Convenient synthesis of the main tridehydropentapeptide skeleton for a macrocyclic antibiotic, sulfomycin I

Article abstract of DOI:10.1246/cl.2004.72

A convenient synthesis of the main tridehydropentapeptide skeleton [Fragment B-C derivative] of a thiostrepton-type macrocyclic antibiotic, sulfomycin I, was first achieved.

Full text of DOI:10.1246/cl.2004.72

72
Chemistry Letters Vol.33, No.1 (2004)
Convenient Synthesis of the Main Tridehydropentapeptide Skeleton
for a Macrocyclic Antibiotic, Sulfomycin I
Tetsuya Kayano, Yasuchika Yonezawa, and Chung-gi Shinꢀ
Laboratory of Organic Chemistry, Faculty of Engineering, Kanagawa University, Kanagawa-ku, Yokohama 221-8686
(Received October 9, 2003; CL-030956)
A convenient synthesis of the main tridehydropentapeptide
skeleton [Fragment B–C derivative] of a thiostrepton-type mac-
rocyclic antibiotic, sulfomycin I, was first achieved.
dipeptide,6 N-Boc-N,O-Ip-L-Thr-(Z,S)-ꢀApe(TPS)-OMe (9)
(TPS = t-butyldiphenylsilyl, ꢀApe = 2-amino-4-hydroxy-2-
pentenoic acid), the ester of which was hydrolyzed with 1 M
LiOH to give the hydrolyzate 10. The configuration of the ꢀApe
residue [ꢀ 4.57 (ꢁ-H), 6.48 (=CH–)] was confirmed to be (Z)-ge-
ometry.7 Secondly, coupling of 10 with H-L-Thr-OMe by using
BOP8 and (i-Pr)2NEt, followed by oxidation of the formed tri-
peptide 11 with Jones reagent gave the oxidized ꢀ2-dehydrotri-
peptide 12. Oxazolation9 of 12 with PPh3 and I2 in the presence
of Et3N gave the corresponding 5-methyloxazole-4-carboxylate
13, the ester of which was hydrolyzed with 1 M LiOH to give the
expected hydrolyzate 14, as shown in Scheme 1.
Thirdly, coupling of 14 with ethyl 2-(1-amino-2-hydroxy-
ethyl)thiazole-4-carboxylate (15)10 by the BOP method gave
the corresponding dehydrotripeptide 16. Conversion11 of the
CH2OH group of 16 to AcO group using Pb(OAc)4, followed
by methoxylation11 of the formed ꢂ-acetoxy derivative 17 with
Et3N in MeOH gave the expected Fragment B derivative 1812 as
a mixture of the diastreomeric isomers in a 1:1 ratio. Finally, es-
ter hydrolysis of 18 with 1 M LiOH gave the hydrolyzate 19, as
shown in Scheme 2.
On the other hand, to synthesize the precursor of Fragment C
29, at first, N-Cbz-N,O-Ip-L-Thr-OH (20) (Cbz = benzyloxycar-
bonyl) was coupled with H-L-Thr-OMe by using DCC to give
the dipeptide 21, the hydroxy group of which was dehydrated
with methanesulfonyl chloride (MsCl) in the presence of Et3N
and with DBU gave the expected (Z)-ꢀ2-dehydrodipeptide
22.13 Subsequent bromination7 of 22 with NBS, followed by ox-
azolation of the formed ꢃ-bromo derivative 23 with Cs2CO3
gave the protected 5-methyloxazole-4-carboxylate 24.14 Second-
ly, ester hydrolysis of 24 with 1 M LiOH gave the corresponding
hydrolyzate 25, which was coupled with H-L-Thr(TPS)-OMe by
using diphenyl phosphorazidate (DPPA) and Et3N to give the
corresponding dipeptide 26. Thirdly, consecutive deprotections
of the Ip group with trifluoroacetic acid (TFA) giving O-depro-
tected dipeptide 27, similarly the TPS group with 1 M tetrabuty-
An antibiotic sulfomycin I (1),1 isolated from the culture of
Streptomyces viridchromogenes MCRL-0368, has a unique mac-
rocyclic structure. The natural 1 features two substructures, the
main tridehydropentapeptide segment (2) called Fragment B–C
and the central heterocyclic skeleton (3) called Fragment A,
the former of which includes characteristic structures, a dehy-
drotripeptide skeleton [4, Fragment B] and a didehydro-dipep-
tide skeleton [5, Fragment C], as shown in Figure 1. So far, how-
ever, the geometry of the 3-hydroxy-1-butenyl group and the
configuration of the chiral center of the 2-[(1-amino-1-meth-
oxy)methyl]thiazole-4-carbonyl moiety in Fragment B have
not yet been identified.
Recently, we have already reported briefly a novel synthesis
of the 2,3,6-trisubstituted pyridine segment 3,2 which is the com-
mon structure of similar antibiotics, such as berninamycin A, B,3
and A10225 G, J.4 The interesting structure and bioactivity of 1
attracted our attention and prompted us to investigate its total
synthesis and structure-bioactivity relation-ship. Here, we wish
to report a convenient synthesis of the N,O-protected 2 [(P)-2]
from the two building blocks, the N,O-protected dehydrotripep-
tide 19 as the precursor of 4 [C-component] and the O-protected
dipeptide 29 as the precursor of 5 [N-component]. The final cou-
pling of the C-component with the N-component and then syn-
chronous dehydration of the two OH groups of the formed dehy-
dro-pentapeptide 30 was first achieved to give the desired (P)-2.
First of all, to synthesize the left-half segment of 4, coupling
of phosphorylglycine-OMe (6) with N-Boc-N,O-Ip-L-Thr-OH
(7) (Ip = isopropylidene) using DCC and N-hydroxybenzotri-
azole (HOBt) gave the corresponding dipeptide 8. Subsequently,
Hornor–Emmons reaction of 8 with (S)-2-[(O-TPS)hydroxy]-
propanal5 by using DBU afforded the expected ꢀ2-dehydro-
O
O
O
O
H
N
O
O
(EtO) P:O
2
iv)
H
ii)
i)
H
N
NH
2
N
N
N
H
N
Boc
OMe
N
Boc
OR
quant.
80%
Fragment A (3)
H
91%
(2 steps)
H N
2
COOMe
O
O
N
O
O
Fragment D
(EtO) P:O
2
N
O
6
O
OTPS
9: R=Me
10: R=H
S
N
NH
O
OH
2
8
iii) quant.
HN
HO
HO
HN
R
O
O
O
vi)
O
O
H
N
H
N
OH
HN
O
HN
OR
OMe
O
OH
O
N
Boc
N
H
88%
N
Boc
N
O
HN
N
HN
O
O
O
O
N
O
v)
13: R=Me
14: R=H
vii)
quant.
11: R= OH
12: R= =O
N
OTPS
OTPS
O
O
N
74%
HN
O
Fragment C (5)
NH
N
O
HN
NH
O
Scheme 1. Reagents and conditions: i) 7, DCC, HOBt/DMF, ii)
DBU, CH3-CH(OTPS)CHO/THF, iii) 1 M LiOH/dioxane:H2O,
iv) BOP, (i-Pr)2NEt, H-L-Thr-OMe/DMF, v) 2.67 M Jones
reagent/acetone, vi) I2, PPh3, Et3N/CHCl3, vii) 1 M LiOH/
dioxane:H2O.
N
MeO
Fragment B-C (2)
S
MeO
S
Fragment B (4)
Figure 1. Sulfomycin I (1).
Copyright Ó 2004 The Chemical Society of Japan

Chemistry Letters Vol.33, No.1 (2004)
73
i)
O
O
i)
O
S
S
O
O
H
14
H
N
O
H
N
H
N
H
N
H
19
N
OH
OEt
N
77%
OMe
OMe
O
N
Boc
N
Boc
N
N
N
N
N
N
N
O
O
O
OMe
30
O
O
O
O
O
O
O
OEt
15
OH
H N
2
OH
O
OH
S
OTPS
OTPS
O
76%
16
O
ii)
O
S
N
O
H
N
S
H
N
H
N
O
H
N
H
N
H
N
ii)
OR
70%
N
Boc
N
N
Boc
N
N
O
O
Y
O
OMe
O
iii) 31%
(2 steps, from 16)
17: Y=OAc, R=Et
18: Y=OMe, R=Et
19: Y=OMe, R=H
OTPS
OTPS
Protected Fragment B-C (2)
iv) quant
Scheme 4. Reagents and conditions: i) 29, BOP, (i-Pr)2NEt/
DMF ii) a) MsCl, Et3N/CHCl3, b) DBU/CHCl3.
Scheme 2. Reagents and conditions: i) BOP, (i-Pr)2NEt/DMF,
ii) Pb(OAc)4/EtOAc, iii) Et3N/MeOH, iv) 1 M LiOH/
dioxane:H2O.
Sports, Science and Technology.
References and Notes
O
O
O
O
i)
ii)
iv)
O
X
O
H
N
H
1
2
3
Y. Egawa, K. Umino, Y. Tamura, M. Shimizu, K. Kaneko, M.
Sakurazawa, S. Awataguchi, and T. Okuda, J. Antibiot., 22, 12 (1969).
K. Umemura, S. Ikeda, J. Yoshimura, K. Okumura, H. Saito, and C.
Shin, Chem. Lett., 1997, 1203.
a) J. M. Liesch and K. L. Rinehart, J. Am. Chem. Soc., 99, 1645 (1977).
b) H. Abe, K. Kushida, Y. Shiobara, and M. Kodama, Tetrahedron
Lett., 29, 1401 (1988).
OH
N
O
58%
(3 steps)
from 22
92%
OMe
N
Cbz
OMe
OH
N
Cbz
N
Cbz
N
Cbz
O
O
O
N
OR
O
20
21
vii)
22: X=H
23: X=Br
iii)
24: R=Me
25: R=H
v)
quant.
O
N
OH
vi)
quant.
viii) 77%
(2 steps)
from 26
O
N
O
N
27: X=Cbz, Y=TPS
28: X=Cbz, Y=H
29: X=H, Y=H
O
XHN
OMe
OTPS
O
H
N
H
N
4
a) L. D. Boeck, D. M. Berry, and R. W. Wetzel, J. Antibiot., 45, 1222
(1992). b) M. Debono, R. Molly, J. L. Occolowitz, J. W. Paschal, A. H.
Hunt, K. M. Michel, and J. M. Martin, J. Org. Chem., 45, 1809 (1992).
S. K. Massad, L. D. Hawkins, and D. C. Baker, J. Org. Chem., 48, 5180
(1983).
In this paper, the symbols ꢀ2, ꢀ2;3, and ꢀ2;4;5 indicate the position
number of double bond of ꢂ-dehydroamino acid (ꢀAA) and ꢀAA-
derived oxazole residues from N-terminus in sequence.
R. S. Coleman and A. J. Carpenter, J. Org. Chem., 58, 4452 (1993).
BOP = Benzotriazol-1-yloxy-tris(dimethylamino)phosphonium hexa-
fluorophosphate.
Cbz
OMe
OY
ix) quant.
O
O
26
5
6
Scheme 3. Reagents and conditions: i) DCC, HOBt, H-L-Thr-
OMe/DMF, ii) a) MsCl, Et3N/CHCl3, b) DBU/CHCl3, iii) a)
NBS/THF, b) Et3N/THF, iv) Cs2CO3/dioxane, v) 1 M LiOH/
dioxane:H2O, vi) DPPA, Et3N, H-L-Ser-(OTPS)OMe/DMF,
vii) TFA/CHCl3, viii) 1 M TBAF/THF, ix) 10%Pd-C, H2/
MeOH.
7
8
9
P. Wipf and C. P. Miller, J. Org. Chem., 58, 3604 (1993).
lammonium fluoride (TBAF) to the O,O-free derivative 28 and
then the Cbz group with 10% Pd–C/H2 gave the precursor of
the right-half dipeptide 29 of 2, as shown in Scheme 3. Without
isolation, the obtained 29 was used intact for the next reaction.
Finally, fragment condensation between 19 and 29 by the
BOP method was tried successfully to give the N,O-protected
dehydropentapeptide 30, the two hydroxy groups of which were
then dehydrated simultaneously, similarly to the case of 22, to
give the expected (2Z,4Z)-ꢀ2,4,5-tridehydropentapeptide (P)-
26,15 [70% yield. MALDI–TOFMS Found: m=z 1217.94 (M +
Ag)þ. Calcd for C55H68N8O13SSi 1217.19 (M + Ag)þ] as the
precursor of Fragment B–C, as shown in Scheme 4.
The structure of all new products thus obtained were con-
firmed by the 1H NMR spectral data and the satisfactory results
of the elemental analyses. In particular, from the 1H NMR spec-
trum of 2, the new appearance of the chemical shifts of two pro-
tons of the vinyl group at ꢀ ¼ 5:78 (s) and ꢀ ¼ 6:39{6:45 (m)
and that of the olefinic proton of the 2-propenyl group at
ꢀ ¼ 6:58{6:60 (m) supports the formation of Fragment B–C
(P)-2.
In conclusion, it is important that the synthesis of the main
Fragment B–C skeleton of 1 was readily achieved by fragment
condensation between Fragment B and C. Consequently, the fi-
nal macrocyclization position in the total synthesis of 1 could be
definitely specified.
This work was supported in part by Grant-in Aid for Scien-
tific Research No. 14550829 from the Ministry of Education,
Culture, Sports, Science and Technology and by ‘‘High-Tech
Research Project’’ from the Ministry of Education, Culture,
10 Compound 15 was derived by deprotection of Ip and Boc groups
of ethyl (S)-2-(3-t-butoxycarbonyl-2,2-dimethyloxazolidin-4-yl)thia-
zole-4-carboxylate [ C. Shin, A. Okabe, A. Ito, A. Ito, and Y.
Yonezawa, Bull. Chem. Soc. Jpn., 75, 1583 (2002)].
11 G. Apitz, M. Jager, S. Jaroch, M. Kratzel, L. Scaffeler, and W.
Steglich, Tetrahedron, 36, 8223 (1993).
12 18: Colorless syrup. Diastereomer (1:1). [ꢂ]D ꢁ64:7ꢂ (c 0.94,
26
CHCl3). 1H NMR (DMSO-d6) ꢀ 1.02 (s, 9H, TPS’s t-Bu), 1.16–1.19
(m, 3H, CH3CH(OTPS)), 1.25–1.27 (m, 3H, CH3CH2), 1.28–1.32
(m, 12H, Boc’s t-Bu, Thr’s CH3), 1.41, 1.48 (each s, 6H, Ip’s CH3ꢃ2),
2.59 (s, 3H, oxazole’s CH3), 3.48 (s, 3H, OCH3), 3.80–3.84 (m, 1H,
Thr’s ꢃ-H), 3.89–3.90 (m, 1H, Thr’s ꢂ-H), 4.27–4.32 (m, 2H,
CH2CH3), 4.93 (m, 1H, CH3CH(O-TPS)), 6.38–6.42 (m, 2H, olefin’s
H, NHCHOCH3), 7.33–7.44 and 7.59–7.63 (each m, 10H, TPS’s Ph
ꢃ 2), 8.21 (br s, 1H, NHCHOCH3), 9.11 (br s, 1H, NH), 8.49 (s, 1H,
thiazole’s ring-H), 9.11 (br s, 1H, NH). MALDI–TOFMS Found:
m=z 998.48 (M + Ag)þ. Calcd for C45H59N5O10SSi: 997.99 (M +
Ag)þ.
13 C. Shin, Y. Yonezawa, T. Yamada, and J. Yoshimura, Bull. Chem. Soc.
Jpn., 55, 2147 (1982).
14 a) H. Saito, T. Yamada, K. Okumura, Y. Yonezawa, and C. Shin,
Chem. Lett., 2002, 1098. b) J. Das, J. A. Reid, D. R. Kronenthal, J.
Singh, P. Pansegrau, and R. H. Mueller, Tetrahedron Lett., 33, 7835
(1992).
15 (P)-2: Colorless syrup. Diastereomer (1:1). [ꢂ]D ꢁ11:9ꢂ (c 0.36,
26
CHCl3). 1H NMR (DMSO-d6) ꢀ 1.01 (s, 9H, TPS’s t-Bu), 1.13–1.17
(m, 3H, Thr’s CH3), 1.21–1.24 (m, 3H, CH3CH-(OTPS)), 1.30 (s,
9H, Boc’s t-Bu), 1.39 and 1.47 (each s, 6H, Ip’s CH3 ꢃ 2), 1.75–
1.79 (m, 3H, CH3CH=C), 2.54, 2.55, 2.57, and 2.58 (each s, 6H, ox-
azole’s ring CH3 ꢃ 2), 3.49, 3.50 (each s, 3H, OCH3), 3.73–3.77 (m,
4H, Thr’s ꢃ-H, COOCH3), 3.88 (br s, 1H, Thr’s ꢂ-H), 4.89 (m, 1H,
CH3CH(OTPS)), 5.78 (CHH=C), 6.39–6.45 (m, 3H, olefin’s H,
NHCH, CHH=C), 6.58–6.60 (m, 1H, CH3CH=C), 7.33–7.38 and
7.57–7.62 (each m, 10H, TPS’s Ph ꢃ 2), 8.41–8.47 (m, 2H, thiazole’s
ring-H, NHCH), 9.15, 9.26, and 9.60 (each br s, 3H, NH).
Published on the web (Advance View) December 20, 2003; DOI 10.1246/cl.2004.72