Chemodivergent synthesis of 7-aryl/alkyl-6-hydroxy-1,4-oxazepan-5-ones and 2-[aryl/alkyl(hydroxy)methyl]morpholin-3-ones from a common epoxyamide precursor

Article abstract of DOI:10.1055/s-0030-1260064

We present here a regiospecific synthesis of 7-alkyl- or 7-aryl-6-hydroxy-1,4-oxazepan-5-ones and 2-[aryl(hydroxy)methyl]- or 2-(1-hydroxyalkyl)morpholin-3-ones from a diastereomeric mixture of trans-3-alkyl- or -3-aryl-N-(2-hydroxyethyl)-N-(1-phenylethyl)oxirane-2- carboxamides. This chemodivergent synthesis is easily controlled by an appropriate choice of cyclization reaction conditions. Georg Thieme Verlag Stuttgart - New York.

Full text of DOI:10.1055/s-0030-1260064

2310
PAPER
Chemodivergent Synthesis of 7-Aryl/alkyl-6-hydroxy-1,4-oxazepan-5-ones
and 2-[Aryl/alkyl(hydroxy)methyl]morpholin-3-ones from a Common
Epoxyamide Precursor
C
hemodivergent
S
a
ynthesis fro
v
m
a
Commo
i
n
E
pox
d
yamide Precursor M. Aparicio,a Joel L. Terán,*a Luis F. Roa,b Dino Gnecco,a Jorge R. Juárez,a María L. Orea,a Angel Mendoza,a
Marcos Flores-Alamo,c Laurent Micouind
a
Centro de Química, Benemérita Universidad Autónoma de Puebla, Edif. 103F Complejo de Ciencias, C.U., 72570 Puebla, Pue., México
Fax +52(222)229551; E-mail: joelluisteran@hotmail.com
División Académica de Ciencias Básicas, Universidad Juárez Autónoma de Tabasco, 86690 Cunduacán, Tab., México
Facultad de Química, Universidad Nacional Autónoma de México, 04510 México, DF, México
Laboratoire de Chimie Thérapeutique, UMR 8638 associée au CNRS et à l’Université Paris Descartes,
b
c
d
Faculté des Sciences Pharmaceutiques et Biologiques, 4 av de l’Observatoire, 75270 Paris cedex 06, France
Received 14 January 2011; revised 13 April 2011
showed traces of the corresponding epoxyamide. Best re-
Abstract: We present here a regiospecific synthesis of 7-alkyl- or
sults were obtained when sulfonium salt 3 was treated
with DBU, in dichloromethane, from 0 °C to room tem-
perature (entry 5) giving the corresponding diastereomer-
7-aryl-6-hydroxy-1,4-oxazepan-5-ones and 2-[aryl(hydroxy)meth-
yl]- or 2-(1-hydroxyalkyl)morpholin-3-ones from a diastereomeric
mixture of trans-3-alkyl- or -3-aryl-N-(2-hydroxyethyl)-N-(1-phe-
nylethyl)oxirane-2-carboxamides. This chemodivergent synthesis ic mixture of trans-epoxyamides 4a/4b in 92% yield. The
is easily controlled by an appropriate choice of cyclization reaction
conditions.
NMR spectra show the presence of an E vs. Z rotameric
mixture of each diastereomer. The exclusive formation of
Key words: chemoselectivity, cyclization, alkoxide, oxazepan-5-
ones, morpholin-3-ones
the trans adducts was confirmed by the magnitude of the
coupling constants of the epoxides (J = 2.1 and 1.6 Hz).
OH
Six- and seven-membered nitrogen–oxygen-containing
chiral heterocycles are general scaffolds classically asso-
ciated with diverse biological activity.1 In addition, these
heterocycles frequently exhibit several stereogenic cen-
ters. As a consequence, intensive effort has been devoted
towards the development of efficient strategies for their
synthesis. In our ongoing work on the asymmetric synthe-
sis of nitrogen heterocycles,2 we have reported an expedi-
tious access to chiral nonracemic epoxyamides.3
Epoxyamides are known to be versatile intermediates in
organic synthesis4 offering an extensive range of synthetic
possibilities.5 Among them, the use of controlled intramo-
lecular nucleophilic ring closure6 could deliver, in a
straightforward manner, 1,4-oxazepan-5-ones and/or
morpholin-3-ones with potential biological interest. In
this work, we report that epoxyamide 1 can indeed lead to
both heterocyclic scaffolds using a controlled set of reac-
tion conditions (Scheme 1).
X
Me2S
N
R*
O
R*= (S)-phenylethyl
R = Ar, Alk
RCHO
base
OH
R*
R
OH
O
O
O
O
R
HO
7-endo
6-exo
R
N
N
N
O
O
1
R*
R*
[1,4]-oxazepan-5-one
morpholin-3-one
Scheme 1 Divergent synthesis of nitrogen heterocycles from epo-
xyamide 1
Ph
O
Ph
Ph
Br
a
b, c
Chiral sulfonium salt 3 was synthesized in three steps
starting from (S)-phenylethylamine (2) in 77% overall
yield (Scheme 2).
N
HN
NH2
Me2S
OH
OH
2
3
With the chiral sulfonium salt 3 in hand, the asymmetric
epoxidation with benzaldehyde was then investigated
(Table 1). Standard basic conditions (KOH, t-BuOK, or
NaH as the base)3,7 proved to be inappropriate with this
substrate, as the NMR analysis of the crude reaction only
Scheme 2 Reagents and conditions: (a) ethylene oxide, H2O, soni-
cation, 20 min, 91%; (b) bromoacetyl bromide, Et3N, CH2Cl2, –10 °C;
(c) Me2S, CH2Cl2, r.t., 77% from (S)-phenylethylamine (2).
1
The detection by H NMR spectroscopy of the corre-
sponding morpholinone 4c in the crude reaction mixture
when using inorganic bases such as potassium hydroxide
(entry 3), suggests that the formation of the alkoxide rath-
SYNTHESIS 2011, No. 14, pp 2310–2320
Advanced online publication: 09.06.2011
DOI: 10.1055/s-0030-1260064; Art ID: M11511SS
x
x.
x
x
.
2
0
1
1
© Georg Thieme Verlag Stuttgart · New York

PAPER
Chemodivergent Synthesis from a Common Epoxyamide Precursor
2311
Table 1 Examination of the Conditions for the Epoxidation of 3 with Benzaldehydea
Ph
(R)
Ph
(S)
Ph
O
O
(S)
N
(S)
N
O
+
N
3
+
(S)
(R)
Ph
Ph
O
O
OH
OH
O
4a
4b
4c
Entry
Solvent
THF
Base (equiv)
KOH (15)
KOH (2)
Temp (°C)
0 to r.t.
–30 to 0
0 to r.t.
r.t.
Time (h)
Product
Yieldb (%)
trace
trace
60
1
2
3
4
5
12
10
12
8
–
EtOH
–
CH2Cl2
CH2Cl2
CH2Cl2
KOH (15)
DBU (2)
4c
4c
30
DBU (2)
0 to r.t.
12
4a + 4b
92
a All entries were performed using 2 equiv of benzaldehyde.
b Isolated yield of diastereomeric mixture.
er than the sulfur ylide might be favored under these cy-
clization conditions, whereas DBU cleanly generated the
reactive ylide when the reaction was performed from 0 °C
to room temperature (Table 1).
Table 2 Epoxidation of 3 with Various Aromatic Aldehydes and
Alkanalsa
Ph
(S)
Ph
(R)
O
O
(S)
N
(S)
N
DBU, CH2Cl2
+
3
(S)
(R)
R
R
RCHO, 0 °C to r.t.
The asymmetric epoxidation of chiral sulfonium salt 3
with several aromatic aldehydes was then investigated
(Table 2). In the case of vanillin, the asymmetric epoxida-
tion was unsuccessful; however, high yields of 11a/11b
were obtained when the hydroxy function was protected
with a tosyl group (entry 7). The asymmetric epoxidation
with aliphatic aldehydes was tested giving the corre-
sponding epoxyamides 12a/12b and 13a/13b in good
yields (entries 8 and 9).
O
O
OH
OH
5a–13a
5b–13b
Entry
R
Product
5a/5b
Yieldb (%)
1
2
3
4
5
6
7
8
9
2-O2NC6H4
3-O2NC6H4
4-O2NC6H4
2,6-ClC6H3
3,4-ClC6H3
85
85
90
90
87
35
95
75
70
6a/6b
7a/7b
As the separation of the diastereomers proved to be diffi-
cult at this stage, access to the oxazepanone moiety via a
7-endo-tet ring closure was investigated. Oxirane ring
opening of epoxyamides has been reported using various
Lewis acids, such as: ZnCl2,8 MgI2,9 ZrCl4,10 TFA or
Sc(OTf)3,11 and Zn(OTf)2 or Cu(OTf)2.12 Although a dou-
ble substitution reaction pathway has been proposed in the
presence of magnesium iodide,9 trans-epoxyamides 4a/
4b, led in our hands to the diastereomeric mixture of 1,4-
oxazepan-5-ones 14a/14b, coming from the direct SN2
opening reaction in a low yield (Table 3, entry 1), in
agreement with results reported by Ohnmacht et al.11
8a/8b
9a/9b
3-MeO-4-BnOC6H3
10a/10b
11a/11b
12a/12b
13a/13b
3-MeO-4-TsOC6H3
Pr
Bu
a Reaction conditions: aldehyde (2 equiv), 0 °C to r.t., 12 h.
b Isolated yield of diastereomeric mixture
The use of trifluoroacetic acid activation led to 1,4-ox-
azepan-5-ones 14a/14b in better yield (Table 3, entry 2,).
This reaction proved to be highly sensitive to the electron
density of the aromatic moiety. Thus, only traces of 1,4-
oxazepan-5-ones 15a/15b were obtained with epoxy-
amides containing an electron-withdrawing group (entry
3) even using prolonged reaction times. In contrast, 1,4-
oxazepan-5-ones 20a/20b was obtained in 73% yield (en-
try 4). Lewis acid activation was then investigated in order
to increase the reaction yields. The best results were ob-
tained in the presence of 20 mol% copper(II) triflate, lead-
ing to the desired 1,4-oxazepan-5-ones 14a/14b–21a/21b
in good to excellent yields, even in the presence of deac-
tivating groups on the aromatic ring. This condition also
was tested with epoxyamides containing an aliphatic
group affording the corresponding 1,4-oxazepan-5-ones
22a/22b and 23a/23b in excellent yields (entries 13 and
14).
Diastereomers were easily separated at this stage by chro-
matographic purification (yielding for entry 7; 16a, 50%
and 16b, 42%). Fortunately, the major diastereomer 16a
crystallized, enabling the determination of its absolute
configuration and securing the presence of the 1,4-ox-
Synthesis 2011, No. 14, 2310–2320 © Thieme Stuttgart · New York

2312
D. M. Aparicio et al.
PAPER
Table 3 Synthesis of 1,4-Oxazepanones via 7-endo-tet Ring Closurea
Ph
Ph
O
O
N
O
N
HO
R
O
R
OH
14a–23a
4a–13a
+
Lewis acid
+
solvent, r.t., time
Ph
Ph
O
O
HO
N
N
R
O
OH
O
R
4b–13b
14b–23b
Entry
1
R
Lewis acid
MgI2
Solvent
THF
Time (h)
36
Product
14a/14b
14a/14b
15a/15b
20a/20b
14a/14b
15a/15b
16a/16b
17a/17b
18a/18b
19a/19b
20a/20b
21a/21b
22a/22b
23a/23b
Yieldb (%)
Ph
Ph
23
90
trace
73
95
78
92
95
91
87
96
98
98
98
2
TFA
MeCN–H2O
MeCN–H2O
MeCN–H2O
MeCN
12
3
2-O2NC6H4
3-MeO-4-BnOC6H3
Ph
TFA
360
36
4
TFA
5
Cu(OTf)2
Cu(OTf)2
Cu(OTf)2
Cu(OTf)2
Cu(OTf)2
Cu(OTf)2
Cu(OTf)2
Cu(OTf)2
Cu(OTf)2
Cu(OTf)2
0.3
6
2-O2NC6H4
3-O2NC6H4
4-O2NC6H4
2,6-Cl2C6H4
3,4-Cl2C6H3
3-MeO-4-BnOC6H3
3-MeO-4-TsOC6H3
Pr
MeCN
0.5
7
MeCN
0.3
8
MeCN
0.15
0.08
0.3
9
MeCN
10
11
12
13
14
MeCN
MeCN
0.6
MeCN
0.15
0.08
0.08
MeCN
Bu
MeCN
a All entries except 1–4 were performed using 20 mol% of Cu(OTf)2.
b Isolated yield of diastereomeric mixture.
azepan-5-one ring by X-ray diffraction analysis In this way, Liebscher8 reported the intramolecular open-
(Figure 1).
ing of oxirane carboxamide using DBU in boiling ethanol
forming predominantly the corresponding morpholinone
derivative, however when we applied this methodology to
the corresponding diastereomeric mixture of trans-
epoxyamides even using prolonged reaction times, we ob-
tained the desired morpholinone in low yield.
We then explored the access to the morpholinone ring
based on a regiospecific 6-exo-tet ring closure under basic
conditions.
The use of bases such as potassium hydroxide and potas-
sium tert-butoxide led only to degradation of the starting
material. Better results were obtained when we used a new
procedure based on the in situ sodium alkoxide formation
by the treated of epoxyamides 4a/4b with sodium in anhy-
drous tetrahydrofuran (Table 4, entry 1).13 The total con-
version of the starting material was observed after 20
minutes. The NMR analysis of the crude reaction showed
exclusively the presence of the corresponding diastereo-
Figure 1 X-ray ORTEP diagram of compound 16a
Synthesis 2011, No. 14, 2310–2320 © Thieme Stuttgart · New York

PAPER
Chemodivergent Synthesis from a Common Epoxyamide Precursor
2313
meric mixture of 2-[hydroxy(phenyl)methyl]-4-(1-phe-
Table 4 Intramolecular 6-exo-tet Ring-Closure Reaction
nylethyl)morpholin-3-ones 24a/24b in 95% yield.
Ph
(S)
N
Ph
(S)
Diastereomers were easily separated at this stage by chro-
matographic purification (yields of separated diastereo-
mers: 57% for 24a and 38% for 24b). Fortunately, the
major diastereomer 24a crystallized, enabling the deter-
mination of its absolute configuration and the confirma-
tion of the presence of the morpholinone ring by X-ray
diffraction analysis (Figure 2).
O
O
(S)
N
(R)
R (S)
HO
(S)
O
O
OH
R
4a–13a
24a–33a
Na
+
+
THF, r.t.
Ph
Ph
(R)
O
(S)
N
(S)
O
N
(R)
R
(S)
HO
(R)
O
OH
O
4b–13b
R
24b–33b
Entry
R
Substrate Time Product
(min)
Yield
(%)
1
2
Ph
4a/4b
5a/5b
6a/6b
7a/7b
8a/8b
9a/9b
20
40
70
75
120
70
80
85
40
40
24a/24b
25a/25b
26a/26b
27a/27b
28a/28b
29a/29b
30a/30b
31a/31b
32a/32b
33a/33b
95
96
90
90
40
85
75
85
95
80
2-O2NC6H4
3-O2NC6H4
4-O2NC6H4
3
4
5
2,6-Cl2C6H3
3,4-Cl2C6H3
Figure 2 X-ray ORTEP diagram of compound 24a
6
Epoxyamides 5a/5b–13a/13b were reacted with sodium,
affording the corresponding morpholin-3-ones 25a/25b–
33a/33b in good to excellent yields, even in the presence
of deactivating groups on the aromatic ring (Table 4).
Even, the use of epoxyamides 8a/8b (entry 5) gave the
corresponding morpholinones 28a/28b in good yields de-
spite the presence of two chlorine atoms which could rep-
resent a combination of unfavorable steric and electronic
effects. Also, the use of epoxyamides 9a/9b (entry 6) led
to the corresponding morpholinones 29a/29b in 85%
yield. Epoxyamides containing an aliphatic group 12a/
12b and 13a/13b also gave the corresponding morpholi-
nones 32a/32b and 33a/33b in excellent yields (entries 9
and 10).
7
3-MeO-4-BnOC6H3 10a/10b
3-MeO-4-TsOC6H3 11a/11b
8
9
Pr
12a/12b
13a/13b
10
Bu
epoxyamides, and therefore favors the formation of the
oxazepanone skeleton via a 7-endo-tet process. This
mechanism also explains the influence of the aromatic
substitution in the cyclization process.
Finally, we performed the removal of chiral auxiliary
from 1,4-oxazepan-5-one 14a in two steps. In the first
step, compound 14a was reduced with borane–dimethyl
sulfide complex, affording the cyclic amine 34 in 91%
yield. Finally, compound 34 was selectively N-debenzy-
lated when it was treated under transfer hydrogenation
condition to give the desired 7-phenyl-1,4-oxazepan-6-ol
35 in 90% yield (Scheme 3).
The divergent pathways for the regiospecific ring-closure
reactions can be explained as follows. Under basic condi-
tions, the cyclization through the epoxide opening follows
an exo mode, as a six-membered transition state is more
favored than a seven-membered one, in accordance with
Baldwin’s rules.14 The use of acidic activation favors a
later transition state, having a positive charge developing,
at the benzylic position for aromatic epoxyamides or at
the more stabilized carbon by inductive effect for aliphatic
In summary, we have developed a new strategy to build in
a high yielding, highly functionalized, and regiospecific
manner chiral 1,4-oxazepan-5-ones and morpholin-3-
ones starting from chiral trans-epoxyamides. This strate-
Ph
Ph
H
(S)
N
(S)
N
HCO2NH4
10% Pd/C
O
N
EtOH, reflux, 5 min
BH3⋅SMe2
(S)
(R)
(R)
(S)
HO
HO
HO
90%
THF, 0 °C to r.t.
91%
(R)
(R)
O
O
O
Ph
Ph
Ph
14a
34
35
Scheme 3
Synthesis 2011, No. 14, 2310–2320 © Thieme Stuttgart · New York

2314
D. M. Aparicio et al.
PAPER
(m, 2 H, OH, H6), 6.17 (q, J = 6.9 Hz, 1 H, H1¢), 7.29–7.41 (m, 10
gy opens a new, versatile, and scalable access to chiral
six- and seven-membered N,O-heterocycles for further
pharmacological investigations.
H).
13C NMR (100 MHz, CDCl3): d = 15.3, 44.8, 52.6, 69.8, 73.7, 82.0,
127.4–128.7, 139.2, 174.3.
HRMS (ESI): m/z [M] calcd for C19H21NO3: 311.1521; found:
311.1538.
All moisture-sensitive reactions were performed using syringe-sep-
tum cap techniques under an N2 atmosphere and all glassware was
dried in an oven at 80 °C for 2 h prior to use. Reactions at –10 °C,
0 °C were performed using ultra cold equipment (Mod. SEV
CRYO1-80). Melting points were measured by a hot stage melting
point apparatus (uncorrected). Optical rotations were measured
with a Perkin-Elmer 341 polarimeter, using a 1-dm cell with a total
volume of 1 mL and are referenced Na D-line. For flash chromatog-
raphy, Silica Gel 60, 0.063–0.2 mm/70–230 mesh ASTM was em-
ployed; PE = petroleum ether. 1H NMR spectra were recorded using
a Varian VX400 (400 MHz) spectrometer relative to TMS (in
CDCl3) as internal standard. 13C NMR spectra were recorded using
a Varian VX400 (100 MHz) spectrometer and referenced to the re-
sidual CHCl3 signal. X-ray diffraction data were obtained by using
an Oxford Diffraction Gemini Atlas CCD diffractometer, with
graphite-monochromatic MoKa radiation (l = 0.71073 Å). CrysA-
lis RED program was used to collect and refine cell, CrysAlis RED
program was used to reduce data, and SHELXL97 program was
used to solve structure and refine it. Exact mass (HRMS) spectra
were recorded with a Jeol JEM-AX505HA instrument at a voltage
of 70 eV. Infrared spectra were obtained on a Nicolet FT-IR Magna
750 spectrophotometer.
(–)-(6R,7R)-6-Hydroxy-7-(2-nitrophenyl)-4-[(S)-1-phenyleth-
yl]-1,4-oxazepan-5-one (15a)
Yield: 0.188 mmol (42%); Rf = 0.88 (EtOAc–PE, 40:60).
[a]D20 –223.5 (c 1.1, CH2Cl2).
IR (KBr): 3362, 1658, 1530, 1338, 1127 cm–1.
1H NMR (400 MHz, CDCl3): d = 1.61 (d, J = 7.0 Hz, 3 H), 3.10 (dd,
J = 4.0, 16.4 Hz, 1 H, H3), 3.38 (dd, J = 10.2, 16.4 Hz, 1 H, H3),
3.58 (dd, J = 10.2, 12.9 Hz, 1 H, H2), 4.16 (dd, J = 4.0, 12.9 Hz, 1
H, H2), 4.39 (m, 2 H, OH, H7), 5.28 (d, J = 8.3 Hz, 1 H, H6), 6.16
(q, J = 7.0 Hz, 1 H), 7.29–7.94 (m, 9 H).
13C NMR (100 MHz, CDCl3): d = 16.6, 45.6, 52.6, 71.0, 74.0, 77.3,
124.2, 127.1–128.77, 132.9, 133.9, 139.1, 173.6.
HRMS (ESI): m/z [M] calcd for C19H20N2O5: 356.1372; found:
356.1402.
(–)-(6S,7S)-6-Hydroxy-7-(2-nitrophenyl)-4-[(S)-1-phenylethyl]-
1,4-oxazepan-5-one (15b)
Yield: 0.160 mmol (36%); Rf = 0.53 (EtOAc–PE, 40:60).
[a]D20 –35.4 (c 1.1, CH2Cl2).
IR (KBr): 3375, 1654, 1552, 1347 cm–1.
6-Hydroxy-7-substituted-4-[(S)-1-phenylethyl]-1,4-oxazepan-5-
ones 4a/4b–13a/13b; General Procedure
To a stirred soln of the diastereomeric mixture of trans-N-(2-hy-
droxyethyl)-3-substituted-N-[(S)-1-phenylethyl]oxirane-2-carbox-
amide (0.56 mmol) in MeCN (5 mL) was added Cu(OTf)2 (20%
mol) at r.t. The mixture was stirred until the total disappearance of
the starting material (20 min). The reaction was quenched by addi-
tion of brine (10 mL). The organic phase was separated, dried (an-
hyd Na2SO4), filtered, and the solvent was removed by evaporation.
The resulting diastereomeric mixture was purified via flash column
chromatography (silica gel, EtOAc–PE, 1:4).
1H NMR (400 MHz, CDCl3): d = 1.54 (d, J = 7.0 Hz, 3 H), 2.95 (dd,
J = 10.0, 13.0 Hz, 1 H, H3), 3.17 (dd, J = 3.9, 16.0 Hz, 1 H, H2),
3.58 (dd, J = 10.0, 16.0 Hz, 1 H, H2), 3.78 (dd, J = 3.9, 13.0 Hz, 1
H, H3), 4.32 (dd, J = 4.9, 8.48 Hz, 1 H, H6), 4.41 (d, J = 4.9 Hz, 1
H, OH), 5.24 (d, J = 8.48 Hz, 1 H, H7), 6.17 (q, J = 7.0 Hz, 1 H),
7.29–7.95 (m, 9 H).
13C NMR (100 MHz, CDCl3): d = 15.3, 44.9, 52.6, 70.3, 74.2, 76.3,
124.2, 127.7–128.8, 132.9, 134.0, 139.1, 173.7.
HRMS (ESI): m/z [M] calcd for C19H20N2O5: 356.1372; found:
356.1402.
(–)-(6R,7R)-6-Hydroxy-7-phenyl-4-[(S)-1-phenylethyl]-1,4-ox-
azepan-5-one (14a)
Yield: 0.329 mmol (51%); Rf = 0.65 (EtOAc–PE, 40:60).
[a]D20 –85.8 (c 1.0, CH2Cl2).
IR (KBr): 3380, 1639, 1106, 737 cm–1.
1H NMR (400 MHz, CDCl3): d = 1.59 (d, J = 6.8 Hz, 3 H, CH3),
3.11 (dd, J = 4.1, 16.3 Hz, 1 H, H3), 3.40 (dd, J = 9.9, 16.3 Hz, 1 H,
H3), 3.53 (dd, J = 9.9, 12.9 Hz, 1 H, H2), 4.10 (dd, J = 4.1, 12.9 Hz,
1 H, H2), 4.29 (d, J = 9.0 Hz, 1 H, H7), 4.47 (m, 2 H, OH, H6), 6.15
(q, J = 6.8 Hz, 1 H, H1¢), 7.24–7.39 (m, 10 H).
13C NMR (100 MHz, CDCl3): d = 16.5, 45.5, 52.6, 70.6, 73.5, 82.2,
127.1–128.7, 139.1, 139.2, 174.4.
(–)-(6R,7R)-6-Hydroxy-7-(3-nitrophenyl)-4-[(S)-1-phenyleth-
yl]-1,4-oxazepan-5-one (16a)
Yield: 0.251 mmol (50%); Rf = 0.88 (EtOAc–PE, 40:60).
[a]D20 –75.6 (c 1.1, CH2Cl2).
IR (KBr): 3377, 1640, 1536, 1330 cm–1.
1H NMR (400 MHz, CDCl3): d = 1.61 (d, J = 7.0 Hz, 3 H), 3.14 (dd,
J = 4.2, 16.4 Hz, 1 H), 3.41 (dd, J = 10.0, 16.4 Hz, 1 H), 3.56 (dd,
J = 10.0, 12.9 Hz, 1 H), 4.16 (d, J = 4.2, 12.9 Hz, 1 H), 4.40 (m, 2
H), 4.51 (d, J = 3.5 Hz, 1 H), 6.14 (q, J = 7.0 Hz, 1 H), 7.26–7.41
(m, 5 H), 7.53 (t, J = 7.9 Hz, 1 H), 7.69 (dt, J = 1.2, 7.7 Hz, 1 H),
8.18 (ddd, J = 1.2, 2.2, 8.2 Hz, 1 H), 8.3 (t, J = 1.9 Hz, 1 H).
HRMS (ESI): m/z [M] calcd for C19H21NO3: 311.1521; found:
311.1541.
13C NMR (100 MHz, CDCl3): d = 16.5, 45.5, 52.8, 70.8, 73.4, 80.0,
122.5, 123.0, 127.1, 128.0, 128.8, 134.0, 138.8, 141.2, 173.7.
(–)-(6S,7S)-6-Hydroxy-7-phenyl-4-[(S)-1-phenylethyl]-1,4-ox-
azepan-5-one (14b)
Yield: 0.280 mmol (44%); Rf = 0.55 (EtOAc–PE, 40:60).
HRMS (ESI): m/z [M] calcd for C19H20N2O5: 356.1372; found:
356.1397.
[a]D20 –160 (c 1.0, CH2Cl2).
IR (KBr): 3377, 1642, 1100, 725 cm–1.
1H NMR (400 MHz, CDCl3): d = 1.54 (d, J = 6.9 Hz, 3 H), 2.93
(ddd, J = 0.8, 9.9, 13.0 Hz, 1 H, H3), 3.15 (ddd, J = 0.6, 4.16, 15.8
Hz, 1 H, H2), 3.60 (ddd, J = 0.8, 9.9, 15.8 Hz, 1 H, H2), 3.75 (ddd,
J = 0.9, 4.16, 13.0 Hz, 1 H, H3), 4.19 (d, J = 8.7 Hz, 1 H, H7), 4.45
(–)-(6S,7S)-6-Hydroxy-7-(3-nitrophenyl)-4-[(S)-1-phenylethyl]-
1,4-oxazepan-5-one (16b)
Yield: 0.213 mmol (42%); Rf = 0.55 (EtOAc–PE, 40:60).
[a]D20 –134.4 (c 1.1, CH2Cl2).
IR (KBr): 3370, 1644, 1526, 1347, 1111 cm–1.
Synthesis 2011, No. 14, 2310–2320 © Thieme Stuttgart · New York

PAPER
Chemodivergent Synthesis from a Common Epoxyamide Precursor
[a]D20 –187.4 (c 1.0, CH2Cl2).
2315
1H NMR (400 MHz, CDCl3): d = 1.56 (d, J = 7.0 Hz, 3 H), 2.93 (dd,
J = 9.8, 12.9 Hz, 1 H), 3.22 (dd, J = 3.9, 15.9 Hz, 1 H), 3.63 (dd,
J = 9.8, 15.9 Hz, 1 H), 3.79 (dd, J = 3.5, 13.1 Hz, 1 H), 4.31 (d,
J = 9.0 Hz, 1 H), 4.39 (dd, J = 3.2, 9.0 Hz, 1 H), 4.53 (d, J = 3.5 Hz,
1 H), 6.17 (q, J = 7.0 Hz, 1 H), 7.26–8.29 (m, 9 H).
13C NMR (100 MHz, CDCl3): d = 15.3, 44.8, 52.8, 70.0, 73.6, 80.6,
122.5, 122.9, 127.1, 127.6, 128.2, 128.7, 128.8, 133.9, 141.31,
173.6.
IR (KBr): 3385, 2980, 1646, 1435, 1390, 1110, 778, 740, 701 cm–1.
1H NMR (400 MHz, CDCl3): d = 1.53 (d, J = 7.0 Hz, 3 H), 2.91 (dd,
J = 9.8, 13.0 Hz, 1 H, H3), 3.16 (dd, J = 3.6, 15.9 Hz, 1 H, H2), 3.63
(dd, J = 9.8, 15.9 Hz, 1 H, H2), 3.76 (dd, J = 3.6, 13.0 Hz, 1 H, H3),
4.37 (d, J = 4.3 Hz, 1 H, H7), 5.13 (d, J = 9.2 Hz, 1 H, OH), 5.21
(dd, J = 4.3, 9.2 Hz, 1 H, H6), 6.16 (q, J = 7.0 Hz, 1 H), 7.12–7.41
(m, 8 H).
HRMS (ESI): m/z [M] calcd for C19H20N2O5: 356.1372; found:
356.1399.
13C NMR (100 MHz, CDCl3): d = 15.3, 44.8, 52.5, 70.8, 70.9, 78.5,
127.7–130.1, 134.0, 139.2, 174.5.
HRMS (ESI): m/z [M] calcd for C19H19Cl2NO3: 379.0742; found:
379.0770.
(–)-(6R,7R)-6-Hydroxy-7-(4-nitrophenyl)-4-[(S)-1-phenyleth-
yl]-1,4-oxazepan-5-one (17a)
Yield: 0.314 mmol (52%); Rf = 0.5 (EtOAc–PE, 30:70).
[a]D20 –69.55 (c 1.0, CH2Cl2).
IR (KBr): 3380, 1645, 1526, 1350 cm–1.
(–)-(6R,7R)-7-(3,4-Dichlorophenyl)-6-hydroxy-4-[(S)-1-phenyl-
ethyl]-1,4-oxazepan-5-one (19a)
Yield: 0.247 mmol (47%); Rf = 0.88 (EtOAc–PE, 50:50).
1H NMR (400 MHz, CDCl3): d = 1.62 (d, J = 7.0 Hz, 3 H), 3.14 (dd,
J = 4.0, 16.4 Hz, 1 H, H3), 3.39 (dd, J = 10.0, 16.4 Hz, 1 H, H3),
3.55 (dd, J = 10.0, 12.8 Hz, 1 H, H2), 4.14 (dd, J = 4.0, 12.8 Hz, 1
H, H2), 4.39 (m, J = 9.0 Hz, 2 H, H7, H6), 4.50 (d, J = 3.6 Hz, 1 H,
OH), 6.13 (q, J = 7.0 Hz, 1 H), 7.26–7.56 (m, 7 H), 8.22 (m, 2 H).
13C NMR (100 MHz, CDCl3): d = 16.5, 45.5, 52.8, 70.8, 73.4, 80.9,
123.2, 127.1–128.8, 138.8, 146.3, 147.5, 173.7.
[a]D20 –83.4 (c 1.0, CH2Cl2).
IR (KBr): 3393, 1642, 1464, 1113, 739 cm–1.
1H NMR (400 MHz, CDCl3): d = 1.61 (d, J = 7.1 Hz, 3 H), 3.10 (dd,
J = 4.1, 16.4 Hz, 1 H, H3), 3.35 (dd, J = 9.8, 16.4 Hz, 1 H, H3), 3.50
(dd, J = 9.8, 12.9 Hz, 1 H, H2), 4.10 (dd, J = 3.9, 12.9 Hz, 1 H, H2),
4.22 (d, J = 9.0 Hz, 1 H, OH), 4.36 (dd, J = 4.1, 9.0 Hz, 1 H, H6),
4.48 (d, J = 4.1 Hz, 1 H, H7), 6.11 (q, J = 7.1 Hz, 1 H), 7.18–7.49
(m, 8 H).
HRMS (ESI): m/z [M] calcd for C19H20N2O5: 356.1372; found:
356.1407.
13C NMR (100 MHz, CDCl3): d = 16.4, 45.4, 52.7, 70.6, 73.3, 80.7,
127.0–132.2, 138.8, 139.4, 173.7.
(–)-(6S,7S)-6-Hydroxy-7-(4-nitrophenyl)-4-[(S)-1-phenylethyl]-
1,4-oxazepan-5-one (17b)
Yield: 0.269 mmol (43%); Rf = 0.4 (EtOAc–PE, 30:70).
HRMS (ESI): m/z [M] calcd for C19H19Cl2NO3: 379.0742; found:
379.0773.
[a]D20 –208.3 (c 1.0, CH2Cl2).
IR (KBr): 3277, 1654, 1555, 1264 cm–1.
(–)-(6S,7S)-7-(3,4-Dichlorophenyl)-6-hydroxy-4-[(S)-1-phenyl-
ethyl]-1,4-oxazepan-5-one (19b)
Yield: 0.211 mmol (40%); Rf = 0.79 (EtOAc–PE, 50:50).
[a]D20 –143.6 (c 1.0, CH2Cl2).
IR (KBr): 3397, 1642, 1460, 1390, 1114, 739 cm–1.
1H NMR (400 MHz, CDCl3): d = 1.53 (d, J = 7.0 Hz, 3 H), 2.89 (dd,
J = 9.4, 13.1 Hz, 1 H, H3), 3.18 (dd, J = 3.8, 15.8 Hz, 1 H, H2), 3.57
(dd, J = 9.4, 15.8 Hz, 1 H, H2), 3.73 (dd, J = 3.8, 13.1 Hz, 1 H, H3),
4.15 (d, J = 9.0 Hz, 1 H, OH), 4.33 (dd, J = 4.0, 9.0 Hz, 1 H, H6),
4.49 (d, J = 4.0 Hz, 1 H, H7), 6.15 (q, J = 7.0 Hz, 1 H), 7.19 (dd,
J = 2.0, 8.2 Hz, 1 H), 7.38–7.48 (m, 7 H).
1H NMR (400 MHz, CDCl3): d = 1.55 (d, J = 7.0 Hz, 3 H), 2.93 (dd,
J = 9.5, 13.1 Hz, 1 H, H3), 3.22 (dd, J = 3.9, 15.8 Hz, 1 H, H2), 3.62
(dd, J = 9.5, 15.8 Hz, 1 H, H2), 3.79 (dd, J = 3.4, 13.1 Hz, 1 H, H3),
4.33 (dd, J = 9.0 Hz, 2 H, H6, H7), 4.50 (d, J = 3.9 Hz, 1 H, OH),
6.16 (q, J = 7.0 Hz, 1 H), 7.32–7.43 (m, 5 H), 7.54 (m, 2 H), 8.21
(m, 2 H).
13C NMR (100 MHz, CDCl3): d = 15.4, 44.8, 52.8, 70.1, 73.6, 80.8,
123.2, 127.7–128.8, 139.0, 146.3, 173.6.
HRMS (ESI): m/z [M] calcd for C19H20N2O5: 356.1372; found:
356.1395.
13C NMR (100 MHz, CDCl3): d = 15.3, 44.8, 52.7, 69.9, 73.6, 80.6,
127.0–129.9, 139.0, 139.4, 173.7.
(–)-(6R,7R)-7-(2,6-Dichlorophenyl)-6-hydroxy-4-[(S)-1-phenyl-
ethyl]-1,4-oxazepan-5-one (18a)
Yield: 0.207 mmol (49%); Rf = 0.53 (EtOAc–PE, 10:90).
HRMS (ESI): m/z [M] calcd for C19H19Cl2NO3: 379.0742; found:
379.0778.
[a]D20 –65.90 (c 1.0, CH2Cl2).
IR (KBr): 3383, 2975, 1646, 1437, 1320, 1109, 775, 735, 701 cm–1.
(–)-(6R,7R)-7-[4-(Benzyloxy)-3-methoxyphenyl]-6-hydroxy-4-
[(S)-1-phenylethyl]-1,4-oxazepan-5-one (20a)
Yield: 0.104 mmol (52%); Rf = 0.53 (EtOAc–PE, 40:60).
[a]D20 –139.8 (c 1.0, CH2Cl2).
IR (KBr): 3380, 2924, 1634, 1511, 1460, 1265, 1106 cm–1.
1H NMR (400 MHz, CDCl3): d = 1.53 (d, J = 7.08 Hz, 3 H), 2.91
(dd, J = 9.8, 12.9 Hz, 1 H, H3), 3.16 (dd, J = 3.9, 15.7 Hz, 1 H, H2),
3.59 (dd, J = 9.8, 15.7 Hz, 1 H, H2), 3.73 (dd, J = 3.7, 12.9 Hz, 1 H,
H3), 3.90 (s, 3 H, OCH3), 4.15 (d, J = 8.6 Hz, 1 H, OH), 4.45 (m, 2
H, H6, H7), 5.14 (s, 2 H, CH2Ph), 6.16 (q, J = 7.08 Hz, 1 H, H1¢),
6.85–6.92 (m, 3 H), 7.25–7.42 (m, 10 H).
1H NMR (400 MHz, CDCl3): d = 1.61 (d, J = 7.1 Hz, 3 H), 3.10 (dd,
J = 4.2, 16.3 Hz, 1 H, H3), 3.50 (dd, J = 9.9, 16.3 Hz, 1 H, H3), 3.55
(dd, J = 9.9, 12.7 Hz, 1 H, H2), 4.15 (dd, J = 4.2, 12.7 Hz, 1 H, H2),
4.38 (d, J = 4.3 Hz, 1 H, H7), 5.19 (d, J = 9.3 Hz, 1 H, OH), 5.25
(dd, J = 4.3, 9.3 Hz, 1 H, H6), 6.14 (q, J = 7.1 Hz, 1 H, H1¢), 7.13–
7.39 (m, 8 H).
13C NMR (100 MHz, CDCl3): d = 16.6, 45.4, 52.4, 70.6, 71.5, 78.6,
127.1–130.0, 134.0, 134.5, 136.4, 139.0, 174.5.
HRMS (ESI): m/z [M] calcd for C19H19Cl2NO3: 379.0742; found:
379.0775.
13C NMR (100 MHz, CDCl3): d = 15.4, 44.8, 52.6, 55.9, 69.8, 70.9,
73.7, 81.9, 110.8, 113.4, 119.9, 127.2–128.8, 132.4, 137.2, 139.2,
148.0, 149.4, 174.3.
(–)-(6S,7S)-7-(2,6-Dichlorophenyl)-6-hydroxy-4-[(S)-1-phenyl-
ethyl]-1,4-oxazepan-5-one (18b)
Yield: 0.176 mmol (42%); Rf = 0.41 (EtOAc–PE, 10:90).
Synthesis 2011, No. 14, 2310–2320 © Thieme Stuttgart · New York

2316
D. M. Aparicio et al.
PAPER
HRMS (ESI): m/z [M] calcd for C27H29NO5: 447.2046; found:
447.2080.
1H NMR (400 MHz, CDCl3): d = 0.92 (t, J = 7.2 Hz, 3 H), 1.37 (m,
2 H), 1.53 (d, J = 7.0 Hz, 3 H), 1.58 (m, 2 H), 1.89 (m, 1 H), 2.98
(dd, J = 4.0, 16.1 Hz, 1 H), 3.17–3.37 (m, 2 H), 3.97 (dd, J = 4.0,
12.7 Hz, 1 H), 4.12 (dd, J = 4.2, 8.9 Hz, 1 H), 4.45 (d, J = 4.3 Hz, 1
H), 6.08 (q, J = 7.0 Hz, 1 H), 7.23–7.36 (m, 5 H).
(–)-(6S,7S)-7-[4-(Benzyloxy)-3-methoxyphenyl]-6-hydroxy-4-
[(S)-1-phenylethyl]-1,4-oxazepan-5-one (20b)
Yield: 0.088 mmol (44%); Rf = 0.37 (EtOAc–PE, 40:60).
[a]D20 –62.8 (c 1.0, CH2Cl2).
13C NMR (100 MHz, CDCl3): d = 13.9, 16.3, 18.0, 34.0, 45.5, 52.2,
70.1, 73.3, 79.3, 127.0, 127.6, 128.5, 139.1, 175.0.
IR (KBr): 3390, 2929, 1634, 1509, 1455, 1270, 1110 cm–1.
HRMS (ESI): m/z [M] calcd for C16H23NO3: 277.1678; found:
277.1680.
1H NMR (400 MHz, CDCl3): d = 1.59 (d, J = 7.08 Hz, 3 H), 3.09
(dd, J = 4.0, 16.3 Hz, 1 H, H3), 3.38 (dd, J = 9.8, 16.3 Hz, 1 H, H3),
3.51 (dd, J = 9.8, 12.7 Hz, 1 H, H2), 3.90 (s, 3 H, OCH3), 4.09 (dd,
J = 4.0, 12.7 Hz, 1 H, H2), 4.22 (d, J = 8.5 Hz, 1 H, OH), 4.48 (m,
2 H, H6, H7), 5.14 (s, 2 H, CH2Ph), 6.13 (q, J = 7.08 Hz, 1 H, H1¢),
6.86–6.94 (m, 3 H), 7.26–7.43 (m, 10 H).
(–)-(6S,7S)-6-Hydroxy-4-[(S)-1-phenylethyl]-7-propyl-1,4-ox-
azepan-5-one (22b)
Yield: 0.165 mmol (44%); Rf = 0.71 (EtOAc–PE, 30:70).
[a]D20 –254.4 (c 1.0, CH2Cl2).
13C NMR (100 MHz, CDCl3): d = 16.53, 45.55, 52.65, 55.91, 70.60,
70.90, 73.50, 82.12, 110.79, 113.45, 120.0, 127.1–132.3, 137.2,
139.1, 148.1, 149.4, 174.4.
IR (KBr): 2957, 1638, 1112 cm–1.
1H NMR (400 MHz, CDCl3): d = 0.90 (t, J = 7.3 Hz, 3 H), 1.33 (m,
2 H), 1.49 (d, J = 7.1 Hz, 3 H), 1.54 (m, 1 H), 1.87 (m, 1 H), 2.73
(dd, J = 10.0, 13.0 Hz, 1 H), 3.06 (dd, J = 4.0, 15.7 Hz, 1 H), 3.22
(td, J = 2.8, 8.7 Hz, 1 H), 3.41 (dd, J = 10.0, 15.7 Hz, 1 H), 3.62 (dd,
J = 4.0, 13.0 Hz, 1 H), 4.09 (dd, J = 3.5, 8.9 Hz, 1 H), 4.46 (d,
J = 3.8 Hz, 1 H), 6.11 (q, J = 7.1 Hz, 1 H), 7.27–7.38 (m, 5 H).
HRMS (ESI): m/z [M] calcd for C27H29NO5: 447.2046; found:
447.2080.
(–)-(6R,7R)-6-Hydroxy-7-[3-methoxy-4-(tosyloxy)phenyl]-4-
[(S)-1-phenylethyl]-1,4-oxazepan-5-one (21a)
Yield: 0.155 mmol (52%); Rf = 0.68 (EtOAc–PE, 50:50).
[a]D20 –52.3 (c 1.0, CH2Cl2).
IR (KBr): 3449, 2929, 1642, 1371, 1177, 1112, 855 cm–1.
13C NMR (100 MHz, CDCl3): d = 14.3, 15.6, 18.37, 34.4, 45.1,
52.6, 69.7, 73.9, 79.5, 127.9, 128.2, 128.9, 139.5, 175.3.
HRMS (ESI): m/z [M] calcd for C16H23NO3: 277.1678; found:
277.1680.
1H NMR (400 MHz, CDCl3): d = 1.59 (d, J = 7.1 Hz, 3 H), 2.42 (s,
3 H, CH3-Ph), 3.10 (dd, J = 4.0, 16.3 Hz, 1 H, H3), 3.37 (dd, J = 9.8,
16.3 Hz, 1 H, H3), 3.51 (dd, J = 9.8, 12.7 Hz, 1 H, H2), 3.56 (s, 3
H, OCH3), 4.10 (dd, J = 3.5, 12.7 Hz, 1 H, H2), 4.22 (d, J = 8.8 Hz,
1 H, OH), 4.41 (m, 2 H, H6, H7), 6.12 (q, J = 7.1 Hz, 1 H, H1¢),
6.86–6.90 (m, 2 H), 7.11 (d, J = 8.2 Hz, 1 H), 7.26–7.36 (m, 8 H),
7.74 (d, J = 8.3 Hz, 1 H).
13C NMR (100 MHz, CDCl3): d = 16.5, 21.6, 45.4, 52.7, 55.5, 70.6,
73.4, 76.7, 81.6, 111.8, 123.5, 127.1, 127.9, 128.6, 128.8, 129.3,
139.3, 144.8, 151.4, 174.0.
(–)-(6R,7R)-7-Butyl-6-hydroxy-4-[(S)-1-phenylethyl]-1,4-ox-
azepan-5-one (23a)
Yield: 0.2 mmol (54%); Rf = 0.86 (EtOAc–PE, 30:70).
[a]D20 –61.65 (c 1.0, CH2Cl2).
IR (KBr): 2957, 1638, 1112 cm–1.
1H NMR (400 MHz, CDCl3): d = 0.90 (t, J = 7.2 Hz, 3 H), 1.3 (m,
3 H), 1.53 (d, J = 7.0 Hz, 3 H), 1.58 (m, 2 H), 1.93 (m, 1 H), 2.97
(dd, J = 3.9, 16.1 Hz, 1 H), 3.17–3.37 (m, 3 H), 3.98 (dd, J = 3.8,
12.6 Hz, 1 H), 4.13 (dd, J = 4.4, 8.8 Hz, 1 H), 4.45 (d, J = 4.4 Hz, 1
H), 6.08 (q, J = 7.0 Hz, 1 H), 7.23–7.36 (m, 5 H).
HRMS (ESI): m/z [M] calcd for C27H29NO7S: 511.1665; found:
511.1691.
13C NMR (100 MHz, CDCl3): d = 14.0, 16.3, 22.6, 27.0, 31.7, 45.5,
52.2, 70.1, 73.3, 79.5, 127.0, 127.6, 128.5, 139.1, 175.0.
(–)-(6S,7S)-6-Hydroxy-7-[3-methoxy-4-(tosyloxy)phenyl]-4-
[(S)-1-phenylethyl]-1,4-oxazepan-5-one (21b)
Yield: 0.132 mmol (46%); Rf = 0.57 (EtOAc–PE, 50:50).
HRMS (ESI): m/z [M] calcd for C17H25NO3: 291.1833; found:
291.1843.
[a]D20 –120.3 (c 1.0, CH2Cl2).
IR (KBr): 3421, 2929, 1638, 1365, 1112, 860 cm–1.
(–)-(6S,7S)-7-Butyl-6-hydroxy-4-[(S)-1-phenylethyl]-1,4-ox-
azepan-5-one (23b)
Yield: 0.164 mmol (44%); Rf = 0.76 (EtOAc–PE, 30:70).
[a]D20 –197.1 (c 1.0, CH2Cl2).
IR (KBr): 2957, 1638, 1112 cm–1.
1H NMR (400 MHz, CDCl3): d = 0.89 (t, J = 7.3 Hz, 3 H), 1.29 (m,
3 H), 1.49 (d, J = 7.08 Hz, 3 H), 1.54 (m, 2 H), 1.91 (m, 1 H), 2.73
(dd, J = 10.0, 12.9 Hz, 1 H), 3.05 (dd, J = 4.0, 15.7 Hz, 1 H), 3.21
(td, J = 2.9, 8.7 Hz, 1 H), 3.41 (dd, J = 10.0, 15.7 Hz, 1 H), 3.62 (dd,
J = 4.0, 12.9 Hz, 1 H), 4.10 (dd, J = 3.5, 8.9 Hz, 1 H), 4.46 (d,
J = 4.1 Hz, 1 H), 6.13 (q, J = 7.08 Hz, 1 H), 7.28–7.38 (m, 5 H).
1H NMR (400 MHz, CDCl3): d = 1.53 (d, J = 7.08 Hz, 3 H), 2.42 (s,
3 H, CH3-Ph), 2.89 (dd, J = 9.4, 13.0 Hz, 1 H, H3), 3.17 (dd, J = 3.9,
15.7 Hz, 1 H, H2), 3.56 (s, 3 H, OCH3), 3.58 (m, 1 H), 3.72 (m, 1
H), 4.15 (d, J = 8.9 Hz, 1 H, OH), 4.36 (dd, J = 4.0, 8.9 Hz, 1 H,
H6), 4.44 (d, J = 4.0 Hz, 1 H, H7), 6.14 (q, J = 7.08 Hz, 1 H, H1¢),
6.87 (m, 2 H), 7.11 (m, 1 H), 7.26–7.39 (m, 8 H), 7.73 (d, J = 8.3
Hz, 1 H).
13C NMR (100 MHz, CDCl3): d = 15.4, 21.6, 44.7, 52.7, 55.5, 69.8,
73.6, 81.4, 111.8, 119.7, 123.5, 127.6, 128.1, 128.6, 128.8, 129.3,
139.1, 139.3, 144.8, 151.4, 174.0.
13C NMR (100 MHz, CDCl3): d = 14.0, 15.2, 22.6, 27.0, 31.7, 44.8,
52.2, 69.4, 73.5, 79.4, 127.5, 127.8, 128.5, 139.2, 175.0.
HRMS (ESI): m/z [M] calcd for C27H29NO7S: 511.1665; found:
511.1687.
HRMS (ESI): m/z [M] calcd for C17H25NO3: 291.1833; found:
291.1843.
(–)-(6R,7R)-6-Hydroxy-4-[(S)-1-phenylethyl]-7-propyl-1,4-ox-
azepan-5-one (22a)
2-[Hydroxymethyl]-4-[(S)-1-phenylethyl]morpholin-3-ones
24a/24b–33a/33b; General Procedure
To a stirred suspension of Na (14–18 mg) in anhyd THF (3.5 mL),
was added a soln of the corresponding trans-diastereomeric mixture
Yield: 0.2 mmol (54%); Rf = 0.82 (EtOAc–PE, 30:70).
[a]D20 –87.3 (c 1.0, CH2Cl2).
IR (KBr): 2957, 1639, 1111 cm–1.
Synthesis 2011, No. 14, 2310–2320 © Thieme Stuttgart · New York

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Chemodivergent Synthesis from a Common Epoxyamide Precursor
2317
of epoxyamide (0.64 mmol) in anhyd THF (5.0 mL) at r.t. The re-
sulting mixture was stirred until the total conversion of the starting
material. Finally, the reaction was filtered and quenched by addition
of aq brine (20 mL) and the organic phase was separated, dried (an-
hyd Na2SO4), filtered, and the solvent was removed by evaporation.
The resulting diastereomeric mixture was purified via flash column
chromatography (silica gel, EtOAc–PE, 1:1).
1H NMR (400 MHz, CDCl3): d = 1.54 (d, J = 7.1 Hz, 3 H), 2.98 (m,
2 H, H5, H6), 3.59 (td, J = 3.4, 8.8, 12.0 Hz, 1 H, H5), 3.75 (dt,
J = 3.7, 11.8 Hz, 1 H, H6), 4.02 (d, J = 8.4 Hz, 1 H, H1¢¢), 5.53 (br,
1 H, OH), 5.86 (d, J = 8.4 Hz, 1 H, H2), 6.04 (q, J = 7.1 Hz, 1 H,
H1¢), 7.29–7.45 (m, 6 H), 7.64 (m, 1 H), 7.82 (dd, J = 1.2, 8.0 Hz, 1
H), 7.99 (d, J = 8.0 Hz, 1 H).
13C NMR (100 MHz, CDCl3): d = 15.2, 40.5, 50.3, 62.9, 68.4, 78.5,
123.8, 127.3–128.8, 132.8, 134.7, 138.3, 168.8.
(–)-(2S)-2-[(S)-Hydroxy(phenyl)methyl]-4-[(S)-1-phenyleth-
yl]morpholin-3-one (24a)
Yield: 0.333 mmol (57%); Rf = 0.51 (EtOAc–PE, 40:60).
HRMS (ESI): m/z [M] calcd for C19H20N2O5: 356.1372; found:
356.1385.
[a]D20 –144 (c 1.1, CH2Cl2).
IR (KBr): 3405, 1630, 1447, 701 cm–1.
(–)-(2S)-2-[(S)-Hydroxy(3-nitrophenyl)methyl]-4-[(S)-1-phe-
nylethyl]morpholin-3-one (26a)
Yield: 0.204 mmol (49%).
[a]D20 –134 (c 1.1, CH2Cl2); Rf = 0.79 (EtOAc–PE, 50:50).
IR (KBr): 3414, 2926, 1628, 1528, 1347 cm–1.
1H NMR (400 MHz, CDCl3): d = 1.50 (d, J = 7.1 Hz, 3 H), 2.77 (m,
1 H), 3.32 (td, J = 4.2, 11.5 Hz, 1 H), 3.47 (td, J = 2.9, 11.5 Hz, 1
H), 3.87 (ddd, J = 1.4, 4.2, 11.8 Hz, 1 H), 4.19 (d, J = 7.7 Hz, 1 H,
H1¢¢), 5.08 (d, J = 7.7 Hz, 1 H, H2), 5.51 (br, OH), 6.06 (q, J = 7.2
Hz, 1 H, H1¢), 7.28–7.37 (m, 5 H), 7.51 (t, J = 7.9 Hz, 1 H), 7.81 (m,
1 H), 8.16 (m, 1 H), 8.34 (m, 1 H).
1H NMR (400 MHz, CDCl3): d = 1.40 (d, J = 7.2 Hz, 3 H), 2.67 (d,
J = 12.2 Hz, 1 H, H5), 3.17 (td, J = 4.1, 11.5 Hz, 1 H, H6), 3.42 (td,
J = 2.9, 11.5 Hz, 1 H, H6), 3.80 (ddd, J = 1.3, 3.9, 11.8 Hz, 1 H,
H5), 4.28 (d, J = 7.1 Hz, 1 H, H2), 4.99 (d, J = 7.1 Hz, 1 H, H1¢¢),
6.02 (q, J = 7.2 Hz, 1 H), 7.26–7.45 (m, 10 H).
13C NMR (100 MHz, CDCl3): d = 15.0, 39.9, 49.8, 63.0, 74.4, 78.8,
127.1–128.5, 138.9, 139.9, 168.4.
HRMS (ESI): m/z [M] calcd for C19H21NO3: 311.1521; found:
311.1539.
13C NMR (100 MHz, CDCl3): d = 15.2, 40.0, 50.1, 63.2, 73.5, 78.3,
(+)-(2R)-2-[(R)-Hydroxy(phenyl)methyl]-4-[(S)-1-phenyleth-
yl]morpholin-3-one (24b)
Yield: 0.283 mmol (38%); Rf = 0.35 (EtOAc–PE, 40:60).
[a]D20 +1.53 (c 1.0, CH2Cl2).
122.6, 127.1–128.7, 133.7, 138.7, 142.3, 168.3.
HRMS (ESI): m/z [M] calcd for C19H20N2O5: 356.1372; found:
356.1389.
IR (KBr): 3416, 1623, 1454, 700 cm–1.
(–)-(2R)-2-[(R)-Hydroxy(3-nitrophenyl)methyl]-4-[(S)-1-phe-
nylethyl]morpholin-3-one (26b)
Yield: 0.174 mmol (41%); Rf = 0.41 (EtOAc–PE, 50:50).
[a]D20 –0.6 (c 1.1, CH2Cl2).
IR (KBr): 3378, 2940, 1640, 1527, 1330 cm–1.
1H NMR (400 MHz, CDCl3): d = 1.53 (d, J = 7.1 Hz, 3 H), 2.86 (m,
1 H), 3.00 (dt, J = 2.4, 12.6 Hz, 1 H), 3.67 (m, 1 H), 3.86 (ddd,
J = 2.3, 4.1, 11.9 Hz, 1 H), 4.22 (d, J = 7.4 Hz, 1 H, H1¢¢), 5.09 (d,
J = 7.4 Hz, 1 H, H2), 6.00 (q, J = 7.1 Hz, 1 H, H1¢), 7.15–7.35 (m,
5 H), 7.49 (t, J = 7.9 Hz, 1 H), 7.78 (d, J = 7.6 Hz, 1 H), 8.1 (m, 1
H), 8.33 (m, 1 H).
1H NMR (400 MHz, CDCl3): d = 1.49 (d, J = 7.1 Hz, 3 H), 2.78 (m,
1 H, H5), 2.92 (dt, J = 2.7, 12.6 Hz, 1 H, H5), 3.61 (td, J = 3.2,
10.12, 11.9 Hz, 1 H, H6), 3.80 (ddd, J = 2.7, 4.15, 11.9 Hz, 1 H,
H6), 4.32 (d, J = 7.0 Hz, 1 H, H1¢¢), 5.03 (d, J = 7.0 Hz, 1 H, H2),
5.97 (q, J = 7.1 Hz, 1 H, H1¢), 7.05–7.44 (m, 10 H).
13C NMR (100 MHz, CDCl3): d = 15.0, 40.4, 49.9, 63.0, 74.4, 79.1,
127.3–128.5, 138.5, 140.0, 168.2.
HRMS (ESI): m/z [M] calcd for C19H21NO3: 311.1521; found:
311.1537.
(+)-(2S)-2-[(S)-Hydroxy(2-nitrophenyl)methyl]-4-[(S)-1-phe-
nylethyl]morpholin-3-one (25a)
Yield: 0.363 mmol (52%); Rf = 0.85 (EtOAc–PE, 50:50).
[a]D20 +113.3 (c 1.1, CH2Cl2).
IR (KBr): 3374, 1627, 1528, 737 cm–1.
13C NMR (100 MHz, CDCl3): d = 15.0, 40.3, 50.1, 63.0, 73.4, 78.4,
122.7, 127.2–128.7, 133.8, 138.2, 142.3, 168.0.
HRMS (ESI): m/z [M] calcd for C19H20N2O5: 356.1372; found:
356.1389.
(–)-(2S)-2-[(S)-Hydroxy(4-nitrophenyl)methyl]-4-[(S)-1-phe-
nylethyl]morpholin-3-one (27a)
Yield: 0.341 mmol (48%); Rf = 0.8 (EtOAc–PE, 50:50).
[a]D20 –75.4 (c 1.0, CH2Cl2).
IR (KBr): 3450, 2925, 1630, 1528, 1340 cm–1.
1H NMR (400 MHz, CDCl3): d = 1.49 (d, J = 7.2 Hz, 3 H), 2.75 (m,
1 H), 3.29 (td, J = 4.2, 11.6 Hz, 1 H), 3.47 (td, J = 2.9, 11.6 Hz, 1
H), 3.85 (ddd, J = 1.4, 4.1, 11.8 Hz, 1 H), 4.19 (d, J = 7.5 Hz, 1 H),
5.09 (d, J = 7.5 Hz, 1 H), 6.05 (q, J = 7.2 Hz, 1 H), 7.28–7.37 (m, 5
H), 7.64 (m, 2 H), 8.19 (m, 2 H).
1H NMR (400 MHz, CDCl3): d = 1.58 (d, J = 7.2 Hz, 3 H), 2.75 (m,
1 H), 3.39 (m, 2 H), 3.78 (m, 1 H), 3.99 (d, J = 8.8 Hz, 1 H, H1¢¢),
5.53 (br, 1 H, OH), 5.86 (d, J = 8.8 Hz, 1 H, H2), 6.06 (q, J = 7.2
Hz, 1 H), 7.23–7.37 (m, 5 H), 7.26 (td, J = 1.6, 7.6, 8.0 Hz, 1 H),
7.64 (td, J = 0.8, 7.6, 8.0 Hz, 1 H), 7.81 (dd, J = 0.8, 1.2, 8.2 Hz, 1
H), 7.99 (dd, J = 1.2, 1.6, 7.8 Hz, 1 H).
13C NMR (100 MHz, CDCl3): d = 15.3, 40.0, 50.2, 63.1, 68.4, 78.5,
123.8, 127.2–128.7, 132.8, 134.6, 138.9, 168.9.
HRMS (ESI): m/z [M] calcd for C19H20N2O5: 356.1372; found:
356.1390.
13C NMR (100 MHz, CDCl3): d = 15.5, 40.3, 50.4, 63.5, 73.9, 78.7,
(–)-(2R)-2-[(R)-Hydroxy(2-nitrophenyl)methyl]-4-[(S)-1-phe-
nylethyl]morpholin-3-one (25b)
Yield: 0.309 mmol (44%); Rf = 0.68 (EtOAc–PE, 50:50).
[a]D20 –169 (c 1.1, CH2Cl2).
123.3, 127.4–129.0, 139.0, 147.8, 168.4.
HRMS (ESI): m/z [M] calcd for C19H20N2O5: 356.1372; found:
356.1387.
IR (KBr): 3365, 1630, 1510, 724 cm–1.
(+)-(2R)-2-[(R)-Hydroxy(4-nitrophenyl)methyl]-4-[(S)-1-phe-
nylethyl]morpholin-3-one (27b)
Yield: 0.290 mmol (42%); Rf = 0.44 (EtOAc–PE, 50:50).
Synthesis 2011, No. 14, 2310–2320 © Thieme Stuttgart · New York

2318
D. M. Aparicio et al.
PAPER
[a]D20 +12.8 (c 1.0, CH2Cl2).
IR (KBr): 3398, 2929, 1630, 1526, 1347 cm–1.
1H NMR (400 MHz, CDCl3): d = 1.52 (d, J = 7.1 Hz, 3 H), 2.82 (m,
J = 4.2, 10.4, 12.5 Hz, 1 H), 3.00 (dt, J = 2.6, 12.6 Hz, 1 H), 3.65
(m, J = 3.2, 10.4, 11.9 Hz, 1 H), 3.85 (ddd, J = 2.3, 4.3, 11.9 Hz, 1
H), 4.24 (d, J = 7.1 Hz, 2 H), 5.12 (d, J = 7.1 Hz, 1 H), 6.98 (q,
J = 7.1 Hz, 1 H), 7.14–7.34 (m, 5 H), 7.61 (m, 2 H), 8.16 (m, 2 H).
(+)-(2R)-2-[(R)-(3,4-Dichlorophenyl)hydroxymethyl]-4-[(S)-1-
phenylethyl] morpholin-3-one (29b)
Yield: 0.185 mmol (39.5%); Rf = 0.17 (EtOAc–PE, 50:50).
[a]D20 +3.0 (c 1.0, CH2Cl2).
IR (KBr): 3398, 2929, 1635, 1460, 1130, 1050, 1028 cm–1.
1H NMR (400 MHz, CDCl3): d = 1.51 (d, J = 7.1 Hz, 3 H), 2.81 (m,
J = 4.2, 10.4, 12.6 Hz, 1 H), 2.95 (dt, J = 2.5, 12.6 Hz, 1 H), 3.64
(ddd, J = 3.2, 10.4, 11.9 Hz, 1 H), 3.85 (ddd, J = 2.4, 4.2, 11.9 Hz,
1 H), 4.21 (d, J = 7.0 Hz, 1 H), 4.97 (d, J = 7.0 Hz, 1 H), 5.97 (q,
J = 7.1 Hz, 1 H), 7.10 (m, 2 H), 7.26–7.39 (m, 5 H), 7.57 (d, J = 1.9
Hz, 1 H).
13C NMR (100 MHz, CDCl3): d = 15.1, 40.3, 50.2, 63.1, 73.6, 78.6,
123.0, 127.3–128.6, 138.3, 147.4, 167.8.
HRMS (ESI): m/z [M] calcd for C19H20N2O5: 356.1372; found:
356.1389.
13C NMR (100 MHz, CDCl3): d = 15.0, 40.4, 50.1, 63.1, 73.3, 78.7,
127.2–132.0, 138.3, 140.4, 167.9.
(–)-(2S)-2-[(S)-(2,6-Dichlorophenyl)hydroxymethyl]-4-[(S)-1-
phenylethyl]morpholin-3-one (28a)
Yield: 0.170 mmol (21%); Rf = 0.86 (EtOAc–PE, 50:50).
[a]D20 –6.3 (c 0.9, CH2Cl2).
HRMS (ESI): m/z [M] calcd for C19H19Cl2NO3: 379.0742; found:
379.0770.
(–)-(2S)-2-{(S)-[4-(Benzyloxy)-3-methoxyphenyl]hydroxymeth-
yl}-4-[(S)-1-phenylethyl]morpholin-3-one (30a)
Yield: 0.072 mmol (40.5%); Rf = 0.25 (EtOAc–PE, 90:10).
[a]D20 –87.0 (c 1.1, CH2Cl2).
IR (KBr): 3418, 2927, 1640, 1511, 1265, 1138, 699 cm–1.
1H NMR (400 MHz, CDCl3): d = 1.44 (d, J = 7.2 Hz, 3 H), 2.72 (dt,
J = 1.9, 12.2 Hz, 1 H), 3.25 (dd, J = 4.1, 11.5, 1 H), 3.48 (dd,
J = 2.9, 11.4 Hz, 1 H), 3.86 (ddd, J = 1.6, 4.0, 11.8 Hz, 1 H), 3.91
(s, 3 H), 4.25 (d, J = 7.5, 1 H), 4.90 (d, J = 7.5 Hz, 1 H), 5.07 (br, 1
H), 5.15 (s, 2 H), 6.04 (q, J = 7.2 Hz, 1 H), 6.87 (m, 2 H), 7.07 (d,
J = 1.8 Hz, 1 H), 7.25–7.44 (m, 10 H).
13C NMR (100 MHz, CDCl3): d = 15.2, 40.1, 49.9, 55.9, 63.2, 70.8,
74.4, 78.8, 110.8, 113.2, 120.0, 127.2, 127.7, 127.8, 128.5, 128.7,
133.2, 137.2, 139.1, 147.9, 149.3, 168.8.
IR (KBr): 3401, 2930, 1635, 1464, 1135, 1063, 1037 cm–1.
1H NMR (400 MHz, CDCl3): d = 1.60 (d, J = 7.1 Hz, 3 H), 2.83 (td,
J = 3.2, 12.4 Hz, 1 H), 3.37 (ddd, J = 3.9, 9.2, 12.6 Hz, 1 H), 3.55
(ddd, J = 3.1, 9.2, 12.0 Hz, 1 H), 3.88 (td, J = 3.6, 11.9 Hz, 1 H),
5.01 (d, J = 9.6 Hz, 1 H), 5.41 (d, J = 1.2 Hz, 1 H), 5.76 (dd, J = 1.1,
9.6 Hz, 1 H), 6.11 (q, J = 7.1 Hz, 1 H), 7.14 (dd, J = 7.6, 8.4 Hz, 1
H), 7.29–7.39 (m, 7 H).
13C NMR (100 MHz, CDCl3): d = 15.3, 40.3, 50.0, 63.1, 71.0, 74.7,
127.2, 127.8, 128.7, 129.3, 133.8, 138.8, 169.6.
HRMS (ESI): m/z [M] calcd for C19H19Cl2NO3: 379.0742; found:
379.0755.
(–)-(2R)-2-[(R)-(2,6-Dichlorophenyl)hydroxymethyl]-4-[(S)-1-
phenylethyl]morpholin-3-one (28b)
Yield: 0.145 mmol (19%); Rf = 0.77 (EtOAc–PE, 50:50).
[a]D20 –5.3 (c 0.9, CH2Cl2).
HRMS (ESI): m/z [M] calcd for C27H29NO5: 447.2046; found:
447.2051.
IR (KBr): 3401, 2930, 1635, 1464, 1135, 1063, 1037 cm–1.
(+)-(2R)-2-{(R)-[4-(Benzyloxy)-3-methoxyphenyl]hydroxy-
methyl}-4-[(S)-1-phenylethyl]morpholin-3-one (30b)
Yield: 0.061 mmol (34.5%); Rf = 0.11 (EtOAc–PE, 90:10).
[a]D20 +7.0 (c 1.0, CH2Cl2).
1H NMR (400 MHz, CDCl3): d = 1.57 (d, J = 7.1 Hz, 3 H), 2.93
(ddd, J = 3.9, 7.5, 12.5 Hz, 1 H), 3.17 (ddd, J = 3.5, 5.1, 12.5 Hz, 1
H), 3.69 (ddd, J = 3.5, 7.5, 11.9 Hz, 1 H), 3.84 (ddd, J = 3.9, 5.1,
11.9 Hz, 1 H), 5.06 (d, J = 9.6 Hz, 1 H), 5.39 (d, J = 1.3 Hz, 1 H),
5.78 (dd, J = 1.3, 9.6 Hz, 1 H), 6.12 (q, J = 7.1 Hz, 1 H), 7.13–7.42
(m, 8 H).
IR (KBr): 3418, 2927, 1640, 1511, 1265, 1138, 699 cm–1.
1H NMR (400 MHz, CDCl3): d = 1.51 (d, J = 7.0 Hz, 3 H), 2.82 (m,
1 H), 2.96 (dt, J = 2.7, 12.5 Hz, 1 H), 3.65 (td, J = 3.2, 11.9 Hz, 1
H), 3.84 (dd, J = 2.8, 7.9 Hz, 1 H), 3.87 (s, 3 H), 4.30 (d, J = 7.2 Hz,
1 H), 4.95 (d, J = 7.2 Hz, 1 H), 5.1 (s, 2 H), 5.99 (q, J = 7.0 Hz, 1
H), 6.86 (m, 2 H), 7.0 (m, 1 H), 7.25–7.44 (m, 10 H).
13C NMR (100 MHz, CDCl3): d = 15.0, 40.4, 49.9, 55.9, 63.0, 70.8,
74.3, 79.0, 111.0, 113.1, 120.2, 127.2–128.6, 137.2, 138.5, 148.0,
149.3, 168.4.
13C NMR (100 MHz, CDCl3): d = 15.1, 40.5, 50.0, 62.6, 70.8, 74.5,
122.9, 127.3, 127.8, 128.7, 129.4, 133.9, 138.6, 169.6.
HRMS (ESI): m/z [M] calcd for C19H19Cl2NO3: 379.0742; found:
379.0759.
(–)-(2S)-2-[(S)-(3,4-Dichlorophenyl)hydroxymethyl]-4-[(S)-1-
phenylethyl]morpholin-3-one (29a)
Yield: 0.217 mmol (45.5%); Rf = 0.47 (EtOAc–PE, 50:50).
[a]D20 –129.0 (c 1.0, CH2Cl2).
HRMS (ESI): m/z [M] calcd for C27H29NO5: 447.2046; found:
447.2055.
IR (KBr): 3401, 2930, 1635, 1464, 1135, 1063, 1037 cm–1.
(–)-(2S)-2-{(S)-[3-Methoxy-4-(tosyloxy)phenyl]hydroxymeth-
yl}-4-[(S)-1-phenylethyl]morpholin-3-one (31a)
Yield: 0.116 mmol (46%); Rf = 0.2 (EtOAc–PE, 50:50).
[a]D20 –88.4 (c 1.0, CH2Cl2).
IR (KBr): 3449, 1642, 1271, 1177, 700 cm–1.
1H NMR (400 MHz, CDCl3): d = 1.47 (d, J = 7.2 Hz, 3 H), 2.73 (m,
1 H), 3.26 (td, J = 4.1, 11.5 Hz, 1 H), 3.45 (td, J = 2.9, 11.5 Hz, 1
H), 3.84 (ddd, J = 1.5, 4.1, 11.8 Hz, 1 H), 4.15 (d, J = 7.4 Hz, 1 H),
4.94 (d, J = 7.4 Hz, 1 H), 6.04 (q, J = 7.2 Hz, 1 H), 7.28–7.37 (m, 5
H), 7.64 (m, 2 H), 8.19 (m, 2 H).
13C NMR (100 MHz, CDCl3): d = 15.2, 40.0, 50.0, 63.2, 73.3, 78.5,
1H NMR (400 MHz, CDCl3): d = 1.46 (d, J = 7.2 Hz, 3 H), 2.43 (s,
3 H), 2.73 (m, 1 H), 3.25 (td, J = 4.1, 11.5 Hz, 1 H), 3.46 (td, J = 2.9,
11.8 Hz, 1 H), 3.56 (s, 3 H), 3.85 (ddd, J = 1.5, 4.0, 11.8 Hz, 1 H),
4.17 (d, J = 7.4 Hz, 1 H), 4.93 (d, J = 7.4 Hz, 1 H), 6.03 (q, J = 7.2
Hz, 1 H), 6.94 (dd, J = 1.9, 8.3 Hz, 1 H), 7.0 (d, J = 1.8 Hz, 1 H),
127.0–131.9, 138.8, 140.5, 168.2.
HRMS (ESI): m/z [M] calcd for C19H19Cl2NO3: 379.0742; found:
379.0766.
Synthesis 2011, No. 14, 2310–2320 © Thieme Stuttgart · New York

PAPER
Chemodivergent Synthesis from a Common Epoxyamide Precursor
2319
7.10 (d, J = 8.2 Hz, 1 H), 7.26–7.39 (m, 6 H), 7.74 (d, J = 8.3 Hz, 2
H).
13C NMR (100 MHz, CDCl3): d = 15.2, 21.6, 40.1, 50.0, 55.5, 63.2,
74.1, 78.6, 111.6, 119.9, 123.1, 127.2–129.3, 137.9, 138.9, 140.3,
144.9, 151.4, 168.5.
[a]D20 –162.2 (c 1.0, CH2Cl2).
IR (KBr): 3415, 2955, 1626 cm–1.
1H NMR (400 MHz, CDCl3): d = 0.91 (t, J = 7.3 Hz, 3 H), 1.35 (m,
4 H), 1.53 (d, J = 7.2 Hz, 3 H), 1.69 (m, 1 H), 2.78 (dt, J = 2.0, 12.0
Hz, 1 H), 3.4 (td, J = 4.2, 11.4 Hz, 1 H), 3.56 (td, J = 2.9, 11.4 Hz,
1 H), 3.69 (s, 1 H), 3.96 (m, 3 H), 4.35 (s, 1 H), 6.06 (q, J = 7.2 Hz,
1 H), 7.26–7.37 (m, 5 H).
HRMS (ESI): m/z [M] calcd for C27H29NO7S: 511.1665; found:
511.1684.
13C NMR (100 MHz, CDCl3): d = 13.9, 15.2, 22.6, 27.0, 32.1,
(+)-(2R)-2-{(R)-[3-Methoxy-4-(tosyloxy)phenyl]hydroxymeth-
yl}-4-[(S)-1-phenylethyl]morpholin-3-one (31b)
Yield: 0.098 mmol (39%); Rf = 0.06 (EtOAc–PE, 50:50).
[a]D20 +4.2 (c 1.0, CH2Cl2).
40.21, 49.6, 63.0, 71.9, 78.8, 127.1, 127.6, 128.5, 139.1, 169.0.
HRMS (ESI): m/z [M] calcd for C17H25NO3: 291.1834; found:
291.1838.
IR (KBr): 3450, 1643, 1271, 1177, 700 cm–1.
(–)-(2R)-2-[(R)-1-Hydroxypentyl]-4-[(S)-1-phenylethyl]mor-
pholin-3-one (33b)
Yield: 0.125 mmol (36%); Rf = 0.54 (EtOAc–PE, 50:50).
[a]D20 –98.75 (c 1.0, CH2Cl2).
IR (KBr): 3415, 2955, 1626 cm–1.
1H NMR (400 MHz, CDCl3): d = 0.91 (t, J = 7.2 Hz, 3 H), 1.35 (m,
4 H), 1.53 (d, J = 7.1 Hz, 3 H), 1.67 (m, 1 H), 2.94 (td, J = 4.3, 10.0
Hz, 1 H), 3.03 (dt, J = 2.6, 12.4 Hz, 1 H), 3.71 (td, J = 3.4, 10.0 Hz,
1 H), 3.90–3.99 (m, 3 H), 4.31 (br, 1 H), 6.0 (q, J = 7.1 Hz, 1 H),
7.27–7.32 (m, 5 H).
13C NMR (100 MHz, CDCl3): d = 14.0, 14.9, 22.7, 27.0, 32.3, 40.4,
49.7, 62.9, 71.9, 78.7, 127.3, 127.7, 128.5, 138.7, 169.1.
1H NMR (400 MHz, CDCl3): d = 1.52 (d, J = 7.0 Hz, 3 H), 2.43 (s,
3 H), 2.8 (ddd, J = 4.3, 10.0, 12.6 Hz, 1 H), 2.97 (dt, J = 2.6, 12.6
Hz, 1 H), 3.53 (s, 3 H), 3.61 (m, 2 H), 3.82 (ddd, J = 2.6, 4.1, 11.8
Hz, 1 H), 4.19 (d, J = 7.5 Hz, 1 H), 4.94 (d, J = 7.3 Hz, 1 H), 5.98
(q, J = 7.0 Hz, 1 H), 6.93 (dd, J = 1.8, 8.3 Hz, 1 H), 6.90 (d, J = 1.8
Hz, 1 H), 7.08–7.15 (m, 3 H), 7.26–7.36 (m, 5 H), 7.74 (d, J = 8.3
Hz, 1 H).
13C NMR (100 MHz, CDCl3): d = 15.1, 21.6, 40.5, 50.1, 55.5, 63.0,
73.9, 78.7, 111.8, 120.0, 123.2, 127.2–129.3, 140.3, 144.9, 151.4,
168.3.
HRMS (ESI): m/z [M] calcd for C27H29NO7S: 511.1665; found:
511.1687.
HRMS (ESI): m/z [M] calcd for C17H25NO3: 291.1834; found:
291.1838.
(–)-2S)-2-[(S)-1-Hydroxybutyl]-4-[(S)-1-phenylethyl)morpho-
lin-3-one (32a)
(+)-(6S,7R)-7-Phenyl-4-[(S)-1-phenylethyl]-1,4-oxazepan-6-ol
(34)
Yield: 0.15 mmol (46%); Rf = 0.80 (EtOAc–PE, 50:50).
[a]D20 –194.2 (c 1.0, CH2Cl2).
IR (KBr): 3415, 2955, 1626 cm–1.
1H NMR (400 MHz, CDCl3): d = 0.94 (t, J = 7.0 Hz, 3 H), 1.44 (m,
2 H), 1.53 (d, J = 7.2 Hz, 3 H), 1.60 (m, 2 H), 2.78 (dt, J = 1.9, 11.8
Hz, 1 H), 3.41 (td, J = 4.2, 11.1 Hz, 1 H), 3.56 (td, J = 2.9, 11.1 Hz,
1 H), 3.70 (s, 1 H), 3.93–4.0 (m, 2 H), 4.35 (s, 1 H), 6.06 (q, J = 7.2
Hz, 1 H), 7.27–7.37 (m, 5 H).
13C NMR (100 MHz, CDCl3): d = 14.0, 15.2, 18.1, 34.5, 40.1, 49.6,
63.0, 71.7, 78.8, 127.1, 127.6, 128.5, 139.1, 169.0.
To a stirred soln of 1,4-oxazepan-5-one 14a (0.138 g, 0.443 mmol)
in anhyd THF (6 mL) at 0 °C, under N2, was added BH3·SMe2
(0.084 g, 1.10 mmol). The mixture was stirred at r.t. for 12 h. Later,
the reaction was quenched with MeOH (6 mL) and stirred for 1 h.
Finally, the solvent was evaporated under reduced pressure, and the
crude was purified via flash chromatography column giving the de-
sired compound 34 (0.120 g, 0.403 mmol, 91%) as a white oil;
Rf = 0.7 (EtOAc–PE, 50:50).
[a]D20 +12.0 (c 1.0, CH2Cl2).
IR (KBr): 3416, 2930, 1451, 700 cm–1.
1H NMR (400 MHz, CDCl3): d = 1.42 (d, J = 6.8 Hz, 3 H), 2.71 (m,
2 H), 2.86 (m, 2 H), 3.78–3.91 (m, 3 H), 4.0 (dt, J = 2.6, 13.0 Hz, 1
H), 4.70 (d, J = 2.0 Hz, 1 H), 7.17–7.35 (m, 10 H).
HRMS (ESI): m/z [M] calcd for C16H23NO3: 277.1678; found:
277.1680.
(–)-(2R)-2-[(R)-1-Hydroxybutyl]-4-[(S)-1-phenylethyl]morpho-
lin-3-one (32b)
Yield: 0.126 mmol (49%); Rf = 0.58 (EtOAc–PE, 50:50).
[a]D20 –71.25 (c 1.0, CH2Cl2).
IR (KBr): 3415, 2955, 1626 cm–1.
13C NMR (100 MHz, CDCl3): d = 16.4, 50.9, 55.0, 63.4, 69.4, 74.7,
87.4, 125.8, 127.0, 127.2, 127.5, 128.1, 128.2, 141.5, 142.2.
HRMS (ESI): m/z [M] calcd for C19H23NO2: 297.1729; found:
297.1731.
1H NMR (400 MHz, CDCl3): d = 0.94 (t, J = 7.1 Hz, 3 H), 1.39–
1.51 (m, 2 H), 1.53 (d, J = 7.0 Hz, 3 H), 1.55–1.67 (m, 2 H), 2.94
(td, J = 4.3, 12.5 Hz, 1 H), 3.03 (dt, J = 2.9, 12.3 Hz, 1 H), 3.71
(ddd, J = 3.4, 10.1, 11.7 Hz, 1 H), 3.92 (ddd, J = 2.6, 4.2, 11.8 Hz,
1 H), 3.97 (dd, J = 7 Hz, 1 H), 4.32 (br, 1 H), 6.0 (q, J = 7.0 Hz, 1
H), 7.27–7.38 (m, 5 H).
(–)-(6S,7R)-7-Phenyl-1,4-oxazepan-6-ol (35)
To a stirred suspension of 10% Pd-C (0.08 g) in abs EtOH (6 mL)
at r.t. was added 1,4-oxazepan-6-ol 34 (0.08 g, 0.286 mmol). To the
resulting mixture, ammonium formate (0.09 g, 1.42 mmol) was add-
ed and the mixture was refluxed for 5 min. Finally, the mixture was
filtered through a path of diatomite and the solvent was eliminated
in vacuo giving the desired compound 35 (0.252 mmol, 90%);
Rf = 0.31 (EtOAc–MeOH, 50:50).
13C NMR (100 MHz, CDCl3): d = 14.0, 15.0, 18.1, 34.7, 40.4, 49.8,
62.9, 71.7, 78.7, 127.3, 127.7, 128.5, 138.7, 169.1.
[a]D20 –14.7 (c 1.0, CH2Cl2).
IR (KBr): 3381, 2924, 1597, 1130, 1070, 1020 cm–1.
HRMS (ESI): m/z [M] calcd for C16H23NO3: 277.1678; found:
277.1680.
(–)-(2S)-2-[(S)-1-Hydroxypentyl)-4-[(S)-1-phenylethyl]mor-
pholin-3-one (33a)
Yield: 0.153 mmol (44%); Rf = 0.76 (EtOAc–PE, 50:50).
1H NMR (400 MHz, CDCl3): d = 3.11 (m, 1 H), 3.2 (m, 2 H), 3.97–
4.03 (m, 1 H), 4.13 (m, 2 H), 4.70 (d, J = 3.2, Hz, 1 H), 6.29 (br, 2
H), 7.23–7.38 (m, 5 H).
Synthesis 2011, No. 14, 2310–2320 © Thieme Stuttgart · New York

2320
D. M. Aparicio et al.
PAPER
13C NMR (100 MHz, CDCl3): d = 48.9, 49.8, 68.4, 74.5, 86.9,
Sarabia, F. Tetrahedron Lett. 2004, 45, 9069. For opening
of epoxyamides with halides, see: (e) Righi, G.; Rumboldt,
G.; Bonini, C. Tetrahedron 1995, 51, 1340. (f) Righi, G.;
Pescatore, G.; Bonadies, F.; Bonini, C. Tetrahedron 2001,
57, 5649. (g) Fringuelli, F.; Pizzo, F.; Vaccaro, L. J. Org.
Chem. 2001, 66, 4719. For opening of epoxyamides with
sulfides, see: (h) Caron, M.; Sharpless, K. B. J. Org. Chem.
1985, 50, 1557. (i) Behrens, C. H.; Sharpless, K. B. J. Org.
Chem. 1985, 50, 5696. (j) Chong, J. M.; Sharpless, K. B.
J. Org. Chem. 1985, 50, 1560. (k) Deng, B.-L.;
125.8, 127.6, 128.4, 140.7.
HRMS (ESI): m/z [M] calcd for C11H15NO2: 193.1103; found:
193.1105.
Acknowledgment
We are grateful to CONACyT (Project 83185) for financial support,
D.M.A.S. thanks CONACyT for the scholarship (169011).
Demillequand, M.; Laurent, M.; Touillaux, R.; Belmans, M.;
Kemps, L.; Cérésiat, M.; Marchand-Brynaert, J.
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Synthesis 2011, No. 14, 2310–2320 © Thieme Stuttgart · New York