Total syntheses of bistratamides J, E, and H from two types of δala-containing oligopeptides

Article abstract of DOI:10.1246/bcsj.81.495

The total syntheses of naturally occurring bis- and tris(heterocyclic) cyclopeptide bistratamides J (1), H (2), and E (3) from two types of dehydropeptides are described. The strategy involves the preparation of the promising building blocks: N-{2-[(S)-l-(N-benzyloxycarbonyl)amino-2- methylpropyl]thiazol-4-ylcarbonyl}-L-Val-(5)NH² (4) as the left-half component, and methyl N-(3-bromo-2-oxopropanoyl)-L-Val-O-(tert- butyldiphenylsilyl)-L-threonate (5) as the right- half. The subsequent Hantzsch thiazole synthesis between 4 and 5 afforded a linear N,O-protected bis(heteroeyclic)pep-tide as the precursor of 1. Upon deprotection, the precursor was converted to 1 via macrocyclization under high-dilution condition, using BOP [benzotriazol-l-yloxytris(dimethylamino)phosphonium hexafiuorophosphate] as the condensing agent. Furthermore, 1 was converted to 2, which was transformed into 3 via ring-opening and re-oxazolination.

Full text of DOI:10.1246/bcsj.81.495

ꢀ 2008 The Chemical Society of Japan
Bull. Chem. Soc. Jpn. Vol. 81, No. 4, 495–501 (2008)
495
Total Syntheses of Bistratamides J, E, and H from
Two Types of ÁAla-Containing Oligopeptides
Hiroyuki Suzuki, Masanori Andoh, Yasuchika Yonezawa, Shoji Akai,
ꢀ
Chung-gi Shin, and Ken-ichi Sato
Laboratory of Organic Chemistry, Faculty of Engineering, Kanagawa University,
Rokkakubashi, Kanagawa-ku, Yokohama 221-8686
Received July 18, 2007; E-mail: satouk01@kanagawa-u.ac.jp
The total syntheses of naturally occurring bis- and tris(heterocyclic)cyclopeptide bistratamides J (1), H (2), and E
(3) from two types of dehydropeptides are described. The strategy involves the preparation of the promising building
blocks: N-{2-[(S)-1-(N-benzyloxycarbonyl)amino-2-methylpropyl]thiazol-4-ylcarbonyl}-L-Val-(S)NH2 (4) as the left-
half component, and methyl N-(3-bromo-2-oxopropanoyl)-L-Val-O-(tert-butyldiphenylsilyl)-L-threonate (5) as the right-
half. The subsequent Hantzsch thiazole synthesis between 4 and 5 afforded a linear N,O-protected bis(heterocyclic)pep-
tide as the precursor of 1. Upon deprotection, the precursor was converted to 1 via macrocyclization under high-dilution
condition, using BOP [benzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate] as the condensing
agent. Furthermore, 1 was converted to 2, which was transformed into 3 via ring-opening and re-oxazolination.
Among the many tris(heterocyclic)cyclopeptides recently
isolated from the southern Philippines ascidian Lissoclinum
bistratum, bistratamides have exhibited activities in human
colon tumor HCT-116 cell line assays.1 As shown in Figure 1,
bistratamide J (1), H (2), and E (3) have interesting macro-
cyclic structures that include various heterocyclic (oxazoline,
oxazole, and thiazole) amino acid residues.
Various methodologies for the syntheses of heterocyclic
amino acids have been reported,2 among these, the total syn-
theses of bistratamide-like dendroamide A3 and similar natural
products, featuring stepwise elongation of the above-men-
tioned heterocyclic amino acids4 followed by macrocycliza-
tion, have been achieved by Smith’s and Pattenden’s groups.5,6
In addition, the latter successfully accomplished the assembly
condensation of heterocyclic amino acids using a metal tem-
plate to afford dendroamide A along with several similar com-
binatorial tris(heterocyclic)cyclopeptides.6a Bistratamides E–J
and dendroamide A were synthesized by Kelly’s group7 em-
ploying stepwise elongation in 2004–2005. Bistratamide H
was expeditiously synthesized by Nakamura’s group employ-
ing both stepwise elongation and fluorous chemistry.8 From
the standpoint of the systematic synthesis of a series of bistrat-
amides and their analogs, the above stepwise elongation meth-
od seems to be unfulfilled.
Recently, we reported the total syntheses of dendroamide
9a and bistratamides G9b and H (2) using a new synthetic meth-
A
od.9c As a continuing synthetic program, we present herein a
novel total syntheses of 1–3 using dehydropeptides. As shown
O
S
N
O
H
N
N
O
NH
HN
N
O
H
N
O
S
S
H
N
O
S
BocHN
BocHN
OMe
NH2
N
Bistratamide H (2)
S
O
HO
O
N
H
O
NH
NH
N
4
6
O
HN
N
OTBDPS
OTBDPS
OMe
Br
O
O
O
O
H
N
H
N
O
S
OMe
O
N
H
BocHN
N
H
S
N
H
Bistratamide J (1)
O
O
O
O
N
N
5
7
O
NH
HN
N
O
S
Bistratamide E (3)
Figure 1. Retrosynthesis of 1, 2, and 3.
Published on the web April 10, 2008; doi:10.1246/bcsj.81.495

496 Bull. Chem. Soc. Jpn. Vol. 81, No. 4 (2008)
Total Syntheses of Bistratamides
in Figure 1, our scheme involves Hantzsch thiazole synthe-
sis2f,10 between 49c (Scheme 1) and 5 (Scheme 2), which were
readily derived from ꢀ1-dehydrodipeptide 6 and ꢀ1-dehydro-
tripeptide 7, respectively. Natural product 1 can be synthesized
by macrocyclization of the linear N,O-deprotected peptide
under high-dilution condition. Furthermore, natural product 2
can be derived from 1 using our novel method reported recent-
ly.11 Natural product 3 can be derived by (1) oxazolination of
1, (2) ring-opening of the oxazoline, and (3) re-oxazolination.
Additionally, 2 can be derived by oxidation of 3 using MnO2.
In this paper, we report the synthesis of bistratamide J (1),
H (2), and E (3) according to this outline.
(MsCl) in the presence of Et3N followed by 1,8-diazabicyclo-
[5.4.0]undec-7-ene (DBU)12 afforded ꢀ1-dehydrodipeptide,
N-Boc–ꢀAla–L-Val–(O-TBDPS)–L-Thr–OMe 7 (ꢀAla = ꢀ-
dehydroalanine) as syrupy liquid, which was used without
further purification. Methoxy-bromination of 7 gave the corre-
sponding ꢁ-bromo-ꢀ-methoxylated tripeptide 11, which was
in one-pot deprotected and hydrolyzed (to remove the Boc
and methoxy groups) using TFA, and then H2O to afford
5, which was used without purification in the next step, a
coupling with 4.
The desired linear N,O-protected bis(heterocyclic)peptide
12 was synthesized by Hantzsch thiazole synthesis between
4 and 5. Subsequent removal of the TBDPS group of 12
with 1 M (1 M = 1 mol dmꢁ3) tetrabutylammonium fluoride
(TBAF) gave 13 in 95% yield. As shown in Scheme 3, the
final transformation of 13 into 1 in 72% yield overall was car-
ried out as follows: (1) saponification of the methyl ester using
1 M LiOH aq, (2) removal of the Boc group using TFA, and (3)
macrocyclization of the resulting N,O-deprotected bis(hetero-
cyclic)peptide using BOP and (i-Pr)2NEt in DMF–CH2Cl2
under high-dilution condition (1 mmol Lꢁ1) at room tempera-
ture for 12 h.
Furthermore, the dehydro analog of bistratamide J (1) was
obtained by dehydration of the Thr residue of 1 using MsCl
in the presence of Et3N, followed by treatment with DBU.
As shown in Scheme 4 (step i–iii), bromination of 14 using
NBS in CHCl3 yielded the ꢁ-Br–ꢀAbu 15, which was then
oxazolated13 using Cs2CO3 to give 2 in 70% yield in three
steps without purification of the first and second intermediates.
Alternatively, the oxazoline ring also could be constructed
by treatment of 1 with Burgess reagent. However, this method
may invert the configuration at the ꢁ-carbon in the oxazoline
ring,14 and therefore our strategy was modified to incorporate
Results and Discussion
The syntheses of building blocks 4 (left-half) and 5 (right-
half) were accomplished as described below. As shown in
Scheme 1, 4 was prepared in five steps from N-Boc–N,O-Ip–
L-Ser–L-Val–OMe (Boc = tert-butoxycarbonyl, Ip = isopro-
pylidene group).9c
On the other hand, for the synthesis of 5 (Scheme 2), N-Boc–
N,O-Ip–L-Ser–L-Thr–OMe 8 was protected to afford N-Boc–
N,O-Ip–L-Ser–L-Val–(O-TBDPS)–L-Thr–OMe 9 (TBDPS =
tert-butyldiphenylsilyl group), which was converted into N-
Boc–L-Ser–L-Val–(O-TBDPS)–L-Thr–OMe 10 using trifluoro-
acetic acid (TFA) in CHCl3 (4:96 v/v). Subsequent dehydra-
tion of the Ser residue of 10 using methanesulfonyl chloride
O
H
N
S
S
H
N
BocHN
BocHN
OMe
NH2
N
y. 59%
O
O
(5 steps)
6
4
Scheme 1. Conversion of dehydrodipeptide 6 to 4.
OTBDPS
OMe
OTBDPS
OMe
HO
OR
OMe
O
O
O
H
N
H
N
O
iii)
H
N
ii)
BocHN
N
H
N
H
y. 86%
BocHN
N
H
N
Boc
O
O
O
O
O
O
7
10
8: R = H
9: R = TBDPS y. 93%
i)
OTBDPS
OMe
Br
OMe
H
OTBDPS
OMe
Br
O
H
N
O
v)
y. 92%
iv)
y. 87%
(2 steps)
N
O
N
H
BocHN
N
H
O
O
O
O
5
11
Scheme 2. Reagents and conditions: i) TBDPS–Cl, imidazole, CHCl3; ii) TFA–CHCl3 (4:96 v/v); iii) MsCl, Et3N, DBU, THF;
iv) NBS, MeOH; v) TFA–CHCl3 (1:3 v/v) then H2O.
O
S
HO
O
N
H
OR
OMe
NH
NH
S
N
H
N
S
i)
iii), iv), v)
O
H
N
BocHN
5
4
+
y. 90%
N
y. 72%
(3 steps)
N
N
H
O
HN
O
O
O
N
O
12: R = TBDPS
13: R = H y. 95%
S
1
ii)
Scheme 3. Reagents and conditions: i) [a] K2CO3, DME; [b] TFAA, Pyridine, THF; ii) 1 M TBAF, THF; iii) 1 M LiOH aq, H2O–
dioxane (1:1 v/v); iv) TFA–CHCl3 (1:3 v/v); v) BOP, DIPEA, DMF–CH2Cl2 (1:2 v/v).

H. Suzuki et al.
Bull. Chem. Soc. Jpn. Vol. 81, No. 4 (2008)
497
O
O
O
S
S
S
N
H
HO
O
N
H
HO
O
N
H
O
N
N
NH
NH
NH
NH
N
N
iv)
v)
O
O
O
y. 65%
NH
y. 72%
HN
HN
HN
N
N
N
O
O
O
S
S
S
1
16
17
(epimer of 3 at oxazoline's C-5 position)
(epimer of 1 at threonine's β position)
iv)
i)
y. 65%
O
O
R
O
S
N
S
N
S
N
H
O
H
O
H
N
N
N
N
O
NH
NH
N
iii)
vi)
O
O
NH
O
HN
NH
HN
HN
y. 70%
(3 steps)
y. 73%
N
N
N
O
O
O
S
S
S
Bistratamide H (2)
Bistratamide E (3)
14: R = H
15: R = Br
ii)
Scheme 4. Reagents and conditions: i) MsCl, Et3N, DBU, CHCl3; ii) NBS, Et3N; iii) Cs2CO3; iv) Burgess reagent, THF; v) [a] 1 M
HCl, THF; [b] K2CO3; [c] Al2O3; vi) MnO2, THF.
polarimeter in CHCl3 or MeOH. Mass spectra were obtained on
a SHIMADZU JMS-T100CS.
a double inversion in this position of the Thr moiety. Accord-
ingly, 16 (epimer of 3 at oxazoline’s C-5 position) obtained in
the above reaction was treated with aqueous HCl in THF (ring
opening of the oxazoline ring),15 and then treated with Burgess
reagent (re-oxazolination) to give 3. The structure of 16
N-Boc–N,O-Ip–L-Ser–L-Val–L-(O-TBDPS)–L-Thr–OMe 9.
To a solution of N-Boc–N,O-Ip–L-Ser–L-Val–L-Thr–OMe9c
8
(2.56 g, 5.57 mmol) in CHCl3 (50 mL) at 0 ꢂC were added imi-
dazole (758 mg, 11.1 mmol) and TBDPSCl (2.30 g, 8.36 mmol),
and the mixture was stirred at 0 ꢂC for 1 h, and then at room tem-
perature for 6 h. The reaction mixture was washed with 10% citric
acid (20 mL ꢃ 2) and brine (30 mL ꢃ 2). The combined organic
phases were dried (Na2SO4), and the solvent was evaporated.
The crude residue was purified on a silica gel column eluted
with hexane–EtOAc (3:1 v/v) to give 9 as colorless syrup. Yield
1
was inferred by reaction mechanism, and comparing H and
13C NMR spectra and HR-ESI-MS with those of 3. Additional-
ly, oxidation of 3 using MnO2 also gave 2 in 73% yield, as
shown in Scheme 4 (step vi).
The spectral data (1H and 13C NMR), and specific rotations
for synthetic bistratamides 1–3 are in good agreement with
those reported by Kelly’s group.7,16 Also the structure was sup-
ported by IR, HR-ESI-MS, and elemental analyses. Thus, we
have achieved the total syntheses of bistratamide 1–3.
In conclusion, we have accomplished the total syntheses of
bistratamide J (1), H (2), and E (3) in 7, 10, and 11 steps (36.6,
25.6, and 11.1% overall yields), respectively, from two types
of ꢀAla-containing oligopeptides 6 and 7 employing a modi-
fied Hantzsch thiazole synthesis developed in our laboratory as
the crucial key transformation. Macrocyclization of the linear
hexapeptide was achieved under high-dilution conditions
(1 mmol Lꢁ1 DMF–CH2Cl2 solution) in 72% yield. Our modi-
fied Hantzsch thiazole synthetic method is surely applicable
to the synthesis of not only bistratamide and its analogues, but
also highly complex poly-azole compounds, such as telomesta-
tin, mechercharmycin, etc.
25
93% (3.61 g): ½ꢀꢄD ꢁ44:0ꢂ (c 0.95, CHCl3); IR 3319, 2972,
1
1753, 1708, 1691, 1664, 1658, 1529, 1512, 1500 cmꢁ1; H NMR
(CDCl3) ꢂ 0.91 (d, 3H, Val’s CH3, J ¼ 6:0 Hz), 0.92 (d, 3H, Val’s
CH3, J ¼ 6:0 Hz), 0.99 (s, 9H, TBDPS’s t-Bu), 1.27 (d, 3H, Thr’s
CH3, J ¼ 6:4 Hz), 1.37 (s, 9H, Boc’s t-Bu), 1.45 (s, 3H, Ip’s CH3),
1.55 (s, 3H, Ip’s CH3), 2.05–2.08 (m, 1H, Val’s ꢁ-H), 3.55 (s, 3H,
COOCH3), 3.87 (br m, 1H, Ser’s ꢁ-H), 4.07 (br s, 1H, Ser’s ꢁ-H),
4.35–4.45 (m, 5H, Ser’s ꢀ-H, Thr’s ꢀ-H, Thr’s ꢁ-H, Val’s ꢀ-H,
BocNH), 7.40–7.70 (m, 11H, PhH ꢃ 2 and NH); Anal. Calcd for
C37H55N3O8Si: C, 63.67; H, 7.94; N, 6.02%. Found: C, 63.22; H,
7.52; N, 5.66%.
N-Boc–L-Ser–L-Val–(O-TBDPS)–L-Thr–OMe 10. A solu-
tion of 9 (2.35 g, 3.36 mmol) in a mixture of TFA and CHCl3 (4:96
v/v) (100 mL) was stirred at room temperature for 3 h. The reac-
tion mixture was neutralized with a saturated aqueous NaHCO3
solution, and the organic layer was washed with brine (20 mL ꢃ
2), dried over anhydrous Na2SO4, and concentrated in vacuo giv-
ing a yellow syrup, which was purified on a silica gel column
eluted with hexane–EtOAc (2:3 v/v) to give 10 as colorless syrup.
Experimental
Melting points were measured using a Yanaco Model MP-J3
micro-melting point apparatus, and are uncorrected. IR spectra
were recorded using a SHIMADZU IR Prestige-21 spectrometer
in KBr. 1H and 13C NMR spectra were measured with JEOL
JNM-ECA500 and 600 spectrometers in CDCl3 or DMSO-d6 so-
lution with tetramethylsilane used as internal standard. Specific
rotations were measured in 0.5 dm tubes using a JASCO P-1020
25
Yield 86% (1.92 g): ½ꢀꢄD ꢁ28:1ꢂ (c 1.09, CHCl3); IR 3431, 3319,
2964, 1753, 1720, 1708, 1691, 1664, 1658, 1529, 1512 cmꢁ1
;
1H NMR (CDCl3) ꢂ 0.91 (d, 3H, Val’s CH3, J ¼ 7:2 Hz), 0.92
(d, 3H, Val’s CH3, J ¼ 7:2 Hz), 1.01 (s, 9H, TBDPS’s t-Bu),
1.28 (d, 3H, Thr’s CH3, J ¼ 6:4 Hz), 1.41 (s, 9H, Boc’s t-Bu),

498 Bull. Chem. Soc. Jpn. Vol. 81, No. 4 (2008)
Total Syntheses of Bistratamides
2.18–2.21 (m, 1H, Val’s ꢁ-H), 3.59 (s, 3H, COOCH3), 4.15 (br s,
1H, OH), 4.57–4.75 (m, 6H, Ser’s ꢁ-H ꢃ 2, Ser’s ꢀ-H, Thr’s ꢀ-
H, Thr’s ꢁ-H, BocNH), 7.12 (br s, 1H, NH), 7.26 (br s, 1H, NH),
7.32–7.62 (m, 10H, PhH ꢃ 2); Anal. Calcd for C34H51N3O8Si: C,
62.07; H, 7.81; N, 6.39%. Found: C, 62.01; H, 7.60; N, 6.51%.
N-Boc–ÁAla–L-Val–(O-TBDPS)–L-Thr–OMe 7. A solution
of 10 (2.13 g, 3.24 mmol) in CHCl3 (50 mL) in the presences of
Et3N (721 mg, 7.13 mmol) and MsCl (631 mg, 5.51 mmol) was
stirred at 0 ꢂC for 1 h. Then, DBU (691 mg, 4.54 mmol) was added
to the reaction mixture at 0 ꢂC, and stirred at 0 ꢂC for 30 min,
and then at room temperature for 1 h. The reaction mixture was
diluted with diethyl ether (30 mL), washed successively with 10%
citric acid (30 mL ꢃ 2), a saturated aqueous NaHCO3 solution
(30 mL ꢃ 2), brine (30 mL ꢃ 2), dried over anhydrous Na2SO4,
and concentrated in vacuo to give 7 as colorless syrup, which
was used in the next reaction, without further purification:
1H NMR (CDCl3) ꢂ 1.02 (d, 3H, Thr’s CH3, J ¼ 6:0 Hz), 1.03 (s,
9H, TBDPS’s t-Bu), 1.05 (d, 3H, Val’s CH3, J ¼ 7:2 Hz), 1.06 (d,
3H, Val’s CH3, J ¼ 7:2 Hz), 1.48 (s, 9H, Boc’s t-Bu), 2.22–2.261
(m, 1H, Val’s ꢁ-H), 3.60 (s, 3H, COOCH3), 4.44–4.50 (m, 3H,
Thr’s ꢀ-H, Thr’s ꢁ-H, Val’s ꢁ-H), 5.16 (s, 1H, Olefin’s H),
6.04 (s, 1H, Olefin’s H), 6.52 (d, 1H, NH, J ¼ 9:0 Hz), 6.90 (d,
1H, NH, J ¼ 7:8 Hz), 7.30–7.64 (m, 10H, PhH ꢃ 2).
mL), and the mixture was stirred at 0 ꢂC for 30 min, then at room
temperature for 10 h. The reaction mixture was concentrated in
vacuo to give brown syrup, which was diluted with CHCl3 (10
mL) and washed with water (10 mL). The organic layer was dried
over anhydrous Na2SO4 and concentrated in vacuo to give brown
syrup, which was dissolved with DME (10 mL). To the solution
were added TFAA (trifluoroacetic anhydride) (203 mL, 1.44 mmol)
and pyridine (254 mL, 3.17 mmol) at 0 ꢂC for 30 min. Concentra-
tion in vacuo gave brown syrup, which was further dissolved with
EtOAc (15 mL). The reaction mixture was washed with brine
(10 mL ꢃ 2) and stirred with 28% aqueous NH3 at 0 ꢂC. After stir-
ring for 15 min, the reaction mixture was washed with brine (10
mL) and dried over anhydrous Na2SO4, and concentrated in vacuo
giving a brown syrup, which was purified on a silica gel column
eluted with hexane–EtOAc (2:1 v/v) to give 12 as yellow syrup.
24
Yield 90% (606 mg): ½ꢀꢄD ꢁ35:2ꢂ (c 1.00, MeOH); IR 3399,
2965, 1610, 1530, 1165 cmꢁ1 1H NMR (CDCl3) ꢂ 0.95 (d, 3H,
;
Val’s CH3, J ¼ 6:4 Hz), 0.98 (d, 3H, Val’s CH3, J ¼ 6:4 Hz), 1.01
(s, 9H, TBDPS’s t-Bu), 1.02 (d, 3H, Val’s CH3, J ¼ 6:4 Hz), 1.04
(d, 3H, Val’s CH3, J ¼ 7:2 Hz), 1.06 (d, 3H, Val’s CH3, J ¼ 7:2
Hz), 1.07 (d, 3H, Val’s CH3, J ¼ 6:6 Hz), 1.28 (d, 3H, Thr’s CH3,
J ¼ 7:2 Hz), 1.38 (s, 9H, Boc’s t-Bu), 2.25–2.61 (m, 3H, Val’s ꢁ-
H ꢃ 3), 3.61 (s, 3H, COOCH3), 4.45 (m, 1H, Thr’s ꢁ-H), 4.62 (m,
1H, Val’s ꢀ-H), 4.78 (m, 1H, Thr’s ꢀ-H), 4.87 (dd, 1H, Val’s ꢀ-
H, J ¼ 5:4, 8.6 Hz), 5.16 (d, 1H, NH, J ¼ 8:9 Hz), 5.56 (m, 1H,
Val’s ꢀ-H), 6.61 (d, 1H, NH, J ¼ 5:5 Hz), 7.26–7.63 (m, 10H,
PhH ꢃ 2), 8.01 (d, 1H, NH, J ¼ 5:0 Hz), 8.03 (s, 1H, thiazole’s
ring-H), 8.05 (s, 1H, thiazole’s ring-H), 8.10 (d, 1H, NH, J ¼
6:0 Hz); Anal. Calcd for C47H66N6O8S2Si: C, 60.36; H, 7.11; N,
8.99%. Found: C, 60.54; H, 7.58; N, 9.09%.
N-Boc–DL-(ꢀ-Br–ꢁ-MeO)Ala–L-Val–(O-TBDPS)–L-Thr–
OMe 11. To a solution of 7 (2.01 g, 3.14 mmol) in MeOH
(50 mL) at 0 ꢂC was added NBS (614 mg, 3.45 mmol), and the
mixture was stirred at 0 ꢂC for 30 min. The reaction mixture was
poured into water (50 mL) and the resulting solution was extracted
with EtOAc (30 mL ꢃ 2). The combined organic phases were
dried over anhydrous Na2SO4 and then concentrated in vacuo to
give brown syrup. Purification on a silica gel column eluted with
hexane–EtOAc (2:3 v/v) gave 11 as colorless syrup. Diastereo-
mer. Yield 87% (2.05 g): IR 3356, 2964, 1753, 1737, 1726, 1708,
Methyl (S,S,S)-2-[2-(1-{2-[1-(N-Boc)Amino-2-methylpropyl]-
thiazole-4-carbonylamino}-2-methylpropyl)thiazole-4-carbon-
yl]-L-threonate (13). To a solution of 12 (200 mg, 0.21 mmol) in
THF (2 mL) at 0 ꢂC was added 1 M TBAF (tetrabutylammonium
fluoride 1 mol Lꢁ1 THF solution) (321 mL), and the mixture was
stirred at 0 ꢂC for 1 h, then at room temperature for 1 h. The
reaction mixture was concentrated in vacuo to give brown syrup,
which was purified on a silica gel column eluted with hexane–ace-
tone (3:2 v/v) to give 13 as colorless syrup. Yield 95% (139 mg):
1691, 1678, 1648, 1529 cmꢁ1 1H NMR (CDCl3) ꢂ 1.02, 1.03
;
(each s, 9H, TBDPS’s t-Bu), 1.08, 1.09 (each d, 3H, Val’s CH3,
J ¼ 6:6 Hz), 1.29 (d, 3H, Thr’s CH3, J ¼ 6:4 Hz), 1.45, 1.46 (each
s, 9H, Boc’s t-Bu), 2.18–2.21 (m, 1H, Val’s ꢁ-H), 3.23 (s, 3H,
OCH3), 3.59 (s, 3H, COOCH3), 4.33–4.52 (m, 6H, Ser’s ꢁ-
H ꢃ 2, Ser’s ꢀ-H, Thr’s ꢀ-H, Thr’s ꢁ-H, BocNH), 6.45 (br s,
1H, NH, J ¼ 8:4 Hz), 7.15 (br s, 1H, NH, J ¼ 8:4 Hz), 7.35–7.49
(m, 10H, PhH ꢃ 2); Anal. Calcd for C35H52BrN3O8Si: C, 55.99;
H, 6.98; N, 5.60%. Found: C, 56.18; H, 6.85; N, 5.83%.
24
½ꢀꢄD ꢁ52:2ꢂ (c 1.00, MeOH); IR 3400, 2965, 1610, 1530, 1165
1
cmꢁ1; H NMR (CDCl3) ꢂ 0.95 (d, 3H, Val’s CH3, J ¼ 6:4 Hz),
0.98 (d, 3H, Val’s CH3, J ¼ 6:4 Hz), 1.02 (d, 3H, Val’s CH3, J ¼
6:4 Hz), 1.04 (d, 3H, Val’s CH3, J ¼ 7:2 Hz), 1.06 (d, 3H, Val’s
CH3, J ¼ 7:2 Hz), 1.07 (d, 3H, Val’s CH3, J ¼ 6:6 Hz), 1.28 (d,
3H, Thr’s CH3, J ¼ 7:2 Hz), 1.38 (s, 9H, Boc’s t-Bu), 2.25–2.61
(m, 3H, Val’s ꢁ-H ꢃ 3), 3.61 (s, 3H, COOCH3), 4.45 (m, 1H,
Thr’s ꢁ-H), 4.62 (m, 1H, Val’s ꢀ-H), 4.78 (m, 1H, Thr’s ꢀ-H),
4.87 (dd, 1H, Val’s ꢀ-H, J ¼ 5:4, 8.6 Hz), 5.16 (d, 1H, NH, J ¼
8:9 Hz), 5.56 (m, 1H, Val’s ꢀ-H), 6.61 (d, 1H, NH, J ¼ 5:5 Hz),
8.01 (d, 1H, NH, J ¼ 5:0 Hz), 8.03 (s, 1H, thiazole’s ring-H), 8.05
(s, 1H, thiazole’s ring-H), 8.10 (d, 1H, NH, J ¼ 6:0 Hz); Anal.
Calcd for C31H48N6O8S2: C, 53.43; H, 6.94; N, 12.06%. Found:
C, 53.65; H, 7.08; N, 12.36%.
N-(3-Bromo-2-oxopropanoyl)–L-Val–(O-TBDPS)–L-Thr–
OMe 5. A solution of 11 (1.20 g, 1.60 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, and concentrated in vacuo gave 5 as colorless
syrup, which was used intact in the next reaction, without purifi-
1
cation. Yield 92% (0.91 g): H NMR (CDCl3) ꢂ 1.02, 1.03 (each
s, 9H, TBDPS’s t-Bu), 1.08, 1.09 (each d, 3H, Val’s CH3, J ¼
6:6 Hz), 1.29 (d, 3H, Thr’s CH3, J ¼ 6:4 Hz), 2.18–2.21 (m, 1H,
Val’s ꢁ-H), 3.61 (s, 3H, COOCH3), 4.33–4.62 (m, 5H, Ser’s ꢁ-
H ꢃ 2, Ser’s ꢀ-H, Thr’s ꢀ-H, Thr’s ꢁ-H), 6.45 (br s, 1H, NH,
J ¼ 8:4 Hz), 7.15 (br s, 1H, NH, J ¼ 8:4 Hz), 7.35–7.49 (m, 10H,
PhH ꢃ 2).
Bistratamide J (1). To a solution of 13 (139 mg, 0.20 mmol)
in a mixture of THF and water (1:1 v/v) (20 mL) at 0 ꢂC was add-
ed 1 M LiOH (5 mL), and the mixture was stirred for 1 h and then
at room temperature for 2 h. The reaction mixture was acidified
with citric acid. The resulting solution was extracted with EtOAc
(20 mL ꢃ 3) and the organic phases were washed with brine
(10 mL ꢃ 2) and then dried over anhydrous Na2SO4, and concen-
trated in vacuo giving (S,S,S)-2-[2-(1-{2-[1-(N-Boc)amino-2-meth-
ylpropyl]thiazole-4-carbonylamino}-2-methylpropyl)thiazole-4-car-
Methyl (S,S,S)-2-[2-(1-{2-[1-(N-Boc)Amino-2-methylpropyl]-
thiazole-4-carbonylamino}-2-methylpropyl)thiazole-4-carbon-
yl]-(O-TBDPS)-L-threonate (12). To a solution of 49c (300 mg,
0.72 mmol) in DME (10 mL) at 0 ꢂC were added K2CO3 (796 mg,
5.76 mmol) and a solution of 5 (672 mg, 1.09 mmol) in DME (10

H. Suzuki et al.
Bull. Chem. Soc. Jpn. Vol. 81, No. 4 (2008)
499
bonyl]-L-Thr–OH as colorless syrup. To remove the Boc group,
we stirred a solution of the above product in a mixture of TFA
and CHCl3 (1:3 v/v) (20 mL) at room temperature for 2 h. The
reaction mixture was concentrated in vacuo to give (S,S,S)-2-
(2-{1-[2-(1-amino-2-methylpropyl)thiazole-4-carbonylamino]-2-
methylpropyl}thiazole-4-carbonyl)-L-Thr–OH as colorless crys-
tals. To the solution of this product in a mixture of dry DMF and
CH2Cl2 (1:2 v/v) (20 mL) at 0 ꢂC were added a solution of BOP
(132 mg, 0.30 mmol) and (i-Pr)2NEt (30.0 mg, 0.24 mmol) in dry
DMF (5 mL), and the mixture was stirred at 0 ꢂC for 1 h, then at
room temperature for 2 days. The reaction mixture was diluted
with water (25 mL) and extracted with EtOAc (50 mL ꢃ 4). The
combined extracts were washed with brine (20 mL ꢃ 2) and then
dried over anhydrous Na2SO4, and concentrated in vacuo giving
brown syrup, which was purified on a silica gel column eluted
with hexane–EtOAc (1:3 v/v) to give 1 as white solid. Yield
72% (81 mg).
2.01–2.07 (m, 1H, Val’s ꢁ-H), 2.19–2.24 (m, 1H, Val’s ꢁ-H),
2.32–2.35 (m, 1H, Val’s ꢁ-H), 4.76–4.79 (m, 2H, oxazoline’s
4-H and Val’s ꢀ-H), 5.27 (dq, 1H, oxazoline’s 5-H, J ¼ 6:5,
10.7 Hz), 5.37 (dd, 1H, Val’s ꢀ-H, J ¼ 5:2, 9.5 Hz), 5.51 (dd,
1H, Val’s ꢀ-H, J ¼ 4:8, 8.9 Hz), 7.96 (d, 1H, NH, J ¼ 9:6 Hz),
8.16 (d, 1H, NH, J ¼ 9:8 Hz), 8.36 (s, 1H, thiazole’s ring-H),
8.38 (s, 1H, thiazole’s ring-H), 8.56 (d, 1H, NH, J ¼ 9:8 Hz);
13C NMR (150 MHz, DMSO-d6) ꢂ 16.0, 16.9, 17.5, 18.1, 18.7,
18.8, 22.0, 30.5, 34.4, 34.5, 51.0, 53.8, 54.7, 69.9, 79.6, 125.0,
125.1, 147.6, 148.2, 158.8, 159.3, 167.6, 168.0, 168.1, 168.9;
HR-ESI-MS Calcd for C25H35N6KO4S2: 585.1720. Found: m=z
595.1666 (M þ Kþ).
Compound 17. To a solution of 16 (38.2 mg, 0.07 mmol) in
THF (5 mL) at 0 ꢂC was added 1 M HCl (5 mL), and the mixture
was stirred at 0 ꢂC for 30 min, then at room temperature for 1 h.
The solution was then made alkaline (pH 9.5) by addition of
solid K2CO3. The reaction mixture was extracted with EtOAc
(10 mL ꢃ 2), and the organic phases were concentrated in vacuo
giving colorless syrup. The resulting residue was dissolved in
MeOH (5 mL) at room temperature then to it was added basic alu-
mina (57.1 mg, 0.56 mmol), and the mixture was heated to reflux
for 4 h. The reaction mixture was cooled to room temperature, so-
nicated for 5 min, and then vacuum filtered to remove the alumina.
The filtrate was concentrated in vacuo and purified on a silica gel
column eluted with hexane–acetone (1:3 v/v) to give 17 as clear
25
Synthesized: Mp 165.0–166.0 ꢂC; ½ꢀꢄD ꢁ139:9ꢂ (c 0.50,
MeOH); IR 3380, 2955, 2903, 1661, 1535, 1502, 1490 cmꢁ1
;
1H NMR (600 MHz, DMSO-d6, 1.00 mg/0.75 mL) ꢂ 0.81 (d, 3H,
Val’s CH3, J ¼ 6:5 Hz), 0.91 (d, 3H, Val’s CH3, J ¼ 6:5 Hz),
0.99 (d, 3H, Val’s CH3, J ¼ 6:7 Hz), 1.03 (d, 3H, Val’s CH3, J ¼
6:5 Hz), 1.04 (d, 3H, Val’s CH3, J ¼ 6:5 Hz), 1.05 (d, 3H, Val’s
CH3, J ¼ 6:4 Hz), 1.10 (d, 3H, Thr’s CH3, J ¼ 6:4 Hz), 2.11–
2.19 (m, 2H, Val’s ꢁ-H ꢃ 2), 2.20–2.25 (m, 1H, Val’s ꢁ-H),
4.10–4.15 (m, 1H, Thr’s ꢁ-H), 4.30 (dd, 1H, Thr’s ꢀ-H, J ¼
2:2, 10.0 Hz), 4.34 (t, 1H, Val’s ꢀ-H, J ¼ 10:8 Hz), 5.19 (t, 1H,
Val’s ꢀ-H, J ¼ 9:1 Hz), 5.28 (br d, 1H, OH, J ¼ 4:8 Hz), 5.32
(dd, 1H, Val’s ꢀ-H, J ¼ 7:4, 10.1 Hz), 8.08 (d, 1H, NH, J ¼
10:0 Hz), 8.15 (d, 1H, NH, J ¼ 9:3 Hz), 8.24 (s, 1H, thiazole’s
ring-H), 8.30 (s, 1H, thiazole’s ring-H), 8.44 (d, 1H, NH, J ¼
9:8 Hz), 8.50 (d, 1H, NH, J ¼ 10:7 Hz); 13C NMR (150 MHz,
DMSO-d6) ꢂ 18.6, 18.8, 18.9, 19.4, 19.5, 19.8, 21.2, 30.8,
34.2, 34.6, 55.0, 55.4, 59.0, 61.4, 67.7, 124.1, 125.3, 148.3,
149.0, 159.7, 160.0, 169.4, 169.9, 170.0, 170.1; HR-ESI-MS
Calcd for C25H36N6NaO5S2: 587.2086. Found: m=z 587.2090
(M þ Naþ).
24
crystals. Yield 72% (24.5 mg): ½ꢀꢄD ꢁ42:0ꢂ (c 0.92, CHCl3); IR
3375, 3306, 2955, 1660, 1595, 1535, 1530 cmꢁ1 1H NMR (600
;
MHz, CDCl3) ꢂ 0.85 (d, 3H, Val’s CH3, J ¼ 6:7 Hz), 0.91 (d,
3H, Val’s CH3, J ¼ 6:7 Hz), 0.99 (d, 6H, Val’s CH3 ꢃ 2, J ¼
6:7 Hz), 1.04 (d, 3H, Val’s CH3, J ¼ 6:5 Hz), 1.05 (d, 3H, Val’s
CH3, J ¼ 6:3 Hz), 1.14 (d, 3H, Thr’s CH3, J ¼ 6:5 Hz), 2.10–2.18
(m, 3H, Val’s ꢁ-H ꢃ 3), 4.26 (t, 1H, Val’s ꢀ-H, J ¼ 10:8 Hz),
4.42 (dd, 1H, Thr’s ꢀ-H, J ¼ 3:4, 10.3 Hz), 5.12 (t, 1H, Val’s
ꢀ-H, J ¼ 8:4 Hz), 5.32 (dd, 1H, Val’s ꢀ-H, J ¼ 7:6, 10.0 Hz),
5.46 (br s, 1H, OH), 8.07 (d, 1H, NH, J ¼ 8:9 Hz), 8.24 (s, 1H,
thiazole’s ring-H), 8.29 (s, 1H, thiazole’s ring-H), 8.42 (d, 1H,
NH, J ¼ 10:0 Hz), 8.48 (d, 1H, NH, J ¼ 10:7 Hz); 13C NMR
(150 MHz, CDCl3) ꢂ 17.1, 18.6, 18.9, 19.1, 19.6, 20.2, 29.8, 34.4,
34.7, 56.1, 57.8, 62.2, 67.0, 123.3, 123.4, 147.8, 149.8, 160.0,
161.0, 168.9, 169.1, 170.3, 172.1; HR-ESI-MS Calcd for C25H36-
N6NaO5S2: 587.2086. Found: m=z 587.2069 (M þ Naþ).
Lit:7 White solid, mp 165.0–167.0 ꢂC; ½ꢀꢄD ꢁ134:9ꢂ (c 0.5,
MeOH); 1H NMR (600 MHz, DMSO-d6) ꢂ 0.81 (d, 3H, J ¼
6:6 Hz), 0.91 (d, 3H, J ¼ 6:6 Hz), 0.99 (d, 3H, J ¼ 6:6 Hz), 1.03
(d, 3H, J ¼ 6:6 Hz), 1.04 (d, 3H, J ¼ 5:8 Hz), 1.05 (d, 3H, J ¼
6:1 Hz), 1.11 (d, 3H, J ¼ 6:6 Hz), 2.11–2.16 (m, 2H), 2.22 (m,
1H), 4.14 (m, 1H), 4.32 (dd, 1H, J ¼ 2:0, 10.1 Hz), 4.35 (t, 1H,
J ¼ 11:0 Hz), 5.20 (dd, 1H, J ¼ 9:2, 9.7 Hz), 5.22 (t, 1H, J ¼
4:8 Hz), 5.33 (dd, 1H, J ¼ 7:4, 10.1 Hz), 8.08 (d, 1H, J ¼ 10:1
Hz), 8.13 (d, 1H, J ¼ 9:3 Hz), 8.24 (s, 1H), 8.30 (s, 1H), 8.43 (d,
1H, J ¼ 9:7 Hz), 8.49 (d, 1H, J ¼ 10:5 Hz), 13C NMR (150 MHz,
DMSO-d6) ꢂ 18.6, 18.8, 18.9, 19.4, 19.5, 19.8, 21.3, 30.8, 34.3,
34.7, 55.0, 55.4, 58.8, 61.3, 67.7, 124.2, 125.4, 148.3, 149.0,
159.7, 159.9, 169.4 (2C), 170.1 (2C).
Bistratamide H (2). Method A: Similarly to the case of 7,
the dehydration of 1 (52.3 mg, 0.09 mmol) with Et3N (20.0 mg,
0.20 mmol), MsCl (17.5 mg, 0.15 mmol), and DBU (19.2 mg,
0.13 mmol) in CHCl3 (10 mL) was worked up to give a brown
residue 14. To a solution of the residue in CHCl3 (10 mL) at
0 ꢂC was added NBS (17.6 mg, 0.10 mmol), and the mixture was
stirred at room temperature for 3 h. Then, Et3N (10.1 mg, 0.10
mmol) was added to the reaction mixture at 0 ꢂC, and stirred at
0 ꢂC for 30 min, then at room temperature for 5 h. The reaction
mixture was diluted with diethyl ether (10 mL) and washed suc-
cessively with 10% citric acid (15 mL ꢃ 2), a saturated NaHCO3
solution (15 mL ꢃ 2), brine (15 mL ꢃ 2), then dried over anhy-
drous Na2SO4, and concentrated in vacuo gave brown syrup 15,
which was dissolved with dioxane (10 mL). Cs2CO3 (75.0 mg,
0.23 mmol) was added to the solution at room temperature, the
reaction mixture was stirred overnight at 60 ꢂC. The reaction mix-
ture was diluted with water (10 mL) and extracted with EtOAc
(20 mL ꢃ 3). The organic phases were washed with brine (10
mL), dried over anhydrous Na2SO4, and concentrated in vacuo
to give brown syrup, which was purified on a silica gel column
eluted with hexane–acetone (1:3 v/v) to give 2 as colorless crys-
Compound 16. A solution of 1 (66.7 mg, 0.12 mmol) and
Burgess reagent (methyl N-[(triethylammonio)sulfonyl]carba-
mate) (113 mg, 0.47 mmol) in THF (5 mL) was stirred at 80 ꢂC for
2 h. The reaction mixture was concentrated in vacuo to give brown
syrup, which was purified on a silica gel column with acetone to
give 16 as clear crystals. Yield 65% (42.0 mg): mp 92–94 ꢂC;
25
½ꢀꢄD ꢁ34:6ꢂ (c 0.5, MeOH); IR 3380, 2960, 2903, 1660, 1538,
1
1502, 1494 cmꢁ1; H NMR (600 MHz, DMSO-d6) ꢂ 0.87 (d, 3H,
Val’s CH3, J ¼ 6:9 Hz), 0.89 (d, 3H, Val’s CH3, J ¼ 7:0 Hz), 0.91
(d, 3H, Val’s CH3, J ¼ 6:7 Hz), 0.92 (d, 3H, Val’s CH3, J ¼ 6:9
Hz), 0.95 (d, 3H, Val’s CH3, J ¼ 6:9 Hz), 0.99 (d, 3H, Val’s CH3,
J ¼ 6:9 Hz), 1.25 (d, 3H, oxazoline’s ring CH3, J ¼ 6:5 Hz),

500 Bull. Chem. Soc. Jpn. Vol. 81, No. 4 (2008)
Total Syntheses of Bistratamides
tals. Yield 70% (34.3 mg).
3H, J ¼ 7:0 Hz), 0.90 (d, 3H, J ¼ 7:0 Hz), 0.95 (d, 3H, J ¼ 7:0
Hz), 1.46 (d, 3H, J ¼ 6:0 Hz), 2.04 (m, 1H), 2.21 (m, 1H), 2.32
(m, 1H), 4.22 (dd, 1H, J ¼ 5:0, 9.0 Hz), 4.79 (m, 2H), 5.29 (dd,
1H, J ¼ 5:0, 9.0 Hz), 5.51 (dd, 1H, J ¼ 4:5, 8.5 Hz), 7.78 (d,
1H, J ¼ 9:0 Hz), 8.04 (d, 1H, J ¼ 9:5 Hz), 8.36 (s, 1H), 8.38 (s,
1H), 8.56 (d, 1H, J ¼ 8:5 Hz); 13C NMR (100 MHz, DMSO-d6)
ꢂ 16.0, 17.4, 17.5, 17.9, 18.2, 18.9, 21.4, 30.4, 34.2, 34.3, 51.1,
53.9, 54.7, 72.7, 81.9, 124.7, 124.9, 147.3, 147.8, 158.5, 159.0,
167.5, 167.6, 167.9, 169.0.
Method B: Into a solution of 3 (11.5 mg, 0.02 mmol) in THF
(5 mL) at room temperature was added MnO2 (6.96 mg, 0.08
mmol), and the mixture was stirred at 70 ꢂC for 5 h. The mixture
was cooled to room temperature, and then vacuum filtered to re-
move the MnO2. The filtrate was concentrated in vacuo to give
brown syrup, which was purified on a silica gel column with
acetone to give 2 as white solid. Yield 73% (7.95 mg).
25
Synthesized:
Mp 199.0–200.0 ꢂC; ½ꢀꢄD ꢁ92:5ꢂ (c 1.00,
MeOH); IR 3380, 3305, 2955, 1660, 1595, 1535, 1530 cmꢁ1
;
1H NMR (600 MHz, DMSO-d6, 1.00 mg/0.75 mL) ꢂ 0.91 (d, 3H,
Val’s CH3, J ¼ 6:9 Hz), 0.940 (d, 3H, Val’s CH3, J ¼ 6:9 Hz),
0.943 (d, 3H, Val’s CH3, J ¼ 6:9 Hz), 0.95 (d, 3H, Val’s CH3,
J ¼ 7:2 Hz), 0.97 (d, 3H, Val’s CH3, J ¼ 7:0 Hz), 0.99 (d, 3H,
Val’s CH3, J ¼ 6:7 Hz), 2.16–2.28 (m, 3H, Val’s ꢁ-H ꢃ 3), 2.59
(s, 3H, oxazole’s ring CH3), 5.07 (dd, 1H, Val’s ꢀ-H, J ¼ 5:2, 8.4
Hz), 5.35 (dd, 1H, Val’s ꢀ-H, J ¼ 5:5, 8.6 Hz), 5.45 (dd, 1H,
Val’s ꢀ-H, J ¼ 6:7, 9.8 Hz), 8.33 (s, 1H, thiazole’s ring-H), 8.34
(s, 1H, thiazole’s ring-H), 8.36 (d, 1H, NH, J ¼ 8:6 Hz), 8.50 (d,
1H, NH, J ¼ 8:6 Hz), 8.52 (d, 1H, NH, J ¼ 9:8 Hz); 13C NMR
(150 MHz, DMSO-d6) ꢂ 11.2, 17.9, 18.0, 18.1, 18.3, 18.5, 18.9,
32.8, 34.4, 34.5, 52.2, 54.5, 54.8, 124.8, 125.3, 127.8, 147.8,
148.3, 153.2, 159.0, 159.4, 159.7, 160.5, 168.4, 168.9; HR-ESI-
MS Calcd for C25H33N6NaO4S2: 567.1824. Found: m=z 567.1757
(M þ Naþ).
References
1
247.
2
L. J. Perez, D. J. Faulkner, J. Nat. Prod. 2003, 66,
a) D. L. Evans, D. K. Minster, U. Jordis, S. M. Hecht, A. L.
Mazzu, A. I. Meyers, J. Org. Chem. 1979, 44, 497. b) C. W.
Holzapfel, G. R. Pettit, J. Org. Chem. 1985, 50, 2323. c) R.
Houssin, M. Lohez, J. L. Bernier, J. P. Henichart, J. Org. Chem.
1985, 50, 2787. d) R. C. Kelly, I. Gebhard, N. Wicnienski, J.
Org. Chem. 1986, 51, 4590. e) Y. Hamada, M. Shibata, M.
Sugiura, S. Kato, T. Shioiri, J. Org. Chem. 1987, 52, 1252.
f) M. W. Bredenkamp, C. W. Holzapfel, W. J. van Zyl, Synth.
Commun. 1990, 20, 2235. g) M. North, G. Pattenden, Tetrahedron
1990, 46, 8267. h) P. Wipf, C. P. Miller, J. Org. Chem. 1993, 58,
3604. i) E. Aguilar, A. I. Meyers, Tetrahedron Lett. 1994, 35,
2473. j) P. Wipf, C. P. Miller, S. Venkatraman, P. C. Fritch,
Tetrahedron Lett. 1995, 36, 6395. k) P. Lafargue, P. Guenot,
J. P. Lellouche, Synlett 1995, 171. l) A. I. Meyers, F. X. Tavares,
J. Org. Chem. 1996, 61, 8207. m) D. R. Williams, P.-D. Lowder,
Y.-G. Gu, D. A. Brooks, Tetrahedron Lett. 1997, 38, 331. n) A. J.
Phillips, Y. Uto, P. Wipf, M. J. Reno, D. R. Williams, Org. Lett.
2000, 2, 1165.
Natural: Clear solid; ½ꢀꢄD ꢁ92:9ꢂ (c 1.0, MeOH); IR 3390,
2955, 1670, 1530, 1505, 1490 cmꢁ1; 1H NMR (400 MHz, DMSO-
d6) ꢂ 0.90 (d, 3H, J ¼ 7:0 Hz), 0.93 (d, 3H, J ¼ 7:0 Hz), 0.94 (d,
3H, J ¼ 7:0 Hz), 0.95 (d, 3H, J ¼ 7:0 Hz), 0.96 (d, 3H, J ¼ 7:0
Hz), 0.97 (d, 3H, J ¼ 7:0 Hz), 2.21 (m, 3H, J ¼ 6:0 Hz), 2.58 (s,
3H), 5.06 (dd, 1H, J ¼ 5:0, 8.5 Hz), 5.34 (dd, 1H, J ¼ 5:0,
8.5 Hz), 5.44 (dd, 1H, J ¼ 6:5, 9.5 Hz), 8.32 (s, 1H), 8.34 (s, 1H),
8.35 (d, 1H, J ¼ 9:5 Hz), 8.48 (d, 1H, J ¼ 9:0 Hz), 8.52 (d, 1H,
J ¼ 8:5 Hz); 13C NMR (100 MHz, DMSO-d6) ꢂ 11.3, 18.0, 18.1,
18.2, 18.3, 18.5, 18.9, 32.8, 34.4, 34.5, 52.2, 54.5, 54.7, 124.5,
125.0, 127.6, 147.5, 148.0, 152.9, 158.7, 159.1, 159.4, 160.2,
168.1, 168.6.
3 J. Ogino, R. E. Moore, G. M. L. Patterson, C. D. Smith, J.
Nat. Prod. 1996, 59, 581.
4
a) A. Bertram, G. Pattenden, Synlett 2000, 1519. b) A.
Bertram, G. Pattenden, Synlett 2001, 1873.
5
6
Z. Xia, C. D. Smith, J. Org. Chem. 2001, 66, 3459.
a) A. Bertram, G. Pattenden, Heterocycles 2002, 58, 521.
Bistratamide E (3). Similarly to the case of 16, the cycliza-
tion of 17 (44.0 mg, 0.08 mmol) with Burgess reagent (76.3 mg,
0.32 mmol) in THF (3 mL) was worked up to give 3 as white solid.
Yield 65% (28.4 mg).
b) A. Bertram, N. Maulucci, O. M. New, S. M. M. Nor, G.
Pattenden, Org. Biomol. Chem. 2007, 5, 1541.
7
a) S.-L. You, J. W. Kelly, J. Org. Chem. 2003, 68, 9506.
25
Synthesized: Mp 91.0–96.0 ꢂC; ½ꢀꢄD ꢁ32:3ꢂ (c 1.0, MeOH);
b) S. L. You, J. W. Kelly, Chem. Eur. J. 2004, 10, 71. c) S. L.
You, J. W. Kelly, Tetrahedron 2005, 61, 241.
IR 3380, 3305, 2955, 1660, 1595, 1535, 1530 cmꢁ1; 1H NMR (600
MHz, DMSO-d6, 1.00 mg/0.75 mL) ꢂ 0.85 (d, 6H, Val’s CH3 ꢃ
2, J ¼ 6:6 Hz), 0.86 (d, 3H, Val’s CH3, J ¼ 6:1 Hz), 0.89 (d, 3H,
Val’s CH3, J ¼ 6:6 Hz), 0.90 (d, 3H, Val’s CH3, J ¼ 7:0 Hz), 0.95
(d, 3H, Val’s CH3, J ¼ 7:0 Hz), 1.47 (d, 3H, oxazoline’s CH3, J ¼
6:1 Hz), 2.03–2.06 (m, 1H, Val’s ꢁ-H), 2.20–2.27 (m, 1H, Val’s
ꢁ-H), 2.32–2.36 (m, 1H, Val’s ꢁ-H), 4.24 (dd, 1H, oxazoline’s
4-H, J ¼ 1:8, 8.8 Hz), 4.78 (dq, 1H, oxazoline’s 5-H, J ¼ 6:1,
8.3 Hz), 4.83 (m, 1H, Val’s ꢀ-H), 5.30 (dd, 1H, Val’s ꢀ-H, J ¼
5:3, 8.8 Hz), 5.52 (dd, 1H, Val’s ꢀ-H, J ¼ 4:4, 8.3 Hz), 7.79 (d,
1H, NH, J ¼ 8:8 Hz), 8.05 (d, 1H, NH, J ¼ 9:7 Hz), 8.36 (s,
1H, thiazole’s ring-H), 8.39 (s, 1H, thiazole’s ring-H), 8.57 (d,
1H, NH, J ¼ 8:3 Hz); 13C NMR (150 MHz, DMSO-d6) ꢂ 16.0,
17.4, 17.5, 17.9, 18.1, 18.9, 21.4, 30.5, 34.2, 34.3, 51.2, 53.9,
54.8, 72.8, 81.9, 124.7, 125.0, 147.6, 147.9, 158.8, 159.1, 167.9,
168.0, 168.2, 169.4; HR-ESI-MS Calcd for C25H35N6NaO4S2:
569.1981. Found: m=z 569.1977 (M þ Naþ).
8
Y. Nakamura, K. Okumura, M. Kojima, S. Takeuchi,
Tetrahedron Lett. 2006, 47, 239.
a) Y. Yonezawa, N. Tani, C. Shin, Heterocycles 2005, 65,
9
95. b) C. Shin, C. Abe, Y. Yonezawa, Chem. Lett. 2004, 33, 664.
c) Y. Yonezawa, N. Tani, C. Shin, Bull. Chem. Soc. Jpn. 2005, 78,
1492.
10 a) T. Suzuki, A. Nagasaki, K. Okumura, C. Shin, Hetero-
cycles 2001, 55, 835. b) A. Nagasaki, Y. Adachi, Y. Yonezawa,
C. Shin, Heterocycles 2003, 60, 321.
11 H. Saito, T. Yamada, K. Okumura, Y. Yonezawa, C. Shin,
Chem. Lett. 2002, 1098.
12 T. Yamada, K. Okumura, Y. Yonezawa, C. Shin, Chem.
Lett. 2001, 102.
13 a) N. Endoh, K. Tsuboi, R. Kim, Y. Yonezawa, C. Shin,
Heterocycles 2003, 60, 1567. b) J. Das, J. A. Reid, D. R.
Kronenthal, J. Singh, P. D. Pansegrau, R. H. Mueller, Tetrahedron
Lett. 1992, 33, 7835.
14 a) P. Wipf, C. P. Miller, Tetrahedron Lett. 1992, 33, 907.
b) P. Wipf, C. P. Miller, Tetrahedron Lett. 1992, 33, 6267.
Natural: Clear glass; ½ꢀꢄD ꢁ31:0ꢂ (c 1.0, MeOH); IR 3390,
2955, 1670, 1535, 1510, 1495 cmꢁ1; 1H NMR (400 MHz, DMSO-
d6) ꢂ 0.84 (d, 6H, J ¼ 7:0 Hz), 0.86 (d, 3H, J ¼ 7:0 Hz), 0.88 (d,

H. Suzuki et al.
Bull. Chem. Soc. Jpn. Vol. 81, No. 4 (2008)
501
15 a) P. Wipf, C. P. Miller, J. Am. Chem. Soc. 1992, 114,
10975. b) S. V. Downing, E. Aguilar, A. I. Meyers, J. Org. Chem.
1999, 64, 826.
16 In general, it is known that the chemical shifts of amide
protons change dependent on concentration. In this work,
1H NMR data of synthetic bistratamides 1–3 measured at the con-
centration (1.00 mg/0.75 mL DMSO-d6) were in good agreement
with that reported by Kelly’s group. However, the data measured
at (0.50 mg/0.75 mL DMSO-d6) were not in agreement.