Convenient synthesis of the main dehydrohexapeptide skeleton constituting a macrocyclic antibiotic, berninamycin A

Article abstract of DOI:10.1246/cl.2002.1098

The first convenient synthesis of the main dehydrohexapeptide segment of a macrocyclic antibiotic, berninamycin A, containing a 3-hydroxy-L-valine residue and having three vinyl groups and a 1-propenyl group, was accomplished.

Full text of DOI:10.1246/cl.2002.1098

1098
ChemistryLetters 2002
Convenient Synthesis of the Main Dehydrohexapeptide Skeleton
Constituting a Macrocyclic Antibiotic, Berninamycin A
Hirohumi Saito, Takahiro Yamada, Kazuo Okumura, Yasuchika Yonezawa, and Chung-gi Shinꢀ
Laboratory of Organic Chemistry, Faculty of Engineering, Kanagawa University, Kanagawa-ku, Yokohama 221-8686
(Received February18, 2002; CL-020154)
The first convenient synthesis of the main dehydrohexapep-
coupling with the protected 4. First, the starting N; O-isopropy-
lidene (Isop)-N-Cbz-5-methyloxazole-4-carboxylate 7 (Cbz =
benzyloxycarbonyl) was synthesized by oxazolation of the
protected Ser-ÁAbu(ꢀ-Br)-OMe 6,9 derived from N; O-Isop-N-
Cbz-L-Ser-ÁAbu-OMe 5 (Abu = 2-amino-2-butenoic acid) and
N-bromosuccinimide (NBS), with Cs2CO3.10 Subsequently,
N; O-deprotection of the Isop group of 7 with trifluoroacetic acid
(TFA) and then protection of the hydroxy group with tert-
butyldiphenylsilyl chloride (TPS-Cl) in the presence of imidazole
gave methyl 2-[1-(Cbz)amino-2-(O-TPS)]ethyl-5-methyloxa-
zole-4-carboxylate (8).11 N-Deprotection of the Cbz group of 8
with 10% Pd/C, followed bycoupling with tert-butoxycarbonyl
(Boc)-L-HyVal-OH by using BOP12 and (i-Pr)2NEt gave the
corresponding dipeptide 9. The Boc group of 9 was also
deprotected with TFA and then further coupled with N; O-Isop-
N-Cbz-Ser-OH by the mixed anhydride method using pivaloyl
chloride (Piv-Cl) and Et3N to give the protected Ser-L-HyVal-5-
methyloxazole derivative 10. Next, ester hydrolysis of 10 with
1 M LiOH, followed bystepwise elongation with H- L-Ser(TPS)-
OMe bythe BOP method gave the corresponding tetrapeptide 11,
the Isop group of which was deprotected byusing TFA and then
the formed primaryalcohol was in situ protected with tert-
butyldimethylsilyl chloride (TBS-Cl) to give O-TBS-tetrapeptide
12. Lastly, after deprotecting the Cbz group of 12 with 10% Pd/C,
fragment condensation with 4 bythe BOP method proceeded
smoothlyto give the protected dehydrohexapeptide 1313 as the
precursor of 2 in 67% yield in two steps from 11, as shown in
Scheme 1. As a result, it was suggested that the final
intramolecular cyclization position in the total synthesis of 1
could be definitelyspecified. This fact is veryimportant and
different from the case of berninamycin B.
tide segment of a macrocyclic antibiotic, berninamycin A,
containing a 3-hydroxy-L-valine residue and having three vinyl
groups and a 1-propenyl group, was accomplished.
The antibiotic berninamycin A (1),1;2 isolated from the
culture of Streptomyces bernensis, is a unique macrocyclic
peptide constructed of polyoxazolylthiazole dehydropeptide, as
shown in Figure 1. The peptide 1 features a main dehydrohex-
apeptide skeleton 2 consisted of two substructures, -ÁAla-L-
HyVal-2-(1-amino-1-ethenyl)-5-methyloxazole-4-carbonyl-
ÁAla- (3, Fragment C) (ÁAla = dehydroalanine. HyVal = 3-
hydroxy-L-valine) and -L-Thr-[(Z)-1-amino-1-propenyl]-5-
methyloxazole-4-carbonyl- (4, Fragment B).3
O
H
N
O
NH
N
H
2
Fragment A
O
N
N
O
N
S
O
NH
O
HO
2
O
NH
HN
HO
O
HO
HN
O
O
NH
HN
O
N
NH
O
N
N
O
N
H
N
O
O
O
H
N
O
O
O
N
H
O
N
H
N
H
O
N
H
OH
Fragment C (3)
Fragment B (4)
OH
Fragment B-C (2)
Figure 1. Berninamycin A (1).
Furthermore, to examine whether the selective ꢀ-elimination
of onlythe primaryalcohol of 13 occurs or not, the substrate Boc-
HyVal-Ser(TPS)-OMe was independently prepared by coupling
of Boc-HyVal-OH with H-Ser(TPS)-OMe. After deprotecting the
TPS group with 1 M TBAF (tetrabutylammonium fluoride), ꢀ-
elimination of onlythe primaryalcohol of the formed 14 was
attempted bycombinations of various concentrations of metha-
nesulfonyl chloride (Ms-Cl) and Et3N. As a result, in the case
using Ms-Cl (1.2 equiv) and Et3N (1.5 equiv) at ꢁ20 ꢂC, onlythe
primaryalcohol was selectivelyprotected with Ms group to give
the corresponding mesyloxy derivative 15, accompanied with a
small amount of dehydrovalyldipeptide 16. Subsequently, the O-
Ms group of 15 was ꢀ-eliminated with DBU to give the expected
dipeptide 17,14 as shown in Scheme 2.
Recently, we have reported briefly novel syntheses of the
central pyridine skeleton (Fragment A),4;5 L- and D-HyVal,6 and
the main dehydrohexapeptide of berninamycin B,7 the first of
which is the common structure of similar antibiotics, A10255G
and J.8 The attractive structure as well as the bioactivityof 1
prompted us to studythe total snythesis and the structure-
bioactivityrelationship.
Herein, we wish to report a convenient synthesis of the
protected 2 [(P)-2] byfragment condensation of the precursors of
3 with 4 and then bysimultaneous selective ꢀ-elimination of the
three primaryalcohols of the obtained hexapeptide 18.
Similarlyto the case of berninamycin B, 7 attempts to couple
dehydrotetrapeptide containing a HyVal residue at the C-
terminus with an amine (N-) component dipeptide and,
alternatively, a carboxyl (C-) component dehydrotripeptide with
tripeptide containing HyVal at the N-terminus were both found to
be entirelyunsuccessful. Therefore, the N-component tetrapep-
tide containing the HyVal residue at the second position from the
N-terminus in sequence was synthesized and then subjected to the
Finally, similarly to the case of 17, deprotection of three O-
protecting groups of 13 with 1 M TBAF, followed by ꢀ-
elimination of the formed dehydrohexapeptide 18 with Ms-Cl
and Et3N and then DBU in one-pot gave the expected (P)-215 in
75% yield in two steps, as shown in Scheme 3.
Copyright Ó 2002 The Chemical Societyof Japan

ChemistryLetters 2002
1099
O
O
O
The structures of all new products thus obtained were
confirmed bythe 1H NMR spectral data and the satisfactory
results of the elemental analyses. In particular, from the 1H NMR
spectrum of 2, the appearances of the chemical shifts of six
protons of the three vinyl group at ꢁ ¼ 5:42, 5.67, 5.87, 6.24, 6.54,
and 6.64 and that of the olefinic proton of the propenyl group at
ꢁ ¼ 6:45–6.60 supports the formation of Fragment B-C deriva-
tive [(P)-2] of the natural 1.
In conclusion, it is noteworthythat a convenient synthesis of
the main dehydrohexapeptide was achieved by the selective ꢀ-
elimination of manyprimaryalcohols and the final cyclization
position in the total synthesis of 1 could be definitelyspecified.
O
O
i)
H
N
ii)
O
H
N
N
N
N
OMe
Cbz
OMe
OMe
Cbz
Cbz
85%
(2 steps)
N
87%
O
O
Br
O
5
7
6
OTPS
O
OTPS
O
O
iii)
iv)
RHN
CbzHN
N
H
OMe
OMe
91%
(2 steps)
N
98%
(2 steps)
N
OH
O
O
8
9: R=Boc
O
v)
79%
OTPS
O
O
O
10: R=
H
N
N
vi)
Cbz
(2 steps)
OMe
OTPS
N
O
O
N
H
H
N
Cbz
O
N
49%
(2 steps)
OH
O
11
OTBS
This work was partlysupported by‘‘High-Tech Research
Project’’ from the Ministryof Education, Culture, Sports, Science
and Technology.
OTPS
O
O
H
viii)
vii)
N
O
CbzHN
N
H
H
N
N
O
67%
(2 steps)
80%
(2 steps)
OMe
OH
O
O
OTPS
12
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).
OH
O
O
N
O
H
N
O
H
N
H
N
H
N
N
N
H
Cbz
N
OMe
O
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.
O
O
O
OTBS
OTPS
OTPS
13
Scheme 1. Reagent and conditions: i) a) NBS/THF, b) Et3N/THF, ii)
Cs2CO3/dioxane, iii) a) TFA/CHCl3, b) TPSCl, imidazole/DMF, iv) a)
10%Pd-C, H2/MeOH, b) BOP, (i-Pr)2NEt, Boc-HyVal-OH/DMF, v) a)
TFA/CHCl3, b) PivCl, Et3N, MS4A, Cbz-Isop-Ser-OH/DMF, vi) a) 1 M
LiOH/MeOH, b) BOP, (i-Pr)2NEt, H-Ser(TPS)-OMe/DMF vii) a) TFA/
CHCl3, b) TBSCl, imidazole/DMF, viii) a) 10%Pd-C, H2/MeOH, b)
BOP, (i-Pr)2NEt, Fragment B/DMF.
5
6
7
C. Shin, K. Okumura, A. Ito, and Y. Nakamura, Chem. Lett., 1994, 1301.
Y. Yonezawa, K. Shimizu, K. Yoon, and C. Shin, Synthesis, 2000, 634.
T. Yamada, K. Okumura, Y. Yonezawa, and C. Shin, Chem. Lett., 2001,
102.
8
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).
C. Shin, K. Nanjo, and J. Yoshimura, Tetrahedron Lett., 1974, 521.
9
10 J. Das, J. A. Reid, D. R. Kronenthal, J. Singh, P. Pansegrau, and R. H.
Mueller, Tetrahedron Lett., 33, 7835 (1992).
OH
OMe
OMs
OMe
O
O
O
11 P. Wipf and C. P. Miller, J. Org. Chem., 58, 3604 (1993).
12 BOP: Benzotriazol-1-yloxy-tris(dimethylamino)phosphonium hexa-
fluorophosphate.
ii)
i)
BocHN
BocHN
BocHN
BocHN
OH
N
H
N
H
5%
98%
(2 steps)
O
O
OH
24
13 13: Colorless amorphous material. [ꢂ]D þ6:9ꢂ (c 0.67, MeOH). 1H
OH
ii) 85%
OMs
OMe
16
14
NMR (CDCl3) ꢁ ¼ 0:00 (s, 6H, TBS’s CH3 ꢃ 2), 0.80, 0.88, 0.93 (each
s, 27H, TPS’s But ꢃ 2, TBS’s t-Bu), 1.11, 1.22 (each s, HyVal’s
CH3 ꢃ 2), 1.41 (d, 3H, Thr’s CH3, J ¼ 6:0 Hz), 1.50–1.60 (m, 9H,
Isop’s CH3 ꢃ 2, propenyl’s CH3), 2.45, 2.50 (each s, 6H, oxazole’s
CH3 ꢃ 2), 3.66 (s, 3H, OMe), 3.84–4.06 (m, 7H, Ser’s ꢂ-H ꢃ 3, Ser’s
ꢀ-H ꢃ 3, Thr’s ꢂ-H), 4.20–4.25 (m, 1H, Thr’s ꢀ-H), 4.37 (d, 1H, HyVal
ꢂ-H, J ¼ 8:5 Hz), 4.51 (q, 1H, Ser’s ꢂ-H, J ¼ 4:0 Hz), 4.75 (q, 1H,
Ser’s ꢂ-H, J ¼ 8:5 Hz), 5.04 (s, 2H, Cbz’s CH2), 5.09 (q, 1H, Ser’s ꢂ-H,
J ¼ 8:5 Hz), 6.42 (br s, 1H, propenyl’s H), 7.11–7.52 (m, 20H, TPS’s
Ph ꢃ 2, Cbz’s Ph, NH ꢃ 5). Found: C, 63.36; H, 6.96; N, 7.49%. Calcd
for C80H106N8O16Si3: C, 63.21; H, 7.03; N, 7.37%.
O
O
OMe
iii)
BocHN
N
N
H
H
94%
O
O
OH
OH
17
15
Scheme 2. Reagent and conditions: i) a) BOP, (i-Pr)2NEt, H-
Ser(TPS)-OMe/DMF, b) 1 M TBAF/THF, ii) MsCl, Et3N/CHCl3, iii)
DBU/CHCl3.
14 17: Colorless crystals. Mp 71–73 ꢂC. 1H NMR (CDCl3) ꢁ ¼ 1:22, 1.35
(each s, 6H, HyVal’s CH3 ꢃ 2), 1.44 (s, 9H, Boc’s But), 3.85 (s, 3H,
OMe), 4.17 (m, 1H, HyVal’s CH), 5.60 (br d, 1H, NH), 5.95, 6.60 (each
s, 2H, vinyl’s H ꢃ 2), 8.79 (br s, 1H, NH).
OH
O
O
i)
O
O
H
N
O
H
N
H
N
H
N
13
N
N
N
H
15 (P)-2: Colorless syrup. 1H NMR (CDCl3) ꢁ ¼ 1:21, 1.37 (each s, 6H,
HyVal’s CH3 ꢃ 2), 1.48 (d, 3H, Thr’s CH3, J ¼ 6:0 Hz), 1.51–1.79 (m,
6H, Isop’s CH3 ꢃ 2), 1.67 (s, 3H, propenyl’s CH3), 2.63, 2.94 (each s,
3H, oxazole’s CH3 ꢃ 2), 3.83 (s, 3H, OCH3), 3.96 (d, 1H, Thr’s ꢂ-H,
J ¼ 8:0 Hz), 4.27–4.33 (m, 1H, Thr’s ꢀ-H), 4.63 (br d, 1H, HyVal’s ꢂ-
H, J ¼ 7:5 Hz), 5.09–5.12 (m, 2H, Cbz’s CH2), 5.42, 5.67, 5.87, 6.24,
6.54, 6.64 (each s, 6H, vinyl’s H ꢃ 6), 6.45–6.60 (m, 1H, propenyl’s H),
7.08(d, 1H, NH, J ¼ 8:5 Hz), 7.16–7.27(m, 6H, Cbz’s Ph, NH), 9.25(br
s, 1H, NH), 9.31, 9.62(eachs, 2H, NH ꢃ 2). Found:C, 57.89;H, 5.76;N,
13.05%. Calcd for C42H50N8O13: C, 57.66; H, 5.76; N, 12.81%.
70%
Cbz
N
OMe
O
O
O
O
O
OH
OH
OH
18
OH
O
ii)
O
O
O
N
H
N
O
H
N
H
N
H
N
N
75%
(2 steps)
N
N
H
Cbz
OMe
O
O
O
(P)-2
Scheme 3. Reagent and conditions: i) 1 M TBAF/THF, ii) a) MsCl,
Et3N/CHCl3, b) DBU/CHCl3.