A rapid and highly diastereoselective synthesis of enantiomerically pure (4 R,5 R)- and (4 S,5 S)-isocytoxazone

Article abstract of DOI:10.1055/s-0030-1260561

A three-step protocol for the highly diastereoselective (>98%) synthesis of both (4R,5R)- and (4S,5S)-isocytoxazone from d- or l-tyrosine is reported. The diastereoselection was confirmed by X-ray crystallography. This synthesis is currently the highest y

Full text of DOI:10.1055/s-0030-1260561

LETTER
1399
A Rapid and Highly Diastereoselective Synthesis of Enantiomerically Pure
(4R,5R)- and (4S,5S)-Isocytoxazone
Synthesis of
E
nan
e
tiomerical
n
ly
P
ure
(
4
R
,5
j
R
)- and
a
(4
S
,5
S
)-Is
m
ocytoxazone in R. Buckley,*a Philip C. Bulman Page,b Vickie McKeea
a
Department of Chemistry, Loughborough University, Ashby Road, Loughborough, Leicestershire, LE11 3TU, UK
Fax +44(1509)223925; E-mail: b.r.buckley@lboro.ac.uk
b
School of Chemistry, University of East Anglia, Norwich, Norfolk NR4 7TJ, UK
Received 25 February 2011
Hydrogenation of the nitro group in the formate-protected
amino diol 4 to give the corresponding amino compound
5 proved highly successful (99% yield). The subsequent
diazotization reaction, however, was extremely poor, giv-
Abstract: A three-step protocol for the highly diastereoselective
(>98%) synthesis of both (4R,5R)- and (4S,5S)-isocytoxazone from
D- or L-tyrosine is reported. The diastereoselection was confirmed
by X-ray crystallography. This synthesis is currently the highest
yielding approach towards these enantiomerically pure biologically ing at best 15% yield in our hands (the reaction has previ-
ously been reported to give yields of up to 35%7). Further
active oxazolidinones.
manipulation of product 6 afforded the 4-hydroxyphenyl-
1,3-dioxane 7. Methylation, after some experimentation,
was achieved with caesium carbonate and dimethyl sul-
fate, producing the 4-methoxyformate 8, but separation
from by-products brought through from the initial diazo-
tization reaction proved difficult (Scheme 2). Before this
approach was abandoned, an interesting reaction reported
by Quin and Macdiarmid was attempted, whereby direct
conversion from an amine group to a methoxy group is
possible using isoamyl nitrite in methanol (Scheme 3).8
Unfortunately, when using our substrate, this led to a
complex mixture of products, including loss of the for-
mate protecting group.
Key words: diastereoselective, cytoxazone, tyrosine, oxazolidin-
one, oxidation
During the course of screening for chemical immunomod-
erators from microbial metabolites, Osada found that an
actinomycete strain (RK95-31) produced cytoxazone 1
(Figure 1), an oxazolidinone that interferes with cytokine
IL-4, IL-10 and IgG production.1 Several groups have
synthesized (–)-cytoxazone 1 and (+)-epi-cytoxazone 2
(Figure 1),2 and Šunjic has described the racemic synthe-
ses of all of the stereoisomers and cogeners of isocytox-
azone 3 (Figure 1); enantiomerically pure samples were
isolated by preparative HPLC.3 A theoretical study on the
absolute configurations of 1 and 3 has been carried out by
Berova, as have extensive X-ray crystallographic studies.4
O
O
HN
HN
O
O
Rozwadowska and Tomczak have recently reported the
synthesis of (4S,5S)-(–)-isocytoxazone (3; Figure 1),5 but
the synthesis required seven synthetic steps, the last of
which afforded a mixture of regioisomers in an overall
yield of 8.1%. Prompted by these studies after reporting
several routes to 1,3-amino diols6 we herein report our ef-
forts in this area, utilizing a rapid highly diastereoselec-
tive three-step process from Boc-protected D- or L-
tyrosine.
OH
OH
O
O
(4R,5R)-(–)-cytoxazone (1)
(4R,5S)-(+)-epi-cytoxazone (2)
O
O
O
O
NH
NH
OH
OH
Our original strategy towards (4S,5S)-isocytoxazone was
similar to that of Rozwadowska, using diazotization as a
key reaction step (Scheme 1).
O
O
(4S,5S)-(–)-isocytoxazone (3)
(4R,5R)-(+)-isocytoxazone (ent-3)
Figure 1 The cytoxazones
O
O
HO
O2N
O
HN
H
NH2
NH
OH
O
O
OH OH
O
Scheme 1 Retrosynthetic route towards (4S,5S)-isocytoxazone
SYNLETT 2011, No. 10, pp 1399–1402
x
x
.x
x
.2
0
1
1
Advanced online publication: 13.05.2011
DOI: 10.1055/s-0030-1260561; Art ID: D06711ST
© Georg Thieme Verlag Stuttgart · New York

1400
B. R. Buckley et al.
LETTER
O
O
O
O
O2N
H2N
HN
H
O
O
HN
H
ii
i
i
OH
NHBoc
HN
O
HO
OH OH
O
OH OH
9
10
4
5
O
O
O
Scheme 5 Formation of Boc-protected, dimethylated L-tyrosine 10.
Reagents and conditions: (i) MeI (2.2 equiv), KOH (2.2 equiv), DMF,
0 ºC to r.t., 3.5 h, 74%.
RO
HN
H
HO
HN
H
iii
O
cation, which is believed to be more stable than the ben-
zylic cation of 10, is thought to be a driving force for the
reaction. This was supported by Ohfune’s observation that
only poor yields were obtained from compounds contain-
ing other amino protecting groups, such as the Cbz group.
Confirmation of the stereoselectivity was achieved from
the X-ray crystal structure of compound 11, as shown in
Figure 2.
OH OH
6
7
R = H
R = Me
iv
8
Scheme 2 Initial synthesis of the p-methoxyformate 8. Reagents
and conditions: (i) H2/Pd, EtOH, r.t., 24 h, 99%; (ii) (a) NaNO2,
H2SO4; (b) pH 6, D, 15%; (iii) 2,2-DMP, acetone, CSA, r.t., 4 h, 72%;
(iv) Cs2CO3, Me2SO4, CH2Cl2, 48 h, 72%.
O
O
H2N
O
HN
H
HN
H
i
OH OH
OH OH
Scheme 3 Attempted direct incorporation of the methoxy group
using Quin and Macdiarmid’s method. Reagents and conditions: (i)
(a) H2SO4, MeOH, (CH3)2CHCH2CH2ONO, 0 ºC, 3 h; (b) D, 1 h.
Figure 2 X-ray crystal structure of 1112
We next reasoned that (4S,5S)-isocytoxazone 3 could be
prepared from commercially available Boc-D-tyrosine
(Scheme 4).
Although this reaction is highly stereoselective, some
problems were encountered during the synthesis. Yields
tended to vary on scale-up of the reaction. Initially, the re-
action on 4 mmol of substrate afforded 50% of the desired
product (a good yield given the reported yield of 55%),
but on increasing the scale to 26 mmol a drop in yield to
40% was observed. Optimum conditions were found
when carrying the reaction out on a 16 mmol scale, a 52%
yield of product was obtained. Attempts to drive the reac-
tion to completion proved fruitless. Generally, increased
reaction times and temperatures decreased the overall
yield due to generation of higher levels of the side product
4-methoxy benzaldehyde (a product of over-oxidation).10
Milder reaction conditions resulted in no product forma-
tion.
We initially aimed to prepare the enantiomer of 3 (4R,5R)-
isocytoxazone ent-3 from the cheaper Boc-L-tyrosine
(Schemes 5– 7). Methylation of the acid and phenol com-
ponents within Boc-L-tyrosine with potassium hydroxide
and iodomethane afforded 10,9 the required precursor to
11.
Following the work of Ohfune,10 the benzylic position of
10 was oxidized with potassium persulfate (K2S2O8) and
catalytic copper sulfate to form the oxazolidinone 1111 in
a highly diastereoselective manner (diastereomeric ratio
98% R at C3) (Scheme 6).
The authors suggest that this high selectivity in cyclic car-
bamate formation arises because the reaction proceeds via
the more stable conformer of benzyl cation intermediate
10b. The conformer 10a is more strained than 10b due to
steric interaction between the ester group and the ortho
hydrogen atom. Intramolecular trapping of this cation by
a carboxyl oxygen and subsequent release of the tert-butyl
In order to afford the desired (4R,5R)-isocytoxazone ent-
3
13 the carbamate 11 was then reduced; this was initially
achieved with lithium aluminium hydride, but sodium
borohydride provided a superior yield (91% compared to
77%), probably due to the ease of workup associated with
the sodium borohydride reactions (Scheme 7). (4S,5S)-
Isocytoxazone 3 was prepared by repeating this optimised
O
NH
O
O
O
O
NH
OH
NHBoc
OMe
OH
HO
O
O
O
Scheme 4 A revised retrosynthetic route towards (4S,5S)-isocytoxazone from Boc-D-tyrosine
Synlett 2011, No. 10, 1399–1402 © Thieme Stuttgart · New York

LETTER
Synthesis of Enantiomerically Pure (4R,5R)- and (4S,5S)-Isocytoxazon
1401
O
O
NH
Ar
O
O
H
O
O
H
O
O
NH
10a
NH
O
O
O
O
O
O
O
11
10
O
NH
H
H
O
O
O
H
10b
Scheme 6 Ohfune’s cyclic carbamate formation. Reagents and conditions: K2S2O8, CuSO4, H2O–MeCN (1:1), 70 °C, 3 h, 52%.
(4) (a) Giorgio, E.; Viglione, R. G.; Zanasi, R.; Rosini, C. J. Am.
Chem. Soc. 2004, 126, 12968. (b) Giorgio, E.; Roje, M.;
Tanaka, K.; Hamersak, Z.; Šunjic, V.; Nakanishi, K.; Rosini,
C.; Berova, N. J. Org. Chem. 2005, 70, 6557. (c) Kakeya,
H.; Morishita, M.; Koshino, H.; Morita, T.; Kobayashi, K.;
Osada, H. J. Org. Chem. 1999, 64, 1052.
O
O
O
O
NH
NH
i
OMe
OH
O
O
O
(5) Rozwadowska, M. D.; Tomczak, A. Tetrahedron:
11
ent-3
Asymmetry 2009, 20, 2048.
Scheme 7 Formation of (4R,5R)-isocytoxazone ent-3. Reagents
and conditions: (i) NaBH4, EtOH, 0 °C to r.t., 45 min, 91%.
(6) (a) Page, P. C. B.; Rassias, G. A.; Barros, D.; Adel, A.;
Buckley, B.; Bethell, D.; Smith, T. A. D.; Slawin, A. M. Z.
J. Org. Chem. 2001, 66, 6926. (b) Page, P. C. B.; Barros, D.;
Buckley, B. R.; Marples, B. A. Tetrahedron: Asymmetry
2005, 16, 3488. (c) Page, P. C. B.; Rassias, G. R.; Barros,
D.; Ardakani, A.; Bethell, D.; Merifield, E. Synlett 2002,
580. (d) Page, P. C. B.; Buckley, B. R.; Barros, D.; Blacker,
A. J.; Heaney, H.; Marples, B. A. Tetrahedron 2006, 62,
6607. (e) Page, P. C. B.; Buckley, B. R.; Rassias, G. A.;
Blacker, A. J. Eur. J. Org. Chem. 2006, 803. (f) Page, P. C.
B.; Buckley, B. R.; Heaney, H.; Blacker, A. J. Org. Lett.
2005, 7, 375. (g) Page, P. C. B.; Barros, D.; Buckley, B. R.;
Ardakani, A.; Marples, B. A. J. Org. Chem. 2004, 69, 3595.
(h) Page, P. C. B.; Buckley, B. R.; Blacker, A. J. Org. Lett.
2004, 6, 1543.
sequence using D-tyrosine as the starting material, in an
overall yield of 33%.14
In conclusion we have reported here the highly diastereo-
selective synthesis of (4R,5R)-isocytoxazone ent-3 and
(4S,5S)-isocytoxazone 3 in just three synthetic steps from
D- or L-Boc-tyrosine, and confirmation of the stereoselec-
tion by X-ray crystallography. This is the shortest and
most high yielding approach (35% overall yield compared
to 8.1% overall yield reported previously) currently
known for this class of biologically active oxazolidinones.
(7) Racioppi, R.; Gavagnin, M.; Strazzullo, G.; Sodano, G.
Tetrahedron Lett. 1990, 31, 5177.
Supporting Information for this article is available online at
(8) Macdiarmid, J. E.; Qui, L. D. J. Org. Chem. 1981, 46, 1451.
(9) O-Methyl-N-tert-butoxycarbonyl-l-tyrosine Methyl
Ester (10): A solution of N-tert-butoxycarbonyl-L-tyrosine
(8.00 g, 28.5 mmol) in dimethylformamide (80 mL) was
cooled using an ice bath, treated with freshly ground KOH
(1.72 g, 31.3 mmol), and a cooled solution of iodomethane
(1.95 mL, 31.3 mmol) in dimethylformamide (20 mL) was
added dropwise over 5 min. The mixture was stirred at r.t.
for 30 min, cooled using an ice bath, and additional KOH
(1.72 g, 31.3 mmol) and a cooled solution of iodomethane
(1.95 mL, 31.3 mmol) in dimethylformamide (20 mL) was
added. The mixture was stirred for 3 h, poured onto ice (150
mL), and extracted with EtOAc (3 × 75 mL). The organic
layers were washed with H2O (3 × 50 mL), brine (2 × 50 mL)
and dried (MgSO4). The solvent was removed under reduced
pressure to afford a colourless oil. Crystallization was
achieved from EtOAc–light petroleum, to give 10 as
colourless crystals (6.5 g, 74%); mp 52–53 ºC; [a]20D +58.9
(c 1.2, CHCl3), lit.15 [a]22D +59.2 (c 1.8, CHCl3). IR (film):
2976, 1746, 1716, 1612, 1515, 1391, 1366, 1248, 1175,
http://www.thieme-connect.com/ejournals/toc/synlett.
Acknowledgment
The authors would like to thank Loughborough University for fun-
ding and Research Councils UK for a RCUK fellowship to B.R.B.
References and Notes
(1) Kakeya, H.; Morishita, M.; Kobinta, K.; Osono, M.;
Ishizuka, M.; Osada, H. J. Antibiot. 1998, 51, 1126.
(2) (a) Carter, P. H.; LaPorte, J. R.; Scherle, P. A.; Decicco,
C. P. Bioorg. Med. Chem. Lett. 2003, 13, 1237. (b) Kumar,
A. R.; Bhaskar, G.; Madhan, A.; Rao, B. V. Synth. Commun.
2003, 33, 2907. (c) Narina, S. V.; Kumar, T. S.; George, S.;
Sudalai, A. Tetrahedron Lett. 2007, 48, 65.
(3) Hamersak, Z.; Sepac, D.; Ziher, D.; Šunjic, V. Synthesis
2003, 375.
Synlett 2011, No. 10, 1399–1402 © Thieme Stuttgart · New York

1402
B. R. Buckley et al.
LETTER
1058, 1034 cm–1. 1H NMR (250 MHz, CDCl3): d = 1.42 (s,
9 H), 3.01–3.11 (m, 2 H), 3.71 (s, 3 H), 3.78 (s, 3 H), 4.53 (q,
1 H, J = 5.7 Hz), 5.00 (d, 1 H, J = 6.7 Hz), 6.82 (d, 2 H, J =
8.7 Hz), 7.03 (d, 2 H, J = 8.7 Hz). 13C NMR (100 MHz,
CDCl3): d = 28.3, 37.6, 52.7, 54.7, 55.3, 79.9, 114.1, 128.1,
130.3, 155.1, 158.8, 172.4. HRMS: m/z calcd for
r
calc = 1.386 Mg/cm3. 5035 data (1542 unique, Rint = 0.0157)
collected on an Apex II diffractometer at 150 K. Solved by
direct methods16 and refined by full-matrix least squares on
F2. R1[I > 2s(I)] = 0.0298 and wR2 (all data) = 0.0745.
Goodness of fit on F2 = 1.079. CCDC No. 804096.
(13) (4R,5R)-Isocytoxazone (ent-3): Methyl (4S,5R)-5-[4-
methoxyphenyl]-1,3-oxazolidin-2-one 4-Carboxylate (11;
2.20 g, 8.8 mmol) was dissolved in EtOH (25 mL) and the
solution was cooled using an ice bath. A solution of NaBH4
(0.70 g, 19.3 mmol) in EtOH (8 mL) was added dropwise
with stirring. After the addition was complete the ice bath
was removed and the mixture was stirred for 45 min. The
mixture was cooled to 0 ºC and concd HCl (1.5 mL) was
added, followed by H2O (15 mL). The EtOH was removed
under reduced pressure and the remaining aqueous solution
was extracted with EtOAc (3 × 50 mL). The combined
organic solutions were dried (MgSO4), and the solvents were
removed to afford an off-white solid, which was recrystal-
lized from EtOAc–light petroleum to give (4R,5R)-iso-
cytoxazone (ent-3) as a colourless crystalline solid (1.75 g,
90%); mp 140–142 ºC; [a]20D +74.8 (c 1.08, acetone), lit.3
[a]25D +70 (c = 0.4, MeOH). IR (nujol): 3239, 1725, 1614,
1514, 1459, 1376, 1251, 1174, 1062, 1016, 828 cm–1. 1H
NMR (250 MHz, acetone-d6): d = 3.71–3.87 (m, 3 H), 3.86
(s, 3 H), 5.35 (d, 1 H, J = 5.3 Hz), 7.01 (d, 2 H, J = 8.6 Hz),
7.41 (d, 2 H, J = 8.6 Hz). 13C NMR (100 MHz, CDCl3): d =
56.0, 63.1, 64.2, 80.4, 115.4, 128.7, 133.2, 159.6, 161.3.
HRMS: m/z [M+] calcd for C11H13NO4: 223.0845; found:
223.0842.
C16H23NO5: 309.1576; found: 309.1578.
(10) Shimamoto, K.; Ohfune, Y. Tetrahedron Lett. 1988, 29,
5177.
(11) Methyl (4S,5R)-5-[4-Methoxyphenyl)-1,3-oxazolidin-2-
one 4-Carboxylate (11): A solution of O-methyl-N-tert-
butoxycarbonyl-L-tyrosine methyl ester (10; 5.00 g, 16.2
mmol) in MeCN (200 mL) was treated with a solution of
K2S2O8 (8.75 g, 32.4 mmol) in H2O (210 mL) and a solution
of CuSO4 (0.52 g, 3.2 mmol) in H2O (50 mL). The mixture
was heated to 70 ºC for 3 h under a blanket of N2, allowed to
cool, and extracted with EtOAc (3 × 150 mL). The combined
organic solutions were dried (MgSO4) and concentrated
under reduced pressure to give a dark yellow oil. Column
chromatography, eluting with EtOAc–light petroleum
(1:10–1:1), afforded a colourless solid, which was
recrystallised from EtOAc–light petroleum to give 11 as a
colourless crystalline solid (2.10 g, 52%); mp 94–96 ºC;
[a]20D +83.5 (c 1.15, CHCl3). IR (film): 3316, 2956, 2362,
2337, 1762, 1613, 1515, 1382, 1250, 1224, 1026, 834, 763
cm–1. 1H NMR (400 MHz, CDCl3): d = 3.81 (s, 3 H), 3.83 (s,
3 H), 4.31 (d, 1 H, J = 5.2 Hz), 5.56 (d, 1 H, J = 5.2 Hz), 6.81
(s, 1 H), 6.93 (d, 2 H, J = 4.8 Hz), 7.33 (d, 2 H, J = 4.8 Hz),
13C NMR (100 MHz, CDCl3): d = 53.5, 55.7, 61.8, 79.9,
114.7, 127.5, 130.3, 158.6, 160.6, 170.7. HRMS: m/z [M+]
calcd for C12H13NO5: 251.0794; found: 251.0794.
(14) See the Supporting Information for the experimental data.
(15) Ross, A. J.; Lang, H. L.; Jackson, R. F. W. J. Org. Chem.
2010, 75, 245.
(12) Crystal data for 11: C12H13NO5, M = 251.23, monoclinic,
a = 7.0103 (8), b =5.5734 (6), c = 15.6004 (18) Å, U =
602.01 (12) Å3, space group P21, Z = 2, m = 0.109 mm–1,
(16) Sheldrick, G. M. Acta Crystallogr., Sect. A 2008, 64, 112.
Synlett 2011, No. 10, 1399–1402 © Thieme Stuttgart · New York