NaIO4-mediated asymmetric bromohydroxylation of α,β-unsaturated carboxamides with high diastereoselectivity: a short route to (-)-cytoxazone and droxidopa

Article abstract of DOI:10.1016/j.tetlet.2006.12.109

The NaIO₄-mediated asymmetric bromohydroxylation of α,β-unsaturated carboxamides was achieved using lithium bromide as the bromine source under acidic conditions at rt to afford the corresponding chiral α-bromo-β-hydroxy carboxamides. Excellent

Full text of DOI:10.1016/j.tetlet.2006.12.109

Tetrahedron Letters 48 (2007) 1375–1378
NaIO4-mediated asymmetric bromohydroxylation of
a,b-unsaturated carboxamides with high diastereoselectivity:
a short route to (ꢀ)-cytoxazone and droxidopa
Shyla George, Srinivasarao V. Narina and Arumugam Sudalai*
Chemical Engineering and Process Development Division, National Chemical Laboratory, Pashan Road, Pune 411 008, India
Received 24 October 2006; revised 11 December 2006; accepted 19 December 2006
Available online 23 December 2006
Abstract—The NaIO4-mediated asymmetric bromohydroxylation of a,b-unsaturated carboxamides was achieved using lithium bro-
mide as the bromine source under acidic conditions at rt to afford the corresponding chiral a-bromo-b-hydroxy carboxamides.
Excellent yields (77–90%) and diastereoselectivities (up to 10:1) along with exclusive control over regio- as well as anti-selectivity
are the main features with a good scope of substrates. The method has successfully been applied in the enantioselective syntheses
of two biologically important molecules, viz (ꢀ)-cytoxazone and L-threo-DOPS (droxidopa).
ꢀ 2007 Elsevier Ltd. All rights reserved.
The 1,2-functionalization of electron-deficient olefins
(e.g., a,b-unsaturated acid derivatives) by the selective
addition of two different functional groups, such as
water and halogens (halohydroxylation) in a highly
regio- and enantioselective manner, constitutes an impor-
tant transformation in organic synthesis.1 Such chiral a-
halo-b-hydroxy carboxamides are versatile precursors,
which could readily be transformed into epoxides,
ketones, and unusual b-hydroxy-a-amino acids.2 The
asymmetric bromohydroxylation of alkenes, a poten-
tially straightforward method to obtain such halohyd-
rins, is scarce and known only for limited chiral
substrates.3 Biologically, haloperoxidases, such as vana-
dium bromoperoxidase (V-BrPO),4 are known to cata-
lyze the 2eꢀ oxidation of halides by H2O2, resulting in
the concomitant halogenation of organic substrates,
probably accounting for the biosynthesis of numerous
halogenated marine natural products including terpenes,
indoles, and phenols. Several catalytic functional mimics
of V-BrPO have been reported.5 Recently, Hajra et al.6
reported diastereoselective syntheses of vicinal halo-
hydroxy derivatives of a,b-unsaturated carboxylic acids.
However, the asymmetric version of halohydrin reac-
tions suffers from several disadvantages such as low dia-
stereoselectivities (dr = 2:1), use of expensive metal salts
(Ag, Yb), stoichiometric amounts of corrosive Br2/N-
halosuccinimides or the formation of large amounts of
organic and inorganic waste.6 We have described
sodium metaperiodate (NaIO4)-mediated enantioselec-
tive halohydroxylation of alkenes (encapsulated in b-
cyclodextrin) using alkali metal halides with moderate
enantioselectivity (56% ee).7a
In continuation of our interest in NaIO4-mediated oxy-
functionalization of organic compounds,7 we report
herein the first ‘transition metal-free’ procedure for the
asymmetric bromohydroxylation of a,b-unsaturated
carboxamides with NaIO4 as the oxidant and LiBr as
the halogen source under ambient conditions in a highly
regio- and diastereoselective manner, to afford the corre-
sponding chiral a-bromo-b-hydroxy carboxamides
(Table 1). After initial experimentation, (4S)-N-cinna-
moyl-4-benzyl-2-oxazolidinone (1a), readily derived
from the Evans’ chiral auxiliary obtainable from (S)-
phenylalanine,8 was subjected to oxidative bromination
in the presence of 0.3 equiv. NaIO4 in a 2:1 mixture of
CH3CN and water and LiBr (1.2 equiv) under acidic
conditions (aq HCl), to afford the corresponding bro-
mohydrins 2a and 3a in 81% combined yield and high
diastereoselectivity (dr = 5.5:1) (Scheme 1). A mixture
of CH3CN and H2O (2:1 ratio) was found to be the best
solvent system for the formation of bromohydrins.
There was a marginal increase in the diastereomeric
Keywords: NaIO4; Asymmetric bromohydroxylation; Carboxamide;
Cytoxazone; Droxidopa.
*
Corresponding author. Tel.: +91 20 25902174; fax: +91 20
25902676; e-mail: a.sudalai@ncl.res.in
0040-4039/$ - see front matter ꢀ 2007 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2006.12.109

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S. George et al. / Tetrahedron Letters 48 (2007) 1375–1378
Table 1. NaIO4-mediateda asymmetric bromohydroxylation of a,b-unsaturated carboxamides with LiBr
O
O
OH
O
OH
O
O
O
NaIO4
Ar
N
+
Ar
N
Ar
N
O
O
O
0.3 equiv.
Br
Br
Bn
1a - i
Bn
2a - i
Bn
3a - i
Entry
Substrate (Ar)
Ratio (2:3)b
Yieldc (%)
a
b
c
d
e
f
g
h
i
C6H5
4-MeO–C6H4
4-CH3–C6H4
3,4-Dimethoxy-C6H3
4-Cl–C6H4
3,4,5-Trimethoxy-C6H2
3,4-(O–CH2–O)–C6H3
3,4-Dibenzyloxy-C6H3
Furan
5.5:1
10:1
9:1
7:1
6:1
6:1
5:1
6:1
5:1
81
90
86
82
77
86
84
87
82
a Reaction conditions:17 carboxamides 1a–i (5 mmol), LiBr (6 mmol), 35% aq HCl (0.5 mL), CH3CN/H2O (2:1), 25 ꢁC, 3 h.
b Diastereomeric ratios were determined by GC.
c Combined isolated yield of 2 and 3.
OH
O
OH
O
O
O
O
O
a
N
N
N
O
O
+
O
Br
Br
Bn
Bn
Bn
3a
2a
1a
b
O
OH
4, 99.1% ee
D
α
[ ] 25 -50.58 (c 1, CHCl3)
Scheme 1. Reagents and conditions: (a) NaIO4 (0.3 equiv), LiBr (1.2 equiv), H+, CH3CN/H2O (2:1), 25 ꢁC, 81%, dr = 6:1; (b) LiBH4, Et2O, THF,
MeOH, 0 ꢁC, 1.5 h then 10% NaOH, 25 ꢁC, 85%.
ratio (dr = 6.5:1) when bromohydroxylation of 1a was
conducted at 10 ꢁC, however, lower conversion resulted.
In order to confirm the resulting configuration of the
diastereomers obtained, the oxazolidinones 2a and 3a
were separated by column chromatography and subse-
quently 2a was subjected to reduction with LiBH4 under
basic conditions to give the chiral epoxy alcohol 4 in
99.1% ee (determined by chiral HPLC using a Chiralcel
OD column).9 Encouraged by this result, several (4S)-N-
cinnamoyl-4-benzyl-2-oxazolidinones (entries 1a–i) with
electron-donating and withdrawing substituents on the
aromatic nucleus were prepared and then subjected to
asymmetric bromohydroxylation to produce the corre-
sponding bromohydrins 2 and 3 in excellent yields and
high diastereoselectivities (Table 1). With all the sub-
strates studied, the reaction proceeded in a highly regio-
specific manner, the hydroxyl group adding at the
benzylic position, exclusively. No traces of dibromide
were observed in all the substrates screened. Mono-
substituted electron-donating groups at the para posi-
tion (e.g., OMe, CH3) gave the maximum diastereoselec-
tivities of 10:1 and 9:1, respectively (Table 1, entries b
and c).
It was of interest to apply the present methodology to
the enantioselective synthesis of both (ꢀ)-cytoxazone
(8) and L-threo-DOPS (13). (ꢀ)-Cytoxazone (8) exhibits
cytokine modulating activity by inhibiting the signalling
pathway of Th2 cells. Since Th2 cells play a major role
in mediating the immune response to allergens, (ꢀ)-cyt-
oxazone could be a useful lead compound for the devel-
opment of therapeutic agents for atopic dermatitis and
asthma. Due to its potent bioactivity and relatively
simple structure, several methods for the synthesis of
(ꢀ)-cytoxazone have been reported.10 L-threo-DOPS
[(2S,3R)-3,4-dihydroxy phenylserine] (13), an alternative
biological precursor of norepinephrine, is useful in
treating disorders of the central and sympathetic ner-
vous systems. For example, orthostatic hypotension,
characterized by adrenergic deficiency and certain symp-
toms of Parkinson’s disease, can be alleviated by treat-
ment with L-threo-DOPS.11 To the best of our

S. George et al. / Tetrahedron Letters 48 (2007) 1375–1378
1377
O
OH
O
O
O
O
b
a
OH
N
N
O
O
Br
5
MeO
MeO
c
MeO
d
Bn
N3
Bn
1b
2b
O
HN
NHBoc
OH
O
e
OH
OH
OH
OH
MeO
MeO
MeO
6
7
8
Scheme 2. Reagents and conditions: (a) NaIO4 (0.3 equiv), LiBr, H+, CH3CN:H2O (2:1), 25 ꢁC, 1 h, 82%; (b) LiBH4, Et2O, THF, MeOH, 0 ꢁC, 1.5 h
then 10% NaOH, 25 ꢁC, 86%; (c) NaN3, NH4Cl, MeOH, H2O, 80 ꢁC, 3 h, 84%; (d) (i) 10% Pd/C, MeOH, 25 ꢁC, 12 h; (ii) (Boc)2O, Et3N, CH2Cl2,
25 ꢁC, 2 h, 77% (2 steps); (e) NaH, THF, 25 ꢁC, 2 h, 89%.
OH
O
O
OH
O
O
O
O
BnO
BnO
BnO
BnO
BnO
BnO
N
N
a
b
O
N
O
O
N3
Bn
Br
Bn
Bn
11
10
9
OH
O
OH
O
HO
HO
BnO
BnO
c
OH
d
OH
NH2
N3
12
13
Scheme 3. Reagents and conditions: (a) NaIO4 (0.3 equiv), LiBr, H+, CH3CN:H2O (2:1), 25 ꢁC, 1 h, 75%; (b) NaN3, DMF, 60 ꢁC, 4 h, 82%; (c)
LiOH, 30% H2O2, THF, H2O, 0 ꢁC, 2 h, 88%; (d) 10% Pd/C, MeOH, 25 ꢁC, 12 h, 94%.
25
25
knowledge, there are only two reports in the literature12
which describe the asymmetric synthesis of L-threo-
DOPS.
½aꢁD ꢀ39 (c 0.4, 1 N HCl); lit.12b mp 232–235 ꢁC; ½aꢁD
ꢀ39 (c 0.4, 1 N HCl)} in 94% yield and >99% ee
(Scheme 3).
For the synthesis of (ꢀ)-cytoxazone, carboxamide 1b
was subjected to oxidative bromohydroxylation (NaIO4,
LiBr, H+) to produce bromohydrin 2b18 with excellent
diastereoselectivity (dr = 10:1) in an isolated yield of
82%. The chiral auxiliary in 2b was removed by reduc-
In conclusion, we have described the NaIO4-mediated
asymmetric bromohydroxylation of a,b-unsaturated
carboxamides17,18 with high regio- and diastereoselectiv-
ity using Evans’ chiral auxiliary and LiBr as the halogen
sources. The methodology avoids the use of heavy
metals and molecular bromine as well as N-halo-
succinimides as halogen sources. The enantioselective
syntheses of two medicinally important molecules, (ꢀ)-
cytoxazone 8 and droxidopa 13, were achieved using
the present protocol. This method should find applica-
tion in the synthesis of various biologically active organ-
ic molecules.
tion with LiBH4 followed by treatment with 10%
25
NaOH13 to give epoxy alcohol 5 in 86% yield; ½aꢁD
ꢀ12.5 (c 1.1, CHCl3). The regiospecific opening14 of
epoxide 5 with azide produced azido alcohol 6 in 84%
yield. Azido alcohol 6 was then converted to (ꢀ)-cytox-
25
azone (8) {mp 118–121 ꢁC; ½aꢁD ꢀ71 (c 1, MeOH); lit.10
25
mp 118–121 ꢁC; ½aꢁD ꢀ71 (c 1, MeOH)} in 99.2% ee
(determined by chiral HPLC using a Chirasphereꢂ col-
umn) using a standard sequence of reactions, viz. azide
reduction and amine protection followed by cycliza-
tion15 (Scheme 2).
Acknowledgements
S.G. and N.V.S. thank CSIR, New Delhi, for the award
of research fellowships. The authors are thankful to Dr.
B. D. Kulkarni, Deputy Director, for his support and
encouragement.
For the preparation of droxidopa, carboxamide 9 pre-
pared from (R)-phenylalanine8 was subjected to oxida-
tive bromohydroxylation to produce bromohydrin 1018
in the ratio dr = 6:1. Nucleophilic displacement of bro-
mide group in 10 with sodium azide in DMF furnished
25
azido alcohol 11 in 82% yield; ½aꢁD ꢀ17 (c 1, CHCl3).
References and notes
Subsequent removal of the chiral auxiliary with LiOH
and 30% H2O216 followed by azide reduction and depro-
tection of the benzyl groups with 10% Pd/C, H2 (1 atm)
in MeOH furnished L-threo-DOPS 13 {mp 232–233 ꢁC;
1. (a) Tenaglia, A.; Pardigon, O.; Buono, G. J. Org. Chem.
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1378
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Chem. 1994, 59, 5550–5555; (c) Rodriguez, J.; Dulcere, J. 13. Crimmins, M. T.; Emmitte, K. A. Org. Lett. 1999, 1,
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17. General experimental procedure for bromohydroxylation
of a,b-unsaturated carboxamides: To a stirred solution
of a,b-unsaturated carboxamide (5 mmol), NaIO4
(1.5 mmol), and 35% aq HCl (0.5 mL) in CH3CN/H2O
(2:1, 30 mL) at 25 ꢁC, LiBr (6 mmol) was added portion-
wise. The reaction was monitored by TLC. After comple-
tion of the reaction, it was diluted with water and
extracted with ethyl acetate (50 mL · 3). The combined
organic layers were washed with 5% sodium thiosulfate
(30 mL) followed by brine, dried over anhydrous Na2SO4
and concentrated under reduced pressure to give the crude
bromohydrin products, which were then purified by
column chromatography on silica gel (60–120 mesh)
eluting with petroleum ether and ethyl acetate (7:3) to
afford pure products 2 and 3.
18. All the compounds listed in Table 1 and 4–13 were
characterized by NMR and FT-IR spectroscopy. Spectral
data for selected new compounds:
anti-(4S,20S,30S)-3-[20-Bromo-30-hydroxy-30-(4-methoxyp-
henyl)-propionyl]-4-benzyloxazolidin-2-one (2b): Yield:
25
84%; solid; mp: 103 ꢁC; ½aꢁD +7.76 (c 1.1, CHCl3); IR
(CHCl3): m 3602, 3019, 2927, 2400, 1785, 1701, 1604, 1498,
;
1384, 1215, 1111, 1021, 757, 668 cmꢀ1 1H NMR
(200 MHz, CDCl3): d 2.76 (dd, J = 9.0, 13.7 Hz, 1H),
3.21 (dd, J = 3.6, 13.7 Hz, 1H), 3.37 (d, J = 6.3 Hz, 1H),
3.89 (s, 3H), 4.15–4.31 (m, 2H), 4.68–4.74 (m, 1H), 5.12 (d,
J = 7.6 Hz, 1H), 5.86 (d, J = 8.0 Hz, 1H), 6.90 (d,
J = 8.3 Hz, 2H), 7.10–7.40 (m, 7H); 13C NMR (50 MHz,
CDCl3): d 37.12, 44.56, 55.24, 56.00, 66.02, 74.08, 111.30,
127.20, 128.72, 129.18, 131.86, 132.62, 137.17, 152.36,
155.70, 168.75; Analysis: C20H20BrNO5 requires C, 55.31;
H, 4.64; Br, 18.40; N, 3.23. Found: C, 55.59; H, 4.48; Br,
18.01; N, 3.54.
anti-(4R,20R,30R)-3-[20-Bromo-30-hydroxy-30-(3,4-bis(benz-
yloxy)phenyl)-propionyl]-4-benzyloxazolidin-2-one (10):
25
8. Gage, J. R.; Evans, D. A. Org. Synth. 1989, 68, 77–
82.
9. Gao, Y.; Klunder, J. M.; Hanson, R. M.; Masamune, H.;
Ko, S. Y.; Sharpless, K. B. J. Am. Chem. Soc. 1987, 109,
5765–5780.
10. Paraskar, A. S.; Sudalai, A. Tetrahedron 2006, 62, 5756–
5762, and references cited therein.
11. Tohgi, H.; Abe, T.; Takahashi, S. J. Neural. Trnasm.
[P.D. Sect.] 1993, 5, 27–34.
12. (a) Herbert, B.; Kim, I. H.; Kirk, K. L. J. Org. Chem.
2001, 66, 4892–4897; (b) Hegedus, V. B.; Krasso, A. F.;
Noack, K.; Zeller, P. Helv. Chim. Acta 1975, 58, 147–
162.
Yield: 75%; gum; ½aꢁD ꢀ52.75 (c 3.0, CHCl3); IR (CHCl3):
m 3502, 3019, 2926, 2252, 1787, 1496, 1383, 1250, 1160,
1107, 911, 794, 737 cmꢀ1; 1H NMR (200 MHz, CDCl3): d
2.77 (dd, J = 9.5, 13.5 Hz, 1H), 3.25 (dd, J = 3.3, 13.5 Hz,
1H), 3.58 (br s, 1H), 4.03–4.12 (m, 2H), 4.47–4.58 (m, 1H),
5.10 (s, 2H), 5.15 (s, 2H), 5.48 (d, J = 7.1 Hz, 1H), 6.02 (d,
J = 6.1 Hz, 1H), 7.09–7.44 (m, 18H); 13C NMR (50 MHz,
CDCl3): d 36.82, 43.82, 54.94, 66.03, 71.03, 71.09, 73.32,
114.11, 114.47, 118.11, 127.21, 127.33, 127.49, 127.81,
127.95, 128.38, 128.45, 128.86, 129.37, 130.73, 134.58,
136.23, 136.52, 148.25, 149.52, 152.28, 168.40; Analysis:
C33H30BrNO6 requires C, 64.29; H, 4.90; Br, 12.96; N,
2.27. Found: C, 64.01; H, 5.21; Br, 12.69; N, 2.49.