Asymmetric O-methylhalohydrin reaction of chiral N-enoyl-2-oxazolidinones: Synthesis of N-protected syn-β-methoxyphenylalanine, an unusual amino acid component of cyclomarins

Article abstract of DOI:10.1016/j.tetlet.2004.02.131

Asymmetric O-methylhalohydrin reactions of chiral N-enoyl-2-oxazolidinones were performed with halogens (Br₂/I₂) promoted by silver(I) in methanol with high regio- and anti-selectivity and moderate to good diastereoselectivity. Reage

Full text of DOI:10.1016/j.tetlet.2004.02.131

Tetrahedron
Letters
Tetrahedron Letters 45 (2004) 3185–3188
Asymmetric O-methylhalohydrin reaction of chiral N-enoyl-2-
oxazolidinones: synthesis of N-protected syn-b-
methoxyphenylalanine, an unusual amino acid component
of cyclomarins
Saumen Hajra* and Ananta Karmakar
Department of Chemistry, Indian Institute of Technology, Salua Road, Kharagpur 721 302, India
Received 8 January 2004; revised 14 February 2004; accepted 27February 2004
Abstract—Asymmetric O-methylhalohydrin reactions of chiral N-enoyl-2-oxazolidinones were performed with halogens (Br2/I2)
promoted by silver(I) in methanol with high regio- and anti-selectivity and moderate to good diastereoselectivity. Reagent-controlled
opposite diastereoselectivity was observed especially for cinnamoyl and electron-deficient cinnamoyl substrates. This method was
applied to the short enantioselective synthesis of N-protected syn-b-methoxyphenylalanine, an unusual amino acid component of
cyclomarins.
Ó 2004 Elsevier Ltd. All rights reserved.
b-Methoxy-a-amino acids are the unusual amino acid
constituents of the recently discovered biologically
active cyclic peptide and depsipeptide antibiotics
such as callipeltines,1 papuamides,2 cyclomarins3 and
discokiolide.4 Similar to the carboxyhalohydrins,5
O-methylcarboxyhalohydrins, i.e. a-halo-b-methoxy-
carboxylic acid derivatives, would be an important
direct precursor to the b-methoxyamino acids. Inciden-
tally there have been no reports to date on the asym-
metric synthesis of a-halo-b-methoxycarboxylic acids
and their derivatives, although a number of stereo-
selective methods for accessing a-halo-b-hydroxycarb-
methoxycarbonyls 2 and 3 and their application to the
synthesis of N-protected syn-b-methoxyphenylalanine,
an unusual amino acid component of cyclomarins.
Recently Hamada and co-workers10 reported the dia-
stereoselective synthesis of all the stereoisomers of
b-methoxytyrosine by nucleophilic addition of arylmetal
reagents to the Garner aldehyde followed by methyl-
ation and oxidation of the thus formed hydroxyamino
compounds. Boukhris and Souizi reported11 the reduc-
tion of b-alkoxy-a-oximino acid esters to b-alkoxy-a-
amino esters by NaBH4 in the presence of TiCl3 and
oxylic acid derivatives exist.6–8
A
potentially
L-tartaric acid, but the configuration of the diastereo-
mers and enantioselectivities were not determined.
straightforward method for the synthesis of O-methyl-
carboxyhalohydrins is the regio- and stereoselective
O-methylhalohydrin reaction9 of a,b-unsaturated car-
boxylic acid derivatives. Herein, we report our pre-
liminary results on the asymmetric O-methylhalohydrin
reaction of chiral N-enoyl-2-oxazolidinones 1 for the
highly regio- and anti-selective synthesis of a-halo-b-
There are only a few reports12 of the O-methylhalo-
hydrin reactions of a,b-unsaturated carbonyls. By
screening those methods, we found that the combination
of silver nitrate and halogen (Br2/I2) in MeOH is an
effective system for the regio- and stereoselective O-
methylhalohydrin reaction of chiral N-enoyl-2-oxazo-
lidinones 1. Initial results of the O-methylhalohydrin
reactions of 1 with AgNO3 and Br2/I2 are summarised in
Table 1.
Keywords: Asymmetric; O-Methylhalohydrin; Silver(I); Halogen;
N-Enoyl-2-oxazolidinones; a-Halo-b-methoxycarboxylic acid deriva-
tives; syn-b-Methoxyphenylalanine.
* Corresponding author. Tel.: +91-3222-283340; fax: +91-3222-2553-
03; e-mail: shajra@chem.iitkgp.ernet.in
Towards the development of the asymmetric O-methyl-
halohydrin reaction of chiral N-enoyl-2-oxazolidinones,
a methanolic solution of compound 1a was treated
0040-4039/$ - see front matter Ó 2004 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2004.02.131

3186
S. Hajra, A. Karmakar / Tetrahedron Letters 45 (2004) 3185–3188
Table 1. AgNO3-promoted O-methylhalohydrin reaction of 1a
O
OMe O
X
OMe O
X
AgNO3, X2
R
N
R
N
R
N
+
MeOH, 0-5° C
X2 = Br2, I2
O
O
O
O
O
O
2
3
1
Entry
Substrate
R
X
Ratiob (2:3)
Yieldc (%)
1
2
3
4
5
6
7d
8
1a
1b
1c
1d
1e
1f
Ph
2-NO2C6H4
2-ClC6H4
Br
Br
Br
I
71:29
65:35
60:40
62:38
76:24
74:26
73:27
86:14e
91
84
91
94
91
93
88
62f
4-MeOC6H4
3,4-MeOC6H3
3,4,5-MeOC6H2
2-Naphthyl
CH3
I
I
1g
1h
I
Br
a O-Methylhalohydrin reactions were performed using 1.2 equiv of AgNO3 and 1.2 equiv of halogen (X2) in MeOH at 0–5 °C for 30 min.
b Determined from the 1H NMR spectrum of the crude reaction mixture.
c Combined isolated yields of 2 and 3 after column chromatography.
d 30% CH2Cl2 used due to poor solubility of the substrate 1g in MeOH.
e Including 18% of the other regioisomers.
f Isolated yield of the major isomer 2h only, minor isomer 3h could not be separated from the other regioisomers.
with silver nitrate (1.2 equiv) and bromine (1.2 equiv) at
0–5 °C. Within 20–30 min, the a-bromo-b-methoxycar-
bonyls 2a and 3a were obtained in high yield (91%) with
a diastereomeric ratio of 71:29. The O-methyliodohy-
drin reaction of 1a under the same reaction conditions
gave <5% of the desired compounds, and there was no
improvement even with the use of excess reagents and
under different reaction conditions. This O-methylha-
lohydrin reaction was studied on a variety of cinnamoyl
substrates containing different electron-withdrawing and
-donating substituents on the aromatic ring as well as
alkenoyl substrates. It was found that the electron-
deficient cinnamoyl substrates 1b and 1c smoothly
underwent O-methylbromohydrin reactions (entries 2
and 3) but no O-methyliodohydrin reactions. The elec-
tron-rich cinnamoyl substrates 1d–g preferred to un-
dergo O-methyliodohydrin reactions (entries 4–7);
O-methylbromohydrin reactions gave either a low yield
of the desired compounds or complex reaction mixtures.
The alkenoyl substrate 1h responded to the O-methyl-
bromohydrin reaction with a good diastereomeric ratio
of 86:14 along with 18% of other regioisomers (entry 8).
The stereochemistry of 2 was confirmed from the single
crystal X-ray analysis13 of compound 2d (Fig. 1).
When the O-methylhalohydrin reactions of 1 were per-
formed in the presence of AgOAc instead of AgNO3,
similar results were also obtained, i.e. 2 was the major
diastereomer (results are not included in Table 1). Since,
the chiral auxiliary (3S)-3-(1-methylethyl)-2-oxazolidi-
none gave moderate to good diastereoselectivities, we
have also examined other oxazolidinone chiral auxilia-
ries viz (3S)-3-phenyl- and (3S)-3-(diphenylmethyl)-2-
oxazolidinones. The O-methylhalohydrin reaction of
those substrates having different oxazolidinone chiral
auxiliaries (Ph and Ph2CH) using either Br2 or I2 gave
complex mixtures of products.
To assess whether the counterion of the Ag(I) salt affects
the diastereoselectivity of the O-methylhalodrin reac-
tions, product studies were carried out employing the
electronically different cinnamoyl substrates 1a–b and
Table 2. Ag2O-promoted O-methylhalohydrin reaction of 1a
Entry
Substrate
Additive
X
Ratiob (2:3)
1
2
3
4
5
6
7
8
1a
1b
1d
1e
1a
1b
1d
1e
None
None
None
None
HNO3
HNO3
HNO3
HNO3
Br
Br
I
27:73
35:65
48:52
47:53
I
Br
Br
I
72:28 (70:30)
64:36 (67:33)
61:39 (62:38)
75:25 (73:27)
I
a O-Methylhalohydrin reactions were performed using 0.7equiv of
Ag2O and 1.2 equiv of halogen (X2) in MeOH at 0–5 °C for 30 min.
b Determined from the 1H NMR spectrum of the crude reaction mix-
ture. Ratios in parentheses refer to reactions in the presence of
AcOH.
Figure 1. ORTEP diagram of 2d.

S. Hajra, A. Karmakar / Tetrahedron Letters 45 (2004) 3185–3188
3187
1d–e using Ag2O, which does not produce any acid on
OMe O
OMe
OMe O
a
b
c
COOH
reacting with a halogen in MeOH (Eq. 3), as a promoter
under a variety of reaction conditions (Table 2). The
results showed that the diastereoselectivities for the
Ag2O-mediated reactions were in favour of the diaste-
reomer 3 (Table 2, entries 1–4) and more interestingly,
that 1a and the electron-deficient 1b show opposite
diastereoselectivities (Table 2, entries 1 and 2) compared
to the AgNO3-mediated reactions (Table 1, entries 1
and 2). When the Ag2O-promoted O-methylhalohydrin
reactions of 1 were performed in the presence of either
HNO3 or AcOH as an additive, these showed diastereo-
1a
Ph
Xc
Ph
Ph
Xc
Br
3a
N3
5a
N3
4a
X
c = (S)-3-(methylethyl)-2-oxazolidinone
Scheme 2. Reagents and conditions: (a) Ag2O, Br2, MeOH, 0–5 °C,
30 min, 64%; (b) NaN3, DMF, 60 °C, 3 h, 84%; (c) LiOH, H2O2, THF,
0–5 °C, 2 h, 77%.
electron-donating substituent at the p-position with the
a,b-unsaturated carbonyls.
ꢀ
selectivities (entries 5–8) similar to either AgNO3 or
AgOAc-promoted reactions (Table 1, entries 1, 2, 4 and
5). Reaction of either AgNO3 or AgOAc with halogens
in MeOH generated acid (Eqs. 1 and 2), so it might be
AgNO3 þ X2 þ MeOH ! AgX #
þ MeOX þ HNO3 ð1Þ
ꢀ
concluded here that in either AgNO3 or AgOAc-pro-
moted reactions, the Hþ-chelated S-cis-syn-dipole
conformation 10 might be involved in the O-methyl-
halohydrin reaction. The preferred attack of Xþ from
the Re-face of conformation 10 and subsequent opening
of the halonium intermediate 40 by anti-nucleophilic
attack of MeOH at the b-position yielded 2 as the major
diastereomer (Scheme 1). In the Ag2O-promoted reac-
tion, the Si-face of the unchelated S-cis-anti-dipole
conformation 1 might be involved giving 3 as the major
diastereomer. This is supported by the Ag2O-mediated
reactions performed in the presence of either HNO3 or
AcOH as an additive (Table 2, entries 5–8). The poor
diastereoselectivities of the electron-rich substrates 1d–e
in Ag2O-promoted reactions (Table 2, entries 3 and 4),
might be accounted for by the involvement of both the
equilibrated S-cis- and S-trans-anti-dipole conforma-
tions 1 and 100, due to the extensive conjugation of the
AgOAc þ X2 þ MeOH ! AgX #
þ MeOX þ AcOH ð2Þ
Ag2O þ 2MeOH þ 2X2 ! 2AgX #
þ 2MeOX þ H2O ð3Þ
After achieving the reagent-controlled reverse diastereo-
selectivity of the O-methylhalohydrin reaction, espe-
cially for cinnamoyl and electron-deficient cinnamoyl
systems, the usefulness of the new process was exem-
plified in a short synthesis of N-protected syn-b-meth-
oxyphenylalanine (Scheme 2), an unusual amino acid
component of the biologically active cyclic peptides,
cyclomarins. Ag2O-mediated O-methylbromohydrin
reaction of chiral N-cinnamoyl-2-oxazolidinone 1a gave
a-bromo-b-methoxycarboxylic acid derivative 3a as the
major diastereomer in 68% yield along with a minor
amount of 2a (25%). Reaction of 3a with NaN3 in DMF
at 60 °C gave the syn-a-azido-b-methoxycarboxylic acid
derivative 4a (84%). Subsequent removal of the chiral
auxiliary by treatment with LiOH and H2O2 in THF at
0 °C yielded the syn-a-azido-b-methoxycarboxylic acid
5a (77%). Azido-carboxylic acids serve as N-protected
amino acids in peptide antibiotic syntheses.5a Thus
compound 5a can be directly used as an N-protected
b-methoxyphenylalanine for the synthesis of cycloma-
rins.
H+
N
Re
H+
N
O
O
O
O
MeOH
R
X+
MeOH
O
R
O
X+
Re face attack
2
Si
S-cis-syn-dipole
4'
1'
Re
O
MeOH
O
X+
MeOH
R
N
In summary, we have described the Ag(I)-promoted
asymmetric O-methylhalohydrin reaction of chiral
N-enoyl-2-oxazolidinones 1 with high regio- and anti-
selectivity and moderate to good diastereoselectivity
with good yields. More interestingly the use of Ag2O
reverses the diastereoselectivity, especially for cinnamoyl
and electron-deficient cinnamoyl substrates. This new
process has been applied to the synthesis of N-protected
syn-b-methoxyphenylalanine, an unusual amino acid
component of cyclomarins. This methodology offers an
asymmetric synthesis of b-methoxy amino acids. We are
currently attempting to improve the diastereoselectivity
of this process and are also applying this concept to
other halo-nucleophilic (XþNuꢀ) addition reactions for
the asymmetric hetero-bifunctionalisation of alkenes.
R
N
3
X+
Si face attack
O
O
Si
O
O
S-cis-anti-dipole
4
1
O
O
MeOH
X+
N
N
O
+X
2
O
Re face attack
R
O
R
O
S-trans-anti-dipole
MeOH
1''
4''
Scheme 1.

3188
S. Hajra, A. Karmakar / Tetrahedron Letters 45 (2004) 3185–3188
6. Aldol reaction: (a) Evans, D. A.; Weber, A. E. J. Am.
Acknowledgements
Chem. Soc. 1986, 108, 6757; (b) Abdel-Magid, A.; Pridgen,
L. N.; Eggleston, D. S.; Lantos, I. J. Am. Chem. Soc. 1986,
108, 3595; (c) Evans, D. A.; Sjogren, E. B.; Weber, A. E.;
Conn, R. E. Tetrahedron Lett. 1987, 28, 29; (d) Pridgen, L.
N.; Abdel-Magid, A.; Lantos, I.; Shilcart, S.; Eggleston,
D. S. J. Org. Chem. 1992, 58, 5107.
We thank CSIR, New Delhi and DST, New Delhi for
providing financial support and Dr. K. Biradha for the
single crystal X-ray analysis. A.K. thanks CSIR, New
Delhi for his fellowship.
7. Catalytic enantioselective hydrogenation of a-chloro-b-
ketoesters: Genet, J. P.; Andrade, M. C. C.; Vidal, V. R.
Tetrahedron Lett. 1995, 26, 2062.
8. Regioselective ring opening of epoxides: (a) Bonini, C.;
Righi, G. Synthesis 1993, 225; (b) Righi, G.; Rumboldt,
G.; Bonini, C. Tetrahedron 1995, 51, 12301; (c) Righi, G.;
Chionne, A.; D’Achille, R.; Bonini, C. Tetrahedron:
Asymmetry 1997, 8, 902; (d) Amantini, D.; Fringuelli,
F.; Pizzo, F.; Vaccaro, L. J. Org. Chem. 2001, 66, 3362.
9. (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, 4th ed.; Part B.; Plenum: New York, 2001;
p 203.
References and notes
1. (a) Zampella, A.; D’Auria, M. V.; Paloma, L. G.;
Casapula, 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.; Silva,
E. D.; 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.; Fencil, W.; Lobkov-
sky, E.; Clardy, J. J. Am. Chem. Soc. 1999, 121, 11273.
4. Haruhiko, T.; Takehiko, T.; Yoshihiro, T.; Fumiaki, H.
Chem. Lett. 1992, 431.
5. (a) Dong, L.; Miller, M. J. J. Org. Chem. 2002, 67, 3759;
(b) Evans, D. A.; Ellman, J. A.; De Vries, 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, 1622; (e) Nicolaou,
K. C.; Kataoka, T. C.; Kumazawa, T. J. Am. Chem. Soc.
1988, 110, 7910; (f) Sheehan, J. C.; Mania, D.; Nakamura,
S.; Stock, J. A. J. Am. Chem. Soc. 1968, 90, 362; (g) Tseng,
T. C.; Wu, M. J. Tetrahedron: Asymmetry 1995, 6, 1622;
(h) Boger, D. L.; Memezes, R. F. J. Org. Chem. 1992, 57,
3221.
10. Okamoto, N.; Hara, O.; Makino, K.; Hamada, Y. J. Org.
Chem. 2002, 67, 9210.
11. Boukhris, S.; Souizi, A. Tetrahedron Lett. 1999, 40, 1669.
12. (a) Bose, G.; Modal, 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,
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.
13. Crystallographic data (excluding structure factors) for the
structure, have been deposited with the Cambridge Crys-
tallographic Data Centre as supplementary publication
number CCDC 230141.