Stereoselective synthesis of conformationally constrained (2S,3S)-3-hydroxyornithine

Article abstract of DOI:10.1016/j.tetasy.2006.06.031

A convenient and efficient route is described for the highly stereoselective synthesis of δ-amino protected and conformationally restricted (2S,3S)-3-hydroxyornithine through the N-benzylnitrone adduct to the α,β-unsaturated bicyclic lactam 2 derived from

Full text of DOI:10.1016/j.tetasy.2006.06.031

Tetrahedron: Asymmetry 17 (2006) 1863–1866
Stereoselective synthesis of conformationally constrained
(2S,3S)-3-hydroxyornithine
´
Luis Alvarez de Cienfuegos and Nicole Langlois*
Institut de Chimie des Substances Naturelles, CNRS, Avenue de la Terrasse, 91198 Gif-sur-Yvette, France
Received 25 May 2006; accepted 12 June 2006
Available online 18 July 2006
Abstract—A convenient and efficient route is described for the highly stereoselective synthesis of d-amino protected and conformation-
ally restricted (2S,3S)-3-hydroxyornithine through the N-benzylnitrone adduct to the a,b-unsaturated bicyclic lactam 2 derived from (S)-
pyroglutaminol.
Ó 2006 Elsevier Ltd. All rights reserved.
1. Introduction
of our methodology involving N-alkylnitrone cycloaddition
to a,b-unsaturated bicyclic lactam 2 to introduce suitable
functionalities at the C-3 and C-4 positions.8–10
Conformationally constrained amino acids have received
much attention due to their ability to be incorporated into
novel peptides and peptidomimetics.1,2 They can also be
used as tools to define the shape of subunits in bioactive
peptides and to understand their activities better.3,4 The re-
stricted conformation is generally induced by the presence
of rings and it is well known that cyclic amino acids, such
as proline, exert a considerable influence on the conforma-
tion of peptides containing them.5 In a,x-diamino acids,
five membered rings can also produce a restriction confined
to the side chain.6
2. Results and discussion
Bicyclic lactam 2 is a rigid and versatile substrate derived
from (S)-pyroglutaminol, which gave highly regio- and
stereoselective 1,3-dipolar cycloaddition with N-benzylnit-
rone, giving the adduct 3 in 90% yield.8,10 The compound
3 was converted into 1 as shown in Scheme 1.
In this simple scheme, appropriate protection of the func-
tional groups was not obvious but shown to be crucial.
In the case of 3, the best reagent to cleave the N–O bond
of the isoxazolidine ring was LiAlH4 in THF at reflux. Un-
der these conditions the aminoacetal C–O bond was also
cleaved with quantitative formation of (2R,3S,4S)-1-
benzyl-4-benzylaminomethyl-3-hydroxy-2-hydroxymethyl-
pyrrolidine 4.10 Several attempts to selectively protect the
primary alcohol group of 4 as a tert-butyldimethylsilyl
ether gave moderate results (48% as the highest yield).
On the other hand, the protection of both the secondary
alcohol and the d-amino groups of 4 as oxazinone 5 with
CDI in dichloromethane could only be performed in poor
yield (30%). Thus, the protective oxazolidine ring of 3 was
first hydrolyzed into 6 (100%) with trifluoroacetic acid in a
mixture of THF–H2O. Attempts to directly oxidize this pri-
mary alcohol into a carboxylic acid were unsuccessful but
this route allowed the formation of amides or carbamates
as intermediates before the oxidation step.
To the best of our knowledge, although several rigidified
ornithine derivatives have already been reported,6,7 no con-
formationally restricted 3-hydroxyornithine analogues have
been described so far. We designed the (2S,3S)-d-N-benzyl-
3-hydroxyornithine chimera 1 as our target. Herein we re-
port the practical and efficient synthesis of 1 as an extension
BnHN
OH
O
N
CO2H
N
H
O
Ph
2
1
*
Corresponding author. Tel.: +33 1 69823068; fax: +33 1 69077247;
e-mail: nicole.langlois@icsn.cnrs-gif.fr
0957-4166/$ - see front matter Ó 2006 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetasy.2006.06.031

´
L. A. de Cienfuegos, N. Langlois / Tetrahedron: Asymmetry 17 (2006) 1863–1866
1864
Bn
Bn
N
Bn
HN
O
N
OH
O
O
b
a
OH
OH
O
N
N
H
N
Bn
O
5
Ph
4
3
c
Bn
N
Ac
BnN
Ac
BnN
OAc
O
BnHN
OAc
OH
e
f
h
i
1
OR
OR
O
OEVE
N
N
H
N
CO2H
N
H
Ac
Ac
10 R = CH(Me)OEt
11 R = H
12
6 R = H
7 R = CH(Me)OEt
9 R = Sit-Bu(Me)2
8
g
d
Scheme 1. Reagents and conditions: (a) LiAlH4, THF, D, 100%; (b) CDI, CH2Cl2; (c) CF3CO2H, THF–H2O, 100%; (d) ethylvinylether, CCl3CO2H,
CH2Cl2, 93%; (e) LiAlH4, THF, D, 100%; (f) Ac2O, py, 98%; (g) CH3CO2H–H2O, 96%; (h) Jones’ reagent, acetone, 91%; (i) 3 M HCl (98%).
After efficient protection of the alcohol 6 as ethoxyethoxy
derivative 7 with ethylvinylether and catalytic CCl3CO2H
in CH2Cl2 (93%; OTHP gave a similar result in 72% yield),
the reduction of the lactam carbonyl and the opening of the
isoxazoline ring were accomplished in the same step by
using an excess of LiAlH4 in THF at reflux. The forma-
tion of 4-N-benzylaminomethyl-2-(1-ethoxyethoxymethyl)-
3-hydroxypyrrolidine 8 was quantitative, whereas the tert-
butyldimethylsilylether 9 was shown to be unstable under
the same conditions. The loss of the silyl group during
LiAlH4 reduction has already been reported in similar
cases and could be explained by intramolecular hydride
transfer from the neighbouring NH group.11 Peracetylation
of 8 with acetic anhydride in pyridine furnished triacetate
10 (98%), which was selectively deprotected in a mixture
of CH3CO2H–H2O at 20 °C to afford the primary alcohol
11 in high yield (96%). Jones’ oxidation of 11 gave rise to
12 (91%) and the target diamino acid 1 was obtained as a
dihydrochloride by acid hydrolysis of 12 (3 M HCl,
70 °C, 98%).
CHCl3 d = 7.27 ppm, unless otherwise indicated) from
Bruker AM 300 or 500 (s, d, t, dd and m indicate singlet,
doublet, triplet, doublet of doublets and multiplet, respec-
tively). 13C NMR spectra were recorded on AM 300 or 500
(75 or 125 MHz, CDCl3 centred at 77.14 ppm). Mass spec-
tra and high-resolution mass spectra were measured on a
Navigator (ESI), or a Micromass LC-TOF spectrometer.
Chromatography was performed on silica gel (SDS 230–
400 mesh) and preparative thin layer chromatography on
silica gel (Merck HF 254 + 366). Usual workup means that
the organic layer was dried over magnesium sulfate, filtered
and evaporated under reduced pressure.
4.2. (3aR,6R,6aS)-2-Benzyl-6-(1-ethoxyethoxymethyl)tetra-
hydro-2H-pyrrolo[3,4-d]isoxazol-4(5H)-one 7
Ethylvinylether (0.30 mL, 3.13 mmol) and CCl3CO2H
(15.6 mg, 0.095 mmol) were successively added at rt to a
stirred solution of compound 68 (435 mg, 1.75 mmol) in
dry CH2Cl2 (2.8 mL). The mixture was stirred at rt for
4 h before a second addition of ethylvinylether (0.30 mL),
and the stirring was maintained for an additional 19 h.
An aqueous solution of Na2CO3 (10% w/v) was added after
dilution with CH2Cl2 and the product was extracted four
times with CH2Cl2. After the usual workup, the crude
product was purified by chromatography (eluent CH2Cl2–
MeOH 94:6) to afford compound 7 as a colourless oil
(521 mg, 93%). IR: 3221, 2975, 2926, 1702, 1694, 1682,
1496, 1454, 1385 cmꢀ1. MS (ESI, MeOH) m/z: 343
(MNa+, 100%). HRMS calcd for C17H24N2O4Na:
3. Conclusion
In conclusion, we have developed a practical, highly stereo-
selective and efficient route to (2S,3S,4S)-4-(benzylami-
nomethyl)-3-hydroxyproline,
a
constrained 3-hydr-
oxyornithine chimera, in 70% overall yield from 2.
1
4. Experimental
4.1. General
343.1634, found: 343.1609. H NMR (300 MHz, CDCl3):
7.32 (5H, H–Ar), 6.42 (broad s, 1H, NH), 4.69 (q, 1H,
OCHO), 4.52 (m, 1H, H-6a), 3.97 (broad s, 2H, NCH2Ph),
3.79 (m, 1H), 3.7–3.3 (2OCH2, Ha-3), 3.37 (H-3a), 2.82 (m,
1H), 1.27 (d, 3H, CHCH3), 1.18 (t, 3H, CH2CH3). 13C
NMR (75 MHz): 176.76 (CO), 136.80 (qC, Ar), 128.81,
128.51, 127.51 (CH, Ar), 99.85 (OCHO), 78.77 (C-6a),
66.14 (OCH2), 61.68 (CH2Ph), 61.30 (OCH2), 61.23,
Optical rotations were measured on a Jasco P-1010 polari-
meter and the concentrations were given in g/100 mL. IR
spectra (film, CHCl3) were recorded on Perkin Elmer Spec-
1
trum BX (FT). H NMR spectra were obtained (CDCl3,

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L. A. de Cienfuegos, N. Langlois / Tetrahedron: Asymmetry 17 (2006) 1863–1866
1865
58.15 (C-3), 50.44–50.35 (C-3a), 19.68–19.49 (CHCH3),
15.32 (CH2CH3).
Na2CO3. After removing the salts by filtration, the solution
was washed with aqueous Na2CO3 (10%) and the small
aqueous layer extracted three times with CH2Cl2. The solu-
tion was dried over MgSO4 and gave, after usual workup,
4.3. (2R,3S,4S)-4-(Benzylaminomethyl)-2-(1-ethoxyeth-
oxymethyl)pyrrolidin-3-ol 8
the primary alcohol 11 as a colourless foam (710 mg, 96%).
24
½aꢁD ¼ ꢀ60:2 (c 1.34, CHCl3). IR: 3391, 2935, 2879, 1738,
A solution of LiAlH4 (658 mg, 17.3 mmol) in dry THF
(28 mL) was added to a solution of 7 (696 mg, 2.17 mmol)
in dry THF (7.1 mL), stirred at 0 °C under argon. The mix-
ture was then heated at reflux for 15 h, cooled at 0 °C and
the excess of reagent carefully destroyed by addition of
some drops of a saturated aqueous solution of Na2SO4.
The residue was obtained after usual workup (669 mg,
100%), as a colourless oil, and was used directly in the next
step. IR: 3297, 2924, 1540, 1409 cmꢀ1. MS (ESI, MeOH)
m/z: 331 (MNa+). HRMS (MeOH): cald for C17H28N2O3
1630, 1423, 1375. MS (ESI, MeOH) m/z: 385 (100%,
MNa+). HRMS: calcd for C19H26N2O5Na (MNa+):
1
385.1739, found: 385.1734. H NMR (300 MHz): 7.37 (m,
3H, H–Ar), 7.15 (m, 2H, H–Ar), 5.03 (d, 1H, H-3), 4.62
and 4.42 (2d, 2H, CH2Ph), 4.13 (m, 1H, H-2), 3.77 and
3.62 (2m, 2H, OCH2), 3.70 (m, 1H) and 3.26 (dd, 1H):
NCH2, 3.60 (masked m) and 3.42 (dd, 1H): NCH2, 2.77
(m, 1H, H-4), 2.17 (s, 3H, COCH3), 2.07 (s, 3H, COCH3),
2.04 (s, 3H, COCH3). 13C NMR (75 MHz): 172.05 (CO),
171.69 (CO), 170.34 (CO), 136.22 (qC, Ar), 129.27,
128.15, 126.39, 126.19 (CH, Ar), 75.32 (C-3), 66.86 (C-2),
63.72 (OCH2), 52.86 (NCH2Ph), 50.70 (NCH2), 43.29
(NCH2), 40.55 (C-4), 22.58 (COCH3), 21.87 (COCH3),
21.07 (COCH3).
1
Na: 331.1998, found 331.1985. H NMR (300 MHz): 7.23
(m, 5H, H–Ar), 4.63 (q, 1H, OCHO), 4.01 (dd, 1H, H-3),
3.70 (centre of 2d, 2H, CH2Ph), 3.57, 3.40 (2m, 4H,
2OCH2), 3.04 (2m, 2H, NCHa, H-2), 2.80 (m, 2H,
NCH2), 2.61 (m, 1H, NCHb), 2.18 (m, 1H, H-4). 13C
NMR (75 MHz, 2 diastereomers): 139.27 (qC, Ar),
128.62, 128.23, 127.39 (CH, Ar), 100.06, 99.90 (OCHO),
75.20 (C-3), 66.16, 65.89 (OCH2), 65.89 (C-2), 61.31
(OCH2), 54.04 (NCH2Ph), 49.12 (NCH2), 48.93 (NCH2),
19.89 (CHCH3), 15.37 (CH2CH3).
4.6. (2S,3S,4S)-3-Acetoxy-1-acetyl-4-(benzylacetamido-
methyl)pyrrolidine-2-carboxylic acid 12
Jones’ reagent (690 lL) in acetone (8.7 mL) was added to a
stirred solution of primary alcohol 11 (241 mg, 0.67 mmol)
in acetone (9.4 mL) at 0 °C. The mixture was stirred at 0 °C
for 1 h. After the addition of a few drops of 2-propanol at
0 °C and H2O, the acid was extracted four times with
EtOAc. The organic layers were dried over MgSO4. Usual
4.4. (2R,3S,4S)-3-Acetoxy-1-acetyl-4-(benzylacetamido-
methyl)-2-(1-ethoxyethoxymethyl)pyrrolidine 10
Pyridine (15.0 mL) and Ac2O (5.3 mL) were successively
added under argon to this crude reduction product 8
(646 mg, 2.1 mmol) at 0 °C. The mixture was stirred at rt
for 6 h, cooled again at 0 °C before the addition of MeOH
(15 mL) and the mixture was stirred at rt for 0.5 h and then
evaporated to dryness. A solution of the residue in CH2Cl2
was washed with an aqueous solution of Na2CO3 and the
aqueous layer extracted three times with CH2Cl2. Usual
workup gave the crude triacetate 10 as a colourless oil, pure
enough to be used in the next step (891 mg, 98%). IR: 2976,
2931, 2881, 1737, 1640, 1416, 1376. MS (ESI,
CH3CN + H2O) m/z: 457 (MNa+, 100%). HRMS calcd
for C23H34N2O6Na (MNa+): 457.2315, found: 457.2326.
1H NMR (300 MHz): 7.34 and 7.12 (5H, H–Ar), 5.21 (d,
1H, H-3), 4.70–4.36 (OCHO, NCH2Ph), 4.10 (m, H-2),
3.77–3.17 (2OCH2, 2 NCH2), 2.99 (m, 1H, H-4), 2.16–
1.98 (3COCH3), 1.30 (CHCH3), 1.14 (CH2CH3). 13C
NMR (75 MHz): 171.47, 170.42, 170.09 (CO), 136.28
(qC, Ar), 129.22, 128.87, 128.02, 126.26, 126.15 (CH, Ar),
100.39, 100.15 (OCHO), 76.11, 75.84 (C-3), 64.48 (C-2),
64.18, 63.47 (OCH2), 61.97, 61.86 (OCH2), 52.44, 52.37
(NCH2Ph), 50.62, 50.48 (NCH2), 43.11 (NCH2), 40.28,
40.19 (C-4), 22.77, 22.74 (COCH3), 22.05, 21.91 (COCH3),
21.17, (COCH3), 20.14 (CHCH3), 15.40 (CH2CH3).
workup and washing with pentane afforded 12 (229 mg,
24
91%), as a colourless solid. ½aꢁD ¼ ꢀ56:3 (c 1.37, CHCl3).
IR: 3393, 1732, 1603, 1422, 1376. MS (ESI, MeOH) m/z:
399 (MNa+, 100%). HRMS calcd for C19H24N2O6Na:
399.1532, found 399.1545. 1H NMR (500 MHz): 7.38,
7.32, 7.15 (H–Ar), 5.54 (m, 1H, H-3), 4.62 and 4.47 (2d,
2H, J = 16, N–CH2Ph), 4.57 (masked m, 1H, H-2), 3.77
and 3.27 (2m, 2H, N–CH2), 3.68 and 3.57 (2m, 2H,
NCH2), 2.77 (m, 1H, H-4), 2.16, 2.07 (3s, 3COCH3). 13C
NMR (75 MHz): 172.23, 170.00 (CO), 135.85 (qC, Ar),
129.29, 128.13, 126.33 (CH, Ar), 74.26 (C-3), 65.97 (C-2),
52.39 (NCH2Ph), 50.42 (NCH2), 42.79 (NCH2), 40.98
(C-4), 22.08, 21.77, 21.01 (COCH3).
4.7. (2S,3S,4S)-4-(Benzylaminomethyl)-3-hydroxypyrrol-
idine-2-carboxylic acid 1
Acid 12 (125.2 mg, 0.33 mmol) in 3 M HCl (6.9 mL) was
heated at 70 °C for 48 h. After evaporation to dryness,
the residue was washed with Et2O and dissolved in H2O.
The solution was then filtered and evaporated to give 1,
as dihydrochloride crystallized in a mixture of MeOH–
Et2O (105.4 mg, 98%). Mp with decomposition: 226 °C.
24
½aꢁD ¼ þ2:2 (c 1.22, MeOH). IR: 3350, 3205, 2959, 1737,
1632, 1454, 1422, 1230. MS (ESI, MeOH) m/z: 251
4.5. (2R,3S,4S)-3-Acetoxy-1-acetyl-4-(benzylacetamido-
methyl)-2-hydroxymethylpyrrolidine 11
(MH)+. HRMS calcd for C13H19N2O3 (MH)+: 251.1396,
1
found: 251.1379. H (300 MHz, D2O d = 4.8 ppm): 7.50
(5H, H–Ar), 4.69 (broad d, 1H, J = 4.5, H-3), 4.29 (m,
3H, NCH2Ph, H-2), 3.77 (dd, 1H, J = 11.6, J0 = 8.6) and
3.27 (dd, 1H, J ꢂ J0 ꢂ 11.6): NCH2, 3.39 (dd, 1H,
J = 13.0, J0 = 7.6) and 3.23 (dd, J = 13.0, J0 = 6.2):
NCH2, 2.61 (m, 1H, H-4). 13C (125 MHz, D2O): 170.10
To compound 10 (888 mg, 2.05 mmol) were successively
added H2O (20.7 mL) and AcOH (19.5 mL). The mixture
was stirred at rt for 6.5 h, cooled at 0 °C diluted with
CH2Cl2 and carefully neutralized by the slow addition of

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1866
M.; Lloyd-Williams, P.; Giralt, E. J. Med. Chem. 2004, 47,
5700–5712.
(CO), 129.85, 129.82, 129.39 (CH, Ar), 72.94 (C-3), 69.10
(C-2), 51.74 (NCH2Ph), 46.28 (NCH2), 43.48 (NCH2),
38.75 (C-4).
´
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Acknowledgement
We thank the Department of Organic Chemistry, Univer-
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´
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