Stereoselective synthesis of highly functionalized thiopeptide thiazole fragments from uronic acid/cysteine condensation products: Access to the core dipeptide of the thiazomycins and nocathiacins

Article abstract of DOI:10.1016/j.tet.2012.06.022

We present the stereoselective synthesis of various highly functionalized thiazole dipeptides that are found in thiopeptide antibiotics like thiazomycins and nocathiacins. The condensation of an uronic acid with l-cysteine methyl ester delivers along two different protocols the stereopure thiazolidine lactones or lactams on the multigram scale, respectively. Oxidation of the thiazolidine moiety to the thiazole and tailoring of the sugar chains yield the thiazole dipeptide as present in the core motif of the thiopeptide antibiotics, as well as its epimer and a homolog. The modular assembly of the potent natural products and their analogs relies on the synthetic accessibility of adequately protected building blocks of tailored absolute stereochemistry.

Full text of DOI:10.1016/j.tet.2012.06.022

Tetrahedron 68 (2012) 7166e7178
Contents lists available at SciVerse ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Stereoselective synthesis of highly functionalized thiopeptide thiazole fragments
from uronic acid/cysteine condensation products: access to the core dipeptide of
the thiazomycins and nocathiacins
y
z
x
*
Sebastian Enck , Peter Tremmel , Sonja Eckhardt , Michael Marsch, Armin Geyer
€
Philipps-Universitat Marburg, Fachbereich Chemie, Hans-Meerwein-Strasse, D-35032 Marburg, Germany
a r t i c l e i n f o
a b s t r a c t
Article history:
We present the stereoselective synthesis of various highly functionalized thiazole dipeptides that are
found in thiopeptide antibiotics like thiazomycins and nocathiacins. The condensation of an uronic acid
with L-cysteine methyl ester delivers along two different protocols the stereopure thiazolidine lactones
or lactams on the multigram scale, respectively. Oxidation of the thiazolidine moiety to the thiazole and
tailoring of the sugar chains yield the thiazole dipeptide as present in the core motif of the thiopeptide
antibiotics, as well as its epimer and a homolog. The modular assembly of the potent natural products
and their analogs relies on the synthetic accessibility of adequately protected building blocks of tailored
absolute stereochemistry.
Received 8 February 2012
Received in revised form 5 June 2012
Accepted 7 June 2012
Available online 15 June 2012
Keywords:
Thiopeptides
Thiazoles
Ó 2012 Elsevier Ltd. All rights reserved.
Polyols
Cysteine
Thiazolidine lactams
Sugar amino acids
1. Introduction
stand out as efficient inhibitors of bacterial protein biosynthesis,
being promising therapeutic candidates for the treatment of in-
Thiazoles add rigidity, hydrophobicity, and stability against en-
zymatic degradation to peptides, thus expanding their spectrum of
biological activity.1,2 Thiazole peptides undergo high-affinity in-
teractions with proteins,3 RNA,4 DNA,5,6 metal ions,7 and cell
membranes,8 causing a highly selective mode of biological action.
The five-membered thiazole heterocycle is biosynthetically
generated by cyclization of a cysteine side chain thiol and the ad-
jacent N-terminal backbone amide. This process is carried out for
ribosomally synthesized products by dedicated heterocyclases and
oxidases, as well as non-ribosomally during the peptide chain as-
sembly.9,10 Many non-ribosomal thiazole-containing peptides have
catched attention as potential cancer therapeutics, for example,
acting as powerful inhibitors of cytokinesis11,12 or tubulin poly-
merization.13e15 Among the ribosomal products, the thiopeptides
fections caused by multiresistant bacteria.16e18 Their structural
complexity provides a significant challenge for chemical synthesis
and is demonstrated by the fact that, in spite of the research effort
spent in the past, only a small fraction of the more than 80 mem-
bers of the thiopeptide class have so far succumbed to total syn-
thesis.19 Fig. 1 shows the structure of the nocathiacins and
thiazomycins, which are among the most complex examples.20e22
Their characteristic six-membered hydroxypyridine core and the
highly functionalized thiazole dipeptide both serve as cross-linkers
in a network of 10-, 15-, and 26-membered rings.23 The central
dipeptide can be seen as consisting of the amino acid dihydrox-
yglutamate (Dyg) and thiazole carboxylic acid (Thz). In order to
indicate the backbone-rigidifying second linkage generated by the
thiazole ring we suggest the use of the hyphen ‘<’, resulting in the
denotation Dyg<Thz for the dipeptide unit.24
Over the last years, the possibilities for the chemical synthesis
of thiazoles have been significantly expanded. For example,
modified reaction protocols of the classical Hantzsch procedure
were developed and successfully used within the total synthesis of
thiostrepton by Nicolaou et al.25e28 Bach et al. employed CeC
couplings of metalated thiazoles to access GE2270 and amythia-
* Corresponding author. Tel.: þ49 6421 2822030; fax: þ49 6421 2822021; e-mail
address: geyer@staff.uni-marburg.de (A. Geyer).
y
Present address: The Scripps Research Institute, Wong Laboratory, 10550 North
Torrey Pines Road, La Jolla, CA 92037, USA.
z
€
Present address: INFAI GmbH, Gottfried-Hagen-Strasse 60-62, D-51105 Koln,
Germany.
micin thiopeptides29,30 while Domling, Wessjohann et al. suc-
€
x
Present address: University of Fribourg, Department of Chemistry, Fromm
ꢀ
ceeded in the total synthesis of tubulysin peptides by using
Laboratory, Chemin du Musee 9, CH-1700 Fribourg, Switzerland.
0040-4020/$ e see front matter Ó 2012 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tet.2012.06.022

S. Enck et al. / Tetrahedron 68 (2012) 7166e7178
7167
Fig. 1. Retrosynthetic analysis of the Dyg<Thz dipeptide as present in thiazomycin and nocathiacin antibiotics. The hyphen ‘<’ stands for the inseparable linkage between dihy-
droxyglutamic acid (Dyg) and thiazole carboxylic acid (Thz). Depending on the reaction conditions, the condensation of -glucuronolactone 1 and L-cysteine methyl ester 2 yields
g
either thiazolidine lactones as kinetic products or thiazolidine lactams as thermodynamic products. Both groups of compounds are precursors of Xaa<Thz dipeptides as they are
found in thiopeptide antibiotics. R1¼amino sugar or H, R2¼OH or H, R3¼dehydroalanine (Dha) or NH2.
a three-component coupling similar to the Passerini reaction.31,32
Further synthetic strategies include the aza-Wittig reaction33,34
and the activation of amino acid side chains35,36 or amides37,38
in pre-synthesized peptides, the latter also being applicable to
solid-phase synthesis.39
In spite of the progress that was enabled by these methods, the
access to stereopure thiazole dipeptides with highly functionalized
side chains, as present in the nocathiacin and thiazomycin antibi-
otics, still remains a challenge. While a methodology has been
presented for the synthesis and linkage of the hydroxyindole unit,
no synthetic route has been established so far to the Dyg<Thz di-
peptide core.40 In order to develop an efficient synthetic route to
hydroxylated thiazole dipeptides, we investigated an strategy
based on a saccharide starting material and cysteine as the bio-
mimetic thiazole precursor. Advantages are a minimum of pro-
tecting groups since we start from unprotected sugars and since we
can avoid malodorous and toxic thioxylation reagents. The Dyg side
2.2. Condensation variants and accessible thiazole units
The condensation of
L-cysteine methyl ester with the urono-
lactones -glucuronolactone 1 or
g
D-arabinuronolactone 3, re-
spectively, led to four different thiazolidines (4e7) on a multigram
scale (Scheme 1), which are precursors of the Dyg<Thz dipeptide
and derivatives thereof. Compound 3 was obtained from 1 by
periodate diol cleavage (a) and directly subjected to condensation
(b) with -cysteine methyl ester, yielding thiazolidine 4. Fig. 2
L
shows the crystal structure of 4.44 Schemes 2 and 3 describe sub-
sequent transformations of 4 to the Dyg<Thz dipeptide core 8, its
a-epimer 9, as well as to the depsidipeptide analogs 10 and 11. The
condensation of uronolactone 1 with -cysteine along to two dif-
L
ferent reaction protocols affords two different products, which are
either isolated by crystallization (c, thermodynamic product 5) or
precipitation (d, kinetic product 6), respectively. Finally, Scheme 4
describes the transformation of bicyclic thiazolidine lactam 5 via
thiazolidine 7 to the dipeptide 12 with a trihydroxyhomoglutamate
(Tyh) side chain. Carrying out the condensation of lactone 1 at high
concentrations led to precipitation of the kinetic product 6, which
was isolated in 56% yield by filtration (d). Scheme 5 outlines the
three-step reaction sequence leading to the thiazole 13 with
chain in the Dyg<Thz unit has the stereochemistry of D-arabinur-
osamine (Fig. 1). This led us to the proposal that, instead of creating
the stereocenters of the side chain by chemical synthesis, sugar-
based starting materials are a versatile alternative.41 The work
presented here describes the stereoselective synthesis of the
Dyg<Thz dipeptide as well as of other highly functionalized
derivatives.
a D-gluco configured (Glc) polyol chain.
2.3. Stereoselective synthesis of both a-epimers of the
2. Results and discussion
2.1. Retrosynthetic analysis
Dyg<Thz dipeptide
The strategic bottleneck of a thiazole synthesis from a hydrox-
ylated thiazolidine precursor is to carry out the oxidative de-
hydrogenation to the thiazole by avoiding or minimizing
intramolecular N-acylation, diol cleavage, hydrolysis, benzylic oxi-
dations, and other degradation reactions. Activated MnO2 has by far
been used most often as oxidant to generate thiazoles,45,46 al-
though it is known to generally reduce the yields due to these side
reactions.47e49 In order to make this oxidation applicable to the
highly functionalized thiazolidine lactone 4, its hydroxyl functions
had to be protected appropriately, and silyl ethers proved suffi-
ciently stable to the oxidation conditions. Reaction of the diol 4
with TES chloride and imidazole in DMF (a) yielded the bis(-
triethylsilyl) (TES) ether 14 (Scheme 2), which as a crude product
was directly subjected to oxidation with excess MnO2 in toluene at
70 ꢀC, yielding the desired TES-protected thiazole lactone 15 in 33%
yield over two steps on a multigram scale (b). In order to access the
Fig. 1 shows the retrosynthetic analysis of the Dyg<Thz di-
peptide. O/N-exchange of the hydroxyl group next to the aromatic
thiazole ring of the depsidipeptide introduces the
functionality. The depsidipeptide is accessible from thiazolidine
precursors by oxidation of the thiazolidine ring and tailoring of the
sugar chain. Previous work published by our group describes the
synthesis of the stereopure bicyclic thiazolidine lactams42 as well as
of the epimeric thiazolidine lactones,43 which are directly accessi-
a-nitrogen
ble from condensation reactions of g-glucuronolactone 1 and cys-
teine 2 without protecting groups. The thermodynamic products of
such reactions are the thiazolidine lactams, which are constitu-
tional isomers of the thiazolidine lactones obtained by
kinetic control. Cyclic and bicyclic starting materials minimize the
number of protection and steps while maximizing the chemo-,
stereo-, and regioselectivity of the subsequent transformations like
O/N-exchange and tailoring of the sugar chain.
a-position of the later amino acid side chain, the lactone was
opened in the following step using benzyl alcohol as both reagent

7168
S. Enck et al. / Tetrahedron 68 (2012) 7166e7178
Scheme 1. Synthesis of the thiazolidine precursors and overview of succeeding synthetic routes leading to the various thiazole units. (a) NaIO4 (1.0 equiv), phosphate buffer, 0 ꢀC,
1 h; (b) L-CysOMeꢁHCl (1.0 equiv), MeOH/H2O/pyridine¼15:5:1, rt, 15 h, 53% over two steps; (c) L-CysOMeꢁHCl (1.0 equiv), H2O/pyridine¼10:1, rt, 4 days, 52%; (d) L-CysOMeꢁHCl
(1.0 equiv), H2O/pyridine¼10:1, rt, 15 min, 56%; (e) O/N-exchange and lactam alcoholysis; (f) (de)protection steps, oxidation, sugar chain modifications, and/or O/N-exchange. Sugar
chain configurations: Ara¼D-arabino, Rib¼D-ribo, Tyh¼trihydroxyhomoglutamate, Glc¼D-gluco.
With the
D-arabino configuration of the triol chain, thiazole
16 already represents the 2-oxo analog of the naturally
occuring (1S,2S,3S)Dyg<Thz core motif and was accessible from
g-glucuronolactone and L-cysteine methyl ester in five linear steps
with 14.2% overall yield, yet on the multigram scale. The reaction
sequence requires only one chromatographic purification (after the
oxidation step) and no anhydrous solvents or inert gas. The desired
nitrogen functionality at position 1 could not be installed with all
three hydroxyl groups deprotected. Attempts to maintain the silyl
ethers upon lactone opening (in this case, the more stable TBS
group was chosen) were unsuccessful as protecting group migra-
tion occurred. However, the 3-hydroxyl function of the triol 16 was
protected selectively as tert-butyldimethyl silyl (TBS) ether 17 in
74% yield (d). Treatment with mesyl chloride in pyridine finally
allowed to selectively activate the 1-hydroxy function as mesylate
18 in 62% yield b.r.s.m. (e).
Fig. 2. Perspective drawing of X-ray structure of thiazolidine 4.
and solvent with 0.05 equiv of camphor sulfonic acid at 50 ꢀC (c).
Under these conditions, the thiazole triol 16 with orthogonally
protected carboxyl functions precipitates from the reaction mixture
and was isolated in good purity and in 81% yield by filtration.
In addition to the selective activation, we also sought to selec-
tively invert the stereocenter at position 1 in order to obtain both
Scheme 2. Synthesis of thiazole polyols with D-ribo (Rib) and D-arabino (Ara) configuration. The final products are also shown in the Fischer projection. (a) TESCl (2.4 equiv),
imidazole (2.4 equiv), DMF, 0 ꢀC to rt, 3 h; (b) MnO2 (20þ25 equiv), toluene, 70 ꢀC, 36þ43 h, 33% over two steps; (c) BnOH, CSA (0.05 equiv), 50 ꢀC, 67 h, 81%; (d) TBSCl (1.2 equiv),
imidazole (1.2 equiv), DMF, rt, 18 h, 74% (plus 16% starting material reisolated); (e) MsCl (1.0 equiv), anhydrous pyridine, 0 ꢀC to rt, 13 h, 48% (plus 23% starting material and 20%
dimesylate isolated); (f) IBX (5.0 equiv), EtOAc, 80 ꢀC, 1.5 h, 29% (plus 53% starting material reisolated); (g) BF3ꢁEt2O (2.2 equiv), Bu3SnH (1.2þ1.0 equiv), anhydrous THF, ꢂ78 ꢀC to
rt, 32 h, 75%, dr>99:1; (h) MsCl (1.5þ1.0 equiv), DMAP (cat.), anhydrous pyridine, 0 ꢀC to rt, 17 h, 73% (plus 25% dimesylate).

S. Enck et al. / Tetrahedron 68 (2012) 7166e7178
7169
Scheme 3. O/N-exchange reactions and neighboring group effects in thiazole units with D-ribo (left) and D-arabino configuration (right). (a) NaN3 (1.5þ1.5 equiv), anhydrous DMF,
85 ꢀC, 3.5 h; (b) NaN3 (1.5 equiv), DMF (abs), 85 ꢀC, 2.5 h, 19%; (c) H2SiF6 (2.0 equiv), acetonitrile, rt, 24 h, 13% of 8 and 12% of 9 (over two steps from 18); (d) TBAF (1.3 equiv),
anhydrous THF, 0 ꢀC, 45 min, 42%; (e) TBAF (1.3 equiv), anhydrous THF, 0 ꢀC, 1.5 h, 21%; of 24 and 23% of 27; (f) NaN3 (5.0 equiv), CSA (cat.), anhydrous DMF, 70 ꢀC, 4 h, >95%
conversion (NMR); (g) NaN3 (3.0 equiv), anhydrous DMF, 85 ꢀC, 2 h, 70%; (h) NaN3 (5.0 equiv), DMSO, p-TosOHꢁH2O (cat.), 70 ꢀC, 9 h, >95% conversion (NMR), isolated yield 16%.
R¼CH(OTBS)eCO2Bn.
Scheme 4. Synthetic route to a trihydroxyhomoglutamate(Tyh)<Thz dipeptide, which is a C1-extended (yellow) nocathiacin and thiazomycin thiopeptide core with native ste-
reochemistry. Its synthesis was accomplished by selective tailoring and subsequent alcoholysis of a D-gluco configured 7,5-bicyclic thiazolidin lactam scaffold. (a) DMP (10 equiv),
p-TosOHꢁH2O (cat.), DMF, 60 ꢀC, 38 h, 93%; (b) p-TosOHꢁH2O (cat.), MeOH, rt, 17 h, 67%; (c) Tf2O (1.2 equiv), anhydrous CH2Cl2/pyridine¼3:1, 0 ꢀC to rt, 4.5 h, 94%; (d) DMF/
NEt3¼14:1, 60 ꢀC, 14 h, 81%; (e) NaN3 (1.7 equiv), AcOH (1.7 equiv), DMF, 45e55 ꢀC, 50 h, 39% of 7a and 33% of 32; (f) DMF/AcOH¼130:1, 50 ꢀC, 72 h, 33%; (g) MnO2 (30 equiv), 70 ꢀC,
20 h, 31% (plus 27% of starting material reisolated); (h) formic acid (60% in H2O), 65 ꢀC, 40 min, 69%; (i) Pd/C (5%, wet), H2 (1 bar), EtOAc/MeOH¼2:1, rt, 45 h, 88%; (k) p-TosOHꢁH2O
(cat.), MeOH, 50 ꢀC, 66 h, 22%.
epimers of the Dyg<Thz dipeptide as well as of its depsidipeptide
analog. Since KMnO4, which had been successfully used for anal-
ogous oxidations of sugar substrates,50 led to diol cleavage in the
case of thiazole 17, we investigated the use of IBX in EtOAc.51 Under
optimized reaction conditions (5.0 equiv IBX, 80 ꢀC, 1.5 h), the
extent of decomposition was minimized and 62% b.r.s.m. of the
ketone 19 were obtained (f). Reduction with Bu3SnH in the pres-
52
ence of BF3ꢁOEt2 finally afforded the thiazole triol 20 with
D-ri-
bose (Rib) configuration in 75% yield and >99:1 diastereoselectivity
(g). Analogously to the 1-epimeric triol 17, 20 was subjected
to selective activation of the 1-hydroxyl, yielding 73% of the
mesylate 21 (h).
O/N-exchange reactions were investigated with both mesylates
18 and 21 (Scheme 3). Under identical reaction conditions
(3.0 equiv NaN3 in DMF at 85 ꢀC) the same azide main product was
obtained from both 21 (a) and 18 (b), respectively, which was later
identified as azide 22. As some TBS group migration had occurred,
the silyl ethers were deprotected with hexafluoro silicic acid (c).
However, this resulted in racemization of the stereocenter at po-
sition 1, yielding a 1:1 mixture of the Dyg<Thz epimers 8 and 9 in
an overall yield of 25% over both steps. In order to overcome the low
yields we decided to perform the azide exchange with
TBS-deprotected substrates. The less steric congestion associated
with the removal of the bulky TBS group had also significantly in-
creased the yield of azide product in the total synthesis of the
GE2270 thiopeptides.53
Scheme 5. Synthesis of the thiazole lactone 13 with D-gluco (Glc) configuration,
applicable to the multigram scale. (a) TESCl (3.6 equiv), imidazole (3.6 equiv), anhy-
drous DMF, rt, 3 h; (b) MnO2 (20 equiv), toluene, 70 ꢀC, 28 h, then BrCCl3 (3.0 equiv),
DBU (3.0 equiv), toluene, rt, 14 h, 48% over three steps; (c) H2SiF6 (1.66 M in H2O,
2.0 equiv), acetonitrile, 0 ꢀC to rt, 4.5 h, 98%.

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S. Enck et al. / Tetrahedron 68 (2012) 7166e7178
The products obtained for the TBS-deprotection of 18 and 21
Fig. 3 shows the crystal structure of the analogously synthesized
ethyl ester 7b.44 The yield of lactone 7a was further increased by
heating the lactam 32 in a DMF/AcOH mixture at 50 ꢀC (f); however,
since the lactone 7a was formed reversibly, a mixture of 32 and 7a
was always obtained. The thiazolidine lactone 7a was subsequently
converted into a C-1 extended homolog of the Dyg<Thz dipeptide
(Scheme 4). Again, the use of an excess of activated MnO2 at 70 ꢀC
enabled the oxidation to the corresponding thiazole 34 (g); how-
ever, acetonitrile as solvent proved superior to toluene. Since the
required harsh reaction conditions also resulted in a slow de-
composition of the starting material as well as of the product, the
best results were obtained by stopping the reaction at an early stage
and to separate the formed thiazole from remaining starting ma-
terial by column chromatography. This procedure afforded 42%
b.r.s.m. of the thiazole 34. A comparison of the scalar coupling pa-
rameters via NMR showed that the oxidation did not affect the
stereopurity of the sugar chain. The acetonide in thiazole 34 was
cleaved by treatment with aqueous formic acid at 65 ꢀC, yielding
69% of the diol 35 (h).
also revealed the mechanism of azide introduction in dependence
of the relative stereochemistry. In the case of mesylate 21, the ep-
oxide 23 was the only product obtained after treatment with TBAF
in THF (d), while in contrast identical reaction conditions applied to
mesylate 18 gave the diol 24 (e). The absence of epoxide 25 in the
crude product after azide substitution of mesylate 18 (b) was as-
cribed to the steric congestion which is significantly lower in the
case of mesylate 21 (Scheme 3). Consequently, the azide sub-
stitution in this case proceeded via formation of the TBS-protected
epoxyalcohol 26 (a) and subsequent epoxide opening by the azide
ion, resulting in retention of the configuration (double SN2-type
inversion) while in the case of the epimer 18 a direct SN2 reaction
inverts the stereocenter, affording the same product 22.
The conversion of the TBS-deprotection products 23 and 24 with
5.0 equiv NaN3 in DMF (catalytical amounts of CSA added in the
case of the epoxide; (f) and (g)) supported the postulated reaction
pathways, since the same azide 9 was obtained as the only product
in 70% yield (g). Azide 9 is a protected derivative of the (1R,2S,3S)
Dyg<Thz unit as present in the thiopeptides, with the amine and
carboxylic function protected as azide and ester, respectively.
The key to the synthesis of the epimeric (1S,2S,3S)Dyg<Thz unit,
which is, for example, present in thiazomycin, was the epox-
yalcohol 27, which could be separated from the mesylate diol 26 as
a second product by silica gel chromatography after TBS cleavage of
mesylate 18 (e). Upon treatment with NaN3 (5.0 equiv) and
p-TosOH (cat.) in DMSO at 70 ꢀC (h), one product was isolated in
16% yield, which was identified as epimer 8. The low yield can be
ascribed to decomposition reactions like ester cleavage, as sug-
gested from monitoring the reaction by HPLC and 1H NMR. Al-
though some of the reaction steps yet have to be optimized with
respect to the isolated yields, this route allows the first stereo-
selective chemical access to Dyg<Thz dipeptides. Monitoring of the
azide substitutions by NMR spectroscopy and analytical HPLC
showed a >95% conversion in all cases and the lack of any azide/
azide substitution reactions, which would give rise to epimeriza-
tion under the applied conditions. Comparison of the optical rota-
tions measured for all products shown in Schemes 2 and 3 revealed
that, independently from the functionalization at position 2 and
hydroxyl protection, all 1S configured substrates showed negative
rotations while the 1R configuration always resulted in a positive
rotation. These results are in accordance with the optical rotations
observed for fully deprotected 2,3-dihydroxyglutamates.54
Fig. 3. Perspective drawing of X-ray structure of ethylester 7b.
The azide 34 was hydrogenated under hydrogen atmosphere
(1 bar) in the presence of Pd/C catalyst and the product isolated in
88% yield (i) was d-lactam 36, probably formed by intermediate
aminolysis of the lactone. Lactam 36 resembles a precursor of
XaaeYaa<Thz tripeptides, which can theoretically be obtained by
cleavage of a CeC bond of the triol motif, providing the Xaa and Yaa
side chains. By methanolysis of the lactam, however, it was possible
to synthesize a Tyh<Thz dipeptide, which resembles a C-1 ex-
tended Dyg<Thz analog (extension highlighted in yellow, Scheme
4). Treatment of lactam 36 in acidified MeOH at elevated temper-
atures (k) led to the cleavage of the acetonide, providing the triol 37
as the only observed intermediate, and finally the lactam ring
opened to form the methyl ester 12. Although some optimization is
required in order to increase the yield, for example, by using
modern catalytic techniques for lactone alcoholysis, the reaction is
simple to perform since the product 12 precipitates from the re-
action mixture after neutralization, being isolated in 22% yield and
in good purity by filtration from the reaction mixture containing
mostly unreacted triol 37.
2.4. Stereoselective synthesis of a C1-extended Dyg<Thz
homolog
Scheme 4 shows the conversion of
D-gluco configuration of the
uronic acid chain in lactam 5 to a -altrosamino configuration in
D
only five steps. The reaction sequence starts with the protection of
all four hydroxyl functions as acetonides by treatment with DMP
and p-TosOH in DMF at 60 ꢀC, yielding the bis-acetonide 28 in 93%
yield (a). After cleavage of the 8,9-acetonide using p-TosOH in MeOH
at rt, the diol 29 was obtained in 67% yield (b) and activated
regioselectively as triflate 30 in 94% yield with Tf2O in a DCM/pyr-
idine (c). Treatment with NEt3 in DMF at 60 ꢀC afforded epoxide 31
(81% yield), which was subsequently opened with NaN3 in AcOH
and DMF at temperatures between 45 and 55 ꢀC (e). This reaction
yielded two 1-hydroxyl azide main products, which were both fur-
ther used because they can be converted from one form to the
other.55 Regioselective opening of the epoxide at position 9 in 31
2.5. Synthesis of a
D
-gluco configured thiazole polyol
-gluco configured analog was accom-
The oxidation of the
D
plished without affecting the stereopurity of the sugar side chain
and in a protocol applicable to the multigram scale. The triol 6
was protected for the oxidation step by treatment with TESCl and
imidazole (a), and the resulting TBS ether 38 was subjected to
oxidation without purification (Scheme 5). Excess MnO2 in tolu-
ene at 70 ꢀC effected oxidation, however, it turned out that the
thiazoline intermediate was formed quickly while the second
yielded lactam 32, a D-altrosamino configured sugar chain, in 33%
yield. Compound 32 undergoes alcoholysis by attack of the 8-
hydroxyl group, which opens the seven-membered lactam ring,
thus forming the thiazolidine lactone 7a, which was obtained in 39%
yield after separation from lactam 32 by column chromatography.

S. Enck et al. / Tetrahedron 68 (2012) 7166e7178
7171
oxidation to the thiazole 39 proceeded very slowly. The long re-
action times and decomposition made a different oxidation
method necessary. The use of BrCCl3 and DBU, which had been
shown to effect clean oxidation of a range of partially unsaturated
heterocycles,56,57 proved successful in this case, too. The thiazo-
lidine 38 was treated with MnO2 until no more starting material
was present, then the reaction mixture was cooled to rt, then
BrCCl3 and DBU were added. The thiazole lactone 39 was finally
be isolated in 48% yield over three steps, and subsequent treat-
purchased from Fluka (technical, activated, ꢃ90%) gave the best
results.
Thin layer chromatography (TLC) monitoring of all reactions
was carried out using analytical TLC plates coated with silica gel
(60 F254, Merck). Preparative column chromatography was carried
out at room temperature (rt) with compressed air using flash silica
gel (particle size 40e60 mm, Merck). For analytical HPLC charac-
terizations of purified products, a Dionex system with diode array
detection, a Dionex P680 dual gradient pump, auto sampler, and
58
ment with H2SiF6 afforded the thiazole triol 13 in 98% yield (c).
a reversed-phase Dionex Acclaim 120 (C-18, particle size 5 mm,
X-ray crystallographic analysis (Fig. 4)44 proved the stereopurity
of the sugar chain.
pore diameter 120 A, 4.6ꢁ150 mm) was used with a flow rate of
0.6 mL/min (acetonitrile in 0.06% TFA/H2O) and varying gradients
(specified for the respective substrate). 1H and 13C NMR spectra
were recorded at 300 K on Bruker spectrometers (300e600 MHz).
ꢁ
Chemical shifts
d are given in parts per million (ppm) and were
determined from the center of the respective coupling pattern (s:
singlet, d: doublet, dd: doublet of d, ddd: doublet of dd, t: triplet,
pt: pseudotriplet, m: multiplet). Signals of diastereomeric protons,
which could not be assigned proR/S are assigned u (upfield) and
d (downfield), respectively. The numbering of compounds is
shown below.59 The solvent signals were used as internal standard
(CDCl3:
2.50 ppm,
d
(1H)¼7.26 ppm,
d
(
13C)¼77.16 ppm; DMSO-d6:
d
(1H)¼
d(
13C)¼39.52 ppm). ESI-HMRS measurements were
performed on a LTQ-FT mass spectrometer (Thermo Fisher Sci-
entific), and IR spectra were recorded on a Bruker IFS88 in-
terferometer or a Bruker Alpha spectrometer. All optical rotation
values were determined on
a Perkin-Elmer 241 polarimeter
(length of used vessel 1.0001 dm, values given in mL/mg dm).
Melting points (mp) were recorded on a capillary melting point
apparatus and are given uncorrected.
Fig. 4. Perspective drawing of X-ray structure of thiazole 13 including
molecule.
a MeOH
4.2. Synthesis procedures
3. Conclusion
4.2.1. (2S,4R)-Methyl 2-[((2S,3R,4S)-dihydroxy-5-oxo-tetrahydrofu-
ran-2-yl)]-thiazolidine-4-carboxylate (4). To a solution of g-glucur-
A strategy is presented for the stereoselective synthesis of
highly functionalized Xaa<Thz depsidipeptides and dipeptides
that rely on the condensation of an uronic acid and cysteine.
Assembling the carbon skeleton already in the first step avoids
tedious multi-step protection and deprotection protocols. The
methods described above yield peptidic thiazole motifs that are
present in thiopeptide antibiotics and that have not been avail-
able by other methods so far. This includes the Dyg<Thz unit,
which is an essential core motif of the nocathiacin and thiazo-
mycin antibiotics, as well as of its epimer and a C-1 extended
homolog (Tyh<Thz). The synthetic protocols leading to the thia-
zole polyols are applicable to the multigram scale, and further
work is underway to optimize the protocols leading to the thia-
zole peptides. In addition, we are also concerned with the con-
densation reactions of differently configured uronic acids, which
are expected to further extend the library of available thiazole
compounds.
onolactone 1 (10.0 g, 56.8 mmol) in aq Na2HPO4 (0.05 M,100 mL) at
0 ꢀC NaIO4 (16.6 g, 56.8 mmol) was added, the solution was vigor-
ously stirred at 0 ꢀC for 1 h and then diluted with MeOH (100 mL).
After 30 min the precipitated salts were filtered and the filtrate was
concentrated in vacuo to yield the crude aldehyde 3 as pale yellow
oil. This was dissolved in MeOH/H2O/pyridine¼15:5:1 (90 mL),
L-
cysteine methyl ester hydrochloride 2 (9.77 g, 56.8 mmol) was
added and the solution was stirred at rt for 15 h. The solution was
filtered, the precipitate was washed with cold EtOH, and dried in
vacuo to yield the first fraction of thiazolidine 4 as a colorless solid.
Further product was isolated by concentration of the filtrate in
vacuo, addition of EtOH (50 mL), and storage of the resulting sus-
pension at 5 ꢀC for 30 min. After filtration, washing of the pre-
cipitate with cold EtOH and drying in vacuo the combination of
both fractions gave a 53% (7.93 g over two steps) overall yield of
thiazolidine 4. Rf (EtOAc) 0.26; mp 120 ꢀC (decomposition); IR (KBr)
3434, 3270,1763,1733,1437,1358,1323,1290,1228,1183,1141,1118,
1022, 981, 967, 930, 897, 849, 829, 849, 829, 785, 771, 740,
723 cmꢂ1
;
1H NMR (500 MHz, DMSO-d6):
d
2.69 (dd, 1H,
4. Experimental section
4.1. General information
3
2JThzꢂ5ꢂHproR
¼10.0 Hz, JThzꢂ5ꢂHproR
¼8.2 Hz, Thz-
=Thzꢂ4ꢂH
=Thzꢂ5ꢂHproS
5-HproR), 3.11 (dd, 1H, 2JThzꢂ5ꢂHproS
¼10.0 Hz, 3JThzꢂ5ꢂHproS
=Thzꢂ5ꢂHproR
=
Reactions with substrates, reagents, and catalysts sensitive to
oxygen and/or moisture were run under an atmosphere of nitrogen
in flame-dried glassware. All purchased reagents were not further
purified prior to use. Anhydrous DMF and anhydrous pyridine were
purchased from Acros and not dried further. If no anhydrous DMF
was required, peptide grade DMF (purchased from Iris Biotech) was
used. All other solvents were dried and distilled according to
standard protocols. The solvent mixtures are given in volume ratios
(v/v). For the oxidation step from thiazolidines to thiazoles, MnO2
Thz ꢂ 4 ꢂ H¼6.2 Hz, Thz-5-HproS), 3.67 (dd, 1H, 3JNH/Thz-2-H¼7.8 Hz,
3JNH/Thz-4-H¼11.3 Hz, NH), 3.70 (s, 3H, CO2CH3), 3.93e3.98 (m, 1H,
3
3
3
Thz-4-H), 4.13 (ddd, 1H, J3-H/2-H¼2.9 Hz, J3-H/3-OH¼4.2 Hz, J3-H/4-
3
3
¼4.6 Hz, 3-H), 4.24 (ddd, 1H, J2-H/3-H¼2.9 Hz, J2-H/Thz-2-
H
4
3
¼9.7 Hz, J2-H/3-OH¼0.9 Hz, 1-H), 4.40 (dd, 1H, J4-H/3-H¼4.6 Hz,
H
3J4-H/4-OH¼7.3 Hz, 4-H), 4.82 (dd, 1H,3JThz-2-H/NH¼7.8 Hz, JThz-2-H/2-
3
3
4
¼9.7 Hz, Thz-2-H), 5.47 (dd, 1H, J3-OH/3-H¼4.2 Hz, J3-OH/2-
H
¼0.9 Hz, 3-OH), 5.87 (d, 1H,3J4-OH/4-H¼7.3 Hz, 4-OH); 13C NMR
H
(125 MHz, DMSO-d6): d 36.1 (Thz-C-5), 52.1 (CO2CH3), 63.6 (Thz-C-

7172
S. Enck et al. / Tetrahedron 68 (2012) 7166e7178
4), 67.4 (Thz-C-2), 69.7 (C-3), 70.8 (C-4), 80.1 (C-2), 171.1 (CO2CH3),
1H, 3J4-OH/4-H¼7.4 Hz, 4-OH), NH signal invisible; 13C NMR (75 MHz,
176.1 (C-5); ½a 2D3
ꢄ
ꢂ107.6 (c 0.97, DMSO); ESI-HMRS found 286.0354
DMSO-d6): d 36.7 (Thz-C-5), 52.0 (CO2CH3), 64.2 (Thz-C-4), 69.6 (C-
(calcd for C9H13NO6SþNaþ 286.0356). Suitable crystals for X-ray
X), 70.1 (Thz-C-2, C-3), 70.7 (C-4), 81.9 (C-2), 171.8 (CO2CH3), 175.9
(C-5).
analysis were grown from a MeOH solution.44
4.2.4. Methyl 2-[((2S,3R,4S)-bis[(triethylsilyl)oxy]-5-oxo-tetrahydro-
4.2.2. (3R,6S,7S,8S,9R,9aR)-Methyl octahydro-6,7,8,9-tetrahydroxy-
furan-2-yl)]-thiazole-4-carboxylate (15). Thiazolidine
4 (10.4 g,
5-oxothiazolo[3,2-a]azepine-3-carboxylate (5). A solution of
g-
39.6 mmol) and imidazole (6.47 g, 95.0 mmol) were dissolved in
DMF (50 mL) in a nitrogen atmosphere at 0 ꢀC. TESCl (16.5 mL,
95.0 mmol) was added over 3 min, the solution was stirred at 0 ꢀC
for 3 h, diluted with CH2Cl2 (200 mL), and 5% aq NaHCO3 was added
under vigorous stirring until complete solution of the precipitate.
The layers were separated and the aqueous layer was extracted
twice with CH2Cl2. The combined organic layers were dried with
brine and over MgSO4, filtered, and concentrated in vacuo to yield
the thiazolidine 14 as yellow oil (Rf (toluene/EtOAc¼2:1) 0.52). This
was dissolved in toluene (250 mL), MnO2 (68.8 g, 792 mmol) was
added, the suspension was vigorously stirred at 70 ꢀC for 36 h, fil-
tered over Celite, and concentrated in vacuo. The resulting oil was
again dissolved in toluene (200 mL), MnO2 (51.6 g, 594 mmol) was
added, and the suspension was vigorously stirred at 70 ꢀC for 28 h.
After cooling to rt, additional 34.4 g of MnO2 (activated, Fluka;
396 mmol, 10 equiv) were added and stirring at 70 ꢀC was contin-
ued for another 15 h. After filtration over Celite and concentration
in vacuo, column chromatography (toluene/EtOAc¼6:1 to 4:1)
yielded thiazole 15 (6.30 g, 33% over two steps) as a pale yellow oil.
Rf (toluene/EtOAc¼2:1) 0.67; IR (film) 2954, 2912, 2877, 1811, 1732,
1485, 1458, 1436, 1413, 1379, 1345, 1327, 1216, 1184, 1131, 1097, 989,
941, 920, 843, 813, 784, 727, 683 cmꢂ1; 1H NMR (500 MHz, CDCl3):
glucuronolactone 1 (12.0 g, 68.1 mmol) and -cysteine methyl
L
ester hydrochloride 2 (11.6 g, 68.1 mmol) in H2O/pyridine¼9:1
(150 mL) was stirred at rt for 4 d. The solvents were removed in
vacuo, the residue was dissolved in H2O, and the solution was
allowed to stand at rt in a crystallizing dish. After several days,
the 7,5-bicycle 5 was isolated as colorless crystals (10.3 g, 52%); Rf
(EtOAc/MeOH¼10:1) 0.25; mp 117 ꢀC; IR (KBr) 3371, 3303, 3257,
1715, 1651, 1436, 1371, 1340, 1231, 1180, 1110, 1073, 1010,
810 cmꢂ1
;
1H NMR (300 MHz, DMSO-d6):
d
¼3.27 (dd, 1H,
J2ꢂHu=2ꢂHd ¼11.0 Hz, J2ꢂH =3ꢂH¼7.2 Hz, 2-Hu), 3.31 (dd, 1H,
2
3
u
2J2ꢂHd=2ꢂHu ¼11.0 Hz, J2ꢂHd=3ꢂH¼7.8 Hz, 2-Hd), 3.54 (ddd, 1H,
3
3J9-H/9-OH¼10.9 Hz, 3J9-H/8-H¼3.6 Hz, 4J9-H/7-H¼1.4 Hz, 9-H), 3.64 (s,
3
3H, CO2CH3), 3.77e3.84 (m, 2H, 7-H, 8-H), 4.30 (d, 1H, J9-OH/9-
¼10.9 Hz, 9-OH), 4.51 (d, 1H, 3J6-OH/6-H¼6.6 Hz, 6-OH),
H
3
4.68 (d, 1H, J6-H/6-OH¼6.6 Hz, 6-H), 4.71 (pt, 1H, 3-H), 5.33
3
(d, 1H, J7-OH/7-H¼5.2 Hz, 7-OH), 5.42 (s, 1H, 9a-H), 5.64 (d,
1H,3J8-OH/8-H¼3.4 Hz, 8-OH); 13C NMR (75 MHz, DMSO-d6):
d
¼31.4 (C-
b), 52.2 (CO2CH3), 61.1 (C-9a), 64.0 (C-3), 69.3 (C-6),
70.1 (C-8), 76.1 (C-7), 77.0 (C-9), 170.5 (CO2CH3), 170.7 (C-5); ½a D21
ꢄ
ꢂ63.6 (c 1.00, H2O); ESI-HMRS found 316.0457 (calcd for
C10H15NO7SþNaþ 316.0461).
d
0.32e0.45 (m, 6H, 3ꢁSiCH2CH3), 0.73e0.80 (m, 15H, 3ꢁSiCH2CH3
and 3ꢁSiCH2CH3), 1.01 (t, 9H, 3J¼7.9 Hz, 3ꢁSiCH2CH3), 3.96 (s, 3H,
4.2.3. (2R/S,4R)-Methyl 2-[((R)-(2S,3R,4S)-3,4-dihydroxy-5-oxo-tet-
rahydrofuran-2-yl)(hydroxy)methyl]-thiazolidine-4-carboxylate
3
3
CO2CH3), 4.53 (d, 1H, J4-H/3-H¼3.9 Hz, 4-H), 4.71 (dd, 1H, J3-H/2-
3
3
(6).
g-Glucuronolactone 1 (4.61 g, 26.2 mmol) and L-cysteine
¼2.7 Hz, J3-H/2-H¼3.9 Hz, 3-H), 5.71 (d, 1H, J2-H/3-H¼2.7 Hz, 2-
H
H), 8.26 (s, 1H,Thz-5-H); 13C NMR (125 MHz, CDCl3):
d 4.8, 4.9
methyl ester hydrochloride 2 (4.50 g, 26.2 mmol) were dissolved in
a minimum amount of H2O/pyridine¼10:1 so that a clear solution
was obtained after 5 min (approx. 13 mL required). A voluminous
precipitate formed within approx. 10 min and the mixture was
subsequently cooled to 5 ꢀC for 5 min. The product was filtered,
washed with cold EtOH, and dried in vacuo to yield thiazolidine 6 as
(each SiCH2CH3), 6.6, 6.8 (each SiCH2CH3), 52.7 (CO2CH3), 73.0 (C-
4), 74.1 (C-3), 79.3 (C-2), 129.0 (Thz-C-5), 146.5 (Thz-C-4), 161.8
(CO2CH3), 166.2 (Thz-C-2), 173.3 (C-5); ½a D20
ꢂ46.6 (c 0.92, CHCl3);
ꢄ
ESI-HMRS found 510.1776 (calcd for C21H37NO6SSi2þNaþ 510.1772).
a
colorless solid (4.39 g, 56%). ESI-HMRS found 316.0459
4.2.5. Methyl 2-[(1S,2R,3S)-3-(benzyloxycarbonyl)-1,2,3-
trihydroxypropyl]-thiazole-4-carboxylate (16). To a solution of lac-
tone 15 (3.97 g, 8.14 mmol) in BnOH (20 mL) CSA (93 mg,
0.40 mmol) was added and the solution was stirred at 50 ꢀC for 67 h
during which a colorless solid precipitated. The mixture was cooled
to rt and filtered, the precipitate was washed with toluene and
dried in vacuo to afford the triol 16 (2.42 g, 81%) as a colorless solid.
Rf (EtOAc/MeOH¼5:1) 0.72; mp 104 ꢀC; IR (KBr) 3427, 3237, 2960,
1712, 1495, 1389, 1318, 1294, 1232, 1200, 1124, 1090, 1045, 979, 914,
(calcd for C10H15NO7SþNaþ 316.0461). Major epimer (1R): Rf
(CHCl3/MeOH¼9:1) 0.30; 1H NMR (300 MHz, DMSO-d6):
d
2.70 (pt,
¼9.8 Hz,
2
3
1H, JThzꢂ5ꢂHproS
¼9.8 Hz, JThzꢂ5ꢂHproS
=Thzꢂ5ꢂHproR
=Thzꢂ4ꢂH
Thz-5-HproS), 2.89 (pt, 1H, 3JNH/Thz-4-H¼12.7 Hz, 3JNH/Thz-2-
2
¼12.7 Hz, NH), 3.22 (dd, 1H, JThzꢂ5ꢂHproR
¼9.8 Hz,
=Thzꢂ5ꢂHproS
H
3JThzꢂ5ꢂHproR
¼6.9 Hz, Thz-5-HproR), 3.71 (s, 3H, CO2CH3),
=Thzꢂ4ꢂH
3
3
3.84 (ddd, 1H, JThzꢂ4ꢂH=Thzꢂ5ꢂHproR ¼6.9 Hz, JThzꢂ4ꢂH=Thzꢂ5ꢂHproS
3
3
834, 726, 672, 648 cmꢂ1 1H NMR (600 MHz, DMSO-d6):
; d 3.82 (s,
¼9.8 Hz, JThz-4-H/NH¼12.7 Hz, Thz-4-H), 3.98 (ddd, 1H, JCx-H/Thz-2-
3
3
3H, CO2CH3), 3.98e4.01 (m, 1H, 3-H), 4.16 (dd, 1H, 3J3-H/3-OH¼7.1 Hz,
¼1.1 Hz, JCx-H/Cx-OH¼5.6 Hz, JCx-H/2-H¼8.7 Hz, CX-H), 4.13 (m,
H
1H, 3-H), 4.32 (dd, 1H, 3J2-H/3-H¼2.7 Hz, 3J2-H/3-H¼8.7 Hz, 2-H), 4.51
(dd, 1H, 3J4-H/5-H¼4.5 Hz, 3J4-H/4-OH¼7.3 Hz, 4-H), 4.70 (dd, 1H,3JThz-
3
3J3-H/2-H¼9.1 Hz, 3-H), 5.08 (d, 1H, J2-OH/2-H¼8.2 Hz, 2-OH), 5.08
3
3
(dd, 1H, J1-H/2-H¼1.4 Hz, J1-H/1-OH¼6.7 Hz, 1-H), 5.11 (d, 1H,
2J¼12.8 Hz, CO2CH2Phu), 5.16 (d, 1H, 2J¼12.8 Hz, CO2CH2Phd), 6.00
¼1.1 Hz, 3JThz-2-H/NH¼12.7 Hz, Thz-2-H), 5.45 (d, 1H, 3J3-OH/3-
2-H/Cx-H
¼3.9 Hz, 3-OH), 5.85 (d, 1H,3JCx-OH/Cx-H¼5.6 Hz, CX-OH), 5.90 (d,
3
(d, 1H, J3-OH/3-H¼7.1 Hz, 3-OH), 6.30 (d, 1H,3J1-OH/1-H¼6.7 Hz, 1-
H
1H, J4-OH/4-H¼7.3 Hz, 4-OH); 13C NMR (75 MHz, DMSO-d6):
d 37.0
3
OH), 7.32e7.41 (m, 5H, CO2CH2Ph), 8.43 (s, 1H, Thz-5-H); 13C NMR
(Thz-C-5), 52.3 (CO2CH3), 65.1 (Thz-C-4), 67.7 (C-X), 69.1 (C-3), 69.5
(Thz-C-2), 70.7 (C-4), 81.5 (C-2), 171.4 (CO2CH3), 176.0 (C-5). Minor
epimer (1S): Rf (CHCl3/MeOH¼9:1) 0.18; 1H NMR (300 MHz, DMSO-
(150 MHz, DMSO-d6): d 51.8 (CO2CH3), 65.4 (CO2CH2Ph), 69.6 (C-1),
71.3 (C-3), 74.3 (C-2), 127.6, 127.8, 128.3 (each Bn-CHarom.), 128.9
(Thz-C-5), 136.1 (Bn-Carom., quart.), 145.4 (Thz-C-4), 161.5 (CO2CH3),
2
3
172.8 (C-4), 177.0 (Thz-C-2); ½a D18
ꢄ
ꢂ23.3 (c 1.03, MeOH); ESI-HMRS
d6):
d
2.94 (dd, 1H, JThzꢂ5ꢂHproR
¼10.3 Hz, JThzꢂ5ꢂHproR
=Thzꢂ5ꢂHproS
=
found 390.0625 (calcd for C16H17NO7SþNaþ 390.0618).
Thz ꢂ 4 ꢂ H¼4.9 Hz, Thz-5-HproR), 3.03 (dd, 1H, JThzꢂ5ꢂHproS
2
=
Thz ꢂ 5 ꢂ HproR¼10.3 Hz, 3JThzꢂ5ꢂHproS
¼6.8 Hz, Thz-5-
=Thzꢂ4ꢂH
4.2.6. Methyl 2-[(1S,2R,3S)-3-(benzyloxycarbonyl)-1,2-dihydroxy-3-
(tert-butyl-dimethylsilyloxy)-propyl]-thiazole-4-carboxylate (17). To
a solution of triol 16 (3.59 g, 9.77 mmol) and imidazole (1.77 g,
11.7 mmol) in DMF (24 mL) TBSCl (798 mg, 11.7 mmol) was added
and the solution was stirred at rt for 18 h. After dilution with CH2Cl2
3
3
H
proS), 3.64 (s, 3H, CO2CH3), 3.96 (dd, 1H, JCx-H/2-H¼4.5 Hz, JCx-H/
¼5.9 Hz, CX-H), 4.11e4.19 (m, 2H, 2-H, 3-H), 4.38 (m, 1H, Thz-
Cx-OH
4-H), 4.55 (m, 1H, 4-H), 4.71 (br s, 1H, Thz-2-H), 5.52 (d, 1H, 3JCx-OH/
¼5.9 Hz, CX-OH), 5.55 (d, 1H,3J3-OH/3-H¼3.6 Hz, 3-OH), 5.88 (d,
Cx-H

S. Enck et al. / Tetrahedron 68 (2012) 7166e7178
7173
and 5% aq NaHCO3 the layers were separated and the aqueous layer
was extracted twice with CH2Cl2. The combined organic layers were
dried with brine and over MgSO4, filtered, and concentrated in
vacuo. Column chromatography (toluene/EtOAc¼4:1 to 3:1) affor-
ded silyl ether 17 (3.49 g, 74%) as a colorless oil. Rf (EtOAc/tol-
uene¼1:1) 0.36; IR (film) 3446, 3118, 2954, 2930, 2887, 2857, 1724,
1486, 1461, 1435, 1389, 1348, 1326, 1251, 1170, 1099, 1049, 989, 837,
1H, 2J¼12.1 Hz, CO2CH2Phd), 5.42 (br s, 1H, 2-H), 7.31e7.35 (m, 5H,
CO2CH2Ph), 8.45 (s, 1H, Thz-5-H); 13C NMR (150 MHz, CDCl3): ꢂ5.3,
ꢂ4.6 (each SiCH3), 18.4 (SiC(CH3)3), 25.8 (SiC(CH3)3), 52.6 (CO2CH3),
67.5 (CO2CH2Ph), 76.0 (C-2), 78.4 (C-3), 128.5, 128.6, 128.7 (each Bn-
CHarom.), 133.7 (Thz-C-5), 135.4 (Bn-Carom., quart.), 148.6 (Thz-C-4),
161.0 (CO2CH3), 164.5 (Thz-C-2), 170.2 (C-4), 189.9 (C-1); ½a D25
ꢂ8.6
ꢄ
(c 1.00, CHCl3); ESI-HMRS found 502.1325 (calcd for
C22H29NO7SSiþNaþ 502.1326).
780, 750, 697 cmꢂ1
;
1H NMR (600 MHz, DMSO-d6):
d
ꢂ0.01, 0.06
(each s, 3H, SiCH3), 0.83 (s, 9H, SiC(CH3)3), 3.82 (s, 3H, CO2CH3), 3.95
3
3
3
(ddd, 1H, J2-H/1-H¼1.9 Hz, J2-H/2-OH¼8.1 Hz, J2-H/3-H¼8.9 Hz, 2-H),
4.2.9. Methyl 2-[(1R,2R,3S)-3-(benzyloxycarbonyl)-1,2-dihydroxy-3-
(tert-butyl-dimethylsilyloxy)-propyl]-thiazole-4-carboxylate (20). A
solution of ketone 19 (290 mg, 0.60 mmol) in 20 mL of anhydrous
toluene in a nitrogen atmosphere was cooled to ꢂ78 ꢀC. BF3ꢁOEt2
4.32 (d, 1H, 3J3-H/2-H¼8.9 Hz, 3-H), 4.98 (dd, 1H, 3J1-H/2-H¼1.9 Hz, 3J1-
¼6.4 Hz, 1-H), 5.09 (d, 1H, 2J¼12.5 Hz, CO2CH2Phu), 5.16 (d,
H/1-OH
1H, 2J¼12.5 Hz, CO2CH2Phd), 5.31 (d, 1H, J2-OH/2-H¼8.1 Hz, 2-OH),
3
6.33 (d, 1H, 3J1-OH/1-H¼6.4 Hz, 1-OH), 7.32e7.40 (m, 5H, CO2CH2Ph),
(89.5
mL, 0.73 mmol) was added dropwise and, after 7 min,
8.45 (s, 1H, Thz-5-H); 13C NMR (150 MHz, DMSO-d6):
d
ꢂ4.8, ꢂ4.7
Bu3SnH (194 mL, 0.73 mmol) was added. The mixture was allowed
(each SiCH3), 18.5 (SiC(CH3)3), 26.2 (SiC(CH3)3), 52.7 (CO2CH3), 66.5
(CO2CH2Ph), 70.3 (C-1), 73.3 (C-3), 75.4 (C-2), 128.0, 128.1, 128.3
(each Bn-CHarom.), 129.7 (Thz-C-5), 135.7 (Bn-Carom., quart.), 146.3
to warm to 0 ꢀC under stirring and, after 12 h, additional BF3ꢁOEt2
(73.5 mL, 0.60 mmol) and Bu3SnH (158 mL, 0.60 mmol) were added.
The solution was allowed to warm to rt under stirring, and after
20 h the reaction was subsequently quenched with 5% aq NaHCO3
(15 mL) and vigorously stirred at rt for 4 h. The mixture was
extracted three times with EtOAc, the combined organic layers
were dried with brine and over MgSO4, filtered, and concentrated
in vacuo. Column chromatography (toluene/EtOAc¼4:1 to
2:1) afforded the diol 20 (219 mg, 75%) as a colorless oil. Rf
(toluene/EtOAc¼3:1) 0.21; IR (film) 3446, 3118, 2953, 2928, 2895,
2856, 1724, 1486, 1461, 1435, 1388, 1346, 1326, 1248, 1214, 1145,
(Thz-C-4), 162.2 (CO2CH3), 172.2 (C-4), 177.4 (Thz-C-2); ½a D18
ꢂ45.5
ꢄ
(c 1.08, EtOH); ESI-HMRS found 504.1486 (calcd for
C22H31NO7SSiþNaþ 504.1483).
4.2.7. Methyl 2-[(1S,2R,3S)-3-(benzyloxycarbonyl)-1-methane-
sulfonyloxy-2-hydroxy-3-(tert-butyl-dimethylsilyloxy)-propyl]-thia-
zole-4-carboxylate (18). A solution of diol 17 (988 mg, 2.05 mmol)
in anhydrous pyridine (40 mL) was cooled to 0 ꢀC in a nitrogen
atmosphere. MsCl (159
m
L, 2.05 mmol) was added and the solu-
1099, 1072, 991, 837, 780, 751, 697 cmꢂ1
DMSO-d6): 0.00, 0.08 (each s, 3H, SiCH3), 0.83 (s, 9H, SiC(CH3)3),
3.81 (s, 3H, CO2CH3), 4.06 (ddd, 1H, J2-H/1-H¼4.2 Hz, J2-H/2-
;
1H NMR (400 MHz,
tion was allowed to warm to rt under stirring. After 13 h the
reaction was diluted with CH2Cl2, quenched with ice, and the
layers were separated. The aqueous layer was extracted three
times with CH2Cl2. The combined organic layers were dried with
brine and over MgSO4, filtered, and concentrated in vacuo. Col-
umn chromatography (toluene/EtOAc¼5:1 to 4:1) afforded the
mesylate 18 (547 mg, 48%) as a colorless oil. In addition, starting
material 17 (225 mg, 23%) was reisolated. Rf (CH2Cl2/
MeOH¼35:1) 0.53; IR (film) 3472, 2953, 2931, 2857, 1725, 1472,
1435, 1359, 1250, 1217, 1174, 1120, 987, 963, 910, 836, 780, 752,
d
3
3
3
3
¼5.7 Hz, J2-H/3-H¼6.8 Hz, 2-H), 4.35 (d, 1H, J3-H/2-H¼6.8 Hz, 3-
OH
3
3
H), 4.99 (dd, 1H, J1-H/2-H¼4.2 Hz, J1-H/1-OH¼5.0 Hz, 1-H), 5.10 (s,
3
2H, CO2CH2Ph), 5.62 (d, 1H, J2-OH/2-H¼5.7 Hz, 2-OH), 6.48 (d, 1H,
3J1-OH/1-H¼5.0 Hz, 1-OH), 7.32e7.41 (m, 5H, CO2CH2Ph), 8.47 (s, 1H,
Thz-5-H); 13C NMR (100 MHz, DMSO-d6):
d
ꢂ5.3, ꢂ5.2 (each
SiCH3), 17.9 (SiC(CH3)3), 25.6 (SiC(CH3)3), 51.8 (CO2CH3), 65.7
(CO2CH2Ph), 70.3 (C-1), 73.3 (C-3), 75.6 (C-2), 128.0, 128.1, 128.3
(each Bn-CHarom.), 129.2 (Thz-C-5), 135.8 (Bn-Carom., quart.), 145.0
697 cmꢂ1
;
1H NMR (600 MHz, DMSO-d6):
d
ꢂ0.04, 0.05 (each s,
(Thz-C-4), 161.4 (CO2CH3), 171.3 (C-4), 174.4 (Thz-C-2); ½a D
ꢄ
24 16.0 (c
(calcd for
3H, SiCH3), 0.84 (s, 9H, SiC(CH3)3), 3.15 (s, 3H, Ms-CH3), 3.83 (s,
0.48,
CHCl3);
ESI-HMRS
found
504.1484
3
3
3H, CO2CH3), 4.16 (ddd, 1H, J2-H/1-H¼4.4 Hz, J2-H/3-H¼6.0 Hz,
3J2-H/2-OH¼7.0 Hz, 2-H), 4.32 (d, 1H, 3J3-H/2-H¼6.0 Hz, 3-H), 5.02 (d,
1H, 2J¼12.3 Hz, CO2CH2Phu), 5.07 (d, 1H, 2J¼12.3 Hz, CO2CH2Phd),
C22H31NO7SSiþNaþ 504.1483).
4.2.10. Methyl 2-[(1R,2R,3S)-3-(benzyloxycarbonyl)-1-methane-
sulfonyloxy-2-hydroxy-3-(tert-butyl-dimethylsilyloxy)-propyl]-thia-
3
3
5.86 (d, 1H, J1-H/2-H¼4.4 Hz, 1-H), 6.39 (d, 1H, J2-OH/2-H¼7.0 Hz,
2-OH), 7.36e7.41 (m, 5H, CO2CH2Ph), 8.66 (s, 1H, Thz-H-5);
zole-4-carboxylate (21). A solution of diol 20 (195 mg, 405
and a catalytical amount of DMAP in anhydrous pyridine (6 mL) was
cooled to 0 ꢀC in a nitrogen atmosphere. MsCl (31.3
L, 405 mol)
mmol)
13C NMR (150 MHz, DMSO-d6):
d
ꢂ5.4, ꢂ5.3 (each SiCH3), 17.8
(SiC(CH3)3), 25.5 (SiC(CH3)3), 38.7 (Ms-CH3), 52.1 (CO2CH3), 66.3
(CO2CH2Ph), 73.2 (C-3), 74.0 (C-2), 77.6 (C-1), 128.1, 128.3, 128.4
(each Bn-CHarom.), 131.3 (Thz-C-5), 135.4 (Bn-Carom., quart.), 145.5
m
m
was added and the solution was allowed to warm to rt under stir-
ring. After 14 h, the solution was cooled to 0 ꢀC and more MsCl
(Thz-C-4), 161.0 (CO2CH3), 165.5 (Thz-C-2), 170.3 (C-4); ½a D18
ꢄ
(15.7 mmol, 203 mmol) was added. After warming to rt and stirring
ꢂ42.4 (c 1.04, CHCl3); ESI-HMRS found 582.1263 (calcd for
for another 3 h the reaction was diluted with CH2Cl2, quenched with
ice, and the layers were separated. The aqueous layer was extracted
twice with CH2Cl2. The combined organic layers were dried with
brine and over MgSO4, filtered, and concentrated in vacuo. Column
chromatography (toluene/EtOAc¼5:1) afforded the mesylate 21
(165 mg, 73%) as a colorless oil. Rf (CH2Cl2/MeOH¼35:1) 0.23; IR
(film) 3463, 2954, 2930, 2857, 1727, 1462, 1435, 1412, 1361, 1249,
C23H33NO9S2SiþNaþ 582.1258).
4.2.8. Methyl 2-[(2R,3S)-3-(benzyloxycarbonyl)-1-oxo-2-hydroxy-3-
(tert-butyl-dimethylsilyloxy)-propyl]-thiazole-4-carboxylate (19). To
a solution of the diol 17 (1.02 g, 2.12 mmol) in EtOAc (60 mL) was
added IBX (2.97 g, 10.6 mmol) and the suspension was refluxed at
80 ꢀC for 1.5 h under vigorous stirring. After cooling to rt, filtration
over Celite, washing with EtOAc, and concentration in vacuo, col-
umn chromatography (toluene/EtOAc¼5:1 to 3:1) afforded ketone
19 (294 mg, 29%) as pale yellow oil. In addition, starting material 17
(543 mg, 53%) was reisolated. Rf (toluene/EtOAc¼3:1) 0.59; IR (KBr)
3485, 3113, 2954, 2930, 2887, 2857, 1726, 1697, 1492, 1336, 1250,
;
1216, 1175, 1099, 956, 836, 781, 751, 697 cmꢂ1 1H NMR (600 MHz,
DMSO-d6):
d
ꢂ0.05, 0.05 (each s, 3H, SiCH3), 0.84 (s, 9H, SiC(CH3)3),
3
3.16 (s, 3H, Ms-CH3), 3.84 (s, 3H, CO2CH3), 4.16 (d, 1H, J3-H/2-
¼6.2 Hz, 3-H), 4.38 (m, 1H, 2-H), 5.11 (d, 1H,2J¼12.3 Hz, CO2CH2
H
-
Phu), 5.18 (d, 1H, 2J¼12.3 Hz, CO2CH2Phd), 5.87 (d, 1H, J1-H/2-
3
3
¼4.8 Hz, 1-H), 6.40 (d, 1H, J2-OH/2-H¼6.0 Hz, 2-OH), 7.35e7.42 (m,
H
1216, 1186, 1140, 990, 938, 864, 837, 779, 748, 697 cmꢂ1
;
1H NMR
5H, CO2CH2Ph), 8.65 (s, 1H, Thz-5-H); 13C NMR (150 MHz, DMSO-
(600 MHz, CDCl3): 0.08, 0.12 (each s, 3H, SiCH3), 0.88 (s, 9H,
d
d6):
d
ꢂ5.6, ꢂ5.4 (each SiCH3), 17.8 (SiC(CH3)3), 25.5 (SiC(CH3)3), 38.3
SiC(CH3)3), 3.92 (s, 3H, CO2CH3), 4.00 (br s, 1H, 2-OH), 5.12 (d, 1H,
(Ms-CH3), 52.1 (CO2CH3), 66.3 (CO2CH2Ph), 73.4 (C-3), 73.5 (C-2),
77.7 (C-1), 128.2, 128.3, 128.4 (each Bn-CHarom.), 131.2 (Thz-C-5),
2J¼12.1 Hz, CO2CH2Phu), 5.15 (d, 1H, 3J3-H/2-H¼2.5 Hz, 4-H), 5.22 (d,

7174
S. Enck et al. / Tetrahedron 68 (2012) 7166e7178
135.4 (Bn-Carom., quart.), 145.2 (Thz-C-4), 161.0 (CO2CH3), 165.0 (Thz-
(d, 1H, 3J1-H/2-H¼1.0 Hz, 1-H), 6.04, 6.39 (each br s, 1H, 2-OH, 3-OH),
7.35e7.42 (m, 5H, CO2CH2Ph), 8.61 (s, 1H, Thz-5-H); 13C NMR
C-2), 170.5 (C-4); ½a D22
ꢄ
26.5 (c 2.38, CHCl3); ESI-HMRS found
582.1267 (calcd for C23H33NO9S2SiþNaþ 582.1258).
(100 MHz, DMSO-d6):
d
¼38.1 (Ms-CH3), 52.1 (CO2CH3), 65.9
(CO2CH2Ph), 71.0 (C-1), 73.2 (C-2), 78.6 (C-3), 127.9, 128.2, 128.4
4.2.11. Methyl 2-[(1R,2R,3S)-3-(benzyloxycarbonyl)-1-azido-2-
hydroxy-3-(tert-butyl-dimethylsilyloxy)-propyl]-thiazole-4-
(each Bn-CHarom.), 130.5 (Thz-C-5), 135.8 (Bn-Carom., quart.), 145.3
(Thz-C-4),161.0 (CO2CH3),167.7 (Thz-C-2),171.9 (C-4); ½a D19
ꢄ
ꢂ27.9 (c
carboxylate (22). NaN3 (3.8 mg, 59.0
mmol) was added to a solution
1.54,
CHCl3);
ESI-HMRS
found
468.0398
(calcd for
of the mesylate 18 (22 mg, 39.3 mol) in anhydrous DMF (0.4 mL)
m
C17H19N4O9S2þNaþ 468.0393).
in a nitrogen atmosphere and the mixture was stirred at 85 ꢀC for
2.5 h. After cooling to rt and removal of the DMF in vacuo, CH2Cl2
and H2O were added, the layers were separated, and the aqueous
layer was extracted twice with CH2Cl2. The combined organic layers
were dried with brine and over MgSO4, filtered, and concentrated
in vacuo. Column chromatography (toluene/EtOAc¼6:1) yielded
the azide 22 (2.4 mg, 10%) as a colorless oil, which is available from
mesylate 21 along the same procedure. Rf (toluene/EtOAc¼3:1)
4.2.14. Methyl 2-[(1R,2R,3S)-3-(benzyloxycarbonyl)-1,2-epoxy-3-
hydroxypropyl]-thiazole-4-carboxylate (27). The epoxide 27 was
obtained as a second product (16 mg, 26%) after TBS cleavage of
mesylate 18 (Section 4.2.7) as colorless solid. Rf (EtOAc/tol-
uene¼1:1) 0.30; mp 101 ꢀC; IR (neat) 3237, 3130, 3102, 2956, 2926,
1725, 1495, 1455, 1436, 1322, 1289, 1261, 1242, 1229, 1193, 1096,
1083, 1071, 981, 921, 882, 837, 759, 744, 696 cmꢂ1
(600 MHz, DMSO-d6):
;
1H NMR
0.58; 1H NMR (500 MHz, DMSO-d6):
d
ꢂ0.05, 0.00 (each s, 3H,
d
3.84 (s, 3H, CO2CH3), 3.59 (dd, 1H, J2-H/1-
3
3
3
SiCH3), 0.82 (s, 9H, SiC(CH3)3), 3.83 (s, 3H, CO2CH3), 4.24e4.27 (m,
¼4.0 Hz, J2-H/3-H¼8.5 Hz, 2-H), 3.93 (dd, 1H, J3-H/3-OH¼6.5 Hz,
H
3
3
2H, 2-H, 3-H), 5.03 (d, 1H, J1-H/2-H¼5.4 Hz, 1-H), 5.15 (s, 2H,
3J3-H/2-H¼8.5 Hz, 3-H), 4.62 (d, 1H, J1-H/2-H¼4.0 Hz, 1-H), 5.21 (d,
1H, 2J¼12.7 Hz, CO2CH2Phu), 5.25 (d, 1H, 2J¼12.7 Hz, CO2CH2Phd),
6.11 (d, 1H, 3J3-OH/3-H¼6.5 Hz, 3-OH), 7.33e7.42 (m, 5H, CO2CH2Ph),
CO2CH2Ph), 6.26 (d, 1H, 3J2-OH/2-H¼5.6 Hz, 2-OH), 7.33e7.41 (m, 5H,
CO2CH2Ph), 8.58 (s, 1H, Thz-5-H); 13C NMR (125 MHz, DMSO-d6):
d
ꢂ5.5, ꢂ5.5 (each SiCH3), 17.6 (SiC(CH3)3), 25.2 (SiC(CH3)3), 51.7
8.58 (s, 1H, Thz-5-H); 13C NMR (150 MHz, DMSO-d6):
d 52.1
(CO2CH3), 62.3 (C-1), 66.1 (CO2CH2Ph), 73.4, 73.7 (C-2, C-3), 127.9,
128.0, 128.1 (each Bn-CHarom.), 130.4 (Thz-C-5), 135.5 (Bn-Carom.,
quart.), 145.0 (Thz-C-4), 160.9 (CO2CH3), 165.9 (Thz-C-2), 170.4 (C-4);
(CO2CH3), 53.8 (C-1), 59.0 (C-2), 66.0 (CO2CH2Ph), 67.5 (C-3), 127.1,
128.1, 128.4 (each Bn-CHarom.), 129.6 (Thz-C-5), 135.8 (Bn-Carom.,
quart.), 146.4 (Thz-C-4), 160.9 (CO2CH3), 165.3 (Thz-C-2), 171.3 (C-4);
½
a 1D8
ꢄ
6.0 (c 0.32, CHCl3); ESI-HMRS found 529.1554 (calcd for
½
a 1D3
68.5 (c 1.14, CHCl3); ESI-HMRS found 372.0509 (calcd for
ꢄ
C22H30N4O6SSiþNaþ 529.1548).
C16H15NO6SþNaþ 372.0512).
4.2.12. Methyl 2-[(1S,2R,3S)-3-(benzyloxycarbonyl)-1,2-epoxy-3-
4.2.15. Methyl 2-[(1S,2S,3S)-3-(benzyloxycarbonyl)-1-azido-2,3-
hydroxypropyl]-thiazole-4-carboxylate (23). Mesylate 21 (121 mg,
dihydroxypropyl]-thiazole-4-carboxylate (8). A solution of epoxide
156
atmosphere and cooled to 0 ꢀC. TBAF (1.0 M in THF; 203
203
mol) was added dropwise and the solution was stirred at 0 ꢀC
m
mol) was dissolved in anhydrous THF (10 mL) in a nitrogen
27 (17 mg, 48.7 mmol), NaN3 (16 mg, 244 mmol), and a catalytical
mL,
amount of p-TosOHꢁH2O in DMSO (1.0 mL) was stirred at 70 ꢀC for
9 h in a nitrogen atmosphere. After cooling to rt and addition of H2O
and CH2Cl2 the layers were separated and the aqueous layer was
extracted three times with CH2Cl2. The combined organic layers
were dried with brine and over MgSO4, filtered, and concentrated
in vacuo. Column chromatography (toluene/EtOAc¼2:1) yielded
the azide 8 (3.0 mg,16%) as a pale yellow oil. NMR monitoring of the
reaction in DMSO-d6 showed a >90% conversion after 13.5 h under
identical conditions. Rf (EtOAc/toluene¼3:2) 0.41; IR (film) 3436,
3116, 3012, 2954, 2925, 2108, 1723, 1625, 1498, 1456, 1435, 1319,
m
for 45 min. The reaction mixture was diluted with EtOAc and the
THF was removed in vacuo. The remaining solution was washed
twice with aq NaCl, dried with brine and over MgSO4, filtered, and
evaporated. Column chromatography (toluene/EtOAc¼3:1) yielded
the epoxide 23 (23 mg, 42%) as a colorless solid. Rf (EtOAc/tol-
uene¼1:1) 0.36; mp 89 ꢀC; IR (KBr) 3478, 3111, 2958, 1732, 1715,
1496, 1455, 1440, 1392, 1274, 1237, 1205, 1124, 1093, 1028, 984, 933,
911, 882, 851, 753, 698 cmꢂ1; 1H NMR (500 MHz, DMSO-d6):
d 3.84
3
3
(s, 3H, CO2CH3), 3.62 (dd, 1H, J2-H/1-H¼2.0 Hz, J2-H/3-H¼4.2 Hz, 2-
1214, 1095, 986, 918, 864, 828, 783, 748, 697 cmꢂ1
(500 MHz, DMSO-d6):
;
1H NMR
3
3
3
H), 4.39 (dd, 1H, J3-H/2-H¼4.2 Hz, J3-H/3-OH¼6.5 Hz, 3-H), 4.45 (d,
d
3.83 (s, 3H, CO2CH3), 4.16 (dd, 1H, J3-H/2-
1H, 3J1-H/2-H¼2.0 Hz, 1-H), 5.21 (s, 1H, CO2CH2Ph), 6.18 (d, 1H, 3J3-OH/
¼2.9 Hz, J3-H/3-OH¼6.9 Hz, 3-H), 4.25 (dpt, 1H, J2-H/3-H¼2.9 Hz,
3
3
H
3
3
¼6.5 Hz, 3-OH), 7.33e7.37 (m, 5H, CO2CH2Ph), 8.56 (s, 1H, Thz-5-
3J2-H/1-H¼7.3 Hz, J2-H/2-OH¼7.3 Hz, 2-H), 5.11 (d, 1H, J1-H/2-
3-H
H); 13C NMR (125 MHz, DMSO-d6):
d
¼52.1 (CO2CH3), 52.2 (C-1),
¼7.3 Hz, 1-H), 5.13 (d, 1H, 2J¼12.6 Hz, CO2CH2Phu), 5.17 (d, 1H,
H
66.1 (CO2CH2Ph), 62.4 (C-2), 68.8 (C-3), 127.8, 128.1, 128.4 (each Bn-
2J¼12.6 Hz, CO2CH2Phd), 5.58 (d, 1H, 3J3-OH/3-H¼6.9 Hz, 3-OH), 6.04
(d, 1H, 3J2-OH/2-H¼7.3 Hz, 2-OH), 7.35e7.40 (m, 5H, CO2CH2Ph), 8.56
CHarom.), 129.7 (Thz-C-5), 135.7 (Bn-Carom., quart.), 146.0 (Thz-C-4),
160.9 (CO2CH3), 167.9 (Thz-C-2), 170.5 (C-4); ½a D18
ꢄ
ꢂ0.7 (c 1.77,
(s, 1H, Thz-5-H); 13C NMR (125 MHz, DMSO-d6):
d 52.1 (CO2CH3),
CHCl3); ESI-HMRS found 372.0510 (calcd for C16H15NO6SþNaþ
63.1 (C-1), 65.9 (CO2CH2Ph), 71.2 (C-3), 74.4 (C-2),127.8,128.0,128.4
372.0512).
(each Bn-CHarom.), 130.3 (Thz-C-5), 135.9 (Bn-Carom., quart.), 145.7
(Thz-C-4), 161.0 (CO2CH3), 167.1 (Thz-C-2), 171.8 (C-4); ½a D21
ꢂ30.9
ꢄ
4.2.13. Methyl 2-[((1S,2R,3S)-3-(benzyloxycarbonyl)-1-methane-
sulfonyloxy-2,3-dihydroxybutyl-dimethylsilyloxy)-propyl]-thiazole-4-
(c 0.28, CHCl3); ESI-HMRS found 415.0688 (calcd for
C16H16N4O6SþNaþ 415.0683).
carboxylate (24). A solution of the mesylate 18 (220 mg, 393
in anhydrous THF (25 mL) was cooled to 0 ꢀC in a nitrogen atmo-
sphere. TBAF (1.0 M in THF; 511 L, 511 mol) was added dropwise
mmol)
4.2.16. Methyl 2-[(1R,2S,3S)-3-(benzyloxycarbonyl)-1-azido-2,3-
dihydroxypropyl]-thiazole-4-carboxylate (9).
m
m
and the mixture was stirred at 0 ꢀC for 1.5 h. After removal of the
solvent under reduced pressure at 30 ꢀC the residue was subjected
to column chromatography (EtOAc/toluene¼1:1), which yielded
the mesylate 24 (36 mg, 21%) as pale yellow oil. Rf (EtOAc/tol-
uene¼1:1) 0.15; IR (film) 3435, 3117, 3029, 2955, 1722, 1496, 1485,
1455, 1435, 1351, 1217, 1174, 1095, 964, 908, 854, 812, 787, 751, 734,
(a) from epoxide 23: A solution of epoxide 23 (19 mg, 54.4
mmol),
NaN3 (18 mg, 272 mol), and a catalytical amount of CSA in
m
anhydrous DMF (2.0 mL) was stirred at 85 ꢀC for 4 h in a ni-
trogen atmosphere. After cooling to rt and neutralization with
NEt3 the DMF was removed in vacuo. EtOAc and H2O were
added, the layers were separated, and the aqueous layer was
extracted three times with EtOAc. The combined organic layers
were dried with brine and over MgSO4, filtered, and
697 cmꢂ1 1H NMR (300 MHz, DMSO-d6):
; d 3.27 (s, 3H, Ms-CH3),
3.84 (s, 3H, CO2CH3), 4.08e4.13 (m, 2H, 2-H, 3-H), 5.12 (d, 1H,
2J¼12.6 Hz, CO2CH2Phu), 5.16 (d, 1H, 2J¼12.6 Hz, CO2CH2Phd), 5.99

S. Enck et al. / Tetrahedron 68 (2012) 7166e7178
7175
concentrated in vacuo to obtain the crude product as a pale
yellow oil. NMR monitoring of the reaction with DMSO-d6 in-
stead of anhydrous DMF as solvent showed a >90% conversion
after 3.5 h under otherwise identical conditions.
3000, 2936, 2897, 1754, 1650, 1434, 1204, 1170, 1143, 1081, 1068,
1034, 1007, 829 cmꢂ1
;
1H NMR (300 MHz, DMSO-d6):
d
1.32, 1.38
2
(each s, 3H, isopr-CH3), 3.26 (dd, 1H, J2ꢂHu=2ꢂHd ¼10.7 Hz,
J2ꢂH =3ꢂH¼8.8 Hz, 2-Hu), 3.26 (dd, 1H, J2ꢂHd=2ꢂHu ¼10.7 Hz,
3
2
u
3J2ꢂHd=3ꢂH¼7.6 Hz, 2-Hd), 3.33e3.39 (m, 1H, 9-H), 3.55 (ddd, 1H, 3J8-
(b) from mesylate 24: A solution of mesylate 24 (76 mg, 171
mmol)
3
3
and NaN3 (33 mg, 513 mol) in anhydrous DMF (6.5 mL) was
m
¼5.4 Hz, J8-H/9-H¼7.3 Hz, J8-H/7-H¼9.9 Hz, 8-H), 3.63 (s, 3H,
H/8-OH
CO2CH3), 4.24 (dd, 1H, 3J7-H/6-H¼8.0 Hz, 3J7-H/8-H¼9.8 Hz, 7-H), 4.50
stirred at 85 ꢀC for 2 h in a nitrogen atmosphere. After cooling
to rt and removal of the DMF in vacuo, EtOAc and H2O were
added, the layers were separated, and the aqueous layer was
extracted three times with EtOAc. The combined organic layers
were dried with brine and over MgSO4, filtered, and concen-
trated in vacuo to obtain the crude product as a pale yellow oil.
Column chromatography (EtOAc/toluene¼1:1) yielded the
3
(dd, 1H, 3J3ꢂH=2ꢂHd ¼7.6 Hz, 3J3ꢂH=2ꢂH ¼8.8 Hz, 3-H), 5.01 (d, 1H, J6-
u
¼8.0 Hz, 6-H), 5.24 (d, 1H, 3J9a-H/9-H¼3.2 Hz, 9a-H), 5.32(pt, 2H,
H/7-H
8-OH, 9-OH); 13C NMR (75 MHz, DMSO-d6):
d 24.7, 26.9 (each isopr-
CH3), 32.4 (C-2), 52.0 (CO2CH3), 62.3 (C-3), 62.4 (C-9a), 74.6 (C-8),
74.8 (C-9), 75.0 (C-6), 76.8 (C-7), 108.6, (isopr-Cquart.), 165.8, 169.6
(CO2CH3, C-5); ½a D22
ꢂ95.4 (c 0.95, DMSO); ESI-HMRS found
ꢄ
356.0767 (calcd for C13H19NO7SþNaþ 356.0774).
azide 9 (120 mmol, 70%) as a pale yellow oil. Rf (EtOAc/tol-
uene¼3:2) 0.31; IR (film) 3435, 3115, 2954, 2925, 2854, 2108,
1724, 1482, 1456, 1435, 1324, 1216, 1095, 989, 915, 854, 753,
4.2.19. (9aR)H-(6S,7R)-O-Isopropylidene(8S)-trifuoromethanesulfonyl-
(9R)-hydroxy-5-oxo-octahydro-thiazolo[3,2-a]azepine-(3R)-carboxylic
acid methyl ester (30). A solution of the diol 29 (8.24 g, 24.7 mmol)
in anhydrous CH2Cl2/DMF¼3:1 (160 mL) was cooled to 0 ꢀC under
a nitrogen atmosphere. Tf2O (4.98 mL, 32.1 mmol) was added
dropwise over 15 min and the solution was stirred at 0 ꢀC for 1 h
and at rt for 3.5 h. The reaction was quenched with 170 mL of ice,
the layers were separated and the aqueous layer was extracted
twice with CH2Cl2. The combined organic layers were dried with
brine and over MgSO4, filtered, and concentrated in vacuo. A
fraction of the product was isolated by filtration after addition of
EtOAc/toluene¼2:1 and the filtrate was subjected to column
chromatography (EtOAc/toluene¼2:1), yielding the triflate 30 as
yellow solid (10.9 g, 94%). Rf (EtOAc/toluene 10:1) 0.59; mp 85 ꢀC;
IR (neat) 3328, 2992, 2950, 1747, 1661, 1436, 1411, 1397, 1376, 1352,
697 cmꢂ1
; d 3.83 (s, 3H,
1H NMR (300 MHz, DMSO-d6):
CO2CH3), 3.99e4.03 (m, 1H, 3-H), 4.18e4.22 (m, 1H, 2-H), 5.11
(d, 1H, 2J¼12.6 Hz, CO2CH2Phu), 5.16 (d, 1H, 2J¼12.6 Hz,
CO2CH2Phd), 5.17 (d, 1H, 3J1-H/2-H¼4.8 Hz, 1-H), 6.06 (d, 1H, 3J3-
3
¼6.2 Hz, 3-OH), 6.28 (d, 1H, J2-OH/2-H¼6.2 Hz, 2-OH),
OH/3-H
7.34e7.39 (m, 5H, CO2CH2Ph), 8.58 (s, 1H, Thz-5-H); 13C NMR
(150 MHz, CDCl3):
d
52.7 (CO2CH3), 62.6 (C-1), 68.2
(CO2CH2Ph), 71.9 (C-3), 75.0 (C-2), 128.8 (Thz-C-5), 128.8, 128.9,
128.9 (each Bn-CHarom.), 134.8 (Bn-Carom., quart.), 147.1 (Thz-C-4),
161.5 (CO2CH3), 168.8 (Thz-C-2), 171.8 (C-4); ½a D21
ꢄ
10.5 (c 0.26,
CHCl3); ESI-HMRS found 415.0689 (calcd for C16H16N4O6SþNaþ
415.0683).
4.2.17. (9aR)H-bis-(6S,7S)-(8S,9R)-O-Isopropylidene-5-oxo-octahy-
dro-thiazolo[3,2-a]azepine-(3R)-carboxylic acid methyl ester (28). To
a solution of the tetraol 5 (12.0 g, 40.9 mmol) in anhydrous DMF
(120 mL) under a nitrogen atmosphere were added DMP (50.3 mL,
409 mmol) and a catalytic amount of p-TosOHꢁH2O. The solution
was stirred at 60 ꢀC for 38 h, cooled to rt, neutralized by addition of
NEt3, and concentrated in vacuo. Column chromatography (EtOAc/
toluene/NEt3 300:50:1) yielded the bis-acetonide 28 as colorless
powder (14.19 g, 93%). Rf (EtOAc/toluene¼4:1) 0.54; mp 224 ꢀC; IR
(KBr) 2985, 2939, 2888, 1752, 1647, 1372, 1302, 1213, 1165, 1076,
1329, 1246, 1199, 1141, 1069, 954, 888 cmꢂ1 1H NMR (600 MHz,
;
DMSO-d6):
d
1.35, 1.36 (each s, 3H, isopr-CH3), 3.30 (dd, 1H,
J2ꢂHu=2ꢂHd ¼10.9 Hz, J2ꢂH =3ꢂH¼8.9 Hz, 2-Hu), 3.37 (dd, 1H,
2
3
u
2J2ꢂHd=2ꢂHu ¼10.9 Hz, J2ꢂHd=3ꢂH¼7.3 Hz, 2-Hd), 3.63 (s, 3H,
3
3
3
CO2CH3), 3.91 (dd, 1H, J9-H/9a-H¼3.2 Hz, J9-H/8-H¼7.8 Hz, 9-H),
4.64 (dd, 1H, 3J3ꢂH=2ꢂHd ¼7.3 Hz, 3J3ꢂH=2ꢂH ¼8.9 Hz, 3-H), 4.74 (dd,
u
3
3
3
1H, J7-H/6-H¼8.2 Hz, J7-H/8-H¼10.5 Hz, 7-H), 4.94 (dd, 1H, J8-H/9-
3
3
¼7.8 Hz, J8-H/7-H¼10.5 Hz, 8-H), 5.28 (d, 1H, J6-H/7-H¼8.2 Hz, 6-
H
H), 5.30 (d, 1H, J9a-H/9-H¼3.2 Hz, 9a-H), 6.33 (br s, 1H, 9-OH); 13C
3
998, 851 cmꢂ1 1H NMR (300 MHz, DMSO-d6):
; d 1.34 (s, 3H, isopr-
NMR (125 MHz, DMSO-d6):
d 25.0, 26.1 (each isopr-CH3), 32.1 (C-
CH3), 1.38 (s, 6H, 2ꢁisopr-CH3), 1.44 (s, 3H, isopr-CH3), 3.09 (dd, 1H,
2), 52.1 (CO2CH3), 61.9 (C-9a), 62.2 (C-3), 71.2 (C-9), 72.7 (C-7), 75.3
(C-6), 92.2 (C-8), 110.2 (isopr-Cquart.), 164.4, 169.2 (CO2CH3, C-5);
J2ꢂHu=2ꢂHd ¼12.3 Hz, J2ꢂH =3ꢂH¼1.8 Hz, 2-Hu), 3.26 (dd, 1H,
2
3
u
2J2ꢂHd=2ꢂHu ¼12.3 Hz, 3J2ꢂHd=3ꢂH¼7.3 Hz, 2-Hd), 3.65 (s, 3H,
CO2CH3), 4.29 (dd, 1H, 3J9-H/9a-H¼7.1 Hz, 3J9-H/8-H¼9.4 Hz, 9-H), 4.36
(dd, 1H, 3J7-H/6-H¼5.9 Hz, 3J7-H/8-H¼8.2 Hz, 7-H), 4.52 (dd, 1H, 3J8-H/7-
½
a 2D0
ꢄ
ꢂ78.5 (c 1.00, CHCl3); ESI-HMRS found 488.0269 (calcd for
C14H18F3NO9SþNaþ 488.0267).
3
3
u
¼8.2 Hz, J8-H/9-H¼9.4 Hz, 8-H), 4.78 (dd, 1H, J3ꢂH=2ꢂH ¼1.8 Hz,
H
4.2.20. (9aR)H-(6S,7R)-O-Isopropylidene-(8R,9R)-epoxy-(9R)-5-oxo-
octahydro-thiazolo[3,2-a]azepine-(3R)-carboxylic acid methyl ester
(31). Triflate 30 (10.8 g, 23.2 mmol) was dissolved in DMF
(300 mL), NEt3 (21 mL) was added and the mixture was stirred at
60 ꢀC for 27 h. After cooling to rt and concentrated in vacuo, EtOAc/
toluene¼1:1 (50 mL) were added, the resulting suspension was
stored in the fridge overnight, and filtered. The precipitate was
washed with cold toluene and dried in vacuo to yield the epoxide
31 (5.95 g, 81%) as colorless powder. Rf (EtOAc/toluene¼7:1) 0.31;
mp 189 ꢀC; IR (neat) 2992, 2976, 2949, 2926, 2866, 1766,1655,1430,
1371, 1334, 1281, 1242, 1225, 1199, 1170, 1058, 1016, 952, 906, 888,
863, 842, 809, 798, 784, 724, 713 cmꢂ1; 1H NMR (500 MHz, DMSO-
3J3ꢂH=2ꢂHd ¼7.3 Hz, 3-H), 4.84 (d, 1H, 3J6-H/7-H¼5.9 Hz, 6-H), 5.46 (d,
1H,3J9a-H/9-H¼7.1 Hz, 9a-H); 13C NMR (75 MHz, DMSO-d6):
d 26.2,
26.2, 26.9, 27.0 (each isopr-CH3), 30.6 (C-2), 52.2 (CO2CH3), 62.0 (C-
9a), 63.5 (C-3), 73.5 (C-9), 75.1 (C-6), 75.3 (C-8), 76.9 (C-7), 111.8,
111.9 (each isopr-Cquart.), 166.4, 170.1 (CO2CH3, C-5); ½a D23
ꢄ
57.1 (c
1.02, CHCl3); ESI-HMRS found 396.1089 (calcd for C16H23NO7SþNaþ
396.1087).
4.2.18. (9aR)H-(6S,7S)-Dihydroxy-(8S,9R)-O-isopropylidene-5-oxo-
octahydro-thiazolo[3,2-a]azepine-(3R)-carboxylic acid methyl ester
(29). To a solution of bis-acetonide 28 (14.2 g, 38.0 mmol) in MeOH
(150 mL) was added a catalytic amount of p-TosOHꢁH2O and the
solution was stirred at rt for 17 h during which a fraction of the
product crystallized from the reaction mixture. This was isolated by
filtration, washed with cold MeOH, and dried in vacuo. The filtrate
was neutralized by addition of NEt3 and adsorbed on Celite by re-
moval of the solvent in vacuo. Column chromatography (CH2Cl2/
MeOH¼10:1) yielded the second fraction of product, resulting in an
overall yield of monoacetonide 29 (8.54 g, 67%) as a colorless solid.
Rf (CH2Cl2/MeOH¼10:1) 0.58; mp 207 ꢀC; IR (KBr) 3503, 3434,
d6):
d
1.33, 1.42 (each s, 3H, isopr-CH3), 3.11 (dd, 1H,
J2ꢂHu=2ꢂHd ¼11.8 Hz, J2ꢂH =3ꢂH¼3.5 Hz, 2-Hu), 3.22 (dd, 1H,
2
3
u
2J2ꢂHd=2ꢂHu ¼11.8 Hz, J2ꢂHd=3ꢂH¼6.7 Hz, 2-Hd), 3.33 (d, 1H, J9-H/8-
3
3
3
3
¼4.4 Hz, 9-H), 3.42 (dd, 1H, J8-H/7-H¼3.0 Hz, J8-H/9-H¼4.4 Hz, 8-
H
3
3
H), 3.62 (s, 3H, CO2CH3), 4.56 (dd, 1H, J7-H/8-H¼3.0 Hz, J7-H/6-
3
u
¼6.5 Hz,
7-H),
4.74
(dd,
1H,
J3ꢂH=2ꢂH ¼3.5 Hz,
H
3
3J3ꢂH=2ꢂHd ¼6.7 Hz, 3-H), 4.68 (d, 1H, J6-H/7-H¼6.5 Hz, 6-H), 4.74
(dd, 1H,3J3ꢂH=2ꢂH ¼3.5 Hz, J3ꢂH=2ꢂHd ¼6.7 Hz, 3-H), 5.53 (s, 1H, 9a-
3
u
H); 13C NMR (125 MHz, DMSO-d6):
d 25.8, 26.9 (each isopr-CH3),

7176
S. Enck et al. / Tetrahedron 68 (2012) 7166e7178
31.4 (C-2), 51.5 (C-8), 51.8 (CO2CH3), 54.7 (C-9), 56.2 (C-9a), 63.3
25.6 (each isopr-CH3), 31.0 (C-2), 52.4 (CO2CH3), 61.8 (C-9a), 62.0
(C-3), 73.6 (C-6), 73.7 (C-7), 108.3 (isopr-Cquart.), 166.8, 169.1
(C-3), 67.3 (C-9), 71.3 (C-8), 74.2 (C-6), 74.6 (C-7), 107.9 (isopr-
(CO2CH3, C-5); ½a D23
ꢄ
ꢂ70.7 (c 1.00, CHCl3); ESI-HMRS found
Cquart.), 166.6 (C-5), 170.6 (CO2CH3); ½a D24
ꢄ
3.3 (c 1.16, CHCl3); ESI-
338.0671 (calcd for C13H17NO6SþNaþ 338.0669).
HMRS found 381.0842 (calcd for C13H18N4O6SþNaþ 381.0839).
4.2.23. Methyl 2-[(S)-azido((3aS,4S,6aS)-2,2-dimethyl-6-
oxotetrahydrofuro[3,4-d][1,3]dioxol-4-yl)methyl]-thiazole-4-
4.2.21. (2S,4R)-Methyl 2-[(S)-azido((3aS,4S,6aS)-2,2-dimethyl-6-
oxotetrahydrofuro[3,4-d][1,3]dioxol-4-yl)methyl]-thiazolidine-4-
carboxylate (7a).
carboxylate (34). To
a solution of thiazolidine 7a (661 mg,
1.84 mmol) in acetonitrile (40 mL) was added MnO2 (4.81 mg,
55.3 mmol), the suspension was stirred vigorously at 70 ꢀC for 20 h,
filtered over Celite, and concentrated in vacuo. The residue was
dissolved in EtOAc/toluene¼2:1, adsorbed on Celite, and subjected
to column chromatography (EtOAc/toluene¼5:1 to 3:1) to yield the
thiazole 34 (203 mg, 31%) as pale yellow solid. In addition, starting
material 7a was also isolated (179 mg, 27%). Rf (toluene/EtOAc¼5:1)
0.16; mp 142 ꢀC; IR (KBr) 3098, 2990, 2114, 1790, 1717, 1474, 1377,
1346, 1276, 1244, 1223, 1210, 1166, 1103, 1084, 1065, 1032, 991, 980,
(a) from epoxide 31: Epoxide 31 (2.66 g, 8.44 mmol) and NaN3
(950 mg, 14.3 mmol) were dissolved in DMF/AcOH¼130:1
(38 mL). The mixture was stirred at 45 ꢀC for 23 h, then at 50 ꢀC
for 4 h, and at 55 ꢀC for 47 h. After cooling to rt, the solution was
neutralized with NEt3 and concentrated in vacuo. EtOAc
(200 mL) and H2O (50 mL) were added and the layers were
separated. The aqueous layer was extracted with EtOAc and the
combined organic layers were dried with brine and over
MgSO4, filtered, and concentrated in vacuo. Column chroma-
tography (EtOAc/toluene¼1:1) yielded the thiazolidine lactone
7a as a colorless solid (1.17 g, 39%). After complete elution of 7a
the other species were obtained by elution with pure EtOAc,
which yielded the reaction intermediate 32 as yellow foam
(1.45 g, 33%).52 This was recycled to yield further thiazolidine
lactone 7a as described in the following.
964, 947, 928, 913, 864, 780 cmꢂ1
;
1H NMR (600 MHz, CDCl3):
d
1.41, 1.46 (each s, 3H, isopr-CH3), 3.98 (s, 3H, CO2CH3), 4.87e4.88
3
(m, 2H, 2-H, 3-H), 4.96 (d, 1H, J4-H/3-H¼5.8 Hz, 4-H), 5.35 (d, 1H,
3JCN ꢂH=2ꢂH¼2.6 Hz, CN3-H), 8.30 (s, 1H, Thz-5-H); 13C NMR
3
(150 MHz, CDCl3): d 25.7, 26.7 (each isopr-CH3), 52.8 (CO2CH3), 63.5
(C-N3), 75.2 (C-4), 78.8 (C-3), 82.2 (C-2), 109.9 (isopr-Cquart.), 129.9
(Thz-C-5),147.1 (Thz-C-4), 161.4 (CO2CH3), 164.9 (Thz-C-2),173.1 (C-
5); ½a 2D0
ꢂ103.8 (c 0.99, CHCl3); ESI-HMRS found 377.0527 (calcd for
ꢄ
(b) from intermediate 32: The thiazolidine lactam 32 (1.76 g,
4.91 mmol) was dissolved in DMF/AcOH¼130:1 (38 mL) and the
mixture was stirred at 50 ꢀC for 72 h. The subsequent workup
and purification were performed as described for method (a),
yielding the thiazolidine lactone 7a as a colorless solid (587 mg,
33%). Rf (EtOAc/toluene¼7:1) 0.83; mp 175 ꢀC; IR (neat) 3323,
3296, 2115, 1786, 1735, 1381, 1349, 1294, 1269, 1216, 1176,
C13H14N4O6SþNaþ 377.0526).
4.2.24. Methyl 2-[((S)-azido(2S,3R,4S)-3,4-dihydroxy-5-oxo-tetrahy-
drofuran-2-yl)methyl]-thiazole-4-carboxylate (35). A solution of the
acetonide 34 (110 mg, 0.31 mmol) in 60% HCOOH in H2O (11 mL)
was stirred at 65 ꢀC for 40 min. Upon completion of the reaction the
mixture was cooled to rt and the solvent was removed in vacuo.
Column chromatography (EtOAc/MeOH¼5:1) yielded the diol 35
(67 mg, 69%) as colorless solid. Rf (EtOAc/MeOH¼5:1) 0.23; IR
(neat) 3365, 3117, 2956, 2111, 1781, 1716, 1480, 1435, 1323, 1221,
1145, 1017, 993, 967, 945, 923, 864, 785, 764 cmꢂ1
;
1H NMR
(500 MHz, CDCl3):
d 1.38, 1.45 (each s, 3H, isopr-CH3), 2.94 (dd,
2
3
u
1H, JThzꢂ5ꢂHu=Thzꢂ5ꢂHd ¼10.6 Hz, JThzꢂ5ꢂH =Thzꢂ4ꢂH¼8.5 Hz,
Thz-5-Hu), 3.09 (br s, 1H, NH), 3.34 (dd, 1H, JThzꢂ5ꢂHd=
2
1132, 1061, 979, 956, 922, 905, 863, 843, 757 cmꢂ1
(400 MHz, DMSO-d6):
;
1H NMR
Thz ꢂ 5 ꢂ Hu¼10.6 Hz, JThzꢂ5ꢂHd=Thzꢂ4ꢂH¼6.4 Hz, Thz-5-Hd),
3
3
3.48 (dd, 1H, 3JCN ꢂH=2ꢂH¼1.7 Hz, 3JCN ꢂH=Thzꢂ2ꢂH¼9.6 Hz, CN3-
d
3.84 (s, 3H, CO2CH3), 4.29 (dd, 1H, J3-H/2-
3
3
3
3
H), 3.81 (s, 3H, CO2CH3), 3.95 (dd, 1H, 3JThzꢂ4ꢂH=
¼1.2 Hz, J3-H/4-H¼5.5 Hz, 3-H), 4.57 (d, 1H, J4-H/3-H¼5.5 Hz, 4-
H
3
3
Thz ꢂ 5 ꢂ Hd¼6.4 Hz,
JThzꢂ4ꢂH=Thzꢂ5ꢂH ¼8.5 Hz, Thz-4-H),
3
H), 4.60 (dd, 1H, J2-H/3-H¼1.2 Hz, J2ꢂH=CN ꢂH¼6.2 Hz, 2-H), 5.75
u
3
(d, 1H, 3JCN ꢂH=2ꢂH¼6.2 Hz, CN3-H), 8.63 (s, 1H, Thz-5-H); 13C NMR
3
3
4.66 (d, 1H, J3-H/4-H¼5.8 Hz, 3-H), 4.77 (d, 1H, J2ꢂH=
3
3
(100 MHz, DMSO-d6):
d 52.6 (CO2CH3), 61.9 (C-N3), 68.4 (C-4), 69.1
CN3 ꢂ H¼1.7 Hz, 2-H), 4.86 (d, 1H, J4-H/3-H¼5.8 Hz, 4-H), 4.98
(d, 1H, JThzꢂ2ꢂH=CN ꢂH¼9.6 Hz, Thz-2-H); 13C NMR (125 MHz,
3
(C-3), 85.5 (C-2), 131.0 (Thz-C-5), 146.2 (Thz-C-4), 161.5 (CO2CH3),
3
166.4 (Thz-C-2), 175.7 (C-5); ½a D21
ꢂ98.8 (c 0.60, CHCl3); ESI-HMRS
ꢄ
CDCl3):
d 25.7, 26.8 (each isopr-CH3), 38.3 (Thz-C-5), 53.0
found 337.0207 (calcd for C10H10N4O6SþNaþ 337.0213).
(CO2CH3), 63.6 (Thz-C-4), 66.3 (C-N3), 69.6 (Thz-C-2), 75.0 (C-4),
79.0 (C-3), 81.1 (C-2), 113.8 (isopr-Cquart.), 171.1 (CO2CH3), 173.5
(C-5); ½a 2D2
ꢂ78.5 (c 1.08, CHCl3); ESI-HMRS found 381.0840
ꢄ
4.2.25. Methyl 2-[(2S,3S,4S,5S)-3-hydroxy-4,5-O-isopropylidene-6-
oxo-piperidin-2-yl]-thiazole-4-carboxylate (36). Azide 34 (203 mg,
0.57 mmol) was dissolved in EtOAc/MeOH¼2:1 (15 mL), Pd/C
(400 mg; 5%, wet, Degussa) was added and the mixture was stirred
at rt for 45 h in a H2 atmosphere at 1 bar. During this time period
the H2 atmosphere was renewed twice. After filtration over a Celite
column and concentration in vacuo the lactam 36 was obtained as
a pale yellow solid (165 mg, 88%) and used without further purifi-
cation. Rf (CHCl3/MeOH¼9:1) 0.36; 1H NMR (600 MHz, DMSO-d6):
(calcd for C13H18N4O6SþNaþ 381.0839). Suitable crystals for X-
ray analysis were grown from a EtOAc/petrol ether solution.44
4.2.22. (9aR)H-(6S,7R)-O-Isopropylidene-(8S)-hydroxy-(9S)-azido-
5-oxo-octahydro-thiazolo[3,2-a]azepine-(3R)-carboxylic acid methyl
ester (32). The thiazolidine lactam 32 occurs as intermediate in the
formation of the thiazolidine lactone 7a as described in Section
4.2.21. When the flash chromatographic purification was carried
out with EtOAc/toluene¼2:1 to 5:1 to 9:1 the pure compound was
isolated as colorless foam. Rf (EtOAc/toluene¼7:1) 0.41; IR (neat)
3431, 2961, 2108, 1732, 1669, 1410, 1376, 1356, 1258, 1206, 1169,
d
1.44 (s, 3H, isopr-CH3proR), 1.51 (s, 3H, isopr-CHp3roS), 3.95 (CO2CH3),
4.36 (m, 1H, 3-H), 4.64e4.65 (m, 2H, 4-H, 5-H), 5.03 (m, 1H, 2-H),
6.39 (br s, 1H, CONH), 8.24 (s, 1H, Thz-5-H); 13C NMR (150 MHz,
1095, 1072, 1020, 973, 932, 911, 876, 855, 797, 734 cmꢂ1
;
1H NMR
DMSO-d6): d
24.4 (isopr-CH3proR), 26.0 (isopr-CH3proS), 52.7 (CO2CH3),
(300 MHz, DMSO-d6):
d
1.30, 1.41 (each s, 3H, isopr-CH3), 3.21 (dd,
55.5 (C-2), 66.3 (C-3), 72.2 (C-5), 74.6 (C-4), 111.4 (isopr-Cquart.),
129.3 (Thz-C-5), 146.4 (Thz-C-4), 161.5 (CO2CH3), 167.4 (Thz-C-2),
168.8 (C-6); ESI-HMRS found 351.0621 (calcd for C13H16N2O6SþNaþ
351.0621).
1H, J2ꢂHu=2ꢂHd ¼11.7 Hz, J2ꢂH =3ꢂH¼5.1 Hz, 2-Hu), 3.37 (dd, 1H,
2J2ꢂHd=2ꢂHu ¼11.7 Hz, 3J2ꢂHd=3ꢂH¼7.0 Hz, 2-Hd), 3.67 (s, 3H, CO2CH3),
4.00 (dd, 1H, 3J9-H/8-H¼1.3 Hz, 3J9-H/9a-H¼10.4 Hz, 9-H), 4.07 (m, 1H,
2
3
u
3
3
8-H), 4.47 (dd, 1H, J7-H/8-H¼1.7 Hz, J7-H/6-H¼8.8 Hz, 7-H), 4.86
3
3
u
(dd, 1H, J3ꢂH=2ꢂH ¼5.1 Hz, J3ꢂH=2ꢂHd ¼7.0 Hz, 3-H), 4.96 (d, 1H,
4.2.26. Methyl 2-[(1S,2S,3S,4S)-4-(methoxycarbonyl)-1-amino-2,3,4-
trihydroxybutyl]-thiazole-4-carboxylate (12). To a solution of the
lactam 36 (115 mg, 0.35 mmol) in MeOH (15 mL) was added
3J6-H/7-H¼8.8 Hz, 6-H), 4.99 (d, 1H, 3J9a-H/9-H¼10.4 Hz, 9a-H), 5.05 (d,
3J8-O-H/8-H¼4.9 Hz, 8-OH); 13C NMR (150 MHz, DMSO-d6):
d 23.6,

S. Enck et al. / Tetrahedron 68 (2012) 7166e7178
7177
a catalytical amount of p-TosOHꢁH2O and the mixture was stirred
at 60 ꢀC for 7 h. After cooling to rt the mixture was neutralized with
NEt3 upon which amine 12 precipitated, and filtration and drying in
vacuo yielded the first product fraction (14.2 mg, 13%) as colorless
powder. The residue obtained upon concentration of the filtrate in
vacuo consisted of the starting material 36 and the triol in-
termediate 37 (Rf (EtOAc/MeOH¼5:1) 0.19) in a 60:40 ratio. This
added in small portions until the solution reached pH 6, and solid
MgSO4 (20 g) was subsequently added. The mixture was filtered
over Celite and the residue was washed with acetonitrile (100 mL).
The filtrate was concentrated in vacuo to yield the thiazole triol 13
(933 mg, 98%) as a colorless solid. Rf (EtOAc/MeOH¼5:1) 0.77; mp
105 ꢀC; IR (KBr) 3380, 3097, 1795, 1780, 1718, 1683, 1477, 1417, 1362,
1254, 1220, 1164, 1136, 1114, 1089, 1001, 992, 955, 858, 780, 769,
was dissolved in MeOH (4 mL),
a
catalytical amount of p-
; d 3.83 (s, 3H, CO2CH3),
729 cmꢂ1 1H NMR (300 MHz, DMSO-d6):
3
3
TosOHꢁH2O was added, and the mixture was stirred at 50 ꢀC for
18 h. After cooling to rt and neutralization with NEt3 a second
product fraction was isolated upon filtration (10.0 mg, 8.9%) as
colorless powder. This resulted in an overall 22% yield of amine 12
(24.2 mg). Rf (EtOAc/MeOH¼5:1) 0.09; mp 168 ꢀC; IR (neat) 3419,
3341, 3275, 3118,1741, 1719,1713,1495,1468, 1433,1396,1346,1318,
1265, 1240, 1205, 1166, 1115, 1084, 1071, 1043, 995, 973, 946, 908,
4.29e4.32 (m, 1H, 3-H), 4.55 (dd, 1H, J4-H/3-H¼4.6 Hz, J4-H/4-
3
3
¼7.4 Hz, 4-H), 4.61 (dd, 1H, J2-H/3-H¼2.9 Hz, J2-H/3-H¼7.9 Hz, 2-
OH
3
3
H), 5.15 (dd, 1H, JCx-H/Cx-OH¼5.7 Hz, JCx-H/2-H¼7.9 Hz, CX-H), 5.52
3
3
(d, 1H, J3-OH/3-H¼3.8 Hz, 3-OH), 5.91 (d, 1H, J4-OH/4-H¼7.4 Hz, 4-
3
OH), 6.57 (d, 1H, JCx-OH/Cx-H¼5.7 Hz, CX-OH), 8.57 (s, 1H, Thz-5-
H); 13C NMR (75 MHz, DMSO-d6):
d 52.0 (CO2CH3), 68.5 (C-X),
69.7 (C-3), 70.4 (C-4), 80.9 (C-2), 129.7 (Thz-C-5), 145.5 (Thz-C-4),
871, 847, 827, 773 cmꢂ1; 1H NMR (600 MHz, DMSO-d6):
d
2.28 (br s,
161.2 (CO2CH3), 172.0 (Thz-C-2), 175.8 (C-5); ½a D24
ꢄ
73.3 (c 0.84,
2H, NH2), 3.61 (s, 3H, 5-CO2CH3), 3.82 (m, 4H, 4-H, Thz-CO2CH3),
DMSO); ESI-HMRS found 312.0146 (calcd for C10H11NO7SþNaþ
312.0148). Suitable crystals for X-ray analysis were grown from
a MeOH solution.44
3
4.21 (ddd, 1H, 3J¼1.6 Hz, J2-H/2-OH¼6.9 Hz, 3J¼8.9 Hz, 2-H),
3
4.27e4.29 (m, 2H, 1-H, 4-H), 4.82 (d, 1H, J2-OH/2-H¼6.9 Hz, 2-OH),
5.26 (d, 1H, 3J3-OH/3-H¼6.1 Hz, 3-OH), 5.41 (d, 1H, 3J4-OH/4-H¼6.0 Hz,
4-OH), 8.35 (s, 1H, Thz-5-H); 13C NMR (150 MHz, DMSO-d6):
d 51.1
Acknowledgements
(6-CO2CH3), 51.7 (Thz-CO2CH3), 54.0 (C-1), 72.0 (C-4), 72.5 (C-2),
73.3 (C-3), 128.8 (Thz-C-5), 145.6 (Thz-C-4), 161.6 (Thz-CO2CH3),
172.6 (C-5), 180.2 (Thz-C-2); ½a D30
ꢂ42.3 (c 0.37, DMSO); ESI-HMRS
ꢄ
Financial support by the Deutsche Forschungsgemeinschaft
(DFG) is gratefully acknowledged. S.E. thanks the Studienstiftung
des Deutschen Volkes for a Ph.D. scholarship.
found 343.0570 (calcd for C11H16N2O7SþNaþ 343.0570).
4.2.27. Methyl 2-[((R)-(2S,3S,4S)-5-oxo-3,4-bis(triethylsilyloxy)-tet-
rahydrofuran-2-yl)(triethylsilyloxy)methyl]-thiazole-4-carboxylate
(39). To a solution of thiazolidine 6 (6.64 g, 22.6 mmol) and imid-
azole (5.55 g, 81.5 mmol) in 14 mL of DMF TESCl (13.7 mL,
81.5 mmol) was slowly added. The solution was stirred at rt for 3 h,
diluted with CH2Cl2 (500 mL) and 5% aq NaHCO3 (40 mL), the layers
were separated, and the aqueous layer was extracted once with
CH2Cl2. The combined organic layers were dried with brine and
over MgSO4, filtered, and concentrated in vacuo. The resulting pale
yellow oil (crude thiazolidine 38, Rf (toluene/EtOAc¼7:1) 0.47) was
dissolved in toluene (200 mL), MnO2 (39.4 g, 453 mmol) was
added, and the suspension was vigorously stirred for 28 h at 70 ꢀC.
Upon complete consumption of the starting material the solution
was cooled to rt, BrCCl3 (6.69 mL, 67.8 mmol) and DBU (10.1 mL,
67.8 mmol) were added and the suspension was stirred at rt until
no thiazoline intermediate was visible any more by TLC (Rf (tolu-
ene/EtOAc¼7:1) 0.55). After filtration over Celite, the suspension
was extracted once with satd NaHCO3 and once with satd NH4Cl,
dried with brine and over MgSO4, and concentrated in vacuo. Pu-
rification by column chromatography (CH2Cl2/pentane¼4:1) yiel-
ded the thiazole 39 (6.91 g, 48%) as a colorless oil. Rf (toluene/
References and notes
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d 0.73e0.78 (m, 18H,
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9ꢁSiCH2CH3), 0.90 (t, 9H, J¼8.0 Hz, 3ꢁSiCH2CH3), 0.97e1.01 (m,
3
18H, 6ꢁ SiCH2CH3), 3.91 (s, 3H, CO2CH3), 4.28 (dd, 1H, J2-H/3-
3
3
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3
3
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(125 MHz, CDCl3):
d
¼4.9, 5.1, 5.2 (each SiCH2CH3), 6.8, 6.8, 6.9 (each
SiCH2CH3), 52.3 (CO2CH3), 70.5 (C-X), 72.8 (C-3), 73.5 (C-4), 81.7 (C-
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1207, 1135, 1004, 987, 947, 892, 855, 830, 787, 725 cmꢂ1; ½a D20
ꢂ8.9
ꢄ
(c 2.40, CHCl3); ½a D20
ꢂ8.9 (c 2.4, CHCl3); ESI-HMRS found 654.2744
ꢄ
(calcd for C28H53NO7SSi3þNaþ 654.2743).
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0 ꢀC, H2SiF6 (1.66 M in H2O; 3.96 mL) was added and the solution
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7178
S. Enck et al. / Tetrahedron 68 (2012) 7166e7178
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59. Numbering of compounds: