Synthetic studies on thiostrepton family of peptide antibiotics: Synthesis of the pentapeptide segment containing dihydroxyisoleucine, thiazoline and dehydroamino acid

Article abstract of DOI:10.1016/j.tetlet.2004.03.099

The dihydroxyisoleucine-, thiazoline- and dehydroamino acid-containing pentapeptide of the thiostrepton family of peptide antibiotics was synthesized, which featured the β-lactone opening by phenylselenylation, the vinylzinc addition to the chiral sulfinimine, the Wipf oxazoline-thiazoline conversion method and the oxidative syn-elimination of the phenylseleno group.

Full text of DOI:10.1016/j.tetlet.2004.03.099

Tetrahedron
Letters
Tetrahedron Letters 45 (2004) 3707–3712
Synthetic studies on thiostrepton family of peptide antibiotics:
synthesis of the pentapeptide segment containing
dihydroxyisoleucine, thiazoline and dehydroamino acid
Shuhei Higashibayashi, Mitsunori Kohno, Taiji Goto, Kengo Suzuki, Tomonori Mori,
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 1 March 2004; revised 13 March 2004; accepted 17 March 2004
Abstract—The dihydroxyisoleucine-, thiazoline- and dehydroamino acid-containing pentapeptide of the thiostrepton family of
peptide antibiotics was synthesized, which featured the b-lactone opening by phenylselenylation, the vinylzinc addition to the chiral
sulfinimine, the Wipf oxazoline–thiazoline conversion method and the oxidative syn-elimination of the phenylseleno group.
Ó 2004 Published by Elsevier Ltd.
We have recently reported the synthesis of the dehyd-
ropiperidine1 and dihydroquinoline2 segments (1 and 2,
respectively) of the thiostrepton family of peptide anti-
biotics (Fig. 1).3;4 In this letter, we report the synthesis of
the pentapeptide segment 3 containing the dihydroxy-
isoleucine, thiazoline and dehydroamino acid portions.5
We also report the synthesis of carboxylic acid 4 and
amine 5; both of which will serve as intermediates for
the total synthesis of the thiostrepton family of peptide
antibiotics.
The retrosynthetic analysis is illustrated in Scheme 1.
The thiazoline portion of pentapeptide 3 would be
constructed from b-hydroxyamide 7 through b-hydroxy-
thioamide 6 via the Wipf oxazoline–thiazoline conver-
sion method.6d–f The Z-dehydroamino acid portion of 3
would be obtained by the oxidative syn-elimination of
the phenylseleno group.7 The more suitable intermedi-
ates, 4 and 5, would be derived from 6 by standard
methods. b-Hydroxyamide 7 is divided into carboxylic
acid
8 and the dihydroxyisoleucine derivative 9.
Tripeptide 8 would be obtained from three amino acids
10–12 by consecutive condensations as well as the
phenylselenylation of the b-lactone part. The b-lactone
function would act as not only the protecting group of
the carboxylic acid group for condensation but also the
activating group of the hydroxy group for phenylselen-
ylation. Two amino acids, 10 and 11, could be obtained
In general, the thiazolines are sensitive to epimeriza-
tion;6 therefore, it is necessary to construct the thiazo-
line portion of 3 in the later stage of its synthesis.
Moreover, even if the fully protected pentapeptide 3 is
synthesized, it is predicted that we will have difficulty in
liberating the free carboxylic acid or the free amine from
3 without the thiazoline epimerization. Therefore, we
planned to synthesize the more suitable intermediates,
carboxylic acid 4 and amine 5; both of which would be
derived from the synthetic precursor of 3. The phenyl-
seleno group in 4 and 5, as the masked precursor to the
labile dehydroamino acid portion, is another advantage
of these compounds.
from L-threonine (13). The dihydroxyisoleucine deriva-
tive 9 would be obtained from the trisubstituted olefin
14 by the stereoselective dihydroxylation. The chiral
olefin 14 would be obtained from the chiral sulfinimine
15 by the diastereoselective addition of an organo-
metallic reagent.8 Enantiomerically pure sulfinimines are
versatile intermediates for the asymmetric syntheses of
the amine derivatives and a variety of nucleophiles add
to chiral sulfinimines in a highly diastereoselective
manner.8 If this reaction mainly affords the adduct
having the undesired configuration, all we have to do is
use the enantiomer of 15. Sulfinimine 15 could be easily
obtained from the known thiazole aldehyde 169 and the
Keywords: Thiostrepton; Thiazolines; Thioamides; Sulfinimines;
Dihydroxyisoleucine.
* Corresponding author. Tel.: +81-45-566-1577; fax: +81-45-566-1551;
e-mail: kimikoh@educ.cc.keio.ac.jp
0040-4039/$ - see front matter Ó 2004 Published by Elsevier Ltd.
doi:10.1016/j.tetlet.2004.03.099

3708
S. Higashibayashi et al. / Tetrahedron Letters 45 (2004) 3707–3712
CO2Et
S
O
O
CO2Bn
H
N
O
H
N
H
N
OH
H
N
H
NH2
NHBoc
S
S
N
MeO2C
N
NH
H
O
N
O
O
H
R3
R2
H
H
N
H
N
N
EtO2C
N
S
N
N
H
H
S
H
O
HN
OH
O
H
2
H
N
HO
R1
H
O
N
O
H
1
OH
O
H
H
BocN
NH
H
S
O
N
NH
H
H
O
H
NH
O
HN
O
O
O
OH
R4
H
S
NTeoc
H
NTeoc
H
NH2
H
HO
N
H
N
H
H
H
N
S
CO2Et
S
CO2H
S
CO2Et
S
H
H
HN
O
S
HN
O
HN
O
S
O
H
H
S
H
OH
OH
N
N
N
HO
H
H
N
H
H
OH
PhSe H
PhSe H
HN
N
HN
N
N
H
H
H
H
H
Thiostrepton: R1 = CH2CH3, R2 = CH3, R3 = H, R4 = CH3
O
O
O
3
4
5
TESO
TESO
TESO
H
Siomycin A: R1 = CH3, R2 = R3 = CH2 (dehydroalanine), R4 = CH3
Siomycin D1: R1 = CH3, R2 = R3 = CH2 (dehydroalanine), R4 = H
H
H
OTES
OTES
OTES
Figure 1.
Scheme 1. Retrosynthetic analysis of 3–5.
Ellman chiral sulfinamide 1710 using the Cs2CO3-medi-
ated sulfinimine synthesis recently developed by our
group.11
synthesis of 8 was the b-lactone opening by phenylselenyl-
ation. Phenylselenylation was tested using 19 (derived
from 11) as the model compound. First, Shirahama’s
conditions7a (PhSeNa)15 were applied to 19, resulting in
failure probably because attack of nucleophiles at the b-
position of the threonine b-lactone is disfavored in
contrast to the facile ring openings at the methylene of
the serine-derived b-lactones.13 There are other methods
available for the nucleophilic phenylselenylation reac-
tions: PhSeSiMe3 þ KF,16 PhSeSiMe3 þ ZnI2,17 both of
which had been used for the lactone-opening reactions,
and PhSeSiMe3 and/or PhSeH used for opening of the
Tripeptide 8 was synthesized as follows (Scheme 2).
L
-Threonine (13) was treated with 2-(trimethylsilyl)ethyl
4-nitrophenyl carbonate12 and triethylamine followed by
acetonization to afford 10 quantitatively. b-lactone 11
(TsOH salt) was prepared from 13 by the Vederas
method.13 Coupling of 10 (1.0 equiv) with 11 (1.1 equiv)
was realized with PyBOP14 and i-Pr2NEt in CH2Cl2 to
give 18 in 66% yield from 10. The crucial step for the

S. Higashibayashi et al. / Tetrahedron Letters 45 (2004) 3707–3712
3709
see
ref. 9
EtO OEt
N
OHC
CO2Et
a
H
CO2Et
S
22
16
O
N
S
CO2Et
+
t-Bu
N
S
O
15
S
t-Bu
NH2
b
17
O
H
N
N
N
S
CO2Et
t-Bu
e
S
H
23
c,d
OTES
OH
H
H
H
h
OTES
OH
H
H2N
H
N
N
CO2Et
CO2Et
CO2Et
BocHN
BocHN
S
S
S
9
24
14
f,g
OH
H
Scheme 2. Synthesis of tripeptide 8. Reagents and conditions: (a)
TeocOPh(p-NO2) (1.1 equiv), Et3N (3.0 equiv), dioxane–H2O (1:1), rt,
20 h; (b) acetone dimethylacetal (3.0 equiv), p-TsOH (0.1 equiv), ace-
tone, rt, 6 h, quantitative yield (two steps); (c) 10 (1.0 equiv), 11
(1.1 equiv), PyBop (1.2 equiv), i-Pr2NEt (2.4 equiv), CH2Cl2, rt, 2.5 h,
66% from 10; (d) Boc2O (2.0 equiv), i-Pr2NEt (1.2 equiv), THF, rt,
16 h, 77%; (e) PhSeH (1.5 equiv), DMF, 80 °C, 2 h, quantitative yield;
(f) PhSeH (1.5 equiv), DMF, 80 °C, 2 h, 94%; (g) 21 (1.0 equiv), 12
(1.1 equiv), DMTMM (1.1 equiv), NMM (1.1 equiv), MeOH, rt, 6 h,
82% from 21; (h) 1 M aq NaOH (1.5 equiv), MeOH–dioxane–H2O
(1:1:1), rt, 1 h. Teoc¼ 2-(trimethylsilyl)ethoxycarbonyl, PyBop ¼ benzo-
OH
H
H2N
N
CO2H
S
25 (AcOH salt)
Scheme 3. Synthesis of the dihydroxyisoleucine derivative 9. Reagents
and conditions: (a) 16 (1.0 equiv), 17 (1.0 equiv), Cs2CO3 (1.0 equiv),
CH2Cl2, rt, 2 h, quantitative yield; (b) (Z)-2-bromo-2-butene
(5.0 equiv), 1.62 M t-BuLi (10 equiv) in ether, THF, ꢀ78 °C, 5 min,
then 1 M ZnCl2 (5.0 equiv) in ether, 0 °C, 15 min, then 15 (1.0 equiv) in
THF, ꢀ78 to ꢀ40 °C, 6 h, 87%; (c) 10 wt % HCl–MeOH, rt, 0.5 h; (d)
Boc2O (1.2 equiv), Et3N (1.2 equiv), dioxane, rt, 2 h, 83% (two steps);
(e) OsO4 (0.1 equiv), NMO (3.0 equiv), DABCO (0.2 equiv), t-BuOH–
H2O (85:15), rt, 12 h, 56%; (f) 1 M aq NaOH (1.5 equiv), EtOH–
dioxane (2:1), rt, 0.5 h; (g) 3 M HCl–EtOAc, then DOWEX 50W,
pyridine–acetic acid buffer (pH 3.1), 65% (two steps); (h) TESOTf
(4.0 equiv), 2,6-lutidine (6.0 equiv), CH2Cl2, rt, 1 h, 92%. NMO ¼ N-
methylmorpholine N-oxide, DABCO ¼ 1,4-diazabicyclo[2.2.2]octane,
TES ¼ triethylsilyl, Tf ¼ trifluoromethanesulfonyl.
triazolyloxy-tris(pyrrolidino)-phosphonium
hexafluorophosphate,
Boc ¼ t-butoxycarbonyl, DMTMM ¼ 4-(4,6-dimethoxy-1,3,5-triazin-
2-yl)-4-methylmorpholinium chloride, NMM ¼ N-methylmorpholine.
oxazoline and oxazine rings.18 Among them, the PhSeH
method18 was the best choice in view of the easy
experimental procedures (PhSeH, DMF, 80 °C, 2 h),
quantitatively giving 20.19 To the best of our knowledge,
this is the first example of the opening reaction of b-
substituted b-lactones using PhSeH. b-Lactone 18 was
then subjected to the same conditions to afford the
desired 21 in 94% yield. Condensation of 21 (1.0 equiv)
with 12 (HCl salt, 1.1 equiv) using DMTMM20 and
NMM in MeOH afforded tripeptide (82% yield).
Hydrolysis of this tripeptide with aqueous NaOH gave
the desired tripeptide 8, which was used for the next step
without purification.
or Et2O, resulting in the decomposition of 15. In con-
trast, transmetallation of the above vinyllithium reagent
(in THF) to the vinylzinc reagent by the addition of
ethereal ZnCl2 (1.1 equiv) was realized at 0 °C; to this
was added 15 (1.0 equiv) in THF at ꢀ78 °C. The mixture
was stirred at ꢀ40 °C for 6 h, affording the desired
adduct 23 in ca. 20% yield. Fortunately, using excess
amounts of the vinylzinc reagent (5.0 equiv) afforded 23
in 87% yield as the sole adduct.21 The stereochemistry of
23 was confirmed in the later stage (vide infra). To the
best of our knowledge, this is the first example of the
addition of the vinylzinc reagent to the chiral sulfin-
imine.22 The next crucial step was the dihydroxylation of
the trisubstituted double bond in order to construct the
dihydroxyisoleucine portion. We expected that the
Hauser’s sulfoxide-mediated intramolecular dihydroxyl-
ation of olefins23 was applicable to allylic sulfinamides;
however, only the oxidation of the sulfinamide to the
sulfonamide occurred. Therefore, the sulfinamide 23 was
transformed into carbamate 14 in 83% yield. Dihydr-
oxylation of 14 was conducted under the variety of
conditions including the Sharpless asymmetric dihydr-
oxylation;24 the best result was obtained using OsO4
The synthesis of the dihydroxyisoleucine derivative 9
started with the known thiazole aldehyde 16,9 which was
prepared from ethyl diethoxyacetate (22) (Scheme 3).
Condensation of 16 (1.0 equiv) with the Ellman chiral
sulfinamide 1710 (1.0 equiv) in CH2Cl2 using our recently
developed method with Cs2CO3 (1.0 equiv) as an amine-
activating and dehydrating reagent11 quantitatively
produced 15. The first crucial step in the synthesis of 9
was the regioselective and diastereoselective addition of
the organometallic reagent to the sulfinimine group of
15 in the presence of the ethoxycarbonyl group. To the
vinyllithium reagent prepared from (Z)-2-bromo-2-but-
ene (1.1 equiv) and t-BuLi (2.2 equiv) in THF or Et2O
was added at ꢀ78 °C a solution of 15 (1.0 equiv) in THF

3710
S. Higashibayashi et al. / Tetrahedron Letters 45 (2004) 3707–3712
ducted with CIP,32 HOAt and i-Pr2NEt in CH2Cl2 to
R2M
R1
H
give pentapeptide 7 in 83% yield from 9. Now the crucial
Wipf oxazoline–thiazoline conversion method was
realized as follows.6;33 Treatment of 7 with DAST34 gave
oxazoline 26 in 85% yield, which was subjected to H2S in
MeOH–Et3N (1:1) to afford thioamide 6 in 90% yield.
Thioamide 6 was again treated with DAST34 to give
thiazoline 27, which was subsequently treated with
TBHP in TFE–CH2Cl2 (1:1) to afford the desired pen-
tapeptide 3 in 57% yield from 6. The structure of 3 was
confirmed by its 1H and 13C NMR spectra, including H–
H COSY, HMQC and HMBC. At this stage, we tried
hydrolysis of the ethyl ester of 3 under a variety of
conditions (e.g., aqueous NaOH in EtOH–dioxane (2:1),
aqueous Ba(OH)2 in MeOH,35 Me3SiOK in THF36);
however, but not unexpectedly, the complete epimer-
ization occurred.37 Furthermore, treatment of 3 with
trimethyltin hydroxide, which could be used for hydro-
lysis of methyl phenylacetate,38 afforded carboxylic acid
contaminated with ca. 20% of the epimerization prod-
uct.37 On the other hand, deprotection of the Teoc
O
S
M
t-Bu
O
N
N
R2
R1
t-Bu
(A)
(B)
Figure 2. Transition-state model.
(0.1 equiv), NMO (3 equiv) and DABCO (0.2 equiv)25 in
85:15 t-BuOH–H2O at rt for 12 h, affording a 84% yield
of a 2:1 mixture of 24 and its diastereoisomer, from
which the desired 24 was easily separated by silica-gel
column chromatography. The structure determination
of 24 (and hence 23) was realized by its transformation
into the naturally derived degradation product, thio-
streptine (25),26–28 and comparing the optical rotation
and 1H NMR spectrum. Disilylation of 24 with TESOTf
and 2,6-lutidine afforded, concomitant with cleavage
of the Boc group,29 9 in 92% yield.
39
The high selectivity of the addition of the vinylzinc
reagent to sulfinimine 15 might be rationalized by the
open transition-state model A8;22b;30 shown in Figure 2,
where the addition occurs from the Si face of the imine.
On the basis of the Davis statement,22b we speculate that
the existence of heteroatoms in the thiazole ester dis-
rupts and prevents forming of the chelated transition
state (B in Fig. 2, Re face attack). On the other hand, the
selectivity of the dihydroxylation of 14, albeit it was only
2:1, might be explained by considering that the carba-
mate group serves to deliver the oxidant to the desired
face of the double bond.31
group of 3 with ZnCl2 in nitromethane at 50 °C
resulted in an ca. 20% epimerization.37 Therefore, we
considered that carboxylic acid 4 and amine 5 would be
the more suitable intermediates for elaboration of the
pentapeptide portion usable for the total synthesis of the
thiostrepton family of peptide antibiotics. To this end,
thioamide 6 was treated with aqueous NaOH in EtOH–
dioxane (2:1) to afford carboxylic acid 4 quantitatively.
39
Moreover, treatment of thioamide 6 with ZnCl2 in
nitromethane afforded amine 5 in 58% yield (Scheme 4).
In summary, we have synthesized the pentapeptide
segment 3 of the thiostrepton family of peptide antibio-
tics and the more suitable synthetic intermediates, car-
boxylic acid 4 and amine 5. The key reactions were the
Condensation of carboxylic acid 8 (1.1 equiv) with the
dihydroxyisoleucine derivative 9 (1.0 equiv) was con-
O
HO
H
H
H
N
H
O
TeocN
N
CO2H
H
O
H H
O
HO
O
H
H
H
H
SePh
H
N
H
O
H
N
H
H
N
H
H
N
H
S
O
H
S
8
a
b
TeocN
N
N
CO2Et
TeocN
N
N
CO2Et
+
H
H
O
H H
O
O
O
OTES
SePh
SePh
H
TESO
TESO
H
H
OTES
OTES
OTES
7
26
H
N
CO2Et
H2N
c
S
9
O
O
R2O
HO
S
H
H
H
H
H
H
N
H
H
N
H
H
N
H
H
N
H
H
N
H
S
S
S
S
N
S
N
H
H
e
d
N
TeocN
N
N
CO2Et
TeocN
N
CO2Et
R3R2N
N
CO2R1
H
H
H
O
O
O
H
SePh
O
O
H H
SePh
O
TESO
TESO
TESO
H
H
H
OTES
OTES
OTES
3
27
6: R1 = Et, R2 = acetonide, R3 = Teoc
4: R1 = H, R2 = acetonide, R3 = Teoc
5: R1 = Et, R2 = R3 = H
f
g
Scheme 4. Synthesis of pentapeptides 3–5. Reagents and conditions: (a) 8 (1.1 equiv), 9 (1.0 equiv), CIP (1.2 equiv), HOAt (1.2 equiv), i-Pr2NEt
(2.4 equiv), CH2Cl2, rt, 0.5 h, 83% from 9; (b) DAST (1.5 equiv), CH2Cl2, ꢀ78 °C, 5 min, 85%; (c) H2S, MeOH–Et3N (1:1), rt, 6 h, 90%; (d) DAST
(1.5 equiv), CH2Cl2, ꢀ78 °C, 5 min; (e) TBHP (10 equiv), TFE–CH2Cl2 (1:1), rt, 2 h, 57% from 6; (f) 1 M aq NaOH (3.0 equiv), EtOH–dioxane (2:1),
rt, 5 h, quantitative yield; (g) ZnCl2 (15 equiv), nitromethane, rt, 15 h, 58%. CIP ¼ 2-chloro-1,3-dimethylimidazolidium hexafluorophosphate,
HOAt ¼ 1-hydroxy-7-azabenzotriazole, DAST ¼ diethylaminosulfur trifluoride, TBHP ¼ t-butylhydroperoxide, TFE ¼ 2,2,2-trifluoroethanol.

S. Higashibayashi et al. / Tetrahedron Letters 45 (2004) 3707–3712
3711
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b-lactone opening by phenylselenylation, the vinylzinc
addition to the chiral sulfinimine, the Wipf oxazoline–
thiazoline conversion method and the oxidative syn-
elimination of the phenylseleno group. Synthetic studies
of the thiostrepton family of peptide antibiotics using
segments 1, 2 and 4 (or 5) are now in progress.
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Acknowledgements
This research was supported by a Grant-in Aid for
Scientific Research on Priority Areas (A) ‘Exploitation
of Multi-Element Cyclic Molecules’ from the Ministry
of Education, Culture, Sports, Science and Technology,
Japan.
References and notes
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6. (a) Yonetani, K.; Hirotsu, Y.; Shiba, T. Bull. Chem. Soc.
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28
D
25
D
26. ½aꢁ ꢀ 2:8 (c 1.00, 1 M AcOH) [lit.27a ½aꢁ ꢀ 4 (c 1,
20
D
25
D
1 M AcOH), lit.27b ½aꢁ ꢀ 2:8 (c 1, AcOH), lit.27c ½aꢁ ꢀ
4:4 (c 1, 1 M AcOH)].
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