Total synthesis of siomycin A

Article abstract of DOI:10.1016/j.tetlet.2006.12.121

We have succeeded in the total synthesis of siomycin A, a representative compound of the thiostrepton family of peptide antibiotics, featuring the one-pot cyclization-elongation of our strategic intermediates and the late-stage formations of the thiazolin

Full text of DOI:10.1016/j.tetlet.2006.12.121

Tetrahedron Letters 48 (2007) 1331–1335
Total synthesis of siomycin A
Tomonori Mori, Shuhei Higashibayashi,ꢀ Taiji Goto, Mitsunori Kohno, Yukiko Satouchi,
Kazuyuki Shinko, Kengo Suzuki, Shunya Suzuki, Hiraku Tohmiya,
Kimiko Hashimoto*,ꢁ and Masaya Nakata*
Department of Applied Chemistry, Faculty of Science and Technology, Keio University,
3-14-1 Hiyoshi, Kohoku-ku, Yokohama 223-8522, Japan
Received 4 December 2006; revised 16 December 2006; accepted 21 December 2006
Available online 23 December 2006
Dedicated to Professor Yoshito Kishi on the occasion of his forthcoming 70th birthday
Abstract—We have succeeded in the total synthesis of siomycin A, a representative compound of the thiostrepton family of
peptide antibiotics, featuring the one-pot cyclization–elongation of our strategic intermediates and the late-stage formations of
the thiazoline and dehydroamino acid moieties.
Ó 2007 Elsevier Ltd. All rights reserved.
Siomycin A was isolated in 1961 from the culture broth
of Streptomyces sioyaensis by the Shionogi group1 and is
a representative of the thiostrepton family of peptide
antibiotics (Fig. 1).2 The structure of siomycin A was
elucidated by chemical degradation studies3 and NMR
spectral studies4 by comparison with those of thiostrep-
ton. Other structurally-related antibiotics, the thiopep-
tins, Sch 18640, and Sch 40832, were also isolated.2
The characteristic structure of this family is the bicyclic
skeleton containing dehydropiperidine, dihydroquinol-
ine, four thiazoles, thiazoline, dehydroamino acids,
and dihydroxyisoleucine. Fascinated by their stunningly
complex structural features, we5 and the Nicolaou
group6 have aimed to synthesize these antibiotics.
Recently, Nicolaou and his co-workers have succeeded
in the fascinating total synthesis of thiostrepton.7 Other
efforts have focused on the syntheses of the structur-
ally simpler thiopeptide antibiotics: for example, the
micrococcins,8 promothiocin A,9 amythiamicin D,10
Figure 1. Structure of siomycin A.
Keywords: Siomycin A; One-pot cyclization–elongation; Thiazoline;
Dehydroamino acid.
GE2270A,11 and GE2270T.11 We now report the total
*
Corresponding authors. Tel.: +81 75 595 4673; fax: +81 75 595 4763
(K.H.); tel.: +81 45 566 1577; fax: +81 45 566 1551 (M.N.); e-mail
addresses: kimikoh@mb.kyoto-phu.ac.jp; msynktxa@applc.keio.
ac.jp
r
synthesis of siomycin A by the coupling ( in Fig. 1)
of our strategic intermediates, the cyclic core portion
15e (A-ring, Fig. 1 and Scheme 1) and the pentapeptide
portion 25c (Scheme 1), followed by cyclization ( in
s
ꢀ Present address: Research Center for Molecular-Scale Nanoscience,
Institute for Molecular Science, Okazaki 444-8787, Japan.
ꢁ Present address: Kyoto Pharmaceutical University, 1 Shichono-cho,
Misasagi, Yamashina-ku, Kyoto 607-8412, Japan.
Fig. 1, B-ring) of the resulting coupling product and
t
elongation ( in Fig. 1) of the side chain 3 (Scheme 2)
onto the cyclization product.12 We anticipated that this
0040-4039/$ - see front matter Ó 2007 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2006.12.121

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T. Mori et al. / Tetrahedron Letters 48 (2007) 1331–1335
Scheme 1. Synthesis of the intermediate 11. Boc = tert-butoxycarbonyl, Bpoc = 1-methyl-1-(4-biphenyl)ethoxycarbonyl, Fm = 9-fluorenylmethyl,
TBS = tert-butyldimethylsilyl, TMSE = 2-(trimethylsilyl)ethyl, HATU = O-(7-azabenzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophos-
phate, TES = triethylsilyl, Teoc = 2-(trimethylsilyl)ethoxycarbonyl, DAST = (diethylamino)sulfur trifluoride.
cyclization–elongation step would be realized in the
stepwise manner after the selective deprotection of one
of the two TMSE esters, or more conveniently, in the
one-pot operation via the regioselective cyclization–
elongation of the dicarboxylic acid secured by the simul-
taneous deprotection of the two TMSE esters. Other
challenging tasks included the well-timed constructions
of the easily racemizing thiazoline ring and the fastidious
dehydroamino acids including four dehydroalanines and
the trisubstituted (Z)-olefin next to the thiazoline ring.
which had been used as a deprotection reagent of the
Teoc group,14 would be suitable for the deprotection
of the TMSE ester, and additionally, the simultaneous
deprotection of the Teoc and acetonide groups would
occur. However, under the restricted conditions (ZnCl2
(100 equiv)/ether, nitromethane, rt, 24 h), we could not
realize this requirement; the dicarboxylic acid and a mix-
ture of the monocarboxylic acids were nonselectively
obtained, although the Teoc and acetonide groups were
smoothly cleaved.5c
We have already reported the synthesis of the siomycin
cyclic core portion 15e by the coupling of the dehydropi-
peridine segment 4,5a,e the dihydroquinoline segment
5,5b,d and the masked dehydroalanine (i.e., b-phenyl-
selenoalanine) segment 65e (Scheme 1). For the coupling
partner of 1, we selected 25c which has the hydroxy-
methylthioamide function as the precursor of the thiaz-
oline ring (Scheme 1). The Boc group in 1 was first
deprotected with 4 M HCl/dioxane to afford 7 along
with a small amount of 8. This crude mixture was cou-
pled with 2 (1.0 equiv) using HATU13 (1.0 equiv) and
(i-Pr)2NEt (5.0 equiv) in CH2Cl2, giving 9 and its TBS
ether 10 in 60% and 8% yields, respectively.
We then turned our attention to the regioselective cycli-
zation–elongation of the dicarboxylic acid. Prior to this,
9 was first treated with DAST5c,15 (1.6 equiv) in CH2Cl2
to give thiazoline 11 in 87% yield (Scheme 1). Deprotec-
tion of the three kinds of protecting groups (Teoc, ace-
tonide, and TMSE) in 11 was cleanly realized with
ZnCl214 (100 equiv)/ether in nitromethane (rt, 48 h), giv-
ing the cyclization–elongation precursor 12 (Scheme 2).
The side chain 37c was prepared from the known b-phen-
ylselenoalanine 135e,7c by the following four-step
sequence: (1) amidation, (2) deprotection of the Boc
group, (3) condensation of another 13, and (4) deprotec-
tion of the Boc group. The one-pot operation was car-
ried out under the conditions including, as the
cyclization step, EDC–HOAt–(i-Pr)2NEt–DMF (EDC =
(1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydro-
We first attempted selectively deprotecting one of the
two TMSE esters in 9. It was anticipated that ZnCl2,

T. Mori et al. / Tetrahedron Letters 48 (2007) 1331–1335
1333
Scheme 2. Completion of the total synthesis of siomycin A. Reagents and conditions: (a) 1 M ZnCl2/ether, MeNO2, rt, 48 h; (b) ClCO2Et, Et3N,
THF, À15 °C, 10 min, then 28% NH4OH, À15 °C to rt, 2 h; (c) TFA–CH2Cl2 (1:1), rt, 1.5 h; (d) 13, CIP, HOAt, (i-Pr)2NEt, DMF, rt, 2 h; (e) TFA–
CH2Cl2 (1:1), rt, 2 h, 68% (4 steps); (f) HATU, (i-Pr)2NEt, DMF–CH2Cl2 (1:4), 0 °C, 3 h, then 3, rt, 24 h; (g) HFÆpyridine–THF (1:4), rt, 20 h; (h)
4 M TBHP/CH2Cl2, TFE–CH2Cl2 (1:5), rt, 1 h, 7% from 11. TFA = trifluoroacetic acid, CIP = 2-chloro-1,3-dimethylimidazolidium hexafluoro-
phosphate, HOAt = 1-hydroxy-7-azabenzotriazole, TBHP = tert-butyl hydroperoxide, TFE = 2,2,2-trifluoroethanol.
chloride) and HATU13–(i-Pr)2NEt–solvent (e.g., DMF,
THF, dioxane, DMF–CH2Cl2 (1:4), DMF–CH3CN
(1:4)), followed by the subsequent elongation with 3.
Among them, the best conditions were HATU
(5.0 equiv) and (i-Pr)2NEt (5.0 equiv) in DMF–CH2Cl2
(1:4, 1 mM for 12) at 0 °C for 3 h followed by the addi-
tion of 3 (5.0 equiv, rt, 24 h), affording the crude prod-
ucts including 14 after removing the excess 3 by
Sephadex LH-20 (CHCl3). Although the structure of
14 could not be confirmed at this stage, we proceeded
to the two-step transformation into siomycin A. These
crude products were treated with HFÆpyridine–THF
(1:4)7d to afford the crude products including 15, which
were finally subjected to the oxidative elimination (4 M
TBHP/CH2Cl2, TFE–CH2Cl2 (1:5), rt, 1 h),5c,e,6c,7b,d
giving siomycin A in 7% yield from 11. The synthetic
siomycin A was identical with the natural siomycin A
based on the 1H NMR, 13C NMR, IR, and MS spectra,
TLC, and optical rotation (see Supplementary data). It
is noteworthy that the final two-step operation could
not be reversed, in contrast to Nicolaou’s thiostrepton
synthesis,7b,d because it was found that siomycin A grad-
ually changed into siomycin B,16 which is the side chain
degradation product of siomycin A, under the HFÆpyri-
dine–THF (1:4) conditions (rt, during 24 h). In addition,
when the model pentapeptide 165c was subjected to the
HFÆpyridine–THF (1:4) conditions (rt, 4 h), the Z-olefin
17 was obtained in 70% yield as the sole product
(Scheme 3). The stereochemistry of 17 was confirmed
1
by NOE analysis of the H NMR spectrum, and addi-
tionally, by the transformation (TESOTf, 2,6-lutidine)
into 18 which was identical to the sample5c derived from
16 by syn elimination using TBHP. These facts mean
that the dehydroselenation next to the thiazoline C2-po-
sition affords the thermodynamically stable Z-olefin and
account for the Z-selectivity from 14 to 15. Unfortu-
nately, during the cyclization–elongation step, an almost
equal amount of the product was obtained whose struc-

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T. Mori et al. / Tetrahedron Letters 48 (2007) 1331–1335
of Education, Culture, Sports, Science and Technology,
Japan (MEXT).
Supplementary data
Spectral data of natural and synthetic siomycin A and
the regioisomeric cyclization–elongation product.
Supplementary data associated with this article can be
found, in the online version, at doi:10.1016/j.tetlet.
2006.12.121.
References and notes
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