Enantioselective synthesis of (-)-cytoxazone and (+)-epi-cytoxazone via Rh-catalyzed diastereoselective oxidative C-H aminations

Article abstract of DOI:10.1016/j.tetlet.2006.11.016

An efficient enantioselective synthesis of (-)-cytoxazone (1) and (+)-epi-cytoxazone (2) using proline-catalyzed asymmetric α-amino-oxylation of aldehydes followed by Rh-catalyzed diastereoselective oxidative C-H amination as the key steps is described. s

Full text of DOI:10.1016/j.tetlet.2006.11.016

Tetrahedron Letters 48 (2007) 65–68
Enantioselective synthesis of (ꢀ)-cytoxazone and
(+)-epi-cytoxazone via Rh-catalyzed diastereoselective
oxidative C–H aminations
Srinivasarao V. Narina, Talluri Siva Kumar, Shyla George and Arumugam Sudalai*
Chemical Engineering and Process Development Division, National Chemical Laboratory, Pashan Road, Pune 411 008, India
Received 10 September 2006; revised 27 October 2006; accepted 2 November 2006
Available online 21 November 2006
Abstract—An efficient enantioselective synthesis of (ꢀ)-cytoxazone (1) and (+)-epi-cytoxazone (2) using proline-catalyzed asym-
metric a-amino-oxylation of aldehydes followed by Rh-catalyzed diastereoselective oxidative C–H amination as the key steps is
described. syn or anti 1,2-aminoalcohols were obtained by Rh-catalyzed intramolecular amidation of the C–H bonds of carbamates
or sulfamate esters with good to excellent diastereoselectivity.
Ó 2006 Elsevier Ltd. All rights reserved.
(ꢀ)-Cytoxazone 1, containing a novel 4,5-disubstituted-
2-oxazolidinone moiety, was isolated1 from Strepto-
myces sp., and its absolute configuration was unambigu-
ously established by asymmetric synthesis.2 It exhibits
cytokine-modulating activity by inhibiting the signalling
pathway of Th2 cells. Inhibitors of Th2-dependent cyto-
kine production would be potent chemotherapeutic
agents in the field of immunotherapy. Since Th2 cells
play a major role in mediating the immune response to
allergens, (ꢀ)-cytoxazone 1 could be a useful lead com-
pound for the development of therapeutic agents for
atopic dermatitis and asthma. Due to its potential bioac-
tivity and the simple structure, several methods of syn-
theses of (ꢀ)-cytoxazone (1) have been accomplished.3
The synthesis of (+)-epi-cytoxazone (2) and the stereo-
isomer of (ꢀ)-cytoxazone (1) has also been reported.4
The synthetic precursors of (ꢀ)-cytoxazone and (+)-
epi-cytoxazone are 1,2-aminoalcohols, which have been
the subject of thorough synthetic efforts in recent years.5
Most of the syntheses of cytoxazone described so far
have made use of indirect methods to establish the
anti-amino alcohol functionality. In this letter, we
describe an enantioselective synthesis of (ꢀ)-cytoxazone
(1) and (+)-epi-cytoxazone (2) based on proline-cata-
lyzed asymmetric a-amino-oxylation6 of aldehydes
followed by Rh-catalyzed diastereoselective oxidative
C–H amination7 at the benzylic positions (Fig. 1).
The synthesis of the chiral 1,2-diols 4 and 5, the key
intermediates, in the synthesis of (ꢀ)-cytoxazone (1)
and (+)-epi-cytoxazone (2), respectively, starts with
hydrolytic kinetic resolution (HKR)8 of the racemic
epoxide 39 in the presence of (R,R)-salen-Co(III)OAc
complex to give chiral diol 4 in 44% yield and 98%
25
ee10 {½aꢁD +12.76 (c 2, CHCl3)} and chiral epoxide 6
25
in 52% yield and 92% ee {½aꢁD +0.74 (c 1,
25
CHCl3); lit.11 ½aꢁD +0.8 (c 1, CHCl3)}. In order to
enhance the optical purity of diol 5, epoxide 6 (92%
ee) was again subjected to hydrolytic kinetic resolution
in the presence of (S,S)-salen-Co(III)OAc complex with
0.95 equiv of water, which resulted in the formation of
25
diol 5 in 92% yield and 98% ee {½aꢁD ꢀ12.76 (c 2,
CHCl3)} (Scheme 1).
O
O
HN
O
HN
O
OH
OH
2
1
MeO
MeO
*
Corresponding author. Tel.: +91 20 25902174; fax: +91 20
25902676; e-mail: a.sudalai@ncl.res.in
Figure 1.
0040-4039/$ - see front matter Ó 2006 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2006.11.016

66
S. V. Narina et al. / Tetrahedron Letters 48 (2007) 65–68
a
OH
O
O
+
OH
MeO
MeO
MeO
MeO
6
( )-
3
4
b
OH
OH
5
Scheme 1. Reagents and conditions: (a) (R,R)-salen-cobalt(III)OAc (0.5 mol %), THF (0.55 equiv), H2O (0.45 equiv), 0 °C, 14 h (44%, 98% ee for 4
and 52% and 92% ee for 6); (b) (S,S)-salen-cobalt(III)OAc (0.5 mol %), THF (0.95 equiv), H2O (0.95 equiv), 0 °C, 20 h, 92%, 98% ee.
As HKR generally gives maximum chemical yields up to
50%, we turned our attention to asymmetric a-function-
alization6 of aldehydes by proline, an abundant, inex-
pensive amino acid available in both enantiomeric
forms.12 Thus, aldehyde 713 was converted into the cor-
responding chiral diols 4 and 5 by proline-catalyzed
asymmetric a-amino-oxylation6a in a two-step reaction
sequence: (i) the reaction of aldehyde 7 with nitrosobenz-
ene as the oxygen source in the presence of L- or D-pro-
line in CH3CN at ꢀ20 °C, followed by reduction with
NaBH4 in MeOH, gave the crude aminoxy alcohol
and (ii) subsequent reduction of the crude aminoxy alco-
Having obtained diols 4 and 5 in high enantiomeric
purity, the second chiral centre was readily generated
by Rh-catalyzed diastereoselective intramolecular C–H
amination using either chiral sulfamate or carbamate
esters (10 or 15) as such methods have proven reliable
for the synthesis of amines and amine derivatives.7
Selectivity for either syn or anti 1,2-aminoalcohols can
be achieved by Rh-catalyzed intramolecular amidation
of the C–H bonds of carbamate or sulfamate esters,
respectively. Thus, synthesis of (ꢀ)-cytoxazone started
with bis-TBS-protected silyl ether 8 prepared from 4.
Selective deprotection of the primary OH group in 8
was achieved using camphor sulfonic acid in MeOH14
to produce alcohol 9 in 95% yield, which was readily
converted into sulfamate ester 10 in 76% yield using
known conditions (HCO2H, chlorosulfonyl isocyanate,
0 °C).7b Sulfamate ester 10 underwent selective c-C–H
insertion in the presence of a catalytic amount of
Rh2(OAc)4 (2 mol %), with PhI(OAc)2 as the oxidant
and MgO as the additive in CH2Cl2 at 40 °C with anti
(10:1) diastereoselectivity (determined from 1H NMR
analysis) to afford the corresponding six-membered ring
insertion product 1115 in 82% combined yield. The anti-
diastereomer, oxathiazinane 11, was readily separated
by column chromatography. Deprotection of the TBS
group of 11 using camphor sulfonic acid in MeOH
furnished alcohol 12 in 97% yield. Carbamoylation7b
hol with 10% Pd/C and H2 (1 atm) gave the chiral diols
25
4 in 86% yield and 99% ee10 {½aꢁD +12.90 (c 2, CHCl3)}
25
and 5 in 86% yield and 99% ee {½aꢁD ꢀ12.90 (c 2,
CHCl3)}, respectively (Scheme 2).
CHO
a
b
4
5
MeO
7
Scheme 2. Reagents and conditions: (a) (i) PhNO, L-proline
(25 mol %), ꢀ20 °C, 24 h, then MeOH, NaBH4; (ii) H2 (1 atm), Pd/C
(10%), MeOH, 86% (over two steps); (b) (i) PhNO, D-proline
(25 mol %), ꢀ20 °C, 24 h, then MeOH, NaBH4; (ii) H2 (1 atm), Pd/C
(10%), MeOH, 86% (over two steps).
O
O
O
S
HN
OR'
d
f
OR
OR
MeO
MeO
4, R, R' = H
11, R = TBS
12, R = H
a
e
8, R, R' = TBS
b
9, R = TBS; R' = H
c
10, R = TBS; R' = SO2NH2
O
NHBoc
OH
HN
O
g
OH
OH
MeO
13
1
MeO
Scheme 3. Reagents and conditions: (a) TBSCl, imidazole, DMF, 25 °C, 4 h, 98%; (b) camphor sulfonic acid, MeOH, 95%; (c) HCO2H,
chlorosulfonyl isocyanate, 0 °C, 76%; (d) 2 mol % Rh2(OAc)4, PhI(OAc)2, MgO, CH2Cl2, 40 °C, 82%, anti:syn (10:1); (e) camphor sulfonic acid,
MeOH, 25 °C, 97%; (f) (i) (Boc)2O, DMAP, Et3N, CH2Cl2, 25 °C; (ii) CH3CN:H2O (4:3), 60 °C, 84% (over two steps); (g) NaH, THF, 0 °C, 96%.

S. V. Narina et al. / Tetrahedron Letters 48 (2007) 65–68
67
References and notes
O
HN
O
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OR'
c
OR
OR'
MeO
b
5, R, R' = H
14, R = H, R' = TBS
15, R = CONH2; R' = TBS
a
MeO
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16, R' = TBS
2, R' = H
d
Scheme 4. Reagents and conditions: (a) TBSCl, imidazole, CH2Cl2,
25 °C, 98%; (b) trichloroacetyl isocyanate, CH2Cl2, 0–25 °C, 2 h, then
K2CO3, MeOH, H2O, 0–25 °C, 12 h, 92%; (c) 2 mol % Rh2(OAc)4,
PhI(OAc)2, MgO, CH2Cl2, 40 °C, 87%, syn:anti (5.5:1); (d) TBAF,
THF, 92%.
of the –NH moiety of oxathiazinane 12 with Boc2O and
Et3N in CH2Cl2 followed by ring opening of the crude
N-Boc protected oxathiazinane7b at 60 °C with aq
CH3CN furnished the anti-amino alcohol 13 in 84%
yield. Finally, regioselective intramolecular cyclization16
of 13 using NaH in THF at 0 °C furnished (ꢀ)-cytoxaz-
25
one {mp 118–121 °C; ½aꢁD ꢀ70.3 (c 1, MeOH); lit.1 mp
25
118–121 °C; ½aꢁD ꢀ71 (c 1, MeOH)} in 96% yield and
99% ee (Scheme 3).
In the case of (+)-epi-cytoxazone 2, protection of the
primary alcohol of diol 5 with TBSCl gave the second-
ary alcohol 14, which was converted into carbamate 15
in 92% yield using reported conditions (trichloroacetyl
isocyanate, CH2Cl2, then K2CO3, MeOH, H2O).7a Carb-
amate 15 underwent C–H insertion on treatment with
2 mol % Rh2(OAc)4, PhI(OAc)2 and MgO in CH2Cl2
at 40 °C to afford the corresponding oxazolidinone
1617 with syn diastereoselectivity (5.5:1) (determined
1
from H NMR analysis) in 87% combined yield.7a The
syn-diastereomer, oxazolidinone 16, was readily sepa-
rated by column chromatography. Finally, deprotection
of the TBS group using TBAF in THF furnished (+)-
25
epi-cytoxazone {mp 159–160 °C; ½aꢁD +28.3 (c 1,
25
MeOH); lit.4c mp 158–160 °C; ½aꢁD +28.6 (c 1, MeOH)}
in 92% yield and 99% ee (Scheme 4).
In conclusion, the enantioselective syntheses of (ꢀ)-cytox-
azone 1 and (+)-epi-cytoxazone 2 were achieved in
fewer steps (36% and 53% overall yields, both 99% ee).
The applicability of the two powerful methods, that is,
proline catalyzed asymmetric a-amino-oxylation of
aldehydes as well as Rh-catalyzed diastereoselective
C–H aminations, constitute key steps in the synthesis.
The selectivity for syn- or anti-1,2-aminoalcohol
products was achieved by Rh-catalyzed intramolecular
amidation of the C–H bonds of carbamates or sulfamate
esters with good to excellent diastereoselectivities.
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Acknowledgements
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N.V.S., T.S.K. and S.G. 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.

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S. V. Narina et al. / Tetrahedron Letters 48 (2007) 65–68
9. Yli-Kauhaluoma, J. T.; Harwig, C. W.; Wentworth, P.,
3H), ꢀ0.53 (s, 3H); 13C NMR (50 MHz, CDCl3): d 160.1,
137.4, 130.2, 128.9, 128.5, 114.3, 73.4, 67.5, 63.9, 55.4,
25.3, 17.6, ꢀ5.1, ꢀ5.8; IR (CHCl3) mmax: 3281, 2955, 2931,
2857, 1614, 1518, 1368, 1253, 1193, 1035, 839, 779;
elemental analysis: C16H27NO5SSi requires C, 51.45; H,
7.29; N, 3.75; S, 8.58, found: C, 51.58; H, 7.21; N, 3.67; S,
8.49.
Jr.; Janda, K. D. Tetrahedron Lett. 1998, 39, 2269.
10. Diol 4 was converted into the corresponding 1,2-benzyl-
idene derivative, which underwent reduction selectively
using DIBAL-H to the benzyl protected 1° alcohol, which
was converted into the corresponding Mosher’s ester.
11. Takano, S.; Iwabuchi, Y.; Ogasawara, K. Heterocycles
1989, 29, 1861.
12. For a review of proline-catalyzed asymmetric reactions
see: List, B. Tetrahedron 2002, 58, 5573.
13. Leopold, D.; Fischer, H. J. Chem. Soc., Perkin Trans. 2
1992, 513.
16. Miyata, O.; Asai, H.; Naito, T. Synlett 1999, 12, 1915.
25
17. Spectral data for 16: ½aꢁD +19.6 (c 0.72, EtOH); 1H NMR
(200 MHz, CDCl3): d 7.16 (d, 2H, J = 8.7 Hz), 6.81 (d,
2H, J = 8.7 Hz), 6.43 (br s, 1H), 5.24 (d, 1H, J = 4.8 Hz),
4.60 (m, 1H), 3.78 (s, 3H), 3.08 (dd, 1H, J = 14.7, 8.3 Hz),
2.88 (dd, 1H, J = 14.8, 5.4 Hz), 0.92 (s, 9H), 0.13 (s, 3H),
0.08 (s, 3H); 13C NMR (50 MHz, CDCl3): d 159.21,
158.45, 130.12, 128.63, 113.93, 83.02, 78.25, 55.18, 33.68,
25.67, 17.97, ꢀ4.36, ꢀ4.91; IR (CHCl3) mmax: 780, 838,
1106, 1248, 1514, 1758, 2928, 2954, 3628, 3648; elemental
analysis: C17H27NO4Si requires C, 60.50; H, 8.06; N, 4.15,
found: C, 60.59; H, 7.88; N, 4.25.
14. Pattenden, G.; Plowright, A. T.; Tornos, J. A.; Ye, T.
Tetrahedron Lett. 1998, 39, 6099.
25
15. Spectral data for 11: mp 133–135 °C; ½aꢁD +4.0 (c 1.1,
CHCl3); 1H NMR (200 MHz, CDCl3): d 7.23 (d, 2H,
J = 8.7 Hz), 6.91 (d, 2H, J = 8.7 Hz), 4.62 (d, 1H,
J = 7.6 Hz), 4.51–4.43 (m, 2H), 4.33 (dd, 1H, J = 11.3,
5.3 Hz), 3.97 (m, 1H), 3.81 (s, 3H), 0.07 (s, 9H), ꢀ0.12 (s,