with CH2Cl2 (3 ×
30 mL). The combined organic layers were washed with brine (20
mL), dried (Na2SO4), and concentrated in vacuo. The residue ob-
tained was purified by column chromatography (EtOAc–hexanes,
1:9) to afford TBDMS protected diol (0.64 g, 90%) as a colorless
oil.
[α]D25 –21.5 (c 1.5, CHCl3).
1H NMR (300 MHz, CDCl3): δ = 4.47 (d, J = 2.8, 1 H), 3.91–3.28
(m, 5 H), 2.01–2.04 (m, 1 H), 1.86–1.94 (m, 1 H), 1.46 (s, 9 H), 0.99
(s, 18 H), 0.09 (s, 12 H).
409.1463.
(2S,3S)-2-(2-Azidoethyl)-3-[(tert-butyldimethylsiloxy)meth-
yl]oxirane (13)
MS (ESI): m/z = 468 [M + Na]+.
Tosylate 12 (2.0 g, 5.1 mmol) was dissolved in anhyd DMF (20 mL)
and treated with NaN3 (1.0 g, 15.5 mmol). The mixture was stirred
at 80 °C for 5 h. The mixture was then cooled to r.t. and cold H2O
(20 mL) added. The compound was extracted with Et2O (3 × 20
mL). The combined organic layers were dried (anhyd Na2SO4) and
concentrated in vacuo. The residue was purified by column chroma-
tography (silica gel, hexanes–EtOAc, 9:1) to afford 13 (0.82 g,
60%) as a colorless oil.
[α]D25 –16.6 (c 1.1, CHCl3).
IR (neat): 2932, 2859, 2100, 1465, 1255, 779 cm–1.
1H NMR (300 MHz, CDCl3): δ = 3.75 (dd, J = 8.5, 3.4 Hz, 1 H),
3.64 (dd, J = 7.7, 3.6 Hz, 1 H), 3.39 (t, J = 6.2 Hz, 2 H), 2.86–2.78
(m, 2 H), 1.92–1.81 (m, 1 H), 1.73–1.62 (m, 1 H), 0.91 (s, 9 H), 0.08
(s, 6 H).
tert-Butyl (2R,3S)-3-(tert-Butyldimethylsiloxy)-2-(hydroxy-
methyl)pyrrolidine-1-carboxylate [(2R,3S)-15]
To a soln of the di-TBS-protected diol (0.64 g, 1.4 mmol) in anhyd
THF (10 mL) in a polyethylene vessel was added HF·Py (70%, 0.2
mL) at 0 °C. The mixture was stirred for 4 h at r.t. After completion
of the reaction (TLC monitoring), sat. NH4Cl soln was added and
the aqueous layer was extracted with EtOAc (3 × 10 mL). The com-
bined organic layers were washed with brine (20 mL), dried
(Na2SO4), and concentrated in vacuo. The residue obtained was pu-
rified by column chromatography (EtOAc–hexanes, 1:9) to afford
(2R,3S)-15 (0.38 g, 82%) as a colorless oil.
[α]D25 –8.7 (c 1.2, CHCl3).
IR (neat): 3442, 2952, 2856, 1692, 1674, 1364, 1102 cm–1.
1H NMR (300 MHz, CDCl3): δ = 4.29 (s, 1 H), 4.01 (m, 1 H), 3.75–
3.56 (m, 3 H), 3.36 (m, 1 H), 1.99–1.93 (m, 1 H), 1.79–1.74 (m, 1
H), 1.46 (s, 9 H), 0.91 (s, 9 H), 0.08 (s, 6 H).
13C NMR (75 MHz, CDCl3): δ = 63.4, 59.8, 51.0, 46.1, 31.2, 25.8,
18.1, –5.7.
MS (ESI): m/z = 258 [M + H]+.
HRMS: m/z [M + H]+ calcd for C11H24N3O2Si: 258.1958; found:
MS (ESI): m/z = 332 [M + H]+.
(2S,3S)-1-(tert-Butoxycarbonyl)-3-(tert-butyldimethylsi-
loxy)pyrrolidine-2-carboxylic Acid [(2S,3S)-16]
258.1957.
To a stirred soln of alcohol (2R,3S)-15 (0.38 g, 1.1 mmol) in
MeCN–H2O (1:1, 10 mL) were added TEMPO (0.06 g, 0.33 mmol)
and PhI(OAc)2 (1.5 g, 3.3 mmol) and allowed to stir for 6 h at r.t.
The mixture was quenched by the addition of aq Na2S2O3 soln (10
mL) and the aqueous phase was extracted with CH2Cl2 (3 × 10 mL).
The combined organic extracts were dried (Na2SO4) and concentrat-
ed in vacuo. Purification of the residue by chromatography (silica
gel, MeOH–CH2Cl2, 10:90) afforded (2S,3S)-16 (0.25 g, 65%) as a
colorless oil.
[α]D25 –18.8 (c 1.5, CHCl3).
IR (neat): 3167, 1753, 1660, 1434, 1253 cm–1.
1H NMR (300 MHz, CD3OD): δ = 4.36–4.49 (m, 1 H), 3.68–3.38
(m, 3 H), 2.22–2.04 (m, 1 H), 1.89–1.78 (m, 1 H), 1.45 (s, 9 H), 0.89
(s, 9 H), 0.10 (s, 6 H).
tert-Butyl (2R,3S)-2-[(tert-Butyldimethylsiloxy)methyl]-3-hy-
droxypyrrolidine-1-carboxylate [(2R,3S)-14]
To a soln of azido epoxide 13 (1.0 g, 3.9 mmol) in MeOH (5 mL),
a catalytic amount of 10% Pd/C was added and stirred under a H2
atmosphere for 24 h at r.t. The mixture was filtered through a pad of
Celite, which was washed with MeOH (15 mL), and the MeOH was
removed from the filtrate under reduced pressure. The crude residue
was dissolved in CH2Cl2 (30 mL) and treated with Boc2O (0.84 g,
3.9 mmol) and NaOH (0.18 g, 4.6 mmol) dissolved in H2O (2 mL)
at 0 °C and allowed to stir for 3 h at r.t. After completion of the re-
action, the mixture was neutralized by addition of 10% KHSO4 and
diluted with CH2Cl2. The organic phase was separated and the aque-
ous phase extracted with CH2Cl2 (3 × 20 mL). The combined organ-
ic extracts were washed with H2O (20 mL) and brine (20 mL), dried
(anhyd Na2SO4), and concentrated in vacuo. The residue was puri-
fied by column chromatography (silica gel, hexanes–EtOAc, 7:3) to
afford (2R,3S)-14 (0.54 g, 45%) as a white solid; mp 115–118 °C.
MS (ESI): m/z = 344 [M – H]+.
Synthesis 2012, 44, 2889–2894
© Georg Thieme Verlag Stuttgart · New York

PAPER
Asymmetric Syntheses of All Stereoisomers of 3-Hydroxyproline
2893
(2S,3S)-3-Hydroxyproline (1)
Acknowledgment
A soln of (2S,3S)-16 (66 mg, 0.25 mmol) in 6 M HCI (3 mL) and
EtOH (5 mL) was refluxed for 3 h. After cooling, EtOH was re-
moved and the residue was purified by ion-exchange chromatogra-
phy (Dowex resin, 2 M aq NH3 soln). The solvent was evaporated
to afford 1 (21 mg, 80%) as a white solid; mp 230–232 °C.
T.P.K. thanks CSIR New Delhi for the award of a research fellow-
ship.
Supporting Information for this article is available online at
http://www.thieme-connect.com/ejournals/toc/synthesis.SnoIufproi
[α]D25 –17.8 (c 0.5, H2O).
IR (neat): 3410, 2928, 2768 1705, 1491, 1112, 837 cm–1.
m
tgioSrantnugIifoop
r
itmnatr
1H NMR (300 MHz, D2O): δ = 4.67 (m, 1 H), 4.06 (s, 1 H), 3.48 (m,
1 H), 3.42 (s, 1 H), 2.04 (m, 2 H).
References and Notes
13C NMR (75 MHz, D2O): δ = 174.4, 75.8, 72.1, 46.8, 34.3.
MS (ESI): m/z = 132 [M + H]+.
HRMS: m/z [M + H]+ calcd for C5H10NO3: 132.0655; found:
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132.0656.
(2R,3R)-3-Hydroxyproline (3)
Following the procedures for 1 from ent-10 gave 3 (20.9 mg, 80%)
as a white solid; mp 229–232 °C.
[α]D25 +17.9 (c 0.5, H2O).
Spectral data of 3 are identical to those of 1.
(2S,3R)-3-Hydroxyproline (2)
To a soln of alcohol (2R,3S)-14 (0.7 g, 2.11 mmol), Ph3P (2.8 g,
10.57 mmol), and 4-nitrobenzoic acid (1.4 g, 8.45 mmol) in anhyd
THF (30 mL) was added DEAD (1.7 mL, 10.57 mmol) dropwise at
r.t. and the mixture was stirred at r.t. for 6 h. After completion of the
reaction (TLC monitoring), the mixture was quenched with sat.
NaHCO3 (10 mL) and filtered through Celite; the aqueous layer was
extracted with EtOAc (3 × 10 mL). The combined organic layers
were washed with brine (20 mL), dried (Na2SO4), and concentrated
in vacuo. The crude compound (benzoate ester) was directly used
for the next step.
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A.; Silva, U. F.; Hoelzel, S. C. S. M.; Zachia, R.; Bastos, N.
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To the above benzoate ester (1.2 g, crude weight) in MeOH (20 mL)
was added K2CO3 (0.3 g) at 0 °C and the mixture was stirred at this
temperature for 1 h. After completion of the reaction (TLC monitor-
ing), the mixture was filtered through a pad of Celite and washed
with MeOH (10 mL), and the MeOH was removed from the filtrate
under reduced pressure. Then H2O was added and the aqueous
phase was then extracted with CH2Cl2 (3 × 10 mL). The combined
organic layers were washed with brine (20 mL), dried (Na2SO4),
and concentrated in vacuo. The residue was purified by column
chromatography (silica gel, hexanes–EtOAc, 7:3) to afford inverted
alcohol (2R,3R)-14 (0.55 g, 88%).
Following the procedures for 1 using (2R,3R)-14 gave 2 (20.7 mg,
78%) as a white solid; mp 224–230 °C.
[α]D25 –97.9 (c 0.8, H2O).
IR (neat): 3399, 3076, 2846, 1635, 1491, 1102, 867 cm–1.
1H NMR (300 MHz, D2O): δ = 4.62 (m, 1 H), 4.06 (s, 1 H), 3.46–
3.37 (m, 2 H), 2.04–2.28 (m, 2 H).
13C NMR (75 MHz, D2O): δ = 172.1, 74.2, 70.9, 46.6, 35.9.
MS (ESI): m/z = 132 [M + H]+.
HRMS: m/z [M + H]+ calcd for C5H10NO3: 132. 132.0655; found:
132.0657.
(2R,3S)-3-Hydroxyproline (4)
Following the procedures for 2 using (2S,3R)-14 gave 4 (20.8 mg,
79%) as a white solid; mp 223–228 °C.
[α]D25 +98.4 (c 0.7, H2O).
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Angew. Chem. Int. Ed. 1999, 38, 2300. (d) Michael, J. P.
Spectral data of 4 are identical to those of 2.
© Georg Thieme Verlag Stuttgart · New York
Synthesis 2012, 44, 2889–2894

2894
T. P. Kumar, S. Chandrasekhar
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Synthesis 2012, 44, 2889–2894
© Georg Thieme Verlag Stuttgart · New York