Convergent synthesis of the central heterocyclic domain of micrococcin P1

Article abstract of DOI:10.1055/s-2007-973870

The heterocyclic domain of micrococcin P1 has been prepared from N-Boc-(2S,3R)-threonine in 15 steps and 9% overall yield utilising a microwave-assisted enamine formation in mono- or multimode instruments, Bohlmann-Rahtz pyridine synthesis to form the 2,3,6-trisubstituted pyridine motif, and two-directional elaboration of the 3- and 6-thiazole substituents. Georg Thieme Verlag Stuttgart.

Full text of DOI:10.1055/s-2007-973870

954
LETTER
Convergent Synthesis of the Central Heterocyclic Domain of Micrococcin P1
S
ynthesis of the
l
Micro
e
coccin P1
D
a
omain nor A. Merritt, Mark C. Bagley*
School of Chemistry, Main Building, Cardiff University, Park Place, Cardiff, CF10 3AT, UK
Fax +44(29)20874030; E-mail: Bagleymc@cf.ac.uk
Received 9 January 2007
crococcus found in a sample of sewage from the city of
Abstract: The heterocyclic domain of micrococcin P1 has been
prepared from N-Boc-(2S,3R)-threonine in 15 steps and 9% overall
yield utilising a microwave-assisted enamine formation in mono- or
multimode instruments, Bohlmann–Rahtz pyridine synthesis to
Oxford,3 and subsequently micrococcin P1 was obtained
from a strain of Bacillus pumilus in 1955,4 as the first re-
corded example of a thiopeptide antibiotic.5 Despite being
form the 2,3,6-trisubstituted pyridine motif, and two-directional known for over 50 years, the structure and absolute ste-
elaboration of the 3- and 6-thiazole substituents.
reochemistry of the natural product remains ambiguous,
numerous degradation and NMR studies, and two total
syntheses of epimeric micrococcins, having thus far failed
to confirm the proposed structure.6 In an effort to resolve
this long-standing mystery, we embarked on a new total
synthesis of 2, utilising the Bohlmann–Rahtz pyridine
synthesis, a reaction extensively studied within our
group.7 Herein we describe our synthesis of the ‘series d’
domain1 of micrococcin P1.
Key words: micrococcin, thiopeptide antibiotics, pyridines, thi-
azoles, Bohlmann–Rahtz
The thiopeptide antibiotics are a class of highly modified
macrocyclic sulfur-containing peptides, antibacterial sec-
ondary metabolites isolated from the mycelial cake of ac-
tinomycetes. There are 29 families of thiopeptides and
over 76 structurally distinct members known to date,
some examples of which are illustrated in Figure 1.1
Our approach to the heterocyclic core 3 of micrococcin P1
is illustrated in Scheme 1. It was proposed that enamine 4
would be prepared from N-Boc-(2S,3R)-threonine, and
propargylic ketone 5 from diethoxyacetonitrile. The re-
giospecific heteroannulation of these fragments would af-
ford trisubstituted pyridine 6 by Bohlmann–Rahtz
pyridine synthesis using iodine as the cyclodehydration
catalyst.8 Subsequent simultaneous elaboration of both es-
ter moieties to the corresponding thiazole ethyl esters
would yield the desired heterocyclic motif and complete
the synthesis of 3.
Thiostrepton (1), the parent of the thiopeptide antibiotic
family of compounds was recently the subject of a land-
mark total synthesis by Nicolaou et al., utilising a biomi-
metic aza-Diels–Alder reaction to form the
dehydropiperidine core.2 However, micrococcin P1 (2)
has proven to be a more challenging synthetic target than
its comparatively simple structure would suggest. The
first micrococcin was isolated in 1948 from a strain of Mi-
HN
NH2
O
O
pyridine series d domain
HN
HO
O
dehydropiperidine
O
series b domain
N
O
N
S
S
N
N
O
H
S
H
NH
O
Me
NH
H
S
N
N
N
N
H
S
N
H
H
N
S
N
H
Me
Me
O
Me
HO
HN
N
H
N
S
O
O
N
N
O
HO
H
O
O
H
H
HN
OH
S
N
N
NH
H
O
O
O
HN
N
S
N
H
HN
H
O
O
Me
NH
S
Me
OH
H
N
H
N
H
OH
S
H
O
Me
H
OH
thiostrepton A (1)
micrococcin P1 (2)
HO
Me
Figure 1 Thiostrepton (1) and micrococcin P1 (2), two examples of thiopeptide antibiotics of considerable recent interest
SYNLETT 2007, No. 6, pp 0954–0958
0
3.
0
4.
2
0
0
7
Advanced online publication: 26.03.2007
DOI: 10.1055/s-2007-973870; Art ID: D01107ST
© Georg Thieme Verlag Stuttgart · New York

LETTER
Synthesis of the Micrococcin P1 Domain
955
EtO2C
to stir at room temperature. On stirring for two hours, the
isolated yield of 8 following an aqueous workup and col-
umn chromatography was 72%, falling to 33% if the mix-
ture was stirred overnight.
Hantzsch
N
Hantzsch
N
S
N
CO2Et
O
N
N
N
The conversion of b-ketoester 8 to enamine 4 proved to be
the most challenging step in the synthesis. The unexpect-
ed inertness of 8 is attributed in part to the steric bulk and
constraining effects of the protecting groups used, and
also to the stability of the enol tautomer of 8 which is
clearly visible in the IR and 1H NMR spectra.10 Some of
the conditions investigated for the desired enamine forma-
tion are given in Table 1. The b-ketoester failed to react
with ammonia-saturated solvents at room temperature or
100 °C (entries 1–3), or in the presence of a Lewis acid
catalyst (entry 4). Reaction in the presence of a Brønsted
acid also failed to promote the reaction, either at room
temperature (entry 5) or 120 °C (entry 6). It was hoped
that the increased temperature and pressure and more ef-
ficient heating afforded by microwave irradiation could
be used to force 8 to react. At 150 °C in the presence of 50
equivalents of ammonium acetate, unreacted starting ma-
terial was recovered (entry 7) but on increasing to 120
equivalents of ammonium acetate, enamine 4 was at last
obtained, albeit in 38% yield (entry 8). It was concluded
that the high temperature was necessary in order to de-
compose enough ammonium acetate to provide a suffi-
ciently high pressure of ammonia in the sealed microwave
tube. Evidence for this is provided by the observed pres-
sure jump within the microwave vessel between 145 °C
and 150 °C. The reaction was then attempted under ther-
mal conditions using mesitylene as the solvent in the hope
of providing a method whereby the reaction could be
readily scaled up (entry 9). At 150 °C, the reaction was
successful but the yield poor, most likely as a result of the
sublimation of large quantities of ammonium acetate out
of the reaction mixture, or the evaporation of much of the
ammonia generated. Following this poor yield, the suc-
cessful microwave reaction was optimised further, and it
was found that reducing the reaction time increased the
yield of 4 (entries 10 and 11). The optimum reaction time
was found to be ten minutes, as shorter times led to the
isolation of unreacted starting material which proved dif-
ficult to separate from the product. With a new method for
the formation of enamine 4 in hand, it was necessary to
3
S
S
S
Boc
two-directional
synthesis
thiazole formation
EtO2C
6
O
N
N
S
N
N
CO2Me
S
Boc
Bohlmann–Rahtz
NH2
O
O
CO2Et
N
N
CO2Me
N
4
5
S
S
Boc
Scheme 1 Our synthetic approach to 3
The synthesis of enamine 4 is shown in Scheme 2. Thi-
azole 7 was prepared according to the method used by
Nicolaou et al. in his total synthesis of thiostrepton with
the exception of the thioamide formation.2 The majority
of literature procedures for the conversion of amides to
thioamides utilise Lawesson’s reagent or phosphorus
pentasulfide to perform the transformation directly. How-
ever, in this case, stepwise conversion via the threonine-
derived nitrile was found to be more efficient, thionation
of the nitrile with ammonium sulfide proceeding in
quantitative yield and without the need for column
chromatography.9
Synthesis of b-ketoester 8 proved to be more problematic
than anticipated, a range of methods being tried before the
optimum conditions were established. The use of Mel-
drum’s acid, LDA–ethyl acetate, or treatment of 7 with
methyl acetate and sodium methoxide all returned the car-
boxylic acid with no trace of the desired product. Reaction
of the activated carboxylic acid with a mixture of potassi-
um ethyl malonate and methylmagnesium bromide was
the only method found to afford 8, the yield being highly
dependent on the length of time the solution was allowed
O
O
O
O
HO
iii
iv
i
ii
CO2H
CONH2
CN
CSNH2
N
N
N
N
CO2H
BocHN
Boc
Boc
Boc
Boc
v
O
N
O
O
N
O
O
NH2
O
O
vii
vi
viii
N
N
S
N
N
S
CO2H
CO2Et
N
N
OEt
OEt
Boc
Boc
Boc
Boc
S
S
7
Scheme 2 Reagents and conditions: (i) 2,2-DMP, PPTS, THF, reflux, 6 h, 100%; (ii) EtOCOCl, Et3N, 0 °C, 1 h, then 35% aq NH3, r.t., 24 h,
78%; (iii) POCl3, pyridine, 0 °C, 2 h, 86%; (iv) (NH4)2S, MeOH, r.t., 24 h, 100%; (v) ethyl bromopyruvate, NaHCO3, DME, r.t., 24 h, then
pyridine, TFAA, 0 °C, 2 h, then Et3N, 87%; (vi) LiOH, MeOH–H2O, r.t., 3 h, 100%; (vii) EtOCOCl, Et3N, THF, 0 °C, 1 h, then potassium ethyl
malonate–methylmagnesium bromide mixture in THF, 2 h, 72%; (viii) NH4OAc, toluene–AcOH, microwave irradiation, 150 °C (300 W initial
power), 15 min, 69%.
Synlett 2007, No. 6, 954–958 © Thieme Stuttgart · New York

956
E. A. Merritt, M. C. Bagley
LETTER
Table 1 Formation of Enamine 4 from b-Ketoester 811
Entry Solvent Temperature
Time
Heat source
NH4OAc
(equiv)
Yield
(%)a
(°C)
1
2
NH3 in EtOH
r.t.
24 h
–
–
–
0
0
NH3 in CHCl3
NH3 in EtOH
r.t.
96 h
–
3
100
100
r.t.
30 min
10 min
6 d
MW, 300 Wb
MW, 100 Wb
–
–
0
4
NH3 in CH2Cl2, Sc(OTf3) (10 mol%)
PhMe–AcOH
–
0
5
10
10
50
120
120
120
120
120
0
6
PhMe–AcOH
120
150
150
150
150
150
150
24 h
thermal
0
7
PhMe–AcOH
30 min
30 min
2 h
MW, 300 Wb
MW, 300 Wb
thermal
0
8
PhMe–AcOH
38
28
49
69
68
9
Mesitylene
10
11
12
PhMe–AcOH
15 min
10 min
10 min
MW, 300 Wb
MW, 300Wb
MW, 300 Wc
PhMe–AcOH
PhMe–AcOH
a Where yield is given as 0 only the unreacted starting material was recovered.
b CEM Discover® single-mode synthesiser. Power is moderated throughout the course of the experiment to maintain a constant reaction
temperature.
c Milestone BatchSYNTH® multimode synthesiser. Power is moderated throughout the course of the reaction to maintain a constant reaction
temperature.
scale up the reaction. However, the need for a vast excess This route provided a facile method for the synthesis of
of ammonium acetate meant that only 100 mg of 8 could gram-quantities of the desired alkynone, although 5 itself
be reacted at a time in the standard 10 mL microwave ves- was found to be extremely unstable, decomposing
sels. Use of a large capacity multimodal microwave in- overnight even when stored under an inert atmosphere at
strument with a 60 mL vessel provided the opportunity to –18 °C. For this reason, the propargylic alcohol precursor
scale up the reaction, using 1 gram of b-ketoester and 22 was prepared in large quantities and only oxidised to 5 im-
grams of ammonium acetate. This increase in scale en- mediately prior to use in the subsequent Bohlmann–Rahtz
abled the preparation of 4 in 680 mg batches. The reaction reaction.
temperature and pressure profile was comparable with the
small-scale monomodal reaction, and the yield reproduc-
ible and almost identical (entry 12).
With building blocks 4 and 5 now in hand, the assembly
of the pyridine core 6 was attempted via the proposed
Bohlmann–Rahtz methodology (Scheme 4). The success
With sufficient quantities of enamine 4 available, the sec- of the Michael addition of enamine 4 to alkynone 5 was
ond fragment, propargylic ketone 5, was prepared via the hampered by the instability of 5, the reaction returning
route illustrated in Scheme 3.
aminodienone 9 in 58% yield, with 40% recovery of the
unreacted enamine when 1.5 equivalents of alkynone 5
were used. On increasing to 2 equivalents of 5, the effi-
ciency of the reaction was improved substantially, afford-
ing aminodienone 9 in 81% yield with 12% recovery of
enamine 4. Cyclodehydration was achieved successfully
using iodine as a catalyst, which was chosen as these
EtO
EtO
EtO
EtO
S
EtO
EtO
S
i
ii
CN
N
iii
NH2
CO2Et
O
MeO
S
N
S
N
iv
v
MeO
O
O
CO2Me
CO2Me
CO2Me
NH2
O
N
HO
S
N
S
N
i
ii
OEt
Boc
4 + 5
6
vi
S
N
CO2Me
9
5
S
O
Scheme 3 Reagents and conditions: (i) (NH4)2S, MeOH, r.t., 24 h,
100%; (ii) ethyl bromopyruvate, 4 Å MS, EtOH, reflux, 1 h, 100%;
(iii) PTSA, MeOH, reflux, 24 h, 96%; (iv) 2 M aq HCl, acetone, ref-
lux, 2 h, 86%; (v) ethynylmagnesium bromide, THF, 0 °C, 1 h, 81%;
(vi) activated MnO2, CH2Cl2, r.t., 2 h, 77%.
N
MeO2C
Scheme 4 Reagents and conditions: (i) EtOH, r.t., 18 h, 58–81%;
(ii) I2, EtOH, r.t., 2 h, 100%.
Synlett 2007, No. 6, 954–958 © Thieme Stuttgart · New York

LETTER
Synthesis of the Micrococcin P1 Domain
957
10 R = CO2H
ii
EtO2C
R
11 R = CONH2
iii
i
O
O
N
S
N
N
N
12 R = CN
N
N
CO2Me
R
iv
v
N
N
S
S
S
Boc
Boc
6
13 R = CSNH2
3
Scheme 5 Reagents and conditions: (i) LiOH, MeOH–H2O, reflux, 72 h, 100%; (ii) EtOCOCl, Et3N, THF, 0 °C, 18 h, then 35% aq NH3, r.t.,
24 h, 62%; (iii) POCl3, pyridine, 0 °C, 2 h, 87%; (iv) (NH4)2S, Et3N, MeOH, r.t., 18 h, 70%; (v) ethyl bromopyruvate, KHCO3, DME, r.t., 36 h,
then pyridine, TFAA, 0 °C → r.t., 3 h, then Et3N, r.t., 3 h, 96%.
extremely mild conditions afford the product without the
need for column chromatography.8
References and Notes
(1) Bagley, M. C.; Dale, J. W.; Merritt, E. A.; Xiong, X. Chem.
Rev. 2005, 105, 685.
The final stage in our synthesis of 3 was the simultaneous
elaboration of both the 3- and 6-position carboxylate
groups (Scheme 5). Initial attempts to hydrolyse both es-
ters using lithium hydroxide at room temperature failed,
the 3-position ethyl ester remaining intact. Indeed, this es-
ter proved inert to all but the harshest hydrolysis condi-
tions, bisacid 10 only being formed on prolonged heating
with ten equivalents of base. However, the subsequent
transformations proceeded as anticipated, the low yield
for the amide formation being attributed to the poor solu-
bility of 11 and consequent difficulty in isolation and pu-
rification of the bisamide. As with the synthesis of
enamine 4, standard thionation of 11 to give bisthioamide
13 directly was rejected, as 11 did not react with Lawes-
son’s reagent and purification and recovery of the unreact-
ed starting material proved difficult. Bisnitrile 12 was
formed instead, and again thionation with ammonium sul-
fide afforded the clean product in good yield albeit fol-
lowing purification by chromatography. Subsequent
reaction with ethyl bromopyruvate under Nicolaou’s con-
ditions for thiazole formation gave the target molecule 3
in excellent yield.2
(2) (a) Nicolaou, K. C.; Safina, B. S.; Zak, M.; Lee, S. H.;
Nevalainen, M.; Bella, M.; Estrada, A. A.; Funke, C.; Zécri,
F. J.; Bulat, S. J. Am. Chem. Soc. 2005, 127, 11159.
(b) Nicolaou, K. C.; Zak, M.; Safina, B. S.; Estrada, A. A.;
Lee, S. H.; Nevalainen, M. J. Am. Chem. Soc. 2005, 127,
11176.
(3) Su, T. L. Brit. J. Exp. Path. 1948, 29, 473.
(4) Fuller, A. T. Nature (London) 1955, 175, 722.
(5) Heatley, N. G.; Doery, H. M. Biochem. J. 1951, 50, 247.
(6) (a) Dean, B. M.; Mijović, M. P. V.; Walker, J. J. Chem. Soc.
1961, 3394. (b) Walker, J.; Olesker, A.; Valente, L.;
Rabanal, R.; Lukacs, G. J. Chem. Soc., Chem. Commun.
1977, 706. (c) Bycroft, B. W.; Gowland, M. S. J. Chem.
Soc., Chem. Commun. 1978, 256. (d) Ciufolini, M. A.;
Shen, Y.-C. Org. Lett. 1999, 1, 1843. (e) Okumura, K.; Ito,
A.; Yoshioka, D.; Shin, C.-G. Heterocycles 1998, 48, 1319.
(f) Fenet, B.; Pierre, F.; Cundliffe, E.; Ciufolini, M. A.
Tetrahedron Lett. 2002, 43, 2367. (g) Bagley, M. C.;
Merritt, E. A. J. Antibiot. 2004, 57, 829.
(7) (a) Bohlmann, F.; Rahtz, D. Chem. Ber. 1957, 90, 2265.
(b) Bagley, M. C.; Brace, C.; Dale, J. W.; Ohnesorge, M.;
Phillips, N. G.; Xiong, X.; Bower, J. J. Chem. Soc., Perkin
Trans. 1 2002, 1663.
(8) Bagley, M. C.; Glover, C.; Chevis, D. Synlett 2005, 649.
(9) Bagley, M. C.; Chapaneri, K. C.; Glover, C.; Merritt, E. A.
Synlett 2004, 2615.
In conclusion, we have prepared the central heterocyclic
domain of micrococcin P1 from N-Boc-(2S,3R)-threonine
in 15 steps and 9% overall yield via a highly convergent
strategy utilising the mild iodine-catalysed Bohlmann–
Rahtz pyridine synthesis. Building on this success, it is
hoped that the total synthesis of micrococcin P1 will be
completed in the near future and the ambiguity that has
surrounded the structure of the natural product since its
isolation more than 50 years ago will be resolved.
(10) The enol tautomer of 8 accounts for 22% of the material by
1H NMR integration in CDCl3.
(11) tert-Butyl 4-{4-[2-(ethoxycarbonyl)-1-aminovinyl]thi-
azol-2-yl}-2,2,5-trimethyloxazolidine-3-carboxylate (4)
b-Ketoester 8 (100 mg, 0.24 mmol) was dissolved in
toluene–AcOH (5:1, 3 mL) and NH4OAc (2.24 g, 29.09
mmol, 120 equiv) was added. The mixture was irradiated in
a sealed tube at 150 °C with continuous cooling for 10 min
using a CEM Discover® single-mode microwave synthesiser
(initial power 300 W). The mixture was cooled to r.t.,
evaporated in vacuo and partitioned between H2O (20 mL)
and EtOAc (10 mL). The aqueous layer was further
extracted with EtOAc (2 × 10 mL) and the combined organic
extracts were washed sequentially with sat. aq NaHCO3 (15
mL) and brine (15 mL), dried (Na2SO4) and evaporated in
vacuo. Purification by column chromatography on silica,
eluting with PE–EtOAc (3:1) gave the title compound 412 as
a viscous yellow oil.
Acknowledgment
We thank the EPSRC and Royal Society for funding, Robert L.
Jenkins for valuable technical assistance and the EPSRC Mass
Spectrometry Service at the University of Wales, Swansea UK for
mass spectra. We would also like to thank Dr Matt Burwood (Al-
Envirotech Ltd), Dave (Milestone Inc.) and Dr Laura Favretto
(Milestone Inc.) for technical assistance with multimode micro-
wave irradiation experiments and Dr Chris Mason and CEM UK
Ltd for technical assistance with single-mode microwave irradiation
experiments.
Methyl 2-(propynoyl)thiazole-4-carboxylate (5)
To a stirred solution of methyl 2-[1-(1-hydroxyprop-2-
ynyl)]thiazole-4-carboxylate (882 mg, 4.47 mmol) in
CH2Cl2 (50 mL), activated manganese(IV) oxide (1.94 g,
22.36 mmol, 5 equiv) was added and the mixture was stirred
at r.t. for 30 min. A further portion of activated manga-
Synlett 2007, No. 6, 954–958 © Thieme Stuttgart · New York

958
E. A. Merritt, M. C. Bagley
LETTER
nese(IV) oxide (1.94 g, 22.36 mmol, 5 equiv) was added and
the solution was stirred at r.t. for 2 h, and then filtered
through a pad of Celite®. The pad was washed with CH2Cl2
(25 mL) and the filtrate was evaporated under a stream of
nitrogen. The residue (672 mg, 77%) was used immediately
without further purification. Purification by recrystallisation
afforded the title compound 513 as a yellow solid.
OCH2CH3), 1.64 (br s, 7 H), 1.40 (br s, 3 H), 1.34 (br d, J =
6.2 Hz, 3 H, Thr-Me), 1.24 (t, J = 7.0 Hz, 3 H, OCH2CH3),
1.10 (br s, 6 H). 13C NMR (125 MHz, CDCl3): d = 171.9 (C),
170.4 (C), 151.8 (C), 151.2 (C), 150.6 (C), 124.9 (CH),
116.9 (CH), 95.2 (C), 81.4 (CH), 80.6 (C), 65.9 (CH), 58.9
(CH2), 28.1 (CH3), 26.5 (CH3), 25.5 (CH3), 17.7 (CH3), 14.6
(CH3). MS (APCI): m/z (%) = 412 (7) [M + H+], 356 (17),
312 (30), 241 (30), 227 (23), 183 (15), 134 (100).
MP1 domain (3)
Bisthioamide 13 (140 mg, 0.24 mmol) was dissolved in
anhyd DME (20 mL) and anhyd KHCO3 (389 mg, 3.88
mmol, 16 equiv) was added. Ethyl bromopyruvate (0.183
mL, 284 mg, 1.46 mmol, 6 equiv) was added and the mixture
was stirred at r.t. for 36 h. The solvent was removed in vacuo
and the residue was partitioned between H2O (50 mL) and
Et2O (50 mL). The organic extract was dried (MgSO4) and
evaporated in vacuo, and the residue was dissolved in anhyd
DME (20 mL). The solution was cooled to 0 °C and pyridine
(0.353 mL, 346 mg, 4.37 mmol, 18 equiv) and TFAA (0.275
mL, 408 mg, 1.94 mmol, 8 equiv) were added slowly and
sequentially. The solution was stirred at 0 °C for 3 h, allowed
to warm to r.t. and Et3N (0.135 mL, 98 mg, 0.97 mmol, 4
equiv) was added. The solution was stirred at r.t. for 3 h, and
then evaporated in vacuo. Purification of the residue by
column chromatography on silica eluting with 5% MeOH in
CHCl3 afforded the title compound 314 as a yellow solid.
(13) Methyl 2-(propynoyl)thiazole-4-carboxylate (5)
mp 152 °C (dec.) (CHCl3); Rf 0.47 (PE–EtOAc, 1:1).
HRMS: m/z [MH+] calcd for C8H6NO3S: 196.0068; found:
196.0059. IR (CH2Cl2): 3209, 3128, 2360, 1742, 1641, 1480,
1461, 1427, 1341, 1265, 1240, 1109, 993, 960, 911, 827
cm–1. 1H NMR (250 MHz, CDCl3): d = 8.46 (s, 1 H, 5-H),
3.93 (s, 3 H, CO2Me), 3.66 (s, 1 H, 3¢-H). 13C NMR (125
MHz, CDCl3): d = 169.01 (C), 166.16 (C), 161.06 (C),
149.18 (C), 133.81 (CH), 84.93 (CH), 78.94 (C), 52.84
(CH3). MS (ES+): m/z (%) = 196 (100) [M + H+], 156 (15),
135 (3).
(14) MP1 domain (3)
Rf 0.69 (5% MeOH in CHCl3). HRMS: m/z [MH+] calcd for
C34H37N6O7S4: 769.1601; found: 769.1604. IR (CH2Cl2):
3438, 2966, 2915, 1734, 1700, 1579, 1464, 1438, 1363,
1298, 1258, 1091, 1022 cm–1. 1H NMR (400 MHz, CDCl3):
d = 8.25 (s, 1 H, thz), 8.24 (app. br s, 1 H, py-4), 8.20 (s, 1
H, thz), 8.17 (s, 1 H, thz), 7.95 (app. br s, 1 H, py-5), 6.91 (s,
1 H, thz), 4.95 (s, 0.6 H, Thr-a), 4.83 (d, J = 11.0 Hz, 0.4 H,
Thr-a), 4.39 (q, J = 7.0 Hz, 2 H, OCH2CH3), 4.36 (q, J = 7.0
Hz, 2 H, OCH2CH3), 4.35 (br s, 1 H, Thr-b), 1.61 (br s, 3 H),
1.51 (br s, 6 H), 1.45 (br s, 3 H), 1.38 (t, J = 7.0 Hz, 3 H,
OCH2CH3), 1.31 (t, J = 7.0 Hz, 3 H, OCH2CH3), 1.18 (br s,
6 H). MS (ES+): m/z (%) = 786 (45) [M + Na+], 769 (100)
[M + H+], 656 (8), 639 (8), 224 (8), 141 (8).
(12) tert-Butyl 4-{4-[2-(ethoxycarbonyl)-1-aminovinyl]thi-
azol-2-yl}-2,2,5-trimethyloxazolidine-3-carboxylate (4)
Rf 0.34 (PE–EtOAc, 3:1). HRMS: m/z [MH+] calcd for
C19H30N3O5S: 412.1901; found: 412.1899. IR (film): 3488,
3407, 3146, 2975, 1694, 1478, 1368, 1258, 1217, 1167,
1132, 1087 cm–1. 1H NMR (400 MHz, CDCl3): d = 7.54 (br
s, 1 H, thz), 6.60–7.10 (br s, 1 H, NH), 5.12 (br s, 1 H, Thr-
a), 4.68 (br s, 0.4 H, Thr-b), 4.57 (br d, J = 6.2 Hz, 0.6 H,
Thr-b), 4.14 (s, 1 H, C=CH), 4.12 (q, J = 7.0 Hz, 2 H,
Synlett 2007, No. 6, 954–958 © Thieme Stuttgart · New York

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