β-Hydroxynorbornane amino acid derivatives: valuable synthons for the diastereoselective preparation of substituted cyclopentylglycine derivatives

Article abstract of DOI:10.1016/j.tet.2008.04.038

The behaviour towards the retro-aldol or retro-Dieckmann reactions of several norbornene and norbornane amino acids functionalized with an oxygen atom at C-β and characterized by different features, such as the substitution pattern and the constraints, was investigated. By C₂-C₃ disconnection new differently functionalized cyclopentenyl- and cyclopentylglycines were prepared. This synthetic approach allows to control the stereochemistry from two to four stereocentres depending on the starting norbornane derivative and affords, for each derivative, a couple of epimeric compounds at amino acid stereocentre. Depending on the features of the starting reagent and of the reaction conditions, a partial control of the stereochemistry of the amino acid carbon atom is also possible.

Full text of DOI:10.1016/j.tet.2008.04.038

Tetrahedron 64 (2008) 5657–5665
Contents lists available at ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
b-Hydroxynorbornane amino acid derivatives: valuable synthons for the
diastereoselective preparation of substituted cyclopentylglycine derivatives
*
Sara Pellegrino , Francesca Clerici, Maria Luisa Gelmi
`
`
Istituto di Chimica Organica ‘A. Marchesini’, Facolta di Farmacia, Universita di Milano, via Venezian 21, 20133 Milano, Italy
a r t i c l e i n f o
a b s t r a c t
Article history:
The behaviour towards the retro-aldol or retro-Dieckmann reactions of several norbornene and nor-
Received 18 January 2008
Received in revised form 26 March 2008
Accepted 10 April 2008
bornane amino acids functionalized with an oxygen atom at C-b and characterized by different features,
such as the substitution pattern and the constraints, was investigated. By C2–C3 disconnection new
differently functionalized cyclopentenyl- and cyclopentylglycines were prepared. This synthetic ap-
proach allows to control the stereochemistry from two to four stereocentres depending on the starting
norbornane derivative and affords, for each derivative, a couple of epimeric compounds at amino acid
stereocentre. Depending on the features of the starting reagent and of the reaction conditions, a partial
control of the stereochemistry of the amino acid carbon atom is also possible.
Available online 12 April 2008
Keywords:
Unnatural amino acids
Retro-Dieckmann
Stereochemistry control
Ó 2008 Elsevier Ltd. All rights reserved.
1. Introduction
Here we report the preparation of new functionalized cyclo-
The interest in cyclopentylglycine derivatives is well docu-
mented by recent literature1 and is related to their biological ac-
tivity, which is strictly dependent on the substitution pattern on the
cyclopentyl ring.
pentenyl- and cyclopentylglycines, such as the epimeric 4-carboxy-
cyclopentylglycines 9 and 10 (Scheme 3), functionalized with two
protected hydroxy groups, the derivatives 18 and 19 (Scheme 5) in
which the cyclopentylglycine scaffold is included in an heterocyclic
system, and the hydroxymethyl-cyclopent-2-enylglycines 22
and 23 (Scheme 6), which are valuable synthons for further
functionalizations.
These compounds are of particular biological interest because
hydroxylated cyclopentylglycines can be considered carbasugar
amino acids: molecules mimicking the furanose skeleton and
containing the amino acid function.4 The presence of the hydroxy
groups, involved into hydrogen bonds, favours the interaction with
the bioactive site. Furthermore, the insertion of a carbasugar amino
acid moiety in bioactive peptides leads to peptidomimetics with
improved stability towards metabolic degradation.5
Recently, we reported a very efficient method to prepare the
above amino acid using an innovative procedure, which comprised
the combination of the Diels–Alder and the retro-aldol or retro-
Dieckmann reactions.2,3 As shown in the retro-synthetic Scheme 1,
both 3-formylcyclopent-3-enylglycines (R¼H; see Scheme 6 for
details, compounds 20,21), and 3-carboxy-cyclopentylglycines
(R¼OH; see Scheme 7 for details, compounds 25,26) were prepared
using as key starting materials for their preparation the 2-amino-3-
hydroxy-norbornene-2-carboxylic acid derivatives exo-1 and endo-
2 obtained in excellent yield both in racemic and enantiopure form
through a Diels–Alder reaction.
Concerning their synthesis, it should be pointed out that
the match polyfunctionalized norbornane compounds and the
retro-condensation reaction are an useful way to synthesize new
hetero-functionalized cyclopentylglycines with control of the ste-
reochemistry of different centres (from two to four stereocentres),
which were generated in an unambiguous, stereochemically de-
fined manner. During these studies it was shown that the result of
the retro-condensation reaction is strictly dependent both on the
features of the starting norbornane derivative, mainly the presence
of substituents influencing its stiffness, and on the reaction con-
ditions, which influence the distribution of the epimers generated
by disconnection of the C2–C3 bond in the retro-condensation
reaction.
EtO2C
NHCOPh
CO2Et
NHCOPh
X
Y
COR
exo-1: X = H, Y = OCO2Et
endo-2: X = OCO2Et, Y = H
R = H, OH
Scheme 1. Retrosynthesis of cyclopentyl and cyclopentenyl derivatives.
* Corresponding author.
E-mail address: sara.pellegrino@unimi.it (S. Pellegrino).
0040-4020/$ – see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2008.04.038

5658
S. Pellegrino et al. / Tetrahedron 64 (2008) 5657–5665
R
O
O
RO2C
R
RO2C
iv
R
O
O
PhCONH
R
S
PhCONH
a: 91%
b: 85%
O
HO
exo-8a,b
exo-7a,b
a: 94%
b: 95%
iii
7
10
4
1
7
O
OH
RO2C
ii
i
RO2C
6
6
RO2C
PhCONH
2
8
O
5
OH
4
3
PhCONH
1
9
PhCONH
2
OCO2Et
OCO2Et
OCO2Et
exo-3a,b
a: 89%
b: 91%
a: 92%
b: 89%
exo-5a,b
exo-1a,b
O
S
R NHCOPh
OCO2Et
SCO2R
HO
HO
NHCOPh
OCO2Et
CO2R
NHCOPh
ii
i
O
S
OCO2Et
94%
S
85%
R
CO2R
endo-6a
endo-4a
endo-2a
iii
R: a = Et
R: b = (-)-8-Ph-menthyl
NO REACTION
Scheme 2. Preparation of dihydroxy norbornane derivatives 8. Reagents and conditions: (i) OsO4, NMO, acetone/H2O; (ii) DMP, p-TSA, THF; (iii) EtOH, Na2CO3,
D; (iv) CH2Cl2,
PCC.
2. Results
Norbornene derivatives exo-1 and endo-2 are the starting ma-
The fact that the choice of the base can induce a different dis-
tribution of the two epimers has already been observed2 in similar
cases (see Scheme 7 and discussion).
terials for the preparation of the new cyclopentylglycine derivatives
9, 10, 18, 19, 22 and 23.
It was possible to isolate the major stereoisomer 9a (58%) by
crystallization from the enriched mixture of epimers obtained us-
ing pyridine. Instead, enantiopure compounds 9b and 10b could
not be separated as such. This target was achieved by transforming
the acids 9b and 10b into the corresponding methyl esters (þ)-11
and (þ)-12 (99%) using trimethylsilyldiazomethane (Scheme 3).
The above epimers were separated by column chromatography and
characterized by NMR spectroscopic analyses. The absolute con-
figurations (3aS,4R,6R,6aR) and (3aS,4R,6R,6aR) were given to epi-
mers 11 and 12, respectively, considering that the configuration of
all stereocentres in the starting ketone was unequivocally assigned
and that in the retro-condensation reaction only the C2–C3 bond
was broken. In particular, the cis configuration of the carbon groups
linked to the cyclopentyl ring in both compounds 11 and 12 was
assured by the mechanism of retro-Dieckmann reaction. The
As depicted in Scheme 2, compound exo-1a was transformed
into the diol derivative exo-3a (92%) by reaction with catalytic os-
mium tetroxide in the presence of N-methylmorpholine-N-oxide
(NMO) in a mixture of acetone/H2O.6 The enantiopure diol (ꢀ)-exo-
3b (89%) was also prepared from (ꢀ)-exo-1b3 according to the
above procedure. The hydroxy groups, cis to the carbon of the
bridge, were protected using 2,2-dimethoxypropane (DMP) in
the presence of catalytic p-toluenesulfonic acid. Acetals exo-5a
and (þ)-exo-5b were isolated in 89% and 91% yields, starting from
exo-3a and (ꢀ)-exo-3b, respectively. Following the same synthetic
protocol, it was possible to prepare endo-6a (80%, overall yield)
from endo-2a, through intermediate endo-4a.
In order to remove the carbonate function, derivatives exo-5a,b
and endo-6a were then treated with Na2CO3 in EtOH. None of these
compounds reacted at room temperature but operating at reflux
the hydroxynorbornanes exo-7a and (ꢀ)-exo-7b were formed from
compounds exo-5a,b (a: 4 h, 94%; b: 4 h, 95%). Instead, endo-6a did
not react confirming the lower reactivity of this group when it is
located in the exo position.2
The hydroxy group in compounds exo-7a,b was oxidized using
PCC in CH2Cl2 at room temperature and the keto derivatives exo-
8a (91%) and (ꢀ)-exo-8b (85%) were formed. By applying the
base-induced retro-Dieckmann reaction, the ketones exo-8a and
exo-8b were transformed into the racemic epimeric glycines 9a
and 10a and the enantiopure epimers 9b and 10b, respectively.
Ketones exo-8 were made to react both with a mixture of pyri-
dine/water at reflux and with a mixture of acetone and DMF
(9:1) using NaHCO3 as the base. The distribution of compounds 9
and 10 was strictly dependent on the choice of the base. The use
of pyridine gave a mixture of 9a,10a (87%) and 9b,10b (83%) in
a 2:1 ratio (HPLC analyses), the major isomer 9 having the R
RO2C
H
NHCOPh
H
NHCOPh
CO2R
O
RO2C
H
H
O
O
O
O
i or ii
O
+
PhCONH
O
i, a: 87%
b: 89%
ii, a: 98%
b: 40%
H
CO2H
H
CO2H
9a,b
exo-8a,b
10a,b
iii
R = (-)-8-Ph-menthyl
RO2C
99%
a: R = Et
b: R = (-)-8-Ph-menthyl
NHCOPh
S NHCOPh
H
R
H
6a
CO2R
H
H
R
O
O
O
6
R
R
5
+
2
4
O
3a
S
H
CO2Me
H
CO2Me
(+)-11
(+)-12
configuration at the
a-amino acid centre. Instead, the use of
NaHCO3 produced a 1:1 mixture of epimers (9a,10a: 98%; 9b,10b:
Scheme 3. Retro-Dieckmann reaction. Reagent and conditions: (i) Py, H2O, reflux; (ii)
40%).
NaHCO3, acetone, DMF, reflux; (iii) (CH3)3SiCHN2, MeOH.

S. Pellegrino et al. / Tetrahedron 64 (2008) 5657–5665
5659
configuration of the two hydroxy groups in compounds 11,12 is
trans with respect to the other substituent. The NOESY experiment
7.99) and the carbonate group (
15 (mixture with 17) showed spatial proximity between H-3
d
¼4.35, 1.22). NOESY experiment on
on 12 showed spatial proximity between H-5 (
with aliphatic protons of Ph-menthyl) and H-3a (
¼4.32) indicating the cis relationship between these three pro-
d
¼1.63, overlapped
(
d
¼5.02–4.98) and H-9y (
d
¼1.46), and between H-10 ( ¼4.64) and
d
d
¼4.73) and H-6a
H-9x
(d
¼1.76) indicating the endo stereochemistry of the hydroxy
(d
group. The change of stereochemistry of C-10 in compound 16 was
confirmed by NOESY experiment. Of relevance, it was observed the
spatial proximity between H-10 (
between H-3 (
¼4.85–4.81) and H-9y (
imity between H-10 and H-9x
tons. Spatial proximity between H-6a and H-6 (
d
¼2.17, overlapped
with H-50) was not observed proving that H-6a and H-6 are trans.
Furthermore, compounds 11 and 12 showed the typical signals of
d
¼3.78) and endo H-2 ( ¼1.08),
d
d
d
¼1.6) and no spatial prox-
NH (11:
(11:
d
¼6.75, d, J¼8.7 Hz; 12:
d
¼6.61, d, J¼7.7 Hz) and of CH-
(
d
¼2.34). 1H NMR spectrum of
a
d
¼4.84, dd, J¼8.7, 5.0 Hz; 12:
d
¼4.02, dd, J¼7.4, 6.7 Hz). As
compound 17 (mixture with 15) showed a signal at
d¼5.28 corre-
demonstrated for cyclopentylglycine derivatives synthesized pre-
sponding at H-2, which has an Overhauser effect with H-10x
¼1.57). H-8 resonates at ¼4.24 which, in the NOESY experiment,
showed spatial proximity with H-10y (
¼1.57), indicating the endo
viously in our laboratory,2 the stereochemistry of epimeric carbon
(d
d
is correlated to NH and CH-
coupling constant (1H NMR experiment). The R epimers are char-
acterized by signals associated to NH and CH- protons at lower
a
chemical shift as well as to their
d
stereochemistry of the hydroxy group. The assigned structure 17,
containing the oxazoline ring, was confirmed by the chemical shift
of H-2, which is at lower field with respect to the same proton on
oxazine derivatives 13–16. Furthermore, the 13C NMR analyses
revealed, as significant differences, the chemical shifts of the C-4
and of the quaternary phenyl carbon, which are at lower and at
a
field with respect to those of the S epimers. Furthermore, R epimers
possess a bigger NH–CHa and a smaller CHa–CH coupling constant
values with respect to those of the S ones. On the basis of this
consideration, the (3aS,4R,6R,6aR,10R) and (3aS,4R,6R,6aR,10S) ab-
solute configurations were assigned to epimers 11 and 12,
respectively.
Norbornane derivative 14, containing the oxazine ring, was
prepared via iodooxazine 13 obtained in quantitative yield from
compound exo-1a and N-iodosuccinimide (NIS) in the presence of
catalytic bis-dibutylchlorotin oxide in CH2Cl2 at room temperature.
Iodine was easily removed by treating compound 13 with (n-
Bu)3SnH in CH2Cl2 at reflux and compound 14 (87%) was isolated
(Scheme 4).
The deprotection of the hydroxy group in oxazine 14 with
Na2CO3 in EtOH was difficult. It did not occur at room temperature
and required prolonged heating. Interestingly, the 1H NMR spec-
troscopic analysis of the crude reaction mixture revealed the
formation of different compounds. In particular, trace amounts of
signals corresponding to the aldehyde proton are present, and as
main compounds, a mixture of epimeric hydroxynorbornanes 15
and 16 besides the dihydrooxazole derivative 17 (1:1:3 ratio). The
reaction mixture was chromatographed but only compound 16 was
isolated in pure form. Every attempt to separate oxazoline 17 from
oxazine 15 failed. NOESY experiment on 13 showed spatial prox-
higher field, respectively (17: C-4,
bon, ¼154.3, quaternary phenyl carbon,
¼126.9; 13: C-5,
14: C-5, ¼134.0; 15: C-5,
¼154.2, quaternary phenyl carbon,
¼156.5, quaternary phenyl carbon, ¼133.4; 16: C-5, ¼153.1,
quaternary phenyl carbon,
¼133.7).
d
¼167.7, quaternary phenyl car-
d
d
d
¼133.2;
d
d
d
d
d
d
These results suggest that, after deprotection of O-10, a retro-
aldol condensation first occurred giving the intermediate A from
which the two epimeric 10-hydroxy compounds 15 and 16 were
formed by a new condensation reaction. This behaviour had never
been observed in the case of less constrained norbornanes and
suggests that the strain generated by the oxazine ring favours the
retro-condensation reaction and that the protonation process of
anionic intermediate A is slower with respect to the condensation
process. Oxazoline 17 derives from 15 through an intramolecular
reaction of OH-10 at C-5 affording the stable oxazoline ring. Aiming
to verify these hypotheses, both pure 16 and the mixture of 15/17
were treated with Na2CO3 in EtOH at reflux for 24 h. The TLC and 1H
NMR spectroscopic analyses of the crude reaction mixtures
revealed the presence of the three compounds, as well as of the
proton associated to the aldehydes (trace amount), thus confirming
that an equilibrium exists between these compounds.
imity between H-10 (
¼5.29–5.25) and H-9y
matic protons (
d
¼5.52) and H-9x
(
d
¼2.24), between H-3
(d
(d
¼2.15) and, interestingly, between aro-
Clearly, the oxazoline derivative 17, which is the main com-
pound, is not useful in the retro-condensation reaction. The above
epimerization suggested that we prepare directly the new cyclo-
pentenylglycine derivatives 18 and 19 using a ‘one-pot’ reaction
consisting in the deprotection of O-10 (hydroxy compounds 15 and
16), the retro-condensation reaction and the direct reduction of the
aldehyde function. The reaction was successfully performed start-
ing from 14 operating in EtOH at reflux in the presence of Na2CO3
and NaBH4 (4 equiv). The new epimeric derivatives 18 and 19, in
d
¼8.01–7.98) and the carbonate group ( ¼4.2, 1.20)
d
confirming the stereochemistry assigned to C-3 and C-10. The exo
stereochemistry of iodine substituent was assured by the fact that
H-2 (
d
¼4.30–4.05) has no Overhauser effect with H-9y.
As a confirmation of the above assigned stereochemistry, NOESY
experiment on parent compound 14 showed spatial proximity
between H-10 (
4.79) and H-9y
d
¼5.57) and H-9x
(
d
¼2.03), between H-3 ( ¼4.88–
d
(d
¼1.48), and between aromatic protons (
d
¼8.01–
9
I
2
1
10CO2Et
OCO2Et
CO2Et
i
ii
iii
CO2Et
OCO2Et
NHCOPh
3
100%
8
87%
80%
7
N
OCO2Et
O
O
N
5
exo-1a
Ph
13
Ph
14
R*
R*
S*CO2Et
OH
CHO
CO2Et
S*
R* OH
CO2Et
CO2Et
O
R*
+
+
R*
NR*
R*
R* R*
N
O
N
OH
O
N
O
Ph
Ph
Ph
15
Ph
16
17
A
Scheme 4. Preparation of oxazine norbornane derivatives. Reagents and conditions: (i) NIS, bis-dibutylchlorotin oxide, CH2Cl2; (ii) (n-Bu)3SnH, CH2Cl2, reflux; (iii) Na2CO3, EtOH,
reflux.

5660
S. Pellegrino et al. / Tetrahedron 64 (2008) 5657–5665
CH2OH
CO2Et
CO2Et
OCO2Et
O
i
A
80%
N
O
N
O
N
EtO2C
O
CO2Et
H H
N
H
H
H
H
H
Ph
14
Ph
CH2O
H
H
2
H
1
B
H
CH2OH
H
H
4
5
H
H
3 H
H
22
23
3
H
2
H
4
Ph
Ph
N
N
CO2Et
CO2Et
H
5
Figure 1. Conformation of compounds 22 and 23 according to NOESY experiments.
S*
R*
1
O
O
4a
H
R* R*
7a
+
6
7
R*
which reacted slower (7 h) with respect to the exo adduct, or from
the mixture exo-1a, endo-2a. This synthetic method is comple-
mentary to the treatment of compound exo-1a with Na2CO3 in
EtOH at reflux,2 which allowed the preparation of 3,4-cyclo-
pentenylglycines 20 and 21 (Scheme 6) in which conjugation of the
double bond to the formyl group occurred.
H
CH2OH
H
CH2OH
18
19
Scheme 5. Synthesis of epimeric 6-hydroxymethyl-hexahydro-cyclopenta[e][1,3]-
oxazine-4-carboxylic acid derivatives 18 and 19. Reagents and conditions: (i) Na2CO3,
NaBH4, EtOH, reflux.
The new compounds are characterized by a cis relationship be-
tween the two carbon residues and are epimers at the amino acid
stereocentre (Fig.1). The stereochemistry of amino acid stereocentre
on 22 and 23 was tentatively assigned by NOESY experiments. Of
which the cyclopentylglycine skeleton is included in a heterocyclic
system, were obtained in 80% yield (Scheme 5). The reaction is
highly stereoselective and occurred with control of the stereo-
chemistry of three stereocentres and with a partial control of the
amino acid stereocentre. Isomer 19 is the more abundant (18/19,
1:4). The epimers were separated by column chromatography, and
were characterized by NMR spectroscopic techniques. 1H NMR
relevance for compound (1S
observed between OH (
¼2.36) and both NH (
protons of phenyl group (
¼7.84–7.80) demonstrating their spatial
proximity. No NOE effect was evidenced between H-1 (
¼3.48–3.40)
and H-4 (
¼2.94–2.90) thus confirming the conformation assigned
to this molecule. H-
¼4.85) showed spatial proximity with the
protons of olefin ( ¼1.71–1.52. The
¼5.75–5.69) but not with H-5 at
positive Overhauser effect between H-5 at
¼1.71–1.52 and NH, and
proton at
¼3.64–3.61 of CH2OH group confirm the cis relationship
between this proton and the two carbon residues. As a consequence
the chemical shift assigned to the parent proton H-5 is
¼2.18–2.06.
The conformation of epimer (1S ,4R )-23 is slightly different
,10S
with respect to 22, since NOE effects were observed between H-4
¼3.00–2.95) and H-1 ( ¼3.46–3.43, weak), H-2 ( ¼5.73–5.69,
weak) and H-3 ( ¼4.80) showed spatial
¼5.90–5.87, strong). H-
proximity with both H-2 (weak) and H-5 (
¼1.62–1.53, strong).
Proton H-5, trans to the carbon residues, resonates at
¼2.39–2.28.
Spatial proximity was found between NH (
¼6.83) and H-2, H-5
(weak). Of relevance the Ph protons do not have spatial proximity
with OH (
*
,4R
*
,10R
*
)-22, an Overhauser effect was
d
d¼7.65) and ortho
d
d
spectrum of 18 showed a signal at
7a. Spatial proximity was observed between H-7a and H-4 (
d, J¼4.9 Hz), H-4a ( ¼2.74–2.70), H-7 ( ¼2.21–2.14), and H-6
¼2.46–2.35, weak), thus confirming the stereochemistry assigned
to the molecule. Methylene protons of CH2OH resonate at
¼3.50
and have a strong Overhauser effect with H-7 (
¼1.93) and H-5
¼1.37–1.32) demonstrating their cis relationship. From these data
we can postulate that the stereochemistry assigned to compound
18 is (4R ,4aR ,6R ,7aR
). 1H NMR spectrum of compound 19 shows
a signal at
¼4.68 (br s) corresponding to H-7a. H-4 resonates at
d
¼4.69 (br s) corresponding at H-
d
d
¼4.56,
a (d
d
d
d
d
(d
d
d
d
d
(d
d
*
*
*
*
*
*
*
d
(d
d
d
d
¼4.33 (s). No spatial proximity was observed between H-7a and
d
a (d
H-4. H-5 (
d
¼1.2) has a positive NOE effect with H-4 and H-7 ( ¼
d
d
1.9). Methylene protons of CH2OH resonate at 3.54 and have
Overhauser effect with H-5 (
¼2.20) and H-7. From these data we
can postulate that the stereochemistry assigned to compound 19 is
(4S ,4aR ,6R ,7aR ).
Considering this positive result, the above synthetic protocol
d
d
d
*
*
*
*
d¼1.62–1.53).
Having the results related to the synthesis of a series of cyclo-
pentenyl- and cyclopentylglycines obtained from the trans-
(NaBH4, 4 equiv; EtOH, 25 ꢁC, 4 h) was applied to exo-1a. As
expected, epimeric 4-hydroxymethyl-2,3-cyclopenten-2-ylglycines
22 and 23 were isolated in good yields (90%) and in a 1:1 ratio
(Scheme 6). The same result was achieved starting from endo-2a,
formation of several
b-oxygen-substituted norbornene and
norbornane amino acids characterized by different features and
substitution pattern, some considerations can be made relating to
the retro-condensation reactions also including results concerning
the already reported retro-condensation reactions on exo-1 and
keto compound exo-243 (see Scheme 7). The reactivity of the car-
bonate group in the endo position is higher than when it is located
in position exo (Schemes 2 and 6) thus confirming our previous
results.2,3 The retro-aldol reaction does not occur starting from 3-
hydroxy-norbornane compounds (see Ref. 2 and Scheme 2) except
when a further constraint is present on the ring. This is the case of
oxazine derivatives (see Schemes 4 and 5) where the epimerization
reaction at the oxygen-substituted carbon was observed indicating
that this process is operative. The presence of sp2 carbon atoms in
the ring increases the strain too, thus favouring the retro-aldol
process. In fact, depending on the reaction conditions, the direct
formation of cyclopentenylglycines 20,21 or 22,23 was observed
during the deprotection of 3-ethoxycarbonyloxy-derivatives exo-1
and endo-2 containing the double bond in the norbornane skeleton
(Scheme 6). Instead, the dioxolane ring does not seem to produce
sufficient strain (Scheme 2, compounds 7). As a result, the retro-
aldol condensation does not occur.
EtO2C
H
NHCOPh
S*NHCOPh
H
R*CO2Et
H
H
CO2Et
OCO2Et
NHCOPh
+
i
CHO
CHO
80%
exo-1a
21
20
+
OCO2Et
NHCOPh
ii
90%
NHCOPh
EtO2C
H
S*
R*CO2Et
H
CO2Et
endo-2a
H
NHCOPh
H
S*
R*
S*
R*
+
H
CH2OH
H
CH2OH
23
22
Scheme 6. Preparation of epimeric 4-hydroxymethyl-cyclopenten-2-ylglycines.
Reagents and conditions: (i) Na2CO3, EtOH, reflux; (ii) NaBH4, EtOH, rt.

S. Pellegrino et al. / Tetrahedron 64 (2008) 5657–5665
5661
contrast, starting from ketone 8 (method B) a 1:1 mixture of
epimers was formed. The increase of the isomer in which in-
tramolecular protonation occurred (corresponding to retention of
configuration, via intermediate D) balances the competitive pro-
tonation of the less hindered face in the intermediate C giving a 1:1
ratio of the two epimers.
X
RO2C
X
PhCONH
O
exo-8,24
i or ii
A similar stereochemical behaviour was observed starting from
the phenylmenthyl derivative exo-8b. These results show that the
(ꢀ)-8-phenylmenthyl chiral auxiliary does not induce asymmetric
protonation of the enolate intermediate.
As reported before, the stereochemical outcome observed
starting from oxazine derivative 14 gave (10S)-19 as the major
isomer, the epimer in which a retention of configuration was ob-
served. Our interpretation is that the structure of the carbanion
intermediate B (Scheme 5), containing the hydroxymethyl group, is
similar to the starting norbornane even if the C2–C3 bond is dis-
connected and that an intramolecular protonation occurs affording
the S epimer as the main compound.
Concerning the cyclopentenylglycines 22 and 23, as observed for
the parent compounds 21,22, no control in the formation of amino
acid stereocentre was found and this can probably be ascribed to
the formation of an unsaturated enolate intermediate like C.
OR
NHCOPh
-O
RO2C
PhCONH
X
H
X
X
-CO2
X
H
O
O-
O
H
CO2H
O
D
C
-CO2
NHR1
RO2C
H
S
R
H
CO2R
NHR1
H
3. Conclusion
H
X
X
X
+
In conclusion, we have demonstrated that the norbornene and
norbornane amino acid derivatives functionalized with an oxygen
atom at C-b are valuable key reagents for the preparation of func-
X
H
CO2H
9,25
H
CO2H
8,9,10: X = OC(Me)2O
24,25,26: X = H
10,26
tionalized cyclopentenyl- and cyclopentylglycine derivatives char-
acterized by a various substitution pattern on the ring by the way of
a retro-aldol or retro-Dieckmann reaction. In particular, the ring
strain and the substitution pattern on the norbornane ring
Scheme 7. Mechanism of retro-Dieckmann reaction. Reagents and conditions: (i)
Py/H2O; (ii) NaHCO3, acetone/DMF.
The possibility to induce the cleavage of the C2–C3 bond is fav-
oured in the presence of the keto function at C-3. The retro-Die-
ckmann reaction is operative in the case of compounds 8 as well as
observed for the unsubstituted keto amino acid 24 (Scheme 7).
The distribution of epimeric products formed in the retro-con-
densation reaction depends on the features, the substitution pat-
tern of the starting material and the reaction conditions. This aspect
is intriguing since the stereochemical result observed in the
formation of compounds 9,10 from exo-8 ring differs from that
observed starting from exo-24 from which unsubstituted 3-car-
boxycyclopentylglycines 25 and 26 have been obtained. The data of
the retro-Dieckmann reaction both starting from exo-8 and from
exo-24 are summarized in Table 1 and a rationalization of the ste-
reochemical results is proposed.
In principle, two intermediates could be involved in the retro-
Dieckmann reaction: the enolate ester C and the monoester of
carbonic acid D, when hydrogen carbonate was used as base
(Scheme 7). Intermediate C was symmetrically protonated (method
A), thus giving a 1:1 mixture of epimers 25 and 26 when starting
from unsubstituted keto compound 24. Instead, starting from 8
(method A), containing the oxolane ring, the protonation of enolate
C probably occurs from the less hindered face and the (10R)-9 epi-
mer was formed as the main compound. When method B was used,
an opposite stereochemical result was observed. Starting from 24,
through the intermediate D, the epimer (10S)-26 was formed as the
main compound by the way of an intramolecular protonation to the
amino acid carbon atom when the C2–C3 bond was broken. In
play
a pivotal role in this last reaction. The new epimeric
(1R,2S,3R,4R,10R)- and (1R,2S,3R,4R,10S)-4-(amino-carboxylmethyl)-
2,3-dihydroxycyclopentanecarboxylic acid derivatives9a,b and 10a,b
and the new epimeric (4R
*
,4aR
*
,6R
*
,7aR
*
)- and (4S
*
,4aR
*
,6R
*
,7aR )-6-
*
hydroxymethyl-hexahydro-cyclopenta[e][1,3]oxazine-4-carboxylic
acid derivatives 18 and 19 were prepared controlling unequivocally
the stereochemistry of four and three stereocentres, respectively. A
partial control of the stereochemistry of the amino acid carbon atom
is also possible. Finally, the new 4-hydroxymethyl-cyclopent-2-
enylglycines 22 and 23 were also efficiently prepared, which are
valuable synthons for further functionalizations.
4. Experimental section
4.1. General remarks
Melting points were measured with a Bu¨chi B-540 heating unit.
1H NMR spectra were recorded on 200 or 500 MHz spectrometers.
TLC analyses were performed on ready-to-use silica gel plates.
Column chromatography was performed on silica gel [Kieselgel 60
70–230 mesh ASTM] with the solvents indicated. IR spectra were
taken with a FTIR spectrophotometer. exo-1a,b,2,3 endo-2a,2 exo-3a6
and endo-4a6 are known compounds.
4.2. (L)-8-Phenylmenthyl (1R,2R,3S,4R,5S,6R)-
2-benzoylamino-3-ethoxycarbonyloxy-5,6-
dihydroxybicyclo[2.2.1]eptane-2-carboxylate (exo-3b)
Table 1
Stereochemical data for the retro-Dieckmann reaction
Compound exo-1b (559 mg, 1 mmol) was suspended in a mix-
ture of acetone/H2O (10:1, 11 mL). After addition of N-methyl-
morpholine-N-oxide (400 mg, 3.42 mmol) and OsO4 (6.84 mg,
0.02 mmol) the solution turned brown. The reaction mixture was
stirred at room temperature for 2 h, then the solvent was evapo-
rated. The crude reaction mixture was taken up with a solution of
Reagent
Products
R/S ratioa (yield)
R/S ratiob (yield)
exo-8
exo-24
9a,10a
25,26
A, 2:1 (87%)
A, 1:1 (83%)2
B, 1:1 (98%)
B, 1:2 (75%)2
a
Py/H2O, D.
NaHCO3, acetone/DMF (9:1), D.
b

5662
S. Pellegrino et al. / Tetrahedron 64 (2008) 5657–5665
Na2S2O4 (20%, 12 mL) and extracted with AcOEt/THF (1:1, 24 mL).
The organic layer was then washed with a solution of HCl (10%,
20 mL) and dried over Na2SO4. After crystallization from i-Pr2O,
5.67 (d, J¼1.9 Hz, 1H, H-9), 4.40–4.02 (m, 6H, H-2, H-6, OCH2CH3),
2.53 (s, 1H, H-1), 2.47 (s, 1H, H-7), 2.09 (AB system, J¼12.4 Hz, 1H,
H-10),1.97 (AB system, J¼12.4 Hz,1H, H-10),1.44 (s, 3H, Me),1.42 (s,
3H, Me), 1.23 (t, J¼7.3 Hz, 3H, OCH2CH3), 1.14 (t, J¼7.3 Hz, 3H,
pure compound exo-3b (546 mg, 92%) was obtained. Mp 127 ꢁC;
25
[
a
]
ꢀ5 (c 1, CHCl3); IR (Nujol) nmax 3380,1750,1625 cmꢀ1; 1H NMR
OCH2CH3); 13C NMR (CDCl3):
d
¼170.0, 168.0, 154.0, 133.7, 132.0,
D
(CDCl3):
d
¼7.62–7.08 (m, 10H, Ar), 6.53 (s, 1H, exch., NH), 5.11 (d,
128.8, 127.3, 110.6, 77.8, 77.3, 75.9, 66.1, 64.3, 62.1, 49.2, 48.1, 30.2,
27.1, 25.5, 24.3, 14.4, 14.3. Anal. Calcd for C23H29NO8: C, 61.73; H,
6.53; N, 3.13. Found: C, 61.56; H, 6.71; N, 3.00.
J¼4.4 Hz, 1H, H-3), 4.90–4.70 (m, 1H, CHO-Phenylmenthyl), 4.21 (q,
J¼7.0 Hz, 2H, OCH2CH3), 4.09 (AB system, J¼5.9 Hz, 1H, H-5), 3.96
(AB system, J¼5.9 Hz, 1H, H-6), 2.98 (br s, 1H, H-1), 2.90–2.60 (br s,
2H, exch., OH), 2.45 (d, J¼4.0 Hz, 1H, H-4), 2.08–1.90 (m, 2H), 1.87
(d, J¼12.1 Hz, 1H), 1.60–0.70 (m, 7H), 1.28 (t, J¼7.0 Hz, 3H,
OCH2CH3), 1.12 (s, 3H, Me), 1.09 (s, 3H, Me), 0.84 (d, J¼6.2 Hz, 3H,
4.4. Ethyl (1S
*
,2S
*
,3S
*
,7R
*
,8R
*
,10S )-10-ethoxycarbonyloxy-2-
*
iodo-5-phenyl-4-oxa-6-aza-tricyclo[5.2.1.03,8]dec-5-ene-7-
carboxylate (13)
Me) ppm; 13C NMR (CDCl3):
d
¼170.8, 168.3, 153.6, 151.2, 133.4,
132.3, 128.9, 128.4, 127.3, 125.8, 125.5, 78.1, 76.7, 68.9, 67.4, 65.1,
62.2, 50.3, 50.2, 47.5, 41.3, 40.2, 34.7, 31.6, 28.1, 27.8, 27.4, 26.0, 22.0,
14.5 ppm. Anal. Calcd for C34H43NO8: C, 68.78; H, 7.30; N, 2.36.
Found: C, 68.55; H, 7.49; N, 2.21.
To a solution of exo-1a (2 g, 5.4 mmol) in CH2Cl2 (50 mL), NIS
(1.35 g, 6 mmol) and a catalytic amount of bis-dibutylchlorotin
oxide were added. The mixture turned purple and was left under
stirring for 2 h (TLC cyclohexane/EtOAc, 1:1). The solution was
washed with Na2S2O4 (5%, 2ꢂ10 mL) and water (10 mL). The or-
ganic layer was anhydrified over Na2SO4 and concentrated under
vacuum giving 13 in quantitative yield. Mp 109 ꢁC (CH2Cl2/i-Pr2O);
IR (Nujol) nmax 3051–2903, 1757, 1738, 1657 cmꢀ1; 1H NMR (CDCl3)
4.3. General procedure for the protection of dioles
Compound exo-3a,b or endo-4a (1.4 mmol) was dissolved in THF
(30 mL). 2,2-Dimethoxypropane (2.0 g, 16 mmol) and a catalytic
amount of p-toluenesulfonic acid were added. The reaction mixture
was stirred at room temperature for 2.5 h. (TLC: CH2Cl2/Et2O; 2:1).
The solvent was eliminated under vacuum, then CH2Cl2 (8 mL) was
added and the solution was washed with water (4 mL) and dried
over Na2SO4. After evaporation of the solvent, product exo-5 (a:
530 mg, 85%; b: 790 mg, 89%) orendo-6 (588 mg, 94%) was obtained.
d
¼8.01–7.98 (m, 2H, Ar), 7.84–7.43 (m, 3H, Ar), 5.52 (d, J¼4.0 Hz,1H,
H-10), 5.29–5.25 (m, 1H, H-3), 4.36–4.08 (m, 5H, H-2, OCH2CH3),
2.88 (d, J¼4.0 Hz, 1H, H-8), 2.26 (d, J¼4.8 Hz, 1H, H-1), 2.24–2.10 (m,
2H, H-9), 1.29 (t, J¼7.0 Hz, 3H, OCH2CH3), 1.20 (t, J¼7.0 Hz, 3H,
OCH2CH3); 13C NMR (CDCl3):
d¼173.0, 154.3, 153.5, 133.2, 131.4,
128.3, 127.9, 84.4, 78.7, 64.7, 62.2, 58.5, 49.7, 40.4, 31.4, 30.1, 24.6,
14.5. MS (ESI) 500.1 (MþH)þ. Anal. Calcd for C20H22INO6: C, 48.11;
H, 4.44; N, 2.81. Found: C, 48.00; H, 4.60; N, 2.61.
4.3.1. Ethyl (1R
*
,2S
*
,6R
*
,7R
*
,8R
*
,9S )-8-benzoylamino-9-
*
ethoxycarbonyloxy-4,4-dimethyl-3,5-dioxa-
4.5. Ethyl (1R
*
,3R
*
,7R
*
,8R
*
,10S )-10-ethoxycarbonyloxy-5-
*
tricyclo[5.2.1.02,6]decano-8-carboxylate (exo-5a)
phenyl-4-oxa-6-aza-tricyclo[5.2.1.03,8]dec-5-ene-7-
carboxylate 14
Mp 130 ꢁC (CH2Cl2/i-Pr2O/n-pentane); IR (Nujol) nmax 3370,1725,
1
1645 cmꢀ1
;
H NMR (CDCl3):
d
¼7.83–7.45 (m, 5H, Ar), 6.76 (s, 1H,
exch., NH), 5.18 (d, J¼4.8 Hz,1H, H-9), 4.48 (AB system, J¼5.1 Hz,1H,
H-2), 4.38 (AB system, J¼5.1 Hz, 1H, H-6), 4.35–4.16 (m, 4H,
OCH2CH3), 3.42 (br s, 1H, H-1), 2.74 (d, J¼4.1 Hz, 1H, H-7), 1.97 (AB
system, J¼12.1 Hz, 1H, H-10), 1.73 (AB system, J¼12.1 Hz, 1H, H-10),
1.47 (s, 3H, Me),1.37 (t, J¼7.3 Hz, 3H, OCH2CH3),1.28 (s, 3H, Me),1.23
To a solution of 13 (600 mg, 1.19 mmol) in anhydrous CH2Cl2
(6 mL), (n-Bu)3SnH was added (346 mg, 1.19 mmol) under nitrogen
atmosphere. The mixture was refluxed under stirring for 2 h and
further a drop of (n-Bu)3SnH was added (346 mg, 1.19 mmol). After
5 h the reaction was completed (TLC cyclohexane/EtOAc, 2:1). The
solution was concentrated under vacuum and after column chro-
matography (cyclohexane/EtOAc, 100:0–1:1) 14 (387 mg, 87%) was
obtained. Mp 117 ꢁC (CH2Cl2/i-Pr2O); IR (Nujol) nmax 3068–2873,
(t, J¼7.0 Hz, 3H, OCH2CH3); 13C NMR (CDCl3):
¼171.8, 167.7, 153.7,
d
133.9, 132.4, 129.1, 127.5, 109.5, 77.9, 77.2, 75.7, 65.5, 62.3, 61.8, 47.3,
44.7, 28.1, 25.8, 24.5,14.6,14.4. Anal. Calcd for C23H29NO8: C, 61.73; H,
6.53; N, 3.13. Found: C, 61.55; H, 6.70; N, 3.00.
1722, 1653 cmꢀ1
;
1H NMR (CDCl3):
d¼8.01–7.9 (m, 2H, Ar), 7.46–
7.28 (m, 3H, Ar), 5.57 (dd, J¼4.0, 2.2 Hz, 1H, H-10), 4.88–4.79 (m, 1H,
H-3), 4.36–4.07 (m, 4H, OCH2CH3), 2.57 (br s, 1H, H-1), 2.25 (d,
J¼4.0 Hz,1H, H-8), 2.15–2.03 (m, 2H, H-2, H-9), 1.73–1.48 (m, 2H, H-
2, H-9), 1.32 (t, J¼7.0 Hz, 3H, OCH2CH3), 1.22 (t, J¼7.0 Hz, 3H,
4.3.2. (ꢀ)-8-Phenylmenthyl (1R,2S,6R,7R,8R,9S)-8-benzoylamino-
9-ethoxycarbonyloxy-4,4-dimethyl-3,5-dioxa-
tricyclo[5.2.1.02,6]decane-8-carboxylate (exo-5b)
25
Oil; [
a
]
D
þ5.5 (c 1, CHCl3); IR (Nujol) nmax 3380, 1750,
OCH2CH3); 13C NMR (CDCl3):
d
¼173.7, 154.7, 154.2, 134.0, 130.9,
1625 cmꢀ1
;
1H NMR (CDCl3):
d
¼780–7.02 (m, 10H, Ar), 6.27 (s, 1H,
128.2,127.8, 79.4, 73.2, 64.3, 61.9, 60.1, 38.9, 38.0, 32.4, 31.5,14.5. MS
(ESI) 374.6 (MþH)þ. Anal. Calcd for C20H23NO6: C, 64.33; H, 6.21; N,
3.75. Found: C, 64.17; H, 6.39; N, 3.51.
exch., NH), 5.27 (d, J¼4.0 Hz, 1H, H-9), 4.90–4.77 (m, 1H, CHO-
Phenylmenthyl), 4.44 (AB system, J¼5.1 Hz, 1H, H-2), 4.27 (AB
system, J¼5.1 Hz, 1H, H-6), 4.24 (q, J¼7.4 Hz, 2H, OCH2CH3), 3.03 (br
s, 1H, H-1), 2.61 (d, J¼4.0 Hz, 1H, H-7), 2.20–1.90 (m, 2H), 1.73 (d,
J¼11.7 Hz, 1H), 1.60–0.75 (m, 7H), 1.60 (s, 3H, Me), 1.45 (s, 3H, Me),
1.28 (t, J¼7.4 Hz, 3H, OCH2CH3), 1.17 (s, 3H), 1.12 (s, 3H), 0.86 (d,
4.6. General procedure for the deprotection of the 3-hydroxy
group
J¼6.3 Hz, 3H) ppm; 13C NMR (CDCl3):
d
¼170.8, 167.6, 153.7, 151.6,
Compound exo-5a,b, endo-6a or 14 (1 mmol) was dissolved in
anhydrous EtOH (20 mL). Lyophilized Na2CO3 (1.2 mmol) was
added under stirring at reflux (TLC: CH2Cl2/Et2O, 10:1). Na2CO3 was
filtered over a Celite pad and the solvent was evaporated. Starting
from compound exo-5a,b after crystallization of the crude reaction
mixture, pure compound exo-7 (a: 530 mg, 94%; b: 356 mg, 95%)
was obtained. Instead starting from exo-14, a mixture of com-
pounds 15–17 (20:20:60, 240 mg, 80%) was formed. It is possible to
isolate compound 16 (50 mg, 17%) from 15,17 (150 mg, 50%) by
column chromatography (from cyclohexane to cyclohexane/EtOAc,
2:1). Instead endo-6a was recovered unreacted.
133.9, 132.1, 128.8, 128.4, 127.5, 125.8, 125.4, 109.3, 78.1, 77.5, 76.0,
75.7, 64.9, 62.1, 50.3, 46.9, 44.7, 41.2, 40.1, 34.7, 31.6, 27.5, 27.4, 27.2,
26.4, 25.6, 24.4, 22.0, 14.5 ppm. Anal. Calcd for C37H47NO8: C, 70.12;
H, 7.47; N, 2.21. Found: C, 70.00; H, 7.60; N, 2.01.
4.3.3. Ethyl (1R
*
,2S
*
,6R
*
,7R
*
,8S
*
,9R )-8-Benzoylamino-
*
9-ethoxycarbonyloxy-4,4-dimethyl-3,5-dioxa-
tricyclo[5.2.1.02,6]decano-8-carboxylate (endo-6a)
Mp 83 ꢁC (cyclohexane); IR (Nujol) nmax 3344, 1747, 1643 cmꢀ1
;
1H NMR (CDCl3):
d¼7.76–7.40 (m, 5H, Ar), 6.18 (s, 1H, exch., NH),

S. Pellegrino et al. / Tetrahedron 64 (2008) 5657–5665
5663
4.6.1. Ethyl (1R
*
,2S
*
,6R
*
,7R
*
,8R
*
,9S
*
)-8-Benzoylamino-9-hydroxy-
solution was stirred at room temperature for 3 h (TLC: cyclohexane/
AcOEt, 1:1). The reaction mixture was filtered through a silica gel
column (CH2Cl2/Et2O, 10:1). Keto compound exo-8 (a: 508 mg, 91%;
b: 317 mg, 85%) was obtained after crystallization.
4,4-dimethyl-3,5-dioxa-tricyclo[5.2.1.02,6]decano-8-carboxylate
(exo-7a)
Mp 176 ꢁC (Et2O); IR (Nujol) nmax 3280, 1715, 1630 cmꢀ1 1H
;
NMR (CDCl3):
d
¼7.84–7.43 (m, 5H, Ar), 7.15 (s, 1H, exch., NH), 4.60
(AB system, J¼6.1 Hz, 1H, H-2), 4.36 (AB system, J¼6.1 Hz, 1H, H-6),
4.48–4.39 (m, 1H, H-9), 4.28–4.14 (m, 2H, OCH2CH3), 3.84 (d,
J¼4.8 Hz,1H, exch., OH) 3.28 (br s, 1H, H-1), 2.54 (d, J¼4.4 Hz,1H, H-
7), 1.87 (AB system, J¼11.7 Hz,1H, H-10), 1.56 (AB system, J¼11.7 Hz,
1H, H-10), 1.47 (s, 3H, Me), 1.28 (s, 3H, Me), 1.22 (t, J¼6.9 Hz, 3H,
4.7.1. Ethyl (1R
*
,2S
*
,6R
*
,7R
*
,8R )-8-benzoylamino-9-oxo-4,4-
*
dimethyl-3,4-dioxa-tricyclo[5.2.1.02,6]decano-8-carboxylate (exo-
8a)
Mp 175 ꢁC (i-Pr2O); IR (Nujol) nmax 3400, 1765, 1725, 1674 cmꢀ1
;
1H NMR (CDCl3):
d
¼7.83–7.40 (m, 5H, Ar), 6.56 (s, 1H, exch., NH),
OCH2CH3); 13C NMR (CDCl3):
d¼172.9, 167.7, 133.6, 132.0, 128.7,
4.48 (AB system, J¼5.5 Hz, 1H, H-2), 4.38 (AB system, J¼5.5 Hz, 1H,
H-6), 4.31–4.16 (m, 2H, OCH2CH3), 3.69 (s, 1H, H-7), 2.96 (s, 1H, H-
1), 2.43–2.33 (br s, 2H, H-10), 1.52 (s, 3H, Me), 1.30 (s, 3H, Me), 1.24
127.2, 108.9, 77.5, 75.4, 73.4, 61.9, 61.7, 46.9, 46.1, 27.6, 25.5, 24.2,
14.2. Anal. Calcd for C20H25NO6: C, 63.99; H, 6.71; N, 3.73. Found: C,
64.03; H, 6.81; N, 3.50.
(t, J¼7.0 Hz, 3H, OCH2CH3); 13C NMR (CDCl3):
¼206.5, 168.2. 166.4,
d
133.2, 132.6,128.9,127.4, 111.5, 78.6, 78.0, 68.6, 63.0, 54.7, 48.3, 28.3,
25.5, 24.5, 14.2. Anal. Calcd for C20H23NO6: C, 64.33; H, 6.21; N, 3.75.
Found: C, 64.21; H, 6.40; N, 3.73.
4.6.2. (ꢀ)-8-Phenylmenthyl (1S,2S,6R,7R,8R,9S)-8-Benzoylamino-
9-hydroxy-4,4-dimethyl-3,5-dioxa-tricyclo[5.2.1.02,6]decane-8-
carboxylate (exo-7b)
25
Mp 253 ꢁC (i-Pr2O); [
a
]
þ60 (c 1, CHCl3); IR (Nujol) nmax 3360,
4.7.2. (ꢀ)-8-Phenylmenthyl (1R,2S,6R,7R,8R)-8-benzoylamino-9-
D
1733, 1640 cmꢀ1; 1H NMR (CDCl3):
d
¼7.76–7.10 (m, 10H, Ar), 6.06 (s,
oxo-4,4-dimethyl-3,5-dioxa-tricyclo[5.2.1.02,6]decane-8-carboxylate
1H, exch., NH), 4.83–4.70 (m, 1H, CHO-Phenylmenthyl), 4.59 (AB
system, J¼5.5 Hz,1H, H-2), 4.24 (AB system, J¼5.5 Hz, 1H, H-6), 4.42
(br s, 1H, H-9), 2.74 (br s, 1H, H-1), 2.70 (br s, 1H, exch., OH), 2.46 (d,
J¼4.4 Hz, 1H, H-7), 2.20–0.80 (m, 10H), 1.46 (s, 3H, Me), 1.30 (s, 3H,
(exo-8b)
25
Mp 260 ꢁC (i-Pr2O); [
a
]
D
þ30 (c 1, CHCl3); IR (Nujol) nmax 3400,
1765, 1725, 1674 cmꢀ1
;
1H NMR (CDCl3):
d
¼7.74–7.06 (m, 10H, Ar),
6.34 (s, 1H, exch., NH), 5.00–4.90 (m,1H, CHO-Phenylmenthyl), 4.46
(AB system, J¼5.1 Hz, 1H, H-2), 4.39 (AB system, J¼5.1 Hz, 1H, H-6),
3.47 (br s, 1H, H-7), 2.84 (br s, 1H, H-1), 2.18 (d, J¼8.4 Hz, 1H), 2.15–
1.89 (m, 2H),1.70–0.80 (m, 7H),1.49 (s, 3H, Me),1.27 (s, 3H, Me),1.17
(s, 6H, Me), 0.86 (d, J¼6.6 Hz, 3H, Me) ppm; 13C NMR (CDCl3):
Me), 1.22 (s, 3H, Me), 1.11 (s, 3H, Me), 0.88 (d, J¼6.3 Hz, 3H, Me); 13
C
NMR (CDCl3):
d
¼172.0, 169.6, 152.2, 134.0, 132.2, 128.8, 128.3, 127.5,
125.7, 125.4, 109.1, 77.6, 77.3, 75.6, 73.0, 63.0, 50.1, 47.6, 46.1, 41.4,
39.9, 34.8, 31.5, 28.1, 27.1, 26.9, 25.7, 25.6, 24.4, 22.0. Anal. Calcd for
C
34H43NO6: C, 72.70; H, 7.72; N, 2.49. Found: C, 72.59; H, 7.97; N,
d
¼205.4, 167.6. 166.4, 151.0, 133.3, 132.4, 128.8, 128.5, 127.5, 125.7,
2.57.
125.6 111.3, 78.9 78.5, 78.0, 68.5, 55.1, 50.1, 48.6, 41.9, 40.2, 34.5,
31.6, 28.0, 27.9, 27.3, 26.0, 25.5, 24.5, 21.9 ppm. Anal. Calcd for
4.6.3. Ethyl (1R
*
,3R
*
,7R
*
,8R
*
,10S
*
)-10-Hydroxy-5-phenyl-4-oxa-6-
C34H41NO6: C, 72.96; H, 7.38; N, 2.50. Found: C, 72.84; H, 7.58; N,
2.30.
aza-tricyclo[5.2.1.03,8]dec-5-ene-7-carboxylate (15)
Mixture with 17; 1H NMR (CDCl3):
d
¼8.02–8.01 (m, 2H, Ar),
7.47–7.37 (m, 3H, Ar), 5.02–4.98 (m, 1H, H-3), 4.64 (br s, 1H, H-10),
4.31–4.18 (m, 2H, OCH2CH3), 2.61 (br s, 1H, exch., OH), 2.48 (d,
J¼4.4 Hz, 1H, H-8), 2.40 (br s, 1H, H-1), 2.10–1.31 (m, 7H, H-2, H-9,
4.8. General procedure for the retro-Dieckmann reaction on
ketones 8a,b
OCH2CH3); 13C NMR (CDCl3):
d
¼173.9, 156.5, 133.4, 131.6, 129.0,
Method a. Pure ketone exo-8a or exo-8b (1 mmol) was dissolved
in pyridine (3 mL) and H2O (1.5 mL). The reaction mixture was
heated at reflux for 3 h (TLC: CH2Cl2/Et2O, 2:1). The solvent was
evaporated and the residue was taken up with a HCl solution (10%,
20 mL), which was then extracted with a mixture of THF/AcOEt
(8 mL, 1:1). The organic layer was separated and dried over Na2SO4
giving a mixture of the two epimeric acids 9 and 10 (2:1, a: 500 mg,
87%; b: 320 mg, 83%). HPLC analyses of mixture 9,10a was per-
formed using a Licrosphere RP 18 column (12 cmꢂ4.6 mm, H2O/
MeCN 70:30, pH¼4, 0.8 mL/min; 9a: tR¼7.9 min; 10a: tR¼8.8 min).
The crystallization of the mixture of acids 9,10a from CH2Cl2/i-Pr2O
gave pure major diastereomer 9a (330 mg, 58%). Any attempt to
separate epimers 9,10b failed. Method b. NaHCO3 (46 mg,
0.55 mmol) was suspended in a mixture of acetone (4 mL) and DMF
(0.4 mL). The solution was heated at reflux under nitrogen and then
the ketone exo-8a or exo-8b (0.5 mmol) was added. Heating was
continued for 12 h (TLC: CH2Cl2/Et2O, 2:1). The solvent was evap-
orated and the crude reaction mixture was taken up with an
aqueous solution of HCl (10%, 7 mL) and the solution was extracted
with a mixture THF/EtOAc (5 mL, 1:1). The organic layer was
washed with brine (2ꢂ5 mL) and dried over Na2SO4 giving a mix-
ture of the two diastereomeric acids 9 and 10 (1:1, a: 230 mg, 98%;
b: 385 mg, 40%).
127.9, 87.0, 76.0, 74.3, 61.4, 40.3, 38.0, 32.3, 30.1, 14.6.
4.6.4. Ethyl (1R
*
,3R
*
,7R
*
,8R
*
,10R )-10-hydroxy-5-phenyl-4-oxa-6-
*
aza-tricyclo[5.2.1.03,8]dec-5-ene-7-carboxylate (16)
Mp 188 ꢁC (AcOEt/hexane); IR (Nujol) nmax 3415, 1728,
1652 cmꢀ1; 1H NMR (CDCl3):
d
¼7.96–7.92 (m, 2H, Ar), 7.46–7.34 (m,
3H, Ar), 4.85–4.81 (m, 1H, H-3), 4.30–4.24 (m, 2H, OCH2CH3), 3.78
(br s,1H, H-10), 3.23 (br s,1H, exch., OH), 2.58 (d, J¼3.2 Hz,1H, H-8),
2.36 (AB system, J¼11.1 Hz, 1H, H-9), 1.60 (AB system, J¼11.1 Hz, 1H,
H-9), 2.34–2.23 (m, 2H, H-2, H-1), 1.61–1.05 (m, 4H, H-2, OCH2CH3);
13C NMR (CDCl3):
d
¼172.1, 153.1, 133.7, 131.1, 128.9, 127.8, 85.2, 73.1,
69.7, 61.8, 40.3, 36.5, 36.3, 34.3, 14.7. MS (ESI) 324.3 (MþNa)þ. Anal.
Calcd for C17H19NO4: C, 67.76; H, 6.36; N, 4.65. Found: C, 67.74; H,
6.48; N, 4.43.
4.6.5. Ethyl (1R
aza-tricyclo[5.2.1.02,6]dec-4-ene-6-carboxylate (17)
Mixture with 15; 1H NMR (CDCl3):
*
,2S
*
,6R
*
,7R
*
,8R )-8-hydroxy-4-phenyl-3-oxa-5-
*
d¼8.02–8.01 (m, 2H, Ar),
7.57–7.37 (m, 3H, Ar), 5.28 (d, J¼4.5 Hz, 1H, H-2), 4.31–4.18 (m, 3H,
H-8, OCH2CH3), 3.85 (d, J¼11.3 Hz, 1H, exch., OH), 3.08 (br s, 1H, H-
7), 2.74 (br s, 1H, H-1), 2.10–1.31 (m, 7H, H-2, H-9, OCH2CH3); 13C
NMR (CDCl3):
d
¼172.0, 167.8, 132.9, 129.2, 129.0, 126.9, 87.0, 83.4,
74.9, 62.3, 49.3, 42.0, 33.7, 29.0, 14.6.
4.8.1. (3aS
*
,4R
*
,6R
*
,6aR
*
,10R
)-6-(Benzoylamino-ethoxycarbonyl-
*
4.7. General procedure for the oxidation reaction
methyl)-2,2-dimethyl-tetrahydro-cyclopenta[1,3]dioxole-4-
carboxylic acid 9a
Operating under nitrogen atmosphere, PCC (1.3 g, 6 mmol) was
Mp 165 ꢁC (CH2Cl2/i-Pr2O); IR (Nujol) nmax 1730, 1636 cmꢀ1 1H
;
added to pure exo-7a,b (1 mmol) dissolved in CH2Cl2 (10 mL). The
NMR (CDCl3):
d
¼7.82–7.38 (m, 5H, Ar), 6.94 (d, J¼8.4 Hz, 1H, exch.,

5664
S. Pellegrino et al. / Tetrahedron 64 (2008) 5657–5665
NH), 4.98 (dd, J¼8.1, 6.1 Hz, 1H, H-
a
), 4.80–4.59 (m, 2H, H-3a, H-6a),
(CDCl3):
d
¼173.7, 170.8, 167.4, 151.8, 134.3, 132.0, 128.8, 128.3, 127.4,
4.26 (q, J¼7.0 Hz, 2H, OCH2CH3), 3.50 (br s, 1H, exch.), 3.00–2.88 (m,
1H, H-4), 2.64–2.56 (m, 1H, H-6), 2.36–2.22 (m, 1H, H-5), 1.98–1.81
(m, 1H, H-5), 1.49 (s, 6H, Me), 1.30 (t, J¼7.0 Hz, 3H, OCH2CH3) ppm;
125.6, 125.5, 114.0, 82.3, 81.7, 76.7, 53.7, 52.3, 50.8, 49.5, 48.7, 41.6,
39.7, 34.7, 33.1, 29.9, 29.0, 27.6, 26.7, 25.3, 22.0 ppm. Anal. Calcd for
C35H45NO7: C, 71.04; H, 7.67; N, 2.37. Found: C, 69.90; H, 7.80; N,
13C NMR (CDCl3):
d
¼177.7, 171.5, 167.7, 137.8, 132.2, 128.9, 127.4,
2.18.
113.5, 82.7, 82.2, 62.2, 53.5, 49.4, 48.6, 30.9, 27.7, 25.3, 14.3. Anal.
Calcd for C20H25NO7: C, 61.37; H, 6.44; N, 3.58. Found: C, 61.35; H,
6.59; N, 3.40.
4.10. Ethyl 6-hydroxymethyl-2-phenyl-4,4a,5,6,7,7a-
hexahydro-cyclopentane[1,3]oxazine-4-carboxylate (18,19)
4.8.2. (3aS
*
,4R
*
,6R
*
,6aR
*
,10S
)-6-(Benzoylamino-ethoxycarbonyl-
*
NaBH4 (10 mg, 0.25 mmol) and lyophilized Na2CO3 (50 mg,
0.47 mmol) were added to a solution of compound 14 (100 mg,
0.25 mmol) in EtOH (10 mL). The mixture was stirred at reflux for
2 h (TLC: cyclohexane/AcOEt, 2:1). Na2CO3 was filtered over a Celite
pad and the solvent was evaporated giving the mixture of epimers
18 and 19 (1:4, 60 mg, 80%). It is possible to separate compound 18
(10 mg,13%) from 19 (45 mg, 63%) by flash column chromatography
on silica gel (CH2Cl2/Et2O, 5:1).
methyl)-2,2-dimethyl-tetrahydro-cyclopenta[1,3]dioxole-4-
carboxylic acid 10a
Mixture with 9a; IR (Nujol) nmax 1740, 1650 cmꢀ1 1H NMR
;
(CDCl3):
d
¼7.82–7.38 (m, 5H, Ar), 7.02–6.96 (d, J¼7.4 Hz, 1H, exch.,
NH), 4.74–4.20 (m, 2H, H-3a, H-6a), 4.63 (t, J¼6.9 Hz,1H, H-
a
), 4.31–
4.20 (m, 2H, OCH2CH3), 3.00–2.24 (m, 3H, H-4, H-5, H-6), 2.00–1.79
(m, 1H, H-5), 1.49 (s, 6H, Me), 1.24 (m, 3H, OCH2CH3) ppm.
4.8.3. (3aS,4R,6R,6aR,10R)- and (3aS,4R,6R,6aR,10S)-6-
(Benzoylamino-(ꢀ)-phenylmenthoxycarbonyl-methyl)-2,2-
dimethyl-tetrahydro-cyclopenta[1,3]dioxole-4-carboxylic acids (9b)
and (10b)
4.10.1. Compound (4R
Mp 157 ꢁC (AcOEt/hexane); IR (Nujol) nmax 3461, 1725,
1650 cmꢀ1; 1H NMR (CDCl3):
*
,4aR
*
,6R
*
,7aR
*
)-18
d
¼8.01–7.94 (m, 2H, Ar), 7.44–7.30 (m,
3H, Ar), 4.69 (br s, 1H, H-7a), 4.56 (d, J¼4.9 Hz, 1H, H-4), 4.31–4.22
(m, 2H, OCH2CH3), 3.50 (d, J¼6.9 Hz, 2H, CH2OH), 2.97 (br s, 1H,
exch., OH), 2.74–2.70 (m, 1H, H-4a), 2.46–2.35 (m, 1H, H-6), 2.21–
2.14 (m, 1H, H-7), 1.95–1.83 (m, 2H, H-5, H-7), 1.37–1.32 (m, 1H, H-
Mixture of epimers; IR (Nujol) nmax 1740, 1650 cmꢀ1 1H NMR
;
(CDCl3):
d
¼7.82–7.08 (m, 20H, Ar), 6.65 (9b: d, J¼8.1 Hz, 1H, exch.,
NH), 6.64 (10b: d, J¼7.0 Hz, 1H, exch., NH), 4.97–4.60 (m, 6H), 4.32–
4.00 (m, 2H), 3.80–3.20 (br s, 2H, exch., OH), 3.00–2.78 (m, 2H),
2.70–2.56 (m, 1H), 2.33–0.83 (m, 39H), 1.50 (s, 3H, Me), 1.47 (s, 3H,
Me), 0.96 (d, J¼6.3 Hz, 3H, Me), 0.88 (d, J¼5.2 Hz, 3H, Me) ppm.
5), 1.30 (t, J¼6.9 Hz, 3H, OCH2CH3); 13C NMR (CDCl3):
¼172.2,
d
155.6, 133.8, 131.1, 129.1, 127.8, 79.4, 68.0, 61.4, 56.1, 39.8, 39.2, 36.0,
27.6, 14.7. MS (ESI) 326.4 (MþNa)þ. Anal. Calcd for C17H21NO4: C,
67.31; H, 6.98; N, 4.62. Found: C, 67.21; H, 7.17; N, 4.49.
4.9. General procedure for the esterification reaction
4.10.2. Compound (4S
Mp 177 ꢁC (AcOEt/hexane); IR (Nujol) nmax 3461, 1725,
1650 cmꢀ1; 1H NMR (CDCl3):
*
,4aR
*
,6R
*
,7aR
*
)-19
To a mixture of 9,10b (2:1, 100 mg, 0.2 mmol) in MeOH (6 mL),
(CH3)3SiCHN2 (2 M in Et2O, 1 mmol, 0.5 mL) was added. After stir-
ring under nitrogen for 30 min, the solvent was removed under
vacuum and a mixture 11,12 (2:1, 115 mg, 99%) was obtained.
Compound 11 (76 mg, 65%) was separated from 12 (38 mg, 32%) by
column chromatography (SiO2 deactivated with 1% TEA; hexane/
EtOAc, 9:1).
d
¼7.98–7.94 (m, 2H, Ar), 7.45–7.38 (m,
3H, Ar), 4.68 (br s, 1H, H-7a), 4.33 (s, 1H, H-4), 4.33–4.22 (m, 2H,
OCH2CH3), 3.54 (d, J¼6.9 Hz, 2H, CH2OH), 2.50–2.27 (m, 2H, H-4a,
H-6), 2.23–2.18 (m, 2H, H-5, H-7), 1.97–1.82 (m, 1H, H-7), 1.73 (br s,
1H, exch., OH),1.30 (t, J¼6.9 Hz, 3H, OCH2CH3), 1.25–1.19 (m, 1H, H-
5); 13C NMR (CDCl3):
d
¼172.9, 156.5, 139.0, 131.1, 129.0, 128.4, 127.8,
76.5, 68.0, 61.74, 57.4, 39.3, 38.9, 36.1, 31.4, 14.6. MS (ESI) 326.4
(MþNa)þ. Anal. Calcd for C17H21NO4: C, 67.31; H, 6.98; N, 4.62.
Found: C, 67.17; H, 7.15; N, 4.52.
4.9.1. Methyl (3aS,4R,6R,6aR,10R)-6-(benzoylamino-phenyl-
menthoxycarbonyl-methyl)-2,2-dimethyl-tetrahydro-
cyclopenta[1,3]dioxole-4-carboxylate (11)
25
Oil; [
a]
þ6 (c 1, CHCl3). IR (Nujol) nmax 1760, 1680 cmꢀ1
;
1H
D
NMR (CDCl3):
d
¼7.85–7.08 (m, 10H, Ar), 6.75 (d, J¼8.7 Hz, 1H, exch.,
4.11. Ethyl benzoylamino-(4-hydroxymethyl-cyclopent-2-
enyl)-acetate (22 and 23)
NH), 4.98–4.91 (m, 1H, CHO-Phenylmenthyl), 4.84 (dd, J¼8.7,
5.0 Hz, 1H, H
a
), 4.69 (dd, J¼6.4, 4.8 Hz, 1H, H-3a), 4.60 (dd, J¼6.4,
4.4 Hz, 1H, H-6a), 3.72 (s, 3H, OCH3), 2.95–2.91 (m, 1H, H-4), 2.72–
2.69 (m, 1H, H-6), 2.25–2.19 (m, 1H), 2.05–1.98 (m, 2H), 1.95–1.85
(m, 1H), 1.60–0.80 (m, 6H), 1.52 (s, 3H), 1.32 (s, 6H), 1.28 (s, 3H, Me),
NaBH4 (40 mg, 1 mmol) was added to a solution of compound
exo-1a or endo-2a (400 mg,1.2 mmol) in EtOH (40 mL). The mixture
was stirred at room temperature (TLC: cyclohexane/AcOEt, 2:1;
exo-1a: 4 h; endo-2a: 7 h). The solvent was evaporated giving the
epimers 22 and 23 (1:1 ratio). It is possible to separate compound
22 (160 mg, 44%) from 23 (140 mg, 40%) by flash column chroma-
tography on silica gel (cyclohexane/AcOEt 2:1).
0.89 (d, J¼6.3 Hz, 3H, Me) ppm; 13C NMR (CDCl3):
¼174.5, 170.0,
d
167.1, 150.3, 133.7, 131.8, 128.6, 128.0, 127.2, 125.5, 112.6, 83.3, 83.0,
77.3, 53.7, 52.2, 50.1, 50.0, 47.5, 41.6, 40.1, 34.3, 31.3, 29.5, 28.5, 27.5,
27.2, 25.3, 21.7 ppm. Anal. Calcd for C35H45NO7: C, 71.04; H, 7.67; N,
2.37. Found: C, 70.80; H, 7.80; N, 2.22.
4.11.1. Compound (1S
Mp 164 ꢁC (AcOEt/hexane); IR (Nujol) nmax 3306, 1731,
1644 cmꢀ1 1H NMR (CDCl3):
¼7.84–7.80 (m, 2H, Ar), 7.65 (d,
J¼6.8 Hz, 1H, exch., NH), 7.50–7.41 (m, 3H, Ar), 5.75–5.69 (s, 2H, H-
), 4.30–4.17 (m, 2H,
*
,4R
*
,10R
*
)-22
4.9.2. Methyl (3aS,4R,6R,6aR,10S)-6-(benzoylamino-
phenylmenthoxycarbonyl-methyl)-2,2-dimethyl-tetrahydro-
;
d
cyclopenta[1,3]dioxole-4-carboxylate (12)
25
Oil; [
a]
þ24 (c 1, CHCl3); IR (Nujol) nmax 1765, 1685 cmꢀ1
;
1H
3, H-2), 4.85 (dd, J¼6.8, 4.7 Hz, 1H, H-
a
D
NMR (CDCl3):
d
¼7.83–7.15 (m, 10H, Ar), 6.61 (d, J¼7.7 Hz, 1H, exch.,
OCH2CH3), 3.79–3.75 (m, 1H, CH2OH), 3.64–3.61 (m, 1H, CH2OH),
3.48–3.40 (m, 1H, H-1), 2.94–2.90 (m, 1H, H-4), 2.36 (br s, 1H, exch.,
OH), 2.18–2.06 (m, 1H, H-5), 1.71–1.52 (m, 1H, H-5), 1.32 (t, J¼7.1 Hz,
NH), 4.90–4.82 (m, 1H, H-Phenylmenthyl), 4.73 (dd, J¼7.3, 5.8 Hz,
1H, H-3a), 4.32 (dd, J¼7.2, 6.2 Hz, 1H, H-6a), 4.02 (dd, J¼7.0, 6.7 Hz,
1H, H
a), 3.72 (s, 3H, OCH3), 2.87–2.82 (m, 1H, H-4), 2.20–2.15 (m,
3H, OCH2CH3); 13C NMR (CDCl3):
d
¼172.3, 168.4, 136.1, 134.5, 133.2,
2H, H-5, H-6), 2.15–2.13 (m, 1H), 2.12–2.10 (m, 1H), 1.85–1.80 (m,
1H), 1.75–0.90 (m, 6H), 1.48 (s, 3H, Me), 1.35 (s, 3H, Me), 1.27 (s, 3H,
Me), 1.24 (s, 3H, Me), 0.88 (d, J¼6.8 Hz, 3H, Me) ppm; 13C NMR
131.8, 128.7, 127.7, 65.4, 61.7, 56.1, 47.9, 47.7, 26.3, 14.6. Anal. Calcd
for C17H21NO4: C, 67.31; H, 6.98; N, 4.62. Found: C, 67.15; H, 7.20; N,
4.40.

S. Pellegrino et al. / Tetrahedron 64 (2008) 5657–5665
5665
,10S
*
)-23
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4.11.2. Compound (1S
Mp 181 ꢁC (AcOEt/hexane); IR (Nujol) nmax 3306,1731,1644 cmꢀ1
1H NMR (CDCl3):
¼7.83–7.79 (m, 2H, Ar), 7.51–7.40 (m, 3H, Ar), 6.83
(d, J¼7.6 Hz,1H, exch., NH), 5.90–5.87 (m,1H, H-3), 5.73–5.69 (m,1H,
*
,4R
*
;
d
H-2), 4.80 (dd, J¼7.6, 4.5 Hz,1H, H ), 4.26 (q, J¼7.1 Hz, 2H, OCH2CH3),
a
3.67 (dd, J¼10.4, 5.1 Hz, 1H, CH2OH), 3.56 (dd, J¼10.4, 5.1 Hz, 1H,
CH2OH),3.46–3.43(m,1H, H-1), 3.00–2.95(m,1H, H-4),2.39–2.28(m,
1H, H-5), 1.62–1.53 (m, 2H, H-5, OH, 1H exch.), 1.33 (t, J¼7.1 Hz, 3H,
OCH2CH3); 13C NMR (CDCl3):
d¼172.2, 168.1, 136.1, 134.4, 132.1, 131.9,
128.9, 127.7, 66.2, 61.8, 55.9, 48.6, 47.9, 26.5, 14.6. Anal. Calcd for
17H21NO4: C, 67.31; H, 6.98; N, 4.62. Found: C, 67.25; H, 7.10; N, 4.50.
C
Acknowledgements
We thank Miur (PRIN 2005) for financial support.
Supplementary data
2. Clerici, F.; Gelmi, M. L.; Pellegrino, S.; Pilati, T. J. Org. Chem. 2003, 68, 5286–5291.
3. Caputo, F.; Clerici, F.; Gelmi, M. L.; Pellegrino, S.; Pilati, T. Tetrahedron: Asymmetry
2006, 17, 61–67.
4. (a) Rassu, G.; Auzzas, L.; Pinna, L.; Zambrano, V.; Zanardi, F.; Battistini, L.; Mar-
zocchi, L.; Acquatti, D.; Casiraghi, G. J. Org. Chem. 2002, 67, 5338–5342; (b)
Lastdrager, B.; Timmer, M. S. M.; van der Marel, G. A.; Overkleeft, H. S.; Over-
hand, M. J. Carbohydr. Chem. 2007, 26, 41–59.
Supplementary data associated with this article can be found in
the online version, at doi:10.1016/j.tet.2008.04.038.
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