New chiral building blocks of β-peptoid analogs

Article abstract of DOI:10.1016/j.tet.2009.09.041

The synthesis of chiral functionalized β-amino esters via the hydride reductive amination of chiral allenes was explored. These compounds can be regarded as β-peptoids building blocks bearing a chiral side chain at the nitrogen and at the same time retaining the β-amino acid side chain. β-Enamino esters were obtained from the nucleophilic addition of α-amino esters (l-Ala, d-Ala, l-Phe, l-Leu, l-Trp and d-Trp methyl esters) to 2,3-allenoates bearing a chiral auxiliary, which determines the stereochemistry outcome of the subsequent reduction reaction. It was also demonstrated that in the reduction of β-enamino esters derived from l-Pro and d-Pro methyl esters the chirality of the new chiral center is controlled by the α-amino ester moiety.

Full text of DOI:10.1016/j.tet.2009.09.041

Tetrahedron 65 (2009) 9116–9124
Contents lists available at ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
New chiral building blocks of b-peptoid analogs
a
a
b
b
´
Ana Lucia Cardoso , Susana M.M. Lopes , Ana Matos Beja , Manuela Ramos Silva ,
c
a,
c
*
´
Jesus M. de los Santos , Teresa M.V.D. Pinho e Melo , Francisco Palacios
a Department of Chemistry, University of Coimbra, 3004-535 Coimbra, Portugal
b Department of Physics, University of Coimbra, 3004-516 Coimbra, Portugal
c Department of Organic Chemistry I, Faculty of Pharmacy, University of the Basque Country, P.O. Box 450, 01080 Vitoria, Spain
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 27 June 2009
Received in revised form 8 September 2009
Accepted 10 September 2009
Available online 15 September 2009
The synthesis of chiral functionalized
b
-amino esters via the hydride reductive amination of chiral al-
lenes was explored. These compounds can be regarded as
chain at the nitrogen and at the same time retaining the
obtained from the nucleophilic addition of -amino esters (
methyl esters) to 2,3-allenoates bearing a chiral auxiliary, which determines the stereochemistry out-
come of the subsequent reduction reaction. It was also demonstrated that in the reduction of -enamino
esters derived from -Pro and -Pro methyl esters the chirality of the new chiral center is controlled by
the -amino ester moiety.
b
b
-peptoids building blocks bearing a chiral side
-amino acid side chain. -Enamino esters were
-Ala, -Ala, -Phe, -Leu, -Trp and -Trp
b
L
a
L
D
L
L
D
b
Keywords:
Chiral allenes
L
D
a
b-Amino acids
b-Amino esters
b-Enamino esters
b-Peptoids
Ó 2009 Elsevier Ltd. All rights reserved.
Asymmetric reduction
R2
1. Introduction
H
H
O
1. R2NH2, MeOH, rt HN
O
O
•
O
b-Amino acids are an important class of compounds due to their
R1
2. Hydride reduction
SO2Ph
O
2
R1
SO2Ph
unique biological properties, their occurrence in natural products
and their use as precursors of biologically and medicinally impor-
1
tant molecules.1 Some
b-amino acids play an important role in the
biological activity of complex molecules such as taxol, one of the
most active antitumor agents. Therefore, the development of new
H
1. R2NH2, MeOH, rt
2. Hydride reduction
H
O
N
H
R1
O
•
R2
synthetic methodologies for the asymmetric synthesis of b-amino
R1
acids is an important goal in organic synthesis.2–7 On the other
hand, the construction of new peptidomimetic backbone aiming to
achieve new structural features and diverse biological activities is
particularly interesting. In fact, distinct folding properties have
O
SO2Ph
SO2Ph
3
4
R1 = H, Me, i-Pr, t-Bu, Bn
R
2 = Bn, C6H4OMe-p, CH2CH=CH2
Scheme 1.
been observed for several unnatural backbones such as
acids and
-peptoids.8
We have recently described a highly selective two-step ap-
proach to chiral -amino esters via the hydride reductive ami-
nation of chiral allenes (1 and 3). It was demonstrated that this
route to chiral -amino esters allows the control of the stereo-
b-amino
b
In connection with our interest in the chemistry of amino-acid10
and aminophosphonate11 derivatives, we now describe a methodo
b
logy to construct molecules with the general structure 5, which can
be regarded as
at the nitrogen and at the same time retaining the
b
-peptoids building blocks bearing a chiral side chain
b
b
-amino acid side
chemistry outcome by the selection of the chiral auxiliary
(Scheme 1).9
chain. These structures with specific spatial disposition of functional
groups can lead to new peptidomimetics. Our approach was to carry
out the reaction of chiral allenes with
reduction. It was also our aim to determine if the presence of
an extra chiral center in the -enamino ester moiety would in-
fluence the stereochemistry outcome of the hydride reduction.
a-amino esters followed by
b
* Corresponding author. Tel.: þ351 239 854475; fax: þ351 23982 6068.
E-mail address: tmelo@ci.uc.pt (T.M.V.D. Pinho e Melo).
0040-4020/$ – see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2009.09.041

A.L. Cardoso et al. / Tetrahedron 65 (2009) 9116–9124
9117
H
N
spectra of some of these compounds recorded at ambient tem-
perature but, as previously observed for -amino esters 2 and 4, the
O
*
*
R
R
b
O
CO2Me
5
spectra are simpler at higher temperature.
The structure of (1R)-(ꢁ)-10-phenylsulfonylisobornyl (S)-3-[(1S)-
1-methoxycarbonylethylamino]butanoate (13a) was determined by
X-ray crystallography (Fig. 1). This allowed us to establish the S con-
2. Results and discussion
figuration to the new chiral center of
b
-amino esters 13, the same
Initially, the hydride reductive amination of an achiral allene
configuration obtained from
b-amino esters derived from achiral
was studied (Scheme 2). Thus, benzyl 2,3-butadienoate (6)12 was
amines and chiral allenes 1,9 with (1R)-(ꢁ)-10-phenylsulfonyliso-
bornyl group as the chiral auxiliary (Scheme 1). Thus, the stereoselec-
tivity was again determined by the (1R)-(ꢁ)-10-phenylsulfonyliso-
bornyl moiety.
reacted with
L-Ala, D-Ala, L-Trp and D-Trp methyl esters followed by
the subsequent reduction with sodium triacetoxyborohydride giv-
ing the corresponding b-amino esters in good yields. Mixtures of
diastereoisomers were obtained as shown by the 1H NMR and 13C
NMR spectra of the products. In fact, we observed that in the 1H
NMR spectrum of 8a recorded at 120 ꢀC is still clear the presence of
a mixture of stereoisomers.
BnO
D-Ala or D-Trp
•
L-Ala or L-Trp
methyl ester
methyl ester
O
MeOH, rt
MeOH, rt
6
BnO
BnO
O
HN
O
HN
R
R
CO2Me
CO2Me
7a 75%
7b 75%
9a 81%
9b 73%
NaBH(OAc)3/AcOH
0 °C, 4h
NaBH(OAc)3/AcOH
0 °C, 4h
H
H
N
a R = H
b R =
BnO
N
BnO
*
*
R
R
O
CO2Me
O
CO2Me
N
8a 89% (57:43)
8b 78% (66:34)
10a 96% (56:44)
10b 78% (66:34)
H
Scheme 2.
Aiming to achieve stereoselective synthesis of this type of
functionalized -amino esters, the hydride reductive amination of
chiral allenes 1a13 and 3a13 with
-amino esters was carried out
(Scheme 3). The reaction of chiral allenes 1a and 3a with methyl
esters of -alanine, -phenylalanine, -leucine and -tryptophan
gave the corresponding -enamino esters (11 and 12), obtained in
yields ranging from 69 to 94%. The reduction of chiral -enamino
b
a
L
L
L
L
b
b
Figure 1. X-ray structure of (1R)-(ꢁ)-10-phenylsulfonylisobornyl (S)-3-[(1S)-1-
methoxycarbonylethylamino]butanoate (13a).
esters 11a–11d and 12a–12d was carried out with sodium tri-
acetoxyborohydride9,14 in acetic acid giving the corresponding
chiral
b-amino esters stereoselectively and in good yields (Table 1).
However, two rotamers are observed in the 1H NMR and 13C NMR
These results indicate that the presence of the (1R)-(ꢁ)-10-
phenylsulfonylisobornyl or (1S)-(þ)-10-phenylsulfonylisobornyl
unit of allenonates 1a and 3a, respectively, is a requirement to
achieve the selective synthesis of the chiral
To confirm this observation we carried out the Michael addition
-amino acids to chiral allene 3a followed by reduction
(Scheme 4). The -amino esters 16a and 16b derived from -alanine
methyl ester and -tryptophan methyl ester, respectively, were
b-amino esters.
•
O
O
•
of
D-a
b
D
1a
O
O
3a
SO2Ph
SO2Ph
D
-amino ester
MeOH, rt
α
α-amino ester
obtained selectively. The structure of (1S)-(þ)-10-phenylsulfonyl-
isobornyl (R)-3-[(1R)-1-methoxycarbonylethylamino]butanoate (16a)
was determined by X-ray crystallography showing that the new
chiral center has R configuration (Fig. 2). This is the expected
configuration considering that the chirality was induced by the
(1S)-(ꢁ)-10-phenylsulfonylisobornyl unit. In fact, compound 16a
MeOH, rt
O
O
MeO2C
R
NH
O
SO2Ph
O
HN
R
SO2Ph
CO2Me
12
11
is the enantiomer of b-amino ester 13a showing opposite values
for the optical rotation. In a similar way it was observed that
a new chiral center with R configuration was created in the
11a R = H
11b R = Ph
11c R = Me2CH
69%
81%
86%
12a R = H
88%
80%
70%
12b R = Ph
12c R = Me2CH
12d R = 3-indolyl 76%
synthesis of 16b. Compound 16b is the enantiomer of
b-amino
11d R = 3-indolyl 94%
ester 13d as indicated also by the opposite value of the optical
Scheme 3.
rotation.

9118
A.L. Cardoso et al. / Tetrahedron 65 (2009) 9116–9124
Table 1
Reduction of
b-Enamino Esters 11 and 12 to b-Amino Esters 13 and 14
CO2Me
R
H
N
O
HN
O
O
O
R
i
i
MeO2C
R
NH
O
O
O HN
SO2Ph
SO2Ph
SO2Ph
O
CO2Me
R
SO2Ph
CO2Me
13
11
12
14
i NaBH(OAc)3/AcOH, 0 °C, 4h
i NaBH(OAc)3/AcOH, 0 °C, 4h
D
D
Entry
Product
R
Yield, %
[
a
]
Entry
Product
R
Yield, %
[a]
20
20
1
2
3
4
13a
13b
13c
13d
H
Ph
Me2CH
3-Indolyl
88
98
93
75a
þ20
þ35
þ30
þ40
5
6
7
8
14a
14b
14c
14d
H
Ph
Me2CH
3-Indolyl
88
95
95
95a
ꢁ30
ꢁ45
ꢁ30
ꢁ45
a
Reaction time: 12 h.
In order to get further insight into the role of both chiral
auxiliaries, the 10-phenylsulfonylisobornyl unit and the -amino
ester moiety, the reduction of -enamino esters derived from
and -Pro methyl esters was also studied.
The reaction of benzyl 2,3-butadienoate with
a
D-Ala or D-Trp
b
L
-Pro
methyl ester
O
O
•
D
MeOH, rt
O
HN
L
-Pro and
D
-Pro
R
O
SO2Ph
3a
SO2Ph
methyl esters followed by reduction with triacetoxyborohydride
was carried out (Scheme 5). The corresponding -amino esters
CO2Me
b
D
α
[ ]
20 = - 85
15a 80%
15b 82%
were obtained as mixtures of diastereoisomers in good yields.
However, in this case the 1H NMR and 13C NMR spectra of the
products 18 and 20 show clearly a major stereoisomer indicating
a R = H
b R =
D
α
[ ]
20 = + 20
that the a-amino esters act as a chiral auxiliary in the reduction
NaBH(OAc)3/AcOH
0 °C, 4h
N
H
reaction. The mixture of stereoisomers in the 1H NMR spectrum of
18 recorded at 120 ꢀC is still very clear.
H
N
BnO
•
[α]D
O
16a 74%
16b 84%
20 = - 20
R
O
[α]2D0 = - 40
O
CO2Me
D-Pro
L-Pro
6
SO2Ph
methyl ester
methyl ester
MeOH, rt
96%
MeOH, rt
Scheme 4.
94%
BnO
BnO
O
N
O
N
CO2Me
CO2Me
D
[ ]D
20 = - 80
[ ]20
17
19
α
= + 80
α
NaBH(OAc)3/AcOH
0 °C, 4h
NaBH(OAc)3/AcOH 78% (71:29)
0 °C, 4h
86% (70:30)
BnO
BnO
O
N
O
N
CO2Me
CO2Me
D
D
18
= - 40
= + 43
[α]20
[α]20
20
Scheme 5.
The reductive amination of chiral allenes 1a and 3a using the
-amino methyl esters of -Pro and -Pro led to a different outcome
(Scheme 6). The -enamino esters 21, 23, 25 and 27 were obtained
in yields ranging from 78% to 89% and its reduction led to the
corresponding chiral -amino esters as single stereoisomers in high
yield. The structure of (1S)-(þ)-10-phenylsulfonylisobornyl (S)-3-
[(2S)-(2-methoxycarbonylpyrrolid-1-yl)]butanoate (28) was also
determined by X-ray crystallography showing that the new chiral
center has S configuration (Fig. 3).
a
L
D
b
Figure 2. ORTEP diagram of (1S)-(þ)-10-phenylsulfonylisobornyl (R)-3-[(1R)-1-me-
thoxycarbonylethylamino]butanoate (16a).
b
These results support the conclusion that the chiral auxiliary in
the ester moiety of the
b-enamino esters is responsible for the
chiral induction of the reduction reaction. We can therefore assert
that a chiral center with S configuration was created in the syn-
If the stereochemistry outcome was controlled by the selection
of the chiral auxiliary in the ester moiety, the (1S)-(þ)-10-phenyl-
thesis of
b-amino esters 13a–13d whereas in the synthesis of
b
-
sulfonylisobornyl unit in b-enamino ester 27 should induce the
amino esters 14a–14d a chiral center with R configuration was
created.
generation of a chiral center with R configuration. In fact, we also
observed that
-amino ester 24, with the (1R)-(ꢁ)-10-
b

A.L. Cardoso et al. / Tetrahedron 65 (2009) 9116–9124
9119
iii
iii
O
N
O
O
N
O
MeO2C
CO2Me
N
O
O
O
O
N
MeO2C
SO2Ph
= + 75
SO2Ph
CO2Me
SO2Ph
SO2Ph
[ ]D
D
D
D
α
21 81%
α
25 78%
α
20 = - 73
[ ]20
22 91% [ ]
α
20 = - 14
20 = + 20
26 95%
[ ]
i L-Pro methyl ester, MeOH, rt
ii D-Pro methyl ester, MeOH, rt
iii NaBH(OAc)3/AcOH 0 °C, 4h
ii
i
3a
1a
i
ii
iii
iii
O
O
N
O
O
N
O
N
N
O
MeO2C
CO2Me
O
CO2Me
O
MeO2C
SO2Ph
SO2Ph
SO2Ph
SO2Ph
D
D
[α]2D0 = + 130
[α]20
28 96% [α]D
20 = - 66
23 89%
24 90%
= + 65
= - 130
27 85% [α]20
Scheme 6.
esters. The Michael addition of
L-Ala,
D-Ala, L-Phe, L-Leu, L-Trp and
D-Trp methyl esters to chiral allenes followed by hydride reduction
gave functionalized
b
-amino esters as single diastereoisomers. The
-enamino
-amino esters, which are
obtained exclusively: (1R)-(ꢁ)-10-phenylsulfonylisobornyl -enam-
inoesters gave -amino esters with S configurationwhereas the (1S)-
(þ)-10-phenylsulfonylisobornyl -enamino esters led to -amino
esters with R configuration. However, in the reduction of -enamino
esters derived from -Pro and -Pro methyl esters, the chirality of the
newchiral center is controlled by the -amino ester moiety, although
the presence of the 10-phenylsulfonylisobornyl unit is a requirement
to ensure the formation of a single diastereoisomer. Reduction of
enamino esters derived from -Pro leads to -amino esters with S
configuration, whereas the configuration of the new chiral center of
-amino esters derived from -Pro is R.
nature of the chiral auxiliary in the ester moiety of the
esters determines the chirality of the
b
b
b
b
b
b
b
L
D
a
b-
L
b
b
D
4. Experimental
4.1. General
Figure 3. X-ray structure of (1S)-(þ)-10-phenylsulfonylisobornyl (S)-3-[(2S)-(2-me-
thoxycarbonylpyrrolid-1-yl)]butanoate (28).
1H NMR spectra were recorded on a Bruker Avance III in-
strument operating at 400 MHz. 13C NMR spectra were recorded
on a Bruker Avance III instrument operating at 100 MHz. The
solvent is deuteriochloroform except where indicated otherwise.
IR spectra were recorded on a Perkin Elmer 1720X FTIR spec-
phenylsulfonylisobornyl unit, showed opposite value for the optical
rotation of the one of
b-amino ester 28 indicating that they are
indeed enantiomers. Therefore, the new chiral center of
b
-amino
ester 24 has R configuration. In a similar way, we conclude that
amino esters 22 and 26 are enantiomers.
b-
trometer. Mass spectra were recorded on
a HP GC 6890/
MSD5973 instrument under electron impact (EI) except where
indicated otherwise. HRMS spectra were recorded on a Finnigan
MAT95 S instrument. Optical rotations were measured on an
Optical Activity AA-5 electrical polarimeter. Mp were recorded
on a Reichert hot stage and are uncorrected. Flash column
chromatography was performed with Merck 9385 silica as the
stationary phase.
These results show that in the case of
from -proline and -proline methyl esters the chirality of the
-amino ester influences the stereochemistry of the new chiral
center leading to an inversion of the configuration. However, the
presence of the -amino ester moiety does not in itself justify the
observed stereoselectivity in the formation of -amino esters 22,
24, 26 and 28. Therefore, we can conclude that to obtain the ex-
clusive formation of -amino esters derived from -Pro and -Pro
methyl esters it is necessary the presence of both chiral auxiliaries,
b-enamino esters derived
L
D
a
a
b
b
L
D
4.2. General procedure for the synthesis of b-enamino esters
the 10-phenylsulfonylisobornyl unit and the a-amino ester.
The appropriated allene (5 mmol) was dissolved in dry metha-
nol (50 mL) followed by the dropwise addition of the amino ester15
(5 mmol). The reaction mixture was stirred overnight at room
temperature. The solvent was evaporated off and the product
crystallized.
3. Conclusion
Herein, we report the synthesis of new chiral
blocks via the reductive amination of chiral allenes with
b
-peptoids building
a-amino

9120
A.L. Cardoso et al. / Tetrahedron 65 (2009) 9116–9124
4.2.1. Benzyl (Z)-3-[(S)-1-ethoxycarbonylethylamino]but-2-enoate
7a. Obtained as an oil (75%); IR (film) 1147, 1263, 1607, 1655 and
7.43–7.60 (3H, m, Ar-H), 7.85–7.93 (2H, m, Ar-H), 8.75 (1H, br d,
J¼9.4 Hz, NH); 13C NMR 19.2, 19.9, 20.3, 27.1, 29.3, 39.9, 40.0, 44.1,
48.8, 49.9, 52.4, 55.1, 57.9, 75.3, 84.8, 127.0, 127.8, 128.6, 129.1, 129.3,
133.5, 136.2, 140.5, 159.5, 168.4, 172.0; MS (CI) m/z 540 (MHþ, 82),
1745; 1H NMR (400 MHz, CDCl3)
d
1.48 (3H, d, J¼6.8 Hz), 1.89 (3H,
s), 3.75 (3H, s), 4.15–4.23 (1H, m), 4.61 (1H, s), 5.12 (2H, br s), 7.26–
7.35 (5H, m, ArH), 8.75 (1H, br d, J¼7.6 Hz, NH); 13C NMR (100 MHz,
277 (37), 246 (100); HRMS (CI) m/z 540.2415 (C30H38NO6S [MHþ],
D
CDCl3)
d
19.3, 19.4, 51.4, 52.5, 64.5, 84.3, 127.7, 127.9, 128.4, 137.3,
540.2419). [
a]
20 ꢁ50 (c 1, CH2Cl2).
160.4, 169.9, 173.2; MS (EI) m/z 277 (Mþ, 34%), 218 (43), 186 (24),
143 (25), 110 (38), 91 (100); HRMS (EI) m/z 277.1316 (C15H19NO4
4.2.7. (1R)-(ꢁ)-10-Phenylsulfonylisobornyl (Z)-3-[(1S)-3-methyl-1-me-
thoxycarbonylbutylamino]but-2-enoate 11c. Obtained as an oil (86%).
D
[Mþ], 277.1314). [
a
]
20
þ130 (c 1, CH2Cl2).
IR (KBr) 1613,1660, 1750, 2964 cmꢁ1; 1H NMR
d 0.84–0.96 (12H, m),
4.2.2. Benzyl (Z)-3-[(R)-1-ethoxycarbonylethylamino]but-2-enoate
9a. Obtained as an oil (81%); IR (film) 1147, 1263, 1607, 1654 and
1.14–1.25 (2H, m), 1.54–2.02 (6H, m), 1.88 (3H, s), 3.00 (1H, d,
J¼14.4 Hz), 3.73 (1H, d, J¼14.4 Hz), 3.79 (3H, s), 4.10–4.12 (1H, m),
4.21 (1H, dd, J¼3.2 and 7.7 Hz), 4.37 (1H, s), 7.48–7.65 (3H, m, Ar-H),
7.86–7.93 (2H, m, Ar-H), 8.51 (1H, br d, J¼8.9 Hz, NH); 13C NMR 19.4,
19.9, 20.4, 21.7, 22.7, 24.5, 27.1, 29.3, 39.9, 41.9, 44.1, 48.8, 49.9, 52.4,
54.3, 55.1, 75.2, 84.6, 127.9, 129.2, 133.6, 140.5, 160.1, 168.5, 173.3;
1744; 1H NMR (400 MHz, CDCl3)
d
1.48 (3H, d, J¼7.2 Hz), 1.89 (3H, d,
J¼0.4 Hz), 3.75 (3H, s), 4.15–4.23 (1H, m), 4.61 (1H, d, J¼0.4 Hz), 5.11
(2H, d, J¼2.4 Hz), 7.25–7.38 (5H, m, ArH), 8.75 (1H, br d, J¼8.4 Hz,
NH); 13C NMR (100 MHz, CDCl3)
d 19.3, 19.4, 51.4, 52.5, 64.4, 84.3,
127.7, 127.9, 128.4, 137.3, 160.4, 169.9, 173.2; MS (EI) m/z 277 (Mþ,
MS (CI) m/z 506 (MHþ, 94), 277 (99), 212 (100); HRMS (CI) m/z
D
27%), 218 (35), 186 (20), 143 (22), 110 (42), 91 (100), 84 (24); HRMS
506.2578 (C27H40NO6S [MHþ], 506.2576). [
a
]
20 þ70 (c 1, CH2Cl2).
D
(EI) m/z 277.1322 (C15H19NO4 [Mþ], 277.1314). [
CH2Cl2).
a]
ꢁ130 (c 1,
20
4.2.8. (1R)-(ꢁ)-10-Phenylsulfonylisobornyl (Z)-3-[(1S)-2-(1H-indol-3-
yl)-1-methoxycarbonylethylamino]but-2-enoate 11d. Obtained as an
4.2.3. Benzyl
amino]but-2-enoate 7b. Obtained as an oil (75%); IR (film) 1167,
1263, 1603, 1649, 1741 and 3414; 1H NMR (400 MHz, CDCl3)
1.65
(Z)-3-[(S)-1-ethoxycarbonyl-2-(1H-indol-3-yl)ethyl-
oil (94%). IR (KBr) 1607, 1647, 1740, 2969 cmꢁ1; 1H NMR
d 0.84 (3 h,
s), 0.94 (3H, s),1.14–1.21 (1H, m),1.63 (3H, s),1.67–1.99 (6H, m), 2.95
(1H, d, J¼13.9 Hz), 3.21 (1H, dd, J¼7.7 and 14.4 Hz), 3.34 (1H, dd,
J¼5.1 and 14.4 Hz), 3.48 (1H, d, J¼13.9 Hz), 3.74 (3H, s), 4.26–4.30
(1H, m), 4.29 (1H, s), 4.35–4.45 (1H, m), 4.97–5.01 (1H, m), 7.11–
7.20 (3H, m, Ar-H), 7.35–7.66 (5H, m, Ar-H), 7.84–7.94 (2H, m, Ar-H),
8.17 (1H, br s, NH), 8.77 (1H, br d, J¼9.2 Hz, NH); 13C NMR 19.3, 19.8,
20.2, 27.1, 29.3, 29.9, 39.4, 44.0, 49.5, 49.9, 52.5, 55.0, 56.6, 75.2,
84.5, 109.9, 111.2, 118.3, 119.6, 122.1, 123.6, 127.0, 127.7, 129.3, 133.6,
136.1,140.5, 159.8,168.4,172.5; MS (CI) m/z 579 (MHþ, 54), 277 (77),
d
(3H, s), 3.19 (1H, dd, J1¼8.0 Hz and J2¼14.4 Hz), 3.35 (1H, dd,
J1¼4.8 Hz and J2¼14.4 Hz), 3.68 (3H, s), 4.37–4.43 (1H, m), 4.52 (1H,
s), 5.09 (1H, d, J¼12.8 Hz), 5.13 (1H, d, J¼12.4 Hz), 7.07–7.36 (9H, m,
ArH), 7.56 (1H, d, J¼8.0 Hz, ArH), 8.10 (1H, br s, NH), 8.93 (1H, bd,
J¼9.2 Hz, NH); 13C NMR (100 MHz, CDCl3)
d 19.4, 29.8, 52.5, 56.7,
64.4, 84.2, 109.9, 111.3, 118.3, 119.6, 122.2, 123.6, 127.1, 127.7, 127.9,
128.4, 136.1, 137.3, 160.5, 169.9, 172.6; MS (ES) m/z 393 ([MHþ],
100%); HRMS (ES) m/z 393.18088 (C23H25N2O4 [MHþ], 393.18143).
135 (100); HRMS (CI) m/z 579.2644 (C32H39N2O6S [MHþ],
D
D
[
a]
20 ꢁ105 (c 1, CH2Cl2).
579.2654). [
a
]
20 ꢁ20 (c 1, CH2Cl2).
4.2.4. Benzyl
amino]but-2-enoate 9b. Obtained as an oil (73%); IR (film) 1167,
1263, 1603, 1649, 1741 and 3414; 1H NMR (400 MHz, CDCl3)
1.65
(Z)-3-[(R)-1-ethoxycarbonyl-2-(1H-indol-3-yl)ethyl-
4.2.9. (1S)-(þ)-10-Phenylsulfonylisobornyl (Z)-3-[(1S)-1-methoxy
carbonylethylamino]but-2-enoate 12a. Obtained as an oil (88%). IR
d
(KBr) 1615, 1661, 1748, 2960 cmꢁ1; 1H NMR
d 0.86 (3H, s), 0.95 (3H,
(3H, s), 3.19 (1H, dd, J1¼8.0 Hz and J2¼14.4 Hz), 3.35 (1H, dd,
J1¼4.8 Hz and J2¼14.4 Hz), 3.68 (3H, s), 4.37–4.43 (1H, m), 4.52 (1H,
s), 5.09 (1H, d, J¼12.8 Hz), 5.13 (1H, d, J¼12.4 Hz), 7.07–7.36 (9H, m,
ArH), 7.56 (1H, d, J¼8.0 Hz, ArH), 8.10 (1H, br s, NH), 8.93 (1H, br d,
s), 1.14–1.21 (1H, m), 1.56 (3H, d, J¼7.1 Hz), 1.56–1.98 (6H, m), 1.90
(3H, s), 2.98 (1H, d, J¼14.1 Hz), 3.67 (1H, d, J¼14.1 Hz), 3.75 (3H, s),
4.20 (1H, d, J¼7.1 Hz), 4.44 (1H, s), 4.58–4.61 (1H, m), 7.46–7.58 (3H,
m, Ar-H), 7.89–7.91 (2H, m, Ar-H), 8.69 (1H, br d, J¼8.5 Hz, NH); 13C
NMR 19.1, 19.2, 19.9, 20.3, 27.1, 29.4, 39.8, 44.0, 49.0, 49.7, 51.2, 52.4,
55.0, 75.5, 84.5, 127.7, 129.0, 133.1, 141.1, 159.7, 168.7, 173.2; MS (CI)
J¼9.2 Hz, NH); 13C NMR (100 MHz, CDCl3)
d 19.4, 29.8, 52.5, 56.7,
64.4, 84.2, 109.9, 111.3, 118.3, 119.6, 122.2, 123.6, 127.1, 127.7, 127.9,
128.4, 136.1, 137.3, 160.5, 169.9, 172.6; MS (ES) m/z 393 (MHþ, 100%);
m/z 464 (MHþ, 83), 277 (70), 170 (100); HRMS (CI) m/z 463.2025
D
D
HRMS (ES) m/z 393.18088 (C23H25N2O4 [MHþ], 393.18143). [
þ105 (c 1, CH2Cl2).
a
]
(C24H33NO6S [Mþ], 463.2028). [
a]
þ40 (c 1, CH2Cl2).
20
20
4.2.10. (1S)-(þ)-10-Phenylsulfonylisobornyl (Z)-3-[(1S)-2-phenyl-1-
methoxycarbonylethylamino]but-2-enoate 12b. Obtained as an oil
4.2.5. (1R)-(ꢁ)-10-Phenylsulfonylisobornyl (Z)-3-[(1S)-1-methoxycar-
bonylethylamino]but-2-enoate 11a. Obtained as a white solid (69%),
mp 51.8–53.1 ꢀC (from ethanol). IR (KBr) 1611, 1655, 1744,
(80%). IR (KBr) 1611, 1655, 1743, 2960 cmꢁ1; 1H NMR
d 0.86 (3H, s),
0.93 (3H, s), 1.14–1.21 (1H, m), 1.56–2.05 (6H, m), 1.67 (3H, s), 2.93–
3.00 (2H, m), 3.21 (1H, dd, J¼4.9 and 13.7 Hz), 3.67 (1H, d, J¼14.2 Hz),
3.72 (3H, s), 4.29–4.32 (1H, m), 4.31 (1H, s), 4.59 (1H, dd, J¼2.8 and
7.7 Hz), 7.24–7.44 (7H, m, Ar-H), 7.57–7.66 (1H, m, Ar-H), 7.85–7.94
(2H, m, Ar-H), 8.81 (1H, br d, J¼9.6 Hz, NH); 13C NMR 19.2,19.9, 20.3,
27.1, 29.4, 39.3, 40.0, 44.0, 49.1, 49.8, 52.4, 55.1, 57.8, 75.6, 84.9,127.0,
127.6, 128.7, 129.0, 129.2, 133.1, 136.3, 141.1, 159.5, 168.6, 171.9; MS
2956 cmꢁ1 1H NMR
; d 0.88 (3H, s), 0.93 (3H, s), 1.14–1.21 (1H, m),
1.48 (3H, d, J¼7.0 Hz), 1.56–2.05 (6H, m), 1.89 (3H, s), 3.00 (1H, d,
J¼14.4 Hz), 3.73 (1H, d, J¼14.4 Hz), 3.80 (3H, s), 4.19 (1H, q,
J¼7.0 Hz), 4.27 (1H, dd, J¼3.0 and 7.8 Hz), 4.38 (1H, s), 7.49–7.66
(3H, m, Ar-H), 7.87–7.94 (2H, m, Ar-H), 8.58 (1H, br d, J¼8.6 Hz, NH);
13C NMR 19.2, 19.3, 19.9, 20.4, 27.1, 29.4, 39.9, 44.1, 48.8, 49.9, 51.3,
52.5, 55.1, 75.3, 84.6, 127.8, 129.2, 133.5, 140.5, 159.8, 168.6, 173.3;
(CI) m/z 540 (MHþ, 82), 277 (95), 246 (100); HRMS (CI) m/z 540.2406
MS (CI) m/z 464 (MHþ, 94), 277 (97), 170 (100); HRMS (CI) m/z
(C30H38NO6S [MHþ], 540.2419). [
a
]
20 ꢁ70 (c 1, CH2Cl2).
D
D
463.2027 (C24H33NO6S [Mþ], 463.2028). [
a
]
þ85 (c 1, CH2Cl2).
20
4.2.11. (1S)-(þ)-10-Phenylsulfonylisobornyl (Z)-3-[(1S)-3-methyl-1-
methoxycarbonylbutylamino]but-2-enoate 12c. Obtained as an oil
4.2.6. (1R)-(ꢁ)-10-Phenylsulfonylisobornyl (Z)-3-[(1S)-2-phenyl-1-me-
thoxycarbonylethylamino]but-2-enoate 11b. Obtained as an oil (81%).
(70%). IR (KBr) 1612, 1654, 1744, 2957 cmꢁ1; 1H NMR
d 0.86 (3H, s),
IR (KBr) 1612, 1654, 1746, 2959 cmꢁ1
;
1H NMR
d
0.87 (3H, s), 0.93
0.94 (3H, s), 0.98 and 1.00 (6H, d, J¼8.8 Hz), 1.16–1.26 (2H, m), 1.58–
1.98 (6H, m), 1.89 (3H, s), 2.99 (1H, d, J¼14.1 Hz), 3.70 (1H, d,
J¼14.1 Hz), 3.73 (3H, s), 4.10–4.16 (1H, m), 4.41 (1H, s), 4.44–4.47
(1H, m), 7.44–7.58 (3H, m, Ar-H), 7.88–7.93 (2H, m, Ar-H), 8.58 (1H,
(3H, s), 1.14–1.21 (1H, m), 1.56–2.05 (6H, m), 1.66 (3H, s), 2.94–3.01
(2H, m), 3.17 (1H, dd, J¼5.3 and 13.6 Hz), 3.71 (1H, d, J¼14.3 Hz),
3.77 (3H, s), 4.25–4.33 (2H, m), 4.30 (1H, s), 7.19–7.32 (5H, m, Ar-H),

A.L. Cardoso et al. / Tetrahedron 65 (2009) 9116–9124
9121
br d, J¼9.8 Hz, NH); 13C NMR 19.4, 19.9, 20.3, 21.6, 22.9, 24.5, 27.2,
29.4, 39.9, 41.8, 44.1, 49.0, 49.9, 52.3, 53.3, 55.0, 75.6, 84.6, 127.7,
129.2, 133.1, 141.1, 160.0, 168.7, 173.3; MS (CI) m/z 506 (MHþ, 72),
159.1, 168.6, 173.0; MS (EI) m/z 303 (Mþ, 26%), 244 (82), 212 (100),
196 (24), 167 (45); HRMS (EI) m/z 303.1469 (C17H21NO4 [Mþ],
D
303.1471). [
a]
20 þ80 (c 1, CH2Cl2).
277 (100), 212 (89); HRMS (CI) m/z 506.2583 (C27H40NO6S [MHþ],
D
506.2576). [
a
]
þ10 (c 1, CH2Cl2).
4.2.17. (1R)-(ꢁ)-10-Phenylsulfonylisobornyl (Z)-3-[(2S)-(2-methoxy-
carbonylpyrrolid-1-yl)]but-2-enoate 21. Obtained as a yellow oil
20
4.2.12. (1S)-(þ)-10-Phenylsulfonylisobornyl (Z)-3-[(1S)-2-(1H-indol-
3-yl)-1-methoxycarbonylethylamino]but-2-enoate 12d. Obtained as
(81%). IR (KBr) 1691, 1742, 1749, 2870 cmꢁ1; 1H NMR
d 0.84 and 0.86
(3H, s), 0.94 and 0.96 (3H,s), 1.14–1.21 (1H, m), 1.69–2.04 (10H, m),
2.98 (1H, d, J¼14.1 Hz), 3.14–3.50 (2H, m), 3.71 (1H, d, J¼14.1 Hz),
3.77 (3H, s), 4.33–4.38 (2H, m), 7.49–7.61 (3H, m, Ar-H), 7.86–7.88
(2H, m, Ar-H); 13C NMR 16.4, 20.1, 20.4, 23.3, 27.2, 29.5, 31.0, 40.1,
44.1, 48.5, 48.9, 52.5, 55.2, 60.4, 75.5, 86.1, 127.7, 129.1, 133.2, 140.9,
an oil (76%). IR (KBr) 1663, 1741, 2966 cmꢁ1; 1H NMR
d 0.84 (3H, s),
0.94 (3H, s), 1.14–1.21 (1H, m), 1.54 (3H, s), 1.67–1.99 (6H, m), 2.99
(1H, d, J¼14.0 Hz), 3.16 (1H, dd, J¼9.2 and 14.4 Hz), 3.41 (1H, dd,
J¼4.2 and 14.4 Hz), 3.63 (1H, d, J¼14.0 Hz), 3.73 (3H, s), 4.34 (1H, s),
4.34–4.42 (1H, m), 4.98–5.02 (1H, m), 7.08–7.27 (4H, m, Ar-H), 7.41–
7.60 (5H, m, Ar-H), 7.87–7.94 (2H, m, Ar-H), 8.46 (1H, br s, NH), 8.86
(NH, br d, J¼9.9 Hz); 13C NMR 19.3, 19.9, 20.3, 27.2, 29.5, 30.1, 39.7,
44.2, 49.5, 49.8, 52.5, 55.2, 56.4, 75.5, 84.7, 108.7, 111.5, 117.8, 119.3,
121.6,125.3,127.0,127.6,129.2,133.3,136.0,141.5,160.4,168.9,172.3;
158.4, 167.2, 173.3; MS (ESI) m/z 490 (MHþ, 11), 417 (100), 277 (35);
D
HRMS (CI) m/z 490.2258 (C26H36NO6S [MHþ], 490.2263). [
(c 1, CH2Cl2).
a]
20 þ75
4.2.18. (1R)-(ꢁ)-10-Phenylsulfonylisobornyl (Z)-3-[(2R)-(2-methoxy-
carbonylpyrrolid-1-yl)]but-2-enoate 23. Obtained as a white solid
(89%), mp 165.0–166.2 ꢀC (from Ethyl Acetate/Hexane); IR (film)
MS (CI) m/z 579 (MHþ, 100), 277 (87), 135 (93); HRMS (CI) m/z
D
580.2610 (C32H40N2O6S [MHþ2 ], 580.2607). [
a]
20 ꢁ90 (c 1, CH2Cl2).
1136, 1567, 1685, 1739 and 2930; 1H NMR (300 MHz, CDCl3)
d 0.86
4.2.13. (1S)-(þ)-10-Phenylsulfonylisobornyl (Z)-3-[(1R)-1-methoxy-
carbonylethylamino]but-2-enoate 15a. Obtained as an oil (80%). IR
(3H, s), 0.94 (3H, s), 1.11–1.20 (1H, m), 1.55–2.27 (10H, m), 2.33 (3H,
s), 3.00 (1H, d, J¼14.1 Hz), 3.32 (1H, br s), 3.45 (1H, br s), 3.71 (1H, d,
J¼14.0 Hz), 3.74 (3H, s), 4.24 (1H, br s), 4.30–4.42 (2H, m), 7.47–7.60
(3H, m, ArH), 7.88–7.91 (2H, m, ArH); 13C NMR (100 MHz, CDCl3)
(film) 1610, 1658, 1745, 2958 cmꢁ1; 1H NMR
d 0.86 (3H, s), 0.93 (3H,
s), 1.14–1.21 (1H, m), 1.48 (3H, d, J¼7.1 Hz), 1.69–2.05 (7H, m), 1.89
(3H, s), 3.00 (1H, d, J¼14.3 Hz), 3.73 (1H, d, J¼14.3 Hz), 3.70–3.76
(1H, m), 3.80 (3H, s), 4.17–4.27 (1H, m), 4.39 (1H, s), 7.48–7.66 (3H,
m, Ar-H), 7.87–7.94 (2H, m, Ar-H), 8.54 (1H, br d, NH); 13C NMR 19.2,
19.3, 20.0, 20.4, 27.2, 29.4, 40.0, 44.1, 48.9, 49.9, 51.3, 52.5, 55.2, 75.4,
84.6, 127.9, 129.2, 133.5, 140.6, 159.8, 168.6, 173.0; MS (CI) m/z 464
d
16.3, 20.0, 20.4, 23.2, 27.2, 29.5, 30.5, 40.0, 44.2, 48.5, 49.0, 49.9,
52.4, 55.4, 60.4, 75.4, 86.2, 127.9, 129.1, 133.3, 141.1, 158.3, 167.1,
173.3; MS (EI) m/z 489 (Mþ, 16), 467 (35), 443 (55), 430 (53), 393
(58), 381 (56), 231 (51), 212 (42), 181 (84), 118 (100); HRMS (EI) m/z
D
489.2191 (C26H35NO6S [Mþ], 489.2185). [
a
]
20 þ130 (c 1, CH2Cl2).
(MHþ, 46), 277 (87), 236 (82), 135 (96); HRMS (CI) m/z 464.2107
D
(C24H33NO6S [MHþ], 464.2108). [
a]
20 ꢁ85 (c 1, CH2Cl2).
4.2.19. (1S)-(þ)-10-phenylsulfonylisobornyl (Z)-3-[(2R)-(2-methoxy-
carbonylpyrrolid-1-yl)]but-2-enoate 25. Obtained as an oil (78%); IR
4.2.14. (1S)-(ꢁ)-10-Phenylsulfonylisobornyl (Z)-3-[(1R)-2-(1H-indol-
3-yl)-1-methoxycarbonylethylamino]but-2-enoate 15b. Crystallized
as a solid (82%), mp 65.2–67.8 ꢀC (from ethyl acetate–hexane). IR
(film) 1128, 1568, 1682, 1739 and 2955 cmꢁ1 1H NMR (300 MHz,
;
CDCl3) d 0.87 (3H, s), 0.96 (3H, s), 1.12–1.20 (1H, m), 1.50–2.33 (10H,
m), 2.37 (3H, s), 2.98 (1H, d, J¼14.1 Hz), 3.36–3.42 (1H, m), 3.52 (1H,
bs), 3.71 (1H, d, J¼14.0 Hz), 3.76 (3H, s), 4.31–4.37 (3H, m), 7.46–
7.60 (3H, m, ArH), 7.86–7.89 (2H, m, ArH); 13C NMR (75 MHz, CDCl3)
(KBr) 1610, 1653, 1742, 2954 cmꢁ1; 1H NMR
d 0.87 (3H, s), 0.93 (3H,
s), 1.14–1.21 (1H, m), 1.69 (3H, s), 1.67–1.99 (6H, m), 2.99 (1H, d,
J¼14.3 Hz), 3.20 (1H, dd, J¼7.6 and 14.4 Hz), 3.33 (1H, dd, J¼5.1 and
14.4 Hz), 3.70 (1H, d, J¼14.3 Hz), 3.73 (3H, s), 4.28–4.30 (1H, m),
4.29 (1H, bs), 4.31–4.42 (1H, m), 7.09–7.21 (3H, m, Ar-H), 7.34–7.60
(5H, m, Ar-H), 7.84–7.93 (2H, m, Ar-H), 8.26 (1H, br s, J¼8.5 Hz NH),
8.78 (1H, br d, J¼9.2 Hz, NH); 13C NMR 19.3, 19.9, 20.4, 27.2, 29.3,
29.6, 39.9, 44.1, 48.9, 49.9, 52.4, 55.1, 56.6, 75.2, 84.5, 109.8, 111.3,
118.3, 119.5, 122.1, 123.6, 127.0, 127.8, 129.1, 133.5, 136.1, 140.5, 159.8,
168.5, 172.4; MS (CI) m/z 579 (MHþ, 15), 277 (66), 236 (82), 130
d
16.6, 20.3, 20.6, 23.5, 27.4, 29.7, 30.8, 40.3, 44.4, 48.8, 49.2, 50.1,
52.7, 55.5, 60.6, 75.8, 86.5, 128.2, 129.3, 133.4, 141.3, 158.7, 167.4,
173.5; MS (EI) m/z 489 (Mþ, 12%), 292 (17), 219 (20), 212 (30), 196
(100), 169 (62); HRMS (EI) m/z 489.2188 (C26H35NO6S [Mþ],
D
489.2185). [
a]
ꢁ73 (c 1, CH2Cl2).
20
4.2.20. (1S)-(þ)-10-phenylsulfonylisobornyl (Z)-3-[(2S)-(2-methoxy-
carbonylpyrrolid-1-yl)]but-2-enoate 27. Obtained as a white solid
(85%), mp 125.3–126.9 ꢀC (from ethanol). IR (KBr) 1686, 1740, 1747,
(100); HRMS (CI) m/z 579.2528 (C32H39N2O6S [MHþ], 579.2520).
D
[
a]
þ20 (c 1, CH2Cl2).
2865 cmꢁ1 1H NMR
; d 0.87 (3H, s), 0.94 (3H, s), 1.14–1.25 (1H, m),
20
1.56–2.31 (10H, m), 2.34 (3H, s), 3.01 (1H, d, J¼14.3 Hz), 3.34–3.50
(2H, m), 3.74 (1H, d, J¼14.3 Hz), 3.76 (3H, s), 4.31 (1H, s), 4.36–4.41
(2H, m), 7.48–7.59 (3H, m, Ar-H), 7.89–7.92 (2H, m, Ar-H); 13C NMR
16.3, 19.9, 20.4, 23.2, 27.1, 29.5, 30.5, 39.9, 44.1, 48.4, 48.9, 49.8, 52.4,
55.3, 60.3, 75.3, 86.1, 127.8, 129.1, 133.2, 141.0, 158.3, 167.1, 173.2; MS
4.2.15. (S,Z)-Methyl 1-(4-(benzyloxy)-4-oxobut-2-en-2-yl)pyrroli-
dine-2-carboxylate 17. Obtained as an oil (96%); IR (film) 1122,
1414, 1562, 1679, 1739 and 2949 cmꢁ1 1H NMR (300 MHz, CDCl3)
;
d
1.96–2.28 (4H, m), 2.44 (3H, s), 3.36 (bs,1H), 3.50 (br s,1H), 3.74 (s,
3H), 4.35 (br s, 1H), 4.59 (br s, 1H), 5.06 (d, 1H, J¼12.6 Hz), 5.13 (d,
(CI) m/z 490 (MHþ, 88), 277 (50), 196 (100); HRMS (CI) m/z
1H, J¼12.6 Hz), 7.25–7.40 (m, 5H, ArH); 13C NMR (75 MHz, CDCl3)
490.2266 (C26H36NO6S [MHþ], 490.2263). [
a]
20 ꢁ130 (c 1, CH2Cl2).
D
d
16.8, 23.5, 30.8, 48.8, 52.7, 60.7, 64.6, 85.8, 127.8, 128.2, 128.6,
137.9, 159.4, 168.9, 173.3; MS (EI) m/z 303 (Mþ, 19%), 244 (100), 212
4.3. General procedure for the reduction of
esters9
b-enamino
(46), 196 (26), 169 (57); HRMS (EI) m/z 303.1465 (C17H21NO4 [Mþ],
303.1471). [
D
a]
ꢁ80 (c 1, CH2Cl2).
20
A solution of NaBH(OAc)3 was prepared by adding NaBH4
(0.34 g, 9.0 mmol) in glacial acetic acid (5 mL) while keeping the
temperature between 10 and 20 ꢀC. After the H2 evolution ceased
(1 h), acetonitrile (5 mL) was added and the solution was cooled to
4.2.16. (R,Z)-Methyl 1-(4-(benzyloxy)-4-oxobut-2-en-2-yl)pyrrolidine-
2-carboxylate 19. Obtained as an oil (94%); IR (film) 1124, 1422,
1566, 1681, 1737 and 2951 cmꢁ1; 1H NMR (400 MHz, CDCl3)
d 1.96–
2.25 (4H, m), 2.43 (3H, s), 3.35 (br s, 1H), 3.49 (br s, 1H), 3.73 (s, 3H),
4.34 (br s, 1H), 4.59 (br s, 1H), 5.05 (d, 1H, J¼12.6 Hz), 5.11 (d, 1H,
J¼12.6 Hz), 7.25–7.38 (m, 5H, ArH); 13C NMR (100 MHz, CDCl3)
0 ꢀC. The
b-enamino ester (3.0 mmol) was added in one portion and
the reaction stirred for 4 h at 0 ꢀC. The acetic acid and acetonitrile
were evaporated off and the residue dissolved in CH2Cl2 and the
combined organic layers were washed with saturated aqueous
d
16.5, 23.1, 30.5, 48.5, 52.4, 60.4, 64.3, 85.6,127.5,127.9,128.3,137.6,

9122
A.L. Cardoso et al. / Tetrahedron 65 (2009) 9116–9124
D
solution of Na2CO3 and dried over magnesium sulfate affording the
-amino ester after removal of the solvent.
(ES) m/z 395.19653 (C23H27N2O4 [MHþ], 395.19708). [
CH2Cl2).
a]
ꢁ5 (c 1,
20
b
4.3.1. Benzyl 3-[(S)-1-ethoxycarbonylethylamino]butanoate 8a. Mixture
of diastereoisomers (57:43) was obtained as an oil (89%); IR (film) 1169,
1456, 1735 and 2974; 1H NMR (400 MHz, CDCl3) Major component:
4.3.5. (1R)-(ꢁ)-10-Phenylsulfonylisobornyl
(S)-3-[(1S)-1-methoxy
carbonylethylamino]butanoate 13a. Obtained as a white solid (88%),
mp 84.3–85.6 ꢀC (from ethanol). IR (film) 1447, 1732, 2967 cmꢁ1; 1H
d
1.08 (3H, d, J¼6.0 Hz), 1.27 (3H, d, J¼6.8 Hz), 2.33–2.52 (2H, m), 3.07–
3.12 (1H, m), 3.39–3.49 (1H, m), 3.69 (3H, s), 5.13 (2H, s), 7.27–7.35 (5H,
m, ArH); Minor Component:
NMR
d
0.85 (3H, s), 0.96 (3H, s), 1.12 (3H, d, J¼6.3 Hz) and 1.13 (3H, d,
J¼6.3 Hz),1.14–1.21 (1H, m),1.28 and 1.29 (3H, d, J¼4.3 Hz),1.56–1.97
(6H, m), 2.18–2.48 (2H, m), 2.97 and 2.98 (1H, d, J¼14.0 Hz), 3.00–
3.10 (1H, m), 3.43–3.56 (2H, m), 3.71 and 3.72 (3H, s), 4.88–4.91 (1H,
m), 7.56–7.66 (3H, m, Ar-H), 7.89–7.94 (2H, m, Ar-H); 13C NMR 19.5,
19.9, 20.3, 21.1, 27.1, 29.8, 39.6, 41.9, 44.0, 48.1, 49.3, 49.9, 51.9, 54.4,
55.0, 77.8, 127.7, 129.3, 133.5, 141.3, 170.5, 176.5; MS (CI) m/z 466
d
1.11 (3H, d, J¼6.4 Hz), 1.23 (3H, d,
J¼6.8 Hz), 2.33–2.52 (2H, m), 3.07–3.12 (1H, m), 3.39–3.49 (1H, m), 3.70
(3H, s), 5.12 (2H, s), 7.27–7.35 (5H, m, ArH); 13C NMR (100 MHz, CDCl3)
Major Component:
128.6, 135.9, 171.7, 176.1; Minor Component:
54.4, 128.2, 128.3, 128.6, 135.9, 171.9, 176.5; MS (ES) m/z 280 (MHþ,
100%); HRMS (ES) m/z 280.15433 (C15H22NO4 [MHþ], 280.15488). [a 2D0
d
19.6, 20.2, 42.2, 48.3, 51.8, 53.6, 66.3, 128.2, 128.3,
d
19.5, 21.2, 41.8, 49.1, 51.9,
(MHþ, 100), 406 (89), 277 (75), 190 (90); HRMS (CI) m/z 466.2251
D
]
(C24H36NO6S [MHþ], 466.2263). [
a]
20 þ20 (c 1, CH2Cl2).
ꢁ35 (c 1, CH2Cl2).
4.3.6. (1R)-(ꢁ)-10-Phenylsulfonylisobornyl (S)-3-[(1S)-2-phenyl-1-
methoxycarbonylethylamino]butanoate 13b. Obtained as an oil
4.3.2. Benzyl 3-[(R)-1-ethoxycarbonylethylamino]butanoate 10a. Mixture
of diastereoisomers (56:44) obtained as an oil (96%); IR (film) 1169,
1455, 1735 and 2974; 1H NMR (400 MHz, CDCl3) Major component:
(98%). IR (film) 1447, 1734, 2956 cmꢁ1; 1H NMR
d 0.85 (3H, s), 0.94
and 0.95 (3H, s), 1.05 and 1.10 (3H, d, J¼6.3 Hz), 1.14–1.21 (1H, m),
1.56–2.07 (7H, m), 2.08–2.18 (2H, m), 2.89–2.95 (3H, m), 3.00–
3.06 (1H, m), 3.47–3.65 (2H, m), 3.60 and 3.62 (3H, s), 4.85–4.88
(1H, m), 7.15–7.31 (5H, m, Ar-H), 7.52–7.67 (3H, m, Ar-H), 7.88–
7.92 (2H, m, Ar-H); 13C NMR 19.9, 20.0, 20.3, 21.2, 27.1, 29.8, 39.6,
40.0, 42.4, 44.0, 48.4, 49.3, 49.9, 51.7, 55.1, 60.4, 77.8, 126.7, 127.7,
128.4, 129.1, 129.3, 133.5, 137.2, 141.3, 170.4, 174.8; MS (CI) m/z 542
d
1.08 (3H, d, J¼6.4 Hz), 1.28 (3H, d, J¼6.8 Hz), 2.33–2.52 (2H, m),
3.05–3.14 (1H, m), 3.39–3.49 (1H, m), 3.69 (3H, s), 5.13 (2H, s), 7.27–
7.35 (5H, m, ArH); Minor Component:
d
1.11 (3H, d, J¼6.4 Hz), 1.23
(3H, d, J¼6.8 Hz), 2.33–2.52 (2H, m), 3.05–3.14 (1H, m), 3.39–3.49
(1H, m), 3.70 (3H, s), 5.12 (2H, s), 7.27–7.35 (5H, m, ArH); 13C NMR
(100 MHz, CDCl3) Major Component:
53.6, 66.3, 128.2, 128.3, 128.6, 135.9, 171.7, 176.1; Minor Component:
d 19.6, 20.2, 42.2, 48.3, 51.8,
(MHþ, 100), 450 (37), 277 (76), 135 (71); HRMS (CI) m/z 542.2575
D
d
19.5, 21.2, 41.8, 49.1, 51.9, 54.4, 128.2, 128.3, 128.6, 135.9, 171.9,
(C30H40NO6S [MHþ], 542.2576). [
a
]
þ35 (c 1, CH2Cl2).
20
176.5; MS (ES) m/z 280 (MHþ,100%), 213 (3),197 (14); HRMS (ES) m/z
D
280.15433 (C15H22NO4 [MHþ], 280.15488). [
a]
20 þ15 (c 1, CH2Cl2).
4.3.7. (1R)-(ꢁ)-10-Phenylsulfonylisobornyl (S)-3-[(1S)-3-methyl-1-me-
thoxycarbonylbutylamino]butanoate 13c. Obtained as an oil (93%). IR
4.3.3. Benzyl 3-[(S)-1-ethoxycarbonyl-2-(1H-indol-3-yl)ethylamino]-
butanoate 8b. Mixture of diastereoisomers (66:34) obtained as
a white solid (78%), mp 45.2–46.6 ꢀC (from ethyl acetate/hexane);
IR (KBr) 743, 1209, 1455, 1728, 2963 and 3280; 1H NMR (400 MHz,
(film) 1447, 1733, 2957 cmꢁ1; 1H NMR
d 0.85–0.96 (12H, m), 1.10 and
1.11 (3H, d J¼6.3 Hz), 1.14–1.21 (1H, m), 1.26–1.98 (7H, m), 2.05–2.43
(2H, m), 2.96–3.04 (2H, m), 3.30–3.42 (1H, m), 3.51 and 3.54 (1H, d,
J¼14.0 Hz), 3.70 and 3.71 (3H, s), 4.86–4.90 (1H, m), 7.57–7.65 (3H, m,
Ar-H), 7.89–7.93 (2H, m, Ar-H); 13C NMR 19.9, 20.0, 20.3, 22.4, 22.7,
24.8, 27.1, 29.8, 39.6, 41.9, 43.1, 44.0, 48.3, 49.3, 49.9, 51.7, 55.1, 77.7,
127.7, 129.3, 133.5, 141.3, 170.5, 176.2; MS (CI) m/z 508 (MHþ,100), 448
CDCl3) Major component:
d
1.01 (3H, d, J¼6.0 Hz), 2.38–2.48 (2H,
m), 3.01–3.16 (2H, m), 3.58 (3H, s), 3.73 (1H, t, J¼6.4 Hz), 5.07 (2H,
s), 7.02–7.33 (10H, m), 7.58 (1H, t, J¼7.6 Hz, NH), 8.01 (1H, s, NH);
Minor Component:
d
1.08 (3H, d, J¼6.0 Hz), 2.27–2.35 (2H, m),
(98), 277 (94), 135 (83); HRMS (CI) m/z 508.2735 (C27H42NO6S [MHþ],
508.2733). [
D
3.01–3.16 (2H, m), 3.60 (3H, s), 3.68 (1H, t, J¼6.4 Hz), 4.96 (1H, d,
J¼12.4 Hz), 5.02 (1H, d, J¼12.4 Hz), 7.02–7.33 (10H, m, ArH), 7.58
(1H, t, J¼7.6 Hz, NH), 8.01 (1H, s, NH); 13C NMR (100 MHz, CDCl3)
a]
20 þ30 (c 1, CH2Cl2).
4.3.8. (1R)-(ꢁ)-10-Phenylsulfonylisobornyl (S)-3-[(1S)-2-(1H-indol-
3-yl)-1-methoxycarbonylethylamino]butanoate 13d. Obtained as an
Major Component:
d 20.0, 29.6, 42.3, 48.6, 51.7, 59.2, 66.2, 111.1,
111.3, 118.7, 119.4, 122.1, 122.8, 128.2, 128.3, 128.5, 136.1, 171.7, 175.4;
Minor Component: 21.3, 29.5, 41.6, 49.5, 51.8, 60.0, 66.1, 111.2,
oil (75%). IR (film) 1479, 1732, 2956 cmꢁ1 1H NMR
; d 0.84 (3H, s),
d
0.90 and 0.92 (3H, s), 1.05 and 1.10 (3H, d, J¼6.3 Hz), 1.14–1.21 (1H,
m), 1.56–1.96 (7H, m), 2.08–2.27 (1H, m), 2.33–2.40 (1H, m), 2.96
(1H, d, J¼14.0 Hz), 3.03–3.19 (3H, m), 3.49 and 3.51 (1H, d,
J¼14.0 Hz), 3.60 and 3.61 (3H, s), 3.68–3.76 (1H, m), 4.82–4.87 (1H,
m), 7.06–7.20 (3H, m, Ar-H), 7.33–7.36 (1H, m, Ar-H), 7.47–7.65 (4H,
m, Ar-H), 7.87–7.90 (2H, m, Ar-H), 8.06 and 8.13 (1H, br s, NH); 13C
NMR 19.9, 20.3, 21.2, 27.1, 29.6, 29.8, 30.9, 39.6, 41.9, 44.0, 49.3, 49.9,
51.8, 55.1, 59.3, 60.0, 77.8, 111.0, 111.2, 118.7, 119.4, 122.0, 122.7, 123.1,
127.4, 127.6, 133.5, 136.1, 141.3, 170.4, 175.3; MS (CI) m/z 581 (MHþ,
111.3, 118.7, 119.4, 122.0, 122.9, 127.5, 128.3, 135.9, 171.8, 175.8; MS
MS (ES) m/z 395 (MHþ, 100%); HRMS (ES) m/z 395.19653
D
(C23H27N2O4 [MHþ], 395.19708). [
a
]
20 ꢁ5 (c 1, CH2Cl2).
4.3.4. Benzyl 3-[(R)-1-ethoxycarbonyl-2-(1H-indol-3-yl)ethylamino]-
butanoate 10b. Mixture of diastereoisomers (66:34) obtained as
a white solid (78%), mp 45.0–46.8 ꢀC (from ethyl acetate/hexane);
IR (KBr) 743, 1209, 1455, 1728, 2963 and 3280; 1H NMR (400 MHz,
CDCl3) Major component:
d
1.01 (3H, d, J¼6.4 Hz), 2.38–2.48 (2H,
100), 450 (46), 277 (81), 135 (71); HRMS (CI) m/z 581.2687
D
m), 3.01–3.16 (2H, m), 3.58 (3H, s), 3.73 (1H, t, J¼6.8 Hz), 5.08 (2H,
s), 7.03 (1H, br s, ArH), 7.08–7.12 (1H, m, ArH), 7.28–7.37 (8H, m,
ArH), 7.58 (1H, t, J¼7.6 Hz, NH), 7.97 (1H, bs, NH); Minor Compo-
(C32H41N2O6S [MHþ], 581.2685). [
a]
20 þ40 (c 1, CH2Cl2).
4.3.9. (1S)-(þ)-10-phenylsulfonylisobornyl (R)-3-[(1S)-1-methoxy-
carbonylethylamino]butanoate 14a. Obtained as an oil (88%). IR
nent:
d
1.09 (3H, d, J¼6.4 Hz), 2.27–2.35 (2H, m), 3.01–3.16 (2H, m),
3.60 (3H, s), 3.68 (1H, t, J¼6.8 Hz), 4.96 (1H, d, J¼12.0 Hz), 5.02 (1H,
d, J¼12.4 Hz), 7.03 (1H, br s, ArH), 7.16–7.19 (1H, m, ArH), 7.28–7.37
(8H, m, ArH), 7.58 (1H, t, J¼7.6 Hz, NH), 7.97 (1H, s, NH); 13C NMR
(film) 1448, 1733, 2960 cmꢁ1 1H NMR
; d 0.85 (3H, s), 0.96 (3H, s),
1.10 (3H, d, J¼6.3 Hz) and 1.14 (3H, d, J¼6.3 Hz), 1.14–1.21 (1H, m),
1.27 and 1.29 (3H, d, J¼6.9 Hz), 1.61–2.05 (6H, m), 2.22–2.42 (2H,
m), 2.97 (1H, d, J¼14.0 Hz), 3.06–3.10 (1H, m), 3.42–3.57 (2H, m),
3.71 (3H, s), 4.86–4.89 (1H, m), 7.54–7.67 (3H, m, Ar-H), 7.89–7.94
(2H, m, Ar-H); 13C NMR 19.5, 19.9, 20.3, 21.1, 27.1, 29.8, 39.6, 42.3,
44.0, 48.0, 49.3, 49.9, 51.8, 53.5, 55.1, 77.8, 127.7, 129.3, 133.5, 141.3,
170.3, 176.1; MS (CI) m/z 466 (MHþ, 63), 277 (92), 135 (100); HRMS
(100 MHz, CDCl3) Major Component:
d 20.0, 29.7, 42.3, 48.6, 51.7,
59.2, 66.2, 111.1, 111.4, 118.8, 119.5, 122.1, 122.7, 128.2, 128.5, 136.2,
171.7, 175.4; Minor Component: 21.3, 29.6, 41.7, 49.6, 51.8, 60.0,
d
66.1, 111.3, 111.4, 118.8, 119.4, 122.1, 122.8, 127.5, 128.3, 128.5, 136.0,
171.8, 175.8; MS (ES) m/z 395 (MHþ, 100%), 213 (6), 197 (18); HRMS

A.L. Cardoso et al. / Tetrahedron 65 (2009) 9116–9124
9123
D
(CI) m/z 465.2140 (C24H35NO6S [Mþ], 465.2162). [
CH2Cl2).
a
]
ꢁ30 (c 1
4.87 (1H, m), 7.05–7.18 (3H, m, Ar-H), 7.33–7.36 (1H, m), 7.47–7.62
(4H, m), 7.87–7.90 (2H, m), 8.15 (1H, br d, NH); 13C NMR 19.9, 20.3,
21.2, 27.1, 29.5, 29.9, 39.6, 42.4, 44.0, 48.6, 49.3, 49.9, 51.8, 55.1, 59.4,
77.8, 111.0, 111.2, 118.7, 119.4, 122.0, 128.8, 127.4, 129.3, 133.6, 136.2,
141.3, 170.5, 175.8; MS (CI) m/z 581 (MHþ, 40), 305 (42), 277 (35),
20
4.3.10. (1S)-(þ)-10-Phenylsulfonylisobornyl (R)-3-[(1S)-2-phenyl-1-
methoxycarbonylethylamino]butanoate 14b. Obtained as an oil
(95%). IR (film) IR (film) 1447, 1733, 2961 cmꢁ1; 1H NMR
d
0.85 (3H,
111 (100); HRMS (CI) m/z 581.2685 (C32H41N2O6S [MHþ], 581.2673).
D
s), 0.94 (3H, s), 1.03 and 1.11 (3H, d, J¼6.3 Hz), 1.14–1.21 (1H, m),
1.56–2.05 (7H, m), 2.23 (1H, dd, J¼6.4 Hz and 15.1 Hz), 2.37 (1H, dd,
J¼6.7 Hz and 15.1 Hz), 2.88–2.95 (3H, m), 2.99–3.08 (1H, m), 3.48–
3.66 (4H, m), 4.84–4.88 (1H, m), 7.16–7.27 (5H, m, Ar-H), 7.53–7.64
(3H, m, Ar-H), 7.90–7.92 (2H, m, Ar-H); 13C NMR 19.8, 19.9, 20.2,
27.1, 29.8, 30.9, 39.6, 40.0, 42.4, 44.0, 48.3, 49.3, 49.9, 51.6, 55.1, 60.2,
77.8, 126.6, 127.7, 128.3, 129.1, 129.2, 133.5, 137.2, 141.3, 170.3, 174.9;
[a
]
20 ꢁ40 (c 1, CH2Cl2).
4.3.15. Methyl 1-[(S)-4-(benzyloxy)-4-oxobutan-2-yl]pyrrolidine-2-
carboxylate 18. Mixture of diastereoisomers (70:30) was obtained
as an oil (86%); IR (film) 1166, 1195, 1727 and 2949 cmꢁ1; 1H NMR
(300 MHz, CDCl3) Major component:
2.07 (4H, m), 2.26–2.39 (1H, m), 2.55–2.68 (2H, m), 3.02–3.10
(1H, m), 3.26–3.48 (2H, m), 3.67 (3H, s), 5.04–5.18 (2H, m), 7.27–
d
1.12 (3H, d, J¼6.6 Hz), 1.69–
MS (CI) m/z 542 (MHþ, 86), 450 (63), 277 (86), 135 (100); HRMS (CI)
D
m/z 541.2453 (C30H39NO6S [MHþ], 541.2454). [
a
]
ꢁ45 (c 1,
7.35 (5H, m, ArH); Minor Component:
d
1.05 (3H, d, J¼6.3 Hz),
20
CH2Cl2).
1.69–2.07 (4H, m), 2.26–2.39 (1H, m), 2.56–2.68 (2H, m), 2.96–
3.10 (1H, m), 3.26–3.48 (2H, m), 3.66 (3H, s), 5.04–5.18 (2H, m),
7.27–7.35 (5H, m, ArH); 13C NMR (75 MHz, CDCl3) Major Com-
4.3.11. (1S)-(þ)-10-Phenylsulfonylisobornyl (R)-3-[(1S)-3-methyl-1-
methoxycarbonylbutylamino]butanoate 14c. Obtained as an oil
ponent:
d
18.5, 23.9, 30.4, 38.8, 49.2, 52.1, 53.2, 61.9, 66.5, 128.3,
15.7,
(95%). IR (film) 1446, 1731, 2960 cmꢁ1
;
1H NMR
d
0.85–0.97 (12H,
128.4, 128.4, 128.7, 136.2, 172.3, 175.7; Minor Component: d
m), 1.08 and 1.11 (3H, d J¼6.3 Hz), 1.14–1.21 (1H, m), 1.40–1.46 (1H,
m), 1.56–1.96 (6H, m), 1.98–2.36 (2H, m), 2.95–3.03 (2H, m), 3.33–
3.42 (1H, m), 3.50–3.57 (1H, m), 3.70 (3H, s), 4.82–4.89 (1H, m),
7.57–7.65 (3H, m, Ar-H), 7.91–7.94 (2H, m, Ar-H); 13C NMR 19.8,19.9,
20.3, 22.2, 22.7, 24.8, 27.1, 29.8, 39.6, 42.6, 43.0, 44.0, 48.2, 49.3,
49.9, 51.6, 55.1, 77.8, 127.7, 129.3, 133.5, 141.3, 170.3, 176.3; MS (CI)
24.1, 30.2, 40.7, 48.0, 52.8, 62.0, 66.4, 128.3, 128.4, 128.4, 128.7,
136.3, 172.2, 175.6; MS (EI) m/z 305 (Mþ, 1%), 246 (100), 156 (31);
HRMS (EI) m/z 305.1632 (C17H23NO4 [Mþ], 305.1627). [
1, CH2Cl2).
a
]
20 ꢁ40 (c
D
4.3.16. Methyl 1-[(R)-4-(benzyloxy)-4-oxobutan-2-yl]pyrrolidine-2-
carboxylate 20. Mixture of diastereoisomers (71:29) was obtained
as an oil (78%); IR (film) 1163, 1192, 1727 and 2952 cmꢁ1; 1H NMR
m/z 508 (MHþ, 100), 448 (15), 277 (19), 135 (16); HRMS (CI) m/z
D
508.2744 (C27H42NO6S [MHþ], 508.2733). [
a]
ꢁ30 (c 1, CH2Cl2).
20
(300 MHz, CDCl3) Major component:
d
1.12 (3H, d, J¼6.6 Hz),
4.3.12. (1S)-(þ)-10-Phenylsulfonylisobornyl (R)-3-[(1S)-2-(1H-indol-
3-yl)-1-methoxycarbonylethylamino]butanoate 14d. Obtained as an
1.83–2.07 (4H, m), 2.26–2.40 (1H, m), 2.56–2.68 (2H, m), 3.03–
3.10 (1H, m), 3.26–3.40 (1H, m), 3.44–3.48 (1H, m), 3.67 (3H, s),
5.0–5.19 (2H, m), 7.27–7.37 (5H, m, ArH); Minor Component:
oil (95%). IR (film) 1448, 1456, 1730, 2958 cmꢁ1; 1H NMR
d 0.83 and
0.84 (3H, s), 0.88 and 0.92 (3H, s), 1.04 and 1.10 (3H, d, J¼6.3 Hz),
1.19–1.24 (1H, m), 1.61–1.96 (7H, m), 2.24 (1H, dd, J¼6.7 and
15.1 Hz), 2.39 (1H, dd, J¼6.7 and 15.1 Hz), 2.96 (1H, d, J¼14.0 Hz),
3.05–3.14 (3H, m), 3.51 (1H, d, J¼14.0 Hz), 3.59 (3H, s), 3.75 (1H,
approx. t, J¼6.7 Hz), 4.83–4.87 (1H, m), 7.07–7.20 (3H, m, Ar-H),
7.33–7.37 (1H, m, Ar-H), 7.50–7.64 (4H, m, Ar-H), 7.85–7.91 (2H, m,
Ar-H), 8.09 (1H, br s, NH);13C NMR 19.8, 19.9, 21.1, 27.1, 29.5, 29.8,
39.6, 42.4, 44.0, 48.3, 49.3, 49.9, 51.7, 55.1, 59.1, 77.8, 111.1, 111.2,
118.7, 119.3, 122.0, 122.8, 127.4, 127.7, 129.3, 133.5, 136.1, 141.2, 170.4,
d
1.05 (3H, d, J¼6.3 Hz), 1.69–1.81 (4H, m), 2.26–2.40 (1H, m),
2.56–2.68 (2H, m), 2.97–3.02 (1H, m), 3.26–3.40 (1H, m), 3.44–
3.48 (1H, m), 3.66 (3H, s), 5.05–5.18 (2H, m), 7.27–7.57 (5H, m,
ArH); 13C NMR (75 MHz, CDCl3) Major Component:
d
18.5, 23.9,
30.3, 38.9, 49.1, 52.0, 53.2, 61.9, 66.4, 128.3, 128.3, 128.4, 128.5,
128.7, 136.2, 172.3, 175.7; Minor Component: 15.7, 24.1, 30.1,
d
40.7, 47.9, 51.9, 52.8, 62.0, 66.3, 128.3, 128.3, 128.4, 128.5, 128.7,
136.3, 172.1, 175.6; MS (EI) m/z 305 (Mþ, 1%), 247 (16), 246 (100),
156 (10); HRMS (EI) m/z 305.1628 (C17H23NO4 [Mþ], 305.1627).
D
175.3; MS (CI) m/z 581 (MHþ, 100), 450 (71), 277 (69), 135 (80);
[
a
]
þ43 (c 1, CH2Cl2).
20
D
HRMS (CI) m/z 581.2680 (C32H41N2O6S [MHþ], 581.2685). [
(c 1, CH2Cl2).
a
]
20 ꢁ45
4.3.17. (1R)-(ꢁ)-10-Phenylsulfonylisobornyl (S)-3-[(2S)-(2-methoxy-
carbonylpyrrolid-1-yl)]butanoate 22. Obtained as an oil (91%). IR
4.3.13. (1S)-(þ)-10-phenylsulfonylisobornyl (R)-3-[(1R)-1-methoxy-
carbonylethylamino]butanoate 16a. Prepared from the reduction
of 15a and was obtained as an oil (74%). IR (film) 1652, 1443,
(film) 1147, 1447, 1334, 2955 cmꢁ1; 1H NMR
d 0.85 (3H, s), 0.95 and
0.96 (3H, s), 1.10 and 1.15 (3H, d, J¼6.3 Hz), 1.14–1.21 (1H, m), 1.60–
2.23 (11H, m), 2.57–2.63 (2H, m), 2.98 (1H, d, J¼14.0 Hz), 3.01–3.27
(2H, m), 3.45–3.54 (2H, m), 3.69 (3H, s), 4.87–4.91 (1H, m), 7.57–
7.64 (3H, m, Ar-H), 7.89–7.92 (2H, m, Ar-H); 13C NMR 18.2,19.8, 20.2,
23.7, 27.1, 29.8, 30.1, 39.1, 39.6, 44.0, 49.2, 49.4, 49.8, 51.8, 53.5, 55.0,
61.7, 77.9, 127.6, 129.2, 133.5, 141.3, 170.6, 175.5; MS (CI) m/z 492
1731, 2959 cmꢁ1 1H NMR
; d 0.85 (3H, s), 0.96 (3H, s), 1.04 (3H, d,
J¼6.0 Hz), 1.14–1.21 (1H, m), 1.17 (3H, d, J¼6.8 Hz), 1.57–2.05 (6H,
m), 2.18–2.43 (2H, m), 2.97 (1H, d, J¼13.9 Hz), 3.00–3.10 (1H, m),
3.43–3.56 (2H, m), 3.63 (3H, s), 4.88–4.91 (1H, m), 7.55–7.66
(3H, m, Ar-H), 7.89–7.94 (2H, m, Ar-H); 13C NMR 19.5, 19.9, 20.2,
21.1, 27.1, 29.8, 39.6, 41.9, 42.3, 44.0, 48.1, 49.3, 49.8, 51.9, 53.6,
54.4, 55.0, 77.9, 127.7, 129.2, 133.5, 141.3, 170.5, 176.5; MS (CI)
(MHþ, 96), 432 (47), 277 (84), 156 (100); HRMS (CI) m/z 492.2419
(C26H38NO6S [MHþ], 492.2411). [
a
]
20 þ20 (c 1, CH2Cl2).
D
m/z 466 (MHþ, 55), 277 (87), 277 (46), 135 (82), 111 (100); HRMS
4.3.18. (1R)-(ꢁ)-10-Phenylsulfonylisobornyl (R)-3-[(2R)-(2-methoxy-
carbonylpyrrolid-1-yl)]butanoate 24. Obtained as a white solid
(90%), mp 94.3–95.5 ꢀC (from Ethyl Acetate/Hexane); IR (film) 1138,
D
(CI) m/z 466.2263 (C24H33NO6S [MHþ], 466.2267). [
CH2Cl2).
a
]
ꢁ20 (c 1,
20
1312, 1720 and 2958; 1H NMR (400 MHz, CDCl3)
d 0.82 (3H, s), 0.91
4.3.14. (1S)-(þ)-10-Phenylsulfonylisobornyl (R)-3-[(1R)-2-(1H-indol-
3-yl)-1-methoxycarbonylethylamino]butanoate 16b. Prepared from
the reduction of 15b and was obtained as an oil (84%). IR (film) 1447,
and 0.93 (3H, s), 1.07 and 1.15 (3H, d, J¼6.8 Hz), 1.55–2.07 (11H, m),
2.13–2.23 (1H, m), 2.52–2.58 (2H, m), 2.95 (1H, d, J¼14.0 Hz), 3.05–
3.12 (1H, m), 3.19–3.29 (1H, m), 3.40–3.51 (2H, m), 3.67 (3H, s),
4.78–4.81 and 4.84–4.87 (1H, m), 7.52–7.57 (2H, m, ArH), 7.60–7.64
(1H, m, ArH), 7.84–7.86 (2H, m, ArH); 13C NMR (100 MHz, CDCl3)
1457, 1732, 2958 cmꢁ1; 1H NMR
d 0.84 (3H, s), 0.90 and 0.92 (3H, s),
1.05 and 1.10 (3H, d, J¼6.3 Hz), 1.17–1.25 (1H, m), 1.57–1.90 (6H, m),
2.25–2.35 (2H, m), 2.96 (1H, d, J¼14.0 Hz), 3.05–3.14 (3H, m), 3.49
and 3.51 (1H, d, J¼14.0 Hz), 3.60 (3H, s), 3.68–3.74 (1H, m), 4.82–
d
18.6, 19.9, 20.3, 23.6, 27.1, 29.8, 30.1, 38.7, 39.5, 44.0, 49.0, 49.3,
49.8, 51.8, 52.9, 55.0, 61.9, 127.6, 129.2, 133.5, 141.4, 170.7, 175.4; MS

9124
A.L. Cardoso et al. / Tetrahedron 65 (2009) 9116–9124
(EI) m/z 491 (Mþ, 1%), 432 (100); HRMS (EI) m/z 491.2341
Cu Ka radiation (
l
¼1.5418 Å). Intensities were recorded as full
D
(C26H37NO6S [Mþ], 491.2342). [
a]
þ65 (c 1, CH2Cl2).
profiles of u–q scans. The structures were solved by direct methods
20
as implemented in SHELXS97a and refined by full-matrix least-
squares using SHELXL97a.16
4.3.19. (1S)-(þ)-10-Phenylsulfonylisobornyl (R)-3-[(2R)-(2-methoxy-
carbonylpyrrolid-1-yl)]butanoate 26. Obtained as a white solid
(95%), mp 98.4–99.8 ꢀC (from Ethyl Acetate/Hexane); IR (film) 1136,
C24H35NO6S, M¼465.59, orthorhombic, P212121 with unit cell,
a¼8.0614(17) Å, b¼17.596(3) Å, c¼17.318(2) Å,
a
¼b
¼g
¼90ꢀ, V¼245
1301, 1716, 1740 and 2963; 1H NMR (400 MHz, CDCl3)
d
0.80 (3H, s),
6.5(7) Å3. It contains four molecules/unit cell. rcalcd¼1.256 g cmꢁ3
,
0.89 and 0.91 (3H, s), 1.04 and 1.10 (3H, d, J¼6.5 Hz), 1.13–1.20 (1H,
m), 1.53–2.06 (10H, m), 2.11–2.18 (1H, m), 2.43–2.60 (2H, m), 2.93
(1H, d, J¼14.0 Hz), 3.04–3.09 (1H, m), 3.18–3.28 (1H, m), 3.36–3.45
(2H, m), 3.48 (3H, s), 4.75–4.77 and 4.80–4.83 (1H, m), 7.50–7.62
(3H, m, ArH), 7.84–7.86 (2H, m, ArH); 13C NMR (100 MHz, CDCl3)
Z¼4,
m
¼1.489 mmꢁ1. R (I>2
(I))¼0.0358 and Rw¼0.0732 for 2042
s
independent reflections.
H atoms were placed at calculated
positions and refined as riding on their parent atoms. The Flack
parameter refined to 0.0(2).17
Crystallographic data (excluding structure factors) for the
structures in this paper have been deposited with the Cambridge
Crystallographic Data Centre as supplementary publication nos.
CCDC 739375–739377. Copies of the data can be obtained, free of
charge, on application to CCDC, 12 Union Road, Cambridge CB2 1EZ,
UK (fax: þ44 (0)1223 336 033 or e-mail: deposit@ccdc.cam.ac.uk).
d
18.2, 19.8, 20.2, 23.7, 27.0, 29.7, 30.1, 39.1, 39.6, 43.9, 49.2, 49.8,
51.8, 53.4, 54.9, 61.6, 127.5, 129.2, 133.5, 141.3, 170.5, 175.5; MS (EI)
m/z 491 (Mþ, 2%), 432 (100), 156 (19), 135 (14); HRMS (EI) m/z
D
491.2340 (C26H37NO6S [Mþ], 491.2342). [
a
]
20 ꢁ14 (c 1, CH2Cl2).
4.3.20. (1S)-(þ)-10-Phenylsulfonylisobornyl (S)-3-[(2S)-(2-methoxy-
carbonylpyrrolid-1-yl)]butanoate 28. Obtained as a white solid
(96%), mp 98.4–100.2 ꢀC (from ethanol). IR (KBr) 1160, 1317, 1727,
2960 cmꢁ1 1H NMR
; d 0.85 (3H, s), 0.95 and 0.96 (3H, s), 1.10 and
Acknowledgements
1.18 (3H, d, J¼6.5 Hz), 1.14–1.21 (1H, m), 1.56–2.27 (11H, m), 2.57–
2.62 (2H, m), 2.98 (1H, d, J¼14.0 Hz), 3.01–3.14 (1H, m), 3.20–3.30
(1H, m), 3.46 (1H, dd, J¼4.5 and 9.0 Hz), 3.52 and 3.53 (1H, d,
J¼14.0 Hz), 3.70 (3H, s), 4.82 and 4.89 (1H, dd, J¼3.0 and 8.0 Hz),
7.54–7.65 (3H, m, Ar-H), 7.89–7.93 (2H, m, Ar-H); 13C NMR 18.6,
19.9, 20.3, 23.6, 27.1, 29.8, 30.1, 38.7, 39.5, 44.0, 49.1, 49.3, 49.9, 51.9,
53.0, 55.0, 62.0, 77.7, 127.6, 129.2, 133.5, 141.3, 170.7, 175.5; MS (CI)
Thanks are due to FCT (Project: PTDC/QUI/64470/2006; Grants:
SFRH/BPD/34569/2007 and SFRH/BD/45128/2008) as well as the
´
´
Departamento de Educacion, Universidades e Investigacion del
´
Gobierno Vasco (GV, IT-277/07 and UPV, GIU 06/51), the Direccion
´
´
General de Investigacion del Ministerio de Ciencia y Tecnologıa
(MCYT, Madrid DGI, CTQ2006-09323) and FEDER for financial
support. We acknowledge the Nuclear Magnetic Resonance Labo-
ratory of the Coimbra Chemical Centre (www.nmrccc.uc.pt), Uni-
versity of Coimbra for obtaining the NMR data.
m/z 492 (MHþ, 99), 432 (100), 277 (57), 156 (99); HRMS (CI) m/z
D
492.2416 (C26H38NO6S [MHþ], 492.2419). [
a]
ꢁ66 (c 1, CH2Cl2).
20
4.4. Crystal data for (1R)-(L)-10-phenylsulfonylisobornyl (S)-
3-[(1S)-1-methoxycarbonylethylamino]butanoate 13a
References and notes
The X-ray data were collected on a Bruker Apex II single crystal
diffractometer at room temperature. The structure of this com-
pound was determined using a transparent thin rectangular plate
single crystal with dimensions 0.24ꢂ0.12ꢂ0.05 mm (P212121) with
unit cell, a¼8.0876(4) Å, b¼17.3058(12) Å, c¼17.6137(12) Å and
1. Enantioselective Synthesis of b-Amino Acids, 2nd ed.; Juaristi, E., Soloshonok, V. A.,
Eds.; Wiley-Interscience: New York, NY, 2005.
2. Liu, M.; Sibi, M. P. Tetrahedron 2002, 58, 7991–8035.
3. Cardillo, G.; Tomasini, C. Chem. Soc. Rev. 1996, 117–128.
4. Cheng, R. P.; Gellman, S. H.; DeGrado, W. F. Chem. Rev. 2001, 101, 3219–3232.
5. Seebach, D.; Kimmerlin, T.; Sebesta, R.; Campo, M. A.; Beck, A. K. Tetrahedron
2004, 60, 7455–7506.
V¼2465.2(3) Å3. It contains four molecules/unit cell. rcalcd
¼
1.254 g cmꢁ3
(0.71073 Å). A total of 2479 reflections with I>2
R¼0.0479.
,
m¼0.169 mmꢁ1
.
MoKa radiation was used
6. Abele, S.; Seebach, D. Eur. J. Org. Chem. 2000, 1–15.
s(I) were used.
7. Qiu, X.-L.; Meng, W.-D.; Qing, F.-L. Tetrahedron 2004, 60, 6711–6745.
8. (a) Hill, D. J.; Mio, M. J.; Prince, R. B.; Hughes, T. S.; Moore, J. S. Chem. Rev. 2001,
101, 3893–4011; (b) Goodman, C. M.; Choi, S.; Handler, S.; DeGrado, W. F. Nat.
Chem. Biol. 2007, 3, 252–262.
9. Pinho e Melo, T. M. V. D.; Cardoso, A. L.; Palacios, F.; de los Santos, J. M.; Pais, A.
A. C. C.; Abreu, P. E.; Paixa˜o, J. A.; Matos Beja, A.; Ramos Silva, M. Tetrahedron
2008, 64, 8141–8148.
4.5. Crystal data for (1S)-(D)-10-phenylsulfonylisobornyl (R)-
3-[(2R)-(2-methoxycarbonylpyrrolid-1-yl)]butanoate 28
10. (a) Palacios, F.; Vicario, J.; Maliszewska, A.; Aparicio, D. J. Org. Chem. 2007, 72,
2682–2685; (b) Palacios, F.; Aparicio, D.; Vicario, J. J. Org. Chem. 2006, 71, 7690–
7696.
11. (a) Palacios, F.; Alonso, C.; de los Santos, J. M. Chem. Rev. 2005, 105, 899–931; (b)
Vicario, J.; Aparicio, D.; Palacios, F. J. Org. Chem. 2009, 74, 452–455.
12. (a) Benzyl 2,3-butadienoate was prepared via Wittig reaction of benzyl tri-
phenylphosphoranylideneacetate with ketene following the general procedure
described in Ref. 13; (b) Lambert, T. H.; MacMillan, D. C. W. J. Am. Chem. Soc.
2002, 124, 13646–13647.
The X-ray data were collected on a Bruker Apex II single crystal
diffractometer at room temperature. The structure of this com-
pound was determined using a transparent thin rectangular plate
single crystal with dimensions 0.20ꢂ0.10ꢂ0.03 mm (P21) with unit
cell, a¼7.9904(3) Å, b¼12.0055(5) Å, c¼13.9100(5) Å, ¼98.177(2)
b
and V¼1320.8(9) Å3. It contains two molecules/unit cell.
rcalcd¼1.171 g cmꢁ3
,
m¼0.158 mmꢁ1
. MoKa radiation was used
13. Pinho e Melo, T. M. V. D.; Cardoso, Ana L.; Rocha Gonsalves, A. M. d’A.; Costa
Pessoa, J.; Paixa˜o, J. A.; Beja, A. M. Eur. J. Org. Chem. 2004, 4830–4839.
14. Cimarelli, C.; Palmieri, G. J. Org. Chem. 1996, 61, 5557–5563.
(0.71073 Å). A total of 3329 reflections with I>2
R¼0.0531.
s(I) were used.
15. The
-amino acids by reacting with SOCl2 in MeOH. The
chlorides were treated with NEt3 in THF, then the ammonium salt was filtered
and the solvent evaporated off giving the corresponding -amino ester. In the
case of -alanine and -alanine methyl ester the corresponding hydrochloride
a
-amino esters hydrochlorides were prepared from the corresponding
a
a
-amino ester hydro-
4.6. Crystal data for (1S)-(D)-10-Phenylsulfonylisobornyl (R)-
3-[(1R)-1-methoxycarbonylethylamino]butanoate 16a
a
L
D
were used and 1 equiv of NaHCO3 was added to the reaction mixture.
16. Sheldrick, G. M. SHELXS97 & SHELXL97; University of Go¨ttingen: Germany, 1997.
17. Flack, H. D. Acta Crystallogr. 1983, A39, 876–881.
The X-ray data were collected on an Enraf-nonius Mach-3 single
crystal diffractometer, at 298(3) K, using graphite-monochromated