Synthesis of jadomycin A and related jadomycin aglycons: Structural re-examination of jadomycins S and T may be needed

Article abstract of DOI:10.1016/j.tetlet.2011.10.160

Jadomycin A and related jadomycin M and W aglycons were synthesized. Easy re-construction of 4-(hydroxymethyl)-1,3-oxazolidin-5-one system into an isomeric 1,3-oxazolidine-4-carboxylic acid system during the synthetic trial of jadomycin S aglycon requests

Full text of DOI:10.1016/j.tetlet.2011.10.160

Tetrahedron Letters 53 (2012) 383–387
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Synthesis of jadomycin A and related jadomycin aglycons: structural
re-examination of jadomycins S and T may be needed
⇑
Takayoshi Tajima, Yuhsuke Akagi, Takuya Kumamoto, Noriyuki Suzuki, Tsutomu Ishikawa
Graduate School of Pharmaceutical Sciences, Chiba University, 1-8-1 Inohana, Chuo, Chiba 260-8675, Japan
a r t i c l e i n f o
a b s t r a c t
Article history:
Jadomycin A and related jadomycin M and W aglycons were synthesized. Easy re-construction of 4-
(hydroxymethyl)-1,3-oxazolidin-5-one system into an isomeric 1,3-oxazolidine-4-carboxylic acid system
during the synthetic trial of jadomycin S aglycon requests us to more precisely re-examine the structures
Received 19 August 2011
Revised 27 October 2011
Accepted 31 October 2011
Available online 18 November 2011
proposed for jadomycins S and T, derived from hydroxyl-containing amino acids of
nine, respectively.
L-serine and L-threo-
Ó 2011 Elsevier Ltd. All rights reserved.
Keywords:
Jadomycin
Aglycon
Synthesis
Oxazolidone
Oxazolidine
Jadomycin antibiotics have a unique 8H-benzo[b]oxazolo[3,2-
f]phenanthridine skeleton incorporating an amino acid unit in the
1,3-oxazolidin-5-one ring1–4 and biogenetically derived from the
In the synthesis of dimethyljadomycin A (3), spontaneous iso-
quinoline–oxazolidone cyclization was successfully applied to the
final construction of jadomycin skeleton by oxidation of the benzyl
alcohol unit on the aryl pendant of 2-aryl-1,4-naphthoquinone
core carrying amino acid function located at the adjacent position
of the aryl group.8 Thus, we decided the use of the same cyclization
procedure in the synthesis of jadomycin A (1) and related jadomy-
cin aglycons. Retrosynthetic analysis is shown in Scheme 1, in
same precursor that gilvocarcins.5 The
L-isoleucine-containing ana-
logs, jadomycins A (1) and B (2), were firstly isolated from Strepto-
myces venezuelae in 1991.1–3 After then a range of jadomycin B (2)
congeners carrying L-digitoxose at the 12-phenolic function has
been artificially produced by addition of the corresponding amino
acid component to culture medium during cultivation and interest-
ing biological activities such as anti-MRSA,6 DNA cleaving,7 and
which
a
methoxymethyl (MOM)-protected 2-[2-(hydroxy-
methyl)aryl]-1,4-naphthoquinone 8 was designed as a common
synthetic intermediate for jadomycin aglycons.
cytotoxic activities6 were found in jadomycins B (2), L (
L
-leucine),
S (
L
-serine), and T (
L
-threonine).
The coupling partners, benzoxaborole 910 and bromojuglone
10,11 were prepared from commercially available 3,5-dimethyl-
phenol and 1,5-dihydroxynaphthalene in 27% and 59% yields,
respectively, through each four steps. Suzuki–Miyaura cross-cou-
pling reaction of 9 and 10 was optimized by the use of PdCl2(dppf)
as palladium catalyst and CsF as base12 in aqueous THF (THF/
H2O = 10:1) at room temperature for 28 h. Thus, a common 2-[2-
(hydroxymethyl)aryl]-1,4-naphthoquinone 8 was provided in an
87% yield as a ca 2:1 mixture of atropisomers. Treatment of
In the previous Letter,8 we reported the synthesis of dimethylj-
adomycin A (3) through spirolactonyltetralone as a synthetic inter-
mediate based on our arnottin II synthesis;9 however, this approach
could not be applied to the synthesis of natural jadomycin A (1) itself
because of resistant demethylation. Therefore, we further ap-
proached to the development of synthetic method applicable to di-
verse jadomycin analogs by improving our previous method. In this
communication we report the syntheses of jadomycin A (1) and re-
lated jadomycins M 4 and W 5 aglycons. In addition, we would like to
propose to re-examine the 4-(hydroxymethyl)-1,3-oxazolidin-5-
one system in jadomycins S and T, derived from hydroxy-containing
2-aryl-1,4-naphthoquinone 8 with L-isoleucine in aqueous ethanol
in the presence of triethylamine gave amino acid-inserted naph-
thoquinone 11 in a 56% yield by Michael addition–air oxidation
reactions.13 Oxidation of 11 with Dess–Martin periodinane (DMP)
afforded the MOM-protected jadomycin A 12. Removal of protect-
ing group in 12 with 4 N HCl smoothly yielded jadomycin A14 (1) as
a diastereomeric mixture of the 3aS- and 3aR-isomers at the ratio
of ca 5:115 (Scheme 2). Jadomycin M aglycon 4 was similarly syn-
amino acids of L-serine and L-threonine, respectively, because of its
easy re-construction to an isomeric 1,3-oxazolidin-4-carboxylic
acid system during the synthetic trials of jadomycin S aglycon 6.
⇑
Corresponding author. Tel./fax: +81 43 226 2944.
E-mail address: benti@faculty.chiba-u.jp (T. Ishikawa).
thesized from 8 using L-methionine as an amino acid component.
0040-4039/$ - see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2011.10.160

384
T. Tajima et al. / Tetrahedron Letters 53 (2012) 383–387
10
11
9
O
12
OR2
HO
O(L-digitoxose)
O
H
1O
7
R
8
13
O
H
R
6
5
O
N
H Me 4'
Me
3a
N
H
Me
1'
O
4
1
O
Me
3'
O
2
2'
3
O
SMe
jadomycin M: R =
1
2
1
jadomycin A ( : R = R = H)
jadomycin B (2: R1 = H; R2 = L-digitoxose)
dimethyljadomycin A (3: R1 = R2 = Me)
jadomycin W: R =
N
H
jadomycin S: R =
jadomycin T: R =
OH
Me
OH
In this reaction sequence, changes of reaction conditions were
requested; the reaction under anaerobic condition in the introduc-
tion of the amino acid unit and the use of manganese oxide in place
of DMP in the second oxidation step for isoquinoline–oxazolidone
cyclization due to possible oxidation of the sulfide function in the
methionine unit (Scheme 2).
combination of TMSOTf and 2,6-lutidine in the presence of p-thio-
cresol16 afforded jadomycin W aglycon 5 in a 54% yield as an insep-
arable mixture containing a major 3aS-isomer.
Finally, the synthesis of jadomycin S aglycon 6 derived from
serine was attempted (Scheme 4). Treatment of the naphthoqui-
none 8 with -serine afforded an amino acid-inserted product 18
L-
L
Next, we targeted jadomycin W aglycon 5 carrying
as an amino acid unit (Scheme 3). -Tryptophan was successfully
introduced to the naphthoquinone core 8; however, the following
oxidative cyclization disappointed us. Replacement of -tryptophan
by its N-Boc-protected derivative gave an intended jadomycin
skeleton 17 in a 66% yield in two steps. Although only a complex
mixture was formed in trials for the removal of protecting group
under various conditions including with routinely used HCl, a
L
-tryptophan
in a 56% yield; however, the following oxidative cyclization failed,
similar to the use of unprotected tryptophan as shown in Scheme 3.
Protection of the hydroxy group as tert-butyl ether gave a jadomy-
cin skeleton 21 in high two steps yield from 8, but only a complex
mixture was formed in the next deprotection trials. On the other
hand, when TBS-protection was applied, expected deprotection in
jadomycin skeleton 22 was suggested by disappearance of both
MOM and TBS functions in the 1H NMR spectrum of a crude
L
L
O
O
HO
OH
OMOM
MOMO
O
H
R
O
H
N
HN
oxidation
Me
R
Me
H
isoquinoline-oxazolidone
cyclization
O
CO2H
OH
O
7
1
jadomycin A ( ) and
jadomycin aglycons
amino acid
Michael addition-
air-oxidation
O
Br
O
MOMO
Me
OMOM
O
OMOM
O
MOMO
OH
10
"Pd"
B
Suzuki-Miyaura
cross coupling
O
OH
Me
8
9
Scheme 1.

T. Tajima et al. / Tetrahedron Letters 53 (2012) 383–387
385
PdCl2(dppf)
CsF
THF-H2O
O
amino acid, Et3N
EtOH-H2O, 50 °C
MOMO
OMOM
9
+
8
O
H
R
10
rt, 28 h
(87%)
HN
OH
for 11: L-isoleucine, 15 h
(56%)
for 13: L-methionine, 8 h
under Ar
Me
CO2H
11: R = (
S
)-isobutyl
13
: R = methylthioethyl
on 11: DMP, CH2Cl2, 2 h
(87%)
on 13: MnO2, CH2Cl2, 4 d
(64% in 2 steps)
oxidant
rt
O
O
HO
OH
MOMO
OMOM
HCl, THF, rt
O
H
R
O
H
R
3a
N
on 12: 4 NHCl, 23 h (80%)
on 14: 6 NHCl, 18 h (65%)
N
Me
Me
H
H
O
O
O
O
1: R = (
(3a
S
)-isobutyl
R
12: R = ( )-isobutyl
S
S
: 3a = ca 5 : 1)
14
: R = methylthioethyl
4: R = methylthioethyl
(3a
S
: 3a
R
= ca 8 : 3)
Scheme 2.
O
L-tryptophan, Et3N
EtOH-H2O, 40 °C, 5 h
MOMO
OMOM
O
8
H
HN
OH
or
Me
N-Boc-L-tryptophan, Et3N
MeOH-H2O, 40 °C, 5 h
CO2H
N
R
15: R = H (31%)
16
: R = Boc
on 16
DMP, NaHCO3
CH2Cl2, rt, 1.5 h
66%
in 2 steps
TMSOTf
2,6-lutidine
p-thiocresol
O
H
O
HO
OH
MOMO
OMOM
O
H
O
3a
H
N
N
CH2Cl2
5 °C, 3 h
Me
Me
H
O
O
O
O
54%
N
H
N
Boc
5
17
(3aS : 3aR = ca 8 : 3)
Scheme 3.
reaction product 24, in spite of unsuccessful isolation of the prod-
uct as a pure form due to its instability.
The 1,3-oxazolidin-5-one system in jadomycin skeletons, as ex-
pected, shows a characteristic carbonyl absorption at around

386
T. Tajima et al. / Tetrahedron Letters 53 (2012) 383–387
O
L-serine, Et3N
MOMO
OMOM
EtOH-H2O, 50 °C, 15 h
O
H
8
or
HN
OH
Me
OtBu-serine, Et3N
MeOH-H2O, 40 °C, 5 h
OR
CO2H
or
18: R = H (58%)
OTBS-serine, Et3N
MeOH-H2O, rt, 5 h
t
19
20
: R = Bu
: R = TBS
DMP, CH 2Cl2
rt, 2 h
O
O
H
6N HCl
THF
MOMO
OMOM
OR
HO
OH
O
H
O
H
rt, 6 h
N
N
Me
H
Me
on 22
OH
O
O
O
O
21: R = tBu (77% in 2 steps)
reported jadomycin S aglycon 6
22
: R = TBS (42% in 2 steps)
O
O
HO
OH
OH
HO
OH
O
H
O
H
N+
N
Me
Me
CO2H
H
HO
O
O
24
23
TMSCHN2
MeOH
0°C, 1 h
O
HO
O(l-digitoxose)
O
HO
OH
O
H
O
H
N
Me
CO2H
N
H
Me
O
CO2Me
H
O
R
Possible structures for
jadomycins S (R = H) and T (R = Me)
25a (3aS) (20%)
25b
(3aR) (10%)
Scheme 4.
1800 cmÀ1 in the IR spectrum [e.g. 1806 cmÀ1 for jadomycin B (2)
and 1804 cmÀ1 for jadomycin F ( -phenylalanine)17] (entries 1 and
skeleton 22 was re-constructed to 1,3-oxazolidine-4-carboxylic
acid system in 24 through a ring-opened isoquinolinium salt 23,
in which a more nucleophilic hydroxy group than carboxyl one
was generated. This speculation was confirmed by the conversion
of a crude deprotection product 24 to methyl ester derivative 25
for characterization. Treatment of 24 with trimethylsilyldiazome-
thane gave two isolable products 25a and 25b, showing carbonyl
absorptions at 1736 and 1748 cmÀ1 due to an ester function in
the IR spectra (entries 13 and 14, Table 1), in 20% and 10% yields,
L
5, Table 1). In fact, a carbonyl absorption at 1807 cmÀ1, in addition
to 1664 cmÀ1 due to quinone carbonyl absorption, was detected in
the isoquinoline–oxazolidone cyclization product 22 as well as our
synthesized related compounds (e.g. entries 10–12, Table 1), while
two carbonyl absorptions at 1717 and 1637 cmÀ1 were observed in
a crude deprotected product 24. These facts indicated that 4-
(hydroxymethyl)-1,3-oxazolidin-5-one system in
a jadomycin

T. Tajima et al. / Tetrahedron Letters 53 (2012) 383–387
387
Table 1
in the feeding experiment of
L
-threonine methyl ester by S. venezu-
Carbonyl absorptions in the IR and chemical shifts assignable to the C3a–H signals in
elae ISP 5230, anticipating that hydroxy functionality would poten-
tially cyclize with aldimine intermediate like 23 to form an
oxazolidine ring,4 our observation of ring re-construction of oxaz-
olidone to oxazolidine, albeit under non-physiological conditions,
could claim that the 4-(hydroxymethyl)-1,3-oxazolidin-5-one ring
system proposed for hydroxy-containing amino acid-derived jad-
omycins may be more precisely re-examined.
In conclusion, jadomycin A and related jadomycin aglycons
were synthesized from a common 2-aryl-1,4-naphthoquinone pre-
cursor by introducing an appropriate amino acid unit. Our syn-
thetic method could be applicable to the synthesis of other
jadomycin aglycons containing a different amino acid unit. In addi-
tion, we observed easy re-construction of 4-(hydroxymethyl)-1,3-
oxazolidin-5-one system to 1,3-oxazolidine-4-carboxylic acid one
in the synthetic trial of jadomycin S aglycon, suggesting the possi-
bility to revise the 4-(hydroxymethyl)-1,3-oxazolidin-5-one sys-
the NMR spectra of jadomycins in literatures6,17 and aglycons prepareda
Entry
Compounds
m
maxcmÀ1
dH
dC
Jadomycins
1.
B (
L
-isoleucine) (2)17
-valine)17
-alanine)17
1806
n.d.b
n.d.b
n.d.b
1804
n.d.b
n.d.b
6.31 (3aS)
6.72 (3aR)
6.30 (3aS)
6.77 (3aR)
6.39 (3aS)
6.80 (3aR)
6.20 (3aS)
6.50 (3aR)
6.08 (3aS)
5.93(3aR)
5.92 (3aS)
5.25 (3aR)
5.96 (3aS)
5.11 (3aR)
5.84 (3aR)
5.87 (3aR)
88.1
88.5
n.d.b
n.d.b
88.3
87.1
87.5
87.4
88.0
87.9
87.2
87.8
n.d.b
n.d.b
89.8
89.4
2.
3.
4.
5.
6.
7.
V (
L
ALA (
M (
F (
-phenylalanine)17
-tyrosine)6
-tryptophan)6
L
L
-methionine)6
L
Y (
L
W (
L
8.
9.
S (
T (
L
-serine)17
-threonine)17
1685
1690
tem in jadomycins S (or DS from D-serine) and T (or DT from D-
L
threonine) incorporating a hydroxy-containing amino acid to an
isomeric 1,3-oxazolidine-4-carboxylic acid system. At present fur-
ther synthetic approaches to natural jadomycin antibiotics carry-
ing L-digitoxose as a sugar unit is under investigation in our
laboratory.
Aglycons
10.
B (1)
1808
1801
1804
6.17 (major)
6.54 (minor)
6.19 (major)
6.62 (minor)
5.90 (major)
5.28 (minor)
5.96 (3aS)
87.1
88.1
87.3
87.4
87.1
88.0
89.0
89.4
11.
12.
M (4)
W (5)
13.
14.
Ester 25a
Ester 25b
1736
1748
Supplementary data
5.85 (3aR)
a
Supplementary data (experimental procedures and spectral
data for all new compounds) associated with this article can be
found, in the online version, at doi:10.1016/j.tetlet.2011.10.160.
The NMR and the IR data of jadomycins were measured in acetone-d6 and with
KBr, respectively, in Ref. 17, but no description in Ref. 6. On jadomycin A (1),
aglycons M 4 and W 5, and esters 25a and 25b prepared by us CDCl3 and ATR were
used in the NMR and the IR measurement, respectively.
b
No data cited.
References and notes
1. Ayer, S. W.; Mclnnes, A. G.; Thibault, P.; Walter, J. A.; Doull, J. L.; Parnell, T.;
Vining, L. C. Tetrahedron Lett. 1991, 32, 6301–6304.
2. Doull, J. L.; Ayer, S. W.; Singh, A. K.; Thibault, P. J. Antibiotics 1993, 46, 869–871.
3. Doull, J. L.; Singh, A. K.; Hoare, M.; Ayer, S. W. J. Ind. Microbiol. 1994, 13, 120–
125.
4. Syvitski, R. T.; Borissow, C. N.; Graham, C. L.; Jakeman, D. L. Org. Lett. 2006, 8,
697–700.
5. Kharel, M. K.; Zhu, L.; Liu, T.; Rohr, J. J. Am. Chem. Soc. 2007, 129, 3780–3781.
6. Borissou, C. N.; Graham, C. L.; Syvitski, R. T.; Reid, T. R.; Blay, J.; Jakeman, D. L.
Chem. Biol. Chem. 2007, 8, 1198–1203.
7. Cottreaw, K. M.; Spencer, C.; Wentzell, J. R.; Graham, C. L.; Borissou, C. N.;
Jakeman, D. L.; McFarland, S. A. Org. Lett. 2010, 12, 1172–1175.
8. Akagi, Y.; Yamada, S.-I.; Etomi, N.; Kumamto, T.; Nakanishi, W.; Ishikawa, T.
Tetrahedron Lett. 2010, 51, 1338–1340.
9. Konno, F.; Ishikwa, T.; Kawahata, M.; Yamaguchi, K. J. Org. Chem. 2006, 71,
9818–9823.
respectively. Precise examination of them using NMR spectra (NOE,
HMQC, HMBC) allowed us to deduce a major isomer 25a to be
methyl 1,3-oxazolidine-4-carboxylate with 3aS stereochemistry.
It has been reported that jadomycins S and T incorporating a hy-
droxy-containing amino acid show
a carbonyl absorption at
1685 cmÀ1 and 1690 cmÀ1
,
respectively, but not at around
1800 cmÀ1, in their IR spectra17 (entries 8 and 9, Table 1). Strong
hydrogen bond between the side chain hydroxy and the C13-car-
bonyl group, locking the oxazolidone ring into place, is proposed
for them based on molecular modeling experiments;17 however,
it may be difficult to clearly explain the lack of a characteristic
absorption at around 1800 cmÀ1 for an oxazolidone system in the
IR spectra even if the ring is fixed.
10. The protocol for the preparation of 9: Mohri, S.-I.; Stefinovic, M.; Snieckus, V. J.
Org. Chem. 1997, 62, 7072–7073.
Chemical shifts assignable to the C3a-H signals of natural jad-
omycins in the NMR spectra in literature6,17 and aglycons prepared
here are also summarized in Table 1. In the latter aglycons, esters
25a and 25b carrying a 1,3-oxazolidine-4-carboxylic acid system
(entries 13 and 14) showed slightly lower-field shifted signals in
the 13C NMR spectra compared to other aglycons carrying a 1,3-
oxazolidin-5-one system (entries 10–12), and showed slightly
higher-field shifted signals in the 1H NMR spectra compared to
other aglycons except an aglycon carrying an aromatic side chain
such as a tryptophan-inserted aglycon W 5 (entry 12).18 In the for-
mer jadomycin series, the same tendency19 was observed in jad-
omycins S and T (entries 8 and 9), possibly suggesting that these
hydroxy-containing amino acid-derived jadomycins have 1,3-oxa-
zolidine-4-carboxylic acid, but not 1,3-oxazolidin-5-one, system.
11. Lei, X.; Porco, J. A., Jr J. Am. Chem. Soc. 2006, 128, 14790–14791.
12. Wright, S. M.; Hageman, D. L.; MacClure, L. D. J. Org. Chem. 1994, 59, 6095–
6097.
13. (a) Shrestha-Dawadi, P. B.; Bittner, S.; Fridkin, M.; Rahimipour, S. Synthesis
1996, 1468–1472; (b) Katrizky, A. R.; Huang, L.; Sakhuja, R. Synthesis 2010,
2011–2016.
14. Shan, M.; Sharif, E. V.; O’Doherty, G. A. Angew. Chem., Int. Ed. 2010, 49, 9492–
9495.
15. A natural jadomycin A (1) had been isolated as a ca 10: 1 diastereomeric
mixture of the 3aS- and 3aR-isomers (see, Ref. 4).
16. Rapid and selective MOM-deprotection using a combination of ZnBr2 and
propanethiol had been reported by Ryu et al (Tetrahedron Lett. 2010, 66, 1673–
1677). Lower yields were obtained in the deprotection reactions either without
p-thiocresol (27%) or in the use of alternative additives (anisole: 24%, AcONa:
31%).
17. Rix, U.; Zheng, J.; Remsing Rix, L. L.; Greenwell, L.; Yang, K.; Rohr, J. J. Am. Chem.
Soc. 2004, 126, 4496–4497.
18. The presence of an aromatic ring in the C1-side chain of jadomycin skeletons
could cause anisotropic effect of the C3a–H signal in the 1H NMR spectra.
19. Jadomycins F, Y, and W (entries 5–7) are corresponding to the exceptional
cases of aromatic side chain-containing jadomycins in the 1H NMR spectra.
Furthermore, in jadomycin N (L-aspargine) a pyrimidone sys-
tem, not an oxazolidone one, resulting from more preferential
cyclization by the amide than the carboxylic acid functions, has
been formed.6,17 Although no positive results have been obtained