New approach to exclusive formation of both enantiomers of β-amino acid derivatives

Article abstract of DOI:10.1016/j.tet.2008.06.053

A highly selective two-step approach to chiral β-amino esters via the hydride reductive amination of chiral allenes is reported. β-Enamino esters were obtained from the nucleophilic addition of amines to 2,3-allenoates bearing a chiral auxiliary. The reduction of the (1R)-(-)-10-phenylsulfonylisobornyl β-enamino esters gave the corresponding β-amino esters with S configuration whereas the reduction of the (1S)-(+)-10-phenylsulfonylisobornyl β-enamino esters led to β-amino esters with R configuration. The rationalization of the observed selectivity was supported by semi-empirical molecular orbital calculations (PM3).

Full text of DOI:10.1016/j.tet.2008.06.053

Tetrahedron 64 (2008) 8141–8148
Contents lists available at ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
New approach to exclusive formation of both enantiomers
of
b-amino acid derivatives
,
a
b
b
Teresa M.V.D. Pinho e Melo a , Ana Lucia Cardoso , Francisco Palacios , Jesus M. de los Santos ,
*
´
´
a
a
c
c
c
´
˜
Alberto A.C.C. Pais , Paulo E. Abreu , Jose A. Paixao , Ana Matos Beja , Manuela Ramos Silva
a Department of Chemistry, University of Coimbra, 3004-535 Coimbra, Portugal
b Department of Organic Chemistry I, Faculty of Pharmacy, University of the Basque Country, Apartado 450, 01080 Vitoria, Spain
c Department of Physics, University of Coimbra, 3004-516 Coimbra, Portugal
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 6 May 2008
Received in revised form 9 June 2008
Accepted 16 June 2008
Available online 19 June 2008
A highly selective two-step approach to chiral
b
-amino esters via the hydride reductive amination of
chiral allenes is reported.
2,3-allenoates bearing a chiral auxiliary. The reduction of the (1R)-(ꢀ)-10-phenylsulfonylisobornyl
-enamino esters gave the corresponding -amino esters with S configuration whereas the reduction of
-enamino esters led to -amino esters with R configuration.
b-Enamino esters were obtained from the nucleophilic addition of amines to
b
b
the (1S)-(þ)-10-phenylsulfonylisobornyl
b
b
The rationalization of the observed selectivity was supported by semi-empirical molecular orbital cal-
Keywords:
Chiral allenes
culations (PM3).
Ó 2008 Elsevier Ltd. All rights reserved.
b
b
-Amino esters
-Enamino esters
Asymmetric reduction
1. Introduction
a chiral auxiliary in the ester moiety, the higher diastereoselectivity
was obtained by the use of (ꢀ)-8-phenylmenthol group (de 60%).9
The design of new synthetic methodologies for the asymmetric
On the other hand, the stereoselective reduction of b-enamino es-
synthesis of
b
-amino acids is a research area of considerable current
ters using sodium triacetoxyborohydride in acetic acid has also
been reported.10 In this case, the
-enamino esters were prepared
from the condensation of chiral amines with -keto esters or by
acylation of lithium imines with carbonates or chloroformates.
Moderate asymmetric induction was observed, ranging from de
30% to 69% and the stereochemistry outcome was determined by
interest.1 The importance of this class of compounds lies in their
unique biological properties, their occurrence in natural products,
and their use as precursors of biologically and medicinally impor-
b
b
tant molecules.
present in a variety of bioactive molecules such as taxol, one of the
most active antitumor agents. Furthermore, -amino acids, al-
though not as abundant as their -analogues, are also segments in
peptide natural products with various biological activities. There is
also considerable interest in the synthesis of unnatural -amino
acids for the construction of -peptides, which are a class of un-
b-Amino acids are precursors of b-lactams and are
b
the bulkiness of the substituent at the b-position. Therefore, the
a
trend of asymmetric induction was not modulated by the nature of
the chiral auxiliary.10
b
In connection with our interest in the chemistry of amino ester
derivatives,11 in this paper an alternative and highly selective two-
b
natural biopolymers that present interesting secondary structures,
step approach to chiral b-amino esters with control of the stereo-
chemistry outcome via the hydride reductive amination of chiral
allenes is reported.
as well as increased potency and enzymatic stability.2–7
Asymmetric hydrogenation of
to prepare -enamino acids either by the use of chiral auxiliaries or
by the use of chiral catalysts.8 Stereoselective reduction of fluori-
nated -enamino esters obtained from fluorinated imidoyl chlo-
rides and chiral ester enolates has been reported.9 However, in the
b-enamino esters has been used
b
2. Results and discussion
b
Functionalized hydrazones,12 oximes,13 and
b
-enamines14 can
reported Lewis acid/NaBH4 reduction of b-enamino esters bearing
be obtained from the nucleophilic addition of hydrazines, hydroxyl-
amines, or amines, respectively, to allenes.15 If allenes bearing
a chiral auxiliary are used chiral b-amino esters could be obtained.
We have previously described a new asymmetric Wittig reaction
* Corresponding author. Tel.: þ351 239 854475.
E-mail address: tmelo@ci.uc.pt (T.M.V.D. Pinho e Melo).
that allows the synthesis of allenic esters with axial chirality.16 The
0040-4020/$ – see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2008.06.053

8142
T.M.V.D. Pinho e Melo et al. / Tetrahedron 64 (2008) 8141–8148
reaction between 10-phenylsulfonylisobornyl (triphenylphosphor-
anylidene)acetates and ketenes results in asymmetric induction:
the use of (1R)-(ꢀ)-10-phenylsulfonylisoborneol unit allows the
synthesis of allenes with S configuration, whereas use of the (1S)-
(þ)-10-phenylsulfonylisoborneol unit produces allenes with R
configuration. Having available these allene derivatives we set out
to explore their reactivity toward amines and to study the re-
triacetoxyborohydride in acetic acid, the corresponding chiral
amino esters 5 are obtained in good yields (Table 2, entries 1–3, 5–7,
9, and 10). The 1H NMR spectra of
-amino esters 5 showed signals
b-
b
for single diastereoisomer. However, two rotamers are observed in
the 1H NMR and 13C NMR spectra of these compounds recorded at
ambient temperature but the spectra are simpler at higher tem-
perature. In fact, we found that the 1H NMR spectrum of (1R)-
(ꢀ)-10-phenylsulfonylisobornyl (S)-3-(benzylamino)butanoate 5a
recorded at room temperature, showed two sets of signals corre-
sponding to the AB system of the 10-phenylsulfonylisobornyl group
but when recorded at 70 ꢁC, showed a single set of signals. The
duction of the corresponding
b
-enamino esters in order to find
a route to chiral -amino esters.
b
The synthesis of (1R)-(ꢀ)-10-phenylsulfonylisobornyl
b
-enam-
ino esters (2) was achieved by carrying the reaction at room tem-
perature of the corresponding allenic esters (1) with the selected
amines (benzylamine, 4-methoxyaniline, and prop-2-en-1-amine)
(Table 1). The reaction works smoothly giving the desired products
chiral
rotation.
Interestingly,
sulfonylisobornyl
hydride in acetic acid led to the efficient and stereoselective
synthesis of -amino esters 6a–6g (Scheme 2 and Supplementary
data), which are enantiomers of the corresponding -amino esters
5a–5g. In fact, both series of chiral -amino esters show the same
physical properties and values for the optical rotation with opposite
sign. The reduction of 4d led to -amino ester 6d in 55% yield to-
b-amino esters 5 showed positive values for the optical
the
reduction
of
(1S)-(þ)-10-phenyl-
in good to high yields (50–85%). However, the synthesis of
b
-
b-enamino esters 4 with sodium triacetoxyboro-
enamino ester 2c was carried out by heating the reaction mixture at
45 ꢁC resulting in an improvement of the yield from 38% to 74%.
Using the same synthetic methodology (1S)-(þ)-10-phenyl-
b
b
sulfonylisobornyl
b
-enamino esters (4), bearing a chiral auxiliary
b
enantiomeric to the one of
b
-enamino esters 2, were also obtained
in yields ranging from 61% to 90% (Scheme 1 and Supplementary
data).
b
gether with the recovery of the starting material (45%). However,
increasing the reaction time to 18 h compound 6d could be
obtained in 91% yield.
The structure of (1S)-(ꢀ)-10-phenylsulfonylisobornyl (R)-3-
(benzylamino)-5,5-dimethylhexanoate 6d was determined by X-
ray crystallography (Fig. 1b). This allowed us to establish the R
Table 1
Synthesis of
b-enamino esters 2
H
•
H
O
R1NH2
MeOH, r.t.
O
configuration to the new chiral center of
conclude that the enantiomeric series of
have S configuration.
b
b
-amino esters 6 and to
-amino esters 5 must
R
R
NH
O
O
R1
SO2Ph
SO2Ph
2
1
The stereochemical outcome of the
with sodium triacetoxyborohydride in acetic acid can be rational-
ized as follows (Scheme 3). Ligand exchange between -enamino
esters 2 and one of the acetoxy ligands of NaHB(OAc)3 leads to enol
ester-diacetoxyborohydrides 7. These intermediates undergo
intramolecular hydride reduction affording 8. The chiral auxiliary
shields one of the diastereofaces of the protonated imines 7 thus
allowing for the observed selectivity. Intermediates 8 are converted
b-enamino esters reduction
R1
Yield (%)
[a]
D
25
Entry
Product
R
b
1
2
3
4
5
6
7
2a
2b
2c
2d
2e
2f
H
Bn
Bn
Bn
Bn
Bn
75
50
74a
82
84
85
76
þ30
þ35
þ20
þ30
þ35
þ20
þ30
Me
i-Pr
t-Bu
Bn
H
p-MeOC6H4
CH2CH]CH2
2g
H
into b-amino esters 5 by action of acetic acid.
a
Reaction mixture heated at 45 ꢁC.
Semi-empirical molecular orbital calculations using the PM3
Hamiltonian were carried in order to further corroborate the
rationalization of the observed selectivity. We concentrated on the
reduction of
b-enamino ester 2b with sodium triacetoxyborohy-
dride leading to
b
-amino ester 5b (Table 2). Therefore, we have
H
R1NH2
MeOH, r.t.
H
O
O
•
examined the intramolecular hydride transfer in the case of 7b
R
R
O
HN
(R¼Me
and
R1¼Bn)
bearing
the
(1R)-(ꢀ)-10-phenyl-
O
R1
SO2Ph
SO2Ph
sulfonylisobornyl chiral auxiliary.
4a R = H; R1 = Bn
4b R = Me; R1 = Bn
4c R = i-Pr;R1 = Bn
4d R = t-Bu;R1 = Bn
4e R = R1= Bn
3a R = H
We have conducted a very thorough search for the transition
states corresponding to the two possibilities depicted in Scheme 3,
the hydride attack to the two diastereofaces of the immonium
function. For the calculation of the transition state (TS I), the Hes-
sian (matrix of the second derivatives of the energy in order to the
nuclear coordinates) was calculated at every point as to provide
a suitable guide for finding the transition state and, also a small
enough trust radius (0.01 Å) in order not to overshoot the saddle
point. After the localization of this point, its character was con-
firmed by inspecting the corresponding Hessian matrix, in which
only one imaginary frequency should be present. The normal mode
associated to the imaginary frequency (i997.78 cmꢀ1) corresponds
to the motion of the hydrogen atom between the carbon and boron
atoms. In the transition state, this hydrogen is at a distance of
1.407 Å from the boron atom, and 1.529 Å from the carbon atom,
with a boron–hydrogen–carbon angle of 129.42ꢁ (Fig. 2). The
MOPAC charges of the atoms involved directly in this hydrogen
transit are q(B)¼0.035, q(C)¼0.249, and q(H)¼ꢀ0.026e. The corre-
sponding Mulliken charges are q(B)¼0.184, q(C)¼0.234, and
3b R = Me
3c R = i-Pr
3d R = t-Bu
3e R = Bn
4f R = H; R1 = C6H4OMe-p
4g R = H; R1 = CH2CH=CH2
Scheme 1.
The downfield chemical shift observed for the N–H proton
(8.87–10.11 ppm) of the -enamino esters (2 and 4) is typical of
a hydrogen bond with the carbonyl group oxygen, which indicates Z
configuration.9 In fact, the structure of
-enamino ester 4d de-
termined by X-ray crystallography confirms the Z enamine geom-
etry (Fig. 1a). It was also observed that in the solid state the
compound is stabilized by the intramolecular hydrogen bond be-
b
b
tween the
We observed that carrying out the reduction of (1R)-(ꢀ)-10-
phenylsulfonylisobornyl -enamino esters 2a–2g with sodium
b-enamino proton and the carbonyl group.
b

T.M.V.D. Pinho e Melo et al. / Tetrahedron 64 (2008) 8141–8148
8143
Figure 1. X-ray structures: (a) (1S)-(þ)-10-phenylsulfonylisobornyl (Z)-3-(benzylamino)-5,5-dimethylhex-2-enoate 4d; (b) (1S)-(ꢀ)-10-phenylsulfonylisobornyl (R)-3-(benzyl-
amino)-5,5-dimethylhexanoate 6d.
q(H)¼ꢀ0.047e. The bond orders for the two transition state bonds
are B.O.(C–H)¼0.364 and B.O.(B–H)¼0.524. The calculated heat of
formation is ꢀ318.7 kcal/mol.
q(H)¼ꢀ0.056e. In what concerns bond orders, we have
B.O.(C–H)¼0.294 and B.O.(B–H)¼0.597. The heat of formation cal-
culated is ꢀ310.6 kcal/mol, i.e., 8.1 kcal/mol above the other one.
Therefore, the calculated difference in energy between the
transition state that leads to the synthesis of b-amino ester 5b (TS I)
and the one leading to the corresponding diastereoisomer 9 (TS II)
For the other transition state (TS II), which corresponds to the
attack to the more hindered face of the imine, we started from the
previous geometry and changed the position of the groups attached
to the carbon atom, so as to provide an initial geometry. This search
used the same criteria as above, and only one transition state was
located with a single imaginary frequency. Inspection of the mode
corresponding to this imaginary frequency (i972.20 cmꢀ1) showed
that the motion again corresponds to hydrogen atom moving be-
tween the carbon and the boron atoms. In the transition state,
distance B–H is 1.330 Å, with 1.611 Å for C–H. The B–H–C angle is
133.22ꢁ. The MOPAC charges of the atoms involved directly in the
hydrogen transit were q(B)¼0.062, q(C)¼0.268, and q(H)¼ꢀ0.034e,
while the Mulliken values are q(B)¼0.155, q(C)¼0.255, and
justifies the observed exclusive formation of the former.
In a similar way, the stereoselective formation of
b-amino esters
6 with R configuration from -enamino esters 4 can be explained
b
considering the intramolecular selective reduction of intermediates
10 (Scheme 4).
The reduction of
formed using ZnI2 and NaBH4,9 affording the corresponding
amino esters (5c and 5e) as single diastereoisomers (Table 2, entries
4 and 8). On the other hand, -amino esters with R configuration at
the new chiral center were obtained carrying out the reduction of
-enamino esters 4a, 4b, and 4d with ZnI2 and NaBH4 (see Sup-
b-enamino esters 2c and 2e was also per-
b
-
b
b
plementary data). However, using these reduction conditions,
compound 4a gave a mixture of the expected 6a together with the
N-unprotected derivative.
Table 2
Reduction of
b-enamino esters 2 to b-amino esters 5
The stereoselectivity observed in the reduction of the
ino esters with ZnI2/NaBH4 can be explained as outlined in Scheme
5. Starting from -enamino esters 2 the initially formed Zn(II)-
complex 11 undergoes the hydride attack by the re-face since the
b-enam-
R1
HN
O
A or B
O
R
b
O
NH
O
R1
R
SO2Ph
SO2Ph
chiral auxiliary shields the si-face. Therefore,
b
-amino esters with S
2
5
Procedure A: NaBH(OAc)3/AcOH, 0 °C, 4h
Procedure B: NaBH4/ZnI2, r.t.
25
Entry
Product
R
R1
Yield (%)
[a]
D
H
O
N
O
R1
1
2
3
4
5
6
7
8
9
10
5a
5b
5c
5c
5d
5d
5e
5e
5f
H
Bn
Bn
Bn
Bn
Bn
Bn
Bn
Bn
A
A
A
B
A
A
A
B
A
A
94
90
88
85
52a
93b
91
68
68
91
þ40
þ25
þ30
þ30
þ45
þ45
þ35
þ35
þ35
þ35
A or B
R
Me
i-Pr
i-Pr
t-Bu
t-Bu
Bn
Bn
H
H
O
O
HN
R1
SO2Ph
SO2Ph
R
4a R = H;R1 = Bn
6a R = H;R1 = Bn
6b R = Me; R1= Bn
6c R = i-Pr; R1= Bn
6d R = t-Bu;R1= Bn
6e R = R1 = Bn
4b R = Me; R1 = Bn
4c R = i-Pr;R1 = Bn
4d R = t-Bu;R1 = Bn
4e R = R1= Bn
p-MeOC6H4
CH2CH]CH2
4f R = H;R1 = C6H4OMe-p
4g R = H; R1 = CH2CH=CH2
6f R = H; R1 = C6H4OMe-p
6g R = H; R1 = CH2CH=CH2
5g
a
Starting material (2d) recovered (46%).
Reaction time: 18 h.
b
Scheme 2.

8144
T.M.V.D. Pinho e Melo et al. / Tetrahedron 64 (2008) 8141–8148
O
O
H
N
R1
SO2Ph
R
2
NaHB(OAc)3
AcO
OAc
OAc
O
OAc
O
AcO
NH
AcO
B
B
R1
HN
H
H
B
R1
R1
N
O
O
AcOH
H
O
R1HN
R
R
R
- B(OAc)3
O
O
O
SO2Ph
R
SO2Ph
S
SO2Ph
TSI
5
8
O2
7
AcO OAc
B
R1
HN
AcOH
- B(OAc)3
H
O
O
O
R
O
SO2Ph
R1HN
R
SO2Ph
9
TS II
Scheme 3.
I
I
Zn
R1
HN
R1
N
O
O
O
R
NaBH4
O
SO2Ph
R
S
O2
5
Re
11
I
I
Zn
R1
N
O
R
O
H
N
NaBH4
O
R1
S
O2
O
Si
SO2Ph
R
12
6
Scheme 5.
Figure 2. Reduction of b-enamino ester 2b into b-amino ester 5b with sodium tri-
acetoxyborohydride: geometry of the PM3 transition state I (TS I) for the intra-
molecular hydride transfer in the case of intermediate 7b (R¼Me and R1¼Bn). The
brown atom is boron, light blue carbon, light gray hydrogen, red oxygen, dark blue
nitrogen, and yellow sulfur. Image produced using VMD.17
3. Conclusion
Herein, we reported an approach to chiral
b-amino esters in-
OAc
AcO
volving the stereoselective reduction of -enamino esters bearing
b
B
a chiral auxiliary in the ester moiety, obtained from the nucleo-
philic addition of amines to chiral 2,3-allenoates. The nature of the
H
H
R1
O
N
H
N
R
AcOH
O
chiral auxiliary of these
of the
-amino esters, which are obtained exclusively: (1R)-(ꢀ)-10-
phenylsulfonylisobornyl -enamino esters gave -amino
esters with
configuration whereas the (1S)-(þ)-10-phenyl-
sulfonylisobornyl -enamino esters led to -amino esters with R
configuration. Therefore, it has been shown that this route to chiral
-amino esters is very versatile, high stereoselective and allows the
b-enamino esters determines the chirality
R1
O
- B(OAc)3
b
O
SO2Ph
R
S
b
b
O2
6
10
S
b
b
Scheme 4.
b
configuration are obtained. On the other hand, starting from
enamino esters 4 the hydride attack occurs at the si-face of Zn(II)-
complex 12 giving -amino esters with R configuration (6).
b
-
control of the stereochemistry outcome by the selection of the
chiral auxiliary. Computational studies corroborated the ration-
alization of the observed selectivity.
b

T.M.V.D. Pinho e Melo et al. / Tetrahedron 64 (2008) 8141–8148
8145
4. Experimental
4.1. General
4.2.3. (1R)-(ꢀ)-10-Phenylsulfonylisobornyl (Z)-3-(benzylamino)-5-
methylhex-2-enoate 2c and (1S)-(þ)-10-phenylsulfonylisobornyl
(Z)-3-(benzylamino)-5-methylhex-2-enoate 4c
IR (KBr) 1597,1651, 2950 cmꢀ1; 1H NMR 0.87 (3H, s), 0.95 (3H, s),
1.00 (3H, d, J¼6.6 Hz), 1.03 (3H, d, J¼6.6 Hz), 1.14–1.21 (1H, m),
1.61–2.17 (9H, m), 2.97 (1H, d, J¼14.1 Hz), 3.69 (1H, d, J¼14.1 Hz),
4.40–4.43 (3H, m), 4.51 (1H, dd, J¼3.0 and 7.7 Hz), 7.26–7.51 (8H, m,
Ar–H), 7.88–7.91 (2H, m, Ar–H), 8.87 (NH, br t, J¼6.0 Hz); 13C NMR
20.0, 20.4, 22.5, 27.2, 27.4, 29.3, 39.9, 41.5, 44.1, 46.7, 49.0, 49.8, 54.9,
75.3, 83.7, 126.9, 127.4, 127.8, 128.7, 129.0, 133.2, 138.7, 141.1, 164.1,
169.1.
1H NMR spectra were recorded on a Bruker Avance 300
instrument operating at 300 MHz. 13C NMR spectra were recorded
on a Bruker Avance 300 instrument operating at 75.5 MHz. The
solvent is deuteriochloroform except where indicated otherwise. IR
spectra were recorded on a Perkin Elmer 1720X FTIR spectrometer.
Mass spectra were recorded on a HP GC 6890/MSD5973 instrument
under electron impact (EI) except where indicated otherwise. Op-
tical rotations were measured on an Optical Activity AA-5 electrical
polarimeter. Microanalyses were performed using an EA 1108-HNS-
O Fisons instrument. Mps were recorded on a Reichert hot stage
and are uncorrected. Flash column chromatography was performed
with Merck 9385 silica as the stationary phase.
(1R)-(ꢀ)-10-Phenylsulfonylisobornyl (Z)-3-(benzylamino)-5-methyl-
hex-2-enoate 2c was obtained as a white þsolid (74%), mp 112.3–
113.4 ꢁC (from ethanol). MS (CI) m/z 510 (MH , 81), 467 (19), 277 (28),
216 (100); HRMS (CI) m/z 509.2599 (C30H39NO4S [Mþ], 509.2592).
25
[
a
]
þ20 (c 1, CH2Cl2).
D
(1S)-(þ)-10-Phenylsulfonylisobornyl (Z)-3-(benzylamino)-5-methyl-
4.2. General procedure for the synthesis of
b
-enamino esters
hex-2-enoate 4c was obtained as a white solid (77%), mp 111.9–
113.2 ꢁC. MS (CI) m/z 510 (MHþ, 74), 277 (33), 216 (100); HRMS (CI)
25
The appropriate allene (5 mmol) was dissolved in dry methanol
(50 mL) followed by the dropwise addition of the amine (5 mmol).
The reaction mixture was stirred overnight at room temperature.
The solvent was evaporated off and the product crystallized.
m/z 509.2599 (C30H39NO4S [Mþ], 509.2583). [
a]
ꢀ20 (c 1, CH2Cl2).
D
4.2.4. (1R)-(ꢀ)-10-Phenylsulfonylisobornyl (Z)-3-(benzylamino)-
5,5-dimethylhex-2-enoate 2d and (1S)-(þ)-10-phenylsulfony-
lisobornyl (Z)-3-(benzylamino)-5,5-dimethylhex-2-enoate 4d
IR (KBr) 1598, 1648, 2952 cmꢀ1; 1H NMR 0.87 (3H, s), 0.95 (3H,
s), 1.09 (9H, s), 1.15–1.21 (1H, m), 1.58–2.03 (6H, m), 2.15 (1H, d,
J¼13.4 Hz), 2.20 (1H, d, J¼13.4 Hz), 2.96 (1H, d, J¼14.0 Hz), 3.70
(1H, d, J¼14.0 Hz), 4.37 (1H, s), 4.43–4.51 (3H, m), 7.26–7.52 (8H,
m, Ar–H), 7.87–7.91 (2H, m, Ar–H), 9.02 (NH, br t, J¼6.2 Hz); 13C
NMR 20.0, 20.4, 27.2, 29.3, 30.2, 32.3, 39.9, 44.1, 47.5, 49.1, 49.8,
54.9, 75.3, 85.6, 127.0, 127.4, 127.8, 128.8, 129.0, 133.2, 138.7, 141.1,
163.1, 168.9.
4.2.1. (1R)-(ꢀ)-10-Phenylsulfonylisobornyl (Z)-3-(benzyl-
amino)but-2-enoate 2a and (1S)-(þ)-10-phenylsulfony-
lisobornyl (Z)-3-(benzylamino)but-2-enoate 4a
IR (KBr) 1598, 1643, 2953 cmꢀ1 1H NMR 0.86 (3H, s), 0.95 (3H,
;
s), 1.17–1.27 (1H, m), 1.56–1.91 (6H, m), 1.94 (3H, s), 2.98 (1H, d,
J¼14.1 Hz), 3.69 (1H, d, J¼14.1 Hz), 4.41–4.44 (3H, m), 4.49–4.53
(1H, m), 7.26–7.39 (5H, m, Ar–H), 7.44–7.55 (3H, m, Ar–H), 7.88–
7.92 (2H, m, Ar–H), 8.88 (NH, br t, J¼6.2 Hz); 13C NMR 19.8, 20.4,
20.8, 27.6, 29.9, 40.4, 44.6, 47.3, 49.6, 50.3, 55.6, 75.9, 83.8, 127.3,
127.8, 128.3, 129.2, 129.4, 133.6, 139.1, 141.6, 161.9, 169.4.
(1R)-(ꢀ)-10-Phenylsulfonylisobornyl
(Z)-3-(benzylamino)-5,5-
dimethylhex-2-enoate 2d was obtained as a white solid (82%), mp
134.0–134.9 ꢁC (from ethanol). MS (CI) m/z 524 (MHþ, 60), 467 (72),
277 (21); HRMS (ESI-TOF) m/z 524.2829 (C31H42NO4S [MHþ],
(1R)-(ꢀ)-10-Phenylsulfonylisobornyl (Z)-3-(benzylamino)but-2-
enoate 2a was obtained as a white solid (75%), mp 132.0–133.2 ꢁC
(from ethanol). MS (CI) m/z 468 (MHþ, 34), 277 (13), 174 (100);
524.2830). Calcd for C31H41NO4S: C, 71.09; H, 7.89; N, 2.67; S, 6.12.
25
HRMS (CI) m/z 467.2130 (C27H33NO4S [Mþ], 467.2119); HRMS (ESI-
Found: C, 70.70; H, 8.05; N, 2.79; S, 6.24. [
a
]
þ30 (c 1, CH2Cl2).
D
25
TOF) m/z 468.2203 (C27H34NO4S [MHþ], 468.2203). [
a]
þ30 (c 1,
(1S)-(þ)-10-Phenylsulfonylisobornyl
(Z)-3-(benzylamino)-5,5-
D
CH2Cl2).
dimethylhex-2-enoate 4d was obtainedþas a white solid (88%), mp
134.1–135.5 ꢁC. MS (CI) m/z 524 (MH , 62), 467 (74), 277 (20);
HRMS (ESI-TOF) m/z 524.2829 (C31H42NO4S [MHþ], 524.2829).
(1S)-(þ)-10-Phenylsulfonylisobornyl (Z)-3-(benzylamino)but-2-
enoate 4a was obtained as a white solid (90%), mp 132.3–132.8 ꢁC
(from ethanol). MS (CI) m/z 468 (MHþ, 45), 277 (10), 174 (100);
Calcd for C31H41NO4S: C, 71.09; H, 7.89; N, 2.67; S, 6.12. Found: C,
25
HRMS (ESI-TOF) m/z 490.2023 (C27H33NNaO4S [MNaþ], 490.2024).
70.69; H, 7.79; N, 2.79; S, 5.94. [
a
]
ꢀ30 (c 1, CH2Cl2).
D
25
[
a]
ꢀ30 (c 1, CH2Cl2).
D
4.2.5. (1R)-(ꢀ)-10-Phenylsulfonylisobornyl (Z)-3-(benzylamino)-5-
phenylpent-2-enoate 2e and (1S)-(þ)-10-phenylsulfonylisobornyl
(Z)-3-(benzylamino)-5-phenylpent-2-enoate 4e
4.2.2. (1R)-(ꢀ)-10-Phenylsulfonylisobornyl (Z)-3-(benzyl-
amino)pent-2-enoate 2b and (1S)-(þ)-10-phenylsulfony-
lisobornyl (Z)-3-(benzylamino)pent-2-enoate 4b
IR (KBr) 1603, 1649, 2948 cmꢀ1; 1H NMR 0.87 (3H, s), 0.96 (3H,
s), 1.14–1.21 (1H, m), 1.56–2.00 (6H, m), 2.48–2.54 (2H, m), 2.81–
2.87 (2H, m), 2.99 (1H, d, J¼14.1 Hz), 3.70 (1H, d, J¼14.1 Hz),
4.39–4.42 (2H, m), 4.49 (1H, s), 4.51–4.54 (1H, m), 7.16–7.53 (13H,
m, Ar–H), 7.87–7.92 (2H, m, Ar–H), 8.92 (NH, br t, J¼6.2 Hz); 13C
NMR 20.0, 20.4, 27.2, 29.4, 34.1, 34.7, 39.9, 44.1, 46.6, 49.1, 49.8, 55.1,
75.5, 82.7, 126.4, 126.9, 127.5, 127.8, 128.2, 128.6, 128.8, 129.0, 133.2,
138.6, 140.4, 141.2, 164.4, 169.2.
IR (KBr) 1600, 1645, 2953 cmꢀ1; 1H NMR 0.87 (3H, s), 0.96 (3H,
s), 1.16 (3H, t, J¼7.5 Hz), 1.14–1.21 (1H, m), 1.57–1.98 (6H, m), 2.26
(2H, q, J¼7.5 Hz), 2.99 (1H, d, J¼14.1 Hz), 3.71 (1H, d, J¼14.1 Hz),
4.41–4.44 (3H, m), 4.50 (1H, dd, J¼3.0 and 7.7 Hz), 7.28–7.54 (8H, m,
Ar–H), 7.89–7.93 (2H, m, Ar–H), 8.88 (NH, br t, J¼6.0 Hz); 13C NMR
12.3, 20.0, 20.4, 25.2, 27.2, 29.4, 39.9, 44.1, 46.4, 49.1, 49.8, 55.1, 75.4,
81.4, 126.9, 127.4, 127.8, 128.8, 129.0, 133.2, 138.7, 141.1, 166.5, 169.4.
(1R)-(ꢀ)-10-Phenylsulfonylisobornyl (Z)-3-(benzylamino)pent-2-
enoate 2b was obtained as a white solid (50%), mp 135.1–136.4 ꢁC
(1R)-(ꢀ)-10-Phenylsulfonylisobornyl (Z)-3-(benzylamino)-5-phe-
nylpent-2-enoate 2e was obtained as a white soþlid (84%), mp 144.9–
(from ethanol). MS (APCI) m/z 482 (MHþ, 100), 277 (33), 135 (55);
146.0 ꢁC (from ethanol). MS (CI) m/z 558 (MH , 33), 277 (19), 264
HRMS (CI) m/z 481.2286 (C28H35NO4S [Mþ], 481.2282). [
a
]
þ35 (c
(100); HRMS (CI) m/z 557.2599 (C34H39NO4S [Mþ], 557.2599). [
þ35 (c 1, CH2Cl2).
a]
D
25
25
D
1, CH2Cl2).
(1S)-(þ)-10-Phenylsulfonylisobornyl (Z)-3-(benzylamino)pent-2-
(1S)-(þ)-10-Phenylsulfonylisobornyl (Z)-3-(benzylamino)-5-phe-
nylpent-2-enoate 4e was obtained as a white solid (71%), mp 145.4–
enoate 4b was obtained as a white solid (68%), mp 135.3–136.6 ꢁC
(from ethanol). MS (APCI) m/z 482 (MHþ, 100), 277 (20), 135 (38);
146.6 ꢁC. MS (CI) m/z 558 (MHþ, 30), 277 (40), 264 (100); HRMS (CI)
HRMS (CI) m/z 481.2286 (C28H35NO4S [Mþ], 481.2278). [
a
]
ꢀ30 (c
m/z 558.2678 (C34H40NO4S [MHþ], 558.2674). [
a
]
ꢀ35 (c 1,
25
25
D
D
1, CH2Cl2).
CH2Cl2).

8146
T.M.V.D. Pinho e Melo et al. / Tetrahedron 64 (2008) 8141–8148
4.2.6. (1R)-(ꢀ)-10-Phenylsulfonylisobornyl (Z)-3-(4-methoxy-
phenylamino)but-2-enoate 2f and (1S)-(þ)-10-phenylsul-
the 1H NMR spectrum of (1R)-(ꢀ)-10-phenylsulfonylisobornyl (R)-
3-(benzylamino)butanoate 5a recorded at room temperature
showed two sets of signals corresponding to the AB system of the
10-phenylsulfonylisobornyl group but when recorded at 70 ꢁC
showed a single set of signals. The 13C NMR spectra were described
considering only the main conformer. On the other hand, the 1H
NMR spectrum of (1S)-(þ)-10-phenylsulfonylisobornyl (R)-3-
fonylisobornyl (Z)-3-(4-methoxyphenylamino)but-2-enoate 4f
IR (film) 1582, 1647, 2946 cmꢀ1; 1H NMR 0.87 (3H, s), 0.98 (3H,
s), 1.17–1.27 (1H, m), 1.59–1.87 (6H, m), 1.91 (3H, s), 3.01 (1H, d,
J¼14.1 Hz), 3.70 (1H, d, J¼14.1 Hz), 3.81 (3H, s), 4.54 (1H, s), 4.62–
4.65 (1H, m), 6.86–6.88 (2H, m, Ar–H), 7.02–7.06 (2H, m, Ar–H),
7.49–7.60 (3H, m, Ar–H), 7.92–7.94 (2H, m, Ar–H), 10.11 (NH, s); 13
C
[(2S)-2-(2-methoxycarbonylpyrrolid-1-yl)ethyl]butanoate
(16e)
NMR 19.8,19.9, 20.2, 27.1, 29.4, 39.8, 44.0, 49.0, 49.7, 55.0, 55.3, 75.6,
84.7, 114.1, 126.5, 127.6, 129.0, 131.9, 133.1, 141.1, 157.2, 159.6, 168.8.
recorded at room temperature, showed two sets of signals corre-
sponding to the proton at C-1 of the 10-phenylsulfonylisobornyl
group but when recorded at 100 ꢁC, showed a single set of signals.
(1R)-(ꢀ)-10-Phenylsulfonylisobornyl
(Z)-3-(4-methoxyphenyl-
amino)but-2-enoate 2f was obtained as an oil (85%). MS (CI) m/z 484
(MHþ, 91), 277 (36), 190 (100); HRMS (CI) m/z 484.2157
4.3.1. (1R)-(ꢀ)-10-Phenylsulfonylisobornyl (S)-3-(benzylamino)-
butanoate 5a and (1S)-(þ)-10-phenylsulfonylisobornyl
(R)-3-(benzylamino)butanoate 6a
25
(C27H34NO5S [Mþ], 484.2144). [
a
]
þ20 (c 1, CH2Cl2).
D
(1S)-(þ)-10-Phenylsulfonylisobornyl
(Z)-3-(4-methoxyphenyl-
25
amino)but-2-enoate 4f was obtained as an oil (61%). [
a
]
ꢀ20 (c 1,
IR (film) 1447, 1636, 1729, 2953 cmꢀ1 1H NMR 0.84 (3H, br s),
;
D
CH2Cl2).
0.90 and 0.92 (3H, s), 1.16–1.19 (4H, m), 1.63–1.81 (6H, m), 1.93–2.00
(1H, m), 2.26–2.35 (1H, m), 2.41–2.51 (1H, m), 2.96 and 2.98 (1H, d,
J¼14.0 Hz), 3.13–3.19 (1H, m), 3.50 and 3.51 (1H, d, J¼14.0 Hz),
3.72–3.87 (2H, m), 4.86–4.90 (1H, m), 7.24–7.32 (5H, m, Ar–H),
7.52–7.63 (3H, m, Ar–H), 7.87–7.91 (2H, m, Ar–H); 13C NMR 19.8,
20.2, 20.4, 27.1, 29.8, 39.6, 41.5, 41.9, 43.9, 49.2, 49.6, 51.1, 55.0, 77.7,
126.8, 127.6, 128.1, 128.3, 129.2, 133.5, 140.2, 141.2, 170.8.
4.2.7. (1R)-(ꢀ)-10-Phenylsulfonylisobornyl (Z)-3-(but-3-
enylamino)but-2-enoate 2g and (1S)-(þ)-10-
phenylsulfonylisobornyl (Z)-3-(but-3-enylamino)but-2-enoate 4g
IR (KBr) 1457, 1477, 1739, 2987 cmꢀ1; 1H NMR 0.86 (3H, s), 0.95
(3H, s), 1.14–1.21 (1H, m),1.56–2.00 (6H, m),1.93 (3H, s), 2.98 (1H, d,
J¼14.1 Hz), 3.69 (1H, d, J¼14.1 Hz), 3.82–3.86 (2H, m), 4.38 (1H, s),
4.54 (1H, dd, J¼3.0 and 7.8 Hz), 5.16–5.28 (2H, m), 5.82–5.95 (1H,
m), 7.46–7.51 (2H, m, Ar–H), 7.55–7.61 (1H, m, Ar–H), 7.89–7.93 (2H,
m, Ar–H), 8.61 (NH, br t, J¼6.1 Hz); 13C NMR 19.5, 20.4, 20.8, 27.6,
29.9, 40.4, 44.6, 45.6, 49.6, 50.2, 55.5, 75.8, 83.4, 116.4, 128.3, 129.4,
133.6, 135.2, 141.7, 162.0, 169.4.
(1R)-(ꢀ)-10-Phenylsulfonylisobornyl
(S)-3-(benzylamino)buta-
noate 5a was obtained as a colorless oil. MS (CI) m/z 470 (MHþ, 77),
277 (20), 134 (100); HRMS (ESI-TOF) m/z 470.2360 (C27H36NO4S
[MHþ], 470.2355). [
a
]
þ40 (c 1, CH2Cl2).
25
D
(1S)-(þ)-10-Phenylsulfonylisobornyl
(R)-3-(benzylamino)buta-
noate 6a was obtained as a colorless oil. MS (CI) m/z 470 (MHþ,100),
(1R)-(ꢀ)-10-Phenylsulfonylisobornyl (Z)-3-(but-3-enylamino)but-
277 (21), 134 (83); HRMS (ESI-TOF) m/z 470.2360 (C27H36NO4S
25
2-enoate 2g was obtained as a white solid (76%), mp 147.2–149.0 ꢁC
[MHþ], 470.2353). [
a
]
ꢀ40 (c 1, CH2Cl2).
D
(from ethanol); MS (CI) m/z 418 (MHþ, 94), 277 (57), 124 (100);
25
HRMS (CI) m/z 418.2052 (C23H32NO4S [MHþ], 418.2053). [
(c 1, CH2Cl2).
a
]
þ30
4.3.2. (1R)-(ꢀ)-10-Phenylsulfonylisobornyl (S)-3-(benzylamino)-
pentanoate 5b and (1S)-(þ)-10-phenylsulfonylisobornyl
(R)-3-(benzylamino)pentanoate 6b
D
(1S)-(þ)-10-Phenylsulfonylisobornyl (Z)-3-(but-3-enylamino)but-
2-enoate 4g was obtained as a white solid (80%), mp 148.3–150.2 ꢁC
IR (KBr) 1450,1727, 2945 cmꢀ1; 1H NMR 0.84–0.96 (9H, m),1.16–
1.19 (1H, m), 1.49–1.99 (8H, m), 2.38–2.41 (2H, m), 2.95–3.00 (2H,
m), 3.51 (1H, d, J¼14.0 Hz), 3.74–3.79 (2H, m), 4.86–4.89 (1H, m),
7.21–7.34 (5H, m, Ar–H), 7.51–7.63 (3H, m, Ar–H), 7.88–7.91 (2H, m,
Ar–H); 13C NMR 9.7, 19.9, 20.2, 26.4, 27.1, 29.8, 39.0, 39.6, 44.0, 49.3,
49.8, 50.8, 55.0, 55.3, 77.7, 126.8, 127.6, 128.1, 128.3, 129.2, 133.5,
140.4, 171.1.
(from ethanol); MS (CI) m/z 418 (MHþ, 90), 277 (16), 124 (100);
25
HRMS (CI) m/z 417.1970 (C23H31NO4S [Mþ], 417.1974). [
CH2Cl2).
a
]
ꢀ30 (c 1,
D
4.3. General procedure for the reduction of b-enamino esters
Procedure A.10c A solution of NaBH(OAc)3 was prepared by add-
ing NaBH4 (0.34 g, 9.0 mmol) in glacial acetic acid (5 mL) while
keeping the temperature between 10 ꢁC and 20 ꢁC. After the H2
evolution ceased (1 h), acetonitrile (5 mL) was added and the so-
(1R)-(ꢀ)-10-Phenylsulfonylisobornyl (S)-3-(benzylamino)penta-
noate 5b was obtained as an oil. MS (APCI) m/z 484 (MHþ, 100), 277
(34), 135 (29); HRMS (CI) m/z 484.2521 (C28H38NO4S [MHþ],
25
484.2522). [
a
]
þ25 (c 1, CH2Cl2).
D
lution was cooled to 0 ꢁC. The
b
-enamino ester (3.0 mmol) was
(1S)-(þ)-10-Phenylsulfonylisobornyl (R)-3-(benzylamino)penta-
added in one portion and the reaction mixture stirred for 4 h at
0 ꢁC. Acetic acid and acetonitrile were evaporated off and the res-
idue dissolved in CH2Cl2 and the combined organic layers were
washed with saturated aqueous solution of Na2CO3 and dried over
noate 6b was obtained as an oil. MS (APCI) m/z 484 (MHþ, 100), 277
(87), 135 (81); HRMS (CI) m/z 484.2521 (C28H38NO4S [MHþ],
25
484.2511). [
a
]
ꢀ30 (c 1, CH2Cl2).
D
magnesium sulfate affording the
solvent.
b
-amino ester after removal of the
4.3.3. (1R)-(ꢀ)-10-Phenylsulfonylisobornyl (S)-3-(benzylamino)-5-
methylhexanoate 5c and (1S)-(þ)-10-phenylsulfonylisobornyl (R)-
3-(benzylamino)-5-methylhexanoate 6c
Procedure B.9 To a solution of anhydrous zinc iodide (1.91 g,
6.0 mmol) in dry CH2Cl2 (20 mL) at 0 ꢁC was added the
b-enamino
IR (film) 1451, 1732, 2947 cmꢀ1 1H NMR 0.84–0.92 (12H, m),
;
ester (2.0 mmol). The resulting mixture was stirred at the same
temperature for 1 h after which NaBH4 (0.375 g, 10 mmol) was
added, also at 0 ꢁC. The solution was allowed to reach room tem-
perature and left overnight. The reaction was then quenched with
saturated ammonium chloride solution. The reaction mixture was
extracted with CH2Cl2 and the combined organic layers were
washed with brine and dried over magnesium sulfate affording the
1.18–1.30 (2H, m), 1.44–1.50 (1H, m), 1.61–1.84 (5H, m), 1.94–1.99
(1H, m), 2.39–2.42 (2H, m), 2.96 and 2.98 (1H, d, J¼14.0 Hz), 3.05–
3.08 (1H, m), 3.52 (1H, d, J¼14.0 Hz), 3.73–3.81 (2H, m), 4.89 (1H,
dd, J¼3 and 8 Hz), 7.21–7.34 (5H, m, Ar–H), 7.51–7.64 (3H, m, Ar–H),
7.88–7.92 (2H, m, Ar–H); 13C NMR 19.9, 20.3, 22.5, 22.8, 23.0, 24.9,
27.1, 29.9, 39.3, 39.6, 44.0, 49.3, 49.9, 50.7, 52.3, 55.1, 77.8, 126.9,
127.7, 128.3, 129.2, 133.5, 140.4, 141.3, 171.0.
b
-amino ester after removal of the solvent.
(1R)-(ꢀ)-10-Phenylsulfonylisobornyl
(S)-3-(benzylamino)-5-
methylhexanoate 5c was obtained as an oil (88%). MS (CI) m/z 512
The 1H NMR and 13C NMR spectra of
b
-amino ester recorded at
ambient temperature showed the existence of two rotamers but
the spectra are simpler at higher temperature. In fact, we found that
(MHþ, 100), 454 (21), 277 (79); HRMS (CI) m/z 511.2756
25
(C30H41NO5S [Mþ], 511.2741). [
a]
þ30 (c 1, CH2Cl2).
D

T.M.V.D. Pinho e Melo et al. / Tetrahedron 64 (2008) 8141–8148
8147
(1S)-(þ)-10-Phenylsulfonylisobornyl (R)-3-(benzylamino)-5-methyl-
4.3.7. (1R)-(ꢀ)-10-Phenylsulfonylisobornyl (S)-3-(but-3-
hexanoate 6c was obtained as an oil. MS (CI) m/z 512 (MHþ, 100),
enylamino)butanoate 5g and (1S)-(þ)-10-phenylsulfonylisobornyl
(R)-3-(but-3-enylamino)butanoate 6g
454 (21), 277 (82); HRMS (CI) m/z 512.2834 (C30H42NO5S [MHþ],
25
512.2824). [
a
]
ꢀ30 (c 1, CH2Cl2).
IR (film) 1479, 1730, 2961 cmꢀ1; 1H NMR 0.85 (3H, s), 0.96 (3H,
s), 1.14 and 1.16 (3H, d, J¼2.7 Hz), 1.14–1.21 (1H, m), 1.56–2.01 (6H,
m), 2.25–2.33 (1H, m), 2.39–2.49 (1H, m), 2.98 (1H, d, J¼13.9 Hz)
and 2.99 (1H, d, J¼14.0 Hz), 3.14–3.30 (3H, m), 3.52 and 3.53 (1H, d,
J¼14.0 Hz), 4.89–4.92 (1H, m), 5.05–5.09 (1H, m), 5.14–5.21 (1H, m),
5.82–5.95 (1H, m), 7.54–7.65 (3H, m, Ar–H), 7.89–7.94 (2H, m, Ar–
H); 13C NMR 19.9, 20.2, 20.3, 27.1, 29.8, 32.6, 39.6, 41.6, 41.8, 44.0,
49.3, 49.8, 55.0, 77.7, 115.9, 127.6, 129.4, 133.5, 136.7, 141.3, 170.8.
(1R)-(ꢀ)-10-Phenylsulfonylisobornyl (S)-3-(but-3-enylamino)bu-
tanoate 5g was obtained as an oil. MS (CI) m/z 420 (MHþ, 100), 277
D
4.3.4. (1R)-(ꢀ)-10-Phenylsulfonylisobornyl (S)-3-(benzylamino)-
5,5-dimethylhexanoate 5d and (1S)-(þ)-10-phenylsulfonylisobornyl
(R)-3-(benzylamino)-5,5-dimethylhexanoate 6d
IR (film) 1448, 1729, 2955 cmꢀ1; 1H NMR 0.84 (3H, s), 0.92 (3H,
s), 0.95 (9H, s), 1.19–1.98 (7H, m), 2.42–2.45 (2H, m), 2.97 and 2.98
(1H, d, J¼14.0 Hz), 3.06–3.12 (1H, m), 3.51 and 3.52 (1H, d,
J¼14.0 Hz), 3.71–3.82 (2H, m), 4.89–4.93 (1H, m), 7.21–7.34 (5H, m,
Ar–H), 7.52–7.64 (3H, m, Ar–H), 7.87–7.92 (2H, m, Ar–H); 13C NMR
19.9, 20.3, 27.1, 29.9, 30.0, 30.1, 30.5, 39.6, 41.0, 41.6, 44.0, 48.5, 49.3,
49.9, 51.1, 51.9, 55.2, 77.8, 126.8, 127.7, 128.3, 129.2, 133.5, 140.4,
141.3, 170.9.
(50), 135 (76); HRMS (CI) m/z 420.2209 (C23H34NO4S [MHþ],
25
420.2193). [
a
]
þ35 (c 1, CH2Cl2).
D
(1S)-(þ)-10-Phenylsulfonylisobornyl (R)-3-(but-3-enylamino)bu-
tanoate 6g was obtained as an oil. MS (CI) m/z 420 (MHþ, 100), 277
(1R)-(ꢀ)-10-Phenylsulfonylisobornyl
(S)-3-(benzylamino)-5,5-
(17), 135 (28); HRMS (CI) m/z 420.2209 (C23H34NO4S [MHþ],
dimethylhexanoate 5d was obtained as an oil. MS (CI) m/z 526 (MHþ,
25
420.2199). [
a]
ꢀ35 (c 1, CH2Cl2).
D
100), 454 (17), 277 (27); HRMS (ESI-TOF) m/z 526.2986
(C31H44NO4S [MHþ], 526.2980). [
a
]
þ45 (c 1, CH2Cl2).
25
D
4.4. Crystallographic data
(1S)-(þ)-10-Phenylsulfonylisobornyl
(R)-3-(benzylamino)-5,5-
dimethylhexanoate 6d was obtained as a solid, mp 48.6–50.1 ꢁC. MS
The X-ray data were collected on an Enraf-nonius Mach-3 single
crystal diffractometer, at 298(3) K, using graphite-monochromated
(CI) m/z 526 (MHþ, 67), 454 (17), 277 (24); HRMS (ESI-TOF) m/z
25
526.2986 (C31H44NO4S [MHþ], 526.2981). [
a
]
ꢀ45 (c 1, CH2Cl2).
D
Cu K
profiles of
a
radiation (
l
¼1.5418 Å). Intensities were recorded as full
u–q scans. The structures were solved by direct methods
and refined by full-matrix least-squares using SHELXL97a. Exami-
nation of the structure with PLATON confirmed the absence of
voids in the crystal structures, which might be occupied by solvent
molecules.
4.3.5. (1R)-(ꢀ)-10-Phenylsulfonylisobornyl (S)-3-(benzylamino)-5-
phenylpentanoate 5e and (1S)-(þ)-10-phenylsulfonylisobornyl (R)-
3-(benzylamino)-5-phenylpentanoate 6e
IR (film) 1448, 1724, 2957 cmꢀ1 1H NMR 0.83 (3H, s), 0.88 and
;
0.90 (3H, s), 1.16–1.20 (1H, m), 1.59–1.99 (8H, m), 2.44–2.47 (2H, m),
2.66–2.75 (2H, m), 2.97 and 2.98 (1H, d, J¼14.0 Hz), 3.07–3.11 (1H,
m), 3.50 (1H, d, J¼14.0 Hz), 3.74–3.83 (2H, m), 4.87–4.92 (1H, m),
7.15–7.33 (10H, m, Ar–H), 7.50–7.63 (3H, m, Ar–H), 7.87–7.91 (2H,
m, Ar–H); 13C NMR 19.9, 20.3, 27.1, 29.9, 31.9, 35.7, 39.3, 39.6, 44.0,
49.3, 49.9, 50.7, 53.6, 55.1, 77.7, 125.8, 126.9, 127.7, 128.3, 128.4,
129.3, 133.5, 140.4, 141.3, 142.0, 171.1.
4.4.1. Crystal data for (1S)-(þ)-10-phenylsulfonylisobornyl (Z)-3-
(benzylamino)-5,5-dimethylhex-2-enoate 4d
C
31H43NO4S,
M¼525.72, monoclinic,
P21
with unit
cell, a¼9.293(4) Å, b¼14.5697(8) Å, c¼11.5070(14) Å,
a
¼90ꢁ,
b
¼104.120(18)ꢁ,
g
¼90ꢁ, V¼1510.9(6) Å3. It contains two molecules/
unit
cell.
rcalcd¼1.156 g cmꢀ3
,
Z¼2,
m
¼1.214 mmꢀ1
.
(1R)-(ꢀ)-10-Phenylsulfonylisobornyl (S)-3-(benzylamino)-5-phe-
R(I>2
s(I))¼0.0793 and Rw¼0.2197 for 5931 independent re-
nylpentanoate 5e was obtained as an oil. MS (CI) m/z 560 (MHþ,
flections. H atoms were placed at calculated positions and refined
as riding on their parent atoms.
100), 277 (55), 224 (77); HRMS (CI) m/z 560.2834 (C34H42NO5S
25
[MHþ], 560.2830). [
a]
þ35 (c 1, CH2Cl2).
D
(1S)-(þ)-10-Phenylsulfonylisobornyl (R)-3-(benzylamino)-5-phe-
4.4.2. Crystal data for (1S)-(ꢀ)-10-phenylsulfonylisobornyl (R)-3-
(benzylamino)-5,5-dimethylhexanoate 6d
nylpentanoate 6e was obtained as an oil. MS (CI) m/z 560 (MHþ,
100), 277 (83), 224 (81); HRMS (CI) m/z 559.2756 (C34H41NO5S
The X-ray data were collected on a Bruker Apex II single crystal
diffractometerat roomtemperature. Thestructure of this compound
was determined using a transparent very thin rectangular plate
single crystal with dimensions 0.37ꢂ0.12ꢂ0.02 mm (P212121) with
unit cell, a¼10.5297(7) Å, b¼13.4361(9) Å, c¼21.1730(14) Å, and
V¼2995.5(5) Å3. It contains four molecules/unit cell. rcalcd¼1.1616 g/
25
[Mþ], 559.2741). [
a]
ꢀ35 (c 1, CH2Cl2).
D
4.3.6. (1R)-(ꢀ)-10-Phenylsulfonylisobornyl (S)-3-(4-methoxy-
phenylamino)butanoate 5f and (1S)-(þ)-10-phenylsulfonyl-
isobornyl (R)-3-(4-methoxyphenylamino)butanoate 6f
IR (film) 1727, 2942 cmꢀ1
;
1H NMR 0.84 (3H, s), 0.89–0.95 (3H,
cm3,
m
¼0.142 mmꢀ1. Mo K
a
radiationwas used (0.71073 Å). Atotal of
m), 1.18–1.31 (4H, m), 1.58–1.97 (6H, m), 2.32–2.39 (1H, m), 2.54–
2.64 (1H, m), 2.98 and 2.99 (1H, d, J¼14.0 Hz), 3.51 and 3.53 (1H, d,
J¼14.0 Hz), 3.73 and 3.74 (3H, s), 3.81–3.85 (1H, m), 4.90–4.93 (1H,
m), 6.58–6.62 (2H, m, Ar–H), 6.74–6.78 (2H, m, Ar–H), 7.49–7.54
(2H, m, Ar–H), 7.59–7.63 (1H, m, Ar–H), 7.85–7.88 (2H, m, Ar–H);
13C NMR 19.8, 20.2, 27.0, 29.8, 39.6, 40.8, 41.0, 43.9, 46.8, 49.3, 49.8,
55.1, 55.7, 77.8, 114.9, 115.1, 127.5, 129.2, 133.5, 140.8, 141.2, 152.2,
170.3.
2747 reflections with I>2s
(I) were used. R¼0.0549.
4.5. Computational methods
The calculations were carried out on Intel-based computers,
running Linux, using MOPAC2007.18 The geometry of the transition
state was optimized first with MOPAC2007, and a subsequent
Hessian calculation was performed to assess the rank of the critical
point obtained. All the calculations in MOPAC2007 used the PM3
Hamiltonian,19–22 and the localization of the transition state ge-
ometry was performed until the gradient was less than 0.01 kcal/Å.
(1R)-(ꢀ)-10-Phenylsulfonylisobornyl
(S)-3-(4-methoxyphenyl-
amino)butanoate 5f was obtained as a colorless oil. MS (CI) m/z 485
(Mþ, 100), 277 (12), 150 (74); HRMS (ESI-TOF) m/z 486.2309
25
(C27H36NO5S [MHþ], 486.2305). [
a
]
þ35 (c 1, CH2Cl2).
D
(1S)-(þ)-10-Phenylsulfonylisobornyl
(R)-3-(4-methoxyphenyl-
Acknowledgements
amino)butanoate 6f wasobtained as a colorless oil. MS (CI) m/z 485
(Mþ, 100), 277 (29), 150 (69); HRMS (ESI-TOF) m/z 486.2309
We thank Fundaçao para a Ciencia e a Tecnologia (PTDC/QUI/
64470/2006), FEDER, the University of the Basque Country (UPV, GIU
˜
ˆ
25
(C27H36NO5S [MHþ], 486.2306). [
a
]
ꢀ35 (c 1, CH2Cl2).
D

8148
T.M.V.D. Pinho e Melo et al. / Tetrahedron 64 (2008) 8141–8148
R. D.; Spindler, F.; Malan, C. J. Am. Chem. Soc. 2004, 126, 9918–9919; (c) Kubryk,
´
´
06/51), and Direccion General de Investigacion del Ministerio de
Ciencia y Tecnologıa (MCYT, Madrid DGI, CTQ2006-09323) for fi-
nancial support. A Ramon y Cajal contract to J.M.S. from Ministerio
M.; Hansen, K. B. Tetrahedron: Asymmetry 2006, 17, 205–209.
9. Fustero, S.; Pina, B.; Salavert, E.; Navarro, A.; Ramirez de Arellano, M. C.;
Fuentes, A. S. J. Org. Chem. 2002, 67, 4667–4679.
´
´
10. (a) Noe¨l, R.; Vanucci-Bacque´, C.; Fargeau-Bellassoued, M.-C.; Lhommet, G. Eur. J.
Org. Chem. 2007, 476–486; (b) Calvet-Vitale, S.; Vanucci-Bacque´, C.; Fargeau-
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Supplementary data
´
11. (a) Palacios, F.; Herran, E.; Rubiales, G.; Ezpeleta, J. M. J. Org. Chem. 2002, 67,
2131–2135; (b) Palacios, F.; Herra´n, E.; Rubiales, G. J. Org. Chem. 1999, 64, 6239–
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Data regarding the synthesis of
b-enamino esters 4 and the re-
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b
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