Stereoselective intramolecular cyclization of γ-allylbenzamide via π-allylpalladium complex catalyzed by Pd(0)

Article abstract of DOI:10.1016/j.tet.2010.01.075

An efficient procedure for synthesizing oxazines was developed by the palladium(0)-catalyzed intramolecular cyclization of a benzamide through a π-allylpalladium (II) complex. Interestingly, the diastereoselectivity of oxazine ring formation was dominantly controlled by the bulkiness of various protecting groups on the secondary alcohols.

Full text of DOI:10.1016/j.tet.2010.01.075

Tetrahedron 66 (2010) 2123–2131
Contents lists available at ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Stereoselective intramolecular cyclization of
g-allylbenzamide
via –allylpalladium complex catalyzed by Pd(0)
p
,
Van-Thoai Pham a, Jae-Eun Joo a, Kee-Young Lee b, Tai-Won Kim a, Yu Mu a, Won-Hun Ham a
*
a School of Pharmacy, Sungkyunkwan University, Suwon 440-746, Republic of Korea
b Yonsung Fine Chemicals Co., Ltd., 129-9 Suchon-ri, Jangan-myeon, Hwaseong-si, Gyeonggi-do 445-944, Republic of Korea
a r t i c l e i n f o
a b s t r a c t
Article history:
An efficient procedure for synthesizing oxazines was developed by the palladium(0)-catalyzed intra-
molecular cyclization of a benzamide through a -allylpalladium (II) complex. Interestingly, the dia-
stereoselectivity of oxazine ring formation was dominantly controlled by the bulkiness of various
protecting groups on the secondary alcohols.
Received 2 December 2009
Received in revised form 19 January 2010
Accepted 20 January 2010
Available online 28 January 2010
p
Ó 2010 Elsevier Ltd. All rights reserved.
Keywords:
Chiral oxazine
Palladium catalysis
Enantioselective catalysis
Intramolecular cyclization
Chiral building block
1. Introduction
To extend the scope of this method, we replaced the syn-ami-
noalcohols with anti-aminoalcohols, which are interesting because
of their selectivity in the formation of corresponding oxazines. This
paper discusses the results of stereoselective intramolecular oxa-
zine formation.
In our previous papers,1–3 we described a procedure for highly
stereoselective formation of oxazines from –allyl amides having
g
a benzoyl substituent as N-protecting group in the presence of
Pd(PPh3)4, NaH, and n-Bu4NI in THF. Unlike in other palladium-
catalyzed reactions, the diastereoselectivity of oxazine ring for-
mation is predominantly controlled by the temperature. Our study
of intramolecular oxazine formation from 1a–d shows that the
stereoselectivity of these cyclizations can be critically dependent
upon whether the reaction temperature results in kinetic or ther-
modynamic control of the products (Scheme 1). Oxazines syn,syn-
2a–d required conditions giving kinetic control (0 ꢀC), whereas
syn,anti-2a–d are observed under thermodynamic control (40 ꢀC).
2. Results and discussion
The requisite cyclization precursor was prepared in high yield
from the commercially available N-benzoyl leucine methyl ester 3d
by the three-step sequence shown in Scheme 2.
O
O
n-Bu3Sn
Cl
CH3NHOCH3.HCl
R
OMe
R
5
N
OMe
NHBz
Me3Al, CH2Cl2
MeLi, THF
-78 o
Me
NHBz
0 oC - rt
C
OTBS
OTBS
4a) R = Phenyl (98%)
4b) R = Benzyl (91%)
4c) R = Isopropyl (98%)
4d) R = Isobutyl (91%)
3a) R = Phenyl
3b) R = Benzyl
3c) R = Isopropyl
3d) R = Isobutyl
Pd(PPh3)4, NaH
R
OTBS
R
+
n-Bu4NI, THF
R
Cl
0oC : 73-89%
8.3-14:1
N
O
N
O
NHBz
1a-d
Ph
Ph
40oC : 68-77%
1:7.5-16
O
R
OH
R
thermodynamic products
syn,anti-oxazines
kinetic products
syn,syn-oxazines
(syn,syn-2a-d)
Cl
LiAlH(OtBu)3
Cl
(syn,anti-2a-d)
EtOH
NHBz
R = (a) C6H5CH2, (b) (CH3)2CH, (c) (CH3)2CHCH2, (d) C6H11CH2
NHBz
-78 oC
Scheme 1. Palladium catalyzed oxazine formation.
7a) R = Phenyl (79%, anti:syn = 10:1)
7b) R = Benzyl (70%, anti:syn = 10:1)
6a) R = Phenyl (87%)
6b) R = Benzyl (73%)
6c) R = Isopropyl (64%)
6d) R = Isobutyl (75%)
7c) R = Isopropyl (77%, anti:syn = 10:1)
7d) R = Isobutyl (66%, anti:syn = 10:1)
* Corresponding author. Tel.: þ82 31 290 7706; fax: þ82 31 292 8800.
E-mail address: whham@skku.edu (W.-H. Ham).
Scheme 2.
0040-4020/$ – see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2010.01.075

2124
V.-T. Pham et al. / Tetrahedron 66 (2010) 2123–2131
Table 2
The synthesis of 7d commenced with preparation of the
Oxazine formation catalyzed by Pd(0)a
Weinreb amide 4d from ester 3d by treatment of N,O-dime-
thylhydroxylamine in the presence of trimethylaluminum in 91%
yield.4 Reaction of the Weinreb amide 4d with vinyltin 5 and MeLi
OR'
OR'
OR'
Pd(PPh3)4, NaH
Cl
+
in THF at ꢁ78 ꢀC gave the
a,b–unsaturated ketone 6d in 75% yield.
TBAI, THF
N
O
N
O
NHBz
Chelating-controlled hydride reduction of 6d using LiAlH(t-BuO)3
yielded anti-alcohol 7d with excellent stereoselectivity (anti/
syn¼10:1, as determined by 1H NMR).5–9
Ph
anti,syn-10a-e
Ph
anti,anti-10a-e'
9a-e
R' = (a) Me (b) Bn (c) MOM (d) BOM (e) TBS
Entry Substrate Temp (ꢀC) Time (h) Yieldb (%) Ratioc (anti,syn/anti,anti)
Under the same conditions [Pd(PPh3)4, NaH, and n-Bu4NI inTHFat
0 ꢀC] that were used in the formation of oxazines (syn,syn-2a–d and
syn,anti-2a–d, Scheme 1),1 the intramolecular cyclization of allyl
chloride 7d afford oxazines 8 and 80 as a 1:1 syn/anti mixture (as
determined by 1H NMR) in moderate yield (Scheme 3).y
1
2
3
4
5
9a
9b
9c
9d
9e
0
0
0
0
0
5
5
5
5
5
51
70
76
90
65
6:1
5:1
8:1
15:1
>30:1
a
Reaction conditions: Pd(PPh3)4 (0.2 equiv), NaH (2 equiv), n-Bu4NI (1 equiv),
OH
OH
OH
Pd(PPh3)4, NaH
and THF.
Cl
+
b
Yield refers to the isolated and mixed products.
n-Bu4NI, THF
c
Ratio was determined by 1H NMR of anti,syn-oxazines and anti,anti-oxazines.
N
O
N
O
NHBz
0
oC, 60 %
7d
anti,syn : anti,anti = 1:1
Ph
anti,syn-8
Ph
anti,anti-8'
These reaction conditions were then extended to other sub-
strates in order to investigate the influence of the R0 groups on the
reactivity. The substrates were synthesized according to the pro-
cedure shown in Scheme 4. This method afforded high diaster-
eoselectivity and chemical yield.
Scheme 3. Palladium catalyzed oxazine formation.
Based on our previous research, we anticipated that the palla-
dium(0)-catalyzed oxazine formation of -allylbenzamide with
g
various alcohol protection substitutes might proceed with high
stereoselectivity.1–3 In order to investigate the influence of the
bulkiness of the protection group, these reaction conditions were
extended to other substrates used to investigate the influence of
the R0 group on selectivity. These substrates were simply prepared
under the reaction conditions shown in Table 1.
OMe
OH
OTBS
MeI, NaH
THF, 0 o
TBSCl, Imid
DMF, rt
R
Cl
R
Cl
R
Cl
NHBz
11a
C
NHBz
NHBz
) R = phenyl: 63%
11b) R = benzyl: 57%
11c) R = isopropyl: 57%
7a
) R = phenyl
12a
) R = phenyl: 85%
7b) R = benzyl
12b) R = benzyl: 95%
7c) R = isopropyl
12c) R = isopropyl: 82%
Scheme 4.
Table 1
Preparation of various alcohol protection cyclization precursors
The reaction of 11a–c and 12a–c, which have phenyl, benzyl, and
isopropyl as substituent groups and methyl or TBS protecting
groups on the secondary alcohol, with NaH, n-Bu4NI in presence of
Pd(PPh3)4 in THF at 0 ꢀC afforded the anti,syn-oxazines, 13a–c and
14a–c, as the major products, along with minor amounts of the
anti,anti-oxazine products, 13a–c0 and 14a–c0. The results are
summarized in Table 3.
OR'
OH
reagents
Cl
Cl
and conditions
NHBz
NHBz
9a-e
7d
Substrate R0
Reagents
Temp (ꢀC) Time (h) Yielda (%)
9a
9b
9c
9d
9e
Me
Bn
MeI, NaH, THF
BnBr, NaH, THF
0-rt
rt
2
2
24
3
73
70
80
76
95
Table 3
Oxazine formation catalyzed by Pd(0)a
MeOCH2 MOMCl, TEA, CH2Cl2 0-rt
BnOCH2 BOMCl, TEA, CH2Cl2
TBS TBSCl, Imid, DMF
OR'
OR'
0
rt
OR'
Pd(PPh3)4, NaH
TBAI, THF
R
R
2
R
Cl
+
a
N
O
N
O
Yield refer to the isolated products.
NHBz
Ph
Ph
11a-c and 12 a-c
R = (a) phenyl (b) benzyl (c) isopropyl
The reaction of 9a–e, which had methyl, benzyl, methoxy-
methyl, benzyloxymethyl, and tert-butyldimethylsilyl as the pro-
tection groups with NaH and n-Bu4NI in the presence of Pd(PPh3)4
in THF at 0 ꢀC afforded the anti,syn-oxazines 10a–e as the major
products along with minor amounts of the anti,anti-oxazine
products 10a–e0. The results are summarized in Table 2.
The diastereoselectivity decreased with sterically less bulky
groups, such as methyl, benzyl, methoxymethyl, and benzyloxy-
methyl (entries 1–4, Table 2). The diastereoselectivity was im-
proved to >30:1 when R0 was the TBS group (entry 5). It is clear
from these experiments that steric bulkiness at the R0 groups highly
influences the level of diastereoselectivity (Table 2).
anti,syn-oxazines
anti,anti-oxazines
13a-c (R' = CH3)
13a-c' (R' = CH3)
14a-c
(R' = TBS)
14a-c'
(R' = TBS)
Entry Substrate Temp (ꢀC) Time (h) Yieldb (%) Ratioc (anti,syn/anti,anti)
1
2
3
4
5
6
11a
12a
11b
12b
11c
12c
0
0
0
0
0
0
5
5
5
5
5
5
62
57
65
65
58
57
2:1
13:1
3:1
12:1
4:1
13:1
a
Reaction conditions: Pd(PPh3)4 (0.2 equiv), NaH (2 equiv), n-Bu4NI (1 equiv),
and THF.
b
Yield refers to the isolated and mixed products.
Ratio was determined by 1H NMR of anti,syn-oxazines and anti,anti-oxazines.
c
The diastereoselectivity of oxazine ring formation is dominantly
controlled by the bulkiness of R0. This result verified that the bulky
TBS group plays an important role in determining the stereo-
selectivity during oxazine formation. Upon extensive examination
of R0, we found that reaction of 12a–c using TBS as the protection
group gave the desired diastereomer as the major compound with
high diastereoselectivity and in good yield.
y
The ratio of oxazines 8 and 80 from the reaction of 7d under above condition
[Pd(PPh3)4, NaH, and n-Bu4NI in THF] at higher temperature (such as room tem-
perature or 40 ꢀC) was a 1:1 syn/anti mixture in a lower yield. Later, we tested the
cyclization reaction of 9a–e at 40 ꢀC and the same result ratio (1:1 syn/anti mix-
tures) at a lower yield for 10a–e and 10a–e0 as determined by TLC. These experi-
ments show that the stereoselectivity of these cyclizations of anti-aminoalcohols
moieties 7a–d and 9a–e is not depended on the reaction temperature.

V.-T. Pham et al. / Tetrahedron 66 (2010) 2123–2131
2125
Table 4
One possible explanation for the stereoselective formation of C
1H NMR (CDCl3) coupling constants of oxazines
or D is as follows (Scheme 5). The chair-like transition states A and
B, which have OR0 in an equatorial orientation, are proposed to
explain the stereochemical outcome of the cyclization. The initial
H
H
R
R
N
N
5
5
4
J5,6
4
OR'
OR'
O
O
p
-allylpalladium complexes A and B were equilibrated by
p–s–p
6
6
H
isomerization.10,11 Although the axially disposed
p-allylpalladium
H
Ph
Ph
7
J5,6
H
H
complex in transition state A might suffer from a non-bonding
gauche repulsion with OR0, the transition state B appears to be
further destabilized by non-bonded steric repulsion between the
D
C
anti,anti-oxazine
anti,syn-oxazine
p
-allylpalladium complex and OR0. The stereoselectivity
Substrate
R
R0
Isomer
J 5,6
equatorial
of cyclization may also arise from differences in steric interactions
between the bulky R0 group and the
-allylpalladium complex in
10a
10a0
10e
13a
13a0
14a
13b
13b0
14b
13c
13c0
14c
Isobutyl
Isobutyl
Isobutyl
Phenyl
Phenyl
Phenyl
Benzyl
Benzyl
Benzyl
Me
Me
TBS
Me
Me
TBS
Me
Me
TBS
Me
Me
TBS
C
D
C
C
D
C
C
D
C
C
D
C
3.5
9.0
2.5
4.0
8.5
4.5
3.5
8.0
3.0
4.5
7.5
4.0
p
the transition states A and B. Consequently, cyclization proceeds
through the more favored transition state A as shown in Scheme 5.
OR'
R
Cl
N
Isopropyl
Isopropyl
Isopropyl
NHBz
Pd(0)
H
H
H
R
R
R
N
OR'
OR'
O-
O-
O
H
+
Pd
The relative configuration of each diastereomer of the oxazine
products obtained after the silica gel column separation was de-
termined by comparing their coupling constants (Table 4). Small
coupling constants of J5,6¼2.5–4.5 Hz, as in anti,syn-oxazine (C), are
caused by the axial–equatorial relationship between the two ad-
jacent protons in six-membered rings. The large coupling constants
of J5,6¼7.5–9.0 Hz, as in anti,anti-oxazine (D), are typically due to
the diaxial relationship between the two adjacent protons in six-
membered rings.
+
Ph
Ph
Ph
H
Pd
B
A
R
H
N
OR'
N
OR'
O
H
H
Ph
H
H
OR'
OR'
In addition, the coupling constants of the newly generated chiral
center (H5–H6) of C have similar values of 2.5–4.5 Hz compared to
those previously reported for syn,syn-oxazine compounds. In con-
trast, the coupling constants of the newly generated chiral center
(H5–H6) of D have the same values of 7.5–9.0 Hz as the syn,anti-
isomer.
R
R
N
O
N
O
Ph
C
Ph
D
We utilized this method for the synthesis of a-hydroxy statine
anti,syn-oxazines
anti,anti-oxazines
16.12 Ozonolysis of the terminal olefin of oxazine 10e gave the
corresponding aldehyde, and further oxidation with sodium chlo-
rite afforded acid 15 in 65% yield (Scheme 6). Deprotection of silyl
ether and oxazine cleavage with 6 N-HCl at reflux temperature gave
Scheme 5.
To verify the stereochemical outcome at the newly generated
stereocenter C-6, the NOE spectra of the oxazine were studied
under the assumption that there must be a NOE difference between
the two isomers A and B. This technique has been mentioned in
previous reports. 1,z
a
-hydroxy statine 16 in excellent yield.
TBSO
O
1. O3, MeOH, -78 o
2. NaClO2, NaH2PO4
C
OH
O
OTBS
6N-HCl
OH
OH
The stereochemistries of the oxazines were elucidated by 1H
NMR, as shown in Table 4.
Reflux
95%
2-Me-2-butene
N
O
N
O
NH2 OH
t-BuOH
(2R, 3S, 4S)
16
Ph
15
65%
Ph
10e
Scheme 6.
z
The assignment of relative configuration was confirmed by observation of the
larger NOE enhancement for anti,syn-oxazines 10a, 10e and anti,anti-oxazine 10a0 as
shown below: in the anti,syn-oxazines case, for compound 10a and 10e: there is
NOE between H-5 and H-6, but no NOE effective between H-4 and H-6; in the
anti,anti-oxazine case, for compound 10a0: there are 1.59% between H-4 and H-6, 0.
37% between H-5 and H-6.
3. Conclusion
This study examined the stereoselective intramolecular oxazine
formation by palladium(0). Diastereoselectivity of oxazine ring
formation is dominantly controlled by the bulkiness of R0. Also,
there is excellent correlation between the diastereoselectivity ratio
and the bulkiness of R0 in the palladium(0)-catalyzed oxazine ring
formation. A means of stereoselectively generating an alcohol
nOe
0 %
nOe
nOe
0 %
1.59 %
nOe
nOe
nOe
1.96 %
2.30 %
0.37 %
H
H
H
OTBS
OMe
moiety in the g-position of the amine is important from a synthetic
OMe
H
N
H
N
H
N
H
H
H
point of view. The mildness of the reaction, the simplicity of the
procedure, and rather high de values offer a convenient and effi-
cient method for the synthesis of optically pure oxazines. Further
applications of this formation catalyzed by Pd(0) will be reported in
due course.
O
O
O
Ph
anti,syn-oxazine
10a
Ph
anti,syn-oxazine
10e
Ph
anti,anti-oxazine
10a'

2126
V.-T. Pham et al. / Tetrahedron 66 (2010) 2123–2131
4. Experimental section
138.6, 171.6, 176.8; HRMS calcd for C14H21O3N2 (MþþH) 265.1552;
found, 265.1555.
4.1. General methods and materials
4.2.4. (S)-N-(1-(Methoxy(methyl)amino)-4-methyl-1-oxopentan-2-
Optical rotations were measured on a polarimeter in the solvent
specified. 1H NMR and 13C NMR spectra were recorded on FT-NMR
125, or 500 MHz spectrometers. Chemical shifts values are reported
in parts per million relative to TMS or CDCl3 as an internal standard
and coupling constants in Hertz. IR spectra were measured on
a FTIR spectrometer. Mass spectral data were obtained from the
Korea Basic Science Institute (Daegu) on Jeol JMS 700 high reso-
lution mass spectrometer. Flash chromatography was executed
using mixtures of ethyl acetate and hexane as eluents. Unless
otherwise noted, all non-aqueous reactions were carried out under
an argon atmosphere with commercial grade reagents and sol-
vents. Tetrahydrofuran (THF) was distilled over sodium and ben-
zophenone (indicator). Methylene chloride (CH2Cl2) was distilled
from calcium hydride.
yl)benzamide (4d). Yield 91%; as a white solid; mp¼95–96 ꢀC;
Rf¼0.3 (ethyl acetate/hexanes¼1/2); IR (neat) nmax: 998, 1069,
25
1456, 2921, 3306 cmꢁ1; [
a
]
ꢁ25.36 (c 1.0, CHCl3); 1H NMR (CDCl3,
D
300 MHz) d 0.93–1.01 (m, 6H),1.57–1.64 (m, 2H),1.73–1.78 (m,1H),
3.22 (s, 3H), 3.85 (s, 3H), 5.28 (t, J¼2.1, 2.4 Hz,1H), 7.02 (d, J¼5.4,1H-
NH), 7.36–7.46 (m, 3H), 7.78–7.80 (m, 2H); 13C NMR (CDCl3,
125 MHz) d 21.9, 23.6, 25.2, 32.4, 42.2, 48.4, 61.9,127.3,127.4,128.6,
131.7, 134.3, 167.4, 173.7; HRMS calcd for C15H23O3N2 (MþþH)
279.1709; found, 279.1710.
4.3. General procedure for synthesis of amino ketones (6a–d)
Vinyltin 5 (3.0 equiv) was dissolved in dry THF (0.1 M) and
cooled to ꢁ78 ꢀC. MeLi (1.6 M solution in hexanes, 3.0 equiv) was
added dropwise. The mixture was stirred for 30 min at same
temperature. Subsequently, a solution of amide 4a–d (1.0 equiv) in
dry THF (0.1 M) was added dropwise and stirring was allowed to
continue for 30 min, after which time TLC analysis indicated com-
plete reaction. The reaction was quenched by aqueous saturated
NH4Cl then warmed to room temperature. The layers were sepa-
rated and the aqueous layer was extracted with ethyl acetate. The
combined organic layer washed with satd NaHCO3 solution, brine,
dried with MgSO4, and filtered. The filtrate was concentrated in
vacuo. The resulting substance was purified by silica gel column
chromatography gave the amino ketone 6a–d as white wax
materials.
4.2. General procedure for synthesis of Weinreb amides
(4a–d)
To a solution of N,O-dimethylhydroxylamine hydrochloride
(3.0 equiv) in CH2Cl2 was added trimethylaluminum (2 M solution
in hexane, 3.0 equiv) at 0 ꢀC (Caution: CH4 evolution). The mixture
was stirred for 30 min at room temperature. Subsequently, a solu-
tion of methyl ester (3a–d) (1.0 equiv) in CH2Cl2 was added drop-
wise. The mixture was stirred at room temperature for 1 h, after,
which time TLC analysis indicated complete reaction. The reaction
mixture was cooled to 0 ꢀC and carefully quenched with 10% so-
dium potassium tartarate. After being stirred for 1 h at room tem-
perature, the resulting suspension was filtered through Celite pad,
washed with CH2Cl2. The filtrate was concentrated in vacuo to give
the crude product, which upon purification by column chroma-
tography on silica gel gave the Weinreb amide 4a–d as a white
solid.
4.3.1. (S,E)-N-(5-Chloro-2-oxo-1-phenylpent-3-enyl)benzamide
(6a). Yield 87%; as a wax material; Rf¼0.5 (ethyl acetate/hexanes¼1/
2); IR (neat) nmax: 1332, 1516, 1645, 2358, 3404, 3740, 3852 cmꢁ1
;
25
[a]
þ242.68 (c 1.0, CHCl3); 1H NMR (CDCl3, 300 MHz)
d 4.16 (dd,
D
J¼1.5, 6.0 Hz, 2H), 5.97 (d, J¼6.3 Hz,1H), 6.46 (d, J¼12.9 Hz,1H), 7.05–
7.10 (m, 1H), 7.40–7.50 (m, 8H), 7.54 (d, J¼7.2 Hz, 1H-NH), 7.85–7.88
4.2.1. (S)-N-(2-(Methoxy(methyl)amino)-2-oxo-1-phenylethyl)benz-
(m, 2H); 13C NMR (CDCl3, 125 MHz)
d 42.9, 62.6, 127.4, 127.9, 128.7,
amide (4a). Yield 98%; as a white solid; mp¼101–103 ꢀC; Rf¼0.2
128.8, 129.1, 129.6, 132.1, 133.9, 136.1, 142.4, 166.6,193.9; HRMS calcd
(ethyl acetate/hexanes¼1/2); IR (neat) nmax: 1515, 1650, 1688, 2358,
for C18H17O2NCl (MþþH) 314.0948; found, 314.0948.
25
3618, 3740, 3851 cmꢁ1; [
a]
þ93.23 (c 1.0, CHCl3); 1H NMR (CDCl3,
D
300 MHz)
d
3.25 (s, 3H), 3.51 (s, 3H), 6.23 (d, J¼7.5 Hz), 7.31–7.55
4.3.2. (S,E)-N-(6-Chloro-3-oxo-1-phenylhex-4-en-2-yl)benzamide
(m, 8H), 7.58 (d, J¼7.2 Hz, 1H-NH), 7.84–7.86 (m, 2H); 13C NMR
(6b). Yield 73%; as a wax material; Rf¼0.7 (ethyl acetate/hexanes¼1/
(CDCl3, 125 Hz)
d
32.6, 54.5, 61.4, 127.4, 128.3, 128.5, 128.7, 129.1,
2); IR (neat) nmax: 680, 1524, 1643, 1700, 2358, 3618, 3681, 3740,
25
131.9, 134.2, 137.9, 166.5, 171.2; HRMS calcd for C17H19O3N2 (MþþH)
3852 cmꢁ1; [
d
a]
D
þ59.67 (c 1.0, CHCl3); 1H NMR (CDCl3, 300 MHz)
299.1396; found, 299.1399.
3.23 (m, 2H), 4.22 (dd, J¼1.8, 5.7 Hz, 2H), 6.52 (ddd, J¼1.8, 1.8,
16.0 Hz, 1H), 6.92 (d, J¼6.6 Hz, 1H-NH), 6.99–7.19 (m, 1H), 7.25–7.29
4.2.2. (S)-N-(1-(Methoxy(methyl)amino)-1-oxo-3-phenylpropan-2-
(m, 2H), 7.30–7.37 (m, 4H), 7.45–7.51 (m, 2H), 7.53–7.59 (m, 2H), 7.75–
yl)benzamide (4b). Yield 91% as a white solid; mp¼115–116 ꢀC;
7.81 (m,1H); 13C NMR (CDCl3,125 MHz)
d 37.8, 42.9, 58.5,127.0,127.4,
Rf¼0.4 (ethyl acetate/hexanes¼1/2); IR (neat) nmax: 704, 1295, 1533,
128.6, 128.8, 128.9, 129.1, 129.5, 132.0, 134.2, 135.8, 132.3, 167.1, 196.7;
25
1646, 2936, 3328 cmꢁ1; [
a
]
þ38.74 (c 1.0, CHCl3); 1H NMR (CDCl3,
HRMS calcd for C19H19O2NCl (MþþH) 328.1104; found, 328.1100.
D
300 MHz)
d
3.15 (dd, J¼6.3, 13.5 Hz, 1H), 3.25–3.31 (m, 4H), 3.78 (s,
3H), 5.49–5.52 (m, 1H), 6.86 (d, J¼7.5, 1H-NH), 7.22–7.36 (m, 5H),
4.3.3. (S,E)-N-(7-Chloro-2-methyl-4-oxohept-5-en-3-yl)benzamide
7.43–7.56 (m, 3H), 7.77–7.80 (m, 2H); 13C NMR (CDCl3, 125 MHz)
(6c). Yield 64%; as
a
wax material; Rf¼0.5 (ethyl acetate/
d
32.4, 38.4, 51.1, 51.9, 127.2, 127.3, 128.7, 129.7, 131.8, 134.3, 136.8,
hexanes¼1/4); IR (neat) nmax: 703, 1524, 1645, 1709, 2358, 2965,
167.1, 172.2; HRMS calcd for C18H21O3N2 (MþþH) 313.1552; found,
3681, 3740, 3852 cmꢁ1; [
300 MHz)
a
]
D
þ86.69 (c 1.0, CHCl3); 1H NMR (CDCl3,
25
313.1550.
d
0.94 (d, J¼6.9 Hz, 3H), 1.12 (d, J¼6.6 Hz, 3H), 2.32–2.38
(m,1H), 4.28 (dd, J¼1.8, 6.0 Hz, 2H), 5.14 (dd, J¼4.2, 4.2 Hz,1H), 6.59
(ddd, J¼1.8, 1.8, 13.8 Hz, 1H), 6.89 (d, J¼7.8 Hz, 1H), 7.04–7.14 (m,
1H), 7.46–7.59 (m, 3H), 7.85–7.89 (m, 2H); 13C NMR (CDCl3,
4.2.3. (S)-N-(1-(Methoxy(methyl)amino)-3-methyl-1-oxobutan-2-
yl)benzamide (4c). Yield 98%; as a white solid; mp¼92–94 ꢀC;
Rf¼0.5 (ethyl acetate/hexanes¼1/2); IR (neat) nmax: 706, 1174, 1319,
125 MHz) d 21.5, 24.3, 35.4, 47.1, 65.8, 131.4, 132.9, 133.2, 136.1,
25
1527, 1643, 2966, 3322 cmꢁ1; [
a]
þ33.85 (c 1.0, CHCl3); 1H NMR
138.5, 146.1, 171.8, 201.9; HRMS calcd for C15H19O2NCl (MþþH)
D
(CDCl3, 300 MHz)
d
0.398–1.02 (m, 6H), 2.12–2.19 (m, 1H), 3.21 (s,
280.1104; found, 280.1100.
3H), 3.81 (s, 3H), 5.15 (dd, J¼7.5, 15.5 Hz, 1H), 6.94 (d, J¼6.0 Hz, 1H-
NH), 7.36–7.49 (m, 3H), 7.77–7.81 (m, 2H); 13C NMR (CDCl3,
4.3.4. (S,E)-N-(8-Chloro-2-methyl-5-oxooct-6-en-4-yl)benzamide
125 MHz)
d
22.3, 23.8, 35.9, 36.2, 58.3, 65.9, 131.4, 132.8, 135.8,
(6d). Yield 60%; as
a
wax material; Rf¼0.2 (Ethyl acetate/

V.-T. Pham et al. / Tetrahedron 66 (2010) 2123–2131
2127
Hexane¼1/4); IR (neat) nmax: 1040, 1294, 1530, 1642, 1714, 2358,
J¼4.2 Hz, 2H), 4.35 (ddd, J¼2.1, 2.4, 7.2 Hz,1H), 5.83 (dd, J¼3.0, 9.0 Hz,
1H), 5.94–5.99 (m, 1H), 6.34 (d, J¼5.1 Hz, 1H-NH), 7.39–7.42 (m, 2H),
7.48–7.52 (m, 1H), 7.74–7.76 (m, 2H); 13C NMR (CDCl3, 125 MHz)
25
2954, 3307, 3740, 3852 cmꢁ1; [
(CDCl3, 300 MHz)
a
]
þ20.85 (c 1.0, CHCl3); 1H NMR
D
d
0.97 (d, J¼6.3 Hz, 3H), 1.06 (d, J¼6.0 Hz, 3H),
1.53–1.62 (m, 1H), 1.69–1.82 (m, 2H), 4.23 (dd, J¼1.5, 6.0 Hz, 2H),
5.12–5.19 (m, 1H), 6.55 (ddd, J¼1.5, 1.5, 15.5 Hz, 1H), 6.99 (d,
J¼8.4 Hz, 1H-NH), 7.06 (ddd, J¼6.0, 6.0, 15.3 Hz, 1H), 7.403–7.54 (m,
d 22.0, 23.7, 25.3, 53.5, 74.8, 127.3, 128.5, 128.9, 131.9, 133.5, 134.4,
168.9; HRMS calcd for C16H23O2NCl (MþþH) 296.1417; found,
296.1420.
3H), 7.81–7.84 (m, 2H); 13C NMR (CDCl3, 125 MHz)
d 22.3, 23.6, 41.4,
42.9, 55.9, 127.3, 128.6, 128.8, 131.9, 134.2, 141.9, 167.5, 198.3; HRMS
4.5. General procedure for alcohol protection (with
methyl group)
calcd for C16H21O2NCl (MþþH) 294.1261; found, 294.1255.
4.4. General procedure for synthesis of amino alcohols (7a–d)
NaH (60% dispersion in mineral oil, 3.0 equiv) was added to
a stirring solution of amino alcohol 7a–d (1.0 equiv) in THF (0.1 M)
at 0 ꢀC. After 10 min, MeI (3.0 equiv) was added dropwise and the
reaction mixture was warmed to room temperature. After 2 h, the
reaction mixture was quenched by adding H2O and Et2O was
added. The phases were separated and the aqueous phase was
extracted twice with Et2O. The combined organic layers were
washed with brine, dried, and concentrated. Flash column chro-
matography of the crude material yielded methyl ether 9a, 11a–c
as a colorless oil.
To a solution of amino ketone 6a–d (1.0 equiv) in ethanol (0.1 M)
was added lithium tri-tert-butoxyaluminohydride (1 N solution in
THF, 2.0 equiv) at ꢁ78 ꢀC. After the reaction mixture was stirred at
the same temperature for 4 h, 10% aqueous solution of citric acid
was added. The resulting mixture was warmed to room tempera-
ture and extracted with ethyl acetate. The organic layers were
combined, washed with brine, dried over MgSO4, filtered, and
concentrated in vacuo to give the crude products. Column chro-
matography on silica gel gave amino alcohol 7a–d as colorless oil or
a white solid.
4.5.1. N-((1S,2R,E)-5-Chloro-2-methoxy-1-phenylpent-3-enyl)benza-
mide (11a). Yield 63%; as a colorless oil; Rf¼0.4 (ethyl acetate/
hexanes¼1/2); IR (neat) nmax: 1099, 1527, 1638, 1724, 2354, 3620,
4.4.1. N-((1S,2R,E)-5-Chloro-2-hydroxy-1-phenylpent-3-enyl)benza-
mide (7a). Yield 79%; as a white solid; mp¼152–153 ꢀC; Rf¼0.15
3678, 3740, 3854 cmꢁ1; [ 25 18.42 (c 0.5, CHCl3); 1H NMR (CDCl3,
a]
D
(ethyl acetate/hexanes¼1/2); IR (neat) nmax: 1321, 1533, 1637, 2357,
300 MHz)
d
3.41 (s, 3H), 4.04 (d, J¼6.6 hz, 2H), 4.13–4.21 (m, 1H),
25
3304 cmꢁ1; [
d
a
]
ꢁ3.38 (c 1.0, CHCl3); 1H NMR (CDCl3, 300 MHz)
5.30–5.59 (m, 2H), 5.94–6.09 (m, 1H), 7.00 (d. J¼8.1 Hz, 1H-NH),
D
2.90 (d, J¼6.0 Hz, 1H), 4.06 (d, J¼6.9 Hz, 2H), 4.64–4.66 (m, 1H),
7.31–7.58 (m, 8H), 7.23–7.86 (m, 2H); 13C NMR (CDCl3, 125 MHz)
5.38 (dd, J¼3.6, 7.5 Hz, 1H), 5.77 (dd, J¼6.0, 15.0 Hz, 1H), 5.95 (ddd,
J¼1.2, 6.3, 7.5 Hz, 1H), 6.89 (d, J¼6.9 Hz, 1H-NH), 7.30–7.59 (m, 8H),
d 31.2, 44.0, 56.5, 57.3, 83.2, 127.1, 127.3, 127.8, 128.3, 128.8, 128.8,
129.7, 131.5, 131.8, 134.8, 137.3, 138.4, 166.7; HRMS calcd for
7.83–7.86 (m, 2H); 13C NMR (CDCl3, 125 MHz)
d
44.2, 58.9, 74.6,
C19H21O2NCl (MþþH) 330.1261; found, 330.1263.
127.3,127.8, 128.3, 128.9, 129.0, 129.2, 129.3 132.1, 132.9, 134.3, 137.7,
167.8; HRMS calcd for C18H19O2NCl (MþþH) 316.1104; found,
316.1100.
4.5.2. N-((2S,3R,E)-6-Chloro-3-methoxy-1-phenylhex-4-en-2-yl)-
benzamide (11b). Yield 57%; as a colorless oil; Rf¼0.5 (ethyl acetate/
hexanes¼1/2); IR (neat) nmax: 1100, 1532, 1642, 1701, 2358, 3618,
25
4.4.2. N-((2S,3R,E)-6-Chloro-3-hydroxy-1-phenylhex-4-en-2-yl)benz-
3681, 3740, 3852 cmꢁ1; [
a
]
ꢁ16.91 (c 0.5, CHCl3); 1H NMR (CDCl3,
D
amide (7b). Yield 70%; as a white solid; mp¼169–170 ꢀC; Rf¼0.4
300 MHz)
d
2.97 (dd, J¼5.0, 9.0 Hz, 1H), 3.04 (dd, J¼3.0, 9.0 Hz, 1H),
(ethyl acetate/hexanes¼1/1); IR (neat) nmax: 1532, 1642, 1701,
3.36 (s, 3H), 3.86 (dd, J¼3.0, 3.5 Hz, 1H), 4.01–4.11 (m, 2H), 4.52–
4.58 (m, 1H), 5.78 (dd, J¼4.2, 9.3 Hz, 1H), 5.93–5.98 (m, 1H), 6.17 (d,
J¼5.1 Hz, 1H-NH), 7.20–7.31 (m, 5H), 7.33–7.49 (m, 3H), 7.62–7.66
25
2358, 3279, 3618, 3681, 3740, 3852 cmꢁ1; [
a
]
ꢁ63.44 (c 1.0,
D
CHCl3); 1H NMR (CD3OD, 300 MHz)
d
2.80 (dd, J¼6.0, 8.4 Hz, 1H),
3.03 (d, J¼8.4 Hz, 1H), 4.12–4.23 (m, 4H), 5.60 (ddd, J¼4.2, 4.5,
9.0 Hz, 1H), 5.96 (ddd, J¼2.4, 4.5, 4.5 Hz, 1H), 7.11–7.13 (m, 1H),
7.15–7.29 (m, 4H), 7.39–7.57 (m, 3H), 7.67–7.76 (m, 2H), 8.16–8.18
(m, 2H); 13C NMR (CDCl3, 125 MHz)
d 35.38, 44.18, 53.73, 57.44,
82.47, 126.77, 127.05, 127.08, 127.14, 128.75, 128.80, 128.83, 129.50,
130.75, 131.62, 131.96, 134.99, 138.06, 167.23; HRMS calcd for
C20H23O2NCl (MþþH) 344.1417; found, 344.1419.
(m, 1H); 13C NMR (CD3OD, 125 MHz)
d 35.7, 45.7, 56.25, 73.3, 126.5,
127.2, 127.8, 127.9, 127.9, 128.7, 128.8, 129.8, 131.6, 135.6, 137.0,
140.4, 166.9; HRMS calcd for C19H21O2NCl (MþþH) 330.1261;
found, 330.1262.
4.5.3. N-((3S,4R,E)-7-Chloro-4-methoxy-2-methylhept-5-en-3-yl)-
benzamide (11c). Yield 57%; as a colorless oil; Rf¼0.4 (ethyl acetate/
hexanes¼1/2); IR (neat) nmax: 1093, 1261, 1610, 1720, 2355, 2960,
25
4.4.3. N-((3S,4R,E)-7-Chloro-4-hydroxy-2-methylhept-5-en-3-yl)-
3615, 3682, 3740, 3855 cmꢁ1; [
a]
5.68 (c 1.0, CHCl3); 1H NMR
D
benzamide (7c). Yield 77%; as a white solid; mp¼84–85 ꢀC; Rf¼0.2
(CDCl3, 300 MHz) d 0.99–1.14 (m, 6H), 2.08–2.14 (m, 1H), 3.34 (s,
(ethyl acetate/hexanes¼1/4); IR (neat) nmax: 696, 1525, 1643, 1700,
3H), 3.80 (dd, J¼6.3, 6.6 Hz, 1H), 4.10 (d, J¼6.6 Hz, 2H), 4.23–4.30
(m, 1H), 5.80 (dd, J¼6.9, 9.3 Hz, 1H), 5.91–5.97 (m, 1H), 6.17 (d,
J¼9.3 Hz, 1H-NH), 7.43–7.55 (m, 3H), 7.77–7.82 (m, 2H); 13C NMR
25
2358, 2961, 3353, 3681, 3851 cmꢁ1; [
NMR (CDCl3, 300 MHz)
a]
ꢁ66.35 (c 1.0, CHCl3); 1H
D
d 1.05–1.12 (m, 6H), 1.91–2.06 (m, 1H), 3.69
(br, 1H), 4.08 (d, J¼6.6 Hz, 2H), 4.11–4.18 (m, 1H), 4.49 (br, 1H), 5.89
(dd, J¼6.0, 12.0 Hz, 1H), 6.01 (ddd, J¼1.2, 6.0, 15.0 Hz, 1H), 6.21 (d,
J¼9.0 Hz, 1H-NH) 7.42–7.57 (m, 3H), 7.77–7.82 (m, 2H); 13C NMR
(CDCl3, 125 MHz) d 17.8, 20.8, 28.8, 44.3, 56.3, 57.3, 82.3, 127.1, 127.2,
128.8, 128.9, 130.6, 131.7, 131.8, 132.2, 135.20, 167.8; HRMS calcd for
C16H23O2NCl (MþþH) 296.1417; found, 296.1414.
(CDCl3, 125 MHz)
d 19.1, 19.4, 29.5, 44.6, 72.8, 127.3, 128.8, 128.9,
132.0, 133.2, 134.5, 169.4; HRMS calcd for C15H21O2NCl (MþþH)
4.5.4. N-((4S,5R,E)-8-Chloro-5-methoxy-2-methyloct-6-en-4-yl)benz-
282.1261; found, 282.1258.
amide (9a). Yield 73%; as a colorless oil; Rf¼0.4 (ethyl acetate/
hexanes¼1/3); IR (neat) nmax: 1462, 1525, 1642, 1688, 2357, 2948,
25
4.4.4. N-((4S,5R,E)-8-Chloro-5-hydroxy-2-methyloct-6-en-4-yl)benz-
3618, 3680, 3740, 3851 cmꢁ1; [
a
]
D
ꢁ32.76 (c 1.0, CHCl3); 1H NMR
amide (7d). Yield 66%; as a white solid; mp¼125–126 ꢀC; Rf¼0.4
(CDCl3, 300 MHz) d 0.92–1.06 (m, 6H), 1.38–1.59 (m, 2H), 1.63–1.74
(ethyl acetate/hexanes¼1/2); IR (neat) nmax: 1075, 1533, 1636, 2358,
(m, 1H), 3.34 (s, 3H), 3.84 (dd, J¼3.9, 6.6 Hz, 1H), 4.11 (d, J¼6.6 Hz,
2H), 4.33–4.39 (m, 1H), 5.73–5.84 (m, 1H), 5.89–5.98 (m, 1H), 6.33
(d, J¼9.3 Hz, 1H-NH), 7.31–7.55 (m, 3H), 0, 7.79–7.81 (m, 2H); 13C
25
2950, 3297, 3740, 3852 cmꢁ1; [
(CDCl3, 300 MHz)
a]
D
ꢁ64.46 (c 1.0, CHCl3); 1H NMR
d 0.94–0.97 (m, 6H), 1.36–1.41 (m, 1H), 1.46–1.52
(m, 1H), 1.66–1.71 (m, 1H), 3.91 (d, J¼2.4 Hz, 1H-OH), 4.06 (d,
NMR (CDCl3, 125 MHz) d 21.9, 23.9, 25.2, 38.4, 44.2, 51.2, 57.6, 83.9,

2128
V.-T. Pham et al. / Tetrahedron 66 (2010) 2123–2131
126.8, 127.0, 127.2, 128.8, 129.9, 131.6, 132.0, 135.0, 167.2; HRMS
134.9, 167.0; HRMS calcd for C22H37O2NClSi (MþþH) 410.2282;
calcd for C17H25O2NCl (MþþH) 310.1574; found, 310.1574.
found, 410.2277.
4.6. General procedure for alcohol protection (with
tert-butyldimethylsilyl group)
4.7. Protection of alcohol with benzyl, methyoxymethyl
and benzyloxymethyl groups
Imidazole (1.2 equiv) and tert-butyldimethyl chlorosilane
(1.2 equiv) were added to a stirred solution of alcohol 7a–d
(1.0 equiv) in DMF (0.1 M) at room temperature. And stirring was
allowed to continue for 2 h. The reaction mixture was quenched with
H2O, extracted twice with Ethyl acetate. The organic layer was
washed with brine, dried with MgSO4, and evaporated in vacuo.
Purification by silica gel chromatography gave silyl ether 9e,12a–c as
a white solid.
4.7.1. N-((4S,5R,E)-5-(Benzyloxy)-8-chloro-2-methyloct-6-en-4-yl)-
benzamide (9b). A solution of alcohol 7d (1.0 mmol) in tetrahy-
drofuran (5 mL) was added to a rapidly stirred suspension of sodium
hydride (60%, 100 mg, 2.5 mmol) in tetrahydrofuran (10 mL). After
the reaction mixture was stirred at room temperature for 10 min,
a solution of benzyl bromide (1.16 mmol) in tetrahydrofuran (2 mL)
was added. The reaction mixture was stirred at room temperature
for 2 h, and poured into aqueous ammonium chloride solution (15%,
2 mL), and concentrated under reduced pressure. The residue was
extracted with ethyl acetate (3ꢂ20 mL). The combined organic
layers were washed with brine, dried, filtered, and evaporated to
afford crude product under reduced pressure. Purification on silica
gel afforded benzyl ether product 9b; Yield 70%; as a white solid;
mp¼118–120 ꢀC; Rf¼0.4 (ethyl acetate/hexanes¼1/4); IR (neat)
4.6.1. N-((1S,2R,E)-2-(tert-Butyldimethylsilyloxy)-5-chloro-1-phe-
nylpent-3-enyl)-benzamide (12a). Yield 85%; as a white solid;
mp¼105–107 ꢀC; Rf¼0.3 (ethyl acetate/hexanes¼1/8); IR (neat)
nmax: 1083, 1255, 1533, 1639, 2358, 2857, 2942, 3291, 3741,
25
3852 cmꢁ1; [
d
a]
ꢁ0.27 (c 1.0, CHCl3); 1H NMR (CDCl3, 300 MHz)
D
0.10 (d, J¼3.6 Hz, 6H), 0.94–0.96 (m, 9H), 4.03 (dd, J¼1.2, 6.6 Hz,
nmax: 1079, 1279, 1532, 1642, 2358, 2953, 3305, 3681, 3741,
25
2H), 4.70 (dd, J¼4.8, 5.4 Hz, 1H), 5.25 (dd, J¼4.2, 8.1 Hz, 1H), 5.59
(ddd, J¼0.6, 6.0, 15.3 Hz, 1H), 6.81 (d, J¼7.8 Hz, 1H-NH), 7.31–7.42
(m, 5H), 7.46–7.55 (m, 3H), 7.81–7.85 (m, 2H); 13C NMR (CDCl3,
3852 cmꢁ1; [
d
a
]
ꢁ50.21 (c 1.0, CHCl3); 1H NMR (CDCl3, 300 MHz)
D
0.93 (d, J¼6.6 Hz, 6H), 1.42–1.64 (m, 3H), 4.05–4.12 (m, 3H), 4.32–
4.36 (m, 2H), 4.65 (d, J¼12.0 Hz, 1H), 5.77–5.85 (m, 1H), 5.93–6.01
(m, 1H), 6.13 (d, J¼9.5 Hz, 1H-NH), 7.24–7.49 (m, 8H), 7.64–7.67 (m,
125 MHz)
d
ꢁ4.7, ꢁ4.1, 18.4, 26.1, 44.3, 58.6, 74.8, 127.1, 127.9, 128.1,
128.6, 128.7, 128.9, 131.8, 134.2, 134.7, 138.4, 166.9; HRMS calcd for
2H); 13C NMR (CDCl3, 125 MHz)
d 21.8, 24.0, 25.2, 38.2, 44.3, 51.2,
C24H33O2NClSi (MþþH) 430.1969; found, 430.1967.
71.4, 81.2, 127.1, 128.0, 128.1, 128.7, 128.6, 130.2, 131.6, 132.2, 134.9,
138.3 167.1; HRMS calcd for C23H29O2NCl (MþþH) 386.1887; found,
386.1887.
4.6.2. N-((2S,3R,E)-3-(tert-Butyldimethylsilyloxy)-6-chloro-1-phe-
nylhex-4-en-2-yl)benzamide (12b). Yield 95%; as a white solid;
mp¼120–122 ꢀC; Rf¼0.7 (ethyl acetate/hexanes¼1/4); IR (neat)
4.7.2. N-((4S,5R,E)-8-Chloro-5-(methoxymethoxy)-2-methyloct-6-
en-4-yl)benzamide (9c). To a solution of amino alcohol 7d
nmax: 1082, 1548, 1640, 1700, 2357, 2858, 2952, 3281, 3681, 3740,
25
3852 cmꢁ1; [
d
a
]
D
ꢁ23.05 (c 1.0, CHCl3); 1H NMR (CDCl3, 300 MHz)
(1.0 equiv) in anhydrous CH2Cl2 (20 mL) was added N,N-diisopro-
pylethylamine (4.0 equiv) and MOMCl (2.0 equiv) dropwise at 0 ꢀC
under N2. The reaction mixture was stirred at room temperature for
24 h. After the starting material disappeared, saturated aqueous
NaHCO3 (10 mL) was added to quench the reaction. The layers were
separated, and the aqueous layer was extracted with CH2Cl2
(20 mLꢂ3). The combined organic layers were washed with brine
(20 mLꢂ3), dried (MgSO4), and concentrated. The residue was pu-
rified by flash column chromatography on silica gel gave the MOM-
protective product 9c; Yield 90%; as a white solid; mp¼107–109 ꢀC;
ꢁ0.1 to 0.09 (m, 6H), 0.91–0.98 (m, 6H), 2.93 (dd, J¼5.5, 9.0 Hz,
1H), 3.03 (dd, J¼4.5, 9.0 Hz, 1H), 4.08 (d, J¼3.9 Hz, 2H), 4.43–4.48
(m, 1H), 4.54 (t, J¼2.4, 2.4 Hz, 1H), 5.89–6.00 (m, 2H), 6.07 (d,
J¼5.1 Hz, 1H-NH), 7.20–7.34 (m, 5H), 7.38–7.49 (m, 3H), 7.60–7.71
(m, 2H); 13C NMR (CDCl3, 125 MHz)
d
ꢁ4.8, ꢁ4.0, 18.4, 26.1, 34.9,
44.4, 55.5, 73.5, 126.7, 126.9, 128.2, 128.8, 128.8, 129.37, 131.6, 134.8,
134.9, 138.4, 167.2; HRMS calcd for C25H35O2NClSi (MþþH)
444.2126; found, 444.2120.
4.6.3. N-((3S,4R,E)-4-(tert-Butyldimethylsilyloxy)-7-chloro-2-meth-
ylhept-5-en-3-yl)benzamide (12c). Yield 82%; as a white solid;
mp¼110–112 ꢀC; Rf¼0.2 (ethyl acetate/hexanes¼1/6); IR (neat)
Rf¼0.35 (ethyl acetate/hexanes¼1/4); IR (neat) nmax: 1542, 1636,
25
1688, 2358, 2952, 3311, 3681, 3740, 3852 cmꢁ1; [
a]
ꢁ55.07 (c 1.0,
D
CHCl3); 1H NMR (CDCl3, 300 MHz)
d 0.95–1.01 (m, 6H),1.41–1.55 (m,
nma2x5: 697, 1086, 1532, 1642, 2358, 2862, 2956, 3303, 3740 cmꢁ1
;
2H), 1.68–1.71 (m, 1H), 3.37 (s, 3H), 4.10 (d, J¼4.2 Hz, 2H), 4.27 (dd,
J¼3.0, 5.0 Hz, 1H), 4.36–4.40 (m, 1H), 4.66 (s, 2H), 5.80 (ddd, J¼1.0,
5.0, 15.5 Hz, H), 5.94–5.99 (m, 1H), 6.47 (d, J¼9.5 Hz, 1H-NH), 7.43–
[
a]
ꢁ9.08 (c 1.0, CHCl3); 1H NMR (CDCl3, 300 MHz)
d 0.032–0.072
D
(m, 6H), 0.90–0.95 (m, 9H), 1.02–1.05 (m, 6H), 2.06–2.10 (m, 1H),
4.09–4.17 (m, 3H), 4.41 (dd, J¼4.2, 4.8 Hz, 1H), 5.91–5.93 (m, 2H),
6.11 (d, J¼9.9 Hz, 1H-NH), 7.44–7.53 (m, 3H), 7.77–7.81 (m, 2H); 13C
7.52 (m, 3H), 7.79–7.81 (m, 2H); 13C NMR (CDCl3, 125 MHz)
d 21.9,
23.9, 25.2, 38.7, 44.3, 51.1, 56.0, 80.1, 95.8, 127.1, 128.8, 129.8, 131.6,
131.9, 134.9, 167.1; HRMS calcd for C18H27O3NCl (MþþH) 340.1679;
found, 340.1679.
NMR (CDCl3, 125 MHz)
d
ꢁ4.8, ꢁ3.9, 18.0, 18.3, 21.2, 26.0, 26.1, 28.7,
44.5, 58.1, 73.6, 126.9, 128.1, 128.8, 128.9, 131.6, 131.6, 134.9, 135.3,
167.6; HRMS calcd for C21H35O2NClSi (MþþH) 396.2126; found,
396.2127.
4.7.3. N-((4S,5R,E)-5-(Benzyloxymethoxy)-8-chloro-2-methyloct-6-
en-4-yl)-benzamide (9d). To a solution of amino alcohol 7d in THF
(6.0 mL) were added DIEA (0.83 mL, 4.7 mmol) and BOMCl
(0.73 mL, 4.7 mmol). After being stirred for 3 h at 60 ꢀC, the solution
was cooled and diluted with ethyl acetate(100 mL). The organic
layer was washed with brine (50 mLꢂ3), dried (MgSO4), and con-
centrated. The residue was purified on a column of silica gel to yield
BOM-protective product 9d; Yield 76%; as a white solid; mp¼119–
4.6.4. N-((4S,5R,E)-5-(tert-Butyldimethylsilyloxy)-8-chloro-2-meth-
yloct-6-en-4-yl)benzamide (9e). Yield 95%; as white solid; mp¼127–
128 ꢀC; Rf¼0.4 (ethyl acetate/hexanes¼1/10); IR (neat) nmax: 1084,
1642, 1547, 1641, 1688, 2357, 2949, 3296, 3618, 3681, 3740,
3851 cmꢁ1; [
d
a]
D
ꢁ10.51 (c 1.0, CHCl3); 1H NMR (CDCl3, 300 MHz)
25
ꢁ0.024 to 0.04 (m, 6H), 0.87–0.98 (m,15H),1.37–1.42 (m,1H),1.45–
1.52 (m, 1H), 1.65–1.70 (m, 1H), 1.09 (d, J¼4.2 Hz, 2H), 4.22–4.28 (m,
1H), 4.43 (t, J¼2.4 Hz, 1H), 5.84 (dd, J¼3.0, 9.0 Hz, 1H), 5.92 (ddd,
J¼4.2, 4.5, 9.0 Hz, 1H), 6.03 (d, J¼5.7 Hz, 1H-NH), 7.28–7.53 (m, 3H),
121 ꢀC; Rf¼0.4 (Ethyl acetate/Hexane¼1/4); IR (neat) nmax: 1032,
25
1532,1640, 2358, 2953, 3309, 3740, 3852 cmꢁ1; [
a
]
ꢁ51.87 (c¼1.0,
D
CHCl3); 1H NMR (CDCl3, 300 MHz)
d 0.94–1.00 (m, 6H), 1.43–1.48
7.76–7.78 (m, 2H); 13C NMR (CDCl3, 125 MHz)
d
ꢁ4.7, ꢁ4.1, 18.4, 21.9,
(m, 1H), 1.52–1.58 (m, 1H), 1.67–1.71 (m, 1H), 4.09 (d, J¼4.2 Hz, 2H),
23.9, 25.2, 25.9, 26.1, 38.0, 44.5, 42.7, 126.9, 127.9, 128.8, 131.6, 134.9,
4.33 (dd, J¼3.0, 5.0 Hz, 1H), 4.39–4.44 (m, 1H), 4.55 (d, J¼6.9 Hz,

V.-T. Pham et al. / Tetrahedron 66 (2010) 2123–2131
2129
1H), 4.69 (d, J¼6.3 Hz, 1H), 4.77 (d, J¼4.2 Hz, 1H), 4.86–4.88 (m, 1H),
5.82 (dd, J¼3.9, 9.3 Hz, 1H), 5.98 (ddd, J¼4.2, 4.2, 8.4 Hz, 1H), 6.53
(d, J¼5.7 Hz, 1H), 7.28–7.49 (m, 8H), 7.73–7.75 (m, 2H); 13C NMR
6.12 (ddd, J¼6.0, 10.5, 17.0 Hz, 1H), 7.38–7.46 (m, 3H), 8.01–8.04 (m,
2H); 13C NMR (CDCl3, 125 MHz)
: 22.2, 24.3, 24.6, 43.8, 56.8, 60.6,
78.1, 81.1, 118.45, 127.7, 128.2, 130.6, 133.5, 135.0, 152.7; HRMS calcd
for C17H23O2N (Mþ) 273.1729; found, 273.1730.
d
(CDCl3, 125 MHz)
d 21.9, 23.9, 25.2, 38.7, 44.3, 51.1, 70.5, 80.6, 94.2,
127.1, 127.2, 127.8, 128.1, 128.7, 128.7, 128.7, 129.9, 131.6, 131.9, 134.8,
137.6, 167.2; HRMS calcd for C24H31O3NCl (MþþH) 416.1992; found,
416.1987.
4.8.5. (4S,5S,6S)-5-(Benzyloxy)-4-isobutyl-2-phenyl-6-vinyl-5,6-di-
hydro-4H-1,3-oxazine (10b). Yield 70%; ratio anti,syn/anti,anti¼5/1;
as a colorless oil; Rf¼0.4 (Ethyl acetate/Hexane¼1/20); IR (neat)
25
4.8. General procedure for oxazine formation
nmax: 9.29, 1025, 1102, 1282, 1455, 1657, 2950, 3744 cmꢁ1; [
a]
D
ꢁ70.21 (c 0.5, CHCl3); 1H NMR (CDCl3, 300 MHz)
d 0.96–1.06 (m,
NaH(60% in mineral oil, 2 equiv) and n-Bu4NI (1.0 equiv) were
added to a stirred solution of methyl ether or silyl ether (1.0 equiv) in
dry THF(0.05 M) at 0 ꢀC. After being stirred for 5 min, Pd (PPh3)4
(0.2 equiv) was added to a mixture and stirring was allowed to con-
tinue for 5 h. at same temperature. The reaction mixture was filtered
throughapadofsilicaandthenevaporatedunderreduced pressureto
give the crude product. Purification of this material by silica gel
chromatography gave mixtures of anti,anti/anti,syn-oxazines.
6H), 1.41–1.50 (m, 2H), 2.06–2.11 (m, 1H), 3.50–3.51 (m, 1H), 3.67
(dd, J¼3.5, 7.5 Hz, 1H), 4.64–4.79 (m, 2H), 5.40 (ddd, J¼4.5, 5.5,
14.5 Hz, 2H), 6.13 (ddd, J¼3.3, 6.6, 10.0 Hz, 1H), 7.31–7.44 (m, 8H),
8.01–8.03 (m, 2H); 13C NMR (CDCl3, 125 MHz)
d 22.8, 23.8, 24.8,
44.8, 52.8, 72.1, 74.0, 75.6, 117.9, 127.6, 127.8, 128.1, 128.2, 128.2,
128.7, 128.7, 130.6, 130.7, 133.5, 133.8, 134.9, 138.1, 138.2, 152.8;
HRMS calcd for C23H28O2N (MþþH) 350.2120; found, 350.2124.
4.8.6. (4S,5S,6R)-5-(Benzyloxy)-4-isobutyl-2-phenyl-6-vinyl-5,6-di-
4.8.1. (4S,5S,6S)-4-Isobutyl-2-phenyl-6-vinyl-5,6-dihydro-4H-1,3-
hydro-4H-1,3-oxazine (10b0). Yield 70%; ratio anti,syn/anti,anti¼5/1;
oxazin-5-ol (8). Yield 62%; ratio anti,syn/anti,anti¼2/1; as a color-
as a colorless oil; Rf¼0.42 (ethyl acetate/hexanes¼1/20); IR (neat)
25
less oil; Rf¼0.4 (ethyl acetate/hexanes¼1/6); IR (neat) nmax: 926,
nmax: 929,1027,1102,1280,1461,1658, 2944, 3750 cmꢁ1
[a]
ꢁ40.80
D
1082,1265, 1330,1460,1653,1721, 2922, 3385 cmꢁ1; [
a]
ꢁ35.93 (c
(c 1.0, CHCl3); 1H NMR (CDCl3, 300 MHz)
d 0.89–1.05 (m, 6H), 1.34–
25
D
1.0, CHCl3); 1H NMR (CDCl3, 300 MHz)
d
0.99–1.12 (m, 6H), 1.42–
1.37 (m, 1H), 1.58–1.67 (m, 1H), 2.17–2.24 (m, 1H), 3.15 (t, J¼8.5 Hz,
1H), 3.55 (ddd, J¼3.6, 7.5, 11.0 Hz, 1H), 4.52 (dd, J¼6.3, 8.6 Hz, 1H),
4.61 (d, J¼11.0 Hz, 1H), 4.73 (d, J¼11.0 Hz, 1H), 5.41 (dt, J¼1.4, 1.4,
10.5 Hz, 1H), 5.58 (dt, J¼1.4, 1.4, 17.2 Hz, 1H), 6.10 (ddd, J¼6.3, 10.0,
16.3 Hz, 1H), 7.33–7.39 (m, 8H), 7.96–7.99 (m, 2H); 13C NMR (CDCl3,
1.58 (m, 2H), 2.01–2.13 (m,1H), 3.67–3.72 (m,1H), 3.79 (br,1H), 4.76
(ddd, J¼2.0, 2.1, 3.5 Hz, 1H), 5.52 (ddd, J¼1.5, 1.5, 10.5 Hz, 1H), 5.62
(ddd, J¼1.5, 1.5, 17.5 Hz, 1H), 6.08 (ddd, J¼5.1, 10.5, 17.5 Hz, 1H),
7.39–7.52 (m, 3H), 7.75–7.77 (m, 1H), 8.03–8.07 (m, 1H); 13C NMR
(CDCl3, 125 MHz)
d
22.9, 23.1, 25.1, 31.2, 45.9, 46.3, 66.0, 66.7, 73.7,
125 MHz) d 22.7, 23.7, 24.8, 44.7, 52.8, 72.1, 74.0, 75.6, 118.0, 127.6,
74.7, 87.2, 87.6, 118.0, 119.0, 127.5, 128.5, 131.5, 131.6, 135.3, 162.3;
128.1,128.2,128.2,128.7,130.7,133.7,133.8,138.1,138.2,152.8; HRMS
HRMS calcd for C16H21O2N (MþþH) 259.1572; found, 259.1570.
calcd for C23H28O2N (MþþH) 350.2120; found, 350.2115.
4.8.2. (4S,5S,6R)-4-Isobutyl-2-phenyl-6-vinyl-5,6-dihydro-4H-1,3-
4.8.7. (4S,5S,6S)-4-Isobutyl-5-(methoxymethoxy)-2-phenyl-6-vinyl-
5,6-dihydro-4H-1,3-oxazine (10c). Yield 80%; ratio anti,syn/anti,
anti¼8/1; as a colorless oil; Rf¼0.16 (ethyl acetate/hexanes¼1/20);
oxazin-5-ol (80). Yield 62%; ratio anti,syn/anti,anti¼2/1; as a color-
less oil; Rf¼0.5 (ethyl acetate/hexanes¼1/6); IR (neat) nmax: 928,
25
1076, 1275, 1330, 1456, 1646, 1713, 2954, 3380 cmꢁ1; [
a]
5.66 (c
IR (neat) nmax: 1038, 1110, 1217, 1367, 1459, 1526, 1656, 1738, 2358,
D
25
0.5, CHCl3); 1H NMR (CDCl3, 300 MHz)
d
1.05–1.10 (m, 6H), 1.37–
2950, 3742, 3850 cmꢁ1; [
a
]
D
ꢁ54.59 (c 0.5, CHCl3); 1H NMR (CDCl3,
1.46 (m, 1H), 1.71–1.78 (m, 1H), 1.21–1.28 (m, 1H), 3.34 (ddd, J¼3.9,
4.5, 8.4 Hz, 1H), 3.50 (ddd, J¼3.6, 7.5, 11.0 Hz, 1H), 4.42 (dd, J¼6.8,
9.2 Hz, 5.57) (ddd, J¼1.2, 1.5, 9.5 Hz, 2H), 6.06 (ddd, J¼6.8, 9.5,
17.5 Hz, 1H), 7.38–7.47 (m, 3H), 7.34–7.77 (m, 1H), 8.00–8.03 (m,
300 MHz)
d
0.94 (d, J¼6.0 Hz, 6H), 1.46–1.52 (m, 2H), 2.11–2.13 (m,
1H), 3.46 (s, 3H), 3.68 (t, J¼1.5, 6.3 Hz, 1H), 3.74 (ddd, J¼1.5, 3.0,
6.0 Hz,1H), 4.78 (dd, J¼6.9,19.0 Hz, 2H), 4.85 (ddd, J¼1.5,1.5, 5.0 Hz,
1H), 5.42 (ddd, J¼1.5, 1.5, 9.5 Hz, 1H), 5.51 (ddd, J¼1.2, 1.5, 16.0 Hz,
1H), 6.14 (ddd, J¼5.4,10.5,17.5 Hz,1H), 7.38–7.49 (m, 3H), 8.02–8.06
1H); 13C NMR (CDCl3, 125 MHz)
d 22.2, 24.2, 24.5, 30.0, 43.8, 57.3,
70.6, 79.5, 116.5, 120.3, 127.7, 128.2, 130.7, 133.4, 134.4, 152.8; HRMS
(m, 2H); 13C NMR (CDCl3,125 MHz)
d 22.7, 22.9, 29.9, 43.4, 44.9, 53.4,
calcd for C16H21O2N (MþþH) 259.1572; found, 259.1568.
56.1, 74.1, 74.3, 78.3, 118.1, 127.6, 127.7, 128.2, 130.7, 133.8, 152.9;
HRMS calcd for C18H26O3N (MþþH) 304.1913; found, 304.1912.
4.8.3. (4S,5S,6S)-4-isobutyl-5-methoxy-2-phenyl-6-vinyl-5,6-dihy-
dro-4H-1,3-oxazine (10a). Yield 51%; ratio anti,syn/anti,anti¼6/1; as
4.8.8. (4S,5S,6R)-4-Isobutyl-5-(methoxymethoxy)-2-phenyl-6-vinyl-
5,6-dihydro-4H-1,3-oxazine (10c0). Yield 80%; ratio anti,syn/anti,
anti¼8/1; as a colorless oil; Rf¼0.2 (ethyl acetate/hexanes¼1/20); IR
a colorless oil; Rf¼0.4 (ethyl acetate/hexanes¼1/20); IR (neat) nmax
:
25
931, 1109, 1284, 1366, 1455, 1657, 1738, 2950 cmꢁ1; [
1.0, CHCl3); 1H NMR (CDCl3, 300 MHz)
a
]
ꢁ84.74 (c
D
d
1.08 (d, J¼6.9 Hz, 6H), 1.50
(neat) nmax: 1032,1111,1218,1366,1455,1526,1657,1722, 2357, 2949,
25
(t, J¼6.9, 7.2 Hz, 2H), 2.11–2.20 (m, 1H), 3.32 (dd, J¼3.5, 5.0 Hz, 1H),
3.51 (s, 3H), 3.68 (ddd, J¼3.5, 5.1, 10.3 Hz, 1H), 4.87 (ddd, J¼1.5, 3.5,
7.0 Hz, 1H), 5.41 (ddd, J¼1.2, 1.2, 11.7 Hz, 1H), 5.48 (ddd, J¼1.2, 1.2,
17.0 Hz, 1H), 6.13 (ddd, J¼5.4, 10.6, 17.2 Hz, 1H), 7.38–7.46 (m, 3H),
3748, 3850 cmꢁ1; [
300 MHz)
a]
D
ꢁ127.01 (c 1.0, CHCl3); 1H NMR (CDCl3,
d 0.99–1.03 (m, 6H), 1.35–1.40 (m. 1H), 1.60–1.69 (m, 1H),
2.17–2.25 (m,1H), 3.32 (t, J¼8.0 Hz,1H), 3.42 (s, 3H), 3.51 (ddd, J¼3.6,
4.0, 11.0 Hz, 1H), 4.48 (dd, J¼6.6, 8.2 Hz, 1H), 4.68 (d, J¼6.9 Hz, 1H),
4.75 (d, J¼6.9 Hz,1H), 5.38 (dt, J¼1.3, 1.3, 10.5 Hz, 1H), 5.52 (dt, J¼1.5,
1.5,17.0 Hz,1H), 6.02 (ddd, J¼6.5,10.5,17.0 Hz,1H), 7.35–7.39 (m, 3H),
8.03–8.06 (m, 2H); 13C NMR (CDCl3,125 MHz)
d 22.7, 23,7, 24.9, 44.9,
52.4, 57.8, 73.7, 78.1, 117.9, 127.6, 128.2, 130.6, 133.6, 133.9, 152.8;
HRMS calcd for C17H24O2N (MþþH) 274.1807; found, 274.1812.
7.95–7.99 (m, 2H); 13C NMR (CDCl3, 125 MHz)
d 22.1, 24.3, 24.6, 43.4,
56.5, 56.7, 78.3, 97.8, 119.1, 127.7, 128.2, 130.6, 133.4, 134.7, 152.9;
4.8.4. (4S,5S,6R)-4-isobutyl-5-methoxy-2-phenyl-6-vinyl-5,6-dihy-
HRMS calcd for C18H26O3N (MþþH) 304.1913; found, 304.1914.
dro-4H-1,3-oxazine (10a0). Yield 51%; ratio anti,syn/anti,anti¼6/1; as
a colorless oil; Rf¼0.5 (ethyl acetate/hexanes¼1/20); IR (neat) nmax
:
4.8.9. (4S,5S,6S)-5-(Benzyloxymethoxy)-4-isobutyl-2-phenyl-6-vi-
nyl-5,6-dihydro-4H-1,3-oxazine (10d). Yield 90%; ratio anti,syn/
anti,anti¼15/1; as a colorless oil; Rf¼0.2 (ethyl acetate/hexanes¼1/
25
930, 1109, 1280, 1366, 1454, 1656, 1721, 2942 cmꢁ1; [
a]
ꢁ88.39 (c
D
1.0, CHCl3); 1H NMR (CDCl3, 300 MHz)
d
1.06–1.10 (m, 6H), 1.37–1.46
(m, 1H), 1.64–1.72 (m, 1H), 2.27–2.32 (m, 1H), 2.92 (t, J¼8.4, 8.7 Hz,
1H), 3.48–3.52 (m, 1H), 3.56 (s, 3H), 4.49 (ddd, J¼1.5, 6.0, 9.0 Hz,1H),
5.44 (ddd, J¼1.2, 1.5, 10.5 Hz, 1H), 5.61 (ddd, J¼1.2, 1.5. 17.0 Hz, 1H),
20); IR (neat) nmax: 1042, 1113, 1516, 1655, 2951, 3672, 3744,
25
3841 cmꢁ1; [
d
a]
ꢁ50.25 (c 0.5, CHCl3); 1H NMR (CDCl3, 300 MHz)
D
0.89–0.96 (m, 6H), 1.48–1.52 (m, 2H), 2.11–2.16 (m, 1H), 3.70–3.76

2130
V.-T. Pham et al. / Tetrahedron 66 (2010) 2123–2131
(m, 1H), 3.84 (dd, J¼3.0, 4.5 Hz, 1H), 4.70 (dd, J¼11.7, 22.0 Hz, 1H),
4.86–4.95 (m, 2H), 5.43 (ddd, J¼1.5,1.5, 9.0 Hz,1H), 5.52 (ddd, J¼1.6,
1.6, 16.0 Hz, 1H), 6.16 (ddd, J¼5.4, 10.5, 17.0 Hz, 1H), 7.30–7.49 (m,
d
ꢁ0.23 (s, 6H), 0.89–0.91 (m, 9H), 3.91 (dd, J¼3.9, 6.6 Hz, 1H), 4.60
(d, J¼6.9 Hz, 1H), 4.78 (ddd, J¼2.0, 2.4, 5.9 Hz, 1H), 5.39 (ddd, J¼1.5,
1.5, 4.5 Hz, 1H), 5.43 (ddd, J¼1.2, 1.5, 4.5 Hz, 1H), 6.16 (ddd, J¼4.5,
10.5, 17.7 Hz, 1H), 7.29–7.51 (m, 8H), 8.12–8.15 (m, 2H); 13C NMR
8H), 8.04–8.07 (m, 2H); 13C NMR (CDCl3,125 MHz)
d 22.8, 23.7, 24.9,
45.0, 53.5, 70.2, 74.3, 94.3, 118.2, 127.6, 127.8, 127.9, 128.1, 128.1,
128.2, 128.8, 130.6, 133.8, 137.8, 152.9; HRMS calcd for C24H30O3N
(MþþH) 380.2226; found, 380.2231.
(CDCl3, 125 MHz)
d
ꢁ5.2, ꢁ4.7, 18.2, 25.9, 61.6, 71.4, 75.8, 117.9,
127.5, 127.8, 128.3, 128.5, 130.9, 133.3, 133.6, 141.9, 154.3; HRMS
calcd for C24H32O2NSi (MþþH) 394.2202; found, 394.2198.
4.8.10. (4S,5S,6R)-5-(Benzyloxymethoxy)-4-isobutyl-2-phenyl-6-vi-
nyl-5,6-dihydro-4H-1,3-oxazine (10d0). Yield 90%; ratio anti,syn/
anti,anti¼15/1; as a colorless oil; Rf¼0.21 (ethyl acetate/hexanes¼1/
4.8.15. (4S,5S,6S)-4-Benzyl-5-methoxy-2-phenyl-6-vinyl-5,6-dihy-
dro-4H-1,3-oxazine (13b). Yield 65%; ratio anti,syn/anti,anti¼3/1; as
a colorless oil; Rf¼0.3 (ethyl acetate/hexanes¼1/20); IR (neat) nmax
:
25
20); IR (neat) nmax: 1042, 1113, 1515, 1658, 2944, 3672, 3746,
772, 1109, 1217, 1516, 1651, 1739, 2357, 3678, 3742, 3850 cmꢁ1; [
a]
D
25
3845 cmꢁ1; [
d
a]
D
ꢁ11.86 (c 1.0, CHCl3); 1H NMR (CDCl3, 300 MHz)
ꢁ4.72 (c 0.5, CHCl3); 1H NMR (CDCl3, 300 MHz)
d
2.99 (dd, J¼6.0,
0.92–1.01 (m, 6H), 1.32–1.38 (m, 1H), 1.64–1.72 (m, 1H), 3.41 (t,
13.5 Hz,1H), 3.11 (dd, J¼6.5,13.5 Hz,1H), 3.31 (dd, J¼3.6, 5.4 Hz,1H),
3.84 (dd, J¼6.5, 12.5 Hz, 1H), 4.90 (ddd, J¼1.8, 3.8, 7.0 Hz, 1H), 5.36–
5.45 (m, 2H), 6.08 (ddd, J¼5.5, 11.5, 18.5 Hz, 1H), 7.26–7.48 (m, 8H),
J¼8.0 Hz, 1H), 3.54 (ddd, J¼3.6, 3.6, 10.5 Hz, 1H), 4.50 (dd, J¼6.5,
8.0 Hz, 1H), 4.63 (d, J¼12.0 Hz, 1H), 4.74 (d, J¼12.0 Hz, 1H), 4.86 (m,
2H), 5.35 (dt, J¼1.3, 1.3, 10.5 Hz, 1H), 5.52 (dt, J¼1.4, 1.4, 17.3 Hz, 1H),
6.02 (ddd, J¼6.5, 10.5, 17.3 Hz, 1H), 7.33–7.39 (m, 8H), 7.96–7.99 (m,
8.02–8.05 (m, 2H); 13C NMR (CDCl3,125 MHz)
d 40.6, 55.5, 57.4, 73.5,
75.9, 118.0, 126.6, 127.6, 128.3, 128.5, 130.0, 130.7, 133.2, 133.5, 138.7,
2H); 13C NMR (CDCl3,125 MHz)
d 22.7, 23.6, 24.9, 44.9, 53.5, 70.1, 74.2,
153.4; HRMS calcd for C20H21O2N (Mþ) 307.1572; found, 307.1568.
94.2, 118.1, 127.6, 128.0, 128.1, 128.2, 128.7, 130.6, 133.8, 133.9, 137.8,
152.9; HRMS calcd for C24H30O3N (MþþH) 380.2226; found,
380.2225.
4.8.16. (4S,5S,6R)-4-benzyl-5-methoxy-2-phenyl-6-vinyl-5,6-dihy-
dro-4H-1,3-oxazine (13b0). Yield 65%; ratio anti,syn/anti,anti¼3/1; as
a colorless oil; Rf¼0.32 (ethyl acetate/hexanes¼1/20); IR (neat) nmax
:
25
4.8.11. (4S,5S,6S)-5-(tert-Butyldimethylsilyloxy)-4- isobutyl-2-phe-
nyl-6-vinyl-5,6-dihydro-4H-1,3-oxazine (10e). Yield 65%; ratio
anti,syn/anti,anti¼30/1; as a colorless oil; Rf¼0.35 (ethyl acetate/
772, 1116, 1516, 1654, 3257, 3616, 3742, 3849 cmꢁ1; [
a]
ꢁ1.52 (c 0.5,
D
CHCl3); 1H NMR (CDCl3, 300 MHz)
d
2.91–3.02 (m, 2H), 3.25 (dd,
J¼5.0,14.0 Hz,1H), 3.79 (ddd, J¼4.0, 4.5,12.0 Hz,1H), 4.50 (ddd, J¼3.7,
6.6, 7.8 Hz,1H), 5.44 (ddd, J¼1.2, 1.2, 10.8 Hz, 1H), 5.60 (ddd, J¼1.2, 1.5,
17.0 Hz, 1H), 6.08 (ddd, J¼6.3, 10.5, 17.0 Hz, 1H), 7.26–7.47 (m, 8H),
hexanes¼1/20); IR (neat) nmax: 1115, 1259, 1462, 1513, 1655, 2928,
25
3680, 3742, 3852 cmꢁ1; [
a
]
ꢁ61.54 (c 0.5, CHCl3); 1H NMR (CDCl3,
D
300 MHz)
d
0.081–0.14 (m, 6H), 0.86–0.89 (m, 9H), 0.99–1.05 (m,
7.99–8.05 (m, 2H); 13C NMR (CDCl3, 125 MHz)
d 40.6, 55.5, 57.4, 73.5,
6H), 1.32–1.37 (m, 1H), 1.45–1.50 (m, 1H), 2.12–2.19 (m, 1H), 3.41
(ddd, J¼3.0, 3.0, 6.0 Hz, 1H), 3.70 (t, J¼2.4, 3.3 Hz, 1H), 4.72 (t, J¼2.4,
3.0 Hz, 1H), 5.35 (t, J¼7.2, 11.7 Hz, 12H), 6.07 (ddd, J¼3.0, 6.3,
10.5 Hz, 1H), 7.37–7.44 (m, 3H), 7.99–8.01 (m, 2H); 13C NMR (CDCl3,
75.8, 118.0, 126.6, 127.6, 128.3, 128.5, 130.0, 130.7, 133.1, 138.7, 153.4;
HRMS calcd for C20H21O2N (Mþ) 307.1572; found, 307.1568.
4.8.17. (4S,5S,6S)-4-Benzyl-5-(tert-butyldimethylsilyloxy)-2-phenyl-
6-vinyl-5,6-dihydro-4H-1,3-oxazine (14b). Yield 65%; ratio anti,syn/
anti,anti¼12/1; as a colorless oil; Rf¼0.4 (ethyl acetate/hexanes¼1/
125 MHz)
d
ꢁ4.4, ꢁ4.1, 18.3, 22.5, 24.1, 24.7, 25.9, 44.4, 55.4, 69.9,
75.9, 117.5, 127.6, 128.2, 130.4, 133.7, 134.0, 152.1; HRMS calcd for
C22H36O2NSi (MþþH) 374.2515; found, 374.2513.
20); IR (neat) nmax: 772, 1034, 1518, 1695, 2354, 3673, 3743,
25
3848 cmꢁ1; [
d
a
]
D
ꢁ0.94 (c 0.5, CHCl3); 1H NMR (CDCl3, 300 MHz)
4.8.12. (4S,5S,6S)-5-Methoxy-2,4-diphenyl-6-vinyl-5,6-dihydro-4H-
0.16 (d, J¼9.0 Hz, 6H), 0.92–0.94 (m, 9H), 2.92–2.96 (m, 1H), 3.66
1,3-oxazine (13a). Yield 62%; ratio anti,syn/anti,anti¼2/1; as a col-
(ddd, J¼6.0 Hz, 6.8 Hz, 14.0 Hz, 1H), 3.81 (ddd, J¼3.0, 3.6, 5.0 Hz,
1H), 5.33 (ddd, J¼1.2, 1.8, 7.8 Hz, 1H), 5.38 (ddd, J¼1.5, 1.5, 14.4 Hz,
1H), 6.08 (ddd, J¼4.8,11.3,18.0 Hz,1H), 7.27–7.48 (m, 8H), 8.01–8.04
orless oil; Rf¼0.32 (ethyl acetate/hexanes¼1/20); IR (neat) nmax
:
;
699, 1115, 1270, 1531, 1653, 2356, 2928, 3354, 3732, 3850 cmꢁ1
25
[
a]
ꢁ16.36 (c 0.5, CHCl3); 1H NMR (CDCl3, 300 MHz)
d
3.50 (s, 3H),
(m, 2H); 13C NMR (CDCl3, 125 MHz)
d
ꢁ4.5, ꢁ4.1, 18.3, 26.0, 26.3,
D
3.53 (dd, J¼2.7, 3.9 Hz, 1H), 4.72 (ddd, J¼1.2, 1.5, 4.8 Hz, 1H), 4.93 (d,
J¼3.9 Hz, 1H), 5.38–5.47 (m, 2H), 6.10 (ddd, J¼5.4, 10.5, 17.4 Hz, 1H),
7.33–7.51 (m, 7H), 7.73–7.75 (m, 1H), 8.13–8.16 (m, 2H); 13C NMR
40.9, 59.4, 68.0, 75.7, 117.8, 126.3, 126.57, 127.6, 128.1, 128.3, 128.4,
128.6, 130.4, 133.6, 139.3, 153.1; HRMS calcd for C25H33O2NSi (Mþ)
407.2281; found, 407.2274.
(CDCl3, 125 MHz)
d 58.2, 58.5, 73.2, 79.7, 118.3, 127.4, 127.8, 127.8,
127.9, 127.9, 128.7, 130.9, 133.4, 135.47, 141.8, 155.2; HRMS calcd for
4.8.18. (4S,5S,6S)-4-Isopropyl-5-methoxy-2-phenyl-6-vinyl-5,6-di-
C19H20O2N (MþþH) 294.1494; found, 294.1493.
hydro-4H-1,3-oxazine(13c). Yield 58%; ratio anti,syn/anti,anti¼4/1;
as a colorless oil; Rf¼0.4 (ethyl acetate/hexanes¼1/20); IR (neat)
25
4.8.13. (4S,5S,6R)-5-Methoxy-2,4-diphenyl-6-vinyl-5,6-dihydro-4H-
nmax: 772, 1113, 1520, 1654, 3672, 3742, 3847 cmꢁ1; [
a
]
D
ꢁ45.74 (c
1,3-oxazine (13a0). Yield 62%; ratio anti,syn/anti,anti¼2/1; as a col-
1.0, CHCl3); 1H NMR (CDCl3, 300 MHz)
d
1.01 (d, J¼6.6 Hz, 3H), 1.20
orless oil; Rf¼0.3 (ethyl acetate/hexanes¼1/30); IR (neat) nmax: 698,
(d, J¼9.3 Hz, 3H), 2.02–2.08 (m, 1H), 3.33 (ddd, J¼3.65, 4.5, 4.5 Hz,
1H), 3.50–3.53 (m, 4H), 4.95–4.99 (m, 1H), 5.36–5.45 (m, 2H), 6.09
(ddd, J¼5.1, 11.4, 18.0 Hz, 1H), 7.31–7.47 (m, 3H), 8.03–8.07 (m, 2H);
25
1115, 1270, 1530, 1653, 2355, 2918, 3360, 3741, 3854 cmꢁ1; [
a]
D
ꢁ4.27 (c 1.0, CHCl3); 1H NMR (CDCl3, 300 MHz)
d
3.06 (t, J¼9.0 Hz,
1H), 3.13 (s, 3H), 4.61 (d, J¼8.7 Hz, 1H), 4.66 (dd, J¼6.0, 6.0 Hz, 1H),
5.43 (ddd, J¼1.2, 1.5, 11.0 Hz, 1H), 5.64 (ddd, J¼1.2, 1.2, 17.5 Hz, 1H),
6.10 (ddd, J¼6.0, 11.0, 17.0 Hz, 1H), 7.31–7.53 (m, 8H), 8.09–8.13 (m,
13C NMR (CDCl3, 125 MHz)
d 17.5, 20.3, 57.6, 59.1, 73.6, 75.2, 117.9,
125.8, 127.6, 128.2, 130.6, 133.0, 133.7, 152.8; HRMS calcd for
C16H22O2N (MþþH) 260.1651; found, 260.1654.
2H); 13C NMR (CDCl3, 125 MHz)
d 58.2, 58.5, 73.2, 79.6, 118.3, 127.4,
127.8, 128.3, 128.7, 131.0, 133.4, 141.8, 155.2; HRMS calcd for
4.8.19. (4S,5S,6R)-4-Isopropyl-5-methoxy-2-phenyl-6-vinyl-5,6-di-
C19H20O2N (MþþH) 294.1494; found, 294.1492.
hydro-4H-1,3-oxazine (13c0). Yield 58%; ratio anti,syn/anti,anti¼4/1;
as a colorless oil; Rf¼0.42 (ethyl acetate/hexanes¼1/20); IR (neat)
25
4.8.14. (4S,5S,6S)-5-(tert-Butyldimethylsilyloxy)-2,4-diphenyl-6-vi-
nyl-5,6-dihydro-4H-1,3-oxazine (14a). Yield 57%; ratio anti,syn/
anti,anti¼13/1; as a colorless oil; Rf¼0.3 (ethyl acetate/hexanes¼1/
nmax: 780, 1112, 1520, 1661, 3670, 3760, 3850 cmꢁ1; [
a]
ꢁ2.00 (c
D
0.5, CHCl3); 1H NMR (CDCl3, 300 MHz)
d
0.92 (d, J¼6.9 Hz, 3H), 1.25
(d, J¼6.6 Hz, 3H), 2.18–2.34 (m, 1H), 3.07 (t, J¼9.0 Hz, 1H), 3.40 (dd,
J¼2.7, 10.0 Hz, 1H), 3.55 (s, 3H), 4.42 (ddd, J¼4.0, 6.0, 7.5 Hz, 1H),
5.45 (dd, J¼1.5, 7.5 Hz, 1H), 5.62 (dd, J¼1.5, 17.0 Hz, 1H), 6.14 (ddd,
30); IR (neat) nmax: 1117, 1512, 1655, 1739, 2375, 2944, 3742,
25
3850 cmꢁ1; [
a]
ꢁ40.22 (c 0.5, CHCl3); 1H NMR (CDCl3, 300 MHz)
D

V.-T. Pham et al. / Tetrahedron 66 (2010) 2123–2131
2131
J¼6.0, 10.5, 17.0 Hz, 1H), 7.38–7.49 (m, 3H), 8.01–8.04 (m, 2H); 13C
6 N-HCl (3 mL) and the mixture was kept at room temperature for
5 h. After concentration under reduced pressure, the residue was
dissolved in aqueous ammonium hydroxide (0.6 M; 1 mL) and
chromatographed through a column of Dowex 50 W X8 (Hþ) to give
NMR (CDCl3, 125 MHz) d 16.3, 20.7, 29.2, 31.2, 60.5, 63.6, 78.2, 118.7,
127.7, 128.2, 130.6, 133.4, 134.9, 153.87; HRMS calcd for C16H22O2N
(MþþH) 260.1651; found, 260.1650.
a
-hydroxy statine 16 (45 mg, 95%) as a white solid; mp: 97–99 ꢀC;
4.8.20. (4S,5S,6S)-5-(tert-Butyldimethylsilyloxy)-4-isopropyl-2-phe-
nyl-6-vinyl-5,6-dihydro-4H-1,3-oxazine (14c). Yield 57%; ratio
anti,syn/anti,anti¼13/1; as a colorless oil; Rf¼0.25 (ethyl acetate/
IR (neat) nmax: 37.36, 3393, 2956, 2550, 2357, 1605, 1507, 1379, 1062,
25
cmꢁ1; [
a
]
D
ꢁ3.2 (c 0.5, MeOH); 1H NMR (500 MHz, D2O)
d 0.88–
0.92 (m, 6H), 1.56–1.58 (m, 2H), 1.66–1.71 (m, 1H), 3.49 (dd, J¼7.0,
hexanes¼1/30); IR (neat) nmax: 775, 1114, 1262, 1463, 1662, 2953,
12.0 Hz, 1H), 4.07 (d, J¼3.3 Hz, 1H), 4.15 (d, J¼1.8 Hz, 1H); 13C NMR
25
3745 cmꢁ1; [
d
a
]
ꢁ54.86 (c 0.5, CHCl3); 1H NMR (CDCl3, 300 MHz)
(125 MHz, D2O) d 21.3, 22.2, 24.0, 53.9, 70.0, 72.4,178.2; HRMS calcd
D
0.14–0.20 (m, 6H), 0.93–0.99 (m, 12H), 1.24–1.26 (m, 3H), 2.02–
for C8H18O4N (MþþH) 192.1236; found, 192.1233.
2.10 (m, 1H), 3.24–3.28 (m, 1H), 3.94 (dd, J¼4.8, 7.8 Hz, 1H), 4.83
(ddd, J¼2.0, 2.5, 4.0 Hz, 1H), 5.34–5.41 (m, 2H), 6.08–6.18 (m, 1H),
7.38–7.50 (m, 3H), 8.06–8.08 (m, 2H); 13C NMR (CDCl3, 125 MHz)
Acknowledgements
d
ꢁ4.5, ꢁ3.9, 16.5, 18.2, 20.7, 25.9, 26.2, 28.8, 61.2, 66.7, 76.2, 117.3,
This work was financially supported from Yonsung Fine Chem-
icals Co., Ltd., and Seoul R & BD program (10541).
127.6, 127.7, 128.3, 130.5, 133.1, 133.8, 152.6; HRMS calcd for
C21H34O2NSi (MþþH) 360.2359; found, 360.2359.
Supplementary data
4.8.21. (4S,5S,6R)-5-(tert-Butyldimethylsilyloxy)-4-isobutyl-2-phe-
nyl-5,6-dihydro-4H-1,3-oxazine-6-carboxylic acid (15). O3 was bul-
bed through the solution of oxazine 10e (0.50 g, 1.34 mmol) in
methanol (50 mL) at ꢁ78 ꢀC until pale blue (about 30 min), then
Me2S (0.5 mL) was added; the mixture was warmed to room tem-
perature during 1 h and concentrated to a colorless oil, which was
used directly. To the solution of the above residue in t-BuOH (21 mL)
and H2O (4.2 mL) at 0 ꢀC, was added NaH2PO4 (313 mg, 2.01 mmol)
and 2-methyl-2-butene (0.57 mL, 5.35 mmol), NaClO2 (363 mg,
4.01 mmol, in three portions); the mixture was warmed to room
temperature and stirred overnight. Saturated aqueous Na2S2O3
solution(10 mL) was added to the reaction mixture and t-BuOH was
removed in vacuo, the residue aqueous was acidified to pH 3–4 and
extracted by CH2Cl2, the organic layer was washed by brine, dried
over anhydrous Na2SO4, filtered and concentrated, the residue was
purified by flash column chromatography to give the acid 15
Supplementary data associated with this article can be found, in
the online version, at doi:10.1016/j.tet.2010.01.075.
References and notes
1. Joo, J. E.; Lee, K. Y.; Pham, V. T.; Ham, W. H. Eur. J. Org. Chem. 2007, 1586.
2. Joo, J. E.; Lee, K. Y.; Pham, V. T.; Tian, Y. S.; Ham, W. H. Org. Lett. 2007, 9, 3627.
3. Joo, J. E.; Pham, V. T.; Tian, Y. S.; Chung, Y. S.; Oh, C. Y.; Lee, K. Y.; Ham, W. H. Org.
Biomol. Chem. 2008, 6, 1498.
4. Basha, A.; Lipton, M.; Weinreb, S. M. Tetrahedron Lett. 1977, 18, 4171.
5. Hoffman, R. V.; Maslouh, N.; Cervantes-Lee, F. J. Org. Chem. 2002, 67, 1045.
6. So, R. C.; Ndonye, R.; Izmirian, D. P.; Richardson, S. K.; Guerrera, R. L.; Howell, A.
R. J. Org. Chem. 2004, 69, 3233.
7. Haug, B. E.; Rich, D. H. Org. Lett. 2004, 6, 4783.
8. Suyama, T. L.; Gerwick, W. H. Org. Lett. 2006, 8, 4541.
9. Pham, V. T.; Joo, J. E.; Tian, Y. S.; Kim, Y. H.; Lee, K. Y.; Oh, C. Y.; Jeong, J. H.; Ham,
W. H. Heterocycles 2008, 75, 2817.
10. Ogasawara, M.; Takizawa, K.; Hayashi, T. Organometallics 2002, 21, 4853.
11. Van Haaren, R. J.; Van Strijdonck, G. P. F.; Oevering, H.; Reek, J. N. H.; Kamer, P. C.
J.; Van Leeuwen, P. W. N. M. Eur. J. Inorg. Chem. 2001, 837.
(341 mg, 65%) as a white solid; mp: 125–127 ꢀC; IR (neat) nmax 3242,
25
2952, 2261, 1726, 1458, 1373, 1260, 1118, 846 cmꢁ1; [
a
]
þ4.78 (c
D
0.4, CHCl3); 1H NMR (500 MHz, CDCl3)
d
ꢁ0.02–0.17 (m, 6H), 0.82–
12. For some references of a-hydroxy statine, see for examples: (a) Umezawa, H.;
Aoyagi, H.; Marishima, H.; Matsuzaki, M.; Hamada, M.; Takeuchi, T. J. Antibiot.
1970, 23, 259; (b) Hom, R. K.; Fang, L. Y.; Mamo, S.; Tung, J. S.; Guinn, A. C.;
Walker, D. E.; Davies, D. L.; Gailunas, A. F.; Thorsett, E. D.; Sinha, S.; Knops, J. E.;
Jewett, N. E.; Anderson, J. P.; John, V. J. Med. Chem. 2003, 46, 1799; (c) Moore, M.
L.; Bryan, W. M.; Fakhury, S. A.; Magaard, V. W.; Huffan, W. F.; Dayton, B. D.;
Meek, T. K.; Hyland, L. J.; Dreyer, G. B.; Metcalf, B. W.; Gorniak, J. G.; Debouck, C.
Biochem. Biophys. Res. Commun. 1989, 159, 420; (d) Boger, J.; Lohr, N. S.; Ulm, E.
H.; Poe, M.; Blaine, E. H.; Fanelli, G. M.; Lin, T.-H.; Payne, L. S.; Schorn, T. W.;
LaMont, B. I.; Vassil, T. C.; Stabilito, I. I.; Veber, D.; Rich, D. H.; Bopari, A. S. Nature
(London) 1983, 303, 81; (e) Dee, M. F.; Rosati, R. L. Bioorg. Med. Chem. Lett. 1995,
5, 949; (f) Oh, J. S.; Park, D. Y.; Song, B. S.; Bae, J. G.; Yoon, S. W.; Kim, Y. G.
Tetrahedron Lett. 2002, 43, 7209.
0.91 (m, 9H), 0.94–1.05 (m, 6H),1.45–1.51 (m,1H),1.61–1.66 (m,1H),
1.71–1.75 (m, 1H), 3.54 (ddd, J¼3.5, 6.5, 10.0 Hz, 1H), 4.25 (t, J¼6.5,
7.5 Hz,1H), 4.78 (s,1H-OH), 5.62 (d, J¼7.5 Hz,1H), 7.44–7.49 (m, 3H),
8.07–8.12 (m, 2H); 13C NMR (125 MHz, CDCl3)
d
ꢁ4.7, ꢁ4.1,18.1, 22.0,
23.6, 25.8, 43.2, 56.6, 77.9, 78.8, 128.6, 130.2, 133.6, 165.6, 170.5;
HRMS calcd for C21H34O4NSi (MþþH) 392.2257; found, 392.2258.
4.8.22. (2R,3S,4S)-4-Amino-2,3-dihydroxy-6-methyl-heptanoic acid
(16). To the acid 15 (96 mg, 0.25 mmol) in MeOH (3 mL) was added