The first stereoselective total synthesis of antiviral antibiotic, xanthocillin X dimethylether and its stereoisomer

Article abstract of DOI:10.1016/j.tetlet.2005.05.077

Xanthocillin X dimethylether (1) has been stereoselectively synthesized from the propiolic acid 6 through an oxidative rearrangement of the stannyl vinyl amide 27 to give the vinyl isocyanate 30 and a homocoupling of the stannyl N-formylenamine 31.

Full text of DOI:10.1016/j.tetlet.2005.05.077

Tetrahedron
Letters
Tetrahedron Letters 46 (2005) 5017–5020
The first stereoselective total synthesis of antiviral antibiotic,
xanthocillin X dimethylether and its stereoisomer
Kuniaki Tatsuta* and Takahiro Yamaguchi
Department of Applied Chemistry, School of Science and Engineering, Waseda University, 3-4-1 Ohkubo,
Shinjuku-ku, Tokyo 169-8555, Japan
Received 16 April 2005; revised 19 May 2005; accepted 19 May 2005
Available online 9 June 2005
Abstract—Xanthocillin X dimethylether (1) has been stereoselectively synthesized from the propiolic acid 6 through an oxidative rear-
rangement of the stannyl vinyl amide 27 to give the vinyl isocyanate 30 and a homocoupling of the stannyl N-formylenamine 31.
Ó 2005 Elsevier Ltd. All rights reserved.
Xanthocillin X dimethylether (1) and mono-methylether,
which showed antiviral activity against Newcastle disease
virus, vaccinia and herpes simplex viruses, were produced
by Aspergillus sp. and determined spectrometrically to be
the derivatives of 1,4-bis-(4-hydroxyphenyl)-2,3-diisoni-
trilo-1,3-butadiene.1,2 The configuration of 1 was de-
duced from the structure of xanthocillin X (2), which
was confirmed by X-ray crystallographic analysis.3 Fur-
ther investigation has been hampered by the scarcity
and instability of such natural products, although the
synthesis of 1 was reported in 1962 before isolation of
the natural product without any detailed experimental
data and references to the stereochemistry.4
Needless to say, the challenge of creating the vinyl isoni-
trile structure in the laboratory added to the attractive-
ness of the project.5–7
Herein, we describe the first stereoselective total synthe-
sis of xanthocillin X dimethylether (1) to demonstrate
the utility and the versatility of our method.
Figure 1 illustrates two possible routes to 1 by our retro-
synthetic analysis.
Route 1 is based on a cross-coupling reaction of the
vinyl bromide 4 and the vinylstannane 5 followed by
HO2C
Route 1
Br
Sn(n-Bu)3
CO2R2
Ar
Ar
Ar
Ar
+
OMe
CO2R1
CO2R
NC
3
4
5
NC
MeO
1: Xanthocillin X dimethylether
2 (Me = H): Xanthocillin X
Sn(n-Bu)3
Sn(n-Bu)3
CONH2
CO2H
Route 2
Ar
Ar
HN
OR
O
MeO
7
8
6
Ar =
OMe
Figure 1.
Keywords: Total synthesis; Stannyl enamines; Antiviral; Vinyl isonitrile.
*
Corresponding author. Tel./fax: +81 3 3200 3203; e-mail: tatsuta@waseda.jp
0040-4039/$ - see front matter Ó 2005 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2005.05.077

5018
K. Tatsuta, T. Yamaguchi / Tetrahedron Letters 46 (2005) 5017–5020
step-wise Curtius rearrangements of the mono-carboxylic
acid 3. On the other hand, Route 2 is based on a homo-
coupling of the stannyl enamine derivative 7, which is
prepared from the stannyl vinyl amide 8 by oxidative
rearrangement. Namely, the key point of the routes de-
pends on the rearrangements before or after coupling of
the properly constructed vinyl derivatives, which could
be derived from the common propiolic acid 6.
(DPPA) and NaH to give the isocyanate followed by
trapping with TMS ethanol to yield the N-Teoc-enamine
16. However, the NOE studies between NH and H-1 re-
vealed 16 to be the (E,Z)-isomer, showing that unex-
pected isomerization occurred during the rearrangement.
The carbamate 16 was further converted to the other
mono-carboxylic acid 17. The Curtius rearrangement
was conducted under the aforesaid conditions to give
the (E,E)-diene 18, the NMR spectrum of which showed
the simple signal pattern due to the symmetrical struc-
ture. N-Formylation of 18 with acetic formic anhydride
to give 19 was successively followed by deprotection and
dehydration to give the very labile diisonitrile 20. This
corresponded to the (E,E)-isomer of the natural product
1.
First of all, the synthesis was carried out according to
Route 1 (Scheme 1).
The (E)-vinyl bromide 12 and (E)-vinylstannane 13 were
prepared from anisaldehyde according to the modified
procedures of the Tanabe Seiyaku group8 as follows.
The propiolic acid 69 was obtained from anisaldehyde
by treatment with PPh3 and CBr4 to give the dibromo-
olefin followed by carboxylation of the lithiated com-
pound.8 The carboxylic acid 6 was converted into two
esters 9 and 10 by treatment with MOM-Cl and trimeth-
ylsilylethanol, respectively. Hydrostannation of 9 and 10
gave the (E)-vinylstannanes 11 and 13, respectively, the
former of which was brominated to the (E)-vinyl bro-
mide 12. The configurations of 11 and 13 were con-
firmed by the NMR studies, especially their coupling
constants between the vinyl proton and the Sn atom
(JH,Sn = 29.6 and 30.4 Hz) in comparison with those of
the (Z)-isomers 21 and 23 (JH,Sn = 51.2 and 52.8 Hz)
according to the experimental rule.11
Also, the (E,E)-isomer 20 was synthesized from the (Z)-
isomers 22 and 23 (Scheme 2).
Radical hydrostannation of 9 and 10 gave the (Z)-
vinylstannanes 21 and 23, the former of which was con-
verted to the (Z)-vinyl bromide 22. Coupling of 22 and
23 under the aforementioned Pd-catalyzed conditions
provided the (E,E)-diene 24, which was transformed to
18 in six steps through 25 without isomerization under
similar conditions as shown in the synthesis of 18 from
14.
These findings showed that the Curtius rearrangements
using DPPA gave stereochemically more stable (E)-car-
bamates 16 and 25 than the corresponding (Z)-isomers.
Thereby, before coupling of two segments, a proper
rearrangement was reasonably required for the con-
struction of the (Z)-enamine structures.
Coupling of both segments 12 and 13 with Pd(PPh3)2Cl2
and CuI gave the (Z,Z)-diene 14, which was selectively
and quantitatively deprotected to the mono-carboxylic
acid 15. This was submitted to Curtius rearrange-
ment12,13 by reaction with diphenylphosphoryl azide
JH,Sn = 29.6 Hz (R=MOM)
JH,Sn = 30.4 Hz (R=SE)
HO2C
H
SEO2C
a
b
e
CO2R
X
Ar
f, g
d
Ar
Ar
Ar
Ar
6
Ar
CO2R
CO2MOM
CO2MOM
9 : R=MOM
10 : R=SE
11: X=Sn(n-Bu)3, R=MOM
12: X=Br, R=MOM
13: X=Sn(n-Bu)3, R=SE
14
15
c
TMS
SE =
OMe
NOE
2.6%
O
O
O
O
OHC
Ar
HN
OSE
H
HN
3
OSE
H
Ar HN
OSE
N
OSE
NC
k
l, m
h
i, j
SEO
4
2
1
Ar
Ar
NOE
5.2%
HO2C
17
Ar
MOMO2C
Ar
NH Ar
SEO
N
O
Ar
CHO
NC
20
O
16
18
19
OMe
Scheme 1. Reagents and conditions: (a) MOM-Cl, i-Pr2NEt, CH2Cl2, 0 °C to rt, 4 h, 98% or TMS(CH2)2OH, DCC, DMAP, CH2Cl2, À20 °C to rt,
12 h, 96%; (b) n-Bu3SnH, Pd(PPh3)4, THF, 0 °C, 0.5 h, 11: 82%, 13: 85%; (c) Br2, CH2Cl2, 0 °C, 0.5 h, 97%; (d) Pd(PPh3)2Cl2, CuI, DMF, 60 °C, 6 h,
54%; (e) TBAF, THF, rt, 7 h, quant.; (f) DPPA, NaH, DMF, 0 °C to rt, 3 h, 63%; (g) TMS(CH2)2OH, Py., THF, 60 °C, 12 h, 62%; (h) MgBr2ÆOEt2,
Et2O, rt, 5 h, 70%; (i) DPPA, NaH, DMF, 0 °C to rt, 2 h, 50%; (j) TMS(CH2)2OH, Py., THF, 60 °C, 12 h, 50%; (k) LHMDS, HMPA, acetic formic
anhydride, THF, À78 °C, 2 h, 32%; (l) TBAF, THF, 0 to rt, 6 h, 29%; (m) POCl3, Py., 0 °C, 0.5 h, 72%.

K. Tatsuta, T. Yamaguchi / Tetrahedron Letters 46 (2005) 5017–5020
5019
OMe
JH,Sn = 51.2 Hz (R=MOM)
JH,Sn = 52.8 Hz (R=SE)
O
O
Ar CO2SE
d, e, f
HN
OSE
H
Ar HN
OSE
H
NOE
4.5%
g, h, i
a
c
CO2R
Ar
9 or 10
MOMO2C
Ar
SEO
NH
X
MOMO2C
Ar
21: X=Sn(n-Bu)3, R=MOM
22: X=Br, R=MOM
b
O
24
25
23: X=Sn(n-Bu)3, R=SE
18
OMe
Scheme 2. Reagents and conditions: (a) n-Bu3SnH, AIBN, PhH, rt, 5 h, 21: 75%, 23: 67%; (b) Br2, CH2Cl2, 0 °C, 2 h, 91%; (c) Pd(PPh3)2Cl2, CuI,
DMF, 70 °C, 4 h, 69%; (d) TBAF, THF, rt, 18 h, quant.; (e) DPPA, NaH, DMF, 0 °C to rt, 2 h, 89%; (f) TMS(CH2)2OH, Py., THF, 60 °C, 12 h,
78%; (g) MgBr2ÆOEt2, Et2O, rt, 5 h, quant.; (h) DPPA, NaH, DMF, 0 °C to rt, 2 h, 32%; (i) TMS(CH2)2OH, Py., THF, 60 °C, 12 h, 42%.
O
JH,Sn= 30.4 Hz
JH,Sn= 21.6 Hz
H
H
CONH2
b
SEO
NH
Sn(n-Bu)3
OSE
a
Sn(n-Bu)3
CONH2
c
d
Ar
Ar
Ar
Ar
6
Ar
Ar
HN
HN
OSE
MeO
27
28
29
O
O
26
e, f
JH,Sn= 20.8 Hz
e, f
g
OHC
H
NH
Sn(n-Bu)3
Sn(n-Bu)3
h
d
Ar
Ar
NCO
30
HN
31
HN
CHO
CHO
i
32
OMe
NC
NC
MeO
1
Scheme 3. Reagents and conditions: (a) ClCO2Et, Et3N, THF; aq NH3, 0 °C, 1 h, 95%; (b) n-Bu3SnH, Pd(PPh3)4, THF, 0 °C, 0.5 h, 68%; (c)
Pb(OAc)4, TMS(CH2)2OH, DMF, 0 °C to 50 °C, 8 h, 67%; (d) Pd(OAc)2, CuCl2, THF, 0 °C, 0.5 h, 29: 41%, 32: 62%; (e) LHMDS, HMPA, acetic
formic anhydride, THF, À78 °C, 2 h; (f) TBAF, THF, 0 °C to rt, 2 h, 31: 66% (in two steps), 32: 33% (in two steps); (g) Pb(OAc)4, THF, rt, 0.5 h,
88%; (h) LiEt3BH, THF, À78 to À30 °C, 2 h, 70%; (i) POCl3, Py., 0 °C, 1 h, 59%.
The Route 2 was examined in practice as follows
(Scheme 3).
showed a complex NMR signal pattern due to the rota-
tional hindrance of its N-formyl groups, while 29
showed a simple pattern as expected from the symmetri-
cal structure.
The mixed anhydride of 6 was treated with ammonia to
give the amide 26, which was converted to the (E)-
vinylstannane 27. The configurations of 27 and 31 were
also supported by their coupling constants11
(JH,Sn = 30.4 and 20.8 Hz) in comparison with those of
(Z)-isomers 33 and 34 (JH,Sn = 52.0 and 41.6 Hz). After
some experimentation, a remarkable procedure for con-
verting 27 into 28 was discovered. The Baumgarten oxi-
dative rearrangement14 of 27 with Pb(OAc)4 and TMS
ethanol stereoselectively gave the carbamoyl (E)-vinylst-
annane 28, the configuration of which was also deter-
mined by the magnitude of the coupling constant
JH,Sn. Compound 28 was submitted to Pd-catalyzed
homocoupling15 to give the symmetrical (Z,Z)-diene 29
(mp 140 °C). Finally, the (Z,Z)-configuration was veri-
fied by X-ray crystallographic analysis to show the reac-
tions to proceed from 27 to 29 with retention of the
configurations.16 Compound 29 was formylated to the
diformimide, followed by deprotection to 32. This
Alternatively, the intermediate 28 was first formylated
and deprotected to the stannyl N-formylenamine 31.
This was converted to the (Z,Z)-diene 32 by homocou-
pling with Pd(OAc)2 and CuCl2.
The shorter processes from 27 to 31 were tested under
various conditions, and the best result was realized by
oxidative rearrangement of 27 to give the isocyanate
30. This was isolated to be reduced by LiEt3BH to the
N-formamide 31.12
In the final stage, dehydration of 32 with POCl3 in pyr-
idine smoothly proceeded to afford the (Z,Z)-diisonitrile
1, which was fairly stable even in the solid states.
The IR and 1H NMR spectra of the synthetic isonitrile 1
were identical with the reported data17 of the natural

5020
K. Tatsuta, T. Yamaguchi / Tetrahedron Letters 46 (2005) 5017–5020
OMe
JH,Sn= 41.6 Hz
H
JH,Sn= 52.0 Hz
H
CONH2
NC
H
N
CONH2
Ar
CHO
d, e
a
b, c
Ar
Sn(n-Bu)3
Sn(n-Bu)3
NC
MeO
26
33
34
20
OMe
Scheme 4. Reagents and conditions: (a) n-Bu3SnH, AIBN, THF, 0 °C, 3.5 h, 63%; (b) Pb(OAc)4, THF, rt, 0.5 h, 90%; (c) LiEt3BH, THF, À78 °C,
2 h, 79%; (d) Pd(OAc)2, CuCl2, THF, 0 °C, 0.5 h, 66%; (e) POCl3, Py., 0 °C, 0.5 h, 72%.
7. Isshiki, K.; Imoto, M.; Sawa, T.; Umezawa, K.; Takeuchi,
T.; Umezawa, H.; Tsuchida, T.; Yoshioka, T.; Tatsuta, K.
J. Antibiot. 1987, 40, 1209.
xanthocillin X dimethylether, completing the stereose-
lective total synthesis of the natural product 1 to confirm
its absolute structure.
8. Sai, H.; Ogiku, T.; Nishitani, T.; Hiramatsu, H.;
Horikawa, H.; Iwasaki, T. Synthesis 1995, 582.
9. All compounds were purified by silica-gel column chro-
matography and/or recrystallization, and were fully
characterized by spectroscopic means. 1H NMR spectra
(300, 400 MHz, d; TMS = 0) were in CDCl3 solution,
unless otherwise stated. Significant 1H NMR spectral
data of 1, 20 and other compounds (only vinyl protons)
are the following. Compound 1: 7.79 (4H, d, J = 8.8 Hz),
7.02 (2H, s), 6.99 (4H, d, J = 8.8 Hz), 3.88 (6H, s).
Compound 11: 6.66 (1H, s). Compound 12: 7.34 (1H, s).
Compound 13: 6.61 (1H, s). Compound 14: 6.82 (1H, s),
6.79 (1H, s). Compound 16: 6.92 (2H, br s). Compound
16 (in C6D6): 7.37 (1H, br s), 6.89 (1H, s). 18: 7.00 (2H,
br s). Compound 19: 6.46 (2H, s). Compound 20: 7.34
(4H, d, J = 8.8 Hz), 6.99 (2H, s), 6.85 (4H, d,
J = 8.8 Hz), 3.81 (6H, s). Compound 21: 8.38 (1H, s).
Compound 22: 8.23 (1H, s). Compound 23: 8.30 (1H, s).
Compound 24: 7.92 (1H, s), 7.88 (1H, s). Compound 25:
7.79 (1H, s), 7.12 (1H, br s). Compound 27: 6.58 (1H, s).
Compound 28: 5.69 (1H, s). Compound 29: 6.43 (2H, s).
Compound 30: 5.89 (1H, s). Compound 31: 5.92 (1H, s,
major),10 5.75 (1H, s, minor). Compound 33: 7.33 (1H,
s). Compound 34: 7.04 (1H, s, major),10 6.99 (1H, s,
minor).
As the present synthesis through 30 and 31 proved to be
quite effective, a similar process was applied to the syn-
thesis of the unnatural product 20 (Scheme 4).
Radical hydrostannation of the amide 26 gave the (Z)-
isomer 33, which was led to the N-formamide 34 with
retention of the configuration. Homocoupling of 34 fol-
lowed by dehydration afforded the unnatural 2018 as
expected.
Now that the utility of this unique methodology for syn-
thesis of the vinyl isonitrile derivatives has been illus-
trated, its application for the construction of other
related substances is an exciting prospect.
Acknowledgements
The present work was financially supported by Grant-
in-Aid for Specially Promoted Research and Scientific
Research A from MEXT. We are grateful to 21COE
ꢀPractical Nano-Chemistryꢁ and Consolidated Research
Institute for Advanced Science and Medical Care from
MEXT.
10. Compounds 31 and 34 are mixture due to the rotational
hindrance of their N-formyl groups.
11. Leusink, A. J.; Budding, H. A.; Marsman, J. W. J.
Organomet. Chem. 1967, 9, 285.
References and notes
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1975, 40, 3554.
15. Parrish, J. P.; Flanders, V. L.; Floyd, R. J.; Jung, K. W.
Tetrahedron Lett. 2001, 42, 7729.
16. The X-ray data of 29 has been deposited with CCDC
(CCDC 267408).
17. Morino, T.; Nishimoto, M.; Itou, N.; Nishikiori, T. J.
Antibiot. 1994, 47, 1546.
18. Biological activities of 1 and 20 including SAR studies will
be published elsewhere.
1. Takatsuki, A.; Suzuki, S.; Ando, K.; Tamura, G.; Arima,
K. J. Antibiot. 1968, 56, 671.
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