Photochemical synthesis of N-substituted 3-hydroxy-2-pyrrolidinones

Article abstract of DOI:10.1055/s-2005-865229

A new three-step synthesis to 3-hydroxy-2-pyrrolidinones starting from β-amino acids has been developed. The key step is a novel reductive photocyclization.

Full text of DOI:10.1055/s-2005-865229

1182
LETTER
Photochemical Synthesis of N-Substituted 3-Hydroxy-2-pyrrolidinones
P
hotochemical Synthe
a
u
r
k
3-Hydroxy-
2
u
-pyrrolidino
s
nes Obkircher, Wolfgang Seufert, Bernd Giese*
Department of Chemistry, University of Basel, St. Johanns-Ring 19, 4056 Basel, Switzerland
Fax +41(61)2671105; E-mail: bernd.giese@unibas.ch
Received 24 February 2005
Table 1 Irradiation of a-Keto Methyl Esters 2a–c
Abstract: A new three-step synthesis to 3-hydroxy-2-pyrrolidi-
nones starting from b-amino acids has been developed. The key step
is a novel reductive photocyclization.
Educt
2a
X
Product
3a
Yield (%)
Boc
Z-Gly
Z-Ala
62
46
62
Key words: 3-hydroxy-2-pyrrolidinone, 4-hydroxypyroglutamic
acid, a-keto ester, b-amino acid, reductive photocyclization
2b
3b
2c
3c
Hydroxy-substituted pyrrolidinones are components of
many natural products, which exhibit valuable pharmaco-
logical properties.1 For instance, the N-substituted deriva-
tives are of interest for the treatment of brain disorders or
as cognition activators.2 Due to their low toxicity they
have attracted much attention in current pharmaceutical
research.3 Syntheses of the racemic core as well as
enzymatic and stereoconservative preparations have been
described.4 Herein we present a novel three-step synthesis
of N-substituted 3-hydroxy-2-pyrrolidinones and 4-hy-
droxypyroglutamic acids starting from b-amino acids
with a novel reductive photocyclization as the key reac-
tion step.
Following the Wasserman methodology,5 b-alanine deriv-
atives 1a–c were coupled with (cyanomethylene)triphe-
nylphosphorane yielding cyano keto phosphoranes.
Oxidative cleavage with ozone led to a,b-diketo nitriles,
which were converted into the a-keto methyl esters 2a–c
(Scheme 1). Photolysis of the keto esters gave the 3-hy-
droxy-2-pyrrolidinones 3a–c in 46% to 62% yields
(Table 1).6
The carboxylic acid side chains of N-terminal substituted
aspartic acids 4a–c were modified in the same way lead-
ing to a-keto methyl ester derivatives 5a–c (Scheme 2).
After irradiation of 5a–c the N-substituted 4-hydroxy-py-
roglutamic acids 6a–c were obtained in good to excellent
yields as 1:1 mixtures of diastereomers (Table 2). Only a
few other synthetic pathways to 4-hydroxy-pyroglutamic
acids have been described, and these start either from
nitrones7 or from 4-hydroxy prolines.8
OCH3
HO
O
O
O
(i)
Ot-Bu
Ot-Bu
XHN
XHN
O
O
4a–c
5a–c
OH
(ii)
O
t-BuO2C
N
X
O
O
(i)
OCH3
XHN
OH
XHN
6a–c
O
1a–c
2a–c
Scheme 2 Reagents and conditions: (i) a) Ph3P=CHCN, EDC,
DMAP, CH2Cl2, 0 °C, 18 h; b) O3, CH2Cl2, MeOH, –78 °C, 1 h; (ii)
hn, CH2Cl2, 20 °C, 14 h.
OH
(ii)
O
N
X
Table 2 Irradiation of a-Keto Methyl Esters 5a–c
Educt
5a
X
Product
6a
Yield (%)
3a–c
Scheme 1 Reagents and conditions: (i) a) Ph3P=CHCN, EDC,
DMAP, CH2Cl2, 0 °C, 18 h; b) O3, CH2Cl2, MeOH, –78 °C, 1 h; (ii)
hn, CH2Cl2, 20 °C, 14 h.
Boc
91
63
61
5b
Boc-Gly
Boc-Pro
6b
5c
6c
This novel photocyclization reaction (2 → 3 and 5 → 6)
provides an easy access to the 3-hydroxy-2-pyrrolidinone
and 4-hydroxypyroglutamic acid building blocks, espe-
cially to the pharmaceutically interesting N-substituted
SYNLETT 2005, No. 7, pp 1182–1184
Advanced online publication: 14.04.2005
DOI: 10.1055/s-2005-865229; Art ID: D04905ST
© Georg Thieme Verlag Stuttgart · New York
0
2.
0
5.
2
0
0
5

LETTER
Photochemical Synthesis of N-Substituted 3-Hydroxy-2-pyrrolidinones
1183
derivatives.2,3 Enantiopure pyrrolidinone derivatives
could be prepared through esterification with a chiral acid,
and separation of the diastereomers.9
O
OCH3
2
XHN
O
The cyclization reactions (2 → 3 and 5 → 6) are surpris-
ing, because a reduction of the ketone group in the educts
to the alcohol function in the photoproducts has occurred
during the photolysis. To elucidate the mechanism of this,
to our knowledge, new reductive photocyclization reac-
tion, additional experiments were carried out. Photocy-
clization of ketoester 7a, which is perdeuterated at the
methoxy group, led to the pyrrolidinone 8 with a deuteri-
um at C-3 (Scheme 3). This experiment was carried out in
CH2Cl2; experiments with undeuterated a-ketoesters 2 in
CD2Cl2 led to undeuterated cyclization products 3. Thus,
the ring deuterium in 8 has to come from the OCD3-group
of 7a. As the ketone is reduced by hydrogen transfer from
the alcohol group of the ester, we assumed that this alco-
hol becomes oxidized during the photocyclization. In or-
der to check this, the benzyl ester 7b was photolyzed,
which led not only to the cyclization product 3a but also
to benzaldehyde, the oxidation product of benzyl alcohol
(Scheme 3).
hν
OH
OCH3
9
XN
O
OH
H
OH
CO2CH3
XN
10
CH2
O
N
O
X
2
OH
H
CH2O
+
O
OH
D
N
X
O
hν
OCD3
Z-AlaHN
3
O
62%
N
O
Z-Ala
Scheme 4 Possible mechanism for the reductive photocyclization.
7a
8
OH
OH
O
hν
OCH2Ph
3c
+ PhCHO
O
N
BocHN
O
N
42%
O
O
Z-Ala
Boc
hν
Ot-Bu
7b
3a
Z-AlaHN
O
OH
OH
Scheme 3
Z-AlaHN
Z-AlaHN
11
CO2t-Bu
CO2t-Bu
32%
A possible mechanism that could explain these observa-
tions is the formation of diradical 9 as reactive intermedi-
ate, which could either react back to the starting material
12
2 via the strained hemiaminal 10, or undergo a cyclization Scheme 5 Irradiation of a-keto tert-butyl ester 11.
and intramolecular H-atom transfer yielding pyrrolidi-
none 3 (Scheme 4).
According to this reaction mechanism a tert-butyl ester
Acknowledgment
should not lead to the hydroxypyrrolidinone. We demon-
strated this by photolysis of the a-keto ester 11, which did
not form the cyclization product 3c but yielded dimer 12
(Scheme 5). This dimerization is in accord with diradical
9 as intermediate, which dimerizes if the concerted cy-
clization/H-transfer is not possible.
This work was supported by the Swiss National Science Founda-
tion.
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In summary we present a new and short synthesis of N-
substituted 3-hydroxy-2-pyrrolidinones and 4-hydroxy-
pyroglutamic acids. The key step is a reductive photocy-
clization, which is to our knowledge a new reaction type.
Synlett 2005, No. 7, 1182–1184 © Thieme Stuttgart · New York

1184
M. Obkircher et al.
LETTER
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Hz, 1 H), 2.44 (dddd, J = 12.4, 8.2, 6.6, 1.5 Hz, 1 H), 3.31
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13C NMR (101 MHz, CDCl3): d = 27.1 (CH2), 28.1 (CH3),
42.2 (CH2), 70.7 (CH), 83.6 (C), 149.9 (C), 174.8 (C). MS
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168 (48) [M – t-Bu + Na]+.
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The a-keto ester modified b-amino acids (2 or 4) were
dissolved in 200 mL CH2Cl2 in a 250 mL pyrex flask. The
solution was degassed with argon during 30 min and
irradiated with a cooled 180 W mercury high-pressure lamp,
Synlett 2005, No. 7, 1182–1184 © Thieme Stuttgart · New York