Total synthesis of bistratamides G and H from various kinds of ΔAla and ΔAbu-containing oligopeptides

Article abstract of DOI:10.1246/bcsj.78.1492

The total synthesis of naturally occurring bistratamides G (1) and H (2) from various kinds of dehydrooligopeptides is described. First of all, the promising building blocks of 1 and 2: N 2-[(S)-1-(N-benzyloxycarbonyl)amino-2- methyl-propyl]oxazole (4)- a

Full text of DOI:10.1246/bcsj.78.1492

1492 Bull. Chem. Soc. Jpn., 78, 1492–1499 (2005)
ꢀ 2005 The Chemical Society of Japan
Total Synthesis of Bistratamides G and H from Various Kinds
of ꢀAla and ꢀAbu-Containing Oligopeptides
ꢀ
Yasuchika Yonezawa, Naoki Tani, and Chung-gi Shin
Laboratory of Organic Chemistry, Faculty of Engineering, Kanagawa University,
Rokkakubashi, Kanagawa-ku, Yokohama 221-8686
Received January 11, 2005; E-mail: yonezy01@kanagawa-u.ac.jp
The total synthesis of naturally occurring bistratamides G (1) and H (2) from various kinds of dehydrooligopeptides
is described. First of all, the promising building blocks of 1 and 2: N-{2-[(S)-1-(N-benzyloxycarbonyl)amino-2-methyl-
propyl]oxazole (4)- and N-{2-[(S)-1-(N-t-butoxycarbonyl)amino-2-methylpropyl]thiazol-4-ylcarbonyl}-L-Val-(S)NH2
(5), and methyl (S)-2-{1-[N-(3-bromo-2-oxopropanoyl)amino-2-methylpropyl]}-5-methyloxazole-4-carboxylate (6), as
the left- and right-half components of the linear precursor of 1 and 2, were synthesized. Subsequent thiazolation between
4 or 5 and 6, respectively, followed by deprotection of both N- and O-protecting groups of the two formed linear tris-
heterocyclic peptides. By final macrocyclization using BOP as condensing agent under high-dilution conditions these
peptides gave the expected 1 and 2.
Bistratamides G (1) and H (2),1,2 two of many bistratamide-
type polyheterocyclic cyclopeptides, isolated recently from the
southern Philippines ascidian, Rissoclinum bistrrum, exhibit
activity in colon tumor HCT-116 cell line assay. The natural
products 1 and 2 feature interesting macrocyclic structures,
which include various kinds of heterocyclic (thiazole and ox-
azole) amino acids, (S)-2-[1-amino-2-methylpropyl]thiazole-
4-carboxylic acid, (S)-2-[1-amino-2-methylpropyl]oxazole-4-
carboxylic acid, and (S)-2-[1-amino-2-methylpropyl]-5-meth-
yloxazole-4-carboxylic acid residues, as shown in Fig. 1.
Various useful synthetic methods for the heterocyclic amino
acids have been already reported by a number of investiga-
tors.3 Accordingly, the total synthesis of bistratamide-type
dendroamide A (3)4 (Fig. 2) and a few similar natural products
has been already achieved by stepwise elongation of the
above-mentioned heterocyclic amino acids5 and by macrocy-
clization, by three groups of workers.6–8 Furthermore, interest-
ingly, one of the groups has reported that the metal-templated
assembly condensation of the heterocyclic amino acids gave
various similar combinatorial trisheterocyclic cyclopeptides
together with 3.7 The development of a new and general syn-
thetic method of the polyheterocyclic cyclopeptides attracted
our attention and prompted us to study the chemical modifica-
tion and structure-bioactivity relationship.
Recently, we have reported briefly the total synthesis of 1 by
a new synthetic method.9 Herein, we wish to report in detail
the total syntheses of both 1 and 2 from various dehydrooligo-
peptides. That is, the two kinds of desirable straight-chain tris-
heterocyclic peptides were synthesized from N-{2-[(S)-1-(N-
benzyloxycarbonyl)amino-2-methylpropyl]oxazole (4)- and
N-{2-[(S)-1-(N-t-butoxycarbonyl)amino-2-methylpropyl]thia-
zol-4-ylcarbonyl}-L-Val-(S)NH2 (5), and methyl (S)-2-{1-[N-
(3-bromo-2-oxopropanoyl)]amino-2-methylpropyl}-5-methyl-
oxazole-4-carboxylate (6) (Fig. 1). These materials were com-
paratively readily derived from ꢀ1-, ꢀ2-, and ꢀ3-dehydrodi-
and tripeptides.10 Subsequent macrocyclization of the obtained
two kinds of the N,O-deprotected linear peptides, derived by
thiazolation between 4 or 5 and 6 under high-dilution condi-
tions, gave 1 and 2. This widely applicable synthesis of the
polyheterocyclic cyclopeptide is thought to be attributable to
a newly developed method for thiazolation11 and oxazolation
from dehydropeptides.12
Results and Discussion
The syntheses of three kinds of building blocks, 4 or 5, and
6 were accomplished as follows. First of all, to synthesize 4 as
the left-half component, the starting ꢀ2-dehydrotripeptide12
S
Z
O
H
N
XHN
Z
NH2
N
N
H
O
O
O
N
N
4 : Z = O, X = Cbz
5 : Z = S, X = Boc
S
N
O
H
O
NH
HN
N
N
+
N
Br
O
O
H
N
O
O
NH
HN
OMe
S
N
N
O
O
Bistratamide G (1) : Z = O
Bistratamide H (2) : Z = S
O
6
S
Fig. 1. Retrosynthesis of 1 and 2.
Fig. 2. Dendroamide A (3).
Published on the web August 4, 2005; DOI 10.1246/bcsj.78.1492

Y. Yonezawa et al.
Bull. Chem. Soc. Jpn., 78, No. 8 (2005) 1493
[Cbz-L-Val-ꢀAla-L-Val-OMe (8). ꢀAla = ꢀ-dehydroalanine
residue. Cbz = benzyloxycarbonyl] was prepared by the usual
dehydration of the Ser residue of the authentic Cbz-L-Val-L-
Ser-L-Val-OMe (7) with methanesulfonyl chloride (Ms-Cl) in
the presence of Et3N and then with DBU (1,8-diazabicy-
clo[5.4.0]undec-7-ene).13 Subsequently, the ꢀAla residue of
8 was subjected to bromination. However, in the case of bro-
mination of an ꢀ-dehydroalanine (ꢀAla) residue with NBS
(N-bromosuccinimide) in CHCl3, it has been already found
that various brominated derivatives formed as a mixture. Ac-
cordingly, simultaneous bromination and methoxylation of 8
with NBS in MeOH were performed to give the corresponding
ꢀ-methoxylated ꢁ-bromoalanyltripeptide 9, by the method re-
ported earlier.14 Then, oxazolination of 9 with Cs2CO3 in diox-
ꢀAla-L-Val-OMe (16)] (Boc = t-butoxycarbonyl) by consec-
utive deprotection of N-Boc-N,O-Ip-L-Ser-L-Val-OMe (14)
(Ip = isopropylidene group), derived from N-Boc-N,O-Ip-L-
Ser-OH and H-L-Val-OMe, with a mixture of trifluoroacetic
acid (TFA) and CHCl3 (4:96 v/v) and by the usual dehydration
of the formed N-Boc-L-Ser-L-Val-OMe (15), similarly to the
case of 8. Furthermore, similarly to the case of 9, the me-
thoxy-bromination of 16 gave the corresponding ꢁ-bromo-ꢀ-
methoxylated dipeptide 17; both Boc and methoxy groups of
which were synchronously deprotected and hydrolyzed with
TFA and H2O to give N-(3-bromo-2-oxopropanoyl)-L-Val-
OMe (18). Because of the unstability, without purification,
the syrupy 18 was used intact for the next reaction. Subsequent
Hantzsch thiazolation between 18 and the authentic N-Boc-L-
Val-(S)NH2 (19) by successive treatments with KHCO3 in
1,2-dimethoxyethane (DME), with trifluoroacetic anhydride
(TFAA) and pyridine, and then with 28% aq NH3 gave the
corresponding thiazoloyl-dipeptide 20. Similarly to the case
of 4, after the ester hydrolysis of 20 with 1 M LiOH, the
successive amidation of the hydrolysate by the MA method
and thioamidation of the formed carboxamide 21 with
Lawesson’s reagent were employed to give the required 5 in
89% yield, as shown in Scheme 2.
ꢁ
ane at 60 C proceeded to give the corresponding 4-methoxy-
oxazoline derivative 10, the methoxy group of whiꢁch was ꢁ-
eliminated with camphorsulfonic acid (CSA) at 70 C to give
the required oxazole dipeptide derivative 11. After hydrolysis
of the methyl ester of 11 with 1 M LiOH, the obtained hydro-
lysate 12 was amidated with ClCOOEt in the presence of Et3N
and then 28% aq NH3 (mixed acid anhydride method: MA
method) to give the corresponding carboxamide 13. Finally,
thioamidation of 13 with Lawesson’s reagent gave the desired
thiocarboxamide 4 in 92% yield, as shown in Scheme 1.
Furthermore, to synthesize 5 as the one more left-half com-
ponent, we prepared the starting ꢀ1-dehydrodipeptide [Boc-
On the other hand, to synthesize 6, which is the common
right-half component of 1 and 2, firstly, similarly to the
case of 8, N-Boc-N,O-Ip-L-Ser-L-Val-(Z)-ꢀAbu-OMe (23)
O
H
O
O
H
H
N
i)
ii)
N
OMe
N
OMe
OMe
N
H
N
H
N
H
CbzHN
CbzHN
93%
CbzHN
85%
O
O
O
O
O
O
OMe
OH
Br
8
7
9
O
O
O
vi)
iv)
iii)
OMe
N
N
OR
N
NH2
N
H
N
H
N
H
CbzHN
CbzHN
CbzHN
81%
60%
60%
O
O
O
O
X
OMe
10
O
11 : R = Me
12 : [R = H]
13 X = O
X = S
vii)
v)
4
92 %
Scheme 1. Reagents and conditions: i) MsCl, Et3N, DBU; ii) NBS, MeOH, rt, 1 h; iii) Cs2CO3, dioxane, 60 ꢁC, 6 h; iv) CSA,
ꢁ
toluene, 70 C; v) 1 M LiOH; vi) ClCOOEt, Et3N, then 28% aq NH3; vii) Lawesson’s reagent.
HO
O
O
H
N
O
O
H
N
H
N
i)
ii)
OMe
BocHN
BocHN
OMe
N
Boc
OMe
Br
92%
O
O
O
16
14
15
OMe
Br
O
NH2
O
O
H
N
H
N
BocHN
19
iii)
iv)
S
97%
OMe
OMe
BocHN
80%
O
v)
O
17
18
O
O
N
vi)
86%
N
NH2
OMe
BocHN
N
H
BocHN
N
H
X
21: X = O
5 : X = S
S
O
S
vii)
20
89%
ꢁ
Scheme 2. Reagents and conditions: i) TFA:CHCl3 (4:96 v/v); ii) MsCl, Et3N, CHCl3, 0 C, 1 h, then DBU, rt, 30 min; iii) NBS,
MꢁeOH, rt, 1 h; iv) TFA, rt, 30 ꢁmin, then H2O, rt, 10 min; v) a) KHCO3, DME, 0 ꢁC, 30 min, 50 ꢁC, overnight, b) TFAA, pyridine,
0 C, 1 h, c) 28% aq NH3, 0 C, 5 min; vi) a) 1 M LiOH, b) ClCOOEt, Et3N, then 28% aq NH3; vii) Lawesson’s reagent.

1494 Bull. Chem. Soc. Jpn., 78, No. 8 (2005)
Synthesis of Bistratamides G, H
O
OH
OMe
O
X
O
O
O
O
H
N
H
N
H
N
i)
iii)
OMe
OMe
N
Boc
N
H
N
Boc
N
H
N
Boc
N
98%
87%
O
O
O
O
O
O
23: X = H
24: X = Br
25
22
ii)
80%
HO
BocHN
O
O
N
H
N
H
N
iv)
v)
i)
OMe
OMe
BocHN
N
90%
96%
O
O
O
O
26
27
Br OMe
Br
O
O
vi)
H
N
H
N
OMe
OMe
BocHN
N
O
N
80%
O
O
O
O
28
6
ꢁ
Scheme 3. Reagents and conditions: i) MsCl, Et3N, CHCl3, 0 C, 1 h, then DBU, rt, 30 min; ii) NBS, CHCl3, rt, 1 h, Et3N, rt, 30
ꢁ
min; iii) Cs2CO3, dioxane, 60 C, 6 h; iv) TFA:CHCl3 (4:96 v/v), rt, 5 h; v) NBS, MeOH, rt, 30 min; vi) TFA, rt, 30 min, then
H2O, rt, 10 min.
(ꢀAbu = 2-amino-2-butenoic acid) was prepared by the dehy-
dration of the Thr residue of the authentic N-Boc-N,O-Ip-L-
Ser-L-Val-L-Thr-OMe (22). In the case of the bromination of
the ꢀAbu residue with NBS, it has been also already found
that the formed peptide containing the ꢁ-brominated ꢀAbu
residue was smoothly oxazolated.15 Accordingly, the bromina-
tion of 23 with NBS in CHCl3, in place of MeOH, was carried
out to give the corresponding (E,Z)-ꢀ3-dehydrotripeptide 24
containing the ꢀAbu(ꢁ-Bꢁr) residue, which was then oxazol-
Br
O
O
H
N
i)
N
NH2
+
OMe
XHN
XHN
N
H
O
N
90%
S
Z
O
O
4 : X = Cbz, Z = O
5 : X = Boc, Z = S
6
Z
S
O
H
N
H
N
iii)
1 (51%)
2 (53%)
OY
N
N
N
O
O
16
O
ated with Cs2CO3 at 60 C to give the required 5-methylox-
30 : X = Boc, Y = Me, Z = S
[32 : X = Boc, Y = H, Z = S]
[34 : X = Y = H, Z = S]
29 : X = Cbz, Y = Me, Z = O
[31 : X = Cbz, Y = H, Z = O]
[33 : X = Y = H, Z = O]
azole derivative 25. Secondly, selective deprotection of the Ip
group with TFA and CHCl3 (4:96 v/v) was followed by dehy-
dration of the formed N-Boc-serinyldipeptide 26, similarly to
the cases of 8 and 23. That is, repeated consecutive dehydra-
tion of the Ser residue of 26 and bromination of the obtained
ꢀ1-dehydrodipeptide 27 with NBS in MeOH were performed
to give the corresponding N-terminal ꢀ-methoxylated ꢁ-bro-
moalanyldipeptide derivative 28. Thirdly, similarly to the case
of 18, deprotection of the Boc group of 28 with TFA and then
hydrolysis were employed to give 6 in 80% yield, as shown in
Scheme 3. However, because of its lability, without purifica-
tion, the formed 6 as well was used intact in the next thiazola-
tion with 4 or 5.
Finally, similarly to the cases of the thiazole ring formation
mentioned above, thiazolation between 4 or 5 and 6 gave the
desired N,O-diprotected linear trisheterocyclic peptides 29
and 30. Then, one pot hydrolysis of the methyl ester of 29
and 30 with 1 M LiOH and deprotection of the Cbz group of
the hydrolysates 31 with 10% Pd–C/H2 and deprotection of
the Boc group of 32 with TFA, followed by final macrocycli-
zation of the obtained N,O-deprotected trisheterocyclic pep-
tides 33 and 34 with BOP17 and (i-Pr)2NEt in DMF under
high-dilution conditions (1 mmol/L) at room temperature for
12 h gave the expected 1 and 2 in 51% and 53% yields from
33 and 34, respectively, as shown in Scheme 4.
iia)
iic)
iia)
iib)
Scheme 4. Reagents and conditions: i) a) KHCO3, DME, 0
ꢁC, 30 min, 50 ꢁC, overnight, b) TFAA, pyridine, 0 ꢁC,
1 h, c) 28% aq NH3, 0 ꢁC, 5 min; ii) a) 1 M LiOH,
H2O–dioxane (1:1 v/v), 0 C, 1 h, rt, 7 h, b) 10% Pd–C,
H2, rt, 3 h, c) TFA, CHCl3, rt, 1 h; iii) BOP, (i-Pr)2NEt,
DMF, rt, 12 h.
ꢁ
8.03 and 8.17 and the oxazole ring methyl protons at ꢂ 2.61
each as a singlet in 29, and two thiazole ring protons at ꢂ
8.03 and 8.07 and the oxazole ring methyl protons at ꢂ 2.62
in 30 supports the formation of the expected linear trishetero-
cyclic peptides 29 and 30. Furthermore, it was found that the
1H and 13C NMR spectral data and the specific rotations of
the synthetic 1 and 2 were fully identical with the spectral data
and rotations of the natural 1 and 2. Accordingly, the configu-
rational structure of 1 and 2 could be clearly confirmed by the
identification of the chemical and physical properties as well
as by the satisfactory elemental analysis and MALDI-
TOF MS [1; Found: m=z 528.1092 ðM þ HÞþ. Calcd for
C25H32N6O5S: 528.2155 ðM þ HÞþ. 2; Found: m=z 544.1931
ðM þ HÞþ. Calcd for C25H32N6O4S2: 544.1926 ðM þ HÞþ].
In conclusion, it is noteworthy that convenient formation of
both the thiazole and oxazole rings in peptides from various
dehydrooligopeptides was first developed and resulted in the
synthesis of various bistratamide-type natural products. Fur-
ther investigations of the new syntheses of other heterocyclic
cyclopeptides are currently under way in our laboratory.
The structures of all the new products thus obtained were
confirmed by the spectral data (1H and 13C NMR, IR, and spe-
cific rotation) and satisfactory elemental analyses.
1
From the H NMR spectra of 29 and 30, the appearance of
the chemical shifts of the oxazole and thiazole ring protons at ꢂ

Y. Yonezawa et al.
Bull. Chem. Soc. Jpn., 78, No. 8 (2005) 1495
with brine (30 mL ꢂ 2) and then dried over anhydrous Na2SO4.
Concentration in vacuo gave a brown syrup, which was purified
on a silica-gel column using a mixture of hexane and EtOAc
(2:3 v/v) to give 10 as a colorless syrup. Yield 60% (438 mg).
Experimental
The melting points were measured using a Yamato (Model Mp-
21) micro-melting point apparatus, and are uncorrected. The IR
spectra were recorded using an EPI-G2 spectrometer in KBr.
The 1H and 13C NMR spectra were measured with JEOL EX
200, JNE 500, and 600 spectrometers in CDCl3 or DMSO-d6
solution with tetramethylsilane used as the internal standard.
The specific rotations were measured in a 0.5 dm tube using a
JASCO DIP-4 polarimeter in MeOH. The mass spectrometers
were obtained by SHIMADZU/KRATOS COMPACT MALDI
IV tDE.
26
½ꢀꢄD þ11:6ꢁ (c 1.02, CHCl3). IR 3419, 3336, 2964, 1741,
1735, 1691, 1656, 1535, 1512 cmꢃ1. 1H NMR (CDCl3) diastereo-
mer: ꢂ 0.92, 0.94, 0.96, 0.97, 0.98, 1.01 (d, 3H ꢂ 4, CH(CH3)2,
J ¼ 7:2 Hz, J ¼ 7:2 Hz, J ¼ 6:6 Hz, J ¼ 6:6 Hz, J ¼ 6:6 Hz, J ¼
6:6 Hz), 2.18–2.21 (m, 1H ꢂ 2, CH(CH3)2), 3.25 and 3.31 (each s,
3H ꢂ 1=2, OCH3), 3.71 and 3.75 (each s, 3H ꢂ 1=2, COOCH3),
4.29–4.33 (m, 1H, CHCH(CH3)2), 4.42–4.47 (m, 1H,
CHCH(CH3)2), 4.48–4.56 (m, 2H, oxazoline’s CH2), 5.10–5.15
(m, 2H, Cbz’s CH2), 5.37 (br d, 1H ꢂ 1=2, NH, J ¼ 8:4 Hz),
7.23 (br d, 1H ꢂ 1=2, NH, J ¼ 7:8 Hz), 7.24 (br d, 1H ꢂ 1=2,
NH, J ¼ 7:8 Hz), 7.32–7.37 (m, 5H, Cbz’s Ph). Found: C,
59.24; H, 6.87; N, 9.38%. Calcd for C23H33N3O7: C, 59.60; H,
7.18; N, 9.07%.
Cbz-L-Val-L-Ser-L-Val-OMe (7). The compound 7 was ob-
tained by the coupling of Cbz-L-Val-OH with H-L-Ser-L-Val-
OMe by the usual method.
Cbz-L-Val-ꢀAla-L-Val-OMe (8). A solution of 7 (1.52 g,
3.37 mmol) in CHCl3 (30 mL) in the presences of Et3N (0.75 g,
7.41 mmol) and of Ms-Cl (0.66 g, 5.73 mmol) was stirred at 0
ꢁC for 1 h. To the solution was further added, with stirring,
DBU (1.04 g, 0.67 mmol) at 0 ꢁC for 30 min and then at room
temperature for 1 h. The reaction mixture was diluted with diethyl
ether (30 mL) and was washed successively with 10% citric acid
(30 mL ꢂ 2), saturated aqueous NaHCO3 solution (30 mL ꢂ 2),
and brine (30 mL ꢂ 2) and then dried over anhydrous Na2SO4.
Concentration in vacuo gave 8 as a colorless syrup. Yield 85%
(1.39 g). Without purification, the syrup was used in the next re-
action. 1H NMR (CDCl3) ꢂ 0.93 (d, 3H, CHCH3, J ¼ 7:2 Hz),
0.95 (d, 3H, CHCH3, J ¼ 6:6 Hz), 0.96 (d, 3H, CHCH3, J ¼
7:2 Hz), 0.99 (d, 3H, CHCH3, J ¼ 6:6 Hz), 2.19–2.25 (m,
1H ꢂ 2, CH(CH3)2), 3.77 (s, 3H, COOCH3), 4.13–4.15 (m, 1H,
CHCH(CH3)2), 4.57 (dd, 1H, CHCH(CH3)2, J ¼ 4:8 Hz, J ¼
8:4 Hz), 5.11 (ABq, 2H, Cbz’s CH2, J ¼ 12:6 Hz, J ¼ 23:4
Hz), 5.36 and 6.52 (each s, 1H ꢂ 2, vinyl’s H), 6.51 (br d, Cbz’s
NH, J ¼ 8:4 Hz), 6.61 (br s, 1H, NH), 7.31–7.35 (m, 5H, Cbz’s
Ph), 8.37 (br s, 1H, NH).
(S)-2-[1-(N-Cbz)Amino-2-methylpropyl]oxazole-4-carbon-
yl-L-Val-OMe (11). A solution of 10 (780 mg, 1.68 mmol) and
CSA (1.95 mg, 0.84 mmol) in toluene (10 mL) was stirred at 70
ꢁC for 48 h. The reaction mixture was washed with brine
(10 mL ꢂ 2) and saturated aqueous NaHCO3 solution (10 mL)
and then dried over anhydrous Na2SO4. Concentration in vacuo
gave a syrup, which was purified on a silica-gel column using a
mixture of hexane and EtOAc (2:3 v/v) to give 11 as a colorless
26
syrup. Yield 60% (438 mg). ½ꢀꢄD þ11:6ꢁ (c 1.02, CHCl3). IR
3404, 3317, 2964, 1737, 1726, 1710, 1678, 1597, 1529, 1512,
1502 cmꢃ1
.
1H NMR (CDCl3) ꢂ 0.94, 0.97, 1.00, 1.02 (d, 3H ꢂ
4, CH(CH3)2, J ¼ 6:9 Hz), 2.21–2.31 (m, 1H ꢂ 2, CH(CH3)2),
3.77 (s, 3H, COOCH3), 4.60–4.69 and 4.85–4.88 (each m,
1H ꢂ 2, CHCH(CH3)2), 5.11–5.17 (m, 2H, Cbz’s CH2), 5.38 (br
d, 1H, CbzNH, J ¼ 9:6 Hz), 7.31–7.38 (m, 6H, Cbz’s Ph and
NH), 8.31 (s, 1H, oxazole’s ring-H). Found: C, 61.56; H, 7.15;
N, 10.09%. Calcd for C22H29N3O6: C, 61.24; H, 6.77; N, 9.74%.
(S)-2-[1-(N-Cbz)Amino-2-methylpropyl]oxazole-4-carbon-
yl-L-Val-OH (12). A solution of 11 (548 mg, 1.27 mmol) and
1 M LiOH (1.9 mL, 1.90 mmol) in a mixture of THF–water
(1:1 v/v) (40 mL) was stirred at 0 ꢁC for 30 min and at room tem-
perature for 1 h. The reaction mixture was washed with diethyl
ether (50 mL ꢂ 2) and the aqueous layer was acidified with citric
acid and washed with EtOAc (50 mL ꢂ 2) and brine (50 mL ꢂ 2),
and then dried over anhydrous Na2SO4. Concentration in vacuo
gave a crude 12 as a colorless syrup, which was used intact in
the next reaction.
Cbz-L-Val-DL-(ꢀ-Br-ꢁ-MeO)Ala-L-Val-OMe (9). A solu-
tion of 8 (1.39 g, 3.20 mmol) and NBS (0.63 g, 3.54 mmol) in
ꢁ
THF (20 mL) was stirred at 0 C for 5 min and continuously in
MeOH (30 mL) for 30 min. The reaction mixture was diluted with
water (50 mL) and then extracted with EtOAc (50 mL ꢂ 2). The
combined extracts were washed with saturated aqueous NaHCO3
solution (50 mL ꢂ 2) and brine (50 mL ꢂ 2) and then dried over
anhydrous Na2SO4. Concentration in vacuo gave a brownish syr-
up, which was purified on a silica-gel column using a mixture of
hexane and EtOAc (3:2 v/v) to give 9 as a colorless syrup. Yield
93% (1.70 g). IR 3356, 2976, 1722, 1689, 1676, 1670, 1527, 1512,
(S)-2-[1-(N-Cbz)Amino-2-methylpropyl]oxazole-4-carbon-
yl-L-Val-NH2 (13). A solution of the obtained 12, Et3N (141 mg,
1.34 mmol), and ClCOOEt (145 mg, 1.34 mmol) in THF (50 mL)
was stirred at 0 ꢁC for 10 min and continuously with 28% NH3 (10
mL) for 5 min. The reaction mixture was mixed with saturated
aqueous NH4Cl solution (30 mL) and the organic layer was dried
over anhydrous Na2SO4. Concentration in vacuo gave a yellow
syrup, which was purified on a silica-gel column using EtOAc
to give a colorless solid. Recrystallization from a mixture of hex-
ane and EtOAc gave 13 as colorless powder. Yield 81% (428 mg).
1492, 1483 cmꢃ1 1H NMR (CDCl3) diastereomer: ꢂ 0.83–0.99
.
(m, 3H ꢂ 4, CH(CH3)2), 2.18–2.25 (m, 1H ꢂ 2, CH(CH3)2),
3.25 and 3.31 (each s, 3H ꢂ 1=2, OCH3), 3.65–3.70 (m, 1H,
BrCH2C), 3.71 and 3.75 (each s, 3H ꢂ 1=2, COOCH3), 4.13–
4.18 (m, 2H, BrCHC), 4.29–4.35 (m, 1H, CHCH(CH3)2), 4.42–
4.47 (m, 1H, CHCH(CH3)2), 5.10–5.15 (m, 2H, Cbz’s CH2),
5.37 (br d, 1H, CbzNH, J ¼ 8:4 Hz), 7.23 and 7.86 (br d, 1H,
NH, J ¼ 7:8 Hz), 7.32–7.37 (m, 5H, Cbz’s Ph). Found: C,
51.05; H, 6.56; N, 7.35%. Calcd for C23H34BrN3O7: C, 50.74;
H, 6.29; N, 7.72%.
25
ꢁ
mp 135–136 C. ½ꢀꢄD ꢃ6:46ꢁ (c 0.92, CHCl3). IR 3412, 3317,
2964, 1720, 1708, 1689, 1676, 1664, 1656, 1597, 1529 cmꢃ1
.
(RS,S)-2-[1-(N-Cbz)Amino]-2-methylpropyl]-4-methoxyox-
azole-4-carbonyl-L-Val-OMe (10). A solution of 9 (857 mg,
1.57 mmol) and Cs2CO3 (1.28 g, 3.92 mmol) in dioxane (20
mL) was stirred at 60 C overnight. The reaction mixture was di-
luted with water (20 mL) and the aqueous solution was extracted
1H NMR (CDCl3) ꢂ 0.91, 0.95, 1.00, 1.03 (d, 3H ꢂ 4, CH(CH3)2,
J ¼ 7:2 Hz, J ¼ 7:2 Hz, J ¼ 6:6 Hz, J ¼ 6:6 Hz), 2.17–2.27 (m,
1H ꢂ 2, CH(CH3)2), 4.41–4.44 (m, 1H, CHCH(CH3)2), 4.83 (dd,
1H, CHCH(CH3)2, J ¼ 7:2 Hz, J ¼ 9:0 Hz), 5.10–5.26 (m, 2H,
Cbz’s CH2), 5.64 (br d, 1H, CbzNH, J ¼ 9:6 Hz), 5.85 and 6.31
(each br d, 1H ꢂ 2, NH2, J ¼ 13:8 Hz), 7.32–7.37 (m, 6H, Cbz’s
ꢁ
with EtOAc (50 mL ꢂ 3). The combined extracts were washed

1496 Bull. Chem. Soc. Jpn., 78, No. 8 (2005)
Synthesis of Bistratamides G, H
Ph and NH), 8.12 (s, 1H, oxazole’s ring-H). Found: C, 60.14; H,
7.04; N, 13.1%. Calcd for C21H28N4O5: C, 60.56; H, 6.78; N,
13.45%.
(each d, 1H ꢂ 1=2, CH2Br, J ¼ 13:2 Hz), 4.51–4.57 (m, 1H,
CHCH(CH3)2), 6.99 and 7.03 (br d, 1H, NH, J ¼ 8:5 Hz), 7.37
and 7.39 (each br s, 1H, NH). Found: C, 43.41; H, 6.48; N,
6.47%. Calcd for C15H27BrN2O6: C, 43.80; H, 6.62; N, 6.81%.
N-(3-Bromo-2-oxopropanoyl)-L-Val-OMe (18). A solution
of 17 (1.20 g, 2.91 mmol) and TFA (20 mL) in CHCl3 (20 mL)
was stirred at room temperature for 30 min. The resulting solution
was further stirred with water (20 mL) for 10 min. The reaction
mixture was neutralized with saturated aqueous NaHCO3 solution
(20 mL) and the organic layer was dried over anhydrous Na2SO4.
Concentration in vacuo gave 18 as a colorless syrup, which was
used intact in the next reaction, without purification. 1H NMR
(CDCl3) ꢂ 0.91 (d, 3H, CH(CH3)2, J ¼ 7:2 Hz), 0.94 (d, 3H,
CH(CH3)2, J ¼ 6:6 Hz), 2.24–2.37 (m, 1H, CH(CH3)2), 3.82 (s,
3H, COOCH3), 4.49 (m, 2H, COCH2Br), 5.02 (m, 1H,
CHCH(CH3)2), 7.49 (br s, 1H, NH).
N-{2-[(S)-1-(N-Cbz)Amino-2-methylpropyl]oxazol-4-ylcar-
bonyl}-L-Val-(S)NH2 (4). A solution of 13 (963 mg, 2.31 mmol)
and Lawesson’s reagent (467 mg, 1.15 mmol) in THF (15 mL)
was stirred at room temperature overnight. After excess
Lawesson’s reagent was filtered off, the filtrate was concentrated
in vacuo. The obtained syrup was purified on a silica-gel column
using a mixture of hexane and EtOAc (1:2 v/v) to give a colorless
solid. Recrystallization from a mixture of hexane and EtOAc gave
26
4 as a colorless powder. Yield 92% (1.00 g). mp 67–68 ꢁC. ½ꢀꢄD
ꢃ64:8ꢁ (c 0.98, CHCl3). IR 3327, 2968, 1722, 1710, 1691, 1678,
1664, 1546, 1529 cmꢃ1 1H NMR (CDCl3) ꢂ 0.94 (d, 6H,
.
CH(CH3)2, J ¼ 5:4 Hz), 1.03 (d, 6H, CH(CH3)2, J ¼ 6:0 Hz),
2.20–2.24 and 2.33–2.36 (each m, 1H ꢂ 2, CH(CH3)2), 4.63–
4.68 and 4.84–4.87 (m, 1H ꢂ 2, CHCH(CH3)2), 5.11–5.17 (m,
2H, Cbz’s CH2), 5.47 (br d, 1H, CbzNH, J ¼ 9:0 Hz), 7.33–
7.38 (m, 5H, Cbz’s Ph), 7.59 (br d, 1H, NH, J ¼ 8:4 Hz),
7.75 and 8.16 (each br s, 1H ꢂ 2, NH2), 8.11 (s, 1H, oxazole’s
ring-H). Found: C, 58.69; H, 6.21; N, 12.53%. Calcd for
C21H28N4O4S: C, 58.31; H, 6.52; N, 12.95%.
N-Boc-L-Val-(S)NH2 (19). The compound 19 was obtained
by the thioamidation of N-Boc-L-Val-NH2 with Lawesson’s re-
agent by the usual method.
(S)-2-[1-(N-Boc)Amino-2-methylpropyl]oxazole-4-carbonyl-
L-Val-OMe (20). To a solution of 19 (590 mg, 2.54 mmol) in
DMF (10 mL) were added, with stirring, K2CO3 (2.800 g, 20.32
mmol) and a solution of 18 (1.060 g, 3.80 mmol) in DME (10
mL) at 0 ꢁC. After stirring for overnight at room temperature,
the resulting solution was concentrated in vacuo to give a brown
syrup, which was dissolved in CHCl3 (20 mL) and washed with
water (20 mL). The organic layer was dried over anhydrous
Na2SO4 and concentrated in vacuo to give a brown syrup, which
was dissolved in DME (10 mL). To the solution were added, with
stirring, TFAA (trifluoroacetic anhydrideꢁ) (704 mL, 5.08 mmol)
and pyridine (897 mL, 11.18 mmol) at 0 C for 30 min. Concen-
tration in vacuo gave a brown syrup, which was further dissolved
in EtOAc (30 mL). The resulting solution was washed with brine
(20 mL) and stirred with 28% aqueous NH3 at 0 ꢁC. After stirring
for 15 min, the reaction mixture was washed with brine
(20 mL ꢂ 2) and dried over anhydrous Na2SO4. Concentration
in vacuo gave a brown syrup, which was purified on a silica-gel
column using a mixture of hexane and EtOAc (1:2 v/v) to give
N-Boc-N,O-Ip-L-Ser-L-Val-OMe (14).
The compound 14
was obtained by the coupling of N-Boc-N,O-Ip-L-Ser-OH with
H-L-Val-OMe by the usual method.
N-Boc-L-Ser-L-Val-OMe (15). A solution of 14 (1.98 g, 5.53
mmol) in a mixture of TFA and CHCl3 (4:96 v/v) (35 mL) was
stirred at room temperature for 3 h. The reaction mixture was neu-
tralized with saturated aqueous NaHCO3 solution and the organic
layer was washed with brine (10 mL ꢂ 2), and dried over anhy-
drous Na2SO4. Concentration in vacuo gave a yellow syrup,
which was purified on a silica-gel column using a mixture of hex-
ane and EtOAc (1:2 v/v) to give 15 as a colorless syrup. Yield
25
92% (1.65 g). ½ꢀꢄD ꢃ32:6ꢁ (c 0.78, CHCl3). IR 3417, 3302,
2983, 2949, 1730, 1707, 1676, 1560, 1490 cmꢃ1 1H NMR
.
(CDCl3) ꢂ 0.00 (s, 3H, COOCH3), 0.91 (d, 3H, CH(CH3)2, J ¼
6:6 Hz), 0.95 (d, 3H, CH(CH3)2, J ¼ 7:2 Hz), 1.46 (s, 9H, Boc’s
t-Bu), 2.17–2.26 (m, 1H, CH(CH3)2), 3.64–3.70 (m, 1H,
CHCHHOH, J ¼ 10:2 Hz), 4.09 (br d, 1H, CHCHHOH, J ¼
10:2 Hz), 4.20 (br s, 1H, OH), 4.49–4.54 (m, 1H, CHCH2OH),
5.63 (br s, 1H, BocNH), 7.13 (br d, 1H, NH, J ¼ 6:0 Hz). Found:
C, 52.56; H, 8.62; N, 8.48%. Calcd for C14H26N2O6: C, 52.82; H,
8.23; N, 8.80%.
N-Boc-ꢀAla-L-Val-OMe (16). Similarly to the case of 8, the
dehydration of 15 (1.530 g, 4.80 mmol) with Et3N (1.070 g, 10.56
mmol), Ms-Cl (935 mg, 8.16 mmol), and DBU (1.04 g, 6.71
mmol) in CHCl3 (50 mL) was worked up to give 17 as a colorless
syrup, which was used in the next reaction, without purification.
N-Boc-DL-(ꢀ-Br-ꢁ-MeO)Ala-L-Val-OMe (17). A solution of
16 (1.40 g, 4.66 mmol) and NBS (940 mg, 5.28 mmol) in MeOH
(50 mL) was stirred at 0 ꢁC for 30 min. The reaction mixture was
poured into water (50 mL) and the resulting solution was extracted
with EtOAc (30 mL ꢂ 2). The combined extracts were dried over
anhydrous Na2SO4 and then concentrated in vacuo to give a
brown syrup. Purification on a silica-gel column using a mixture
of hexane and EtOAc (3:2 v/v) gave 17 as a colorless syrup.
Diastereomer. Yield 80% (1.280 g). IR 3307, 2968, 1726, 1709,
1671 cmꢃ1. 1H NMR (CDCl3) ꢂ 0.93 and 0.94 (d, 3H, CH(CH3)2,
J ¼ 7:2 Hz), 0.95–1.00 (d, 3H, CH(CH3)2, J ¼ 6:6 Hz), 1.46 (s,
9H, Boc’s t-Bu), 2.23–2.29 (m, 1H, CH(CH3)2), 3.29 and 3.32
(each s, 3H, OCH3), 3.72 and 4.27 (each br d, 1H ꢂ 1=2, CH2Br,
J ¼ 10:8 Hz), 3.77 and 3.78 (s, 3H, COOCH3), 4.50 and 4.53
25
20 as a colorless syrup. Yield 97% (1.02 g). ½ꢀꢄD ꢃ9:5ꢁ (c
1.07, CHCl3). IR 3315, 2966, 1743, 1722, 1708, 1691, 1664,
1658, 1546, 1535 cmꢃ1 1H NMR (CDCl3) ꢂ 0.94 (d, 3H,
.
CH(CH3)2, J ¼ 6:6 Hz), 0.98 (d, 3H, CH(CH3)2, J ¼ 7:2 Hz),
1.00 (d, 3H, CH(CH3)2, J ¼ 7:2 Hz), 1.01 (d, 3H, CH(CH3)2, J ¼
6:6 Hz), 1.47 (s, 9H, Boc’s t-Bu), 2.27–2.40 (m, 1H ꢂ 2,
CH(CH3)2), 3.78 (s, 3H, COOCH3), 4.70 (dd, 1H, CHCH(CH3)2,
J ¼ 5:4 Hz, J ¼ 9:0 Hz), 4.89 (m, 1H, CHCH(CH3)2), 5.15 (br d,
1H, BocNH, J ¼ 8:4 Hz), 7.72 (br d, 1H, NH, J ¼ 9:0 Hz), 8.01
(s, 1H, thiazole’s ring-H). Found: C, 55.52; H, 7.28; N, 10.48%.
Calcd for C19H31N3O5S: C, 55.18; H, 7.56; N, 10.16%.
(S)-2-[1-(N-Boc)Amino-2-methylpropyl]oxazole-4-carbonyl-
L-Val-NH2 (21). A solution of 20 (1.05 g, 2.53 mmol) and 1 M
LiOH (5 mL, 5.06 mmol) in a mixture of water and dioxane (1:1
v/v) (10 mL) was stirred at 0 ꢁC for 30 min and then at room tem-
perature for 3 h. The resulting solution was washed with diethyl
ether (5 mL ꢂ 2) and acidified with citric acid and then extracted
with EtOAc (10 mL ꢂ 2). The combined extracts were washed
with brine (10 mL ꢂ 2) and dried over anhydrous Na2SO4. Con-
centration in vacuo gave the corresponding free carboxylic acid
as a colorless syrup, which was used intact in the next reaction.
Similarly to the case of 13, the amidation of the obtained syrup
with Et3N (281 mg, 2.78 mmol), ClCOOEt (302 mg, 2.78 mmol),
and 28% aqueous NH3 (10 mL) in THF (100 mL) was worked up

Y. Yonezawa et al.
Bull. Chem. Soc. Jpn., 78, No. 8 (2005) 1497
to give 21 as a colorless amorphous material. Yield 86% (903
25
ꢀAbu’s CH3), 3.77 (s, 3H, COOCH3), 4.14–4.16 and 4.22–4.26
(each m, 1H ꢂ 2, OCH2), 4.40–4.45 (m, 1H, CHCH(CH3)2),
4.54–4.58 (m, 1H ꢂ 2, CHNH and CHNH), 7.88 (br s, 1H, NH),
8.27 (br s, 1H, NH). Found: C, 48.07; H, 6.17; N, 7.75%. Calcd
for C21H34BrN3O7: C, 48.47; H, 6.56; N, 8.07%.
mg). ½ꢀꢄD ꢃ46:9ꢁ (c 1.37, CHCl3). IR 3396, 2966, 2933,
1
1720, 1707, 1689, 1666, 1544, 1533, 1500, 1492 cmꢃ1. H NMR
(CDCl3) ꢂ 0.92 (d, 3H, CH(CH3)2, J ¼ 6:9 Hz), 1.00 (d, 3H,
CH(CH3)2, J ¼ 6:9 Hz), 1.03 (d, 3H, CH(CH3)2, J ¼ 6:9 Hz),
1.05 (d, 3H, CH(CH3)2, J ¼ 6:9 Hz), 1.47 (s, 9H, Boc’s t-Bu),
2.26–2.32 and 2.37–2.40 (each m, 1H ꢂ 2, CH(CH3)2), 4.46
(dd, 1H, CHCH(CH3)2, J ¼ 7:2 Hz, J ¼ 9:0 Hz), 4.87 (dd, 1H,
CHCH(CH3)2, J ¼ 6:0 Hz, J ¼ 9:0 Hz), 5.22 (br d, 1H, BocNH,
J ¼ 9:0 Hz), 5.79 and 6.40 (each br s, 1H ꢂ 2, NH2), 7.76 (br d,
1H, NH, J ¼ 9:0 Hz), 8.00 (s, 1H, thiazole’s ring-H). Found: C,
54.59; H, 7.28; N, 14.41%. Calcd for C18H30N4O4S: C, 54.25;
H, 7.59; N, 14.06%.
Methyl (S)-2-[1-(N-Boc-N,O-Ip-L-Ser)Amino-2-methylpro-
pyl]-5-methyl-oxazole-4-carboxylate (25). A solution of 24
(1.45 g, 2.79 mmol) and Cs2CO3 (2.27 g, 6.95 mmol) in dioxane
(30 mL) was stirred at 60 ꢁC overnight. The reaction mixture was
diluted with water (30 mL) and extracted with EtOAc
(50 mL ꢂ 3). The combined extracts were washed with brine
(30 mL ꢂ 2) and dried over anhydrous Na2SO4. Concentration
in vacuo gave a brown syrup, which was purified on a silica-gel
column using a mixture of hexane and EtOAc (3:2 v/v) to give
N-{2-[(S)-1-(N-Boc)Amino-2-methylpropyl]thiazol-4-ylcarbon-
Similarly to the case of 4, the thio-
26
yl}-L-Val-(S)NH2 (5).
25 as a colorless syrup. Yield 87% (1.07 g). ½ꢀꢄD ꢃ85:4ꢁ (c
amidation of 21 (876 mg, 2.20 mmol) with Lawesson’s reagent
(490 mg, 1.21 mmol) in DME (30 mL) was worked up to give
5 as a yellow powder. mp 113–114 ꢁC. Yield 89% (811 mg).
1.08, CHCl3). IR 3233, 2980, 1756, 1708, 1691, 1678, 1546,
1529 cmꢃ1
.
1H NMR (CDCl3) ꢂ 0.91 and 0.95 (d, 3H ꢂ 2,
CH(CH3)2, J ¼ 6:6 Hz), 1.38–1.76 (m, 15H, Ip’s CH3 ꢂ 2, Boc’s
t-Bu), 2.25–2.28 (m, 1H, CH(CH3)2), 2.60 (s, 3H, oxazole’s ring-
CH3), 3.88–4.55 (m, 3H, OCH2 and NCHCH2O), 3.89 (s, 3H,
COOCH3), 5.07 (dd, 1H, CHCH(CH3)2, J ¼ 6:6 Hz, J ¼ 9:0
Hz), 7.50 (br s, 1H, NH). Found: C, 57.63; H, 7.28; N, 9.14%.
Calcd for C21H33N3O7: C, 57.39; H, 7.57; N, 9.56%.
25
½ꢀꢄD ꢃ54:8ꢁ (c 0.94, CHCl3). IR 3214, 2966, 1726, 1701,
1
1689, 1666, 1544, 1528 cmꢃ1. H NMR (CDCl3) ꢂ 0.94 (d, 3H,
CH(CH3)2, J ¼ 6:9 Hz), 1.03 (d, 3H, CH(CH3)2, J ¼ 6:9 Hz),
1.05 (d, 3H, CH(CH3)2, J ¼ 6:9 Hz), 1.08 (d, 3H, CH(CH3)2, J ¼
6:9 Hz), 1.51 (s, 9H, Boc’s t-Bu), 2.38–2.42 (m, 1H ꢂ 2,
CH(CH3)2), 4.67–4.69 (m, 1H, CHCH(CH3)2), 4.89–4.91 (m,
1H, CHCH(CH3)2), 5.22 (br d, 1H, BocNH, J ¼ 9:0 Hz), 7.23
and 8.15 (each br s, 1H ꢂ 2, NH2), 7.53 (br d, 1H, NH, J ¼ 9:0
Hz), 8.02 (s, 1H, thiazole’s ring-H). Found: C, 52.05; H, 7.14;
N, 13.61%. Calcd for C18H30N4O3S2: C, 51.99; H, 7.22; N,
13.48%.
Methyl
(S)-2-[1-(N-Boc-L-Ser)Amino-2-methylpropyl]-5-
methyloxazole-4-carboxylate (26). A solution of 25 (2.35 g,
5.35 mmol) in a mixture of TFA and CHCl3 (4:96 v/v) (200
mL) was stirred at room temperature for 2 h. The reaction mixture
was neutralized with saturated aqueous NaHCO3 solution (150
mL) and the organic layer was washed with brine (100 mL ꢂ 2)
and then dried over anhydrous Na2SO4. Concentration in vacuo
gave a residual substance, which was purified on a silica-gel col-
umn using a mixture of hexane and EtOAc to give 26 as a color-
N-Boc-N,O-Ip-L-Ser-L-Val-L-Thr-OMe (22). The compound
22 was obtained by the coupling of N-Boc-N,O-Ip-L-Ser-L-Val-
OH with H-L-Thr-OMe by the usual method.
26
ꢁ
N-Boc-N,O-Ip-L-Ser-L-Val-(Z)-ꢀAbu-OMe (23). Similarly
to the cases of 8 and 16, the dehydration of 22 (3.12 g, 6.79 mmol)
of Et3N (1.51 g, 14.94 mmol), Ms-Cl (1.32 g, 11.54 mmol), and
DBU (1.46 g, 9.50 mmol) in CHCl3 (30 mL) was worked up to
give 23 as a colorless powder. Yield 98% (2.94 g). mp 124–125
less powder. Yield 90% (1.92 g). mp 153–154 C. ½ꢀꢄD ꢃ64:8ꢁ
(c 0.98, CHCl3). IR 3327, 2968, 1722, 1710, 1691, 1678, 1664,
1529 cmꢃ1
.
1H NMR (CDCl3) ꢂ 0.91 and 0.95 (d, 3H ꢂ 2,
CH(CH3)2, J ¼ 6:6 Hz), 1.61 (s, 9H, Boc’s t-Bu), 2.25–2.28 (m,
1H, CH(CH3)2), 2.60 (s, 3H, oxazole’s ring-CH3), 3.67 (br d,
1H, CHCH2OH, J ¼ 7:0 Hz), 3.89 (s, 3H, COOCH3), 4.10 (br
d, 2H, CHCH2O, J ¼ 7:0 Hz), 4.30 (br s, 1H, OH), 5.23 (dd,
1H, CHCH(CH3)2, J ¼ 6:6 Hz, J ¼ 9:0 Hz), 6.85 (br s, 1H,
BocNH), 7.50 (br s, 1H, NH). Found: C, 54.54; H, 7.71; N,
10.13%. Calcd for C18H29N3O7: C, 54.12; H, 7.32; N, 10.52%.
26
ꢁC. ½ꢀꢄD ꢃ74:1ꢁ (c 1.02, CHCl3). IR 3327, 2968, 1722, 1710,
1691, 1678, 1664, 1546, 1529 cmꢃ1 1H NMR (CDCl3) ꢂ 0.98
.
and 1.01 (d, 3H ꢂ 2, CH(CH3)2, J ¼ 6:6 Hz), 1.43–1.60 (m,
15H, Ip’s CH3 ꢂ 2, Boc’s t-Bu), 1.81 (d, 3H, ꢀAbu’s CH3, J ¼
7:2 Hz), 2.43–2.47 (m, 1H, CH(CH3)2), 3.74 (s, 3H, COOCH3),
4.11–4.46 (m, 4H, –OCH2, NCH ꢂ 2), 6.82 (br q, 1H, olefin’s
H, J ¼ 7:2 Hz), 6.98 (br s, 1H, NH), 8.98 (br s, 1H, NH). Found:
C, 57.51; H, 7.64; N, 9.28%. Calcd for C21H35N3O7: C, 57.13; H,
7.99; N, 9.52%.
Methyl
methyloxazole-4-carboxylate (27).
(S)-2-[1-(N-Boc-ꢀAla)Amino-2-methylpropyl]-5-
Similarly to the case of
23, the dehydration of 26 (532 mg, 1.33 mmol) with Et3N (228
mg, 2.26 mmol), Ms-Cl (228 mg, 2.00 mmol), and DBU (287
mg, 1.86 mmol) in CHCl3 (10 mL) was worked up to give 27
as a crude syrup, which was intact used in the next reaction.
1H NMR (CDCl3) ꢂ 0.93 and 0.99 (d, 3H ꢂ 2, CH(CH3)2, J ¼
7:8 Hz), 1.48 (s, 9H, Boc’s t-Bu), 2.26–2.31 (m, 1H, CH(CH3)2),
2.63 (s, 3H, oxazole’s ring-CH3), 3.92 (s, 3H, COOCH3), 5.09
(dd, 1H, CHCH(CH3)2, J ¼ 4:6 Hz, J ¼ 8:4 Hz), 5.18 and 6.06
(each s, 1H ꢂ 2, vinyl’s H), 6.73 (br d, 1H, NH, J ¼ 8:4 Hz),
7.24 (br s, 1H, BocNH).
N-Boc-N,O-Ip-L-Ser-L-Val-(Z)-ꢀAbu(ꢀ-Br)-OMe (24).
A
solution of 23 (2.89 g, 6.55 mmol) and NBS (1.28 g, 7.20 mmol)
in CHCl3 (30 mL) was stirred at room temperature for 3 h. The
resulting solution was further stirred with Et3N (0.73 g, 7.21
ꢁ
mmol) at 0 C for 30 min and then at room temperature for 5 h.
The reaction mixture was diluted with diethyl ether (20 mL)
and washed successively with 10% citric acid (20 mL ꢂ 2), satu-
rated NaHCO3 (20 mL ꢂ 2), and brine (20 mL ꢂ 2), and then
dried over anhydrous Na2SO4. Concentration in vacuo gave a
brown syrup, which was purified on a silica-gel column using a
mixture of hexane and EtOAc (1:1 v/v) to give 24 as colorless
crystals. Yield 80% (2.73 g). mp 124–125 ꢁC. IR 3327, 2975,
Methyl
(S)-2-{1-[N-Boc-DL-(ꢀ-Br-ꢁ-MeO)Ala]Amino-2-
methylpropyl}-5-methyloxazole-4-carboxylate (28). Similarly
to the case of 9, the bromination of 27 (508 mg, 1.33 mmol) with
NBS (267 mg, 1.50 mmol) in THF (20 mL) and MeOH (30 mL)
was worked up to give 28 as a yellow syrup. Yield 96% (630 mg).
IR 3327, 2972, 1722, 1710, 1691, 1483 cmꢃ1. 1H NMR (CDCl3) ꢂ
0.95 and 1.00 (d, 3H ꢂ 2, CH(CH3)2, J ¼ 7:2 Hz), 1.45 (s, 9H,
Boc’s t-Bu), 2.26–2.33 (m, 1H, CH(CH3)2), 2.61 and 2.77 (each
1765, 1726, 1701, 1695, 1664, 1529, 1500 cmꢃ1 1H NMR
.
(CDCl3) ꢂ 0.92–1.00 (m, 3H ꢂ 2, CH(CH3)2), 1.53 and 1.65 (each
s, 3H ꢂ 2, Ip’s CH3), 1.49 (s, 9H, Boc’s t-Bu), 2.41 (s, 3H ꢂ 1=2,
ꢀAbu’s CH3), 2.47–2.49 (m, 1H, CH(CH3)2), 2.59 (s, 3H ꢂ 1=2,

1498 Bull. Chem. Soc. Jpn., 78, No. 8 (2005)
Synthesis of Bistratamides G, H
s, 3H, oxazole’s ring-CH3), 3.33 and 3.49 (each s, 3H, OCH3),
3.67 and 4.13 (each br d, 1H ꢂ 2, CH2Br, J ¼ 10:8 Hz), 3.91
(s, 3H, COOCH3), 5.02 (dd, 1H, CHCH(CH3)2, J ¼ 6:6 Hz, J ¼
9:6 Hz), 5.98 (br s, 1H, BocNH), 7.13 (br d, 1H, NH, J ¼ 9:6 Hz).
Found: C, 46.68; H, 6.48; N, 8.18%. Calcd for C19H30BrN3O7: C,
46.36; H, 6.14; N, 8.53%.
Methyl (S)-2-[1-(3-Bromo-2-oxopropanoyl)amino-2-methyl-
propyl]-5-methyloxazole-4-carboxylate (6). Similarly to the
case of 18, the hydrolysis of 28 (4.56 g, 9.26 mmol) with TFA
(50 mL) in CHCl3 (50 mL) was worked up for 1 h to give 6 as
a colorless syrup. Because of the unstability, the obtained 6 was
used intact in the next reaction. Yield 80% (2.67 g). 1H NMR
(CDCl3) ꢂ 0.93 (d, 3H, CH(CH3)2, J ¼ 7:2 Hz), 0.97 (d, 3H,
CH(CH3)2, J ¼ 6:6 Hz), 2.24–2.37 (m, 1H, CH(CH3)2), 2.67 (s,
3H, oxazole’s ring-CH3), 3.67 (s, 3H, COOCH3), 4.49 (q, 2H,
CH2Br, J ¼ 13:7 Hz), 5.02 (dd, 1H, CHCH(CH3)2, J ¼ 6:6 Hz,
J ¼ 9:6 Hz), 7.49 (br d, 1H, NH, J ¼ 9:6 Hz).
6.35; N, 12.57%. Calcd for C31H44N6O7S2: C, 55.01; H, 6.55;
N, 12.42%.
Bistratamide G (1). A solution of 29 (458 mg, 0.66 mmol)
and 1 M LiOH (2 mL) in a mixture of THF and water (1:1 v/v)
ꢁ
(40 mL) at 0 C was stirred for 1 h and then at room temperature
for 7 h. The resultant solution was washed with diethyl ether (20
mL) and the aqueous solution was acidified with citric acid. The
resulting solution was extracted with EtOAc (50 mL ꢂ 2) and
the combined extracts were washed with brine (30 mL ꢂ 2) and
then dried over anhydrous Na2SO4. Concentration in vacuo
gave (S,S,S)-2-{1-[2-(1-{2-[1-(N-Cbz)amino-2-methylpropyl]oxa-
zole-4-carbonylamino}-2-methylpropyl)thiazole-4-carbonylami-
no]-2-methylpropyl}-5-methyloxazole-4-carboxylic acid (31) as a
colorless syrup, which was dissolved in MeOH (50 mL). The so-
lution was stirred with 10% Pd–C under H2 gas stream at room
temperature for 4 h. The reaction mixture was concentrated in
vacuo to give (S,S,S)-2-[1-(2-{1-[2-(1-amino-2-methylpropyl)oxa-
zole-4-carbonylamino]-2-methylpropyl}thiazole-4-carbonylami-
no)-2-methylpropyl]-5-methyloxazole-4-carboxylic acid (33) as a
colorless syrup. To the solution of 33 (350 mg, 0.64 mmol) in dry
DMF (458 mL) was slowly added, with stirring, a solution of BOP
(42.4 mg, 0.96 mmol) and (i-Pr)2NEt (16.5 mg, 1.28 mmol) in dry
Methyl (S,S,S)-2-{1-[2-(1-{2-[1-(N-Cbz)Amino-2-methylpro-
pyl]oxazole-4-carbonylamino}-2-methylpropyl)thiazole-4-car-
bonylamino]-2-methylpropyl}-5-methyloxazole-4-carboxylate
(29). Similarly to the case of 20, the thiazolation of 4 (0.80 g,
1.84 mmol) in DME (20 mL) with 6 (1.66 g, 4.60 mmol) in
DME (20 mL) in the presence of KHCO3 (1.47 g, 14.72 mmol)
was worked up to give a brown syrup, which was purified on a
silica-gel column using a mixture of hexane and EtOAc (2:1
v/v) to give 29 as a colorless powder. Yield 90% (1.15 g). mp
ꢁ
DMF (20 mL) at 0 C for 1 h. After stirring at room temperature
overnight, the reaction mixture was mixed with water (458 mL)
and extracted with EtOAc (50 mL ꢂ 3). The combined extracts
were washed with brine (30 mL ꢂ 2) and then dried over anhy-
drous Na2SO4. Concentration in vacuo gave a brown syrup, which
was purified on a silica gel column using a mixture of hexane and
EtOAc (1:3 v/v) to give 1 as colorless crystals. Yield 51% (178
26
71–72 ꢁC. ½ꢀꢄD þ4:2ꢁ (c 0.93, CHCl3). IR 3404, 3323, 2964,
1718, 1676, 1670, 1612, 1541, 1533, 1498 cmꢃ1 1H NMR
.
(CDCl3) ꢂ 0.91 (d, 3H, CH(CH3)2, J ¼ 6:6 Hz), 0.93 (d, 3H,
CH(CH3)2, J ¼ 6:6 Hz), 0.95 (d, 3H, CH(CH3)2, J ¼ 7:2 Hz),
0.97 (d, 3H, CH(CH3)2, J ¼ 7:2 Hz), 0.99 (d, 3H, CH(CH3)2, J ¼
7:2 Hz), 1.12 (d, 3H, CH(CH3)2, J ¼ 7:2 Hz), 2.23–2.25, 2.35–
2.37, and 2.56–2.62 (each m, 1H ꢂ 3, CH(CH3)2), 2.61 (s, 3H,
oxazole’s ring-CH3), 3.91 (s, 3H, COOCH3), 4.83–4.88 (m, 1H,
CHCH(CH3)2), 5.13 (ABq, 2H, Cbz’s CH2, J ¼ 13:8 Hz,
J ¼ 21:0 Hz), 5.17–5.20 and 5.32–5.38 (each m, 1H ꢂ 2,
CHCH(CH3)2), 5.52 (br s, 1H, NH, J ¼ 9:6 Hz), 7.33–7.36 (m,
5H, Cbz’s Ph), 7.45 and 7.85 (each br d, 1H ꢂ 2, NH, J ¼ 9:6
Hz), 8.03 (s, 1H, oxazole’s ring-H), 8.17 (s, 1H, thiazole’s ring-
H). Found: C, 58.38; H, 6.23; N, 12.48%. Calcd for
C34H42N6O8S: C, 58.77; H, 6.09; N, 12.19%.
26
mg). mp 85–86 ꢁC. ½ꢀꢄD ꢃ82:3ꢁ (c 1.00, MeOH). IR 3396,
2964, 1685, 1676, 1597, 1533, 1508 cmꢃ1 1H NMR (DMSO-
.
d6) ꢂ 0.79 (d, 3H, CH(CH3)2, J ¼ 6:6 Hz), 0.80 (d, 3H,
CH(CH3)2, J ¼ 6:6 Hz), 0.83 (d, 3H, CH(CH3)2, J ¼ 7:2 Hz),
0.84 (d, 3H, CH(CH3)2, J ¼ 7:2 Hz), 0.86 (d, 3H, CH(CH3)2, J ¼
7:2 Hz), 0.87 (d, 3H, CH(CH3)2, J ¼ 7:2 Hz), 2.04–2.09, 2.11–
2.14, and 2.17–2.21 (each m, 1H ꢂ 3, CH(CH3)2), 2.46 (s, 3H, ox-
azole’s ring-CH3), 4.91 (dd, 1H, CHCH(CH3)2, J ¼ 4:2 Hz, J ¼
7:2 Hz), 4.97 (dd, 1H, CHCH(CH3)2, J ¼ 6:0 Hz, J ¼ 9:0 Hz),
5.28 (dd, 1H, CHCH(CH3)2, J ¼ 6:0 Hz, J ¼ 9:0 Hz), 8.20 (br
d, 1H, NH, J ¼ 7:2 Hz), 8.22 (br d, 1H, NH, J ¼ 9:0 Hz), 8.23
(s, 1H, oxazole’s ring-H), 8.36 (br d, 1H, NH, J ¼ 9:0 Hz), 8.68
(s, 1H, thiazole’s ring-H). 13C NMR (DMSO-d6) ꢂ 11.1, 18.03,
18.05, 18.l, 18.2, 18.3, 18.6, 32.6, 32.9, 34.6, 52.1, 52.7, 54.8,
125.2, 128.0, 134.5, 143.0, 147.9, 152.9, 158.4, 159.3, 160.3,
160.6, 163.2, 168.3. MALDI-TOFMS Found: m=z 528.l092
(M þ Hþ). Calcd for C25H32N6O5S: 528.2155 (M þ Hþ).
Methyl (S,S,S)-2-{1-[2-(1-{2-[1-(N-Boc)Amino-2-methylpro-
pyl]thiazole-4-carbonylamino}-2-methylpropyl)thiazole-4-car-
bonylamino]-2-methylpropyl}-5-methyloxazole-4-carboxylate
(30). Similarly to the case of 29, the thiazolation of 5 (356 mg,
0.86 mmol) in DME (10 mL) with 6 (931 mg, 2.58 mmol) in DME
(20 mL) in the presence of KHCO3 (688 mg, 6.88 mmol) was
worked up to give a brown syrup, which was purified on a
silica-gel column using a mixture of hexane and EtOAc (3:1
v/v) to give 32 as a colorless syrup. Yield 92% (529 mg).
Bistratamide H (2). Similarly to the case of 1, the ester
hydrolysis of 30 (371 mg, 0.55 mmol) with 1 M LiOH (0.90
mL) in MeOH (20 mL) was worked up to give (S,S,S)-2-{1-[2-
(1-{2-[1-(N-Boc)amino-2-methylpropyl]thiazole-4-carbonylami-
no}-2-methylpropyl)thiazole-4-carbonylamino]-2-methylpropyl}-
5-methyloxazole-4-carboxylic acid (32) as colorless crystals. To
deprotect the Boc group, we stirred a solution of 32 (327 mg,
0.49 mmol) and TFA (10 mL) in CHCl3 (15 mL) at room temper-
ature for 1 h. Concentration of the resulting solution in vacuo gave
(S,S,S)-2-[1-(2-{1-[2-(1-amino-2-methylpropyl)thiazole-4-carbon-
ylamino]-2-methylpropyl}thiazole-4-carbonylamino)-2-methyl-
propyl]-5-methyloxazole-4-carboxylic acid (34) as colorless crys-
tals. The cyclization of 34 (350 mg, 0.62 mmol) was also similarly
worked up to give 2 as colorless crystals. Yield 53% (217 mg). mp
26
½ꢀꢄD ꢃ12:6ꢁ (c 0.95, CHCl3). IR 3402, 2974, 2933, 1720,
1656, 1544 cmꢃ1 1H NMR (CDCl3) ꢂ 0.95 (d, 3H, CH(CH3)2,
.
J ¼ 7:2 Hz), 0.98 (d, 3H, CH(CH3)2, J ¼ 6:6 Hz), 1.02 (d, 3H,
CH(CH3)2, J ¼ 6:6 Hz), 1.04 (d, 3H, CH(CH3)2, J ¼ 7:2 Hz),
1.06 (d, 3H, CH(CH3)2, J ¼ 7:2 Hz), 1.07 (d, 3H, CH(CH3)2,
J ¼ 6:6 Hz), 1.46 (s, 9H, Boc’s t-Bu), 2.34–2.40 (m, 1H ꢂ 2,
CH(CH3)2), 2.60–2.65 (m, 1H, CH(CH3)2), 2.62 (s, 3H, oxazole’s
ring-CH3), 3.91 (s, 3H, COOCH3), 4.91 (br s, 1H, BocNH), 5.18
(dd, 1H ꢂ 2, CHCH(CH3)2, J ¼ 7:2 Hz, J ¼ 9:0 Hz), 5.37 (dd,
1H, CHCH(CH3)2, J ¼ 6:0 Hz, J ¼ 9:0 Hz), 7.79 (br d, 1H,
NH, J ¼ 9:0 Hz), 7.81 (br d, 1H, NH, J ¼ 9:0 Hz), 8.03 and
8.07 (each s, 1H ꢂ 2, thiazole’s ring-H). Found: C, 55.27; H,
25
199–200 ꢁC. Yield 53% (217 mg). ½ꢀꢄD ꢃ92:5ꢁ (c 1.00, MeOH).
1
IR 3390, 2955, 1670, 1530, 1505, 1490 cmꢃ1. H NMR (DMSO-

Y. Yonezawa et al.
Bull. Chem. Soc. Jpn., 78, No. 8 (2005) 1499
d6) ꢂ 0.91 (d, 3H, CH(CH3)2, J ¼ 7:2 Hz), 0.94 (d, 3H,
CH(CH3)2, J ¼ 7:2 Hz), 0.95 (d, 3H, CH(CH3)2, J ¼ 7:2 Hz),
0.97 (d, 3H, CH(CH3)2, J ¼ 7:2 Hz), 0.99 (d, 3H, CH(CH3)2, J ¼
7:2 Hz), 1.00 (d, 3H, CH(CH3)2, J ¼ 7:2 Hz), 2.16–2.28 (m,
1H ꢂ 3, CH(CH3)2), 2.59 (s, 3H, oxazole’s ring-CH3), 5.07 (dd,
1H, CHCH(CH3)2, J ¼ 4:8 Hz, J ¼ 8:4 Hz), 5.35 (dd, 1H,
CHCH(CH3)2, J ¼ 5:4 Hz, J ¼ 8:4 Hz), 5.46 (dd, 1H,
CHCH(CH3)2, J ¼ 6:6 Hz, J ¼ 9:5 Hz), 8.32 and 8.34 (each s,
1H ꢂ 2, thiazole’s ring-H), 8.34 (br d, 1H, NH, J ¼ 9:5 Hz),
8.49 (br d, 1H, NH, J ¼ 8:4 Hz), 8.52 (br d, 1H, NH, J ¼ 8:4
Hz). 13C NMR (DMSO-d6) ꢂ 11.2, 17.9, 18.0, 18.1, 18.2, 18.4,
18.8, 32.7, 34.3, 34.5, 52.2, 54.5, 54.7, 124.7, 125.2, 127.8,
147.8, 148.3, 153.2, 158.9, 159.4, 159.6, 160.4, 168.4, 168.9.
MALDI-TOFMS Found: m=z 544.1931 (M þ Hþ). Calcd for
C25H32N6O4S2: 544.1926 (M þ Hþ).
Miller, J. Org. Chem., 58, 3604 (1993). i) E. Anguilar and A. I.
Meyers, Tetrahedron Lett., 35, 2473 (1994). j) P. Wipf, C. P.
Miller, S. Venkatraman, and P. C. Fritch, Tetrahedron Lett., 36,
6395 (1995). k) P. Larfargue, P. Guenot, and J.-P. Lellouche,
Synlett, 1995, 171. l) A. I. Meyers and F. X. Tavares, J. Org.
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J. Nat. Prod., 59, 581 (1996).
5
1873.
A. Vertram and G. Pattenden, Synlett, 2000, 1519; 2001,
6
Z. Xiz and C. D. Smith, J. Org. Chem., 66, 3459 (2001).
A. Vertram and G. Pattenden, Heterocycles, 58, 521
7
(2002).
8
a) S. L. You and J. W. Kelly, J. Org. Chem., 68, 9606
(2003). b) S. L. You and J. W. Kelly, Chem.—Eur. J., 10, 71
(2004).
This work was supported in part by a Grant-in-Aid for
Scientific Research No. 14550829 from the Ministry of
Education, Culture, Sports, Science and Technology and by
a ‘‘High-Tech Research Project’’ from the Ministry of
Education, Culture, Sports, Science and Technology.
9
C. Shin, C. Abe, and Y. Yonezawa, Chem. Lett., 33, 664
(2004).
10 In this paper, the symbols ꢀ1, ꢀ2, and ꢀ3 indicate the
position number of the ꢀ-dehydroamino acid residue from the
N-terminus in sequence.
11 a) T. Suzuki, A. Nagasaki, K. Okumura, and C. Shin,
Heterocycles, 55, 835 (2001). b) A. Nagasaki, Y. Adachi, Y.
Yonezawa, and C. Shin, Heterocycles, 60, 321 (2003).
12 H. Saito, T. Yamada, K. Okumura, Y. Yonezawa, and C.
Shin, Chem. Lett., 2002, 1098.
13 T. Yamada, K. Okumura, Y. Yonezawa, and C. Shin,
Chem. Lett., 2001, 102.
14 C. Shin, Y. Sato, and J. Yoshimura, Bull. Chem. Soc. Jpn.,
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15 N. Endoh, K. Tsuboi, R. Kim, Y. Yonezawa, and C. Shin,
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16 J. Das, J. A. Reid, D. R. Kronenthal, J. Singh, P.
Pansegrau, and R. H. Mueller, Tetrahedron Lett., 33, 7835 (1992).
17 BOP = Benzotriazol-1-yloxytris(dimethylamino)phospho-
nium hexafluorophosphate.
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