An improved asymmetric synthesis of unusual amino acid (2S,3S)-3-hydroxyproline

Article abstract of DOI:10.1081/SCC-120030686

An improved three-steps method for the conversion of N-benzyl (S)-3-hydroxypyrrolidin-2-one 6 to (2S,3S)-3-hydroxyproline 1 is reported. The key step is the reductive cyanation of 6. The synthesis of 1 constitutes a formal asymmetric synthesis of (2S,3S)-3-hydroxyproline betaines 2.

Full text of DOI:10.1081/SCC-120030686

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An Improved Asymmetric Synthesis of Unusual Amino
Acid (2S,3S)‐3‐Hydroxyproline
Pei‐Qiang Huang a & Hui‐Ying Huang a
a Department of Chemistry, Xiamen University, Xiamen, Fujian, 361005, P.R. China
Version of record first published: 21 Aug 2006.
To cite this article: Pei‐Qiang Huang & Hui‐Ying Huang (2004): An Improved Asymmetric Synthesis of Unusual Amino Acid
(2S,3S)‐3‐Hydroxyproline, Synthetic Communications: An International Journal for Rapid Communication of Synthetic
Organic Chemistry, 34:8, 1377-1382
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SYNTHETIC COMMUNICATIONSw
Vol. 34, No. 8, pp. 1377–1382, 2004
An Improved Asymmetric Synthesis of
Unusual Amino Acid (2S,3S)-
3-Hydroxyproline
*
Pei-Qiang Huang and Hui-Ying Huang
Department of Chemistry, Xiamen University, Xiamen, Fujian,
P.R. China
ABSTRACT
An improved three-steps method for the conversion of N-benzyl
(S)-3-hydroxypyrrolidin-2-one
6 to (2S,3S)-3-hydroxyproline 1 is
reported. The key step is the reductive cyanation of 6. The synthesis
of 1 constitutes a formal asymmetric synthesis of (2S,3S)-3-hydroxypro-
line betaines 2.
Key Words: 3-Hydroxyproline; 3-Hydroxyproline betaines; Reductive
cyanation.
*
Correspondence: Pei-Qiang Huang, Department of Chemistry, Xiamen University,
Xiamen, Fujian 361005, P.R. China; E-mail: pqhuang@xmu.edu.cn.
1377
DOI: 10.1081/SCC-120030686
0039-7911 (Print); 1532-2432 (Online)
www.dekker.com
Copyright # 2004 by Marcel Dekker, Inc.

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Huang and Huang
INTRODUCTION
(2S,3S)-3-Hydroxyproline (trans-3-hydroxy-L-proline)
1 is a non-
proteinogenic amino acid first isolated from hydrolysates of Mediterranean
sponge,[1] and later from hydrolysates of the seeds of Delonix regia.[2,3] It is
also a component in a number of bioactive natural peptides such as mucrorin-
D,[4] tetomycin,[5] and cyclic peptide alkaloids.[6] It has been used as a valuable
chiral building block in the asymmetric synthesis of (þ)-castanospermine,[7]
and 3-substituted prolines.[8] Dimethylated derivative of 3-hydroxyproline,
namely 3-hydroxyproline betaines (L-trans-3-hydroxystachydrine a 2[9]) was
isolated from Courbonia virgata.[9a] In addition, (2R,3S)-2-hydroxymethyl-3-
hydroxypyrrolidine 3 (CYB-3 or trans-3-hydroxy-L-prolinol), the reduced
form of trans-3-hydroxy-L-proline, is also, a natural product isolated from the
seeds of the legume castarospermum australe (Fig. 1).[10]
A number of asymmetric syntheses[11] of 1 have been reported (For other
synthesesof 1 see Refs.[1b,12]). Recently, we reported an approach to N-substituted
(S)-3-hydroxypyrrolidin-2-ones (e.g., 6) starting from (S)-malic acid.[13] We now
wish to report an improved procedure for the transformation of 6 into 1.
ˆ
Previously, Larcheveque and coworkers have developed an attractive syn-
thesis of (2S,3S)-3-hydroxyproline 1,[11e] which used the one-pot reductive
cyanation[14] of 4 (to 5) as the key step (Sch. 1). In order to develop a more
efficient approach to 1, we sought to use the O-unprotected 6 in the reductive
ˆ
cyanation. Although the reductive cyanation of 8 using Larchveque’s condi-
tions[11e] (DIBAL-H, THF, 2788C; then KCN, H2O, 80% yield) was success-
ful, attempt to use the same conditions to 6 led to complex products.
A search of literature revealed that, under controlled conditions, lithium
aluminum hydride could be used to perform chemoselective reduction of
lactams.[14c,14d,15] Indeed, when 3-hydroxylactam 6 was treated with 5.7
molar equivalents of hydride in THF at 2358C for 50 min, followed by
addition of methanol at the same temperature, and then reacted with an aqu-
eous solution of potassium cyanide at 2158C,[14c] trans-2-cyano-3-hydroxy-
pyrrolidine (trans-7) and its cis-isomer were obtained in yields that ranged
from 66% to 74% (Sch. 2). The diastereomeric ratio of trans-7 and cis-7
Figure 1. Structure of compounds 1–3.

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1379
Scheme 1.
was determined to be 7 : 1 by flash chromatography separation on silica gel. It
is interesting to note that in CDCl3, pure cis-isomer epimerized at rt to give a
1
1 : 1 diastereomeric mixture as indicated by H-NMR. The final transform-
ation of trans-7 into known (2S,3S)-1 allowed to attribute the stereochemistry
of the major diastereomer as trans, which is in agreement with that observed
[11e]
ˆ
by Larcheveque in a similar system.
Next, acidic hydrolysis of the cyano group into carboxyl group (10) was
achieved using 37% HCl (45–508C, 8 hr). In this way, (2S,3S)-10 was obtained
as a white solid in high yield. Finally, under catalytic hydrogenolysis conditions,
(2S,3S)-10 was debenzylated to give (2S,3S)-1 in 90% yield. All physical data of
(2S,3S)-1 were identical with those reported in the literature.[11] (For other
syntheses of 1, see Refs.[11,12].)
In summary, we have demonstrated that the reductive cyanation of
O-unprotected (S)-1-benzyl-3-hydroxypyrrolidin-2-one 6 with LAH pro-
ceeded with good diastereoselectivity and satisfied yield. Based on this key
reaction, a three-steps procedure for the transformation of 6 to (2S,3S)-3-
hydroxyproline 1 was achieved. Since (2S,3S)-3-hydroxyproline 1 has
been converted to 3-hydroxyproline betaines 2 by N-dimethylation,[9b,c] our
approach to (2S,3S)-1 constitutes a formal synthesis of (2S,3S)-2.
EXPERIMENTAL
Melting points were determined on a Yanaco M-500 micro melting point
apparatus and the thermometer was uncorrected. IR spectra were obtained on a
Scheme 2.

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Huang and Huang
Nicholet Avatar 360 FT-IR spectrophotometer. 1H-NMR spectra were taken at
a Varian Unity þ500 spectrometer. Mass spectra were recorded on a Finnigan
MAT-GCQ (direct injection, EI). Column chromatography was performed on
silica gel H (Qingdao, 400 Mesh).
trans-2-Cyano-3-hydroxypyrrolidine (trans-7). To an ice-bath cooled
suspension of LAH (17 mg, 0.43 mmol) in anhydrous tetrahydrofuran
(0.4 mL), was added, under an atmosphere of N2, a solution of (S)-6[13]
(56 mg, 0.3 mmol) in tetrahydrofuran (0.3 mL). After being stirred at 2358C
for 20 min, methanol (0.3 mL) was added. The temperature was then allowed
to rise to 215 8C, and a solution of potassium cyanide (75 mg, 1.2 mmol) in
water (0.3 mL) was added. After being stirred for 10 min, the mixture was
diluted with ether (1 mL), and the mixture was allowed to reach room tempera-
ture. The mixture was filtered through celite, and the filtrate was extracted with
ether. The combined organic phases were washed with brine, dried over anhy-
drous Na2SO4. After concentrated at reduced pressure, the residue was purified
by flash chromatography on silica gel (eluent: AcOEt/PE) to afford trans-7
(35 mg) and cis-7 (5 mg) with a total yield 66%. trans-7: white solid, m.p.
52–538C (EtOAc/PE). [a]D20 ¼ 295 (c 1.1, CHCl3). IR (KBr) ymax: 3444,
1
2930, 2815, 1454, 1126, 1076, 754, 701 cm21. H NMR (500 MHz, CDCl3)
d: 1.70 (s br, 0.5H, OH), 1.85 (m, 1H, H-4), 2.39 (m, 1H, H-4), 2.61 (m, 1H,
H-5), 3.09 (m, 1H, H-5), 3.64 (s, 1H, H-2), 3.70 (d, J ¼ 12.9 Hz, 1H,
NCH2Ph), 3.94 (d, J ¼ 12.9 Hz, 1H, NCH2Ph), 4.49 (t, J ¼ 6.9 Hz, 1H, H-3),
7.20–7.40 (m, 5H, ArH) ppm. 13C NMR (125 MHz, CDCl3) d: 33.2, 49.7,
56.26, 61.4, 74.9, 115.5, 127.8, 137.0, 128.6, 128.8 ppm. MS (ESI, m/z): 225
(M þ Naþ, 21), 203 (M þ Hþ, 100). Anal. calcd for C12H14N2O: C, 71.3; H,
7.0; N, 13.9. Found: C, 71.1; H, 7.0; N, 13.9. Found: C, 71.14; H, 7.00;
N, 13.90. HRMS calcd for [C12H14N2O þ H]þ: 203.1179; found: 203.1180.
cis-7: IR (KBr) ymax: 3442, 2928, 2816, 2227, 1495, 1454, 1129, 1102, 754,
1
701 cm21. H NMR (500 MHz, CDCl3, a 1 : 1 diastereomeric mixture was
formed during taking the 1H-NMR spectral, only the data for cis-7 was showed)
d: 1.82 (m, 1H, H-4), 2.30 (br, 1H, OH), 2.38 (m, 1H, H-4), 2.82 (m, 2H, H-5),
3.67 (d, J ¼ 12.0 Hz, 1H, NCH2Ph), 3.80 (d, J ¼ 5.8 Hz, 1H, C-2), 3.91
(d, J ¼ 12.0 Hz, 1H, NCH2Ph), 4.49 (br, 1H, H-3), 7.20–7.40 (m, 5H, ArH).
MS (ESI, m/z): 203 (M þ Hþ, 100).
(2S,3S)-3-N-Benzyl-3-hydroxyproline 10. trans-7 (88 mg, 0.4 mmol)
in a 37% aqueous solution hydrochloric acid (0.2 mL), was heated to 45–
508C for 8 hr. The resulting mixture was concentrated at reduced pressure
to give a residue, which was washed by ethyl acetate, and recrystallized
(EtOAc/MeOH ¼ 6 : 1) to afford 10 (85 mg, yield, 83%) as a white solid.
M.p. 183–184.58C (EtOAc/MeOH). [a]2D0 ¼ þ32.4 (c 1.0, MeOH). IR
(KBr) ymax: 3339, 3261, 3166, 1701, 1400, 1111, 988, 886, 764, 701 cm21
.
1H NMR (500 MHz, CD3OD) d: 2.10 (m, 2H, H-4), 3.62 (m, 1H, H-5),

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Asymmetric Synthesis of (2S,3S)-3-Hydroxyproline
1381
3.80 (m, 1H, H-5), 4.10 (d, J ¼ 2.6 Hz, 1H, H-2), 4.37 (d, J ¼ 12.9 Hz, 1H,
NCH2Ph), 4.46 (m, 1H, H-3), 4.55 (d, J ¼ 12.9 Hz, 1H, NCH2Ph), 7.40–
7.58 (m, 5H, ArH) ppm. 13C NMR (125 MHz, CD3OD) d: 33.9, 55.0, 60.9,
74.9, 75.7, 130.5, 131.3, 132.0, 169.2 ppm. MS (ESI, m/z): 221 (Mþ, 100),
222 (M þ Hþ, 15). HRMS calcd for C12H15NO3: 221.1284; found: 221.1284.
(2S,3S)-3-Hydroxyproline 1. To a mixture of 10 (58 mg, 0.26 mmol)
and 10% Pd-C (26 mg) was added methanol (1.3 mL). The mixture was stirred
at room temperature and under an atmosphere of H2 for 13 hr. The reaction
mixture was filtered over celite. The filtrate was concentrated under reduced
pressure to give the crude 1 as a yellow solid (39 mg, yield, 98%), which
was then recrystallized (EtOAc/MeOH or EtOH/H2O) to afford 1 as a
white solid. M.p. 228–2308C (EtOAc/MeOH) (lit.[1b] 220–2308C; lit.[11e]
m.p. 230–2368C). [a]D20 ¼ 218.6 (c 1.0, H2O) flit.[11e] [a]D20 ¼ 218.3 (c
0.9, H2O); lit.[11b] [a]D20 ¼ 218.8 (c 0.14, H2O)g. IR (KBr, cm21) ymax
:
3317, 3163, 3014 1688, 1611, 1411, 1103, 1041, 615 cm21 1H NMR
.
(500 MHz, D2O) d: 2.10 (m, 2H, H-4), 3.48 (m, 1H, H-5), 3.58 (m, 1H,
H-5), 4.32 (m, 1H, H-2), 4.65 (m, 1H, H-3) ppm. 13C NMR (125 MHz,
D2O) d: 34.43, 47.34, 69.41, 77.00, 172.11 ppm. MS (ESI, m/z): 131 (Mþ,
100). HRMS calcd for C5H9NO3: 131.0816; found: 131.0815.
ACKNOWLEDGMENT
We are grateful to the NNSC for financial support.
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Received in Japan September 30, 2003

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