Synthesis of (2S,4S)-4-hydroxyproline from D-glucose

Article abstract of DOI:10.1080/00397911.2010.539753

Diacetone-D-glucose 1 gives 3-O-methylxanthate 2 on reaction with NaH=Me I. Reductive deoxygenation of compound 2 by Bu₃SnH gives the corresponding 3-deoxy glucose derivative 3 and on acid-catalyzed regioselective deprotection of C-5,6-acetonide gives the diol 4. The diol on oxidative cleavage with NaIO₄ gives the aldehyde 5, which on further condensation with benzylamine followed by reduction with NaBH₄ gives the amine 7. Z-Protection of the amine followed by methanolysis gives methyl furanoside 9. Reaction of 9 with methanesulfonyl chloride=Et₃N gives the corresponding C-3-O-mesylate derivative 10. Catalytic hydrogenation of compound 10 (Pd=C=H₂=MeOH 3 kg) gives bicyclic oxaazo compound 11, due to deprotection of the N-benzyl- and Z-protecting groups and intramolecular nucleophilic displacement of the C-2-O-mesylate by the C-5 amine in a one-pot reaction. Z-Protection of the amine 11 followed by acid-catalyzed hydrolysis gives acetal 13. Reduction of acetal by use of NaBH₄ gives Z-prolinol 14. Selective oxidation of diol 14 by (2,2,6,6-tetramethylpiperidin-1-yl)-oxyl (TEMPO)=[(bis)(acetoxy)iodo]-benzene (BAIB) and NaClO₂=NaH ₂PO₄, followed by Z-deprotection, gives the title compound I in 3.5% overall yield from D-glucose. Copyright Taylor & Francis Group, LLC.

Full text of DOI:10.1080/00397911.2010.539753

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Synthesis of (2S,4S)-4-Hydroxyproline
from D-Glucose
Hari Babu Mereyala a , Gopal Pathuri b & Lingaiah Nagarapu b
a Jupiter Biosciences, Secunderabad, India
b Organic Chemistry Division II, Indian Institute of Chemical
Technology, Hyderabad, India
Accepted author version posted online: 21 Oct 2011. Version of
record first published: 11 Jan 2012
To cite this article: Hari Babu Mereyala, Gopal Pathuri & Lingaiah Nagarapu (2012): Synthesis of
(2S,4S)-4-Hydroxyproline from D-Glucose, Synthetic Communications: An International Journal for
Rapid Communication of Synthetic Organic Chemistry, 42:9, 1278-1287
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Synthetic Communications1, 42: 1278–1287, 2012
Copyright # Taylor & Francis Group, LLC
ISSN: 0039-7911 print=1532-2432 online
DOI: 10.1080/00397911.2010.539753
SYNTHESIS OF (2S,4S)-4-HYDROXYPROLINE FROM
D-GLUCOSE
Hari Babu Mereyala,1 Gopal Pathuri,2 and
Lingaiah Nagarapu2
1Jupiter Biosciences, Secunderabad, India
2Organic Chemistry Division II, Indian Institute of Chemical Technology,
Hyderabad, India
GRAPHICAL ABSTRACT
Abstract Diacetone-D-glucose 1 gives 3-O-methylxanthate 2 on reaction with NaH=Me I.
Reductive deoxygenation of compound 2 by Bu3SnH gives the corresponding 3-deoxy glu-
cose derivative 3 and on acid-catalyzed regioselective deprotection of C-5,6-acetonide gives
the diol 4. The diol on oxidative cleavage with NaIO4 gives the aldehyde 5, which on further
condensation with benzylamine followed by reduction with NaBH4 gives the amine 7.
Z-Protection of the amine followed by methanolysis gives methyl furanoside 9. Reaction
of 9 with methanesulfonyl chloride=Et3N gives the corresponding C-3-O-mesylate derivative
10. Catalytic hydrogenation of compound 10 (Pd=C=H2=MeOH 3 kg) gives bicyclic
oxaazo compound 11, due to deprotection of the N-benzyl- and Z-protecting groups and
intramolecular nucleophilic displacement of the C-2-O-mesylate by the C-5 amine in a
one-pot reaction. Z-Protection of the amine 11 followed by acid-catalyzed hydrolysis gives
acetal 13. Reduction of acetal by use of NaBH4 gives Z-prolinol 14. Selective oxidation of
diol 14 by (2,2,6,6-tetramethylpiperidin-1-yl)-oxyl (TEMPO)=[(bis)(acetoxy)iodo]-
benzene (BAIB) and NaClO2=NaH2PO4, followed by Z-deprotection, gives the title
compound I in 3.5% overall yield from D-glucose.
Keywords Carbohydrates; diacetone-D-glucose; (2S,4S)-4-hydroxy-L-proline; reductive
debenzylation; reductive deoxygenation
Received September 21, 2010.
Address correspondence to Lingaiah Nagarapu, Organic Chemistry Division II, Indian Institute of
Chemical Technology, Hyderabad 500 007, India. E-mail: nagarapu@iict.res.in, lnagarapuiict@
yahoo.com
1278

(2S,4S)-4-HYDROXYPROLINE
1279
INTRODUCTION
(2S,4S)-4-Hydroxyproline (I) is a naturally occurring amino acid and constitu-
ent of phalloidine, the toxic polypeptide of Amanita phalloidine.[1] It has attracted
attention as a chiral building block for the synthesis of valuable compounds such
as glycopeptides,[2] antimetabolites of glutamic acid,[3] ACE inhibitors,[4] and
1-b-methylcarbapenem antibiotics.[5] Therefore, an efficient synthetic method for I,
as well as one with the elegance to produce various chiral forms, is required.
Papaioannou et al.[6] and Seki et al.[7] have prepared I by inversion of the hydroxyl
group of (2S,4R)-4-hydroxyproline by Mitsunobu reagent and N,N-dicyclohexyl-
carbodiimide (DCC) respectively. Thirring et al.[8] have synthesized I following
Takano et al.’s strategy[9] starting from (ꢀ)-menthyl ester of hippuric acid.[10] The
synthesis involved separation of diastereomers to obtain the cis-isomer I.[8] Sandri
et al. have reported enantioselective synthesis through stereocontrolled 1,4-trans
alkylation of (6S)-methyl-4-(1S)-phenylethyl-1,4-morpholine-2,5-diones via stereo-
controlled double iodocyclization.[11] Earlier Fleet et al. have reported synthesis of
several dihydroxy prolines from carbohydrates.[12]
RESULTS AND DISCUSSION
We report herein for the first time a new route to synthesize I from naturally
occurring carbohydrate raw material (viz., D-glucose). The present protocol is also
aimed at preparation of various isomeric forms and analogs of I needed for drug dis-
covery research. Retrosynthetic analysis (Scheme 1) indicated diacetone-D-glucose 1
as a suitable substrate to achieve synthesis of amino acid derivative I. To synthesize
the target compound from D-glucose would require synthetic transformations such
as (i) reductive deoxygenation of C-3 hydroxyl group, (ii) removal of C-6 carbon,
(iii) introduction of amino function at C-5, and (iv) inversion of configuration at C-2.
The reaction scheme was demonstrated as follows (Scheme 2). Diacetone-D-
glucose 1 was transformed to the known 3-deoxy glucofuranose derivative 3 via
the methyl xanthate derivative 2.[13] Regioselective deprotection of diacetonide 3
afforded the C-5,6-diol 4. Cleavage of the vicinal diol 4 with NaIO4=MeOH gave
the aldehyde 5, which was immediately condensed with benzylamine to the imine
6. The imine 6 was reduced with NaBH4=MeOH to afford the amine 7 in good yield
1
(62%). The amino derivative 7 was characterized by H NMR from the appearance
of H-5 (2H) at d 2.90 (dd, 1H, Jgem ¼ 14.0 Hz, J4,5 ¼ 4.5 Hz) and d 2.70 (dd, 1H,
Scheme 1. Retrosynthesis of (2S,4S)-4-hydroxyproline I.

1280
H. B. MEREYALA, G. PATHURI, AND L. NAGARAPU
Scheme 2. Reagents and conditions: (a) NaH, CS2, MeI, THF, 0 ꢁC, 15 min., 94%; (b) TBTH, AIBN, tolu-
ene, reflux, 8 h, 75%; (c) 0.8% aq. H2SO4, MeOH, rt, 2 h, 76%; (d) NaIO4, MeOH, rt, 2 h; (e) BnNH2,
CH2Cl2, rt, 5 h; (f) NaBH4, MeOH, rt, 1 h, 62%; (g) Cbz-Cl, aq. Na2CO3, CH2Cl2, rt, 4 h, 82%;
(h) p-TSA, MeOH, rt, 8 h, 82%; (i) MsCl, Et3N, DMAP, CH2Cl2, rt, 4 h, 90%; (j) H2 (3 kg=cm2), Pd=C,
MeOH, 80 ꢁC, 8 h, 66%; (k) Cbz-Cl, aq. Na2CO3, CH2Cl2, rt, 8 h, 73%; (l) 60% aq. AcOH, catalytic
HCl, 60 ꢁC, 0.5 h, 94%; (m) NaBH4, MeOH, reflux, 0.5 h, 57%; (n) TEMPO, BAIB, CH2Cl2, rt, 2 h then
t
NaClO2, NaH2PO4, BuOH, rt, 1.5 h, 60%; (o) H2, 10% Pd=C, MeOH, rt, 8 h, 64%.
0
Jgem ¼ 14.0 Hz, J4,5 ¼ 7.0 Hz) and benzylic protons (2H) at d 3.85. The amine 7 was
protected as Z-amino derivative 8. Methanolysis of compound 8 with para-toluene-
sulfonic acid (p-TSA)=MeOH gave a diastereomeric mixture of methyl furanoside
1
derivative 9. Formation of methyl furanoside was evident from H NMR by the
appearance of characteristic methoxy protons (3H) at d 3.30. Reaction of hydroxy
derivative 9 with methanesulfonyl chloride gave the corresponding mesylate 10.
Compound 10 was hydrogenated by use of 10% Pd=C=H2 (3 kg=cm2) in methanol
to afford oxaazo bicyclic compound 11 (diastereomeric mixture) due to removal
of the N-benzyl- and Z-protecting groups, followed by intramolecular nucleophilic
displacement of the C-2-O-mesylate group by the C-5 amine in a one-pot reaction.
1
The bicyclic compound 11 was characterized from H NMR by the appearance of
H-3 at d 5.10 (s, 0.5H) and 5.04 (d, 0.5H, J1,2 ¼ 3.1 Hz) and H-1 at d 4.65–4.30 as
a multiplet, and also by 13C NMR from the appearance of C-3 at d 108.7(a) and
104.1(b). Compound 11 was transformed to the corresponding Z-protected deriva-
tive 12, which on acid-catalyzed hydrolysis afforded the lactal 13. Reduction of lactal
13 with NaBH4=MeOH gave the diol 14. The diol 14 was characterized by 1H NMR
spectrum from the appearance of CH2OH at d 4.30–3.95 (2H) as a multiplet, H-4 at d
4.17 as a double doublet (J ¼ 9.0, 3.0 Hz). Regioselective oxidation of diol 14 with
TEMPO and BAIB[14a] gave the corresponding aldehyde, which on further oxidation
[14b]
t
with NaH2PO4 and NaClO2
in BuOH gave the Z-protected cis-hydroxyproline
derivative 15. Catalytic hydrogenation of 15 gave the desired (2S,4S)-4-
hydroxyproline (I). Compound I was characterized by comparison of spectral data;
it was fully in agreement with those reported in the literature.[7]

(2S,4S)-4-HYDROXYPROLINE
1281
In conclusion, an elegant approach to the synthesis of (2S,4S)-4-hydroxy-
proline (I) from D-glucose in 3.5% overall yield was demonstrated for the first time.
The utility carbohydrate template for the synthesis of several other natural and
unnatural proline derivatives is in progress.
EXPERIMENTAL
Melting points were determined using Fisher John’s melting-point apparatus
and are uncorrected. Infrared (IR) spectra were recorded on a Thermo Nicolet
Nexus 670 Fourier transform (FT)–IR spectrometer. Accurate mass measurement
1
was performed on a Q-STAR mass spectrometer (Applied Biosystems USA). H
NMR and 13C NMR spectra were recorded at 300 MHz on Bruker Avance and at
200 MHz on Unity FT-NMR spectrometers with tetramethylsilane (TMS) as an
internal standard (chemical shifts in d, ppm). Optical rotations were measured with
a Jasco DIP-370 instrument. For column chromatography, silica gel (60–120 mesh)
was used. For thin-layer chromatography (TLC), silica gel 60 F254 (Merck) was used.
1,2:5,6-Di-O-isopropylidene-3-O-(methyldithiocarbonate)-a-
D-glucofuranose (2)
Sodium hydride (60%, 7.2 g, 150 mmol) was added to a solution of
diacetone-D-glucose 1 (26.0 g, 100 mmol), imidazole (25 mg) in dry THF (400 mL)
at 0 ꢁC. The reaction mixture was stirred for 15 min, and carbon disulfide
(22.8 g, 300 mmol) was added. After stirring for an additional 30 min, iodomethane
(25.3 g, 177 mmol) was added. The reaction was quenched by addition of glacial
acetic acid (5 mL). The reaction mixture was worked up to obtain a residue, which
was extracted into EtOAc (3 ꢂ 100 mL). The organic layer was washed with satu-
rated NaHCO3 solution (3 ꢂ 100 mL) and water (3 ꢂ 100 mL), dried (Na2SO4),
filtered, and concentrated to obtain the title compound 2. Yield: 33.04 g (94.4%);
27
syrup; ½aꢃD ꢀ 30.0 (c ¼ 0.5, CHCl3). IR (neat): nmax 2987, 2930, 1456, 1377,
1201, 1162, 1072, 1021, 845 cmꢀ1 1H NMR (200 MHz, CDCl3): d 5.90 (d,
.
J ¼ 3.9 Hz, 1H, H-1), 5.88 (m, 1H, H-3), 4.65 (d, J ¼ 3.9 Hz, 1H, H-2), 4.35–4.25
(m, 2H, H-4, 5), 4.10–4.01 (m, 2H, H- 6, 60), 2.62 (s, 3H, S-Me), 1.38, 1.42, 1.52
(3s, 12H, 4 ꢂ CH3). 13C NMR (75 MHz, CDCl3): d 112.4, 109.3 (CMe2 ꢂ 2),
105.0 (C-1), 84.2, 82.8, 79.7, 72.4, 66.9 (C-2, 3, 4, 5, 6), 29.7, 26.8, 26.6, 26.2,
19.3 (CMe2, SMe). ESI MS: m=z ¼ 373 [M þ Na]þ. HRMS (ESI): m=z calcd. for
C14H22O6NaS2: 373.0755; found: 373.0765.
3-Deoxy-1,2:5,6-di-O-isopropylidene-a-D-ribohexofuranose (3)
A solution of xanthate 2 (17.5 g, 50 mmol), tri-n-butyltin hydride (29.06 g,
100 mmol), and azobisisobutyronitrile (AIBN, 10 mg) in toluene (500 mL) was
refluxed for 6 h, and the solvent was removed under reduced pressure to obtain a
residue, which was column chromatographed (hexane=EtOAc, 6:1) to obtain the title
27
compound 3. Yield 9.16 g (75%); oil. ½aꢃD ꢀ 7.8 (c ¼ 1.0, CHCl3). IR (neat): nmax
1
2987, 2936, 2896, 1456, 1371, 1215, 1162, 1064, 846 cmꢀ1. H NMR (200 MHz,
CDCl3): d 5.75 (d, J1,2 ¼ 4.1 Hz, 1H, H-1), 4.70 (dt, J ¼ 4.1 Hz, H-2), 4.20–3.75 (m,

1282
H. B. MEREYALA, G. PATHURI, AND L. NAGARAPU
3H, H-5, 6, 60), 2.18 (dd, J ¼ 9.2, 4.0 Hz, 1H, H-3), 1.80–1.55 (m, 1H, H-3), 1.52,
1.40, 1.35, 1.30 (4s, 12H, 4 ꢂ CH3). 13C NMR (75 MHz, CDCl3): d 111.2, 109.6
(CMe2 ꢂ 2), 105.5 (C-1), 80.3, 78.6, 77.4, 67.1 (C-2, 4, 5, 6), 35.2, 26.7, 26.4, 26.0,
25.1 (CMe2 ꢂ 2, C-3). ESI MS: m=z ¼ 245 [M þ H]þ. HRMS (ESI): m=z calcd. for
C12H20O5Na: 267.1208; found: 267.1213.
3-Deoxy-1,2-O-isopropylidene-a-D-ribohexofuranose (4)
A solution of compound 3 (7.5 g, 30 mmol) in methanol (90 mL) and 0.8%
aqueous H2SO4 (40 mL) was stirred at rt for 3 h. After completion of the reaction,
solid Ba2CO3 (10 g) was added to the reaction mass and filtered; the filtrate was con-
centrated to a syrupy residue and chromatographed (hexane=EtOAc, 1:1) to obtain
27
the title compound 4. Yield: 4.8 g (76.6%); white solid; mp 75–77 ꢁC; ½aꢃD ꢀ 14.8
1
(c ¼ 1.0, CHCl3). IR (neat): nmax 3422 cmꢀ1. H NMR (300 MHz, CDCl3): d 5.80
(d, J1,2 ¼ 3.9 Hz, 1H, H-1), 4.74 (dt, J ¼ 3.9 Hz, 1H, H-2), 4.30–4.18 (m, 1H, H-4),
3.90–3.52 (m, 3H, H-5, 6, 60), 2.45 (br s, OH), 2.06 (dd, J ¼ 9.2, 3.9 Hz, 1H, H-3),
1.85–1.70 (m, 1H, H-30), 1.51, 1.32 (2s, 6H, 2 ꢂ CH3). 13C NMR (75 MHz, CDCl3):
d 111.2 (CMe2), 105.5 (C-1), 80.4, 78.2, 72.2, 63.4 (C-2, 4, 5, 6), 33.6, 26.5, 25.9
(CMe2, C-3). ESI MS: m=z ¼ 205 [ Mþ H]þ. HRMS (ESI): m=z calcd. for
C9H16O5Na: 227.0895; found: 227.0890.
N-Benzyl-((3aR,5S,6aR)-2,2-dimethyltetrahydrofuro[2,3-d]
[1,3]dioxol-5-yl)methanamine (7)
Sodium metaperiodate (5.13 g, 24 mmol) was added to a solution of 4 (4.08 g,
20 mmol) in methanol (80 mL) at 0 ꢁC and vigorously stirred at room temperature
for 2 h. The reaction mixture was filtered through a bed of celite and washed with
methanol (2 ꢂ 25 mL); the filtrate was concentrated to obtain the title aldehyde 5
(3.27 g, 95.0%) as thick syrup. The aldehyde 5 (3.27 g, 19 mmol) was immediately dis-
solved in dry dichloromethane (30 mL), benzyl amine (2.44 g, 22.8 mmol) and
MgSO4 (5.0 g) were added, and the mixture was stirred at room temperature for
5 h. After completion of the reaction, the solids were filtered off on a Buchnner
funnel and washed with dichloromethane (2 ꢂ 10 mL). Filtrate was evaporated on
a rotary evaporator to isolate imine 6 (5.94 g, 95.9%) as a thick syrup. The imine
6 (5.94 g, 22.7 mmol) was dissolved in methanol (60 mL), and NaBH4 (1.73 g,
45.4 mmol) was added and stirred at room temperature for 1 h. Progress of the reac-
tion was monitored by TLC. After completion of the reaction, the reaction mixture
was quenched with a few drops of acetic acid and evaporated on a rotary evaporator
to a residue. The residue was extracted into EtOAc (2 ꢂ 50 mL), washed with H2O
(2 ꢂ 25 mL), dried (Na2SO4), and evaporated on a rotary evaporator to obtain the
27
title compound 7. Yield 4.75 g (79.4%); thick syrup; ½aꢃD ꢀ 12.6 (c ¼ 1.0, CHCl3).
IR (neat): nmax 3345 cmꢀ1 1H NMR (200 MHz, CDCl3): d 7.50–7.10 (m, 5 H,
.
Ar-H), 5.80 (d, J1,2 ¼ 3.5 Hz, 1H, H-1), 4.70 (dt, J1,2 ¼ J2,3e ¼ 5.2 Hz, J2,3a ¼ 3.5 Hz,
H-2), 4.46–4.30 (m, 1H, H-4), 3.85 (s, 2H, CH2Ph), 3.30–3.10 (m, 1H, NH), 2.90
(dd, 1H, Jgem ¼ 14.0 Hz, J4,5 ¼ 4.5 Hz, H-5), 2.70 (dd, 1H, Jgem ¼ 14.0 Hz,
J40;5 ¼ 7.0 Hz, H-50), 2.10–1.95 (m, 1H, H-3e), 1.72–1.20 (m, 1 H, H-3a), 1.44, 1.25
(2s, 6H, 2 ꢂ CH3). 13C NMR (75 MHz, CDCl3): d 136.8, 129.0, 128.0, 127.6 (Arom),

(2S,4S)-4-HYDROXYPROLINE
1283
111.1 (CMe2), 105.4 (C-1), 79.9, 76.0 (C-2, 4), 52.7, 50.3 (C-5, PhCH2NH), 36.4,
26.4, 26.1 (C-3, CMe2). ESI MS: m=z ¼ 264 [M þ H]þ. HRMS (ESI): m=z calcd.
for C15H22NO3: 264.1599; found: 264.1596.
Benzyl Benzyl(((3aR,5S,6aR)-2,2-dimethyl-tetrahydrofuro[2,3-d]
[1,3dioxol-5-yl)methyl)carbamate (8)
Na2CO3 (1.76 g, 16.6 mmol), H2O (3 mL), and benzyloxycarbonyl chloride
(3.27 g, 19.2 mmol) were added to a solution of amine 7 (4.21 g, 16 mmol) in CH2Cl2
(20 mL) at 0 ꢁC and stirred at room temperature for 4 h. TLC monitored the progress
of the reaction. After completion of the reaction, the reaction mixture was diluted
with H2O (10 mL) and extracted into CH2Cl2 (2 ꢂ 20 mL). The organic layer was
washed with H2O (2 ꢂ 20 mL) and brine (2 ꢂ 20 mL). The organic layer was sepa-
rated, dried (Na2SO4), and concentrated to obtain a residue. The residue was
purified by column chromatography (hexane=EtOAc, 9:1) to obtain the title com-
27
pound 8. Yield: 5.25 g (82.6%); thick syrup; ½aꢃD ꢀ 0.81 (c ¼ 1.0, CHCl3). IR (neat):
n
max 1701 cmꢀ1. 1H NMR (200 MHz, CDCl3): d 7.40–7.10 (m, 5H, Ar-H), 5.70 (brs,
1H, H-1), 5.12 (s, 2H, OCH2Ph), 4.80–4.10 (m, 4H, H-2, 4 and PhCH2N), 3.70–3.10
(m, 2H, H-5, 50), 2.20–1.80 (m, 2H, H-3, 30), 1.50, 1.25 (2s, 6H, CMe2). 13C NMR
(75 MHz, CDCl3): d 156.5 (CO), 136.7, 136.4, 128.4, 2 ꢂ 127.9, 127.3, 127.1, 126.8
(Arom), 110.9 (CMe2), 105.4 (C-1), 80.1, 77.4 (C-2, 4), 67.3 (PhCH2O), 51.2, 49.2
(C-5 and PhCH2N), 36.4, 26.5, 26.09 (C-3 and CMe2). ESI MS: m=z ¼ 398 [M þ H]þ.
HRMS (ESI): m=z calcd. for C23H28NO5: 398.1967; found: 398.1960.
Benzyl Benzyl(((3R)-hydroxy-2-(R/S)-methoxy-(5S)-tetrahydrofuran-
2-yl)methyl)Carbamate (9)
p-TSA (1.26 g, 6.60 mmol) was added to a stirred solution of 8 (5.25 g,
13.2 mmol) in methanol (25 mL) at 0 ꢁC. The reaction mixture was brought to room
temperature and stirred overnight. After completion of the reaction, the reaction
mixture was quenched with triethylamine (1 mL), and solvent was evaporated to
obtain a residue. The residue was extracted into CH2Cl2 (2 ꢂ 25 mL), washed with
brine (2 ꢂ 25 mL), dried (Na2SO4), and evaporated on a rotary evaporator to obtain
27
the title compound 9. Yield: 4.02 g (82.0%); thick syrup; ½aꢃD þ 18.2 (c ¼ 1.0, CHCl3).
IR (neat): nmax 3442, 1696 cmꢀ1. 1H NMR (200 MHz, CDCl3): d 7.40–7.05 (m, 10H,
Ar-H), 5.25–5.00 (s, 2H, PhCH2O), 4.90–4.40 (m, 4H, PhCH2N and H-2, 4), 4.10 (br
s, 1H, H-1), 3.70–3.40 (m, 2H, H-5, 50), 3.30 (s, 3H, OMe), 2.10–1.30 (m, 2 H, H-3,
30).13C NMR (75 Hz, CDCl3): d 156.5 (CO), 137.7, 136.5, 128.5, 128.4, 127.9, 127.7,
127.2, 127.0 (Arom), 109.6 (C-1), 78.3, 75.6 (C-2, 4), 67.3 (PhCH2O), 54.7, 2 ꢂ 51.0
(C-5, PhCH2N and OMe), 35.8 (C-3). ESI MS: m=z ¼ 372 [M þ H]þ. HRMS (ESI):
m=z calcd. for C21H25NO5Na: 394.1630; found: 394.1637.
(3R,5S)-5-[((Phenylmethyl(benzyloxycarbonyl)amino)methyl)-2-
(R,S)-methoxy-tetrahydrofuran-3-yl]methanesulfonate (10)
Et3N (3.27 g, 32.3 mmol), methanesulfonyl chloride (1.48 g, 12.9 mmol), and
dimethylaminopyridine (DMAP; 20 mg) were added to a solution of 9 (4.0 g,

1284
H. B. MEREYALA, G. PATHURI, AND L. NAGARAPU
10.7 mmol) in dichloromethane (20 mL) at 0 ꢁC, under N2 atmosphere. The reaction
mixture was brought to room temperature and stirred for 4 h. TLC monitored the
progress of the reaction. After completion of the reaction, the reaction mixture
was extracted into CH2Cl2 (2 ꢂ 20 mL). The combined organic phases were washed
with H2O (2 ꢂ 15 mL) and brine (2 ꢂ 15 mL) and separated. The organic layer was
dried (Na2SO4) and evaporated on a rotary evaporator to obtain a residue. The resi-
due was purified by column chromatography (SiO2, 60–120 mesh EtOAc=hexane,
1:4) to obtain the title compound 10. Yield: 4.06 g (90.3%); thick syrup;
27
½aꢃD þ 13.0 (c ¼ 1.0, CHCl3). IR (neat): nmax 3029, 2931, 1698, 1459, 1419, 1360,
1238, 1175 and 970 cmꢀ1 1H NMR (300 MHz, CDCl3): d 7.40–7.10 (m, 10H,
.
Ar-H), 5.15 (s, 2H, PhCH2), 5.05–4.40 (m, 5H, PhCH2N and H-1, 2, 4), 3.70–3.40
(m, 2H, H-5, 50), 3.40, 3.35, 3.08, 3.30 (4s, 6H, OMe, SO2Me), 2.35–1.80 (m, 2H,
H-3, 30). 13C NMR (50 MHz, CDCl3): d 156.4 (CO), 137.6, 136.4, 128.4 ꢂ 2, 127.9,
127.8, 127.3, 127.0 (Ar), 106.8 (C-1), 82.4, 78.6 (C-2, 4), 67.3 (PhCH2O), 54.9,
52.2 ꢂ 2 (C-5, PhCHN and OMe), 38.4, 33.7 (C-3 and SO2Me). ESI MS:
m=z ¼ 472 [M þ H]þ. HRMS (ESI): m=z calcd. for C22H27NO7NaS: 472.1405;
found: 472.1401.
(1R,4S)-(3R/S)-Methoxy-2-oxa-5-aza-bicyclo[2.2.1]heptane (11)
To a solution of 10 (3.60 g, 8.6 mmol) in methanol (150 mL) was added 10%
Pd=C (0.5 g), and the mixture was hydrogenated in an autoclave (3 kg=cm2) at
80 ꢁC for 8 h. TLC monitored the progress of the reaction. After completion of
the reaction, the catalyst was filtered on a Buckner funnel, and the filtrate was
concentrated to obtain the title compound 11. Yield: 0.74 g (66.6%); thick syrup;
.
1H NMR (300 MHz,
½aꢃD ꢀ 6.0 (c ¼ 0.5, MeOH). IR (neat): nmax 3417 cmꢀ1
27
CD3OD): d 5.10 (s, 0.5H, H-3a), 5.04 (d, J1,2 ¼ 3.1 Hz, 0.5 H, H-3b), 4.65–4.30
(m, 1H, H-1), 3.42 (s, 3H, OMe), 3.20–3.05 (m, 2H, H-4, 6), 2.90–2.75 (m, 1H,
H-60), 2.40–2.30 (m, 1H, H-7), 2.20–2.00 (m, 1H, H-70). 13C NMR (75 MHz, CDCl3):
d 108.7 (C-3a), 104.1 (C-3b), 84.1 (C-1), 52.5 (OMe), 46.4 (C-6), 38.3 (C-4), 34.5
(C-7). EI MS: m=z ¼ 129 [Mþ.]. HRMS (ESI): m=z calcd. for C6H12NO2:
130.0868; found: 130.0872.
(1S,4R)-N-Cbz-3-(R/S)-methoxy-5-oxa-2-aza-bicyclo[2.2.1]heptane (12)
Na2CO3 (0.55 g, 5.2 mmol) in H2O (0.5 mL) and benzyloxycarbonyl chloride
(1.07 g, 10 mmol) was added to a solution of 11 (0.64 g, 5 mmol) in dichloromethane
(10 mL) at 0 ꢁC and stirred at room temperature for 8 h. TLC monitored the progress
of the reaction. After completion of the reaction, the reaction mixture was diluted
with H2O (10 mL) and extracted into CH2Cl2 (2 ꢂ 10 mL). The organic phase was
washed with H2O (2 ꢂ 25 mL) and brine (2 ꢂ 5 mL). The organic layer was separated,
dried (Na2SO4), and evaporated on a rotary evaporator to obtain a residue. The resi-
due was purified by column chromatography (hexane=EtOAc, 4:1) to obtain the title
27
compound 12. Yield: 0.96 g (73.2%); thick syrup; ½aꢃD ꢀ 9.6 (c ¼ 0.25, CHCl3). IR
1
(neat): nmax 3355, 2935, 1708, 1528, 1359, 1174 and 968 cmꢀ1. H NMR (300 MHz,
CDCl3): d 7.40–7.20 (m, 5H, Ar-H), 5.20–4.90 (m, 3H, H-3 and PhCH2O),
4.50–4.40 (m,1H, H-1), 3.50–3.40 (m,1H, H-6), 3.90 (s, 3H, OMe), 3.36–3.12 (m,

(2S,4S)-4-HYDROXYPROLINE
1285
1H, H-60), 2.25–2.20 (m, 2H, H-7, 70). 13C NMR (75 MHz, CDCl3): d 156.6 (CO),
136.5, 128.5, 128.1, 128.0 (Arom), 106.7, (C-3a), 101.3 (C-3b), 82.7 (PhCH2O),
78.6 (C-1), 55.0 (OMe), 45.4, 38.6 (C-4, 6), 32.6 (C-7). ESI MS: m=z ¼ 286 [M þ Na]þ.
. HRMS (ESI): m=z calcd. for C14H17NO4Na: 286.1055; found: 286.1058.
(1S,4R)-N-Cbz-3-(R/S)-hydroxy-5-oxa-2-aza-bicyclo[2.2.1]heptane (13)
Two drops of concentrated HCl were added to a solution of 12 (0.79 g, 3 mmol)
in 60% aqueous AcOH (12 mL) and heated to reflux for 30 min. TLC monitored the
progress of the reaction. After completion of the reaction, the reaction mixture was
cooled to room temperature, treated with aqueous NaHCO3 (12 g in 50 mL water),
and extracted into ethylacetate (50 mL). The aqueous layer was separated and
extracted with ethylacetate (2 ꢂ 25 mL). The organic phase was separated and
washed with aqueous NaHCO3 (2 ꢂ 25 mL), water (2 ꢂ 25 mL), and brine
(2 ꢂ 25 mL) and dried (Na2SO4). The solvent was evaporated to obtain a residue.
The residue was purified by flash column chromatography [EtOAc=hexane 1:1] to
27
obtain the title compound 13. Yield: 0.70 g (94.3%); thick syrup; ½aD ꢀ 29.0
1
(c ¼ 0.5, CHCl3). IR (neat): nmax 3402, 1721 cmꢀ1. H NMR (300 MHz, CDCl3): d
7.50–7.30 (m, 5H, Ar-H), 5.30–5.10 (m, 2H, PhCH2O), 5.08-4.90 (m, 1H, H-3 a
b), 4.40–4.20 (m, 1H, H-1), 3.80–3.20 (m, 3H, H-4, 6, 60), 2.20–1.95 (m, 2H, H-7, 70).
(2S,4S)-N-Cbz-4-hydroxyprolinol (14)
NaBH4 (0.42 g, 11.1 mmol) was added to a solution of 13 (0.69 g, 2.7 mmol) in
methanol (10 mL) at 0 ꢁC and heated to reflux for 30 min. The reaction mixture was
cooled to rt, quenched by addition of four drops of saturated NH4Cl solution, and
stirred at room temperature for 30 min. Methanol was evaporated on a rotary evap-
orator to obtain a residue. The residue was extracted several times with EtOAc
(25 mL ꢂ 4) and concentrated to obtain a residue. The residue was purified by col-
umn chromatography by eluting with EtOAc–hexane 3:2 to obtain the title com-
27
pound 14. Yield: 0.4 g (57.0%); syrup; ½aꢃD ꢀ 15.0 (c ¼ 0.5, CHCl3). IR (neat):
nmax 3381 cmꢀ1 1H NMR (300 MHz, CDCl3): d 7.40–7.20 (m, 5H, Ar-H),
.
4.30–4.15 (m, 1H, CH2OH), 4.17 (dd, J ¼ 9.0, 3.0 Hz, 1H, H-4), 4.05–3.95 (m, 1H,
CH2OH), 5.20–5.00 (m, 2H, benzyl), 3.60–3.40 (m, 3H, H-2, 5), 2.40–1.80 (m, 2H,
H-3 and OH). 13C NMR (75 MHz, CDCl3): d 155.7 (CO), 136.0, 128.4, 127.8,
119.3 (Arom), 69.6 (C-4), 66.9 (PhCH2), 63.5 (CH2OH), 58.9, 56.7 (C-2, 5), 37.4
(C-3). EI MS: m=z ¼ 251 [Mþ.]. HRMS (EI): m=z calcd. for C13H17NO4Na:
274.1055; found: 274.1068.
(2S,4S)-N-Cbz-4-hydroxyproline (15)
TEMPO (0.07 g, 0.45 mmol), was added to a solution of 14 (0.37 g, 1.5 mmol)
in CH2Cl2 (5 mL), followed by iodobenzene diacetate (0.534 g, 4.5 mmol) at rt, and
stirred for 2 h. TLC monitored the progress of the reaction. After completion of the
reaction, the reaction mixture was treated with 5% aqueous Na2S2O5 (5 mL) and
saturated aqueous NaHCO3 (5 mL). After 15 min, the organic phase was separated
and the aqueous phase was extracted into CH2Cl2 (2 ꢂ 10 mL). The organic phase

1286
H. B. MEREYALA, G. PATHURI, AND L. NAGARAPU
was separated, dried (Na2SO4), and concentrated to obtain a residue. The residue
was filtered through a bed of silica gel (eluted with 2:3 EtOAc=hexane) to obtain
the aldehyde. The aldehyde was immediately oxidized to the acid without further
purification.
Methyl-2-butene (5 mL), 20% aqueous NaH2PO4 ꢄ 2H2O (5 mL) solution, and
NaClO2 (1.43 g, 16.5 mmol) were added to a solution of aldehyde in t-BuOH
(5 mL) at 0 ꢁC. The reaction mixture was warmed to room temperature and stirred
for 1.5 h. TLC monitored the progress of the reaction. After completion of the reac-
tion, the reaction mixture was extracted into EtOAc (2 ꢂ 25 mL). The organic phase
was evaporated, washed with 20% aqueous NaH2PO4 ꢄ 2H2O solution (2 ꢂ 10 mL)
and brine (2 ꢂ 10 mL), and dried (Na2SO4). The organic phase was evaporated to
obtain a solid and triturated with i-Pr2O to isolate the title compound 15. Yield:
27
0.24 g (60.2%); white solid; mp 105–107 ꢁC; ½aꢃD ꢀ 38.5 (c ¼ 1.5, MeOH). IR
1
(KBr): nmax 3267, 1765, 1686 cmꢀ1. H NMR (300 MHz, DMSO-d6): d 7.45–7.22
(m, 5H, Ar-H), 5.12–4.97 (m, 2H, benzyl), 4.32–4.16 (m, 2H, H-2, 4), 3.65–3.17
(m, 2H, H-5, 50), 2.38–2.20 (m, 1H, H-3), 1.98–1.82 (m, 1H, H-30). LC MS:
m=z ¼ 288 [M þ Na]þ. HRMS (ESI): m=z calcd. for C13H15NO5Na: 288.0847; found:
288.0840.
(2S,4S)-4-Hydroxyproline (I)
To a solution of compound 15 (0.132 g, 0.5 mmol) in methanol (l2 mL) was
added 10% Pd=C (0.1 g), which was hydrogenated (1 atm) at room temperature for
4 h. The catalyst was filtered on a Buchnner funnel, and the filtrate was concentrated
to obtain the title compound I. Yield: 0.04 g (64.0%); solid; mp 245–246 ꢁC [lit.[15]
[15]
248 ꢁC]; ½aꢃD ꢀ 57.2 (c ¼ 2.0, H2O) [lit. ꢀ 58 (c ¼ 2.0, H2O)]. IR (KBr): nmax
27
3210, 1629, 1565 cmꢀ1. H NMR (300 MHz, D2O): d 4.62–4.56 (m, 1H, H-2), 4.22
1
(dd, J ¼ 3.8, 10 Hz, 1H, H-4), 3.52–3.44 (m, 1H, H-5), 3.37 (dd, J ¼ 3.8, 12.5 Hz,
1H, H-50), 2.62–2.42 (m, 1H, H-3), 2.30–2.20 (m, 1H, H-30). 13C NMR (75 MHz,
CDCl3): d 177.2 (COOH), 71.9 (C-2), 62.5 (C-4), 55.7 (C-5), 39.9 (C-3). LC MS:
m=z ¼ 132 [M þ H]þ. HRMS (ESI): m=z calcd. for C5H10 N O3: 132.0660; found:
132.0664.
ACKNOWLEDGMENT
G. P. thanks the director and head, Organic Chemistry Division II, Indian
Institute of Chemical Technology, Hyderabad, for financial assistance and support
of this work.
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