[2+2] Photocycloadditions with chiral uracil derivatives: Access to all four stereoisomers of 2-aminocyclobutanecarboxylic acid

Article abstract of DOI:10.1055/s-2007-983759

Starting from a single, chiral, bicyclic derivative of uracil, all four stereoisomers of 2-aminocyclobutanecarboxylic acid have been prepared in enantiomerically pure form, using a synthetic sequence which begins with a key photochemical [2+2] cycloaddition reaction and includes a practical cis to trans β-amino acid isomerisation procedure. Georg Thieme Verlag Stuttgart.

Full text of DOI:10.1055/s-2007-983759

2222
FEATURE ARTICLE
[2+2] Photocycloadditions with Chiral Uracil Derivatives: Access to All Four
Stereoisomers of 2-Aminocyclobutanecarboxylic Acid
P
a
hotochemical
R
a
r
ntiomeri
l
callyP
o
ure Cyclobut
s
ane
b
-Amino
A
c
ids ernandes,a Christine Gauzy,a Yi Yang,a Olivier Roy,a Elisabeth Pereira,a Sophie Faure,a David J. Aitken*a,b
Laboratoire de Synthèse et Etude de Systèmes d’Intérêt Biologique, SEESIB (UMR 6504–CNRS), Département de Chimie, Université
Blaise Pascal – Clermont-Ferrand II, 24 Avenue des Landais, 63177 Aubière cedex, France
b
Laboratoire de Synthèse Organique et Méthodologie, ICMMO (UMR 8182–CNRS), Université Paris-Sud XI, Bât. 420, 15 rue Georges
Clemenceau, 91405 Orsay cedex, France
Fax +33(1)69156278; E-mail: David.Aitken@icmo.u-psud.fr
Received 28 February 2007; revised 14 May 2007
compounds.16,17 Indeed, only two enantioselective synthe-
ses of cis-1 have been described so far, by the groups of
Ortuño14,18 and Bolm.19 Both procedures are based on the
enantioselective desymmetrisation of meso-1,2-cyclobu-
Abstract: Starting from a single, chiral, bicyclic derivative of
uracil, all four stereoisomers of 2-aminocyclobutanecarboxylic acid
have been prepared in enantiomerically pure form, using a synthetic
sequence which begins with a key photochemical [2+2] cycloaddi-
tion reaction and includes a practical cis to trans b-amino acid isom- tanedicarboxylic acid, via enzymatic hydrolysis of a di-
erisation procedure.
ester in the first case and alkaloid-mediated opening of the
anhydride in the second. The only syntheses of trans-1
(and a few of its derivatives) have provided racemic ma-
terials via desymmetrisation of the racemic trans-diacid.20
Key words: photochemistry, heterocycles, b-amino acids, cyclo-
butanes, stereoselective synthesis
We recently established a simple strategy for the prepara-
tion of ( )-cis-1 as well as a variety of C1- or C2-substi-
tuted derivatives, in which the key step was the
photochemical [2+2] cycloaddition reaction of ethylene
with a uracil (Scheme 1).21,22,23 In this paper, we describe
a practical ‘chiral adaptation’ of this photochemical ap-
proach in order to prepare enantiomerically pure samples
of all four stereoisomers of the parent cyclobutane b-ami-
no acid 1 (Figure 1).24
The impact of b-amino acids and b-peptides in nature,1 in
medicinal chemistry,2 and in the controlled design of pep-
tide folding structures3 is evident from the exponential in-
crease in the volume of published research on these
substances.4 Commensurately, an increasing variety of
methods have been described for the synthesis of b-amino
acids in both racemic and enantiomerically enriched
form.5 A particular interest has developed for alicyclic b-
amino acids;6 these compounds are of biological interest
in their own right,6,7 while hybrid or homo-oligomers
which contain these rigid cyclic motifs pre-organize in a
well-defined manner leading to unique ‘foldamer’ struc-
tures. Thus, stable helical motifs have been prepared using
oligomers of trans-2-aminocyclohexanecarboxylic acid8
and trans-2-aminocyclopentanecarboxylic acid,8b,9 and
some of these oligopeptides are bestowed with biological
activities10 or liquid crystal properties.11 In marked con-
trast, oligomers of cis-2-aminocyclopentanecarboxylic
acid adopt a sheet-like structure.12 Much less work has
been done using small-ring b-amino acids, although initial
results have been promising: for example, cis-2-aminocy-
clopropanecarboxylic acid derived oligopeptides adopt
stable helical conformations.13 In the only studies involv-
ing cyclobutane b-amino acid building blocks described
to date, b-dipeptide derivatives of cis-2-aminocyclobutane-
carboxylic acid (cis-1) displayed strong hydrogen-bond-
forming propensities,14 while b-tetrapeptides containing
two cis-1 units and two b-alanine residues formed 14-he-
lices in solution.15 There is an obvious interest in pursuing
studies on cyclobutane b-amino acids, but progress has
been hampered because of the limited access to these
O
O
R1
R1
R1
R2
CO2H
NH2
a) NaOH
H2C CH2
NH
NH
b) NaNO2
HCl
hν
O
N
H
O
N
H
R2
R2
Scheme 1 Photochemical approach for the general synthesis of
racemic cis-2-aminocyclobutanecarboxylic acids.
H
H
H
H
H
H
CO2H
NH2
CO2H
NH2
CO2H
NH2
CO2H
NH2
H
H
(1R,2R)-trans-1
(1S,2S)-trans-1
(1S,2R)-cis-1
(1R,2S)-cis-1
Figure 1 The four stereoisomers of 2-aminocyclobutanecarboxylic
acid 1, target molecules in this work.
We decided to study the photochemical [2+2] cycloaddi-
tion reactions of ethylene with uracils bearing a chiral
auxiliary.25 N1-Substituted uracils with the stereogenic
centre close to the reactive C5–C6 double bond seemed
appropriate, and two different chiral moieties were select-
ed on the basis of their simplicity and ready availability:
an a-methylbenzyl group and a ribose moiety. The five
compounds 2–6 were, therefore, selected for reactivity
and stereoselectivity evaluation (Figure 2).
SYNTHESIS 2007, No. 14, pp 2222–2232
x
x.
x
x
.
2
0
0
7
Advanced online publication: 03.07.2007
DOI: 10.1055/s-2007-983759; Art ID: T04407SS
© Georg Thieme Verlag Stuttgart · New York

FEATURE ARTICLE
Biographical Sketches
Photochemical Route to Enantiomerically Pure Cyclobutane b-Amino Acids
2223
Carlos Fernandes was born in has worked on the reactivity of paring his Ph.D. under the supervi-
Clermont-Ferrand (France) in
1978. He studied chemistry and
biology at the University Blaise
Pascal in Clermont-Ferrand. He
chiral organomagnesium amides, sion of Prof. D. J. Aitken, working
and on the synthesis of iodobenz- on synthetic access to cyclobutane
amide derivatives for melanoma amino acids and their use in b-pep-
research, and he is currently pre- tide synthesis.
Christine Gauzy was born the
tained her Ph.D. in 2003. She did R&D medicinal chemist with
French Mediterranean city of Sète, post-doctoral work with Dr. S. Bull Sanofi-Aventis in Vitry-sur-Seine,
in 1975. She first studied organic at the University of Bath, then with on CNS and oncology programmes.
chemistry at the University of Prof. G. Guillaumet at the Universi- She is currently looking to pursue
Montpellier II then moved in 1999 ty of Orléans, the latter in collabo- work in these fields.
to Clermont-Ferrand to join Prof. ration with the CEA-Le Ripault
D. J. Aitken’s group, where she ob- until 2005. She then worked as an
Yi Yang studied chemistry at the
Lanzhou University (China), where
he enrolled in a joint education pro-
gram with The Shanghai Institute
of Organic Chemistry (Chinese
Academy of Sciences). Working in
the field of total synthesis, he ob- (Chinese Academy of Sciences).
taining his Ph.D. in 2003, then Currently, he works as a post-doc-
joined Prof. D. J. Aitken’s group in toral fellow in Nanyang Technolog-
Clermont-Ferrand as a postdoctoral ical
University
(Singapore)
fellow (2004). He then went to focusing on chemical biology.
Guangzhou Institute of Chemistry
Olivier Roy was born in Reims working on catalysed asymmetric 2004, he moved to the University
(France) in 1974. He studied chem- protonation of enolic species. He Blaise Pascal in Clermont-Ferrand
istry in the University of Reims- did a first post-doc with Prof. G. as temporary Lecturer and in 2006
Champagne-Ardennes where he
Pattenden in Nottingham working he was given tenure. He currently
obtained his Ph.D. in 2001 under on taxanes, then a second post-doc works on the synthesis of glycosy-
the supervision of Dr. J. Muzart,
in Lyon with Dr. B. Langlois. In lated b-peptides.
Elisabeth Pereira was born in Me-
synthesis of protein kinase C inhib- ken where she currently works on
lun (France) in 1969. She received itors. After a post-doctoral stay at the synthesis of conformationally
her Ph.D. in 1996 from the Univer-
sity Blaise Pascal in Clermont-Fer-
rand under the supervision of Prof. at University Blaise Pascal and
the University of Kyoto with Prof. constrained b-amino acids espe-
Y. Ito, she became Lecturer in 1998
cially cyclobutane derivatives and
a-aminonitriles.
M. Prudhomme, working on the
joined the group of Prof. D. J. Ait-
Sophie Faure, born in 1973, stud-
ied chemistry at the University
She worked in the group of Prof. D.
Enders in Aachen as a postdoctoral Aitken in Clermont-Ferrand. Her
cherche in the group of Prof. D. J.
of Reims-Champagne-Ardennes fellow in 2000. Following post- research interests include synthesis
where she received her Ph.D. in doctoral work in medicinal chemis-
1999 under the supervision of Prof. try with Prof. H.-P. Husson at Uni-
O. Piva, working on photocycload- versity of Paris V, she joined the
of macrocyclic peptides and con-
formationally constrained amino
acids, especially cyclobutane deriv-
ditions and photoisomerisations. CNRS in 2002 as Chargé de Re- atives.
David Aitken was born in 1963
and studied chemistry at the Uni- searcher in 1990, in Prof. H.-P. clude all aspects of synthetic meth-
versity of Strathclyde, Scotland, Husson’s group at the University of odology, including photochemistry,
obtaining his Ph.D. in 1986. Thanks Paris V. In 1998, he became Profes- and the preparation of molecules
to a two-year NATO–Royal Soci- sor at Blaise Pascal University in and molecular scaffolds of biologi-
and was appointed CNRS Re-
at Orsay. His research interests in-
ety post-doctoral Fellowship at the Clermont-Ferrand. In 2006, he cal and therapeutic interest.
ICSN in Gif-sur-Yvette, he ac- transferred to his present position
quired a taste for research in France as Professor of Organic Chemistry
Synthesis 2007, No. 14, 2222–2232 © Thieme Stuttgart · New York

2224
C. Fernandes et al.
FEATURE ARTICLE
O
N
O
O
O
O
N
NH
NBz
NH
NBn
N
O
O
N
O
N
R
O
N
R
O
HO
HO
O
O
Ph
( )-4 R = CHPhMe
7 R = H
( )-5 R = CHPhMe
8 R = H
(R)-6
O
O
O
O
2
3
Figure 2 Chirally adapted uracils used in photochemical reactions.
O
Uridine 3 was prepared by reaction of the commercial
product 2 with benzyl bromide in the presence of sodium
carbonate and tetrabutylammonium bromide.26 Com-
pound ( )-4 was prepared by direct reaction of uracil (7)
with racemic (1-bromoethyl)benzene in the presence of
sodium hydride in N,N-dimethylformamide; these condi-
tions are known to give high N1-alkylation selectivity.27
This method was superior to the alternative Mitsunobu
procedure,28 which gave mixtures of O- and N-alkylated
uracils as well as dialkylated material. Similarly, com-
pound ( )-5 was obtained by N1-alkylation of 3-benzoyl-
uracil (8).29 Due to their ready availability, the racemic
forms of 4 and 5 were used in this initial study, which was
designed to examine the diastereoselectivity of the photo-
chemical reactions. Compound (R)-6 was prepared in two
steps from commercial (R)-phenylglycinol, again follow-
ing the literature.30
O
R2
N
H
R2
H2C CH2
N
hν, Pyrex
N
O
N
O
H
acetone, r.t.
3 h
R1
R1
2–6
9–13
Scheme 2 Photochemical reactions of chiral uracils 2–6 with ethy-
the photochemistry of compounds of type 4 and 5 has not
been disclosed. In a general context, ethylene is a cooper-
ative partner for [2+2] photocycloaddition reactions with
enones;32 however with chiral versions of the latter re-
agents the diastereomeric excess values vary considerably
and can be difficult to control.33
Rather than continue the uncertain search for an alterna-
tive chiral auxiliary in the hope of improving stereoselec-
tivity, we sought to exploit the chiral adducts in hand.
Uridine-derived cyclobutane diastereomer mixtures 9a/
9b and 10a/10b (Table 1, entries 1 and 2) could not be
separated by column chromatography nor by crystallisa-
tion. Similarly, the cyclobutane diastereomer mixtures
11a/11b and 12a/12b obtained from the N1-a-methylben-
zyl uracils (Table 1, entries 3 and 4) were barely separable
by chromatography; furthermore, useful exploitation of
either of these adducts would require their preparation in
enantiomerically pure form from single antipodes of 4 or
5, for which a synthesis had not yet been devised. The
most useful result was obtained using (R)-6, since separa-
tion of the diastereomers (–)-13a and (–)-13b was possi-
Each of the five uracil derivatives 2–6 was engaged in a
[2+2] photocycloaddition reaction with ethylene. Thus,
ethylene was bubbled through a solution (c = 5–10 mM)
of the substrate in acetone at room temperature, which
was irradiated over a three-hour period with a 400 W me-
dium-pressure mercury lamp fitted with a Pyrex filter
(Scheme 2). Results are presented in Table 1. In each
case, the desired cyclobutane adduct was obtained in good
to excellent yield (53–89%). As with previous [2+2] pho-
tocycloadditions involving olefins and uracil deriva-
tives,21,31 all cyclobutane compounds had cis
configuration at the ring junction. The diastereomeric ex-
cesses, however, determined from signal integration in 1H
NMR spectra of the initial isolates, were invariably weak
(4–26%). In particular, the bicyclic constraints present in
(R)-6 (conceived as an analogue of 4 that had been rigidi-
fied by a bond between O2 and the a-methyl carbon atom
of the N1 substituent) imparted no beneficial effects to the
selectivity (18% de; entry 5).
Table 1 Results of Photochemical Reactions of Chirally Adapted
Uracils with Ethylene (Scheme 2)
Entry
Starting
material
Products
Yield (%) de (%)
Reports of intermolecular [2+2] photocycloaddition reac-
tions between simple alkenes and uracil derivatives are
relatively rare.21,31 Uridines similar to 2 and 3 undergo ste-
reoselective photochemical [2+2] cycloadditions with the
sterically demanding tetramethylethylene,31a–d but reac-
tions with ethylene have not been described. Compound
(R)-6 undergoes highly stereoselective Michael addition
of nucleophiles at the b-carbon,30 but its photochemical
reactivity has not been examined previously. Likewise,
1
2
3
4
5
2
9a + 9b
67
53
89
57
80
4
26
4
3
10a + 10b
( )-4
( )-5
(R)-6
( )-11a + ( )-11b
( )-12a + ( )-12b
(–)-13a + (–)-13b
5
18
Synthesis 2007, No. 14, 2222–2232 © Thieme Stuttgart · New York

FEATURE ARTICLE
Photochemical Route to Enantiomerically Pure Cyclobutane b-Amino Acids
2225
ble by straightforward column chromatography of the
crude reaction product (Table 1, entry 5). These com-
pounds were thus obtained in 49% and 31% yield, respec-
tively, each in enantiomerically pure form. We expected
that the major diastereomer (–)-13a would be derived
from the approach of ethylene from the least hindered face
of the enone reaction centre, and would thus have a syn re-
lationship between both bridgehead hydrogens and the
phenyl group; this hypothesis was confirmed by an X-ray
diffraction study of
a single crystal of (–)-13a
(Figure 3).34 The future configuration of the 2-aminocy-
clobutanecarboxylic acid to be derived from this com-
pound was therefore 1S,2R. Given the rapid access to
enantiomerically pure (R)-6 and the ease of product sepa-
ration, we retained the reaction in Scheme 3 for the next
part of our synthesis.
O
O
O
H
Figure 3 X-ray diffraction structure of major diastereomer (–)-13a.
H
N
CH2
H2C
N
N
+
( )-14.21a The controlled two-step degradation of the het-
erocyclic rings of (+)-14 and (–)-14 was performed by
treatment with mild base, providing the N-carbamoyl-b-
amino acids (+)-15 and (–)-15 then diazotization with one
equivalent of sodium nitrite in acidic medium36 followed
by purification on cation-exchange resin, to provide the
target cis-b-amino acids (+)-(1S,2R)-1 and (–)-(1R,2S)-1
in good yields (Scheme 4). The enantiomeric excess of
each sample was established as >97% by chiral HPLC
analysis. The attribution of a 1R,2S absolute configuration
for the (–)-cis-1 enantiomer correlates with the previous
assertions made by Ortuño14,18 and Bolm.19
hν, Pyrex
N
N
O
N
O
O
H
acetone, r.t.
3 h
H
Ph
Ph
Ph
(R)-6
(–)-13a
(–)-13b
31%
49%
Scheme 3 Photochemical preparation of the key intermediates.
Selective opening of the five-membered rings of (–)-13a
and (–)-13b was achieved by hydrogenolysis in the pres-
ence of palladium on charcoal, as described by Agami et
al. for related heterocyclic structures.30 Single stereoiso-
mers (–)-11b and (–)-11a, respectively, were thus ob-
tained in quantitative yield and were correlated with
racemic materials available from the appropriate reaction
on Scheme 2 (see Table 1, entry 3). The a-methylbenzyl
group was removed cleanly and efficiently from each of
these compounds by refluxing in formic acid for 15
hours.35 Enantiomers (+)-14 and (–)-14 were each ob-
tained in 78% yield; spectroscopic data were identical
with those obtained previously for the racemic material
An attempt to carry out heterocyclic ring opening prior to
removal of the a-methylbenzyl group produced unexpect-
ed results (Scheme 5). A long reaction time (4 days) was
required for the sodium hydroxide mediated transforma-
tion of a sample of ( )-11b (available from Table 1, entry
3); the intermediate urea-acid 16 was not isolated, evi-
dently having been further transformed during this time
into the N-a-methylbenzylated cyclobutane b-amino acid
O
O
O
H
H
H
H
H
H
CO2H
NH2
CO2H
O
a
b
d
c
N
NH
NH
100%
78%
92%
88%
N
O
N
N
H
NH2
O
O
N
H
H
H
H
H
Ph
Ph
(–)-11b
(–)-13a
(+)-14
(+)-15
(+)-(1S,2R)-1
O
N
N
O
O
H
H
H
H
H
H
CO2H
CO2H
a
b
NH
c
d
NH
O
99%
78%
99%
91%
O
N
O
O
N
H
NH2
N
H
NH2
H
H
H
H
Ph
Ph
(–)-13b
(–)-11a
(–)-(1R,2S)-1
(–)-14
(–)-15
Scheme 4 Reagents and conditions: (a) H2 (4 bar), Pd/C, EtOH, r.t., 3 h; (b) HCO2H, reflux, 15 h; (c) 0.5 M NaOH, r.t., 18 h; (d) NaNO2, 3.5
M HCl, r.t., 18 h.
Synthesis 2007, No. 14, 2222–2232 © Thieme Stuttgart · New York

2226
C. Fernandes et al.
FEATURE ARTICLE
H
17. This material proved to have limited stability in protic
solution, and attempts to obtain cis-1 through catalytic hy-
drogenation failed. Instead, a mixture of acyclic products
was obtained, amongst which 5-aminopentanoic acid 18
and the amino diacid 19 were identified. These products
arise from the facile push–pull ring opening of the cyclo-
butane system, as we described in a recent communication
(Scheme 5).37
H
H
H
H
CO2Me
CO2H
CO2H
NH2
a
b
94%
93%
NHBoc
NHBoc
H
( )-cis-1
( )-20
( )-21
60% best yield
(see Table 2)
c
H
H
H
H
CO2H
CO2Me
NHBoc
O
CO2H
O
d
e
H
H
H
CO2H
O
a
NH
100%
a
OH
NH
88%
NHBoc
NH2
H
H
75%
O
N
NH2
N
H
H
H
( )-trans-1
( )-23
( )-22
Ph
Ph
Ph
17
( )-11b
16
b
H
H
(see reference 37)
H
CO2H
CO2H
N
a–e
H2N
+
CO2H
NH2
NH2
H
H
CO2H
HO2C
19
(+)-(1S,2R)-1
18
average
yield 31%
(–)-(1R,2R)-1
(38% when corrected for
recovered cis material)
Scheme 5 Reagents and conditions: (a) 0.5 M NaOH, r.t., 4 d; (b)
H2 (3 bar), Pd(OH)2/C, MeOH–H2O, r.t., 3 d.
H
H
CO2H
CO2H
Our next objective was to develop an entry to trans-2-
aminocyclobutanecarboxylic acid (trans-1). For this pur-
pose, regiospecific base-mediated C1-epimerisation of a
cis-1 derivative was envisaged. To facilitate handling and
to avoid stability problems arising from the push–pull
ring-opening process, both amine and acid functions were
protected. We carried out initial optimisation studies on
racemic samples. Thus, fully protected derivative ( )-21
was obtained uneventfully from ( )-cis-1 in two steps and
in good yield (Scheme 6).
a–e
NH2
NH2
H
H
(+)-(1S,2S)-1
(–)-(1R,2S)-1
Scheme 6 Preparation of ( )-trans-1, (1R,2R)-trans-1 and (1S,2S)-
trans-1 from the appropriate cis-1 precursors. Reagents and condi-
tions: (a) Boc2O, NaOH, H2O–dioxane, 0 °C to r.t., 4 h; (b) DCC,
DMAP, MeOH, 0 °C to r.t., 20 h; (c) see Table 2; (d) LiOH, THF–
H2O, r.t., 1 h; (e) TFA, CH2Cl2, r.t., 30 min.
Results of epimerisation studies are presented in Table 2.
Davies et al. described the epimerisation of related five-
and six-membered alicyclic b-amino acid derivatives us-
ing lithium hexamethyldisilazane in the presence of tert-
butyl alcohol;38 however, these conditions provoked total
degradation of ( )-21 (entry 1). The same result was ob-
tained using potassium tert-butoxide39 as base (entry 2).
An excess of 1,8-diazabicyclo[5.4.0]undec-7-ene in N,N-
dimethylformamide induced no change whatsoever in ( )-
21 over a 24 hour period at ambient temperature (entry 3),
but after 18 hours at 100 °C, all starting material had been
consumed. The desired trans-isomer ( )-22 was indeed
formed, but was isolated in poor yield (24%; entry 4); ev-
idently, degradation was still a significant problem. A
similar result was obtained when sodium hydride was
used as the base (entry 5). We finally succeeded in im-
proving the conversion/degradation profile by employing
sodium methoxide in methanol17e (entry 6). The epimeri-
sation was sensitive to the precise experimental condi-
tions; a slightly better result was obtained using five
equivalents of sodium methoxide under reflux for one
hour (entry 7). Longer reaction times resulted in lower
material recovery. In the best run, the required trans-iso-
mer ( )-22 was obtained in a satisfactory 60% isolated
yield and the recovered cis starting material ( )-21 (12%
isolated) could be reused later in a repeat isomerisation
procedure. In practice, repeat runs using the conditions of
entry 7 provided ( )-22 in yields that varied from 45–
60%, while ( )-21 was recovered in 10–25% yield. These
two isomers were easily separated by column chromatog-
raphy.
For the deprotection of compound ( )-22, methyl ester hy-
drolysis was performed by employing exactly one equiv-
alent (or even a slight deficit) of lithium hydroxide over
one hour, to give ( )-23 quantitatively. If the base was
present in slight excess, or if the reaction was left too long,
the cis-isomer ( )-20 was formed instead. Trifluoroacetic
acid mediated cleavage of the tert-butyl carbamate group
of ( )-23 in standard conditions provided the target trans-
2-aminocyclobutanecarboxylic acid, ( )-trans-1, in 88%
yield. Spectroscopic data were identical with those de-
scribed by Kennewell.20a
Synthesis 2007, No. 14, 2222–2232 © Thieme Stuttgart · New York

FEATURE ARTICLE
Photochemical Route to Enantiomerically Pure Cyclobutane b-Amino Acids
2227
Table 2 Epimerisation Conditions for Conversion of ( )-21 into ( )-22
Entry
Base
Solvent
Temp
Time
Recovered
Yield (%)
( )-21 (%)
of ( )-22
a
1
2
3
4
5
6
7
LiHMDS (4 equiv)/t-BuOH (8 equiv)
t-BuOK (2 equiv)
THF
r.t.
24 h
24 h
24 h
18 h
0.5 h
36 h
1 h
0
0
–
a
THF
r.t.
–
DBU (5 equiv)
DMF
DMF
THF
r.t.
100
0
–
DBU (5 equiv)
100 °C
reflux
r.t.
24
20
40
60
NaH (1.1 equiv)
0
NaOMe (5 equiv)
MeOH
MeOH
13
12
NaOMe (5 equiv)
reflux
a Degradation of materials.
1,21 3,26 and 829 were synthesised following published procedures or
minor modifications thereof. Compound (R)-6 was synthesised
from (R)-phenylglycinol according to the literature;30 its enantio-
meric excess was determined as >97% by 1H NMR experiments in
the presence of Eu(hfc)3.
The five-step sequence was then applied, essentially with-
out modification, to samples of each of the two enantio-
merically pure samples of cis-1. As anticipated, this
operation furnished successfully the corresponding trans-
1 compounds, each as a single enantiomer (Scheme 6). In
four five-step runs, the average overall yield was 31%
(corrected to 38% if recovered cis material is taken into
account at the isomerisation step). The enantiomeric ex-
cess of each sample of trans-1 obtained in this way was
established as >97% by chiral HPLC analysis.
1-(1-Phenylethyl)uracil [( )-4]
To a suspension of NaH (60% in oil, 0.393 g, 9.82 mmol) in anhyd
DMF (15 mL) was added a suspension of uracil 7 (1.00 g, 8.92
mmol) in DMF (15 mL) in small aliquots. The mixture was stirred
under argon at r.t. for 2 h then ( )-(1-bromoethyl)benzene (1.60 mL,
11.7 mmol) was added dropwise. The mixture was refluxed for 2 h
then cooled. H2O (15 mL) and CH2Cl2 (15 mL) were added succes-
sively. The organic phase was isolated and the aqueous phase was
extracted with CH2Cl2 (2 × 15 mL). The organic extracts were com-
bined, dried (MgSO4), filtered, and concentrated under reduced
pressure. The crude mixture was purified by chromatography (cy-
clohexane–EtOAc, gradient from 75:25 to 50:50) to give ( )-4 as a
white solid (1.16 g, 60%); mp 115–118 °C; Rf = 0.3 (cyclohexane–
EtOAc, 50:50). Spectroscopic data were identical with those in the
literature.40
In conclusion, we have prepared all four possible stereo-
isomers of the prototype cyclobutane b-amino acid 1 via
the [2+2] photocycloaddition reaction of a single, readily
prepared chiral uracil derivative. Although the diastereo-
meric excess was modest in the cyclobutane-forming step,
the easy separation of the resulting diastereomers guaran-
tees the enantiomeric purity of all subsequently derived
materials. Each of the final products was obtained in enan-
tiomerically pure form, and this work provides the first ac-
cess to either enantiomer of trans-1.
3-Benzoyl-1-(1-phenylethyl)uracil [( )-5]
To a suspension of NaH (60% in oil, 0.142 g, 3.55 mmol) in anhyd
DMF (8 mL) was added 3-benzoyluracil (8) in portions (0.640 g,
2.96 mmol). The mixture was stirred under argon at r.t. for 2 h then
( )-(1-bromoethyl)benzene (0.527 mL, 3.86 mmol) was added
dropwise and the mixture was stirred for a further 2 h. H2O (15 mL)
and CH2Cl2 (15 mL) were added successively. The organic phase
was isolated and the aqueous phase was extracted with CH2Cl2 (4 ×
15 mL). The organic extracts were combined, dried (MgSO4), fil-
tered, and concentrated under reduced pressure. The crude mixture
was purified by chromatography (cyclohexane–EtOAc, 70:30) to
give ( )-5 as a white foam (0.726 g, 77%); mp 46–48 °C; Rf = 0.5
(cyclohexane–EtOAc, 50:50).
Melting points were determined with a Reichert microscope appa-
ratus. Elemental analyses were carried out on a Thermofinnigan
Flash EA 1112 apparatus. 1H (400 MHz) and 13C (100 MHz) NMR
spectra were obtained on a Bruker AC 400 spectrometer. IR spectra
were recorded on a Perkin Elmer Paragon 500 FTIR spectrometer;
only structurally important peaks are presented. MS spectra were
recorded on an HP 5989 B instrument in chemical ionisation mode
(150 eV) using isobutane as the vector gas. HRMS were recorded in
ESI (3000 V) on a Micromass micro q-tof with an internal lock mass
(H3PO4) and an external lock mass (Leu-enkephalin). Specific opti-
cal rotations were measured with a Jasco DIP-370 polarimeter. Re-
actions were analysed by TLC on silica gel 60 F254 (Merck).
Preparative chromatography was performed on silica gel 60 (40–60
mm) (Merck) using 15-cm length columns. HPLC analysis was per-
formed on a Waters 590 instrument equipped with a Crownpak
CR(+) column (i.d. 0.4 cm × 15 cm) and a Waters 484 UV detector,
using the following conditions: 0.17 M HClO4 (pH = 1) as mobile
phase; T = 4 °C; l = 220 nm; flow rate = 0.3 mL·min–1.
IR (KBr): 1745, 1702, 1664, 1438, 1362, 1255 cm–1.
1H NMR (CDCl3): d = 1.75 (d, J = 7.0 Hz, 3 H, CH3), 5.76 (d,
J = 8.1 Hz, 1 H, H5), 5.98 (q, J = 7.0 Hz, 1 H, CH–CH3), 7.13 (d,
J = 8.2 Hz, 1 H, H6), 7.36–7.46 (m, 5 H, Ph), 7.52 (t, J = 7.5 Hz, 2
H, Ph); 7.67 (t, J = 7.4 Hz, 1 H, Ph), 7.95 (d, J = 7.7 Hz, 2 H, Ph).
13C NMR (CDCl3): d = 18.5, 53.9, 102.7, 127.4 (2 C), 128.8, 129.3
(4 C), 130.5 (2 C), 131.6, 135.1, 138.3, 140.8, 150.1, 162.0, 168.9.
HRMS (ESI): m/z [M + Na]+ calcd for C19H16N2NaO3: 343.1059;
found: 343.1067.
All organic solvents were dried and purified by standard procedures
prior to use. Compounds 2 and 7 and all other standard reagents
were obtained commercially and used as supplied. Compounds ( )-
Synthesis 2007, No. 14, 2222–2232 © Thieme Stuttgart · New York

2228
C. Fernandes et al.
FEATURE ARTICLE
[2+2] Photocycloaddition of Uracils with Ethylene; General
Procedure
1H NMR (CDCl3): d = 1.53 (d, J = 7.2 Hz, 3 H, CH3), 2.09–2.21 (m,
2 H), 2.30–2.42 (m, 2 H), 3.11 (m, 1 H, H6), 3.75 (q, J = 8.2 Hz, 1
H, H1), 5.80 (q, J = 7.2 Hz, 1 H, CH–CH3), 7.30–7.40 (m, 5 H, Ph),
8.18 (br s, 1 H, NH).
13C NMR (CDCl3): d = 18.4, 21.9, 32.7, 40.2, 46.3, 51.6, 127.2,
127.9, 128.8, 139.9, 151.9, 172.7.
Photochemical reactions were carried out at r.t. in an annular reactor
equipped with a water-cooling circuit using a 400 W medium-pres-
sure Hg lamp fitted with a Pyrex filter. A soln of the uracil deriva-
tive in acetone was deoxygenated with an argon stream for 15 min,
then irradiated for 3 h while ethylene was bubbled through. The sol-
vent was then removed under reduced pressure and the crude prod-
uct was purified by chromatography.
HRMS (ESI): m/z [M + Na]+ calcd for C14H16N2NaO2: 267.1109;
found: 267.1113.
Diastereomer ( )-11b
Mp: 122–124 °C; Rf = 0.4 (cyclohexane–EtOAc, 50:50).
IR (KBr): 3240, 1700 cm–1.
1H NMR (CDCl3): d = 1.23–1.28 (m, 1 H), 1.57 (d, J = 7.0 Hz, 3 H,
CH3), 1.76–1.82 (m, 1 H), 1.93–2.07 (m, 2 H), 3.22 (m, 1 H, H6),
3.93 (q, J = 8.0 Hz, 1 H, H1), 5.83 (q, J = 7.0 Hz, 1 H, CH–CH3),
7.26–7.38 (m, 5 H, Ph), 8.15 (br s, 1 H, NH).
13C NMR (CDCl3): d = 15.9, 21.6, 31.7, 40.3, 46.5, 51.3, 127.9,
128.0, 128.6, 139.4, 151.7, 172.7.
2-(2,3-O-Isopropylidene-b-D-ribofuranosyl)-cis-2,4-diazabicy-
clo[4.2.0]octane-3,5-dione (9a/9b)
A soln of compound 2 (0.250 g, 0.88 mmol) in acetone (170 mL)
was irradiated following the general photocycloaddition procedure.
After chromatography (CH2Cl2–MeOH, 97:3) a mixture of two dia-
stereomers 9a and 9b was isolated as a white solid (0.185 g, 67%);
Rf = 0.2 (CH2Cl2–MeOH, 97:3).
IR (KBr): 3447, 3244, 1698 cm–1.
1H NMR (CDCl3): d = 1.31 (s, 3 H, CH3), 1.32 (s, 3 H, CH3), 1.51
(s, 3 H, CH3), 1.52 (s, 3 H, CH3), 2.14–2.39 (m, 8 H, CH2), 3.28–
3.37 (m, 2 H), 3.68–3.73 (m, 2 H), 3.79–3.86 (td, J = 12, 2.8 Hz, 2
H), 4.09–4.19 (m, 4 H), 4.86 (m, 2 H), 4.92 (dd, J = 6.4, 3.6 Hz, 1
H), 5.03 (dd, J = 6.4, 3.2 Hz, 1 H), 5.11 (d, J = 3.2 Hz, 1 H), 5.24
(d, J = 3.2 Hz, 1 H), 8.61 (br s, 2 H, NH).
13C NMR (CDCl3): d = 21.7, 22.0, 25.4 (2 C), 27.4 (2 C), 30.6, 30.7,
38.7, 39.4, 50.8, 51.7, 62.8, 62.9, 80.3, 80.6, 82.4 (2 C), 85.3, 85.5,
94.2, 94.7, 114.1, 114.2, 151.9, 152.0, 172.0, 172.4.
HRMS (ESI): m/z [M + Na]+ calcd for C14H16N2NaO2: 267.1109;
found: 267.1115.
4-Benzoyl-2-(1-phenylethyl)-cis-2,4-diazabicyclo[4.2.0]octane-
3,5-dione [( )-12a and ( )-12b]
A soln of compound ( )-5 (0.200 g, 0.62 mmol) in acetone (150
mL) was irradiated following the general photocycloaddition proce-
dure. After chromatography (cyclohexane–EtOAc, 60:40) two dia-
stereomers ( )-12a (0.057 g, 26%) and ( )-12b (0.067 g, 31%) were
isolated as viscous liquids in 57% overall yield. Overlapping elution
profiles of the two components made the chromatographic separa-
tion difficult.
HRMS (ESI): m/z [M + Na]+ calcd for C14H20N2NaO6: 335.1219;
found: 335.1230.
4-Benzyl-2-(2,3-O-isopropylidene-b-D-ribofuranosyl)-cis-2,4-
diazabicyclo[4.2.0]octane-3,5-dione (10a/10b)
A soln of compound 3 (0.154 g, 0.41 mmol) in acetone (170 mL)
was irradiated following the general photocycloaddition procedure.
After chromatography (CH2Cl2–MeOH, 97:3) a mixture of two dia-
stereomers 10a and 10b was isolated as a white solid (0.088 g,
53%); Rf = 0.5 (CH2Cl2–MeOH, 98:2).
Diastereomer ( )-12a
Rf = 0.6 (cyclohexane–EtOAc, 50:50).
IR (CCl4): 3020, 1743, 1701, 1669, 1442, 1215 cm–1.
1H NMR (CDCl3): d = 1.57 (d, J = 7.1 Hz, 3 H, CH3), 2.27 (m, 1 H),
2.42 (m, 2 H), 2.54 (m, 1 H), 3.28 (m, 1 H, H6), 3.83 (q, J = 7.9 Hz,
1 H, H1), 5.77 (q, J = 7.1 Hz, 1 H, CH–CH3), 7.40 (m, 5 H, Ph),
7.53 (m, 2 H, Ph), 7.67 (m, 1 H, Ph), 7.96 (d, J = 7.5 Hz, 2 H, Ph).
13C NMR (CDCl3): d = 17.0, 22.1, 33.3, 40.4, 45.7, 52.0, 127.4,
128.0, 128.9, 129.0, 130.1, 132.6, 134.4, 139.5, 151.1, 170.0, 171.7.
IR (KBr): 3457, 1710, 1666 cm–1.
1H NMR (CDCl3): d = 1.26 (s, 3 H, CH3), 1.27 (s, 3 H, CH3), 1.46
(s, 3 H, CH3), 1.47 (s, 3 H, CH3), 2.05–2.30 (m, 8 H, CH2), 3.33 (m,
2 H), 3.36 (s, 2 H, OH), 3.64 (dd, J = 12.2, 3.0 Hz, 2 H), 3.73–3.77
(m, 2 H), 3.99–4.07 (m, 4 H), 4.82–4.98 (2 m, 8 H), 5.03 (d, J = 3.6
Hz, 1 H), 5.15 (d, J = 3.6 Hz, 1 H), 7.17 (d, J = 7.2 Hz, 2 H), 7.22
(t, J = 6.8 Hz, 4 H), 7.29 (d, J = 7.6 Hz, 4 H).
HRMS (ESI): m/z [M + Na]+ calcd for C21H20N2NaO3: 371.1372;
found: 371.1388.
13C NMR (CDCl3): d = 22.3, 22.7, 25.3, 27.3 (2 C), 29.2, 30.6, 30.6,
38.5, 39.2, 43.8, 43.9, 49.3, 50.1, 62.8, 62.9, 80.1, 80.5, 82.2, 82.3,
85.1, 85.3, 95.3, 95.7, 113.9, 114.1, 127.4 (2 C), 128.4 (4 C), 128.6
(4 C), 137.3, 137.4, 152.3, 152.4, 170.9, 171.4.
HRMS (ESI): m/z [M + Na]+ calcd for C21H26N2NaO2: 425.1689;
found: 425.1675.
Diastereomer ( )-12b
Rf = 0.5 (cyclohexane–EtOAc, 50:50).
IR (CCl4): 3025, 1749, 1704, 1672, 1440, 1253 cm–1.
1H NMR (CDCl3): d = 1.36 (m, 1 H), 1.62 (d, J = 7.0 Hz, 3 H, CH3),
1.92 (m, 1 H), 2.09 (m, 2 H), 3.41 (m, 1 H, H6), 4.02 (q, J = 8.0 Hz,
1 H, H1), 5.79 (q, J = 7.0 Hz, 1 H, CH–CH3), 7.37 (m, 5 H, Ph),
7.52 (m, 2 H, Ph), 7.65 (m, 1 H, Ph), 7.94 (d, J = 7.5 Hz, 2 H, Ph).
13C NMR (CDCl3): d = 15.8, 21.9, 32.2, 40.6, 43.4, 51.7, 127.2,
127.9, 128.2, 128.9, 130.1, 132.6, 134.6, 139.0, 150.9, 170.0, 171.7.
2-(1-Phenylethyl)-cis-2,4-diazabicyclo[4.2.0]octane-3,5-dione
[( )-11a/( )-11b]
A soln of compound ( )-4 (2.50 g, 11.6 mmol) in acetone (1 L) was
irradiated following the general photocycloaddition procedure. Af-
ter chromatography (cyclohexane–EtOAc, 60:40), two diastereo-
mers ( )-11a (1.24 g, 44%) and ( )-11b (1.27 g, 45%) were isolated
as white solids in 89% overall yield.
HRMS (ESI): m/z [M + Na]+ calcd for C21H20N2NaO3: 371.1372;
found: 371.1387.
1-Phenyl-1,2,5a,6,7,7a-hexahydro-5H-cyclobuta[e][1,3]oxazo-
lo[3,2-a]pyrimidin-5-one (13a/13b)
A soln of compound (R)-6 (1.10 g, 5.13 mmol) in acetone (1 L) was
irradiated following the general photocycloaddition procedure. Af-
ter chromatography (gradient of EtOAc–MeOH from 100:0 to
95:5), two diastereomers (–)-13a (0.609 g, 49%) and (–)-13b (0.390
g, 31%) were isolated as white solids.
Diastereomer ( )-11a
Mp 151–154 °C; Rf = 0.5 (cyclohexane–EtOAc, 50:50).
IR (KBr): 3240, 1700 cm–1.
Synthesis 2007, No. 14, 2222–2232 © Thieme Stuttgart · New York

FEATURE ARTICLE
Photochemical Route to Enantiomerically Pure Cyclobutane b-Amino Acids
2229
(–)-(1R,5aS,7aR)-13a
1H NMR (DMSO-d6): d = 1.92 (m, 2 H, H7), 2.18 (m, 2 H, H8),
3.11 (m, 1 H, H6), 3.90 (m, 1 H, H1), 7.68 (s, 1 H, NH), 10.02 (s, 1
H, NH).
Mp >300 °C; [a]D25 –187 (c 1.00, CHCl3); Rf = 0.2 (EtOAc–MeOH,
95:5).
IR (KBr): 2950, 1660 cm–1.
13C NMR (DMSO-d6): d = 21.4, 30.6, 37.2, 44.8, 152.7, 173.3.
MS (CI): m/z = 141 [M + H]+.
1H NMR (CDCl3): d = 2.23–2.29 (m, 2 H, H9), 2.38–2.44 (m, 2 H,
H8), 3.26 (q, J = 8.2 Hz, 1 H, H6), 3.83 (dt, J = 8.6, 6.4 Hz, 1 H,
H7), 4.36 (dt, J = 12.9, 7.0 Hz, 1 H, H11), 4.87–4.95 (m, 2 H, H1,
H11), 7.30 (m, 2 H, Ph), 7.46 (m, 3 H, Ph).
Anal. Calcd for C6H8N2O2: C, 51.42; H, 5.75; N, 19.99. Found: C,
51.35; H, 5.77; N, 19.83.
13C NMR (CDCl3): d = 24.2, 26.8, 35.9, 47.3, 59.9, 72.6, 127.0,
(–)-(1S,6R)-2,4-Diazabicyclo[4.2.0]octane-3,5-dione [(–)-14]
A soln of compound (–)-11a (2.43 g, 9.94 mmol) in 97% HCO2H
(100 mL) was stirred under reflux for 15 h. Elimination of HCO2H
under reduce pressure left a brown solid which was washed with
Et2O and then recovered by filtration. Compound (–)-14 was ob-
tained as an off-white solid after drying under vacuum (1.08 g,
78%); mp 249–251 °C. Other data: as for (+)-14.
129.5, 129.6, 134.9, 167.0, 181.0.
MS (CI): m/z = 243 [M + H]+.
Anal. Calcd for C14H14N2O2: C, 69.40; H, 5.83; N, 11.56. Found: C,
68.91; H, 5.89; N, 11.38.
(–)-(1R,5aR,7aS)-13b
Mp 179–182 °C; [a]D –8 (c 1.00, CHCl3); Rf = 0.1 (EtOAc–
MeOH, 95:5).
[a]D25 –24 (c 1.00, HCO2H).
25
(+)-(1S,2R)-2-[(Aminocarbonyl)amino]cyclobutanecarboxylic
Acid [(+)-15]
IR (KBr): 2950, 1670 cm–1.
1H NMR (CDCl3): d = 1.75–1.80 (m, 1 H, H9), 1.89–1.94 (m, 1 H,
H9), 2.18–2.32 (m, 2 H, H8), 3.17–3.23 (m, 1 H, H6), 4.03 (q,
J = 8.5 Hz, 1 H, H7), 4.40 (m, 1 H, H11), 4.82–4.88 (m, 2 H, H1,
H11), 7.35–7.39 (m, 2 H, Ph), 7.42–7.47 (m, 3 H, Ph).
13C NMR (CDCl3): d = 23.9, 29.6, 36.7, 49.8, 63.1, 72.7, 127.4,
129.2, 129.5, 136.2, 167.0, 181.6.
Compound (+)-14 (1.64 g, 11.7 mmol) was dissolved in 0.5 M
NaOH (140 mL) and stirred overnight at r.t. Cation exchange resin
(Bio-Rad AG 50W-X8, H+, 20–50 mesh) was then added until pH
was about 4. Filtration and then evaporation of H2O from the filtrate
left (+)-15 as a white solid (1.70 g, 92%); mp 149–154 °C; Rf = 0.2
(EtOAc–MeOH, 90:10).
[a]D25 +143 (c 1.02, HCO2H).
IR (KBr): 3400, 3320, 3220, 1700, 1650 cm–1.
1H NMR (DMSO-d6): d = 1.79 (m, 2 H, H4), 2.08 (quint, J = 9.9
Hz, 1 H, H3), 2.17 (m, 1 H, H3), 3.14 (m, 1 H, H1), 4.40 (m, 1 H,
H2), 5.56 (s, 2 H, NH2), 6.23 (br s, 1 H, NH).
13C NMR (DMSO-d6): d = 17.4, 29.2, 44.9, 45.8, 157.4, 174.7.
MS (CI): m/z = 159 [M + H]+.
MS (CI): m/z = 243 [M + H]+.
Anal. Calcd for C14H14N2O2: C, 69.40; H, 5.83; N, 11.56. Found: C,
68.96; H, 6.11; N, 11.17.
(–)-(1R,6S)-2-[(1S)-1-Phenylethyl]-2,4-diazabicyclo[4.2.0]oc-
tane-3,5-dione [(–)-11b]
A soln of compound (–)-13a (2.00 g, 8.18 mmol) in EtOH (200 mL)
was stirred under H2 (4 bar) in presence of 10% Pd/C (0.890 g, 0.84
mmol) for 4 h. After filtration through a pad of Celite, the filtrate
was concentrated to give compound (–)-11b as colourless crystals
(1.99 g, 100%); mp 130–131 °C. Other data: as for ( )-11b.
Anal. Calcd for C6H10N2O3: C, 45.57; H, 6.37; N, 17.71. Found: C,
45.68; H, 6.48; N, 17.64.
(–)-(1R,2S)-2-[(Aminocarbonyl)amino]cyclobutanecarboxylic
Acid [(–)-15]
[a]D25 –139 (c 1.00, CHCl3).
Anal. Calcd for C14H16N2O2: C, 68.83; H, 6.60; N, 11.47. Found: C,
68.41; H, 6.70; N, 11.25.
Compound (–)-14 (1.00 g, 7.14 mmol) was dissolved in 0.5 M
NaOH (50 mL) and stirred overnight at r.t. Cation exchange resin
(Bio-Rad AG 50W-X8, H+, 20–50 mesh) was then added until pH
was about 4. Filtration and then evaporation of H2O from the filtrate
left (–)-15 as a white solid (1.12 g, 99%); mp 149–151 °C. Other
data: as for (+)-15.
(–)-(1S,6R)-2-[(1S)-1-Phenylethyl]-2,4-diazabicyclo[4.2.0]oc-
tane-3,5-dione [(–)-11a]
A soln of compound (–)-13b (0.920 g, 3.77 mmol) in EtOH (200
mL) was stirred under H2 (4 bar) in presence of 10% Pd/C (0.413 g,
0.39 mmol) for 3 h. After filtration through a pad of Celite, the fil-
trate was concentrated to give compound (–)-11a as colourless crys-
tals (0.910 g, 99%); mp 171–173 °C. Other data: as for ( )-11a.
[a]D25 –143 (c 1.02, HCO2H).
(+)-(1S,2R)-2-Aminocyclobutanecarboxylic Acid [(+)-(1S,2R)-
1]
[a]D25 –33 (c 1.00, CHCl3).
Compound (+)-15 (1.70 g, 10.7 mmol) was dissolved in 3.5 M HCl
(250 mL). NaNO2 (0.75 g, 10.7 mmol) was added and the mixture
was stirred overnight at r.t. The soln was deposited on a cation-
exchange column (Dowex 50WX8-100, H+, 50–100 mesh). The
column was washed with H2O until the eluent was neutral, then the
product was eluted with 1 M NH4OH soln. After pooling and evap-
oration of appropriate fractions, pure (+)-(1S,2R)-1 was obtained as
a white solid (1.08 g, 88%); mp 128–130 °C; Rf = 0.4 (PrOH–H2O,
70:30); HPLC: tR = 7.2 min, >97% ee.
[a]D25 +71 (c 1.02, H2O).
IR (KBr): 3422, 2957, 1542, 1406, 1293 cm–1.
1H NMR (D2O): d = 2.05 (m, 1 H, H4), 2.25 (m, 2 H, H4, H3), 2.35
(m, 1 H, H3), 3.22 (m, 1 H, H1), 3.92 (q, J = 7.2 Hz, 1 H, H2).
Anal. Calcd for C14H16N2O2: C, 68.83; H, 6.60; N, 11.47. Found: C,
68.68; H, 6.64; N, 11.46.
(+)-(1R,6S)-2,4-Diazabicyclo[4.2.0]octane-3,5-dione [(+)-14]
A soln of compound (–)-11b (3.67 g, 15.0 mmol) in 97% HCO2H
(147 mL) was stirred under reflux for 15 h. Elimination of HCO2H
under reduced pressure left a brown solid which was washed with
Et2O and then recovered by filtration. Compound (+)-14 was ob-
tained as an off-white solid after drying under vacuum (1.64 g,
78%); mp 247–249 °C; Rf = 0.3 (EtOAc).
[a]D25 +24 (c 1.00, HCO2H).
IR (KBr): 3230, 3080, 1720 cm–1.
13C NMR (D2O): d = 21.1, 24.9, 41.3, 45.4, 180.9.
Synthesis 2007, No. 14, 2222–2232 © Thieme Stuttgart · New York

2230
C. Fernandes et al.
FEATURE ARTICLE
HRMS (ESI): m/z [M + H]+ calcd for C5H10NO2: 116.0712; found:
116.0706.
13C NMR (CDCl3): d = 16.7, 27.7, 28.1, 45.9, 47.3, 81.3, 157.6,
177.0.
HRMS (ESI): m/z [M + Na]+ calcd for C10H17NNaO4: 238.1065;
found: 238.1055.
(–)-(1R,2S)-2-Aminocyclobutanecarboxylic Acid [(–)-(1R,2S)-1]
Compound (–)-15 (0.660 g, 4.20 mmol) was dissolved in 3.5 M HCl
(92 mL). NaNO2 (0.29 g, 4.20 mmol) was added and the mixture
was stirred overnight at r.t. The soln was deposited on a cation-
exchange column (Dowex 50WX8-100, H+, 50–100 mesh). The
column was washed with H2O until the eluent was neutral, then the
product was eluted with 1 M NH4OH soln. After pooling and evap-
oration of appropriate fractions, pure (–)-(1R,2S)-1 was obtained as
a white solid (0.440 g, 91%); mp 126–128 °C; HPLC: tR = 10.9 min,
>97% ee. Other data: as for (+)-(1R,2S)-1.
Anal. Calcd for C10H17NO4: C, 55.80; H, 7.96; N, 6.51. Found: C,
55.31; H, 7.86; N, 6.57.
Methyl ( )-cis-2-[(tert-Butyloxycarbonyl)amino]cyclobutane-
carboxylate [( )-21]
To a soln of ( )-20 (2.95 g, 13.7 mmol) in anhyd CH2Cl2 (150 mL)
under argon, were added DMAP (0.180 g, 1.5 mmol) then MeOH
(1.79 mL, 44.2 mmol). After cooling at 0 °C in an ice bath, DCC
(2.95 g, 14.9 mmol) was introduced and the stirring was maintained
at 0 °C for 5 min then at r.t. for 20 h. Evaporation of solvent under
reduced pressure left a slightly brown solid that was purified by
chromatography (EtOAc–cyclohexane, 90:10) to afford ( )-21 as a
white powder (2.91 g, 93%); mp 46–48 °C; Rf = 0.7 (EtOAc–cyclo-
hexane, 60:40).
[a]D25 –70 (c 1.03, H2O).
2-[(1-Phenylethyl)amino]cyclobutanecarboxylic Acid (17)
Compound ( )-11b (0.100 g, 0.41 mmol) was dissolved in 0.5 M
NaOH (5 mL) and stirred at r.t. for 4 d. Then the soln was deposited
on a cation-exchange column (Dowex 50WX8-100, H+, 50–100
mesh). The column was washed with H2O until the eluent was neu-
tral, then the product was eluted with 1 M NH4OH. After pooling
and evaporation of appropriate fractions, 17 was obtained as a white
solid (0.067 g, 75%), which had limited stability in protic soln.37
1H NMR (D2O): d = 1.49 (d, J = 6.8 Hz, 3 H, CH3), 1.69 (m, 1 H),
1.97 (quint, J = 9.3 Hz, 1 H), 2.07–2.21 (m, 2 H), 2.42 (m, 1 H, H1),
3.58 (q, J = 8.2 Hz, 1 H, H2), 4.11 (q, J = 6.9 Hz, 1 H, CH–CH3),
7.32 (br s, 5 H, Ph).
(+)-(1S,2R)-21
Mp 47–49 °C; [a]D27 +122 (c 1.17, CHCl3).
(–)-(1R,2S)-21
Mp 47–49 °C; [a]D27 –122 (c 1.09, CHCl3) [Lit.14a [a]D –131.0
(c 0.62, CH2Cl2)].
IR (KBr): 3337, 1685, 1527 cm–1.
1H NMR (CDCl3): d = 1.44 (s, 9 H, t-Bu), 1.95 (m, 2 H, H4), 2.19
(quint, J = 10 Hz, 1 H, H3), 2.33 (m, 1 H, H3), 3.37 (m, 1 H, H1),
3.69 (s, 3 H, CH3), 4.45 (t, J = 7 Hz, 1 H, H2), 5.33 (br s, 1 H, NH).
13C NMR (CDCl3): d = 18.5, 28.3, 29.5, 45.2, 45.8, 51.7, 79.3,
154.7, 174.7.
HRMS (ESI): m/z [M + Na]+ calcd for C11H19NNaO4: 252.1205;
found: 252.1212.
13C NMR (D2O): d = 18.6, 20.8, 25.9, 42.0, 50.4, 56.5, 127.7, 129.1,
129.2, 136.9, 181.8.
MS (CI): m/z = 220 [M + H]+.
Catalytic Hydrogenation of Compound 17
A soln of compound 17 (0.030 g, 0.14 mmol) in a mixture of
MeOH–H2O (20 mL:2.5 mL) was stirred under H2 (3 bar) in pres-
ence of 20% Pd(OH)2/C (0.030 g) for 3 d. After filtration through a
pad of Celite, the filtrate was concentrated to dryness to leave a
white solid (0.030 g).The analysis of this crude material by 1H and
13C NMR spectroscopy revealed a mixture of several products,
amongst which 2 major compounds were identified: 5-amino-
pentanoic acid (18) (by comparison with a commercial sample),
and 5-(4-carboxybutylamino)pentanoic acid (19) (described
previously37).
Anal. Calcd for C11H19NO4: C, 57.62; H, 8.35; N, 6.11. Found C,
57.96; H, 8.20; N, 6.13.
Methyl ( )-trans-2-[(tert-Butyloxycarbonyl)amino]cyclobutane-
carboxylate [( )-22]
Na (0.190 g, 8.26 mmol) was dissolved in anhyd MeOH (85 mL) at
r.t. under argon. Compound ( )-21 (0.420 g, 1.83 mmol) was added
to the resulting soln and the mixture was stirred at reflux for 1 h. Af-
ter cooling in an ice bath, the reaction was quenched by addition of
1 M HCl (17 mL). Excess MeOH was evaporated under reduced
pressure and the aqueous layer was extracted with EtOAc (3 × 40
mL). The combined organic layers were dried (MgSO4), filtered and
evaporated to give a white solid that was purified by chromatogra-
phy (cyclohexane–EtOAc, 90:10) to afford starting material ( )-21
recovered as a white powder (0.050 g, 12%) and ( )-22 as a white
powder (0.250 g, 60%); mp 73–75 °C; Rf = 0.5 (EtOAc–cyclohex-
ane, 70:30).
( )-cis-2-[(tert-Butyloxycarbonyl)amino]cyclobutanecarboxyl-
ic Acid [( )-20]
To a soln of ( )-cis-1 (1.66 g, 14.6 mmol) in a mixture of dioxane–
1 M NaOH (34 mL, 2:1, v/v) at 0 °C was added Boc2O (3.32 g, 15.9
mmol). The soln was stirred at 0 °C for 5 min then at r.t. for 4 h. Sol-
vents were evaporated and H2O (15 mL) was added, followed by
acidification to pH 1 by addition of 1 M HCl . The aqueous mixture
was extracted with EtOAc (3 × 90 mL) and the combined organic
layers were dried (MgSO4), filtered, and evaporated to give ( )-20
as a white powder (2.95 g, 94%); mp 169–172 °C; Rf = 0.6 (EtOAc).
(+)-(1S,2S)-22
Mp 73–75 °C; [a]D27 +54 (c 1.07, CHCl3).
(+)-(1S,2R)-20
Mp 116–119 °C; [a]D27 +48 (c 0.85, CHCl3).
(–)-(1R,2R)-22
Mp 74–76 °C; [a]D27 –55 (c 0.97, CHCl3).
(–)-(1R,2S)-20
IR (KBr): 3422, 1636, 1525 cm–1.
27
Mp 116–119 °C; [a]D –47 (c 0.90, CHCl3) [Lit.14a [a]D –48.6
1H NMR (CDCl3): d = 1.43 (s, 9 H, t-Bu), 1.93 (m, 3 H, H4, H3),
2.25 (qd, J = 8, 2 Hz, 1 H, H3), 2.98 (m, 1 H, H1), 3.67 (s, 3 H,
CH3), 4.21 (m, 1 H, H2), 4.77 (br s, 1 H, NH).
13C NMR (CDCl3): d = 18.2, 27.3, 28.3, 46.8, 48.9, 51.7, 79.3,
154.6, 173.4.
(c 0.74, CH2Cl2)].
IR (KBr): 3347, 2985, 1696, 1516 cm–1.
1H NMR (CDCl3): d = 1.45 (s, 9 H, t-Bu), 1.82 (m, 1 H, H4), 2.09
(m, 1 H, H4), 2.33 (m, 2 H, H3), 3.37 (m, 1 H, H1), 4.35 (quint,
J = 8.6 Hz, 1 H, H2), 7.22 (br s, 1 H, NH).
HRMS (ESI): m/z [M + Na]+ calcd for C11H19NNaO4: 252.1205;
found: 252.1215.
Synthesis 2007, No. 14, 2222–2232 © Thieme Stuttgart · New York

FEATURE ARTICLE
Photochemical Route to Enantiomerically Pure Cyclobutane b-Amino Acids
2231
Anal. Calcd for C11H19NO4: C, 57.62; H, 8.35; N, 6.11. Found: C,
57.78; H, 8.42; N, 6.11.
References
(1) (a) Spiteller, P.; von Nussbaum, F. In Enantioselective
Synthesis of b-Amino Acids, 2nd ed.; Juaristi, E.;
( )-trans-2-[(tert-Butyloxycarbonyl)amino]cyclobutanecarbox-
ylic Acid [( )-23]
Soloshonok, V. A., Eds.; Wiley-VCH: Weinheim, 2005, 19.
(b) von Nussbaum, F.; Spiteller, P. In Highlights in
Bioorganic Chemistry: Methods and Applications;
Schmuck, C.; Wennemers, H., Eds.; Wiley-VCH:
Weinheim, 2004, 63.
At r.t., LiOH·H2O (0.050 g, 1.00 mmol) was added to a soln of ( )-
22 (0.250 g, 1.00 mmol) in THF–H2O (1:1, 30 mL). The mixture
was stirred 1 h and the solvent was evaporated. Successively, H2O
(10 mL) and 1 M HCl (2.5 mL) were added and the aqueous layer
was extracted with EtOAc (3 × 20 mL). The combined organic lay-
ers were dried (MgSO4), filtered, and evaporated giving compound
( )-23 as a white powder (0.220 g, 100%); mp 155–157 °C; Rf = 0.6
(EtOAc).
(2) (a) Arvidsson, P. I.; Ryder, N. S.; Weiss, H. M.; Hook, D. F.;
Escalante, J.; Seebach, D. Chem. Biodivers. 2005, 2, 401.
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424.
(+)-(1R,2R)-23
Mp 103–105 °C; [a]D27 +45 (c 1.00, CHCl3).
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(–)-(1S,2S)-23
Mp 103–105 °C; [a]D27 –44 (c 0.52, CHCl3).
IR (KBr): 3372, 2989, 1702, 1527 cm–1.
1H NMR (CDCl3): d = 1.45 (s, 9 H, t-Bu), 1.79 (quint, J = 10 Hz, 1
H, H4), 2.20 (m, 3 H, H3, H4), 3.13 (q, J = 8.0 Hz, 1 H, H1), 4.10
(m, 1 H, H2), 5.05 (br s, 1 H, NH).
13C NMR (CDCl3): d = 18.6, 23.7, 28.2, 47.8, 48.7, 82.0, 157.3,
174.3.
HRMS (ESI): m/z [M + Na]+ calcd for C10H17NNaO4: 238.1065;
found: 238.1069.
( )-trans-2-Aminocyclobutanecarboxylic Acid [( )-trans-1]
To a soln of compound ( )-23 (0.220 g, 1.02 mmol) in anhyd
CH2Cl2 (2.5 mL) was added dropwise TFA (2.6 mL, 34.8 mmol).
The soln was stirred 30 min, then evaporated under reduced pres-
sure to afford a brown solid, which was dissolved in H2O. The soln
was deposited on a cation-exchange column (Dowex 50WX8-100,
H+, 50–100 mesh). The column was washed with H2O until the elu-
ent was neutral, then the product was eluted with 1 M NH4OH . Af-
ter pooling and evaporation of appropriate fractions, pure (+)-trans-
1 was obtained as a white solid (0.100 g, 88%); mp 151–154 °C;
Rf = 0.3 (PrOH–H2O, 9:1).
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(+)-(1S,2S)-1
Mp 152–154 °C; HPLC: tR = 12.5 min, >97% ee; [a]D27 +99 (c 0.39,
H2O).
(–)-(1R,2R)-1
Mp 152–154 °C; HPLC: tR = 19.3 min, >97% ee; [a]D27 –99 (c 0.52,
H2O).
IR (KBr): 3449, 2989, 1560, 1415 cm–1.
1H NMR (D2O): d = 1.90 (quint, J = 9.8, 1 Hz, 1 H, H4), 2.02
(quint, J = 9.2 Hz, 1 H, H4), 2.22 (q, J = 9.1 Hz, 2 H, H3), 3.13 (q,
J = 9.3 Hz, 1 H, H1), 3.88 (q, J = 8 Hz, 1 H, H2).
13C NMR (D2O): d = 19.8, 22.6, 45.7, 47.6, 180.4.
HRMS (ESI): m/z [M + H]+ calcd for C5H10NO2: 116.0712; found:
116.0719.
Acknowledgments
We thank Prof. B. Viossat and Dr. P. Lemoine, Université Paris V,
for performing the X-ray diffraction study. We are grateful for fun-
ding from the French Ministry for Research and Technology (grants
to C.F. and C.G.) and the French Ministry for Foreign Affairs (grant
to Y.Y.). We acknowledge the help of A. Job with some of the ex-
periments.
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Synthesis 2007, No. 14, 2222–2232 © Thieme Stuttgart · New York

2232
C. Fernandes et al.
FEATURE ARTICLE
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g = 120.00°, Z = 6, V = 1730.12 (16) Å3, rcalcd = 1.395 g/
cm–3. Full crystallographic data have been deposited with the
Cambridge Crystallographic Data Centre (CCDC) as
supplementary publication number CCDC 626949. Copies
of the data can be obtained free of charge on application to
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