Reversible diastereoselective photocyclization of phenylglyoxylamides of α-amino acid methyl esters to 3-hydroxy β-lactams

Article abstract of DOI:10.1055/s-2002-19335

Phenylglyoxylamides 1a-m were prepared from enantiomerically pure (1b-l) α-amino acid methyl esters in high yields and irradiated in acetonitrile solutions with λ = 300 nm to give the β-lactams 2a-m as photocyclization products in moderate (38 and 40perce

Full text of DOI:10.1055/s-2002-19335

LETTER
131
Reversible Diastereoselective Photocyclization of Phenylglyoxylamides of
-Amino Acid Methyl Esters to 3-Hydroxy -Lactams
R
eversible Diaste
r
x
eoselective
P
e
hotocycliz
l
P
he
n
Gs
. Griesbeck,* Heike Heckroth1
Institute of Organic Chemistry, Universität zu Köln, Greinstr. 4, 50939 Köln, Germany
Fax +49(221)4705057; E-mail: griesbeck@uni-koeln.de
Received 22 September 2001
in the triplet photochemistry of chiral N-phthaloyl amino
acid derivatives.15 Thus, we investigated the photochem-
istry of phenylglyoxylamides of enantiomerically pure -
amino acid esters as well as of glycine and sarcosine. For
Abstract: Phenylglyoxylamides 1a–m were prepared from enan-
tiomerically pure (1b–l) -amino acid methyl esters in high yields
and irradiated in acetonitrile solutions with = 300 nm to give the
-lactams 2a–m as photocyclization products in moderate (38 and
40% for 2j and 2k) to excellent yields (85–100%) as racemic mix- the synthesis of the starting materials from the HCl salts
tures. The photocyclization is completely reversible in the absence
of the amino acid methyl esters we used the DCC/DMAP
coupling method.16 Products 1a–m were isolated as color-
of trace amounts of acid and the diastereoselectivity of the lactam
formation largely depends on the amount of acid in the reaction me-
less oils after column chromatography in good yields
dium. The isoleucine and a dipeptide derivative 1f and 5, respec-
tively, enabled NMR-spectral evidence for the zero degree of
chirality memory in the photocyclization.
(Scheme 1). For photolyses of these substrates 2 mM so-
lutions in acetonitrile were used and irradiated at = 300
nm until complete conversion (Table).
Key words: amino acids, cyclizations, hydrogen transfer, lactams,
photochemistry
The alkyl-functionalized substrates were converted quan-
titatively (from NMR of the crude reaction mixtures) into
the corresponding -lactams 2, only the sarcosine deriva-
tive 1m gave additionally ca. 40% of a photoreduction/N-
demethylation product 3. In some cases (a in the Table) it
was possible to isolate and purify the -lactams, in most
cases, however, they rapidly reverted to the starting mate-
rials by retro-aldol reaction. Under the irradiation condi-
tions, the products were photochemically stable and did
not isomerize.17
The synthesis of -lactams and their derivatives as well as
the improvement of their antibiotic activity has played a
central role in medicinal chemistry since the discovery of
penicillin by A. Fleming in 1928 and the first application
as a chemotherapeutic agent by H. W. Florey et al. in
1940.2 The efficacy of classical -lactam antibiotics could
be strongly increased in the last decades by the application
of partly synthetic penicillins and cephalosporins.3 Nu-
merous synthetic approaches have been developed,4 most
of them thermal reactions and only a handful of photo-
chemical processes.5 The latter fact is surprising in that
four-membered ring formation is an archetype photo-
chemical reaction (e.g. the Norrish–Yang reaction)6 and
photochemical transformations of amino acids have been
widely explored.7
hν
O
R
R
H
R
CH3CN
HN
HN
N
COOMe
COOMe
+
Ph
COOMe
O
O
OH
Ph
Ph
O
1a-1j
OH
2a-2j
γ-H transfer
hν
OH
H
N
N
COOMe
Ph
OH
2k (40%)
OH
R
H
The first report on the photocyclization of N,N-dialkyl-
phenyl glyoxylamides was published by Aoyama and co-
workers.8 In these cases, -lactam formation was always
accompanied by oxazolidinones as side products which
indicated a 1,4-zwitterion as probable intermediate.9 In
further studies, this photochemical reaction using achiral
starting materials has been further investigated with re-
spect to the ionic chiral auxiliary method10 and in absolute
asymmetric synthesis11 using the chiral crystal method.12
To the best of our knowledge, chiral acyclic amino acid-
derived substrates have not yet been investigated. This ap-
proach looked especially promising in light of recent re-
sults on chirality memory effects13 in the singlet
photochemistry of chiral -keto esters by Giese et al.14 and
Ph
O
N
COOMe
Ph
O
COOMe
O
3
Scheme 1
Recently, we found that both simple and induced diastere-
oselectivities of the Norrish–Yang cyclization reaction
are high starting with chiral -amido acetophenone deriv-
atives.18 This phenomenon was rationalized by hydrogen-
bonding at the stage of the triplet biradical. Likewise, the
photocyclization of the ketoamides 1a–g19 gave the -lac-
tams 2a–g in moderate to high simple diastereoselectivi-
ties with the cis-isomers (with respect to the -hydroxy
and the ester group) as the major components.20 The dias-
tereoselectivity decreased for substrates with side-chain
functional groups capable of additional H-bonding inter-
actions such as the acidic amino acids 1h,i as well as the
Synlett 2002, No. 1, 28 12 2001. Article Identifier:
1437-2096,E;2002,0,01,0131,0133,ftx,en;G20201ST.pdf.
© Georg Thieme Verlag Stuttgart · New York
ISSN 0936-5214

132
A. G. Griesbeck,.H. Heckroth
LETTER
proach to the penam skeleton (or other polycyclic -lac-
tams),24 which most likely involves an electron transfer
process involving the single-electron oxidation of the
thioether sulfur with a subsequent deprotonation/cycliza-
tion sequence which is often observed in carbonyl–thioet-
her photochemistry.25
Table Synthesis and Photocyclization of Phenylglyoxamides
Amino acid
derivative
Yield 1 Yield 2
d.r.
d.r.
(%)a
(%)
(con. A)d (con. B)e
glycine
a
b
c
d
e
f
78
100b
78:12
80:20
80:20
86:14
82:16
75:25
62:38
41:59
57:43
66:34
98:2
n.d.f
alanine
71
69
91
86
76
69
82
74
56
65
78
66
100b/85a
100b
31:69
n.d.
We investigated the degree of chirality memory by using
chiral photoactive starting materials with two stereogenic
centers, namly the enantiomerically pure isoleucine deriv-
ative 1f26 and the Ala-Ala-dipeptide 5. In both cases the
photolysis gave the -lactams 2f and 6 (Scheme 3), re-
spectively, in excellent yields of 91 and 86%, respective-
ly. The cis/trans-isomers (d.r. = 75:25 and 58:42) were
produced as mixtures of diastereoisomers in 50:50 ( 1%)
ratios.
phenylalanine
valine
100b
41:59
33:67
n.d.
leucine
100b
isoleucine
t-leucine
100b/91a
100b/35a
100b
g
h
i
aspartic acid
glutamic acid
threonine
proline
100b
j
38a
36:64
n.d.
O
O
hν
HN
HN
H
N
COOMe
OH
Ph
COOMe
+
CH3CN
(91%)
k
l
40a
O
O
OH
Ph
Ph
Ph
COOMe
O
(1 : 1)
O
O
thiaproline
sarcosine
a Isolated product.
10/65c
51a
62:38
37:63
1f
cis-2f
m
O
H
N
H
N
N
hν
COOMe
N
H
COOMe
H
O
b Determined by NMR spectroscopy of the crude reaction mixture.
c Mixture of regioisomers.
CH3CN
(86%)
OH
Ph
5
6
d In neat acetonitrile.
e In the presence of 0.5% HCl.
Scheme 3
f n.d. = not determined.
These selectivities were already detected after a small de-
gree of conversion proving that there is no memory of
chirality (and likewise no asymmetric induction by the
stereogenic spectator groups) in the homogeneous photo-
cyclization of phenylglyoxylamides. Further experiments
to modify the reaction conditions and/or the properties of
the electronic excited states involved in the photocycliza-
tion are in progress.
threonine derivative 1j. In the presence of catalytic
amounts of HCl in the reaction mixture, however, also the
diastereomeric ratios for 1b–e gave were strongly reduced
and inverted. One explanation for this effect is that the cis-
isomers originate from kinetic control due to spin-orbit
coupling determined reactive triplet biradicals21 preorga-
nized by intramolecular hydrogen-bonding. The presence
of acid also stabilized the -lactams and supressed the ret-
ro-aldol reactivity appreciable.22
References
The results obtained for the thiaproline substrate 1l dif-
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chemical approach to the penam skeleton.23 In contrast to
the literature procedure, where only 8% of the desired
product 4l was formed, we obtained, beside 10% of the
methyl -lactam-4-carboxylate 2l, 65% of a mixture of di-
astereoisomeric penam products 4l (Scheme 2).
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S
Ph
S
HO
+
O
hν
S
N
COOMe
Ph
OH
2l (10%)
N
CH3CN
N
Ph
O
O
COOMe
O
1l
COOMe
4l (65%)
Scheme 2
Synlett 2002, No. 1, 131–133 ISSN 0936-5214 © Thieme Stuttgart · New York

LETTER
Reversible Diastereoselective Photocyclization of Phenylglyoxamides
133
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CH3), 1.83 (dqq, 1 H, J = 0.8, 6.6, 6.7 Hz, CH), 3.72 (s, 3 H),
7.44 (mc, 5 H), 9.11 (d, 1 H, J = 0.8 Hz, NH). 13C NMR of
cis-2d: = 16.9 (CH3), 18.4 (CH3), 31.6 (CH), 51.8 (CH3),
74.3 (Cq), 89.6 (Cq), 125.7 (Cq), 127.2 (CH), 128.1 (CH),
129.4 (CH), 133.1 (Cq), 137.6 (CH), 168.6 (Cq), 171.1 (Cq).
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(dqq, 1 H, J = 0.8, 6.7, 6.8 Hz, CH), 3.04 (s, 3 H), 7.44 (mc,
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(19) Experimental Procedure: The substrates were synthesized
from the amino acid methyl ester HCl salts which were
coupled with equimolar amounts of phenyl glyoxylic acid,
triethylamine, DCC and 10% of DMAP in CH2Cl2 and
purified by column chromatography on silica. For
photolysis, a 2 mM solution of the substrate in acetonitrile
(water cooled) was irradiated at 300 nm (Rayonet
Synlett 2002, No. 1, 131–133 ISSN 0936-5214 © Thieme Stuttgart · New York