Silver(I)-promoted asymmetric halomethoxylation of chiral α,β-unsaturated carboxylic acid derivatives: Enantioselective synthesis of N-protected syn-β-methoxy-α-amino acids

Article abstract of DOI:10.1016/j.tetasy.2005.12.014

Asymmetric halomethoxylation of chiral α,β-unsaturated carboxylic acid derivatives was performed with halogens (Br₂/I ₂) promoted by silver(I) salts with high regio- and anti-selectivity and moderate to good diastereoselectivity. Rea

Full text of DOI:10.1016/j.tetasy.2005.12.014

Tetrahedron:
Asymmetry
Tetrahedron: Asymmetry 17 (2006) 210–222
Silver(I)-promoted asymmetric halomethoxylation of chiral
a,b-unsaturated carboxylic acid derivatives: enantioselective
synthesis of N-protected syn-b-methoxy-a-amino acids
Saumen Hajra,* Ananta Karmakar and Manishabrata Bhowmick
Department of Chemistry, Indian Institute of Technology, Kharagpur, West Bengal 721 302, India
Received 31 October 2005; revised 6 December 2005; accepted 7 December 2005
Abstract—Asymmetric halomethoxylation of chiral a,b-unsaturated carboxylic acid derivatives was performed with halogens
(Br2/I2) promoted by silver(I) salts with high regio- and anti-selectivity and moderate to good diastereoselectivity. Reagent
controlled diastereoselectivity was observed for N-cinnamoyl-2-oxazolidinone substrates especially for cinnamoyl and electron-
deficient cinnamoyl substrates, when Ag2O was used as a promoter instead of AgNO3. Enoyl substrates containing Oppolzer’s
sultam chiral auxiliary are independent of the counter ion of the Ag(I) salt. This method was applied to a short synthesis of both
enantiomers of N-protected syn-b-methoxyphenylalanine, and N- and O-protected syn-b-methoxytyrosine, unusual amino acid
components of biologically active cyclic peptide and depsipeptide antibiotics.
Ó 2006 Elsevier Ltd. All rights reserved.
1. Introduction
tion of b-alkoxy-a-oximino acid esters to b-alkoxy-a-
amino esters by NaBH4 in the presence of TiCl3 and L-
tartaric acid, but the configuration of the diastereomers
and the enantioselectivities were not determined.
b-Methoxy-a-amino acids are the unusual amino acid
components of many biologically active cyclic peptide
and depsipeptide antibiotics such as callipeltines,1 papu-
amides,2 cyclomarins,3 neamphamide A4 and discokio-
lides.5 There are only a few reports on asymmetric
synthesis of b-methoxy-a-amino acids.6–11 Hamada and
co-workers reported the diastereoselective synthesis of
all stereoisomers of b-methoxytyrosine based on Gar-
ner’s aldehyde and determined the absolute stereochem-
istry of the residue in papuamide A.6 A catalytic and
asymmetric method for the synthesis of an anti disposed
aromatic b-hydroxy-a-amino acid, a key intermediate
for the synthesis of anti-b-methoxyamino acid, has also
been described by the same group.7 Recently, D’Auria
et al. determined the absolute configuration of b-meth-
oxytyrosine in callipeltin A by synthesizing all the stereo-
isomers of that residue.8 Gustafson et al. described the
complete stereochemistry of neamphamide A and abso-
lute configuration of the b-methoxytyrosine residue in
papuamide B.9 Synthesis of four stereoisomers of b-
methoxytyrosine from serine has also been reported by
a-Halo-b-methoxy-carboxylic acid derivatives, similar
to carboxyhalohydrins,12 would be an important direct
precursor to the b-methoxyamino acids. A potentially
straight forward method for the synthesis of a-halo-b-
methoxy-carboxylic acid derivatives is the regio- and
stereoselective halomethoxylation reaction of a,b-unsatu-
rated carboxylic acid derivatives.13
Herein, we report,14 in detail, the silver(I)-promoted
asymmetric halomethoxylation of chiral a,b-unsatu-
rated carboxylic acid derivatives with high regio- and
diastereoselectivities up to 86:14 of anti-a-halo-b-meth-
oxy carbonyls. Their application to the short synthesis
of both enantiomers of N-protected syn-b-methoxyphen-
ylalanine and N- and O-protected syn-b-methoxytyro-
sine, unusual amino acid components of cyclomarins
and neamphamide A are also described.
Joullie et al.10 Boukhris and Souizi described11 the reduc-
´
2. Results and discussion
*
Initially, (4S)-N-cinnamoyl-4-(1-methylethyl)-2-oxazoli-
Corresponding author. Tel.: +91 3222 283340; fax: +91 3222
255303; e-mail: shajra@chem.iitkgp.ernet.in
dinones15 were selected as substrates for the development
0957-4166/$ - see front matter Ó 2006 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetasy.2005.12.014

S. Hajra et al. / Tetrahedron: Asymmetry 17 (2006) 210–222
211
MeO:
O
O
H
Ag(I), X2
X = Br, I
R
N
R
N
X+
O
O
O
O
O
2
1
MeOH
O
OMe O
OMe O
X
R
N
O
R
N
R
N
+
X
O
O
O
O
1'
3
4
Scheme 1.
Table 1. AgNO3-promoted halomethoxylation of 1 under different
of the diastereoselective halomethoxylation reaction.
It was assumed that the b-aryl group of the three
membered halonium intermediate 2 would enhance elec-
trophilicity towards the methanol nucleophile to achieve
high regioselectivity (Scheme 1, R = Ar), thus affording
the b-methoxyamino acid components of the biolo-
gically active natural cyclic peptide and depsipeptide
antibiotics possessing a b-aryl group.1–5 The auxiliary
of choice was an oxazolidinone derived from readily
available L-valine.15a,b It is well known that chelated
N-cinnamoyl-2-oxazolidinone usually exists in the s-cis-
syn-dipole conformation 10 and unchelated one in the
s-cis-anti-dipole conformation 1. So, it was expected to
provide different diastereoselectivity depending on the
reaction conditions. Initially, it was presumed that
the halomethoxylation reaction of 1 would yield 4 as
the major diastereoisomer.
reaction conditionsa
Entry Substrate
R
X
Ratiob (3:4)
Yieldc (%)
1d
2
3
4
1a
1a
1a
1b
1b
1c
1c
1c
Ph
Ph
Ph
Br 67:33 (65:35) 80
Br 71:29 (70:30) 92
I
ND
<5e
4-NO2C6H4 Br 65:35 (65:35) 84
5
4-NO2C6H4
4-MeOC6H4
4-MeOC6H4
4-MeOC6H4 Br 65:35f (66:34) 96g
I
I
I
—
NR
6d
7
60:40 (62:38) 89
62:38 (61:39) 94
8
ND: Not determined; NR: no reaction.
a Halomethoxylation reactions were performed using 1.2 equiv of
AgNO3 and 1.2 equiv of halogen (X2) in methanol at 0–5 °C for
30 min.
b Determined from the 1H NMR spectrum of the crude reaction mix
ture. Ratios in the parentheses refer to the ratio of isolated 3 and 4
after column chromatography.
c Combined isolated yields of 3 and 4 after chromatography.
d Reaction at room temperature (25 °C).
There are only a few reports16 on the halomethoxylation
of a,b-unsaturated carbonyls. By screening those
methods we found that the combination of silver nitrate
and halogen (Br2/I2) in methanol favours the regio- and
stereoselective halomethoxylation of chiral N-enoyl-2-
oxazolidinones 1 over aromatic electrophilic substitu-
tion. Initially, AgNO3 promoted halomethoxylation of
three electronically different cinnamoyl substrates 1a–
1c, containing (4S)-4-(1-methylethyl)-2-oxazolidinone
as a chiral auxiliary were studied (Table 1). Therefore,
a methanolic solution of substrate 1a was treated with
silver nitrate (1.2 equiv) and bromine (1.2 equiv) at rt
(25 °C). Within 20 min, it gave the desired a-bromo-b-
methoxycarbonyls 3a and 4a with a diastereomeric ratio
(dr) of 67:33 in 80% yield (entry 1). A little improvement
in dr, as well as yield, was obtained when the reaction
was performed at 0–5 °C (entry 2). However, bromo-
methoxylation of 1a in the absence of AgNO3 gave
a mixture of products. Among them, the desired
compounds 3a/4a (25%) and a non-separable mixture
of diastereoisomers (dr 60:40) of dibromo compounds
anti-(4S)-3-(20,30-dibromo-30-phenyl-propionyl)-4-(1-
methylethyl)-2-oxazolidinone (28%) were obtained.17
The iodomethoxylation of 1a under the same reaction
conditions, using I2 as halogen source gave <5% of the
desired products, and there was no improvement even
e >90% of 1a was recovered.
f Ratio of compounds 30c and 40c.
g Combined isolated yields of 30c and 40c after chromatography, when
excess AgNO3 (2.5 equiv) and Br2 (2.5 equiv) were used.
with the use of excess reagents and under different reac-
tion conditions (entry 3). Electron-deficient cinnamoyl
substrate 1b also underwent bromomethoxylation, but
no iodomethoxylation. Alternatively, substrate 1c read-
ily underwent the iodomethoxylation with moderate
diastereoselectivity, while the bromomethoxylation
reaction provided two undesired products 30c and 40c
(65:35) in 41% yield (43% of 1c was recovered) and later
these two undesired compounds were characterized as
diastereomers of anti-(4S)-3-[20-bromo-30-methoxy-30-
(3-bromo-4-methoxyphenyl)-propionyl]-4-(1-methyleth-
yl)-2-oxazolidinone 30c and 40c, whereby the p-methoxy
phenyl fragment had also been brominated (Fig. 1).
When the same reaction was again performed with an
excess of AgNO3 (2.5 equiv) and Br2 (2.5 equiv) under
the same conditions, compounds 30c and 40c were
obtained in 96% yield (entry 8). The halomethoxylation
of 1a–1c was also studied under different temperatures.
It was found that at ꢀ10 °C, all three substrates 1a–1c

212
S. Hajra et al. / Tetrahedron: Asymmetry 17 (2006) 210–222
of products. One of the undesired products was identified
as a halocarbocyclized product.17,20 This halomethoxyl-
ation reaction was further studied for the cinnamoyl sub-
strates 5a–5c containing another well-known chiral
auxiliary, Oppolzer’s bornane sultam.21 AgNO3-pro-
moted halomethoxylation of 5a–5c showed improved
diastereoselectivity22 (Table 2). Substrates 5a and 5c
responded well to both bromomethoxylation and iodo-
methoxylation reactions. Unlike 1c, 5c provided only
bromomethoxylated products 6c and 7c (entry 5), no
arene bromination was observed. Bromomethoxylation
reaction of 5a gave a lower yield of a non-separable
mixture of diastereomers; Br-6a and Br-7a, while the
iodomethoxylation products of 5c could not be obtained
in pure form since purification by chromatography
resulted in decomposition via an elimination pathway
to afford 5c. Similar to 1b, substrate 5b underwent only
bromomethoxylation reaction (entry 3).
OMe O
OMe O
Br
Br
N
N
Br
O
Br
O
MeO
MeO
O
O
3'c
4'c
Figure 1.
smoothly underwent halomethoxylation without any
appreciable change in dr and yields. However, at
ꢀ20 °C, it gave poor yields with incomplete conversion
and there was no reaction at ꢀ40 °C. Compounds 1a–
1c also responded to the halomethoxylation reaction in
other non-nucleophilic solvents such as CH2Cl2,
CH3COCH3, CH3CN containing 5–20% of methanol
and showed similar dr and yields, but 1a and 1b did
not undergo any reaction in methanolic THF, whereas
1c responded to the iodomethoxylation reaction in
methanolic THF. The stereochemistry of 3 was con-
firmed by a single crystal X-ray analysis of compound
3c (Fig. 2).18
To assess whether the counter ion of Ag(I) salt affects
the diastereoselectivity of halomethoxylation reactions,
studies were carried out employing the electronically dif-
ferent cinnamoyl substrates 1a–1c and 5a–5c using
AgOAc and Ag2O instead of AgNO3 as a promoter
under a variety of reaction conditions (Table 3). AgNO3
(Eq. 1) and AgOAc (Eq. 2) produce nitric acid and ace-
tic acid, respectively, on reaction with a halogen in
MeOH, whereas Ag2O produces water as a by-product
(Eq. 3) under the same conditions. When the halometh-
oxylation reactions of 1a–1c were performed in the pres-
ence of AgOAc instead of AgNO3, similar results were
obtained with 3 being produced as the major diastereo-
mer (entries 1–3).23 However, in the case of Ag2O-medi-
ated reactions,23 diastereoselectivities were in favour of
the diastereomers 4 (entries 4–6) and more interestingly,
compounds 1a and the electron-deficient 1b showed
opposite diastereoselectivities (entries 4 and 5) com-
pared to the AgNO3 (Table 1, entries 2 and 4) or AgOAc
(Table 3, entries 1 and 2) mediated reactions. When the
Ag2O-promoted halomethoxylation reactions of 1a–1c
were performed in the presence of either AcOH or
HNO3 as an additive,24 diastereoselectivities (entries
7–9) similar to either AgNO3 or AgOAc-promoted reac-
tions were obtained. However, no counter ion effect on
Figure 2. ORTEP diagram of 3c.
Since, the chiral auxiliary (4S)-4-(1-methylethyl)-2-oxa-
zolidinone gave moderate to good diastereoselectivities,
we have also examined other oxazolidinone chiral auxil-
iaries viz (4S)-4-phenyl- and (4S)-4-(diphenylmethyl)-2-
oxazolidinones.15,19 Halomethoxylation of substrates
containing different oxazolidinone chiral auxiliaries (Ph
and Ph2CH) using either Br2 or I2 gave complex mixtures
Table 2. AgNO3-promoted halomethoxylation reactions of 5
O
O
OMe
R
O
OMe
R
AgNO3, X2
+
N
R
N
N
MeOH, 0-5o C
X2 = Br2, I2
SO2
SO2
SO2
X
X
7
6
5
Entry
Substrate
R
X
Ratio (6:7)a
Yield (%)b
1
2
3
4
5
6
5a
5a
5b
5b
5c
5c
Ph
Ph
Br
I
Br
I
Br
I
65:35
77:23
72:28
—
71:29
—
76
95
94
NR
2-NO2C6H4
2-NO2C6H4
4-MeOC6H4
4-MeOC6H4
92
c
a Ratio of isolated 6 and 7 after column purification.
b Combined isolated yield of 6 and 7 after column chromatography.
c Compounds I-6c and I-7c could not be isolated in pure form as they decomposed during silica gel (230–400 mesh) column purification.

S. Hajra et al. / Tetrahedron: Asymmetry 17 (2006) 210–222
Table 3. AgOAc- and Ag2O-promoted halomethoxylation reactiona
213
Entry
Substrate
Ag(I) salt
Additive
X
drb (3:4)/(6:7)
Yield (%)c
1
2
3
4
5
6
7
8
1a
1b
1c
1a
1b
1c
1a
1b
1c
5a
5b
5c
AgOAc
AgOAc
AgOAc
Ag2O
Ag2O
Ag2O
Ag2O
Ag2O
Ag2O
Ag2O
Ag2O
Ag2O
None
None
None
None
None
None
HNO3
HNO3
HNO3
None
None
None
Br
Br
I
Br
Br
I
Br
Br
I
70:30
63:37
61:39
27:73
35:65
48:52
72:28 (70:30)
64:36 (67:33)
61:39 (62:38)
75:25
86
92
97
89
83
91
79 (82)
83 (81)
74 (78)
84
9
10
11
12
I
Br
Br
70:30
70:30
91
93
a Ag2O-promoted halomethoxylation reactions were performed using 0.7 equiv of Ag2O and 1.2 equiv of halogen (X2) in methanol at 0–5 °C for
30 min and the AgOAc-promoted reaction was the same as AgNO3 in Table 1.
b Determined from the 1H NMR spectrum of the crude reaction mixture. Ratios in parentheses refer to reactions in the presence of AcOH.
c Combined isolated yields.
the diastereoselectivities of halomethoxylation of sub-
strates 5a–5c containing the sultam chiral auxiliary
(entries 10–12) was observed. Reactions of either
AgNO3 or AgOAc with halogens in methanol generate
acid (Eqs. 1 and 2), so it may be proposed that a
H+-chelated s-cis-syn-dipole conformation 10 might be
involved in these halomethoxylation reactions. The
preferred attack of X+ from the Re-face of conforma-
tion 10 and subsequent (anti) opening of the halonium
intermediate 20 by nucleophilic attack of MeOH at the
b-position yielded 3 as the major diastereomer (Scheme
2). In the Ag2O-promoted reaction, the Si-face of the
unchelated s-cis-anti-dipole conformation 1 might be
involved giving 4 as a major diastereomer. This model
H+
H+
Re
O
O
O
O
MeOH
R
X+
MeOH
3
R
N
N
O
O
X+
Re-face attack
Si
s-cis-syn-dipole
2'
1'
Re
O
O
O
MeOH
R
X+
MeOH
4
R
N
N
X+
Si-face attack
O
O
O
Si
s-cis-anti-dipole
2
1
O
N
O
X+
MeOH
3
N
X+
Re-face attack
O
O
R
O
R
O
MeOH
2''
s-trans-anti-dipole
1''
Scheme 2.

214
S. Hajra et al. / Tetrahedron: Asymmetry 17 (2006) 210–222
is supported by the Ag2O-mediated reactions performed
in the presence of either HNO3 or AcOH as an additive
(Table 3, entries 7–9). The poor diastereoselectivities of
the electron-rich substrate 1c in Ag2O-promoted reac-
tions (Table 3, entry 6) might be accounted for by the
involvement of both the equilibrated s-cis- and s-trans-
anti-dipole conformations 1 and 100, due to extensive
conjugation of the electron donating substituent at the
p-position with the a,b-unsaturated carbonyls.
acids of potential interest for exploring the structure–
activity relationship study of derived biologically active
peptide and depsipeptides.1–5 It was found that sub-
strates 1a–1c smoothly underwent haloalkoxylation
with EtOH and MeOCH2CH2OH, however, none of
the desired products were obtained using n-hexanol,
PhCH2OH, CH2: CHCH2OH, i-PrOH as nucleophiles.
It was found that using AgNO3/AgOAc as a promoter
with (4S)-4-(1-methylethyl)-2-oxazolidinone as a chiral
auxiliary or the use of any Ag(I) salt with Oppolzer’s
sultam chiral auxiliary provide the best combination
for these types of Ag(I)-promoted halomethoxylation
reactions. To investigate further the scope and limitation
of this asymmetric reaction, a variety of other enoyl sub-
strates containing (4S)-4-(1-methylethyl)-2-oxazolidi-
AgNO3 + X2 + MeOH ! AgX# + MeOX + HNO3
ð1Þ
AgOAc + X2 + MeOH ! AgX# + MeOX + AcOH
ð2Þ
Table 5. AgNO3-promoted halomethoxylation of different enoyl
substrates 1a
Ag2O + 2MeOH + 2X2 ! 2AgX# + 2MeOX + H2O
ð3Þ
Entry Substrate
R
X
Ratiob (3:4)
Yieldc
(%)
It was found that in the absence of the AgNO3, bromo-
methoxylation of 1a gave a mixture of bromomethoxyl-
ated products and dibromo compounds with almost
no selectivity. So, Ag(I) is necessary as a Xꢀ scavenger
for the selective formation of halomethoxylated com-
pounds. Further, the counter ion effect of Ag(I) salts
on the diastereoselectivity of the halomethoxylation
reaction and the effect of HNO3 and AcOH as additives
in Ag2O promoted reactions also support the role of
Ag(I) salt as a Xꢀ scavenger but not as Lewis acid.
Otherwise, compound 3 would always have the major
diastereomer irrespective of the counter ion of Ag(I)
salts.
1
2
3
4
5d
6
1d
1e
1f
2-ClC6H4
Br 60:40 (60:40) 91
4-BnOC6H4
3,4-MeOC6H3
3,4,5-MeOC6H2
2-Naphthyl
CH3
I
I
I
I
77:23 (75:25) 92
76:24 (75:25) 91
74:26 (75:25) 93
73:27 (73:27) 88
1g
1h
1i
Br 86:14e (85:15) 62f
a Halomethoxylation reactions were performed using 1.2 equiv of
AgNO3 and 1.2 equiv of halogen (X2) in methanol at 0–5 °C for
30 min.
b Determined from the 1H NMR spectrum of the crude reaction mix-
ture. Ratios in the parentheses refer to the ratio of isolated 3 and 4
after column chromatography.
c Combined isolated yields of 3 and 4 after column chromatography.
d 30% CH2Cl2 used due to poor solubility of the substrate 1h in
methanol.
e Including 18% of the other regioisomers.
We also attempted to extend our methodology for the
synthesis of other haloalkoxylated carbonyl compounds
(Table 4), as key intermediates for b-alkoxy-a-amino
f Isolated yield of the major isomer 3i only, minor isomer 4i could not
be separated from the other regioisomers.
Table 4. AgNO3-promoted haloalkoxylation of 1
OR1
O
O
O
OR1
X
O
O
AgNO3, X2
Ar
N
Ar
N
Ar
N
+
X
R1OH, 0-5 C
˚
O
O
O
O
1
9
8
X2 = Br2 or I2
Entry
Substrate
R1OH
EtOH
2-MeOCH2CH2OH
EtOH
2-MeOCH2CH2OH
EtOH
2-MeOCH2CH2OH
n-Hexanol
X
Ratioa (8:9)
Yieldb (%)
1
2
3
4
5
6
7
8
1a
1a
1b
1b
1c
1c
1a
1a
Br
Br
Br
Br
I
I
Br
Br
70:30
71:29
66:34
68:32
—
67:33
ND
—
89
84
92
88
51c
85
d
PhCH2OH, Allyl alcohol, i-PrOH
NR
NR: No reaction; ND: not determined.
a Ratio of isolated 8 and 9 after column purification.
b Combined isolated yields of 8 and 9 after column chromatography.
c Isolated yield of isomer 8, due to instability of minor isomer 9 in silica gel during column chromatography.
d Mixture of products.

S. Hajra et al. / Tetrahedron: Asymmetry 17 (2006) 210–222
215
none as a chiral auxiliary were studied (Table 5).
Another electron-deficient cinnamoyl substrate 1d
smoothly underwent the bromomethoxylation reaction
under the same reaction conditions with moderate dia-
stereoselectivity (entry 1). Similar to 1b, no iodohydrin
reaction was observed for 1d. Electron-rich cinnamoyl
substrates 1e–1g preferred to undergo the iodomethoxy-
lation reaction with good diastereoselectivity (entries 2–
4), while the bromomethoxylation reaction of 1e–1g
gave a mixture of products. Substrate 1h behaved like
an electron-rich cinnamoyl substrate, that is it
responded to the iodomethoxylation reaction (entry 5),
whilst alkenoyl substrate 1i underwent bromomethoxy-
lation reaction with a good dr of 86:14 along with
18% of other regioisomers (entry 6).
absolute stereostructure of b-methoxytyrosine residue
in neamphamide A9 is syn. Both enantiomers of syn-2-
azido-3-(4-benzyloxy-phenyl)-3-methoxy-propionic acids
12e and 120e were similarly synthesized from 1e,
which can directly be used as N- and O-protected
b-methoxytyrosine building blocks for the synthesis
of peptides.
3. Conclusion
In conclusion, we have described the Ag(I)-promoted
asymmetric halomethoxylation reaction of chiral a,b-
unsaturated carboxylic acid derivatives 1 and 5 with high
regio- and anti-selectivity and moderate to good diastereo-
selectivity in good yields. Alkenoyl, cinnamoyl and elec-
tron-deficient cinnamoyl substrates smoothly underwent
bromomethoxylation, whereas the electron-rich cinna-
moyl substrates were best suited to the iodomethoxyl-
ation reaction. More interestingly for halomethoxylation
of N-cinnamoyl-2-oxazolidinones 1, the use of Ag2O
reverses the diastereoselectivity, with greatest stereocon-
trol being observed for cinnamoyl and electron-deficient
cinnamoyl substrates. However, no counter ion effect for
the Ag(I) salt was observed for cinnamoyl substrates
containing sultam chiral auxiliary. This process has
been applied to the synthesis of both enantiomers of
N-protected syn-b-methoxyphenylalanine and N- and
O-protected syn-b-methoxytyrosine. Thus, this method-
ology offers a general asymmetric method for the synthe-
sis of syn-b-methoxy-a-amino acids.
After achieving the reagent controlled reverse diastereo-
selectivity of the halomethoxylation reaction of oxazo-
lidinone derived cinnamoyl substrates, the usefulness
of the process was exemplified in the short synthesis of
both enantiomers of N-protected syn-b-methoxyphenyl-
alanine, and N- and O-protected syn-b-methoxytyrosine
(Scheme 3). Ag2O mediated halomethoxylation reaction
of 1a gave a-bromo-b-methoxy-carboxylic acid deriva-
tive 4a as major product in 64% yield. Reaction of 4a
with NaN3 in DMF at 60 °C gave syn-a-azido-b-meth-
oxy-carboxylic acid derivative 10a (84%). Subsequent
removal of the chiral auxiliary by treatment with LiOH
and H2O2 in THF at 0 °C yielded syn-a-azido-b-meth-
oxy-carboxylic acid 12a (77%). Compound 12a can be
used directly as N-protected b-methoxyphenylalanine
for the synthesis of cyclomarins, as azido-carboxylic
acids serve as N-protected amino acids in peptide anti-
biotic syntheses.12b In the same way, the other syn-enan-
tiomer of N-protected-b-methoxyphenylalanine 120a
was synthesized from the major isomer 3a, obtained
by AgNO3-mediated bromomethoxylation reaction of
1a. The absolute stereochemistry of the b-methoxytyro-
sine fragment of callipeltins7 and papuamides6,9 have
recently been determined and found to be anti and the
4. Experimental
All reactions were conducted using oven-dried glassware
under an atmosphere of Argon (Ar). Commercial grade
reagents were used without further purification. Solvents
were dried and distilled following usual protocols. Flash
chromatography was carried out using Spectrochem
OMe O
c
OMe O
N3
OMe O
N3
d
Ar
Xc
Ar
Xc
Ar
OH
X
12a 77%
[α]D27 = -92.5 (
10a 84%
10e 88%
4a 64%, X = Br
4e 43%, X = I
a
c
1.0, CHCl3)
O
12e 81%
[α]D27 = -94.2 (
Ar
Xc
c 1.0, CHCl3)
b
OMe O
OMe O
OMe O
1a (Ar = C6H5)
1e (Ar = 4-BnOC6H4)
d
c
Ar
OH
Ar
Xc
Ar
Xc
N3
12'a 80%
[α]D27 = +92.5 (
N3
X
11a 87%
11e 92%
3a 65%, X = Br
3e 71%, X = I
c
1.0, CHCl3)
12'e 91%
[α]D27 = +94.2 (
c 1.0, CHCl3)
Xc = (S)-3-(methylethyl)-2-oxazolidinone
Scheme 3. Reagents and conditions: (a) Ag2O, X2, MeOH, 0–5 °C, 30 min; (b) AgNO3, X2, MeOH, 0–5 °C, 30 min; (c) NaN3, DMF, 60 °C, 2.5–3 h;
(d) LiOH, H2O2, THF, 0–5 °C, 2 h.

216
S. Hajra et al. / Tetrahedron: Asymmetry 17 (2006) 210–222
Silica gel (230–400 mesh) purchased from Spectrochem,
India. TLC was performed on aluminium-backed plates
coated with Silica gel 60 with F254 indicator (Merck).
4.4. anti-(4S,20S,30S)-3-[20-Bromo-30-methoxy-30-(2-
nitrophenyl)-propionyl]-4-(1-methylethyl)-2-oxazolidi-
none 3b
27
The 1H NMR spectra were measured on a Bruker-
200 (200 MHz) and 13C NMR spectra were measured
with Bruker-200 (50 MHz) using CDCl3 as a solvent.
1H NMR chemical shifts are expressed in parts
per million (d) downfield to CHCl3 (d = 7.26); 13C
NMR chemical shifts are expressed in parts per million
(d) relative to the central CDCl3 resonance (d = 77.0).
Gummy liquid; ½aꢁD ¼ þ171:35 (c 1.0, CHCl3); 1H
NMR (CDCl3, 200 MHz): d 7.86 (d, J = 7.96, 1H),
7.78–7.65 (m, 3H), 5.83 (d, J = 10.0 Hz, 1H), 5.61 (d,
J = 10.0 Hz, 1H), 4.60–4.75 (m, 1H), 4.45–4.20 (m,
2H), 3.30 (s, 3H), 2.52–2.30 (m, 1H), 0.93 (d,
J = 5.6 Hz, 3H), 0.88 (d, J = 5.6 Hz, 3H). 13C NMR
(CDCl3, 50 MHz):
d 167.1, 153.8, 150.6, 132.9,
1
Coupling constants in H NMR are expressed in Hertz.
132.2, 129.4, 129.3, 123.9, 76.8, 63.5, 58.4, 58.2, 44.2,
27.9, 17.7, 14.7. Anal. Calcd for C16H19BrN2O6: C,
46.28; H, 4.61; N, 6.75. Found: C, 46.15; H, 4.51; N,
6.79.
Elemental analyses were carried out on a Perkin–Elmer
2400-II. Melting points were measured using Toshniwal
(India) melting point apparatus. Substrates 1 and 5 were
synthesized following the literature procedures.15,21,25
4.5. anti-(4S,20R,30R)-3-[20-Bromo-30-methoxy-30-(2-
nitrophenyl)-propionyl]-4-(1-methylethyl)-2-oxazolidi-
none 4b
4.1. General experimental procedure for the halomethoxyl-
ation reaction
27
To a well-stirred solution of the substrate 1 or 5
(1 mmol) in MeOH (20 ml), Ag(I) salt (for AgNO3
1.2 mmol and Ag2O 0.7 mmol) and X2 (Br2 or I2,
1.2 mmol) were added, respectively, at 0–5 °C and al-
lowed to stir under argon for 20–30 min. On completion,
the reaction mixture was diluted with H2O and extracted
with Et2O at least three times. The combined organic
layer was washed with water and dried over Na2SO4.
The organic solution was filtered through a small Celite
pad (otherwise locking problem or poor base line was
found in the 1H NMR of the crude mixture) and the fil-
trate was concentrated under vacuum. Flash column
chromatography of the crude mixture using petroleum
ether–EtOAc as eluent gave the desired halomethoxyl-
ated compounds in pure form.
White solid; Mp 83–85 °C; ½aꢁD ¼ þ18:6 (c 1.0, CHCl3);
1H NMR (CDCl3, 200 MHz): d 7.90–7.60 (m, 3H), 7.59–
7.49 (m, 1H), 5.88 (d, J = 9.7 Hz, 1H), 5.59 (d,
J = 9.7 Hz, 1H), 4.57–4.45 (m, 1H), 4.40–4.20 (m, 2H),
3.29 (s, 3H), 2.52–2.30 (m, 1H), 0.98 (d, J = 4.6 Hz,
3H), 0.95 (d, J = 4.6 Hz, 3H). 13C NMR (CDCl3,
50 MHz): d 167.5, 153.2, 150.8, 133.0, 132.3, 129.4,
129.1, 123.8, 78.0, 63.5, 59.0, 58.0, 43.8, 28.3, 17.7,
14.5. Anal. Calcd for C16H19BrN2O6: C, 46.28; H,
4.61; N, 6.75. Found: C, 46.33; H, 4.68; N, 6.71.
4.6. anti-(4S,20S,30S)-3-[20-Iodo-30-methoxy-30-(4-meth-
oxyphenyl)-propionyl]-4-(1-methylethyl)-2-oxazolidinone
3c
27
White solid; Mp 141–143 °C; ½aꢁD ¼ þ22:5 (c 1.0,
4.2. anti-(4S,20S,30S)-3-[20-Bromo-30-methoxy-30-phenyl-
propionyl]-4-(1-methylethyl)-2-oxazolidinone 3a
CHCl3); 1H NMR (CDCl3, 200 MHz): d 7.30 (d,
J = 8.5 Hz, 2H), 6.91 (d, J = 8.5 Hz, 2H), 6.01 (d,
J = 10.3 Hz, 1H), 4.70 (d, J = 10.3 Hz, 1H), 4.65–4.50
(m, 1H), 4.45–4.20 (m, 2H), 3.83 (s, 3H), 3.16 (s, 3H),
2.55–2.32 (m, 1H), 0.97 (t, J = 1.7 Hz, 3H), 0.88 (d,
J = 1.7 Hz, 3H). 13C NMR (CDCl3, 50 MHz): d 169.8,
159.9, 153.1, 129.5 (3C), 113.6 (2C), 83.8, 63.3, 58.4,
57.6, 55.2, 27.9, 24.4, 17.8, 15.0. Anal. Calcd for
C17H22INO5: C, 45.65; H, 4.96; N, 3.13. Found: C,
45.46; H, 4.99; N, 3.03.
27
White solid, Mp 75–77 °C; ½aꢁD ¼ þ84:3 (c 1.0, CHCl3);
1H NMR (CDCl3, 200 MHz): d 7.50–7.30 (m, 5H), 5.83
(d, J = 10.0 Hz, 1H), 4.68 (d, J = 10.0 Hz, 1H), 4.65–
4.50 (m, 1H), 4.40–4.20 (m, 2H), 3.19 (s, 3H), 2.52–
2.35 (m, 1H), 0.96 (d, J = 4.2 Hz, 3H), 0.93 (d,
J = 4.2 Hz, 3H); 13C NMR (CDCl3, 50 MHz): d 168.3,
153.1, 136.9, 128.8, 128.3 (4C), 83.4, 63.5, 58.5, 57.4,
44.1, 28.1, 17.7, 14.8. Anal. Calcd for C16H20BrNO4:
C, 51.90; H, 5.44; N, 3.78. Found: C, 51.87; H, 5.42;
N, 3.89.
4.7. anti-(4S,20S,30S)-3-[20-Iodo-30-methoxy-30-(4-meth-
oxyphenyl)-propionyl]-4-(1-methylethyl)-2-oxazolidinone
4c
4.3. anti-(4S,20R,30R)-3-[20-Bromo-30-methoxy-30-phenyl-
propionyl]-4-(1-methylethyl)-2-oxazolidinone 4a
27
White solid; Mp 87–89 °C; ½aꢁD ¼ ꢀ19:5 (c 1.0, CHCl3);
1H NMR (CDCl3, 200 MHz): d 7.30 (d, J = 8.6 Hz, 2H),
6.91 (d, J = 8.6 Hz, 2H), 6.05 (d, J = 10.3 Hz, 1H), 4.65
(d, J = 10.3 Hz, 1H), 4.55–4.45 (m, 1H), 4.33 (t,
J = 8.8 Hz, 1H), 4.22 (dd, J = 9.0, 3.3 Hz, 1H), 3.82 (s,
3H), 3.14 (s, 3H), 2.55–2.30 (m, 1H), 0.95 (d,
J = 3.8 Hz, 3H), 0.92 (d, J = 3.8 Hz, 3H). 13C NMR
(CDCl3, 50 MHz): d 172.0, 159.9, 153.3, 129.5 (2C),
129.4, 113.5 (2C), 85.0, 63.3, 58.9, 57.3, 55.1, 28.4,
24.0, 17.7, 14.5. Anal. Calcd for C17H22INO5: C,
45.65; H, 4.96; N, 3.13. Found: C, 45.77; H, 4.90; N,
2.99.
27
White solid, Mp 71–73 °C; ½aꢁD ¼ ꢀ4:8 (c 1.0, CHCl3);
1H NMR (CDCl3, 200 MHz): d 7.50–7.30 (m, 5H),
5.94 (d, J = 10.0 Hz, 1H), 4.63 (d, J = 10.0 Hz, 1H),
4.60–4.50 (m, 1H), 4.50–4.20 (m, 2H), 3.16 (s, 3H),
2.52–2.30 (m, 1H), 0.97 (d, J = 2.9 Hz, 3H), 0.93 (d,
J = 2.9 Hz, 3H). 13C NMR (CDCl3, 50 MHz): d 168.7,
153.2, 136.8, 128.8, 128.3 (4C), 84.7, 63.4, 58.9, 57.2,
44.0, 28.3, 17.7, 14.5. Anal. Calcd for C16H20BrNO4:
C, 51.90; H, 5.44; N, 3.78. Found: C, 51.91; H, 5.47;
N, 3.81.

S. Hajra et al. / Tetrahedron: Asymmetry 17 (2006) 210–222
217
4.8. anti-(4S,20S,30S)-3-[20-Bromo-30-methoxy-30-(3-
4.12. anti-(4S,20S,30S)-3-[20-Iodo-30-methoxy-30-(4-
bromo-4-methoxyphenyl)-propionyl]-4-(1-methylethyl)-2-
oxazolidinone 30c
benzyloxyphenyl)-propionyl]-4-(1-methylethyl)-2-oxazo-
lidinone 3e
28
27
1
Liquid; ½aꢁD ¼ þ88:9 (c 1.0, CHCl3); H NMR (CDCl3,
200 MHz): d 7.58 (d, J = 2.11 Hz, 1H), 7.32 (dd,
J = 8.38, 2.11 Hz, 1H), 6.91 (d, J = 8.38 Hz, 1H), 5.74
(d, J = 10.07 Hz, 1H), 4.60 (d, J = 10.07 Hz, 1H),
4.56–4.44 (m, 1H), 4.42–4.16 (m, 2H), 3.91 (s, 3H),
3.17 (s, 3H), 2.60–2.25 (m, 1H), 0.98 (d, J = 4.86 Hz,
3H), 0.92 (d, J = 4.86 Hz, 3H). 13C NMR (CDCl3,
50 MHz): d 168.3, 156.0, 152.9, 132.7, 130.4, 128.4,
111.4, 111.3, 82.2, 63.4, 58.3, 57.3, 56.0, 44.0, 29.4,
28.4, 17.5 and 14.6. Anal. Calcd for C21H21Br2NO5: C,
42.61; H, 4.42; N, 2.92. Found: C, 42.73 H, 4.75; N,
2.78.
White solid; Mp 147–149 °C; ½aꢁD ¼ þ78:9 (c 1.0,
CHCl3); 1H NMR (CDCl3, 200 MHz): d 7.50–7.23
(m, 7H), 6.99 (d, J = 8.57 Hz, 2H), 6.02 (d, J =
10.3 Hz, 1H), 5.07 (s, 2H), 4.70 (d, J = 10.3 Hz, 1H),
4.60–4.50 (m, 1H), 4.33 (t, J = 7.94 Hz, 1H), 4.25
(dd, J = 9.0, 3.28 Hz, 1H), 3.17 (s, 3H), 2.55–2.35 (m,
1H), 0.97 (d, J = 2.14 Hz, 3H), 0.94 (d, J = 2.14 Hz,
3H). 13C NMR (CDCl3, 50 MHz): d 169.7, 159.2,
153.1, 136.7, 129.8, 129.5 (2C), 128.5 (2C), 127.9,
127.5 (2C), 114.5 (2C), 83.7, 69.9, 63.3, 58.4, 57.6,
27.8, 24.4, 17.8, 15.0. Anal. Calcd for C23H26INO5: C,
52.78; H, 5.01; N, 2.68. Found: C, 52.83; H, 5.13; N,
2.67.
4.9. anti-(4S,20R,30R)-3-[20-Bromo-30-methoxy-30-(3-
bromo-4-methoxyphenyl)-propionyl]-4-(1-methylethyl)-2-
oxazolidinone 40c
4.13. anti-(4S,20R,30R)-3-[20-Iodo-30-methoxy-30-(4-
benzyloxyphenyl)-propionyl]-4-(1-methylethyl)-2-oxazo-
lidinone 4e
28
1
Liquid; ½aꢁD ¼ þ8:4 (c 1.0, CHCl3); H NMR (CDCl3,
200 MHz): d 7.60 (d, J = 2.04 Hz, 1H), 7.35 (dd,
J = 8.40, 2.04 Hz, 1H), 6.91 (d, J = 8.40 Hz, 1H), 5.85
(d, J = 10.09 Hz, 1H), 4.59–4.48 (m, 2H), 4.34 (t,
J = 9.05 Hz, 1H), 4.24 (dd, J = 9.05, 3.30 Hz, 1H), 3.91
(s, 3H), 3.15 (s, 3H), 2.52–2.30 (m, 1H), 0.96 (d,
J = 3.62 Hz, 3H), 0.93 (d, J = 3.62 Hz, 3H). 13C NMR
(CDCl3, 50 MHz): d 168.3, 156.0, 153.2, 132.8, 130.4,
128.4, 111.4 (2C), 83.6, 63.3, 58.8, 57.1, 56.0, 29.4,
28.2, 17.5 and 14.4. Anal. Calcd for (C21H21Br2NO5 + 1-
H2O): C, 41.07; H, 4.66; N, 2.82. Found: C, 41.43 H,
4.76; N, 3.01.
27
1
Gummy liquid; ½aꢁD ¼ þ21:8 (c 1.0, CHCl3); H NMR
(CDCl3, 200 MHz): d 7.50–7.25 (m, 7H), 6.99 (d,
J = 8.48 Hz, 2H), 6.06 (d, J = 10.2 Hz, 1H), 5.07 (s,
2H), 4.66 (d, J = 10.2 Hz, 1H), 4.60–4.45 (m, 1H), 4.34
(t, J = 8.30 Hz, 1H), 4.23 (dd, J = 9.01, 3.16 Hz, 1H),
3.15 (s, 3H), 2.52–2.30 (m, 1H), 0.96 (d, J = 3.80 Hz,
3H), 0.92 (d, J = 3.80 Hz, 3H). 13C NMR (CDCl3,
50 MHz): d 170.1, 159.2, 153.4, 136.8, 129.8, 129.6
(2C), 128.6 (2C), 128.0, 127.5 (2C), 114.5 (2C), 85.1,
70.0, 63.4, 59.0, 57.5, 28.5, 24.1, 17.8, 14.6. Anal. Calcd
for C23H26INO5: C, 52.78; H, 5.01; N, 2.68. Found: C,
52.89; H, 5.00; N, 2.54.
4.10. anti-(4S,20S,30S)-3-[20-Bromo-30-methoxy-30-(2-
chlorophenyl)-propionyl]-4-(1-methylethyl)-2-oxazolidi-
none 3d
4.14. anti-(4S,20S,30S)-3-[20-Iodo-30-methoxy-30-(3,4-
dimethoxyphenyl)-propionyl]-4-(1-methylethyl)-2-oxazo-
lidinone 3f
27
White solid; Mp 97–99 °C; ½aꢁD ¼ þ77:8 (c 1.0, CHCl3);
27
1H NMR (CDCl3, 200 MHz): d 7.60–7.20 (m, 4H), 5.91
(d, J = 9.9 Hz, 1H), 5.41 (d, J = 9.9 Hz, 1H), 4.60–4.52
(m, 1H), 4.40–4.22 (m, 2H), 3.20 (s, 3H), 2.55–2.32 (m,
1H), 0.96 (d, J = 3.8 Hz, 3H), 0.93 (d, J = 3.8 Hz, 3H).
13C NMR (CDCl3, 50 MHz): d 167.7, 153.0, 135.3,
135.0, 129.8, 129.3, 128.7, 127.3, 78.4, 63.4, 58.5, 57.6,
43.4, 28.0, 17.7, 14.7. Anal. Calcd for C16H19BrClNO4:
C, 47.49; H, 4.73; N, 3.46. Found: C, 47.28; H, 4.67;
N, 3.49.
White solid; Mp 160–162 °C; ½aꢁD ¼ þ75:0 (c 1.0,
CHCl3); 1H NMR (CDCl3, 200 MHz):
d 7.00–
6.81 (m, 3H), 6.01 (d, J = 10.4 Hz, 1H), 4.68 (d,
J = 10.4 Hz, 1H), 4.62–4.50 (m, 1H), 4.40–4.21 (m,
2H), 3.91 (s, 3H), 3.89 (s, 3H), 3.18 (s, 3H), 2.52–
2.32 (m, 1H), 0.96 (d, J = 6.8 Hz, 6H). 13C NMR
(CDCl3, 50 MHz): d 169.7, 153.1, 149.3, 148.8, 129.9,
121.4, 110.3 (2C), 84.1, 63.3, 58.4, 57.6, 55.8, 55.7,
27.9, 24.3, 17.8, 15.0. Anal. Calcd for C18H24INO6: C,
45.30; H, 5.07; N, 2.93. Found: C, 45.42; H, 5.11; N,
3.02.
4.11. anti-(4S,20R,30R)-3-[20-Bromo-30-methoxy-30-(2-
chlorophenyl)-propionyl]-4-(1-methylethyl)-2-oxazolidi-
none 4d
4.15. anti-(4S,20R,30R)-3-[20-Iodo-30-methoxy-30-(3,4-
dimethoxyphenyl)-propionyl]-4-(1-methylethyl)-2-oxazo-
lidinone 4f
27
1
Gummy liquid; ½aꢁD ¼ þ7:3 (c 1.0, CHCl3); H NMR
(CDCl3, 200 MHz): d 7.55 (d, J = 7.2 Hz, 1H), 7.45–
7.20 (m, 3H), 6.01 (d, J = 9.9 Hz, 1H), 5.37 (d,
J = 9.9 Hz, 1H), 4.62–4.49 (m, 1H), 4.45–4.15 (m, 2H),
3.18 (s, 3H), 2.55–2.32 (m, 1H), 0.94 (t, J = 6.3 Hz,
6H). 13C NMR (CDCl3, 50 MHz): d 168.1, 153.2,
135.3, 134.9, 129.7, 129.2, 128.6, 127.3, 79.5, 63.4,
58.9, 57.3, 43.2, 28.2, 17.6, 14.4. Anal. Calcd for
C16H19BrClNO4: C, 47.49; H, 4.73; N, 3.46. Found: C,
47.54; H, 4.76; N, 3.48.
27
1
Gummy liquid; ½aꢁD ¼ ꢀ3:85 (c 1.0, CHCl3); H NMR
(CDCl3, 200 MHz): d 7.00–6.80 (m, 3H), 6.06 (d,
J = 10.2 Hz, 1H), 4.64 (d, J = 10.2 Hz, 1H), 4.56–4.45
(m, 1H), 4.34 (t, J = 8.0 Hz, 1H), 4.23 (dd, J = 8.9,
3.3 Hz, 1H), 3.92 (s, 3H), 3.90 (s, 3H), 3.16 (s, 3H),
2.52–2.35 (m, 1H), 0.96 (d, J = 3.8 Hz, 3H), 0.92 (d,
J = 3.8 Hz, 3H). 13C NMR (CDCl3, 50 MHz): d 170.0,
153.4, 149.3, 149.0, 129.8, 127.5, 110.3, 110.2, 85.4,

218
S. Hajra et al. / Tetrahedron: Asymmetry 17 (2006) 210–222
63.4, 59.0, 57.5, 55.9, 55.7, 28.4, 24.0, 17.7, 14.6. Anal.
Calcd for C18H24INO6: C, 45.30; H, 5.07; N, 2.93.
Found: C, 45.47; H, 5.18; N, 3.02.
50 MHz): d 170.1, 153.4, 134.7, 133.7, 132.7, 128.7,
128.5, 128.1, 127.7, 126.4, 126.2, 124.8, 89.2, 63.4,
59.1, 57.7, 28.5, 23.3, 17.8, 15.6. Anal. Calcd for
C20H22INO4: C, 51.40; H, 4.75; N, 3.00. Found: C,
51.98; H, 4.99; N, 3.04.
4.16. anti-(4S,20S,30S)-3-[20-Iodo-30-methoxy-30-(3,4,5-
trimethoxyphenyl)-propionyl]-4-(1-methylethyl)-2-oxazo-
lidinone 3g
4.20. anti-(4S,20S,30S)-3-(20-Bromo-30-methoxy-bution-
yl)-4-(1-methylethyl)-2-oxazolidinone 3i
27
White solid; Mp 105–107 °C; ½aꢁD ¼ þ86:6 (c 1.0,
27
1
1
CHCl3); H NMR (CDCl3, 200 MHz): d 6.75 (s, 2H),
Gummy liquid; ½aꢁD ¼ þ60:6 (c 1.0, CHCl3); H NMR
(CDCl3, 200 MHz): d 5.52 (d, J = 9.30 Hz, 1H), 4.53–
4.42 (m, 1H), 4.36–4.20 (m, 2H), 3.95–3.83 (m, 1H),
3.33 (s, 3H), 2.52–2.30 (m, 1H), 1.39 (d, J = 6.2 Hz,
3H), 0.94 (d, J = 1.5 Hz, 3H), 0.91 (d, J = 1.5 Hz, 3H).
13C NMR (CDCl3, 50 MHz): d 168.2, 153.0, 76.6,
63.3, 58.4, 57.5, 44.8, 27.9, 17.7, 16.3, 14.7. Anal. Calcd
for C11H18BrNO4: C, 42.87; H, 5.89; N, 4.55. Found: C,
42.98; H, 6.00; N, 4.67.
6.02 (d, J = 9.98 Hz, 1H), 5.37 (d, J = 9.98 Hz, 1H),
4.64–4.50 (m, 1H), 4.45–4.15 (m, 2H), 3.90 (s, 3H),
3.88 (s, 3H), 3.87 (s, 3H), 3.22 (s, 3H), 2.55–2.35 (m,
1H), 0.97 (d, J = 2.6 Hz, 3H), 0.93 (d, J = 2.6 Hz, 3H).
13C NMR (CDCl3, 50 MHz): d 169.6, 153.1, 152.9
(2C), 138.0, 133.0, 105.0 (2C), 84.4, 63.3, 60.8, 58.3,
57.8, 56.0 (2C), 27.8, 23.9, 17.8, 14.9. Anal. Calcd for
C19H26INO7: C, 44.98; H, 5.17; N, 2.76. Found: C,
45.13; H, 5.18; N, 2.72.
4.21. anti-(2R,20R,30R)-N-[20-Iodo-30-methoxy-30-phenyl-
propionyl]-bornanesultam 6a
4.17. anti-(4S,20R,30R)-3-[20-Iodo-30-methoxy-30-(3,4,5-
trimethoxyphenyl)-propionyl]-4-(1-methylethyl)-2-oxazo-
lidinone 4g
27
White solid; Mp 154–156 °C; ½aꢁD ¼ ꢀ102:2 (c 1.0,
1
CHCl3); H NMR (CDCl3, 200 MHz): d 7.50–7.25 (m,
27
White solid; Mp 149–151 °C; ½aꢁD ¼ ꢀ17:1 (c 1.0,
5H), 5.07 (d, J = 9.68 Hz, 1H), 4.70 (d, J = 9.68 Hz,
1H), 4.09–4.00 (m, 1H), 3.50 (s, 2H), 3.19 (s, 3H),
2.20–2.05 (m, 2H), 2.00–1.85 (m, 3H), 1.60–1.30 (m,
2H), 1.88 (s, 3H), 0.98 (s, 3H). 13C NMR (CDCl3,
50 MHz): d 168.4, 137.6, 128.8, 128.4 (2C), 128.2 (2C),
84.2, 64.9, 57.9, 52.8, 48.7, 47.8, 44.3, 37.2, 32.7, 26.4,
25.8, 20.6, 19.8. Anal. Calcd for C20H26INO4S: C,
47.72; H, 5.21; N, 2.78. Found: C, 47.90 H, 5.34; N,
2.75.
1
CHCl3); H NMR (CDCl3, 200 MHz): d 6.82 (s, 2H),
6.08 (d, J = 9.72 Hz, 1H), 5.32 (d, J = 9.72 Hz, 1H),
4.53–4.45 (m, 1H), 4.34 (t, J = 8.8 Hz, 1H), 4.22 (dd,
J = 8.99, 2.9 Hz, 1H), 3.90 (s, 3H), 3.88 (s, 6H), 3.21
(s, 3H), 2.52–2.32 (m, 1H), 0.94 (d, J = 6.9 Hz, 3H),
0.89 (d, J = 6.9 Hz, 3H). 13C NMR (CDCl3, 50 MHz):
d 169.8, 153.3, 152.9 (2C), 138.0, 132.9, 105.0 (2C),
85.6, 63.3, 60.7, 58.9, 57.7, 56.0 (2C), 28.3, 23.6, 17.7,
14.5. Anal. Calcd for C19H26INO7: C, 44.98; H, 5.17;
N, 2.76. Found: C, 45.10; H, 5.23; N, 2.88.
4.22. anti-(2R,20S,30S)-N-[20-Iodo-30-methoxy-30-phenyl-
propionyl]-bornanesultam 7a
4.18. anti-(4S,20S,30S)-3-[20-Iodo-30-methoxy-30-(2-naph-
thyl)-propionyl]-4-(1-methylethyl)-2-oxazolidinone 3h
27
White solid; Mp 163–165 °C; ½aꢁD ¼ ꢀ7:0 (c 1.0,
1
CHCl3); H NMR (CDCl3, 200 MHz): d 7.45–7.27 (m,
27
White solid; Mp 177–179 °C; ½aꢁD ¼ þ108:6 (c 1.0,
5H), 5.05 (d, J = 9.74 Hz, 1H), 4.64 (d, J = 9.74 Hz,
1H), 4.00–3.85 (m, 1H), 3.60–3.40 (m, 2H), 3.14 (s,
3H), 2.30–2.10 (m, 2H), 2.07–1.80 (m, 3H), 1.55–1.25
(m, 2H), 1.21 (s, 3H), 0.99 (s, 3H). 13C NMR (CDCl3,
50 MHz): d 168.1, 137.1, 128.9, 128.3 (2C), 128.2 (2C),
87.0, 65.6, 57.5, 52.7, 48.6, 47.8, 44.6, 38.0, 32.7, 26.3,
25.6, 20.4, 19.9. Anal. Calcd for C20H26INO4S: C,
47.72; H, 5.21; N, 2.78. Found: C, 48.03 H, 5.42; N,
2.77.
1
CHCl3); H NMR (CDCl3, 200 MHz): d 7.95–7.82 (m,
4H), 7.60–7.45 (m, 3H) 6.15 (d, J = 10.32 Hz, 1H),
4.92 (d, J = 10.32 Hz, 1H), 4.64–4.52 (m, 1H), 4.36 (t,
J = 8.96 Hz, 1H), 4.27 (dd, J = 9.00, 3.15 Hz, 1H),
3.21 (s, 3H), 2.55–2.40 (m, 1H), 0.99 (d, J = 1.00 Hz,
3H), 0.95 (d, J = 1.00 Hz, 3H). 13C NMR (CDCl3,
50 MHz): d 169.7, 153.1, 134.8, 133.6, 132.6, 128.6,
128.4, 128.0, 127.7, 126.3, 126.2, 124.8, 84.4, 63.3,
58.4, 57.8, 27.9, 23.6, 17.8, 15.0. Anal. Calcd for
C20H22INO4: C, 51.40; H, 4.75; N, 3.00. Found: C,
51.67; H, 4.54; N, 2.98.
4.23. anti-(2R,20R,30R)-N-[20-Bromo-30-methoxy-30-
phenyl-propionyl]-bornanesultam Br-6a and anti-
(2R,20S,30S)-N-[20-bromo-30-methoxy-30-phenyl-
propionyl]-bornanesultam Br-7a
4.19. anti-(4S,20R,30R)-3-[20-Iodo-30-methoxy-30-(2-
naphthyl)-propionyl]-4-(1-methylethyl)-2-oxazolidinone
4h
Non-separable mixture of diastereomers (65:35); 1H
NMR (CDCl3, 200 MHz): d 7.50–7.25 (m, 5H), 4.93
(d, J = 9.60 Hz, 0.65H), 4.85 (d, J = 9.60 Hz, 0.35H),
4.67 (d, J = 9.70 Hz, 0.65H), 4.58 (d, J = 9.70 Hz,
0.35H), 4.10–3.90 (m, 1H), 3.60–3.45 (m, 2H), 3.20 (s,
1.95H), 3.13 (s, 1.05H), 2.30–2.05 (m, 2H), 2.04–1.75
(m, 3H), 1.60–1.25 (m, 2H), 1.21 (s, 1.05H), 1.16 (s,
1.95H), 0.93 (s, 1.05H), 0.91 (s, 1.95H). 13C NMR
(CDCl3, 50 MHz): major d 166.7, 136.9, 128.7, 128.2
27
White solid; Mp 94–96 °C; ½aꢁD ¼ ꢀ39:5 (c 1.0, CHCl3);
1H NMR (CDCl3, 200 MHz): d 7.95–7.80 (m, 4H), 7.60–
7.45 (m, 3H), 6.20 (d, J = 10.25 Hz, 1H), 4.88 (d,
J = 10.25 Hz, 1H), 4.60–4.50 (m, 1H), 4.35 (t,
J = 8.23 Hz, 1H), 4.25 (dd, J = 8.90, 3.08 Hz, 1H),
3.20 (s, 3H), 2.55–2.35 (m, 1H), 0.97 (d, J = 3.98 Hz,
3H), 0.94 (d, J = 3.98 Hz, 3H). 13C NMR (CDCl3,

S. Hajra et al. / Tetrahedron: Asymmetry 17 (2006) 210–222
219
(2C), 128.1 (2C), 83.0, 64.8, 57.6, 52.7, 47.7, 45.9, 44.4,
4.28. anti-(4S,20S,30S)-3-[20-Bromo-30-ethoxy-30-phenyl-
propionyl]-4-(1-methylethyl)-2-oxazolidinone EO-8a
37.7, 32.5, 26.3 (2C), 20.5, 19.7. Minor d 166.9, 136.7,
128.8, 128.2 (2C), 128.1 (2C), 85.7, 65.2, 57.1, 48.6,
48.5, 46.5, 44.5, 37.5, 31.7, 29.5 (2C), 20.3, 19.8.
27
White solid; Mp 81–83 °C; ½aꢁD ¼ þ0:7 (c 1.0, CHCl3);
1H NMR (CDCl3, 200 MHz): d 7.65–7.20 (m, 5H),
5.81 (d, J = 10.04 Hz, 1H), 4.76 (d, J = 10.04 Hz, 1H),
4.63–4.48 (m, 1H), 4.45–4.15 (m, 2H), 3.35 (q,
J = 7.00 Hz, 2H), 2.60–2.30 (m, 1H), 1.05 (t,
J = 7.00 Hz, 3H), 0.96 (d, J = 4.0 Hz, 3H), 0.93 (d,
J = 4.0 Hz, 3H). 13C NMR (CDCl3, 50 MHz): d 168.6,
153.1, 137.5, 128.6, 128.2 (2C), 128.1 (2C), 82.5, 65.1,
63.3, 58.7, 44.0, 28.2, 17.7, 14.9, 14.7. Anal. Calcd for
C17H22BrNO4: C, 53.14; H, 5.77; N, 3.65. Found: C,
53.79; H, 5.73; N, 3.82.
4.24. anti-(2R,20R,30R)-N-[20-Bromo-30-methoxy-30-(2-
nitrophenyl)-propionyl]-bornanesultam 6b
27
Liquid; ½aꢁD ¼ ꢀ109:1 (c 1.0, CHCl3); 1H NMR (CDCl3,
200 MHz): d 7.95–7.40 (m, 4H), 5.61 (d, J = 9.14 Hz,
1H), 4.91 (d, J = 9.14 Hz, 1H), 3.98 (dd, J = 7.23,
5.44 Hz, 1H), 3.50 (d, J = 1.62 Hz, 2H), 3.32 (s, 3H),
2.20–2.00 (m, 2H), 2.00–1.80 (m, 3H), 1.55–1.25 (m,
2H), 1.14 (s, 3H), 0.96 (s, 3H). 13C NMR (CDCl3,
50 MHz): d 165.8, 150.5, 133.2, 129.6 (2C), 124.0 (2C),
64.9, 58.4, 52.8, 48.7, 47.8, 45.7, 44.4, 37.5, 32.6, 29.6,
26.3, 20.6, 19.8. Anal. Calcd for C20H25BrN2O6S: C,
47.91; H, 5.03; N, 5.59. Found: C, 48.21; H, 5.23; N,
5.67.
4.29. anti-(4S,20R,30R)-3-[20-Bromo-30-ethoxy-30-phenyl-
propionyl]-4-(1-methylethyl)-2-oxazolidinone EO-9a
27
White solid; Mp 91–93 °C; ½aꢁD ¼ þ94:5 (c 1.0, CHCl3);
1H NMR (CDCl3, 200 MHz): d 7.55–7.25 (m, 5H), 5.87
(d, J = 10.11 Hz, 1H), 4.75 (d, J = 10.11 Hz, 1H), 4.60–
4.45 (m, 1H), 4.34 (t, J = 8.96 Hz, 1H), 4.24 (dd,
J = 9.00, 3.33 Hz, 1H), 3.33 (q, J = 7.08 Hz, 2H),
2.55–2.30 (m, 1H), 1.03 (t, J = 7.08 Hz, 3H), 0.97 (d,
J = 2.4 Hz, 3H), 0.94 (d, J = 2.4 Hz, 3H). 13C NMR
(CDCl3, 50 MHz): d 168.2, 153.1, 137.7, 128.6, 128.3
(2C), 128.2 (2C), 81.6, 65.2, 63.4, 58.5, 44.6, 28.2,
17.7, 15.0, 14.8. Anal. Calcd for C17H22BrNO4: C,
53.14; H, 5.77; N, 3.65. Found: C, 53.45; H, 5.86; N,
3.72.
4.25. anti-(2R,20S,30S)-N-[20-Bromo-30-methoxy-30-(2-
nitrophenyl)-propionyl]-bornanesultam 7b
27
1
Liquid; ½aꢁD ¼ þ56:2 (c 1.0, CHCl3); H NMR (CDCl3,
200 MHz): d 7.98–7.40 (m, 4H), 5.52 (d, J = 8.88 Hz,
1H), 4.95 (d, J = 8.88 Hz, 1H), 4.05–3.90 (m, 1H), 3.50
(d, J = 4.16 Hz, 2H), 3.29 (s, 3H), 2.18–2.06 (m, 2H),
2.05–1.85 (m, 3H), 1.55–1.35 (m, 2H), 1.13 (s, 3H),
0.98 (s, 3H). 13C NMR (CDCl3, 50 MHz): d 165.9,
150.6, 133.2, 129.6 (2C), 124.0 (2C), 65.4, 58.2, 52.8,
48.7, 47.8, 46.1, 44.6, 37.9, 32.7, 29.6, 26.3, 20.4, 19.9.
Anal. Calcd for C20H25BrN2O6S: C, 47.91; H, 5.03; N,
5.59. Found: C, 48.22; H, 5.08; N, 5.34.
4.30. anti-(4S,20S,30S)-3-[20-Bromo-30-(2-methoxy-ethoxy)-
30-phenyl-propionyl]-4-(1-methylethyl)-2-oxazolidinone
MOE-8a
4.26. anti-(2R,20R,30R)-N-[20-Bromo-30-methoxy-30-(4-
methoxyphenyl)-propionyl]-bornanesultam 6c
27
White solid; Mp 77–79 °C; ½aꢁD ¼ þ99:8 (c 1.0, CHCl3);
1H NMR (CDCl3, 200 MHz): d 7.70–7.27 (m, 5H), 5.81
(d, J = 9.97 Hz, 1H), 4.77 (d, J = 9.97 Hz, 1H), 4.58–
4.45 (m, 1H), 4.32 (t, J = 8.00 Hz, 1H), 4.23 (dd,
J = 9.07, 3.24 Hz, 1H), 3.55–3.00 (m, 4H), 3.24 (s,
3H), 2.60–2.25 (m, 1H), 0.94 (d, J = 4.25 Hz, 3H), 0.91
(d, J = 4.25 Hz, 3H). 13C NMR (CDCl3, 50 MHz): d
168.1, 153.1, 137.1, 128.7, 128.3 (2C), 128.2 (2C), 82.2,
71.3, 68.7, 63.5, 58.6, 58.5, 44.3, 28.2, 17.7, 14.8. Anal.
Calcd for C18H24BrNO5: C, 52.18; H, 5.14; N, 3.38.
Found: C, 52.35; H, 5.11; N, 3.51.
27
1
Liquid; ½aꢁD ¼ ꢀ90:3 (c 1.0, CHCl3); H NMR (CDCl3,
200 MHz): d 7.33 (d, J = 8.69 Hz, 2H), 6.90 (d,
J = 8.69 Hz, 2H), 4.83 (d, J = 9.79 Hz, 1H), 4.62 (d,
J = 9.79 Hz, 1H), 4.07–3.90 (m, 1H), 3.81 (s, 3H), 3.48
(s, 2H), 3.18 (s, 3H), 2.25–2.05 (m, 2H), 2.04–1.80 (m,
3H), 1.55–1.25 (m, 2H), 1.17 (s, 3H), 0.97 (s, 3H). 13C
NMR (CDCl3, 50 MHz): d 166.8, 159.8, 129.4 (2C),
128.9, 113.6 (2C), 82.6, 64.8, 57.4, 55.1, 52.8, 48.6,
47.7, 46.3, 44.4, 37.5, 32.6, 26.3, 20.6, 19.8. Anal. Calcd
for C21H28BrNO5S: C, 51.85; H, 5.80; N, 2.88. Found:
C, 51.73 H, 5.75; N, 2.68.
4.31. anti-(4S,20R,30R)-3-[20-Bromo-30-(2-methoxy-
ethoxy)-30-phenyl-propionyl]-4-(1-methylethyl)-2-oxazo-
lidinone MOE-9a
4.27. anti-(2R,20S,30S)-N-[20-Bromo-30-methoxy-30-(4-
methoxyphenyl)-propionyl]-bornanesultam 7c
27
1
Gummy liquid; ½aꢁD ¼ ꢀ4:7 (c 1.0, CHCl3); H NMR
(CDCl3, 200 MHz): d 7.60–7.25 (m, 5H), 5.85 (d,
J = 10.02 Hz, 1H), 4.82 (d, J = 10.02 Hz, 1H), 4.60–
4.50 (m, 1H), 4.34 (t, J = 7.98 Hz, 1H), 4.27 (dd,
J = 7.98, 3.36 Hz, 1H), 3.50–3.30 (m, 4H), 3.23 (s,
3H), 2.55–2.32 (m, 1H), 0.97 (d, J = 3.17 Hz, 3H),
0.94 (d, J = 3.17 Hz, 3H). 13C NMR (CDCl3,
50 MHz): d 168.9, 153.4, 135.5, 128.6, 128.3 (2C),
128.2 (2C), 83.0, 71.5, 69.0, 63.8, 59.0, 58.8, 44.1,
28.6, 17.9, 14.8. Anal. Calcd for C18H24BrNO5: C,
52.18; H, 5.14; N, 3.38. Found: C, 52.15; H, 5.23; N,
3.39.
27
1
Liquid; ½aꢁD ¼ þ19:3 (c 1.0, CHCl3); H NMR (CDCl3,
200 MHz): d 7.33 (d, J = 8.61 Hz, 2H), 6.90 (d,
J = 8.61 Hz, 2H), 4.91 (d, J = 9.46 Hz, 1H), 4.53 (d,
J = 9.46 Hz, 1H), 4.10–3.85 (m, 1H), 3.81 (s, 3H),
3.60–3.40 (s, 2H), 3.11 (s, 3H), 2.25–2.02 (m, 2H),
2.00–1.75 (m, 3H), 1.55–1.25 (m, 2H), 1.21 (s, 3H),
0.98 (s, 3H). 13C NMR (CDCl3, 50 MHz): d 167.2,
159.9, 129.4 (2C), 128.7, 113.6 (2C), 85.4, 65.3, 57.0,
55.1, 52.8, 48.6, 47.7, 46.9, 44.6, 37.8, 32.7, 26.3, 20.4,
19.9. Anal. Calcd for C21H28BrNO5S: C, 51.85; H,
5.80; N, 2.88. Found: C, 51.88; H, 5.94; N, 3.01.

220
S. Hajra et al. / Tetrahedron: Asymmetry 17 (2006) 210–222
4.32. anti-(4S,20S,30S)-3-[20-Bromo-30-ethoxy-30-(2-
nitrophenyl)-propionyl]-4-(1-methylethyl)-2-oxazolidi-
none EO-8b
4.36. anti-(4S,20S,30S)-3-[20-Iodo-30-ethoxy-30-(4-meth-
oxyphenyl)-propionyl]-4-(1-methylethyl)-2-oxazolidinone
EO-8c
27
27
1
Gummy liquid; ½aꢁD ¼ þ101:4 (c 1.0, CHCl3); 1H
Gummy liquid; ½aꢁD ¼ þ89:8 (c 1.0, CHCl3); H NMR
(CDCl3, 200 MHz): d 7.28 (d, J = 8.67 Hz, 2H), 6.87
(d, J = 8.67 Hz, 2H), 5.95 (d, J = 10.30 Hz, 1H), 4.76
(d, J = 10.30 Hz, 1H), 4.60–4.45 (m, 1H), 4.32 (t,
J = 7.98 Hz, 1H), 4.23 (dd, J = 9.07, 3.28 Hz, 1H),
3.80 (s, 3H), 3.31 (dq, J = 6.94, 3.18 Hz, 2H), 2.60–
2.30 (m, 1H), 1.00 (t, J = 6.94 Hz, 3H), 0.95 (d,
J = 1.69 Hz, 3H), 0.91 (d, J = 1.69 Hz, 3H). 13C NMR
(CDCl3, 50 MHz): d 169.7, 159.7, 153.1, 130.3, 129.4
(2C), 113.5 (2C), 81.8, 65.3, 63.3, 58.4, 55.1, 27.9, 25.0,
17.8, 15.0 (2C). Anal. Calcd for C18H24INO5: C, 46.87;
H, 5.24; N, 3.04. Found: C, 47.01; H, 5.19; N, 3.12.
NMR (CDCl3, 200 MHz): d 7.85–7.40 (m, 4H), 5.80
(d, J = 9.73 Hz, 1H), 5.66 (d, J = 9.73 Hz, 1H), 4.60–
4.45 (m, 1H), 4.34 (t, J = 9.27 Hz, 1H), 4.24 (dd,
J = 8.57, 1.95 Hz, 1H), 3.60–3.30 (m, 2H), 2.52–2.30
(m, 1H), 1.07 (t, J = 6.93 Hz, 3H), 0.90 (t,
J = 6.60 Hz, 6H). 13C NMR (CDCl3, 50 MHz): d
167.1, 152.9, 150.5, 133.1, 132.9, 129.5, 129.3, 123.8,
75.2, 66.3, 63.5, 58.4, 44.6, 28.0, 17.7, 15.0, 14.7. Anal.
Calcd for C17H21BrN2O6: C, 47.57; H, 4.93; N, 6.93.
Found: C, 47.50; H, 4.95; N, 6.88.
4.33. anti-(4S,20R,30R)-3-[20-Bromo-30-ethoxy-30-(2-
nitrophenyl)-propionyl]-4-(1-methylethyl)-2-oxazolidi-
none EO-9b
4.37. anti-(4S,20S,30S)-3-[20-Iodo-30-(2-methoxy-ethoxy)-
30-(4-methoxyphenyl)-propionyl]-4-(1-methylethyl)-2-
oxazolidinone MOE-8c
27
1
Gummy liquid; ½aꢁD ¼ ꢀ92:7 (c 1.0, CHCl3); H NMR
(CDCl3, 200 MHz): d 7.85–7.40 (m, 4H), 5.84 (d,
J = 10.08 Hz, 1H), 5.68 (d, J = 10.08 Hz, 1H), 4.57–
4.45 (m, 1H), 4.34 (t, J = 7.91 Hz, 1H), 4.24 (dd,
J = 9.02, 3.30 Hz, 1H), 3.60–3.35 (m, 2H), 2.60–2.30
(m, 1H), 1.06 (t, J = 7.13 Hz, 3H), 0.96 (d,
J = 4.16 Hz, 3H), 0.93 (d, J = 4.16 Hz, 3H). 13C NMR
(CDCl3, 50 MHz): d 167.6, 153.2, 150.7, 133.0, 132.9,
129.4 (2C), 123.8, 76.3, 66.2, 63.5, 58.9, 43.8, 28.3,
17.8, 14.9, 14.8. Anal. Calcd for C17H21BrN2O6: C,
47.57; H, 4.93; N, 6.93. Found: C, 47.77; H, 4.89; N,
6.99.
27
1
Gummy liquid; ½aꢁD ¼ þ86:1 (c 1.0, CHCl3); H NMR
(CDCl3, 200 MHz): d 7.30 (d, J = 8.71 Hz, 2H), 6.88
(d, J = 8.71 Hz, 2H), 5.96 (d, J = 10.35 Hz, 1H), 4.81
(d, J = 10.36 Hz, 1H), 4.58–4.45 (m, 1H), 4.32 (t,
J = 8.91 Hz, 1H), 4.23 (dd, J = 8.91, 3.00 Hz, 1H), 3.80
(s, 3H), 3.55–3.20 (m, 4H), 3.24 (s, 3H), 2.55–2.30 (m,
1H), 0.94 (d, J = 6.83 Hz, 6H). 13C NMR (CDCl3,
50 MHz): d 169.5, 159.8, 153.1, 129.8, 129.5 (2C), 113.5
(2C), 82.5, 71.4, 68.8, 63.4, 58.5, 58.4, 55.1, 27.9, 24.9,
17.8, 15.0. Anal. Calcd for C19H26INO6: C, 46.45; H,
5.33; N, 2.85. Found: C, 46.78; H, 5.32; N, 2.90.
4.34. anti-(4S,20S,30S)-3-[20-Bromo-30-(2-methoxy-
ethoxy)-30-(2-nitrophenyl)-propionyl]-4-(1-methylethyl)-
2-oxazolidinone MOE-8b
4.38. anti-(4S,20R,30R)-3-[20-Iodo-30-(2-methoxy-eth-
oxy)-30-(3,4-dimethoxyphenyl)-propionyl]-4-(1-methyl-
ethyl)-2-oxazolidinone MOE-9c
27
27
Gummy liquid; ½aꢁD ¼ þ147:3 (c 1.0, CHCl3); 1H NMR
Gummy liquid; ½aꢁD ¼ ꢀ12:95 (c 1.0, CHCl3); 1H NMR
(CDCl3, 200 MHz): d 7.95–7.35 (m, 4H), 5.82 (d,
J = 10.00 Hz, 1H), 5.75 (d, J = 10.00 Hz, 1H), 4.60–
4.45 (m, 1H), 4.34 (t, J = 7.98 Hz, 1H), 4.24 (dd,
J = 8.90, 3.14 Hz, 1H), 3.75–3.45 (m, 4H), 3.20 (s,
3H), 2.65–2.30 (m, 1H), 0.94 (d, J = 5.36 Hz, 3H), 0.90
(d, J = 5.36 Hz, 3H). 13C NMR (CDCl3, 50 MHz): d
167.0, 153.1, 150.4, 133.0, 132.8, 129.5, 129.3, 123.8,
75.5, 71.2, 69.7, 63.5, 58.5 (2C), 44.6, 28.0, 17.7, 14.7.
Anal. Calcd for C18H23BrN2O7: C, 47.07; H, 5.05; N,
6.10. Found: C, 47.32; H, 4.98; N, 6.11.
(CDCl3, 200 MHz): d 7.33 (d, J = 8.58 Hz, 2H), 6.89 (d,
J = 8.58 Hz, 2H), 5.99 (d, J = 10.37 Hz, 1H), 4.83 (d,
J = 10.37 Hz, 1H), 4.58–4.45 (m, 1H), 4.29 (t,
J = 7.45 Hz, 1H), 4.23 (dd, J = 8.99, 3.18 Hz, 1H),
3.81 (s, 3H), 3.60–3.20 (m, 4H), 3.23 (s, 3H), 2.55–2.30
(m, 1H), 0.95 (d, J = 3.53 Hz, 3H), 0.92 (d,
J = 3.53 Hz, 3H). 13C NMR (CDCl3, 50 MHz): d
169.9, 159.8, 153.2, 129.7 (2C), 129.6, 113.5 (2C), 83.3,
71.4, 68.9, 63.3, 58.9, 58.6, 55.2, 28.3, 24.1, 17.9, 14.7.
Anal. Calcd for C19H26INO6: C, 46.45; H, 5.33; N,
2.85. Found: C, 46.67; H, 5.37; N, 2.98.
4.35. anti-(4S,20R,30R)-3-[20-Bromo-30-(2-methoxy-
ethoxy)-30-(2-nitrophenyl)-propionyl]-4-(1-methylethyl)-
2-oxazolidinone MOE-9b
4.39. syn-(4S,20S,30R)-3-[20-Azido-30-methoxy-30-phenyl-
propionyl]-4-(1-methylethyl)-2-oxazolidinone 10a
27
27
1
Gummy liquid; ½aꢁD ¼ ꢀ89:9 (c 1.0, CHCl3); H NMR
(CDCl3, 200 MHz): d 7.95–7.35 (m, 4H), 5.80 (s, 2H),
4.62–4.45 (m, 1H), 4.33 (t, J = 8.00 Hz, 1H), 4.24 (dd,
J = 8.90, 3.27 Hz, 1H), 3.80–3.50 (m, 4H), 3.20 (s,
3H), 2.65–2.30 (m, 1H), 0.96 (d, J = 4.92 Hz, 3H), 0.93
(d, J = 4.92 Hz, 3H). 13C NMR (CDCl3, 50 MHz): d
167.3, 153.1, 150.6, 133.0, 132.8, 129.3 (2C), 123.8,
76.3, 71.2, 69.8, 63.5, 58.9, 58.5, 43.6, 28.3, 17.8, 14.6.
Anal. Calcd for C18H23BrN2O7: C, 47.07; H, 5.05; N,
6.10. Found: C, 47.23; H, 5.15; N, 6.18.
Gummy liquid; ½aꢁD ¼ þ48:75 (c 1.0, CHCl3); 1H NMR
(CDCl3, 200 MHz): d 7.50–7.22 (m, 5H), 5.42 (d,
J = 7.18 Hz, 1H), 4.61 (d, J = 7.18 Hz, 1H), 4.15–3.90
(m, 2H), 3.76 (t, J = 9.20 Hz, 1H), 4.18 (dd, J = 9.14,
3.54 Hz, 1H), 3.31 (s, 3H), 2.45–2.25 (m, 1H), 0.84 (t,
J = 8.12 Hz, 6H). 13C NMR (CDCl3, 50 MHz): d
167.9, 153.0, 136.3, 128.6, 128.4 (2C), 127.4 (2C), 88.7,
64.1, 63.5, 58.8, 57.0, 28.2, 17.7, 14.4. Anal. Calcd for
C16H20N4O4: C, 57.82; H, 6.07; N, 16.86. Found: C,
58.01; H, 6.12; N, 16.78.

S. Hajra et al. / Tetrahedron: Asymmetry 17 (2006) 210–222
221
4.40. syn-(4S,20R,30S)-3-[20-Azido-30-methoxy-30-phenyl-
propionyl]-4-(1-methylethyl)-2-oxazolidinone 11a
50 MHz): d 168.0, 158.9, 153.4, 136.7, 128.7 (2C),
128.5 (3C), 127.9, 127.3 (2C), 114.7 (2C), 83.2, 69.8,
64.6, 63.7, 58.1, 56.8, 28.2, 17.5, 14.3. Anal. Calcd for
C23H26N4O5: C, 63.00; H, 5.98; N, 12.78. Found: C,
63.43; H, 6.11; N, 12.87.
27
1
Gummy liquid; ½aꢁD ¼ þ44:3 (c 1.0, CHCl3); H NMR
(CDCl3, 200 MHz): d 7.50–7.23 (m, 5H), 5.15 (d,
J = 4.85 Hz, 1H), 4.86 (d, J = 4.85 Hz, 1H), 4.55–4.40
(m, 1H), 4.31 (t, J = 8.42 Hz, 1H), 4.18 (dd, J = 9.14,
3.54 Hz, 1H), 3.26 (s, 3H), 2.30–2.10 (m, 1H), 0.80 (d,
J = 9.16 Hz, 3H), 0.63 (d, J = 9.16 Hz, 3H). 13C NMR
(CDCl3, 50 MHz): d 168.0, 153.5, 136.5, 128.5 (2C),
128.3, 127.3 (2C), 83.6, 64.7, 63.8, 58.2, 57.1, 28.2,
17.5, 14.4. Anal. Calcd for C16H20N4O4: C, 57.82; H,
6.07; N, 16.86. Found: C, 57.92; H, 6.25; N, 16.98.
4.45. syn-(2S,3R)-2-Azido-3-(4-benzyloxyphenyl)-3-
methoxy-propionic acid 12e
27
White solid; Mp 162–164 °C; ½aꢁD ¼ ꢀ94:2 (c 1.0,
1
CHCl3); H NMR (CDCl3, 200 MHz): d 7.50–7.20 (m,
7H), 6.99 (d, J = 8.61 Hz, 2H), 5.05 (s, 2H), 4.74 (d,
J = 4.19 Hz, 1H), 3.90 (d, J = 4.19 Hz, 1H), 3.27 (s,
3H). 13C NMR (CDCl3, 50 MHz): d 173.6, 159.1,
136.6, 128.5 (3C), 128.4 (2C), 128.0, 127.4 (2C), 114.9
(2C), 83.0, 69.9, 66.9, 57.3. Anal. Calcd for
C17H17N3O4: C, 62.38; H, 5.23; N, 12.84. Found: C,
62.33 H, 5.34; N, 12.65.
4.41. syn-(2S,3R)-2-Azido-3-methoxy-3-phenyl-propionic
acid 12a
27
1
Liquid; ½aꢁD ¼ ꢀ92:5 (c 1.0, CHCl3); H NMR (CDCl3,
200 MHz): d 7.50–7.20 (m, 5H), 4.83 (d, J = 3.96 Hz,
1H), 3.92 (d, J = 3.96 Hz, 1H), 3.32 (s, 3H). 13C NMR
(CDCl3, 50 MHz): d 173.1, 136.4, 128.7 (3C), 127.0
(2C), 83.5, 66.8, 57.6. Anal. Calcd for C10H11N3O3: C,
54.29; H, 5.01; N, 19.00. Found: C, 54.38 H, 5.04; N,
18.98.
4.46. syn-(2R,3S)-2-Azido-3-(4-benzyloxyphenyl)-3-
methoxy-propionic acid 120e
27
White solid; Mp 92–94 °C; ½aꢁD ¼ þ94:2 (c 1.0, CHCl3);
1H NMR (CDCl3, 200 MHz): d 7.50–7.20 (m, 7H), 6.99
(d, J = 8.61 Hz, 2H), 5.05 (s, 2H), 4.74 (d, J = 4.19 Hz,
1H), 3.90 (d, J = 4.19 Hz, 1H), 3.27 (s, 3H). 13C NMR
(CDCl3, 50 MHz): d 173.6, 159.1, 136.6, 128.5 (3C),
128.4 (2C), 128.0, 127.4 (2C), 114.9 (2C), 83.0, 69.9,
66.9, 57.3. Anal. Calcd for C17H17N3O4: C, 62.38; H,
5.23; N, 12.84. Found: C, 62.34 H, 5.49; N, 12.76.
4.42. syn-(2R,3S)-2-Azido-3-methoxy-3-phenyl-propionic
acid 120a
27
1
Liquid; ½aꢁD ¼ þ92:5 (c 1.0, CHCl3); H NMR (CDCl3,
200 MHz): d 7.50–7.20 (m, 5H), 4.83 (d, J = 3.96 Hz,
1H), 3.92 (d, J = 3.96 Hz, 1H), 3.32 (s, 3H). 13C NMR
(CDCl3, 50 MHz): d 173.1, 136.4, 128.7 (3C), 127.0
(2C), 83.5, 66.8, 57.6. Anal. Calcd for C10H11N3O3: C,
54.29; H, 5.01; N, 19.00. Found: C, 54.23 H, 5.12; N,
18.90.
Acknowledgements
We thank CSIR, New Delhi and DST, New Delhi for
providing financial support. A.K. thanks CSIR, New
Delhi and M.B. thanks IIT, Kharagpur for their
fellowships.
4.43. syn-(4S,20S,30R)-3-[20-Azido-30-methoxy-30-(4-
benzyloxyphenyl)-propionyl]-4-(1-methylethyl)-2-oxazo-
lidinone 10e
27
1
Gummy liquid; ½aꢁD ¼ þ21:5 (c 1.0, CHCl3); H NMR
(CDCl3, 200 MHz): d 7.50–7.20 (m, 7H), 6.97 (d,
J = 8.69 Hz, 2H), 5.41 (d, J = 7.32 Hz, 1H), 5.07 (s,
2H), 4.55 (d, J = 7.32 Hz, 1H), 4.10–3.95 (m, 2H), 3.70
(t, J = 9.18 Hz, 1H), 3.28 (s, 3H), 2.45–2.15 (m, 1H),
0.83 (t, J = 7.12 Hz, 6H). 13C NMR (CDCl3, 50 MHz):
d 168.1, 159.0, 153.1, 136.6, 128.8 (2C), 128.6 (3C),
128.0, 127.4 (2C), 114.7 (2C), 83.6, 69.9, 64.1, 63.5,
58.9, 56.9, 28.3, 17.8, 14.5. Anal. Calcd for
C23H26N4O5: C, 63.00; H, 5.98; N, 12.78. Found: C,
63.14 H, 5.89; N, 12.90.
References
1. (a) Zampella, A.; D’Auria, M. V.; Paloma, L. G.;
Casapullo, A.; Minale, L.; Debitus, C.; Henin, Y. J. Am.
Chem. Soc. 1996, 118, 6202; (b) Zampella, A.; Randazzo,
A.; Borbone, N.; Luciani, S.; Trevisi, L.; Debitus, C.;
D’Auria, M. V. Tetrahedron Lett. 2002, 43, 6163.
2. Ford, P. W.; Gustafson, K. R.; McKee, T. C.; Shigematsu,
N.; Maurizi, L. K.; Pannell, L. K.; Williams, D. E.; Dilip
de Silva, E.; Lassota, P.; Allen, T. M.; Soest, R. V.;
Andersen, R. J.; Boyd, M. R. J. Am. Chem. Soc. 1999,
121, 5899.
3. Renner, M. K.; Shen, Y. C.; Cheng, X. C.; Jensen, P. R.;
Frankmoelle, W.; Kauffman, C. A.; Fenical, W.; Lobkov-
sky, E.; Clardy, J. J. Am. Chem. Soc. 1999, 121, 11273.
4. Oku, N.; Gustafson, K. R.; Cartner, L. K.; Wilson, J. A.;
Shigematsu, N.; Hess, S.; Pannell, L. K.; Boyd, M. R.;
McMahon, J. B. J. Nat. Prod. 2004, 67, 1407.
5. Tada, H.; Tozyo, T.; Terui, Y.; Hayashi, F. Chem. Lett.
1992, 431.
6. (a) Okamoto, N.; Hara, O.; Makino, K.; Hamada, Y. J.
Org. Chem. 2002, 67, 9210; (b) Makino, K.; Nagata, E.;
Hamada, Y. Tetrahedron Lett. 2005, 46, 6827.
4.44. syn-(4S,20R,30S)-3-[20-Azido-30-methoxy-30-(4-benz-
yloxyphenyl)-propionyl]-4-(1-methylethyl)-2-oxazolidi-
none 11e
27
1
Gummy liquid; ½aꢁD ¼ þ87:6 (c 1.0, CHCl3); H NMR
(CDCl3, 200 MHz): d 7.55–7.20 (m, 7H), 6.98 (d,
J = 8.42 Hz, 2H), 5.18 (d, J = 5.05 Hz, 1H), 5.05 (s,
2H), 4.81 (d, J = 5.05 Hz, 1H), 4.57–4.40 (m, 1H), 4.31
(t, J = 8.60 Hz, 1H), 4.19 (dd, J = 9.11, 3.29 Hz, 1H),
3.26 (s, 3H), 2.30–2.05 (m, 1H), 0.85 (d, J = 6.80 Hz,
3H), 0.62 (d, J = 6.80 Hz, 3H). 13C NMR (CDCl3,
7. Makino, K.; Hiroki, Y.; Hamada, Y. J. Am. Chem. Soc.
2005, 127, 5784.

222
S. Hajra et al. / Tetrahedron: Asymmetry 17 (2006) 210–222
8. Zampella, A.; D’Orsi, R.; Sepe, V.; Casapullo, A.; Monti,
T. Y.; Stanley, M. S.; Shellhamer, D. F.; Heasley, G. E. J.
Org. Chem. 1988, 53, 2199; (d) Vishwakarma, L. C.;
Walia, J. S. J. Ind. Chem. Soc. 1976, 53, 156.
M. C.; D’Auria, M. V. Org. Lett. 2005, 7, 3585.
9. Oku, N.; Krishnamoorthy, R.; Benson, A. G.; Ferguson,
R. L.; Lipton, M. A.; Phillips, L. R.; Gustafson, K. R.;
McMahon, J. B. J. Org. Chem. 2005, 70, 6842.
17. Dibromo compound was characterized by spectral analy-
sis earlier; Hajra, S.; Karmakar, A.; Bhowmick, M.
Tetrahedron 2005, 61, 2279.
´
10. Hansen, D. B.; Wan, X.; Carroll, P. J.; Joullie, M. M. J.
Org. Chem. 2005, 70, 3120.
11. Boukhris, S.; Souizi, A. Tetrahedron Lett. 1999, 40,
1669.
18. Crystallographic data (excluding structure factors) for the
structure have been deposited with the Cambridge Crys-
tallographic Data Centre as supplementary publication
number CCDC 230141.
19. Sibi, M. P.; Deshpande, P. K.; La Loggia, A. J.;
Christensen, J. W. Tetrahedron Lett. 1995, 36, 8961.
12. (a) Dong, L.; Miller, M. J. J. Org. Chem. 2002, 67, 4759;
(b) Evans, D. A.; Ellman, J. A.; DeVries, K. M. J. Am.
Chem. Soc. 1989, 111, 8912; (c) Evans, D. A.; Weber, A. E.
J. Am. Chem. Soc. 1987, 109, 7151; (d) Tseng, T. C.; Wu,
M. J. Tetrahedron: Asymmetry 1995, 6, 1633; (e) Nicolaou,
K. C.; Caulfield, T.; Kataoka, H.; Kumazawa, T. J. Am.
Chem. Soc. 1988, 110, 7910; (f) Sheehan, J. C.; Mania, D.;
Nakamura, S.; Stock, J. A.; Maeda, K. J. Am. Chem. Soc.
1968, 90, 462; (g) Boger, D. L.; Menezes, R. F. J. Org.
Chem. 1992, 57, 4331.
13. (a) House, H. O. Modern Synthetic Reactions, 2nd ed.; W.
A. Benjamin: Menlo Park, CA, 1972; p 432; (b) March, J.
Advanced Organic Chemistry, 4th ed.; Wiley: New York,
1992; p 815; (c) Carey, F.; Sundberg, R. Advanced Organic
Chemistry, Part B, 4th ed.; Plenum Press: New York,
2001; p 203.
´
´
20. Barluenga, J.; Alvarez-Perez, M.; Rodriguez, F.; Fananas,
˜
F. J.; Cuesta, J. A.; Garcia-Granda, S. J. Org. Chem. 2003,
68, 6583.
21. Vandewalle, M.; Van der Eycken, J.; Oppolzer, W.;
Vullioud, C. Tetrahedron 1986, 42, 4035.
22. Stereochemistry of the major diastereomer 6 was assigned
by analogy with our earlier work; Hajra, S.; Bhowmick,
M.; Karmakar, A. Tetrahedron Lett. 2005, 46, 3073.
23. In the AgOAc and Ag2O promoted reaction, haloacet-
oxylation and halohydroxylation are also the possible side
reactions, respectively. However, we have not found any
of those products by the 1H NMR spectrum analysis of
the crude reaction mixture. It might be because of the
amount of generated H2O and AcOH are small compared
to the bulk MeOH solvent. Moreover, nucleophilicity of
MeOꢀ/MeOH is more than that of AcOꢀ/AcOH and is
comparable with that of HOꢀ/H2O.
24. Hydromethoxylated product is also a possible side prod-
uct by electrophilic addition of MeOH during Ag2O
promoted reaction in the presence of HNO3. However, no
such product was observed by the 1H NMR spectrum
analysis of the crude reaction mixture. It might be because
of very fast halomethoxylation reaction (takes only
ꢂ20 min) compared to the hydromethoxylation reaction.
25. Rajagopalan, S.; Raman, P. V. A. In Org. Synth.; Wiley,
1955; Coll. Vol. III, p 425.
14. Hajra, S.; Karmakar, A. Tetrahedron Lett. 2004, 45,
3185.
15. (a) McKennon, M. J.; Meyers, A. I.; Drauz, K.; Schwarm,
M. J. Org. Chem. 1993, 58, 3568; (b) Evans, D. A.;
Mathre, D. J.; Scott, W. L. J. Org. Chem. 1985, 50, 1830;
(c) Evans, D. A.; Dow, R. L.; Shih, T. L.; Takacs, J. M.;
Zahler, R. J. Am. Chem. Soc. 1990, 112, 5290.
16. (a) Bose, G.; Mondal, E.; Khan, A. T.; Bordoloi, M. J.
Tetrahedron Lett. 2001, 42, 8907; (b) Kajigaeshi, S.;
Masayuki, M.; Fujisaki, S.; Kakinami, T.; Okamto, T.
Bull. Chem. Soc. Jpn. 1990, 63, 3033; (c) Heasley, V. L.;
Louie, T. J.; Luttrull, D. K.; Millar, M. D.; Moore, H. B.;
Nogales, D. F.; Sauerbrey, A. M.; Shevel, A. B.; Shibuya,