Useful synthesis of the main dehydrohexapeptide segment of a macrocyclic antibiotic, berninamycin B

Article abstract of DOI:10.1246/cl.2001.102

The useful synthesis of tetradehydrohexapeptide segment 2, which is the main skeleton of a macrocyclic antibiotic, berninamycin B, was first achieved. The skeleton 2 is constructed, in turn, of 2-[(Z)-1-amino-1-propenyl]-5-methyl-oxazole-4-carboxylic acid, α-dehydroalanine (ΔAla), L-Val, 2-[1-amino-1-ethenyl]-5-methyloxazole-4-carboxylic acid residues, besides L-Thr and ΔAla at the N- and C-termini, respectively.

Full text of DOI:10.1246/cl.2001.102

102
Chemistry Letters 2001
Useful Synthesis of the Main Dehydrohexapeptide Segment of
a Macrocyclic Antibiotic, Berninamycin B
Takahiro Yamada, Kazuo Okumura, Yasuchika Yonezawa, and Chung-gi Shin*
Laboratory of Organic Chemistry, Faculty of Technology, Kanagawa University, Kanagawa-ku, Yokohama 221-8686
(Received October 26, 2000; CL-000977)
caboxylic acid (6) 3 as the C-component by using BOP6 as a con-
densing agent and (i-Pr)2NEt gave the corresponding dehydrote-
trapeptide methyl ester 7 containing Ser(TBS) residue.
Deprotection of TBS group with 1 M tetrabutylammonium fluo-
ride (TBAF) gave the expected 2-{N-Cbz-N,O-Ip-L-Thr-[(Z)-1-
amino-1-propenyl]}-5-methyloxazole-4-carbonyl-L-Ser-L-Val-
OMe (8).7 Ester hydrolysis of 8 with 1 M LiOH gave the corre-
sponding Fragment B derivative 9, which was immediately sub-
jected to the later condensation, without purification, as shown in
Scheme 1.
The useful synthesis of tetradehydrohexapeptide segment
2, which is the main skeleton of a macrocyclic antibiotic, berni-
namycin B, was first achieved. The skeleton 2 is constructed,
in turn, of 2-[(Z)-1-amino-1-propenyl]-5-methyl-oxazole-4-car-
boxylic acid, α-dehydroalanine (∆Ala), L-Val, 2-[1-amino-1-
ethenyl]-5-methyloxazole-4-carboxylic acid residues, besides
L-Thr and ∆Ala at the N- and C-termini, respectively.
Antibiotic berninamycin B (1),1,2 isolated from the culture
of Streptomyces bernensis, is a unique macrocyclic polyoxazole
dehydropeptide. The natural product (1) features two interest-
ing substructures, the main dehydrohexapeptide segment 2
called the Fragment B-C and the central heterocyclic skeleton 3
called the Fragment A, the former of which contains three vinyl
and one 1-propenyl functional groups, as shown in Figure 1.
Recently, we have reported briefly on the novel syntheses of
partial Fragment B3 and pyridine skeleton (3),4 the latter of which
is the common structure of similar antibiotics A10255 G and J.5
The attractive structure as well as the bioactivity of 1 prompted
us to study the total synthesis and the structure–bioactivity rela-
tionship.
Herein, we wish to report convenient synthesis of 2 from the
two building blocks, the N,O-protected dehydrotetrapeptide 9
[carboxy (C-) component] and the N,O-protected dipeptide 18
[amine (N-) component]. Furthermore, final fragment condensa-
tion between the C- and N-components and then stepwise β-elim-
ination of the three OH groups of the Ser residue were first
achieved to give the desired N,O-protected tetradehydrohexapep-
tide 2 [(P)-2].
At first, to synthesize 9, N-benzyloxycarbonyl(Cbz)-Ser-
OMe was protected with t-butyldimethylsilyl chloride (TBSCl) to
give the corresponding Ser(TBS) derivative 4. Ester hydrolysis
with 1 M LiOH in dioxane, followed by coupling with L-Val-
OMe gave Cbz-Ser(TBS)-L-Val-OMe (5) in two steps.
Subsequently, after deprotecting the Cbz group of 5 with 10%
Pd-C, fragment condensation with 2-{N-Cbz-N,O-isopropyli-
dene(Ip)-L-Thr-[(Z)-1-amino-1-propenyl]}-5-methyloxazole-4-
On the other hand, to synthesize the precursor of Fragment
C derivative 18, coupling of N-Cbz-N,O-Ip-L-Ser-OH (10),
derived from L-Ser for 4 steps, with L-Thr(TBS)-OMe by using
DCC and HOBt, followed by deprotection of the TBS group
with 1 M TBAF gave the corresponding Ser-Thr-OMe (11).
Intramolecular cyclization of 11 by the oxidations with Jones
reagent and then with PPh3 and I2 proceeded to give the corre-
sponding 5-methyloxazole-4-carboxylate 13 via unstable α-
acetyldipeptide intermediate 12. Subsequently, firstly, ester
hydrolysis of 13 with 1 M LiOH, followed by elongation of the
obtained carboxylic acid 14 with H-Ser(TPS)-OMe (TPS = t-
butyldiphenylsilyl) by using diphenylphosphoryl azide (DPPA)
in the presence of Et3N gave the corresponding 5-methyloxa-
zole-4-carbonyl-Ser(TPS)-OMe 15. Secondarily, selective
cleavage of the Ip group of 15 with trifluoroacetic acid (TFA)
gave 2-(1-amino-2-hydroxy)ethyl-5-methyloxazole derivative
16, the OH group of which was protected with triethylsilyl
chloride (TESCl) to give 2-[1-N-(Cbz)amino-2-O-
(TES)hydroxy]ethyl-5-methyloxazole derivative 17.8 Finally,
hydrogenolysis of Cbz group of 17 gave the expected N-depro-
tected dipeptide 18 as the precursor of the N-component of 2, as
shown in Scheme 2.
Copyright © 2001 The Chemical Society of Japan

Chemistry Letters 2001
103
The central Ser residue was converted to α-dehydroalanine
(∆Ala) by successive mesylation with MsCl and β-elimination
with DBU to give didehydrohexapeptide 20 by the method
reported earlier.9 After selective deprotection of the TES group
with 70% AcOH, the OH group of the formed 21 was further
mesylated and then β-eliminated to give the corresponding tride-
hydrohexapeptide 22. Finally, similarly to the case of 21, depro-
tection of TPS group of 22 with TBAF gave tridehydrohexapep-
tide 23, followed by β-elimination gave the expected main skele-
tal tetradehydrohexapeptide 2,10 as shown in Scheme 3.
The structures of all the new products thus obtained were
1
confirmed by the H NMR spectral data and the satisfactory
1
results of the elemental analyses. In particular, from the H
NMR spectrum of 2, the chemical shifts of six protons of the
three vinyl group at δ = 5.45, 5.77, 5.95, 6.45, 6.56 and 6.69
ppm and that of olefinic proton of the propenyl group at δ =
6.56 ppm were found to be very similar to those of the natural
berninamycin B (1).
In conclusion, a convenient synthesis of the main tetrade-
hydrohexapeptide segment 2 of 1 was first accomplished. By
using this result, further investigation on the total synthesis of 1
is currently under way in our laboratory.
This work was supported in part by a Grant-in-Aid for
Scientific Research Nos. 10640532 and 12640529 from the
Ministry of Education, Science, Sports, and Culture.
Furthermore, coupling of 9 with 18 by the BOP method
gave the expected O-TES protected dehydrohexapeptide 19,
which was then subjected to the simultaneous β-elimination of
the three hydroxy groups. At present, however, the satisfactory
results have not been obtained yet. Therefore, the stepwise
elimination was tried successfully to give the expected 2 as fol-
lows.
References and Notes
1
2
J. M. Liesch and K. L. Rinehart, J. Am. Chem. Soc., 99, 1645(1977).
H. Abe, K. Kushida, Y. Shiobara, and M. Kodama, Tetrahedron
Lett., 29, 1401 (1988).
3
4
C. Shin, Y. Nakamura, and K. Okumura, Chem. Lett., 1993, 1405.
K. Umemura, S. Ikeda, J. Yoshimura, K. Okumura, H. Saito, and C.
Shin, Chem. Lett., 1997, 1203.
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).
5
6
BOP: Benzotriazol-1-yloxy-tris(dimethylamino)phosphonium hexa-
fluorophosphate.
1
7
8: Colorless syrup. [α]D27 +4.45° (c 1.03, MeOH). H NMR(CDCl3)
δ = 0.88, 0.90(each d, 6H, Val's CH3 × 2, J = 8.5, 9.0 Hz), 1.51(d,
3H, Thr's CH3, J = 6.0 Hz), 1.56–1.85(m, 9H, Ip and propenyl's
CH3), 2.18(m, 1H, Val's β-H), 2.60(s, 3H, oxazole's CH3), 3.47(s,
3H, OCH3), 4.05(d, 1H, Thr's α-H, J = 6.0 Hz), 4.14(m, 1H, Ser's
α-H), 4.35(m, 1H, Thr's β-H), 4.50(d, 1H, Val's α-H, J = 8.5 Hz),
4.60(m, 1H, Ser's α-H), 5.13(m, 2H, Cbz's CH2), 6.50(br s, 1H,
propenyl's H), 7.19–7.27(m, 6H, Cbz's Ph and NH), 7.48(br s, 1H,
NH), 7.78(br d, 1H, NH, J = 6.0 Hz).
8
9
17: Colorless syrup. [α]D2 7 –21.6° (c 1.10, MeOH). 1H NMR δ =
0.58(q, 6H, TES's CH2, J = 8.0 Hz), 0.89(t, 9H, TES's CH3, J = 8.0
Hz), 1.04(s, 9H, TPS's t-Bu), 3.60(s, 3H, oxazole's CH3), 3.76(s,
3H, OCH3), 4.01(m, 2H, Ser's β-H), 4.04(m, 1H, Ser's α -H),
4.79(m, 2H, Ser's β-H), 4.99(m, 1H, Ser's α-H), 5.15(ABq, 2H,
Cbz's CH2, J = 12.3 Hz), 5.63(br s, 1H, NH), 7.31–7.62(m, 15H,
Cbz's Ph and TPS's Ph × 2), 7.73(m, 1H, NH, J = 6.0 Hz).
C. Shin, K. Okumura, A. Ito, and Y. Nakamura, Chem. Lett., 1994,
1301.
10 2: Colorless amorphous material. [α]D26 –21.7° (c 0.94, CHCl3).1H
NMR δ = 1.06, 1.09(each d, 6H, Val's CH3 × 2, J = 6.5, 7.0 Hz),
1.52(d, 3H, Thr's CH3, J = 6.0 Hz), 1.60–1.75(m, 9H, Ip and
propenyl's CH3), 2.30(m, 1H, Val's β-H), 2.61, 2.70(each s, 6H,
oxazole's CH3 × 2), 3.88(s, 3H, OCH3), 4.02(d, 1H, Thr's α-H, J =
7.5 Hz), 4.37(m, 1H, Thr's β-H), 4.54, 4.55(each d, 1H, Val's α-H, J
= 6.5, 7.5 Hz), 5.15(m, 2H, Cbz's CH2), 5.45, 5.77, 5.95, 6.45, 6.56,
6.69(each s, 6H, vinyl's H), 6.56(br s, 1H, propenyl's H), 6.89(m,
1H, NH), 7.05–7.47(br s, 6H, Cbz's Ph and NH), 8.18(s, 1H, NH),
9.15(s, 1H, NH), 9.29(br s, 1H, NH).