Intramolecular conjugate addition of γ- and δ-trichloroacetimidoyloxy-α,β-unsaturated esters in an acyclic system

Article abstract of DOI:10.1016/j.tet.2008.02.061

An intramolecular conjugate addition of γ- and δ-trichloroacetimidoyloxy-α,β-unsaturated esters, a new way to construct 1,2-amino or 1,3-amino alcohol moieties in an acyclic system, is described. Very concise synthesis of d-vancosamine and 3-epi-d-vancosa

Full text of DOI:10.1016/j.tet.2008.02.061

Available online at www.sciencedirect.com
Tetrahedron 64 (2008) 3943e3952
www.elsevier.com/locate/tet
Intramolecular conjugate addition of g- and d-trichloroacetimidoyloxy-
a,b-unsaturated esters in an acyclic system
*
Yoshitaka Matsushima , Jun Kino
Department of Chemistry, Hamamatsu University School of Medicine, Handayama, Hamamatsu 431-3192, Japan
Received 28 December 2007; received in revised form 15 February 2008; accepted 19 February 2008
Available online 23 February 2008
Abstract
An intramolecular conjugate addition of g- and d-trichloroacetimidoyloxy-a,b-unsaturated esters, a new way to construct 1,2-amino or
1,3-amino alcohol moieties in an acyclic system, is described. Very concise synthesis of D-vancosamine and 3-epi-D-vancosamine derivatives
was also achieved utilizing this methodology.
Ó 2008 Elsevier Ltd. All rights reserved.
Keywords: Intramolecular conjugate addition; Trichloroacetimidate; Vancosamine
1. Introduction
a variety of stereoselective synthetic methods especially for
1,2-amino alcohol moieties have been developed,7 there are
relatively few methods for 1,3-amino alcohols.8 During our
course of developing a simple synthetic strategy to deoxy-
amino sugars, an intramolecular conjugate addition of g-tri-
chloroacetimidoyloxy-a,b-unsaturated esters was found.6,9
We here disclose the details of the trichloroacetimidate-medi-
ated functionalization useful for the introduction of a nitrogen
functionality10 on the b-carbon of g- and d-hydroxy-a,b-
unsaturated esters, a new way to construct 1,2-amino or
1,3-amino alcohol moieties in an acyclic system.
Amino sugars, especially deoxyamino sugars, are found in
clinically important antibiotics such as antimicrobial macro-
lides and anthracycline antitumor antibiotics.1 In most
instances, the sugar parts of these antibiotics are essential
for biological activity; however, the functions of the sugar
moieties have not yet been evaluated.2 We envisaged that
a modification of the sugar moieties of these antibiotics may
serve as a tool for investigating the significance of amino
sugars and the structureeactivity relationship, and elucidating
the biosynthetic route of antibiotics.3,4 For this purpose, a ver-
satile and synthetic route for deoxyamino sugars is highly
desirable. We were especially interested in developing a new
synthetic route for deoxyamino sugars from non-sugar
materials.5,6
2. Results and discussion
2.1. Intramolecular conjugate additions
of g-trichloroacetimidoyloxy-a,b-unsaturated esters
1,2- and 1,3-amino alcohol moieties are often found in
natural products and potent drugs, as seen in deoxyamino
sugars, and they have also been used as synthetic intermedi-
ates. Thus, an effective method for the introduction of func-
tionality to acyclic olefinic systems is required. While
In order to estimate this intramolecular conjugate addition,
we first investigated the cyclization reaction of several kinds of
g-trichloroacetimidoyloxy-a,b-unsaturated esters (Table 1),
which were prepared from the corresponding allylic alcohols11
by treatment with 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU)
and trichloroacetonitrile in good to excellent yields.12 When
the substrate trichloroacetimidates 1aed were treated with
* Corresponding author. Tel./fax: þ81 53 435 2319.
E-mail address: ymatsu@hama-med.ac.jp (Y. Matsushima).
0040-4020/$ - see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2008.02.061

3944
Y. Matsushima, J. Kino / Tetrahedron 64 (2008) 3943e3952
Table 1
Intramolecular conjugate addition of g-trichloroacetimidoyloxy-a,b-unsatu-
rated esters 1a
CCl3
N
CCl3
O
O
N
CO2Et
H4
CO2Et
H4
<
R
EtO2C
H
CO2Et
H
CO2Et
H
H
H
R
R
R
base
(25 mM)
H
O
NH
CCl3
R
+
H5
H5
N
N
O
O
cis-TS model
unfavorable
trans-TS model
favorable
CCl3
trans-oxazoline 2
CCl3
cis-oxazoline 3
1
Figure 1. Proposed transition state models for cyclization.
13
Entry Substrate
R
Conditions
Product
Ratio Yieldb
2/3 (%)
0
0
constants (JH-4 ,H-5 ), and it was also confirmed by nuclear
Overhauser enhancement (NOE) experiments.6 In the case of
substrate 1a, the ratio of 2a/3a was not affected by changing
the conditions with maintained moderate trans-selectivity
(entries 1e4). In the series with more sterically bulky R
groups, when DBU was used as a base, higher trans-selectivity
was observed (entry 5, 9, 11). Cyclization was also performed
with stoichiometric amount of sodium hydride (NaH) in THF
(entry 4, 13), showing little difference in the stereoselectivity.
The trans-selectivity observed in the cyclization can be antic-
ipated using the transition state (TS) models shown in Figure 1.
The cyclization is thought to proceed through trans-TS model
to give the trans-oxazolines, since cis-TS model is unfavorable
than the trans-TS model due to its steric hindrance between the
side chain R and the alkenyl group. With the exception of the
compound 1c, trans-selectivity was not so high like the case of
the carbamate-mediated intramolecular conjugate additions.14
Interestingly, reversal of diastereofacial selectivity was
found (entry 6 and 10). In fact, upon treatment with potassium
tert-butoxide (tert-BuOK) in THF, cis-oxazoline was domi-
nantly produced. A notable temperature effect; namely, the ratio
of cis-oxazoline increased with decreasing the reaction temper-
ature, was also found (entries 6e8). These results indicated that
trans-oxazoline was the thermodynamically controlled product
as compared with the result of DBU. The reversal of diastereo-
facial selectivity was realized only at very low temperature as
not reported in the carbamate-mediated intramolecular conju-
gate additions. It might be anticipated that the energy difference
between trans-TS model and cis-TS model was somewhat
smaller than those of the carbamate derivatives.
1
2
3
4
1a
1a
1a
1a
Me
Me
Me
Me
DBU (0.1 equiv), ꢀ10 ꢁC
tert-BuOK (1.0 equiv), 0 ꢁC
73:27c 93
66:34c 62
tert-BuOK (0.5 equiv), ꢀ78 ꢁC 65:35c 85
NaH (1.4 equiv), ꢀ20 ꢁC
68:32c 81
78:22d 86
TBSO
TBSO
TBSO
TBSO
TBSO
5
1b
1b
1b
1b
1c
1c
DBU (0.3 equiv), 0 ꢁC
6
tert-BuOK (1.0 equiv), 0 ꢁC
49:51d 65
7
tert-BuOK (0.1 equiv), ꢀ20 ꢁC 47:53d 79
tert-BuOK (0.1 equiv), ꢀ78 ꢁC 28:72d 81
8
9e
DBU (0.1 equiv), 0 ꢁC
96:4d 97
TBSO
CCl3
10e
tert-BuOK (0.1 equiv), ꢀ62 ꢁC 40:60f 90
11
12
1d
1d
DBU (1.6 equiv), ꢀ20 ꢁC
86:14c 66
HN
O
CCl3
O
tert-BuOK (0.6 equiv), ꢀ100 ꢁC 50:50c 82
HN
HN
It is interesting to note that bis-trichloroacetimidate 1d
showed a marked tendency to cyclize five-membered oxazo-
line ring in the competitive cyclization between allylic and
homoallylic trichloroacetimidates (entries 11e13). In this
case, moderate trans-selectivity was observed by the treatment
of DBU or NaH, while reversal of the selectivity was not fully
realized with tert-BuOK even at ꢀ100 ꢁC.
CCl3
O
13
1d
NaH (2.2 equiv), ꢀ20 ꢁC
67:33c 82
a
All reactions were performed in CH3CN (DBU) or THF (tert-BuOK,
NaH).
b
Combined yield.
Inseparable products ratio determined by 270 MHz 1H NMR spectroscopy.
Products ratio calculated from their own isolated yield.
Experimental results obtained when ent-1c was used.
c
d
e
f
2.2. Intramolecular conjugate additions
of d-trichloroacetimidoyloxy-a,b-unsaturated esters
Separation of the isomers was not fully carried out and its ratio was
determined by 270 MHz 1H NMR spectroscopy.
Next, we investigated the intramolecular conjugate addi-
tions of d-trichloroacetimidoyloxy-a,b-unsaturated esters 4
(Table 2), which were prepared from the corresponding
homoallylic alcohols.15 They were smoothly cyclized to
six-membered cyclic compounds; namely, dihydrooxazines 5
(cis) and 6 (trans) by the treatment with tert-BuOK or NaH.
a catalytic amount of DBU in CH3CN, a facile cyclization
occurred producing the oxazolines 2 (trans) and 3 (cis) (Table
1). The cisetrans stereochemistry of the oxazolines was
determined according to the value of their proton coupling

Y. Matsushima, J. Kino / Tetrahedron 64 (2008) 3943e3952
3945
Table 2
Intramolecular conjugate addition of d-trichloroacetimidoyloxy-a,b-unsaturated esters 4a
CCl3 CCl
CCl3
N
3
O
O
NH
base
N
O
H6
H6
H4
H4
+
CO2Et
CO2Et
CO2Et
(25 mM)
R1 R2
R1 R2
R2
R1
4
trans-dihydrooxazine 6
cis-dihydrooxazine 5
Entry
Substrate
Conditions
Product
R1
R2
Ratio 5/6
Yieldb (%)
1
4a
4a
H
H
H
H
H
H
H
tert-BuOK (0.4 equiv), 0 ꢁC
NaH (1.1 equiv), 0 ꢁC
88:12c
87:13c
d
86
86
2
H
3
4a
H
DBU (0.4 equiv), rt
dd
79
4
4be
4be
4be
4c
OMe
OMe
OMe
H
tert-BuOK (0.34 equiv), ꢀ20 ꢁC
NaH (1.2 equiv), ꢀ20 ꢁC
DBU (0.4 equiv), rt
Exclusively cis
Exclusively cis
d
28:72f
24:76f
41:59f
28:72f
d
5
88
6
dd
79
7
OPMP
OPMP
OTBS
OTBS
OTBS
tert-BuOK (0.4 equiv), ꢀ20 ꢁC
8
4c
H
NaH (1.1 equiv), 0 ꢁC
89
76
9
4d
4d
4d
H
tert-BuOK (0.4 equiv), 0 ꢁC
NaH (1.1 equiv), 0 ꢁC
DBU (2.3 equiv), rt
10
11
a
H
79
dg
H
All reactions were performed in CH3CN (DBU) or THF (tert-BuOK, NaH).
Combined yield.
Inseparable products ratio determined by 270 MHz 1H NMR spectroscopy.
Removal of O-trichloroacetimino group was mainly observed.
Racemic material was used.
b
c
d
e
f
Products ratio calculated from their own isolated yield.
Removal of O-trichloroacetimino group and subsequent TBS group migration was observed.
g
It should be noted that in the d-trichloroacetimidoyloxy series
tert-butyldimethylsilyloxy (TBSO) group, the reaction was
found to be carried out with moderate trans-selectivity (entries
7e10). Similar reversal of selectivity was also observed in the
case of the carbamate-mediated intramolecular conjugate
addition, and it was explained as cooperation of the steric
and stereoelectronic effects.14
the cyclization was not realized with DBU even at rt, and
gradual removal of O-trichloroacetimino group was mainly
observed instead (entry 3, 6, 11). The stereochemistry of the
obtained dihydrooxazines was determined by NOE experi-
ments, and it was also confirmed according to the value of
their proton coupling constants.16 In the case of substrate 4a,
cyclization was observed with moderate cis-selectivity (entry
1, 2). The g-substituents played an important role for switch-
ing the diastereofacial selectivity. Actually, when a methoxy
group was introduced at R2 position, the cyclization proceeded
with complete cis-selectivity (entry 4, 5), while when R1 group
was substituted by p-methoxyphenyloxy (PMPO) group or
2.3. Concise synthesis of D-vancosamine and its 3-epimer
We planned to utilize the oxazoline ring formation for the
synthesis of C-branched deoxyamino sugars, especially for
vancosamine,17 the deoxyamino sugar constituent of vanco-
mycin, and other antibiotics (Scheme 1). For the introduction
R
OH
CO2Et
Me
O
H
OH Me
NHCOPh
O
DIBAL
3 M HCl, EtOH;
N
THF
(52%)
Me
NHCOPh
BzCl, acetone
sat. NaHCO3 aq
(85%)
O
O
O
CCl3
10 (cis)
R = C(=NH)CCl3
OH
R
12
N-Bz-D-vancosamine
O
base in THF (25 mM)
CO2Et
(a) tert-BuOK (0.8 eq), –90 °C
(90%) (10: 11 = 59: 41)
(b) NaH (2.1 eq), –20 °C
(99%) (10: 11 = 54: 46)
R
Me
OH
CO2Et
Me
N
O
H
OH
O
NHCOPh
R
O
as above
(82%)
as above
(72%)
Me
NHCOPh
O
O
7:R = C(CH3)2
8:R = H
9:R = C(=NH)CCl3
3 M HCl,THF (96%)
DBU, Cl3CCN, CH3CN (97%)
CCl3
11 (trans)
R = C(=NH)CCl3
O
OH
N-Bz-3-epi-D-vancosamine
13
Scheme 1. Concise synthesis of D-vancosamine and 3-epi-D-vancosamine derivatives.

3946
Y. Matsushima, J. Kino / Tetrahedron 64 (2008) 3943e3952
of the C(3) methyl-branched amino group of the vancosamine,
we envisioned the methyl-branched bis-trichloroacetimidate 9
as a substrate for the intramolecular conjugate addition. The
bis-imidate 9 was synthesized from the chiral diol 8, which
was prepared from the known acetonide 7,18 in 97% yield.
Bis-trichloroacetimidate 9 underwent a smooth conjugate
addition constructing the oxazolines 10 (cis) and 11 (trans)
by the treatment of tert-BuOK (10/11¼59:41; 90% yield) or
NaH (10/11¼54:46; 99% yield) in THF. When DBU was
used as a base, effective cyclization was not realized, since
unknown by-products formation was observed while the start-
ing imidate 9 still remained. The cisetrans stereochemistry of
the oxazolines was confirmed by nuclear Overhauser enhance-
ment (NOE) experiments,19 and it was ultimately determined
by conversion to the vancosamine derivatives. Introduction
of the methyl group on the double bond was expected to
reduce the energy difference between trans-TS model and
cis-TS model in Figure 1, but the effect was not so strong as
expected. Then high cis-selectivity was not fully realized,
however, the obtained oxazolines in high yield were fortu-
nately separable, different from the case of 2d and 3d. Next,
the hydrolysis of oxazoline ring and spontaneous g-lactone
formation and N-benzoylation were, respectively, carried out
to give the g-lactone 12 and 13 in good yields (85% for 12;
82% for 13). Final half reduction was successfully effected
by diisopropylaluminum hydride (DIBAL) to produce N-Bz-
D-vancosamine (52%) and N-Bz-3-epi-D-vancosamine (72%),
respectively. The ratios of a- and b-anomers after ca. 1 month
in DMSO-d6 (a/b¼ca. 1:3 for N-Bz-D-vancosamine; ca. 1:1
for N-Bz-3-epi-D-vancosamine) together with the detection
of a small amount of the furanose forms were well accorded
with that reported in the literature.20 Additionally, their
absolute values of specific optical rotation were also in good
agreement with the enantiomers.20
transform infrared spectrometer. Optical rotations were
measured on a Rudolph Research Analytical AUTOPOL V
polarimeter and [a]D values are given in units of
10ꢀ1 deg cm2 gꢀ1. Mass spectra were measured on a Applied
Biosystems QSTAR XL hybrid Q-TOF or a JEOL JMS-
SX102A (FAB and EI) mass spectrometer. Flash silica gel
column chromatography was carried out on KANTO CHEM-
ICAL CO., INC. Silica Gel 60 N (spherical, neutral, 40e
50 mm) or Merck Kieselgel 60 (230e400 mesh), Art. Nr. 9385.
4.2. General procedure for the trichloroacetimidates
To a cooled (bath temp below ꢀ20 ꢁC) solution of corre-
sponding alcohol and trichloroacetonitrile (10 equiv) in aceto-
nitrile was added dropwise DBU (ca. 1.1e1.2 equiv), and the
mixture was stirred for ca. 30 min under a dry atmosphere
(calcium chloride tube). The reaction mixture was poured
into cold saturated aq NH4Cl and extracted with EtOAc. The
extract was washed successively with saturated aq NH4Cl
and brine, dried (MgSO4), and concentrated in vacuo. The
residue was purified by flash column chromatography to give
the trichloroacetimidate.
4.3. Data of the trichloroacetimidates
4.3.1. Ethyl (2E,4S)-4-trichloroacetimidoyloxypent-2-
enoate (1a)
Yield: 77%; colorless oil; [a]2D7.1 ꢀ0.637 (c 1.57, CHCl3);
nmax (neat) 3344, 2983, 1722, 1664, 1308, 1282, 1182, 1076,
1043, 976, 796, 648 cmꢀ1 1H NMR (270 MHz, CDCl3)
;
d 8.39 (br s, 1H), 6.96 (dd, J¼4.5, 15.8 Hz, 1H), 6.09 (dd,
J¼1.7, 15.6 Hz, 1H), 5.65 (ddq, J¼1.7, 4.7, 6.6 Hz, 1H), 4.21
(q, J¼7.1 Hz, 2H), 1.49 (d, J¼6.6 Hz, 3H), 1.30 (t, J¼7.2 Hz,
3H); 13C NMR (67.8 MHz, CDCl3) d 166.1, 161.5, 145.5,
121.1, 91.3, 73.6, 60.6, 19.0, 14.2. Anal. Calcd for
C9H12Cl3NO3: C, 37.46; H, 4.19; N, 4.85. Found: C, 37.02; H,
3.89; N, 4.66%.
3. Conclusion
In conclusion, we have succeeded in developing a trichloro-
acetimidate-mediated method for the introduction of a nitrogen
functionality on the b-carbon of g- and d-hydroxy-a,b-unsat-
urated esters, a novel way for constructing 1,2-amino or 1,3-
amino alcohol moieties in an acyclic system. Very concise
synthesis of D-vancosamine derivatives and its 3-epimer was
also achieved utilizing this methodology. Further investiga-
tions concerning the scope of this methodology are in
progress.
4.3.2. Ethyl (2E,4R,5R)-5-tert-butyldimethylsilyloxy-4-
trichloroacetimidoyloxyhex-2-enoate (1b)
Yield: 99%; colorless oil; [a]2D4.5 þ40.0 (c 1.17, CHCl3); nmax
(neat) 3348, 2956, 2931, 2858, 1724, 1670, 1660, 1311, 1259,
1
1180, 1099, 1078, 1049, 835, 798, 777, 648 cmꢀ1; H NMR
(270 MHz, CDCl3) d 8.43 (br s, 1H), 7.05 (dd, J¼4.0, 15.9 Hz,
1H), 6.14 (dd, J¼1.8, 15.9 Hz, 1H), 5.52 (ddd, J¼1.9, 4.6,
4.6 Hz, 1H), 4.23e4.10 (m, 1H), 4.21 (q, J¼7.0 Hz, 2H), 1.30
(t, J¼7.0 Hz, 3H), 1.15 (d, J¼6.2 Hz, 3H), 0.90 (s, 9H), 0.11
(s, 3H), 0.10 (s, 3H); 13C NMR (67.8 MHz, CDCl3) d 165.9,
161.9, 141.8, 122.6, 91.2, 79.5, 67.5, 60.5, 25.7, 18.5, 17.9,
14.2, ꢀ4.9. Anal. Calcd for C16H28Cl3NO4Si: C, 44.40; H,
6.52; N, 3.24. Found: C, 44.47; H, 6.23; N, 3.15%.
4. Experimental section
4.1. General
All melting points are uncorrected. NMR spectra were
1
recorded on a JEOL GSX-270 spectrometer. H NMR and
4.3.3. Ethyl (2E,4S,5R)-5-tert-butyldimethylsilyloxy-4-
trichloroacetimidoyloxyhex-2-enoate (ent-1c)
13C NMR chemical shifts were reported in d values based on
internal tetramethylsilane (dH¼0) or solvent signal (CDCl3
dC¼77.0; DMSO-d6 dC¼39.5; C6D6 dH¼7.15) as reference.
IR spectra were recorded on a HORIBA FT-720 Fourier-
Yield: 94%; colorless oil; [a]2D3.7 ꢀ7.60 (c 2.31, CHCl3); nmax
(neat) 3348, 2956, 2931, 2858, 1724, 1670, 1377, 1311, 1259,
1180, 1117, 1080, 1047, 984, 831, 796, 777, 648 cmꢀ1; H
1

Y. Matsushima, J. Kino / Tetrahedron 64 (2008) 3943e3952
3947
NMR (270 MHz, CDCl3) d 8.40 (br s, 1H), 7.01 (dd, J¼5.1,
16.0 Hz, 1H), 6.07 (dd, J¼1.5, 15.8 Hz, 1H), 5.39 (ddd, J¼1.5,
5.1, 5.1 Hz, 1H), 4.20 (q, J¼7.1 Hz, 2H), 4.06 (dq, J¼5.3,
6.3 Hz, 1H), 1.29 (t, J¼7.2 Hz, 3H), 1.25 (d, J¼6.4 Hz, 3H),
0.88 (s, 9H), 0.07 (s, 6H); 13C NMR (67.8 MHz, CDCl3)
d 165.8, 161.7, 142.3, 122.9, 91.3, 81.0, 69.8, 60.5, 25.7, 20.1,
17.9, 14.2, ꢀ4.5, ꢀ5.0. Anal. Calcd for C16H28Cl3NO4Si: C,
44.40; H, 6.52; N, 3.24. Found: C, 44.70; H, 6.31; N, 3.12%.
(dq, J¼7.1, 11.2 Hz, 1H), 4.19 (dq, J¼7.1, 11.4 Hz, 1H), 3.76
(s, 3H), 1.40 (d, J¼6.4 Hz, 3H), 1.28 (t, J¼7.2 Hz, 3H); 13C
NMR (67.8 MHz, CDCl3) d 165.8, 161.9, 154.5, 151.7, 142.4,
124.3, 117.1, 114.6, 91.3, 77.9, 75.2, 60.6, 55.6, 14.3, 14.2.
Anal. Calcd for C17H20Cl3NO5: C, 48.08; H, 4.75; N, 3.30.
Found: C, 47.99; H, 4.63; N, 3.18%.
4.3.8. Ethyl (2E,4R,5R)-4-tert-butyldimethylsilyloxy-5-
(trichloroacetimidoyloxy)hex-2-enoate (4d)
4.3.4. Ethyl (2E,4R,5R)-4,5-bis(trichloroacetimidoyloxy)-
hex-2-enoate (1d)
Yield: 96%; colorless oil; [a]2D5.9 þ55.7 (c 0.620, CHCl3);
nmax (neat) 3348, 2956, 2931, 1724, 1664, 1298, 1288, 1261,
1084, 1063, 835, 798, 650 cmꢀ1; 1H NMR (270 MHz, CDCl3)
d 8.38 (br s, 1H), 7.02 (dd, J¼4.1, 15.6 Hz, 1H), 6.11 (dd,
J¼1.9, 15.6 Hz, 1H), 5.07 (dq, J¼5.0, 6.4 Hz, 1H), 4.65 (ddd,
J¼1.8, 4.1, 4.8 Hz, 1H), 4.21 (dd, J¼7.1, 10.9 Hz, 1H), 4.20
(dq, J¼7.1, 10.9 Hz, 1H), 1.30 (t, J¼7.2 Hz, 3H), 1.25 (d,
J¼6.4 Hz, 3H), 0.93 (s, 9H), 0.13 (s, 3H), 0.08 (s, 3H); 13C
NMR (67.8 MHz, CDCl3) d 166.3, 161.9, 146.1, 122.6, 91.5,
76.9, 70.8, 60.4, 25.7, 18.1, 14.2, 13.3, ꢀ4.9, ꢀ5.0. Anal. Calcd
for C16H28Cl3NO4Si: C, 44.40; H, 6.52; N, 3.24. Found: C,
44.56; H, 6.48; N, 3.11%.
Yield: 96%; colorless oil; [a]2D8.1 þ26.1 (c 0.980, CHCl3);
nmax (neat) 3344, 2985, 1724, 1664, 1300, 1282, 1184, 1074,
831, 796, 648, 490 cmꢀ1; 1H NMR (270 MHz, CDCl3) d 8.52
(br s, 1H), 8.44 (br s, 1H), 6.98 (dd, J¼4.7, 15.8 Hz, 1H), 6.21
(dd, J¼1.7, 15.8 Hz, 1H), 5.86 (ddd, J¼1.7, 4.9, 4.9 Hz, 1H),
5.41 (dq, J¼5.3, 6.4 Hz, 1H), 4.21 (dq, J¼7.2, 11.0 Hz, 1H),
4.20 (dq, J¼7.1, 10.9 Hz, 1H), 1.42 (d, J¼6.4 Hz, 3H), 1.29 (t,
J¼7.2 Hz, 3H); 13C NMR (67.8 MHz, CDCl3) d 165.5, 161.6,
161.3, 140.0, 124.2, 91.2, 90.9, 76.7, 74.1, 60.7, 14.5, 14.2.
Anal. Calcd for C12H14Cl6N2O4: C, 31.13; H, 3.05; N, 6.05.
Found: C, 31.12; H, 3.08; N, 5.89%.
4.4. Typical procedure of the conjugate additions using DBU:
ethyl 2-((4R,5S)-2-(trichloromethyl)-4,5-dihydro-5-((1R)-tert-
butyldimethylsilyloxyethyl)oxazol-4-yl)acetate (ent-2c) and
ethyl 2-((4S,5S)-2-(trichloromethyl)-4,5-dihydro-5-((1R)-tert-
butyldimethylsilyloxyethyl)oxazol-4-yl)acetate (ent-3c)
4.3.5. Ethyl (2E,5R)-5-(trichloroacetimidoyloxy)hex-2-
enoate (4a)
Yield: 85%; colorless oil; [a]2D9.4 þ6.12 (c 1.05, CHCl3); nmax
(neat) 3344, 2981, 1720, 1662, 1321, 1306, 1292, 1273, 1180,
1
1080, 1057, 1045, 980, 796, 648 cmꢀ1; H NMR (270 MHz,
CDCl3) d 8.31 (br s, 1H), 6.95 (ddd, J¼7.4, 7.4, 15.6 Hz, 1H),
5.91 (ddd, J¼1.4, 1.4, 15.7 Hz, 1H), 5.16 (ddq, J¼6.2, 6.2,
6.2 Hz, 1H), 4.18 (q, J¼7.1 Hz, 2H), 2.63 (dddd, J¼1.4, 6.5,
7.4, 14.7 Hz, 1H), 2.59 (dddd, J¼1.6, 5.6, 7.4, 14.7 Hz, 1H),
1.82 (d, J¼6.2 Hz, 3H), 1.28 (t, J¼7.2 Hz, 3H); 13C NMR
(67.8 MHz, CDCl3) d 166.1, 161.9, 143.2, 124.4, 91.6, 74.2,
60.3, 37.9, 18.8, 14.2. Anal. Calcd for C10H14Cl3NO3: C,
39.69; H, 4.66; N, 4.63. Found: C, 39.64; H, 4.38; N, 4.54%.
To an ice-cooled solution of the trichloroacetimidate ent-1c
(58.2 mg, 0.134 mmol) in acetonitrile (5.5 mL) was added drop-
wise DBU (2.0 mL, 0.013 mmol), and the mixturewas stirred for
ca. 16 h under Ar atmosphere. The reaction mixture was poured
into cold saturated aq NH4Cl and extracted with EtOAc. The
extract was washed with brine, dried (MgSO4), and concen-
trated in vacuo. The residue was purified by flash column chro-
matography (hexane/EtOAc¼5:1) to give trans-oxazoline
ent-2c (colorless oil, less polar, 53.4 mg, 92%) and cis-oxazo-
line ent-3c (colorless oil, more polar, 2.0 mg, 3.4%).
4.3.6. Ethyl (2E,4S*,5R*)-5-(trichloroacetimidoyloxy)-4-
methoxyhex-2-enoate (4b)
Yield: 96%; colorless oil; nmax (neat) 3344, 2985, 1722, 1664,
1300, 1176, 1078, 796, 648 cmꢀ1; 1H NMR (270 MHz, CDCl3)
d 8.34 (br s, 1H), 6.85 (dd, J¼5.9, 15.7 Hz, 1H), 6.11 (dd, J¼1.5,
15.8 Hz, 1H), 5.10 (dq, J¼4.3, 6.4 Hz, 1H), 4.21 (q, J¼7.1 Hz,
2H), 4.03 (ddd, J¼1.5, 4.3, 5.9 Hz, 1H), 3.42 (s, 3H), 1.35 (d,
J¼6.6 Hz, 3H), 1.29 (t, J¼7.2 Hz, 3H); 13C NMR (67.8 MHz,
CDCl3) d 165.8, 161.8, 143.8, 124.1, 91.5, 81.8, 76.6, 60.5,
58.3, 14.2, 14.1. Anal. Calcd for C11H16Cl3NO4: C, 39.72; H,
4.85; N, 4.21. Found: C, 39.41; H, 4.79; N, 3.99%.
4.4.1. trans-Oxazoline ent-2c
[a]D27.4 þ40.8 (c 0.495, CHCl3); nmax (neat) 2956, 2931, 2858,
1736, 1664, 1375, 1257, 1182, 1159, 1115, 1078, 1032, 991,
837, 795, 777 cmꢀ1; 1H NMR (270 MHz, CDCl3) d 4.57 (ddd,
J¼5.6, 5.8, 6.6 Hz, 1H), 4.51 (dd, J¼4.5, 6.6 Hz, 1H), 4.165
(dq, J¼7.2, 10.8 Hz, 1H), 4.164 (dq, J¼7.1, 10.8 Hz, 1H),
4.02 (dq, J¼4.4, 6.3 Hz, 1H), 2.72 (dd, J¼5.8, 15.6 Hz, 1H),
2.66 (dd, J¼5.6, 15.8 Hz, 1H), 1.27 (t, J¼7.2 Hz, 3H), 1.20 (d,
J¼6.4 Hz, 3H), 0.88 (s, 9H), 0.10 (s, 3H), 0.09 (s, 3H); 13C
NMR (67.8 MHz, CDCl3) d 170.1, 162.4, 91.0, 86.5, 68.6,
64.6, 60.8, 39.3, 25.8, 19.3, 17.9, 14.2, ꢀ4.1, ꢀ4.8. Anal. Calcd
for C16H28Cl3NO4Si: C, 44.40; H, 6.52; N, 3.24. Found: C,
44.67; H, 6.37; N, 3.08%.
4.3.7. Ethyl (2E,4R,5R)-5-(trichloroacetimidoyloxy)-4-(4-
methoxyphenoxy)hex-2-enoate (4c)
Yield: 94%; colorless oil; [a]2D5.1 þ17.1 (c 0.575, CHCl3);
nmax (neat) 3340, 2985, 1720, 1664, 1508, 1304, 1227, 1180,
1
1059, 796, 648 cmꢀ1; H NMR (270 MHz, CDCl3) d 8.43 (br
4.4.2. cis-Oxazoline ent-3c
[a]D27.5 ꢀ40.1 (c 0.635, CHCl3); nmax (neat) 2956, 2931,
s, 1H), 7.03 (dd, J¼4.6, 15.7 Hz, 1H), 6.95e6.87 (m, 2H),
6.85e6.77 (m, 2H), 6.19 (dd, J¼1.6, 15.7 Hz, 1H), 5.36 (dq,
J¼5.3, 6.4 Hz, 1H), 4.99 (ddd, J¼1.6, 5.0, 5.0 Hz, 1H), 4.20
2858, 1736, 1662, 1379, 1257, 1180, 1107, 1036, 993, 835,
793, 777, 669 cmꢀ1 1H NMR (270 MHz, CDCl3) d 4.83
;

3948
Y. Matsushima, J. Kino / Tetrahedron 64 (2008) 3943e3952
(ddd, J¼5.8, 8.1, 9.6 Hz, 1H), 4.68 (dd, J¼5.3, 9.6 Hz, 1H),
4.194 (dq, J¼7.2, 10.9 Hz, 1H), 4.190 (dq, J¼5.6, 6.4 Hz,
1H), 4.18 (dq, J¼7.1, 10.8 Hz, 1H), 3.00 (dd, J¼5.9,
16.3 Hz, 1H), 2.65 (dd, J¼8.0, 16.3 Hz, 1H), 1.30 (d,
J¼6.4 Hz, 3H), 1.21 (t, J¼7.1 Hz, 3H), 0.89 (s, 9H), 0.108
(s, 3H), 0.105 (s, 3H); 13C NMR (67.8 MHz, CDCl3)
d 171.1, 162.3, 91.0, 88.7, 67.1, 64.5, 60.8, 35.1, 25.8, 20.5,
17.9, 14.2, ꢀ3.8, ꢀ4.7. Anal. Calcd for C16H28Cl3NO4Si:
C, 44.40; H, 6.52; N, 3.24. Found: C, 44.63; H, 6.55; N,
3.09%.
4.6. Data of the oxazolines
4.6.1. Ethyl 2-((4S,5S)-2-(trichloromethyl)-4,5-dihydro-
5-methyloxazol-4-yl)acetate (2a) and ethyl 2-((4R,5S)-
2-(trichloromethyl)-4,5-dihydro-5-methyloxazol-4-yl)-
acetate (3a)
Colorless oil; [a]2D8.6 ꢀ35.6 (c 1.00, CHCl3, sample cyclized
with DBU); nmax (neat) 2983, 1734, 1658, 1375, 1238, 1184,
1024, 893, 829, 795, 665 cmꢀ1; H NMR (270 MHz, C6D6)
1
d major (trans) 4.26 (dq, J¼6.3, 6.3 Hz, 1H), 3.94 (ddd,
J¼5.0, 6.3, 9.1 Hz, 1H), 3.81 (q, J¼7.3 Hz, 2H), 2.46 (dd,
J¼4.9, 16.7 Hz, 1H), 2.03 (dd, J¼9.1, 16.6 Hz, 1H), 1.04 (d, J¼
6.2 Hz, 3H), 0.863 (t, J¼7.1 Hz, 3H); minor (cis) 4.55 (dq,
J¼6.4, 9.2 Hz, 1H), 4.43 (ddd, J¼6.3, 8.7, 9.2 Hz, 1H), 3.88e
3.73 (overlapping m, 2H), 2.50 (dd, J¼6.3, 16.8 Hz, 1H), 2.14
(dd, J¼8.5, 16.7 Hz, 1H), 0.865 (t, J¼7.2 Hz, 3H), 0.77 (d,
J¼6.6 Hz, 3H); 13C NMR (67.8 MHz, CDCl3) d major (trans)
170.4, 162.2, 86.6, 85.6, 69.5, 60.9, 38.7, 20.4, 14.14; minor
(cis) 170.9, 162.3, 86.7, 82.9, 65.0, 61.0, 34.5, 14.5, 14.11.
Anal. Calcd for C9H12Cl3NO3: C, 37.46; H, 4.19; N, 4.85.
Found: C, 37.38; H, 4.23; N, 4.58%.
4.5. Typical procedure of the conjugate additions using tert-
BuOK: ethyl 2-((4S,5R)-2-(trichloromethyl)-4,5-dihydro-5-
((1R)-tert-butyldimethylsilyloxyethyl)oxazol-4-yl)acetate (2b)
and ethyl 2-((4R,5R)-2-(trichloromethyl)-4,5-dihydro-5-
((1R)-tert-butyldimethylsilyloxyethyl)oxazol-4-yl)acetate (3b)
To a solution of the trichloroacetimidate 1b (56.0 mg,
0.129 mmol) in THF (5.5 mL) was added tert-BuOK (1.7 mg,
0.015 mmol) in one portion under Ar atmosphere at ꢀ78 ꢁC,
and the mixture was stirred for ca. 2 h. The reaction mixture
was poured into cold saturated aq NH4Cl and extracted with
EtOAc. The extract was washed with brine, dried (MgSO4),
and concentrated in vacuo. The residue was purified by flash
column chromatography (hexane/EtOAc¼11:1) to give trans-
oxazoline 2b (colorless solid, less polar, 12.9 mg, 23%) and
cis-oxazoline 3b (colorless oil, more polar, 32.7 mg, 58%).
Analytical sample (colorless powder) of 2b was obtained by
recrystallization from MeOH (ꢀ15 ꢁC).
4.6.2. Ethyl 2-((4S,5R)-5-(R)-1-(trichloroacetimidoyl-
oxy)ethyl)-2-(trichloromethyl)-4,5-dihydro-oxazol-4-
yl)acetate (2d) and ethyl 2-((4R,5R)-5-(R)-1-(trichloro-
acetimidoyloxy)ethyl)-2-(trichloromethyl)-4,5-dihydro-
oxazol-4-yl)acetate (3d)
Colorless oil; [a]2D8.2 ꢀ53 (c 0.42, CHCl3, sample cyclized
with tert-BuOK at ꢀ100 ꢁC); nmax (neat) 3344, 2983, 1732,
1668, 1375, 1348, 1300, 1284, 1236, 1186, 1080, 1032, 987,
930, 839, 795, 650 cmꢀ1; 1H NMR (270 MHz, CDCl3) d major
(trans) 8.43 (s, 1H), 5.35 (dq, J¼2.2, 6.5 Hz, 1H), 4.78 (dd,
J¼2.2, 5.7 Hz, 1H), 4.50 (ddd, J¼4.1, 5.8, 9.8 Hz, 1H), 4.18
(q, J¼7.2 Hz, 2H), 2.92 (dd, J¼4.0, 17.0 Hz, 1H), 2.62 (dd,
J¼9.8, 16.9 Hz, 1H), 1.50 (d, J¼6.4 Hz, 3H), 1.28 (t,
J¼7.2 Hz, 3H); minor (cis) 8.49 (s, 1H), 5.18 (br q, J¼6.6 Hz,
1H), 5.12 (dd, J¼1.0, 9.9 Hz, 1H), 4.82 (ddd, J¼4.9, 9.9,
10.7 Hz, 1H), 4.11e4.28 (overlapping, 2H), 3.11 (dd, J¼5.0,
17.8 Hz, 1H), 2.71 (dd, J¼10.7, 18.0 Hz, 1H), 1.46 (d,
J¼6.4 Hz, 3H), 1.28 (t, J¼7.2 Hz, 3H); 13C NMR (67.8 MHz,
CDCl3) d major (trans) 170.4, 162.3, 160.8, 91.1, 89.2, 86.3,
75.2, 65.3, 61.0, 38.5, 14.7, 14.1; minor (cis) 171.5, 162.0,
161.8, 90.9, 86.7, 86.4, 73.1, 64.9, 61.1, 34.2, 15.2, 14.1;
HRMS (ESI-TOF) calcd for C12H15Cl6N2O4 [MþH]þ:
460.9157, found: 460.9157.
4.5.1. trans-Oxazoline 2b
Mp 52.0e52.5 ꢁC; [a]D27.6 ꢀ78 (c 0.18, CHCl3); nmax (KBr)
2958, 2931, 2858, 1728, 1664, 1375, 1244, 1186, 1149, 1063,
1038, 941, 920, 839, 798, 777, 663 cmꢀ1; 1H NMR (270 MHz,
CDCl3) d 4.51 (dd, J¼2.6, 6.0 Hz, 1H), 4.48 (ddd, J¼4.3, 6.0,
8.1 Hz, 1H), 4.17 (q, J¼7.1 Hz, 2H), 4.05 (dq, J¼2.4, 6.4 Hz,
1H), 2.84 (dd, J¼4.3, 16.7 Hz, 1H), 2.60 (dd, J¼8.4, 16.6 Hz,
1H), 1.28 (t, J¼7.2 Hz, 3H), 1.26 (d, J¼6.4 Hz, 3H), 0.87 (s,
9H), 0.10 (s, 3H), 0.08 (s, 3H); 13C NMR (67.8 MHz, CDCl3)
d 170.5, 162.5, 91.3, 86.6, 68.8, 64.8, 60.8, 39.0, 25.6, 19.0,
17.9, 14.2, ꢀ4.2, ꢀ5.0. Anal. Calcd for C16H28Cl3NO4Si: C,
44.40; H, 6.52; N, 3.24. Found: C, 44.47; H, 6.31; N, 3.18%.
4.5.2. cis-Oxazoline 3b
[a]D27.3 ꢀ41.7 (c 0.620, CHCl3); nmax (neat) 2958, 2931,
2858, 1732, 1664, 1329, 1255, 1184, 1093, 1030, 1001, 926,
837, 793, 777, 671 cmꢀ1 1H NMR (270 MHz, CDCl3)
;
4.7. Data of the dihydrooxazines
d 4.80 (dd, J¼2.1, 9.6 Hz, 1H), 4.72 (ddd, J¼5.3, 9.2,
9.6 Hz, 1H), 4.20 (dq, J¼7.2, 10.7 Hz, 1H), 4.17 (dq, J¼7.2,
10.7 Hz, 1H), 4.01 (dq, J¼2.1, 6.4 Hz, 1H), 3.13 (dd, J¼9.2,
17.3 Hz, 1H), 3.03 (dd, J¼5.3, 17.3 Hz, 1H), 1.31 (d,
J¼6.4 Hz, 3H), 1.28 (t, J¼7.2 Hz, 3H), 0.89 (s, 9H), 0.09 (s,
3H), 0.08 (s, 3H); 13C NMR (67.8 MHz, CDCl3) d 171.7,
162.4, 88.9, 86.8, 67.6, 64.8, 60.9, 34.3, 26.0, 20.6, 18.0,
14.2, ꢀ3.1, ꢀ4.9. Anal. Calcd for C16H28Cl3NO4Si: C,
44.40; H, 6.52; N, 3.24. Found: C, 44.77; H, 6.33; N, 2.99%.
4.7.1. Ethyl 2-((4R,6R)-2-(trichloromethyl)-5,6-dihydro-6-
methyl-4H-1,3-oxazin-4-yl)acetate (5a) and ethyl 2-
((4S,6R)-2-(trichloromethyl)-5,6-dihydro-6-methyl-
4H-1,3-oxazin-4-yl)acetate (6a)
Colorless oil; [a]2D9.3 þ26.0 (c 1.11, CHCl3, sample cyclized
with tert-BuOK); nmax (neat) 2981, 1734, 1676, 1446, 1375,
1340, 1240, 1203, 1180, 1122, 1026, 958, 791, 667 cmꢀ1; H
1
NMR (270 MHz, C6D6) d major (cis) 3.96 (q, J¼7.1 Hz, 2H),
3.72 (dddd, J¼4.6, 6.5, 7.9, 11.1 Hz, 1H), 3.57 (ddq, J¼2.6,

Y. Matsushima, J. Kino / Tetrahedron 64 (2008) 3943e3952
3949
6.3, 11.4 Hz, 1H), 2.56 (dd, J¼6.3, 15.7 Hz, 1H), 2.13 (dd,
4.7.5. Ethyl 2-((4S,5R,6R)-5-tert-butyldimethylsilyloxy-2-
(trichloromethyl)-5,6-dihydro-6-methyl-4H-1,3-oxazin-4-
yl)acetate (5d)
J¼7.8, 15.7 Hz, 1H), 1.36 (ddd, J¼2.6, 4.5, 13.5 Hz, 1H),
0.96 (t, J¼7.2 Hz, 3H), 0.84 (d, J¼6.2 Hz, 3H), 0.73 (ddd,
J¼11.3, 11.3, 13.6 Hz, 1H); minor (trans) 4.02e3.80 (overlap-
ping m, 4H), 2.52 (dd, J¼6.2, 15.4 Hz, 1H), 2.06 (dd, J¼8.3,
15.4 Hz, 1H), 1.17 (ddd, J¼4.6, 6.5, 14.0 Hz, 1H), 1.15 (ddd,
J¼5.7, 5.7, 14.0 Hz, 1H), 0.94 (t, J¼7.2 Hz, 3H), 0.80 (d,
J¼6.4 Hz, 3H); 13C NMR (67.8 MHz, CDCl3) d major (cis)
171.3, 154.1, 92.3, 74.3, 60.56, 51.1, 41.4, 34.4, 20.8, 14.2; mi-
nor (trans) 171.0, 153.8, 92.5, 71.2, 60.65, 47.6, 40.8, 31.4, 20.2,
14.2. Anal. Calcd for C10H14Cl3NO3: C, 39.69; H, 4.66; N, 4.63.
Found: C, 40.02; H, 4.59; N, 4.48%.
Colorless oil; [a]2D6.6 ꢀ0.198 (c 0.505, CHCl3); nmax
(neat) 2931, 1732, 1684, 1375, 1255, 1228, 1180, 1165,
1
1057, 839, 795 cmꢀ1; H NMR (270 MHz, CDCl3) d 4.44
(ddq, J¼1.2, 1.2, 6.6 Hz, 1H), 4.17 (q, J¼7.1 Hz, 2H),
4.04 (dd, J¼1.1, 2.4 Hz, 1H), 4.01 (dddd, J¼1.3, 2.5, 5.8,
8.6 Hz, 1H), 2.74 (dd, J¼5.8, 17.5 Hz, 1H), 2.70 (dd,
J¼8.7, 17.2 Hz, 1H), 1.39 (d, J¼6.4 Hz, 3H), 1.28 (t,
J¼7.2 Hz, 3H), 0.90 (s, 9H), 0.10 (s, 3H), 0.03 (s, 3H);
13C NMR (67.8 MHz, CDCl3) d 172.0, 153.2, 92.0, 77.04,
65.6, 60.5, 56.1, 36.8, 25.8, 18.3, 17.4, 14.2, ꢀ3.9, ꢀ4.2;
HRMS (FAB) calcd for C16H29Cl3NO4Si [MþH]þ:
432.09314, found: 432.0931.
4.7.2. Ethyl 2-((4S*,5S*,6R*)-2-(trichloromethyl)-5,6-
dihydro-5-methoxy-6-methyl-4H-1,3-oxazin-4-yl)-
acetate (5b)
Colorless oil;nmax (neat) 2983, 1736, 1684, 1215, 1124, 1099,
1
4.7.6. Ethyl 2-((4R,5R,6R)-5-tert-butyldimethylsilyloxy-2-
(trichloromethyl)-5,6-dihydro-6-methyl-4H-1,3-oxazin-4-
yl)acetate (6d)
818, 793, 665 cmꢀ1; H NMR (270 MHz, CDCl3) d 4.18 (q,
J¼7.1 Hz, 2H), 4.14 (dq, J¼6.3, 9.2 Hz, 1H), 3.82 (ddd,
J¼5.8, 6.5, 8.9 Hz, 1H), 3.55 (s, 3H), 3.11 (dd, J¼9.0, 9.0 Hz,
1H), 2.79 (dd, J¼5.8, 14.7 Hz, 1H), 2.64 (dd, J¼6.5, 14.9 Hz,
1H), 1.53 (d, J¼6.2 Hz, 3H), 1.27 (t, J¼7.1 Hz, 3H); 13C NMR
(67.8 MHz, CDCl3) d 171.0, 152.7, 91.6, 79.4, 76.5, 60.6,
60.5, 56.6, 38.1, 17.8, 14.2. Anal. Calcd for C11H16Cl3NO4: C,
39.72; H, 4.85; N, 4.21. Found: C, 39.85; H, 4.85; N, 4.13%.
Colorless oil; [a]D25.5 þ54.1 (c 0.765, CHCl3); nmax (neat)
2956, 2931, 1736, 1682, 1261, 1223, 1128, 839, 795,
1
667 cmꢀ1; H NMR (270 MHz, CDCl3) d 4.38 (dq, J¼2.9,
6.5 Hz, 1H), 4.182 (dq, J¼7.2, 10.8 Hz, 1H), 4.178 (dq,
J¼7.0, 11.3 Hz, 1H), 3.95 (ddd, J¼4.6, 5.6, 8.2 Hz, 1H),
3.83 (dd, J¼2.9, 4.6 Hz, 1H), 2.68 (dd, J¼5.8, 15.6 Hz, 1H),
2.48 (dd, J¼8.2, 15.7 Hz, 1H), 1.37 (d, J¼6.4 Hz, 3H), 1.28
(t, J¼7.2 Hz, 3H), 0.89 (s, 9H), 0.14 (s, 3H), 0.10 (s, 3H);
13C NMR (67.8 MHz, CDCl3) d 170.6, 153.0, 92.1, 73.1,
66.8, 60.8, 55.4, 38.3, 25.6, 17.9, 15.2, 14.2, ꢀ4.7, ꢀ4.8.
Anal. Calcd for C16H28Cl3NO4Si: C, 44.40; H, 6.52; N,
3.24. Found: C, 44.70; H, 6.58; N, 3.09%.
4.7.3. Ethyl 2-((4S,5R,6R)-2-(trichloromethyl)-5,6-dihydro-
5-(4-methoxyphenoxy)-6-methyl-4H-1,3-oxazin-4-yl)-
acetate (5c)
Colorless oil; [a]2D7.6 þ5.0 (c 0.10, CHCl3); nmax (neat)
2933, 1728, 1682, 1506, 1225, 1180, 1039, 793 cmꢀ1 1H
;
NMR (270 MHz, CDCl3) d 6.89e6.76 (m, 4H), 4.70 (dd,
J¼1.3, 3.2 Hz, 1H), 4.60 (ddq, J¼1.3, 1.3, 6.6 Hz, 1H), 4.21
(dddd, J¼1.3, 3.0, 5.3, 9.8 Hz, 1H), 4.05 (dq, J¼7.2,
10.7 Hz, 1H), 4.02 (dq, J¼7.1, 10.7 Hz, 1H), 3.76 (s, 3H),
2.83 (dd, J¼5.3, 17.1 Hz, 1H), 2.74 (dd, J¼9.8, 17.3 Hz,
1H), 1.42 (d, J¼6.4 Hz, 3H), 1.14 (t, J¼7.2 Hz, 3H); 13C
NMR (67.8 MHz, CDCl3) d 171.8, 154.3, 153.6, 153.3,
116.5, 114.7, 91.9, 76.3, 71.0, 60.6, 55.7, 55.2, 36.5, 17.1,
14.1; HRMS (EI) calcd for C17H20Cl3NO5 [M]þ: 423.04071,
found: 423.0405.
4.8. Syntheses of N-Bz-3-D-vancosamine and N-Bz-3-epi-D-
vancosamine
4.8.1. Ethyl (2E,4R,5R)-4,5-dihydroxy-3-methylhex-2-
enoate (8)
To a solution of the known acetonide 7 (1.35 g, 5.91 mmol)
in THF (32 mL) was added dropwise 3 M HCl (32 mL), and
the mixture was stirred for 2.5 h. Then excess amount of
NaHCO3 powder was carefully added portionwise to the reac-
tion mixture. The aqueous mixture was saturated with NaCl,
and extracted with EtOAc and CH2Cl2. The extract was dried
(MgSO4) and concentrated in vacuo. The residue was purified
by flash column chromatography (hexane/EtOAc¼1:2) to give
diol 8 (1.07 g, 96%) as a colorless solid. Analytical sample
(colorless powder) was obtained by recrystallization from
EtOAc/hexane (0 ꢁC); mp 40.0e43.5 ꢁC; [a]2D9.4 ꢀ0.995 (c
1.01, CHCl3); nmax (KBr) 3446, 3396, 2981, 1709, 1647,
4.7.4. Ethyl 2-((4R,5R,6R)-2-(trichloromethyl)-5,6-dihydro-
5-(4-methoxyphenoxy)-6-methyl-4H-1,3-oxazin-4-yl)-
acetate (6c)
Colorless oil; [a]D27.2 þ36.7 (c 0.570, CHCl3); nmax (neat)
2983, 1732, 1682, 1506, 1223, 1184, 1036, 823, 793,
671 cmꢀ1 1H NMR (270 MHz, CDCl3) d 6.98e6.90 (m,
;
2H), 6. 87e6.80 (m, 2H), 4.63 (dq, J¼3.1, 6.5 Hz, 1H), 4.39
(dd, J¼3.1, 4.8 Hz, 1H), 4.22 (ddd, J¼4.8, 5.5, 8.3 Hz, 1H),
4.17 (dq, J¼7.2, 10.8 Hz, 1H), 4.16 (dq, J¼7.1, 10.8 Hz,
1H), 3.77 (s, 3H), 2.78 (dd, J¼5.6, 15.6 Hz, 1H), 2.57 (dd,
J¼8.3, 15.6 Hz, 1H), 1.48 (d, J¼6.4 Hz, 3H), 1.24 (t,
J¼7.1 Hz, 3H); 13C NMR (67.8 MHz, CDCl3) d 170.5,
154.8, 153.2, 150.7, 117.6, 114.8, 91.9, 72.7, 71.6, 60.9,
55.7, 52.1, 38.4, 15.1, 14.2; HRMS (EI) calcd for
C17H20Cl3NO5 [M]þ: 423.04071, found: 423.0407.
1
1223, 1153, 1038, 860 cmꢀ1; H NMR (270 MHz, CDCl3)
d 5.95e5.91 (m, 1H), 4.17 (q, J¼7.1 Hz, 2H), 3.91e3.79
(m, 2H), 2.81 (br d, 1H), 2.43 (br s, 1H), 2.13 (d, J¼1.5 Hz,
3H), 1.29 (t, J¼7.1 Hz, 3H), 1.20 (d, J¼6.2 Hz, 3H); 13C
NMR (67.8 MHz, CDCl3) d 166.5, 156.9 117.6, 81.0, 68.4,
60.0, 19.4, 15.1, 14.2. Anal. Calcd for C9H16O4: C, 57.43;
H, 8.57. Found: C, 57.46; H, 8.61%.

3950
Y. Matsushima, J. Kino / Tetrahedron 64 (2008) 3943e3952
4.8.2. Ethyl (2E,4R,5R)-4,5-bis(trichloroacetimidoyloxy)-3-
methylhex-2-enoate (9)
4.8.3.2. trans-Oxazoline 11. Colorless needles; mp 69.5e
70.3 ꢁC; [a]2D7.9 ꢀ66.5 (c 0.580, CHCl3); nmax (KBr) 3327,
2991, 1718, 1668, 1331, 1284, 1248, 1109, 1072, 1028, 796,
To a cooled (bath temp below ꢀ20 ꢁC) solution of the diol
8 (122.2 mg, 0.649 mmol) and trichloroacetonitrile (1.30 mL,
13.0 mmol) in acetonitrile (3.5 mL) was added dropwise
DBU (213.5 mL, 1.43 mmol), and the mixture was stirred
for ca. 30 min under a dry atmosphere (calcium chloride
tube). The reaction mixture was poured into cold saturated
aq NH4Cl and extracted with EtOAc. The extract was
washed successively with saturated aq NH4Cl and brine,
dried (MgSO4), and concentrated in vacuo. The residue
was purified by flash column chromatography (hexane/
EtOAc¼5.5:1) to give bis-trichloroacetimidate 9 (301.7 mg,
97%) as a colorless solid. Analytical sample (colorless nee-
dles) was obtained by recrystallization from hexane; mp
71.5e74.5 ꢁC; [a]D26.1 þ1.07 (c 0.655, CHCl3); nmax (KBr)
3336, 2989, 1718, 1658, 1313, 1227, 1167, 1076, 1059,
1
677, 650 cmꢀ1; H NMR (270 MHz, CDCl3) d 8.45 (br s,
1H), 5.34 (dq, J¼1.1, 6.4 Hz, 1H), 5.07 (d, J¼1.1 Hz, 1H),
4.17 (q, J¼7.1 Hz, 2H), 2.69 (d, J¼15.6 Hz, 1H), 2.59 (d,
J¼15.6 Hz, 1H), 1.502 (s, 3H), 1.497 (d, J¼6.4 Hz, 3H),
1.28 (t, J¼7.2 Hz, 3H); 13C NMR (67.8 MHz, CDCl3)
d 170.1, 161.4, 160.9, 91.1, 90.0, 86.5, 73.1, 71.0, 60.9,
45.5, 19.8, 15.8, 14.2. Anal. Calcd for C13H16Cl6N2O4: C,
32.73; H, 3.38; N, 5.87. Found: C, 32.95; H, 3.37; N, 5.87%.
4.8.4. (3R,4R,5R)-3-Benzamido-5-hydroxy-3-methyl-4-
hexanolide (12)
To
a solution of the cis-oxazoline 10 (586.1 mg,
1.23 mmol) in EtOH (21 mL) was added 3 M HCl (21 mL)
and the mixture was refluxed for ca. 19 h. The reaction mix-
ture was concentrated in vacuo and added acetone (9 mL)
and saturated aq NaHCO3 (22 mL). To the mixture was added
dropwise benzoyl chloride (428 mL, 3.68 mmol), and the mix-
ture was stirred for ca. 1 h at rt. The mixture was concentrated
in vacuo and the residue was diluted with brine and the whole
mixture was extracted with EtOAc. The extract was dried
(MgSO4) and concentrated in vacuo. The residue was purified
by flash column chromatography (hexane/EtOAc¼1:2.5) to
give lactone 12 (275.0 mg, 85%). Analytical sample (colorless
rod) was obtained by recrystallization from EtOAc/hexane;
mp 173.0e174.5 ꢁC; [a]D26.6 þ46.3 (c 0.580, EtOH); nmax
(KBr) 3452, 3346, 3309, 2987, 1780, 1759, 1666, 1635,
1009, 872, 800, 650, 571 cmꢀ1
;
1H NMR (270 MHz,
CDCl3) d 8.45 (br s, 1H), 8.37 (br s, 1H), 6.09e6.05 (m,
1H), 5.51e5.40 (m, 2H), 4.17 (dd, J¼7.2, 10.9 Hz, 1H),
4.14 (dd, J¼7.1, 10.9 Hz, 1H), 2.27 (d, J¼1.5 Hz, 3H),
1.41 (d, J¼6.2 Hz, 3H), 1.27 (t, J¼7.2 Hz, 3H); 13C NMR
(67.8 MHz, CDCl3) d 166.0, 161.8, 161.3, 150.9, 119.3,
91.3, 91.0, 82.7, 74.2, 60.0, 16.0, 15.2, 14.2. Anal. Calcd
for C13H16Cl6N2O4: C, 32.73; H, 3.38; N, 5.87. Found: C,
32.74; H, 3.41; N, 5.82%.
4.8.3. Ethyl 2-((4R,5R)-5-((R)-1-(trichloroacetimidoyl-
oxy)ethyl)-2-(trichloromethyl)-4,5-dihydro-4-methyloxazol-
4-yl)acetate (10) and ethyl 2-((4S,5R)-5-((R)-1-(trichloro-
acetimidoyloxy)ethyl)-2-(trichloromethyl)-4,5-dihydro-4-
methyloxazol-4-yl)acetate (11)
To a solution of the trichloroacetimidate 9 (517.9 mg,
1.09 mmol) in THF (44 mL) was added tert-BuOK (99.8 mg,
0.889 mmol) in one portion under N2 atmosphere at below
ꢀ90 ꢁC, and the mixture was stirred for ca. 2 h. The reaction
mixture was poured into cold saturated aq NH4Cl and
extracted with EtOAc. The extract was washed with brine,
dried (MgSO4), and concentrated in vacuo. The residue was
purified by flash column chromatography (hexane/
EtOAc¼5:1) to give cis-oxazoline 10 (less polar, 277.1 mg,
54%) and trans-oxazoline 11 (more polar, 189.9 mg, 37%).
Analytical sample of 10 and 11 were obtained by recrystalli-
zation from EtOAc/hexane.
1541, 1522, 1315, 1292, 1194, 1142, 989, 725, 694 cmꢀ1
1H NMR (270 MHz, CDCl3)
7.77e7.68 (m, 2H),
;
d
7.57e7.40 (m, 3H), 6.14 (br s, 1H), 4.84 (d, J¼1.9 Hz, 1H),
4.22 (ddq, J¼1.9, 6.4, 6.4 Hz, 1H), 2.94 (d, J¼17.5 Hz, 1H),
2.88 (d, J¼17.5 Hz, 1H), 1.78 (s, 3H), 1.54 (d, J¼6.2 Hz,
3H), 1.38 (d, J¼6.4 Hz, 3H); 13C NMR (67.8 MHz, CDCl3)
d 175.2, 167.5, 134.1, 132.0, 128.7, 126.8, 87.7, 66.3, 59.7,
42.5, 20.7, 20.3. Anal. Calcd for C14H17NO4: C, 63.87; H,
6.51; N, 5.32. Found: C, 63.74; H, 6.51; N, 5.27%.
4.8.5. (3S,4R,5R)-3-Benzamido-5-hydroxy-3-methyl-4-
hexanolide (13)
To a solution of the trans-oxazoline 11 (111.7 mg,
0.234 mmol) in EtOH (5 mL) was added 3 M HCl (5 mL)
and the mixture was refluxed for ca. 15 h. The reaction mix-
ture was concentrated in vacuo and added acetone (1.65 mL)
and saturated aq NaHCO3 (4.2 mL). To the mixture was added
dropwise benzoyl chloride (81.5 mL, 0.702 mmmol), and the
mixture was stirred for ca. 1 h at rt. The mixture was concen-
trated in vacuo and the residue was diluted with brine and the
whole mixture was extracted with EtOAc. The extract was
dried (MgSO4) and concentrated in vacuo. The residue was
purified by flash column chromatography (hexane/
EtOAc¼1:2.5) to give lactone 13 (50.8 mg, 82%). Analytical
sample (colorless rod) was obtained by recrystallization
from EtOAc/hexane; mp 124.5e126.0 ꢁC; [a]D27.0 ꢀ37.7 (c
0.560, EtOH); nmax (KBr) 3321, 2976, 1782, 1645, 1541,
4.8.3.1. cis-Oxazoline 10. Colorless needles; mp 95.3e
97.5 ꢁC; [a]D27.4 ꢀ104 (c 0.575, CHCl3); nmax (KBr) 3338,
2989, 1718, 1660, 1338, 1306, 1228, 1201, 1119, 1080, 796,
1
687, 652 cmꢀ1; H NMR (270 MHz, CDCl3) d 8.43 (br s,
1H), 5.45 (dq, J¼0.9, 6.4 Hz, 1H), 4.75 (d, J¼0.9 Hz, 1H),
4.19 (dd, J¼7.2, 10.8 Hz, 1H), 4.17 (dd, J¼7.1, 10.9 Hz,
1H), 2.98 (d, J¼17.7 Hz, 1H), 2.85 (d, J¼18.2 Hz, 1H), 1.46
(d, J¼6.4 Hz, 3H), 1.44 (d, J¼0.6 Hz, 3H), 1.28 (t,
J¼7.1 Hz, 3H); 13C NMR (67.8 MHz, CDCl3) d 171.4,
161.1, 160.8, 92.0, 91.0, 86.7, 73.9, 70.4, 61.0, 39.8, 26.5,
15.3, 14.1. Anal. Calcd for C13H16Cl6N2O4: C, 32.73; H,
3.38; N, 5.87. Found: C, 33.02; H, 3.38; N, 5.81%.
1300, 1159, 1138, 985, 729 cmꢀ1 1H NMR (270 MHz,
;

Y. Matsushima, J. Kino / Tetrahedron 64 (2008) 3943e3952
3951
CDCl3) d 8.59 (br s, 1H), 7.80e7.72 (m, 2H), 7.54e7.37 (m,
3H), 4.31 (dq, J¼6.7, 9.5 Hz, 1H), 4.09 (s, 1H), 3.59 (d,
J¼17.5 Hz, 1H), 2.62 (d, J¼17.5 Hz, 1H), 2.24 (d,
J¼9.8 Hz, 1H), 1.74 (s, 3H), 1.51 (d, J¼6.6 Hz, 3H); 13C
NMR (67.8 MHz, CDCl3) d 174.6, 167.3, 134.2, 131.8,
128.6, 126.9, 87.4, 65.1, 59.9, 41.8, 22.3 (2). Anal. Calcd
for C14H17NO4: C, 63.87; H, 6.51; N, 5.32. Found: C,
63.76; H, 6.52; N, 5.27%.
NMR (270 MHz, DMSO-d6, after 1 month) data were in
agreement with the reported in lit. 20; 13C NMR (67.8 MHz,
DMSO-d6) d a-isomer 164.9, 135.4, 131.1, 128.5, 126.3,
90.5, 67.6, 62.5, 54.7, 35.4, 22.8, 17.34; b-isomer 166.7,
135.8, 130.8, 127.9, 127.3, 92.1, 68.4, 67.9, 57.1, 37.0, 23.3,
17.31. Anal. Calcd for C14H19NO4: C, 63.38; H, 7.22; N,
5.28. Found: C, 63.18; H, 7.23; N, 5.23%.
Acknowledgements
4.8.6. 3-Benzamido-2,3,6-trideoxy-3-C-methyl-D-lyxo-
hexopyranose (N-Bz-D-vancosamine)
This work was supported by a Grant-in-Aid for Scientific
Research (17780089) and a 21st century COE program
(Hamamatsu University School of Medicine, Medical Photon-
ics) from the Ministry of Education, Culture, Sports, Science
and Technology of Japan. The authors thank the technical
staffs (M. Suzuki and M. Toyama) for their supports.
To a solution of the lactone 12 (75.6 mg, 0.287 mmol) in
dry THF (4.2 mL) was added dropwise DIBAL (1.46 mL,
0.98 M in hexane, 1.43 mmol) under Ar atmosphere at
ꢀ60 ꢁC, and the reaction mixture was stirred for 1.5 h at
ꢀ60ꢁ to ꢀ50 ꢁC. The reaction was quenched by the dropwise
addition of acetone/MeOH (1:1, 3 mL) and the mixture was
allowed to warm gradually to rt with stirring for ca. 4 h. The
mixture was filtered through a pad of Celite. The filter cake
was washed with acetone/MeOH (1:1) and then the filtrate
was concentrated in vacuo. The residue was purified by flash
column chromatography (EtOAc) to give N-Bz-D-vancosamine
(39.9 mg, 52%) along with over-reduced triol (11.8 mg, 15%).
Analytical sample (colorless rod) was obtained by recrystalli-
zation from EtOAc/hexane; mp 152.0e154.0 ꢁC (lit.20
155 ꢁC); [a]2D9.1 þ81.9 (after 10 min), þ34.7 (after 1 day,
constant) (c 0.525, MeOH) (lit.20 L-form [a]D20 ꢀ86.6 (c 0.5,
MeOH)); nmax (KBr) 3332, 2931, 1645, 1581, 1533, 1491,
References and notes
1. Weymouth-Wilson, A. C. Nat. Prod. Rep. 1997, 14, 99e110.
2. Paloma, L. G.; Smith, J. A.; Chazin, W. J.; Nicolaou, K. C. J. Am. Chem.
Soc. 1994, 116, 3697e3708.
3. Nedal, A.; Zotchev, S. B. Appl. Microbiol. Biotechnol. 2004, 64, 7e15.
4. Yu, T.-W.; Muller, R.; Muller, M.; Zhang, X.; Draeger, G.; Kim, C.-G.;
¨
¨
Leistner, E.; Floss, H. G. J. Biol. Chem. 2001, 276, 12546e12555.
5. Matsushima, Y.; Kino, J. Tetrahedron Lett. 2005, 46, 8609e8612.
6. Matsushima, Y.; Kino, J. Tetrahedron Lett. 2006, 47, 8777e8780.
7. Bergmeier, S. C. Tetrahedron 2000, 56, 2561e2576.
8. Kochi, T.; Tang, T. P.; Ellman, J. A. J. Am. Chem. Soc. 2002, 124, 6518e
6519; J. Am. Chem. Soc. 2003, 125, 11276e11282 and references therein.
9. A few examples of intramolecular conjugate additions of trichloroacet-
imidates, which were prepared in situ, in a cyclic system were reported:
(a) For a,b-unsaturated ester, see: Brown, J. R.; Nishimura, Y.; Esko,
J. D. Bioorg. Med. Chem. Lett. 2006, 16, 532e536; (b) For a,b-unsatu-
rated nitrile, see: Fraser-Reid, B.; Burgey, C. S.; Vollerthum, R. Pure
Appl. Chem. 1998, 70, 285e288; (c) For a,b-unsaturated sulfones, see:
Li, X. C.; Fuchs, P. L. Synlett 1994, 629e630.
10. There are some useful reactions involving the trichloroacetimidates for the
introduction of a nitrogen functionality. (a) For electrophile-promoted
intramolecular aminations of trichloroacetimidates derived from allylic
and homoallylic alcohols, see: Lee, H.-S.; Kang, S. H. Synlett 2004,
1673e1685 and references therein, (b) For acid-promoted intramolecular
epoxide opening of trichloroacetimidates, see: Bernet, B.; Vasella, A.
Tetrahedron Lett. 1983, 24, 5491e5494; Schmidt, U.; Respondek, M.;
Lieberknecht, A.; Werner, J.; Fischer, O. Synthesis 1989, 256e261;
Hatakeyama, S.; Matsumoto, H.; Fukuyama, H.; Mukugin, Y.; Irie, H.
J. Org. Chem. 1997, 62, 2275e2279; Matsushima, Y.; Nakayama, T.;
Tohyama, S.; Eguchi, T.; Kakinuma, K. J. Chem. Soc., Perkin Trans. 1
2001, 569e577 and see also: Rondot, C.; Retailleau, P.; Zhu, J. Org.
Lett. 2007, 9, 247e250 and references therein; (c) For Overman rear-
rangement, see: Overman, L. E. Acc. Chem. Res. 1980, 13, 218e224.
11. Starting allylic alcohols were, respectively, prepared according to the
literatures below: (a) Trost, B. M.; Suriveta, J.-P.; Toste, F. D. J. Am.
Chem. Soc. 2004, 126, 11592e11602; (b) lit. 5; (c) lit. 6; (d) Xu, D.;
Crispino, G. A.; Sharpless, K. B. J. Am. Chem. Soc. 1992, 114,
7570e7571; Becker, H.; Soler, M. A.; Sharpless, K. B. Tetrahedron
1995, 51, 1345e1376.
1
1284, 1097, 1016, 710 cmꢀ1; H NMR (270 MHz, DMSO-
d6, after 1 month) data were in agreement with the reported
in lit. 20; 13C NMR (67.8 MHz, DMSO-d6) d a-isomer
165.6, 135.7, 130.9, 128.1, 126.9, 90.1, 71.2, 62.6, 54.3,
35.2, 23.2, 17.47; b-isomer 165.7, 135.6, 130.8, 128.0,
127.0, 92.0, 70.0, 68.2, 56.1, 38.7, 21.4, 17.52. Anal. Calcd
for C14H19NO4: C, 63.38; H, 7.22; N, 5.28. Found: C,
63.21; H, 7.20; N, 5.24%.
4.8.7. 3-Benzamido-2,3,6-trideoxy-3-C-methyl-D-xylo-
hexopyranose (N-Bz-3-epi-D-vancosamine)
To a solution of the lactone 13 (33.1 mg, 0.126 mmol) in
dry THF (1.9 mL) was added dropwise DIBAL (641 mL,
0.98 M in hexane, 0.628 mmol) under Ar atmosphere at
ꢀ60 ꢁC, and the reaction mixture was stirred for 1 h at ꢀ60ꢁ
to ꢀ55 ꢁC. The reaction was quenched by the dropwise addi-
tion of acetone/MeOH (1:1, 2 mL) and the mixture was
allowed to warm gradually to rt with stirring for ca. 4 h. The
mixture was filtered through a pad of Celite. The filter cake
was washed with acetone/MeOH (1:1), and then the filtrate
was concentrated in vacuo. The residue was purified by flash
column chromatography (EtOAc) to give N-Bz-3-epi-D-van-
cosamine (24.1 mg, 72%). Analytical sample (colorless solid)
was obtained by recrystallization from EtOAc/hexane; mp
222.0e224.0 ꢁC (lit.20 230e233 ꢁC); [a]2D8.0 þ69.6 (after
10 min), [a]2D9.7 þ45.7 (after 1 day, constant) (c 0.505,
MeOH) (lit.20 L-form [a]D20 ꢀ61.3 (c 0.5, MeOH)); nmax
(KBr) 3361, 3239, 2979, 1643, 1549, 1362, 1327, 1261,
12. During the imidate formation a trace amount of conjugate adducts was
obtained at low temperature and prolonged time or increased temperature
afforded the products, but only in low yield.
13. It was reported that in an oxazoline ring the small coupling constant (ca.
6 Hz) corresponded to trans form and the large one (ca. 9 Hz) to cis form;
see: Roush, W. R.; Straub, J. A.; Brown, R. J. J. Org. Chem. 1987, 52,
5127e5136.
1113, 1099, 1016, 964, 868, 802, 723, 694, 631 cmꢀ1; H
1

3952
Y. Matsushima, J. Kino / Tetrahedron 64 (2008) 3943e3952
ˆ
14. Hirama, M.; Shigemoto, T.; Ito, S. Tetrahedron Lett. 1985, 26,
4133e4136, 4137e4140, and references therein.
17. Syntheses of vancosamine derivatives, see: Hsu, D.-S.; Matsumoto, T.;
Suzuki, K. Synlett 2006, 469e471; Trost, B. M.; Jiang, C.; Hammer, K.
Synthesis 2005, 3335e3345 and references therein.
15. Starting homoallylic alcohols were, respectively, prepared according to
the literatures below: (a) Garaas, S. D.; Hunter, T. J.; O’Doherty, G. A.
J. Org. Chem. 2002, 67, 2682e2685; (b) Moinuddin, M.; O’Doherty,
G. A. Carbohydr. Res. 2006, 341, 1505e1521; (c) lit. 5; (d) Uchida, K.;
Ishigami, K.; Watanabe, H.; Kitahara, T. Tetrahedron 2007, 63,
1281e1287.
18. The known acetonide 7 was prepared from L-threonine, see: Aoyagi, S.;
Wang, T.-C.; Kibayashi, C. J. Am. Chem. Soc. 1993, 115, 11393e11409
and references therein.
19. The irradiation of methyne hydrogen (H-50) on the cis-oxazoline 10
yielded no NOE on the methylene protons (H-2). On the contrary, the
irradiation of the hydrogen corresponding to the trans-oxazoline 11
yielded an NOE of ca. 4% on the one methylene proton (H-2).
20. Fronza, G.; Fuganti, C.; Grasselli, P.; Pedrocchi-Fantoni, G. Tetrahedron
Lett. 1981, 22, 5073e5076; J. Carbohydr. Chem. 1983, 2, 225e248.
16. For example, the irradiation of H-40 on the cis-dihydrooxazine 5a yielded
an NOE of ca. 6% on H-60, and this result was supported by their
0
0
0
0
trans-diaxial large coupling constants (JH-4 ,H-5 ax and JH-5 ax,H-6 ¼ca.
11 Hz) of 5a.