A new efficient synthesis of enantiopure diastereomeric 3′-aminocyclopentylglycines

Article abstract of DOI:10.1016/j.tetasy.2008.01.022

A new synthesis of enantiopure (1′S,3′R,2R)- and (1′R,3′S,2R)-3′-aminocyclopentylglycines (-)-12a and (-)-12b was performed by taking advantage of (±)-2-amino-3-oxo-norbornane-2-carboxylic acid derivative exo-2 as the starting material. The use of an acylase from Aspergillus melleus in phosphate buffer allowed the 'one-pot' transformation of the β-ketoester (±)-exo-2 into 3′-carboxycyclopentylglycine (±)-3a and (±)-3b, via a retro-Dieckman reaction, which, by direct kinetic resolution, were isolated as compounds (-)-3a and (-)-3b. Starting from a mixture of (-)-3a and (-)-3b, enantiopure 3′-aminocyclopentylglycines (-)-12a and (-)-12b as well as differently substituted 3-amino derivatives were prepared efficiently using a very simple synthetic protocol that requires a single chromatographic purification.

Full text of DOI:10.1016/j.tetasy.2008.01.022

Available online at www.sciencedirect.com
Tetrahedron: Asymmetry 19 (2008) 584–592
A new efficient synthesis of enantiopure diastereomeric
30-aminocyclopentylglycines
Maria Luisa Gelmi, Francesca Clerici, Raffaella Gandolfi and Sara Pellegrino*
` `
Istituto di Chimica Organica ‘A. Marchesini’, Facolta di Farmacia, Universita di Milano, Via Venezian 21, I-20133 Milano, Italy
Received 21 December 2007; accepted 16 January 2008
Available online 5 February 2008
Abstract—A new synthesis of enantiopure (10S,30R,2R)- and (10R,30S,2R)-30-aminocyclopentylglycines (ꢀ)-12a and (ꢀ)-12b was per-
formed by taking advantage of ( )-2-amino-3-oxo-norbornane-2-carboxylic acid derivative exo-2 as the starting material. The use of
an acylase from Aspergillus melleus in phosphate buffer allowed the ‘one-pot’ transformation of the b-ketoester ( )-exo-2 into 30-carboxy-
cyclopentylglycine ( )-3a and ( )-3b, via a retro-Dieckman reaction, which, by direct kinetic resolution, were isolated as compounds
(ꢀ)-3a and (ꢀ)-3b.
Starting from a mixture of (ꢀ)-3a and (ꢀ)-3b, enantiopure 30-aminocyclopentylglycines (ꢀ)-12a and (ꢀ)-12b as well as differently substi-
tuted 3-amino derivatives were prepared efficiently using a very simple synthetic protocol that requires a single chromatographic
purification.
Ó 2008 Elsevier Ltd. All rights reserved.
1. Introduction
potential activity as antibiotic drug, an inhibitor of the bio-
synthesis of amino acid based siderophores.2 Amino acid 1,
functionalized at C-3 with a guanidino group, has been in-
serted into a peptide chain instead of the natural arginine
and tested in the prevention and treatment of conditions
characterized by abnormal thrombosis in mammals.3 Other
activities are reported such as the inhibitor activity
of metalloprotease4 and of influenza neuraminidase.5
Recently, functionalized 30-amino cyclopentylglycines were
tested as dipeptidyl peptidase IV inhibitors.6 Finally, many
efforts were devoted to the preparation of polyhydroxylat-
ed compounds, which mimics the sugar portion of poliox-
ines and nikkomicynes, compounds characterized by
antifungal activity.7
30-Aminocyclopentylglycine derivatives 1 (Fig. 1) are con-
strained amino acid in which both the skeleton of lysine
and ornithine are included.
NH2
CO2H
R2
NHR1
1
Figure 1. 30-Aminocyclopentylglycine derivatives.
Owing to the general biological importance of the amino
acids of class 1, we planned the preparation of a couple
of diastereomeric 30-aminocyclopentylglycines following a
different synthetic reaction path with respect to those
reported in the literature1,2,6,7a–c,8 by taking advantage of
the 3-oxygen substituted 2-amino-norbornane-2-carboxylic
acid derivatives. Recent studies in our group revealed that
norbornane amino acids are interesting key starting mate-
rials to obtain new constrained amino acids with control of
the stereochemistry of several centres.9 In particular, 3-hy-
droxy substituted compounds allowed us to synthesize two
epimeric cyclopentylglycine derivatives by disconnection of
the C2–C3 bond.9c
The interest towards these nonnatural amino acids is
related to their different biological activities depending on
the substitution pattern on the ring, on 30-amino group
and on the stereochemistry of the three stereocentres. As
examples, the inhibition of the NO-synthase enzymes
(NOS), responsible for the transformation of arginine into
citrulline,1 is reported for the above compound, where the
amino group was transformed into an amidino group. The
N-acetyl-N-hydroxyl derivative has been synthesized for its
*
Corresponding author. E-mail: sara.pellegrino@unimi.it
0957-4166/$ - see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetasy.2008.01.022

M. L. Gelmi et al. / Tetrahedron: Asymmetry 19 (2008) 584–592
585
Following this synthetic strategy, we planned the prepara-
tion of diastereomeric 30-aminocyclopentylglycines 12
starting from the 2-amino-3-oxo-norbornane-2-carboxylic
acid derivative 2. As shown in the retrosynthetic Scheme
1, by performing a retro-Dieckman reaction on ketone
( )-2, it is possible to obtain two 30-carboxycyclopentyl-
glycines 3 (see also Scheme 4), epimeric at the amino acid
Furthermore, by starting from racemic ( )-2, and using a
very efficient protocol consisting of a ‘one-pot’ retro-Dieck-
man reaction-chemoenzymatic resolution of each pair of
epimeric 3-carboxycyclopentylglicine derivatives, followed
by a ‘one-pot’ transformation of the 30-carboxylic acid
group into the amino one, enantiopure 30-aminocyclo-
pentylglycine derivatives were generated (Scheme 4).
stereocentre and characterized by
a cis-relationship
between the two carbon substituents on the ring. Their
transformation into the targeted compounds 12 can be
achieved by the way of a Curtius transposition.
It should be emphasized that the whole synthetic protocol
required only one chromatographic purification.
2. Results and discussion
NH2
CO2H
NHCOPh
CO2Et
The two epimeric cyclopentylglycines ( )-3a,b9b were the
key starting materials for the preparation of the corre-
sponding 30-amino compounds 12.
CO2Et
NHCOPh
O
A modified Curtius reaction was first used with the aim of
transforming the 30-carboxy group into the 30-amino one.
According to the Ninomiya method,10 acid 3a was made
to react with diphenylphosphoryl azide (DPPA) operating
in t-butanol and triethylamine. The reaction gave a mixture
of compounds in which urea 4a was the main product
(50%). The expected N-Boc-carbamate 5a was isolated in
only 5% yield (Scheme 2). In principle, starting from race-
mic compound 3a a mixture of diastereomers of symmetric
urea 4a was expected to be formed. Since any attempt to
NH2
12
CO2H
( )-2
3
Scheme 1. Retrosynthesis of 12.
The above transformation was efficiently realized without
isolation of the different intermediates obtaining both func-
tionalized or unfunctionalized derivatives at the 30-amino
group (Schemes 2, 3, 5, and 6).
EtO2C
H
EtO2C
CO2Et
EtO2C
NHCOPh
+
NHCOPh
PhCONH
S*
H
NHCOPh
H
H
R*
S*
DPPA, TEA
tBuOH, reflux
H NHCO2tBu
NHCONH
H CO2H
( )-4a
( )-5a
( )-3a
50 %
5 %
SOCl2 100%
EtO2C
H
EtO2C
H
EtO2C
H
NHCOPh
NaN3, Bu4NBr
NHCOPh
NHCOPh
H
H
H
CHCl3
toluene, 25 ˚C
25 ˚C
90 %
85 %
H CON3
H COCl
H NCO
( )-7a
( )-6a
( )-8a
CHCl3
EtOH
95 %
EtO2C
H
EtO2C
H
NHCOPh
H
NHCOPh
H
H NCO
H NHCO2Et
( )-8a
( )-9a
Scheme 2. Curtius transposition of 3a.

586
M. L. Gelmi et al. / Tetrahedron: Asymmetry 19 (2008) 584–592
NHCOPh
NHCOPh
NHCOPh
NHCOPh
R*CO2Et
H
H
H
H
H
CO2Et
H
CO2Et
H
CO2Et
H
SOCl2
R*
S*
+
NaN3, Bu4NBr
toluene, 25 ˚C
H CO2H
H CON3
H NHCON3
H COCl
( )-3b
( )-7b
( )-10
( )-6b
CHCl3, EtOH
25 ˚C
NHCOPh
NHCOPh
H
H
CO2Et
H
CO2Et
H
75 %
H NCO
H NHCO2Et
( )-9b
( )-8b
Scheme 3. Curtius transposition of 3b.
1
separate the isomers (HPLC technique) failed, and H and
13C NMR analyses presented unitary signals, we were
unable to determine if a single diastereomer or a mixture
of diastereomers was obtained.
the acidity of the medium, which probably catalyzed the
transformation of the acyl azide into isocyanate from
which, by addition of EtOH, the corresponding ethyl car-
bamate was formed.
The goal of the preparation of N-protected amino deriva-
tives was achieved performing the classical Curtius reaction
(Scheme 2). Since the intermediates of the above transfor-
mation were not stable and could not be isolated in pure
form, a step-by-step study was first carried out on the crude
reaction mixtures, characterizing all intermediates by IR
With the stability and reactivity of the above intermediates
established, we planned a very quick synthesis, without
purification and in some cases isolation of the intermedi-
ates testing the single transformation step by step with
IR and 1H NMR techniques starting from both 3a and 3b.
1
and H NMR analyses.
The ethyl carbamate 9a was obtained from 3a in 80% over-
all yield.
The reaction of acid 3a with thionyl chloride (10 °C, 2 h)
gave the corresponding acyl chloride 6a in quantitative
yields (IR: 1791 cmꢀ1, COCl; 1H NMR: d 3.32–3.25,
H-30). Any attempt to purify this compound gave the start-
ing material. According to a reported procedure,11 the
crude compound 6a was then treated with sodium azide
operating in a mixture of H2O/acetone at 0 °C; however,
these reaction conditions hydrolyzed the acyl chloride
group to the corresponding starting acid 3a. This problem
was overcome by operating under solid liquid phase trans-
fer catalysis conditions using anhydrous toluene, sodium
azide (1.1 equiv) and tetrabutylammonium bromide as
the catalyst, operating at 25 °C. Acyl azide 7a was obtained
from 6a after 4 h in 85% yield (crude compound). The
structure of the acyl azide was confirmed by IR
The same transformations were made for epimer 3b
(Scheme 3). According to the above procedure, acyl chlo-
ride 6b was first prepared, which was then transformed into
1
acyl azide 7b using NaN3 (1.1 equiv, 4 h). The H NMR
analysis revealed the presence of a mixture of compounds
corresponding to the expected acyl azide 7b (d 2.93–2.80,
H-30) together with isocyanate 8b (d 3.90–3.60, H-30) and
trace amounts of a new compound (d 6.0 d, J = 6.9 Hz,
exch.; d 4.18–4.03, H-30). The mixture was treated directly
with CHCl3 containing EtOH (12 h) to give complete trans-
formation of isocyanate 8b into ethyl carbamate 9b, which
was isolated in 75% overall yield after column chromato-
graphy A trace amount of byproduct 10 (5%) correspond-
ing to a carbamoylazide was also isolated.
1
(2163 cmꢀ1, CON3) and H NMR (d 2.99–2.83, H-30).
Interestingly, it was found that when 7a was stood in
CHCl3 (24 h), the acyl azide was not stable and was trans-
formed into the corresponding isocyanate 8a (90%, crude
With a good protocol to obtain the epimeric 30-aminocyclo-
pentylglycine derivatives in hand, we planned their prep-
aration in an enantiopure form. Recently, we reported on
the preparation of enantiopure 30-carboxy-cyclopentyl-
glycines 3 using an enzymatic resolution starting from
the corresponding racemic compounds.9b Acylase from
Aspergillus melleus is able to selectively hydrolyze the (S)-
enantiomer of both pure racemic substrates ( )-3a and
1
compound; IR: 2258 cmꢀ1; H NMR: d 3.97–3.88, H-30).
Instead, the use of CHCl3 stabilized with EtOH gave
the ‘one-pot’ transformation of the acyl azide 7a into the
ethyl carbamate 9a (12 h, 95%), via isocyanate 8a, which
could not be isolated. This behaviour can be ascribed to

M. L. Gelmi et al. / Tetrahedron: Asymmetry 19 (2008) 584–592
587
CO2Et
H
HO2C
H
EtO2C
H
PhCONH R
H
S NHCOPh
H
S*
NHCOPh
H
S
R
R
S
R*
S*
+
HO2C H
(-)-3a
H CO2H
(-)-11a
H CO2H
CO2Et
( )-3a
Acylase
phosphate
buffer
NHCOPh
O
NHCOPh
H
NHCOPh
NHCOPh
S
R
R*CO2Et
H
CO2Et
H
H
HO2C
( )-2
H
H
R*
S*
R
+
S
R
S
HO2C H
H CO2H
H CO2H
(-)-11b
( )-3b
(-)-3b
40%
45%
1. SOCl2
2. NaN3, Bu4NBr
toluene, 25 ºC
3. CHCl3, EtOH, 25 ºC
NHCOPh
CO2Et
H
CO2H
H
NH3+Cl-
PhCONH R
H
R
Cl-+H3N R
H
H
R
CO2Et
H
H
CO2H
H
6M HCl
95%
6M HCl
R
S
S
R
R
S
S
R
Δ
95%
Δ
H NHCO2Et
-Cl+H3N H
H NH3+Cl-
EtO2CNH H
(-)-9b
(-)-9a
(-)-12a
(-)-12b
35 %
38 %
Scheme 4. ‘One-pot’ retro-Dieckmann reaction/enzymatic resolution/Curtius transposition.
( )-3b to give bicarboxylic acid (ꢀ)-(1S)-12a and ester (ꢀ)-
(1R)-3a from ( )-3a and (ꢀ)-(1S)-12b and ester (ꢀ)-(1R)-
3b from ( )-3b with an ee >99% and 50% molar
conversion.
stood in CHCl3 stabilized with EtOH (12 h, 25 °C). The
corresponding ethyl carbamates 9a,b were formed and effi-
ciently separated by column chromatography. Compounds
(ꢀ)-9a and (ꢀ)-9b were isolated in pure form in 38% and
35% overall yields, respectively (Scheme 4).
Here, we report on an improvement of this enzymatic pro-
cedure using the same enzyme and, as a starting material
for this kinetic resolution, the b-ketoester ( )-exo-2 (2 g)
in the phosphate buffer (0.1 M, pH 7) was first trans-
formed, via a retro-Dieckman reaction, into the epimeric
mixture of ( )-3a and ( )-3b. Their direct enzymatic reso-
lution allowed us to obtain a mixture of esters (ꢀ)-3a and
(ꢀ)-3b and bicarboxylic acids (ꢀ)-11a and (ꢀ)-11b. Bi-
carboxylic acids 11 were easily separated from esters 3 by
crystallization in dichloromethane. The mother liquor
containing the mixture of esters (ꢀ)-3a and (ꢀ)-3b was iso-
lated in 45% yield and used for further transformation into
the 30-amino compounds (Scheme 4).
The hydrolysis of (ꢀ)-9a and (ꢀ)-9b with 6 M HCl at 90 °C
for 24 h afforded (ꢀ)-12a and (ꢀ)-12b in 95% yield. The 1H
NMR analysis of 12a (d 3.76, d, J = 7.6 Hz, H-2) revealed
the presence of a trace amount of a second epimer (95:5
ratio), deriving from partial epimerization at an amino acid
stereocentre. The same behaviour was observed when
starting from 12b (95:5 ratio; d 3.84, d, J = 6.2 Hz, H-2)
(Scheme 4).
Since carbamates and asymmetric ureas of cyclopentyl-
glycine derivatives are compounds of biological interest,6
we planned their preparation using the above synthetic
way, which represents a valuable and faster synthetic pro-
cedure with respect to those reported in the literature.
Starting from pure (ꢀ)-3a, the corresponding enantiopure
isocyanate 8a was obtained in 90%. Different selective
transformations of isocyanate were performed.
According to the above procedures, the mixture of enantio-
pure esters (ꢀ)-3a and (ꢀ)-3b was first transformed into the
acyl chlorides (compounds 6a,b). Their reaction with NaN3
(1.1 equiv, 3 h) afforded acyl azides 7a,b, which were then

588
M. L. Gelmi et al. / Tetrahedron: Asymmetry 19 (2008) 584–592
Its reaction with t-BuOH and in presence of a catalytic
amount of SnCl4 gave t-butylcarbamate (ꢀ)-5a (60%)
(Scheme 5).
Staudinger procedure12 using Bu3P in Et2O operating at
room temperature for 6 h. The corresponding urea (ꢀ)-15
was isolated in 73% yield (Scheme 6).
When isocyanate 8a was made to react with the p-methoxy-
benzylamine, the asymmetric urea (ꢀ)-13a was isolated in
80% yield (Scheme 5).
NHCOPh
NHCOPh
R
R
H
H
CO2Et
CO2Et
H
H
Finally, the transformation of isocyanate group in the free
amine was studied. Compound 8a was treated with pyri-
dine (1 equiv) in water. The reaction is very fast (10 min),
and urea 4a was isolated in 70% yield (Scheme 5). The
NMR spectra of enantiopure compound 4a are superim-
posable to those of 4a prepared as reported in synthetic
Scheme 2.
NaN3 (3 eq.)
SOCl2
R
R
(-)-3b
S
S
Bu4NBr
toluene, 25 ˚C
80%
H NHCON3
H CO2Cl
6b
(+)-10
Bu3P
Et2O,
73%
Instead, when the reaction was performed in CHCl3 and in
the presence of p-toluensulfonic acid (1 equiv), p-toluen-
sulfonate (+)-14a was formed in quantitative yield from
enantiopure 8a (Scheme 5).
then H2O
NHCOPh
R
H
CO2Et
H
Furthermore, it is possible to obtain the free amino acid
(ꢀ)-12a (95%), via direct hydrolysis of isocyanate 8a with
6 N HCl at reflux.
R
S
H NHCONH2
Since the transformation of racemic acyl chloride 6b in the
presence of NaN3 gave the functionality as a byproduct, we
evaluated the possibility of increasing the yield of com-
pound 10. Enantiopure acyl chloride 6b, obtained from
(ꢀ)-3b, was made to react with an excess of NaN3 (3 equiv)
in toluene in the presence of a catalytic amount of TBABr
(25 °C, 12 h). The purification of the crude reaction mix-
ture by chromatography on silica gel gave carbamoylazide
(+)-10 (80%). Its reduction was performed according to
(-)-15
Scheme 6. Synthesis of ureido derivative (ꢀ)-15.
It should be noted that when starting from epimer 3a and
using an excess of NaN3 (3 equiv), the formation of the
corresponding carbamoyl azide was never detected by
NMR. It can be concluded that isocyanate 8b is more reac-
tive with respect to isocyanate 8a.
CO2H
H
CO2Et
H
-Cl+H3NR
tBuOH, SnCl4
PhCONH R
Δ
6M HCl,
H
H
60%
95%
S
R
S
R
-Cl+H3N H
tBuO2CNH H
(-)-5a
(-)-12a
1. SOCl2
2. NaN3, Bu4NBr
toluene, 25 ºC
CO2Et
H
CO2Et
H
CO2Et
H
PhCONH R
PhCONH R
H
R
PhCONH
H
H
pMeOC6H4CH2NH2
3. CHCl3, 25 ºC
S
R
S
R
S
R
87 %
90%
pMeOC6H6CH2NHOCNH H
OCN H
HO2C H
(-)-3a
8a
(-)-13a
CO2Et
H
EtO2C
H
CO2Et
H
PhCONH R
RNHR RNH R
H
H
H
pTSA,THF
Py, H2O
, 70%
S
R
S
R
S
R
25 ºC, 85%
Me
25 ºC
-
+H3N H
SO3
H NH
HN H
O
(+)-14a
4a:R = PhCO
Scheme 5. Synthesis of 30-amino derivatives.

M. L. Gelmi et al. / Tetrahedron: Asymmetry 19 (2008) 584–592
589
3. Conclusions
under nitrogen. A catalytic amount of TBABr (20 mg,
0.063 mmol) and NaN3 (55 mg, 0.75 mmol) was added to
the solution, which was stirred at room temperature for
3 h (1H NMR and IR analyses). The reaction mixture
was taken up in H2O (5 mL) and the phases were sepa-
rated. The aqueous solution was extracted with AcOEt
(3 ꢁ 10 mL) and the combined organic layers were dried
over Na2SO4. After evaporation of the solvent, crude acyl
azide 7a and/or 7b was obtained. The residue was taken up
with CHCl3 stabilized with EtOH (10 mL) and the mixture
was stirred for 12 h (TLC: cyclohexane/AcOEt, 1:1). The
solvent was removed under vacuum and the crude mixture
was purified by flash chromatography (cyclohexane/
AcOEt, 2:1) to obtain pure compound 9 [from 3a, 9a
(180 mg, 80%); from mixture (ꢀ)-3a/(ꢀ)-3b, 9a (85 mg,
38%) and 9b (80 mg, 35%) from pure 3b, 9b (170 mg,
75%)]. Trace amount of 10 (10 mg, 5%) was detected when
9b was prepared (see below).
In conclusion, the synthesis of a series of diastereomeric 30-
amino cyclopentylglycine derivatives was performed start-
ing from 2-amino-3-oxo-norbornane-2-carboxylic acid
derivative ( )-exo-2 taking advantage of the retro-Dieck-
man and Curtius reactions as key steps. Even if different
synthetic steps are involved in the synthesis of amino acids
12, the whole synthetic procedure does not require the iso-
lation of the intermediates and a single chromatographic
purification step is needed to separate the mixture of
diastereomers.
4. Experimental
4.1. General
Melting points were measured with a Buchi B-540 heating
¨
unit and are uncorrected. H NMR spectra were recorded
1
4.3.1. Ethyl (10S,30R,2R)-2-benzoylamino-(30-chlorocar-
bonyl-cyclopentyl)-acetate 6a. Crude compound. IR (Nu-
jol) mmax 1791, 1731, 1640 cmꢀ1; 1H NMR (CDCl3) d 7.84–
7.40 (m, 5H), 6.77 (d, J = 8.0 Hz, 1H, exch.), 4.90 (dd,
J = 8.0, 5.5 Hz, 1H), 4.24 (q, J = 7.0 Hz, 2H), 3.32–3.25
(m, 1H), 2.62–2.55 (m, 1H), 2.21–1.56 (m, 6H), 1.31 (t,
J = 7.0 Hz, 3H).
on 200 or 500 MHz spectrometers. Thin Layer Chromato-
graphy (TLC) analyses were performed on ready-to-use
silica gel carbamoyl azide 10, which could be transformed
into the corresponding urea derivative by reduction of
the azido plates. Column chromatography was performed
on silica gel [Kieselgel 60–70 230 ASTM] with the solvents
indicated. IR spectra were taken with a FT-IR spectro-
photometer. If not specified, ethanol free CHCl3 was used
in all experiments. Compounds 2, (ꢀ)-3a and (ꢀ)-3b are
known compounds.9b
4.3.2. Ethyl (10R,30S,2R)-2-benzoylamino-(30-chlorocar-
bonyl-cyclopentyl)acetate 6b. Crude compound. IR (Nu-
jol) mmax 1790, 1728, 1640 cmꢀ1 1H NMR (CDCl3) d
;
7.81–7.40 (m, 5H), 6.73 (d, J = 8.5 Hz, 1H, exch.), 4.90
(dd, J = 8.5, 6.2 Hz, 1H), 4.26 (q, J = 7.4 Hz, 2H), 3.35–
3.20 (m, 1H), 2.59–2.42 (m, 1H), 2.32–1.52 (m, 6H), 1.30
(t, J = 7.4 Hz, 3H).
4.2. ‘One-pot’ retro-condensation reaction/enantiomer
resolution
Ketone ( )-exo-2 (2 g, 6.65 mmol) was suspended in phos-
phate buffer (400 mL, 0.1 M, pH 7) and Acylase from A.
melleus (10 g/L) was added. The biotransformation system
was incubated at 30 °C with magnetic stirring. After 48 h
(HPLC analysis: Chiralcel OD column, hexane/i-PrOH/
TFA: 85:15:1, flow: 0.5 mL/min, k = 230 nm), the reaction
mixture was extracted with ethyl acetate. The aqueous
phase was treated with 5% HCl (pH 2) and extracted with
a mixture of ethyl acetate/THF (1:1, 3 ꢁ 20 mL). All the
combined organic phases were dried over Na2SO4 and
the solvent removed under vacuum. A mixture of com-
pounds (ꢀ)-11a and (ꢀ)-11b (770 mg, 40%) was separated
from the mixture of esters (ꢀ)-3a and (ꢀ)-3b (955 mg,
45%) by crystallization with CH2Cl2. It is possible to isolate
compound (ꢀ)-11a from (ꢀ)-11b and compound (ꢀ)-3a
from (ꢀ)-3b by column chromatography.9b
4.3.3. Ethyl (10S,30R,2R)-2-benzoylamino-(30-azidocarbonyl-
cyclopentyl)acetate 7a. Crude compound. IR (Nujol):
1
mmax 2163, 1700, 1665 cmꢀ1; H NMR d (ppm) (CDCl3) d
7.88–7.40 (m, 5H), 6.80 (d, J = 8.1 Hz, 1H, exch.), 4.89
(dd, J = 8.1, 5.1 Hz, 1H), 4.25 (q, J = 7.0 Hz, 2H), 2.99–
2.83 (m, 1H), 2.78–2.53 (m, 1H), 2.30–1.60 (m, 6H), 1.32
(t, J = 7.0 Hz, 3H).
4.3.4. Ethyl (10R,30S,2R)-2-benzoylamino-(30-azidocarbonyl-
cyclopentyl)acetate 7b. (Mixture with 15) IR (Nujol) 2163,
1
1700, 1665 cmꢀ1; H NMR (CDCl3) d 7.85–7.42 (m, 5H),
6.86 (d, J = 7.7 Hz, 1H, exch.), 4.88 (dd, J = 7.7, 5.9 Hz,
1H), 4.26 (q, J = 7.0 Hz, 2H), 2.93–2.80 (m, 1H), 2.80–
2.45 (m, 1H), 2.30–1.60 (m, 6H), 1.33 (t, J = 7.0 Hz, 3H).
4.3.5. Ethyl (10S,30R,2R)-2-benzoylamino-(30-ethoxycarbon-
25
4.3. ‘One-pot’ synthesis of ethyl benzoylamino-(30-ethoxy-
carbonylamino-cyclopentyl)-acetates 9a and 9b
ylamino-cyclopentyl)acetate 9a. ½aꢂD ¼ ꢀ5:3 (c 0.3,
CHCl3); mp 175 °C (CH2Cl2/i-Pr2O); IR (Nujol) mmax
1728, 1689, 1641 cmꢀ1 1H NMR (CDCl3) d 7.83–7.44
;
Operating at 10 °C with stirring, compound ( )-3a, or
( )-3b, or (ꢀ)-3a or (ꢀ)-3b or the 1:1 mixture of (ꢀ)-3a/
(ꢀ)-3b (200 mg, 0.63 mmol) was dissolved in SOCl2
(2 mL). After 2 h (1H NMR analysis), SOCl2 was evapo-
rated. The crude reaction mixture was treated with anhy-
drous toluene (3 ꢁ 10 mL) and evaporated under vacuum
to give acyl chloride, 6a and/or 6b. Compound 6 was then
dissolved in anhydrous toluene (5 mL) operating
(m, 5H), 6.73 (d, J = 8.4 Hz, 1H, exch.), 4.82 (dd,
J = 8.4, 7.0 Hz, 1H), 4.65 (br s, 1H, exch.), 4.23 (q,
J = 7.0 Hz, 2H), 4.07 (q, J = 7.0 Hz, 2H), 4.10–3.97 (m,
1H), 2.55–2.38 (m, 1H), 2.35–2.13 (m, 1H), 2.10–1.95 (m,
1H), 1.80–1.27 (m, 4H), 1.30 (t, J = 7.0 Hz, 3H), 1.21 (t,
J = 7.0 Hz, 3H), 13C NMR (CDCl3) d 172.3, 167.6,
156.3, 134.1, 132.1, 128.8, 127.3, 61.8, 60.8, 55.5, 52.2,
41.2, 36.7, 32.5, 25.9, 14.8, 14.4. MS (ESI) m/z 363.6

590
M. L. Gelmi et al. / Tetrahedron: Asymmetry 19 (2008) 584–592
(M+H)+. Anal. Calcd: C, 62.97; H, 7.23; N, 7.73; Found:
C, 62.95; H, 7.27; N, 7.70.
(ppm) (CDCl3) 172.4, 167.6, 155.6, 134.1, 132.0, 128.8,
127.3, 85.4, 61.8, 55.4, 52.0, 41.4, 36.7, 32.5, 28.6, 26.0,
14.4. MS (ESI) m/z 413.1 (M+Na)+. Anal. Calcd: C,
64.59; H, 7.74; N, 7.17; Found: C, 64.55; H, 7.78; N, 7.14.
4.3.6. Ethyl (10R,30S,2R)-2-benzoylamino-(30-ethoxycarbon-
25
ylamino-cyclopentyl)acetate 9b. ½aꢂD ¼ ꢀ21:2 (c 1, CHCl3);
mp 140 °C (CH2Cl2/i-Pr2O); IR (Nujol) mmax 1725,
1
1689 cmꢀ1; H NMR (CDCl3) d 7.82–7.40 (m, 5H), 6.75
4.6. (10S,30R,2R)-N,N0-Bis-[3-(benzoylamino-ethoxycarbon-
ylmethyl)-cyclopentyl]urea 4a
(d, J = 8.4 Hz, 1H, exch.), 4.86 (br s, 1H, exch.), 4.81 (dd,
J = 8.4, 7.8 Hz, 1H), 4.24 (q, J = 7.0 Hz, 2H), 4.09 (q,
J = 6.9 Hz, 2H), 4.03–3.94 (m, 1H), 2.50–2.34 (m, 1H),
2.20–1.35 (m, 6H), 1.29 (t, J = 7.0 Hz, 3H),1.21 (t, J =
6.9 Hz, 3H); 13C NMR (CDCl3) d 172.3, 167.7, 156.5,
134.1, 132.1, 128.8, 127.3, 61.8, 60.9, 55.5, 52.0, 41.6, 35.9,
32.8, 26.9, 14.8, 14.4. MS (ESI) m/z 363.6 (M+H)+. Anal.
Calcd: C, 62.97; H, 7.23; N, 7.73; Found: C, 62.93; H,
7.28; N, 7.69.
Method a: Pure compound ( )-3a (100 mg, 0.3 mmol) was
dissolved in t-BuOH. TEA (188 lL, 0.3 mmol) and DPPA
(64 lL, 0.3 mmol) were then added. The mixture was
heated at reflux for 3 h (TLC: CH2Cl2/Et2O 2:1). The sol-
vent was removed and the mixture was taken up with
AcOEt and extracted with a solution of citric acid (5%,
3 ꢁ 5 mL), with H2O (3 ꢁ 5 mL) and with brine (3 ꢁ
5 mL). The organic layer was dried over Na2SO4 and evap-
orated under vacuum. The residue was chromatographed
on silica gel (CH2Cl2/Et2O 10:1) affording compound 4a
(79 mg, 50%) and a trace amount of 5a (7 mg, 5%). Method
b: A solution of isocyanate 8a in CHCl3 (obtained from
0.63 mmol of (ꢀ)-3a, see above) was dissolved in H2O
(2 mL) and pyridine (50 lL, 0.63 mmol). The mixture was
stirred for 10 min after which a solid was separated and fil-
tered. The solid was washed with THF and dried under
vacuum and pure compound 4a was isolated (235 mg,
70%). Any attempt to completely dissolve compound 4a
in order to determine the specific rotation failed. Mp
4.4. Ethyl (10S,30R,2R)-benzoylamino-(30-isocyanate-cyclo-
pentyl)acetate 8a
Operating at 10 °C under stirring, (ꢀ)-3a (200 mg,
0.63 mmol) was dissolved in SOCl2 (2 mL). The reaction
was monitored by 1H NMR analysis. After 2 h, SOCl2
was evaporated. The crude reaction mixture was treated
with anhydrous toluene (3 ꢁ 10 mL) and evaporated under
vacuum to obtain acyl chloride 6a, which was then dis-
solved in anhydrous toluene (5 mL) operating under nitro-
gen. A catalytic amount of TBABr (20 mg, 0.063 mmol)
and NaN3 (55 mg, 0.75 mmol) was added to the solution,
which was stirred at room temperature for 3 h (IR, NMR
analyses). The reaction mixture was taken up with H2O
(5 mL) and the phases were separated. The aqueous solu-
tion was extracted with AcOEt (3 ꢁ 5 mL). All the organic
layers were dried over Na2SO4 and evaporated to obtain
acyl azide 7a, which was stood in ethanol free CHCl3
(10 mL) for 24 h under stirring until complete transforma-
tion of 7a into isocyanate 8a (NMR analysis). Crude iso-
cyanate 8a (85%) can be obtained after solvent
evaporation. IR (Nujol) mmax 3334, 2258, 1715,
1
200 °C; IR (Nujol) mmax 3340, 1728, 1700, 1665 cmꢀ1; H
NMR (DMSO) d 8.67 (d, J = 7.3 Hz, 2H, exch.), 7.86–
7.41 (m, 10H), 5.75 (d, J = 7.7 Hz, 2H, exch.), 4.26 (t,
J = 7.3 Hz, 2H), 4.13–4.06 (m, 4H), 3.92–3.82 (m, 2H),
2.39–2.30 (m, 2H), 2.26–2.06 (m, 2H), 1.82–1.34 (m,
10H), 1.16 (t, J = 7.0 Hz, 6H). 13C NMR d (DMSO)
172.5, 167.5, 157.9, 134.5, 132.1, 128.4, 128.3, 61.0, 58.0,
51.2, 42.1, 38.2, 32.6, 27.7, 14.8. MS (ESI) m/z 605.0
(MꢀH)+. Anal. Calcd: C, 65.33; H, 6.98; N, 9.23; Found:
C, 65.30; H, 7.01; N, 9.20.
1
1662 cmꢀ1; H NMR d (CDCl3) 7.84–7.40 (m, 5H), 6.77
(d, J = 8.4 Hz, 1H, exch.), 4.86 (dd, J = 8.4, 6.3 Hz, 1H),
4.22 (q, J = 7.0 Hz, 2H), 3.97–3.88 (m, 1H), 2.57–2.44
(m, 1H), 2.26–2.04 (m, 1H), 1.98–1.54 (m, 5H), 1.30 (t,
J = 7.0 Hz, 3H).
4.7. Synthesis of ethyl (10S,30R,2R)-2-benzoylamino-[30-(N0-
p-methoxybenzyl)ureido-cyclopentyl]acetate (ꢀ)-13a
p-Methoxybenzylamine (80 lL, 0.62 mmol) was added to a
solution of isocyanate 8a in CHCl3 (obtained from
0.63 mmol of (ꢀ)-3a, see above). The mixture was stirred
overnight. A white solid was separated, filtered and washed
4.5. Ethyl (10S,30R,2R)-2-benzoylamino-(30-t-butoxycarbon-
ylamino-cyclopentyl)acetate (ꢀ)-5a
t-BuOH (5 mL) and a catalytic amount of SnCl4 were
added to a solution of isocyanate 8a in CHCl3 (obtained
from 0.63 mmol of (ꢀ)-3a, see above). After 24 h (TLC:
CH2Cl2/Et2O, 2:1), the solvent was evaporated and the
crude reaction mixture was chromatographed on silica gel
with CH2Cl2. The solid was dried under vacuum obtaining
25
compound (ꢀ)-13a (230 mg, 87%). ½aꢂD ¼ ꢀ6:9 (c 0.4,
DMSO) Mp 165 °C; IR (Nujol) mmax 3344, 3264, 1745,
1
1632 cmꢀ1; H NMR (DMSO) d 8.68 (d, J = 7.7 Hz, 1H,
exch.), 7.87–7.40 (m, 5H), 6.87, 6.82 (AA0XX0 system,
J = 8.8 Hz, 4H), 6.06 (t, J = 5.5 Hz, 1H, exch.), 5.98 (d,
J = 7.3 Hz, 1H, exch.), 4.26 (dd, J = 7.7, 3.9 Hz, 1H),
4.22–4.02 (m, 4H), 3.88–3.85 (m, 1H), 3.70 (s, 3H), 2.46–
2.30 (m, 1H), 2.06–1.93 (m, 1H), 1.82–1.75 (m, 2H),
1.46–1.20 (m, 3H), 1.16 (t, J = 7.0 Hz, 3H). 13C NMR d
(ppm) (DMSO) 172.5, 167.5, 158.7, 158.3, 134.5, 133.5,
132.1, 129.0, 128.3, 114.3, 61.0, 58.1, 55.7, 51.4, 43.0,
41.5, 37.4, 32.6, 27.8, 14.8. Anal. Calcd: C, 66.21; H,
6.89; N, 9.27; Found C, 66.18; H, 6.93; N, 9.25.
(CH2Cl2/Et2O, 20:1 to 5:1). Pure compound (ꢀ)-5a was
25
obtained after crystallization (180 mg, 60%). ½aꢂD ¼ ꢀ10:3
(c 1, CHCl3); mp 200 °C (CH2Cl2/Et2O); IR (Nujol) mmax
1
3340, 1728, 1700, 1665 cmꢀ1; H NMR (CDCl3) d 7.80–
7.42 (m, 5H), 6.74 (d, J = 8.1 Hz, 1H, exch.), 4.79 (t,
J = 8.1, 3.0 Hz, 1H), 4.55 (d, J = 6.2 Hz, 1H, exch.), 4.20
(q, J = 7.0 Hz, 2H), 3.95–3.85 (m, 1H), 2.43–2.35 (m,
1H), 2.29–2.12 (m, 1H), 2.11–1.91 (m, 1H), 1.87–1.24 (m,
4H), 1.28 (s, 9H), 1.15 (t, J = 7.0 Hz, 3H). 13C NMR d

M. L. Gelmi et al. / Tetrahedron: Asymmetry 19 (2008) 584–592
591
4.8. Synthesis of ethyl (10S,30R,2R)-2-benzoylamino-(30-
amino-cyclopentyl)acetate p-toluensulfonate (+)-14a
(108 mg, 73%) was obtained. Mp 190 °C (AcOEt/
25
CH2Cl2/i-Pr2O); ½aꢂD ¼ ꢀ10:2 (c 1, MeOH); IR (Nujol)
1
mmax 3240, 1730, 1700, 1665 cmꢀ1; H NMR (CD3OD) d
p-Toluensulfonic acid (87 lL, 0.62 mmol) was added to a
solution of isocyanate 8a in CHCl3 (obtained from
0.63 mmol of (ꢀ)-3a, see above). The mixture was stirred
overnight. A white solid was separated, filtered and washed
7.85–7.41 (m, 5H), 4.48 (d, J = 9.5 Hz, 1H), 4.25 (q,
J = 7.0 Hz, 2H), 4.02–3.92 (m, 1H), 2.52–2.39 (m, 1H),
2.36–2.19 (m, 1H), 2.02–1.44 (m, 5H), 1.27 (t, J = 7.0 Hz,
3H); MS (ESI) m/z 356.2 (M+H)+. 13C NMR d (CD3OD)
172.1, 169.4, 160.6, 134.1, 131.7, 128.4, 127.4, 61.1, 57.9,
50.8, 39.8, 37.2, 32.2, 26.9, 13.3. Anal. Calcd: C, 61.25;
H, 6.95; N, 12.60; Found: C, 61.20; H, 6.98; N, 12.55.
with CH2Cl2. The solid was dried under vacuum obtaining
25
compound (+)-14a (240 mg, 85%). ½aꢂD ¼ þ8:9 (c 0.4,
DMSO) Mp 192–193 °C; IR (Nujol) mmax 3347, 3060,
1736, 1642 cmꢀ1
;
1H NMR (DMSO)
d
8.67 (d,
J = 7.3 Hz, 1H, exch.), 7.86–7.41 (m, 7H), 7.09 (d,
J = 7.7 Hz, 2H), 4.37 (t, J = 7.3 Hz, 1H), 4.18–4.02 (m,
2H), 3.47–3.13 (m, 1H), 2.50–2.16 (m, 1H), 2.26 (s, 3H),
2.24–2.06 (m, 1H), 1.82–1.34 (m, 8H), 1.16 (t, J = 7.0 Hz,
3H). 13C NMR d (ppm) (DMSO) 172.2, 167.5, 146.2,
138.4, 134.4, 132.1, 128.9, 128.8, 128.3, 126.1, 61.1, 57.2,
55.6, 51.3, 39.8, 35.2, 30.1, 27.7, 21.5, 14.8. Anal. Calcd:
C, 59.72; H, 6.54; N, 6.06; Found C, 59.66; H, 6.60; N,
6.00.
4.11. General procedure for the preparation of amino acids
12
Operating in a sealed tube, ethylcarbamate (ꢀ)-9a or
(ꢀ)-9b (70 mg, 0.19 mmol) or isocyanate 6a (55 mg,
0.19 mmol) was suspended in HCl (6N, 0.6 mL). The mix-
ture was heated at 90 °C for 24 h (TLC: CH2Cl2/Et2O, 2:1).
The mixture was cooled at 0 °C. A solid was separated, and
filtered. The aqueous layer was washed with Et2O
(3 ꢁ 5 mL) and then was evaporated to dryness under re-
duced pressure affording amino acid (ꢀ)-12a or (ꢀ)-12b
(40 mg, 95%) and trace amount of its epimer (+)-12b or
(+)-12a (5 mg, 5%).
4.9. Ethyl (10R,30S,2R)-benzoylamino-(30-carbamoyl-cyclo-
pentyl)acetate 10
Operating at 10 °C under stirring, (ꢀ)-3b (200 mg,
0.63 mmol) was dissolved in SOCl2 (2 mL). The reaction
was monitored by 1H NMR analysis. After 2 h, SOCl2
was evaporated. The crude reaction mixture was treated
with anhydrous toluene (3 ꢁ 10 mL) and evaporated under
vacuum obtaining acyl chloride 6b, which was then dis-
solved in anhydrous toluene (5 mL) operating under nitro-
gen. A catalytic amount of TBABr (20 mg, 0.063 mmol)
and NaN3 (165 mg, 1.9 mmol) was added to the solution,
which was stirred at room temperature for 3 h (IR analy-
sis). The reaction mixture was taken up with H2O (5 mL)
and the phases were separated. The aqueous solution was
extracted with AcOEt (3 ꢁ 5 mL). The combined organic
layers were dried over Na2SO4 and evaporated obtaining
4.11.1. (10S,30R,2R)-2,30-Diamino-cyclopentyl-acetic acid
25
dihydrochloride 12a. Oil, ½aꢂD ¼ ꢀ17:7 (c 1, MeOH); IR
1
(Nujol): 3340, 2520, 1700, 1631 cmꢀ1; H NMR d (D2O)
3.76 (d, J = 7.6 Hz, 1H), 3.75–3.50 (m, 1H), 2.45–2.20
(m, 2H), 2.10–1.30 (m, 5H), 13C NMR d (D2O) 173.5,
57.9, 51.2, 39.7, 34.3, 29.2, 27.0. Anal. Calcd: C, 36.38;
H, 6.98; N, 12.12; Found: C, 36.35; H, 7.02; N, 12.10.
4.11.2. (10R,30S,2R)-2,30-Diamino-cyclopentyl-acetic acid
25
dihydrochloride 12b. Oil, ½aꢂD ¼ ꢀ15:2 (c 1, MeOH); IR
1
(Nujol): 3340, 2523, 1700, 1631 cmꢀ1; H NMR d (D2O)
3.84 (d, J = 6.2 Hz, 1H), 3.65–3.51 (m, 1H), 2.45–2.18
(m, 2H), 2.05–1.30 (m, 5H); 13C NMR d (D2O) 172.6,
56.8, 50.8, 39.5, 34.3, 29.4, 25.9. Anal. Calcd: C, 36.38;
H, 6.98; N, 12.12; Found: C, 36.34; H, 7.03; N, 12.10.
carbamoyl azide (+)-10 (180 mg, 80%). Mp 167 °C
25
(CH2Cl2/i-Pr2O); ½aꢂD ¼ þ3:0 (c 1, CHCl3); IR (Nujol)
mmax 3324, 2137, 1741, 1674 cmꢀ1 1H NMR (CDCl3) d
;
7.82–7.40 (m, 5H), 6.85 (d, J = 8.4 Hz, 1H, exch.), 6.0 (d,
J = 6.9 Hz, 1H, exch.), 4.76 (dd, J = 8.4, 5.9 Hz, 1H),
4.24 (q, J = 7.0 Hz, 2H), 4.18–4.03 (m, 1H), 2.46–2.43
(m, 1H), 2.39–2.00 (m, 2H), 1.99–1.45 (m, 4H), 1.30 (t,
J = 7.0 Hz, 3H). 13C NMR d (CDCl3) 172.2, 167.9,
156.2, 133.8, 132.2, 128.9, 127.3, 62.0, 55.7, 52.0, 42.1,
35.4, 32.7, 27.3, 14.4. MS (ESI) m/z 382.2 (M+Na)+. Anal.
Calcd: C, 56.82; H, 5.89; N, 19.49; Found: C, 56.78; H,
5.91; N, 19.47.
Acknowledgement
We thank Miur (PRIN 2005) for financial support.
References
4.10. Ethyl (10R,30S,2R)-benzoylamino-(30-ureido-cyclo-
pentyl)acetate 15
1. Eustache, J.; Grob, A.; Lam, C.; Sellier, O.; Schulz, G.
Bioorg. Med. Chem. Lett. 1998, 8, 2961–2966.
2. Surman, M. D.; Miller, M. J. Org. Lett. 2001, 3, 519–521.
3. Semple, J. E.; Brunck, T. K.; Levy, O. E.; Tamura, S. Y. PTC
Int. Appl., 2001, PIXXD2 WO 0127141; Chem. Abstr. 2001,
134, 311435.
4. Natchus, M. G.; Pikul, S.; Almstead, N. G.; Laufersweiler,
M. J.; Bookland, R. G.; Tullis, J. S.; De, B. U.S. Pat. Appl.
Publ., 2003, PCT/US01/08784. CODEN: USXXCO US
2003162778 A1 20030828; Chem. Abstr. 2003, 139, 214712.
5. Liu, Z.; Wei, Y.; Li, Z. Zhongguo Kangshengsu Zazhi 2002,
27, 529–531; . Chem. Abstr. 2003, 139, 374214.
Carbamoyl azide (+)-10 (150 mg, 0.417 mmol) was dis-
solved in anhydrous Et2O operating under nitrogen. Ph3P
(85 lL, 0.834 mmol) was added to the solution and the
reaction was stirred for 6 h at room temperature (TLC:
CH2Cl2/Et2O 2:1). The solvent was removed under vac-
uum; H2O (3 mL) and THF (3 mL) were added to the res-
idue. The mixture was stirred at reflux for 14 h. After the
removal of H2O and crystallization, compound (ꢀ)-15

592
M. L. Gelmi et al. / Tetrahedron: Asymmetry 19 (2008) 584–592
6. Ashton, W. T.; Dong, H.; Sisco, R. M.; Doss, G. A.; Leiting,
Tetrahedron 2006, 62, 3502–3508; (c) Caputo, F.; Clerici, F.;
Gelmi, M. L.; Pellegrino, S.; Pilati, T. Tetrahedron: Asym-
metry 2006, 17, 61–67; (d) Caputo, F.; Clerici, F.; Gelmi, M.
L.; Pellegrino, S.; Pocar, D. Tetrahedron: Asymmetry 2006,
17, 1430–1436; (e) Caputo, F.; Cattaneo, C.; Clerici, F.;
Gelmi, M. L.; Pellegrino, S. J. Org. Chem. 2006, 71, 8467–
8472.
B.; Patel, R. A.; Wu, J. K.; Marsilio, F.; Thornberry, N. A.;
Weber, A. E. Bioorg. Med. Chem. Lett. 2004, 14, 859–863.
7. (a) Li, F.; Brogan, J. B.; Gage, J. L.; Zhang, D.; Miller, M. J.
J. Org. Chem. 2004, 69, 4538–4540; (b) Zhang, D.; Miller, M.
J. J. Org. Chem. 1998, 63, 755–759; (c) Aggarwal, V. K.;
Monteiro, N. J. Chem. Soc., Perkin Trans. 1 1997, 2531–
2537.
8. Shimodoi, Y.; Murata, N. Kogyo Kagaku Zasshi 1962, 65,
561–566; . Chem. Abstr. 1963, 58, 33373.
9. (a) Clerici, F.; Gelmi, M. L.; Pellegrino, S.; Pilati, T. J. Org.
Chem. 2003, 68, 5286–5291; (b) Cabrele, C.; Clerici, F.;
Gelmi, M. L.; Gandolfi, R.; Molinari, F.; Pellegrino, S.
10. Ninomiya, K.; Shioiri, T.; Yamada, S. Tetrahedron 1974, 30,
2151–2157.
11. Hodgson, D. M.; Thompson, A.; Wadman, S.; Keats, J. C.
Tetrahedron 1999, 55, 10815–10834.
12. Staudinger, H.; Hauser, E. Helv. Chim. Acta 1921, 4, 861–
886.