Unified azoline and azole syntheses by optimized aza-wittig chemistry

Article abstract of DOI:10.1002/ejoc.201300160

Intramolecular aza-Wittig ring closures were applied to synthesize thiazolines, oxazolines, and imidazolines from β-azido thioester, ester, and amide precursors. The cyclization precursors were obtained from amino acid derivatives. Optimized conditions fo

Full text of DOI:10.1002/ejoc.201300160

Job/Unit: O30160
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Date: 10-04-13 10:52:37
Pages: 27
FULL PAPER
DOI: 10.1002/ejoc.201300160
Unified Azoline and Azole Syntheses by Optimized Aza-Wittig Chemistry
Patrick Loos,[a] Cyril Ronco,[a] Matthias Riedrich,[a][‡] and Hans-Dieter Arndt*[a]
Keywords: Synthetic methods / Wittig reactions / Azides / Cyclization / Heterocycles
Intramolecular aza-Wittig ring closures were applied to syn-
thesize thiazolines, oxazolines, and imidazolines from β-
azido thioester, ester, and amide precursors. The cyclization
precursors were obtained from amino acid derivatives. Opti-
mized conditions for diazo transfer with a fast rate and race-
found to be highly chemoselective for five-membered rings.
If amide groups were activated with tosyl groups, smooth in-
tramolecular ring closure of iminophosphoranes furnished
enantiopure imidazoline products with position-specific tosyl
protection. This aza-Wittig-based azoline synthesis was then
mization suppression, (thio)esterification, and amide cou- extended to double azoline ring closures to furnish catenated
pling reactions are described. The ring closure reaction can
be executed with PPh3 under neutral conditions and was
azoline building blocks common to peptide natural product
building blocks and their analogues.
Introduction
Reactions between azides and phosphanes to generate
iminophosphoranes were first described by Staudinger and
Meyer in 1919. They also used these reactive intermediates
to form carbon-nitrogen double bonds from carbonyl com-
pounds.[1–2] Typically, iminophosphoranes are less nucleo-
philic than the corresponding phosphorus ylides and there-
fore attracted less attention than their carbon-based ana-
logues described 35 years later by Wittig.[3] This notwith-
standing, the aza-Wittig reaction has since developed into
a powerful tool for organic synthesis and has been used in a
variety of inter- and intramolecular reactions (Scheme 1).[4]
Iminophosphoranes 1 have been converted into isocyan-
ates 2a and isothiocyanates 2b by treatment with CO2 or
CS2, respectively. They can also be used to synthesize
carbodiimides 3 by treatment with isocyanates or isothiocy-
anates.[4] The synthesis of ketimines 4 is possible through
transformation of ketenes. Whereas all of these reactions
form C=N double bonds, the use of iminophosphoranes 1
to connect nitrogen to other elements has also been de-
scribed. One example is the formation of sulfimides 5 by
treatment of iminophosphoranes 1 with sulfoxides.[5] Most
important, however, are the reactions with carbonyl com-
pounds to form imines 6 through formal exchange of C=O
for C=NR.
Scheme 1. Examples of reactions of iminophosphoranes (X = O,
S).
All these transformations can be regarded as condensa-
tion reactions under kinetic control and have been utilized
for a wide variety of iminophosphoranes and carbonyl com-
pounds in inter- and intramolecular processes.[4] Recent de-
velopments have extended to the application of chiral phos-
phorus(III) compounds to induce enantioselective desym-
metrization,[6] to catalytic use of the phosphorus-containing
mediator,[7] and to the direct amination of alcohols through
redox coupling.[8] Typically, aza-Wittig reactions are rather
inefficient when performed in an intermolecular fashion,
but cyclic imine-containing heterocycles can be accessed in-
tramolecularly in a variety of ways. Rate acceleration by
supramolecular complex formation has been demon-
strated.[9]
[a] Friedrich-Schiller-Universität, Institut für Organische und
Makromolekulare Chemie,
Humboldtstr. 10, 07743 Jena, Germany
Fax: +49-3641-948212
E-mail: hd.arndt@uni-jena.de
Homepage: www.arndtgroup.uni-jena.de
[‡] Current address: BayerCropScience,
Alfred-Nobel-Str. 50, 40789 Monheim, Germany
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.201300160.
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P. Loos, C. Ronco, M. Riedrich, H.-D. Arndt
FULL PAPER
Iminophosphoranes can also be treated with acylating be applied for aza-Wittig-mediated azole formations. Nei-
agents R–COX to form amides.[10] Given that the formation ther strong acid or base need to be used, and nor do
of imidoyl chlorides 7 has been observed after reactions be- strongly dehydrating conditions or reagentshave to be em-
tween iminophosphoranes and acid chlorides[11] and that ployed, as are commonly used to synthesize azol(in)es. As
imido esters have been isolated from intramolecular acyl- a consequence, the aza-Wittig reaction has recently been
ation attempts,[12] aza-Wittig-type transformations are finding applications in tandem transformations[20] and in
likely to be involved in these transformations as well.
the synthesis of complex target molecules.[21] Here we wish
By analogy to the Wittig reaction, the aza-Wittig reac- to give a full account on the scope and limitations of these
tion is typically assumed to conform to a quasi-concerted transformations when applied to amino acid substrates,
[2+2] cycloaddition mechanism, followed by cycloreversion which are common elements of many peptide-derived bio-
to release phosphane oxide and the imine product. This as- active natural products.
sumption is supported mostly by theoretical studies[13]
and – in one instance – by the isolation of a stable four-
membered ring oxazaphosphetidine intermediate.[14] Beta-
Results and Discussion
ine-type, open-chain intermediates have not yet been found
by 31P NMR spectroscopy.
Obvious starting materials for amino-acid-derived natu-
We set out to explore intramolecular aza-Wittig reactions
ral product fragments are amino acid derivatives that can
to form azolines from β-azido-substituted thioesters, esters,
be converted into azides through diazo transfer reactions
and amides 8 (Scheme 2). Treatment of these azides with
phosphorus(III) reagents should furnish iminophos-
phoranes 9 after extrusion of nitrogen. These compounds
should then undergo aza-Wittig ring closure to afford azol-
ines 11 with release of phosphorus(V) oxide byproducts, in
a process favored by the antiparallel arrangement of the
C=O and P=N dipoles (10). In a follow-up step, the corre-
sponding azoles 12 should be obtainable by oxidation, as
desired. Through the employment of the azide group as a
latent, preactivated functionality, the ring closure remains
redox-neutral, exposes the substrate only to mild PIII rea-
gents, and avoids strongly activated reagents such as dehy-
drating phosphonium(V) salts.[15] Furthermore, chain-like
assembly of precursor molecules might be envisioned, be-
(Scheme 3).[22] Such reactions often employ electrophilically
activated azides such as TfN3,[23] NfN3,[24] or ImSO2N3.[25]
These methods vary mainly in the diazo transfer reagent,
the base, and the catalyst. However, the synthesis of a chiral
azide requires the conversion of the enantiomerically pure
amine. When the azide is derived from an amino acid deriv-
ative, product racemization can be a serious problem.
Scheme 3. Diazo transfer with amino-acid-derived amines.
cause the azido group would preclude OǞN or SǞN acyl
shift reactions.
In our initial attempts to generate linear azido cyclization
precursors for the aza-Wittig ring closures, we applied the
procedure described by Wong and co-workers.[23h,23i] With
amino-acid-derived substrates, however, the outcomes were
somewhat variable, and decreases in ee resulted in several
cases (Table 1, Entries a–d). Although epimerization might
occur at any point in the whole reaction sequence, the re-
sulting α-azido esters 14 are certainly more prone to epi-
merization than the starting amino esters 13, because of the
increased acidity of their α-protons. The most demanding
substrate for the diazo transfer was amine 13d,[19b] which
gave a very low enantiomeric excess of 46% (Entry d).
When using the shelf-stable imidazole-1-sulfonyl azide
Scheme 2. Conceptual blueprint for azol(in)e synthesis by aza-Wit-
hydrochloride,[25] we observed the formation of side prod-
tig reactions (PG = protecting group).
ucts resulting from cleavage of sulfonyl azide from the imid-
Isolated examples of such aza-Wittig-driven formation of azole. These results prompted us to focus on freshly pre-
thiazolines and oxazolines have been reported.[16] The syn- pared trifluoromethanesulfonyl azide as diazo donor.
thesis of imidazolines has been reported only for unusually
We observed that the use of a CH2Cl2/DMF mixture in-
activated systems.[17–18] Thereby, accessible substitution pat- stead of the usual aqueous methanol, combined with a
terns are limited or forcing reaction conditions had to be higher loading of catalyst, showed better reaction rates, and
applied.[18]
the products obtained in this way displayed very high enan-
Our initial results showed that this synthetic pathway is tiomeric excesses (Table 1, Entries e–h) although the yields
general and the reactions can be conducted in a highly were slightly reduced. Under these conditions, the metal
chemoselective fashion.[19] Mild conditions could typically ions of the catalysts should be less hydrated, which might
2
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Unified Azoline and Azole Syntheses
Table 1. Comparison of diazo transfer conditions and substrates.
The tendency of these salts to form different complexes
in aqueous media might contribute to this effect. ZnCl2 is
known to exist in several hydration states, but the chloride
ligands stay bound tightly to the metal center.[26,27] In con-
trast, the sulfate counterion has been found to bind much
less tightly to the metal[28] and will thereby render the tetra-
or hexacoordinate Zn2+ much more Lewis-acidic and hence
catalytically active.
Although these findings are certainly of practical value,
they are more difficult to interpret in mechanistic terms. We
hypothesize that the metal ion assists either adduct forma-
tion between amine and sulfonyl azide or the decomposi-
tion of the putative intermediate, likely by the chelating
ability of the metal ion. However, although some possible
mechanisms for the azide transfer have been discussed (see
ref.[23h]), there only are few experimental data and consider-
able disagreement on the actual intermediates involved. The
racemization suppression could be a result of increased
turnover of activated intermediates. Qualitatively, we ob-
served that prolonged reaction times (Ͼ3 h) generally led to
decreasing optical purity, suggesting that prolonged expo-
sure of α-azido ester products to the basic medium contrib-
utes to the degree of racemization observed.
Entry Compound
X
R
Method[a] Yield [%] ee [%][b]
a
b
c
14a
14b
14c
14d
OH
OH
STr
NHTs
H
Me
H
A
A
B
B
99
52
71
84
57[b]
93[b]
Ͻ42[b]
46[b,c]
d
H
e
f
g
h
14a
14b
14c
14d
OH
OH
STr
NHTs
H
Me
H
C
C
D
D
85
68
54
71
Ͼ99[b]
Ͼ99[b]
Ͼ95[b]
96[b]
H
i
j
k
l
14a
14b
14c
14d
OH
OH
STr
NHTs
H
Me
H
E
E
E
E
91
84
98
97
Ͼ92[d]
Ͼ99[c]
Ͼ98[d]
Ͼ94[d]
H
[a] Reagents and conditions. A: TfN3 (3 equiv.), NEt3 (3–4 equiv.),
ZnCl2 (1 mol-%), H2O/MeOH/CH2Cl2, room temp., 2–14 h. B:
TfN3 (3 equiv.), NEt3 (1.5 equiv.), CuSO4 (1 mol-%), H2O/MeOH/
CH2Cl2, room temp., 2–14 h. C: TfN3 (3 equiv.), EtNiPr2
(2.5 equiv.), ZnCl2 (5 mol-%), CH2Cl2/DMF, 0 °CǞr.t., 1.5 h. D:
TfN3 (3 equiv.), EtNiPr2 (2.5 equiv.), CuSO4 (5 mol-%), CH2Cl2/
DMF, 0 °CǞr.t., 1.5–2 h. E:TfN3 (3 equiv.), Et3N (2.5 equiv.),
ZnSO4 (2 mol-%), H2O/MeOH/CH2Cl2, 1:5:2, v/v/v, 0 °C, 1 h.
[b] Determined by HPLC with chiral modified columns. [c] Deter-
1
mined by H NMR after derivatization. [d] Determined by optical
rotation.
Free α-amino acids were also found to be suitable sub-
strates for the diazo transfer (Scheme 4). Trityl-protected
cysteine 13e was converted into the azide and protected as
its allyl ester with cesium carbonate and allyl bromide to
furnish the fully protected cysteine derivative 14e in 88%
yield.
explain the enhancement of their activity. We also noticed
that free hydroxy groups (Entries a, b, e, f) were tolerated
in this transformation as long as ZnCl2 was used[23h] instead
of CuSO4 as promoter.
In further experiments we noticed that ZnSO4 displayed
a considerably higher catalytic activity for these transforma-
tions than ZnCl2. Clean and full conversion was achieved
for substrate 13c in less than one hour (Table 2), without
the need to use chromatography. In contrast, use of CuSO4
always led to the formation of side products and required
chromatographic purification. The optimized conditions
with ZnSO4 were then applied to substrates 13a–d. Gratify-
ingly, the isolated yields ranged from 84% to 98% and the
stereoretention remained high (Table 1, Entries i–l). In an
attempt to optimize the reaction times, turnover was moni-
tored for substrate 13d, for which 95% conversion could be
reached after 11.5 min in the presence of 2 mol-% of cata-
lyst, and after 15.5 min if 1 mol-% was used.
Scheme 4. Synthesis of an azido allyl ester. Reagents and condi-
tions: a) TfN3 (3 equiv.), NEt3 (1.5 equiv.), ZnSO4 (1 mol-%), H2O/
MeOH/CH2Cl2 (1:5:2), 0 °C, 30 min; b) Cs2CO3 (0.5 equiv.),
MeOH, room temp., 10 min, then AllBr (5 equiv.), DMF, room
temp., 5 h.
Table 2. Comparison of metal salt promoters with amine 13c.[a]
Synthesis of Thiazoles and Oxazoles
Entry
Reaction time
Catalyst
Yield [%]
a
b
c
3 h
1 h
3 h
3 h
ZnCl2
ZnSO4
CuSO4
–
84
Azides 14a–c and 14e were used as starting materials for
the synthesis of thioesters 15a–e and esters 15f–o
(Scheme 5, Table 3). We found that the thiols 14c and 14e
had to be freshly deprotected before being immediately cou-
pled to the acids, because they were prone to oxidation.
The protected amino acid was activated in each case with
a combination of carbodiimide, HOBt, and EtNiPr2. The
98
73[b]
76[c]
d
[a] Reagents and conditions: TfN3 (3 equiv.), Et3N (2.5 equiv.), cat-
alyst (2 mol-%), H2O/MeOH/CH2Cl2, 1:5:2, v/v/v, 0 °C. [b] After
flash chromatography. [c] The reaction was stopped after 3 h.
The reaction rate enhancement due to ZnSO4 in relation coupling furnished thioesters 15a–e in good yields except in
[23h]
to ZnCl2
was rather unexpected. In line with the early the case of the proline thioester 15d, which might be due to
literature[23] we found that TfN3 reacts with primary amines its high steric demand. The coupling with alcohols 14a and
to form azides, but conversion was sluggish and stayed in- 14b with the aid of DIC and DMAP proceeded with good
complete in the absence of catalyst.
to excellent yield in all cases to give esters 15f–o.
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P. Loos, C. Ronco, M. Riedrich, H.-D. Arndt
FULL PAPER
Azido esters 15f–o were found to be less reactive than
the thioesters 15a–e. In the ring closure process, elevated
temperatures (Ͼ40 °C) had to be employed. Under these
conditions most substrates were ring-closed in good yields
(Table 3, Entries g–l, o) but β-branched substrates such as
proline, threonine, and valine derivatives in particular still
gave low yields (Entries f, m, n). The oxidation of the oxaz-
olines proceeded less swiftly than that of the thiazolines.
These data indicated that the cyclization protocol would
have to be optimized for sterically demanding esters. The
influence of solvent, temperature, and phosphane were
therefore studied in detail for the ring closure of the de-
manding threonine-derived ester 15m.
Scheme 5. Thiazole and oxazole synthesis. For conditions, see
Table 3.
Table 3. Overview of thiazole and oxazole synthesis.[a]
Optimization of Solvent
Entry Amino
acid
X
RЈ RЈЈ
Yield [%]
16
ee [%]
Apart from theoretical calculations,[30] the influence of
solvents in aza-Wittig ring closures has not been systemati-
cally investigated before. The common solvents for these
conversions found in the literature were tested in the ring
closure of the sterically congested substrate 15m
(Scheme 6). The results are compiled in Table 4.
15
17
a
b
c
d
e
Ala
His(Bn)
Val
Pro
Glu(Cy)
S
S
S
S
S
H
H
H
H
H
Me
Me
Me
allyl
Me
69
74
98
95
91
97
92
94
23
85
94
86
94[b,c]
98[c]
95[b]
99[c]
70[c]
80
54[d]
80[d]
[f,h]
f
Pro
Ala
Ala
Phe
Cys(Tr)
Glu(Cy)
Tyr(Bn)
Thr(Bn)
Val
O
O
O
O
O
O
O
O
O
O
H
H
Me
Me
84
92
86
88
87
99
84
–
23[g] Ͼ95
g
h
i
j
k
l
m
n
o
84
78
78
97
62
79
78
62
89–98[b,c]
Me Me
Ͼ96[b]
95[b]
H
H
H
H
H
H
H
Me
Me
Me
Me
Me
Me
Me
23[c]
[f]
–
69[g] Ͼ98[c]
62
56
Ͼ95
Ͼ96[b,e]
94[c]
–
98 18,75[h] 56
95 13,48[h] 43
[f]
Gly
93
–
64[g]
[a] Reagents and conditions: a) X = S: i. TFA/CH2Cl2 (1:9),
Et3SiH, room temp., 10 min; ii. DIC or EDC, HOBt, EtNiPr2, pro-
tected amino acid, 0.5–16 h, 0Ǟ20 °C; X = O: DIC, 1–5 mol-%
DMAP, CH2Cl2, 0.5–16 h, 0Ǟ20 °C; b) PPh3, THF, –20Ǟ40 °C,
2–18 h; c) BrCCl3, DBU, CH2Cl2, 0Ǟ20 °C, 2–4 h. [b] Determined
by 1H NMR examination of diastereomers after derivatization.
[c] Determined by HPLC with chiral modified columns
(Daicel AD). [d] EDC, HOBt, NEt3, CH2Cl2, 0 °C. [e] One dia-
stereomer in 1H NMR. [f] Could not be separated from OPPh3.
[g] Yield over two steps. [h] Modified conditions: b) PPh3, 2,6-
lutidine, 80 °C, 4–6 h.
Scheme 6. Screening of different conditions for the aza-Wittig ring
closure.
Table 4. Optimization of solvent and temperature.
Entry Solvent
T [°C]
t [h]
Yield [%]
In order to transform the azido (thio)esters into azolines
effectively, several conditions for the aza-Wittig transforma-
tion were studied. Treatment of substrates 15a–o with PPh3
furnished the corresponding iminophosphoranes, which
underwent ring closure to yield thiazolines 16a–e and oxa-
zolines 16f–o. Azolines 16a–o could be oxidized to the thi-
azoles 17a–e and oxazoles 17f–o with DBU and BrCCl3.[29]
In some cases it was very difficult to separate the oxazolines
from the triphenylphosphane oxide formed during the reac-
tion. In these cases the oxazoles were directly generated by
oxidation of the crude oxazolines 16f, 16k, and 16o.
1
2
3
4
5
6
7
8
9
CH2Cl2
toluene
MeOH
THF
40
40
40
40/80
40/80
80
40/80
80
19
19
19
19/5
19/5
5
19/5
5
4
–
9
–
23/42
21/44
33
37/75
75
DMF
DMSO
pyridine
2,6-lutidine
pyridine/DMF 80
(1:1–9:1)
38–43
In CH2Cl2 and toluene the formation of iminophos-
The synthesis of the thiazolines 16a–e was highly efficient phorane 18 was observed (LC-MS, 31P NMR), but the cy-
and gave excellent yields without exception (Table 3, En- clization either did not occur (Entry 1) or was very low-
tries a–e). Oxidation to the thiazoles 17a–e worked equally yielding (Entry 2). In MeOH, transesterification of 15m led
well, except in the case of the benzyl-protected histidine de- to the formation of threonine methyl ester 19 (Entry 3), in-
rivative. In this case interference by the nucleophilic nitro- dicating considerable basicity of the generated iminophos-
gen might be a reason for the low yield.
phorane intermediate. Formation of the desired oxazoline
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Unified Azoline and Azole Syntheses
could not be observed. Better results were achieved with Wittig ring closures in a similar fashion to oxazolines and
polar aprotic solvents such as THF, DMF, and DMSO, es- thiazolines. Our data indicated that esters were less reactive
pecially at elevated temperature (Entries 4–6). The slightly than the corresponding thioesters in aza-Wittig ring closure
basic solvents pyridine and 2,6-lutidine gave the best results events. Amides should be even less reactive, and had in fact
(Entries 7 and 8). Evidence for the importance of a basic, been found to be inert under the conditions described pre-
aromatic solvent in this reaction is given by the fact that viously. The few examples of amides undergoing aza-Wittig
the yield dropped to 38–43% in mixtures of pyridine and reactions employed highly activated (i.e., electron-poor)
DMF (1:1, 1:3, 1:9; Entry 9). We further noticed that oxaz- substrates or harsh conditions.[17c,17g,18]
olines derived from sterically unhindered amino acids were
To improve the electrophilicity of the amide carbonyl
prone to hydrolysis, which could be prevented by using pyr- group we introduced a tosyl group onto the amide nitrogen.
idine or 2,6-lutidine as solvent. We therefore hypothesize This group was anticipated to activate the amide oxygen
that the slightly basic medium suppresses protonation and towards undergoing ring closure with an iminophos-
consequently improves the reactivity of the iminophos- phorane in the β-position. Secondly, it should serve as a
phorane.
protecting group on the imidazole nitrogen after oxidation
Elevated temperatures were also beneficial. Increasing to the imidazole. Thirdly, it should allow the N(1) and N(3)
the temperature from 40 °C to 80 °C resulted in doubling positions in the imidazole ring to be distinguished.
of the yields in THF and DMF (Entries 4 and 5) and re-
In order to explore this strategy, Nα-Boc-l-asparagine
duced the reaction times from 19 to 5 h. This effect was was subjected to a diacetoxyiodobenzene-mediated Hof-
even stronger in pyridine, in which the yield rose from 37 mann degradation[33] and converted into ammonium salt
to 75%. The conditions with 2,6-lutidine as solvent and a 13d.[19b] After diazo transfer, azide 14d was obtained in
temperature of 80 °C were chosen for studying the phos- good yield and high enantiomeric excess (Table 1).
phane source.
The synthesis of N-acyl-sulfonamides 20a–g by acylation
of sulfonamide 14d (Scheme 7) was studied next. Unfortu-
nately, precedence for sulfonamide acylation was found to
be rather limited. β-Lactams have been cyclized by use of
DCC and 4-pyrrolidinopyridine.[34] Ligation of sulfonyl
azides with thioacids[33] can be used to make secondary
sulfonamides, and PyBOP has been used to acylate so-
called “safety-catch” linkers.[35] However, the use of car-
bodiimides and 4-aminopyridines was very low-yielding in
our hands. Examples of acylation of secondary sulfon-
amides were even more scarce and seem to require strong
activation. In one case, acid anhydrides and Lewis acids
have been used for this purpose.[36] We wanted to avoid acti-
vation by anhydrides and acid chlorides, firstly because
such strong activation often leads to epimerization and sec-
ondly because Boc-protected amino acid chlorides tend to
form oxazolones.[37]
Optimization of Phosphanes
Immediate formation of gas was apparent upon addition
of triphenylphosphane to the azides. 31P and 13C NMR ex-
periments with substrate 15m showed that the azide was
quickly transformed into the corresponding iminophos-
phorane (31P NMR: 10.81 ppm in [D5]pyridine for imino-
phosphorane 18). This iminophosphorane was relatively
stable and was slowly consumed over several hours. Inter-
estingly, when we replaced triphenylphosphane by an alkyl
phosphane such as PBu3, PEt2Ph, or P(CH2OH)3, only
decomposition was observed. With PEtPh2 and
P(C6H4SO3Na)3, oxazoline 16m could be isolated in less
than 30% yield. Apparently, stabilized iminophosphoranes
derived from triphenylphosphane were more suitable than
less stable alkyl-substituted iminophosphoranes. (We attri-
bute this finding to the increased reactivity of an ester or
thioester of an amino acid with an α-azido substituent
towards nucleophilic attack, relative to an aromatic hetero-
cycle.) Under optimized conditions (PPh3, 2,6-lutidine,
80 °C, 6 h) the sterically congested oxazolines 16m and 16n
(Table 2) could be effectively obtained. Threonine-derived
15m was cyclized in a yield of 75% (before 18%) and the
valine-derived 15n was transformed into 16n in 48% yield
(previously 13%). These conditions were also used for the
cyclization of several azido amides to imidazolines.
Scheme 7. Imidazoline and imidazole synthesis from azide 14d. For
conditions, see Table 5.
Acid fluorides are more stable than acid chlorides but
still highly reactive.[38] Initial experiments with freshly pre-
Imidazol(in)e Synthesis and Enantiopurity
Several methods to form chiral imidazol(in)es have been pared Boc-protected amino acid fluorides[39] gave clean
described in the literature,[31] but enantiomerically pure couplings with Boc-alanine and Boc-phenylalanine
imidazolines with a stereogenic center α to the C-2 position (Table 5, Entries a and b) without any detectable epimeriz-
pose considerable challenges to synthesis.[32] We hypothe- ation. However with sterically hindered amino acids (En-
sized that imidazolines might be accessible through aza- tries c, d, and e) yields were lower. After some experimenta-
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FULL PAPER
tion we found that a combination of HATU and solid
Importantly, the stereochemical purity of the products
Cs2CO3 in CH2Cl2 gave excellent yields and ee values in was found to be preserved. Among the imidazoles 22a–e,
these cases. Surprisingly, cesium carbonate could not be re- 22c had an ee value of more than 98%, as evidenced by
placed by EtNiPr2 or K2CO3; we hypothesize that a soluble NMR and HPLC analysis. Only cysteine-derived 22e
sulfonamide cesium salt might be involved. The HATU/ showed a slightly lower ee (96%), which was identical to
Cs2CO3 combination proved excellent for all other tested that of 20e and hence unaffected by the ring closure/oxi-
substrates (Entries c–g); only cysteine derivative 20e showed dation sequence. Acylated sulfonamide 20g showed an ee =
a measurable amount of a second diastereomer in a ratio 94%. After ring closure in 2,6-lutidine the ee was deter-
of 98:2.
mined to 82%, indicating a somewhat increased acidity of
the hydrogen in the 4-position.
Treatment of imidazoline 21a with an excess of DBU led
to clean formation of the free imidazole 23 (Scheme 8), pre-
sumably through elimination of sulfinate. This process was
found to be slower than oxidation with BrCCl3 und DBU,
with complete conversion being observed after three hours.
The elimination could therefore easily be suppressed by
adding BrCCl3, which produced the protected imidazole.
Surprisingly, no loss of enantiomeric excess could be de-
tected in this transformation.
Table 5. Synthesis of imidazoles from azide 14d and ee determi-
nation.[a]
Scheme 8. Imidazoline oxidation by elimination. Reagents and con-
ditions: DBU (15 equiv.), DMF, 0 °CǞ20 °C, 3 h. [a] Determined
by HPLC with chiral modified columns.
Microwave-Assisted Ring Closure
As shown above, the outcomes of the aza-Wittig ring clo-
sures were dependent on the solvent and on the reaction
temperature. For sterically congested substrates, ring clo-
sure with use of conventional heating took several hours.
Heating by microwave irradiation was therefore studied for
ester 15m and N-acyl-sulfonamide 20e (Table 6).
[a] Reagents and conditions. a) Entries a and b: acid fluoride
(2 equiv.), EtNiPr2 (2 equiv.), CH2Cl2, 0 °CǞ20 °C, 1–2.5 h; En-
tries c–g: carboxylic acid (1.1 equiv.), HATU (1.1 equiv.), Cs2CO3
(4 equiv.), CH2Cl2, 0 °C, 1–4 h. b) Entries a–d, f: PPh3 (1.5 equiv.),
THF, –20 °CǞreflux, 2.5–6 h; Entries e and g: PPh3 (1.5 equiv.),
2,6-lutidine, –20 °CǞ80 °C, 2–6 h. c) DBU (2 equiv.), BrCCl3
(1.1 equiv.), CH2Cl2, room temp., 2.5–6 h. [b] Determined by 1H
NMR and HPLC. [c] Determined by HPLC with chiral modified
columns.
Table 6. Microwave assisted aza-Wittig ring closure.
Entry Azide Solvent
Microwave, 100 °C Heating bath, 80 °C
Time
[h]
Yield[a]
[%]
Time
[h]
Yield[b]
[%]
1
2
3
4
5
15m DMF
15m 2,6-lutidine
20e THF
20e pyridine
20e 2,6-lutidine
0.5
0.5
0.5
0.5
0.5
55
71
63
64
75
5
5
21
6
44
75
46[c]
55
With the cyclization precursors in hand we proceeded to
the critical ring closure step, using the previously optimized
conditions (THF, reflux or 2,6-lutidine, 80 °C). Gratify-
ingly, all substrates were obtained in good to excellent iso-
lated yields. Imidazoline 21a was prone to hydrolysis of the
amidine unit, which occurred upon column chromatog-
raphy or upon prolonged exposure to CDCl3. Addition of
6
80
[a] Reagents and conditions: PPh3 (1.5 equiv.), 0 °CǞ100 °C, mi-
crowave (200 W). [b] PPh3 (1.5 equiv.), 0 °CǞ80 °C, heating bath.
[c] PPh3 (1.5 equiv.), 0 °CǞreflux, heating bath.
Overall, microwave heating for 30 min delivered the azol-
base during chromatography and the use of [D5]pyridine or ines in yields comparable to those obtained after 5–6 h con-
[D6]benzene as NMR solvent suppressed this side reaction. ventional heating. The ring closure of 20e in THF (Entry 3)
Phenylalanine derivative 21b also showed hydrolytic ring is remarkable: microwave heating delivered the imidazoline
opening, but to a much lower extent. The oxidation of imid- with a yield of 63% after 30 min, whereas cyclization in
azolines 21a–g under standard conditions[29] with DBU and THF at reflux resulted in an isolated yield of only 46%
BrCCl3 performed cleanly in excellent yields.
after 21 h.
6
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Unified Azoline and Azole Syntheses
Synthesis of Fused Azole Dimers
Table 7. Multiple ring closures to afford mixed azole-azole dimers
(Tr = trityl. Mmt = 4,4Ј-dimethoxytrityl).
Besides monomeric imidazoles, oxazoles, and thiazoles,
the homodimers or mixed dimers of these heterocycles are
important substructures in biologically relevant natural
products.[40] Such heterocyclic frameworks could be access-
ible through multiple (parallel) ring closures of linear cycli-
zation precursors. To investigate the feasibility of such
transformations the synthesis of bisazides 27a–e (Scheme 9)
was envisaged. The bisazides 27a–e were expected to form
the corresponding bisiminophosphoranes with 2 equiv. of
triphenylphosphane. These could undergo regioselective
double ring closures to furnish the dimeric heterocycles
28a–e. Five different heterocyclic dimers were generated by
this synthetic strategy. The results are listed in Table 7.
Entry
Y
X
R
Yield [%]
26
27
29
a
b
c
d
e
O
S
S
NTs
NTs
O
S
O
O
S
Tr
Mmt
Tr
H
H
92
68
59
61
70
64
51
47
88
51
27
60
64
74
81
BocAlaF. Minimum amounts of base, short reaction times,
and rigorous exclusion of water were crucial for this sulfon-
amide acylation. However, both acylation products were
isolated as mixtures of diastereomers (27d: 84% de, 27e:
11% de), which can be attributed to the highly acidified
proton α to the (thio)ester.
All bisazides were then doubly cyclized with PPh3 in
THF. Only for 27a was the bisazoline product 28a isolated
(83%); the other azolines 28b–e were all directly oxidized
without isolation. The bisthiazoline derived from 27b was
highly prone to autooxidation, whereas cyclization of 27c
led to a mixture of tautomers, presumably enamine isomers.
Even though the two intermediates 27d and 27e were highly
unstable in the presence of base, both underwent clean and
regioselective conversion to the corresponding bisazolines.
Both intermediates were directly oxidized, because they
were prone to acid-catalyzed hydrolysis and, in the case of
27e, to autooxidation.
Oxidation to the bisazoles 29a–e proceeded smoothly, ex-
cept in the case of 29a, which was found to form slowly and
in lower yield. During these experiments we observed that
azoline oxidations with DBU and BrCCl3 were highly de-
pendent on the presence of an electron-withdrawing group
on the azoline, which might promote deprotonation when
DBU is added. We assume that these positions are oxidized
first. On the other hand, oxidation was slower for azolines
that are only remotely activated. Whereas thiazolines are
well known to be oxidized easily (Y = S, Entries b and c)
and tosyl imidazolines were also easily oxidized (Y = NTs,
Entries d and e), the corresponding oxazolines seem to be
more difficult to oxidize without direct activation.
We did not observe the formation of alternative ring clo-
sure products; this demonstrates the exceptional selectivity
of the aza-Wittig reaction for the formation of five-mem-
bered rings. Similar observations were also made during the
total syntheses of the halipeptins A and D.[21d] In these
cases the formation of a five-membered ring (79–83%) was
favored over the alternative aza-Wittig ring closure to a six-
membered ring (16–17%).
Scheme 9. Multiple aza-Wittig ring closures of bisazides. Reagents
and conditions: a) 26a or 26c: carboxylic acid (1.3 equiv.), DIC
(1.4 equiv.), DMAP (0.1 equiv.), CH2Cl2, 0 °CǞ20 °C; 26b:
carboxylic acid (1.3 equiv.), IPCF (1.3 equiv.), NMM (2.3 equiv.),
THF, –20 °C; 26d or 26e: carboxylic acid (1.1 equiv.), EDC·HCl
(2.2 equiv.), HOBt (2.2 equiv.), CH2Cl2/DMF (5:1), 0 °CǞ20 °C,
2 h. b) 27a: Et3SiH (1.05 equiv.), CH2Cl2/TFA (10:1), room temp.,
10 min; BocAlaOH (1.3 equiv.), DIC (1.4 equiv.), DMAP
(0.13 equiv.), CH2Cl2/DMF (10:1), 0 °CǞ20 °C; 27b: Et3SiH
(1.1 equiv.), CH2Cl2/TFA (3:1), room temp., 30 min; BocAlaOH
(2 equiv.), DIC (2 equiv.), DMAP (0.2 equiv.), CH2Cl2,
0 °CǞ20 °C, 12 h; 27c: Et3SiH (1.1 equiv.), CH2Cl2/TFA (2:1),
room temp., 1.5 h; BocAlaOH (1.05 equiv.), DIC (1.2 equiv.), Et-
NiPr2 (1.2 equiv.), CH2Cl2/DMF (10:1), 0 °CǞ20 °C, 13 h; 27d:
BocAlaF (2 equiv.), EtNiPr2 (1.1 equiv.), CH2Cl2, 0 °C, 30 min;
27e: BocAlaF (1.05 equiv.), EtNiPr2 (1.05 equiv.), CH2Cl2, 0 °C,
45 min. c) 28a or 28b: PPh3 (3 equiv.), THF, –20 °CǞ40 °C; 28c:
PPh3 (4 equiv.), THF, –20 °CǞ40 °C; 28d or 28e: PPh3 (3 equiv.),
THF, –40 °CǞreflux, 6 h. d) 29a or 29b: DBU (10 equiv.), BrCCl3
(5 equiv.), CH2Cl2, 0 °CǞ20 °C; 29c: DBU (12 equiv.), BrCCl3
(6 equiv.), CH2Cl2, 0 °CǞ20 °C; 29d or 29e: DBU (10 equiv.),
BrCCl3 (5 equiv.), CH2Cl2, 0 °CǞ20 °C, 30 min.
Hydroxyazide 14a and freshly deprotected mercaptoaz-
ide 24 (X = S) were coupled to the acids 25a–c with the aid
of carbodiimides or isopropyl chloroformate (IPCF). In the
Ligand Scaffolds
Chiral bisoxazoline or pybox ligands have been success-
synthesis of 26d and 26e the use of base led to decomposi- fully used in transition-metal-catalyzed asymmetric trans-
tion, especially with thioester 26e. Compounds 26a–c were formations,[41] but little is known about the catalytic proper-
deprotected with TFA and coupled to Boc-alanine (DIC/ ties of their sulfur analogues.[42] The bisthiazolinepyridines
DMAP). The bisazides 26d and 26e were coupled to 32a and 32b (Scheme 10, Table 8) were each synthesized
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P. Loos, C. Ronco, M. Riedrich, H.-D. Arndt
FULL PAPER
through parallel aza-Wittig ring closures, in two steps from 1,3-azolines was possible with DBU and BrCCl3, but oxaz-
the commercially available bisacids 30a and 30b .
olines not bearing an electron-withdrawing substituent (e.g.,
an ester) were sometimes found to be difficult to oxidize
(Table 7, Entry 1.)
We have shown that these transformations allow the syn-
thesis of 1,3-azolines and 1,3-azoles with high ee values.
Double aza-Wittig ring closures showed that five-membered
rings are formed with high selectivity. These conditions
could be applied to a wide variety of protected amino acids,
demonstrating that the transformations tolerate other carb-
onyl groups, such as esters, amides, and urethanes, as well
as protected thiols and alcohols. Reaction times could be
shortened by use of microwave irradiation, and the aromati-
zation of a N-tosylimidazole was achieved in the absence of
the oxidative agent BrCCl3.
Scheme 10. Synthesis of pyridine-fused thiazolines.
This method constitutes an alternative to standard dehy-
dration approaches to azoles, especially in densely function-
alized substrates. It allows the retention of stereogenic cen-
ters directly attached to the azoline units and does not em-
ploy acid or base catalysis. All three types of 1,3-azolines
are accessible through the use of similar reaction condi-
tions, and imidazoles can be obtained in a protected form.
We hope that these findings will be found useful for late-
stage ring formation in total synthesis and for multiple re-
gioselective ring closures.
Table 8. Synthesis of bisthiazolinepyridine derivatives through mul-
tiple aza-Wittig ring closures.[a]
Entry
Y
Z
Yield [%]
31
32
a
b
N
CH
CH
N
31
15
88
82
[a] Reagents and conditions: a) HOBt, EDC, NEt3, 24, CH2Cl2,
0 °CǞ20 °C, 14 h; b) PPh3, THF, 0 °CǞ40 °C, 14 h.
In the first step, bisacids 30a and 30b were each coupled
to thiol 24. Under unoptimized conditions the bisthioesters
were formed in 31% and 15% yields. However, the parallel
ring closures of the linear cyclization precursors 31a and
31b proceeded cleanly and delivered the desired dia-
stereomerically pure bisthiazolines in high yields. This ap-
proach could be used to synthesize a variety of Pybox ana-
logue ligands with high diastereomeric excess.
Experimental Section
Diazo Transfer According to Wong (GP A):[23g,23h] A solution of
NaN3 (6 equiv. per amino group) in H2O (6 m) was mixed with an
equal volume of CH2Cl2 and cooled to 0 °C. Tf2O (6 equiv. per
amino group) was added dropwise over 5 min and the reaction mix-
ture was stirred vigorously for 2 h at 0 °C. The biphasic mixture
was neutralized with saturated Na2CO3 solution and the aqueous
layer was extracted twice with the same volume of CH2Cl2. The
combined organic extracts were washed with saturated Na2CO3
solution, and the obtained TfN3 solution was used without further
purification. The substrate and the catalyst (1 mol-% of CuSO4 or
ZnCl2) were dissolved in H2O (same volume as the TfN3 solution),
and base (K2CO3 or NEt3, 3 equiv.) was added. TfN3 solution was
added and the biphasic reaction mixture was diluted to homo-
geneity with MeOH and stirred until full conversion (monitored by
TLC). The organic solvents were evaporated, and the aqueous layer
was diluted with H2O, neutralized with formic acid, and extracted
with CH2Cl2 (5ϫ). The combined organic extracts were dried with
MgSO4 and concentrated in vacuo.
Summary and Conclusion
We have found that the aza-Wittig reaction can be em-
ployed for the synthesis of valuable 1,3-azolines from read-
ily available amino acids. We therefore optimized the syn-
thesis of amino-acid-derived azides with high ee values. Im-
portantly, when ZnSO4 was used as a superior catalyst,
azide transfers performed cleanly in very high ee values
even when applied to sensitive amino acid derivatives. The
azides have been converted into thioesters, esters, and N-
acyl-sulfonamides with excellent yields. Whereas thioesters
and esters could be synthesized with the aid of carbodiim-
ides, efficient acylation of sulfonamides required acid fluo-
rides or activation with HATU und Cs2CO3.
The aza-Wittig syntheses of thiazolines, oxazolines, and
imidazolines have been found to be highly advantageous
reactions. The investigated thiazolines were formed ef-
ficiently even at room temperature, although higher tem-
peratures were necessary to obtain imidazolines and oxazol-
ines in high yields. Sterically congested esters were shown
to be the most demanding substrates for these ring closures
(Table 3, Entries m and n); they could be obtained in yields
of 48% and 75% after optimization of temperature, solvent,
Diazo Transfer Procedure in Nonhydroxylic Solvent (GP B): NaN3
(6 equiv. per amino group) was suspended in water (to a concentra-
tion of 8 m) and an equal volume of CH2Cl2 and cooled to –20 °C.
Tf2O (3 equiv. per amino group) was added, and the resulting bi-
phasic solution was stirred at 0 °C for 30 min. Cold satd. NaHCO3
solution (200 vol.-% of the reaction mixture) was added slowly and
the layers were separated. The aqueous layer was extracted with
cold CH2Cl2 (2ϫ, 2.5 times the CH2Cl2 volume used), and the
combined organic extracts were washed with cold satd. NaHCO3
solution (1ϫ reaction volume). The obtained TfN3 solution was
used without further purification. Substrate and catalyst (0.5 mol-
% CuSO4 or ZnCl2) were dissolved in DMF (same volume as the
TfN3/CH2Cl2 solution) and cooled to 0 °C. EtNiPr2 (2.5 equiv.)
and phosphane source. The oxidation of all investigated and TfN3 solution were added, and the mixture was stirred at room
8
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Unified Azoline and Azole Syntheses
temp. until conversion was complete (monitored by TLC). The
CH2Cl2 was evaporated at room temp. under reduced pressure.
Water was added, and the aqueous layer was extracted four times
with Et2O. The combined organic extracts were dried (MgSO4) and
coevaporated in vacuo (room temperature) with toluene until the
ether was completely removed.
saturated NaCl solution. The organic layer was dried with MgSO4
and concentrated in vacuo.
General Procedure for the Formation of Azolines through Aza-Wittig
Ring Closures (GP F): The azido (thio)ester or N-acyltosylamide
was dissolved in THF (to a concentration of 0.05 m) and treated
dropwise at –20 °C with PPh3 (1.5 equiv.) in THF (final concentra-
tion: 0.03–0.05 m). After 15 min stirring at –20 °C the reaction mix-
ture was warmed to 40 °C and stirred for 6 h, unless stated other-
wise. The reaction mixture was allowed to cool to room temp. and
the solvent was removed under reduced pressure.
General Procedure for Diazo Transfer with ZnSO4 (GP C): A solu-
tion of NaN3 (6 mmol) in H2O (1 mL) was mixed with CH2Cl2
(1 mL) and cooled to 0 °C. Tf2O (3 mmol) was added dropwise,
and the reaction mixture was stirred vigorously for 2 h at 0 °C. The
biphasic mixture was neutralized with saturated aqueous NaHCO3
solution (1 mL), and the aqueous layer was extracted twice with
CH2Cl2 (2ϫ 1 mL). The combined organic extracts were washed
with saturated aqueous NaHCO3 solution (2ϫ 1 mL), and the re-
sulting TfN3 solution in CH2Cl2 was used directly afterwards with-
out further purification. The hydrochloride salt of the amine sub-
strate (1 mmol) and ZnSO4 (0.02 mmol) were dissolved in MeOH
(6.7 mL) and water (1.3 mL). The mixture was cooled to 0 °C, and
Et3N (2.5 mmol) was added slowly, followed by the dropwise ad-
dition of the TfN3 solution prepared as above. The homogeneous
mixture was stirred at 0 °C until full conversion was reached (TLC
monitoring) and was then quenched by addition of phosphate
buffer (pH 3). The pH of the aqueous layer was carefully adjusted
to pH 2 by addition of dilute aqueous HCl. The phases were sepa-
rated, and the aqueous layer was extracted three times with
CH2Cl2. The combined organic layers were washed with brine,
dried with Na2SO4 and concentrated in vacuo.
General Procedure for the Formation of Azoles (GP G): The azoline
was dissolved in CH2Cl2 (to a concentration of 0.05 m) cooled to
–10 °C and treated with DBU (2.1 equiv.). After the mixture had
been stirred at –10 °C for 10 min, BrCCl3 (1.1 equiv.) was added
dropwise, and the reaction mixture was allowed to warm slowly to
room temp. until conversion was complete (TLC monitoring). The
crude reaction mixture was diluted with EtOAc, (500 vol.-% of the
reaction mixture) and washed with NaHSO4 (1 m) and saturated
NaCl solution (200 vol.-% of the reaction mixture each). The or-
ganic layer was dried with MgSO4 and concentrated in vacuo.
Synthesis of N-Acyl-Sulfonamides with DAST (GP H): The acid
(2 equiv.) was dissolved in anhydrous CH2Cl2 (0.4 m) and cooled to
0 °C. Pyridine (2 equiv.) and DAST (diethylaminosulfur trifluoride,
2.4 equiv.) were added, and the mixture was stirred at 0 °C for
40 min. The organic layer was washed with water, and the com-
bined aqueous layers were washed with CH2Cl2. The combined or-
ganic extracts were dried (MgSO4) and the solvent was evaporated
in vacuo to afford the acid fluoride. Methyl (S)-2-azido-3-(tolyl-4Ј-
sulfonylamino)propionate (14d, 1 equiv.) was dissolved in anhy-
drous CH2Cl2 (0.8 m) and cooled to 0 °C. EtNiPr2 (2 equiv.) and
the freshly prepared acid fluoride (2 equiv.) were added, and the
mixture was stirred at room temperature until full conversion was
reached (monitored by TLC). Water was added, and the pH of the
aqueous layer was adjusted to pH 5 with citric acid (5% in H2O).
The layers were separated, and the aqueous phase was extracted
with CH2Cl2 (1000 vol.-%, 4ϫ). The combined extracts were dried
(MgSO4) and concentrated.
Caution: Although we have never experienced any instability in the
course of this work, TfN3 has been reported to be unstable by
others.[43] We recommend taking proper precautions (blast shield)
when the reaction mixture or crude reaction product is heated or
evaporated. To enhance safety, the TfN3-containing solutions were
not concentrated completely. The mixture either was only partly
concentrated and used directly for purification by FCC or was fil-
tered through a short pad of silica before partial concentration.
Excess TfN3 was immediately poured into satd. NaHCO3 solution
(pH 9) and stored for 24 h, to ensure complete hydrolysis of the
reagent, before the solution was discarded.
Synthesis of N-Acyl-Sulfonamides with HATU and Cs2CO3 (GP I):
The acid (2 equiv.) was dissolved in anhydrous CH2Cl2 (to a con-
centration of 0.2 m), and the mixture was cooled to 0 °C. After
addition of HATU (1.1 equiv.) and Cs2CO3 (1 equiv.) the mixture
was stirred at this temperature for 15 min. More Cs2CO3 (3 equiv.)
and sulfonamide 14d (1 equiv.) in anhydrous CH2Cl2 (0.3 m) were
added, and the mixture was stirred at 0 °C until conversion was
complete (TLC monitoring). Water was added, and the pH of the
aqueous layer was adjusted to pH 5 with citric acid (5% in H2O).
The layers were separated, and the aqueous phase was extracted
with CH2Cl2 (700 vol.-%, 4ϫ). The combined extracts were dried
(MgSO4) and concentrated in vacuo.
General Procedure for the Formation of Thioesters (GP D): The tri-
tyl-protected thiol (1.0 equiv.) was dissolved in CH2Cl2 (to a con-
centration of 0.1 m) and treated with TFA (5 vol.-%) and Et3SiH
(1.1 equiv.) at room temp. for 1 h. All volatiles were evaporated,
and the residue was dissolved in CH2Cl2 (to a concentration of
0.5 m). The carboxylic acid (1.0 equiv.) and HOBt (1.2 equiv.) were
dissolved in CH2Cl2/DMF (10:1, to a concentration of 0.1 m) and
subsequently treated at 0 °C with carbodiimide (DIC or EDC,
1.25 equiv.) and base (EtNiPr2 or Et3N, 1.2 equiv.). After the mix-
ture had been stirred at 0 °C for 30 min, the freshly prepared thiol
solution was added dropwise and the reaction mixture was stirred
at 0 °C Ǟroom temp. with TLC monitoring. The crude reaction
mixture was diluted with EtOAc, (500 vol.-% of the reaction mix-
ture) and washed subsequently with NaHSO4 (1 m) and saturated
NaCl solution (200 vol.-% of the reaction mixture each). The or-
ganic layer was dried with MgSO4 and concentrated in vacuo.
Methyl (2R,2ЈS)-2-Azido-3-(N-Boc-alanylthio)propionate (15a): N-
Boc-alanine (47 mg, 0.25 mmol) and trityl-thiol 14c (100 mg,
0.25 mmol) were coupled by GP D with DIC (40 μL, 0.30 mmol),
HOBt (46 mg, 0.30 mmol), and EtNiPr2 (30 μL, 0.30 mmol). After
FCC (5 g, light petroleum/EtOAc, 4:1), thioester 15a was isolated
as a colorless oil (57 mg, 0.17 mmol, 69%). Rf = 0.29 (cyclohexane/
General Procedure for the Formation of Azido Esters (GP E): The
carboxylic acid (4 equiv.) was dissolved in CH2Cl2 (to a concentra-
tion of 0.2 m) and cooled to 0 °C. A carbodiimide (DCC, DIC, or
EDC, 2 equiv.) and DMAP (10 mol-%) were added, and the mix-
ture was stirred at 0 °C for 15 min. The alcohol in CH2Cl2 (0.5 m)
was added dropwise, and the mixture was stirred at room temp.
until full conversion (monitored by TLC). The crude reaction mix-
ture was diluted with EtOAc, and washed with NaHSO4 (1 m) and
1
EtOAc, 2:1). [α]2D0 = –59.3 (CHCl3, c = 1.0). H NMR (400 MHz,
CDCl3): δ = 5.00 (d, J = 6.7 Hz, 1 H, NH), 4.40–4.29 (m, 1 H,
CHCH3), 4.03 (dd, J = 5.6, 7.6 Hz, 1 H, CHN3), 3.76 (s, 3 H,
CO2CH3), 3.30 (dd, J = 5.4, 14.0 Hz, 1 H, CHHCHN3), 3.13 (dd,
J = 7.7, 13.9 Hz, 1 H, CHHCHN3), 1.41 [s, 9 H, C(CH3)3], 1.33
(d, J = 7.2 Hz, 3 H, CHCH3) ppm. 13C NMR (100 MHz, CDCl3):
δ = 201.2 [C(O)S], 169.2 (CO2Me), 155.1 (CO2tBu), 80.7 [C(CH3)
Eur. J. Org. Chem. 0000, 0–0
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9

Job/Unit: O30160
/KAP1
Date: 10-04-13 10:52:38
Pages: 27
P. Loos, C. Ronco, M. Riedrich, H.-D. Arndt
FULL PAPER
3], 61.5 (CHN3), 56.5 (CHCH3), 53.1 (CO2CH3), 30.1 (CH2S), 28.5 10.2 Hz, 1 H, CH=CHH), 4.67 (d, J = 5.2 Hz, 2 H, CH2CH=CH2),
[C(CH ) ], 18.6 (CHCH ) ppm. IR (KBr): ν = 3382 (bs), 2980 (bs), 4.50–4.32 (m, 1 H, 2-H), 4.04 (dd, J = 5.4, 7.8 Hz, 1 H, CHN3),
2503 (w), 2118 (s), 1714 (s), 1504 (m), 1454 (m), 1169 (s), 1049 (m), 3.59–3.27 (m, 3 H, 5-H, CH2CHN3), 3.25–3.08 (m, 1 H, 5-H), 2.27–
˜
3 3
3
968 (s), 915 (m), 859 (m), 785 (m), 626 (w), 551 (m) cm–1. LC-MS
(ESI): tR = 9.6 min, C18; calcd. for C12H20N4O5S [M]+ 332.1;
found 332.6. HRMS (ESI): calcd. for C12H21N4O5S [M + H]+
333.1227; found 333.1230.
2.10 (m, 1 H, 3-H), 2.02–1.84 (m, 3 H, 3-H, 4-H2), 1.46/ 1.41 [each
s, 9 H, C(CH3)3 – rotamers] ppm. 13C NMR (100 MHz, CDCl3): δ
=
201.0 [C(O)S], 168.6 (CO2All), 154.0 (CO2tBu), 131.3
(CH=CH2), 119.8 (CH=CH2), 81.0 [C(CH3)3], 67.0
(CH2CH=CH2), 66.4/ 66.2 (C-2 – rotamers), 61.6 (CHN3), 47.2/
46.9 (CH2CHN3), 31.8 (C-3), 30.2/ 29.8 (C-5), 28.6/ 28.5
Methyl (2R,2ЈS)-2-Azido-3-[3-(1-benzyl-1H-imidazol-4-yl)-2-(tert-
butoxycarbonylamino)propanoylthio]propionate (15b): Nα-Boc-Nε-
benzylhistidine (380 mg, 1.1 mmol) and trityl-thiol 14c (322 mg,
0.80 mmol) were coupled as described in GP D with EDC (211 mg,
1.1 mmol). After chromatography on silica gel (CH2Cl2/MeOH
20:1), thioester 15b was isolated as a colorless oil (287 mg,
0.59 mmol, 74%). Rf = 0.52 (CH2Cl2/MeOH 20:1). [α]2D0 = –91.2
[C(CH ) ], 24.4/ 23.6 (C-4) ppm. IR (KBr): ν = 3418 (bm), 2936
˜
3 3
(bm), 2118 (s), 1731 (s), 1714 (s), 1695 (s), 1556 (w), 1538 (w), 1504
(m), 1455 (m), 1370 (w), 1217 (m), 1176 (s), 861 (s), 800 (s), 666
(w) cm–1. LC-MS (ESI): tR = 10.3 min; calcd. for C16H24N4O5SNa
[M
+
Na]+ 407.1; found 407.1. HRMS (ESI): calcd. for
C16H25N4O5S [M + H]+ 385.1540; found 385.1541.
1
(CHCl3, c = 1.0). H NMR (400 MHz, CDCl3): δ = 7.41 (s, 1 H,
2ЈЈ-H), 7.35–7.05 (m, 5 H, Ph), 6.62 (s, 1 H, 5ЈЈ-H), 6.56 (d, J =
Methyl (2R,2ЈS)-2-Azido-3-(N-Boc-ω-cyclohexyl-α-glutamylthio)-
7.8 Hz, 1 H, NH), 5.00 (d, J = 2.0 Hz, 2 H, CH2Ph), 4.57–4.50 (m, propionate
1 H, 2Ј-H), 3.93–3.83 (m, 1 H, 2-H), 3.75 (s, 3 H, CO2CH3), 3.21 0.50 mmol) and trityl-thiol 14c (242 mg, 0.60 mmol) were coupled
(ddd, J = 5.4, 8.5, 13.9 Hz, 1 H, 3-Ha), 3.11 (dt, J = 4.8, 14.8 Hz, as described in GP D with EDC (124 mg, 0.65 mmol), HOBt
(15e):
N-Boc-ω-cyclohexylglutamine
(165 mg,
1 H, 3Ј-Ha), 3.02–2.88 (m, 2 H, 3-Hb, 3Ј-Hb), 1.43 [s, 9 H, (101 mg, 0.75 mmol), and Et3N (100 μL, 0.75 mmol). After
C(CH3)3] ppm. 13C NMR (100 MHz, CDCl3): δ = 201.6 (COS),
169.2 (CO2Me), 155.7 (CO2tBu), 137.4, 137.3 (C-2ЈЈ, C-4ЈЈ), 136.1,
chromatography on silica gel (cyclohexane/EtOAc, 4:1), thioester
15e was isolated as a colorless oil (188 mg, 0.40 mmol, 80%). Rf =
129.6, 128.5, 127.4 (Ph), 117.5 (C-5ЈЈ), 80.3 [C(CH3)3], 61.5 (C-2), 0.37 (cyclohexane/EtOAc, 2:1). [α]2D0 = –26.0 (CHCl3, c = 0.1). H
60.5 (C-2Ј), 53.0 (CO2CH3), 51.0 (CH2Ph), 30.2, 30.0 (C-3, C-3Ј), NMR (400 MHz, CDCl3): δ = 5.22 (d, J = 7.6 Hz, 1 H, NH), 4.80–
1
28.5 [C(CH ) ] ppm. IR (KBr): ν = 3338 (bw), 3066 (w), 2979 (m),
4.74 (m, 1 H, Cy), 4.36 (dd, J = 8.5, 12.6 Hz, 1 H, CHN3), 4.07
(dd, J = 5.6, 7.7 Hz, 1 H, CHNHBoc), 3.82 (s, 3 H, CO2CH3), 3.36
(ddd, J = 5.5, 10.7, 13.9 Hz, 1 H, CHHCHN3), 3.23–3.11 (m, 1
˜
3 3
2931 (m), 2118 (s), 1747 (s), 1713 (s), 1601 (w), 1497 (s), 1455 (m),
1393 (w), 1367 (m), 1249 (m), 1170 (s), 1079 (w), 1050 (w), 1025
(w), 953 (m), 913 (m), 857 (s), 817 (s), 722 (m), 648 (w) cm–1. LC- H, CHHCHN3), 2.42 (m, 2 H, CH2CO2Cy), 2.25–2.12 (m, 1 H,
MS (ESI): tR = 7.3 min; calcd. for C22H29N6O5S [M + H]+ 489.2;
found 488.9. HRMS (ESI): calcd. for C22H29N6O5S [M + H]+ (m, 2 H, Cy), 1.74–1.69 (m, 2 H, Cy), 1.61–1.53 (m, 1 H, Cy), 1.45
CHHCH2CO2Cy), 2.01–1.89 (m, 1 H, CHHCH2CO2Cy), 1.88–1.81
489.1915; found 489.1909.
[s, 9 H, C(CH ) ], 1.41–1.19 (m, 5 H, Cy) ppm. IR (KBr): ν = 3418
˜
3 3
(bw), 2979 (bm), 2118 (s), 1747 (m), 1732 (m), 1695 (s), 1682 (s),
1556 (w), 1538 (w), 1505 (m), 1455 (m), 1394 (m), 1209 (m), 1170
Methyl (2R,2ЈS)-2-Azido-3-(N-Boc-valylthio)propionate (15c): N-
Boc-valine (239 mg, 1.1 mmol) and trityl-thiol 14c (322 mg,
0.80 mmol) were coupled as described in GP D with EDC (211 mg,
1.1 mmol). After chromatography on silica gel (light petroleum/
EtOAc, 9:1), thioester 15c was isolated as a colorless oil (239 mg,
(s), 1127 (w), 856 (s), 800 (s), 666 (w) cm–1. LC-MS (ESI): tR
=
11.0 min; calcd. for C20H32N4O7S [M]+ 472.2; found 472.6.
Methyl (2S,2ЈS)-2-Azido-3-(N-Boc-prolyloxy)propionate (15f): N-
Boc-proline (244 mg, 1.1 mmol) and alcohol 14a (150 mg,
1.0 mmol) were coupled as described in GP E with DIC (208 μL,
1.3 mmol). After chromatography on silica gel (light petroleum/
EtOAc, 4:1), ester 15f was isolated as a colorless oil (296 mg,
0.64 mmol, 80%). Rf = 0.42 (light petroleum/EtOAc, 4:1). [α]2D0
=
1
–44.6 (CHCl3, c = 1.0). H NMR (400 MHz, CDCl3): δ = 4.93 (d,
J = 8.9 Hz, 1 H, NH), 4.26 (dd, J = 4.5, 9.2 Hz, 1 H, 2Ј-H), 4.04
(dd, J = 5.6, 7.6 Hz, 1 H, 2-H), 3.79 (s, 3 H, CO2CH3), 3.34 (td, J
= 5.6, 13.9 Hz, 1 H, 3-Ha), 3.18 (dd, J = 7.7, 13.9 Hz, 1 H, 3-Hb),
2.33–2.20 (m, 1 H, 3Ј-H), 1.44 [s, 9 H, C(CH3)3], 0.97 (d, J =
0.9 mmol, 84%). Rf = 0.23 (light petroleum/EtOAc, 2:1). [α]2D0
–74.2 (CHCl3, c = 1.0). 1H NMR (400 MHz, CDCl3): δ = 4.43 (2ϫ
=
6.9 Hz, 3 H, 3Ј-CH3), 0.85 (d, J = 6.8 Hz, 3 H, 3Ј-CH3) ppm. 13C dd, J = 3.8, 11.6 Hz, 1 H, CHHCHN3 – rotamers), 4.41 (dd, J =
NMR (100 MHz, CDCl3): δ = 200.5 (COS), 169.2 (CO2Me), 155.7 1.6, 4.8 Hz, 1 H, CHHCHN3), 4.24 (2ϫ dd, J = 3.8, 8.6 Hz, 1 H,
(CO2tBu), 80.7 [C(CH3)3], 65.7 (C-2Ј), 61.5 (C-2), 53.2 (CO2CH3),
2-H – rotamers), 4.08 (q, J = 5.4 Hz, 1 H, CHN3), 3.78 (s, 3 H,
31.1 (C-3Ј), 30.2 (C-3), 28.5 [C(CH3)3], 19.6, 17.0 [CH(CH3)2] ppm. CO2CH3), 3.54–3.28 (m, 2 H, 5-H2), 2.27–2.08 (m, 1 H, 3-H), 1.88
IR (KBr): ν = 3371 (bw), 2968 (m), 2934 (m), 2119 (s), 1824 (w),
(m, 3 H, 3-H, 4-H2), 1.41, 1.36 [each s, 9 H, C(CH3)3 - rota-
˜
1748 (s), 1713 (s), 1505 (m), 1455 (w), 1438 (w), 1393 (w), 1368
(m), 1307 (w), 1247 (m), 1169 (w), 1079 (w), 1040 (w) cm–1. LC-
MS (ESI): tR = 10.4 min; calcd. for C14H24N4O5S [M]+ 360.1;
mers] ppm. 13C NMR (100 MHz, CDCl3): δ = 172.7/ 172.4
(CO2CH2
– rotamers), 168.2/ 168.1 (CO2Me), 154.5/ 153.7
(CO2tBu), 80.1/ 80.0 [C(CH3)3], 64.2/ 64.1 (CH2CHN3), 60.5/ 60.4
found 360.4. HRMS (ESI): calcd. for C14H25N4O5S [M + H]+ (CHN3), 59.1/ 58.9 (C-2), 53.2 (CO2CH3), 46.7/ 46.4 (C-5), 31.0/
361.1540; found 361.1545.
30.0 (C-3), 28.5/ 28.4 [C(CH ) ], 24.5/ 23.8 (C-4) ppm. IR (KBr): ν
˜
3 3
= 3492 (w), 3370 (w), 2977 (s), 2884 (w), 2521 (w), 2359 (w), 2340
(w), 2112 (s), 1755 (s), 1698 (s), 1478 (m), 1396 (s), 1176 (s), 1088
Allyl (2R,2ЈS)-2-Azido-3-(N-Boc-prolylthio)propionate (15d): N-
Boc-proline (50 mg, 0.23 mmol) and allyl (R)-2-azido-3-(trityl-
thio)propionate (14e, 101 mg, 0.23 mmol) were coupled as de-
scribed in GP D with EDC (55 mg, 0.30 mmol), HOBt (47 mg,
0.35 mmol), and Et3N (50 μL, 0.35 mmol). After chromatography
on silica gel (light petroleum/EtOAc, 4:1), thioester 15d was iso-
lated as a colorless oil (48 mg, 0.13 mmol, 54%). Rf = 0.29 (cyclo-
hexane/EtOAc, 2:1). [α]2D0 = –70.2 (CHCl3, c = 0.5). 1H NMR
(400 MHz, CDCl3): δ = 5.92 (ddt, J = 5.9, 10.4, 16.3 Hz, 1 H,
CH=CH2), 5.36 (d, J = 17.0 Hz, 1 H, CH=CHH), 5.28 (d, J =
(m), 970 (m), 919 (m), 888 (m), 773 (m) cm–1. LC-MS (ESI): tR
=
9.7 min, C18; calcd. for C14H22N4O6 [M]+ 342.2; found 342.6.
HRMS (ESI): calcd. for C14H23N4O6 [M + H]+ 343.1612; found
344.1614.
Methyl (2S,2ЈS)-2-Azido-3-(N-Boc-alanyloxy)propionate (15g): N-
Boc-alanine (756 mg, 4.0 mmol) and alcohol 14a (145 mg,
1.0 mmol) were coupled as described in GP E with DCC (413 mg,
2.0 mmol) and DMAP (14 mg, 10 mol-%). After FCC (15 g, light
10
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© 0000 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 0000, 0–0

Job/Unit: O30160
/KAP1
Date: 10-04-13 10:52:38
Pages: 27
Unified Azoline and Azole Syntheses
petroleum/EtOAc, 5:1), ester 15g was obtained as a colorless oil
CDCl3): δ = 7.44–7.14 (m, 15 H, Tr), 4.93 (d, J = 7.5 Hz, 1 H,
(290 mg, 0.9 mmol, 92%). Rf = 0.33 (light petroleum/EtOAc, 2:1). NH), 4.43 (dt, J = 3.8, 11.5 Hz, 1 H, CHHCHN3), 4.35 (ddd, J =
1
[α]2D0 = –24.6 (CHCl3, c = 1.0). H NMR (400 MHz, CDCl3): δ =
5.1, 6.4, 11.5 Hz, 1 H, CHHCHN3), 4.23 (dd, J = 4.3, 5.9 Hz, 1 H,
4.95 (s, 1 H, NH), 4.52 (dd, J = 3.9, 11.6 Hz, 1 H, CHHCHN3), CHN3), 4.09 (ddd, J = 1.7, 4.6, 8.6 Hz, 1 H, CHNHBoc), 3.76/
4.40 (dd, J = 5.8, 11.6 Hz, 1 H, CHHCHN3), 4.34–4.28 (m, 1 H,
CHN3), 4.12 (dd, J = 4.0, 5.7 Hz, 1 H, CHCH3), 3.81 (s, 3 H,
CO2CH3), 1.42 [s, 9 H, C(CH3)3], 1.38 (d, J = 7.2 Hz, 3 H,
3.73 [2ϫ s (diastereomers 2:1), 3 H, CO2CH3], 2.64 (dd, J = 6.5,
11.6 Hz, 1 H, CHHSTr), 2.55 (ddd, J = 4.8, 11.3, 12.3 Hz, 1 H,
CHHSTr), 1.41 [s, 9 H, C(CH3)3] ppm. 13C NMR (100 MHz,
CHCH3) ppm. 13C NMR (100 MHz, CDCl3): δ = 173.0 (CO2CH2), CDCl3): δ = 170.5 (CO2Me), 168.0 (CO2CH2), 155.1 (CO2tBu),
168.2 (CO2Me), 155.0 (CO2tBu), 80.0 [C(CH3)3], 64.3 (CH2CHN3),
60.5 (CHCH3), 53.3 (CO2CH3), 49.4 (CHN3), 28.5 [C(CH3)3], 18.6
144.4, 129.7, 128.3, 127.1 (Tr), 80.4 [C(CH3)3], 64.5 (CH2CHN3),
60.5 (CHNHBoc), 53.3 (CO2CH3), 52.7 (CHN3), 34.1 (CH2STr),
(CHCH ) ppm. IR (KBr): ν = 3389 cm–1 (s), 2979 (s), 2524 (w),
28.5 [C(CH ) ] ppm. IR (KBr): ν = 3413 (w), 3059 (w), 2978 (m),
˜
˜
3
3 3
2110 (s), 1745 (s), 1712 (s), 1504 (s), 1454 (m), 1164 (m),1066 (w),
856 (w), 783 (w). LC-MS (ESI): tR = 9.4 min, C18; calcd. for
C12H20N4O6 [M]+ 316.1; found 316.5.
2930 (w), 2112 (s), 1755 (s), 1715 (s), 1504 (s), 1446 (m), 1368 (m),
1211 (m), 1172 (s), 856 (s), 800 (s), 745 (m), 701 (m), 621 (w) cm–1.
LC-MS (ESI): tR = 11.7 min, C18; calcd. for C31H34N4O6S [M]+
590.2; found 590.1. HRMS (ESI): calcd. for C31H34N4O6SNa [M
+ H]+ 613.2091; found 613.2088.
Methyl (2S,3R,2ЈS)-2-Azido-3-(N-Boc-alanyloxy)butanoate (15h):
N-Boc-alanine (196 mg, 1.0 mmol) and alcohol 14b (150 mg,
0.9 mmol) were coupled as described in GP E with DIC (190 μL,
1.2 mmol). After FCC (light petroleum/EtOAc, 4:1), ester 15h was
isolated as a colorless oil (267 mg, 0.8 mmol, 86%). Rf = 0.42 (light
Methyl (2S,2ЈS)-2-Azido-3-(N-Boc-ω-cyclohexyl-glutamyloxy)prop-
ionate (15k): N-Boc-glutamic acid ω-cyclohexyl ester (659 mg,
2 mmol) and alcohol 14a (73 mg, 0.5 mmol) were coupled as de-
scribed in GP E with DCC (208 mg, 2 mmol). After FCC (light
petroleum/EtOAc, 7:1Ǟ4:1), ester 15k was isolated as a colorless
oil (227 mg, 0.5 mmol, 99%). Rf = 0.13 (light petroleum/EtOAc,
petroleum/EtOAc, 2:1). [α]2D0 = +21.4 (CHCl3, c = 1.0). H NMR
1
(400 MHz, CDCl3): δ = 5.41 (qd, J = 3.7, 6.4 Hz, 1 H, 3-H), 4.91
(s, 1 H, NH), 4.29–4.16 (m, 1 H, CHN3), 3.78 (s, 3 H, CO2CH3),
3.74 (d, J = 3.5 Hz, 1 H, 2Ј-H), 1.42 [s, 9 H, C(CH3)3], 1.36 (d, J
= 6.5 Hz, 3 H, 4-H3), 1.34, (d, J = 7.3, 3 H, 3Ј-H3) ppm. 13C NMR
(100 MHz, CDCl3): δ = 172.2 (C-1Ј), 168.6 (CO2Me), 155.2
(CO2tBu), 80.1 [C(CH3)3], 71.5 (C-3), 64.7 (C-2Ј), 53.2 (CO2CH3),
49.7 (CHN3), 28.5 [C(CH3)3], 18.5 (C-3Ј), 17.2 (C-4) ppm. IR
5:1). [α]2D0 = –8.6 (CHCl3, c = 0.5). H NMR (400 MHz, CDCl3):
1
δ = 5.09 (d, J = 7.4 Hz, 1 H, NH), 4.81–4.67 (m, 1 H, Cy), 4.51
(dd, J = 4.1, 11.5 Hz, 1 H, CHHCHN3), 4.39 (dd, J = 5.9, 11.6 Hz,
1 H, CHHCHN3), 4.32 (dd, J = 7.1, 11.0 Hz, 1 H, CHN3), 4.15
(dd, J = 4.1, 5.8 Hz, 1 H, CHNHBoc), 3.81 (s, 3 H, CO2CH3),
2.41–2.33 (m,
2
H, CH2CO2Cy), 2.22–2.08 (m,
1
H,
(KBr): ν = 3385 (m), 2982 (s), 2939 (m), 2114 (s), 1748 (s), 1715
˜
CHHCH2CO2Cy), 2.02–1.89 (m, 1 H, CHHCH2CO2Cy), 1.86–1.77
(m, 2 H, Cy), 1.69 (m, 2 H, Cy), 1.51 (m, 1 H, Cy), 1.41 [s, 9
H, C(CH3)3], 1.37–1.19 (m, 5 H, Cy) ppm. 13C NMR (100 MHz,
CDCl3): δ = 172.3 (CO2Cy), 171.9 (CO2Me), 168.1 (CO2CH2),
155.5 (CO2tBu), 80.4 [C(CH3)3], 73.3 (Cy), 64.3 (CH2CHN3), 60.5
(CHNHBoc), 53.4 (CO2CH3), 53.2 (CHN3), 31.8 (Cy), 30.9
(CH2CO2Cy), 28.5 [C(CH3)3], 27.5 (CH2CH2CO2Cy), 25.6, 24.0
(s), 1505 (m), 1455 (m), 1382 (m), 1248 (m), 1210 (m), 1168 (s),
1067 (w), 892 (m), 857 (m), 798 (m) cm–1. LC-MS (ESI): tR
=
9.6 min, C18; calcd. for C13H22N4O6 [M]+ 330.2; found 330.4.
HRMS (ESI): calcd. for C13H23N4O6 [M + H]+ 331.1612; found
331.1614.
Methyl
(2S,2ЈS)-2-Azido-3-(N-Boc-phenylalanyloxy)propionate
(15i): N-Boc-phenylalanine (265 mg, 1.0 mmol) and alcohol 14a
(73 mg, 0.5 mmol) were coupled as described in GP E with DCC
(108 mg, 0.5 mmol). After chromatography on silica gel (light pe-
troleum/EtOAc, 4:1), ester 15i was isolated as a colorless oil
(173 mg, 0.4 mmol, 88%). Rf = 0.37 (light petroleum/EtOAc, 2:1).
[α]2D0 = +1.3 (CHCl3, c = 1.0). 1H NMR (400 MHz, CDCl3): δ =
7.41–7.04 (m, 5 H, Ph), 4.90 (d, J = 7.6 Hz, 1 H, NH), 4.58 (dd, J
= 5.8, 12.5 Hz, 1 H, CHN3), 4.44 (dd, J = 4.0, 11.6 Hz, 1 H,
CHHCHN3), 4.36 (dd, J = 6.1, 11.6 Hz, 1 H, CHHCHN3), 4.05
(dd, J = 4.0, 6.0 Hz, 1 H, CHBn), 3.81 (s, 3 H, CO2CH3), 3.10 (dd,
J = 5.9, 13.8 Hz, 1 H CHHPh), 3.03 (dd, J = 6.4, 14.1 Hz, 1 H,
CHHPh), 1.39 [s, 9 H, C(CH3)3] ppm. 13C NMR (100 MHz,
CDCl3): δ = 171.6 (CO2CH2), 168.1 (CO2Me), 155.2 (CO2tBu),
135.9, 129.5, 128.9, 127.4 (Ph), 80.3 [C(CH3)3], 64.4 (CH2CHN3),
60.5 (CHBn), 54.6 (CHN3), 53.4 (CO2CH3), 38.4 (CH2Ph), 28.5
(Cy) ppm. IR (KBr): ν = 3364 (w), 2938 (m), 2862 (w), 2110 (m),
˜
1730 (s), 1539 (m), 1506 (m), 1455 (m), 1393 (m), 1207 (m), 1175
(s), 1057 (w), 860 (s), 799 (s) cm–1. LC-MS (ESI): tR = 10.9 min,
C18; calcd. for C20H32N4O8 [M]+ 456.2; found 456.6. HRMS (ESI):
calcd. for C20H33N4O8 [M + H]+ 457.2293; found 457.2289.
Methyl (2S,2ЈS)-2-Azido-3-(O-Benzyl-N-Boc-tyrosyloxy)propionate
(15l): O-Benzyl-N-Boc-tyrosine (422 mg, 1.1 mmol) and alcohol
14a (150 mg, 1.0 mmol) were coupled as described in GP E with
DIC (208 μL, 1.3 mmol) and DMAP (13 mg, 10 mol-%). After
FCC (light petroleum/EtOAc, 4:1), ester 15l was isolated as a color-
less oil (435 mg, 0.9 mmol, 84%). Rf = 0.35 (light petroleum/
EtOAc, 2:1). [α]2D0 = –6.3 (CHCl3, c = 1.0). 1H NMR (400 MHz,
CDCl3): δ = 7.43–7.26 (m, 5 H, Ph), 7.08–6.99 (m, 2 H, Tyr-Ar),
6.92–6.85 (m, 2 H, Tyr-Ar), 5.02 (s, 2 H, CH2Ph), 4.88 (d, J =
6.2 Hz, 1 H, NH), 4.54 (dd, J = 5.9, 12.7 Hz, 1 H, CHN3), 4.45
(ddd, J = 4.1, 5.2, 11.6 Hz, 1 H, CHHCHN3), 4.37 (ddd, J = 2.1,
6.3, 11.6 Hz, 1 H, CHHCHN3), 4.15–4.01 (m, 1 H, CHNHBoc),
3.81 (s, 3 H, CO2CH3), 3.10–2.89 (m, 2 H, Tyr-CH2), 1.40 [s, 9 H,
[C(CH ) ] ppm. IR (KBr): ν = 3385 (m), 2979 (m), 2111 (s), 1749
˜
3 3
(s), 1715 (s), 1504 (m), 1455 (m), 1368 (m), 1247 (m), 1210 (m),
1171 (s), 1059 (w), 957 (m), 858 (s), 798 (s), 701 (m) cm–1. LC-MS
(ESI): tR = 10.3 min, C18; calcd. for C18H24N4O6 [M]+ 392.2;
found 392.5. HRMS (ESI): calcd. for C18H25N4O6 [M + H]+
393.1769; found 393.1768.
C(CH3)3] ppm. 13C NMR (100 MHz, CDCl3):
δ = 171.6
(CO2CH2), 168.1 (CO2Me), 158.2 (CO2tBu), 137.2, 130.5, 130.5,
128.8, 128.2, 127.7, 115.3 (Ph, Tyr-Ar), 80.3 [C(CH3)3], 70.3
Methyl (2S,2ЈR)- and (2S,2ЈS)-2-Azido-3-(N-Boc-S-trityl-cystein- (OCH2Ph), 64.3 (CH2CHN3), 60.5 (CHNHBoc), 54.7 (CHN3),
yloxy)propionate (15j): S-Trityl-N-Boc-(R)-cysteine (510 mg,
1.1 mmol) and alcohol 14a (73 mg, 0.5 mmol) were coupled as de-
scribed in GP E with DCC (108 mg, 0.6 mmol). After FCC (light
petroleum/EtOAc, 4:1), ester 15j was isolated as a colorless oil
(258 mg, 0.4 mmol, 87%, dr = 3:2). Rf = 0.19 (light petroleum/
EtOAc, 4:1). [α]2D0 = –6.5 (CHCl3, c = 1.0). 1H NMR (400 MHz,
53.4 (CO CH ), 37.5 (Tyr-CH ), 28.5 [C(CH ) ] ppm. IR (KBr): ν
˜
2 3 2 3 3
= 3390 (m), 3033 (m), 2977 (s), 2528 (w), 2112 (s), 1747 (s), 1714
(s), 1611 (m), 1511 (s), 1454 (m), 1367 (s), 1243 (s), 1173 (s), 1021
(m), 823 (m), 739 (m) cm–1. LC-MS (ESI): tR = 11.0 min, C18;
calcd. for C25H30N4O7 [M]+ 498.2; found 497.8. HRMS (ESI):
calcd. for C25H30N4O7Na [M + Na]+ 521.2007; found 521.1998.
Eur. J. Org. Chem. 0000, 0–0
© 0000 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
11

Job/Unit: O30160
/KAP1
Date: 10-04-13 10:52:38
Pages: 27
P. Loos, C. Ronco, M. Riedrich, H.-D. Arndt
FULL PAPER
Methyl (2S,2ЈS,3ЈS)-2-Azido-3-(O-benzyl-N-Boc-threonyloxy)prop- Methyl
(4R,1ЈS)-2-[1-(tert-Butoxycarbonylamino)ethyl]-4,5-dihy-
ionate (15m): O-Benzyl-N-Boc-threonine (2.69 g, 8.8 mmol) and
alcohol 14a (584 mg, 4.0 mmol) were coupled as described in GP E
with DCC (914 mg, 4.4 mmol) and DMAP (54 mg, 10 mol-%). Af-
ter FCC (light petroleum/EtOAc, 4:1), ester 15m was isolated as a
colorless oil (1.73 g, 4.0 mmol, 98%). Rf = 0.45 (light petroleum/
drothiazole-4-carboxylate (16a): Thioester 15a (55 mg, 0.17 mmol)
was cyclized as described in GP F. After FCC (cyclohexane/EtOAc,
2:1), ester 16a was isolated as a colorless resin (47 mg, 0.16 mmol,
98%). Rf = 0.25 (cyclohexane/EtOAc, 1:1). [α]2D0 = +31.4 (CHCl3,
1
c = 0.5). H NMR (400 MHz, CDCl3): δ = 5.25 (br. s, 1 H, NH),
1
EtOAc, 2:1). [α]2D0 = –18.6 (CHCl3, c = 1.0). H NMR (400 MHz,
5.05 (td, J = 1.6, 9.3 Hz, 1 H, CHCH3), 4.60–4.47 (m, 1 H, 4-H),
3.76 (s, 3 H, CO2CH3), 3.61–3.41 (m, 2 H, 5-H2), 1.39 [s, 9 H,
C(CH3)3], 1.38 (d, J = 4.1 Hz, 3 H, CHCH3) ppm. 13C NMR
CDCl3): δ = 7.38–7.21 (m, 5 H Ph), 5.26 (d, J = 9.7 Hz, 1 H, NH),
4.55 (d, J = 11.8 Hz, 1 H, CHHPh), 4.42–4.24 (m, 4 H, CHHPh,
CHNHBoc, CH2CHN3), 4.17–4.04 (m, 1 H, CHOBn), 3.98 (dd, J (100 MHz, CDCl3): δ = 177.4 (CO2Me), 171.2 (C=N), 155.0
= 5.0 Hz, 1 H, CHN3), 3.78 (s, 3 H, CO2CH3), 1.43 [s, 9 H, C(CH3) (CO2tBu), 79.9 [C(CH3)3], 78.1 (C-4), 52.9 (CO2CH3), 49.4
3], 1.25 (d, J = 6.3 Hz, 3 H, CHCH3) ppm. 13C NMR (100 MHz,
(CHCH3), 35.6 (C-5), 28.5 [C(CH3)3], 20.7 (CHCH3) ppm. IR
CDCl3):
δ
=
170.8 (CO2CH2CHN3), 168.0 (CO2Me), 156.3
(KBr): ν = 3345 (bw), 2979 (m), 2933 (w), 1799 (w), 1745 (s), 1714
˜
(CO2tBu), 138.1, 128.6, 128.0, 127.9 (Ph), 80.2 [C(CH3)3], 74.5
(s), 1622 (m), 1505 (m), 1454 (m), 1393 (w), 1367 (m), 1244 (m),
(CHOBn), 71.0 (CH2Ph), 64.4 (CH2CHN3), 60.5 (CHN3), 58.5 1203 (m), 1172 (s), 1088 (w), 862 (s), 798 (s) cm–1. LC-MS (ESI):
(CHNHBoc),
53.3
(CO2CH3),
28.5
[C(CH3)3],
16.4 tR = 8.5 min; calcd. for C12H21N2O4S [M + H]+ 289.1; found 288.8.
[CH(CH )] ppm. IR (KBr): ν = 3444 (w), 2979 (m), 2933 (m), 2111 HRMS (ESI): calcd. for C12H21N2O4S [M + H]+ 289.1217; found
˜
3
(s), 1756 (s), 1715 (s), 1505 (s), 1279 (m), 1210 (m), 1165 (s), 1073
289.1218.
(w), 861 (s), 798 (s), 747 (m), 699 (m) cm–1. HPLC: tR = 11.2 min
Methyl (4R,1ЈS)-2-[2-(1-Benzyl-1H-imidazol-4-yl)-1-(tert-butoxy-
carbonylamino)ethyl]-4,5-dihydrothiazole-4-carboxylate (16b): Thio-
ester 15b (264 mg, 0.54 mmol) was cyclized as described in GP F.
After FCC (CH2Cl2/MeOH 20:1), thiazoline 16b was isolated as a
colorless resin (228 mg, 0.51 mmol, 95%, dr = 3.5:1). Rf = 0.40
(CH2Cl2/MeOH 10:1). [α]2D0 = –1.7 (CHCl3, c = 1.0). 1H NMR
(400 MHz, CDCl3): δ = 7.44 (s, 1 H, 2ЈЈ-H), 7.35–7.27 (m, 3 H,
Ph), 7.16–7.06 (m, 2 H, Ph), 6.71/ 6.65 [2ϫ s (1:3.5), 1 H, 5ЈЈ-H,
diastereomers], 6.35/ 6.29 [2ϫ d (1:3.5), J = 7.9 Hz, 1 H, NH], 5.05
(d, J = 15.3 Hz, 1 H, CHHPh), 5.01 (d, J = 15.3 Hz, 1 H, CHHPh),
4.95 (t, J = 9.3 Hz, 1 H, 4-H), 4.80 (br. s, 1 H, 1Ј-H), 3.76/ 3.70
[2ϫ s (3.5:1), 3 H, CO2CH3], 3.49–3.21 (m, 2 H, 5-H2), 3.15–2.94
(m, 2 H, 2Ј-H2), 1.41 [s, 9 H, C(CH3)3] ppm. 13C NMR (100 MHz,
CDCl3): δ = 179.4/ 178.6 (C-2), 171.3 (CO2Me), 155.5 (CO2tBu),
138.2/ 137.9 (C-4ЈЈ), 137.2/ 137.1 (C-2ЈЈ), 136.4/ 129.1/ 128.4/ 127.4
(Ph), 117.9/ 117.6 (C-5ЈЈ), 79.7 [C(CH3)3], 78.8/ 78.6 (C-4), 53.5 (C-
1Ј), 52.8 (CO2CH3), 51.0 (CH2Ph), 35.0/ 34.8 (C-5), 32.3 (C-2Ј),
(method 1). LC-MS (ESI): tR
= 10.6 min, C18; calcd. for
C20H29N4O7 [M + H]+ 437.2; found 436.7. HRMS (ESI): calcd. for
C20H29N4O7 [M + H]+ 437.2031; found 436.2030.
Methyl (2S,2ЈS)-2-Azido-3-(N-Boc-valyloxy)propionate (15n): N-
Boc-valine (435 mg, 2.0 mmol) and alcohol 14a (144 mg, 1.0 mmol)
were coupled as described in GP E with DIC (343 μL, 2.2 mmol)
and DMAP (24 mg, 10 mol-%). After FCC (light petroleum/
EtOAc, 4:1), ester 15n was isolated as a colorless oil (324 mg,
0.9 mmol, 95%). Rf = 0.20 (light petroleum/EtOAc, 4:1). [α]2D0
=
–17.1 (CHCl3, c = 1.0). 1H NMR (400 MHz, [D5]pyridine): δ =
7.21 (d, J = 8.4 Hz, 1 H, NH), 3.83–3.80 (m, 2 H, CHN3,
CHHCHN3), 3.74 (dd, J = 6.2, 12.2 Hz, 1 H, CHHCHN3), 3.65
(dd, J = 5.9, 8.6 Hz, 1 H, CHNHBoc), 2.76 (s, 3 H, CO2CH3), 1.40
[m, 1 H, CH(CH3)2], 0.54 [s, 9 H, C(CH3)3], 0.14/ 0.12 [2ϫ d, J =
6.8 Hz, 2ϫ3 H, CH(CH3)2] ppm. 13C NMR (100 MHz, [D5]pyr-
idine):
δ = 173.0 (CO2CH2CHN3), 169.1 (CO2CH3), 157.3
28.5 [C(CH ) ] ppm. IR (KBr): ν = 2979 (w), 2930 (w), 2360 (s),
˜
3 3
(CO2tBu), 79.3 [C(CH3)3], 64.7 (CH2), 61.6 (CHN3), 60.6 (CHiPr),
53.3 (CO2CH3), 31.6 [CH(CH3)2], 28.9 [C(CH3)3], 19.8, 18.8 [2ϫ
2341 (s), 1714 (s), 1616 (w), 1557 (w), 1539 (w), 1497 (s), 1455 (m),
1436 (m), 1393 (w), 1367 (m), 1277 (w), 1234 (m), 1202 (m), 1171
(s), 1046 (w), 1026 (w), 859 (s), 799 (s), 721 (m), 697 (w), 669
(w) cm–1. LC-MS (ESI): tR = 6.8 min; calcd. for C22H29N4O4S [M
+ H]+ 445.2; found 444.9. HRMS (ESI): calcd. for C22H29N4O4S
[M + H]+ 445.1904; found 445.1901.
CH(CH ) ] ppm. IR (KBr): ν = 3389 (m), 2969 (s), 2112 (s), 1748
˜
3 2
(s), 1714 (s), 1504 (m), 1454 (m), 1367 (w), 1177 (m), 1018 (w), 871
(w), 553 (w) cm–1. LC-MS (ESI): tR = 10.1 min, C18; calcd. for
C14H24N4O6 [M]+ 344.2; found 344.6. HRMS (FAB): calcd. for
C14H24N4O6 [M + H]+ 344.1774; found 344.1802.
Methyl (4R,1ЈS)-2-[1-(tert-Butoxycarbonylamino)-2-methylpropyl]-
4,5-dihydrothiazole-4-carboxylate (16c): Thioester 15c (210 mg,
0.58 mmol) was cyclized as described in GP F. After FCC (light
petroleum/EtOAc, 4:1), thiazoline 16c was isolated as a colorless
resin (167 mg, 0.53 mmol, 91%). Rf = 0.27 (light petroleum/EtOAc,
Methyl (2S)-2-Azido-3-(N-Boc-glycyloxy)propionate (15o): N-Boc-
glycine (350 mg, 2.0 mmol) and alcohol 14a (147 mg, 1.0 mmol)
were coupled as described in GP E with DIC (340 μL, 2.2 mmol)
and DMAP (24 mg, 20 mol-%). After FCC (light petroleum/
EtOAc, 4:1), ester 15o was isolated as a colorless oil (286 mg,
2:1). [α]2D0 = +42.6 (CHCl3, c = 0.5). H NMR (400 MHz, CDCl3):
1
0.9 mmol, 93%). Rf = 0.28 (light petroleum/EtOAc, 2:1). [α]2D0
=
δ = 5.20 (d, J = 8.3 Hz, 1 H, NH), 5.13 (ddd, J = 1.5, 8.1, 9.5 Hz,
1 H, 4-H), 4.51–4.44 (m, 1 H, 1Ј-H), 3.79 (s, 3 H, CO2Me), 3.62–
3.47 (m, 2 H, 5-H2), 2.18 (m, 1 H, 2Ј-H), 1.44 [s, 9 H, C(CH3)3],
0.99 (d, J = 6.8 Hz, 3 H, 2Ј-CH3), 0.89 (d, J = 6.8 Hz, 3 H, 2Ј-
CH3) ppm. 13C NMR (100 MHz, CDCl3): δ = 176.2 (C-2), 171.3
(CO2Me), 155.7 (CO2tBu), 79.9 [C(CH3)3], 77.9 (C-4), 58.2 (C-1Ј),
52.9 (CO2CH3), 35.8 (C-5), 32.7 (C-2Ј), 28.5 [C(CH3)3], 19.6, 16.8
1
–14.4 (CHCl3, c = 1.0). H NMR (400 MHz, CDCl3): δ = 5.01 (s,
1 H, NH), 4.49 (dd, J = 4.0, 11.6 Hz, 1 H, CHHCHN3), 4.41 (dd,
J = 6.0, 11.6 Hz, 1 H, CHHCHN3), 4.12 (dd, J = 4.1, 5.9 Hz, 1 H,
CHN3), 3.91 (d, J = 5.6 Hz, 2 H, CH2NHBoc), 3.79 (s, 3 H,
CO2CH3), 1.41 [s, 9 H, C(CH3)3] ppm. 13C NMR (100 MHz,
CDCl3): δ = 170.0 (CO2CH2), 168.1 (CO2Me), 155.8 (CO2tBu),
80.4 [C(CH3)3], 64.3 (CH2CHN3), 60.4 (CH2NHBoc), 53.1
[CH(CH ) ] ppm. IR (KBr): ν = 3384 (bw), 2967 (m), 1715 (s),
˜
3 2
1620 (m), 1497 (s), 1455 (w), 1392 (w), 1367 (m), 1307 (w), 1234
(m), 1171 (s), 1040 (w), 1012 (w), 929 (s), 875 (s), 798 (s), 665
(w) cm–1. LC-MS (ESI): tR = 9.5 min; calcd. for C14H24N2O4S [M
+ H]+ 317.2; found 316.8. HRMS (ESI): calcd. for C14H24N2O4S
[M + H]+ 317.1530; found 317.1531.
(CO CH ), 42.4 (CHN ), 28.4 [C(CH ) ] ppm. IR (KBr): ν = 3401
(s), 2978 (s), 2112 (s), 1747 (s), 1714 (s), 1504 (m), 1454 (m),
1392 (m), 1368 (m), 1162 (s), 1056 (m), 949 (m), 863 (m), 784
˜
2
3
3
3 3
(m) cm–1. HPLC: tR = 7.8 min (method 4). LC-MS (ESI): tR
=
9.1 min, C18; calcd. for C11H18N4O6 [M]+ 302.1; found 302.4.
HRMS (ESI): calcd. for C11H19N4O6 [M + H]+ 303.1299; found
303.1301.
Allyl (4R,1ЈS)-2-[1-(tert-Butoxycarbonyl)pyrrolidin-2-yl]-4,5-dihy-
drothiazole-4-carboxylate (16d): Thioester 15d (40 mg, 0.10 mmol)
12
www.eurjoc.org
© 0000 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 0000, 0–0

Job/Unit: O30160
/KAP1
Date: 10-04-13 10:52:38
Pages: 27
Unified Azoline and Azole Syntheses
was cyclized as described in GP F. After FCC (light petroleum/
EtOAc, 2:1), thiazoline 16d was isolated as a colorless foam (33 mg,
(CO2Me), 170.4 (C=N), 155.1 (CO2tBu), 80.0, 79.9 [OCHCH3,
C(CH3)3], 74.5 (CHCO2Me), 52.8 (CO2CH3), 45.1 (CHNHBoc),
28.6 [C(CH3)3], 21.0 (OCHCH3), 19.9 (BocHNCHCH3) ppm. IR
0.10 mmol, 97%). Rf = 0.29 (cyclohexane/EtOAc, 1:1). [α]2D0 = –89.0
1
(CHCl3, c = 0.5). H NMR (400 MHz, CDCl3): δ = 5.92 (ddt, J = (KBr): ν = 3384 (mb), 2981 (m), 2932 (m), 1746 (s), 1715 (s), 1661
˜
5.9, 10.4, 17.1 Hz, 1 H, CH=CH2), 5.33 (dq, J = 1.5, 17.2 Hz, 1 H,
CH=CHH), 5.24 (dd, J = 1.0, 10.4 Hz, 1 H, CH=CHH), 5.10 (t, J
(m), 1505 (m), 1455 (m), 1367 (m), 1244 (m), 1208 (m), 1174 (s),
1055 (w), 1026 (w), 954 (m), 867 (s), 798 (s) cm–1. HRMS (ESI):
= 9.0 Hz, 1 H, 4Ј-H), 4.73–4.61 (m, 3 H, CH2CH=CH2, 2-H), 3.62– calcd. for C13H23N2O5 [M + H]+ 287.1602; found 287.1602.
3.52 (m, 1 H, 5Ј-H), 3.47 (dd, J = 8.6, 12.5 Hz, 3 H, 5Ј-H, 5-H2),
Methyl
(4S,1ЈS)-2-[1-(tert-Butoxycarbonylamino)-2-phenylethyl]-
2.29–1.69 (m, 4 H, 3-,4-H2), 1.44/ 1.40 [each s, 9 H, C(CH3)3
–
4,5-dihydrooxazole-4-carboxylate (16i): Ester 15i (127 mg,
0.32 mmol) was cyclized as described in GP F. After FCC (light
petroleum/EtOAc, 5:2), oxazoline 16i was isolated as a colorless
solid (87 mg, 0.25 mmol, 78%). Rf = 0.28 (light petroleum/EtOAc,
1:1), m.p. 73–74 °C. [α]2D0 = +75.7 (CHCl3, c = 1.0). 1H NMR
(400 MHz, CDCl3): δ = 7.26–7.05 (m, 5 H, Ph), 5.14 (d, J = 8.0 Hz,
1 H, NH), 4.66 (m, J = 9.8 Hz, 2 H, CHCO2Me, CHBn), 4.53 (dd,
J = 8.3, 8.2 Hz, 1 H, OCHH), 4.39 (dd, J = 8.7, 10.5 Hz, 1 H,
OCHH), 3.69 (s, 3 H, CO2CH3), 3.09 (dd, J = 5.7, 13.6 Hz, 1 H,
CHHPh), 2.99 (dd, J = 5.4, 13.6 Hz, 1 H, CHHPh), 1.36 [s, 9 H,
C(CH3)3] ppm. 13C NMR (100 MHz, CDCl3): δ = 171.0 (CO2Me),
169.4 (C=N), 155.0 (CO2tBu), 135.9, 129.5, 128.4, 126.9 (Ph), 79.8
[C(CH3)3], 70.1 (OCH2), 67.9 (CHCO2Me), 52.7 (CO2CH3), 49.7
rotamers] ppm. IR (KBr): ν = 3094 (w), 2977 (m), 2930 (m), 2882
˜
(m), 1732 (m), 1697 (s), 1645 (w), 1556 (w), 1505 (m), 1496 (m),
1486 (m), 1455 (m), 1385 (s), 1270 (w), 1228 (m), 1202 (s), 1173
(m), 1110 (m), 919 (s), 871 (s), 797 (s) cm–1. LC-MS (ESI): tR
=
9.3 min; calcd. for C16H24N2O4S [M]+ 340.4; found 340.9.
Methyl (4R,1ЈS)-2-[1-(tert-Butoxycarbonylamino)-3-(cyclohexyloxy-
carbonyl)propyl]-4,5-dihydrothiazole-4-carboxylate (16e): Thioester
15e (178 mg, 0.38 mmol) was cyclized as described in GP F. After
FCC (cyclohexane/EtOAc, 4:1), ester 16e was isolated as a colorless
resin (148 mg, 0.35 mmol, 92%). Rf = 0.48 (cyclohexane/EtOAc,
1:1). [α]2D0 = +0.7 (CHCl3, c = 1.0). H NMR (400 MHz, CDCl3):
1
δ = 7.17 (br. s, 1 H, NH), 4.85–4.79 (m, 1 H, 1Ј-H), 4.74 (dt, J =
4.3, 8.7 Hz, 1 H, Cy), 4.18 (br. s, 1 H, 4-H), 3.76 (s, 3 H, CO2CH3),
(CHBn), 38.9 (CH Ph), 28.4 [C(CH ) ] ppm. IR (KBr): ν = 3382
˜
2 3 3
3.22–2.87 (m, 2 H, 2Ј-H2), 2.50–2.34 (m, 2 H, 3Ј-H2), 2.16–2.08 (m, (mb), 3030 (w), 2977 (m), 2932 (w), 1746 (s), 1714 (s), 1667 (m),
1 H, 5-Ha), 2.01–1.88 (m, 1 H, 5-Hb), 1.84–1.81 (m, 2 H, Cy), 1.70–
1.69 (m, 2 H, Cy), 1.50–1.49 (m, 1 H, Cy), 1.42 [s, 9 H, C(CH3)3],
1505 (s), 1392 (m), 1367 (m), 1337 (w), 1211 (m), 1174 (s), 960 (s),
916 (s), 862 (s), 798 (s), 701 (m) cm–1. HRMS (ESI): calcd. for
1.37–1.18 (m, 5 H, Cy) ppm. 13C NMR (100 MHz, CDCl3): δ = C18H25N2O5 [M + H]+ 349.1758; found 349.1759.
172.9 (CO2Cy), 171.8 (C=N), 170.4 (CO2Me), 155.8 (CO2tBu), 80.4
Methyl
(4S,1ЈR)-2-[1-(tert-Butoxycarbonylamino)-2-(tritylthio)-
[C(CH3)3], 73.4 (Cy), 54.0 (C-4), 53.8 (C-1Ј), 52.9 (CO2CH3), 31.8
(Cy), 31.1 (C-3Ј), 28.5 [C(CH3)3], 27.6 (C-5), 26.8 (C-2Ј), 25.5, 23.9
ethyl]-4,5-dihydrooxazole-4-carboxylate (16j): Ester 15j (123 mg,
0.21 mmol) was cyclized as described in GP F. After FCC (light
petroleum/EtOAc, 2:1), 16j was isolated as a colorless oil (110 mg,
0.20 mmol, 97%, dr = 3:2). Rf = 0.15 (light petroleum/EtOAc, 1:1).
(Cy) ppm. IR (KBr): ν = 3361 (bm), 2937 (s), 2859 (m), 1731 (s),
˜
1715 (s), 1615 (w), 1538 (w), 1505 (w), 1454 (m), 1392 (w), 1367
(m), 1176 (m), 1021 (w), 866 (s), 799 (s), 666 (w) cm–1. LC-MS
(ESI): tR = 10.5 min; calcd. for C20H33N2O6S [M + H]+ 429.2;
found 428.8. HRMS (ESI): calcd. for C20H33N2O6S [M + H]+
429.2054; found 429.2051.
[α]2D0 = +13.4 (CHCl3, c = 0.5). H NMR (400 MHz, CDCl3): δ =
1
7.47–7.13 (m, 15 H, Tr), 5.12 (d, J = 6.8 Hz, 1 H, NH), 4.76–4.68
(m, 1 H, CHCO2Me), 4.55–4.48 (m, 1 H, OCHH), 4.40 (m, 2 H,
CH, CHNHBoc), 3.74/ 3.73 (2ϫ s, diastereomers 84:16, 3 H,
CO2CH3), 2.66–2.48 (m, 2 H, CH2STr), 1.41/ 1.40 (2ϫ s, 9 H) ppm.
Methyl
(S)-2-[(S)-1-(tert-Butoxycarbonylamino)ethyl]-4,5-dihy-
drooxazole-4-carboxylate (16g): Ester 15g (100 mg, 0.32 mmol) was 13C NMR (100 MHz, CDCl3): δ = 171.2 (CO2Me), 168.9 (C=N),
cyclized as described in GP F. After FCC (cyclohexane/EtOAc,
154.3 (CO2tBu), 144.7, 129.8, 128.2, 127.0 (Tr), 80.2 [C(CH3)3],
70.4 (OCH2), 68.2 (CHCO2Me), 52.9 (CO2CH3), 48.2
(CHNHBoc), 35.2 (CH STr), 28.5 [C(CH ) ] ppm. IR (KBr): ν =
˜
2 3 3
2:1), oxazoline 16g was isolated as
a colorless oil (72 mg,
0.27 mmol, 84%). Rf = 0.14 (cyclohexane/EtOAc, 1:1). [α]2D0
=
1
+46.6 (CHCl3, c = 1.0). H NMR (400 MHz, CDCl3): δ = 5.23 (d,
3405 (wb), 3059 (w), 2977 (w), 2926 (m), 2854 (w), 1747 (s), 1715
J = 3.2 Hz, 1 H, NH), 4.69 (dd, J = 8.6, 9.9 Hz, 1 H, CHCO2Me), (s), 1696 (s), 1505 (m), 1446 (m), 1393 (w), 1368 (w), 1218 (m),
4.45 (m, 3 H, OCH2, CHCH3), 3.73 (s, 3 H, CO2CH3), 1.37 [s, 9 1169 (s), 857 (s), 799 (s), 753 (s), 702 (m) cm–1. LC-MS (ESI): tR
H, C(CH3)3], 1.34 (d, J = 7.0 Hz, 3 H, CHCH3) ppm. 13C NMR 11.5 min, C18; calcd. for C31H34N2O5S [M]+ 546.2; found 546.2.
(100 MHz, CDCl3): δ = 171.4 (CO2Me), 171.2 (C=N), 155.0
HRMS (ESI): calcd. for C31H35N2O5S [M + H]+ 547.2261; found
=
(CO2tBu), 79.8 [C(CH3)3], 70.3 (OCH2), 67.9 (CHCO2Me), 52.8 547.2258.
(CO2CH3), 44.8 (CHCH3), 28.5 [C(CH3)3], 19.7 (CHCH3) ppm. IR
Methyl (4S,1ЈS)-2-{2-[4-(Benzyloxy)phenyl]-1-(tert-butoxycarbonyl-
(KBr): ν = 3381 (mb), 2979 (m), 2929 (m), 1746 (s), 1715 (s), 1667
˜
amino)ethyl}-4,5-dihydrooxazole-4-carboxylate (16l): Ester 15l
(50 mg, 0.10 mmol) was cyclized at 80 °C as described in GP F with
2,6-lutidine as solvent. After FCC (light petroleum/EtOAc, 2:1),
oxazoline 16l was isolated as a colorless oil (28 mg, 0.06 mmol,
62%). Rf = 0.17 (light petroleum/EtOAc, 1:1). [α]2D0 = +54.6
(m), 1505 (m), 1454 (m), 1367 (m), 1245 (m), 1211 (s), 1172 (s),
1057 (w), 958 (s), 862 (s), 798 (s) cm–1. HRMS (ESI): calcd. for
C12H21N2O5 [M + H]+ 273.1445; found 273.1446.
Methyl
(4S,5R,1ЈS)-2-[1-(tert-Butoxycarbonylamino)ethyl]-5-
1
methyl-4,5-dihydrooxazole-4-carboxylate (16h): Ester 15h (108 mg,
0.33 mmol) was cyclized as described in GP F. After FCC (light
petroleum/EtOAc, 2:1), oxazoline 16h was isolated as a colorless
oil (72 mg, 0.25 mmol, 78%). Rf = 0.17 (light petroleum/EtOAc,
(CHCl3, c = 1.0). H NMR (400 MHz, CDCl3): δ = 7.44–7.25 (m,
5 H, Ph), 7.07–6.95 (m, 2 H, ArTyr), 6.90–6.81 (m, 2 H, ArTyr), 5.12
(d, J = 8.1 Hz, 1 H, NH), 5.01 (s, 2 H, OCH2Ph), 4.69 (m, 2 H,
CHCO2Me, CHNHBoc), 4.56 (dd, J = 8.1, 8.4 Hz, 1 H, oxazoline-
CHH), 4.42 (dd, J = 8.7, 10.4 Hz, 1 H, oxazoline-CHH), 3.76/ 3.73
(2ϫ s, 3 H, CO2CH3), 3.06 (dd, J = 5.6, 13.7 Hz, 1 H,
CHHNHBoc), 2.97 (dd, J = 5.0, 13.4 Hz, 1 H, CHHNHBoc), 1.39
[s, 9 H, C(CH3)3] ppm. 13C NMR (100 MHz, CDCl3): δ = 171.1
H, (CO2Me), 169.6 (C=N), 158.0 (COBn), 155.1 (CO2tBu), 137.3 (Ph),
131.1 (ArTyr), 130.8, (Ph), 129.0 (ArTyr), 128.8, 127.6 (Ph), 114.9
1
1:1). [α]2D0 = +73.8 (CHCl3, c = 1.0). H NMR (400 MHz, CDCl3):
δ = 5.25 (br. s, 1 H, NH), 4.83 (dq, J = 6.3, 12.7 Hz, 1 H,
OCHCH3), 4.46–4.35 (m, 1 H, BocHNCHCH3), 4.24 (dd, J = 1.5,
7.4 Hz, 1 H, CHCO2Me), 3.76 (s, 3 H, CO2CH3), 1.42 [m, 12 H,
OCHCH3, C(CH3)3], 1.38 (d,
J
=
7.0 Hz,
3
BocHNCHCH3) ppm. 13C NMR (100 MHz, CDCl3): δ = 171.4
Eur. J. Org. Chem. 0000, 0–0
© 0000 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
13

Job/Unit: O30160
/KAP1
Date: 10-04-13 10:52:38
Pages: 27
P. Loos, C. Ronco, M. Riedrich, H.-D. Arndt
FULL PAPER
(ArTyr), 79.9 [C(CH3)3], 70.2 (CH2Ph, oxazoline-CH2), 68.0
[C(CH3)3], 52.6 (CO2CH3), 49.1 (CHCH3), 28.5 [C(CH3)3], 21.9
(CHCO2Me), 52.8 (CO2CH3), 50.0 (CHNHBoc), 38.2 (CHCH ) ppm. IR (KBr): ν = 3354 (bm), 3114 (w), 2980 (m), 2933
˜
3
CH CHNHBoc, 28.5 [C(CH ) ] ppm. IR (KBr): ν = 3392 (mb),
(w), 1715 (s), 1567 (w), 1505 (s), 1455 (m), 1393 (w), 1368 (m), 1338
(w), 1294 (w), 1243 (s), 1217 (s), 1171 (s), 1097 (w), 1059 (w), 989
˜
2
3 3
3032 (w), 2976 (m), 2928 (m), 2857 (w), 1745 (s), 1715 (s), 1661
(m), 1505 (s), 1455 (m), 1367 (m), 1242 (m), 1176 (s), 960 (m), 911 (w), 910 (s), 857 (s), 783 (s), 667 (w), 612 (w) cm–1. HPLC: tR
=
(m), 861 (s), 812 (s), 743 (m), 697 (w) cm–1. LC-MS (ESI): tR
=
8.0 min (method 5). LC-MS (ESI): tR = 8.6 min; calcd. for
10.4 min, C18; calcd. for C25H31N2O6 [M + H]+ 455.2; found 454.9.
HRMS (ESI): calcd. for C25H31N2O6 [M + H]+ 455.2177; found
455.2171.
C12H19N2O4S [M + H]+ 287.1; found 286.7. HRMS (ESI): calcd.
for C12H19N2O4S [M
+
H]+ 287.1060; found 287.1062.
C12H18N2O4S: calcd. C 50.3, H 6.3, N 9.8; found C 50.8, H 6.6, N
9.6.
Methyl
(4S,1ЈS,2ЈR)-2-[2-(Benzyloxy)-1-(tert-butoxycarbonyl-
amino)propyl]-4,5-dihydrooxazole-4-carboxylate (16m): Ester 15m
(50 mg, 0.12 mmol) was cyclized at 80 °C as described in GP F with
2,6-lutidine as solvent. After FCC (light petroleum/EtOAc, 3:1),
oxazoline 16m was isolated as a colorless oil (34 mg, 0.09 mmol,
Methyl
(S)-2-[2-(1-Benzyl-1H-imidazol-4-yl)-1-(tert-butoxycarb-
onylamino)ethyl]thiazole-4-carboxylate (17b): Thiazoline 16b
(59 mg, 0.13 mmol) was oxidized as described in GP G. After FCC
(CH2Cl2/MeOH 20:1), thiazole 17b was isolated as a colorless solid
(14 mg, 0.03 mmol, 23%). Rf = 0.24 (CH2Cl2/MeOH 20:1), m.p.
75%). Rf = 0.28 (light petroleum/EtOAc, 1:1). [α]2D0 = +51.2
(CHCl3, c = 1.0). H NMR (400 MHz, CDCl3): δ = 7.39–7.19 (m, 158–159 °C. [α]2D0 = –33.6 (CHCl3, c = 0.5). 1H NMR (400 MHz,
1
5 H, Ph), 5.40 (d, J = 9.5 Hz, 1 H, NH), 4.73 (dd, J = 8.3, 10.1 Hz,
H, CHCO2Me), 4.48 (m, H, oxazoline-CH2, CH2Ph,
CDCl3): δ = 7.92 (s, 1 H, 5-H), 7.40 (s, 1 H, 2ЈЈ-H), 7.33–7.25 (m,
3 H, Ph), 6.96 (d, J = 3.5 Hz, 2 H, Ph), 6.90 (d, J = 6.1 Hz, 1 H,
1
5
CHNHBoc), 4.00 (qd, J = 2.1, 6.2 Hz, 1 H, CHOBn), 3.73 (s, 3 NH), 6.42 (s, 1 H, 5ЈЈ-H), 5.28 (br. s, 1 H, 1Ј-H), 4.94 (s, 2 H,
H, CO2CH3), 1.43 [s, 9 H, C(CH3)3], 1.23 (d, J = 6.3 Hz, 4 H, CH2Ph), 3.90 (s, 3 H, CO2CH3), 3.29 (br. d, J = 13.1 Hz, 1 H, 2Ј-
CHCH3) ppm. 13C NMR (100 MHz, CDCl3): δ = 171.4 (CO2Me), Ha), 3.15 (dd, J = 4.3, 14.4 Hz, 1 H, 2Ј-Hb), 1.42 [s, 9 H,
169.2 (C=N), 156.0 (CO2tBu), 138.3, 128.5, 127.9, 127.8 (Ph), 80.0
[C(CH3)3], 74.7 (CHCH3), 71.4 (CH2Ph), 70.2 (OCH2), 68.2
C(CH3)3] ppm. 13C NMR (100 MHz, CDCl3): δ = 176.5 (C-2),
162.2 (CO2Me), 155.7 (CO2tBu), 147.1 (C-4), 138.0 (C-4ЈЈ), 137.2
(CHCO2Me), 53.6 (CHNHBoc), 52.8 (CO2CH3), 28.5 [C(CH3)3], (C-2ЈЈ), 136.2 (Ph), 129.1 (Ph), 128.4 (Ph), 127.2 (Ph, C-5), 117.8
16.6 (CHCH ) ppm. IR (KBr): ν = 3445 (w), 3064 (w), 2979 (m), (C-5ЈЈ), 80.1 [C(CH3)3], 53.6 (C-1Ј), 52.5 (CH2Ph), 50.9 (CO2CH3),
˜
3
2933 (w), 1744 (s), 1716 (s), 1667 (m), 1505 (s), 1455 (m) 1368 (m), 33.0 (C-2Ј), 28.6 [C(CH ) ] ppm. IR (KBr): ν = 3225 (bw), 2924
˜
3 3
1285 (w), 1209 (m), 1173 (s), 1100 (w), 1071 (w), 961 (s), 924 (s), (s), 2854 (m), 1715 (s), 1504 (m), 1455 (m), 1436 (m), 1393 (w),
872 (s), 799 (s), 747 (m), 700 (m) cm–1. LC-MS (ESI): tR
=
1367 (m), 1275 (w), 1242 (s), 1215 (s), 1171 (s), 1119 (m), 1095 (m),
1046 (w), 1027 (w), 858 (s), 813 (s), 722 (s), 697 (m), 650 (w) cm–1.
LC-MS (ESI): tR = 6.7 min; calcd. for C22H27N4O4S [M + H]+
443.2; found 442.9. HRMS (ESI): calcd. for C22H27N4O4S [M +
H]+ 443.1748; found 443.1745. C22H26N4O4S: calcd. C 59.7, H 5.9,
N 12.7; found C 59.8, H 6.2, N 12.3.
10.1 min, C18; calcd. for C20H29N2O6 [M + H]+ 393.2; found 392.8.
HRMS (ESI): calcd. for C20H29N2O6 [M + H]+ 393.2020; found
393.2015.
Methyl (4S,1ЈS)-2-[1-(tert-Butoxycarbonylamino)-2-methylpropyl]-
4,5-dihydrooxazole-4-carboxylate (16n): Ester 15n (50 mg,
0.15 mmol) was cyclized at 80 °C as described in GP F with 2,6-
lutidine as solvent. After FCC (light petroleum/EtOAc, 4:1), oxaz-
oline 16n was isolated as a colorless oil (21 mg, 0.07 mmol, 48%).
Methyl
(S)-2-[1-(tert-Butoxycarbonylamino)-2-methylpropyl]thi-
azole-4-carboxylate (17c): Thiazoline 16c (56 mg, 0.18 mmol) was
oxidized as described in GP G. After FCC (light petroleum/EtOAc,
4:1), thiazole 17c was isolated as a colorless solid (47 mg,
Rf = 0.20 (light petroleum/EtOAc, 4:1). [α]2D0 = +52.5 (CHCl3, c =
1
1.0). H NMR (400 MHz, CDCl3): δ = 5.18 (d, J = 8.6 Hz, 1 H, 0.15 mmol, 85%). Rf = 0.23 (light petroleum/EtOAc, 3:1), m.p.
NH), 4.78–4.68 (m, 1 H, CHCO2Me), 4.50 (t, J = 8.2 Hz, 1 H, 119–120 °C. [α]2D0 = –35.3 (CHCl3, c = 1). 1H NMR (400 MHz,
OCHH), 4.46–4.39 (m, 1 H, OCHH), 4.32 (dd, J = 4.6, 9.1 Hz, 1
H, CHiPr), 3.75 (s, 3 H, CO2CH3), 2.14–2.01 [m, 1 H, CH(CH3)2], H, 1Ј-H), 3.90 (s, 3 H, CO2CH3), 2.40 (m, 1 H, 2Ј-H), 1.40 [s, 9 H,
1.40 [s, 9 H, C(CH3)3], 0.93/ 0.88 [2ϫ d, J = 6.8 Hz, 2ϫ3 H, C(CH3)3], 0.94 (d, J = 6.8 Hz, 3 H, 2Ј-CH3), 0.86 (d, J = 6.9 Hz,
CH(CH3)2] ppm. 13C NMR (100 MHz, CDCl3): 171.6 3 H, 2Ј-CH3) ppm. 13C NMR (100 MHz, CDCl3): δ = 173.7 (C-2),
(CO2Me), 170.5 (C=N), 155.7 (CO2tBu), 79.9 [C(CH3)3], 70.3 162.0 (CO2CH3), 155.6 (CO2tBu), 147.2 (C-4), 127.2 (C-5), 80.3
(OCH2), 67.9 (CHCO2Me), 53.9 (CHiPr), 52.9 (CO2CH3), 32.0 [C(CH3)3], 58.3 (C-1Ј), 52.6 (CO2CH3), 33.4 (C-2Ј), 28.5
[CH(CH3)2], 28.5 [C(CH3)3], 19.0, 17.5 [CH(CH3)2] ppm. IR (KBr): [C(CH ) ], 19.6, 17.4 [CH(CH ) ] ppm. IR (KBr): ν = 3353 (m),
CDCl3): δ = 8.05 (s, 1 H, 5-H), 5.23 (br. s, 1 H, NH), 4.85 (br. s, 1
δ
=
˜
3 3
3 2
ν = 3388, 3276 (wb), 2966 (s), 2931 (m), 2876 (w), 1747 (s), 1716 3119 (w), 2966 (s), 2932 (m), 2876 (w), 1725 (s), 1505 (s), 1435 (w),
˜
(s), 1661 (m), 1505 (s), 1392 (m), 1368 (m), 1284 (w), 1241 (m),
1392 (w), 1367 (m), 1346 (w), 1240 (s), 1215 (s), 1170 (s), 1096 (m),
1206 (m), 1175 (s), 960 (s), 925 (s), 874 (s), 798 (s) cm–1. LC-MS 1042 (w), 990 (w), 915 (s), 872 (s), 795 (s), 635 (w) cm–1. LC-MS
(ESI): tR = 9.0 min, C18; calcd. for C14H25N2O5 [M + H]+ 301.2;
found 300.9. HRMS (ESI): calcd. for C14H25N2O5 [M + H]+
301.1758; found 301.1759.
(ESI): tR = 9.4 min; calcd. for C14H23N2O4S [M + H]+ 315.1; found
314.7. HRMS (ESI): calcd. for C14H23N2O4S [M + H]+ 315.1373;
found 315.1375. C14H22N2O4S: calcd. C 53.5, H 7.1, N 8.9; found
C 54.0, H 6.7, N 8.8.
Methyl (S)-2-[1-(tert-Butoxycarbonylamino)ethyl]thiazole-4-carb-
oxylate (17a): Thiazoline 16a (45 mg, 0.16 mmol) was oxidized as
described in GP G. After FCC (cyclohexane/EtOAc, 2:1), thiazole
17a was isolated as a colorless solid (42 mg, 0.15 mmol, 94%). Rf
Allyl (S)-2-[1-(tert-Butoxycarbonyl)pyrrolidin-2-yl]thiazole-4-carb-
oxylate (17d): Thiazoline 16d (24 mg, 0.07 mmol) was oxidized as
described in GP G. After FCC (light petroleum/EtOAc, 4:1), thi-
azole 17d was isolated as a colorless solid (23 mg, 0.07 mmol,
= 0.19 (cyclohexane/EtOAc, 2:1), m.p. 97–98 °C. [α]2D0 = –35.0
1
(CHCl3, c = 1.0). H NMR (400 MHz, CDCl3): δ = 8.06 (s, 1 H, 94%). Rf = 0.42 (light petroleum/EtOAc, 1:1), m.p. 92–93 °C.
1
5-H), 5.20 (br. s, 1 H, NH), 5.06 (br. s, 1 H, CHCH3), 3.90 (s, 3 H, [α]2D0 = –94.6 (CHCl3, c = 0.5). H NMR (400 MHz, CDCl3): δ =
CO2CH3), 1.58 (d, J = 6.9 Hz, 3 H, CHCH3), 1.40 [s, 9 H,
8.08 (s, 1 H, 5Ј-H), 6.03 (ddt, J = 5.7, 11.1, 16.4 Hz, 1 H,
CH=CH2), 5.39 (dd, J = 1.2, 17.2 Hz, 1 H, CH=CHH), 5.28 (d, J
C(CH3)3] ppm. 13C NMR (100 MHz, CDCl3): δ = 175.3 (C-2),
162.0 (CO2Me), 155.1 (CO2tBu), 147.0 (C-4), 127.6 (C-5), 80.5 = 10.5 Hz, 1 H, CH=CHH), 5.19 (br. s, 1 H, 2-H), 4.84 (d, J =
14
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© 0000 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 0000, 0–0

Job/Unit: O30160
/KAP1
Date: 10-04-13 10:52:38
Pages: 27
Unified Azoline and Azole Syntheses
5.7 Hz, 2 H, CH2CH=CH2), 3.67–3.36 (m, 2 H, 5-H2), 2.29 (m, 2 (d, J = 7.0 Hz, 3 H, CHCH3), 1.47 [s, 9 H, C(CH3)3] ppm. 13C
H, 3-H2), 1.99–1.83 (m, 2 H, 4-H2), 1.47/ 1.32 [2ϫ s, rotamers, 9
NMR (100 MHz, MeOD): δ = 168.2 (C=N), 163.2 (CO2Me), 157.8
(CO2tBu), 146.3 (C-5), 134.2 (C-4), 81.0 [C(CH3)3], 52.8 (CO2CH3),
H, C(CH3)3] ppm. 13C NMR (100 MHz, CDCl3): δ = 177.3 (C=N),
161.2 (CO2All), 154.4 (CO2tBu), 147.1 (C-4Ј), 132.2 (CH=CH2), 46.2 (CHCH ), 29.0 [C(CH ) ], 19.5 (CHCH ) ppm. IR (KBr): ν =
˜
3
3 3
3
127.3 (C-5Ј), 119.0 (C=CH2), 80.7 [C(CH3)3], 66.1 (CH2CH=CH2), 3357 (s), 3151 (w), 3113 (m), 2985 (m), 2499 (m), 1720 (s), 1687 (s),
59.8 (C-2), 46.9 (C-5), 34.4 (C-3), 28.5 [C(CH3)3], 23.4 (C-4) ppm. 1582 (m), 1528 (s), 1420 (m), 1318 (m), 1247 (w), 1208 (s), 1119
IR (KBr): ν = 3102 (w), 2978 (m), 2931 (m), 2883 (m), 1731 (s), (m), 1066 (w), 996 (m), 944 (m), 928 (w), 869 (m), 810 (m), 778 (s),
˜
1698 (s), 1575 (w), 1557 (w), 1481 (m), 1455 (m), 1386 (s), 1318
(w), 1228 (s), 1202 (s), 1171 (s), 1110 (m), 1023 (w), 919 (s), 871
(s), 797 (s), 620 (w) cm–1. LC-MS (ESI): tR = 9.6 min; calcd. for
C16H23N2O4S [M + H]+ 339.1; found 338.9. HRMS (ESI): calcd.
for C16H23N2O4S [M + H]+ 339.1373; found 339.1375.
603 (w) cm–1. HPLC: tR = 7.6 min (method 6). HRMS (ESI): calcd.
for C12H19N2O5 [M + H]+ 271.1288; found 271.1285. C12H18N2O5:
C 53.3, H 6.7, N 10.4; found C 53.6, H 7.1, N 10.1.
Methyl (S)-2-[1-(tert-Butoxycarbonylamino)ethyl]-5-methyloxazole-
4-carboxylate (17h): Oxazoline 16h (69 mg, 0.24 mmol) was oxid-
Methyl
(S)-2-[1-(tert-Butoxycarbonylamino)-3-(cyclohexyloxy- ized as described in GP G. After FCC (cyclohexane/EtOAc, 2:1),
carbonyl)propyl]thiazole-4-carboxylate (17e): Thiazoline 16e
(58 mg, 0.14 mmol) was oxidized as described in GP G. After FCC
(cyclohexane/EtOAc, 3:1), thiazole 17e was isolated as a colorless
solid (50 mg, 0.12 mmol, 86%). Rf = 0.17 (cyclohexane/EtOAc,
3:1), m.p. 110–111 °C. [α]2D0 = –22.6 (CHCl3, c = 1.0). 1H NMR
(400 MHz, CDCl3): δ = 8.07 (s, 1 H, 5-H), 5.48 (br. s, 1 H, NH),
oxazole 17h was isolated as a colorless solid (54 mg, 0.19 mmol,
79%). Rf = 0.33 (light petroleum/EtOAc, 1:1), m.p. 89–90 °C.
[α]2D0 = –46.2 (CHCl3, c = 1.0). H NMR (400 MHz, CD3OD): δ =
1
5.19 (m, 1 H, NH), 4.91 (m, 1 H, CHCH3), 3.88 (s, 3 H, CO2CH3),
2.58 (s, 3 H, 5-CH3), 1.50 (d, J = 7.0 Hz, 3 H, CHCH3), 1.41 [s, 9
H, C(CH3)3] ppm. 13C NMR (100 MHz, CD3OD): δ = 163.2
5.01 (br. s, 1 H, 1Ј-H), 4.72 (td, J = 3.9, 9.0 Hz, 1 H, Cy), 3.90 (s, (C=N), 162.8 (CO2Me), 156.7 (C-5), 155.0 (CO2tBu), 127.5 (C-4),
3 H, CO2Me), 2.48–2.32 (m, 3 H, 3Ј-H2, 2Ј-Ha), 2.16 (m, 1 H, 2Ј- 80.2 [C(CH3)3], 52.1 (CO2CH3), 44.8 (CHCH3), 28.5 [C(CH3)3],
Hb), 1.87–1.75 (m, 2 H, Cy), 1.68 (m, 2 H, Cy), 1.51 (dd, J = 5.0,
20.5 (CHCH ), 12.2 (C-5-CH ) ppm. IR (KBr): ν = 3356 (s), 2986
˜
3 3
7.4 Hz, 1 H, Cy), 1.40 [s, 9 H, C(CH3)3], 1.36–1.16 (m, 5 H, (m), 2937 (m), 1718 (s), 1688 (s), 1620 (m), 1525 (s), 1444 (m), 1348
Cy) ppm. 13C NMR (100 MHz, CDCl3): δ = 173.9 (C-2), 172.7
(m), 1248 (m), 1206 (m), 1175 (s), 1100 (s), 1063 (m), 958 (m), 865
(CO2Cy), 162.0 (CO2Me), 155.4 (CO2tBu), 147.2 (C-4Ј), 127.7 (C- (s), 823 (s), 785 (s), 647 (w) cm–1. HPLC: tR = 9.0 min (method 7).
5), 80.5 [C(CH3)3], 73.4 (Cy), 53.1 (C-1Ј), 52.6 (CO2CH3), 31.8 LC-MS (ESI): tR = 8.7 min, C18; calcd. for C13H21N2O5S [M + H]
+
(Cy), 31.3 (C-3Ј), 30.6 (C-2Ј), 28.5 [C(CH3)3], 25.5, 24.0 (Cy) ppm.
285.1; found 284.7. HRMS (FAB): calcd. for C13H21N2O5
IR (KBr): ν = 3347 (m), 3118 (w), 2938 (s), 2860 (m), 2357 (w),
[M + H]+ 285.145; found 285.143.
˜
2330 (w), 1715 (s), 1574 (w), 1568 (w), 1556 (w), 1505 (s), 1455 (m),
1435 (w), 1418 (w), 1392 (m), 1367 (m), 1336 (m), 1242 (s), 1215
(s), 1174 (s), 1124 (w), 1096 (w), 1042 (w), 1021 (w), 913 (s), 863
(s), 798 (s), 667 (w) cm–1. LC-MS (ESI): tR = 10.6 min; calcd. for
C20H31N2O6S [M + H]+ 427.2; found 426.8. HRMS (ESI): calcd.
Methyl (S)-2-[1-(tert-Butoxycarbonylamino)-2-phenylethyl]oxazole-
4-carboxylate (17i): Oxazoline 16i (43 mg, 0.12 mmol) was oxidized
as described in GP G. After chromatography on silica gel (light
petroleum/EtOAc, 6:1), oxazole 17i was isolated as a colorless solid
(33 mg, 0.10 mmol, 78%). Rf = 0.25 (light petroleum/EtOAc, 4:1),
m.p. 119–120 °C. [α]2D0 = –11.9 (CHCl3, c = 1.0). 1H NMR
(400 MHz, CDCl3): δ = 8.10 (s, 1 H, oxazole), 7.24–6.94 (m, 5 H,
Ph), 5.19 (m, 2 H, NH, CHBn), 3.88 (s, 3 H, CO2CH3), 3.26–3.11
(m, 2 H, CH2Ph), 1.37 [s, 9 H, C(CH3)3] ppm. 13C NMR
(100 MHz, CDCl3): δ = 165.1 (C=N), 161.4 (CO2Me), 155.0
(CO2tBu) 144.1 (C-5), 135.8 (Ph), 133.4 (C-4), 129.4, 128.8, 127.5
(Ph), 80.5 [C(CH3)3], 52.3 (CO2CH3), 50.4 (CHBn), 40.3 (CH2Ph),
for C20H31N2O6SNa [M
C20H30N2O6S: C 56.3, H 7.1, N 6.6; found C 56.3, H 7.2, N 6.3.
+
H]+ 427.1897; found 427.1895.
Methyl (S)-2-[1-(tert-Butoxycarbonyl)pyrrolidin-2-yl]oxazole-4-
carboxylate (17f): Ester 16f (85.5 mg, 0.25 mmol) was cyclized at
80 °C as described in GP F with 2,6-lutidine as solvent and sub-
sequently oxidized as described in GP G. After FCC (light petro-
leum/EtOAc, 2:1), oxazole 17f was isolated as a colorless solid
(17 mg, 0.06 mmol, 23%). Rf = 0.26 (light petroleum/EtOAc, 1:1), 28.5 [C(CH ) ] ppm. IR (KBr): ν = 3361 (s), 3063 (w), 2978 (m),
˜
3 3
m.p. 85–86 °C. [α]2D0 = –49.8 (CHCl3, c = 1.0). 1H NMR (400 MHz,
CDCl3): δ = 8.15 (s, 1 H, 5-H), 4.96 (2ϫ br. s, rotamers, 1 H, 2Ј-
2928 (m), 1732 (s), 1715 (s), 1586 (w), 1520 (m), 1368 (w), 1323
(w), 1330 (m), 1251 (m), 1172 (s), 1109 (m), 964 (m), 936 (m), 893
CH), 3.90 (s, 3 H, CO2CH3), 3.67–3.39 (m, 2 H, 5Ј-H2), 2.38–2.21 (s), 871 (s), 768 (m), 702 (m) cm–1. LC-MS (ESI): tR = 9.7 min,
(m, 1 H, 3Ј-CHH), 2.20–2.00 (m, 2 H, 3Ј-CHH, 4Ј-CHH), 1.99–
C18; calcd. for C18H22N2O5 [M]+ 346.2; found 346.6. HRMS
1.88 (m, 1 H, 4Ј-CHH), 1.35 [2ϫ s (rotamers), 9 H, C(CH3)3] ppm. (FAB): calcd. for C18H23N2O5 [M + H]+ 347.161; found 347.164.
13C NMR (100 MHz, CDCl3): δ = 166.5 (C=N), 161.9 (CO2Me), C18H22N2O5: C 62.4, H 6.4, N 8.1; found C 62.2, H 6.3, N 8.0.
156.2 (CO2tBu), 144.0, 143.5 (C-5), 133.5 (C-4), 80.3 [C(CH3)3],
Methyl (R)-2-[1-(tert-Butoxycarbonylamino)-2-(tritylthio)ethyl]ox-
azole-4-carboxylate (17j): Oxazoline 16j (50 mg, 0.09 mmol) was
55.1, 54.7 (C-2Ј), 52.4 (CO2CH3), 47.0, 46.7 (C-5Ј), 32.8, 31.7 (C-
3Ј), 28.4 [C(CH ) ], 24.6, 23.9 (C-4Ј) ppm. IR (KBr): ν = 2927 (m),
˜
3 3
oxidized as described in GP G. After chromatography on silica gel
(cyclohexane/EtOAc, 4:1), oxazole 17j was isolated as a colorless
foam (31 mg, 0.06 mmol, 62%). Rf = 0.19 (cyclohexane/EtOAc,
2853 (m), 1747 (s), 1698 (s), 1583 (m), 1455 (w), 1394 (s), 1246 (w),
1164 (m), 1113 (m), 874 (s), 802 (s) cm–1. LC-MS (ESI): tR
=
8.8 min, C18; calcd. for C14H20N2O5 [M]+ 296.1; found 296.6.
HRMS (FAB): calcd. for C14H21N2O5 [M + H]+ 297.1445; found
297.1446.
1
5:1). [α]2D0 = –3.9 (CHCl3, c = 1.0). H NMR (400 MHz, CDCl3):
δ = 8.09 (s, 1 H, oxazole), 7.26 (m, 15 H, Tr), 5.14 (d, J = 6.8 Hz,
1 H, NH), 4.81 (br. s, 1 H, CHNHBoc), 3.88 (s, 3 H, CO2CH3),
2.80–2.65 (m, 2 H, CH2STr), 1.39 [s, 9 H, C(CH3)3] ppm. 13C NMR
(100 MHz, CDCl3): δ = 164.0 (C=N), 161.6 (CO2Me), 144.5 (C-5),
144.2 (Tr), 133.3 (C-4), 129.8, 128.1, 127.0 (Tr), 80.3 [C(CH3)3],
67.2 (CPh3), 52.3 (CO2CH3), 48.1 (CHNHBoc), 35.7 (CH2STr),
Methyl
(S)-2-[1-(tert-Butoxycarbonylamino)ethyl]oxazole-4-carb-
oxylate (17g): Oxazoline 16g (72 mg, 0.27 mmol) was oxidized as
described in GP G. After FCC (cyclohexane/EtOAc, 2:1), oxazole
17g was isolated as a colorless solid (44 mg, 0.16 mmol, 62%). Rf
= 0.31 (light petroleum/EtOAc, 1:1), m.p. 99–100 °C. [α]2D0 = –44.6
28.5 [C(CH ) ] ppm. IR (KBr): ν = 3355 (bw), 3161 (w), 3059 (w),
˜
3 3
1
(CHCl3, c = 0.9). H NMR (400 MHz, MeOD): δ = 8.51 (s, 1 H,
2978 (m), 2928 (m), 2854 (w), 1715 (s), 1583 (w), 1505 (m), 1495
(m), 1445 (w), 1368 (w), 1323 (w), 1247 (m), 1202 (s), 1111 (m),
oxazole); 4.90 (br. m, 1 H, CHCH3), 3.91 (s, 3 H, CO2CH3), 1.55
Eur. J. Org. Chem. 0000, 0–0
© 0000 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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15

Job/Unit: O30160
/KAP1
Date: 10-04-13 10:52:38
Pages: 27
P. Loos, C. Ronco, M. Riedrich, H.-D. Arndt
FULL PAPER
855 (s), 801 (s), 744 (s), 701 (s), 621 (w) cm–1. LC-MS (ESI): tR
=
4), 128.5, 128.0, 127.9 (Ph), 80.4 [C(CH3)3], 75.5 (CHOBn), 71.3
(CH2Ph), 54.0 (CHNHBoc), 52.4 (CO2CH3), 28.5 [C(CH3)3], 16.4
11.4 min, C18; calcd, for C31H32N2O5SNa [M + Na]+ 567.2; found
567.1. HRMS (FAB): calcd. for C31H33N2O5S [M + H]+ 545.211; (CHCH ) ppm. IR (KBr): ν = 3441 (w), 3162 (w), 2979 (m), 2927
˜
3
found 545.214.
(m), 1716 (s), 1586 (w), 1504 (m), 1455 (w), 1368 (w), 1325 (w),
1232 (m), 1205 (m), 1172 (s), 1111 (m), 1028 (w), 868 (s), 800 (s),
700 (w) cm–1. LC-MS (ESI): tR = 10.2 min, C18; calcd. for
C20H26N2O6 [M]+ 390.2; found 390.6. HRMS (ESI): calcd. for
C20H27N2O6 [M + H]+ 391.1864; found 391.1866.
Methyl
(S)-2-[1-(tert-Butoxycarbonylamino)-3-(cyclohexyloxy-
carbonyl)propyl]oxazole-4-carboxylate (17k): Ester 16k (56 mg,
0.12 mmol) was cyclized as described in GP F, in THF at 40 °C,
and subsequently oxidized as described in GP G. After FCC (light
petroleum/EtOAc, 2:1), oxazole 17k was isolated as a colorless oil
Methyl
(S)-2-[1-(tert-Butoxycarbonylamino)-2-methylpropyl]ox-
(35 mg, 0.09 mmol, 69%). Rf = 0.26 (light petroleum/EtOAc, 2:1). azole-4-carboxylate (17n): Oxazoline 16n (15 mg, 0.05 mmol) was
[α]2D0 = –18.7 (CHCl3, c = 1.0). H NMR (400 MHz, CDCl3): δ =
oxidized as described in GP G. After FCC (light petroleum/EtOAc,
1
8.17 (s, 1 H, oxazolyl), 5.30 (d, J = 7.5 Hz, 1 H, NH), 4.98 (m, 1 3:1), oxazole 17n was isolated as a colorless oil (6 mg, 0.02 mmol,
H, CHNHBoc), 4.72 (td, J = 4.0, 8.9 Hz, 1 H, Cy-CH), 3.90 (s, 3 43%). Rf = 0.26 (light petroleum/EtOAc, 2:1). [α]2D0 = –30.2
1
H, CO2CH3), 2.42–2.34 (m, 2 H, CH2CO2Cy), 2.33–2.21 (m, 1 H,
(CHCl3, c = 0.5). H NMR (400 MHz, CDCl3): δ = 8.16 (s, 1 H,
CHHCH2CO2Cy), 2.14–2.08 (m, 1 H, CHHCH2CO2Cy), 1.82 (dd, 5-H), 5.27 (d, J = 8.7 Hz, 1 H, NH), 4.77 (dd, J = 6.4, 8.8 Hz, 1
J = 3.0, 7.4 Hz, 2 H, Cy), 1.70 (dd, J = 3.4, 9.0 Hz, 2 H, Cy), 1.53 H, CHiPr), 3.89 (s, 3 H, CO2CH3), 2.17 [dq, J = 6.5, 12.9 Hz, 1 H,
(dd, J = 6.6, 10.9 Hz, 1 H, Cy), 1.42 [s, 9 H, C(CH3)3], 1.37–1.24 CH(CH3)2], 1.41 [s, 9 H, C(CH3)3], 0.91 [d, J = 7.3 Hz, 3 H,
(m, 5 H, Cy) ppm. 13C NMR (100 MHz, CDCl3): δ = 172.1
(CO2Cy), 165.0 (C=N), 161.6 (CO2Me), 155.4 (CO2tBu), 144.3 (C-
5), 133.5 (C-4), 80.5 [C(CH3)3], 73.3 (Cy), 52.4 (CO2CH3), 48.7
(CHNHBoc), 31.8 (Cy), 30.7 (CH2CO2Cy), 29.5 (CH2CH2CO2Cy),
CH(CH3)2], 0.89 [d, J = 6.8 Hz, 3 H, CH(CH3)2] ppm. 13C NMR
(100 MHz, CDCl3): δ = 165.4 (C=N), 161.8 (CO2Me), 155.6
(CO2tBu), 144.0 (C-5), 133.4 (C-4), 80.3 [C(CH3)3], 54.5 (CHiPr),
52.4 (CO2CH3), 33.2 [CH(CH3)2], 28.5 [C(CH3)3], 18.9/ 18.2
28.5 [C(CH ) ], 25.5, 23.9 (Cy) ppm. IR (KBr): ν = 3354 (bm), [CH(CH ) ] ppm. IR (KBr): ν = 3354 (w), 3155 (w), 2970 (m), 1790
˜
˜
3 3
3 2
3162 (w), 2938 (s), 2860 (m), 1727 (s), 1585 (m), 1505 (m), 1454
(m), 1393 (w), 1367 (m), 1324 (m), 1246 (m) 1175 (s), 1112 (m), (w), 1392 (w), 1368 (m), 1324 (w), 1236 (m), 1203 (m), 1172 (s),
1004 (w), 867 (s), 800 (s) cm–1. LC-MS (ESI): tR = 10.3 min, C18; 1110 (m), 875 (s), 800 (s), 666 (w) cm–1. LC-MS (ESI): tR = 9.3 min,
(s), 1747 (s), 1715 (s), 1584 (w), 1539 (w), 1531 (w), 1505 (m), 1471
calcd. for C20H30N2O7 [M]+ 410.2; found 410.7. HRMS (FAB): C18; calcd. for C14H22N2O5 [M]+ 298.2; found 298.6. HRMS (ESI):
calcd. for C20H31N2O7 [M + H]+ 411.213; found 411.212.
calcd. for C14H23N2O5 [M + H]+ 299.1602; found 299.1601.
Methyl (S)-2-{2-[4-(Benzyloxy)phenyl]-1-(tert-butoxycarbonyl-
Methyl 2-[(tert-Butoxycarbonylamino)methyl]oxazole-4-carboxylate
(17o): Ester 16o (48 mg, 0.16 mmol) was cyclized as described in
GP F, in THF at 40 °C, and subsequently oxidized as described in
GP G. After FCC (light petroleum/EtOAc, 2:1), oxazole 17o was
amino)ethyl}oxazole-4-carboxylate (17l): Oxazoline 16l (44 mg,
0.10 mmol) was oxidized as described in GP G. After FCC (light
petroleum/EtOAc, 4:1), oxazole 17l was isolated as a colorless solid
(24 mg, 0.05 mmol, 56%). Rf = 0.45 (light petroleum/EtOAc, 1:1), isolated as a colorless solid (26 mg, 0.10 mmol, 64%). Rf = 0.24
1
m.p. 130–131 °C. [α]2D0 = –3.8 (CHCl3, c = 1.0). 1H NMR
(400 MHz, MeOD): δ = 8.10 (s, 1 H, oxazole), 7.42–7.26 (m, 5 H,
Ph), 6.92 (d, J = 8.3 Hz, 2 H, ArTyr), 6.83 (d, J = 8.6 Hz, 2 H,
ArTyr), 5.20 (d, J = 7.9 Hz, 1 H, NH), 5.13 (m, 1 H, CHNHBoc),
4.99 (s, 2 H, CH2Ph), 3.89 (s, 3 H, CO2CH3), 3.14 (d, J = 6.1 Hz,
(light petroleum/EtOAc, 1:1), m.p. 72–73 °C. H NMR (400 MHz,
CDCl3): δ = 8.15 (s, 1 H, oxazole), 5.24 (s, 1 H, NH), 4.45 (d, J =
5.7 Hz, 2 H, CH2NHBoc), 3.87 (s, 3 H, CO2CH3), 1.41 [s, 9 H,
C(CH3)3] ppm. 13C NMR (100 MHz, CDCl3): δ = 162.5 (C=N),
161.6 (CO2Me), 155.6 (CO2tBu), 144.4 (C-5), 133.5 (C-4), 80.5
2 H, CH2CHNHBoc), 1.38 [s, 9 H, C(CH3)3] ppm. 13C NMR [C(CH3)3], 52.4 (CO2CH3), 38.1 (CH2NHBoc), 28.5 [C(CH3)
(100 MHz, MeOD): δ = 165.0 (C=N), 161.7 (CO2Me), 158.1
(COBn), 155.1 (CO2tBu), 144.0 (C-5), 137.2 (Ph), 133.5 (C-4),
130.5 (ArTyr), 128.8 (Ph), 128.1 (ArTyr), 128.0 (Ph), 127.6 (Ph),
] ppm. IR (KBr): ν = 3363 (bm), 3161 (w), 2980 (m), 1715 (s),
˜
3
1589 (m), 1505 (m), 1455 (m), 1437 (w), 1393 (w), 1368 (m), 1323
(m), 1277 (m), 1248 (m), 1207 (m), 1173 (s), 1111 (m), 1053 (w),
115.2 (ArTyr), 80.4 [C(CH3)3], 70.2 (CH2Ph), 52.4 (CO2CH3), 50.5 1002 (w), 906 (s), 862 (s), 806 (s), 666 (w) cm–1. LC-MS (ESI): tR
(CHNHBoc), 39.7 (CH2CHNHBoc), 28.5 [C(CH3)3] ppm. IR
= 8.0 min, C18; calcd. for C11H16N2O5 [M]+ 256.1; found 256.6.
(KBr): ν = 3366 (m), 3160 (w), 3032 (w), 2978 (m), 2930 (m), 1747 HRMS (ESI): calcd. for C11H17N2O5 [M + H]+ 257.1132; found
˜
(s), 1730 (s), 1715 (s), 1613 (w), 1584 (m), 1506 (s), 1455 (m), 1368
(w), 1318 (w), 1242 (m), 1171 (m), 1111 (m), 861 (s), 802 (s), 739
(m), 697 (w) cm–1. LC-MS (ESI): tR = 10.5 min, C18; calcd. for
C25H28N2O6 [M]+ 452.2; found 452.5. HRMS (ESI): calcd. for
C25H29N2O6 [M + H]+ 453.2020; found 453.2010.
257.1133.
Methyl (S)-2-Azido-3-{[(S)-2-tert-butoxycarbonylaminopropionyl]-
(tolyl-4Ј-sulfonyl)amino}propionate
(4.42 g, 23.4 mmol) was activated as described in GP H and cou-
pled to 2-azido-3-(tolyl-4Ј-sulfonylamino)propionic acid methyl es-
(20a):
(S)-N-Boc-alanine
Methyl (1ЈS,2ЈR)-2-[2-(Benzyloxy)-1-(tert-butoxycarbonylamino)- ter 14d (3.50 g, 11.7 mmol). The crude product was purified by
propyl]oxazole-4-carboxylate (17m): Oxazoline 16m (29 mg,
0.08 mmol) was oxidized as described in GP G. After FCC (light
petroleum/EtOAc, 3:1), oxazole 17m was isolated as a colorless oil
FCC (750 g silica, light petroleum/EtOAc, 8:2) to yield N-acyl-sulf-
onamide 20a (5.30 g, 11.3 mmol, 97%) as a colorless oil. Rf = 0.57
1
(light petroleum/EtOAc, 1:1). [α]2D0 = –56.5 (c = 2.0 in CHCl3). H
(16 mg, 0.042 mmol, 56%). Rf = 0.45 (light petroleum/EtOAc, 1:1). NMR (400 MHz, CDCl3, 25 °C): δ = 7.92 (d, J = 7.9 Hz, 2 H,
1
[α]2D0 = –17.0 (CHCl3, c = 0.5). H NMR (400 MHz, CDCl3): δ =
8.11 (s, 1 H, 5-H), 7.28–7.18 (m, 3 H, Ph), 7.15–7.03 (m, 2 H, Ph),
5.52 (d, J = 9.3 Hz, 1 H, NH), 4.94 (d, J = 9.3 Hz, 1 H,
CHNHBoc), 4.48 (d, J = 11.8 Hz, 1 H, CHHPh), 4.29 (d, J =
SO2CCH), 7.34 (d, J = 8.1 Hz, 2 H, CH3CCH), 5.23–5.09 (m, 1 H,
2Ј-H), 4.98 (d, J = 8.1 Hz, 1 H, NH), 4.36 (dd, J = 5.6, 14.8 Hz, 1
H, 2-H), 4.21 (dd, J = 5.6, 14.8 Hz, 1 H, 3-Ha), 3.95 (dd, J = 8.6,
14.8 Hz, 1 H, 3-Hb), 3.79 (s, 3 H, COOCH3), 2.42 (s, 3 H, ArCH3),
11.8 Hz, 1 H, CHHPh), 4.08 (m, 1 H, CHOBn), 3.90 (s, 3 H, 1.40–1.35 [m, 12 H, CHCH3, C(CH3)3] ppm. 13C NMR (100 MHz,
CO2CH3), 1.43 [s, 9 H, C(CH3)3], 1.25 (d, J = 6.3 Hz, 3 H,
CDCl3, 25 °C): δ = 175.6 (C-1Ј), 168.8 (C-1), 155.2 [COC(CH3)3],
CHCH3) ppm. 13C NMR (100 MHz, CDCl3): δ = 164.3 (C=N), 145.6 (CH3CCH), 135.6 (CHCSO2), 130.2 (CH3CCH), 128.2
161.8 (CO2Me), 156.0 (CO2tBu), 144.1 (C-5), 138.0 (Ph), 133.6 (C- (CHCSO2), 80.2 [C(CH3)3], 60.7 (C-2), 53.2 (COOCH3), 49.9 (C-
16
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© 0000 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 0000, 0–0

Job/Unit: O30160
/KAP1
Date: 10-04-13 10:52:38
Pages: 27
Unified Azoline and Azole Syntheses
2Ј), 46.4 (C-3), 28.4 [C(CH3)3], 21.8 (ArCH3), 19.6 (CH3CH) ppm.
leum/EtOAc, 3:2). [α]2D0 = –96.7 (c = 2.0 in CHCl3). 1H NMR
(400 MHz, CDCl3, 25 °C): δ = 7.90 (d, J = 8.1 Hz, 2 H, SO2CCH),
7.31 (d, J = 8.2 Hz, 2 H, CH3CCH), 5.15 (br. s, 1 H, 2Ј-H), 4.96
(d, J = 9.6 Hz, 1 H, NH), 4.34 (dd, J = 4.8, 7.9 Hz, 1 H, 2-H), 4.14
(dd, J = 5.0, 14.7 Hz, 1 H, 3-Ha), 3.94 (dd, J = 8.2, 13.9 Hz, 1 H,
3-Hb), 3.79 (s, 3 H, COOCH3), 2.40 (s, 3 H, ArCH3), 2.15 (dd, J
= 6.4, 11.8 Hz, 1 H, 3Ј-H), 1.38 [s, 9 H, C(CH3)3], 0.99 (d, J =
6.7 Hz, 3 H, 4Ј-Ha), 0.81 (d, J = 6.9 Hz, 3 H, 4Ј-Hb) ppm. 13C
NMR (100 MHz, CDCl3, 25 °C): δ = 174.4 (C-1Ј), 168.7 (C-1),
155.7 [COC(CH3)3], 145.5 (CH3CCH), 135.8 (CHCSO2), 130.1
(CH3CCH), 128.2 (CHCSO2), 80.0 [C(CH3)3], 60.5 (C-2), 58.3 (C-
2Ј), 53.1 (COOCH3), 46.4 (C-3), 32.0 (C-3Ј), 28.3 [C(CH3)3], 21.7
IR (KBr): ν = 2981 (m), 2118 (s), 1749 (m), 1703 (s), 1505 (m),
˜
1363 (m), 1166 (s) cm–1. HPLC: tR = 9.7 min (method 2). LC-MS
(ESI): tR = 10.4 min, C18; calcd. for C19H28N5O7S [M + H]+ 470.2;
found 469.6. HRMS (ESI): calcd. for C19H28N5O7S [M + H]+
470.1704; found 470.1699.
Methyl
(S)-2-Azido-3-{[(S)-N-tert-butoxycarbonylphenylalanyl]-
(tolyl-4Ј-sulfonyl)amino}propionate (20b): (S)-N-Boc-phenylalanine
(534 mg, 2.01 mmol) was activated as described in GP H and cou-
pled to azide 14d (200 mg, 0.67 mmol). Workup and FCC (60 g,
n-hexane/EtOAc, 41:8) gave 20b (293 mg, 0.54 mmol, 80%) as a
colorless oil. Rf = 0.62 (light petroleum/EtOAc, 3:2). [α]2D0 = –64.1
(ArCH ), 19.8 (C-4Ј ), 16.4 (C-4Ј ) ppm. IR (KBr): ν = 2973 (m),
˜
3
a
b
1
(c = 2.0 in CHCl3). H NMR (400 MHz, [D6]DMSO, 25 °C): δ =
2120 (s), 1750 (m), 1701 (s), 1502 (m), 1366 (s), 1167 (s), 815
7.93 (d, J = 8.1 Hz, 2 H, SO2CCH), 7.33 (d, J = 8.2 Hz, 2 H,
CH3CCH), 7.31–7.19 (m, 5 H, 3ЈЈ-H, 4ЈЈ-H, 2ЈЈ-H), 5.44–5.30 (m,
1 H, 2Ј-H), 4.97 (d, J = 8.9 Hz, 1 H, NH), 4.38 (dd, J = 5.3, 8.2 Hz,
2-H), 4.11 (dd, J = 5.2, 15.0 Hz, 1 H, 3-Ha), 3.95 (dd, J = 8.8,
14.9 Hz, 1 H, 3-Hb), 3.81 (s, 3 H, COOCH3), 3.28 (dd, J = 4.8,
13.9 Hz, 1 H, 3Ј-Ha), 2.74 (dd, J = 8.8, 13.6 Hz, 1 H, 3Ј-Hb), 2.42
(s, 3 H, ArCH3), 1.30 [s, 9 H, C(CH3)3] ppm. 13C NMR (100 MHz,
CDCl3, 25 °C): δ = 174.1 (C-1Ј), 168.8 (C-1), 155.1 [COC(CH3)3],
145.5 (CH3CCH), 136.0 (C-1ЈЈ), 135.6 (CHCSO2), 130.1
(CH3CCH), 129.5 (C-2ЈЈ), 128.7 (C-3ЈЈ), 128.3 (CHCSO2), 127.2
(C-4ЈЈ), 80.1 [C(CH3)3], 60.5 (C-3), 55.1 (C-2Ј), 53.2 (COOCH3),
46.3 (C-2), 39.6 (C-3Ј), 28.3 [C(CH3)3], 21.2 (ArCH3) ppm. IR
(w) cm–1. HPLC: tR = 10.6 min (method 2). LC-MS (ESI): tR
=
10.8 min, C18; calcd. for C21H32N5O7S [M + H]+ 498.2; found
497.5. HRMS (ESI): calcd. for C21H32N5O7S [M + H]+ 498.2017;
found 498.2006.
tert-Butyl (R)-4-[(S)-2-(Azido-2-methoxycarbonylethyl)(tolyl-4Ј-
sulfonyl)aminocarbonyl]-2,2-dimethylthiazolidine-3-carboxylate
(20e): (R)-3-(tert-Butoxycarbonyl)-2,2-dimethylthiazolidine-4-
carboxylic acid (194 mg, 0.74 mmol) was coupled to azide 14d
(200 mg, 0.67 mmol) as described in GP I. The crude product was
purified by FCC (70 g silica, cyclohexane/EtOAc, 21:4) to yield N-
acyl-sulfonamide 20e (326 mg, 0.60 mmol, 90%) as a colorless oil.
Rf = 0.34 (light petroleum/EtOAc, 4:1). [α]2D0 = –63.5 (c = 4.0 in
CHCl3). 1H NMR (400 MHz, CDCl3, 25 °C): δ = 7.92 (d, J =
6.2 Hz, 2 H, SO2CCH)*, 7.80 (br. s, 2 H, SO2CCH)*, 7.32 (d, J =
7.7 Hz, 2 H, CH3CCH), 5.71 (br. s, 1 H, 4Ј-H)*, 5.56 (br. s, 1 H,
4Ј-H)*, 4.30 (dd, J = 5.8, 8.3 Hz, 1 H, 2-H), 4.13 (dd, J = 4.5,
13.9 Hz, 1 H, 3-Ha), 3.76 (s, 3 H, COOCH3), 3.66 (dd, J = 8.2,
13.4 Hz, 1 H, 3-Hb), 3.43 (dd, J = 7.1, 11.3 Hz, 1 H, 5Ј-Ha), 3.14
(d, J = 11.5 Hz, 1 H, 5Ј-Hb), 2.40/ 2.31 (s each, 3 H, ArCH3)*, 1.80
[s, 3 H, C(CH3)2a], 1.73 [s, 3 H, C(CH3)2b], 1.39/ 1.26 [s each, 9 H,
C(CH3)3]* ppm. * Rotamers. 13C NMR (100 MHz, CDCl3, 25 °C):
δ = 171.7 (OCNSO2), 168.8 (C-1), 152.8 [COC(CH3)3], 145.3
(CH3CCH), 135.3 (CHCSO2), 130.1 (CH3CCH), 128.0 (CHCSO2),
81.0 [C(CH3)3], 70.5 (C-2Ј), 67.9 (C-4Ј), 60.2 (C-2), 53.2 (CO-
OCH3), 46.6 (C-3), 31.2 (C-5Ј), 30.8 [C(CH3)2a], 28.6 [C(CH3)2b],
(KBr): ν = 2981 (m), 2119 (s), 1749 (m), 1703 (s), 1499 (m), 1365
˜
(s), 1167 (s) cm–1. HPLC: tR = 10.7 min (method 2). LC-MS (ESI):
tR = 11.1 min, C18; calcd. for C25H32N5O7S [M + H]+ 546.2; found
545.5. HRMS (ESI): calcd. for C25H32N5O7S [M + H]+ 546.2017;
found 546.2012.
Methyl (S)-2-Azido-3-{[(2S,3R)-2-tert-butoxycarbonylamino-3-(tert-
butyldimethylsilyloxy)butyryl](tolyl-4Ј-sulfonyl)amino}propionate
(20c): (2S,3R)-N-Boc-O-TBS-threonine (246 mg, 0.74 mmol) was
coupled to azide 14d (200 mg, 0.67 mmol) as described in GP I.
The crude product was purified by FCC (100 g, light petroleum/
EtOAc, 4:1) to yield 20c (352 mg, 0.57 mmol, 86%) as a colorless
oil. Rf = 0.73 (light petroleum/EtOAc, 3:2). [α]2D0 = –28.1 (c = 5.0
1
in CHCl3). H NMR (400 MHz, CDCl3, 25 °C): δ = 7.96 (d, J =
8.3 Hz, 2 H, CHCSO2), 7.35 (d, J = 8.0 Hz, 2 H, CH3CCH), 5.32
(d, J = 9.3 Hz, 1 H, NH), 5.15 (d, J = 10.0 Hz, 1 H, 2Ј-H), 4.38–
4.28 (m, 1 H, 3Ј-H), 4.25 (dd, J = 4.0, 9.7 Hz, 1 H, 2-H), 4.08 (dd,
J = 3.9, 14.7 Hz, 1 H, 3-Ha), 3.91 (dd, J = 9.8, 14.7 Hz, 1 H, 3-
Hb), 3.79 (s, 3 H, COOCH3), 2.43 (s, 3 H, ArCH3), 1.42 [s, 9 H,
OC(CH3)3], 1.23 (d, J = 6.2 Hz, 3 H, 4Ј-H), 0.87 [s, 9 H, SiC-
(CH3)3], 0.07 (s, 3 H, SiCH3a), 0.03 (s, 3 H, SiCH3b) ppm. 13C
NMR (100 MHz, CDCl3, 25 °C): δ = 173.0 (C-1Ј), 168.9 (CO-
OCH3), 156.3 [COC(CH3)3], 145.5 (CHCSO2), 135.8 (CH3CCH),
130.2 (CH3CCH), 128.2 (CHCSO2), 80.1 [OC(CH3)3], 69.5 (C-3Ј),
60.0 (C-2), 59.4 (C-2Ј), 53.2 (COOCH3), 46.9 (C-3), 28.5 [OC-
(CH3)3], 26.0 [SiC(CH3)3], 21.9 (ArCH3), 21.4 (C-4Ј), 18.2
28.4 [C(CH ) ], 21.7 (ArCH ) ppm. IR (KBr): ν = 2979 (m), 2117
˜
3 3
3
(s), 1749 (m), 1682 (s), 1361 (s), 1170 (s), 820 (w) cm–1. HPLC: tR
= 11.3 min (method 2) B, 1 mLmin–1. LC-MS (ESI): tR = 11.5 min,
C18; calcd. for C22H32N5O7S2 [M + H]+ 542.2; found 541.6.
HRMS (ESI): calcd. for C22H32N5O7S2 [M + H]+ 542.1731; found
542.1738.
tert-Butyl (S)-4-{[(S)-2-Azido-2-methoxycarbonylethyl](tolyl-4Ј-sulf-
onyl)amino}-2-tert-butoxycarbonylamino-4-oxobutyrate (20f): 1-tert-
Butyl (S)-2-(tert-butoxycarbonylamino)succinate (216 mg,
0.74 mmol) was coupled to azide 14d (90 mg, 0.67 mmol) as de-
scribed in GP I. The crude product was purified by FCC (60 g sil-
ica, cyclohexane/EtOAc, 7:3) to yield N-acyl-sulfonamide 20f
(384 mg, 0.67 mmol, 100%) as a colorless oil. Rf = 0.56 (light petro-
leum/EtOAc, 3:2). [α]2D0 = –5.0 (c = 1.0 in CHCl3). 1H NMR
(400 MHz, CDCl3, 25 °C): δ = 7.80 (d, J = 8.4 Hz, 2 H, SO2CCH),
7.35 (d, J = 8.1 Hz, 2 H, CH3CCH), 5.41 (d, J = 8.3 Hz, 1 H, NH),
4.37 (m, 2 H, 2-H, 2Ј-H), 4.15 (dd, J = 5.7, 14.7 Hz, 2 H, 1-Ha),
4.08 (dd, J = 8.7, 14.7 Hz, 1 H, 1-Hb), 3.82 (s, 3 H, COOCH3),
[SiC(CH3)3], –4.0 (SiCH3a), –4.8 (SiCH3b) ppm. IR (KBr): ν = 2954
˜
(m), 2862 (w), 2121 (s), 1750 (m), 1708 (s), 1489 (m), 1367 (s), 1167
(s), 833 (w) cm–1. HPLC: tR = 12.8 min (method 2). LC-MS (ESI):
tR = 12.5 min, C18; calcd. for C26H44N5O8SSi [M + H]+ 614.3;
found 613.7. HRMS (ESI): calcd. for C26H44N5O8SSi [M + H]+
614.2674; found 614.2672.
Methyl (S)-2-Azido-3-{[(S)-2-tert-butoxycarbonylamino-3-methyl- 3.35 (dd, J = 4.1, 18.0 Hz, 1 H, 3Ј-Ha), 3.19 (dd, J = 4.0, 18.0 Hz,
butyryl](tolyl-4Ј-sulfonyl)amino}propionate (20d): (S)-N-Boc-valine 1 H, 3Ј-Hb), 2.43 (s, 3 H, ArCH3), 1.39 [s, 9 H, C(CH3)3a], 1.33 [s,
(120 mg, 0.55 mmol) was coupled to azide 14d (150 mg, 0.50 mmol)
as described in GP I. The crude product was purified by 171.6 (OCNSO2), 169.8 (C-1Ј), 168.9 (COOCH3), 155.7
9 H, C(CH3)3b] ppm. 13C NMR (100 MHz, CDCl3, 25 °C): δ =
chromatography (50 g silica, cyclohexane/EtOAc, 4:1) to yield 20d
(213 mg, 0.43 mmol, 86%) as a colorless oil. Rf = 0.57 (light petro-
[OC(O)NH], 145.7 (CH3 CCH), 136.1 (CHCSO2), 130.3
(CH3CCH), 128.0 (CHCSO2), 82.3 [Ca(CH3)3], 80.0 [Cb(CH3)3],
Eur. J. Org. Chem. 0000, 0–0
© 0000 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
17

Job/Unit: O30160
/KAP1
Date: 10-04-13 10:52:38
Pages: 27
P. Loos, C. Ronco, M. Riedrich, H.-D. Arndt
FULL PAPER
60.7 (C-2), 53.2 (COOCH3), 50.5 (C-2Ј), 46.5 (C-1), 39.6 (C-3Ј),
NMR (400 MHz, CDCl3, 25 °C): δ = 7.90 (d, J = 8.1 Hz, 2 H,
28.5 [C(C H ) ], 27.9 [C(C H ) ], 21.8 (ArCH ) ppm. IR (KBr): ν CHCSO2), 7.33 (d, J = 8.0 Hz, 2 H, CH3CCH), 7.30–7.17 (m, 5 H,
˜
a
3 3
b
3 3
3
= 2971 (m), 2119 (s), 1744 (s), 1707 (s), 1498 (m), 1364 (s), 1163
3ЈЈ-H, 4ЈЈ-H, 2ЈЈ-H), 5.62 (dd, J = 8.5, 12.2 Hz, 1 H, 1Ј-H), 5.20
(d, J = 9.5 Hz, 1 H, NH), 4.44 (dd, J = 7.6, 10.4 Hz, 1 H, 4-H),
(s) cm–1. HPLC: tR = 10.8 min (method 2). LC-MS (ESI): tR
=
11.1 min, C18; calcd. for C24H36N5O9S [M + H]+ 570.2; found 4.19 (dd, J = 7.3, 10.3 Hz, 1 H, 5-Ha), 3.80–3.64 (m, 4 H, 5-Hb,
569.5. HRMS (ESI): calcd. for C24H36N5O9S [M + H]+ 570.2222; COOCH3), 3.36 (dd, J = 4.4, 13.8 Hz, 1 H, 2Ј-Ha), 2.94 (dd, J =
found 570.2228.
7.7, 13.7 Hz, 1 H, 2Ј-Hb), 2.43 (s, 3 H, ArCH3), 1.36 [s, 9 H,
C(CH3)3] ppm. 13C NMR (100 MHz, CDCl3, 25 °C): δ = 170.3
(COOCH3), 162.7 (C-2), 155.0 [COC(CH3)3], 145.3 (CH3CCH),
136.3 (C-1ЈЈ), 134.3 (CHCSO2), 130.4 (CH3CCH), 130.0 (C-2ЈЈ),
128.4 (C-3ЈЈ), 127.9 (CHCSO2), 126.9 (C-4ЈЈ), 79.7 [C(CH3)3], 65.7
(C-4), 53.0 (COOCH3), 50.7 (C-5), 50.4 (C-1Ј), 40.8 (C-2Ј), 28.4
Methyl (S)-2-Azido-3-[(naphth-1-ylcarbonyl)(tolyl-4Ј-sulfonyl)-
amino]propionate (20g): 1-Naphthoic acid (16 mg, 0.09 mmol) was
coupled to azide 14d (25 mg, 0.08 mmol) as described in GP I. The
crude product was purified by FCC (8 g silica, cyclohexane/EtOAc,
17:8) to yield N-acyl-sulfonamide 20g (32 mg, 0.07 mmol, 85%) as
a colorless oil. Rf = 0.64 (light petroleum/EtOAc, 6:4). [α]2D0 = –18.0
[C(CH ) ], 21.8 (ArCH ) ppm. IR (KBr): ν = 2977 (m), 1746 (m),
˜
3 3
3
1712 (s), 1638 (m), 1499 (m), 1364 (s), 1167 (s) cm–1. HPLC: tR
=
1
(c = 1.0 in CHCl3). H NMR (400 MHz, CDCl3, 25 °C): δ = 7.90
11.7 min (method 2). LC-MS (ESI): tR = 10.9 min, C18; calcd. for
C2 5 H3 2 N3 O6 S [M + H]+ 502.2; found 501.9. HRMS for
C25H32N3O6S [M + H]+ 502.2000; found 502.2006.
(d, J = 8.1 Hz, 1 H, 8Ј-H), 7.79 (d, J = 8.1 Hz, 1 H, 2Ј-H), 7.57–
7.41 (m, 6 H, 5Ј-H, 6Ј-H, CHCSO2, 7Ј-H, 3Ј-H), 7.36 (ddd, J =
1.3, 6.9, 8.3 Hz, 1 H, 4Ј-H), 7.05 (d, J = 8.6 Hz, 2 H, CH3CCH),
4.52 (dd, J = 5.1, 8.9 Hz, 1 H, 2-H), 4.42 (dd, J = 5.1, 14.6 Hz, 1
H, 3-Ha), 4.26 (dd, J = 8.9, 14.6 Hz, 1 H, 3-Hb), 3.81 (s, 3 H,
COOCH3), 2.29 (s, 3 H, ArCH3) ppm. 13C NMR (100 MHz,
CDCl3, 25 °C): δ = 170.6 (OCNSO2), 168.8 (COOCH3), 145.3
(CHCSO2), 135.4 (CH3CCH), 133.3 (C-1Ј), 131.8 (C-4aЈ), 131.3
(C-8Ј), 130.0 (C-8aЈ), 129.6 (CH3CCH), 128.6 (CHCSO2), 128.5
(C-2Ј), 127.4 (C-6Ј), 126.9 (C-5Ј), 126.5 (C-7Ј), 124.6 (C-4Ј), 124.5
(C-3Ј), 61.0 (C-2), 53.3 (COOCH3), 46.8 (C-3), 21.7 (ArCH3) ppm.
Methyl (S)-2-[(1R,2R)-1-tert-Butoxycarbonylamino-2-(tert-butyl-
dimethylsilyloxy)propyl]-1-(tolyl-4Ј-sulfonyl)-4,5-dihydroimidazole-
4-carboxylate (21c): N-Acyl-sulfonamide 20c (54 mg, 0.09 mmol)
was cyclized in THF at reflux as described in GP F. The crude
product was purified by FCC (10 g silica, light petroleum/EtOAc,
39:11) to yield imidazoline 21c (45 mg, 0.08 mmol, 91%) as a color-
less oil. Rf = 0.11 (light petroleum/EtOAc, 3:2). [α]2D0 = +100.8 (c
= 1.0 in CHCl3). 1H NMR (400 MHz, CDCl3, 25 °C): δ = 7.93 (d,
J = 8.3 Hz, 2 H, CHCSO2), 7.34 (d, J = 8.0 Hz, 2 H, CH3CCH),
5.39 (d, J = 10.1 Hz, 1 H, NH), 5.29–5.23 (m, 1 H, 1Ј-H), 4.45–
4.37 (m, 1 H, 2Ј-H), 4.37–4.28 (m, 1 H, 5-Ha), 4.13 (dd, J = 9.6,
10.9 Hz, 1 H, 5-Hb), 3.77–3.70 (m, 4 H, 4-H, COOCH3), 2.43 (s, 3
H, ArCH3), 1.47 [s, 9 H, OC(CH3)3], 1.29 (d, J = 5.3 Hz, 3 H, 3Ј-
H), 0.85 [s, 9 H, SiC(CH3)3], 0.04 (s, 3 H, SiCH3a), –0.02 (s, 3
H, SiCH3b) ppm. 13C NMR (100 MHz, CDCl3, 25 °C): δ = 170.2
(COOCH3), 161.6 (C-2), 156.2 [COC(CH3)3], 145.2 (CH3CCH),
134.4 (CHCSO2), 130.4 (CH3CCH), 128.0 (CHCSO2), 79.8
[OC(CH3)3], 69.2 (C-2Ј), 66.5 (C-4), 55.4 (C-1Ј), 52.9 (COOCH3),
50.4 (C-5), 28.6 [OC(CH3)3], 26.0 [SiC(CH3)3], 21.8 (ArCH3), 21.3
(C-3Ј), 18.1 [SiC(CH3)3], –4.3 (SiCH3a), –4.9 (SiCH3b) ppm. IR
IR (KBr): ν = 2120 (s), 1747 (m), 1689 (m), 1358 (m), 1288 (w),
˜
1171 (m) cm–1. HPLC: tR = 11.6 min (method 2). LC-MS (ESI): tR
= 10.7 min, C18; calcd. for C22H21N4O5S [M + H]+ 453.1; found
452.6. HRMS (ESI): calcd. for C22H21N4O5S [M + H]+ 453.1223;
found 453.1227; HPLC with chiral modified columns: tR
=
24.9 min [Chiralpak IA, A: isohexane, B: CH2Cl2/EtOH 100:4; 10
to 50% (50 min) B, 0.5 mLmin–1].
Methyl (S)-2-[(S)-1-tert-Butoxycarbonylaminoethyl]-1-(tolyl-4Ј-sulf-
onyl)-4,5-dihydroimidazole-4-carboxylate (21a): N-Acyl-sulfon-
amide 20a (567 mg, 1.21 mmol) was cyclized in THF at reflux for
2.5 h as described in GP F. The acid-labile crude product was typi-
cally oxidized without further purification. For analytical purposes
the crude product was purified by chromatography (110 g silica, n-
hexane/EtOAc, 3:2 +0.5% NEt3) to yield imidazoline 21a (460 mg,
1.08 mmol, 89 %) as a colorless oil. Rf = 0.49 (light petroleum/
EtOAc, 2:3). [α]2D0 = +176.7 (c = 2.0 in toluene). 1H NMR
(400 MHz, [D6]benzene, 25 °C): δ = 8.00 (d, J = 8.1 Hz, 2 H,
CHCSO2), 6.87 (d, J = 8.1 Hz, 2 H, CH3CCH), 5.80–5.63 (m, 1 H,
CH3CH), 5.35 (d, J = 9.2 Hz, 1 H, NH), 4,12–3.94 (m, 2 H, 4-H,
5-Ha), 3.36–3.29 (m, 1 H, 5-Hb), 3.24 (s, 3 H, COOCH3), 1.86 (s,
3 H, ArCH3), 1.45–1.38 [m, 12 H, CH3CH, C(CH3)3] ppm. 13C
NMR (100 MHz, [D6]benzene, 25 °C): δ = 170.9 (COOCH3), 165.3
(C-2), 155.8 [COC(CH3)3], 144.9 (CH3CCH), 135.4 (CHCSO2),
130.6 (CH3CCH), 128.7 (CHCSO2), 79.5 [C(CH3)3], 66.1 (C-4),
52.3 (COOCH3), 51.6 (C-5), 46.7 (CH3CH), 28.8 [C(CH3)3], 21.6
(KBr): ν = 2932 (m), 2862 (w), 1748 (m), 1715 (s), 1495 (m), 1365
˜
(m), 1166 (s), 833 (m) cm–1. HPLC: tR = 12.5 min (method 2). LC-
MS (ESI): tR = 12.3 min, C18; calcd. for C26H44N3O7SSi
[M + H]+ 570.3; found 569.9. HRMS (ESI): calcd. for
C26H44N3O7SSi [M + H]+ 570.2664; found 570.2656.
Methyl (S)-2-[(S)-1-tert-Butoxycarbonylamino-2-methylpropyl]-1-
(tolyl-4Ј-sulfonyl)-4,5-dihydroimidazole-4-carboxylate (21d): N-
Acyl-sulfonamide 20d (25 mg, 0.050 mmol) was cyclized in THF at
reflux as described in GP F. The crude product was purified by
FCC (5 g silica, light petroleum/EtOAc, 18:7) to yield imidazoline
21d (21 mg, 0.046 mmol, 92%) as a colorless solid. Rf = 0.62 (light
petroleum/EtOAc, 2:3). [α]2D0 = +161.3 (c = 2.0 in CHCl3). 1H
NMR (400 MHz, CDCl3, 25 °C): δ = 7.92 (d, J = 8.2 Hz, 2 H,
SO2CCH), 7.33 (d, J = 8.1 Hz, 2 H, CH3CCH), 5.34 (dd, J = 3.4,
10.2 Hz, 1 H, 1Ј-H), 5.21 (d, J = 10.1 Hz, 1 H, NH), 4.46 (ddd, J
= 1.3, 6.7, 10.9 Hz, 1 H, 4-H), 4.10 (dd, J = 6.8, 10.3 Hz, 1 H, 5-
Ha), 3.74 (s, 3 H, COOCH3), 3.71–3.63 (m, 1 H, 5-Hb), 2.42 (s, 3
H, ArCH3), 2.34–2.21 (m, 1 H, 2Ј-H), 1.44 [s, 9 H, C(CH3)3], 1.06
(d, J = 6.8 Hz, 3 H, 3Ј-Ha), 0.87 (d, J = 6.9 Hz, 3 H, 3Ј-Hb) ppm.
13C NMR (100 MHz, CDCl3, 25 °C): δ = 170.9 (COOCH3), 163.6
(C-2), 155.8 [COC(CH3)3], 145.2 (CH3CCH), 134.0 (CHCSO2),
130.4 (CH3CCH), 128.1 (CHCSO2), 79.7 [OC(CH3)3], 65.5 (C-4),
53.6 (C-1Ј), 52.9 (COOCH3), 51.0 (C-5), 32.8 (C-2Ј), 28.5
[OC(CH3)3], 21.8 (ArCH3), 19.9 (C-3Јa), 16.0 (C-3Јb) ppm. IR
(CH CH), 21.5 (ArCH ) ppm. IR (KBr): ν = 2981 (m), 1753 (m),
˜
3
3
1702 (s), 1643 (m), 1364 (s), 1165 (s), 816 (w) cm–1. HPLC: tR
=
14.3 min (method 2). LC-MS (ESI): tR = 10.0 min, C18; calcd. for
C19H28N3O6S [M + H]+ 426.2; found 425.8. HRMS (ESI): calcd.
for C19H28N3O6S [M + H]+ 426.1693; found 426.1690.
Methyl (S)-2-[(S)-1-tert-Butoxycarbonylamino-2-phenylethyl]-1-
(tolyl-4Ј-sulfonyl)-4,5-dihydroimidazole-4-carboxylate (21b): Acyl-
ated sulfonamide 20b (32 mg, 0.059 mmol) was cyclized in THF at
reflux as described in GP F. The crude product was purified by
FCC (6 g silica, light petroleum/EtOAc, 14:11) to yield imidazoline
21b (22 mg, 0.044 mmol, 75%) as a colorless oil. Rf = 0.42 (light
petroleum/EtOAc, 2:3). [α]2D0 = +109.8 (c = 3.0 in CHCl3). 1H
(KBr): ν = 2973 (m), 1753 (m), 1698 (s), 1644 (m), 1534 (m), 1367
˜
(m), 1167 (s) cm–1. HPLC: tR = 11.5 min (method 2). LC-MS (ESI):
18
www.eurjoc.org
© 0000 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 0000, 0–0

Job/Unit: O30160
/KAP1
Date: 10-04-13 10:52:38
Pages: 27
Unified Azoline and Azole Syntheses
tR = 10.8 min, C18; calcd. for C21H32N3O6S [M + H]+ 454.2; found
(dd, J = 7.2, 8.2 Hz, 1 H, 2Ј-H), 7.43 (ddd, J = 1.1, 6.9, 8.1 Hz, 1
453.9. HRMS (ESI): calcd. for C21H32N3O6S [M + H]+ 454.2006; H, 7Ј-H), 7.34 (ddd, J = 1.2, 6.9, 8.3 Hz, 1 H, 6Ј-H), 7.19 (d, J =
found 454.2000.
8.3 Hz, 2 H, CHCSO2), 6.95 (d, J = 8.1 Hz, 2 H, CH3CCH), 4.88
(dd, J = 7.6, 10.6 Hz, 1 H, 4-H), 4.49–4.27 (m, 2 H, 5-H), 3.75 (s,
3 H, COOCH3), 2.26 (s, 3 H, ArCH3) ppm. 13C NMR (100 MHz,
CDCl3, 25 °C): δ = 171.0 (COOCH3), 159.6 (C-2), 144.7
(CH3CCH), 134.6 (CHCSO2), 133.2 (C-1Ј), 131.4 (C-4aЈ), 131.1
(C-4Ј), 129.5 (CH3CCH), 128.9 (C-3Ј), 128.2 (C-5Ј), 127.7
(CHCSO2), 126.9 (C-6Ј), 126.5 (C-8aЈ), 126.0 (C-7Ј), 125.1 (C-8Ј),
124.4 (C-2Ј), 66.7 (C-4), 52.9 (COOCH3), 50.9 (C-5), 21.5
tert-Butyl (R)-4-[(S)-4-Methoxycarbonyl-1-(tolyl-4Ј-sulfonyl)-4,5-di-
hydroimidazol-2-yl]-2,2-dimethylthiazolidine-3-carboxylate (21e): N-
Acyl-sulfonamide 20e (22 mg, 0.041 mmol) was cyclized in 2,6-lut-
idine at 80 °C as described in GP F. The crude product was purified
by FCC (5 g silica, light petroleum/EtOAc, 19:6) to yield imid-
azoline 21e (16 mg, 0.033 mmol, 80%) as a colorless solid. Rf =
0.30 (light petroleum/EtOAc, 7:3), m.p. 115–116 °C. [α]2D0 = +59.1
(ArCH ) ppm. IR (KBr): ν = 2962 (m), 1743 (s), 1631 (m), 1360
˜
3
1
(c = 1.0 in CHCl3). H NMR (400 MHz, CDCl3, 25 °C): δ = 7.96
(m), 1171 (s), 806 (m) cm–1. HPLC: tR = 9.1 min (method 2). LC-
MS (ESI): tR = 10.0 min, C18; calcd. for C22H21N2O4S [M + H]+
409.1; found 409.0. HRMS (ESI): calcd. for C22H21N2O4S [M +
H]+ 409.1217; found 409.1210; HPLC with chiral modified col-
umns: tR = 38.3 min [Chiralpak IA, A: isohexane, B: CH2Cl2/EtOH
100:4; 20% (70 min) B, 0.5 mLmin–1].
(d, J = 5.6 Hz, 2 H, SO2CCH)*, 7.77 (br. s, 2 H, SO2CCH)*, 7.35
(d, J = 8.1 Hz, 2 H, CH3CCH), 5.87, 5.57 (each br. s, 1 H, 4Ј-H)*,
4.61–4.38 (m, 1 H, 4-H)*, 4.11–3.95, 3.89–3.77 (each m, 2 H, 5-
H)*, 3.71 (s, 3 H, COOCH3), 3.63–3.51 (m, 2 H, 5-H)*, 3.51–3.35
(m, 1 H, 5Ј-Ha)*, 3.24–3.02 (m, 1 H, 5Ј-Hb)*, 2.43 (s, 3 H, ArCH3),
1.91–1.81 [m, 3 H, C(CH3)2a]*, 1.78 [s, 3 H, C(CH3)2b], 1.47, 1.35
[each s, 9 H, C(CH3)3]* ppm. * Rotamers. 13C NMR (100 MHz,
CDCl3, 25 °C): δ = 170.8 (COOCH3), 160.0 (C-2), 152.9
[COC(CH3)3], 144.9 (CH3CCH), 134.1 (CHCSO2), 130.3
(CH3CCH), 128.2 (CHCSO2), 80.7 [OC(CH3)3], 72.0 (C-2Ј)*, 70.5
(C-2Ј)*, 66.2 (C-4), 63.7 (C-4Ј)*, 62.6 (C-4Ј)*, 52.7 (COOCH3),
50.9 (C-5), 31.9 (C-5Ј), 31.6 [C(CH3)2b], 28.7 [C(CH3)3], 28.3
Methyl 2-[(S)-1-tert-Butoxycarbonylaminoethyl]-1-(tolyl-4Ј-sulf-
onyl)imidazole-4-carboxylate (22a): Crude imidazoline 21a (386 mg,
0.91 mmol) was oxidized with DBU (407 μL, 2.72 mmol) and
BrCCl3 (134 μL, 1.36 mmol) as described in GP G. The crude prod-
uct was purified by FCC (90 g silica, light petroleum/EtOAc, 17:8)
to yield imidazole 22a (266 mg, 0.63 mmol, 76%) as a colorless
solid (69% over two steps). Rf = 0.58 (light petroleum/EtOAc, 2:3),
m.p. 141–142 °C. [α]2D0 = –44.8 (c = 4.0 in CHCl3). 1H NMR
(400 MHz, CDCl3, 25 °C): δ = 7.91–7.97 (m, 3 H, CHCSO2, 5-H),
7.35 (d, J = 8.1 Hz, 2 H, CH3CCH), 5.44–5.54 (m, 1 H, CH3CH),
5.40 (d, J = 9.5 Hz, 1 H, NH), 3.86 (s, 3 H, COOCH3), 2.42 (s, 3
H, ArCH3), 1.45 (d, J = 6.6 Hz, 3 H, CH3CH), 1.38 [s, 9 H,
C(CH3)3] ppm. 13C NMR (100 MHz, CDCl3, 25 °C): δ = 162.3
(COOCH3), 154.8 (C-2), 152.1 [COC(CH3)3], 147.0 (CH3CCH),
134.3 (C-4), 132.7 (CHCSO2), 130.7 (CH3CCH), 128.2 (CHCSO2),
124.8 (C-5), 79.8 [C(CH3)3], 52.3 (COOCH3), 44.2 (CH3CH), 28.5
[C(CH ) ], 21.8 (ArCH ) ppm. * Rotamers. IR (KBr): ν = 2977
˜
3 2a
3
(w), 1745 (m), 1692 (m), 1641 (w), 1358 (s), 1098 (s), 811 (w) cm–1.
HPLC: tR = 12.4 min (method 2). LC-MS (ESI): tR = 11.2 min,
C18; calcd. for C22H32N3O6S2 [M + H]+ 498.2; found 497.9.
HRMS (ESI): calcd. for C22H32N3O6S2 [M + H]+ 498.1727; found
498.1720.
Methyl (S)-2-[(S)-2-tert-Butoxycarbonyl-2-tert-butoxycarbonyl-
aminoethyl]-1-(tolyl-4Ј-sulfonyl)-4,5-dihydroimidazole-4-carboxylate
(21f): N-Acyl-sulfonamide 20f (335 mg, 0.59 mmol) was cyclized in
THF at reflux as described in GP F. The crude product was purified
by FCC (50 g silica, light petroleum/EtOAc, 31:19) to yield imid-
azoline 21f (282 mg, 0.54 mmol, 91%) as a colorless oil. Rf = 0.49
[C(CH ) ], 22.8 (CH CH), 21.9 (ArCH ) ppm. IR (KBr): ν = 3337
˜
3 3
3
3
(m), 2984 (m), 1713 (s), 1558 (m), 1386 (m), 1163 (s), 813 (m) cm–1.
HPLC: tR = 10.5 min (method 2). LC-MS (ESI): tR = 10.2 min,
C18; calcd. for C19H26N3O6S [M + H]+ 424.2; found 423.8. HRMS
(ESI): calcd. for C19H26N3O6S [M + H]+ 424.1534; found 424.1537.
C19H25N3O6S: C 53.9, H 6.0, N 9.9; found C 53.6, H 6.0, N 10.0.
1
(light petroleum/EtOAc, 1:1). [α]2D0 = +42.8 (c = 1.0 in CHCl3). H
NMR (400 MHz, CDCl3, 25 °C): δ = 7.74 (d, J = 8.3 Hz, 2 H,
SO2CCH), 7.35 (d, J = 8.0 Hz, 2 H, CH3CCH), 5.77 (d, J = 9.2 Hz,
1 H, NH), 4.63–4.54 (m, 1 H, 1Ј-H), 4.54–4.46 (m, 1 H, 4-H), 4.00–
3.85 (m, 2 H, 5-H), 3.70 (s, 3 H, COOCH3), 3.39 (dd, J = 4.1,
17.6 Hz, 1 H, 2Ј-Ha), 2.99 (dd, J = 3.8, 17.1 Hz, 1 H, 2Ј-Hb), 2.44
Methyl 2-[(S)-1-tert-Butoxycarbonylamino-2-phenylethyl]-1-(tolyl-
4Ј-sulfonyl)imidazole-4-carboxylate (22b): Imidazoline 21b (117 mg,
0.23 mmol) was oxidized as described in GP G. The crude product
was purified by FCC (40 g silica, light petroleum/EtOAc, 18:7) to
yield imidazole 22b (86 mg, 0.17 mmol, 74%) as a colorless oil. Rf
= 0.64 (light petroleum/EtOAc, 1:1). [α]2D0 = –71.3 (c = 2.0 in
(s, 3 H, ArCH3), 1.43 [s, 9 H, C(CH3)3a], 1.39 [s, 9 H, C(CH3)3b
]
ppm. 13C NMR (100 MHz, CDCl3, 25 °C): δ = 171.0 (COOCH3),
170.1 [OC(O)CH], 159.3 (C-2), 155.9 [OC(O)NH], 145.3
(CH3CCH), 135.1 (CHCSO2), 130.4 (CH3CCH), 127.5 (CHCSO2),
81.9 [Ca(CH3)3], 79.7 [Cb(CH3)3], 65.3 (C-4), 52.9 (COOCH3), 51.3
(C-1Ј), 50.6 (C-5), 32.4 (C-2Ј), 28.6 [C(CaH3)3], 28.1 [C(CbH3)3],
1
CHCl3). H NMR (400 MHz, CDCl3, 25 °C): δ = 7.94 (s, 1 H, 5-
H), 7.92 (d, J = 8.1 Hz, 2 H, CHCSO2), 7.29 (d, J = 8.2 Hz, 2 H,
CH3CCH), 7.25–7.13 (m, 5 H, 3ЈЈ-H, 4ЈЈ-H, 2ЈЈ-H), 5.78–5.68 (m,
1 H, 1Ј-H), 5.33 (d, J = 9.8 Hz, 1 H, NH), 3.88 (s, 3 H, COOCH3),
3.27 (dd, J = 5.6, 13.5 Hz, 1 H, 2Ј-Ha), 2.97 (dd, J = 8.9, 13.4 Hz,
1 H, 2Ј-Hb), 2.39 (s, 3 H, ArCH3), 1.28 [s, 9 H, C(CH3)3] ppm.
13C NMR (100 MHz, CDCl3, 25 °C): δ = 162.3 (COOCH3), 154.7
[COC(CH3)3], 150.8 (C-2), 147.0 (CH3CCH), 136.7 (C-1ЈЈ), 134.3
(CHCSO2), 132.8 (C-4), 130.7 (CH3CCH), 129.7 (C-2ЈЈ), 128.5 (C-
3ЈЈ), 128.2 (CHCSO2), 126.9 (C-4ЈЈ), 124.7 (C-5), 79.7 [C(CH3)3],
52.4 (COOCH3), 49.4 (C-1Ј), 43.0 (C-2Ј), 28.3 [C(CH3)3], 21.9
21.8 (ArCH ) ppm. IR (KBr): ν = 2980 (m), 1743 (s), 1717 (s),
˜
3
1499 (m), 1364 (m), 1163 (s), 814 (w) cm–1. HPLC: tR = 10.2 min
(method 2). LC-MS (ESI): tR = 10.8 min, C18; calcd. for
C24H36N3O8S [M + H]+ 526.2; found 525.9. HRMS (ESI): calcd.
for C2 4 H3 6 N3 O8 S [M + H]+ 526.2218; found 526.2210.
C24H35N3O8S: C 54.8, H 6.7, N 8.0; found C 54.6, H 6.5, N 7.9.
Methyl (S)-2-(Naphthalen-1-yl)-1-(tolyl-4Ј-sulfonyl)-4,5-dihydro-
imidazole-4-carboxylate (21g): N-Acyl-sulfonamide 20g (177 mg,
0.39 mmol) was cyclized in 2,6-lutidine at 80 °C as described in
GP F. The crude product was purified by FCC (30 g silica, light
petroleum/EtOAc, 13:12) to yield imidazoline 21g (136 mg,
0.33 mmol, 85 %) as a colorless oil. Rf = 0.34 (light petroleum/
EtOAc, 1:1). [α]2D0 = +43.2 (c = 4.0 in CHCl3). 1H NMR (400 MHz,
CDCl3, 25 °C): δ = 7.92 (d, J = 8.2 Hz, 1 H, 4Ј-H), 7.79 (d, J =
8.5 Hz, 2 H, 5Ј-H, 8Ј-H), 7.62 (dd, J = 1.0, 7.1 Hz, 1 H, 3Ј-H), 7.47
(ArCH ) ppm. IR (KBr): ν = 1711 (s), 1497 (m), 1384 (m), 1162
˜
3
(s), 813 (w), 760 (w), 701 (w) cm–1. HPLC: tR = 11.9 min
(method 2). LC-MS (ESI): tR = 11.0 min, C18; calcd. for
C25H30N3O6S [M + H]+ 500.2; found 499.7. HRMS (ESI): calcd.
for C25H30N3O6S [M + H]+ 500.1844; found 500.1850.
Methyl 2-[(1R,2R)-1-tert-Butoxycarbonylamino-2-(tert-butyldi-
methylsilanyloxy)propyl]-1-(tolyl-4Ј-sulfonyl)imidazole-4-carb-
Eur. J. Org. Chem. 0000, 0–0
© 0000 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
19

Job/Unit: O30160
/KAP1
Date: 10-04-13 10:52:38
Pages: 27
P. Loos, C. Ronco, M. Riedrich, H.-D. Arndt
FULL PAPER
oxylate (22c): Imidazoline 21c (255 mg, 0.43 mmol) was oxidized
as described in GP G. The crude product was purified by FCC
(55 g silica, light petroleum/EtOAc, 21:4) to yield imidazole 22c
(213 mg, 0.38 mmol, 88%) as a colorless oil. Rf = 0.56 (light petro-
leum/EtOAc, 3:2). [α]2D0 = –34.5 (c = 4.0 in CHCl3). 1H NMR
(400 MHz, CDCl3, 25 °C): δ = 7.97 (d, J = 8.4 Hz, 2 H, CHCSO2),
7.93 (s, 1 H, 5-H), 7.33 (d, J = 8.1 Hz, 2 H, CH3CCH), 5.58 (d, J
= 10.1 Hz, 1 H, NH), 5.42 (dd, J = 3.6, 10.1 Hz, 1 H, 1Ј-H), 4.21–
4.07 (m, 1 H, 2Ј-H), 3.83 (s, 3 H, COOCH3), 2.40 (s, 3 H, ArCH3),
1.39 [s, 9 H, OC(CH3)3], 1.20 (d, J = 6.1 Hz, 3 H, 3Ј-H), 0.80 [s, 9
H, SiC(CH3)3], –0.12 (s, 3 H, SiCH3a), –0.21 (s, 3 H, SiCH3b) ppm.
13C NMR (100 MHz, CDCl3, 25 °C): δ = 162.3 (COOCH3), 155.7
[COC(CH3)3], 149.9 (C-2), 147.0 (CH3CCH), 134.6 (CHCSO2),
133.1 (C-4), 130.7 (CH3CCH), 128.2 (CHCSO2), 125.1 (C-5), 79.6
[OC(CH3)3], 71.3 (C-2Ј), 53.8 (C-1Ј), 52.2 (COOCH3), 28.5
[OC(CH3)3], 25.9 [SiC(CH3)3], 21.9 (ArCH3), 21.0 (C-3Ј), 18.1
C22H30N3O6S2 [M + H]+ 496.2; found 495.9. HRMS (ESI): calcd.
for C22H30N3O6S2 [M + H]+ 496.1571; found 496.1563.
Methyl 2-[(S)-2-tert-Butoxycarbonyl-2-tert-butoxycarbonylamino-
ethyl]-1-(tolyl-4Ј-sulfonyl)imidazole-4-carboxylate (22f): Imid-
azoline 21f (189 mg, 0.36 mmol) was oxidized as described in
GP G. The crude product was purified by FCC (45 g silica, light
petroleum/EtOAc, 33:17) to yield imidazole 22f (146 mg,
0.28 mmol, 77 %) as a colorless oil. Rf = 0.67 (light petroleum/
EtOAc, 3:2). [α]2D0 = +16.0 (c = 2.0 in CHCl3). 1H NMR (400 MHz,
CDCl3, 25 °C): δ = 7.98 (s, 1 H, 5-H), 7.80 (d, J = 8.3 Hz, 2 H,
SO2CCH), 7.35 (d, J = 8.1 Hz, 2 H, CH3CCH), 5.55 (d, J = 8.8 Hz,
1 H, NH), 4.68–4.53 (m, 1 H, 1Ј-H), 3.80 (s, 3 H, COOCH3), 3.34
(dd, J = 6.6, 16.1 Hz, 1 H, 2Ј-Ha), 3.26 (dd, J = 4.8, 16.0 Hz, 1 H,
2Ј-Hb ), 2.40 (s, 3 H, ArCH3 ), 1.35 [s, 18 H, C(CH3 )3 a
,
C(CH3)3b] ppm. 13C NMR (100 MHz, CDCl3, 25 °C): δ = 169.8
[OC(O)CH], 162.1 (COOCH3), 155.4 [OC(O)NH], 147.1
(CH3CCH), 146.4 (C-2), 134.2 (CHCSO2), 132.3 (C-4), 130.7
(CH3CCH), 127.9 (CHCSO2), 125.2 (C-5), 82.2 [Ca(CH3)3], 79.7
[Cb(CH3)3], 52.2 (C-1Ј), 52.0 (COOCH3), 31.5 (C-2Ј), 28.4
[SiC(CH3)3], –4.8 (SiCH3a), –5.1 (SiCH3b) ppm. IR (KBr): ν = 2954
˜
(m), 2858 (m), 1745 (m), 1714 (s), 1500 (m), 1383 (m), 1160 (s), 838
(m) cm–1. HPLC: tR = 14.6 min (method 2). LC-MS (ESI): tR
=
12.5 min, C18; calcd. for C26H42N3O7SSi [M + H]+ 568.3; found
567.9. HRMS (ESI): calcd. for C26H42N3O7SSi [M + H]+ 568.2507;
found 568.2508.
[C(C H ) ], 27.9 [C(C H ) ], 21.9 (ArCH ) ppm. IR (KBr): ν =
˜
a
3 3
b
3 3
3
2980 (m), 1739 (s), 1713 (s), 1499 (m), 1370 (m), 1158 (s), 813
(m) cm–1. HPLC: tR = 11.7 min (method 2). LC-MS (ESI): tR
=
10.8 min, C18; calcd. for C24H34N3O8S [M + H]+ 524.2; found
523.9. HRMS (ESI): calcd. for C24H34N3O8S [M + H]+ 524.2061;
found 524.2055. C24H33N3O8S: C 55.1, H 6.4, N 8.0; found C 55.1,
H 6.9, N 7.7.
Methyl 2-[(S)-1-tert-Butoxycarbonylamino-2-methylpropyl]-1-(tolyl-
4Ј-sulfonyl)imidazole-4-carboxylate (22d): Imidazoline 21d (260 mg,
0.52 mmol) was oxidized as described in GP G. The crude product
was purified by FCC (45 g silica, light petroleum/EtOAc, 19:6) to
yield imidazole 22d (217 mg, 0.48 mmol, 92%) as a colorless oil. Rf
= 0.53 (light petroleum/EtOAc, 16:9). [α]2D0 = –54.9 (c = 6.0 in
CHCl3). 1H NMR (400 MHz, CDCl3, 25 °C): δ = 7.94 (d, J =
8.3 Hz, 2 H, SO2CCH), 7.91 (s, 1 H, 5-H), 7.30–7.25 (m, 2 H,
CH3CCH), 5.36–5.19 (m, 2 H, NH, 1Ј-H), 3.80 (s, 3 H, COOCH3),
2.34 (s, 3 H, ArCH3), 2.16–1.98 (m, 1 H, 2Ј-H), 1.33 [s, 9 H,
C(CH3)3], 0.92 (d, J = 6.8 Hz, 3 H, 3Ј-Ha), 0.82 (d, J = 6.7 Hz, 3
H, 3Ј-Hb) ppm. 13C NMR (100 MHz, CDCl3, 25 °C): δ = 162.2
(COOCH3), 155.2 [COC(CH3)3], 151.1 (C-2), 146.8 (CH3CCH),
134.4 (CHCSO2), 132.7 (C-4), 130.6 (CH3CCH), 128.2 (CHCSO2),
124.5 (C-5), 79.4 [OC(CH3)3], 52.6 (C-1Ј), 52.2 (COOCH3), 35.2
(C-2Ј), 28.3 [OC(CH3)3], 21.8 (ArCH3), 19.4 (C-3Јa), 17.7 (C-
Methyl 2-(Naphthalen-1-yl)-1-(tolyl-4Ј-sulfonyl)imidazole-4-carb-
oxylate (22g): Imidazoline 21g (92 mg, 0.23 mmol) was oxidized as
described in GP G. The crude product was purified by FCC (30 g
silica, light petroleum/EtOAc, 33:17) to yield imidazole 22g (76 mg,
0.19 mmol, 82%) as a colorless solid. Rf = 0.62 (light petroleum/
EtOAc, 1:1), m.p. 157–159 °C. 1H NMR (400 MHz, CDCl3, 25 °C):
δ = 8.43 (s, 1 H, 5-H), 8.00–7.88 (m, 1 H, 4Ј-H), 7.76 (d, J = 8.2 Hz,
1 H, 8Ј-H), 7.54–7.42 (m, 2 H, 3Ј-H, 2Ј-H), 7.34 (ddd, J = 1.1, 6.8,
8.1 Hz, 1 H, 7Ј-H), 7.07 (ddd, J = 1.3, 6.8, 8.3 Hz, 1 H, 6Ј-H), 6.89
(d, J = 8.5 Hz, 2 H, CHCSO2), 6.85 (dd, J = 0.8, 8.5 Hz, 1 H, 5Ј-
H), 6.74 (d, J = 8.0 Hz, 2 H, CH3CCH), 3.92 (s, 3 H, COOCH3),
2.13 (s, 3 H, ArCH3) ppm. 13C NMR (100 MHz, CDCl3, 25 °C): δ
= 162.6 (COOCH3), 146.5 (CH3CCH), 146.4 (C-2), 132.9 (C-4aЈ),
132.7 (CHCSO2), 132.7 (C-1Ј), 132.4 (C-4), 130.9 (C-4Ј), 130.4 (C-
3Ј), 129.6 (CH3CCH), 128.1 (CHCSO2), 128.0 (C-8Ј), 126.7 (C-6Ј),
125.9 (C-7Ј), 125.7 (C-8aЈ), 125.4 (C-5), 125.0 (C-5Ј), 124.4 (C-2Ј),
3Ј ) ppm. IR (KBr): ν = 2968 (m), 1713 (s), 1501 (m), 1382 (m),
˜
b
1165 (s), 815 (w) cm–1. HPLC: tR = 11.8 min (method 2). LC-MS
(ESI): tR = 11.0 min, C18; calcd. for C21H30N3O6S [M + H]+ 452.2;
found 451.8. HRMS (ESI): calcd. for C21H30N3O6S [M + H]+
452.1850; found 452.1842.
52.3 (COOCH ), 21.6 (ArCH ) ppm. IR (KBr): ν = 2949 (w), 1740
˜
3
3
(s), 1595 (w), 1530 (w), 1381 (m), 1176 (s), 803 (m), 777 (m) cm–1.
HPLC: tR = 10.9 min (method 2). LC-MS (ESI): tR = 10.4 min,
C18; calcd. for C22H19N2O4S [M + H]+ 407.1; found 407.0. HRMS
(ESI): calcd. for C22H19N2O4S [M + H]+ 407.1060; found 407.1055.
tert-Butyl (R)-4-[4-Methoxycarbonyl-1-(tolyl-4Ј-sulfonyl)imidazol-2-
yl]-2,2-dimethylthiazolidine-3-carboxylate (22e): Imidazoline 21e
(166 mg, 0.33 mmol) was oxidized as described in GP G. The crude
product was purified by FCC (35 g silica, light petroleum/EtOAc,
39:11) to yield imidazole 22e (149 mg, 0.30 mmol, 91%) as a color-
Methyl 2-[(S)-1-tert-Butoxycarbonylaminoethyl]imidazole-4-carb-
oxylate (23): Methyl (S)-2-[(S)-1-tert-butoxycarbonylaminoethyl]-
2.0 in CHCl3). H NMR (400 MHz, CDCl3, 25 °C): δ = 8.06–7.81 1-(tolyl-4Ј-sulfonyl)-4,5-dihydroimidazole-4-carboxylate (21a,
(m, 3 H, 5-H, SO2CCH), 7.37 (d, J = 8.0 Hz, 2 H, CH3CCH), 5.83 192 mg, 0.45 mmol) was dissolved in anhydrous DMF (5.4 mL).
less oil. Rf = 0.49 (light petroleum/EtOAc, 7:3). [α]2D0 = –60.4 (c =
1
(br. s, 1 H, 4Ј-H), 3.81 (s, 3 H, COOCH3), 3.38 (br. s, 1 H, 5Ј-Ha),
DBU (1 mL, 6.76 mmol) was added at 0 °C and the mixture was
2.86 (br. s, 1 H, 5Ј-Hb), 2.44 (s, 3 H, ArCH3), 2.02 [s, 3 H, stirred at room temperature for 3 h. EtOAc, (20 mL) and water
C(CH3 )2 a ], 1.81 [s, 3 H, C(CH3 )2 b ], 1.57–0.87 [m, 9 H, (30 mL) were added and the pH of the aqueous layer was adjusted
C(CH3)3]* ppm. * Rotamers. 13C NMR (100 MHz, CDCl3, 25 °C): to pH 3–4 with NaHSO4 solution (1 m). The layers were separated
δ = 162.5 (COOCH3), 150.0 [COC(CH3)3, C-2], 147.0 (CHCCH3),
134.6 (CHCSO2), 132.7 (C-4), 130.7 (CH3CCH), 128.1 (CHCSO2),
125.1 (C-5), 80.6 [OC(CH3)3], 71.8 (C-2Ј), 61.2 (C-4), 52.0 (CO-
OCH3), 33.3 (C-5), 29.8 [C(CH3)2b], 28.4 [C(CH3)2a, C(CH3)3], 22.0
and the aqueous layer was extracted with EtOAc, (2ϫ 20 mL). The
pH of the aqueous layer was adjusted to pH 9 with satd. NaHCO3
solution and the layer was extracted with EtOAc, (3ϫ 20 mL). The
combined organic extracts were dried (MgSO4) and concentrated
(ArCH ) ppm. IR (KBr): ν = 2978 (m), 1743 (m), 1702 (m), 1354 in vacuo. The crude product was purified by FCC (35 g silica, light
˜
3
(s), 1161 (s), 1088 (m), 816 (w) cm–1. HPLC: tR = 12.3 min
petroleum/EtOAc, 3:7) to yield imidazole 23 (74 mg, 0.27 mmol,
60%) as a colorless oil. Rf = 0.25 (light petroleum/EtOAc, 3:7).
(method 2). LC-MS (ESI): tR = 11.3 min, C18; calcd. for
20
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© 0000 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 0000, 0–0

Job/Unit: O30160
/KAP1
Date: 10-04-13 10:52:38
Pages: 27
Unified Azoline and Azole Syntheses
[α]2D0 = –69.8 (CHCl3, c = 2.0). 1H NMR (400 MHz, CDCl3, 25 °C):
δ = 7.61 (s, 1 H, 5-H), 5.80 (d, J = 7.8 Hz, 1 H, NH), 4.97–4.83
30 mL) and stirred at room temperature for 4 h. All volatiles were
removed in vacuo, and the obtained crude ammonium salt (3.96 g,
(m, 1 H, CHCH3), 3.81 (s, 3 H, COOCH3), 1.55 (d, J = 7.0 Hz, 3 13.43 mmol, 99 %) was converted into the azide as described in
H, CHCH3), 1.36 [s, 9 H, C(CH3)3] ppm. 13C NMR (100 MHz, GP B. The crude product was purified by FCC (400 g silica,
CDCl3, 25 °C): δ = 163.0 (COOCH3), 156.2 [COC(CH3)3], 152.1
(C-2), 129.7 (C-4), 125.9 (C-5), 80.3 [C(CH3)3], 51.8 (COOCH3),
CH2Cl2/MeOH 99:1 +0.5% HCOOH) to yield acid 25d (2.72 g,
9.57 mmol, 71%) as a light yellow oil. Rf = 0.21 (CHCl3/MeOH/
44.9 (CH CH), 28.4 [C(CH ) ], 19.9 (CH CH) ppm. IR (KBr): ν = HCOOH 184:16:1). [α]2D0 = –54.0 (c = 2.0 in MeOH). 1H NMR
˜
3
3 3
3
2981 (m), 1714 (s), 1525 (m), 1250 (m), 1165 (s) cm–1. HPLC: tR
=
(400 MHz, CDCl3, 25 °C): δ = 8.87 (br. s, 1 H, COOH), 7.74 (d, J
= 8.2 Hz, 2 H, SO2CCH), 7.31 (d, J = 8.0 Hz, 2 H, CH3CCH),
5.62 (t, J = 6.1 Hz, 1 H, SO2NH), 4.20 (t, J = 5.7 Hz, 1 H,
5.9 min (method 2). LC-MS (ESI): tR = 4.9 min, C18; calcd. for
C12H20N3O4 [M + H]+ 270.1; found 269.7 min, C18. HRMS (ESI):
calcd. for C12H20N3O4 [M + H]+ 270.1448; found 270.1483.
CH2CH), 3.41–3.18 (m, 2 H, CH2), 2.42 (s, 3 H, ArCH3) ppm. 13
C
NMR (100 MHz, CDCl3, 25 °C): δ = 172.5 (COOH), 144.4 (CSO2),
136.4 (CH3CCH), 130.2 (CHCSO2), 127.2 (CH3CCH), 61.3
(S)-2-Azido-3-(trityloxy)propionic Acid (25a): O-Trityl-serine
(1.04 g, 3.0 mmol) was converted as described in GP A with CuSO4
as catalyst and Et3N as base. After FCC (light petroleum/EtOAc/
AcOH, 20:20:0.1), azide 25a was isolated as a colorless solid
(0.81 g, 2.2 mmol, 72%). Rf = 0.17 (light petroleum/EtOAc/AcOH,
20:20:0.1), m.p. 121–122 °C (dec. Ͼ 126 °C). [α]2D0 = –18.6 (CHCl3,
(CH CH), 43.8 (CH ), 21.7 (ArCH ) ppm. IR (KBr): ν = 2118 (s),
˜
2
2
3
1742 (m), 1327 (m), 1159 (s), 814 (w) cm–1. HPLC: tR = 8.0 min
(method 9). HRMS (ESI): calcd. for C10H13N4O4S [M + H]+
285.0652; found 285.0654.
1
c = 1.0). H NMR (400 MHz, CDCl3): δ = 8.94 (br. s, 1 H, CO2
Methyl (2S,2ЈS)-2-Azido-3-[2-azido-3-(trityloxy)propanoyloxy]-
propionate (26a): Carboxylic acid 25a (280 mg, 0.75 mmol) and
alcohol 14a (83 mg, 0.57 mmol) were coupled with DIC as de-
scribed in GP E. After FCC (light petroleum/EtOAc, 7:1), bisazide
26a was isolated as a colorless oil (264 mg, 0.53 mmol, 92%). Rf =
0.23 (light petroleum/EtOAc, 4:1). [α]2D0 = –25.6 (CHCl3, c = 1.0).
1H NMR (400 MHz, CDCl3): δ = 7.45–7.21 (m, 15 H, Tr), 4.50
(dd, J = 6.2, 11.6 Hz, 1 H, 3-H), 4.43 (dd, J = 3.8, 11.6 Hz, 1 H,
3-H), 4.07 (dd, J = 3.8, 6.3 Hz, 1 H, 2-H), 3.87 (dd, J = 3.8, 4.8 Hz,
1 H, 2Ј-H), 3.79 (s, 3 H, CO2CH3), 3.56 (m, 2 H, 3Ј-H2) ppm. IR
H), 7.42–7.22 (m, 15 H, Tr), 4.16 (dd, J = 2.9, 4.1 Hz, 1 H, CHN3),
3.45 (dd, J = 4.3, 9.6 Hz, 1 H, CHHOTr), 3.29 (dd, J = 2.9, 9.7 Hz,
1 H, CHHOTr) ppm. 13C NMR (100 MHz, CDCl3): δ = 173.8
(CO2 H), 143.0, 128.5, 128.0, 127.3 (Tr), 87.6 (CPh3), 63.9
(CH OTr), 61.5 (CHN ) ppm. IR (KBr): ν = 3391 (s), 3559 (bs),
˜
2
3
2881 (m), 2111 (s), 1757 (m), 1731 (s), 1632 (m), 1490 (m), 1447
(m), 1223 (s), 1092 (m), 1011 (m), 904 (m), 707 (s), 632 (m) cm–1.
HPLC: tR = 9.8 min (method 8). HRMS (ESI): calcd. for
C22H18N3O3 [M – H]– 372.1354; found 372.1340.
(R)-2-Azido-3-[(4-methoxyphenyl)diphenylmethylthio]propionic Acid (KBr): ν = 3375 (bm), 3059 (m), 2973 (m), 2108 (s), 1748 (s), 1712
˜
(25b): S-Methoxytrityl-cysteine (3.94 g, 10 mmol) was converted (m), 1617 (m), 1492 (m), 1449 (m), 1388 (w), 1242 (s), 1179 (s),
into the corresponding azide as described in GP A with CuSO4 as
catalyst and Et3N as base. After FCC (2ϫ, light petroleum/EtOAc/
1092 (m), 1033 (w), 901 (w), 763 (m), 707 (s), 634 (w) cm–1. LC-
MS (ESI): tR = 11.2 min; calcd. for C26H24N6O5Na [M + Na]+
AcOH, 20:20:0.1), azide 25b was isolated as a slightly yellow oil 523.2; found 523.3. HRMS (ESI): calcd. for C26H24N6O5Na [M +
(4.15 g, 9.9 mmol, 99 %). Rf = 0.23 (light petroleum/EtOAc/ Na]+ 523.1700; found 523.1695.
HCOOH, 50:50:0.1). [α]2D0 = –51.2 (CHCl3, c = 0.5). 1H NMR
Methyl (2R,2ЈS)-2-Azido-3-{2-azido-3-[(4-methoxyphenyl)-
diphenylmethylthio]propanoylthio}propionate (26b): Trityl thioether
14c (605 mg, 1.5 mmol) was treated at room temp. with Et3SiH
(0.26 mL, 1.65 mmol) in CH2Cl2/TFA (10 mL, 20:1) for 30 min.
The reaction mixture was diluted with toluene (10 mL) and the
solvent was removed in vacuo. Carboxylic acid 25b (818 mg,
1.95 mmol) was dissolved in THF (15 mL) and cooled to –20 °C.
NMM (0.38 mL, 3.50 mmol), isopropyl chloroformate (0.25 mL,
1.95 mmol), and the crude thiol 24 in THF (3 mL) were added
dropwise. The reaction mixture was stirred for 2 h at –20 °C, fil-
tered through a sinter plate, and diluted with EtOAc, (150 mL).
The organic layer was washed twice with citric acid (5%) and satu-
rated NaCl solution, dried with MgSO4, and concentrated in
vacuo. After FCC (light petroleum/EtOAc, 9:1), bisazide 26b was
isolated as a colorless oil (574 mg, 1.02 mmol, 68%). Rf = 0.42
(light petroleum/EtOAc, 2:1). 1H NMR (400 MHz, CDCl3): δ =
7.47–7.15 (m, 13 H, Mmt), 6.88–6.76 (m, 2 H, Mmt), 4.02 (dt, J =
5.3, 7.8 Hz, 1 H, 2-H), 3.78 (s, 3 H, CO2CH3), 3.77 (s, 3 H, Mmt-
OCH3), 3.30 (dd, J = 5.5, 13.9 Hz, 1 H, 3-Ha), 3.16–3.03 (m, 2 H,
3-Hb, 2Ј-H), 2.73 (dd, J = 5.1, 13.8 Hz, 1 H, 3Ј-Ha), 2.61 (dd, J =
8.8, 13.8 Hz, 1 H, 3Ј-Hb) ppm. 13C NMR (100 MHz, CDCl3): δ =
196.1 (C-1Ј), 168.9 (C-1), 158.5, 144.6, 136.3, 130.9, 129.6, 128.3,
127.1, 113.6, 68.3 (Mmt), 67.3 (C-2), 61.1 (C-2Ј), 55.4 (Mmt-
(400 MHz, CDCl3): δ = 9.72 (s, 1 H, CO2 H), 7.51–7.14 (m, 12 H,
Mmt), 6.81 (d, J = 9.0 Hz, 2 H, Mmt), 3.77 (s, 3 H, OCH3), 3.22
(dd, J = 5.7, 8.2 Hz, 1 H, CHN3), 2.71 (dd, J = 5.7, 13.5 Hz, 1 H,
CHHSMmt), 2.58 (dd, J = 8.2, 13.5 Hz, 1 H, CHHSMmt) ppm.
13C NMR (100 MHz, CDCl3): δ = 173.9 (CO2 H), 158.5, 144.6,
136.4, 130.9, 129.6, 128.3, 127.1, 113.6 (Mmt), 67.1 (CHN3), 55.5
(OCH ), 33.3 (CH SMmt) ppm. IR (KBr): ν = 3055 (ws), 2115 (s),
˜
3
2
1727 (s), 1605 (m), 1506 (s), 1444 (m), 1250 (s), 1181 (s), 1081 (w),
1034 (m), 823 (m), 743 (m), 700 (s), 621 (w), 581 (m) cm–1.
(R)-2-Azido-3-(tritylthio)propionic Acid (25c): S-Trityl-cysteine
(0.73 g, 2.0 mmol) was converted into the corresponding azide as
described in GP A with CuSO4 as catalyst and K2CO3 (0.41 g,
3 mmol) as base. After FCC (light petroleum/EtOAc/AcOH,
20:20:0.1), azide 25c was isolated as a colorless oil (0.73 g,
1.9 mmol, 94 %). Rf = 0.20 (light petroleum/EtOAc/HCOOH,
50:50:0.1). [α]2D0 = –15.2 (CHCl3, c = 0.5). 1H NMR (400 MHz,
CDCl3): δ = 7.43 (d, J = 7.6 Hz, 6 H, Tr), 7.33–7.19 (m, 9 H, Tr),
3.14 (t, J = 6.3 Hz, 1 H, CHN3), 2.71 (dd, J = 5.2, 13.5 Hz, 1 H,
CHHSTr), 2.59 (dd, J = 7.9, 13.3 Hz, 1 H, CHHSTr) ppm; not
detected: CO2H; 13C NMR (100 MHz, CDCl3): δ = 174.3 (CO2 H),
144.3, 129.7, 128.4, 127.2 (Tr), 67.7 (CHN3), 33.3 (CH2STr) ppm.
IR (KBr): ν = 3062 (ws), 2361 (m), 2118 (s), 1958 (w), 1719 (s),
˜
1595 (w), 1489 (m), 1445 (m), 1241 (m), 1080 (w), 1034 (w), 890
(m), 743 (s), 698 (s) cm–1. HRMS (ESI): calcd. for C22H18N3O2S
([M – H]–) 388.1125; found 388.1125.
OCH ), 53.2 (CO CH ), 34.4 (C-3), 30.4 (C-3Ј) ppm. IR (KBr): ν
˜
3
2
3
= 3354 (bw), 3056 (m), 2954 (m), 2837 (m), 2493 (bw), 2115 (s),
1747 (s), 1694 (s), 1651 (w), 1605 (m), 1556 (w), 1506 (s), 1443 (m),
1251 (m), 1081 (m), 1033 (s), 823 (s), 743 (s), 701 (s), 622 (m), 581
(m), 544 (w) cm–1. HPLC: tR = 12.8 min (method 11). MS (ESI):
calcd. for C27H26N6O4S2Na [M + Na]+ 585.1; found 585.2.
(S)-2-Azido-3-(tolyl-4Ј-sulfonylamino)propionic Acid (25d): (S)-2-
(tert-Butoxycarbonylamino)-3-(tolyl-4Ј-sulfonylamino)propionic
acid (4.86 g, 13.57 mmol) was dissolved in HCl in dioxane (4 n,
Eur. J. Org. Chem. 0000, 0–0
© 0000 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
21

Job/Unit: O30160
/KAP1
Date: 10-04-13 10:52:38
Pages: 27
P. Loos, C. Ronco, M. Riedrich, H.-D. Arndt
FULL PAPER
Methyl (2S,2ЈR)-2-Azido-3-[2-azido-3-(tritylthio)propanoyloxy]-
propionate (26c): Methyl ester 14c (450 mg, 1.12 mmol) was dis-
solved in THF (6 mL), cooled to 0 °C, treated with LiOH (1 m,
2.2 mL), and stirred for 20 min at room temp. The reaction mixture
was acidified with citric acid (10%) and the organic solvent was
evaporated. The aqueous residue was extracted with EtOAc, (3ϫ
25 mL). The combined organic layers were washed with saturated
NaCl solution, dried with Na2SO4, and concentrated in vacuo. The
crude carboxylic acid 25c (which was also available by diazo trans-
fer on the free acid; see above) was coupled with alcohol 14a
layer was extracted with ethyl acetate (3ϫ 25 mL), and the com-
bined organic extracts were dried (MgSO4) and concentrated in
vacuo. FCC (150 g silica, light petroleum/EtOAc, 33:17) yielded
thioester 26e (435 mg, 1.02 mmol, 70%) as a yellow oil. Rf = 0.09
(light petroleum/EtOAc, 4:1). [α]2D0 = –61.0 (c = 3.0 in CHCl3). H
1
NMR (500 MHz, CDCl3, 25 °C): δ = 7.75 (d, J = 8.3 Hz, 2 H,
SO2CCH), 7.32 (d, J = 8.0 Hz, 2 H, CH3CCH), 5.13 (t, J = 6.1 Hz,
1 H, NH), 4.20 (dd, J = 5.1, 7.1 Hz, 1 H, 2-H), 4.16–4.05 (m, 1 H,
2Ј-H), 3.82 (m, 3 H, COOCH3), 3.45–3.34 (m, 2 H, 3-Ha, 3Ј-Ha),
3.23–3.15 (m, 2 H, 3Ј-Hb, 3-Hb), 2.43 (s, 3 H, ArCH3) ppm. 13C
(161 mg, 1.1 mmol) as described in GP E with DIC (0.22 mL, NMR (125 MHz, CDCl3, 25 °C): δ = 196.1 (C-1), 169.0 (COOMe),
1.45 mmol). After FCC (light petroleum/EtOAc, 5:1), bisazide 26c
was isolated as a colorless oil (339 mg, 0.66 mmol, 59%). Rf = 0.43
(light petroleum/EtOAc, 2:1). [α]2D0 = –22.8 (CHCl3, c = 0.5). 1H
NMR (400 MHz, CDCl3): δ = 7.45–7.20 (m, 15 H, Tr), 4.47–4.34
144.2 (CH3CCH), 136.7 (CHCSO2), 130.1 (CH3CCH), 127.3
(CHCSO2), 68.6 (C-2), 61.0 (C-2Ј), 53.4 (COOCH3), 44.7 (C-3),
30.4 (C-3Ј), 21.7 (ArCH ) ppm. IR (KBr): ν = 2956 (w), 2926 (w),
˜
3
2110 (s), 1743 (m), 1685 (m), 1328 (m), 1157 (s), 814 (m) cm–1.
(m, 2 H, 3-H2), 4.16–4.05 (m, 1 H, 2-H), 3.74 (2ϫ s, 3 H, CO2CH3), HPLC: tR = 11.0 min (method 3). LC-MS (ESI): tR = 9.7 min, C18;
3.16–3.01 (m, 1 H, 2Ј-H), 2.71 (dd, J = 6.1, 13.6 Hz, 1 H, 3Ј-H),
calcd. for C14H18N7O5S2 [M + H]+ 428.1; found 427.9. HRMS
(ESI): calcd. for C14H18N7O5S2 [M + H]+ 428.0805; found
428.0805.
2.56 (ddd, J = 2.4, 8.1, 13.6 Hz, 1 H, 3Ј-H) ppm. IR (KBr): ν =
˜
3060 (m), 3031 (m), 2957 (w), 2113 (s), 1749 (s), 1595 (w), 1490
(m), 1445 (m), 1211 (s), 1179 (s), 1080 (w), 1034 (w), 855 (s), 800
(s), 747 (m), 702 (m), 676 (w), 620 (w) cm–1. MS (MALDI): calcd.
for C26H24N6O4SNa [M + Na]+ 539.1; found 539.6.
Methyl (2S,2ЈS,2ЈЈS)-2-Azido-3-[2-azido-3-(N-Boc-alanyloxy)-
propanoyloxy]propionate (27a): Trityl ether 26a (125 mg,
0.25 mmol) was treated at room temp. with Et3SiH (0.04 mL,
0.26 mmol) in CH2Cl2/TFA (5.5 mL, 10:1) for 10 min. The reaction
(S)-2-Azido-2-(methoxycarbonyl)ethyl (S)-2-Azido-3-(tolyl-4Ј-sulf-
onylamino)propionate (26d): (S)-2-Azido-3-(tolyl-4Ј-sulfonyl- mixture was carefully neutralized by dropwise addition of saturated
amino)propionic acid (25d, 1.21 g, 4.26 mmol) and HOBt (1.15 g,
NaHCO3 solution and diluted with H2O (10 mL). The layers were
8.5 mmol) were dissolved in anhydrous CH2Cl2 (15 mL) and DMF
separated and the aqueous layer was extracted with CH2Cl2 (2ϫ
(4 mL) and cooled to 0 °C. EDCϫHCl (1.64 g, 8.5 mmol) was 15 mL). The combined organic extracts were dried with MgSO4
added, and the mixture was stirred for 15 min. Methyl (S)-2-azido-
3-hydroxypropionate (14a, 560 mg, 3.86 mmol), dissolved in anhy-
drous CH2Cl2, was added (5 mL). The mixture was stirred for 2 h
at room temp., and the solvent was evaporated in vacuo The crude
product was dissolved in ethyl acetate (100 mL) and washed with
NaHSO4 solution (1 m, 200 mL). The aqueous layer was extracted
with ethyl acetate (3ϫ 100 mL), and the combined organic extracts
were dried (MgSO4) and concentrated in vacuo. FCC (400 g silica,
light petroleum/EtOAc, 33:17) yielded ester 26d (956 mg,
2.35 mmol, 61%) as a light yellow oil. Rf = 0.41 (light petroleum/
EtOAc, 31:19). [α]2D0 = –57.9 (c = 2.0 in CHCl3). 1H NMR
(500 MHz, CDCl3, 25 °C): δ = 7.75 (d, J = 8.3 Hz, 2 H, SO2CCH),
7.32 (d, J = 8.0 Hz, 2 H, CH3CCH), 5.11 (t, J = 6.7 Hz, 1 H, NH),
4.56 (dd, J = 4.0, 11.5 Hz, 1 H, 3Ј-Ha), 4.47 (dd, J = 5.8, 11.5 Hz,
and concentrated in vacuo. The crude alcohol was coupled with N-
Boc-alanine (61 mg, 0.33 mmol) as described in GP E with DIC
(60 µL, 0.35 mmol). After FCC (light petroleum/EtOAc, 2:1), tri-
ester 27a was isolated as a colorless oil (75 mg, 0.18 mmol, 70%).
Rf = 0.19 (light petroleum/EtOAc, 2:1). [α]2D0 = –30.0 (CHCl3, c =
1
0.1). H NMR (400 MHz, CDCl3): δ = 4.98 (d, J = 4.7 Hz, 1 H,
NH), 4.61–4.39 (m, 4 H, 3Ј-H2, 3-H2), 4.32 (br. s, 1 H, 2Ј-H), 4.21
(ddd, J = 4.2, 5.8, 10.0 Hz, 1 H, 2-H), 4.14 (dd, J = 4.7, 9.3 Hz, 1
H, 2ЈЈ-H), 3.83 (s, 3 H, CO2CH3), 1.42 [s, 9 H, CO2C(CH3)3], 1.38
(d, J = 7.2 Hz, 3 H, 3ЈЈ-H3) ppm. 13C NMR (100 MHz, CDCl3): δ
= 172.9 (C-1ЈЈ), 168.0, 167.2 (C-1Ј, C-1), 155.3 (CO2tBu), 80.3
[C(CH3)3], 65.0, 64.2 (C-3Ј, C-3), 60.4, 60.3 (C-2Ј, C-2), 53.5
(CO2CH3), 49.4 (C-2ЈЈ), 28.5 [C(CH3)3], 18.5 (C-3ЈЈ) ppm. IR
(KBr): ν = 3363 (bw), 2979 (m), 2112 (s), 1748 (s), 1714 (s), 1566
˜
1 H, 3Ј-Hb), 4.23 (dd, J = 4.0, 5.7 Hz, 1 H, 2Ј-H), 4.18 (dd, J = (w), 1505 (m), 1455 (m), 1368 (m), 1245 (m), 1167 (s), 1069 (m),
5.6, 6.3 Hz, 1 H, 2-H), 3.85 (s, 3 H, COOCH3), 3.31 (ddd, J = 5.5, 797 (w), 555 (w) cm–1. LC-MS (ESI): tR = 8.9 min; calcd. for
6.7, 13.7 Hz, 1 H, 3-Ha), 3.27–3.19 (m, 1 H, 3-Hb), 2.43 (s, 3 H,
ArCH3) ppm. 13C NMR (125 MHz, CDCl3, 25 °C): δ = 168.1 (CO-
OMe), 167.9 (C-1), 144.2 (CH3CCH), 136.8 (CHCSO2), 130.1
(CH3CCH), 127.2 (CHCSO2), 64.9 (C-3Ј), 61.5 (C-2), 60.3 (C-2Ј),
C15H23N7O8 [M]+ 429.2; found 428.8. HRMS (ESI): calcd. for
C15H24N7O8 [M + H]+ 430.1681; found 430.1681.
Methyl (2R,2ЈS,2ЈЈS)-2-Azido-3-[2-azido-3-(N-Boc-alanylthio)-
propanoylthio]propionate (27b): Methoxytrityl thioether 26b (48 mg,
0.09 mmol) was treated with Et3SiH (20 µL, 0.10 mmol) in CH2Cl2/
TFA (4.0 mL, 3:1) for 30 min at room temp. The reaction mixture
14 was diluted with toluene (10 mL) and concentrated in vacuo. The
crude thiol was coupled to N-Boc-alanine (34 mg, 0.18 mmol) as
described in GP D with DIC (30 µL, 0.18 mmol). After FCC (light
53.6 (COOCH ), 43.9 (C-3), 21.7 (ArCH ) ppm. IR (KBr): ν =
˜
3
3
2958 (w), 2110 (s), 1745 (s), 1157 (s), 814 (m) cm–1. HPLC: tR
=
10.4 min (method 3). LC-MS (ESI): tR = 9.2 min, C18; calcd. for C H18N7O6S
[M + H]+ 412.1; found 411.9. HRMS (ESI): calcd. for
C14H18N7O6S [M + H]+ 412.1032; found 412.1034.
Methyl (R)-2-Azido-3-[(S)-2-azido-3-(tolyl-4Ј-sulfonylamino)- petroleum/EtOAc, 4:1), bisthioester 27b was isolated as a colorless
propionylsulfanyl]propionate (26e): (S)-2-Azido-3-(tolyl-4Ј-sulfon- oil (34 mg, 0.07 mmol, 82%) and directly subjected to the next step
ylamino)propionic acid (25d, 457 mg, 1.61 mmol) and HOBt
(435 mg, 3.22 mmol) were dissolved in anhydrous CH2Cl2 (5 mL)
and DMF (1.5 mL) and cooled to 0 °C. EDCϫHCl (614 mg,
owing to its high lability. Rf = 0.16 (light petroleum/EtOAc, 4:1).
1H NMR (400 MHz, CDCl3): δ = 4.93 (br. s, 1 H, NH), 4.43–4.33
(m, 1 H, 2Ј-H), 4.18–4.06 (m, 2 H, 2-H, 6-H), 3.82 (s, 3
3.22 mmol) was added and the mixture was stirred for 15 min. H,CO2CH3), 3.48–3.35 (m, 2 H, 3Ј-H2), 3.28–3.06 (m, 2 H, 3-H2),
Freshly deprotected methyl (R)-2-azido-3-mercaptopropionate (24,
233 mg, 1.45 mmol; see GP D) in anhydrous CH2Cl2 (2.5 mL) was
added, and the mixture was stirred for 2 h. The solvents were evap-
orated, and the crude product was dissolved in EtOAc, (25 mL)
and washed with phosphate buffer (pH 7, 50 mL). The aqueous
1.44 [s, 9 H, CO2C(CH3)3], 1.37 (d, J = 7.2 Hz, 3 H, 3Ј-H3) ppm.
IR (KBr): ν = 3377 (bm), 2979 (m), 2924 (m), 2118 (s), 1695 (s),
˜
1505 (m), 1454 (m), 1368 (m), 1247 (s), 1170 (s), 1018 (w), 970 (m),
885 (w), 858 (w) cm– 1 . MS (MALDI-TOF): calcd. for
C15H23N7O6S2Na [M + Na]+ 484.1; found 484.6.
22
www.eurjoc.org
© 0000 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 0000, 0–0

Job/Unit: O30160
/KAP1
Date: 10-04-13 10:52:38
Pages: 27
Unified Azoline and Azole Syntheses
Methyl (2S,2ЈR,2ЈЈS)-2-Azido-3-[2-azido-3-(N-Boc-alanylthio)- in vacuo. The crude product was purified by FCC (35 g silica, light
propanoyloxy]propionate (27c): Trityl thioether 26c (300 mg, petroleum/EtOAc, 19:6) to give bis-azide 27e (155 mg, 0.26 mmol,
0.58 mmol) was treated at room temp. with Et3SiH (0.10 mL,
0.64 mmol) in CH2Cl2/TFA (9 mL, 2:1) for 1.5 h. The reaction mix-
ture was diluted with toluene (10 mL) and the solvent was removed
in vacuo. The crude thiol was coupled with N-Boc-alanine (115 mg,
0.61 mmol) as described in GP D with DIC (0.11 mL, 0.70 mmol),
HOBt (107 mg, 0.70 mmol), and EtNiPr2 (0.12 mL, 0.70 mmol).
After FCC (light petroleum/EtOAc, 5:1), thioester 27c was isolated
as a colorless oil (188 mg, 0.42 mmol, 73%). Rf = 0.30 (light petro-
leum/EtOAc, 2:1). [α]2D0 = –35.6 (CHCl3, c = 0.5). 1H NMR
(400 MHz, CDCl3): δ = 4.93 (br. s, 1 H, NH), 4.54 (dt, J = 3.7,
11.5 Hz, 1 H, 3-Ha), 4.47 (ddd, J = 2.3, 5.9, 11.6 Hz, 1 H, 3-Hb),
4.41–4.32 (m, 1 H, 2ЈЈ-H), 4.20 (ddd, J = 4.1, 5.9, 7.3 Hz, 1 H, 2-
51%) together with a second diastereomer (dr: 56:44) as a light
yellow oil. Rf = 0.21 (major diastereomer), 0.19 (minor dia-
stereomer), (light petroleum/EtOAc, 19:6). [α]2D0 = –69.4 (c = 1.0 in
CHCl3). 1H NMR (400 MHz, CDCl3, 25 °C): δ = 7.94 (d, J =
8.1 Hz, 2 H, SO2CCH), 7.35 (d, J = 8.2 Hz, 2 H, CH3CCH), 5.27–
5.13 (m, 1 H, 2ЈЈ-H), 4.97 (d, J = 7.8 Hz, 1 H, NH), 4.51 (dd, J =
5.2, 8.8 Hz, 1 H, 2-H), 4.20 (dd, J = 5.3, 14.8 Hz, 1 H, 3-Ha), 4.13
(dd, J = 5.6, 7.7 Hz, 1 H, 2Ј-H), 3.91 (dd, J = 8.6, 14.7 Hz, 1 H,
3-Hb), 3.84 (s, 3 H, COOCH3), 3.40 (dd, J = 5.6, 13.9 Hz, 1 H, 3Ј-
Ha), 3.18 (dd, J = 7.7, 13.9 Hz, 1 H, 3Ј-Hb), 2.43 (s, 3 H, ArCH3),
1.46–1.32 [m, 12 H, C(CH3)3, CHCH3] ppm. 13C NMR (100 MHz,
CDCl3, 25 °C): δ = 195.7 (C-1), 175.6 (C-1ЈЈ), 169.1 (COOMe),
H), 4.08 (dd, J = 6.0, 7.1 Hz, 1 H, 2Ј-H), 3.83 (s, 3 H, CO2CH3), 155.3 [COC(CH3)3], 145.7 (CH3CCH), 135.5 (CHCSO2), 130.3
3.32 (m, 1 H, 3Ј-Ha), 3.17 (m, 1 H, 3Ј-Hb), 1.44 [s, 9 H, CO2C- (CH3CCH), 128.3 (CHCSO2), 80.3 [C(CH3)3], 67.7 (C-2), 61.1 (C-
(CH3)3], 1.36 (d, J = 7.3 Hz, 3 H, 3ЈЈ-H3) ppm. 13C NMR 2Ј), 53.3 (COOCH3), 50.2 (C-2ЈЈ), 47.1 (C-3), 30.4 (C-3Ј), 28.4
(100 MHz, CDCl3): δ = 201.6 (C-1ЈЈ), 168.2, 168.1 (C-1Ј, C-1), [C(CH ) ], 21.9 (ArCH ), 19.6 (CH CH) ppm. IR (KBr): ν = 2961
155.1 (CO2tBu), 80.8 [C(CH3)3], 65.0 (C-3), 61.4 (C-2Ј), 60.3 (C-2), (w), 2927 (w), 2115 (s), 1746 (m), 1693 (s), 1364 (m), 1161 (s), 814
˜
3 3
3
3
56.6 (C-2ЈЈ), 53.5 (CO2CH3), 30.1 (C-3Ј), 28.5 [C(CH3)3], 18.6 (C-
(m) cm–1. HPLC: major diastereomer tR = 12.0 min, minor dia-
stereomer: tR = 12.2 (method 3). LC-MS (ESI): tR = 10.6 min, C18;
calcd. for C22H31N8O8S2 [M + H]+ 599.2; found 598.7. HRMS
(ESI): calcd. for C22H31N8O8S2 [M + H]+ 599.1701; found
599.1698.
3ЈЈ) ppm. IR (KBr): ν = 3386 (bm), 2980 (m), 2115 (s), 1750 (s),
˜
1714 (s), 1506 (m), 1454 (m), 1369 (w), 1245 (s), 1168 (s), 1051 (w),
962 (s), 914 (s), 856 (s) cm–1. LC-MS (ESI): tR = 10.0 min; calcd.
for C15H23N7O7S [M]+ 445.1; found 445.6. HRMS (ESI): calcd. for
C15H24N7O7S [M + H]+ 446.1452; found 446.1453.
Methyl (4S,4ЈS,1ЈЈS)-2Ј-[1-(tert-Butoxycarbonylamino)ethyl]-
4,4Ј,5Ј-tetrahydro-2,4Ј-bisoxazole-4-carboxylate (28a): Bisazide 27a
(63 mg, 0.15 mmol) was cyclized as described in GP F. After double
purification on silica gel (1. CH2Cl2/MeOH 25:1, 2. CH2Cl2/MeOH
40:1), the bisoxazoline 28a was isolated as a colorless resin (42 mg,
0.12 mmol, 83%). Rf = 0.41 (CH2Cl2/MeOH 20:1). [α]2D0 = –8.0
(S)-2-Azido-2-(methoxycarbonyl)ethyl (S)-2-Azido-3-{[(S)-2-(tert-
butoxycarbonylamino)propionyl](tolyl-4Ј-sulfonyl)amino}propionate
(27d): Bisazide 26d (451 mg, 1.10 mmol) was dissolved in anhy-
drous CH2Cl2 (2.4 mL) and cooled to 0 °C. (S)-N-Boc-alanyl fluo-
ride (419 mg, 2.19 mmol; see GP H) in anhydrous CH2Cl2 (2.4 mL)
and EtNiPr2 (199 μL, 1.21 mmol) were added and the mixture was
stirred at 0 °C. After 45 min, toluene (2 mL) and formic acid
(122 μL, 3.23 mmol) were added and the volatiles were removed in
vacuo. The crude product was purified by FCC (135 g silica, light
petroleum/EtOAc, 37:13) to give N-acyl-sulfonamide 27d (560 mg,
0.96 mmol, 88%), together with a second diastereomer (dr = 92:8),
as a light yellow oil. Rf = 0.26 (light petroleum/EtOAc, 37:13).
[α]2D0 = –61.4 (c = 1.0 in CHCl3). 1H NMR (500 MHz, CDCl3,
25 °C, major isomer): δ = 7.92 (d, J = 7.5 Hz, 2 H, SO2CCH), 7.34
(d, J = 8.1 Hz, 2 H, CH3CCH), 5.21–5.11 (m, 1 H, 2ЈЈ-H), 4.98 (d,
J = 7.6 Hz, 1 H, NH), 4.56 (dd, J = 4.0, 11.5 Hz, 1 H, 3Ј-Ha), 4.50
(dd, J = 5.9, 11.5 Hz, 1 H, 3Ј-Hb), 4.39 (dd, J = 5.5, 7.8 Hz, 1 H,
2-H), 4.27–4.17 (m, 2 H, 2Ј-H, 3-Ha), 4.01 (dd, J = 8.4, 14.9 Hz, 1
H, 3-Hb), 3.84 (s, 3 H, COOCH3), 2.43 (s, 3 H, ArCH3), 1.37 [m, 12
H, C(CH3)3, CHCH3] ppm. 13C NMR (125 MHz, CDCl3, 25 °C): δ
= 175.7 (C-1ЈЈ), 168.0 (COOMe), 167.8 (C-1), 155.2 [COC(CH3)3],
145.6 (CH3CCH), 135.7 (CHCSO2), 130.2 (CH3CCH), 128.2
(CHCSO2), 80.2 [C(CH3)3], 65.0 (C-3Ј), 60.7 (C-2), 60.3 (C-2Ј), 53.4
(COOCH3), 50.0 (C-2ЈЈ), 46.3 (C-3), 28.4 [C(CH3)3], 21.8 (ArCH3),
1
(CHCl3, c = 0.1). H NMR (400 MHz, CDCl3): δ = 5.20 (br. s, 1
H, NH), 4.91–4.71 (m, 2 H, 4-H, 4Ј-H), 4.61–4.38 (m, 5 H, 5-H2,
5Ј-H2, 1ЈЈ-H), 3.75 (s, 3 H, CO2CH3), 1.40 [s, 9 H, CO2C(CH3)3],
1.37 (d, J = 7.0 Hz, 3 H, 2ЈЈ-H3) ppm. 13C NMR (100 MHz,
CDCl3): δ = 171.1 (CO2Me), 168.6, 168.4 (C-2, C-2Ј), 155.1
(CO2tBu), 80.0 [C(CH3)3], 71.0, 70.4 (C-5,C-5Ј), 68.2, 63.5 (C-4,C-
4Ј), 52.3 (CO2CH3), 45.0 (C-1ЈЈ), 28.5 [C(CH3)3], 19.7 (C-2ЈЈ) ppm.
IR (KBr): ν = 3057 (m), 3021 (w), 2923 (w), 2357 (m), 2340 (m),
˜
1979 (w), 1906 (w), 1842 (w), 1732 (m), 1715 (m), 1696 (w), 1682
(w), 1590 (w), 1574 (w), 1505 (m), 1486 (m), 1437 (s), 1394 (w),
1372 (w), 1334 (w), 1309 (w), 1193 (s), 1120 (s), 1070 (w), 1027 (w),
997 (w), 857 (s), 800 (s), 755 (s), 722 (s), 696 (s) cm–1. LC-MS (ESI):
tR = 7.9 min; calcd. for C15H23N3O6 [M]+ 341.2; found 341.5.
Methyl (S)-2Ј-[1-(tert-Butoxycarbonylamino)ethyl]-2,4Ј-bioxazole-4-
carboxylate (29a): Bisoxazoline 28a (17 mg, 0.05 mmol) was oxid-
ized as described in GP G. After FCC (light petroleum/EtOAc,
2:1), bisoxazole 29a was isolated as a colorless solid (6 mg,
0.02 mmol, 33 %). Rf = 0.19 (light petroleum/EtOAc, 1:1), m.p.
184–185 °C. [α]2D0 = –35.3 (CHCl3, c = 0.6). 1H NMR (400 MHz,
CDCl3): δ = 8.28, 8.27 (2ϫ s, 2 ϫ1 H, 5-H, 5Ј-H), 5.18 (br. s, 1 H,
NH), 5.02 (br. s, 1 H, 1ЈЈ-H), 3.92 (s, 3 H, CO2CH3), 1.56 (d, J =
6.9 Hz, 3 H, 2ЈЈ-H3), 1.43 [s, 9 H, CO2C(CH3)3] ppm. 13C NMR
(100 MHz, CDCl3): δ = 171.7 (C-2Ј), 166.6 (C-2), 161.5 (CO2Me),
153.6 (CO2tBu) 143.9 (C-5), 139.8 (C-5Ј), 128.7 (C-4), 110.0 (C-4Ј),
80.5 [C(CH3)3], 52.5 (CO2CH3), 45.0 (C-1ЈЈ), 28.5 [C(CH3)3], 20.4
19.6 (CH CH) ppm. IR (KBr): ν = 2979 (w), 2112 (m), 1749 (m),
˜
3
1699 (m), 1363 (m), 1160 (s), 814 (w) cm–1. HPLC: major dia-
stereomer: tR = 12.7 min, minor diastereomer: tR = 13.0 min,
(method 3). LC-MS (ESI): tR = 10.4 min, C18; calcd. for
C22H31N8O9S [M + H]+ 583.2; found 582.6. HRMS (ESI): calcd.
for C22H31N8O9S [M + H]+ 583.1929; found 583.1927.
Methyl (R)-2-Azido-3-((S)-2-azido-3-{[(S)-2-(tert-butoxycarbonyl-
amino)propionyl](tolyl-4Ј-sulfonyl)amino}propionylsulfanyl)- (C-2ЈЈ) ppm. IR (KBr): ν = 3327 (m), 3141 (w), 3111 (w), 2963 (w),
˜
propionate (27e): Bisazide 26e (218 mg, 0.51 mmol) was dissolved in
anhydrous CH2Cl2 (1 mL) and cooled to –20 °C. (S)-N-Boc-alanyl
fluoride (102 mg, 0.54 mmol; see GP H) in anhydrous CH2Cl2
(1.2 mL) and EtNiPr2 (88 μL, 0.54 mmol) was added and the mix-
ture was stirred at 0 °C. After 45 min, toluene (1 mL) and formic
acid (40 μL, 1.02 mmol) were added and the volatiles were removed
2852 (w), 1726 (s), 1688 (s), 1635 (w), 1574 (m), 1539 (m), 1505
(w), 1393 (w), 1368 (w), 1325 (m), 1272 (w), 1204 (m), 1178 (m),
1114 (w), 1099 (m), 1070 (w), 1031 (w), 867 (s), 799 (s) cm–1. LC-
MS (ESI): tR = 8.5 min; calcd. for C30H38N6O12 [M + M]+ (dimer)
674.3; found 674.6. HRMS (ESI): calcd. for C15H20N3O6
[M + H]+ 338.1347; found 338.1350.
Eur. J. Org. Chem. 0000, 0–0
© 0000 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
23

Job/Unit: O30160
/KAP1
Date: 10-04-13 10:52:38
Pages: 27
P. Loos, C. Ronco, M. Riedrich, H.-D. Arndt
FULL PAPER
Methyl (S)-2Ј-[1-(tert-Butoxycarbonylamino)ethyl]-2,4Ј-bithiazole-4-
carboxylate (29b): Bisazide 27b (40 mg, 0.09 mmol) was cyclized as
described in GP F and subsequently oxidized as described in GP G.
After FCC (cyclohexane/EtOAc, 3:1), bithiazole 29b was isolated
as a colorless solid (19 mg, 0.05 mmol, 60%). Rf = 0.27 (light petro-
leum/EtOAc, 2:1), m.p. 168–169 °C. [α]2D0 = –25.6 (CHCl3, c = 1.0).
1H NMR (400 MHz, CDCl3): δ = 8.15 (s, 1 H, 5-H), 8.03 (s, 1 H,
5Ј-H), 5.16 (br. s, 1 H, NH), 5.08 (br. s, 1 H, 1ЈЈ-H), 3.94 (s, 3 H,
CO2CH3), 1.61 (d, J = 6.8 Hz, 3 H, 1ЈЈ-CH3), 1.43 [s, 9 H,
CO2C(CH3)3] ppm. 13C NMR (100 MHz, CDCl3): δ = 174.9 (C-
2Ј), 163.7 (C-2), 162.1 (CO2Me), 155.1 (CO2tBu), 148.3 (C-5), 147.7
(C-4Ј), 128.2 (C-4), 117.3 (C-5Ј), 80.5 [C(CH3)3], 52.7 (CO2CH3),
for C22H27N4O7S [M + H]+ 491.2; found 490.8. HRMS (ESI):
calcd. for C22H27N4O7S [M + H]+ 491.1595; found 491.1590.
Methyl 2-{2-[(S)-1-(tert-Butoxycarbonylamino)ethyl]-1-(tolyl-4Ј-
sulfonyl)imidazol-4-yl}thiazole-4-carboxylate (29e): N-Acyl-sulfon-
amide 27e (100 mg, 0.17 mmol) was cyclized with triphenylphos-
phane (131 mg, 0.50 mmol) as described in GP F and subsequently
oxidized with DBU (250 μL, 1.67 mmol) and BrCCl3 (82 μL,
0.84 mmol) as described in GP G. The crude product was purified
by FCC (55 g silica, light petroleum/EtOAc, 3:2) to give bis-azole
29e (69 mg, 0.14 mmol, 81%) as a colorless oil. Rf = 0.56 (light
petroleum/EtOAc, 2:3). 1H NMR (400 MHz, CDCl3, 25 °C): δ =
8.12 (s, 1 H, 5-H), 8.05 (s, 1 H, 5Ј-H), 7.94 (d, J = 7.8 Hz, 2 H,
SO2CCH), 7.33 (d, J = 8.3 Hz, 3 H, CH3CCH), 5.58–5.45 (m, 1 H,
CHCH3), 5.32 (d, J = 8.1 Hz, 1 H, NH), 3.95 (s, 3 H, COOCH3),
2.40 (s, 3 H, ArCH3), 1.51 (d, J = 6.7 Hz, 4 H, CHCH3), 1.41 [s, 9
H, C(CH3)3] ppm. 13C NMR (100 MHz, CDCl3, 25 °C): δ = 162.6
(C-2), 162.0 (COOMe), 154.8 [COC(CH3)3], 151.6 (C-2Ј), 147.7 (C-
4), 146.8 (CH3CCH), 135.2 (C-2Ј), 134.6 (CHCSO2), 130.7
(CH3CCH), 128.1 (CHCSO2), 127.6 (C-5), 117.0 (C-5Ј), 79.9
[C(CH3)3], 52.7 (COOCH3), 44.4 (CHCH3), 28.5 [C(CH3)3], 22.9
49.0 (C-1ЈЈ), 28.5 [C(CH ) ], 21.9 (1ЈЈ-CH ) ppm. IR (KBr): ν =
˜
3 3
3
3386 (m), 3329 (m), 3122 (w), 2985 (m), 2935 (w), 1720 (s), 1687
(s), 1502 (m), 1449 (m), 1392 (w), 1368 (w), 1329 (w), 1285 (m),
1242 (s), 1169 (s), 1088 (w), 1060 (w), 1022 (w), 994 (m), 923 (m),
862 (s), 810 (s), 668 (w) cm–1. HPLC: tR = 10.3 min (method 11).
LC-MS (ESI): tR = 8.7 min; calcd. for C15H19N3O4S2Na
[M + Na]+ 392.1; found 391.9. HRMS (ESI): calcd. for
C15H20N3O4S2 [M + H]+ 370.0895; found 370.0929.
(CHCH ), 21.9 (ArCH ) ppm. IR (KBr): ν = 2977 (w), 1708 (s),
˜
3
3
Methyl 2-{2-[(S)-1-(tert-Butoxycarbonylamino)ethyl]thiazol-4-
yl}oxazole-4-carboxylate (29c): Bisazide 27c (22 mg, 0.05 mmol)
was cyclized as described in GP F and subsequently oxidized as
described in GP G. After FCC (cyclohexane/EtOAc, 3:1), bisazole
29c was isolated as a colorless solid (11 mg, 0.03 mmol, 64%). Rf
= 0.25 (light petroleum/EtOAc, 1:1), m.p. 176–177 °C. [α]2D0 = –41.9
1496 (m), 1171 (s), 1084 (s), 814 (w) cm–1. HPLC: tR = 12.7 min
(method 3). LC-MS (ESI): tR = 10.6 min, C18; calcd. for
C22H27N4O6S2 [M + H]+ 507.1; found 506.8. HRMS (ESI): calcd.
for C22H27N4O6S2 [M + H]+ 507.1367; found 507.1361.
(2ЈR,2ЈЈR)-S2,S6-Bis[2-azido-2-(methoxycarbonyl)ethyl] Pyridine-
2,6-dicarbothioate (31a): Trityl thioether 14c (403 mg, 1.0 mmol)
was treated at room temp. with Et3SiH (0.18 mL, 1.1 mmol) in
CH2Cl2/TFA (5.5 mL, 10:1) for 10 min. Toluene (10 mL) was added
and the solvents were removed in vacuo. The crude thiol was dis-
solved in CH2Cl2 (3 mL) and coupled with pyridine-2,6-dicarboxy-
lic acid (30a, 84 mg, 0.5 mmol) as described in GP D with EDC
(240 mg, 1.25 mmol), HOBt (203 mg, 1.50 mmol), and Et3N
(0.2 mL, 1.50 mmol). After FCC (light petroleum/EtOAc, 2:1), bi-
sazide 31a was isolated as a colorless oil (70 mg, 0.15 mmol, 31%).
Rf = 0.44 (light petroleum/EtOAc, 1:1). [α]2D0 = –20.0 (CHCl3, c =
1
(CHCl3, c = 1.0). H NMR (400 MHz, CDCl3): δ = 8.27 (s, 1 H,
5-H), 8.06 (s, 1 H, 5Ј-H), 5.20 (br. s, 1 H, NH), 5.12 (br. s, 1 H,
1ЈЈ-H), 3.93 (s, 3 H, CO2CH3), 1.63 (d, J = 6.8 Hz, 3 H, 1ЈЈ-CH3),
1.43 [s, 9 H, CO2C(CH3)3] ppm. 13C NMR (100 MHz, CDCl3): δ
= 175.8 (C-2Ј), 161.6 (CO2Me), 158.0 (C-2), 155.0 (CO2tBu), 143.9
(C-5), 142.7 (C-4Ј), 134.5 (C-4), 121.4 (C-5Ј), 80.4 [C(CH3)3], 52.3
(CO2CH3), 48.9 (C-1ЈЈ), 28.4 [C(CH3)3], 21.8 (1ЈЈ-CH3) ppm. IR
(KBr): ν = 3363 (s), 3129 (m), 2985 (m), 2929 (m), 2853 (w), 1725
˜
(s), 1688 (s), 1593 (w), 1571 (m), 1515 (s), 1476 (w), 1440 (m), 1390
(w), 1368 (w), 1337 (w), 1322 (m), 1300 (m), 1252 (m), 1224 (m),
1172 (s), 1115 (m), 1062 (w), 1003 (w), 991 (w), 951 (s), 930 (m),
891 (m), 862 (s), 841 (s), 806 (s), 793 (s), 733 (m), 695 (w), 669
1
0.5). H NMR (400 MHz, CDCl3): δ = 8.17 (dd, J = 0.6, 7.7 Hz,
2 H, 3-H, 5-H), 8.06 (dd, J = 7.0, 8.4 Hz, 1 H, 4-H), 4.21 (dd, J =
5.4, 8.2 Hz, 2 H, 2Ј-H), 3.86 (s, 6 H, CO2CH3), 3.58 (ddd, J = 0.6,
5.4, 14.0 Hz, 2 H, 1Ј-Ha), 3.33 (ddd, J = 1.1, 8.2, 14.0 Hz, 2 H, 1Ј-
Hb) ppm. 13C NMR (100 MHz, CDCl3): δ = 191.9 (COS), 169.4
(CO2Me), 150.8 (C-2, C-6), 139.3 (C-4), 124.6 (C-3, C-5), 61.7 (C-
(w) cm–1. HPLC: tR = 10.8 min (method 12). LC-MS (ESI): tR
=
7.8 min; calcd. for C15H19N3O5S [M]+ 353.1; found 353.4. HRMS
(ESI): calcd. for C15H20N3O5S [M + H]+ 354.1118; found 354.1120.
Methyl 2-{2-[(S)-1-(tert-Butoxycarbonylamino)ethyl]-1-(tolyl-4Ј-
sulfonyl)imidazol-4-yl}oxazole-4-carboxylate (29d): Bisazide 27d
(195 mg, 0.33 mmol) was cyclized with triphenylphosphane
(263 mg, 1.00 mmol) in THF as described in GP F and sub-
sequently oxidized with DBU (500 μL, 3.34 mmol) and BrCCl3
(164 μL, 1.67 mmol) as described in GP G. The crude product was
purified by FCC (70 g silica, light petroleum/EtOAc, 27:23) to give
bis-azole 29d (121 mg, 0.25 mmol, 76%) as a colorless oil. Rf =
0.41 (light petroleum/EtOAc, 3:7). 1H NMR (400 MHz, CDCl3,
2Ј), 53.3 (CO CH ), 30.2 (C-1Ј) ppm. IR (KBr): ν = 3330 (bw),
˜
2
3
3084 (w), 3007 (w), 2957 (m), 2925 (w), 2852 (w), 2498 (bw), 2119
(s), 1746 (s), 1674 (s), 1582 (w), 1505 (w), 1437 (m), 1404 (w), 1273
(s), 1209 (s), 1176 (s), 1079 (w), 1014 (w), 999 (w), 913 (s), 827 (s),
777 (m), 739 (m), 646 (m), 624 (w) cm–1. LC-MS (ESI): tR
=
9.5 min; calcd. for C15H16N7O6S2 [M + H]+ 454.1; found 453.8.
HRMS (ESI): calcd. for C15H16N7O6S2 [M + H]+ 454.0598; found
454.0594.
25 °C): δ = 8.23 (s, 1 H, 5-H), 8.04 (s, 1 H, 5Ј-H), 7.96 (d, J = (2ЈR,2ЈЈR)-S3,S5-Bis[2-azido-2-(methoxycarbonyl)ethyl] Pyridine-
7.7 Hz, 2 H, SO2CCH), 7.35 (d, J = 8.5 Hz, 2 H, CH3CCH), 5.60– 3,5-dicarbothioate (31b): Trityl thioether 14c (403 mg, 1.0 mmol)
5.49 (m, 1 H, CHCH3), 5.41 (d, J = 9.5 Hz, 1 H, NH), 3.92 (s, 3
H, COOCH3), 2.42 (s, 3 H, ArCH3), 1.50 (d, J = 6.7 Hz, 3 H,
CHCH3), 1.40 [s, 9 H, C(CH3)3] ppm. 13C NMR (100 MHz,
CDCl3, 25 °C): δ = 161.6 (COOMe), 157.1 (C-2), 154.8 [COC-
was treated at room temp. with Et3SiH (0.18 mL, 1.1 mmol) in
CH2Cl2/TFA (5.5 mL, 10:1) for 10 min. The reaction mixture was
diluted with toluene (10 mL) and the solvent was removed in vacuo.
The crude thiol was dissolved in CH2Cl2 (3 mL) and coupled with
(CH3)3], 152.6 (C-2Ј), 147.1 (CH3CCH), 143.7 (C-5), 134.5 (C-4), pyridine-3,5-dicarboxylic acid (30b, 84 mg, 0.5 mmol) as described
134.4 (CHCSO2), 130.8 (CH3CCH), 129.5 (C-4Ј), 128.2 (CHCSO2), in GP D with EDC (240 mg, 1.25 mmol), HOBt (203 mg,
120.4 (C-5Ј), 79.9 [C(CH3)3], 52.5 (COOCH3), 44.3 (CHCH3), 28.5 1.50 mmol), and Et3N (0.2 mL, 1.50 mmol). After FCC (light pe-
[C(CH ) ], 22.9 (CHCH ), 22.0 (ArCH ) ppm. IR (KBr): ν = 2979
troleum/EtOAc, 2:1), bisazide 31b was isolated as a colorless oil
˜
3 3
3
3
(w), 1747 (m), 1706 (s), 1498 (m), 1170 (s), 815 (w) cm–1. HPLC: (33 mg, 0.07 mmol, 15%). Rf = 0.40 (light petroleum/EtOAc, 1:1).
1
tR = 11.7 min (method 3). LC-MS (ESI): tR = 10.2 min, C18; calcd. [α]2D0 = –18.8 (CHCl3, c = 0.5). H NMR (400 MHz, CDCl3): δ =
24
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Unified Azoline and Azole Syntheses
[4]
Reviews: a) F. Palacios, C. Alonso, D. Aparicio, G. Rubiales,
J. M. de los Santos, Tetrahedron 2007, 63, 523–575; further se-
lected contributions: b) P. Molina, P. M. Fresneda, P. Al-
mendros, Synthesis 1993, 54–56; c) P. Molina, P. M. Fresneda,
S. García-Zafra, P. Almendros, Tetrahedron Lett. 1994, 35,
8851–8854; d) B. Alcaide, P. Almendros, J. M. Alonso, J. Org.
9.33 (d, J = 2.2 Hz, 2 H, 2-H, 6-H), 8.69 (d, J = 2.2 Hz, 1 H, 4-
H), 4.25 (dd, J = 5.4, 7.6 Hz, 2 H, 2Ј-H), 3.87 (s, 6 H, CO2CH3),
3.66 (dd, J = 5.4, 14.0 Hz, 2 H, 1Ј-Ha), 3.43 (dd, J = 7.6, 14.0 Hz,
2 H, 1Ј-Hb) ppm. 13C NMR (100 MHz, CDCl3): δ = 188.5 (COS),
169.1 (CO2Me), 152.5 (C-2, C-6), 133.5 (C-4), 132.2 (C-3, C-5),
61.4 (C-2Ј), 53.4 (CO CH ), 30.5 (C-1Ј) ppm. IR (KBr): ν = 3006
˜
Chem. 2004, 69, 993–996; see also ref.[5–21]
.
2
3
(w), 2956 (w), 2924 (w), 2853 (w), 2498 (bw), 2119 (s), 1746 (s),
1673 (s), 1588 (w), 1505 (w), 1437 (m), 1211 (m), 1172 (s), 1146
(m), 1015 (w), 894 (s), 800 (s), 750 (m), 699 (m) cm–1. LC-MS (ESI):
tR = 9.2 min; calcd. for C15H16N7O6S2 [M + H]+ 454.1; found
453.9. HRMS (ESI): calcd. for C15H16N7O6S2 [M + H]+ 454.0598;
found 454.0592.
[5]
[6]
K. Hemming, C. Loukou, S. Elkatip, R. K. Smalley, Synlett
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[7]
(4ЈR,4ЈЈR)-2,6-Bis(4-methoxycarbonyl-4,5-dihydrothiazol-2-yl)-
pyridine (32a): Bisazide 31a (51 mg, 0.11 mmol) was cyclized as de-
scribed in GP F. After FCC (light petroleum/EtOAc, 1:1), bisthia-
zoline 32a was isolated as a colorless solid (36 mg, 0.10 mmol,
88%). Rf = 0.57 (CH2Cl2/MeOH 20:1). [α]2D0 = +7.4 (CHCl3, c =
1
1.0). H NMR (400 MHz, CDCl3): δ = 8.22 (d, J = 7.8 Hz, 2 H,
[8]
F. Alonso, P. Riente, M. Yus, Eur. J. Org. Chem. 2008, 4908–
4914.
3-H, 5-H), 7.85 (t, J = 7.8 Hz, 1 H, 4-H), 5.36 (td, J = 1.4, 9.5 Hz,
2 H, 4Ј-H), 3.82 (s, 6 H, CO2CH3), 3.61 (qd, J = 9.6, 11.4 Hz, 4
H, 5Ј-H2) ppm. 13C NMR (100 MHz, CDCl3): δ = 173.0 (C-2Ј),
171.0 (CO2Me), 149.9 (C-2, C-6), 137.2 (C-4), 123.6 (C-3, C-5),
[9]
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79.0 (C-4Ј), 52.8 (CO CH ), 34.2 (C-5Ј) ppm. IR (KBr): ν = 3004
˜
2
3
(w), 2954 (m), 2926 (m), 2852 (w), 1740 (s), 1601 (m), 1568 (m),
1505 (w), 1455 (m), 1436 (m), 1316 (m), 1272 (m), 1229 (s), 1202
(s), 1177 (s), 1136 (w), 1053 (w), 996 (w), 935 (s), 823 (s), 797 (s),
742 (m), 723 (w), 695 (w), 646 (w) cm–1. HPLC: tR = 9.9 min
(method 13). LC-MS (ESI): tR = 8.8 min; calcd. for C15H16N3O4S
[M + H]+ 366.1; found 366.0. HRMS (ESI): calcd. for
C15H16N3O4S2 [M + H]+ 366.0577; found 366.0580.
[11]
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(4ЈR,4ЈЈR)-3,5-Bis(4-methoxycarbonyl-4,5-dihydrothiazol-2-yl)-
pyridine (32b): Bisazide 31b (24 mg, 0.05 mmol) was cyclized as de-
scribed in GP F. After FCC (light petroleum/EtOAc, 1:1), bisthi-
azoline 32b (16 mg, 0.04 mmol, 82%) was isolated as a colorless
solid. Rf = 0.46 (CH2Cl2/MeOH 20:1). [α]2D0 = +1.0 (CHCl3, c =
[15]
[16]
[17]
1
1.0). H NMR (400 MHz, CDCl3): δ = 9.13 (d, J = 1.8 Hz, 2 H,
2-H, 6-H), 8.54 (t, J = 3.3 Hz, 1 H, 4-H), 5.31 (t, J = 9.2 Hz, 2 H,
4Ј-H), 3.85 (s, 6 H, CO2CH3), 3.75 (m, 4 H, 5Ј-H2) ppm. 13C NMR
(100 MHz, CDCl3): δ = 170.8 (CO2Me), 167.7 (C-2Ј), 151.8 (C-2,
C-3, C-5, C-6), 135.2 (C-4), 78.5 (C-4Ј), 52.9 (CO2CH3), 35.8 (C-
5Ј) ppm. IR (KBr): ν = 3000 (w), 2954 (m), 2924 (m), 2854 (m),
˜
1743 (s), 1603 (m), 1505 (w), 1485 (w), 1437 (m), 1344 (m), 1272
(m), 1203 (s), 1177 (s), 1120 (w), 1052 (m), 1024 (m), 928 (s), 905
(s), 858 (s), 798 (s), 751 (m), 722 (m), 699 (m) cm–1. HPLC: tR
=
8.8 min (method 13). LC-MS (ESI): tR = 8.4 min; calcd. for
C15H16N3O4S [M + H]+ 366.1; found 366.0. HRMS (ESI): calcd.
for C15H16N3O4S2 [M + H]+ 366.0577; found 366.0578.
Supporting Information (see footnote on the first page of this arti-
cle): Additional experimental procedures, HPLC traces for ee deter-
minations (Figure S1–S4), 1H and 13C NMR spectra of all relevant
intermediates and final products.
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Acknowledgments
Support by the Deutsche Forschungsgemeinschaft (DFG) (AR493-
1, -2) is acknowledged. Dr. S. D. Harkal is thanked for initial con-
tributions to the project.
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© 0000 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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P. Loos, C. Ronco, M. Riedrich, H.-D. Arndt
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Received: January 29, 2013
Published Online: ᭿
26
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Job/Unit: O30160
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Date: 10-04-13 10:52:38
Pages: 27
Unified Azoline and Azole Syntheses
Antiparallel Efficiency
P. Loos, C. Ronco, M. Riedrich,
H.-D. Arndt* .................................. 1–27
Unified Azoline and Azole Syntheses by
Optimized Aza-Wittig Chemistry
Keywords: Synthetic methods / Wittig reac-
tions / Azides / Cyclization / Heterocycles
Intramolecular aza-Wittig ring closures
have been developed to synthesize thi-
azolines, oxazolines, and imidazolines from
β-azido thioester, ester, and amide precur-
sors. Optimized conditions for diazo trans-
fer with ZnSO4 as catalyst are described.
General aza-Wittig-based azoline synthesis
for single and double azoline ring closures
have been studied in depth and optimized.
Eur. J. Org. Chem. 0000, 0–0
© 0000 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
27