The total synthesis of bistratamides F-I

Article abstract of DOI:10.1016/j.tet.2004.10.024

The total synthesis of bistratamides F-I (2-5) have been achieved in overall yields of 3, 10, 13, and 27%, respectively. The thiazole substructure was prepared utilizing a MnO₂ oxidation of a thiazoline, synthesized from a Val-Cys dipeptide usi

Full text of DOI:10.1016/j.tet.2004.10.024

Tetrahedron 61 (2005) 241–249
The total synthesis of bistratamides F–I
*
Shu-Li You and Jeffery W. Kelly
Department of Chemistry and The Skaggs Institute for Chemical Biology, The Scripps Research Institute, 10550 North Torrey Pines Road,
BCC265, La Jolla, CA 92037, USA
Received 6 August 2004; revised 8 October 2004; accepted 8 October 2004
Available online 5 November 2004
Dedicated to Professor Li-Xin Dai on the occasion of his 80th birthday
Abstract—The total synthesis of bistratamides F–I (2–5) have been achieved in overall yields of 3, 10, 13, and 27%, respectively. The
thiazole substructure was prepared utilizing a MnO2 oxidation of a thiazoline, synthesized from a Val-Cys dipeptide using
bis(triphenyl)oxodiphosphonium trifluoromethanesulfonate. The serine-based oxazole substructure was prepared from a Val-Ser dipeptide
using literature methods. The threonine-derived oxazole substructure was synthesized from a ketoamide dipeptide using the bisphosphonium
salt employed for thiazoline preparation. Most of the amide bonds were formed using HBTU and HOBt in the presence of DIEA. The final
macrocyclization step was accomplished efficiently by PyBOP and DMAP in all cases.
q 2004 Elsevier Ltd. All rights reserved.
1. Introduction
Thiazolines are readily converted into thiazoles by oxida-
tion.3a–d Recently, we reported a facile and efficient
biomimetic synthesis of thiazolines accomplished by
treating N-acylated cysteines with bis(triphenyl)oxodiphos-
phonium trifluoromethanesulfonate.10 Dendroamide A, as
well as bistratamides E (1) and J (6) have been recently
efficiently synthesized by taking advantage of this method-
ology.11 In this paper, we report the synthesis of
bistratamides F–I (2–5, respectively) using bis(triphenyl)-
oxodiphosphonium trifluoromethanesulfonate to construct
the thiazoline and threonine-derived oxazole precursors.
Amide bond formation was utilized to stitch the hetero-
cyclic amino acids together while PyBOP and DMAP were
employed to facilitate the final macrolactamization.
Many oxazole and/or thiazole-containing macrocycles have
been recently isolated from marine organisms.1–2 Their
activities as cytotoxic agents and multiple drug resistance
inhibitors, as well as their metal binding and transport
properties have led to much synthetic interest.3 Bistrata-
mides are a family of macrolactams isolated from
Lissoclinum bistratum in the southern Philippines.4 Their
interesting biological activities led to total syntheses of
three bistratamide family members.5 Bistratamides E–J
(1–6) were very recently isolated and exhibit moderate
cytotoxic activity against a human colon tumor (HCT-116)
cell line (Fig. 1).4c The antimicrobial, antitumor and the
anti-drug resistance properties of members of this family of
natural products warrant the synthetic efforts published thus
far to prepare natural products related to bistratamides E–J.
2. Results and discussion
The retrosynthetic analysis for bistratamide F (2) is shown
in Figure 2. Disconnections at the amide bonds result in two
Fmoc-protected a-amino acids and two heterocyclic amino
acids derived from dipeptides.
Construction of the thiazoles in these macrolactams is
central to their total synthesis. Commonly used methods for
the preparation of thiazolines and thiazoles include (1) a
modification of Hantzsch’s procedure using thioamides as
intermediates,6 (2) a condensation reaction between
cysteine esters and N-protected imino esters,7 and (3) the
cyclodehydration of b-hydroxythioamides using either
Mitsunobu conditions or the Burgess reagent.8–9
The thiazole-containing fragment (7) was synthesized as
shown in Scheme 1. The synthesis commences with the
protection of the carboxylic acid of N-Fmoc-S-trityl-L-
cysteine as an allyl ester. Fmoc deprotection allows the
resulting amine to be coupled with an activated ester of
N-Fmoc-L-valine to afford the fully protected dipeptide 9
(84% overall, 3 steps). Bis(triphenyl)oxodiphosphonium
trifluoromethanesulfonate was utilized to convert the trityl
Keywords: Bistratamide; Bis(triphenyl)oxodiphosphonium trifluorometh-
anesulfonate; Oxazole; Thiazole.
* Corresponding author. Tel.: C1 858 784 9880; fax: C1 858 784 9899;
e-mail: jkelly@scripps.edu
0040–4020/$ - see front matter q 2004 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2004.10.024

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S.-L. You, J. W. Kelly / Tetrahedron 61 (2005) 241–249
protected cysteine-containing dipeptide 9 into thiazoline 10
(89%). Thiazoline 10 was oxidized to a thiazole 7 employ-
ing activated manganese oxide (94%; O96% ee).11b
The synthesis of compound 8 is depicted in Scheme 2.
Dipeptide 11 was synthesized by coupling N-Fmoc-L-valine
and L-serine benzyl ester utilizing HBTU (2-(1H-benzo-
triazole-1-yl)-1,1,3,3-tetramethyluronium hexafluoro-
phosphate) and HOBt (N-hydroxybenzotriazole) in the
presence of DIEA (N,N-diisopropylethylamine). Treating
compound 11 with the Burgess reagent in refluxing THF
afforded oxazoline 8 (87%).
Scheme 2. Synthesis of the oxazoline-containing amino acid 8.
Thiazole 7 was coupled with the carboxylic acid resulting
from removal of the benzyl protecting group from oxazoline
8 (using a Pd/C mediated hydrogenation) utilizing HBTU
and HOBt in the presence of DIEA (Scheme 3). The
resulting amide-linked bisheterocycle 12 was obtained in
79% yield. Compound 12 was coupled sequentially with
N-Fmoc-allo-threonine and N-Fmoc-L-valine employing
HBTU/HOBt/DIEA affording 13 (72%) and 14 (86%),
respectively. Treating compound 14 with the Burgess
reagent in refluxing THF afforded 15 (38%).
Figure 1. Bistratamides E–J (1–6).
Removal of the Fmoc group in 15 using diethylamine
followed by cleavage of the allyl ester using a palladium
catalyst,12 generated from Pd(OAc)2 and polymer-
supported triphenylphosphine, gave the amino acid
macrolide precursor. The final cyclization mediated by
PyBOP (benzotriazole-1-yl-oxy-tris-pyrrolidino-phos-
phonium hexafluorophosphate) and DMAP (4-dimethyl-
aminopyridine) yielded 2 (35%). Bistratamide F (2) was
1
obtained as a white semisolid having identical H and 13C
NMR spectra to those reported in the literature.4c
Figure 2. Retrosynthetic analysis for bistratamide F (2).
The retrosynthetic analysis for bistratamide G (3) is outlined
Scheme 1. Synthesis of the thiazole-containing amino acid 7.

S.-L. You, J. W. Kelly / Tetrahedron 61 (2005) 241–249
243
Scheme 3. Completion of the synthesis of bistratamide F (2).
in Figure 3. Disconnections at the amide bonds result in
three heterocyclic amino acids derived from dipeptides. The
synthesis of compound 16 was performed following a
known procedure.5b,13 The synthesis of oxazole 17 is shown
in Scheme 4. Coupling N-Fmoc-L-valine to L-threonine
benzyl ester gave a dipeptide, which afforded ketone 18
when the dipeptide was subjected to a Dess–Martin
oxidation.14 Bis(triphenyl)oxodiphosphonium trifluoro-
methanesulfonate was used to convert the b-ketodipeptide
18 to the protected oxazole amino acid 17 (65%) without
compromising the valine-derived stereocenter.
The carboxylic acid 16 was coupled with the free amine
generated by removing the Fmoc group from 7 (diethyl-
amine) utilizing HBTU and HOBt in the presence of DIEA
Figure 3. Retrosynthetic analysis for bistratamide G (3).
Scheme 4. Synthesis of the oxazole-containing amino acid 17.

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S.-L. You, J. W. Kelly / Tetrahedron 61 (2005) 241–249
Scheme 5. Completion of the synthesis of bistratamide G (3) and an ORTEP diagram of the X-ray structure of bistratamide G (3).
(Scheme 5). The bisheterocyclic amino acid 19 was thus
obtained in 88% yield. The Boc group in 19 was removed by
a TFA treatment. The resulting free amine was coupled with
the amino acid generated from 17 by removal of the benzyl
group (using a Pd/C mediated hydrogenation), yielding 20
(91%). Removal of the Fmoc and allyl groups in 20 as
described above for 15 gave the amino acid macrolide
precursor. The final macrolactamization was mediated by
PyBOP and DMAP yielding 3 (70%). Bistratamide G (3)
The synthesis of bistratamide I (5) is outlined in Scheme 7.
The Boc-protected amine within 19, liberated by TFA
treatment, was coupled sequentially to N-Fmoc-O-trityl-L-
threonine and N-Fmoc-L-valine employing HBTU/HOBt/
DIEA affording 23 (94%) and 24 (92%), respectively.
Removal of the Fmoc and allyl groups within 24 yielded the
amino acid macrolide precursor. The final macrolactamiza-
tion mediated by PyBOP and DMAP afforded 25 (85%).
Bistratamide I (5) was obtained as a white semisolid after
removing the trityl group from 25 utilizing 2% TFA in
1
was obtained as a white solid having identical H and 13C
CH2Cl2 in the presence of 1 equiv of PhSH. Its 1H and 13
C
NMR spectra to those reported in the literature.4c The
structure of 3 was also verified by X-ray crystallography
(Scheme 5).15
NMR spectra are identical to those reported in the
literature.4c
Bistratamide H (4) was synthesized from oxazole 17 and
the bisheterocyclic amino acid 21 (Scheme 6), which
was easily prepared from the coupling of two
differentially protected molecules derived from thiazole
7.11b The bisheterocyclic amino acid 21 was coupled
with the carboxylic acid resulting from deprotection of
17, affording 22 in 97% yield. Removal of the Fmoc
and allyl groups in 22, as described above, afforded the
amino acid macrolide precursor. PyBOP and DMAP
promoted the final macrolactamization yielding
bistratamide H (4) (80%), which exhibited identical
1H and 13C NMR spectra to those reported in the
literature.4c
3. Conclusions
The total synthesis of bistratamides F–I (2–5) have been
accomplished for the first time. The thiazoles were prepared
by oxidation of thiazolines. The latter were synthesized
from cysteine containing amides wherein a Val-Cys
dipeptide was converted to a thiazoline amino acid by
bis(triphenyl)oxodiphosphonium trifluoromethanesulfonate.
The oxazole substructure was synthesized from a ketoamide
dipeptide derived from a Val-Thr dipeptide (Dess–Martin
oxidation) using the same bisphosphonium salt. The serine-
derived oxazole amino acid, a known compound, was

S.-L. You, J. W. Kelly / Tetrahedron 61 (2005) 241–249
245
Scheme 6. Completion of the synthesis of bistratamide H (4).
Scheme 7. Completion of the synthesis of bistratamide I (5).
1
prepared as described previously.5b PyBOP and DMAP
efficiently promoted the final macrolactamizations in all
cases.
pressure to yield the crude product. H NMR spectra were
recorded at 600 MHz on a Bruker DRX spectrometer. 13C
NMR spectra were recorded at 150 MHz on a Bruker DRX-
600 spectrometer. The chemical shift assignments for major
diastereomers, not for minor diastereomers, were reported.
Flash chromatography was performed on silica gel 60 (230–
400 mesh, E. Merck no. 9385). Procedures for synthesis of
compounds 7, 9, 10, 21 were described elsewhere.11b
4. Experimental
4.1. General methods
Unless stated otherwise, all reactions were carried out in
flame-dried glassware under a dry argon atmosphere. All
solvents were purchased from Fisher and were dried prior to
use. ‘Regular workup’ was as follows: the reaction mixture
was diluted with EtOAc, washed with water, 10% NaHCO3
(aq), and brine, the organic layer was dried over anhydrous
Na2SO4 and then filtered and concentrated under reduced
4.1.1. Compound 8. Compound 11 (413 mg, 0.8 mmol) and
the Burgess reagent (214 mg, 0.9 mmol) were suspended in
THF (10 mL). The mixture was refluxed for 2 h. After
regular workup, the resulting crude product was purified by
flash chromatography (EtOAc/hexanesZ1/2) to afford
compound 8 (347 mg, 87%) as a white foam: [a]2D4ZC
1
22.6 (c 0.74, CHCl3); H NMR (600 MHz, CDCl3, 25 8C,

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S.-L. You, J. W. Kelly / Tetrahedron 61 (2005) 241–249
TMS) d 0.91 (d, JZ6.6 Hz, 3H), 0.96 (d, JZ6.6 Hz, 3H),
2.12–2.15 (m, 1H), 4.21 (t, JZ7.0 Hz, 1H), 4.36–4.45 (m,
4H), 4.52 (t, JZ7.5 Hz, 1H), 4.78 (t, JZ8.8 Hz, 1H), 5.16–
5.23 (m, 2H), 5.53 (m, 1H), 7.24–7.39 (m, 9H), 7.60 (dd,
JZ8.3, 8.8 Hz, 2H), 7.75 (d, JZ7.5 Hz, 2H); 13C NMR
(150 MHz, CDCl3) d 17.2, 18.7, 31.6, 47.1, 54.2, 66.9, 67.3,
67.7, 70.3, 119.9, 125.1, 127.0, 127.6, 128.4, 128.5 (2C),
135.1, 141.2, 143.7, 143.9, 156.1, 169.9, 170.7; HRMS
(MALDI-FTMS) calcd for C30H30N2O5 (MCNaC)
521.2047, found 521.2048.
10.5 Hz, 1H), 4.83 (d, JZ5.3 Hz, 2H), 5.19 (dd, JZ7.0,
8.3 Hz, 1H), 5.27 (d, JZ10.5 Hz, 1H), 5.38 (d, JZ17.1 Hz,
1H), 5.57 (d, JZ8.8 Hz, 1H), 5.99–6.03 (m, 1H), 7.29–7.32
(m, 2H), 7.35 (d, JZ8.8 Hz, 1H), 7.39 (t, JZ7.5 Hz, 2H),
7.61 (d, JZ7.9 Hz, 1H), 7.63 (d, JZ7.5 Hz, 1H), 7.76 (d,
JZ7.5 Hz, 2H), 8.11 (s, 1H); 13C NMR (150 MHz, CDCl3)
d 17.7 (2C), 18.8, 19.3, 31.3, 32.9, 47.1, 54.6, 56.1, 65.9,
67.0, 68.2, 70.8, 118.9, 119.9, 125.0, 127.0, 127.6, 131.7,
141.2, 143.7, 143.8, 146.9, 156.1, 160.7, 169.7, 171.2;
HRMS (MALDI-FTMS) calcd for C34H38N4O6S (MCHC)
631.2585, found 631.2566.
4.1.2. Compound 11. To a solution of N-Fmoc-L-valine
(339 mg, 1 mmol), HBTU (417 mg, 1.1 mmol) and
HOBt$H2O (168 mg, 1.1 mmol) in DMF (4 mL), DIEA
(0.54 mL, 3.1 mmol) and L-serine benzyl ester hydro-
chloride (232 mg, 1 mmol) were sequentially added. The
reaction mixture was stirred at 25 8C for 8 h. After regular
workup, the resulting crude product was purified by flash
chromatography (EtOAc/hexanesZ1/1) to afford com-
pound 11 (433 mg, 84%) as a white foam: [a]2D4ZK14.0
4.1.4. Compound 13. Compound 13 was synthesized from
12 in a 72% yield as a white foam by following the
procedure used for the synthesis of 12: [a]2D4ZK23.2 (c
1
0.34, CHCl3); H NMR (600 MHz, CDCl3, 25 8C, TMS) d
0.88 (d, JZ6.6 Hz, 3H), 0.93 (d, JZ6.6 Hz, 3H), 0.96 (d,
JZ7.0 Hz, 3H), 1.01 (d, JZ6.6 Hz, 3H), 1.27 (d, JZ
6.1 Hz, 3H), 2.28–2.31 (m, 1H), 2.35–2.40 (m, 1H), 3.92
(dd, JZ6.1, 6.6 Hz, 1H), 4.21 (m, 2H), 4.33–4.41 (m, 2H),
4.60–4.62 (m, 2H), 4.68 (m, 1H), 4.73–4.75 (m, 1H), 4.86
(d, JZ5.7 Hz, 2H), 4.96 (br, 1H), 5.16 (dd, JZ6.1, 8.3 Hz,
1H), 5.30 (d, JZ10.5 Hz, 1H), 5.41 (d, JZ17.1 Hz, 1H),
5.91 (d, JZ8.3 Hz, 1H), 6.01–6.05 (m, 1H), 7.27–7.30 (m,
3H), 7.39 (t, JZ7.5 Hz, 2H), 7.51 (d, JZ8.3 Hz, 1H), 7.58
(t, JZ7.5 Hz, 2H), 7.75 (d, JZ7.5 Hz, 2H), 8.10 (s, 1H);
13C NMR (150 MHz, CDCl3) d 17.2, 17.7, 18.9 (2C), 19.7,
30.0, 33.4, 38.5, 47.0, 52.9, 56.3, 59.6, 66.1, 67.1, 67.6,
69.3, 71.8, 119.0, 119.9, 125.0 (2C), 127.0, 127.3, 127.6,
131.6, 141.2, 143.6, 143.7, 146.4, 156.3, 160.8, 170.3,
170.7, 171.5; HRMS (MALDI-FTMS) calcd for
C38H45N5O8S (MCHC) 732.3061, found 732.3045.
1
(c 0.25, DMSO); H NMR (600 MHz, DMSO-d6, 25 8C) d
0.85 (d, JZ7.0 Hz, 3H), 0.88 (d, JZ6.6 Hz, 3H), 1.97–2.03
(m, 1H), 3.67–3.71 (m, 1H), 3.76–3.79 (m, 1H), 4.02 (dd,
JZ7.0, 8.8 Hz, 1H), 4.20–4.23 (m, 2H), 4.27–4.31 (m, 1H),
4.44 (d, JZ4.8, 11.8 Hz, 1H), 5.13–5.15 (m, 3H), 7.31–7.36
(m, 7H), 7.41 (t, JZ7.5 Hz, 2H), 7.45 (d, JZ9.2 Hz, 1H),
7.76 (d, JZ7.5 Hz, 2H), 7.89 (d, JZ7.5 Hz, 2H), 8.37 (d,
JZ7.5 Hz, 1H); 13C NMR (150 MHz, DMSO-d6) d 18.1,
19.1, 30.5, 46.7, 54.8, 59.7, 61.2, 65.7, 65.9, 120.1, 125.4,
127.1, 127.6, 127.7, 127.9, 128.3, 135.9, 140.7 (2C), 143.8,
143.9, 156.1, 170.3, 171.5; HRMS (MALDI-FTMS) calcd
for C30H32N2O6 (MCNaC) 539.2152, found 539.2144.
4.1.5. Compound 14. Compound 14 was synthesized from
13 in a 86% yield as a white foam by following the
procedure used for the synthesis of 12: [a]2D4ZK23.1 (c
4.1.3. Compound 12 (general procedure for Pd/C
mediated hydrogenation, diethylamine-mediated depro-
tection of Fmoc group and HBTU, HOBt-mediated
peptide coupling). Pd on activated carbon (30 mg) was
added to a flask containing 8 (329 mg, 0.66 mmol) in MeOH
(5 mL) and THF (5 mL). The reaction flask was fitted with
H2 balloon, and evacuated and purged with H2 three times.
The reaction progress was monitored by TLC and was
complete in 1 h. After removing the solvent, the residue was
passed through a short silica gel column and eluted with
MeOH. The carboxylic acid was used in next step without
further purification. In another flask, diethylamine (3 mL)
was added to a solution of 7 (277 mg, 0.6 mmol) in CH3CN
(3 mL) and the resulting mixture was stirred at 25 8C for
30 min to ensure complete removal of the Fmoc protecting
group. After concentration in vacuo, the reaction mixture
was azeotroped to dryness with CH3CN (2!3 mL) and the
residue was dissolved in DMF (3 mL). This amine solution
was added to a solution of above carboxylic acid, HBTU
(277 mg, 0.73 mmol), HOBt$H2O (112 mg, 0.73 mmol) and
DIEA (0.24 mL, 1.4 mmol) in DMF (3 mL). The reaction
mixture was stirred at 25 8C for 8 h. After regular workup,
the resulting crude product was purified by flash chroma-
tography (EtOAc/hexanesZ1/2) to afford compound 12
(299 mg, 79%) as a white foam: [a]2D4ZK16.8 (c 0.77,
1
0.85, CHCl3); H NMR (600 MHz, CDCl3, 25 8C, TMS) d
0.87 (d, JZ6.6 Hz, 3H), 0.92–0.95 (m, 12H), 0.97 (d, JZ
6.6 Hz, 3H), 1.24 (d, JZ6.1 Hz, 3H), 2.09–2.12 (m, 1H),
2.21–2.23 (m, 1H), 2.36–2.41 (m, 1H), 3.98 (t, JZ6.1 Hz,
1H), 4.15–4.20 (m, 2H), 4.30 (dd, JZ7.0, 10.5 Hz, 1H),
4.40 (dd, JZ7.5, 10.5 Hz, 1H), 4.51 (dd, JZ7.9, 8.8 Hz,
1H), 4.54–4.59 (m, 2H), 4.65–4.70 (m, 2H), 4.85 (t, JZ
5.7 Hz, 2H), 4.93 (br, 1H), 5.16 (dd, JZ6.1, 8.3 Hz, 1H),
5.28 (d, JZ10.5 Hz, 1H), 5.40 (d, JZ17.5 Hz, 1H), 5.74 (d,
JZ9.2 Hz, 1H), 5.98–6.04 (m, 1H), 7.26–7.30 (m, 3H),
7.36–7.39 (m, 2H), 7.41 (d, JZ8.8 Hz, 1H), 7.51 (d, JZ
8.3 Hz, 1H), 7.57 (dd, JZ7.0, 7.5 Hz, 2H), 7.74 (d, JZ
7.9 Hz, 2H), 8.10 (s, 1H); 13C NMR (150 MHz, CDCl3) d
17.4, 17.7, 17.8, 18.8, 18.9, 19.1, 19.8, 30.3, 31.4, 33.4,
47.0, 52.9, 56.3, 57.9, 60.1, 66.1, 67.0, 67.7, 68.9, 71.5,
119.0, 119.9, 125.0, 127.0, 127.3, 127.6, 131.7, 141.2,
143.7, 143.8, 146.5, 156.3, 160.8, 170.2, 170.4, 170.7,
170.0, 171.6; HRMS (MALDI-FTMS) calcd for
C43H54N6O9S (MCHC) 831.3746, found 831.3756.
4.1.6. Compound 15. Compound 15 was synthesized from
14 in a 38% yield as a white foam by following the
procedure used for the synthesis of 8: [a]2D4ZK7.1 (c 0.31,
1
CHCl3); H NMR (600 MHz, CDCl3, 25 8C, TMS) d 0.90
1
(d, JZ6.6 Hz, 3H), 0.93 (d, JZ7.0 Hz, 3H), 0.98 (d, JZ
7.0 Hz, 3H), 1.00 (d, JZ6.6 Hz, 3H), 2.14–2.18 (m, 1H),
2.44–2.50 (m, 1H), 4.25 (t, JZ7.0 Hz, 1H), 4.35–4.38 (m,
1H), 4.42–4.47 (m, 2H), 4.52–4.59 (m, 2H), 4.74 (d, JZ8.8,
CHCl3); H NMR (600 MHz, CDCl3, 25 8C, TMS) d 0.89
(d, JZ7.0 Hz, 3H), 0.92–0.94 (m, 9H), 0.98 (d, JZ8.3 Hz,
3H), 1.00 (d, JZ7.5 Hz, 3H), 1.51 (d, JZ6.1 Hz, 3H), 2.15–
2.17 (m, 1H), 2.47–2.49 (m, 2H), 4.21–4.22 (m, 2H), 4.34–

S.-L. You, J. W. Kelly / Tetrahedron 61 (2005) 241–249
247
4.44 (m, 3H), 4.55–4.59 (m, 2H), 4.67 (dd, JZ5.7, 8.8 Hz,
1H), 4.73–4.77 (m, 1H), 4.78–4.80 (m, 3H), 5.19 (dd, JZ
6.6, 8.8 Hz, 1H), 5.26 (d, JZ10.1 Hz, 1H), 5.36 (dd, JZ
17.1 Hz, 1H), 5.57 (d, JZ8.8 Hz, 1H), 5.96–6.00 (m, 1H),
7.11 (d, JZ9.2 Hz, 1H), 7.27–7.29 (m, 2H), 7.37–7.42 (m,
3H), 7.58 (t, JZ6.6 Hz, 2H), 7.76 (d, JZ7.5 Hz, 2H), 8.04
(s, 1H); 13C NMR (150 MHz, CDCl3) d 17.6, 17.7, 17.9,
18.8, 18.9, 19.4, 21.8, 31.2, 31.4, 33.0, 47.1, 52.2, 54.8,
56.2, 65.9, 67.0, 68.3, 70.8, 74.5, 80.7, 118.9, 120.0, 125.0
(2C), 127.0, 127.2, 127.7, 131.7, 141.2, 143.7, 143.8, 146.9,
156.0, 160.7, 168.9, 169.1, 171.0, 171.3, 171.5; HRMS
(MALDI-FTMS) calcd for C43H52N6O8S (MCHC)
813.3640, found 813.3633.
JZ6.6 Hz, 3H), 2.18–2.23 (m, 1H), 2.57 (s, 3H), 4.21 (t, JZ
7.0 Hz, 1H), 4.36–4.43 (m, 2H), 4.79 (dd, JZ6.1, 6.8 Hz,
1H), 5.35 (AB, JABZ12.3 Hz, 1H), 5.38 (AB, JAB
Z
12.3 Hz, 1H), 5.57 (d, JZ8.8 Hz, 1H), 7.28–7.40 (m, 9H),
7.60 (dd, JZ7.5, 7.9 Hz, 2H), 7.75 (d, JZ7.5 Hz, 2H); 13C
NMR (150 MHz, CDCl3) d 12.2, 18.0, 18.7, 32.7, 47.1,
54.6, 66.6, 67.0, 119.9, 125.0, 127.0, 127.4, 127.6, 128.3,
128.4, 128.5, 135.6, 141.2, 143.6, 143.8, 156.0, 156.3,
161.7, 161.9; HRMS (MALDI-FTMS) calcd for
C31H30N2O5S (MCNaC) 533.2047, found 533.2060.
4.1.9. Compound 18. N-Fmoc-L-valine and L-threonine
benzyl ester oxalate were coupled by following the
procedure used for the synthesis of 12 to give the dipeptide
(5 mmol scale). The resulting dipeptide was suspended in
150 mL CH2Cl2, then Dess–Martin periodinane (3.06 g,
97%, 7 mmol) was added. The resulting reaction mixture
was stirred at 25 8C for 1 h. After regular workup, the
resulting crude product was purified by flash chromato-
graphy (EtOAc/hexanesZ1/3) to afford compound 18
4.1.7. Bistratamide F (2) (general procedure for removal
of the allyl ester protecting group, PyBOP and DMAP-
mediated macrocyclization). Deprotection of the Fmoc
group in 15 (81.3 mg, 0.1 mmol) followed the procedure
described in the synthesis of 12. To remove the allyl group,
Pd(OAc)2 (1.12 mg, 5 mmol) and polystyrene-triphenyl-
phosphine (25.2 mg, 1.59 mol/g, 0.04 mmol) were added to
a flask containing CH2Cl2 (5 mL). After stirring for 10 min,
the above amino ester in CH2Cl2 (2 mL) and PhSiH3
(0.025 mL, 0.2 mmol) were added separately. The reaction
progress was monitored by TLC and completed in 15 min.
After removing the solvent, the residue was passed through
a short silica gel column and eluted with CHCl3/EtOH (1/2).
After removing the solvents, the macrolide precursor was
redissovled in CH2Cl2/DMF (5 mL, v/v: 2/1). This solution
was added to a flask containing PyBOP (104 mg, 0.2 mmol)
and DMAP (24.4 mg, 0.2 mmol) in CH2Cl2/DMF (20 mL,
v/v: 2/1) over 8 h using a syringe pump. After the
completion of addition, the mixture was stirred for 2 h.
Regular workup and purification by flash chromatography
(EtOAc/hexanesZ4/1) gave 2 (18.6 mg, 35%) as a white
foam: [a]2D4ZC25.3 (c 0.30, MeOH) {lit4c [a]2D5ZC23.2 (c
1.0, MeOH)}; 1H NMR (600 MHz, DMSO-d6, 25 8C) d 0.76
(d, JZ7.0 Hz, 3H), 0.80 (d, JZ6.6 Hz, 3H), 0.81 (d, JZ
6.6 Hz, 3H), 0.84 (d, JZ6.9 Hz, 3H), 0.85 (d, JZ7.0 Hz,
3H), 0.89 (d, JZ7.0 Hz, 3H), 1.48 (d, JZ6.1 Hz, 3H), 2.12
(m, 1H), 2.21 (m, 1H), 2.33 (m, 1H), 4.31 (dd, JZ2.2,
8.3 Hz, 1H), 4.38 (t, JZ7.5 Hz, 1H), 4.60 (br, d, JZ8.8 Hz,
1H), 4.78–4.85 (m, 4H), 5.30 (dd, JZ4.8, 7.9 Hz, 1H), 7.64
(d, JZ8.8 Hz, 1H), 7.73 (d, JZ7.5 Hz, 1H), 7.99 (d, JZ
9.2 Hz, 1H), 8.37 (s, 1H); 13C NMR (150 MHz, DMSO-d6)
d 15.9, 16.0, 17.2, 17.8, 18.5, 18.7, 21.4, 30.7, 30.8, 33.7,
51.1, 51.3, 54.7, 66.7, 72.4, 72.7, 81.8, 124.9, 147.9, 159.0,
160.4, 167.6, 168.9, 169.7, 169.8; HRMS (MALDI-FTMS)
calcd for C25H36N6O5S (MCHC) 533.2541, found
533.2519.
(1.66 g, 63%) as a gel: [a]2D4ZK12.9 (c 0.38, CHCl3); H
1
NMR (600 MHz, CDCl3, 25 8C, TMS) d 0.85–0.98 (m, 6H),
2.10–2.13 (m, 1H), 2.28 (s, 3H), 4.19–4.21 (m, 2H), 4.35–
4.43 (m, 2H), 5.16–5.29 (m, 3H), 5.50–5.57 (m, 1H), 7.16–
7.34 (m, 10H), 7.37–7.39 (m, 2H), 7.58–7.76 (m, 2H); 13C
NMR (150 MHz, CDCl3) d 17.7, 19.1, 28.1, 31.3, 47.1,
59.8, 63.2, 67.1, 68.3, 119.9, 125.1, 127.0, 127.7, 128.5
(2C), 128.7, 128.8 (2C), 133.0, 134.4, 141.2, 141.6, 143.7,
143.8, 156.3, 165.5, 171.2, 197.7; HRMS (MALDI-FTMS)
calcd for C31H32N2O6 (MCNaC) 551.2152, found
551.2146.
4.1.10. Compound 19. Compound 19 was synthesized from
7 and 16 in a 88% yield as a white foam by following the
procedure used for the synthesis of 12: [a]2D4ZK57.1 (c
1
0.28, CHCl3); H NMR (600 MHz, CDCl3, 25 8C, TMS) d
0.94 (d, JZ6.6 Hz, 3H), 0.95 (d, JZ8.3 Hz, 3H), 0.99 (d,
JZ7.0 Hz, 3H), 1.05 (d, JZ6.6 Hz, 3H), 1.46 (s, 9H), 2.19–
2.21 (m, 1H), 2.59–2.63 (m, 1H), 4.78 (dd, JZ8.3, 6.1 Hz,
1H), 4.86 (d, JZ5.7 Hz, 2H), 5.17 (d, JZ8.3 Hz, 1H), 5.29–
5.31 (m, 2H), 5.41 (d, JZ17.1 Hz, 1H), 6.01–6.07 (m, 1H),
7.55 (d, JZ9.2 Hz, 1H), 8.12 (s, 1H), 8.15 (s, 1H); 13C
NMR (150 MHz, CDCl3) d 17.9, 18.1, 18.6, 19.6, 28.3,
32.7, 33.0, 54.2, 56.0, 65.9, 80.1, 118.8, 127.3, 131.8, 135.4,
141.2, 147.1, 155.3, 160.2, 160.8, 163.9, 171.3; HRMS
(MALDI-FTMS) calcd for C24H34N4O6S (MCNaC)
529.2091, found 529.2093.
4.1.11. Compound 20. To a solution of 19 (507 mg,
1 mmol) in CH2Cl2 (10 mL), TFA (2.5 mL) was added.
After stirring for 20 min, the solvent was removed. The
residue was azeotroped with toluene to remove TFA. The
resulting oil was dissolved in DMF (4 mL) and DIEA was
added to neutralize. This amine was coupled with 17
yielding 20 (736 mg, 91%) as a white foam by following the
procedure used for the synthesis of 12: [a]2D4ZK37.6 (c 1.0,
4.1.8. Compound 17. To a solution of triphenylphosphine
oxide (835 mg, 3 mmol) in dry CH2Cl2 (10 mL), trifluoro-
methanesulfonic anhydride (0.24 mL, 1.5 mmol) was added
slowly at 0 8C. The reaction mixture was stirred for 10 min
at 0 8C and then adjusted to K20 8C using a brine-ice bath.
Then 18 (528 mg, 1 mmol) was added. The reaction
progress was monitored by TLC and completed in 2 h.
After regular workup, the resulting crude product was
purified by flash chromatography (EtOAc/hexanesZ1/3) to
afford compound 17 (332 mg, 65%) as a white foam:
[a]2D4ZC31.1 (c 0.72, CHCl3); 1H NMR (600 MHz,
CDCl3, 25 8C, TMS) d 0.92 (d, JZ7.0 Hz, 3H), 0.95 (d,
1
CHCl3); H NMR (600 MHz, CDCl3, 25 8C, TMS) d 0.95
(d, JZ6.6 Hz, 3H), 0.96–0.99 (m, 9H), 1.02 (d, JZ7.0 Hz,
3H), 1.04 (d, JZ6.6 Hz, 3H), 2.21–2.25 (m, 1H), 2.30–2.34
(m, 1H), 2.46 (br, 1H), 2.55–2.59 (m, 1H), 2.62 (s, 3H), 4.22
(dd, JZ6.6, 7.0 Hz, 1H), 4.40–4.49 (m, 2H), 4.77 (dd, JZ
7.0, 8.8 Hz, 1H), 4.82 (m, 2H), 5.20 (dd, JZ7.0, 9.2 Hz,
1H), 5.26–5.31 (m, 2H), 5.38 (d, JZ17.1 Hz, 1H), 5.51 (d,

248
S.-L. You, J. W. Kelly / Tetrahedron 61 (2005) 241–249
JZ9.2 Hz, 1H), 5.98–6.02 (m, 1H), 7.26–7.29 (m, 2H),
7.36–7.39 (m, 3H), 7.58 (dd, JZ7.5, 12.7 Hz, 2H), 7.61 (d,
JZ9.7 Hz, 1H), 7.75 (d, JZ7.5 Hz, 2H), 8.06 (s, 1H), 8.10
(s, 1H); 13C NMR (150 MHz, CDCl3) d 11.6, 17.9, 18.0,
18.3, 18.8, 18.9, 19.5, 32.2 (2C), 32.9, 47.1, 52.1, 54.7, 56.0,
65.8, 66.8, 118.7, 119.9, 124.8 (2C), 126.9, 127.2, 127.6,
128.4, 131.7, 135.4, 141.2 (2C), 141.4, 143.5, 143.7, 146.9,
153.6, 155.9, 160.2, 160.4, 160.7, 161.4, 163.1, 171.4;
HRMS (MALDI-FTMS) calcd for C43H48N6O8S (MCHC)
809.3327, found 809.3318.
d6) d 12.2, 18.9, 19.0, 19.1, 19.2, 19.4, 33.7, 35.3, 35.5, 53.2,
55.5, 55.7, 125.7, 126.2, 128.7, 148.7, 149.2, 154.2, 159.9,
160.4, 160.6, 161.4, 169.4, 169.9; HRMS (MALDI-FTMS)
calcd for C25H32N6O4S2 (MCNaC) 567.1819, found
567.1810.
4.1.15. Compound 23. Compound 23 was synthesized from
19 and N-Fmoc-O-trityl-threonine in a 94% yield as a white
foam by following the procedure used for the synthesis of
1
12: [a]2D4ZK15.0 (c 0.50, CHCl3); H NMR (600 MHz,
CDCl3, 25 8C, TMS) d 0.80 (d, JZ7.0 Hz, 3H), 0.88 (d, JZ
6.6 Hz, 3H), 0.97 (d, JZ6.6 Hz, 3H), 1.00 (d, JZ7.0 Hz,
3H), 1.17 (d, JZ6.1 Hz, 3H), 2.21–2.27 (m, 1H), 2.56–2.62
(m, 1H), 3.44 (br, 1H), 4.13 (t, JZ7.5 Hz, 1H), 4.22–4.29
(m, 2H), 4.35 (br, 1H), 4.82 (d, JZ5.7 Hz, 2H), 5.08 (dd,
JZ8.8, 6.6 Hz, 1H), 5.26 (d, JZ10.5 Hz, 1H), 5.37 (d, JZ
17.1 Hz, 1H), 5.41 (dd, JZ8.8, 6.6 Hz, 1H), 5.73 (d, JZ
4.8 Hz, 1H), 5.97–6.02 (m, 1H), 7.23–7.30 (m, 12H), 7.35–
7.38 (m, 2H), 7.52–7.57 (m, 9H), 7.72–7.74 (m, 2H), 8.09
(s, 1H), 8.22 (s, 1H); 13C NMR (150 MHz, CDCl3) d 16.1,
17.6, 18.2, 19.0, 19.5, 31.8, 33.0, 47.0, 53.1, 56.1, 65.9,
66.7, 69.8, 88.6, 118.9, 119.9, 125.0, 125.1, 126.9 (2C),
127.2, 127.5, 127.6, 128.2, 128.7, 131.8, 135.6, 141.2,
141.6, 143.7 (d), 147.2, 155.0, 160.3, 160.8, 163.7, 169.6,
171.9; HRMS (MALDI-FTMS) calcd for C57H57N5O8S
(MCNaC) 994.382, found 994.3805.
4.1.12. Bistratamide G (3). Compound 3 was synthesized
from 20 in a 70% yield as a white solid by following the
procedure used for the synthesis of 2: mp 224–226 8C;
[a]D24ZK84.4 (c 0.97, MeOH) {lit4c [a]2D5ZK73.8 (c 1.0,
MeOH)}; 1H NMR (600 MHz, DMSO-d6, 25 8C) d 0.88 (d,
JZ6.6 Hz, 3H), 0.91 (d, JZ6.6 Hz, 3H), 0.93 (d, JZ
7.0 Hz, 3H), 0.94 (d, JZ7.0 Hz, 3H), 0.96 (d, JZ6.6 Hz,
3H), 0.97 (d, JZ7.0 Hz, 3H), 2.15–2.22 (m, 2H), 2.27–2.31
(m, 1H), 2.54 (s, 3H), 5.01 (dd, JZ4.4, 7.5 Hz, 1H), 5.09
(dd, JZ5.7, 8.8 Hz, 1H), 5.39 (dd, JZ6.1, 8.8 Hz, 1H), 8.30
(d, JZ7.0 Hz, 1H), 8.32 (d, JZ9.2 Hz, 1H), 8.35 (s, 1H),
8.44 (d, JZ8.8 Hz, 1H), 8.78 (s, 1H); 13C NMR (150 MHz,
DMSO-d6) d 11.1, 18.0, 18.1, 18.2, 18.3, 18.6, 32.6, 32.9,
34.6, 52.1, 52.7, 54.8, 125.2, 128.0, 134.5, 142.9, 147.9,
152.8, 158.4, 159.3, 160.2, 160.5, 163.2, 168.3; HRMS
(MALDI-FTMS) calcd for C25H32N6O5S (MCHC)
529.2228, found 529.2221.
4.1.16. Compound 24. Compound 24 was synthesized from
23 in a 92% yield as a white foam by following the
procedure used for the synthesis of 12: [a]2D4ZK25.6 (c
4.1.13. Compound 22. Compound 22 was synthesized from
21 and 17 in a 97% yield as a white foam by following the
procedure used for the synthesis of 12: [a]2D4ZK27.1 (c
1
1.21, CHCl3); H NMR (600 MHz, CDCl3, 25 8C, TMS) d
0.79 (d, JZ6.6 Hz, 3H), 0.84 (d, JZ6.6 Hz, 3H), 0.87 (d,
JZ6.6 Hz, 3H), 0.88 (d, JZ6.6 Hz, 3H), 0.94 (d, JZ
6.6 Hz, 3H), 0.98 (d, JZ6.6 Hz, 3H), 1.13 (d, JZ6.1 Hz,
3H), 2.04–2.06 (m, 1H), 2.20–2.22 (m, 1H), 2.55–2.58 (m,
1H), 3.62 (br, 1H), 4.01 (t, JZ6.1 Hz, 1H), 4.19 (m, 1H),
4.32 (dd, JZ10.5, 7.0 Hz, 1H), 4.37–4.42 (m, 2H), 4.82 (d,
JZ5.7 Hz, 2H), 5.04 (dd, JZ8.3, 6.6 Hz, 1H), 5.26 (d, JZ
10.5 Hz, 1H), 5.37 (d, JZ17.1 Hz, 1H), 5.40 (dd, JZ9.2,
6.1 Hz, 1H), 5.45 (d, JZ8.8 Hz, 1H), 5.96–6.01 (m, 1H),
6.81 (d, JZ4.8 Hz, 1H), 7.22–7.29 (m, 11H), 7.38 (t, JZ
7.0 Hz, 2H), 7.54–7.58 (m, 10H), 7.60 (d, JZ9.2 Hz, 1H),
7.75 (d, JZ7.5 Hz, 1H), 8.07 (s, 1H), 8.20 (s, 1H); 13C
NMR (150 MHz, CDCl3) d 16.3, 17.5, 17.6, 18.2, 18.9,
19.1, 19.5, 31.3, 31.7, 33.0, 47.1, 53.2, 55.4, 56.0, 60.0,
65.9, 66.9, 69.2, 88.6, 118.8, 119.9, 125.0, 127.0, 127.2,
127.5, 127.6, 128.1, 128.7, 131.8, 135.5, 141.2, 141.6,
143.6, 143.7, 143.9, 147.1, 156.2, 160.3, 160.8, 163.6,
169.5, 170.2, 171.8; HRMS (MALDI-FTMS) calcd for
C62H66N6O9S (MCNaC) 1093.4504, found 1093.4547.
1
0.77, CHCl3); H NMR (600 MHz, CDCl3, 25 8C, TMS) d
0.94 (d, JZ6.6 Hz, 3H), 0.97 (d, JZ7.0 Hz, 3H), 1.00 (d,
JZ7.0 Hz, 3H), 1.03 (d, JZ7.5 Hz, 6H), 1.05 (d, JZ
7.9 Hz, 3H), 2.20–2.23 (m, 1H), 2.52–2.55 (m, 1H), 2.62–
2.65 (m, 1H), 2.63 (s, 3H), 4.21 (dd, JZ6.6, 7.0 Hz, 1H),
4.40–4.49 (m, 2H), 4.77 (dd, JZ6.6, 9.2 Hz, 1H), 4.83 (m,
2H), 5.28 (d, JZ10.1 Hz, 1H), 5.31 (dd, JZ6.1, 9.2 Hz,
1H), 5.34 (dd, JZ6.6, 9.2 Hz, 1H), 5.39 (d, JZ17.1 Hz,
1H), 5.45 (m, 1H), 5.99–6.04 (m, 1H), 7.24–7.28 (m, 2H),
7.37 (t, JZ7.5 Hz, 2H), 7.46 (d, JZ8.8 Hz, 1H), 7.57 (dd,
JZ7.9, 8.3 Hz, 2H), 7.75 (d, JZ7.5 Hz, 2H), 7.99 (d, JZ
9.2 Hz, 1H), 8.01 (s, 1H), 8.06 (s, 1H); 13C NMR (150 MHz,
CDCl3) d 11.7, 17.8 (2C), 18.0, 18.9, 19.4, 19.6, 32.3, 32.8,
33.0, 47.1, 54.7, 55.8, 56.4, 65.8, 66.8, 118.7, 119.9, 123.5,
124.8, 124.9, 126.9, 127.2, 127.7, 128.4, 131.8, 141.2 (2C),
143.5, 143.7, 147.0, 149.3, 153.7, 155.9, 160.5, 160.7,
160.8, 161.6, 171.8, 171.9; HRMS (MALDI-FTMS)
calcd for C43H48N6O7S2 (MCHC) 825.3098, found
825.3084.
4.1.17. Compound 25. Compound 25 was synthesized from
24 in a 85% yield as a white foam by following the
procedure used for the synthesis of 2: [a]2D4ZK115.5 (c
4.1.14. Bistratamide H (4). Compound 4 was synthesized
from 22 in a 80% yield as a gel-like solid by following the
procedure used for the synthesis of 2: [a]2D4ZK106.2 (c 1.1,
MeOH) {lit4c [a]D25ZK92.9 (c 1.0, MeOH)}; 1H NMR
(600 MHz, DMSO-d6, 25 8C) d 0.90 (d, JZ6.6 Hz, 3H),
0.93 (d, JZ7.0 Hz, 6H), 0.94 (d, JZ8.3 Hz, 3H), 0.96 (d,
JZ7.0 Hz, 3H), 0.98 (d, JZ7.0 Hz, 3H), 2.16–2.25 (m, 3H),
2.58 (s, 3H), 5.07 (dd, JZ5.3, 8.3 Hz, 1H), 5.35 (dd, JZ5.3,
8.3 Hz, 1H), 5.45 (dd, JZ7.0, 9.6 Hz, 1H), 8.33 (s, 1H),
8.35 (s, 1H), 8.36 (d, JZ9.2 Hz, 1H), 8.49 (d, JZ8.3 Hz,
1H), 8.52 (d, JZ9.7 Hz, 1H); 13C NMR (150 MHz, DMSO-
1
0.27, CHCl3); H NMR (600 MHz, CDCl3, 25 8C, TMS) d
0.75 (d, JZ6.6 Hz, 3H), 0.90 (d, JZ7.0 Hz, 3H), 0.92 (d,
JZ6.6 Hz, 3H), 0.98 (d, JZ6.6 Hz, 3H), 1.00 (d, JZ
7.0 Hz, 3H), 1.09 (d, JZ7.0 Hz, 3H), 1.46 (d, JZ6.6 Hz,
3H), 2.17–2.22 (m, 1H), 2.35–2.38 (m, 1H), 2.54–2.56 (m,
1H), 3.65 (dd, JZ5.3, 4.4 Hz, 1H), 4.53–4.55 (m, 1H), 4.63
(dd, JZ10.5, 3.5 Hz, 1H), 4.76 (dd, JZ6.1, 4.4 Hz, 1H),
5.22 (dd, JZ9.7, 7.0 Hz, 1H), 6.84 (d, JZ5.3 Hz, 1H),
7.26–7.29 (m, 3H), 7.33–7.35 (m, 6H), 7.45 (d, JZ10.1 Hz,

S.-L. You, J. W. Kelly / Tetrahedron 61 (2005) 241–249
249
A.; Pattenden, G. Heterocycles 2002, 58, 521. (d) Boden,
C. D. J.; Pattenden, G. J. Chem. Soc., Perkin Trans. 1 2001,
875. (e) Wipf, P.; Fritchm, P. C. J. Am. Chem. Soc. 1996, 118,
12358. (f) Mckeever, B.; Pattenden, G. Tetrahedron Lett.
2001, 42, 2573. (g) Wipf, P.; Uto, Y. J. Org. Chem. 2000, 65,
1037. (h) Wang, W.; Nan, F. J. Org. Chem. 2003, 68, 1636.
(i) Yokokawa, F.; Sameshima, H.; Katagiri, D.; Aoyama, T.;
Shioiri, T. Tetrahedron 2002, 58, 9445. (j) Yokokawa, F.;
Hamada, Y.; Shioiri, T. Synlett 1992, 149. (k) Yoshihiro, H.;
Tetsuo, S.; Takeo, K. Bull. Chem. Soc. Jpn 1970, 43, 1564.
4. (a) Degnan, B. M.; Hawkins, C. J.; Lavin, M. F.; McCaffrey,
E. J.; Parry, D. L.; Watters, D. J. J. Med. Chem. 1989, 32, 1354.
1H), 7.55–7.57 (m, 7H), 7.95 (s, 1H), 8.09 (s, 1H), 8.11 (d,
JZ6.6 Hz, 1H); 13C NMR (150 MHz, CDCl3) d 16.1, 16.8,
18.0, 18.6, 18.7, 18.8, 19.9, 30.3, 30.4, 34.1, 54.5, 55.0,
56.4, 57.6, 68.8, 89.5, 122.8, 127.6, 128.1, 128.2, 128.8,
135.5, 143.6, 149.7, 160.0, 160.1, 162.5, 168.8, 169.9,
170.1; HRMS (MALDI-FTMS) calcd for C44H50N6O6S
(MCNaC) 813.3405, found 813.3376.
4.1.18. Bistratamide I (5). To a flask containing 25
(158 mg, 0.2 mmol) in CH2Cl2 (5 mL), TFA (0.1 mL) and
PhSH (21 mL, 0.2 mmol) were added. TLC showed that 25
disappeared in 5 min. After removing all of the solvents, the
residue was purified by flash chromatography. Bistratamide
I (5) was obtained as a white semisolid (106 mg, 97%):
[a]D24ZK129.4 (c 0.36, MeOH){lit4c [a]2D5ZK122 (c 0.5,
MeOH)}; 1H NMR (600 MHz, DMSO-d6, 25 8C) d 0.86 (d,
JZ6.6 Hz, 3H), 0.91 (d, JZ6.6 Hz, 3H), 0.96 (d, JZ
7.0 Hz, 3H), 0.99 (d, JZ6.6 Hz, 3H), 1.00 (d, JZ6.6 Hz,
3H), 1.03 (d, JZ6.6 Hz, 3H), 1.11 (d, JZ6.1 Hz, 3H), 2.10–
2.24 (m, 3H), 4.08–4.11 (m, 1H), 4.31 (dd, JZ10.1, 3.1 Hz,
1H), 4.37 (t, JZ11.0 Hz, 1H), 5.06 (dd, JZ8.8, 6.1 Hz, 1H),
5.30 (dd, JZ9.2, 7.0 Hz, 1H), 5.36 (d, JZ7.0 Hz, 1H), 8.04
(d, JZ8.8 Hz, 1H), 8.31 (s, 1H), 8.32 (d, JZ9.2 Hz, 1H),
8.40 (d, JZ10.1 Hz, 1H), 8.56 (d, JZ10.5 Hz, 1H), 8.67 (s,
1H); 13C NMR (150 MHz, DMSO-d6) d 18.2, 18.3, 18.4,
18.9, 19.2, 19.8, 21.1, 30.9, 33.2, 34.7, 52.2, 55.3, 59.1,
61.2, 67.3, 125.6, 135.0, 141.9, 148.0, 159.4, 159.6, 163.2,
169.4, 170.1, 170.3; HRMS (MALDI-FTMS) calcd for
C25H36N6O6S (MCNaC) 571.2309, found 571.2324.
´
(b) Foster, M. P.; Concepcion, G. P.; Caraan, G. B.; Ireland,
C. M. J. Org. Chem. 1992, 57, 6671. (c) Perez, L. J.; Faulkner,
D. J. J. Nat. Prod. 2003, 66, 247.
5. (a) Aguilar, E.; Meyers, A. I. Tetrahedron Lett. 1994, 35, 2477.
(b) Downing, S. V.; Aguilar, E.; Meyers, A. I. J. Org. Chem.
1999, 64, 826. (c) At the same time we completed the synthesis
of bistratamide F–I, there was a report on the synthesis of
bistratamide G: Shin, C.-G.; Abe, C.; Yonezawa, Y. Chem.
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´
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Acknowledgements
We gratefully acknowledge NIH grant GM63212 and the
Skaggs Institute for Chemical Biology for generous
financial support. We thank Professor Evan T. Powers for
helpful discussions and Dr. Raj K. Chadha for the X-ray
structure determination.
J.; Jouin, P. Tetrahedron Lett. 1992, 33, 2807. (b) Wipf, P.;
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Engl. 2003, 42, 83. For synthesis of thiazolines using TiCl4
see: Raman, P.; Razavi, H.; Kelly, J. W. Org. Lett. 2000, 2,
3289. For synthesis of imidazoline-containing amino acids,
see: You, S.-L.; Kelly, J. W. Org. Lett. 2004, 6, 1681.
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References and notes
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´
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15. Crystallographic data for the structure 3 in this paper have
been deposited with the Cambridge Crystallographic Data
Centre as supplementary publication number CCDC 246784.
Copies of the data can be obtained, free of charge, on
application to CCDC, 12 Union Road, Cambridge CB2 1EZ,
UK [fax: C44 1223 336033 or e-mail: deposit@ccdc.cam.ac.
uk].
3. (a) Xia, Z.; Smith, C. D. J. Org. Chem. 2001, 66, 3459.
(b) Bertram, A.; Pattenden, G. Synlett 2000, 1519. (c) Bertram,