Efficient synthesis of orthogonally protected anti-2,3-diamino acids

Article abstract of DOI:10.1016/j.tet.2005.04.046

An asymmetric synthesis of anti-2,3-diamino acids is reported. The enolates of N,N-dibenzylated β³-amino esters were treated with di-tert-butyl azodicarboxylate (DBAD) to afford their N′,N″-di-Boc- 2-hydrazino derivatives with excellent anti di

Full text of DOI:10.1016/j.tet.2005.04.046

Tetrahedron 61 (2005) 6575–6579
Efficient synthesis of orthogonally protected
anti-2,3-diamino acids
*
Stefania Capone, Annalisa Guaragna, Giovanni Palumbo and Silvana Pedatella
`
Dipartimento di Chimica Organica e Biochimica, Universita di Napoli Federico II, Via Cynthia 4, 80126 Napoli, Italy
Received 28 January 2005; revised 5 April 2005; accepted 21 April 2005
Abstract—An asymmetric synthesis of anti-2,3-diamino acids is reported. The enolates of N,N-dibenzylated b3-amino esters were treated
with di-tert-butyl azodicarboxylate (DBAD) to afford their N0,N00-di-Boc-2-hydrazino derivatives with excellent anti diastereoisomeric ratio.
Final Boc removal and reductive cleavage of the hydrazino bond led to the expected 2,3-diamino esters having only one free amino group. In
comparison with other asymmetric C-2 amination procedures, this method does not need the use of expensive chiral reagents and/or chiral
auxiliaries, while leads to products which can be orthogonally protected.
q 2005 Elsevier Ltd. All rights reserved.
1. Introduction
resolve racemic mixtures of chiral allylic alcohols has been
reported as well.16
2,3-Diamino acids are important non-protein amino
acids, usually components of both natural and synthetic
bioactive compounds.1 In fact, they are currently well
recognized as key structural moieties in a variety of
biologically active molecules: (S)-2,3-diamino propanoic
acid (DAP, 1),2 2,3-diamino butanoic acids (DAB, 2 and 3)3
and (2S,3R)-2,3-diamino-4-phenylbutanoic acid (4)4 are
present in some antifungal dipeptides5 and in peptide
antibiotics, like aspartocin,3 glumamycin,6 lavendomycin7
and aminodeoxybestatin.8 Furthermore, (2R,3S)-2,3-di-
amino-3-phenylpropanoic acid (5) has been considered as
an alternative side chain in the anticancer drug Taxol.9
The development of simple and efficient methods to produce
enantiomerically pure 2,3-diamino acids from readily
available starting materials represent a fascinating goal
and several asymmetric syntheses have been reported so far.
The Mitsunobu reaction on serine,17 the Hofmann and
Curtius rearrangements of asparagine derivatives,18 and the
Schmidt reaction on aspartic acid19 were used to access
chiral 2,3-diaminopropanoic acid. A variety of other
syntheses have been also reported: the conjugate addition20
of homochiral lithium N-benzyl-N-a-methylbenzylamide to
a,b-unsaturated esters and in situ amination with trisyl
azide, the asymmetric Rh(I)-phosphine-catalyzed hydro-
genation of diastereoisomeric enamides,21 and the ring
opening of cis-3-alkylaziridine-2-carboxylates coming from
Sharpless asymmetric aminohydroxylation of a,b-unsatu-
rated esters.22
In this paper we report a new inexpensive, general and
highly stereoselective synthesis of anti-2,3-diamino acids
via amination of b3-amino esters.23
The elementary, polyfunctional 2,3-diamino acid unit has
been frequently used to probe several aspects of peptide and
protein structures. In addition, the usefulness of simple
chiral 1,2-diamines as auxiliaries and controller groups in
asymmetric synthesis (e.g., dihydroxylation,10 conjugate
addition,11 olefination,12 allylation,13 epoxidation,14 and
aldol reaction15) is also well documented. Their use to
2. Results and discussion
N,N-Dibenzylated b3-amino esters (7a–c), in dry THF at
K78 8C and under dry nitrogen stream, were treated with
potassium bis(trimethylsilyl)amide (KHMDS) to get the
corresponding enolates. The use of more common bases,
such as LiHMDS and LDA, for the enolate generation was
Keywords: b3-Amino acids; 2,3-Diamino acids; Asymmetric synthesis;
Amination.
*
Corresponding author. Tel.: C39 081 674 118; fax: C39 081 674 102;
e-mail: pedatell@unina.it
0040–4020/$ - see front matter q 2005 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2005.04.046

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S. Capone et al. / Tetrahedron 61 (2005) 6575–6579
neglected since in our experience24 such bases lead to
significantly poorer results. After 1 h, solid di-tert-butyl
azodicarboxylate (DBAD) was added to the reaction
mixture that was kept at K78 8C for an additional hour.
Under such conditions, the Boc-diprotected hydrazino
derivatives of the starting 7a–c were obtained.
Table 1. Functionalization at C-2 of the fully protected b3-amino esters
7a–c
Protected b3-
amino ester
R
Boc protected 2-hydra-
zino derivatives of 7a–c
anti-2,3-Dia-
mino esters
(9a–c), yield
(%)a
Yield (%)b
anti/syn
7a
7b
7c
Ph
Bn
CH2OBn
92
90
90
93:7
97:3
94:6
70
78
65
The double protection of the amino group is necessary to
avoid formation of by-products coming from the abstraction
of the N–H proton in the enolate production step.
Consequently, common protecting groups that are stable
under basic conditions, such as either Boc or Cbz, could not
be used under our reaction conditions. Therefore, in a first
attempt, the 4-methoxybenzyl group, we had already used
elsewhere,24 was chosen for its peculiar removal conditions
(CAN, CH3CN/H2O). Unfortunately, although the group
turned out to be stable under the reaction conditions, we
could not use it because the deprotection of the final 3-[di(4-
methoxybenzyl)amino]-2,3-diamino esters led to a plethora
of products coming from oxidative cleavage of the C2–C3
bond. Eventually, we used a double benzylic protection that
eliminated such deprotection problems and represented at
the same time a very bulky nitrogen substituent, suitable to
affect the stereochemical outcome25 of the enolate coupling
with the electrophile DBAD. As a matter of fact, the
coupling afforded a mixture of anti:syn Boc protected 2-
hydrazino derivatives of 7a–c with excellent diastereoiso-
meric ratio. Due to the complexity of the 1H NMR spectra of
the Boc containing hydrazino derivatives, they were
converted into the corresponding diastereoisomeric mix-
tures of diamino esters (e.g., 9) to determine accurately the
diastereoisomeric ratio.
a Overall yield after Boc removal and reductive cleavage of the hydrazine
moiety in the anti diastereoisomers 8a–c.
b Yield of both diastereoisomers.
temperature and pressure.27 As a matter of fact, the
hydrogenolysis under such conditions was complete after
only 4 h and no traces of C-2 epimerization products could
1
be detected by H NMR spectroscopic analysis.
The anti configuration of the more abundant diastereo-
isomers coming from the couplings of 7a–c with DBAD
could be attributed, in the case of 8a, as follows: the final
product 9a was debenzylated and treated, without isolation,
with 1,10-carbonyldiimidazole to afford the imidazolidinone
10 (Scheme 2).
Scheme 2. Synthesis of cis-imidazolidinone (10).
The synthetic path is depicted in Scheme 1 and the results
obtained for selected b3-amino esters, namely the methyl
esters of b3-phenylglycine (6a), b3-phenylalanine (6b), and
b3-serine (6c), are reported in Table 1.
1
The H NMR spectroscopy coupling constant of 9.6 Hz
supported28 the cis-configuration of the H-4 and H-5 protons
and, thus, the anti-configuration of the starting diamino
compound.
In the light of this result and in agreement with our previous
work on the hydroxylation at C-2 of b3-amino esters, it
seems likely that the stereochemical outcome of the
functionalization at C-2 is independent of the nature of the
electrophile used, being only a function of the relative
stabilities of the enolate conformations.24
3. Conclusion
This amination procedure of b3-amino esters offers several
advantages, if compared with many other reported pro-
cedures. First of all, it does not require the use of either
chiral reagents or chiral auxiliaries: in fact, the observed
selection in the coupling step is merely due to the influence
of the existing chiral center of the starting b3-amino ester,
enhanced by the presence of two bulky substituents on the
nitrogen atom. Moreover, it is noteworthy that the amino
groups in the final 2,3-diamino esters have a different
protection status: this implies a broad flexibility of their use
in peptide synthesis. For instance, the free amino group can
be Boc protected and the benzyl groups then removed
hydrogenolitically to host an Fmoc protecting group, or vice
Scheme 1. Conversion of a-amino acids into monoprotected 2,3-diamino
esters.
The more abundant anti diastereoisomers were submitted to
removal of the Boc protections (TFA in CH2Cl2) and
cleavage of the N–N bond by hydrogenolysis with Ni(Ra) at
low pressure and room temperature in an ultrasound bath.
The reduction of hydrazines to amines is reported to be
accomplished at high temperature, under high hydrogen
pressure.26 The use of ultrasound reduces significantly both

S. Capone et al. / Tetrahedron 61 (2005) 6575–6579
6577
versa should either Boc- or Fmoc-strategy be used.
Accordingly, in connection with our current interest in the
synthesis of glycosyl amino acids, we have prepared the
compound 13 as shown in Scheme 3.
for C24H25NO2: C 80.19, H 7.01, N 3.90. Found: C 80.30, H
7.05, N 3.92.
Under the same conditions, the following N,N-diprotected
esters were also obtained.
Methyl (S)-3-(dibenzylamino)-4-phenylbutanoate (7b). Oil
(83%). [a]2D0 K5.4 (c 1.0). 1H NMR (500 MHz): d 2.33 (dd,
JZ6.4, 14.2 Hz, 1H, H-2a), 2.56 (dd, JZ8.8, 13.2 Hz, 1H,
H-4a), 2.65 (dd, JZ8.3, 14.2 Hz, 1H, H-2b), 3.12 (dd, JZ
5.7, 13.2 Hz, 1H, H-4b), 3.40–3.50 (m, 1H, H-3), 3.56 (s,
3H, OCH3), 3.62 (d, JZ13.7 Hz, 2H, NCHPh), 3.76 (d, JZ
13.7 Hz, 2H, NCHPh), 7.20–7.70 (m, 15H, H-Ar). 13C NMR
(125 MHz): d 35.9, 36.3, 51.6, 53.7, 57.8, 126.4, 127.2,
128.4, 128.6, 129.1, 129.5, 139.7, 139.8, 172.9. IR (KBr,
cmK1): n 1712. Anal. Calcd for C25H27NO2: C 80.40, H
7.29, N 3.75. Found: C 80.25, H 7.32, N 3.77.
Methyl (R)-4-(benzyloxy)-3-(dibenzylamino)butanoate (7c).
Oil (86%). [a]2D0 C31.6 (c 1.8). 1H NMR (500 MHz): d 2.55
(dd, JZ6.3, 14.6 Hz, 1H, H-2a), 2.68 (dd, JZ7.8, 14.6 Hz,
1H, H-2b), 3.47–3.54 (m, 1H, H-3), 3.56–3.62 (m, 4H, H-4a
and OCH3), 3.66 (d, JZ13.7 Hz, 2H, NCHPh), 3.71 (dd,
JZ9.8, 5.4 Hz, 1H, H-4b), 3.75 (d, JZ13.7 Hz, 2H,
NCHPh), 4.49 (d, JZ12.7 Hz, 1H, OCHPh), 4.52 (d, JZ
12.7 Hz, 1H, OCHPh), 7.20–7.45 (m, 15H, H-Ar). 13C NMR
(125 MHz): d 34.7, 51.7, 54.5, 55.2, 70.3, 73.3, 127.1,
127.8, 128.4, 128.6, 129.1, 138.6, 140.1, 173.0. IR (KBr,
cmK1): n 1715. Anal. Calcd for C26H29NO3: C 77.39, H
7.24, N 3.47. Found: C 77.25, H 7.27, N 3.48.
Scheme 3. Preparation of the orthogonally protected 2,3-diamino acid 13.
4. Experimental
4.1. General
NMR spectra were recorded on Varian Inova 500 MHz,
Varian Gemini 200 MHz, Varian Gemini 300 MHz, Bruker
DRX 400 MHz spectrometers: chemical shifts are in ppm
(d) and J coupling constants in Hz; solvent CDCl3, unless
otherwise specified. GC/MS analyses were performed on
Hewlett–Packard 6890 GC/5973N MS. Optical rotations
were determined on Jasco P-1010 polarimeter (1.0 dm cell);
solvent CHCl3, unless otherwise specified. Infrared spectra
were recorded using JASCO FT/IR-430 Spectrometer.
Mps were taken on a Gallenkamp apparatus. Elemental
analyses were performed on a Perkin–Elmer Series II 2400,
CHNS analyzer. TLC were carried out on silica gel Merck
60 F254 plates (0.2 mm layer) and column chromatographies
on Merck Kieselgel 60 (70–230 mesh). Dry solvents were
distilled immediately before use.
4.1.2. Reactions of 70a–c with DBAD. Methyl (2S,3S)-3-
(dibenzylamino)-2-[N ,N00-(di-tert-butoxycarbonyl)-hydra-
zino]-3-phenylpropanoate (8a): typical procedure. To a
magnetically stirred solution of 7a (2.56 g; 7.12 mmol) in
dry THF (75 mL), at K78 8C and under dry argon
atmosphere, 0.5 M KHMDS in toluene (28.5 mL;
14.24 mmol) was added dropwise. After 1 h solid di-tert-
butyl azodicarboxylate (2.85 g; 12.82 mmol) was added in
one portion to the reaction mixture kept at K78 8C under
stirring. Within 1 h the reaction was quenched by addition
of glacial AcOH (1.1 mL) and diluted with EtOAc. The
organic layer was washed with brine until neutral, dried
(Na2SO4), and the solvents evaporated in vacuo. The oily
residue, after chromatography on silica gel (hexane/EtOAc,
9:1), afforded the pure title compound 8a (foam; 3.86 g;
4.1.1. N,N-Dibenzyl protections of 6a–c. Methyl (R)-3-
(dibenzylamino)-3-phenylpropanoate (7a): typical proce-
dure. A magnetically stirred suspension of b3-phenylglycine
methyl ester 6a (1.50 g; 8.38 mmol) and diisopropylethyl-
amine (DIPEA, 7.3 mL; 41.90 mmol) in toluene (18.0 mL)
was warmed gently until a clear solution was obtained.
Then, benzyl bromide (6.0 mL; 50.28 mmol) was added in
one portion and the resulting solution was refluxed for 4 h.
The reaction mixture was then cooled in an ice bath, diluted
with EtOAc (2!100 mL) and extracted with 10% aq
NH4Cl. The organic layer was washed with brine, dried
(Na2SO4), and evaporated under reduced pressure to afford
a crude reaction product whose chromatography on silica
gel (petroleum ether/EtOAc, 95:5) gave the pure crystalline
compound 7a, after recrystallization from hexane (2.56 g;
7.12 mmol; 85%). Mp 51.8–53.0 8C. [a]2D0 C71.6 (c 2.0).
1H NMR (500 MHz): d 2.73 (dd, JZ7.3, 14.6 Hz, 1H, H-
2a), 3.14 (dd, JZ8.8, 14.6 Hz, 1H, H-2b), 3.18 (d, JZ
13.7 Hz, 2H, NCHPh), 3.64 (s, 3H, OCH3), 3.78 (d, JZ
13.7 Hz, 2H, NCHPh), 4.33 (dd, JZ7.3, 8.8 Hz, 1H, H-3),
7.20–7.41 (m, 15H, H-Ar). 13C NMR (125 MHz): d 36.9,
51.8, 53.9, 59.1, 127.2, 127.7, 128.3, 128.4, 128.8, 129.1,
137.6, 139.8, 172.3. IR (KBr, cmK1): n 1714. Anal. Calcd
1
6.55 mmol; 92%). [a]2D0 C65.7 (c 1.6). The H NMR data
were not significant, apparently due to the occurrence of
mixtures of rotamers. IR (KBr, cmK1): n 3260, 1740, 1720.
Anal. Calcd for C34H43N3O6: C 69.25, H 7.35, N 7.13.
Found: C 69.17, H 7.31, N 7.15.
Under the same conditions, the following Boc diprotected 2-
hydrazino derivatives were also obtained.
Methyl (2S,3S)-3-(dibenzylamino)-2-[N0,N00-(di-tert-butoxy-
carbonyl)-hydrazino]-4-phenylbutanoate (8b). Foam (90%).
[a]2D0 K2.3 (c 0.3). IR (KBr, cmK1): n 3250, 1730, 1712.
Anal. Calcd for C35H45N3O6: C 69.63, H 7.51, N 6.96.
Found: C 69.60, H 7.49, N 7.01.
Methyl (2S,3R)-4-(benzyloxy)-3-(dibenzylamino)-2-[N0,N00-
(di-tert-butoxycarbonyl)-hydrazino]butanoate (8c). Foam

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S. Capone et al. / Tetrahedron 61 (2005) 6575–6579
(90%). [a]2D0 C45.0 (c 1.5). IR (KBr, cmK1): n 3270, 1728,
1715. Anal. Calcd for C36H47N3O7: C 68.22, H 7.47, N 6.63.
Found: C 68.19, H 7.40, N 6.68.
hydrogenolysed over 30% Pd/C catalyst (0.006 g) for 2 h at
50 8C, under a slightly positive pressure given by an inflated
balloon (w3 bar). The mixture was then filtered through
Celitew washing with MeOH (10 mL). Removal of the
solvents under reduced pressure gave a residue that was
redissolved in dry THF (1.1 mL). The solution was cooled
to 0 8C. Et3N (0.063 mL, 0.053 mmol) and 1,10-carbonyl-
diimidazole (0.013 g; 0.079 mmol) were then added in
sequence. After 30 min at 0 8C and 2 h at rt the solvents
were evaporated under reduced pressure and the remaining
crude residue was dissolved in EtOAc and filtered on a short
silica gel plug (w3 cm3) with the same solvent (3!10 mL).
By partial evaporation of the solvent under reduced
pressure, a semicrystalline residue could be collected
whose recrystallization by the same solvent afforded the
pure 10 (0.010 g; 0.045 mmol; 88%) as a white solid. Mp
4.1.3. Reductive cleavages of the hydrazino bond in 8a–c.
Methyl (2S,3S)-2-amino-3-(dibenzylamino)-3-phenylpro-
panoate (9a): typical procedure. To a magnetically stirred
solution of 8a (3.86 g; 6.55 mmol) in dry CH2Cl2 (54 mL),
TFA (54 mL) was added in one portion. After 2 h, the
solvent was evaporated under reduced pressure. The crude
reaction product, redissolved in MeOH (26 mL), was trans-
ferred into a flask containing W-2 Raney nickel (3.86 g,
wet) and equipped with a hydrogen inflated balloon. The
flask was dipped into an ultrasound bath filled with water
and sonicated for 4 h at rt till the starting product was
completely consumed (TLC). The reaction mixture was then
filtered through Celitew washing with MeOH (100 mL).
Removal of the solvents under reduced pressure gave a
residue that was redissolved in EtOAc (200 mL), washed
with 10% aq Na2CO3 (2!100 mL), dried (Na2SO4), and
evaporated in vacuo, to afford an oil whose chromatography
on silica gel (hexane/EtOAc, 7:3) led to the pure title
compound 9a (oil; 1.71 g; 4.58 mmol; 70%). [a]2D0 C62.4
1
202–203 8C dec. (lit.27 203–205 8C). H, 13C NMR and IR
spectra were superimposable to those reported.
4.1.5. Methyl (2S,3S)-2-(tert-butoxycarbonylamino)-3-
(dibenzylamino)-3-phenylpropanoate (11). To a solution
of compound 9a (0.67 g; 1.80 mmol) in dioxane (21 mL) at
0 8C, Et3N (0.42 mL; 2.70 mmol) and Boc2O (0.89 g;
3.60 mmol) were added in sequence. The reaction mixture,
warmed up to room temperature and stirred for 1 h, was then
diluted with EtOAc. The organic layer was washed with
brine until neutral, dried (Na2SO4), and the solvents
evaporated in vacuo to give an oil. Its chromatography on
silica gel (hexane/EtOAc, 9:1) afforded the pure title
compound 11 (oil; 0.78 g; 1.66 mmol; 92%). [a]2D0 C50.7
1
(c 1.1). H NMR (300 MHz): d 1.97 (bs, 2H, NH2), 3.05
(d, JZ13.5 Hz, 2H, NCHPh), 3.82 (s, 3H, OCH3), 3.83–
3.88 (m, 3H, H-2 and NCHPh), 4.26 (d, JZ10.3 Hz, 1H, H-
3), 7.20–7.60 (m, 15H, H-Ar). 13C NMR (50 MHz): d 51.7,
54.0, 56.3, 67.3, 126.9, 128.1, 128.3, 128.8, 129.7, 133.5,
139.0, 174.1. IR (KBr, cmK1): n 3500–3200, 1714. Anal.
Calcd for C24H26N2O2: C 76.98, H 7.00, N 7.48. Found: C
76.81, H 7.06, N 7.52.
1
(c 1.5). H NMR (400 MHz): d 1.55 (s, 9H, Boc), 3.04 (d,
JZ13.5 Hz, 2H, NCHPh), 3.86 (s, 3H, OCH3), 3.97–4.02
(m, 3H, H-3, NCHPh), 4.58 (bd, JZ8.3 Hz, 1H, NHBoc),
5.14 (bt, JZ9.7 Hz, 1H, H-2), 7.24–7.44 (m, 15H, H-Ar).
13C NMR (125 MHz): d 28.3, 52.3, 54.1, 54.7, 65.0, 80.2,
127.3, 128.3, 128.5, 129.2, 130.1, 132.6, 139.1, 146.9,
154.9, 172.3. IR (KBr, cmK1): n 1718, 1705. Anal. Calcd for
C29H34N2O4: C 73.39, H 7.22, N 5.90. Found: C 73.25,
H 7.20, N 5.92.
Under the same conditions, the following 2-amino esters
were also obtained.
Methyl (2S,3S)-2-amino-3-(dibenzylamino)-4-phenyl-
1
butanoate (9b). Oil (78%). [a]2D0 C7.9 (c 0.4, MeOH). H
NMR (500 MHz): d 1.63 (bs, 2H, NH2), 2.93 (dd, JZ7.3,
13.7 Hz, 1H, H-4a), 3.09 (dd, JZ6.3, 13.7 Hz, 1H, H-4b),
3.23–3.29 (m, 1H, H-3), 3.60 (s, 3H, OCH3), 3.61–3.67 (m,
3H, H-2 and NCHPh), 3.70 (d, JZ13.7 Hz, 2H, NCHPh),
7.10–7.40 (m, 15H, H-Ar). 13C NMR (100 MHz): d 32.7,
52.2, 55.1, 55.6, 63.8, 126.5, 127.4, 128.5, 128.7, 129.4,
129.9, 139.9, 140.5, 175.9. IR (KBr, cmK1): n 3530–3210,
1712. Anal. Calcd for C25H28N2O2: C 77.29, H 7.26, N 7.21.
Found: C 77.19, H 7.25, N 7.23.
4.1.6. Methyl (2S,3S)-2-(tert-butoxycarbonylamino)-3-
amino-3-phenylpropanoate (12). A magnetically stirred
solution of 11 (0.78 g; 1.66 mmol) in glacial AcOH
(7.4 mL) was hydrogenolysed over 30% Pd/C catalyst
(0.23 g) for 2 h at 50 8C, under a slightly positive pressure
given by an inflated balloon (w3 bar). The mixture was then
filtered trough Celitew and washed with MeOH (100 mL).
The solvent was removed under reduced pressure and the
residue was dissolved in EtOAc (2!100 mL). The organic
layer was washed with 10% aq Na2CO3 (300 mL), dried
(Na2SO4), and the solvents evaporated in vacuo to give
compound 12 as a white crystalline solid, after recrystalli-
zation from hexane/acetone 9:1 (0.44 g; 1.49 mmol; 90%).
Mp 110.3–112.3 8C. [a]2D0 C29.0 (c 0.9). 1H NMR
(400 MHz, C5D5N): d 1.35 (s, 9H, Boc), 3.62 (s, 3H,
OCH3), 5.34 (d, JZ7.1 Hz, 1H, H-3), 5.77 (bt, JZ8.0 Hz,
1H, H-2), 7.21–7.35 (m, 3H, H-Ar), 7.89 (d, JZ7.3 Hz, 2H,
Ar-H), 8.80 (bd, JZ8.6 Hz, 1H, NHBoc). 13C NMR
(100 MHz, C5D5N): d 28.3, 52.4, 57.1, 59.4, 79.3, 128.6,
128.9, 138.0, 140.2, 156.8, 172.0. IR (KBr, cmK1): n 3350,
3200, 1765, 1715. Anal. Calcd for C15H22N2O4: C 61.21, H
7.53, N 9.52. Found: C 61.32, H 7.57, N 9.58.
Methyl (2S,3R)-2-amino-4-(benzyloxy)-3-(dibenzylamino)-
1
butanoate (9c). Oil (65%). [a]2D0 C30.9 (c 1.0). H NMR
(500 MHz, C6D6): d 1.48 (bs, 2H, NH2), 3.22–3.28 (m, 1H,
H-3), 3.29 (s, 3H, OCH3), 3.58 (d, JZ6.8 Hz, 1H, H-2), 3.60
(dd, JZ5.8, 9.8 Hz, 1H, H-4a), 3.65 (d, 2H, JZ13.7 Hz,
NCHPh), 3.72 (dd, 1H, JZ4.9, 9.8 Hz, H-4b), 3.84 (d, 2H,
JZ13.7 Hz, NCHPh), 7.05–7.40 (m, 15H, H-Ar). 13C NMR
(100 MHz): d 52.1, 55.4, 55.6, 61.1, 67.2, 73.7, 127.3,
127.9, 128.0, 128.5, 128.8, 129.4, 138.7, 140.2, 175.7. IR
(KBr, cmK1): n 3510–3200, 1716. Anal. Calcd for
C26H30N2O3: C 74.61, H 7.22, N 6.69. Found: C 74.59, H
7.20, N 7.01.
4.1.4. Methyl (4S,5S)-4-methoxycarbonyl-5-phenyl-2-
imidazolidinone (10). A magnetically stirred solution of
9a (0.020 g; 0.053 mmol) in glacial AcOH (0.5 mL) was

S. Capone et al. / Tetrahedron 61 (2005) 6575–6579
6579
7. Schmidt, U.; Mundinger, K.; Mangold, R.; Lieberknecht, A.
J. Chem. Soc., Chem. Commun. 1990, 1216–1219.
´ ´
8. Herranz, R.; Vinuesa, S.; Castro-Pichel, J.; Perez, C.; Garcıa-
4.1.7. Methyl (2S,3S)-2-(tert-butoxycarbonylamino)-3-
(9H-fluoren-9-ylmethoxycarbonylamino)-3-phenylpro-
panoate (13). To a stirred solution of 12 (0.44 g;
1.48 mmol) in dioxane (5.8 mL) and 10% aq Na2CO3
(0.31 g; 2.96 mmol) at 0 8C, Fmoc–OSu (0.41 g;
1.18 mmol) dissolved in DMF (1.5 mL) was added slowly.
The reaction mixture, after 30 min at 0 8C and 2 h at rt, was
extracted with CH2Cl2. The organic layer was washed with
brine until neutral, dried (Na2SO4), and the solvents
evaporated under reduced pressure to give an oil. The
chromatography on silica gel (CHCl3) afforded the pure
compound 13, white solid after recrystallization from
hexane/acetone 9:1 (0.50 g; 0.96 mmol; 65%). Mp 166.6–
168.1 8C. [a]2D0 C38.7 (c 0.3). 1H NMR (500 MHz, C5D5N):
d 1.20 (s, 9H, Boc), 3.42 (s, 3H, OCH3), 4.14 (t, JZ6.8 Hz,
1H, Fmoc), 4.30 (dd, JZ6.8, 10.3 Hz, 1H, CHFmoc), 4.45
(dd, JZ6.8, 10.3 Hz, 1H, CHFmoc), 5.31 (t, JZ9.3 Hz, 1H,
H-2), 5.69 (t, JZ9.3 Hz, 1H, H-3), 7.05–7.70 (m, 14H, H-Ar
and NHBoc), 9.17 (d, JZ9.3 Hz, 1H, NHFmoc). 13C NMR
(125 MHz): d 28.5, 47.5, 52.9, 57.7, 58.0, 67.3, 120.2,
125.4, 126.8, 127.3, 128.4, 128.9, 141.5, 144.1, 155.9,
156.5, 170.4. IR (KBr, cmK1): n 3395 (br), 1705. Anal.
Calcd for C30H32N2O6: C 69.75, H 6.24, N 5.42. Found: C
69.82, H 6.27, N 5.43.
´
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Acknowledgements
Financial support by M.I.U.R. (PRIN 2003) is gratefully
acknowledged. 1H and 13C NMR spectra were performed at
Centro Interdipartimentale di Metodologie Chimico-
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`
Fisiche, Universita di Napoli Federico II. Varian Inova
500 MHz instrument is property of Consorzio Interuniver-
sitario Nazionale La Chimica per l’Ambiente (INCA) and
was used in the frame of a project by INCA and M.I.U.R. (L.
488/92, Cluster 11-A). The authors are grateful to Professor
Caputo R. for useful discussions.
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