Synthetic studies on thiostrepton: Construction of thiostrepton analogues with the thiazoline-containing macrocycle

Article abstract of DOI:10.1002/anie.200351745

Leading the way: The novel thiostrepton analogue 1 and its 5S, 6S diastereomer were synthesized through macrolactamization reactions. Forays towards the total synthesis of the natural product itself should follow a similar strategy.

Full text of DOI:10.1002/anie.200351745

Communications
eventual total synthesis of 1 and its analogues by addressing
the remaining challenges posed by the imposing and sensitive
structure of the molecule. Specifically, we describe: 1) the
construction of the thiazoline 7 and thiazole 8 fragments,
2) the synthesis of the dehydropyrrolidine isomer 4 of the
dehydropiperidine domain and its 5S,6S diastereoisomer 4’,
and 3) the assembly of these fragments into thiostrepton
analogues 2 and 3, which lack only the quinaldic acid
macrocycle and differ from thiostrepton (1) at the imine-
containing ring core (Scheme 1).
We begin with our previously reported[2] biomimetically
inspired aza-Diels–Alder dimerization, which delivered the
dehydropiperidine domain
9
(5R,6R-diastereoisomer,
Scheme 2) as a 1:1 mixture with its 5S,6S-diastereoisomer 9’
(not shown). In solution, these dehydropiperidine compounds
(9 and 9’) rearrange into their dehydropyrrolidine counter-
parts 4 and 4’, respectively, reaching an equilibrium via aminal
10 and 10’.[4] The six-membered ring imine 9 (and 9’) can be
selectively reduced with NaCNBH3 under acidic conditions
over its five-membered counterpart (4 and 4’), presumably
¼
Natural Product Analogues
due to less steric hindrance around the C Nbond, to render
diamine 11 (and 11’), as we already reported.[2] However,
under standard amide bond-forming conditions (EDC,
HOAt) with alloc-l-Ala-OH (5, Scheme 1), the five-mem-
bered ring imine 4 (and 4’) is selectively captured, leading to
compound 13 (and 13’), obtained as a mixture of 5R,6R- and
5S,6S-diastereoisomers, which were chromatographically sep-
arated (72% combined yield). On the other hand, diamine 11
(and 11’) can also be coupled with alloc-l-Ala-OH (5)
(HOAt, HATU, EtNiPr2) predominantly at the primary
amine site (2:1 ratio of regioisomers) yielding, upon oxidation
with tBuOCl and base-induced elimination of HCl from the
resulting chloroamine, the dehydropiperidine peptide 12 (and
12’) in 21% overall yield (from 9 and 9’). While attempting to
optimize this route to 12 (and 12’), we opted to construct
analogues 2 and 3 utilizing the more available dehydropyrrol-
idine intermediates 13 and 13’ with the dual aim of scouting
the ground for the total synthesis of thiostrepton (1) and to
produce novel thiostrepton analogues for biological evalua-
tion.
Synthetic Studies on Thiostrepton: Construction
of Thiostrepton Analogues with the Thiazoline-
Containing Macrocycle**
K. C. Nicolaou,* Marta Nevalainen, Mark Zak,
Stephan Bulat, Marco Bella, and Brian S. Safina
Thiostrepton (1, Scheme 1)[1] is a highly complex thiopeptide
antibiotic endowed with an unusual molecular architecture
and a mode of action that involves RNA binding. As part of
our program directed towards the total synthesis of this
unique natural product, we have already reported synthetic
approaches to both its dehydropiperidine domain[2] and its
segment corresponding to the quinaldic acid macrocycle.[3]
Herein we disclose further advances that pave the way for an
With ample quantities of the central core 13 and its 5S,6S
diastereoisomer (13’) in hand, we proceeded to construct the
remaining key building blocks 6–8 (Scheme 1). Scheme 3
outlines the synthesis of the thiazole amino acid equivalent 8,
starting from angelic acid methyl ester (14). Thus, sequential
conversion of commercially available 14 into its acid 15 (90%
yield), acid chloride 16, and (ꢀ)-menthyl ester 17 (70% over
two steps) allowed a diastereoselective dihydroxylation with
AD-mix-b and MeSO2NH2, leading to diol 18[5] (90% yield,
d.r. 90:10). The latter compound, 18, was further protected as
acetonide 19 (100% yield) and then reduced with DIBAL-H
(90%) to alcohol 20. In a remarkable one-pot sequence,
alcohol 20 was oxidized with DMP; the aldehyde obtained in
this manner was engaged in situ with benzylamine in the
[*] Prof. Dr. K. C. Nicolaou, Dr. M. Nevalainen, M. Zak, Dr. S. Bulat,
Dr. M. Bella, B. S. Safina
Department of Chemistryand
The Skaggs Institute for Chemical Biology
The Scripps Research Institute
10550 North TorreyPines Road, La Jolla, CA 92037 (USA)
Fax: (+1)858-784-2469
E-mail: kcn@scripps.edu
and
Department of Chemistryand Biochemistry
Universityof California, San Diego
9500 Gilman Drive, La Jolla, CA 92093 (USA)
[**] We thank Dr. D. H. Huang, Dr. G. Siuzdak, and Dr. R. Chadha for
NMR spectroscopic, mass spectrometric, and X-raycrystallographic
assistance, respectively. Financial support for this work was
provided byThe Skaggs Institute for Chemical Biology, the National
Institutes of Health (USA), fellowships from The Academyof
Finland (to M.N.), The Skaggs Institute for Research (to M.Z.), and
Bayer AG (to S.B.), and grants from Abbott, Amgen, ArrayBio-
pharma, Boehringer-Ingelheim, Glaxo, Hoffmann-LaRoche,
DuPont, Merck, Novartis, Pfizer, and Schering Plough.
[6]
presence of Yb(OTf)3 and molecular sieves (4 Š), and the
resulting imine was treated with trimethylsilyl cyanide[7] to
furnish Strecker addition product 21 in 90% overall yield. To
our delight, not only did this sequence produce virtually a
1
single stereoisomer (d.r. > 95:5 according to H NMR spec-
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Scheme 1. Structures of thiostrepton (1) and analogues 2 and 3, and retrosynthetic analysis of the latter two compounds to building blocks 4–8
and 4’. Alloc=allyloxycarbonyl; Boc=tert-butoxycarbonyl; TBS=tert-butyldimethylsilyl; TES=triethylsilyl.
troscopic analysis), but, also, the obtained material possessed
the correct stereochemistry, as proven by X-ray crystallo-
graphic analysis of a subsequent intermediate (i.e. 25, see
ORTEP drawing, Scheme 3). Hydrogenolysis of the benzyl
group of 21 in the presence of (Boc)2O led to Boc derivative
22 in 75% yield. Treatment of 22 with H2S in the presence of
Et3Nin a sealed tube afforded thioamide 23 (90%), which
was then treated with ethyl bromopyruvate under standard
Hantzsch conditions[8] to afford thiazole 24 in 82% yield. For
reasons of protecting-group compatibility in subsequent steps,
we moved to modify the diol and amine functionalities within
the latter substrate by first removing the groups guarding
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Scheme 2. Construction of dehydropiperidine and dehydropyrrolidine systems 12 and 13. Reagents and conditions: a) 1) Alloc-l-Ala-OH (5)
(1.2 equiv), HOAt (1.3 equiv), EDC (1.3 equiv), DMF, 258C, 12 h; 2) separation of diastereomers (silica gel, Et2O/toluene (60–80%), then EtOAc/
hexane(90%)), 72% combined yield; b) NaCNBH3 (2.0 equiv), AcOH/EtOH (1:4), 08C, 1 h, 50%; c) Alloc-l-Ala-OH (5) (1.1 equiv), HOAt
(1.1 equiv), HATU (1.1 equiv), EtNiPr2 (3.0 equiv), DMF, 258C, 2 h, 60%; d) tBuOCl (1.2 equiv), THF, ꢀ788C, 0.5 h, 4-DMAP (0.2 equiv), Et3N
(2.0 equiv), 258C, 10 min, 70%. HATU=O-(7-azabenzotriazol-1-yl)-N,N,N’,N’-tetramethyluronium hexafluorophosphate; EDC=1-ethyl-
(3-dimethylaminopropyl)carbodiimide hydrochloride; DMF=N,N-dimethylformamide; 4-DMAP=4-dimethylaminopyridine; HOAt=1-hydroxy-7-
azabenzotriazole. Compounds 4, 9–13 are accompanied (ca. 1:1) bytheir 5 S,6S diastereoisomers (4’, 9’–13’, respectively, structures not shown).
them and then remasking them in a different way. Thus, 24
was exposed to NaOEt in ethanol, furnishing the crystalline
derivative 25 by removal of the trifluoroacetate group in
quantitative yield. The latter compound (25) was then treated
with TFA to furnish amino diol 26, which was selectively
converted into monosilyl ether 27 by reaction with TBSCl in
the presence of Et3N(81% yield over two steps). Finally,
conversion of the amine within 27 into the corresponding
azide (28) through the diazo-transfer procedure,[9] followed
by basic hydrolysis of the ethyl ester, afforded the targeted
building block 8 in 78% overall yield.
The synthesis of thiazoline moiety 7, a structural element
unique to thiostrepton—the other peptide antibiotics of the
same family contain a thiazole instead—was carried out as
summarized in Scheme 4 (p. 3422). Coupling of commercially
available Fmoc-threonine (29) with d-serine methyl ester
under standard conditions (EDC, HOBt, Et3N) gave dipep-
tide 30 in 70% yield. Silylation of both hydroxy groups of 30
(81% yield), followed by thiocarbonylation with Lawesson's
reagent, gave thioamide 32 (79% yield) via bis-TES-deriva-
tive 31. The next requisite amino acid equivalent, compound
37, was prepared from TBS-protected Boc-l-threonine
methyl ester (34)[10] by first removing the Boc group with
TFA, and then converting the corresponding primary amine
of 35 into an azide functionality through the above-mentioned
diazo-transfer procedure to provide 36 (72% over two steps).
Hydrolysis of the ester provided acid 37 (93% yield), which
was then coupled under standard conditions (HATU, HOAt,
Et3N) with amine 33 generated from its Fmoc derivative 32
through the action of Et2NH to afford tripeptide surrogate 38
(75% from 32). The primary TES group of 38 was selectively
cleaved with THF/AcOH/H2O (3:1:1) at 258C to furnish
alcohol 39, which upon exposure to DAST[11] led smoothly to
the expected thiazoline 40 (90% yield). The final step
required to complete the synthesis of 7 was the Staudinger
reaction[12] of the azide to form the amino group, a trans-
formation smoothly effected with trimethylphosphane and
water (92% yield).
Scheme 5 (p. 3422) depicts the synthesis of the dipeptide
equivalent to the top side chain of thiostrepton, bisseleno
dipeptide 6. This intermediate was synthesized from known l-
serine derivative 41[13] by first generating the amino seleno-
amide 43 (via 42) and then coupling the two (41 and 43) under
the influence of EDC and HOBt (58% over two steps),
followed by removal of the remaining Boc group with TFA
(95% yield).
The assembly of the targeted thiostrepton analogue 2
from the five-membered ring imine core 13 and the described
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building blocks 6–8 proceeded as shown in
Scheme 6 (p. 3423). Thus, the less polar isomer
13 (5R,6R) was treated with TFA/CH2Cl2 (1:1) to
afford amino alcohol 45 while its more polar
diastereoisomer 13’ (5S,6S, not shown) led, under
the same conditions, to the corresponding amino
alcohol 45’ (5S,6S, see Figure 1). Crystallization
experiments with these diastereoisomers pro-
vided a crystalline derivative of the more polar
compound (45’) with l-tartaric acid, whose X-ray
crystallographic analysis revealed its absolute
configuration (see ORTEP drawing, Figure 1),
and, by extension, that of diastereoisomer 45.
Amino alcohol 45 was then coupled with thiazole
amino diol 8 in the presence of HATU and HOAt
to afford peptide 46 (65% yield over two steps,
Scheme 6). The next problematic issue in the
sequence was the differentiation between the two
ethyl esters within compound 46. As a result of
the conjugation of one of the thiazole moieties
with the imine functionality of 46, we expected
the ester on that thiazole to be more electron-
deficient, and, therefore, more prone to hydrol-
ysis. Gratifyingly, we found that, indeed, treat-
ment of the latter compound, 46, with 1 equiv-
alent of lithium hydroxide in a 3:1:1 mixture of
THF/EtOH/H2O generated, regioselectively, a
single carboxylic acid in 52% yield (plus 28%
recovered starting material). More significantly,
Scheme 3. Synthesis of thiazole amino acid equivalent 8. Reagents and
conditions: a) LiOH (0.7 equiv), MeOH/H2O (1:1), reflux, 4 h, 90%;
b) KOH (1.0 equiv), (COCl)2 (5.0 equiv), Et2O, DMF (cat.), 2 h; c) (ꢀ)-
menthol (0.7 equiv), Et2O, 258C, 48 h, 70% (two steps); d) AD-mix-b
(1.5 equiv), MeSO2NH2 (1.0 equiv), tBuOH/H2O (1:1), 08C, 24 h, 90%,
90:10 d.r.; e) Me2C(OMe)2 (22.0 equiv), TsOH (0.05 equiv), 258C, 1 h,
100%; f) DIBAL-H (2.0 equiv), CH2Cl2, ꢀ788C, 2 h, 90%; g) DMP
(1.1 equiv), NaHCO3 (2.0 equiv), CH2Cl2, 258C, 3 h; h) BnNH2 (1.2 equiv),
Yb(OTf)3 (0.2 equiv), molecular sieves (4 Š), CH2Cl2, 258C, 2 h; i) TMSCN
(2.5 equiv), CH2Cl2, 258C, 3 h, 90% (three steps), >95:5 d.r.; j) (Boc)2O
(1.1 equiv), EtOAc, 20% Pd/Pd(OH)2 (0.2 equiv), H2, 258C, 12 h, 75%;
k) H2S, Et3N/EtOH/pyridine (1.7:1.7:1), sealed tube, 258C, 12 h, 90%;
l) BrCH2COCO2Et (3.0 equiv), NaHCO3 (8.0 equiv), DME, 258C, 24 h,
82%; m) TFAA (4.0 equiv), pyridine (9.0 equiv), 08C, 1 h, 82% (two
steps); n) NaOEt (1.0 equiv), EtOH, 08C, 1 h, 100%; o) TFA/EtOH/CH2Cl2
(1:1:1), 0–258C, 4 h; p) TBSCl (2.2 equiv), Et3N (3.0 equiv), CH2Cl2, 0–
258C, 12 h, 81% (two steps); q) TfN3 (3.0 equiv), Et3N (3.0 equiv), CuSO4
(0.05 equiv), MeOH/H2O/CH2Cl2 (3.3:1:1), 258C, 12 h, 82%; r) LiOH
(3.0 equiv), THF/H2O (1:1), 08C, 2 h, 95%. DMP=Dess–Martin periodi-
nane; DIBAL-H=diisobutylaluminum hydride; TMS=trimethylsilyl;
DME=ethylene glycol dimethyl ether; TFAA=trifluoroacetic anhydride;
TFA=trifluoroacetic acid; Ts=p-toluenesulfonyl; Tf=trifluoromethanesul-
fonyl.
Figure 1. ORTEP drawing of 45’ (4S,5S) obtained byX-raycrystallographic
analysis of its 1:1 salt with l-tartaric acid (l-tartaric acid not shown).
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HOAt) to afford product 51 in
75% yield. The obligatory low-
temperature
conditions
employed in this coupling reac-
tion were necessary to avoid
premature elimination of the
OTES group, which would lead
to the conjugated thiazoline
system (see structure 2). Subse-
quent Staudinger reduction of
the azide group within 51 (Me3P,
H2O), followed by Me3SnOH-
induced methyl ester hydrolysis,
led to amino acid 53 via amino
ester 52. Remarkably, the ster-
eochemical integrity of the sen-
sitive thiazoline moiety was pre-
served in the hydrolysis,[14] sug-
gesting that this Me3SnOH-
mediated non-acidolytic and
non-nucleophilic hydrolysis[15]
could be a general mild method
for the benign cleavage of esters
within labile substrates. The key
macrolactamization of amino
acid 53 was smoothly effected
by exposure to HATU and
HOAt (0.3 mm concentration),
leading to macrolactam 54 in
51% overall yield from 51. Crit-
ically, exposure of 54 to
3HF·Et3Nin THF at room tem-
perature resulted in the cleavage
of the two TBS groups, with
Scheme 4. Synthesis of thiazoline moiety 7. Reagents and conditions: a) d-Ser-OMe·HCl (1.0 equiv),
Et3N (3.0 equiv), HOBt (1.2 equiv), EDC (1.2 equiv), CH2Cl2, 258C, 2 h, 70%; b) TESCl (2.2 equiv),
imidazole (3.0 equiv), CH2Cl2, 258C, 12 h, 81%; c) Lawesson's reagent (0.55 equiv), benzene, reflux,
2 h, 79%; d) Et2NH (6.5 equiv), DMF, 258C; e) TFA/CH2Cl2 (1:1), 258C, 2 h; f) TfN3 (3.0 equiv), Et3N
(3.0 equiv), CuSO4 (0.05 equiv), MeOH/H2O/CH2Cl2 (3.3:1:1), 258C, 14 h, 72% (two steps); g) LiOH
(1.0 equiv), THF/H2O (1:1), 08C, 3 h, 93%; h) HATU (1.1 equiv), HOAt (1.1 equiv), Et3N (2.0 equiv),
DMF, 258C, 12 h, 75% (two steps from 32); i) THF/AcOH/H2O (3:1:1), 258C, 12 h, 75% (based on
35% recovered 38); j) DAST (1.2 equiv), CH2Cl2, ꢀ788C, 20 min, 90%; k) Me3P (3.0 equiv), THF/H2O
(20:1), 08C, 1 h, 92%. HOBt=1-hydroxybenzotriazole hydrate; DAST=diethylaminosulfur trifluoride;
Fmoc=fluorenylmethoxycarbonyl.
concomitant
base-promoted
antiperiplanar elimination of
the OTES moiety, furnishing
the desired conjugated thiazo-
line system 55.[16] Finally, the
choice of the PhSe groups as
potential progenitors of the ole-
finic bonds of the top side chain
of the targeted molecule paid
Scheme 5. Synthesis of side-chain precursor 6. Reagents and conditions: a) ethyl chloroformate
(1.05 equiv), NH4OH (30 equiv), EtNiPr2 (1.05 equiv), THF, 0–258C, 1 h, 89%; b) TFA/CH2Cl2 (1:1),
08C, 1 h; c) 41, HOBt (1.1 equiv), EDC (1.1 equiv), EtNiPr2 (1.5 equiv), DMF, 258C, 5 h, 58% (two
steps); d) TFA, CH2Cl2 (1:1), 08C, 1 h, 95%.
extensive NMR studies revealed that carboxylic acid 47 was,
in fact, the product of this hydrolysis reaction. The remaining
ethyl ester of compound 47 was then transesterified to a
methyl ester (MeONa/MeOH, 90% yield), and the carboxylic
acid function of resulting 48 was coupled to side-chain
precursor 6 (HATU, HOAt) to afford tetrapeptide 49 in
83% yield. The inserted transesterification step was necessary
to avoid subsequent complications that arose when attempts
were made to hydrolyze the more robust ethyl ester, leading
to elimination of the rather labile PhSe residues and side
reactions thereof. In contrast, the methyl ester of 49 could be
cleaved with trimethyltin hydroxide in refluxing dichloro-
ethane (85% yield), conditions which avoided the loss of the
selenium moieties otherwise observed in the presence of
other reagents, that is, lithium hydroxide. The resulting acid
50 was then coupled to thiazoline segment 7 at 08C (HATU,
dividends in that treatment of the bisseleno derivative 55 with
tBuOOH at ambient temperature resulted in the smooth
formation of the five-membered imine analogue 2 of thio-
strepton (1), lacking only the macrocycle that contains the
quinaldic acid group. It should be stressed that the introduc-
tion of the last two double bonds into thiostrepton-like
structures was proven to be a real challenge owing to the
unusual sensitivity of the resulting dehydroamino acids.[17]
Thiostrepton analogue 3 (Scheme 1) was synthesized from 4’
via 45’ by an analogous route to that described for 2, and in
similar yields (see Table 1).
Preliminary biological screening[18] with 2 and 3 indicated
the lack of any significant antibacterial activity as compared
to 1, suggesting, perhaps, the importance of both the six-
membered ring imine and the quinaldic acid motifs of
thiostrepton for the recognition of its biological targets.
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Scheme 6. Synthesis of the thiazoline macrocyclic system 2. Reagents and conditions: a) TFA/CH2Cl2 (1:1), 258C, 2 h; b) 8 (1.0 equiv), EtNiPr2 (3.0 equiv),
HOAt (1.1 equiv), HATU (1.1 equiv), DMF, 258C, 12 h, 65% (two steps); c) LiOH (1.0 equiv), THF/EtOH/H2O (3:1:1), 08C, 1.5 h, 52% (28% recovered
46); d) NaOMe (2.0 equiv), MeOH, 08C, 1 h, 90%; e) 6 (1.1 equiv), HOAt (1.2 equiv), HATU (1.2 equiv), DMF, 258C, 5 h, 83%; f) Me3SnOH (13.0 equiv),
1,2-dichloroethane, reflux, 4 h, 85%; g) 7 (1.1 equiv), HOAt (1.2 equiv), HATU (1.2 equiv), DMF, 08C, 15 min, 75%; h) Me3P (3.0 equiv), THF/H2O (20:1),
08C, 30 min; i) Me3SnOH (10.0 equiv), reflux, 1 h; j) HOAt (4.0 equiv), HATU (4.0 equiv), DMF (0.3 mm), 258C, 12 h, 51% (three steps); k) (HF)3·Et3N
(30.0 equiv), THF, 258C, 48 h, 50%; l) tBuOOH (5m in decane, 20.0 equiv), CH2Cl2, 258C, 3 h, 60%.
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putte, J. D. Dutcher, Antibiot. Annu. 1955–1956, 560–561;
c) B. A. Steinberg, W. P. Jambor, L. O. Suydam, Antibiot.
Annu. 1955–1956, 562–565; structure determination: d) C. S.
Bond, M. P. Shaw, M. S. Alphey, W. N. Hunter, Acta Crystallogr.
Sect. D 2001, D57, 755–758; e) B. Anderson, D. C. Hodgkin,
M. A. Viswamitra, Nature 1970, 225, 233–235.
Table 1: Selected data for compounds 2 and 3.
2: Rf =0.32 (silica gel, CH2Cl2/MeOH, 9:1); [a]2D0 =ꢀ104.7 (c=0.20,
MeOH); IR (film): n˜max =3350, 2927, 2857, 1653, 1512, 1482, 1089,
1059 cmꢀ1; 1H NMR (600 MHz, CD3OD, 458C): d=8.52 (s, 1H), 8.19 (s,
1H), 8.08 (s, 1H), 7.44 (s, 1H), 6.63 (q, J=7.0 Hz, 1H), 6.47, (d,
J=1.5 Hz, 1H), 6.21 (d, J=1.0 Hz, 1H), 5.98 (br s, 1H), 5.85 (br s, 1H),
5.70 (d, J=1.5 Hz, 1H), 5.69 (d, J=1.0 Hz, 1H), 5.51 (s, 1H), 5.24 (br d,
J=17.0 Hz, 1H), 5.19 (t, J=9.2 Hz, 1H), 5.13 (br d, J=11.0 Hz, 1H),
5.09 (d, J=4.0 Hz, 1H), 4.47–4.41 (m, 3H), 4.19–4.15 (m, 1H), 4.13 (q,
J=7.0 Hz, 1H), 3.81 (br d, J=10.6 Hz, 1H), 3.70 (dd, J=9.7, 1.8 Hz,
1H), 3.48 (dd, J=8.8, 2.6 Hz, 1H), 2.85 (quintet, J=7.4 Hz, 1H), 2.62
(dt, J=8.3, 3.0 Hz, 1H), 1.82 (d, J=7.0 Hz, 3H), 1.32 (d, J=6.6 Hz,
3H), 1.25 (d, J=7.5 Hz, 3H), 1.24 (s, 3H), 1.21 (d, J=6.6 Hz, 3H),
1.05 ppm (d, J=6.1 Hz, 3H); 13C NMR (125 MHz, CD3OD, 458C):
d=175.4, 173.8, 171.8, 171.5, 169.9, 168.3, 164.6, 164.2, 163.9, 163.4,
161.2, 153.5, 152.2, 150.7, 149.6, 136.4, 136.1, 136.0, 134.4, 130.9, 125.6,
119.3, 117.9, 107.2, 106.1, 102.5, 88.0, 80.14, 76.9, 71.3, 71.0, 69.8, 69.5,
66.9, 59.4, 58.1, 57.5, 37.5, 36.9, 33.7, 30.8, 30.4, 20.9, 19.8, 19.4, 17.5,
14.5 ppm; HRMS (MALDI): calcd for C52H61N15O14S5 [M+H+]:
1280.3199; found: 1280.3184
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[10] J. C. Muir, G. Pattenden, R. M. Thomas, Synthesis 1998, 613–618.
[11] P. Lafargue, P. Guenot, J.-P. Lellouche, Synlett 1995, 171–172.
[12] F. Bravo, Y. Dꢁaz, S. Castillꢃn, Tetrahedron: Asymmetry 2001, 12,
1635–1643.
[13] N. M. Okeley, Y. Zhu, W. A. van der Donk, Org. Lett. 2000, 2,
3603–3606.
[14] Thiazolines are readily epimerizable substrates, see, for instance:
P. Wipf, P. C. Fritch, Tetrahedron Lett. 1994, 35, 5397–5400.
[15] Although transesterifications from methyl esters to tin esters
with Me3SnOH are known (for a review, see: O. A. Mascaretti,
R. L. E. Furlan, C. J. Salomon, E. G. Mata, Phosphorus Sulfur
Silicon Relat. Elem. 1999, 150–151, 89–97), only one application
of this method has been reported dealing with the cleavage of
benzyl esters: R. L. E. Furlan, E. G. Mata, O. A. Mascaretti, C.
Pena, M. P. Coba, Tetrahedron 1998, 54, 13023–13034.
[16] The corresponding Z-conjugated thiazole system of micrococ-
cin P1 was prepared by stereospecific elimination of the acti-
vated hydroxy group: a) F. Yokokawa, T. Shioiri, Tetrahedron
Lett. 2002, 43, 8679–8682; b) M. A. Ciufolini, Y.-C. Shen, Org.
Lett. 1999, 1, 1843–1846.
3: Rf =0.32 (silica gel, CH2Cl2/MeOH, 9:1); [a]2D0 =+98.5 (c=0.55,
MeOH); IR (film): n˜max =3375, 2913, 2853, 1658, 1643, 1449, 1249, 1061,
733 cmꢀ1; 1H NMR (600 MHz, CD3OD, 458C): d=8.51 (s, 1H), 8.21 (s,
1H), 8.12 (s, 1H), 7.34 (br s, 1H), 6.61 (q, J=7.0 Hz, 1H), 6.49, (d,
J=1.5 Hz, 1H), 6.20 (d, J=1.5 Hz, 1H), 5.86–5.78 (br s, 2H), 5.71–5.69
(m, 2H), 5.54 (br s, 1H), 5.23–5.19 (m, 3H), 5.09 (b, 1H). 4.48–4.42 (m,
3H), 4.38–4.32 (m, 3H), 4.19–4.16 (m, 1H), 3.90 (q, J=6.6 Hz, 1H),
3.65 (t, J=10.7 Hz, 1H), 3.45 (dd, J=8.8, 2.2 Hz, 1H), 3.21–3.18 (m,
1H), 2.59 (dt, J=8.3, 3.1 Hz, 1H), 1.80 (d, J=7.0 Hz, 3H), 1.39 (s, 3H),
1.33–1.31 (m, 6H), 1.24–1.22 ppm (m, 6H); 13C NMR (150 MHz,
CD3OD, 458C): d=175.3, 174.8, 174.0, 173.6, 172.0, 171.7, 170.9, 168.3,
164.6, 164.2, 163.7, 161.2, 152.2, 150.6, 149.9, 136.6, 136.4, 136.2, 130.8,
130.2, 119.1, 117.9, 107.3, 106.0, 87.8, 80.1, 76.8, 70.7, 69.8, 69.2, 66.8,
60.2, 59.1, 58.1, 58.0, 37.2, 37.0, 26.4, 20.7, 20.6, 19.5, 18.7, 17.6,
14.6 ppm; HRMS (MALDI): calcd for C52H61N15O14S5 [M+H+]:
1280.3199; found: 1280.3197
Within the described chemistry may lie clues for both the
successful total synthesis of thiostrepton (1) and the design of
bioactive analogues of this intriguing natural product.
[17] P. M. T. Ferreira, H. L. S. Maia, L. S. Monteiro, J. Sacramento, J.
Chem. Soc. Perkin Trans. 1 1999, 3697–3703.
Received: April 24, 2003 [Z51745]
[18] Minimum inhibitory concentration (MIC) assays were per-
formed with the following bacteria: methicillin-resistant Staph-
ylococcus aureus (MRSA) (ATCC 33591), vancomycin-resistant
Enterococcus faecium (VRE) (ATCC 700221), Pseudomonas
aeruginosa (PA) (27853), Escherichia coli (EC1) (ATCC
700336), Escherichia coli (EC2) (ATCC 29425). We thank
Dr. J. Fletcher and Dr. R. Ghadiri for these experiments.
Keywords: amino acids · antibiotics · macrocycles ·
natural products · thiazolines
.
[1] Isolation: a) J. F. Pagano, M. J. Weinstein, H. A. Stout, R.
Donovick, Antibiot. Annu. 1955–1956, 554–559; b) J. Vande-
3424
ꢀ 2003 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.angewandte.org
Angew. Chem. Int. Ed. 2003, 42, 3418 – 3424