Useful synthesis of fragment A-C-D of a thiostrepton-type macrocyclic antibiotic, thiocilline I

Article abstract of DOI:10.1246/cl.2004.814

Useful synthesis of the main Fragment A-C-D segment constructing a thiostrepton-type macrocyclic antibiotic, thiocilline I, was first achieved by coupling of the 2,3,6-polythiazole-substituted pyridine skeleton (Fragment A-C) with Fragment D.

Full text of DOI:10.1246/cl.2004.814

814
Chemistry Letters Vol.33, No.7 (2004)
Useful Synthesis of Fragment A–C–D of a Thiostrepton-type
Macrocyclic Antibiotic, Thiocilline I
Shuusuke Suzuki, Yasuchika Yonezawa, and Chung-gi Shinꢀ
Laboratory of Organic Chemistry, Faculty of Engineering, Kanagawa University, Kanagawa-ku, Yokohama 221-8686
(Received April 1, 2004; CL-040354)
Useful synthesis of the main Fragment A–C–D segment
OH
OH
constructing a thiostrepton-type macrocyclic antibiotic, thiocil-
line I, was first achieved by coupling of the 2,3,6-polythiazole-
substituted pyridine skeleton (Fragment A–C) with Fragment D.
OTPS
S
S
N
ii)
S
BocHN
H
BocHN
NH
2
OR
N
H N
2
N
70%
NH
2
S
O
O
OTPS
2 : R=Et
3 : R=H
4
5
i)
R
N
Thiocilline I (1),1 isolated from the culture of Bucillus bodi-
us, is a unique macrocyclic antibiotic structurally very similar to
micrococcins P and P1,2 which comprise a (2S)-2-(1-amino-2-
methyl)propylthiazole-4-carbonyl moiety as the Fragment C.
On the other hand, in place of the above Val-derived thiazole
moiety, the natural 1 is also composed of a (2S)-2-(1-amino-2-
hydroxy-2-methyl)propylthiazole-4-carbonyl moiety (Fragment
C), derived from a D-hydroxyvaline (HyVal),3 as shown in Fig-
ure 1. Recently, the total synthesis of micrococcins has been re-
ported.4–6 Similarly to the above cases, the interesting structure
as well as the bioactivity of 1 attracted us to investigate its syn-
thesis and structure-bioactivity relationship. Herein, we wish to
report a useful synthesis of the Fragment A–C–D segment 22,
which is the most important skeleton for the total synthesis of 1.
HS
H2N
S
EtOOC
S
N
N
N
OPac
O
N
EtO
S
O
iii)
72%
S
9
O
v)
5
OMe
OMe
OTPS
10
N
HN
O
9% (3 steps)
Br
N
6
BocHN
S
OH
7 : R=CH(OCH )
3 2
iv)
8 : R=CHO
Scheme 1. Reagents and conditions: i) 1 M LiOH/MeOH, ii)
BOP, DIPEA/DMF, iii) a) KHCO3/DME, b) TFAA, pyridine/
DME, c) 28% aq. NH3, iv) 2 M HCl/THF, v) a) 9, Et3N/toluene,
b) MnO2/toluene.
be investigated further. That is, to carry out the reaction by the
Hantzsch method, in place of 8, another substrate 6-thiocarbox-
amide derivative 17 and Pac 2-(bromoacetyl)thiazole-4-carbox-
ylate (14) were synthesized as follows.
To synthesize 14, ꢀ-elimination of Pac 2-[1-(N-Boc)amino-
2-hydroxyethyl]thiazole-4-carboxylate (11), derived by thiazo-
lation of Boc-L-Ser-(S)NH2 with BrCH2COCOOPac by the usu-
al Hantzsch method, with methanesulfonyl chloride (Ms-Cl) in
the presence of Et3N and DBU gave the corresponding vinylthia-
zole derivative 12. Then, bromination with NBS in MeOH gave
2-[1-(N-Boc)amino-1-methoxy-2-bromoethyl]thiazole deriva-
tive 13, which was immediately treated with CF3COOH (TFA)
and H2O to give the expected 14, as shown in Scheme 2.
S
Fragment A
S
S
S
N
N
S
N
N
N
N
O
N
S
N
N
O
N
S
OPac
HN
HN
EtO
Fragment D
O
S
O
OH
O
OTPS
HO
O
HN
HN
N
HN
O
O
NH
S
N
N
H
N
OH
Fragment C (2)
BocHN
S
S
Fragment B
O
10
OH
OH
Figure 1. Thiocilline I (1).
First of all, to synthesize the Fragment A–C segment 10 as
the main structure of 1, ester hydrolysis of the HyVal-derived
N,O-diprotected Fragment C 23b with 1 M LiOH, followed by
coupling of the formed hydrolyzate 3 with L-Thr(TPS)-(S)NH2
(4)7 (TPS = t-butyldiphenylsilyl) using BOP and (i-Pr)2NEt
(DIPEA) gave the dipeptide thiocarboxamide drivative 5.
Thiazolation of 5 with the authentic 2-bromoacetyl-3-[(4-eth-
oxycarbonyl)thiazol-2-yl]-6-dimethoxymethylpyridine (6)4,5 us-
ing KHCO3 and (CF3CO)2O (TFAA) in the presence of pyri-
dine, and then 28% aq. NH3 by the Hantzsch method gave the
precursor of the Fragment A–C structure 7. After conversion
of 6-acetal of 7 to the formyl group with 2 M HCl, the obtained
6-formyl derivative 8 was coupled intact with phenacyl (Pac)
(R)-2-(1-amino-2-mercaptoethyl)thiazole-4-carboxylate (9) to
give 10 by the Shioiri method,8 as shown in Scheme 1. However,
the yield of 10 was very low (only 9% yield in 3 steps from 7),
because of a mass of material decomposed.
O
O
OH
N
ii)
i)
N
S
OPac
OPac
OPac
BocHN
BocHN
50%
90%
S
12
11
O
O
Br
O
Br
iii)
OMe
N
N
S
OPac
90%
BocHN
S
13
14
Scheme 2. Reagents and conditions: i) a) Ms-Cl, Et3N/CHCl3,
b) DBU/CHCl3, ii) a) NBS/THF, b) MeOH, iii) a) TFA, b)
NaHCO3, H2O.
On the other hand, the 6-formyl group of 8 was oxidized
with 2.67 M Jones reagent to give the corresponding 6-carboxy-
pyridine derivative 15, the carboxy group of which was amidated
with ClCOOEt in the presence of Et3N and with 28% NH3 to
give the carboxamide derivative 16. Subsequent thioamidation
Accordingly, an alternative synthetic method for 10 needs to
Copyright Ó 2004 The Chemical Society of Japan

Chemistry Letters Vol.33, No.7 (2004)
815
result, in the case using Ms-Cl (1.30 equiv.) in pyridine (0.73
equiv.) as a solvent at 0 ꢁC for 15 min, firstly, only the secondary
alcohol was selectively protected with the Ms group to give the
corresponding mesyloxy derivative, Boc-HyVal-Thr(Ms)-OMe,
in 90% yield. Secondly, the O-Ms group was ꢀ-eliminated with
DBU in CHCl3 to give the expected Boc-HyVal-ꢀAbu-OMe
(ꢀAbu = 2-amino-2-butenoic acid residue) in 90% yield. Ac-
cordingly, similarly to the above case, the selective ꢀ-elimina-
tion of 21 with Ms-Cl in pyridine and then with DBU was tried
successfully to give only the desired 2211 in 88% yield.
S
R
N
N
S
N
N
S
S
N
N
O
N
N
RO
EtO
EtO
i)
iv)
S
S
O
O
8
OTPS
OTPS
quant
80%
HN
N
HN
N
O
O
BocHN
BocHN
S
S
OH
15:R=COOH
16:R=CONH2 (88%)
17:R=CSNH (85%)
OH
10:R=Pac (80%)
18:R=H (97%)
ii)
iii)
It is believed that the success of the selective ꢀ-elimination
of 21 can be best appreciated for the first total synthesis of 1.
v)
2
Scheme 3. Reagents and conditions: i) 2.67 M Jones reagent/
acetone, ii) a) ClCOOEt, Et3N/THF, b) 28% aq. NH3/THF,
iii) Lawesson’s reagent/DME, iv) a) 14, KHCO3/DME, b)
TFAA, pyridine/DME, c) 28% aq. NH3, v) 1 M LiOH/THF.
This work was supported in part by Grant-in Aid for Scien-
tific Reaserch No. 14550829 from the Ministry of Education,
Culture, Sports, Science and Technology and by ‘‘High-Tech
Research Project’’ from the Ministry of Education, Culture,
Sports, Science and Technology.
with Lawesson’s reagent gave the corresponding thiocarboxa-
mide 17. Consequently, the required thiazolation of 17 with 14
by the Hantzsch method gave 1010 in 80% yield. The Pac ester
was hydrolyzed with 1 M LiOH to give 6-bisthiazole-4-carbox-
ylic acid derivative 18, as shown in Scheme 3.
References and Notes
1
J. Shoji, T. Kato, Y. Yoshimura, and K. Tori, J. Antibiot., 34,
1126 (1981).
2
a) P. Brooks, A. T. Fuller, and J. Walker, J. Chem. Soc., 1959,
689. b) J. Walker, A. Olesker, L. Valente, R. Rabanal, and G.
Lukacs, J. Chem. Soc., Chem. Commun., 1977, 706. c) B. W.
Bycroft and M. S. Gowland, J. Chem. Soc., Chem. Commun.,
1978, 256.
Furthermore, fragment condensation of 18 with (2S,3R)-2-
amino-3-(O-TBS)hydroxy-N-[(S)-2-acetoxypropyl]butanamide
(19)9 by the BOP method was performed to give the precursor of
Fragment A–C–D segment 20. Selective deprotection of the TBS
group of the Thr residue with 70% AcOH, followed by ꢀ-elim-
ination of the deprotected intermediate 21 using Ms-Cl and Et3N
and then DBU in CHCl3 gave the protected Fragment A–C–D
derivative 22, similarly to the case of 12. At that time, however,
besides 22 (56%), undesirable compound 23 (18%), the tertiary
alcohol of 21 also dehydrated, was formed. Accordingly, to ex-
amine what procedure produces the selective ꢀ-elimination of
only the secondary alcohol of 21, the substrate Boc-HyVal-
Thr-OMe was independently prepared and then subjected to
the ꢀ-elimination under various experimental conditions. As a
3
a) Y. Yonezawa, K. Shimizu, K. Yoon, and C. Shin, Synthesis,
2000, 634. b) Y. Yonezawa, H. Saito, S. Suzuki, and C. Shin,
Heterocycles, 57, 903 (2002).
4
5
C. Shin, K. Okumura, M. Shigekuni, and Y. Nakamura, Chem.
Lett., 1998, 139.
K. Okumura, A. Ito, D. Yoshioka, and C. Shin, Heterocycles,
48, 1319 (1998).
6
7
M. A. Ciufolini and Y.-C. Shen, Org. Lett., 1, 1843 (2000).
The compound 4 was derived from the corresponding carbox-
amide and Lawesson’s reagent by the usual method.
Y. Hamada, M. Shibata, T. Sugiura, S. Kata, and T. Shioiri,
J. Org. Chem., 52, 1252 (1987).
8
9
S
N
N
K. Okumura, T. Suzuki, Y. Nakamura, and C. Shin, Bull.
Chem. Soc. Jpn., 72, 2483 (1999).
S
S
N
N
OTBS
H
O
OAc
10 10: Colorless powder. mp 112–115 ꢁC. [ꢁ]D +18.4ꢁ (c 0.98,
CHCl3).
11 22: Pale yellow powder. mp 119–122 ꢁC. IR (KBr) 3400, 2930,
27
N
HN
N
H N
2
EtO
O
S
O
OTPS NH
OR
19
i)
O
iii)
18
HN
N
83%
O
27
2856, 1717, 1670, 1531, 1473, 1241 cmꢂ1. [ꢁ]D +17.1ꢁ
OAc
(c 0.28, CHCl3). 1H NMR (CDCl3) ꢂ ¼ 0:95 (d, 3H,
CH(OTPS)CH3, J ¼ 6:6 Hz), 1.02 (s, 9H, TPS’s t-Bu), 1.24,
1.33 (each s, 6H, C(OH)(CH3)2), 1.27 (d, 3H, CH(OAc)CH3,
J ¼ 6:6 Hz), 1.37 (t, 3H, Et’s CH3, J ¼ 7:2 Hz), 1.45 (s, 9H,
Boc’s t-Bu), 1.87 (d, 3H, ꢀAbu’s CH3, J ¼ 6:6 Hz), 2.02 (s,
3H, Ac’s CH3), 2.76 (br s, 1H, OH), 3.42–3.70 (m, 2H,
CH2CH(OAc)), 4.38 (q, 2H, Et’s CH2, J ¼ 7:2 Hz), 4.51 (br
d, 1H, CH(OTPS)CH3, J ¼ 6:6 Hz), 4.94 (br d, 1H,
BocNHCH, J ¼ 9:0 Hz), 5.03–5.06 (m, 1H, CH(OAc)CH3),
5.35 (br d, 1H, CHCH(OTPS)-CH3, J ¼ 9:0 Hz), 5.63 (br d,
1H, BocNH, J ¼ 9:0 Hz), 6.57 (q, 1H, NHCH2OAc, J ¼
6:6 Hz), 6.65 (q, 1H, ꢀAbu’s CH, J ¼ 6:6 Hz), 7.22–7.62
(m, 10H, TPS’s Ph ꢃ 2), 7.91, 8.01, 8.14, 8.22, 8.25 (each s,
5H, thiazole’s H ꢃ 5), 8.2l, 8.71 (each br s, 2H, CONH ꢃ
2), 8.36, 8.38 (each d, 2H, pyridine’s HH ꢃ 2, J ¼ 8:4 Hz).
Anal. Calcd for C62H70N10S5Si: C, 56.44; H, 5.35; N,
10.61%. Found: C, 55.99; H, 5.50; N, 10.20%.
20:R=TBS
21:R=H (60%)
BocHN
S
ii)
S
OH
S
N
N
N
N
S
S
S
N
N
S
N
N
O
O
N
HN
N
HN
O
EtO
EtO
S
O
OTPS NH
S
+
O
O
OTPS NH
O
HN
N
HN
N
O
OAc
OAc
BocHN
BocHN
S
S
OH
22 (56%)
22 (88%)
iv)
23 (18%)
Scheme 4. Reagents and conditions: i) 19, BOP, DIPEA/DMF,
ii) 70% AcOH/THF, iii) a) Ms-Cl/Et3N, b) DBU/CHCl3, iv) a)
Ms-Cl, pyridine, b) DBU/CHCl3.
Published on the web (Advance View) June 7, 2004; DOI 10.1246/cl.2004.814