α-Amido sulfones from natural α-amino acids and their reaction with carbon nucleophiles

Article abstract of DOI:10.1016/j.tet.2005.10.033

Amides obtained from N-carbamoyl α-amino acids react with aldehydes in the presence of benzenesulfinic acid to give α-amido sulfones in good yield. These derivatives act as equivalents of N-acylimines in the reaction with nucleophiles leading to the corre

Full text of DOI:10.1016/j.tet.2005.10.033

Tetrahedron 62 (2006) 960–967
a-Amido sulfones from natural a-amino acids and their reaction
with carbon nucleophiles
*
Marino Petrini and Mirko Seri
`
Dipartimento di Scienze Chimiche, Universita di Camerino, via S. Agostino 1, I-62032 Camerino, Italy
Received 23 July 2005; revised 29 September 2005; accepted 13 October 2005
Available online 7 November 2005
Abstract—Amides obtained from N-carbamoyl a-amino acids react with aldehydes in the presence of benzenesulfinic acid to give a-amido
sulfones in good yield. These derivatives act as equivalents of N-acylimines in the reaction with nucleophiles leading to the corresponding
addition products. The utilization of the lithium enolate of alkyl acetates as a nucleophile allows the preparation of a,b-dipeptides, while a
two-step procedure involving nitromethylation and Nef conversion leads to the synthesis of a,a-dipeptides.
q 2005 Elsevier Ltd. All rights reserved.
1. Introduction
O
O
X
O
HX
R1
R1
R
NH2
+
R
N
H
H
a-Amino acids contain a well-known structural unit, which
is present in a plethora of important biologically active
compounds. Furthermore, natural a-amino acids represent a
valuable and cheap source of enantiomerically pure
compounds suitable for diastereoselective syntheses.1
Recently proline and other peptide derivatives have been
successfully employed as organocatalysts in a number of
processes devoted to the synthesis of enantiomerically
enriched compounds.2 The carboxylic group in a-amino
acids offers a number of synthetic opportunities of linkage
with other organic frameworks such as amino derivatives
giving N-substituted amides and peptides. A complementary
approach consists of the conversion of the carboxylic group
into an amido group that can be used as substrate in different
coupling processes leading to a functional implementation of
the original a-amino acid framework. Coupling reactions
with diazoesters represent an effective procedure for the
synthesis of peptides and oxazole derivatives.3 Optically
active a-amino amides are known to react with glyoxalate
esters giving a-hydroxy N-acylamino derivatives that,
after acetylation, are converted into biologically active
compounds.4 Condensation of N-unsubstitutedamides 1with
aldehydes 2 in the presence of a nucleophile HX provides a
general and straightforward entry to a-substituted N-acyl-
amino derivatives 3 (Scheme 1).
1
2
3
Scheme 1.
Compounds 3 can be considered as stable precursors of
reactive N-acylimines that are obtained by elimination of
HX from 3 under basic conditions. N-Acylimines are strong
electrophiles that quickly react with a large variety of
nucleophilic reagents giving the corresponding addition
products.5 The utilization of a-amino acid amides in the
synthesis of compounds 3 has been exploited several years
ago by Katritzy et al. who prepared a number of those
derivatives using benzotriazole as nucleophilic reagent.6
2. Results and discussion
In this paper, we report the synthesis of a-amidoalkylphenyl
sulfones from optically active a-amino acid amides and
their utilization as N-acylimino equivalents in the reaction
with different nucleophiles.7 Condensation of N-protected
amino acid amides 48 with aldehydes 5 in the presence
of benzenesulfinic acid affords the corresponding sulfones 6
in good yield (Scheme 2, Table 1).
Contrary to what was observed in the synthesis of a-amido
sulfones from chiral aldehydes that usually occurs with high
syn diastereoselectivity, reaction of amides 4 gives rise to an
almost equimolar mixture of diastereomers in sulfones 6.9
Grignard reagents are particularly effective in promoting
Keywords: Amino acids; Carbanions; Dipeptides; Imines; Sulfones.
*
Corresponding author. Tel.: C39 0737 402253; fax: C39 0737 402297;
e-mail: marino.petrini@unicam.it
0040–4020/$ - see front matter q 2005 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2005.10.033

M. Petrini, M. Seri / Tetrahedron 62 (2006) 960–967
961
The disappointing stereochemical outcome of this reaction
may be ascribed to the equilibrium in which rotamers 8 of
the intermediate N-acylimine are involved (Scheme 4).
O
O
SO Ph
2
R
R
PhSO2H
3
NH
2
N
H
R
3
R CHO
+
N
1
2
CH2Cl2, MgSO4, rt
N
1
2
R
R
R
R
O
O
4
5
6
R
R
3
N
N
R
R1
R2
N
N
4
R
1
2
3
2
1
R
R
R
R
R
a
b
c
PhCH2
PhCH2
PhCH2
Me2CH
Ph
H
H
Boc
Cbz
Phth
s-cis 8
s-trans 8
Scheme 4.
d
e
f
H
H
Boc
Boc
Boc
_(CH2)3
_
As demonstrated for the reaction of structurally related
N-arylacyliminium ion derivatives with nucleophiles, high
diastereoselectivities are obtained when the conformation of
the imino intermediate is locked as in rotamer s-trans-8.11
However, the preferred conformation in N-acylimines is
usually s-cis-8 owing to the lower steric repulsion between
the imino and the chain frameworks. In conformation
s-cis-8 the electrophilic carbon is located too far from the
stereogenic center to ensure a consistent diastereoselection
in the subsequent nucleophilic addition.12 Direct coupling
of amino acids usually represents the most exploited
procedure to prepare dipeptides and related compounds.
Functionalization at the a-position in N-substituted glycine
derivatives also provides a complementary approach to the
synthesis of dipeptide systems.13 Sulfones 6 are amenable to
be used as valuable substrates for the preparation of
a,b-dipeptides using a synthetic approach based on the
direct addition of an ester enolate to the corresponding
N-acylimine. The interest in a,b-dipeptides is justified by
their potential biological activity, furthermore these
compounds are key intermediates in the synthesis of some
interesting molecular targets.14 Thus, reaction of sulfones 6
with the lithium enolate of alkyl acetates 9 at K78 8C
affords the corresponding adducts 10 in good yield
(Scheme 5, Table 3).
Scheme 2.
Table 1. Synthesis of a-amido sulfones 6 from a-amino acid amides 4
Entry
Amide 4
Aldehyde 5, Sulfone 6
R3
Yield (%)a
1
2
3
4
5
6
7
8
4a
4a
4a
4a
4a
4b
4b
4c
4d
4d
4d
4d
4e
4f
Et
Ph(CH2)2
6a
6b
85
95
81
93
81
88
89
78
91
87
90
83
92
90
Me2CHCH2 6c
Me
Ph
Et
6d
6e
6f
Ph(CH2)2
Et
Et
6g
6h
6i
9
10
11
12
13
14
Ph(CH2)2
c-C6H11
n-C9H19
Et
6j
6k
6l
6m
6n
Et
a Yields of pure, isolated products.
the tandem elimination–addition from a-amido sulfones and
therefore, this class of nucleophilic reagents has been
initially tested for the reaction with sulfones 6.10 Reaction of
phenylmagnesium bromide with a-amido sulfones 6 leads
to the corresponding adducts 7 in good yield but poor
diastereoselectivity (drZ3:2) (Scheme 3, Table 2).
3
O
R
O
R
CH3CO2R4 9, LDA
THF, -78˚C
4
N
H
OR
6
O
Ph
R3
N
2
1
R
R
R
PhMgBr
N
H
6
10
9a R4 = Et
9b R4 = Me
N
THF, -78˚C
R1
R2
7
Scheme 5.
Scheme 3.
Table 3. Reaction of a-amido sulfones 6 with lithium enolate of alkyl
acetates 9
Table 2. Reaction of a-amido sulfones 6 with PhMgBr
Entry
Sulfone 6
Amide 7
Yield (%)a
Entry
Sulfone 6
Acetate 2
Dipeptide 10 Yield (%)a
1
2
3
4
5
6
7
8
9
6a
6b
6c
6d
6f
6h
6i
6j
6n
7a
7b
7c
7d
7e
7f
7g
7h
7i
85
90
77
84
88
71
91
82
87
1
2
3
4
5
6
7
8
6e
6f
6g
6h
6i
6k
6l
6m
9a
9a
9b
9a
9a
9a
9b
9a
10a
10b
10c
10d
10e
10f
76
72
69
72
67
75
65
78
10g
10h
a Yields of pure, isolated products.
a Yields of pure, isolated products.

962
M. Petrini, M. Seri / Tetrahedron 62 (2006) 960–967
Similarly to what was observed in the formation of
derivatives 7, the formation of a,b-dipeptides 10 occurs
with poor diastereoselectivity. Attempt to use other metals
such as zinc or titanium enolates did not provide any
improvement in the efficiency of the process both in terms
of chemical yield or in diastereoselectivity. Finally, we
decided to apply our two-step procedure for the synthesis of
a-amino acids to sulfones 6 with the aim to prepare a,a-
dipeptides.7h,15 Thus, representative sulfones 6a,i have been
made to react with nitromethane in the presence of sodium
hydride to give the corresponding nitro derivatives 11
(Scheme 6). Nef conversion16 of the nitromethyl group into
a carboxylic group has been realized in oxidative conditions
using KMnO4 giving dipeptides 12, once again as a
diastereomeric mixture.
hydride and then distilled. Ethyl acetate was dried by
heating over P2O5 and then distilled All chemicals used are
available commercially. N-Carbamoyl a-amino acid amides
4 were prepared as described.8
4.2. General procedure for the preparation of phenyl-
sulfonyl derivatives 6
Amide 4 (6 mmol) was dissolved in dichloromethane
(30 mL) and then benzenesulfinic acid (7.5 mmol), the
appropriate aldehyde 5 (5 mmol) and anhydrous MgSO4
(0.5 g) were sequentially added at room temperature. The
mixture was stirred for 12 h at room temperature and then
filtered over a short pad of Florisil. Removal of the solvent
afforded the crude sulfone 6, which was purified by column
chromatography (7:3 hexanes/ethyl acetate).
NO
2
4.2.1. tert-Butyl N-(1-benzyl-2-oxo-2-[1-(phenyl-
sulfonyl)propyl]aminoethyl)carbamate, 6a. Yield 85%.
White solid mp 85–87 8C. IR (cmK1, KBr) 3400, 1690,
O
MeNO2, NaH
THF, rt
R
KMnO4, KOH-K2HPO4
t-BuOH,rt
N
H
6a,i
1
BocHN
1370, 1145. H NMR diast. A. d (ppm) 0.86 (t, 3H, JZ
7.3 Hz); 1.49 (s, 9H); 1.60–1.83 (m, 2H); 2.79–2.95 (m,
2H); 4.15–4.26 (m, 1H); 4.73 (d, 1H, JZ8.9 Hz); 5.02–5.19
(m, 1H); 6.55 (d, 1H, JZ11.0 Hz); 7.06–7.18 (m, 2H);
7.20–7.37 (m, 3H); 7.48–7.67 (m, 3H); 7.87 (dt, 2H, JZ1.8,
7.0 Hz). Diast. B d: 0.95 (t, 3H, JZ7.3 Hz); 1.49 (s, 9H);
1.60–1.83 (m, 2H); 2.79–2.95 (m, 2H); 4.15–4.26 (m, 1H);
4.66 (d, 1H, JZ8.7 Hz); 5.02–5.19 (m, 1H); 6.75 (d, 1H,
JZ11.0 Hz); 7.06–7.18 (m, 2H); 7.20–7.37 (m, 3H); 7.48–
7.67 (m, 3H); 7.87 (dt, 2H, JZ1.8, 7.0 Hz). 13C NMR d: 9.8,
10.0, 20.3, 20.4, 28.4, 28.5, 37.0, 38.1, 55.4, 56.3, 70.0,
70.3, 81.0, 81.4, 127.3, 129.0, 129.2, 129.4, 129.5, 134.3,
134.4, 136.2, 136.3, 155.4, 155.6, 171.3, 171.5. Anal. Calcd
for C23H30N2O5S (446.56): C, 61.86; H, 6.77; N, 6.27.
Found: C, 61.93; H, 6.73; N, 6.31.
11a R = PhCH2 (77%)
11b R = Me2CH (75%)
O
CO H
2
R
N
H
BocHN
12a R = PhCH2 (82%)
12b R = Me2CH (78%)
Scheme 6.
3. Conclusions
In conclusion, a-amido sulfones 6 can be prepared by
reaction of N-carbamoyl amino acid amides with aldehydes
in the presence of benzenesulfinic acid. These sulfones act
as N-acylimino equivalents in the reaction with nucleophiles
giving the corresponding adducts in good yield albeit with
poor diastereoselectivity. Grignard reagents, lithium
enolates of esters and sodium methanenitronate efficiently
add to a-amido sulfones 6. Among the products obtained
with this procedure there are a,a- and a,b-dipeptide systems
that are valuable synthetic intermediates and biologically
active compounds.
4.2.2. tert-Butyl N-(1-benzyl-2-oxo-2-[3-phenyl-1-
(phenylsulfonyl)propyl]aminoethyl)carbamate, 6b.
Yield 95%. White solid mp 115–117 8C. IR (cmK1, KBr)
1
3405, 1693, 1376, 1148. H NMR d (ppm) 1.39 (s, 9H);
1.60–1.83 (m, 2H); 1.88–2.15 (m, 1H); 2.15–2.95 (m, 5H);
4.15–4.40 (m, 1H); 4.84–4.98 (m, 1H); 5.05–5.26 (m, 1H);
5.77–5.86 (m, 1H); 7.06–7.38 (m, 10H); 7.40–7.72 (m, 3H);
7.78–7.95 (m, 2H). Anal. Calcd for C29H34N2O5S (522.66):
C, 66.64; H, 6.56; N, 5.36. Found: C, 66.70; H, 6.61; N, 5.33.
4.2.3. tert-Butyl N-(1-benzyl-2-[3-methyl-1-(phenyl-
sulfonyl)butyl]amino-2-oxoethyl)carbamate, 6c. Yield
81%. Colorless oil. IR (cmK1, neat) 3390, 1698, 1372,
1
4. Experimental
4.1. General
1145. H NMR d (ppm) 0.70–1.03 (m, 6H); 1.45 (s, 9H);
1.55–1.78 (m, 1H); 1.89–2.12 (m, 2H); 2.65–3.04 (m, 2H);
4.08–4.25 (m, 1H); 4.55–4.78 (m, 1H); 5.15–5.36 (m, 2H);
6.30–6.50 (m, 1H); 7.06–7.18 (m, 2H); 7.20–7.40 (m, 3H);
7.44–7.78 (m, 3H); 7.82–7.95 (m, 2H). Anal. Calcd for
C25H34N2O5S (474.61): C, 63.27; H, 7.22; N, 5.90. Found:
C, 63.22; H, 7.26; N, 5.95.
1H NMR were recorded at 300 MHz on a Varian VXR300 in
CDCl3 as solvent. 13C NMR were recorded at 75 MHz in
CDCl3 as solvent. Microanalyses were performed with a
CHNS-O analyzer Model EA 1108 from Fisons Instru-
ments. IR spectra were recorded with a Perkin-Elmer
Paragon 500 FT-IR. GLC analyses were performed on a
Hewlett-Packard 5890 equipped with a capillary column of
fused silica (0.32 mm!25 m), stationary phase SE54. THF
was dried by heating over sodium wire then distilled.
Dichloromethane was dried by heating over calcium
4.2.4. tert-Butyl N-(1-benzyl-2-oxo-2-[1-(phenylsulfonyl)
ethyl]aminoethyl)carbamate, 6d. Yield 93%. White solid
mp 103–105 8C. IR (cmK1, KBr) 3380, 1695, 1375, 1145.
1H NMR diast. A. d (ppm) 1.40 (s, 9H); 1.45 (d, 3H, JZ
6.6 Hz); 2.62–2.91 (m, 2H); 4.11–4.30 (m, 1H); 4.78 (d, 1H,
JZ8.1 Hz); 5.19–5.37 (m, 1H); 6.64 (d, 1H, JZ10.3 Hz);

M. Petrini, M. Seri / Tetrahedron 62 (2006) 960–967
963
7.06–7.12 (m, 2H); 7.18–7.33 (m, 3H); 7.48–7.67 (m, 3H);
7.85–7.93 (m, 2H). Diast. B. d: 1.41 (s, 9H); 1.60 (d, 3H, JZ
7.0 Hz); 2.75–2.98 (m, 2H); 4.15–4.28 (m, 1H); 4.71 (d, 1H,
JZ8.1 Hz); 5.25–5.30 (m, 1H); 6.84 (d, 1H, JZ10.2 Hz);
7.06–7.12 (m, 2H); 7.18–7.33 (m, 3H); 7.48–7.67 (m, 3H);
7.85–7.93 (m, 2H). 13C NMR d: 13.0, 13.3, 28.4, 37.4, 38.4,
55.4, 56.0, 64.8, 65.0, 80.7, 81.0, 127.2, 127.3, 128.9, 129.2,
129.3, 129.4, 129.5, 134.1, 134.3, 136.2, 136.4, 155.4,
155.6, 170.7, 170.9. Anal. Calcd for C22H28N2O5S (432.53):
C, 61.09; H, 6.52; N, 6.48. Found: C, 61.14; H, 6.56; N,
6.53.
1694, 1373, 1145. 1H NMR d (ppm) diast. A. 0.64–0.88 (m,
6H); 1.04 (t, 3H, JZ7.3 Hz); 1.49 (s, 9H); 1.75–1.95 (m,
1H); 1.98–2.10 (m, 2H); 3.80–3.98 (m, 1H); 4.67 (d, 1H,
JZ8.5 Hz); 5.08–5.27 (m, 1H); 6.58 (d, 1H, JZ9.9 Hz);
7.46–7.70 (m, 3H); 7.85–7.96 (m, 2H). Diast. B. d: 0.64–
0.88 (m, 6H); 1.02 (t, 3H, JZ7.3 Hz); 1.47 (s, 9H); 1.75–
1.95 (m, 1H); 2.20–2.43 (m, 2H); 3.63–3.79 (m, 1H); 4.82
(d, 1H, JZ8.6 Hz); 5.08–5.27 (m, 1H); 6.58 (d, 1H, JZ
9.9 Hz); 7.46–7.70 (m, 3H); 7.85–7.96 (m, 2H). 13C NMR d:
10.0, 17.5, 19.4, 20.5, 20.7, 28.4, 28.5, 29.6, 30.3, 60.2,
70.0, 81.4, 129.3, 129.4, 134.2, 136.9, 155.3, 155.5, 171.5,
171.6. Anal. Calcd for C19H30N2O5S (398.53): C, 57.26; H,
7.59; N, 7.03. Found: C, 57.31; H, 7.63; N, 6.98.
4.2.5. Benzyl N-(1-benzyl-2-oxo-2-[phenyl(phenyl-
sulfonyl)methyl]aminoethyl)carbamate, 6e. Yield 81%.
White solid mp 126–128 8C. IR (cmK1, KBr) 3405, 1690,
4.2.10. tert-Butyl N-[2-methyl-1-([3-phenyl-1-(phenyl-
sulfonyl)propyl]aminocarbonyl)propyl] carbamate, 6j.
Yield 87%. White solid mp 112–114 8C. IR (cmK1, KBr)
1
1378, 1150. H NMR d (ppm) 1.40 (s, 9H); 2.80–3.03 (m,
2H); 4.25–4.40 (m, 1H); 4.70–5.05 (m, 2H); 6.23 (d, 1H,
JZ11.3 Hz); 7.10–7.70 (m, 12H); 7.80–7.97 (m, 2H); 8.10–
8.18 (m, 1H). Anal. Calcd for C30H28N2O5S (528.62): C,
68.16; H, 5.34; N, 5.30. Found: C, 68.21; H, 5.37; N, 5.26.
1
3450, 1695, 1375, 1145. H NMR d (ppm) diast. A. 0.70
(d, 3H, JZ7.0 Hz); 0.84 (d, 3H, JZ7.0 Hz); 1.48 (s, 9H);
1.80–2.25 (m, 3H); 2.42–2.90 (m, 2H); 3.83–3.90 (m, 1H);
4.85 (d, 1H, JZ8.9 Hz); 5.10–5.37 (m, 1H); 7.08–7.30 (m,
6H); 7.46–7.66 (m, 3H); 7.85–7.96 (m, 2H). Diast. B. 0.73
(d, 3H, JZ6.6 Hz); 0.76 (d, 3H, JZ6.6 Hz); 1.43 (s, 9H);
1.80–2.25 (m, 3H); 2.42–2.90 (m, 2H); 3.70–3.79 (m, 1H);
5.02 (d, 1H, JZ8.9 Hz); 5.10–5.37 (m, 1H); 7.08–7.30
(m, 6H); 7.46–7.66 (m, 3H); 7.85–7.96 (m, 2H). 13C NMR
d: 14.3, 17.6, 19.4, 21.2, 28.4, 28.5, 28.6, 28.8, 30.6, 31.5,
59.8, 60.6, 68.3, 68.4, 80.5, 80.6, 126.6, 126.7, 128.4, 128.8,
129.1, 129.3, 134.2, 134.3, 136.6, 139.8, 140.0, 156.0,
156.2, 171.5, 171.9. Anal. Calcd for C25H34N2O5S (474.61):
C, 63.27; H, 7.22; N, 5.90. Found: C, 63.33; H, 7.19;
N, 5.94.
4.2.6. Benzyl N-(1-benzyl-2-oxo-2-[1-(phenylsulfonyl)
propyl]aminoethyl)carbamate, 6f. Yield 88%. White
solid mp 138–140 8C. IR (cmK1, KBr) 3400, 1690, 1370,
1
1145. H NMR d (ppm) 0.72 (t, 3H, JZ7.3 Hz, diast. A);
0.93 (t, 3H, JZ7.3 Hz, diast. B); 1.53–1.86 (m, 1H); 2.08–
2.40 (m, 1H); 2.65–2.97 (m, 2H); 4.40–4.58 (m, 1H); 5.00–
5.30 (m, 3H); 5.46 (d, 1H, JZ8.7 Hz, diast. B); 5.52 (d, 1H,
JZ8.9 Hz, diast. A); 7.06–7.70 (m, 13H); 7.80–7.98 (m,
2H). Anal. Calcd for C26H28N2O5S (480.58): C, 64.98; H,
5.87; N, 5.83. Found: C, 65.03; H, 5.83; N, 5.88.
4.2.7. Benzyl N-(1-benzyl-2-oxo-2-[3-phenyl-1-(phenyl-
sulfonyl)propyl]aminoethyl)carbamate, 6g. Yield 89%.
White solid mp 121–123 8C. IR (cmK1, KBr) 3390, 1696,
1370, 1145. 1H NMR d (ppm) 2.37–2.50 (m, 2H); 2.61–2.69
(m, 2H); 2.80–3.00 (m, 2H); 4.22–4.50 (m, 1H); 4.97 (d, 1H,
JZ8.9 Hz); 5.06–5.35 (m, 3H); 6.83–7.70 (m, 19H); 7.79–
7.90 (m, 2H). 13C NMR d: 28.4, 28.5, 31.2, 31.5, 35.4, 37.3,
38.5, 55.9, 56.4, 67.5, 68.4, 68.8, 126.6, 127.4, 128.3, 128.6,
128.7, 128.8, 129.0, 129.2, 129.3, 129.4, 129.5, 134.3,
134.4, 135.9, 136.0, 136.4, 136.6, 139.9, 140.0, 156.0,
156.3, 170.9. Anal. Calcd for C32H32N2O5S (556.67): C,
69.04; H, 5.79; N, 5.03. Found: C, 69.00; H, 5.82; N, 4.99.
4.2.11. tert-Butyl N-[1-([cyclohexyl(phenylsulfonyl)
methyl]aminocarbonyl)-2-methylpropyl] carbamate,
6k. Yield 90%. Waxy solid. IR (cmK1, neat) 3400, 1690,
1
1375, 1145. H NMR d (ppm) diast. A. 0.66 (d, 3H, JZ
7.0 Hz); 0.81 (d, 3H, JZ7.0 Hz); 0.98–1.45 (m, 5H); 1.50
(s, 9H); 1.60–1.88 (m, 4H); 1.89–2.07 (m, 1H); 2.10–2.22
(m, 1H); 2.40–2.58 (m, 1H); 3.70 (dd, 1H, JZ6.6, 8.8 Hz);
4.68 (d, 1H, JZ8.1 Hz); 5.13 (dd, 1H, JZ3.7, 10.6 Hz);
6.79 (d, 1H, JZ11.0 Hz); 7.47–7.65 (m, 3H); 7.88–7.95
(m, 2H). Diast. B. 1H NMR d: 0.69 (d, 3H, JZ6.6 Hz); 0.78
(d, 3H, JZ6.6 Hz); 0.98–1.45 (m, 5H); 1.48 (s, 9H);
1.60–1.88 (m, 4H); 1.89–2.07 (m, 1H); 2.10–2.22 (m, 1H);
2.40–2.58 (m, 1H); 3.87 (dd, 1H, JZ5.8, 8.1 Hz); 4.85
(d, 1H, JZ8.7 Hz); 5.13 (dd, 1H, JZ3.7, 10.6 Hz); 6.79
(d, 1H, JZ11.0 Hz); 7.47–7.65 (m, 3H); 7.88–7.95 (m, 2H).
13C NMR d: 17.6, 19.4, 19.5, 25.5, 25.8, 27.5, 28.5, 30.9,
36.8, 37.0, 60.2, 72.2, 80.7, 128.7, 128.9, 129.2, 134.1,
137.9, 156.0, 156.2, 171.4, 171.5. Anal. Calcd for
C25H36N2O5S (476.63): C, 63.00; H, 7.61; N, 5.88.
Found: C, 63.06; H, 7.65; N, 5.82.
4.2.8. N1-[1-(Phenylsulfonyl)propyl]-2-(1,3-dioxo-
2,3-dihydro-1H-2-isoindolyl)-3-phenylpropanamide, 6h.
Yield 78%. Colorless oil. IR (cmK1, neat) 3300, 1690, 1370,
1
1145. H NMR d (ppm) 0.98 (t, 3H, JZ7.3 Hz, diast. B);
1.06 (t, 3H, JZ7.3 Hz, diast. A); 1.65–1.90 (m, 1H); 2.20–
2.44 (m, 1H); 3.29–3.35 (m, 2H); 4.79 (t, 1H, JZ8.1 Hz,
diast. A); 4.92 (dd, 1H, JZ7.0, 9.5 Hz, diast. B); 5.18–5.25
(m, 1H); 7.00–7.20 (m, 5H); 7.40–7.90 (m, 9H). 13C NMR
d: 10.0, 10.1, 20.1, 20.3, 34.7, 34.7, 55.8, 55.9, 70.3, 70.5,
123.7, 123.8, 127.2, 127.3, 128.7, 128.9, 129.1, 129.3,
134.2, 134.4, 134.5, 134.6, 136.1, 136.2, 136.4, 136.8,
167.9, 168.2, 168.5. Anal. Calcd for C26H24N2O5S (476.55):
C, 65.53; H, 5.08; N, 5.88. Found: C, 65.59; H, 5.12; N,
5.91.
4.2.12. tert-Butyl N-[2-methyl-1-([1-(phenylsulfonyl)
decyl]aminocarbonyl)propyl]carbamate, 6l. Yield 83%.
White solid mp 95–98 8C. IR (cmK1, KBr) 3400, 1690,
1
1370, 1145. H NMR d (ppm) diast. A. 0.72 (d, 3H, JZ
6.6 Hz); 0.84 (t, 3H, JZ7.0 Hz); 0.88–0.95 (m, 3H); 1.20–
1.38 (m, 14H); 1.49 (s, 9H); 1.60–1.70 (m, 2H); 1.90–2.10
(m, 1H); 3.82–3.90 (m, 1H); 4.71 (d, 1H, JZ8.6 Hz);
5.17–5.35 (m, 1H); 6.64–6.80 (m, 1H); 7.50–7.73 (m, 3H);
7.86–7.95 (m, 2H). Diast. B. 0.71 (d, 3H, JZ6.6 Hz); 0.84
4.2.9. tert-Butyl N-[2-methyl-1-([1-(phenylsulfonyl)
propyl]aminocarbonyl)propyl]carbamate, 6i. Yield
91%. White solid mp 152–154 8C. IR (cmK1, KBr) 3405,

964
M. Petrini, M. Seri / Tetrahedron 62 (2006) 960–967
(t, 3H, JZ7.0 Hz); 0.88–0.95 (m, 3H); 1.20–1.38 (m, 14H);
1.46 (s, 9H); 1.60–1.70 (m, 2H); 2.13–2.35 (m, 1H);
3.69–3.76 (m, 1H); 4.86 (d, 1H, JZ8.8 Hz); 5.17–5.35
(m, 1H); 6.64–6.80 (m, 1H); 7.50–7.73 (m, 3H); 7.86–7.95
(m, 2H). 13C NMR d: 14.3, 17.5, 19.4, 19.5, 22.8, 24.9, 25.3,
27.0, 28.4, 30.4, 59.9, 60.0, 76.9, 81.4, 81.5, 129.1, 129.3,
129.4, 131.7, 134.2, 136.8, 155.9, 156.0, 171.4, 171.5. Anal.
Calcd for C26H44N2O5S (496.70): C, 62.87; H, 8.93;
N, 5.64. Found: C, 62.93; H, 8.89; N, 5.61.
141.7, 141.8, 155.6, 170.4, 170.5. Anal. Calcd for
C23H30N2O3 (382.50): C, 72.22; H, 7.91; N, 7.32. Found:
C, 72.27; H, 7.96; N, 7.33.
4.3.2. tert-Butyl N-1-benzyl-2-[(1,3-diphenylpropyl)
amino]-2-oxoethylcarbamate, 7b. Yield 90%. Waxy
1
solid. IR (cmK1, neat) 3400, 1695. H NMR d (ppm) 1.40
(s, 9H); 1.85–2.10 (m, 2H); 2.38–2.65 (m, 2H); 4.2–4.43
(m, 1H); 4.80–5.10 (m, 2H); 6.00–6.18 (m, 1H); 7.05–7.38
(m, 15H). 13C NMR d: 28.45, 32.4, 32.6, 37.9, 38.4, 53.3,
53.4, 56.3, 80.2, 126.1, 126.7, 127.1, 127.6, 127.8, 128.5,
128.6, 128.8, 128.9, 129.4, 129.5, 133.4, 136.8, 136.9,
141.3, 141.6, 157.1, 170.4, 170.5. Anal. Calcd for
C29H34N2O3 (458.60): C, 75.95; H, 7.47; N, 6.11. Found:
C, 76.01; H, 7.43; N, 6.13.
4.2.13. tert-Butyl N-(2-oxo-1-phenyl-2-[1-(phenyl-
sulfonyl)propyl]aminoethyl)carbamate, 6m. Yield 92%.
White solid mp 143–146 8C. IR (cmK1, KBr) 3390, 1695,
1
1370, 1145. H NMR d diast. A. 0.81 (t, 3H, JZ7.3 Hz);
1.41 (s, 9H); 1.63–1.90 (m, 1H); 2.16–2.47 (m, 1H);
5.08–5.25 (m, 2H); 5.42 (d, 1H, JZ8.0 Hz); 6.60–6.78
(m, 1H); 7.15–7.37 (m, 5H); 7.44–7.67 (m, 3H); 7.87–7.98
(m, 2H). Diast. B. 1.06 (t, 3H, JZ7.3 Hz); 1.41 (s, 9H);
1.63–1.90 (m, 1H); 2.16–2.47 (m, 1H); 5.08–5.25 (m, 2H);
5.59 (d, 1H, JZ8.3 Hz); 6.60–6.78 (m, 1H); 7.15–7.37 (m,
5H); 7.44–7.67 (m, 3H); 7.87–7.98 (m, 2H). 13C NMR d:
9.6, 10.0, 20.3, 20.6, 28.4, 58.6, 58.9, 70.2, 70.3, 77.4 80.5,
80.6, 127.3, 127.4, 128.5, 128.9, 129.3, 133.9, 134.2, 136.4,
136.6, 137.1, 137.2, 155.1, 155.2, 170.4, 171.4. Anal. Calcd
for C22H28N2O5S (432.53): C, 61.09; H, 6.52; N, 6.48.
Found: C, 61.13; H, 6.58; N, 6.52.
4.3.3. tert-Butyl N-1-benzyl-2-[(3-methyl-1-phenylbutyl)
amino]-2-oxoethylcarbamate, 7c. Yield 77%. White solid
1
mp 148–151 8C. IR (cmK1, KBr) 3400, 1690. H NMR d
(ppm) 0.86 (d, 3H, JZ6.6 Hz); 0.89 (d, 3H, JZ6.6 Hz);
1.44 (s, 9H); 1.5–1.83 (m, 3H); 2.91–3.15 (m, 2H);
4.20–4.36 (m, 1H); 4.80–5.20 (m, 2H); 5.90–6.10
(m, 1H); 7.05–7.38 (m, 10H). 13C NMR d: 22.4, 22.5,
24.9, 25.0, 28.4, 38.4, 45.7, 51.7, 51.9, 56.2, 80.4, 126.6,
1271, 127.3, 128.7, 128.9, 129.5, 129.6, 142.4, 142.6, 155.9,
170.3, 170.4. Anal. Calcd for C25H34N2O3 (410.55): C,
73.14; H, 8.35; N, 6.82. Found: C, 73.19; H, 8.31; N, 6.85.
4.2.14. tert-Butyl 2-([1-(phenylsulfonyl)propyl]amino
carbonyl)-1-pyrrolidinecarboxylate, 6n. Yield 90%.
4.3.4. tert-Butyl N-1-benzyl-2-oxo-2-[(1-phenylpropyl)
amino]methylcarbamate, 7d. Yield 84% Spectroscopic
data are in full agreement with those reported.17
1
Yellow oil. IR (cmK1, neat) 3400, 1690, 1370, 1148. H
NMR d diast. A. 1.00 (t, 3H, JZ7.3 Hz); 1.48 (s, 9H);
1.63–1.93 (m, 4H); 2.19–2.40 (m, 2H); 3.16–3.45 (m, 2H);
4.08–4.30 (m, 2H); 5.02–5.29 (m, 1H); 7.44–7.70 (m, 3H);
7.80–7.96 (m, 2H). Diast. B. 1.07 (t, 3H, JZ7.3 Hz); 1.53
(s, 9H); 1.63–1.93 (m, 4H); 2.19–2.40 (m, 2H); 3.16–3.45
(m, 2H); 4.08–4.30 (m, 2H); 5.02–5.29 (m, 1H); 7.44–7.70
(m, 3H); 7.80–7.96 (m, 2H). Anal. Calcd for C19H28N2O5S
(396.50): C, 57.56; H, 7.12; N, 7.07. Found: C, 57.61; H,
7.16; N, 7.03.
4.3.5. Benzyl N-1-benzyl-2-oxo-2-[(1-phenylpropyl)
amino]ethyl carbamate, 7e. Yield 88%. White solid mp
110–112 8C. IR (cmK1, KBr) 3405, 1690. 1H NMR d (ppm)
0.72 (t, 3H, JZ7.5 Hz, diast. A); 0.80 (t, 3H, JZ7.3 Hz,
diast. B); 1.55–1.80 (m, 2H); 2.85–3.20 (m, 2H); 4.33–4.56
(m, 1H); 4.68–4.90 (m, 1H); 5.05 (s, 2H); 5.45–5.70 (m,
1H); 6.15–6.38 (m, 1H); 7.02–7.40 (m, 15H). 13C NMR d:
10.6, 10.7, 29.1, 38.8, 39.0, 55.1, 55.3, 56.6, 67.2, 126.6,
127.0, 127.4, 128.1, 128.3, 127.7, 128.9, 129.4, 129.5,
136.3, 136.7, 141.8, 156.1, 170.2, 170.3. Anal. Calcd for
C26H28N2O3 (416.52): C, 74.98; H, 6.78; N, 6.73. Found: C,
74.92; H, 6.73; N, 6.75.
4.3. General procedure for the reaction of phenyl-
sulfonyl derivatives 6 with PhMgBr
Sulfone 6 (1 mmol) was dissolved in dry THF (15 mL) and
the solution was cooled to K78 8C. Phenylmagnesium
bromide (2 mmol, 1 M in THF) was then added dropwise
over 5 min and after 1 h at K78 8C the mixture was
quenched with saturated aqueous NH4Cl (8 mL). After
extraction of the aqueous phase with CH2Cl2 (3!15 mL)
the organic extracts were dried over MgSO4. Evaporation of
the solvent at reduced pressure gave the crude phenyl
derivative, which was purified by column chromatography
(hexanes/ethyl acetate 8:2).
4.3.6. N1-(1-Phenylpropyl)-2-(1,3-dioxo-2,3-dihydro-1H-
2-isoindolyl)-3-phenylpropanamide, 7f. Yield 71%. Waxy
1
solid. IR (cmK1, neat) 3400, 1695. H NMR d (ppm) 0.70
(t, 3H, JZ7.3 Hz, diast. A); 0.81 (t, 3H, JZ7.3 Hz, diast.
B); 1.50–1.80 (m, 2H); 3.33–3.84 (m, 2H); 4.20–4.36
(m, 1H); 4.55–4.77 (m, 1H); 5.47–5.55 (m, 1H, diast. A);
5.75–5.85 (m, 1H, diast. B); 6.80–7.30 (m, 11H); 7.38–7.60
(m, 2H); 7.78–7.90 (m, 1H). Anal. Calcd for C26H24N2O3
(412.48): C, 75.71; H, 5.86; N, 6.79. Found: C, 75.77; H,
6.85; N, 6.82.
4.3.1. tert-Butyl N-1-benzyl-2-oxo-2-[(1-phenylpropyl)
amino]ethylcarbamate, 7a. Yield 85%. Colorless oil. IR
(cmK1, neat) 3405, 1695. 1H NMR d (ppm) 0.74 (t, 3H, JZ
7.3 Hz, diast. A); 0.83 (t, 3H, JZ7.3 Hz, diast. B); 1.41 (s,
9H); 1.57–1.85 (m, 2H); 2.95–3.18 (m, 2H); 4.23–4.40 (m,
1H); 4.70–4.90 (m, 1H); 5.03–5.21 (m, 1H); 6.10–6.22 (m,
1H); 7.05–7.38 (m, 10H). 13C NMR d: 10.6, 10.7, 27.0, 28.4,
29.2, 38.5, 55.0, 55.1, 56.2, 80.8, 126.7, 127.0, 127.1, 127.3,
127.4, 128.6, 128.8, 128.9, 129.4, 129.5, 136.8, 136.9,
4.3.7. tert-Butyl N-(2-methyl-1-[(1-phenylpropyl)
amino] carbonylpropyl)carbamate, 7g. Yield 91%.
Yellow oil. IR (cmK1, neat) 3390, 1695. 1H NMR d
(ppm) 0.83–1.10 (m, 9H); 1.41 (s, 9H); 1.73–1.89 (m, 2H);
2.05–2.22 (m, 1H); 3.78–3.90 (m, 1H); 4.80–4.97 (m, 1H);
5.00–5.18 (m, 1H); 6.30 (d, 1H, JZ8.4 Hz); 7.18–7.40 (m,
5H). 13C NMR d: 10.9, 11.0, 18.2, 19.5, 19.6, 27.1, 28.5,

M. Petrini, M. Seri / Tetrahedron 62 (2006) 960–967
965
29.3, 29.5, 30.6, 30.8, 55.0, 55.2, 60.6, 80.1, 126.7, 126.8,
127.4, 127.5, 128.8, 142.2, 156.2, 156.3, 171.1, 171.2. Anal.
Calcd for C19H30N2O3 (334.45): C, 68.23; H, 9.04; N, 8.38.
Found: C, 68.26; H, 9.00; N, 8.40.
(m, 1H); 5.02 (s, 2H); 5.63–5.75 (m, 1H); 6.47–6.78
(m, 1H); 7.10–7.38 (m, 10H). 13C NMR d: 10.4, 10.5, 14.2,
26.9, 38.0, 38.3, 38.8, 47.5, 47.7, 56.5, 60.5, 66.8, 126.9,
128.0, 128.1, 128.5, 128.6, 129.3, 136.3, 136.7, 136.8,
155.9, 170.4, 171.4, 171.5. Anal. Calcd for C24H30N2O5
(426.51): C, 67.59; H, 7.09; N, 6.57. Found: C, 67.55;
H, 7.05; N, 6.60.
4.3.8. tert-Butyl N-(1-[(1,3-diphenylpropyl)amino] car-
bonyl-2-methylpropyl)carbamate, 7h. Yield 82%. White
1
solid 133–135 8C. IR (cmK1, KBr) 3395, 1690. H NMR d
(ppm) 0.88 (d, 3H, JZ7.0 Hz); 0.98 (d, 3H, JZ7.0 Hz);
1.41 (s, 9H); 1.62–1.81 (m, 1H); 2.07–2.30 (m, 2H);
2.50–2.76 (m, 2H); 3.78–3.90 (m, 1H); 4.92–5.15 (m, 2H);
6.26–6.42 (m, 1H); 7.15–7.40 (m, 10H). 13C NMR d: 19.5,
19.7, 28.4, 30.5, 30.7, 32.6, 37.9, 38.1, 53.3, 53.4, 60.6,
80.2, 126.2, 126.7, 127.6, 128.5, 128.6, 128.9, 141.4, 141.5,
142.0, 156.1, 171.0. Anal. Calcd for C25H34N2O3 (410.55):
C, 73.14; H, 8.35; N, 6.82. Found: C, 73.18; H, 8.36;
N, 6.88.
4.4.3. Methyl 3-[(2-[(benzyloxy)carbonyl]amino-3-
phenylpropanoyl)amino]-5-phenylpentanoate, 10c.
Yield 69%. White solid mp 89–93 8C. IR (cmK1, KBr)
1
3405, 1738, 1695. H NMR d (ppm) 1.62–1.81 (m, 2H);
2.35–2.57 (m, 4H); 3.00–3.35 (m, 2H); 3.61 (s, 3H); 4.10–
4.25 (m, 1H); 4.28–4.47 (m, 1H); 5.10 (s, 2H); 5.30–5.43
(m, 1H); 6.28–6.40 (m, 1H); 7.10–7.40 (m, 15H). 13C NMR
d: 32.4, 32.6, 35.7, 35.9, 38.2, 38.4, 45.9, 46.1, 51.8, 56.8,
60.0, 60.3, 67.2, 67.5, 126.2, 126.3, 127.0, 127.1127.5,
128.2, 128.3, 128.5, 128.7, 128.8, 128.9, 129.4, 129.5,
136.3, 136.6, 141.3, 141.4, 156.8, 170.3, 170.5, 171.8,
172.0. Anal. Calcd for C29H32N2O5 (488.58): C, 71.29;
H, 6.60; N, 5.73. Found: C, 71.28; H, 6.63; N, 5.70.
4.3.9. tert-Butyl 2-[(1-phenylpropyl)amino]carbonyl-1-
pyrrolidinecarboxylate, 7i. Yield 87%. Yellow oil. IR
(cmK1, neat) 3405, 1695. 1H NMR d (ppm) 0.86 (t, 3H, JZ
7.3 Hz, diast. A); 0.88 (t, 3H, JZ7.5 Hz, diast. B); 1.44
(s, 9H); 1.65–1.98 (m, 4H); 2.10–2.45 (m, 2H); 3.20–3.50
(m, 3H); 4.18–4.45 (m, 1H); 4.80–4.95 (m, 1H); 7.18–7.37
(m, 5H). Anal. Calcd for C19H28N2O3 (332.44): C, 68.65;
H, 8.49; N, 8.43. Found: C, 68.68; H, 8.53; N, 8.39.
4.4.4. Ethyl 3-[2-(1,3-dioxo-2,3-dihydro-1H-2-iso-
indolyl)-3-phenylpropanoyl]aminopentanoate, 10d.
Yield 72%. Waxy solid. IR (cmK1, neat) 3395, 1740,
1
1690. H NMR d (ppm) 0.88 (t, 3H, JZ7.4 Hz, diast. A);
0.89 (t, 3H, JZ7.4 Hz, diast. B); 1.18 (8t, 3H, JZ7.0 Hz);
1.45–1.78 (m 2H); 2.43–2.55 (m, 2H); 3.50–3.63 (m, 2H);
3.95–4.10 (m, 1H); 4.13–4.21 (m, 1H); 5.05–5.15 (m, 1H);
6.68–6.78 (m, 1H); 7.07–7.22 (m, 5H); 7.65–7.70 (m, 2H);
7.75–7.80 (m, 2H). 13C NMR d: 10.7, 10.8, 14.2, 27.0, 27.2,
34.7, 34.9, 37.9, 34.1, 48.1, 48.2, 55.7, 56.0, 60.8, 123.6,
127.0, 128.7, 128.8, 129.0, 129.7, 131.6, 134.3, 136.9,
137.0, 168.0, 168.1, 170.7, 170.8, 171.8, 172.0. Anal. Calcd
for C24H26N2O5 (422.48): C, 68.23; H, 6.20; N, 6.63.
Found: C, 68.28; H, 6.17; N, 6.66.
4.4. General procedure for the preparation of
a,b-dipeptides 10
To a solution of diisopropylamine (3 mmol) in dry THF
(12 mL), BuLi (1.6 M in hexanes, 3.2 mmol, 2.0 mL) was
added at 0 8C and stirring was continued for 0.5 h at 0 8C.
Dry alkyl acetate 9 (3 mmol) was then added at K78 8C and
after stirring at the same temperature for 0.5 h sulfone 6
(1 mmol) dissolved in dry THF (5 mL) was added. Stirring
was continued for 1 h at K78 8C and then the mixture was
quenched by addition of saturated aqueous NH4Cl
(6 mL).The mixture was extracted with CH2Cl2 (4!
15 mL) and dried over MgSO4. The crude product obtained
after evaporation of the solvent was purified by column
chromatography (hexanes/ethyl acetate 75:25).
4.4.5. Ethyl 3-(2-[(tert-butoxycarbonyl)amino]-3-methyl-
butanoylamino)pentanoate, 10e. Yield 67%. White solid
mp 83–86 8C. IR (cmK1, KBr) 3400, 1734, 1695. 1H NMR d
(ppm) 0.88–0.98 (m, 9H); 1.25 (t, 3H, JZ7.0 Hz, diast. B);
1.26 (t, 3H, JZ7.3 Hz, diast. A); 1.44 (s, 9H); 1.50–1.65
(m, 2H); 2.08–2.25 (m, 1H); 2.52 (d, 1H, JZ5.1 Hz, diast.
B); 2.53 (d, 2H, JZ5.5 Hz, diast. A); 3.80–3.95 (m, 1H);
4.10–4.25 (m, 3H); 5.03–5.15 (m, 1H); 6.37–6.57 (m, 1H).
13C NMR d: 10.7, 10.8, 14.3, 19.4, 27.2, 28.4, 30.8, 31.1,
38.3, 38.5, 60.2, 60.3, 79.9, 155.9, 171.1, 171.2, 171.7.
Anal. Calcd for C17H32N2O5 (344.45): C, 59.28; H, 9.36;
N, 8.13. Found: C, 59.26; H, 9.33; N, 8.15.
4.4.1. Ethyl 3-(2-[(tert-butoxycarbonyl)amino]-3-phenyl-
propanoylamino)-3-phenylpropanoate, 10a. Yield 76%.
Colorless oil. IR (cmK1, neat) 3405, 1735, 1690. 1H NMR d
(ppm) 1.12 (t, 3H, JZ7.3 Hz, diast A); 1.13 (t, 3H, JZ
7.3 Hz, diast. B); 1.41 (s, 9H); 2.65–2.85 (m, 2H); 2.93–3.20
(m, 2H); 3.96–4.10 (m, 2H); 4.27–4.44 (m, 1H); 5.05–5.22
(m, 1H); 5.28–5.43 (m, 1H); 6.80–7.00 (m, 1H); 7.05–7.40
(m, 10H). 13C NMR d: 14.0, 14.1, 28.2, 39.7, 39.9, 40.4,
49.3, 49.4, 55.9, 60.6, 60.7, 80.0, 80.1, 126.2, 126.3, 128.5,
128.6, 129.0, 1239.2, 129.3, 129.6, 129.7, 139.0, 140.0,
155.3, 170.3, 170.4, 170.5, 170.7. Anal. Calcd for
C25H32N2O5 (440.53): C, 68.16; H, 7.32; N, 6.36. Found:
C, 68.14; H, 7.35; N, 6.40.
4.4.6. Ethyl 3-(2-[(tert-butoxycarbonyl)amino]-3-methyl
butanoylamino)-3-cyclohexylpropanoate, 10f. Yield
1
75%. Colorless oil. IR (cmK1, neat) 3405, 1735, 1690. H
NMR d (ppm) 0.85–1.00 (m, 8H); 1.10–1.22 (m, 3H); 1.25
(t, 3H, JZ7.3 Hz); 1.42 (s, 9H); 1.60–1.80 (m, 6H); 2.08–
1.30 (1H); 2.50–2.55 (m, 2H); 3.75–3.96 (m, 1H); 4.00–4.20
(m, 3H); 4.95–5.15 (m, 1H); 6.45 (d, 1H, JZ9.1 Hz). Anal.
Calcd for C21H38N2O5 (398.54): C, 63.29; H, 9.61; N, 7.03.
Found: C, 63.33; H, 9.58; N, 7.00.
4.4.2. Ethyl 3-[(2-[(benzyloxy)carbonyl]amino-3-phenyl
propanoyl)amino]pentanoate, 10b. Yield 72%. Colorless
1
oil. IR (cmK1, neat) 3400, 1735, 1690. H NMR d (ppm)
0.65–0.82 (m, 3H); 1.17 (t, 3H, JZ7.0 Hz, diast A); 1.19
(t, 3H, JZ7.0 Hz, diast B); 1.28–1.40 (m, 2H); 2.30–2.48
(m, 2H); 2.90–4.10 (q, 2H, JZ7.0 HzCm, 1H); 4.23–4.42
4.4.7. Ethyl 3-(2-[(tert-butoxycarbonyl)amino]-3-methyl
butanoylamino)dodecanoate, 10g. Yield 65%. Spectro-
scopic data are in full agreement with those reported.14c

966
M. Petrini, M. Seri / Tetrahedron 62 (2006) 960–967
4.4.8. Ethyl 3-(2-[(tert-butoxycarbonyl)amino]-2-phenyl
acetylamino)pentanoate, 10h. Yield 78%. Waxy solid. IR
(cmK1, neat) 3405, 1735, 1690. 1H NMR d (ppm) diast. A.
0.67 (t, 3H, JZ7.0 Hz); 1.23 (dt, 3H, JZ1.1, 7.0 Hz); 1.40
(s, 9H); 1.41–1.60 (m, 2H); 2.50 (d, 2H, JZ5.1 Hz); 4.13
(dq, 2H, JZ1.1, 7.0 Hz); 4.14–4.25 (m, 1H); 5.00–5.17
(m, 1H); 5.78–5.95 (m, 1H); 6.41 (d, 1H, JZ10.0 Hz);
7.22–7.36 (m, 5H). Diast. B. 0.89 (t, 3H, JZ7.0 Hz); 1.15
(dt, 3H, JZ1.1, 7.0 Hz); 1.40 (s, 9H); 1.41–1.60 (m, 2H);
2.39 (d, 2H, JZ5.1 Hz); 3.95 (dq, 2H, JZ1.1, 7.0 Hz);
4.14–4.25 (m, 1H); 5.00–5.17 (m, 1H); 5.78–5.95 (m, 1H);
6.31 (d, 1H, JZ10.0 Hz); 7.22–7.36 (m, 5H). 13C NMR d:
10.4, 10.8, 14.2, 14.3, 27.1, 28.4, 37.9, 38.4, 47.9, 48.0,
58.9, 60.7, 60.7, 77.4, 80.1, 127.6, 128.3, 128.4, 129.0,
129.1, 138.7, 138.9, 155.2, 169.7, 169.8, 171.6, 171.8. Anal.
Calcd for C20H30N2O5 (378.46): C, 63.47; H, 7.99; N, 7.40.
Found: C, 63.43; H, 8.02; N, 7.44.
stirring at room temperature for 1 h the mixture was cooled
by ice bath and then saturated Na2SO3 (10 mL) was added.
The mixture was then acidified with 2 M HCl until pH w5
and then extracted with ethyl acetate (4!15 mL). The
organic solutuion was dried over MgSO4 and after
evaporation of the solvent the crude acid 12 was purified
by column chromatography (dichloromethane/methanol
9:1).
4.6.1. 2-(2-[(tert-Butoxycarbonyl)amino]-2-phenylacetyl
amino)butanoic acid, 12a
Yield 82%. Waxy solid. IR (cmK1, neat) 3400, 1710, 1690.
1H NMR d: 0.78 (t, 3H, JZ7.0 Hz, diast. A); 0.96 (t, 3H,
JZ7.0 Hz, diast. B); 1.39 (s, 9H); 1.65–2.00 (m, 2H);
2.95–3.18 (m, 2H); 4.45–4.68 (m, 2H); 5.36 (m, 1H, diast.
A); 5.58–5.70 (m, 1H, diast. B); 6.55 (br s, 1H); 6.95–7.15
(m, 1H); 7.20–7.35 (m, 5H). Anal. Calcd for C17H24N2O5
(336.38): C, 60.70; H, 7.19; N, 8.33. Found: C, 60.66; H,
7.20; N, 8.29.
4.5. General procedure for preparation of nitro
derivatives 11
To a stirred suspension of NaH (3 mmol) in dry THF
(10 mL), nitromethane (3 mmol) was added dropwise at
room temperature. After stirring for 30 min, the appropriate
sulfone 6 (1 mmol) dissolved in dry THF (5 mL) was added
and the white suspension was stirred at room temperature
for 30 min. The reaction was quenched by addition of
saturated aqueous NH4Cl (4 mL), was extracted with CHCl3
(4!15 mL) and then dried over MgSO4. The crude nitro
derivative 11 obtained after removal of the solvent was
purified by column chromatography (hexanes/ethyl acetate
7:3).
4.6.2. 2-(2-[(tert-Butoxycarbonyl)amino]-3-methyl
butanoylamino)butanoic acid, 12b
Yield 78%. Spectroscopic data are in full agreement with
those reported.18
Acknowledgements
Financial support from University of Camerino and MIUR
`
(National Project “Sintesi e Reattivita-attivita di Sistemi
Insaturi Funzionalizzati”) is gratefully acknowledged.
`
4.5.1. tert-Butyl N-(2-[1-(nitromethyl)propyl]amino-2-
oxo-1-phenylethyl)carbamate, 11a. Yield 77%. White
1
solid mp 73–77 8C. IR (cmK1, KBr) 3400, 1695, 1550. H
NMR d (ppm) 0.87 (t, 3H, JZ7.3 Hz, diast. A); 0.92 (t, 3H,
JZ7.3 Hz, diast. B); 1.42 (s, 9H, diast. A); 1.43 (s, 9H,
diast. B); 1.50–1.70 (m, 2H); 2.98–3.17 (m, 2H); 4.20–4.42
(m, 3H); 4.45–4.55 (m, 1H); 4.90–5.08 (m, 1H); 6.23–6.42
(m, 1H); 7.16–7.40 (m, 5H). Anal. Calcd for C17H25N3O5
(351.40): C, 58.11; H, 7.17; N, 11.96. Found: C, 58.15; H,
7.20; N, 11.99.
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