Enantioselective synthesis of [1,2]-oxazinone scaffolds and [1,2]-oxazine core structures of FR900482

Article abstract of DOI:10.1016/j.tet.2007.07.071

Several chiral unsaturated [1,2]-oxazinone heterocycles have been synthesized by iridium-catalyzed allylic substitution and ring-closing metathesis (RCM) reaction in high yields with excellent enantiomeric excesses. In addition, the synthesis of [1,2]-oxa

Full text of DOI:10.1016/j.tet.2007.07.071

Available online at www.sciencedirect.com
Tetrahedron 64 (2008) 1040–1048
Enantioselective synthesis of [1,2]-oxazinone scaffolds
and [1,2]-oxazine core structures of FR900482
Valluru Krishna Reddy,a Hideto Miyabe,a Masashige Yamauchib and Yoshiji Takemotoa,
*
aGraduate School of Pharmaceutical Sciences, Kyoto University, Yoshida, Sakyo-ku, Kyoto 606-8501, Japan
bFaculty of Pharmaceutical Sciences, Josai University, Keyakidai, Sakado, Saitama 350-0295, Japan
Received 31 May 2007; revised 5 July 2007; accepted 19 July 2007
Available online 28 July 2007
This paper is dedicated to Professor Csaba Szantay on the occasion of his 80th birthday
Abstract—Several chiral unsaturated [1,2]-oxazinone heterocycles have been synthesized by iridium-catalyzed allylic substitution and
ring-closing metathesis (RCM) reaction in high yields with excellent enantiomeric excesses. In addition, the synthesis of [1,2]-oxazine
core structures of FR900482 was achieved via iridium-catalyzed allylic substitution, followed by RCM and Heck reactions, respectively.
Ó 2007 Elsevier Ltd. All rights reserved.
1. Introduction
2. Results and discussion
The potent biological activities of many pharmaceutical
drugs containing heterocyclic ring structures have already
been proved.1 The concept of privileged structures was re-
cently introduced as molecular frameworks capable of bind-
ing to several diverse biological receptors.2 In rational drug
discovery process,3 the design of libraries may involve novel
heterocyclic scaffolds to which diverse side chains are
attached, the trajectories of which seek to explore three-
dimensional space.4 Herein we describe the synthesis of
[1,2]-oxazinones, which are able to introduce multiple hy-
drophobic residues, as new chiral drug scaffolds and further
application to obtain core structures of FR900482 and its
derivatives.
2.1. Synthesis of chiral [1,2]-oxazinones
The RCM precursors 4a–j were prepared as shown in
Scheme 1. Chiral oxime ethers 2a–j and further reduced de-
rivatives 3a–j were prepared via enantioselective iridium-
catalyzed allylic substitution and reduction using BH3$Py
complex according to our previous report.10 Reaction of
3a–j with acryloyl chloride afforded the RCM precursors
4a–j in 86–98% yields.
Ar1
Ar1
Ar2
OP(O)(OEt)2
N
O
Pybox ligand A, [Ir(cod)Cl]2
N
Ba(OH)2·H2O, CH2Cl2, -20 °C
OH
[1,2]-Oxazines are relatively uncommon heterocycles,
which can be generally obtained by [4+2] cycloaddition of
nitroso derivatives with conjugated dienes.5 Recently, Kerr
reported the synthesis of tetrahydro[1,2]-oxazines by [3+2]
cycloaddition of nitrones with cyclopropane.6 Since [1,2]-
oxazine and [1,2]-oxazinone skeletons have recently been
found to be the central features in several antitumor and an-
tibiotic compounds,1a,7 synthetic methods of these skeletons
have been attracting considerable attention.8 As a part of our
program directed toward the synthesis of achiral [1,2]-ox-
azines,9 we newly investigated synthetic routes to obtain chi-
ral [1,2]-oxazinones based on asymmetric iridium-catalyzed
allylic substitution and RCM reactions.10,11
Ar2
2a-j
1
HN
O
Ar1
BH3·Py
CH2=CHCOCl, Et3N
CH2Cl2, 0 °C to rt,
HCl, Et2O
0 °C to 20 °C
Ar2
3a-j
O
N
O
Ar1
O
N
O
N
N
Ar2
4a-j (86-98%)
Ph
Ph
Pybox ligand A
Scheme 1. Preparation of RCM precursors 4a–j.
The RCM precursors 4a–j were treated with Grubbs’ cata-
lyst to obtain the desired six-membered [1,2]-oxazinones
* Corresponding author. Tel.: +81 75 753 4528; fax: +81 75 753 4569;
e-mail: takemoto@pharm.kyoto-u.ac.jp
0040–4020/$ - see front matter Ó 2007 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2007.07.071

V. K. Reddy et al. / Tetrahedron 64 (2008) 1040–1048
Table 1. RCM reaction of 4a–j using catalyst Ba
1041
5a–j (Scheme 2). Initial attempts with Grubbs’ first genera-
Entry Precursor Ar1
Ar2
Yield (%) eeb (%)
tion catalyst A did not give the desired compound though the
reactions were conducted in different solvents like dichloro-
methane or benzene at reflux and the amount of catalyst was
increased to 10 mol %. However, when second generation
Grubbs’ catalyst B was used (5 mol %) in dichloromethane
(10 h, 40 ꢀC), 30% conversion of 4a to 5a was observed
along with 50% recovery of the starting material. To our sur-
prise, by simply switching the solvent from dichloromethane
to benzene (10 h, 70 ꢀC), the conversion rose to 60% and
was further increased to 95% using a higher catalyst loading
(10 mol %). Under the latter conditions, compound 5a was
isolated in 92% yield (Table 1, entry 1). Using these opti-
mum reaction conditions, the other substrates 4b–j were
also treated with catalyst B and cyclization proceeded
smoothly. Although RCM reaction has been widely em-
ployed to construct cyclic compounds,11 the cyclization of
acrylic amide substrates is less common, and in some cases
did not give the desired cyclic ring.12 Therefore, it is worthy
to stress that RCM precursors 4a–j bearing acrylic amide
moiety worked well. Several points are noteworthy to dis-
cuss. Entries 2, 4, and 10 of Table 1 indicate that almost
quantitative conversion was achieved and the corresponding
desired compounds 5b, 5d, and 5j are obtained in excellent
isolated yields. In iridium-catalyzed allylic substitution,
compound 4i was obtained with lower enantioselectivity
(60% ee), it is due to the unstable phosphate (Ar2¼
4-MeO–C6H4) which was used in its crude form without
further purification (Scheme 1). Attempts to purify this phos-
phate by flash column chromatography were unsuccessful
and found to be less stable comparing with other phosphates.
The sterically hindered 2-naphthyl group (entry 8) also pro-
duced the desired compound 5h in high yield (83%) with an
excellent enantioselectivity. Furthermore, after one time re-
crystallization (in hexane), products (entries 1, 2, 5–7) have
given ꢁ97% ee.
1
2
3
4
5
6
4a
4b
4c
4d
4e
4f
Ph
Ph
92
95
82
95
92
91
88
83
95 (99)c
4-CF3–C6H4 Ph
4-MeO–C6H4 Ph
2-NO2–C6H4 Ph
Ph
Ph
92 (99)c
93
92
4-F–C6H4
90 (97)c
89 (98)c
90 (99)c
89
4-Cl–C6H4
4-Me–C6H4
2-Naph
4-MeO–C6H4 88
4-Me–C6H4 94
7
8
9
10
4g
4h
4i
Ph
Ph
Ph
2-I–C6H4
60
85
4j
a
All reactions run in the presence of second generation catalyst B
(10 mol %) in benzene under an atmosphere of argon.
ee was determined by HPLC analysis using chiral AD-H column.
ee after one time recrystallization.
b
c
similarities with antitumor agents, for example, Nutlin-2
(where the ether side chain on phenyl ring is an optimized
functionality for potency of Nutlins (cis-imidazoline ana-
logs) to inhibit p53-MDM2 binding)13 and Naamidine A.13
Additionally, the N–O linkage could be reductively cleaved
to generate chiral amino alcohol functionalities, which are
synthetically valuable.14
O
O
PMB
RO
RO
PMB
N
O
N
O
OsO4, KBrO3
THF-H2O (1:1), 45 °C, 10 h
76%, dr=8:2
Ph
5c
Ph
6: R=H
BzCl, Et3N
77%
PMB=p-methoxybenzyl
7: R=Bz
HO
O
O
N
N
N
CH3
N
N
CH3
N
N
Ar1
Ar
Ar
NH
OMe
O
N
O
O
EtO
Ar2
Naamidine A
Ar1
catalyst B (10 mol%)
benzene, 70 °C, 10 h
N
O
Ar1
N
O
Nutlin-2
H4)
(Ar1 = 4-HO-C6H4, Ar2 = 4-MeO-C6H4)
(Ar = 4-Br-C6
Ar2
5a-j
Ar2
4a-j
Scheme 3. Transformation of 5c to 6 and 7.
2.2. Synthesis of core structures of FR900482
PCy3
N
N
Ph
Cl
Cl
Mes
Ph
Mes
Ru
Cl
[1,2]-Oxazine structures can be efficiently modified to create
compounds for which utility has already been demonstrated,
such as the natural antitumor antibiotics FR900482 and
FR66979 and their synthetic derivatives FK973 and
FK317, etc.1a,7,15 FR900482 and its derivatives hold signif-
icant promise for replacing the structurally related and
widely used antitumor drug Mitomycin C.16 Modification
of these cyclic rings in obtaining the tetracyclic core of
Nakadomarin A has also been proved.6 To prepare the anal-
ogous core structures of FR900482 as drug scaffolds, the
synthetic strategy is demonstrated in Figure 1.
Ru
PCy3
Cl
catalyst A
Scheme 2. RCM of precursors 4a–j.
catalyst B
PCy3
To evaluate the chiral [1,2]-oxazinones 5a–j as drug
scaffolds, the compound 5c having 4-MeO substituent on
N-phenyl ring is further transformed to 6 and 7 via osmium-
catalyzed cis-dihydroxylation and benzoylation (Scheme 3).
The dihydroxylation of 5c produced an 80/20 mixture of dia-
stereomers that were separated by flash chromatography on
silica gel. Relative configuration of the major and minor dia-
stereomers was determined by several NOE experiments.
The major isomer 6 was then treated with benzoyl chloride
in the presence of triethylamine base to give 7 in 77% yield
with 93% ee. The final compound 7 has some structural
Controlling the regioselectivities has been of great impor-
tance in allylic substitution. Our synthetic approach includes
the regioselective allylic substitution of allylated hydroxyl-
amine 8 as a key reaction. Recently, highly regioselective
allylic substitution with allylic alcohol derivatives was

1042
V. K. Reddy et al. / Tetrahedron 64 (2008) 1040–1048
OCONH2
OR2
derivatives 13, 16, and 17 (Scheme 5), because these electro-
OR1
philes have three electrophilic centers, therefore, controlling
the regioselectivity is a challenging and promising task for
the successful preparation. Initial studies using linear phos-
phate 13gavethe undesirable regioisomers 14 and 15 without
formation of the desired isomer 4l. In our previous stud-
ies,9,10,19 the regioselectivity and enantioselectivity were
dramatically influenced by the structure of electrophiles.
As an observed trend, the branched electrophiles gave the
branched products with excellent regioselectivities. It is
also assumed that a stable conjugated diene unit of phosphate
13 influenced the regioselectivity. Thus, we next investigated
the reaction of 8 with the branched acetate 16 in the presence
of 1.0 equiv of Et2Zn as a base. As expected, the selective for-
mation of the branched compound 4l was observed. There-
fore, the desired compound 4l was obtained in 64% yield
with 68% ee using chiral pybox ligand. However, several at-
tempts, like changing the reaction temperature (20 to 40 ꢀC),
solvent (CH2Cl2), or molar ratio of chiral ligand (8–
12 mol %) did not improve the enantioselectivity. In particu-
lar, lower temperatures (0 to ꢂ20 ꢀC) led to produce racemic
compound with lower product conversions. By applying the
reaction conditions shown in Scheme 5, core structure 19 was
obtained with 68% ee. It is noteworthy to state that RCM re-
action of compound 4l exclusively occurred at unsubstituted
olefinic bonds and gave single isomer of product 18. The
Z-configuration of external olefinic bond of compound 19
was confirmed by NOE analysis and the absolute configura-
tion is assumed to be S because the applied reaction condi-
tions are consistent with other compounds 5a–j, whose
absolute configuration is known.10 To confirm the effect of
the branched electrophile on regioselectivity, the reaction
of 8 with diphenyl acetate 17 was studied. As expected, the
FR900482: R=CHO, R1=R2=R3=H
FR66979: R=CH2OH, R1=R2=R3=H
FK317: R=CHO, R1=Me, R2=R3=Ac
FK973: R=CHO, R1=R2=R3=Ac
NR3
O
R
N
Intramolecular
Heck reaction
Ph
H
Enantioselective
Ir-catalyzed reaction
O
N
RCM
Figure 1. [1,2]-Oxazine core structures of FR900482.
achieved by using iridium catalyst.17–19 Therefore, the irid-
ium-catalyzed reaction with diallylic alcohol derivatives
such as 9, 13, 16, and 17 has been a subject of current interest.
We initially investigated the regioselectivity on allylic substi-
tution of allylated hydroxylamine 8 with carbonate 9 to ac-
cess achiral [1,2]-oxazine core structures of FR900482
(Scheme 4). The allylated hydroxylamine 8 was easily pre-
pared from 2-iodonitrobenzene via reduction of nitro group
followed by selective N-allylation of resulting hydroxyl-
amine. Based on our recent studies on allylic substitution
of allylated hydroxylamine,9,10 Et2Zn (1.0 M solution in hex-
ane) was employed as a base.20 Using 5 mol % of iridium cat-
alyst and carbonate 9 (2.0 equiv) as an electrophile gave the
desired O-allylic derivative4k, after being stirred at 20 ꢀC for
1 h. Better results have been obtained using 1.0 equiv of
Et2Zn. As expected, excellent regioselectivity was observed
and 1H NMR analysis of crude compound 4k showed only the
trace formation of linear isomer 10. The compound 4k was
found to be unstable and immediately converted to the stable
form 11 by ring-closing metathesis reaction. Finally, intra-
molecular Heck coupling of 11 gave the desired core struc-
ture 12 in an excellent yield, 98%. The Heck reaction has
been used as a key step in the construction of the core of
molecules of the FR900482 family.15
Pybox ligand
[Ir(cod)Cl]2, Et2Zn
+
8
Ph
OP(O)(OEt)2
THF, rt, 0.5 h
13
41% (14:15 = 40:60)
I
I
I
Ph
+
O
N
O
OCO2Me
N
[Ir(cod)Cl]2, Et2Zn
OH
O
+
Ph
N
THF, rt, 1 h
4k:10 = 93:7
15
14
9 (2.0 equiv)
8
Pybox ligand
OAc
I
I
[Ir(cod)Cl]2, Et2Zn
THF, rt, 3 h
R1
R2
+
8
O
+
N
N
16: R1 = Ph, R2 = H
17: R1 = R2 = Ph
10
4k (69%)
I
benzene,
70 °C, 10 h
catalyst B
catalyst B
O
O
Ph
N
benzene, 70 °C, 10 h
I
Pd(PPh3)4, Et3N
MeCN, 80 °C, 20 h
4l (64%, 68% ee) form 16
O
N
O
Ph
H
N
I
Pd(PPh3)4
Et3N
12 (98%)
11 (76%)
Scheme 4. Synthesis of achiral [1,2]-oxazine structures.
Ph
N
MeCN
N
80 °C, 20 h
18 (79%)
19 (96%, 68% ee)
To approach the chiral core structure, we next investigated
iridium-catalyzed reaction of 8 with diallylic alcohol
Scheme 5. Synthesis of chiral [1,2]-oxazine structures.

V. K. Reddy et al. / Tetrahedron 64 (2008) 1040–1048
1043
reaction proceeded at center carbon of acetate 17 with high
regioselectivity. Additionally, the RCM reaction of this prod-
uct gave a 68% yield of product 18 as racemic form.
7.26–7.37 (7H, m), 7.54 (2H, d, J¼8.3 Hz); MS (EI+) m/z
(%): 361 (M+, 25), 115 (100); [a]D21 ꢂ48.1 (c 0.15, CHCl3).
3.2.3. N-((S)-1-Phenylallyloxy)-N-(4-methoxybenzyl)-
acrylamide (4c). A colorless oil; IR (CHCl3) 3011, 1649,
1614, 1512, 1439, 1249 cmꢂ1; 1H NMR (CDCl3, 500 MHz)
d 3.79 (3H, s), 4.55 (1H, d, J¼15.3 Hz), 4.82 (1H, d,
J¼15.3 Hz), 5.16 (1H, d, J¼7.7 Hz), 5.28–5.33 (2H, m),
5.67 (1H, dd, J¼10.4, 2.2 Hz), 6.08–6.09 (1H, m), 6.40
(1H, dd, J¼17.1, 2.2 Hz), 6.71 (1H, dd, J¼17.1, 10.4 Hz),
6.82 (2H, d, J¼8.5 Hz), 7.20 (2H, d, J¼8.5 Hz), 7.28–7.38
(5H, m); 13C NMR (CDCl3, 126 MHz) d 50.9, 55.4, 88.5,
114.1, 120.3, 127.1, 128.0, 128.9 (2C), 129.1, 129.3, 130.2,
135.7, 138.2, 159.3, 167.8; MS (FAB+) m/z (%): 324
(M+H+, 65), 121 (100); [a]D28 ꢂ17.7 (c 1.2, CHCl3).
In summary, we have demonstrated a synthetic approach to
obtain chiral [1,2]-oxazinone heterocycles in high yields and
with excellent enantioselectivities. In addition, the utility of
this reaction was illustrated in the preparation of FR900482
core structures.
3. Experimental
3.1. General
Infrared (IR) spectra were recorded on an FTIR spectro-
1
meter. H NMR spectra were recorded on a JEOL JNM-
3.2.4. N-((S)-1-Phenylallyloxy)-N-(2-nitrobenzyl)acryl-
amide (4d). A colorless oil; IR (CHCl3) 3012, 1654, 1618,
LA500 MHz spectrometer. 13C NMR spectra were recorded
on a JEOL JNM-LA500 MHz (at 126 MHz) spectrometer.
Chemical shifts are reported in parts per million from tetra-
methylsilane as the internal standard. Enantiomeric ratios
were determined by high-performance liquid chromato-
graphy (HPLC) on Shimadzu chromatograph. Optical rota-
tions were measured using a JASCO DIP-360 digital
1527, 1421, 1354, 1243 cmꢂ1
;
1H NMR (CDCl3,
500 MHz) d 4.12 (1H, d, J¼17.7 Hz), 5.05 (1H, d,
J¼17.7 Hz), 5.21 (1H, d, J¼7.7 Hz), 5.27–5.36 (2H, m),
5.79 (1H, dd, J¼10.4, 1.9 Hz), 6.05–6.12 (1H, m), 6.47
(1H, dd, J¼17.1, 1.9 Hz), 6.79 (1H, dd, J¼17.1, 10.4 Hz),
7.26–8.00 (9H, m); 13C NMR (CDCl3, 126 MHz) d 48.5,
88.7, 120.2, 124.7, 125.8, 127.3, 127.9, 128.5, 128.8,
129.5, 129.9, 131.6, 133.3, 134.8, 137.1, 148.5, 167.6; MS
(FAB+) m/z (%): 339 (M+H+, 68), 117 (100); [a]1D8 ꢂ42.3
(c 0.7, CHCl3).
polarimeter, and [a]D values are given in 10ꢂ1 deg cm2 gꢂ1
.
Melting points were measured on Yanagimoto micro melt-
ing point apparatus and are uncorrected.
3.2. Representative procedure for the acrylation
3.2.5. N-((S)-1-(4-Fluorophenyl)allyloxy)-N-benzylac-
rylamide (4e). A colorless oil; IR (CHCl3) 3019, 1649,
To a solution of compound 3a (50 mg, 0.21 mmol) in
CH2Cl2 (1.0 mL) was added acryloyl chloride (0.020 mL,
0.25 mmol) at 0 ꢀC followed by triethylamine (0.089 mL,
0.63 mmol). Then, the solution was stirred at room temper-
ature for 2 h, diluted with saturated NaHCO3 solution,
and extracted with chloroform. The combined extracts
were dried over MgSO4, filtered, and concentrated under
reduced pressure. The crude compound was purified by
preparative TLC (hexane/EtOAc¼5/1) to give compound
4a (60 mg, 98%). When the reaction was scaled up, the
crude product was purified by flash column chromato-
graphy on silica gel.
1618, 1510, 1423, 1217 cmꢂ1
;
1H NMR (CDCl3,
500 MHz) d 4.63 (1H, d, J¼15.6 Hz), 4.91 (1H, d,
J¼15.6 Hz), 5.15 (1H, d, J¼7.4 Hz), 5.24–5.34 (2H, m),
5.71 (1H, dd, J¼10.4, 1.9 Hz), 6.01–6.07 (1H, m), 6.43
(1H, dd, J¼17.1, 1.9 Hz), 6.69 (1H, dd, J¼17.1, 10.4 Hz),
7.02–7.32 (9H, m); 13C NMR (CDCl3, 126 MHz) d 51.7,
87.6, 116.0 (d, J¼22 Hz), 120.4, 126.8, 127.9, 128.7,
128.8, 129.6, 129.9 (d, J¼8 Hz), 134.0, 135.5, 136.6,
164.2 (d, J¼248 Hz), 167.9; MS (EI+) m/z (%): 311 (M+,
25), 91 (100); [a]2D5 ꢂ34.4 (c 1.0, CHCl3).
3.2.6. N-((S)-1-(4-Chlorophenyl)allyloxy)-N-benzylacryl-
amide (4f). A colorless oil; IR (CHCl3) 3011, 1652, 1618,
3.2.1. N-((S)-1-Phenylallyloxy)-N-benzylacrylamide (4a).
A colorless oil; IR (CHCl3) 3009, 1650, 1617, 1414,
1492, 1412, 1232 cmꢂ1 1H NMR (CDCl3, 500 MHz)
;
1
1231 cmꢂ1; H NMR (CDCl3, 500 MHz) d 4.59 (1H, d,
d 4.66 (1H, d, J¼15.6 Hz), 4.88 (1H, d, J¼15.6 Hz), 5.14
(1H, d, J¼7.4 Hz), 5.24–5.34 (2H, m), 5.72 (1H, dd,
J¼10.3, 1.9 Hz), 5.97–6.04 (1H, m), 6.44 (1H, dd, J¼16.9,
1.9 Hz), 6.69 (1H, dd, J¼16.9, 10.3 Hz), 7.19–7.32 (9H,
m); 13C NMR (CDCl3, 126 MHz) d 51.3, 87.2, 120.2,
126.3, 127.4, 128.2, 128.3, 128.6, 128.8, 129.2, 134.5,
134.8, 136.1 (2C), 167.4; MS (EI+) m/z (%): 327 (M+, 5),
55 (100); [a]2D1 ꢂ87.0 (c 0.7, CHCl3).
J¼15.5 Hz), 4.88 (1H, d, J¼15.5 Hz), 5.16 (1H, d,
J¼7.6 Hz), 5.25–5.33 (2H, m), 5.71 (1H, dd, J¼10.3,
1.9 Hz), 6.03–6.10 (1H, m), 6.44 (1H, dd, J¼17.1, 1.9 Hz),
6.73 (1H, dd, J¼17.1, 10.3 Hz), 7.26–7.38 (10H, m); 13C
NMR (CDCl3, 126 MHz) d 51.5, 88.5, 120.3, 126.9, 127.8,
128.0, 128.7, 128.9, 129.1, 129.5, 135.6, 136.6, 138.0,
167.8, one peak of 13C NMR is missing due to overlapping;
MS (FAB+) m/z (%): 294 (M+H+, 92), 117 (100); [a]2D6
ꢂ33.9 (c 1.1, CHCl3).
3.2.7. N-((S)-1-(4-Methylphenyl)allyloxy)-N-benzylacryl-
amide (4g). A colorless oil; IR (CHCl3) 3012, 1649, 1617,
3.2.2. N-((S)-1-Phenylallyloxy)-N-(4-(trifluoromethyl)-
benzyl)acrylamide (4b). A colorless oil; IR (CHCl3)
1436, 1414, 1216 cmꢂ1 1H NMR (CDCl3, 500 MHz)
;
d 2.35 (3H, s), 4.60 (1H, d, J¼15.3 Hz), 4.88 (1H, d,
J¼15.3 Hz), 5.14 (1H, d, J¼7.4 Hz), 5.23–5.31 (2H, m),
5.70 (1H, dd, J¼10.3, 1.9 Hz), 6.03–6.11 (1H, m), 6.42
(1H, dd, J¼16.9, 1.9 Hz), 6.73 (1H, dd, J¼16.9, 10.3 Hz),
7.15–7.31 (9H, m); 13C NMR (CDCl3, 126 MHz) d 20.9,
51.5, 88.0, 119.5, 126.5, 127.3, 127.5, 128.2, 128.9, 129.1,
3019, 1652, 1618, 1419, 1214 cmꢂ1 1H NMR (CDCl3,
;
500 MHz) d 4.57 (1H, d, J¼15.9 Hz), 4.92 (1H, d,
J¼15.9 Hz), 5.17 (1H, d, J¼7.4 Hz), 5.28–5.35 (2H, m),
5.75 (1H, dd, J¼10.3, 1.9 Hz), 6.04–6.11 (1H, m), 6.46
(1H, dd, J¼17.1, 1.9 Hz), 6.74 (1H, dd, J¼17.1, 10.3 Hz),

1044
V. K. Reddy et al. / Tetrahedron 64 (2008) 1040–1048
134.6, 135.3, 136.2, 138.5, 167.4, one peak of 13C NMR is
missing due to overlapping; MS (FAB+) m/z (%): 308
(M+H+, 65), 131 (100); [a]D26 ꢂ33.5 (c 0.7, CHCl3).
123.3, 127.7, 128.5, 128.6, 129.0, 129.6, 135.5, 136.2,
141.3, 163.9, one peak of 13C NMR is missing due to
overlapping; MS (EI+) m/z (%): 265 (M+, 12), 144 (100).
Anal. Calcd for C17H15NO2: C, 76.96; H, 5.70; N, 5.28,
found: C, 76.70; H, 5.70; N, 5.25; HPLC (chiral AD-H
column, n-hexane/i-PrOH¼90/10, 0.5 mL/min, 254 nm) tR
(S)¼19.7 min, tR (R)¼23.8 min. A sample of 99% ee (S)
by HPLC analysis gave [a]2D6 ꢂ7.7 (c 1.0, CHCl3).
3.2.8. N-((S)-1-(Naphthalen-2-yl)allyloxy)-N-benzylacryl-
amide (4h). A colorless oil; IR (CHCl3) 3011, 1650, 1618,
1496, 1413, 1216 cmꢂ1 1H NMR (CDCl3, 500 MHz)
;
d 4.62 (1H, d, J¼15.6 Hz), 4.89 (1H, d, J¼15.6 Hz), 5.30–
5.33 (2H, m), 5.71 (1H, dd, J¼10.4, 1.9 Hz), 5.82 (1H, d,
J¼7.1 Hz), 6.21–6.28 (1H, m), 6.44 (1H, dd, J¼17.4,
1.9 Hz), 6.79 (1H, dd, J¼17.4, 10.4 Hz), 7.14–7.94 (12H,
m); 13C NMR (CDCl3, 126 MHz) d 51.4, 87.4, 120.2,
125.5, 126.2, 126.4, 126.5, 127.7, 128.6, 128.7, 129.1,
129.2, 129.7, 129.8, 130.4, 134.3, 134.4, 136.7, 167.4, two
peaks of 13C NMR are missing due to overlapping; MS
(FAB+) m/z (%): 344 (M+H+, 75), 167 (100); [a]2D8 ꢂ47.0
(c 0.7, CHCl3).
3.3.2. 2-((4-Trifluoromethyl)benzyl)-6-(S)-phenyl-2H-
1,2-oxazin-3(6H)-one (5b). A colorless crystal; mp 112–
115 ꢀC (n-hexane); IR (CHCl3) 3019, 1671, 1613, 1325,
1
1214 cmꢂ1; H NMR (CDCl3, 500 MHz) d 4.68 (1H, d,
J¼15.3 Hz), 4.74 (1H, d, J¼15.3 Hz), 5.49 (1H, d,
J¼1.9 Hz), 6.24 (1H, d, J¼10.1 Hz), 6.76 (1H, dd, J¼10.1,
1.9 Hz), 7.22–7.30 (5H, m), 7.33 (2H, d, J¼10.0 Hz), 7.42
(2H, d, J¼10.0 Hz); MS (EI+) m/z (%): 333 (M+, 27), 145
(100). Anal. Calcd for C18H14F3NO2: C, 64.86; H, 4.23; N,
4.20, found: C, 64.76; H, 4.41; N, 4.16; HPLC (chiral AD-
H column, n-hexane/i-PrOH¼90/10, 0.5 mL/min, 254 nm)
tR (S)¼17.6 min, tR (R)¼25.8 min. A sample of 99% ee (S)
by HPLC analysis gave [a]2D6 ꢂ70.6 (c 0.5, CHCl3).
3.2.9. N-((S)-1-(4-Methoxyphenyl)allyloxy)-N-benzyl-
acrylamide (4i). A colorless oil; IR (CHCl3) 3012, 1649,
1614, 1512, 1438, 1414, 1216 cmꢂ1 1H NMR (CDCl3,
;
500 MHz) d 3.81 (3H, s), 4.60 (1H, d, J¼15.3 Hz), 4.88
(1H, d, J¼15.3 Hz), 5.13 (1H, d, J¼7.4 Hz), 5.23–5.31
(2H, m), 5.69 (1H, dd, J¼10.4, 2.2 Hz), 6.03–6.11 (1H,
m), 6.41 (1H, dd, J¼17.1, 2.2 Hz), 6.71 (1H, dd, J¼17.1,
10.4 Hz), 6.86–6.89 (2H, m), 7.21–7.31 (7H, m); 13C
NMR (CDCl3, 126 MHz) d 51.5, 55.5, 88.1, 114.3, 119.8,
127.0, 127.8, 128.7, 129.3, 129.5, 130.1, 135.7, 136.7,
160.4, 167.8, one peak of 13C NMR is missing due to over-
lapping; MS (FAB+) m/z (%): 324 (M+H+, 65), 121 (100);
[a]2D8 ꢂ17.7 (c 1.2, CHCl3).
3.3.3. 2-(4-Methoxybenzyl)-6-(S)-phenyl-2H-1,2-oxazin-
3(6H)-one (5c). A colorless oil; IR (CHCl3) 3019, 1668,
1610, 1513, 1213 cmꢂ1 1H NMR (CDCl3, 500 MHz)
;
d 3.78 (3H, s), 4.46 (1H, d, J¼15.2 Hz), 4.78 (1H, d, J¼
15.2 Hz), 5.47 (1H, d, J¼2.1 Hz), 6.19 (1H, d, J¼
10.1 Hz), 6.71 (1H, dd, J¼10.0, 2.1 Hz), 6.77 (2H, d,
J¼8.5 Hz), 7.13 (2H, d, J¼8.5 Hz), 7.26–7.35 (5H, m);
13C NMR (CDCl3, 126 MHz) d 49.5, 54.9, 78.3, 113.5,
122.8, 127.8, 128.0, 128.4, 129.0, 129.5, 135.0, 140.6,
158.8, 163.1; MS (EI+) m/z (%): 295 (M+, 4), 144 (100);
HRMS calcd for C18H17NO3 (M+): 295.1208, found:
295.1205; HPLC (chiral AD-H column, n-hexane/
i-PrOH¼90/10, 0.5 mL/min, 254 nm) tR (S)¼29.1 min, tR
(R)¼33.9 min. A sample of 93% ee (S) by HPLC analysis
gave [a]2D6 ꢂ102 (c 0.6, CHCl3).
3.2.10. N-((S)-1-(4-Methylphenyl)allyloxy)-N-(2-iodo-
benzyl)acrylamide (4j). A colorless oil; IR (CHCl3) 3011,
1650, 1617, 1428, 1216 cmꢂ1
;
1H NMR (CDCl3,
500 MHz) d 2.33 (3H, s), 4.78 (1H, d, J¼16.4 Hz), 4.94
(1H, d, J¼16.4 Hz), 5.16 (1H, d, J¼7.6 Hz), 5.25–5.32
(2H, m), 5.69 (1H, dd, J¼10.4, 1.9 Hz), 6.04–6.12 (1H, m),
6.44 (1H, dd, J¼17.1, 1.9 Hz), 6.78 (1H, dd, J¼17.1,
10.4 Hz), 6.93–7.81 (9H, m); 13C NMR (CDCl3, 126 MHz)
d 21.4, 56.0, 88.5, 98.4, 120.5, 126.8, 128.0, 128.7, 129.2,
129.3, 129.7, 129.8, 134.8, 135.6, 138.5, 139.1, 139.6,
167.4; MS (FAB+) m/z (%): 434 (M+H+, 75), 131 (100);
[a]2D9 ꢂ15.5 (c 0.4, CHCl3).
3.3.4. 2-(2-Nitrobenzyl)-6-(S)-phenyl-2H-1,2-oxazin-
3(6H)-one (5d). A colorless oil; IR (CHCl3) 3013, 1674,
1613, 1529, 1356, 1213 cmꢂ1; 1H NMR (CDCl3, 500 MHz)
d 5.07 (1H, d, J¼17.1 Hz), 5.17 (1H, d, J¼17.1 Hz), 5.58
(1H, d, J¼1.8 Hz), 6.27 (1H, d, J¼10.1 Hz), 6.84 (1H, dd,
J¼10.0, 1.8 Hz), 7.26–7.44 (8H, m), 7.95 (1H, d,
J¼7.9 Hz); 13C NMR (CDCl3, 126 MHz) d 48.5, 78.8,
123.1, 125.1, 128.4, 128.7, 129.1, 129.8, 129.9, 131.6,
133.6, 135.1, 141.8, 148.7, 164.7; MS (FAB+) m/z (%):
311 (M+H+, 100); HRMS calcd for C17H15N2O4 (M+H+):
311.0954, found: 311.1036; HPLC (chiral AD-H column,
n-hexane/i-PrOH¼90/10, 0.5 mL/min, 254 nm) tR (S)¼
34.3 min, tR (R)¼39.5 min. A sample of 92% ee (S) by
HPLC analysis gave [a]2D6 +52.2 (c 2.6, CHCl3).
3.3. Representative procedure for the ring-closing
metathesis (RCM) reaction
A solution of compound 4a (100 mg, 0.34 mmol) and
Grubbs’ second generation catalyst B (28 mg, 0.034 mmol)
in benzene (2.0 mL) was stirred at 70 ꢀC for 10 h under an
atmosphere of argon. The solvent was removed under
reduced pressure and the residue was purified by preparative
TLC (hexane/EtOAc¼5/1) to give compound 5a (83 mg,
92%).
3.3.5. 2-Benzyl-6-(S)-(4-fluorophenyl)-2H-1,2-oxazin-
3(6H)-one (5e). A colorless crystal; mp 75–78 ꢀC (n-hex-
1
3.3.1. 2-Benzyl-6-(S)-phenyl-2H-1,2-oxazin-3(6H)-one
(5a). A colorless crystal; mp 100–102 ꢀC (n-hexane); IR
ane); IR (CHCl3) 3019, 1672, 1606, 1512, 1218 cmꢂ1; H
NMR (CDCl3, 500 MHz) d 4.60 (1H, d, J¼15.2 Hz), 4.76
(1H, d, J¼15.2 Hz), 5.46 (1H, br d, J¼5.0 Hz), 6.22 (1H,
d, J¼10.0 Hz), 6.71 (1H, dd, J¼10.0, 5.0 Hz), 6.97 (2H, d,
J¼10.0 Hz), 7.16–7.26 (7H, m); 13C NMR (CDCl3,
126 MHz) d 50.6, 78.0, 116.0 (d, J¼22 Hz), 123.6, 127.8,
128.6, 128.7, 130.6 (d, J¼7 Hz), 131.2, 136.0, 140.7,
(CHCl3) 3019, 1673, 1638, 1426, 1213 cmꢂ1 1H NMR
;
(CDCl3, 500 MHz) d 4.52 (1H, d, J¼15.5 Hz), 4.88 (1H,
d, J¼15.5 Hz), 5.51 (1H, br d, J¼3.1 Hz), 6.21 (1H, d,
J¼10.1 Hz), 6.74 (1H, dd, J¼10.1, 3.1 Hz), 7.21–7.38
(10H, m); 13C NMR (CDCl3, 126 MHz) d 50.7, 78.9,

V. K. Reddy et al. / Tetrahedron 64 (2008) 1040–1048
1045
162.6 (d, J¼248 Hz), 163.6; MS (EI+) m/z (%): 283 (M+,
n-hexane/i-PrOH¼90/10,
by HPLC analysis gave [a]2D0 ꢂ9.2 (c 0.1, CHCl3).
0.5 mL/min,
254 nm)
tR
65), 163 (100). Anal. Calcd for C17H14FNO2: C, 72.07; H,
4.98; N, 4.94, found: C, 71.81; H, 5.12; N, 4.88; HPLC (chi-
ral AD-H column, n-hexane/i-PrOH¼90/10, 0.5 mL/min,
254 nm) tR (S)¼22.1 min, tR (R)¼26.3 min. A sample of
97% ee (S) by HPLC analysis gave [a]2D6 ꢂ96.8 (c 0.5,
CHCl3).
(S)¼28.7 min, tR (R)¼35.4 min. A sample of 60% ee (S)
3.3.10. 2-(2-Iodobenzyl)-6-(S)-(4-methylphenyl)-2H-1,2-
oxazin-3(6H)-one (5j). A colorless oil; IR (CHCl3) 3018,
1668, 1611, 1216 cmꢂ1; 1H NMR (CDCl3, 500 MHz) d 2.33
(3H, s), 4.65 (1H, d, J¼16.2 Hz), 4.84 (1H, d, J¼16.2 Hz),
5.51 (1H, br dd, J¼3.1, 1.7 Hz), 6.24 (1H, dd, J¼10.1,
1.7 Hz), 6.77 (1H, dd, J¼10.1, 3.1 Hz), 6.88–7.16 (7H, m),
7.73 (1H, d, J¼7.9 Hz); 13C NMR (CDCl3, 126 MHz)
d 21.4, 55.4, 78.6, 98.8, 123.1, 128.3, 128.6, 129.2, 129.5,
129.6, 132.1, 138.1, 139.6, 141.7, 164.1; MS (FAB+) m/z
(%): 406 (M+H+, 70), 296 (100); HRMS calcd for
C18H17INO2 (M+H+): 406.0226, found: 406.0316; HPLC
(chiral AD-H column, n-hexane/i-PrOH¼95/5, 0.5 mL/min,
254 nm) tR (S)¼30.5 min, tR (R)¼33.1 min. A sample of
85% ee (S) by HPLC analysis gave [a]2D6 ꢂ61.5 (c 0.4, CHCl3).
3.3.6. 2-Benzyl-6-(S)-(4-chlorophenyl)-2H-1,2-oxazin-
3(6H)-one (5f). A colorless crystal; mp 71–74 ꢀC (n-hexane);
1
IR (CHCl3) 3012, 1671, 1611, 1492, 1218 cmꢂ1; H NMR
(CDCl3, 500 MHz) d 4.64 (1H, d, J¼15.2 Hz), 4.70 (1H, d,
J¼15.2 Hz), 5.45 (1H, dd, J¼3.4, 1.6 Hz), 6.23 (1H, dd,
J¼9.8, 1.6 Hz), 6.70 (1H, dd, J¼9.8, 3.4 Hz), 7.14–7.26
(9H, m); 13C NMR (CDCl3, 126 MHz) d 50.3, 77.6, 123.4
(2C), 127.5, 128.5, 128.9, 129.6, 133.6, 135.4, 135.7,
140.2, 163.3; MS (EI+) m/z (%): 299 (M+, 12), 178 (100);
HPLC (chiral AD-H column, n-hexane/i-PrOH¼90/10,
0.5 mL/min, 254 nm) tR (S)¼21.2 min, tR (R)¼25.8 min. A
sample of 98% ee (S) by HPLC analysis gave [a]2D5 ꢂ120
(c 1.9, CHCl3).
3.4. Preparation of (4R,5S,6R)-4,5-dihydroxy-2-
(4-methoxybenzyl)-6-phenyl[1,2]oxazin-3-one (6)
3.3.7. 2-Benzyl-6-(S)-(4-methylphenyl)-2H-1,2-oxazin-
3(6H)-one (5g). A colorless crystal; mp 80–83 ꢀC (n-hexane);
To a solution of compound 5c (70 mg, 0.24 mmol) in THF/
H2O (6.0 mL, 1/1, v/v) were added KBrO3 (100 mg,
0.6 mmol) and catalytic amount of OsO4 at room tempera-
ture. Then the resultant solution was stirred at 45 ꢀC for
10 h. The solvent was removed under reduced pressure, fol-
lowed by extraction of the residue with chloroform, dried
over MgSO4, filtered, and concentrated under reduced pres-
sure. The resultant crude product was purified by column
chromatography on silica gel (CHCl3/MeOH¼10/1) to
give major isomer 6 (50 mg, 64%) and minor isomer
(10 mg, 12%). Major isomer 6: a colorless oil; IR (CHCl3)
IR (CHCl3) 3019, 1668, 1608, 1217 cmꢂ1 1H NMR
;
(CDCl3, 500 MHz) d 2.35 (3H, s), 4.50 (1H, d, J¼
15.2 Hz), 4.86 (1H, d, J¼15.2 Hz), 5.46 (1H, br dd, J¼3.1,
1.9 Hz), 6.20 (1H, dd, J¼10.1, 1.9 Hz), 6.72 (1H, dd,
J¼10.1, 3.1 Hz), 7.11–7.26 (9H, m); 13C NMR (CDCl3,
126 MHz) d 21.4, 50.1, 78.3, 122.7, 122.8, 127.1, 128.1
(2C), 129.2, 131.9, 135.8, 139.2, 141.4, 163.3; MS (EI+)
m/z (%): 279 (M+, 15), 159 (100); HRMS calcd for
C18H17NO2 (M+): 279.1259, found: 279.1262; HPLC (chiral
AD-H column, n-hexane/i-PrOH¼90/10, 0.5 mL/min,
254 nm) tR (S)¼19.2 min, tR (R)¼23.1 min. A sample of
99% ee (S) by HPLC analysis gave [a]2D6 ꢂ134 (c 0.1, CHCl3).
3565, 3013, 1674, 1606, 1513, 1220 cmꢂ1 1H NMR
;
(CDCl3, 500 MHz) d 3.01 (1H, br s), 3.81 (3H, s), 4.05
(1H, br s), 4.55 (1H, d, J¼15.3 Hz), 4.58 (1H, dd, J¼4.6,
3.7 Hz), 4.59 (1H, d, J¼3.7 Hz), 4.63 (1H, d, J¼4.6 Hz),
5.04 (1H, d, J¼15.3 Hz), 6.88 (2H, d, J¼8.9 Hz), 7.23–
7.36 (7H, m); 13C NMR (CDCl3, 126 MHz) d 50.27,
55.48, 68.87, 76.48, 89.67, 114.34, 126.97, 127.72,
129.10, 129.30, 130.52, 136.73, 159.85, 169.75; MS
(FAB+) m/z (%): 330 (M+H+, 95), 121 (100); [a]2D1 ꢂ71.0
(c 0.5, CHCl3). Minor isomer (diastereomer): a colorless
3.3.8. 2-Benzyl-6-(S)-(naphthalen-2-yl)-2H-1,2-oxazin-
3(6H)-one (5h). A colorless oil; IR (CHCl3) 3012, 1668,
1608, 1212 cmꢂ1 1H NMR (CDCl3, 500 MHz) d 4.42
;
(1H, d, J¼15.1 Hz), 4.82 (1H, d, J¼15.1 Hz), 6.16 (1H,
dd, J¼3.4, 1.8 Hz), 6.33 (1H, dd, J¼10.1, 1.8 Hz), 6.89
(1H, dd, J¼10.1, 3.4 Hz), 7.05–7.83 (12H, m); 13C NMR
(CDCl3, 126 MHz) d 49.9, 75.4, 123.2, 123.5, 124.5,
125.6, 126.4 (2C), 127.1, 127.8, 128.1, 128.5, 130.1 (2C),
131.3, 133.7, 135.5, 140.9, 163.2; MS (EI+) m/z (%): 315
(M+, 5), 194 (100); HRMS calcd for C21H17NO2 (M+):
315.1259, found: 315.1253; HPLC (chiral AD-H column,
n-hexane/i-PrOH¼90/10, 0.5 mL/min, 254 nm) tR (S)¼
25.8 min, tR (R)¼29.1 min. A sample of 89% ee (S) by
HPLC analysis gave [a]2D9 +112 (c 3.0, CHCl3).
oil; IR (CHCl3) 3562, 3015, 1674, 1604, 1510, 1225 cmꢂ1
;
1H NMR (CDCl3, 500 MHz) d 2.61 (1H, br s), 3.79 (3H,
s), 4.01 (1H, br s), 4.54 (1H, d, J¼3.4 Hz), 4.56 (1H, dd,
J¼3.7, 3.4 Hz), 4.59 (1H, d, J¼15.3 Hz), 5.05 (1H, d,
J¼15.3 Hz), 5.20 (1H, d, J¼3.7 Hz), 6.84 (2H, d, J¼
8.5 Hz), 7.26–7.36 (7H, m); 13C NMR (CDCl3, 126 MHz)
d 50.6, 55.0, 68.8, 69.6, 82.1, 113.9, 127.1, 127.2,
128.2, 128.4, 129.7, 134.7, 159.2, 169.3; MS (FAB+)
m/z (%): 330 (M+H+, 92), 121 (100); [a]2D1 ꢂ38.0 (c 0.1,
CHCl3).
3.3.9. 2-Benzyl-6-(S)-(4-methoxyphenyl)-2H-1,2-oxazin-
3(6H)-one (5i). A colorless oil; IR (CHCl3) 3019, 1673,
1609, 1258 cmꢂ1; 1H NMR (CDCl3, 500 MHz) d 3.80 (3H,
s), 4.51 (1H, d, J¼15.2 Hz), 4.82 (1H, d, J¼15.2 Hz), 5.43
(1H, br dd, J¼3.2, 1.9 Hz), 6.21 (1H, dd, J¼10.1, 1.9 Hz),
6.71 (1H, dd, J¼10.1, 3.2 Hz), 6.82 (1H, dd, J¼6.7,
2.1 Hz), 7.17–7.26 (8H, m); 13C NMR (CDCl3, 126 MHz)
d 50.6, 55.5, 78.5, 114.2, 123.3, 127.3, 127.7, 128.6 (2C),
130.2, 136.2, 141.3, 160.8, 163.9; MS (EI+) m/z (%): 295
(M+, 5), 174 (100); HRMS calcd for C21H17NO2 (M+):
295.1208, found: 295.1204; HPLC (chiral AD-H column,
3.5. Preparation of compound 7
The major isomer 6 (40 mg, 0.13 mmol) was dissolved in
acetone (1.0 mL) followed by the addition of benzoyl chlo-
ride (0.060 mL, 0.52 mmol) and triethylamine (0.50 mL) at
ꢂ10 ꢀC. The resultant solution was stirred at room tempera-
ture for 10 h and concentrated under reduced pressure. The
crude product was purified by column chromatography on
silica gel (hexane/EtOAc¼5/1) to give compound 7

1046
V. K. Reddy et al. / Tetrahedron 64 (2008) 1040–1048
(50 mg, 77%) as a colorless oil; IR (CHCl3) 3030, 1726,
1701, 1607, 1512, 1256 cmꢂ1 1H NMR (CDCl3,
reaction mixture was diluted with saturated aqueous potas-
sium sodium (+)-tartrate and then extracted with EtOAc.
The organic phase was dried over MgSO4, filtered, and con-
centrated. The crude product was purified by flash short col-
umn chromatography on silica gel (hexane/EtOAc¼1/1) to
give compound 4l (48 mg, 64%) as a colorless oil, which
was immediately subjected to the next RCM.
;
500 MHz) d 3.70 (3H, s), 4.41 (1H, d, J¼11.9 Hz), 4.73
(1H, d, J¼2.1 Hz), 5.29 (1H, d, J¼11.9 Hz), 5.99 (1H, dd,
J¼3.9, 2.1 Hz), 6.22 (1H, d, J¼3.9 Hz), 6.71 (2H, d,
J¼8.5 Hz), 7.25–8.06 (17H, m); 13C NMR (CDCl3,
126 MHz) d 50.2, 55.4, 69.5, 78.2, 88.2, 114.3, 127.1,
127.4, 128.7, 128.7, 128.9, 129.2, 129.3, 129.8, 130.3,
130.4, 130.6, 133.8, 134.0, 135.2, 159.8, 165.2, 165.8
(2C); MS (FAB+) m/z (%): 538 (M+H+, 95), 121 (100);
HRMS calcd for C32H28NO7 (M+H+): 538.1788, found:
538.1860; HPLC (chiral AD-H column, n-hexane/
i-PrOH¼10/90, 0.5 mL/min, 254 nm) tR (S)¼26.4 min, tR
(R)¼30.2 min. A sample of 93% ee (S) by HPLC analysis
gave [a]2D6 ꢂ119 (c 2.4, CHCl3).
3.8. Ring-closing metathesis reaction of 4k and 4l
Conversion of 4k and 4l to 11 and 18 was performed accord-
ing to the representative procedure for RCM reaction of 4a.
Compound 11: a pale yellow oil; IR (CHCl3) 3010, 1618,
1
1220 cmꢂ1; H NMR (CDCl3, 500 MHz) d 3.67–3.71 (2H,
m), 5.21–5.26 (2H, m), 5.37 (1H, dd, J¼17.4, 1.5 Hz),
5.87–6.01 (3H, m), 6.87–7.84 (4H, m); 13C NMR (CDCl3,
126 MHz) d 53.1, 79.4, 93.9, 117.8, 120.7, 123.6, 127.1,
128.1, 128.9, 135.5, 139.3, 151.1; MS (EI+) m/z (%): 313
(M+, 6), 130 (100). Compound 18: pale yellow oil; IR
3.6. Preparation of N-allyl-N-hydroxy-2-iodobenzen-
amine (8)
A mixture of 2-iodohydroxylamine21 (0.30 g, 1.3 mmol),
K2CO3 (0.35 g, 2.5 mmol), and allyl bromide (0.12 mL,
1.4 mmol) in N,N-dimethylacetamide (5.0 mL) was stirred
at room temperature overnight. The solvent was evaporated
under reduced pressure. The residue was diluted with
CH2Cl2 and washed with H2O. The organic phase was dried
over MgSO4, filtered, and concentrated under reduced
pressure. The crude product was purified by column chro-
matography on silica gel (hexane/EtOAc¼5/1) to give
compound 8 (0.20 g, 57%) as a pale yellow oil; IR
(CHCl3) 3015, 1635, 1220 cmꢂ1 1H NMR (CDCl3,
;
500 MHz) d 3.62–3.80 (2H, m), 5.36 (1H, m), 5.95 (1H,
dd, J¼10.1, 1.9 Hz), 6.05–6.06 (1H, m), 6.36 (1H, dd,
J¼16.2, 7.4 Hz), 6.67 (1H, d, J¼16.2 Hz), 6.87–6.92 (1H,
m), 7.22–7.85 (9H, m); 13C NMR (CDCl3, 126 MHz)
d 53.6, 79.7, 94.7, 121.0, 121.4, 124.4, 127.0, 127.1, 127.7,
128.2, 128.8, 129.5, 133.6, 136.9, 139.8, 151.6; MS
(EI+) m/z (%): 389 (M+, 10), 346 (100); [a]2D1 ꢂ106 (c 1.1,
CHCl3).
(CHCl3) 3566, 1579, 1461, 1437, 1334, 1018 cmꢂ1
;
1H
3.9. Representative procedure for the Heck reaction
NMR (CDCl3, 500 MHz) d 3.50 (2H, d, J¼6.1 Hz), 5.20–
5.35 (2H, m), 6.04–6.10 (2H, m), 6.84–7.79 (4H, m); 13C
NMR (CDCl3, 126 MHz) d 63.2, 92.6, 118.7, 121.1, 126.7,
128.8, 133.4, 139.0, 153.2; MS (FAB+) m/z (%): 276
(M+H+, 100).
To a solution of compound 11 (7.0 mg, 0.023 mmol) in
CH3CN (1 mL) were added triethylamine (0.010 mL,
0.069 mmol) and Pd(PPh3)4 (5.2 mg, 0.0045 mmol). The re-
action mixture was refluxed under argon atmosphere for
20 h, after which TLC indicated complete consumption of
the starting material. The reaction mixture was cooled to
room temperature and directly absorbed onto the preparative
TLC plate and eluted using hexane/EtOAc (10/1) as an elu-
ent to give compound 12 (4.5 mg, 98%).
3.7. Iridium-catalyzed reaction
3.7.1. Reaction of hydroxylamine 8 with carbonate 9. To
a solution of hydroxylamine 8 (140 mg, 0.52 mmol) in THF
(2.0 mL) was added Et2Zn (1.0 M solution in hexane,
0.52 mL, 0.52 mmol) under argon atmosphere at 20 ꢀC. Af-
ter being stirred at the same temperature for 10–20 min, a so-
lution of carbonate 922 (200 mg, 1.0 mmol) and [Ir(cod)Cl]2
(18 mg, 0.026 mmol) in THF (1.0 mL) was added to the re-
action mixture at 20 ꢀC. After being stirred for 1 h, the reac-
tion mixture was diluted with saturated aqueous potassium
sodium (+)-tartrate and then extracted with EtOAc. The
organic phase was dried over MgSO4, filtered, and concen-
trated under reduced pressure. The crude product was puri-
fied by flash short column chromatography on silica gel
(hexane/EtOAc¼1/1) to give compound 4k (120 mg, 69%)
as a colorless oil, which was immediately subjected to the
next RCM.
3.9.1. Achiral core structure of FR900482 (12). A pale
1
yellow oil; IR (CHCl3) 3010, 1638, 1219 cmꢂ1; H NMR
(CDCl3, 500 MHz) d 3.50 (1H, dd, J¼17.7, 4.9 Hz), 4.48
(1H, dd, J¼17.7, 1.9 Hz), 4.80 (1H, d, J¼1.9 Hz), 5.04
(1H, s), 5.61 (1H, s), 5.74–5.76 (1H, m), 5.93–5.95 (1H,
m), 6.91–7.67 (4H, m); 13C NMR (CDCl3, 126 MHz)
d 54.6, 71.6, 106.0, 120.4, 121.0, 121.4, 123.8, 127.1,
128.6, 137.8, 146.8, one peak of 13C NMR is missing due
to overlapping; MS (EI+) m/z (%): 185 (M+, 100); HRMS
calcd for C12H11NO (M+): 185.0841, found: 185.0835.
3.9.2. Chiral core structure of FR900482 (19). A pale yel-
low oil; IR (CHCl3) 3012, 1628, 1218 cmꢂ1 1H NMR
;
(CDCl3, 500 MHz) d 3.54 (1H, dd, J¼17.7, 2.1 Hz), 4.48
(1H, dd, J¼17.7, 2.1 Hz), 5.23 (1H, s), 5.89–5.92 (1H, m),
6.15–6.17 (1H, m), 7.11–7.42 (7H, m), 7.69 (1H, d,
J¼7.9 Hz); 13C NMR (CDCl3, 126 MHz) d 55.5, 66.1,
120.8, 122.3, 123.0, 123.1, 124.2, 124.4, 126.8, 127.9,
128.6, 128.8, 129.1, 132.2, 136.4, 147.4; MS (EI+) m/z
(%): 261 (M+, 70), 260 (100); HRMS calcd for C18H15NO
(M+): 261.1154, found: 261.1159; HPLC (chiral AD-H
column, n-hexane/i-PrOH¼95/5, 0.5 mL/min, 254 nm)
3.7.2. Reaction of hydroxylamine 8 with acetate 16. To
a solution of hydroxylamine 8 (50 mg, 0.19 mmol) in THF
(1.0 mL) was added Et2Zn (1.0 M solution in hexane,
0.19 mL, 0.19 mmol) under argon atmosphere at 20 ꢀC. Af-
ter being stirred at the same temperature for 10–20 min, a so-
lution of acetate 1622 (74 mg, 0.37 mmol) and [Ir(cod)Cl]2
(7.0 mg, 0.0095 mmol) in THF (1.0 mL) was added to the
reaction mixture at 20 ꢀC. After being stirred for 3 h, the

V. K. Reddy et al. / Tetrahedron 64 (2008) 1040–1048
1047
(g) Inami, M.; Kawamura, I.; Tsujimoto, S.; Nishigaki, F.;
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Acknowledgements
This work was supported in part by 21st Century COE Pro-
gram ‘Knowledge Information Infrastructure for Genome
Science’, a Grant-in-Aid for Scientific Research (C) (Y.T.)
and for Young Scientists (B) (H.M.) from the Ministry of Ed-
ucation, Culture, Sports, Science and Technology of Japan.
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