A convenient and high yield method to prepare 4-hydroxypyroglutamic acids

Article abstract of DOI:10.1016/S0040-4039(01)01030-9

RuO₂/NaIO₄ oxidation of N-Boc-4-silyloxy and 4-acetoxy proline methyl esters under ethyl acetate/water biphase condition gave N-Boc-4-silyloxy and 4-acetoxy pyroglutamic acid derivatives in high yields. Desilylation with TBAF afforded both cis- and trans-N-Boc-methyl-4-hydroxy pyroglutamates.

Full text of DOI:10.1016/S0040-4039(01)01030-9

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 42 (2001) 5335–5338
A convenient and high yield method to prepare
4-hydroxypyroglutamic acids
Xiaojun Zhang,* Aaron C. Schmitt and Wen Jiang
Chemical & Physical Sciences, DuPont Pharmaceuticals Company, Experimental Station, PO Box 80500, Wilmington,
DE 19880, USA
Received 23 May 2001; accepted 8 June 2001
Abstract—RuO2/NaIO4 oxidation of N-Boc-4-silyloxy and 4-acetoxy proline methyl esters under ethyl acetate/water biphase
condition gave N-Boc-4-silyloxy and 4-acetoxy pyroglutamic acid derivatives in high yields. Desilylation with TBAF afforded
both cis- and trans-N-Boc-methyl-4-hydroxy pyroglutamates. © 2001 DuPont Pharmaceuticals Company. Published by Elsevier
Science Ltd. All rights reserved.
Functionalized pyroglutamic acid derivatives are of
great interest because they have been employed as
key intermediates in syntheses of many biologically
interesting heterocycles.1,2 One of the most studied
methods to obtain these functionalized pyrogluta-mates
is alkylation of the lithium enolate derived
from N-protected pyro-glutamic esters to give 4-substi-
tuted derivatives.3–7 This method is particularly good
for reactive electrophiles such as allylic halides and
aryl aldehydes, with moderate to good yields and
stereoselectivity. However, there still does not exist a
practical and stereoselective synthesis of differentially
protected derivatives of 4-hydroxy pyroglutamic acids.
Nozoe et al. has reported a hydroxylation of the
In a medicinal chemistry program that required multi-
gram scale synthesis of optically pure methyl N-Boc-
4-hydroxy pyroglutamates 1a and 1b as synthetic
precursors, we discovered a highly efficient method to
obtain both diastereomers and their derivatives from
cheap, commercially available (4R)-hydroxy proline 2.
The key reaction is a RuO2/NaIO4 oxidation of prop-
erly protected 4-hydroxy proline derivatives under an
ethyl acetate/water biphase condition. This two-phase
oxidation was reported some years ago by Yoshifuji
et al. for the conversion of cyclic a-aminoacids to
a-aminodicarboxylic acids.12–15 Application of this
protocol to the N-Boc-4-silyoxy and 4-acetoxy pro-
tected proline derivatives (4a,b and 6a,b) has led us to
a high yielding preparation of 1a,b and 8a,b.
lithium enolate derived from benzyl N-Boc-(L)-pyro-
glutamate with 2-toluenesulfonyl-3-phenyl oxaziridine
to give trans-4-hydroxy pyroglutamate in moderate
yield and good stereocontrol.8 However, inconsistent
yields with this procedure have been reported, pre-
sumably due to further reaction of the enolate with the
imine liberated from the oxaziridine.9 An efficient
synthesis of racemic cis- and trans-4-hydroxy pyroglu-
tamic acids has been reported.10 More recently,
Merino et al. reported an asymmetric synthesis of 4-
hydroxyl pyroglutamic acids, involving 1,3-dipolar
cycloaddition of furfuryl nitrone with acrylamide
derived from Oppolzer’s chiral sultam.11 Post trans-
formations of the 1,3-dipolar cycloadduct are neces-
sary to yield the desired product.
(4R)-Hydroxy proline 2 was N- and C-protected as
N-Boc-(4R)-hydroxy proline methyl ester 3a in a
quantitative yield (Scheme 1).16 The hydroxyl group
in 3a was further protected as TBDMS ether 4a in
98% yield. Oxidation of 4a with RuO2 (20% mol) and
NaIO4 (250% mol) in ethyl acetate/water at room
temperature gave pyroglutamate 5a in near quantita-
tive yield.17,18 1H and 13C NMR indicated that 5a,
obtained by simple extraction work-up, was practi-
cally pure. This oxidation can be carried out on a 15
g scale of 4a without loss of yield. The TBDMS pro-
tecting group was removed with TBAF to give methyl
(4R)-trans-N-Boc-4-hydroxyl pyroglutamate 1a in
80% yield. The final deprotection could be further
improved to 90% yield with 2 equiv. of acetic acid
present to minimize base hydrolysis of the pyrogluta-
mate.
Keywords: 4-hydroxyl pyroglutamic acid; ruthenium dioxide; oxida-
tion; Mitsunobu reaction; N-acyliminium ion.
* Corresponding author. Fax.: (302)-695-2209; e-mail: xiaojun.zhang
@dupontpharma.com
0040-4039/01/$ - see front matter © 2001 DuPont Pharmaceuticals Company. Published by Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(01)01030-9

5336
X. Zhang et al. / Tetrahedron Letters 42 (2001) 5335–5338
HO
TBDMSO
RO
HO
d
a
c
O
CO2Me
N
Boc
O
CO2Me
N
CO2Me
CO2H
RO
N
N
H
2
Boc
Boc
1a
R = H, 3a
5a
b
R = TBDMS, 4a
HO
TBDMSO
TBDMSO
d
c
e
b
3a
O
O
CO2Me
CO2Me
N
Boc
N
CO2Me
N
CO2Me
N
Boc
Boc
Boc
R = OAc, 6b
R = H, 3b
1b
5b
4b
f
Scheme 1. Preparation of cis and trans-N-Boc-4-hydroxyl pyroglutamates 1a and 1b. (a) 1. MeOH, HCl, reflux, 2. (Boc)2O, Et3N,
CH2Cl2, 100% for 2 steps; (b) TBDMSCl, imidazole, DMF, 98%; (c) RuO2(cat), NaIO4, EtOAc/H2O, >95%; (d) TBAF, HOAc,
THF, 80–90%; (e) PPh3, DEAD, HOAc, THF, >95%; (f) K2CO3, MeOH, >95%.
N-Boc-4-hydroxyl pyroglutamic acid derivatives are
useful chiral intermediates. For example, 1b under-
went Mitsunobu reaction with 4-chloro-1-naphthol to
give trans-N-Boc-4-aryloxy pyroglutamate 9 in 78%
yield. Reduction of 9 with LiBEt3H gave a hemiami-
nal 10, which was further activated to acetate 11.
Treatment of 11 with TMSCN under Lewis acid con-
ditions afforded N-Boc-aminonitrile 12 in 90% yield
through an N-acyliminium ion intermediate.19 Simi-
larly, reduction of 4-acetoxy pyroglutamate 7b gave a
hemiaminal 13. Conversion of 13 to diacetate 14, and
displacement of the 5-acetoxy group in 14 with allyl
trimethylsilane gave 5-allyl-4-acetoxy pyrrolidine 15 as
a 3:1 mixture of two diastereomers. Deprotection of
the Boc group afforded a separable mixture of amines
16. Both 12 and 16 are important intermediates for
the synthesis of bicyclic dipeptide mimetics (Scheme
3).
To prepare methyl (4S)-cis-N-Boc-4-hydroxyl pyro-
glutamate 1b, compound 3a was subjected to a Mit-
sunobu reaction to give the N-Boc-4-acetoxy proline
6b. Acetoxy proline 6b was hydrolyzed to (4S)-cis-
hydroxy proline 3b with K2CO3 in methanol. The
yield of the two-step Mitsunobu inversion and depro-
tection was near quantitative. With no event, protec-
tion of 3b as the sily ether 4b, oxidation of 4b with
RuO2/NaIO4, and deptotection of 5b with TBAF
gave rise to methyl (4S)-cis-N-Boc-4-hydroxyl pyro-
glutamate 1b in high yield.
The oxidation could also be carried out on the ace-
tate 6a and 6b to give N-Boc-4-acetoxy pyroglutamic
acid derivatives 7a and 7b in high yield (Scheme 2).
However, the reaction rate is slower than that of sily
ethers 4a and 4b, presumably because the acetate is
more electron-withdrawing than the sily ether, thus
making them less prone to oxidation. Attempts to
deprotect the acetate with even a catalytic amount of
K2CO3 in methanol resulted in attack of methoxide
on the pyroglutamate ring carbonyl to give g-
hydroxyl glutamic esters 8a and 8b. This result indi-
cated a higher reactivity of the ring carbonyl towards
nucleophilic addition.
In summary, we have discovered a highly efficient
preparation of either cis- or trans-N-Boc-4-hydroxy
pyroglutamic acid derivatives by RuO2/NaIO4 oxida-
tion starting from a common precursor, (4R)-hydroxy
proline 2. These 4-hydroxy pyroglutamic acid deriva-
tives are useful intermediates for the synthesis of
other nitrogen containing heterocycles.
AcO
AcO
O
c
CO2Me
NHBoc
a
b
MeO
MeO
3a
O
CO2Me
CO2Me
N
Boc
7a
CO2Me
N
OH
Boc
8a
6a
AcO
AcO
O
c
CO2Me
NHBoc
b
O
N
Boc
7b
CO2Me
N
OH
Boc
6b
8b
Scheme 2. Preparation of g-hydroxyl glutamic ester 8a and 8b. (a) Ac2O, pyridine, 100%; (b) RuO2(cat), NaIO4, EtOAc/H2O,
>95%; (c) K2CO3, MeOH, >95%.

X. Zhang et al. / Tetrahedron Letters 42 (2001) 5335–5338
5337
Cl
Cl
Cl
d
b
a
1b
O
O
O
NC
CO2Me
O
N
CO2Me
RO
c
N
CO2Me
N
Boc
Boc
Boc
12
9
R = H, 10
R = Ac, 11
AcO
AcO
AcO
e
b
f
7b
RO
CO2Me
CO2Me
CO2Me
N
Boc
N
Boc
N
H
R = H, 13
R = Ac, 14
16
15
Scheme 3. Chemical transformation of N-Boc-hydroxy pyroglutamate derivatives. (a) 4-Chloro-1-naphthol, PPh3, DEAD, THF,
0°C–rt, 78%; (b) LiBEt3H, THF, −78°C; (c) Ac2O, pyridine, 90% for two steps; (d) TMSCN, BF3·Et2O, CH2Cl2, −60°C, 80%;
(e) allyl trimethylsilane, BF3·Et2O, CH2Cl2, −60°C, 70%; (f) TFA, CH2Cl2, 90%.
15. Yoshifuji, S.; Kamame, M. Chem. Pham. Bull. 1995, 43,
1617–1620.
Acknowledgements
16. Rosen, T.; Chu, D. T. W.; Lico, I. M.; Fernades, P. B.;
Marsh, K.; Shen, L.; Cepa, V. G.; Pernet, A. G. J. Med.
Chem. 1988, 31, 1598–1611.
We thank Dr. Carl Decicco for his support of this work
and Dr. David Nugiel for his critical reading of the
manuscript.
17. A representative procedure for preparation of 1a: To a
solution of NaIO4 (7.43 g, 34.75 mmol) in water (107 mL)
was added RuO2·×H2O (0.37 g, 2.7 mmol) under the
protection of nitrogen. The resulting green–yellow solu-
tion was stirred for 5 min followed by addition of 4a (5.0
g, 13.9 mmol) in EtOAc (60 mL) in one portion. The
reaction was stirred at rt for 18 h. The solution remained
yellowish during the reaction. The resulting mixture was
then diluted with EtOAc and filtered through a pad of
Celite. The organic layer was washed with saturated
NaHSO3, which resulted in precipitation of Ru black.
The precipitate was filtered off through a pad of Celite.
The EtOAc layer was then washed with brine and dried
with MgSO4. Evaporation of solvent gave 5a as a color-
less liquid (4.95 g, 95%). To a solution of 5a (3.28 g, 8.78
mmol) in THF (6.0 mL) was added TBAF (1.0 M in
THF, 14.0 mL, 14.0 mmol) at 0°C. The solution was
allowed to warm and stirred at rt for 4 h. Evaporation of
THF and a column chromatography (hexane:EtOAc=1:
1) gave compound 1a (1.90 g, 80%) as a white solid.
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5338
X. Zhang et al. / Tetrahedron Letters 42 (2001) 5335–5338
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